Fibrous dysplasia. Clinical review and therapeutic management

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Clinical review and therapeutic management" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figura 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2374 "Ancho" => 3330 "Tamanyo" => 481139 ] ] "descripcion" => array:1 [ "es" => "Paciente con síndrome de McCune-Albright. A: Manchas «café con leche». B: La gammagrafía ósea muestra una hipercaptación en macizo facial, tercio proximal y medio del fémur derecho y diáfisis tibial derecha. C: Radiografía del tercio proximal del fémur derecho con lesiones insuflantes en «vidrio deslustrado» de contornos esclerosos y ligero engrosamiento de la cortical, con placa de osteosíntesis. D: Tomografía computarizada que muestra cambios escleróticos y quísticos en la base del cráneo, la órbita derecha, la fosa nasal y los senos paranasales derechos. 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Clinical review and therapeutic management" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "547" "paginaFinal" => "553" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Helena Florez, Pilar Peris, Núria Guañabens" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Helena" "apellidos" => "Florez" ] 1 => array:4 [ "nombre" => "Pilar" "apellidos" => "Peris" "email" => array:1 [ 0 => "pperis@clinic.ub.es" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 2 => array:2 [ "nombre" => "Núria" "apellidos" => "Guañabens" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Reumatología, Hospital Clínic, Universidad de Barcelona, Barcelona, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Displasia fibrosa. Revisión clínica y abordaje terapéutico" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2374 "Ancho" => 3330 "Tamanyo" => 481139 ] ] "descripcion" => array:1 [ "en" => "Patient with McCune–Albright syndrome. (A) “Coffee-with-milk” spots. (B) The bone scintigraphy shows a hypercaptation in facial mass, proximal and middle third of the right femur and right tibial diaphysis. (C) Radiograph of the proximal third of the right femur with inflatable lesions in “dull glass” with sclerosing contours and slight thickening of the cortical, with plate osteosynthesis. (D) Computed tomography scan showing sclerotic and cystic changes at the base of the skull, right orbit, nasal fossa, and right paranasal sinuses. The superior orbital fissure and the optic canal on the right side have a reduced size." ] ] ] "textoCompleto" => "IntroductionFibrous dysplasia (FD) is a benign pseudotumoral bone disorder, where osteofibrous connective tissue replaces the normal bone marrow. It can be monostotic or polyostotic FD. It can also be associated with endocrinopathies (particularly precocious puberty, acromegaly, hypercortisolism and hyperthyroidism) and hyperpigmented skin lesions (‘coffee-with-milk’ spots), constituting the so-called McCune–Albright syndrome (MAS), or myxomas of skeletal muscle, being part, in this case, of Mazabraud syndrome. Finally, FD can also be associated with the development of hypophosphatemic osteomalacia due to the increased hormone regulating phosphate metabolism: the fibroblast growth factor 23 (FGF-23, produced by the dysplastic bone tissue.<a class="elsevierStyleCrossRefs" href="#bib0175">1–4</a> It is a rare condition that affects one in 30,000 people and represents 2.5% of overall bone lesions and 1% of primary bone tumors. Monostotic FD is the most frequent FD and its prevalence is similar in both sexes. Only in 2–3% cases FD is associated with endocrine disorders (MAS). In this case it is clearly predominant in females.<a class="elsevierStyleCrossRef" href="#bib0195">5</a>In FD, there is impaired mesenchymal maturation, where the tissue of the medullary cavity is replaced by an abnormal fibrous tissue of plexiform bone. It is caused by a post-genetic mutation activating the GNAS1 gene (it encodes the α unit of G-stimulatory protein [Gsα] that inhibits GTP activity), which can be transmitted to the 3 germ layers (ecto, endo and mesoderm), giving rise to a somatic mosaicism in which the affected tissue encoded by the mutated gene coexists with normal tissue without genetic disorders. Phenotypic variability of FD is determined by the time of development in which the mutation occurs and the differences in size and viability of the clone arising from the mutated cell. In the MAS, multiple tissues arising from the 3 germ layers are involved. Therefore, in this case, the clinical manifestations will depend on the tissues affected, and they may show hyperfunction in skin, ovaries, thyroid, adrenal and/or pituitary glands.<a class="elsevierStyleCrossRefs" href="#bib0200">6–10</a>As a consequence of the mutation, adenyl cyclase is activated (by Gsα) which, in the specific case of bone, affects the osteoprogenitor cells and differentiated osteoblasts, causing their abnormal differentiation into fibrous tissue and subsequent abnormal bone formation. Also, it is a highly vascularized tissue and prone to bleeding, which can lead to hemorrhagic cysts. Also, sensory and sympathetic fibers are modified in dysplastic bone, which might explain, in part, the increased pain in the FD-affected bones frequently reported in these patients.<a class="elsevierStyleCrossRef" href="#bib0225">11</a> In this disorder, mutated osteoblasts show increased IL-6 secretion that induces osteoclast activation and osteoclastogenesis, leading to the development of osteolytic lesions and spread of dysplastic bone tissue. Other factors leading to osteoclast activation in FD are: platelet-derived growth factor β, steroid receptors in osteoblasts, and increased RANK ligand expression (RANKL) in dysplastic tissue, and others.<a class="elsevierStyleCrossRefs" href="#bib0200">6,8</a>Although any bone can be affected by FD, in the monostotic forms the most frequently involved are, in descending order, maxillary bones, proximal femur, tibia, humerus, ribs, skull cap, radius and ilium. In polyosthetic (usually homolateral) forms the distribution varies widely and the proximal femur is the bone most frequently involved.Clinical manifestations related to bone involvement usually appear in childhood and/or adolescence, starting in 80% cases before the age of 15 years. Usually, the lower the age of onset of symptoms, the more severe the disease is. One of the most common symptoms is pain, which can be associated with bone fractures, deformities and/or bone cysts, and very rarely, to the development of a bone sarcoma (0.4–1% cases). The latter is more frequent in polyostotic forms and/or after previous radiotherapy, reason why this treatment is especially contraindicated in FD.<a class="elsevierStyleCrossRefs" href="#bib0200">6,8</a>Monostotic forms can be asymptomatic and detected by chance. Craniofacial lesions usually begin in childhood due to the emergence of a tumor and/or facial asymmetry. They usually cause hemorrhagic cysts and/or hernias through cranial orifices, and depending on their location, they may lead to losing vision due to optical nerve involvement, or hearing loss. Another type of FD-associated skeletal manifestation is hypophosphatemic rickets or osteomalacia. Although this is an uncommon complication, this should be reminded to patients with generalized skeletal pain and hypophosphatemia-associated fractures with increased serum levels of FGF-23 and renal phosphate loss.<a class="elsevierStyleCrossRefs" href="#bib0180">2–4,6</a>As for the extraskeletal manifestations, the most frequent is the occurrence of hyperpigmented lesions (“coffe-with-milk spots”), which might occur prior to bone or endocrine disorders, as part of MAS.<a class="elsevierStyleCrossRefs" href="#bib0200">6–8</a>Diagnosis and monitoringFD is usually diagnosed with a radiological study (simple Rx, computed tomography (CT) and/or MRI). In addition, a bone scintigraphy should be performed to determine the extent and activity of the disease, and a careful study should be conducted to rule out other associated processes, particularly MAS (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<a class="elsevierStyleCrossRef" href="#bib0230">12</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>If diagnosis is not clear, bone biopsy and mutational study are recommended. CT may be useful for monitoring bone lesions, as it defines their extent best, quantifies the diameter of the optic canal in cases of cranial involvement and assesses the occurrence of aneurysmal bone cysts and fissures. Similarly, MRI allows to assess what the intralesional soft tissues consist of and is the technique of choice for follow-up in children because of its lack of radiation. We should remark on the theoretical usefulness of bone densitometry. Although its use is not clearly indicated in the evaluation and/or monitoring of this condition, some authors have assessed the response to antiresorptive treatment (particularly with bisphosphonates) by analyzing the evolution of bone mineral density (BMD) of bone affected with FD, especially if it is the proximal femur.<a class="elsevierStyleCrossRefs" href="#bib0235">13–16</a>Monitoring these patients includes assessment and control of pain, with special attention to the causes of pain (fractures, bone deformities or increased size of the existing lesions). In general terms, FD bone lesions tend to worsen during growth and they become stabilized in adulthood. In some cases an increased activity has been observed during pregnancy and estrogen treatment. This fact, together with the finding of estrogenic receptors in dysplastic bone tissue, evidences a likely hormonal effect in the evolution of the disease.<a class="elsevierStyleCrossRefs" href="#bib0200">6,8</a>Basic laboratory tests including serum and urinary calcium and phosphate levels are recommended, with determination of total alkaline phosphatase, 25-hydroxyvitamin D and bone formation and resorption markers, as they are useful for monitoring the response to treatment. If hypophosphatemia occurs, determining FGF-23 levels is recommended. In those patients with MAS, the associated hormonal disorders (excessive growth hormone, prolactin, thyroid hormones, gonadal axis and/or adrenocorticosteroids) will be evaluated and controlled. This is particularly important in patients with increased growth hormone, since this may influence the evolution of bone lesions.<a class="elsevierStyleCrossRefs" href="#bib0180">2–4,7</a>TreatmentAlthough effective treatment is not yet available in FD, there is now more experience in the medical and surgical approach to these patients, which varies depending on the location, age and disease activity. Likewise, there are preliminary results on the potential therapeutic effect of new drugs that might be useful in this condition.Surgery might be indicated in those cases with pain and not responding to conservative treatment, particularly in case of increased risk of fracture and/or extended bone damage involving neighbor structures (primarily the optic nerve in cranial involvement).<a class="elsevierStyleCrossRef" href="#bib0255">17</a> Some surgical options are: intramedullary nails (technique used in femur and tibia fractures or if there is risk of imminent fracture in these locations); Bone resections (in certain locations, such as the ribs); Osteotomies (especially in children with bone deformities); Craniofacial surgery (in case of hearing and/or vision loss; In case of optic nerve compression it requires urgent surgery associated with glucocorticoid treatment [1mg/kg/day] until intervention, but it is not recommended prophylactically); Curettage and bone grafting (Disused technique, only indicated in some circumscribed forms, noting that in case of an autograft it may contain mutated cells). Another issue to consider is that children can suffer from up to 50% relapses, at least until the end of growth.<a class="elsevierStyleCrossRefs" href="#bib0200">6,8,18</a>The medical approach is analgesic treatment and to try to diminish the activity of the disease and its complications. Thus, for the treatment of pain, we might require paracetamol, NSAIDs or even narcotic drugs. Based on observational studies and controlled studies, the analgesic effectiveness of bisphosphonate treatment has been proved.<a class="elsevierStyleCrossRefs" href="#bib0265">19,20</a> A number of general guidelines has also been recommended, such as the use of calcium and vitamin D supplements, the control and treatment of associated hormonal disease in the case of MAS (especially if there is increased growth hormone), and the control and treatment of hypophosphatemia in those patients with this complication (administering phosphate and calcitriol).<a class="elsevierStyleCrossRef" href="#bib0200">6</a>Antiresorptive drugsInitially and in isolation, calcitonin, mithramycin and etidronate had been prescribed, with poor results. Subsequently, second and third generation bisphosphonates (alendronate, risedronate, pamidronate and zoledronate) were used with increased antiresorptive activity and bone retention. Although most of the initial clinical studies with these drugs showed good therapeutic response, these were observational studies with a small number of patients. Recently, the first controlled clinical trial has been conducted on this condition, comparing alendronate versus placebo, not showing a clear effect of this drug on the evolution of the disease. Therefore, the usefulness of these drugs should be analyzed.The results of the studies performed with different types of antiresorptive drugs to date are shown below (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>AlendronateIn 1997, Weinstein<a class="elsevierStyleCrossRef" href="#bib0235">13</a> published a case of MAS with an expansile femur lesion associated with intense coxalgia. Initially it was treated with iv pamidronate (4 90mg infusions). The patient showed pain remission after treatment, increased BMD in the densitometric study and decreased NTx bone resorption marker. Months later the pain reappeared and NTx increased. Therefore, the oatient initiated treatment with alendronate orally (10mg/day). Within 17 months of treatment the pain had disappeared, NTx levels decreased, BMD in femur increased by 158% and the radiological lesion improved. Subsequently, Lane et al.,<a class="elsevierStyleCrossRef" href="#bib0275">21</a> in a series of 6 patients with FD (4 treated with iv pamidronate followed by alendronate orally and 2 with alendronate orally alone), observed improvement in pain in all patients after 28 months of follow-up, and in 4 of them, a radiological improvement.Kitagawa et al.<a class="elsevierStyleCrossRef" href="#bib0280">22</a> reported the case of a patient with polyostotic FD with associated chronic pain who improved after treatment with alendronate orally, both in the evolution of pain and in bone remodeling markers and radiologically.In 2014, it was conducted the first clinical trial on FD. It was a randomized, double-blind, controlled 2-year-follow-up study (alendronate versus placebo), including 40 patients (24 adults and 16 children)<a class="elsevierStyleCrossRef" href="#bib0240">14</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). The evolution of pain, muscle strength, radiological imaging, markers of bone remodeling (NTx and osteocalcin) and BMD (both in the lumbar spine and in affected FD areas) were analyzed. Although NTx levels were significantly decreased in the group treated with alendronate, the authors did not find differences in pain or radiological images in either group.Currently another clinical trial is being conducted in patients with FD that analyzes the effect of another bisphosphonate, risedronate (PROFIDYS study), on the evolution of pain and disease activity, which is in the phase of patient selection.Bisphosphonates of parenteral administrationThe parenteral administration of bisphosphonates improves the bioavailability of these drugs, and may have an impact on their therapeutic efficacy.Treatment of FD with iv bisphosphonates was initiated in the 1990s,<a class="elsevierStyleCrossRef" href="#bib0285">23</a> in a study that included 9 patients with severe FD who were treated with iv pamidronate (60mg/day, 3 consecutive days, every 6 months) with a 18–48-month Follow-up. The authors observed a decrease in pain and markers of bone remodeling, and in 4 of the 9 patients they evidence a radiological improvement. Subsequently, Chapurlat et al.<a class="elsevierStyleCrossRefs" href="#bib0245">15,24</a> conducted several publications related to a series of 58 DF patients treated with iv pamidronate with a mean 50-month follow-up (between one and 11 years). The standard treatment with pamidronate was 60mg iv for 3 consecutive days every 6 months for 2 years. In case of good response to treatment (defined as decreased pain and radiological improvement), annual schedules were maintained. In children, the dose used was 1mg/kg/day for 3 consecutive days every 6 months. All patients received calcium and vitamin D supplements, and in those who also had a phosphate renal loss associated with FD, oral phosphate and calcitriol were added. The authors described a significant decrease in pain in all patients, which was evident after the first iv bolus of pamidronate and achieved an average decrease of 69% by the end of follow-up. 54% of the patients showed improvement in bone lesions. They also observed increased BMD, around 15% after 6 treatment cycles on average in those patients suffering from FD in their hip. In this study, the authors concluded that this type of therapy seems useful in the treatment of pain and disease activity associated with FD. They found no predictor of response to treatment and the results were similar in either adults, children and adolescents.Parisi et al.,<a class="elsevierStyleCrossRef" href="#bib0250">16</a> in a series of 7 patients with FD treated with similar doses of pamidronate, also observed a decrease in pain and bone markers with treatment and increased BMD in FD affected areas. However, they did not show a radiological improvement in bone lesions, a fact attributed to the shorter treatment time of these patients, which was one year. In the same year, Plotkin et al.<a class="elsevierStyleCrossRef" href="#bib0295">25</a> described the effect of pamidronate treatment in a group of 18 children and adolescents with polyostotic FD. Patients were treated for 3.8 years on average, with 1–1.5mg/kg/day for 3 consecutive days, and every cycle was repeated every 4 months. A total of 16 iliac bone affected by FD were biopsied, 9 before onset of treatment and 7 after 2.2 years of treatment on average. Although pain improved in patients treated with pamidronate, the histological and radiological changes were not significant. The inconclusive results of this study, as indicated by the authors, might be due to several factors, such as the low number of patients included, the severity of the disease or a different behavior of the bone lesions in younger individuals. Thus, the authors suggest that in this population group there could be a more rapid progression of the lesion that would make it difficult to control the disease with the treatment.Following the series of Chapurlat's patients mentioned above,<a class="elsevierStyleCrossRef" href="#bib0300">26</a> in 2006 a new study was released that included 9 patients with polyostotic FD who had shown poor response to previous treatment with pamidronate. Therefore, a new treatment was initiated with a most powerful antiresortive bisphosphonate: zoledronate. The dose used was 4mg iv every 6 months, receiving an overall 2.8 boluses on average (from 1 to 5). The authors described a decrease in pain and markers of bone remodeling after treatment, although this was not significant.<a class="elsevierStyleCrossRef" href="#bib0300">26</a> Again, the small number of patients and the severity of the disease were factors that were related to these results.Subsequently, several isolated cases of patients with FD have been published<a class="elsevierStyleCrossRefs" href="#bib0305">27,28</a> in which iv zoledronate was administered, with good response to this type of treatment both in the evolution of pain and in the markers of bone remodeling.Recently, Thomsen and Rejnmark<a class="elsevierStyleCrossRef" href="#bib0315">29</a> have published a series of 26 patients with DF (17 polyostotic and 4 with MAS), where they reviewed the treatments with bisphosphonates, analyzing their preparation, dosage and duration. The authors reported that at the end of the study, most patients were treated with iv bisphosphonates, especially with zoledronate, but only a minority (2 cases) showed a regression of bone lesions. They also reported that the levels of bone alkaline phosphatase remained high in half of the patients despite the treatment, evidencing that this type of regime, either due to the dose used and/or by the periodicity of administration may be insufficient in some patients. Although the authors acknowledge that bisphosphonate treatment is associated with improved pain in some patients, they indicate that the response to treatment is ambiguous, noting the need for controlled clinical trials. However, the low incidence of this entity and the heterogeneity of its clinical manifestations make it difficult to conduct this type of study, since the response to treatment with these preparations might be different depending on the activity and severity of the disease. It also depends on its dosage. Wu et al.<a class="elsevierStyleCrossRef" href="#bib0320">30</a> have recently released the case of a patient with polyostotic FD with severe bone involvement who received treatment with zoledronate, 4 boluses of 5mg per year. After a 48-month follow-up, the authors reported an improvement in bone pain after the second infusion of zoledronate and a decrease in remodeling markers (CTx and PINP) and bone lesions from the third and fourth infusions, respectively.DenosumabDenosumab is a monoclonal antibody that inhibits RANKL, one of the main regulatory mechanisms of osteoclastogenesis. It is a strong antiresorptive agent indicated for the treatment of osteoporosis and skeletal-related events in patients with bone metastases. Recently, its use has also been approved for the treatment of unresectable giant cell tumor. However, as in metastatic disease, the dose and periodicity of its administration are higher and more frequent than those approved for the treatment of osteoporosis. Denosumab might theoretically be useful in the treatment of FD, since expression of RANKL has increased in the dysplastic lesions of these patients.<a class="elsevierStyleCrossRef" href="#bib0325">31</a> However, we should recall that its use is currently not approved for the treatment of FD.Recently, isolated cases have been published on patients with severe forms of FD treated with denosumab.<a class="elsevierStyleCrossRefs" href="#bib0325">31–33</a> Thus, Boyce et al.<a class="elsevierStyleCrossRef" href="#bib0325">31</a> describe the case of a child affected by FD in a MAS context with an expansile femur lesion with no response to previous pamidronate treatment. Due to the poor evolution of the patient, and after evidence of RANKL expression in the histological study of bone lesions, treatment was initiated with denosumab (monthly dosage, sliding scale every 3 months 1–1.25–1.5–1.75mg/kg). The authors observed a decrease in pain, lesion growth rate and bone remodeling markers after first drug administration. However, after the first dose administered, hypophosphatemia and increased FGF-23 and PTH levels were evidenced, reason why calcium, phosphorus and calcitriol supplements were administered. The patient also had his femur fractured after an accidental fall and he discontinued treatment, showing severe hypercalcemia (18mg/dL) and a marked increase in bone remodeling markers 2 months after drug discontinuation. Calcium levels were normalized within 5 months, after several infusions of iv pamidronate andzoledronate.The authors concluded that denosumab might be an effective treatment in the control of pain and disease activity. However, they highlight the side effects related to this drug in this particular case with severe FD, such as: hypophosphatemia, ascribed to the secondary increase of PTH by denosumab, and marked hypercalcemia ascribed to the rebound effect of increased bone remodeling after drug discontinuation. Therefore, they recommend a close follow-up in FD patients undergoing this type of treatment.Similarly, Ganda and Seibel<a class="elsevierStyleCrossRef" href="#bib0335">33</a> reported 2 cases of adult patients with severe FD who, after previous treatment with zoledronate for several years without evidence of improvement, started treatment with denosumab. Both patients underwent treatment with a 60mg dose, but the rate of administration was different, one receiving the second dose at 9 months and the other at 4 months. Both patients showed a rapid reduction in bone remodeling markers and pain improvement. However, similarly to the case previously described, although none of them suffered from hypercalcemia, earlier and stronger “rebound” effect was observed in the markers of bone remodeling compared to patients treated for osteoporosis when discontinuing treatment.Although these are isolated cases with severe FD, these preliminary results show that although denosumab may be a useful therapy in the treatment of this disease, this drug should be used with caution with close patient monitoring. Studies are necessary to analyze its effectiveness and long-term safety.Other therapiesAs previously indicated, in FD there IL-6 expression is increased, helping the osteoclastogenesis activation and, therefore, osteolytic lesions. Therefore, it has been suggested that tocilizumab, an anti-IL-6 receptor antibody used in the treatment of rheumatoid arthritis, may be useful in this entity. Thus, the case of a patient with symptomatic sphenoid DF not responding to iv bisphosphonates has recently been described. This patient showed a marked improvement in pain and imaging tests after tocilizumab therapy.<a class="elsevierStyleCrossRef" href="#bib0340">34</a> A pahse 2 clinical trial is currently being conducted with this drug (Tocidys study), including FD patients who have not responded to previous treatment with bisphosphonates and are still in the phase of patient selection.Other proposed therapeutic targets would be gene therapy, either acting directly over Gs α or through its cascade of effects.ConclusionsFD can occur with a broad spectrum of clinical manifestations, ranging from localized asymptomatic forms to severe forms with important bone deformities, and even associated endocrinological disorders. Although effective treatment is not available yet, there is now more experience in the medical and surgical approach of these patients, which varies depending on age, location, disease activity and associated complications. Although the medical treatment of choice is bisphosphonates, particularly in case of pain, its effectiveness in controlling disease activity remains uncertain. This review indicates the need to analyze the therapeutic strategy in FD and conduct standard controlled clinical trials that analyze the activity of the disease.FundingThere has been no funding.Conflict of interestsThe authors report no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres798004" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec795993" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres798005" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec795994" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Diagnosis and monitoring" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Treatment" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Antiresorptive drugs" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Alendronate" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Bisphosphonates of parenteral administration" ] 3 => array:2 [ "identificador" => "sec0035" "titulo" => "Denosumab" ] 4 => array:2 [ "identificador" => "sec0040" "titulo" => "Other therapies" ] ] ] 7 => array:2 [ "identificador" => "sec0045" "titulo" => "Conclusions" ] 8 => array:2 [ "identificador" => "sec0050" "titulo" => "Funding" ] 9 => array:2 [ "identificador" => "sec0055" "titulo" => "Conflict of interests" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-06-10" "fechaAceptado" => "2016-07-31" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec795993" "palabras" => array:5 [ 0 => "Fibrous dysplasia" 1 => "McCune–Albright syndrome" 2 => "Bisphosphonates" 3 => "Denosumab" 4 => "FGF-23" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec795994" "palabras" => array:5 [ 0 => "Displasia fibrosa" 1 => "Síndrome de McCune-Albright" 2 => "Bisfosfonatos" 3 => "Denosumab" 4 => "FGF-23" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Fibrous dysplasia is a skeletal disorder that is associated with a wide spectrum of clinical manifestations, including localized asymptomatic forms and extensive severe forms with severe bone deformities and endocrinological alterations, depending on age, location, extent and associated processes. Although the treatment of choice is based on bisphosphonates, the therapeutic efficacy of these agents in the control of disease activity remains uncertain. This article reviews the current data available on the treatment of this disease as well as the preliminary data on new therapeutic approaches." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La displasia fibrosa es un trastorno esquelético que dependiendo de la edad, la localización, la extensión y los procesos asociados puede presentarse con un amplio espectro de manifestaciones clínicas, desde formas localizadas asintomáticas a formas extensas graves con deformidades óseas importantes o incluso alteraciones endocrinológicas. Si bien el tratamiento de elección lo constituyen los bisfosfonato, la eficacia en el control de la actividad de la enfermedad continúa siendo incierta. En este artículo se revisan los datos sobre el tratamiento de esta entidad, así como los resultados preliminares de nuevas dianas terapéuticas." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Florez H, Peris P, Guañabens N. Displasia fibrosa. Revisión clínica y abordaje terapéutico. Med Clin (Barc). 2016;147:547–553." ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2374 "Ancho" => 3330 "Tamanyo" => 481139 ] ] "descripcion" => array:1 [ "en" => "Patient with McCune–Albright syndrome. (A) “Coffee-with-milk” spots. (B) The bone scintigraphy shows a hypercaptation in facial mass, proximal and middle third of the right femur and right tibial diaphysis. (C) Radiograph of the proximal third of the right femur with inflatable lesions in “dull glass” with sclerosing contours and slight thickening of the cortical, with plate osteosynthesis. (D) Computed tomography scan showing sclerotic and cystic changes at the base of the skull, right orbit, nasal fossa, and right paranasal sinuses. The superior orbital fissure and the optic canal on the right side have a reduced size." ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "ALD, alendronate; APD, pamidronate; mFD, monostotic fibrous dysplasia; DFp, polyostotic fibrous dysplasia; DMAB, denosumab; BMD, bone mineral density; GMO, bone scintigraphy; Iv, intravenous; BRM, markers of bone remodeling; Rx, radiologically assessed image; MAS, McCune–Albright syndrome; TCZ, tocilizumab; ZOL, zoledronic acid; →, the following treatment indicated." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Author, year (reference) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">n \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">mFD:pFD (MAS) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Sex, M:F \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Age, years [rank] \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type of study \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Treatment \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Dosage/cadence (cumulative dose) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Follow-up average time \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Parameters tested \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Evolution \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Liens et al.,<a class="elsevierStyleCrossRef" href="#bib0285">23</a> 1994 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1:8 (8 SMA) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4:5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">33 [13–59] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Observational study \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">APD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">60mg/day×3days/6months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">26 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain, BRM and Rx \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain, BRM and Rx improving \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Weinstein,<a class="elsevierStyleCrossRef" href="#bib0235">13</a> 1997 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0:1 (1 MAS) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0:1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">22 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case report \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">APD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">90mg/3–4 weeks×4 boluses (360mg) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain, BRM and BMD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain, BRM and BMD improving \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ALD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10mg/day \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">17 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain, BRM, BMD and Rx \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain, BRM, BMD and Rx improving \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lane et al.,<a class="elsevierStyleCrossRef" href="#bib0275">21</a> 2001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Observational study \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">APD+ALD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">60–90mg/3 month+10mg/day \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">28 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain and safety APD+ALD: Rx and BRM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain improving, preventing from fractures, BRM and Rx \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ALD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10mg/day \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Kitagawa et al.,<a class="elsevierStyleCrossRef" href="#bib0280">22</a> 2001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0:1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0:1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">45 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case report \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ALD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5mg/day \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain, Rx and BRM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain, Rx and BRM improving \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Boyce et al.,<a class="elsevierStyleCrossRef" href="#bib0240">14</a> 2014 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0:40 (26 MAS) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11:9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24.5 [8–52] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Randomized, double-blind, placebo-controlled study \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ALD versus placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">40mg/day if >50kg 20mg/day if 30–50kg 10mg/day if 20–30kg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">APD: pain, BRM, BMD, BSC, functional test and safety \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">BRM and BMD improving \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Chapurlat et al.,<a class="elsevierStyleCrossRef" href="#bib0245">15</a> 2004 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">58 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10:36 PM (7 MAS) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">28:30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">28 [5–63] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Observational study \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">APD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">60mg/day×3days/6 months×2 years. If response is positive, annual boluses Children: 1mg/kg/day×3 days/6 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">50 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain, BRM, Rx and BMD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain, BRM, Rx (in 50% patients) and BMD improving \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Parisi et al.,<a class="elsevierStyleCrossRef" href="#bib0200">6</a> 2003 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0:7 (4 MAS) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1:6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">26 [15–43] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Observational study \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">APD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">60mg/day×3 days/6 months (2 patients only 180mg) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain, BRM, Rx and BMD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain, BRM and BMD improving \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Plotkin et al.,<a class="elsevierStyleCrossRef" href="#bib0295">25</a> 2003 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12:18 AM (4 MAS) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10:8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">[6.2–17.5] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Observational study \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">APD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">First bolus: day 1 0.5mg/kg, and day 2 and 3 1mg/kg/day Following boluses: 1–1.5mg/kg/day×3 days/4 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">120 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain and safety, BRM, histomorphometry and growth \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain and BRM improving \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Chapurlat,<a class="elsevierStyleCrossRef" href="#bib0300">26</a> 2006 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0:9 (3 MAS) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3:6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">39 [22–63] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Observational study \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">APD→ZOL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">180mg/6 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4mg/6 months (1–5 boluses) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain, BRM and Rx \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Non-significant pain, BRM improvement \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Mansoori et al.,<a class="elsevierStyleCrossRef" href="#bib0305">27</a> 2010 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0:1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1:0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">39 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case report \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">APD→ZOL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">60mg/5 months×2 boluses (120mg) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5mg (one bolus) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 months after bolus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain, BRM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain and BRM improving \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ozdemir Kutbay et al.,<a class="elsevierStyleCrossRef" href="#bib0310">28</a> 2015 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3:2 (1 MAS) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2:3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">39.6 [30–53] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Observational study \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">APD (4 patients) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">60mg/day×3 days/6 months (one patient 360mg, 3 patients) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 to 24 months after treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain and BRM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain and BRM improving \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ZOL (one patient) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5mg (one bolus) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain and BRM improving \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Thomsen and Rejnmark,<a class="elsevierStyleCrossRef" href="#bib0315">29</a> 2014 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">26 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9:17 (4 MAS) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10:16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">29 [4–70] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Observational study \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Biphosfonates (23/26 patients) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">48 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain, BRM, Rx and fractures \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain (in 3 patients), BRM and Rx (in 2 patients) improving \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Wu et al.,<a class="elsevierStyleCrossRef" href="#bib0320">30</a> 2015 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0:1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1:0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case report \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ZOL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5mg/year (20mg in 4 years) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">48 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain, BRM and Rx \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain, BRM and Rx improving \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Boyce et al.,<a class="elsevierStyleCrossRef" href="#bib0325">31</a> 2012 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0:1 (1 MAS) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1:0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case report \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">DMAB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1mg/kg/month from first to third month, 1.25mg/kg/month from fourth to sixth month, 1.5mg/kg seventh month (825mg) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lesion extension. BRM, pain, dental development, growth, histomorphometry, immunohistochemistry \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">DEcreased lesion extension. Pain and BRM improving \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ganda and Seibel,<a class="elsevierStyleCrossRef" href="#bib0335">33</a> 2014 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0:2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1:1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">48 and 44 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case report \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ZOL→DMAB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4mg/6 months×5 boluses (20mg) (patient 1) 4mg/6 months×10 boluses+5mg in one bolus (45mg) (patient 2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9.5 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">60mg/9 months×2 doses+third dose at 6 months (180mg) (patient 1) 60mg/4 months×2 doses (120mg) (patient 2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain, BRM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain and BRM improving \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Benhamou et al.,<a class="elsevierStyleCrossRef" href="#bib0330">32</a> 2014 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0:1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1:0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">46 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case report \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">APD→ZOL→DMAB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(3600mg) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10 years with APD+36 months after ZOL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5mg×1 bolus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">60mg/6 months×2 doses \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain, BRM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain and BRM improving \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">De Boysson et al.,<a class="elsevierStyleCrossRef" href="#bib0340">34</a> 2015 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0:1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0:1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">35 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case report \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">iv Biphosphonate→TCZ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bisphosphonate monthly×6 boluses \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">22 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain, BSC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pain and BSC improving \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">600mg/month×4→400mg/2 months×3→200mg/3 months×2→80mg/3 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1338489.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Treatments and characteristics of previous studies conducted in patients with fibrous dysplasia." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:34 [ 0 => array:3 [ "identificador" => "bib0175" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Fibrous dysplasia of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "R.D. Chapurlat" 1 => "P.J. Meunier" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/berh.1999.0071" "Revista" => array:6 [ "tituloSerie" => "Baillieres Best Pract Res Clin Rheumatol" "fecha" => "2000" "volumen" => "14" "paginaInicial" => "385" "paginaFinal" => "398" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10925751" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0180" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Riminucci" 1 => "M.T. Collins" 2 => "N.S. Fedarko" 3 => "N. Cherman" 4 => "A. Corsi" 5 => "K.E. White" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1172/JCI18399" "Revista" => array:6 [ "tituloSerie" => "J Clin Invest" "fecha" => "2003" "volumen" => "112" "paginaInicial" => "683" "paginaFinal" => "692" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12952917" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0185" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Expression of FGF23 is correlated with serum phosphate level in isolated fibrous dysplasia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "K. Kobayashi" 1 => "Y. Imanishi" 2 => "H. Koshiyama" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.lfs.2005.09.052" "Revista" => array:6 [ "tituloSerie" => "Life Sci" "fecha" => "2006" "volumen" => "78" "paginaInicial" => "2295" "paginaFinal" => "2301" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16337659" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0190" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Fibrous dysplasia and fibroblast growth factor-23 regulation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "A.M. Boyce" 1 => "N. Bhattacharyya" 2 => "M.T. Collins" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s11914-013-0144-5" "Revista" => array:6 [ "tituloSerie" => "Curr Osteoporos Rep" "fecha" => "2013" "volumen" => "11" "paginaInicial" => "65" "paginaFinal" => "71" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23532406" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0195" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Displasia fibrosa. Condrodisplasias" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "G. Saló Bru" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:5 [ "titulo" => "Manual de enfermedades óseas" "paginaInicial" => "449" "paginaFinal" => "451" "edicion" => "2.a ed." "serieFecha" => "2010" ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0200" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Fibrous dysplasia of bone and McCune–Albright syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "R.D. Chapurlat" 1 => "P. Orcel" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.berh.2007.11.004" "Revista" => array:6 [ "tituloSerie" => "Best Pract Res Clin Rheumatol" "fecha" => "2008" "volumen" => "22" "paginaInicial" => "55" "paginaFinal" => "69" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18328981" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0205" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "McCune–Albright syndrome and the extraskeletal manifestations of fibrous dysplasia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "M.T. Collins" 1 => "F.R. Singer" 2 => "E. Eugster" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/1750-1172-7-S1-S4" "Revista" => array:6 [ "tituloSerie" => "Orphanet J Rare Dis" "fecha" => "2012" "volumen" => "7" "numero" => "Suppl. 1" "paginaInicial" => "S4" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22640971" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0210" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Fibrous dysplasia of bone: a clinicopathologic review" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "H. Mohan" 1 => "P. Mittal" 2 => "I. Mundi" 3 => "S. Kumar" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Pathol Lab Med Int" "fecha" => "2011" "volumen" => "3" "paginaInicial" => "31" "paginaFinal" => "42" ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0215" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The histopathology of fibrous dysplasia of bone in patients with activating mutations of the Gs alpha gene: site-specific patterns and recurrent histological hallmarks" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Riminucci" 1 => "B. Liu" 2 => "A. Corsi" 3 => "A. Shenker" 4 => "A.M. Spiegel" 5 => "P.G. Robey" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/(SICI)1096-9896(199901)187:2<249::AID-PATH222>3.0.CO;2-J" "Revista" => array:6 [ "tituloSerie" => "J Pathol" "fecha" => "1999" "volumen" => "187" "paginaInicial" => "249" "paginaFinal" => "258" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10365102" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0220" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diagnostic value of investigating GNAS mutations in fibro-osseous lesions: a retrospective study of 91 cases of fibrous dysplasia and 40 other fibro-osseous lesions" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F. Tabareau-Delalande" 1 => "C. Collin" 2 => "A. Gomez-Brouchet" 3 => "A.V. Decouvelaere" 4 => "C. Bouvier" 5 => "F. Larousserie" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/modpathol.2012.223" "Revista" => array:6 [ "tituloSerie" => "Mod Pathol" "fecha" => "2013" "volumen" => "26" "paginaInicial" => "911" "paginaFinal" => "921" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23370769" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0225" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pathophysiology and medical treatment of pain in fibrous dysplasia of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "R.D. Chapurlat" 1 => "D. Gensburger" 2 => "J.M. Jimenez-Andrade" 3 => "J.R. Ghilardi" 4 => "M. Kelly" 5 => "P. Mantyh" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/1750-1172-7-S1-S3" "Revista" => array:6 [ "tituloSerie" => "Orphanet J Rare Dis" "fecha" => "2012" "volumen" => "7" "numero" => "Suppl. 1" "paginaInicial" => "S3" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22640953" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0230" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "An instrument to measure skeletal burden and predict functional outcome in fibrous dysplasia of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.T. Collins" 1 => "H. Kushner" 2 => "J.C. Reynolds" 3 => "C. Chebli" 4 => "M.H. Kelly" 5 => "A. Gupta" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1359/JBMR.041111" "Revista" => array:6 [ "tituloSerie" => "J Bone Miner Res" "fecha" => "2005" "volumen" => "20" "paginaInicial" => "219" "paginaFinal" => "226" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15647815" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0235" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Long-term aminobisphosphonate treatment of fibrous dysplasia: spectacular increase in bone density" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "R.S. Weinstein" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1359/jbmr.1997.12.8.1314" "Revista" => array:6 [ "tituloSerie" => "J Bone Miner Res" "fecha" => "1997" "volumen" => "12" "paginaInicial" => "1314" "paginaFinal" => "1315" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9258763" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0240" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A randomized, double blind, placebo-controlled trial of alendronate treatment for fibrous dysplasia of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A.M. Boyce" 1 => "M.H. Kelly" 2 => "B.A. Brillante" 3 => "H. Kushner" 4 => "S. Wientroub" 5 => "M. Riminucci" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jc.2014-1371" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2014" "volumen" => "99" "paginaInicial" => "4133" "paginaFinal" => "4140" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25033066" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0245" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Treatment of fibrous dysplasia of bone with intravenous pamidronate: predictors of response to treatment and long-term effectiveness" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "R.D. Chapurlat" 1 => "P. Hugueny" 2 => "P.D. Delmas" 3 => "P.J. Meunier" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.bone.2004.03.004" "Revista" => array:6 [ "tituloSerie" => "Bone" "fecha" => "2004" "volumen" => "35" "paginaInicial" => "235" "paginaFinal" => "242" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15207763" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0250" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of intravenous pamidronate on bone markers and local bone mineral density in fibrous dysplasia of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "M.S. Parisi" 1 => "B. Oliveri" 2 => "C.A. Mautalen" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Bone" "fecha" => "2003" "volumen" => "33" "paginaInicial" => "582" "paginaFinal" => "588" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14555262" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0255" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical guidelines for the management of craniofacial fibrous dysplasia" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.S. Lee" 1 => "E.J. Fitzgibbon" 2 => "Y.R. Chen" 3 => "H.J. Kim" 4 => "L.R. Lustig" 5 => "S.O. Akintoye" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/1750-1172-7-S1-S2" "Revista" => array:6 [ "tituloSerie" => "Orphanet J Rare Dis" "fecha" => "2012" "volumen" => "7" "numero" => "Suppl. 1" "paginaInicial" => "S2" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22640797" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0260" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The surgical management of fibrous dysplasia of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "R.P. Stanton" 1 => "E. Ippolito" 2 => "D. Springfield" 3 => "L. Lindaman" 4 => "S. Wientroub" 5 => "A. Leet" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/1750-1172-7-S1-S1" "Revista" => array:6 [ "tituloSerie" => "Orphanet J Rare Dis" "fecha" => "2012" "volumen" => "7" "numero" => "Suppl. 1" "paginaInicial" => "S1" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22640754" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0265" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The nonsurgical treatment of fibrous dysplasia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "R.D. Chapurlat" 1 => "P.J. Meunier" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Rev Rhum Engl Ed" "fecha" => "1999" "volumen" => "66" "paginaInicial" => "1" "paginaFinal" => "3" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10036690" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0270" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Fibrous dysplasia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "M.T. Collins" 1 => "M. Riminucci" 2 => "P. Bianco" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:7 [ "edicion" => "8.a ed." "titulo" => "Primer on the metabolic bone diseases and disorders of mineral metabolism" "fecha" => "2013" "paginaInicial" => "786" "paginaFinal" => "793" "editorial" => "John Wiley & Sons" "editorialLocalizacion" => "Oxford" ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0275" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Bisphosphonate therapy in fibrous dysplasia" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.M. Lane" 1 => "S.N. Khan" 2 => "W.J. O’Connor" 3 => "M. Nydick" 4 => "J.P. Hommen" 5 => "R. Schneider" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Clin Orthop Relat Res" "fecha" => "2001" "volumen" => "382" "paginaInicial" => "6" "paginaFinal" => "12" ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0280" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Oral alendronate treatment for polyostotic fibrous dysplasia: a case report" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Y. Kitagawa" 1 => "K. Tamai" 2 => "H. Ito" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00776-004-0809-0" "Revista" => array:7 [ "tituloSerie" => "J Orthop Sci" "fecha" => "2001" "volumen" => "9" "paginaInicial" => "521" "paginaFinal" => "525" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15449129" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S1472648315004319" "estado" => "S300" "issn" => "14726483" ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0285" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Long-term effects of intravenous pamidronate in fibrous dysplasia of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "D. Liens" 1 => "P.D. Delmas" 2 => "P.J. Meunier" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "1994" "volumen" => "343" "paginaInicial" => "953" "paginaFinal" => "954" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7909013" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0290" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Long-term effects of intravenous pamidronate in fibrous dysplasia of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "R.D. Chapurlat" 1 => "P.D. Delmas" 2 => "D. Liens" 3 => "P.J. Meunier" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1359/jbmr.1997.12.10.1746" "Revista" => array:6 [ "tituloSerie" => "J Bone Miner Res" "fecha" => "1997" "volumen" => "12" "paginaInicial" => "1746" "paginaFinal" => "1752" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9333137" "web" => "Medline" ] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0295" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of pamidronate treatment in children with polyostotic fibrous dysplasia of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "H. Plotkin" 1 => "F. Rauch" 2 => "L. Zeitlin" 3 => "C. Munns" 4 => "R. Travers" 5 => "F.H. Glorieux" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jc.2003-030050" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2003" "volumen" => "88" "paginaInicial" => "4569" "paginaFinal" => "4575" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14557424" "web" => "Medline" ] ] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0300" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Medical therapy in adults with fibrous dysplasia of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "R.D. Chapurlat" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Bone Miner Res" "fecha" => "2006" "volumen" => "21" "numero" => "Suppl. 2" "paginaInicial" => "114" "paginaFinal" => "119" ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0305" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Bisphosphonate treatment in polyostotic fibrous dysplasia of the cranium: case report and literature review" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "L.S. Mansoori" 1 => "C.P. Catel" 2 => "M.S. Rothman" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.4158/EP10136.CR" "Revista" => array:6 [ "tituloSerie" => "Endocr Pract" "fecha" => "2010" "volumen" => "16" "paginaInicial" => "851" "paginaFinal" => "854" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20570808" "web" => "Medline" ] ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0310" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Characteristics and treatment results of 5 patients with fibrous dysplasia and review of the literature" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "N. Ozdemir Kutbay" 1 => "B. Sarer Yurekli" 2 => "E. Kartal Baykan" 3 => "S. Baydur Sahin" 4 => "F. Saygili" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1155/2015/670809" "Revista" => array:5 [ "tituloSerie" => "Case Rep Endocrinol" "fecha" => "2015" "volumen" => "2015" "paginaInicial" => "670809" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26171261" "web" => "Medline" ] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0315" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical and radiological observations in a case series of 26 patients with fibrous fysplasia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "M.D. Thomsen" 1 => "L. Rejnmark" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00223-013-9829-0" "Revista" => array:6 [ "tituloSerie" => "Calcif Tissue Int" "fecha" => "2014" "volumen" => "94" "paginaInicial" => "384" "paginaFinal" => "395" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24390518" "web" => "Medline" ] ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0320" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Continuous effect with long-term safety in zoledronic acid therapy for polyostitic fibrous displasia with severe bone destruction" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "D. Wu" 1 => "J. Ma" 2 => "S. Bao" 3 => "H. 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Fibrous dysplasia. Clinical review and therapeutic management

Displasia fibrosa. Revisión clínica y abordaje terapéutico

Helena Florez, Pilar Peris

Corresponding author

pperis@clinic.ub.es

Corresponding author.

, Núria Guañabens

Servicio de Reumatología, Hospital Clínic, Universidad de Barcelona, Barcelona, Spain

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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Patient with McCune&#8211;Albright syndrome&#46; &#40;A&#41; &#8220;Coffee-with-milk&#8221; spots&#46; &#40;B&#41; The bone scintigraphy shows a hypercaptation in facial mass&#44; proximal and middle third of the right femur and right tibial diaphysis&#46; &#40;C&#41; Radiograph of the proximal third of the right femur with inflatable lesions in &#8220;dull glass&#8221; with sclerosing contours and slight thickening of the cortical&#44; with plate osteosynthesis&#46; &#40;D&#41; Computed tomography scan showing sclerotic and cystic changes at the base of the skull&#44; right orbit&#44; nasal fossa&#44; and right paranasal sinuses&#46; The superior orbital fissure and the optic canal on the right side have a reduced size&#46;</p>"
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Fibrous dysplasia &#40;FD&#41; is a benign pseudotumoral bone disorder&#44; where osteofibrous connective tissue replaces the normal bone marrow&#46; It can be monostotic or polyostotic FD&#46; It can also be associated with endocrinopathies &#40;particularly precocious puberty&#44; acromegaly&#44; hypercortisolism and hyperthyroidism&#41; and hyperpigmented skin lesions &#40;&#8216;coffee-with-milk&#8217; spots&#41;&#44; constituting the so-called McCune&#8211;Albright syndrome &#40;MAS&#41;&#44; or myxomas of skeletal muscle&#44; being part&#44; in this case&#44; of Mazabraud syndrome&#46; Finally&#44; FD can also be associated with the development of hypophosphatemic osteomalacia due to the increased hormone regulating phosphate metabolism&#58; the fibroblast growth factor 23 &#40;FGF-23&#44; produced by the dysplastic bone tissue&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">1&#8211;4</span></a> It is a rare condition that affects one in 30&#44;000 people and represents 2&#46;5&#37; of overall bone lesions and 1&#37; of primary bone tumors&#46; Monostotic FD is the most frequent FD and its prevalence is similar in both sexes&#46; Only in 2&#8211;3&#37; cases FD is associated with endocrine disorders &#40;MAS&#41;&#46; In this case it is clearly predominant in females&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In FD&#44; there is impaired mesenchymal maturation&#44; where the tissue of the medullary cavity is replaced by an abnormal fibrous tissue of plexiform bone&#46; It is caused by a post-genetic mutation activating the <span class="elsevierStyleItalic">GNAS1</span> gene &#40;it encodes the &#945; unit of G-stimulatory protein &#91;G<span class="elsevierStyleInf">s</span>&#945;&#93; that inhibits GTP activity&#41;&#44; which can be transmitted to the 3 germ layers &#40;ecto&#44; endo and mesoderm&#41;&#44; giving rise to a somatic mosaicism in which the affected tissue encoded by the mutated gene coexists with normal tissue without genetic disorders&#46; Phenotypic variability of FD is determined by the time of development in which the mutation occurs and the differences in size and viability of the clone arising from the mutated cell&#46; In the MAS&#44; multiple tissues arising from the 3 germ layers are involved&#46; Therefore&#44; in this case&#44; the clinical manifestations will depend on the tissues affected&#44; and they may show hyperfunction in skin&#44; ovaries&#44; thyroid&#44; adrenal and&#47;or pituitary glands&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">6&#8211;10</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">As a consequence of the mutation&#44; adenyl cyclase is activated &#40;by G<span class="elsevierStyleInf">s</span>&#945;&#41; which&#44; in the specific case of bone&#44; affects the osteoprogenitor cells and differentiated osteoblasts&#44; causing their abnormal differentiation into fibrous tissue and subsequent abnormal bone formation&#46; Also&#44; it is a highly vascularized tissue and prone to bleeding&#44; which can lead to hemorrhagic cysts&#46; Also&#44; sensory and sympathetic fibers are modified in dysplastic bone&#44; which might explain&#44; in part&#44; the increased pain in the FD-affected bones frequently reported in these patients&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">11</span></a> In this disorder&#44; mutated osteoblasts show increased IL-6 secretion that induces osteoclast activation and osteoclastogenesis&#44; leading to the development of osteolytic lesions and spread of dysplastic bone tissue&#46; Other factors leading to osteoclast activation in FD are&#58; platelet-derived growth factor &#946;&#44; steroid receptors in osteoblasts&#44; and increased RANK ligand expression &#40;RANKL&#41; in dysplastic tissue&#44; and others&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">6&#44;8</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Although any bone can be affected by FD&#44; in the monostotic forms the most frequently involved are&#44; in descending order&#44; maxillary bones&#44; proximal femur&#44; tibia&#44; humerus&#44; ribs&#44; skull cap&#44; radius and ilium&#46; In polyosthetic &#40;usually homolateral&#41; forms the distribution varies widely and the proximal femur is the bone most frequently involved&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Clinical manifestations related to bone involvement usually appear in childhood and&#47;or adolescence&#44; starting in 80&#37; cases before the age of 15 years&#46; Usually&#44; the lower the age of onset of symptoms&#44; the more severe the disease is&#46; One of the most common symptoms is pain&#44; which can be associated with bone fractures&#44; deformities and&#47;or bone cysts&#44; and very rarely&#44; to the development of a bone sarcoma &#40;0&#46;4&#8211;1&#37; cases&#41;&#46; The latter is more frequent in polyostotic forms and&#47;or after previous radiotherapy&#44; reason why this treatment is especially contraindicated in FD&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">6&#44;8</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Monostotic forms can be asymptomatic and detected by chance&#46; Craniofacial lesions usually begin in childhood due to the emergence of a tumor and&#47;or facial asymmetry&#46; They usually cause hemorrhagic cysts and&#47;or hernias through cranial orifices&#44; and depending on their location&#44; they may lead to losing vision due to optical nerve involvement&#44; or hearing loss&#46; Another type of FD-associated skeletal manifestation is hypophosphatemic rickets or osteomalacia&#46; Although this is an uncommon complication&#44; this should be reminded to patients with generalized skeletal pain and hypophosphatemia-associated fractures with increased serum levels of FGF-23 and renal phosphate loss&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">2&#8211;4&#44;6</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">As for the extraskeletal manifestations&#44; the most frequent is the occurrence of hyperpigmented lesions &#40;&#8220;coffe-with-milk spots&#8221;&#41;&#44; which might occur prior to bone or endocrine disorders&#44; as part of MAS&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">6&#8211;8</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Diagnosis and monitoring</span><p id="par0040" class="elsevierStylePara elsevierViewall">FD is usually diagnosed with a radiological study &#40;simple Rx&#44; computed tomography &#40;CT&#41; and&#47;or MRI&#41;&#46; In addition&#44; a bone scintigraphy should be performed to determine the extent and activity of the disease&#44; and a careful study should be conducted to rule out other associated processes&#44; particularly MAS &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">12</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">If diagnosis is not clear&#44; bone biopsy and mutational study are recommended&#46; CT may be useful for monitoring bone lesions&#44; as it defines their extent best&#44; quantifies the diameter of the optic canal in cases of cranial involvement and assesses the occurrence of aneurysmal bone cysts and fissures&#46; Similarly&#44; MRI allows to assess what the intralesional soft tissues consist of and is the technique of choice for follow-up in children because of its lack of radiation&#46; We should remark on the theoretical usefulness of bone densitometry&#46; Although its use is not clearly indicated in the evaluation and&#47;or monitoring of this condition&#44; some authors have assessed the response to antiresorptive treatment &#40;particularly with bisphosphonates&#41; by analyzing the evolution of bone mineral density &#40;BMD&#41; of bone affected with FD&#44; especially if it is the proximal femur&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">13&#8211;16</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Monitoring these patients includes assessment and control of pain&#44; with special attention to the causes of pain &#40;fractures&#44; bone deformities or increased size of the existing lesions&#41;&#46; In general terms&#44; FD bone lesions tend to worsen during growth and they become stabilized in adulthood&#46; In some cases an increased activity has been observed during pregnancy and estrogen treatment&#46; This fact&#44; together with the finding of estrogenic receptors in dysplastic bone tissue&#44; evidences a likely hormonal effect in the evolution of the disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">6&#44;8</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Basic laboratory tests including serum and urinary calcium and phosphate levels are recommended&#44; with determination of total alkaline phosphatase&#44; 25-hydroxyvitamin D and bone formation and resorption markers&#44; as they are useful for monitoring the response to treatment&#46; If hypophosphatemia occurs&#44; determining FGF-23 levels is recommended&#46; In those patients with MAS&#44; the associated hormonal disorders &#40;excessive growth hormone&#44; prolactin&#44; thyroid hormones&#44; gonadal axis and&#47;or adrenocorticosteroids&#41; will be evaluated and controlled&#46; This is particularly important in patients with increased growth hormone&#44; since this may influence the evolution of bone lesions&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">2&#8211;4&#44;7</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Treatment</span><p id="par0060" class="elsevierStylePara elsevierViewall">Although effective treatment is not yet available in FD&#44; there is now more experience in the medical and surgical approach to these patients&#44; which varies depending on the location&#44; age and disease activity&#46; Likewise&#44; there are preliminary results on the potential therapeutic effect of new drugs that might be useful in this condition&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Surgery might be indicated in those cases with pain and not responding to conservative treatment&#44; particularly in case of increased risk of fracture and&#47;or extended bone damage involving neighbor structures &#40;primarily the optic nerve in cranial involvement&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">17</span></a> Some surgical options are&#58; intramedullary nails &#40;technique used in femur and tibia fractures or if there is risk of imminent fracture in these locations&#41;&#59; Bone resections &#40;in certain locations&#44; such as the ribs&#41;&#59; Osteotomies &#40;especially in children with bone deformities&#41;&#59; Craniofacial surgery &#40;in case of hearing and&#47;or vision loss&#59; In case of optic nerve compression it requires urgent surgery associated with glucocorticoid treatment &#91;1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#93; until intervention&#44; but it is not recommended prophylactically&#41;&#59; Curettage and bone grafting &#40;Disused technique&#44; only indicated in some circumscribed forms&#44; noting that in case of an autograft it may contain mutated cells&#41;&#46; Another issue to consider is that children can suffer from up to 50&#37; relapses&#44; at least until the end of growth&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">6&#44;8&#44;18</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">The medical approach is analgesic treatment and to try to diminish the activity of the disease and its complications&#46; Thus&#44; for the treatment of pain&#44; we might require paracetamol&#44; NSAIDs or even narcotic drugs&#46; Based on observational studies and controlled studies&#44; the analgesic effectiveness of bisphosphonate treatment has been proved&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">19&#44;20</span></a> A number of general guidelines has also been recommended&#44; such as the use of calcium and vitamin D supplements&#44; the control and treatment of associated hormonal disease in the case of MAS &#40;especially if there is increased growth hormone&#41;&#44; and the control and treatment of hypophosphatemia in those patients with this complication &#40;administering phosphate and calcitriol&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">6</span></a></p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Antiresorptive drugs</span><p id="par0075" class="elsevierStylePara elsevierViewall">Initially and in isolation&#44; calcitonin&#44; mithramycin and etidronate had been prescribed&#44; with poor results&#46; Subsequently&#44; second and third generation bisphosphonates &#40;alendronate&#44; risedronate&#44; pamidronate and zoledronate&#41; were used with increased antiresorptive activity and bone retention&#46; Although most of the initial clinical studies with these drugs showed good therapeutic response&#44; these were observational studies with a small number of patients&#46; Recently&#44; the first controlled clinical trial has been conducted on this condition&#44; comparing alendronate versus placebo&#44; not showing a clear effect of this drug on the evolution of the disease&#46; Therefore&#44; the usefulness of these drugs should be analyzed&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">The results of the studies performed with different types of antiresorptive drugs to date are shown below &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Alendronate</span><p id="par0085" class="elsevierStylePara elsevierViewall">In 1997&#44; Weinstein<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">13</span></a> published a case of MAS with an expansile femur lesion associated with intense coxalgia&#46; Initially it was treated with iv pamidronate &#40;4 90<span class="elsevierStyleHsp" style=""></span>mg infusions&#41;&#46; The patient showed pain remission after treatment&#44; increased BMD in the densitometric study and decreased NTx bone resorption marker&#46; Months later the pain reappeared and NTx increased&#46; Therefore&#44; the oatient initiated treatment with alendronate orally &#40;10<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41;&#46; Within 17 months of treatment the pain had disappeared&#44; NTx levels decreased&#44; BMD in femur increased by 158&#37; and the radiological lesion improved&#46; Subsequently&#44; Lane et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">21</span></a> in a series of 6 patients with FD &#40;4 treated with iv pamidronate followed by alendronate orally and 2 with alendronate orally alone&#41;&#44; observed improvement in pain in all patients after 28 months of follow-up&#44; and in 4 of them&#44; a radiological improvement&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Kitagawa et al&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">22</span></a> reported the case of a patient with polyostotic FD with associated chronic pain who improved after treatment with alendronate orally&#44; both in the evolution of pain and in bone remodeling markers and radiologically&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">In 2014&#44; it was conducted the first clinical trial on FD&#46; It was a randomized&#44; double-blind&#44; controlled 2-year-follow-up study &#40;alendronate versus placebo&#41;&#44; including 40 patients &#40;24 adults and 16 children&#41;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">14</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; The evolution of pain&#44; muscle strength&#44; radiological imaging&#44; markers of bone remodeling &#40;NTx and osteocalcin&#41; and BMD &#40;both in the lumbar spine and in affected FD areas&#41; were analyzed&#46; Although NTx levels were significantly decreased in the group treated with alendronate&#44; the authors did not find differences in pain or radiological images in either group&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Currently another clinical trial is being conducted in patients with FD that analyzes the effect of another bisphosphonate&#44; risedronate &#40;PROFIDYS study&#41;&#44; on the evolution of pain and disease activity&#44; which is in the phase of patient selection&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Bisphosphonates of parenteral administration</span><p id="par0105" class="elsevierStylePara elsevierViewall">The parenteral administration of bisphosphonates improves the bioavailability of these drugs&#44; and may have an impact on their therapeutic efficacy&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Treatment of FD with iv bisphosphonates was initiated in the 1990s&#44;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">23</span></a> in a study that included 9 patients with severe FD who were treated with iv pamidronate &#40;60<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#44; 3 consecutive days&#44; every 6 months&#41; with a 18&#8211;48-month Follow-up&#46; The authors observed a decrease in pain and markers of bone remodeling&#44; and in 4 of the 9 patients they evidence a radiological improvement&#46; Subsequently&#44; Chapurlat et al&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">15&#44;24</span></a> conducted several publications related to a series of 58 DF patients treated with iv pamidronate with a mean 50-month follow-up &#40;between one and 11 years&#41;&#46; The standard treatment with pamidronate was 60<span class="elsevierStyleHsp" style=""></span>mg iv for 3 consecutive days every 6 months for 2 years&#46; In case of good response to treatment &#40;defined as decreased pain and radiological improvement&#41;&#44; annual schedules were maintained&#46; In children&#44; the dose used was 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day for 3 consecutive days every 6 months&#46; All patients received calcium and vitamin D supplements&#44; and in those who also had a phosphate renal loss associated with FD&#44; oral phosphate and calcitriol were added&#46; The authors described a significant decrease in pain in all patients&#44; which was evident after the first iv bolus of pamidronate and achieved an average decrease of 69&#37; by the end of follow-up&#46; 54&#37; of the patients showed improvement in bone lesions&#46; They also observed increased BMD&#44; around 15&#37; after 6 treatment cycles on average in those patients suffering from FD in their hip&#46; In this study&#44; the authors concluded that this type of therapy seems useful in the treatment of pain and disease activity associated with FD&#46; They found no predictor of response to treatment and the results were similar in either adults&#44; children and adolescents&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Parisi et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">16</span></a> in a series of 7 patients with FD treated with similar doses of pamidronate&#44; also observed a decrease in pain and bone markers with treatment and increased BMD in FD affected areas&#46; However&#44; they did not show a radiological improvement in bone lesions&#44; a fact attributed to the shorter treatment time of these patients&#44; which was one year&#46; In the same year&#44; Plotkin et al&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">25</span></a> described the effect of pamidronate treatment in a group of 18 children and adolescents with polyostotic FD&#46; Patients were treated for 3&#46;8 years on average&#44; with 1&#8211;1&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day for 3 consecutive days&#44; and every cycle was repeated every 4 months&#46; A total of 16 iliac bone affected by FD were biopsied&#44; 9 before onset of treatment and 7 after 2&#46;2 years of treatment on average&#46; Although pain improved in patients treated with pamidronate&#44; the histological and radiological changes were not significant&#46; The inconclusive results of this study&#44; as indicated by the authors&#44; might be due to several factors&#44; such as the low number of patients included&#44; the severity of the disease or a different behavior of the bone lesions in younger individuals&#46; Thus&#44; the authors suggest that in this population group there could be a more rapid progression of the lesion that would make it difficult to control the disease with the treatment&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Following the series of Chapurlat&#39;s patients mentioned above&#44;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">26</span></a> in 2006 a new study was released that included 9 patients with polyostotic FD who had shown poor response to previous treatment with pamidronate&#46; Therefore&#44; a new treatment was initiated with a most powerful antiresortive bisphosphonate&#58; zoledronate&#46; The dose used was 4<span class="elsevierStyleHsp" style=""></span>mg iv every 6 months&#44; receiving an overall 2&#46;8 boluses on average &#40;from 1 to 5&#41;&#46; The authors described a decrease in pain and markers of bone remodeling after treatment&#44; although this was not significant&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">26</span></a> Again&#44; the small number of patients and the severity of the disease were factors that were related to these results&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Subsequently&#44; several isolated cases of patients with FD have been published<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">27&#44;28</span></a> in which iv zoledronate was administered&#44; with good response to this type of treatment both in the evolution of pain and in the markers of bone remodeling&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Recently&#44; Thomsen and Rejnmark<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">29</span></a> have published a series of 26 patients with DF &#40;17 polyostotic and 4 with MAS&#41;&#44; where they reviewed the treatments with bisphosphonates&#44; analyzing their preparation&#44; dosage and duration&#46; The authors reported that at the end of the study&#44; most patients were treated with iv bisphosphonates&#44; especially with zoledronate&#44; but only a minority &#40;2 cases&#41; showed a regression of bone lesions&#46; They also reported that the levels of bone alkaline phosphatase remained high in half of the patients despite the treatment&#44; evidencing that this type of regime&#44; either due to the dose used and&#47;or by the periodicity of administration may be insufficient in some patients&#46; Although the authors acknowledge that bisphosphonate treatment is associated with improved pain in some patients&#44; they indicate that the response to treatment is ambiguous&#44; noting the need for controlled clinical trials&#46; However&#44; the low incidence of this entity and the heterogeneity of its clinical manifestations make it difficult to conduct this type of study&#44; since the response to treatment with these preparations might be different depending on the activity and severity of the disease&#46; It also depends on its dosage&#46; Wu et al&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">30</span></a> have recently released the case of a patient with polyostotic FD with severe bone involvement who received treatment with zoledronate&#44; 4 boluses of 5<span class="elsevierStyleHsp" style=""></span>mg per year&#46; After a 48-month follow-up&#44; the authors reported an improvement in bone pain after the second infusion of zoledronate and a decrease in remodeling markers &#40;CTx and PINP&#41; and bone lesions from the third and fourth infusions&#44; respectively&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Denosumab</span><p id="par0135" class="elsevierStylePara elsevierViewall">Denosumab is a monoclonal antibody that inhibits RANKL&#44; one of the main regulatory mechanisms of osteoclastogenesis&#46; It is a strong antiresorptive agent indicated for the treatment of osteoporosis and skeletal-related events in patients with bone metastases&#46; Recently&#44; its use has also been approved for the treatment of unresectable giant cell tumor&#46; However&#44; as in metastatic disease&#44; the dose and periodicity of its administration are higher and more frequent than those approved for the treatment of osteoporosis&#46; Denosumab might theoretically be useful in the treatment of FD&#44; since expression of RANKL has increased in the dysplastic lesions of these patients&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">31</span></a> However&#44; we should recall that its use is currently not approved for the treatment of FD&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Recently&#44; isolated cases have been published on patients with severe forms of FD treated with denosumab&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">31&#8211;33</span></a> Thus&#44; Boyce et al&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">31</span></a> describe the case of a child affected by FD in a MAS context with an expansile femur lesion with no response to previous pamidronate treatment&#46; Due to the poor evolution of the patient&#44; and after evidence of RANKL expression in the histological study of bone lesions&#44; treatment was initiated with denosumab &#40;monthly dosage&#44; sliding scale every 3 months 1&#8211;1&#46;25&#8211;1&#46;5&#8211;1&#46;75<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41;&#46; The authors observed a decrease in pain&#44; lesion growth rate and bone remodeling markers after first drug administration&#46; However&#44; after the first dose administered&#44; hypophosphatemia and increased FGF-23 and PTH levels were evidenced&#44; reason why calcium&#44; phosphorus and calcitriol supplements were administered&#46; The patient also had his femur fractured after an accidental fall and he discontinued treatment&#44; showing severe hypercalcemia &#40;18<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#41; and a marked increase in bone remodeling markers 2 months after drug discontinuation&#46; Calcium levels were normalized within 5 months&#44; after several infusions of iv pamidronate andzoledronate&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">The authors concluded that denosumab might be an effective treatment in the control of pain and disease activity&#46; However&#44; they highlight the side effects related to this drug in this particular case with severe FD&#44; such as&#58; hypophosphatemia&#44; ascribed to the secondary increase of PTH by denosumab&#44; and marked hypercalcemia ascribed to the rebound effect of increased bone remodeling after drug discontinuation&#46; Therefore&#44; they recommend a close follow-up in FD patients undergoing this type of treatment&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Similarly&#44; Ganda and Seibel<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">33</span></a> reported 2 cases of adult patients with severe FD who&#44; after previous treatment with zoledronate for several years without evidence of improvement&#44; started treatment with denosumab&#46; Both patients underwent treatment with a 60<span class="elsevierStyleHsp" style=""></span>mg dose&#44; but the rate of administration was different&#44; one receiving the second dose at 9 months and the other at 4 months&#46; Both patients showed a rapid reduction in bone remodeling markers and pain improvement&#46; However&#44; similarly to the case previously described&#44; although none of them suffered from hypercalcemia&#44; earlier and stronger &#8220;rebound&#8221; effect was observed in the markers of bone remodeling compared to patients treated for osteoporosis when discontinuing treatment&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Although these are isolated cases with severe FD&#44; these preliminary results show that although denosumab may be a useful therapy in the treatment of this disease&#44; this drug should be used with caution with close patient monitoring&#46; Studies are necessary to analyze its effectiveness and long-term safety&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Other therapies</span><p id="par0160" class="elsevierStylePara elsevierViewall">As previously indicated&#44; in FD there IL-6 expression is increased&#44; helping the osteoclastogenesis activation and&#44; therefore&#44; osteolytic lesions&#46; Therefore&#44; it has been suggested that tocilizumab&#44; an anti-IL-6 receptor antibody used in the treatment of rheumatoid arthritis&#44; may be useful in this entity&#46; Thus&#44; the case of a patient with symptomatic sphenoid DF not responding to iv bisphosphonates has recently been described&#46; This patient showed a marked improvement in pain and imaging tests after tocilizumab therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">34</span></a> A pahse 2 clinical trial is currently being conducted with this drug &#40;Tocidys study&#41;&#44; including FD patients who have not responded to previous treatment with bisphosphonates and are still in the phase of patient selection&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Other proposed therapeutic targets would be gene therapy&#44; either acting directly over Gs &#945; or through its cascade of effects&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conclusions</span><p id="par0170" class="elsevierStylePara elsevierViewall">FD can occur with a broad spectrum of clinical manifestations&#44; ranging from localized asymptomatic forms to severe forms with important bone deformities&#44; and even associated endocrinological disorders&#46; Although effective treatment is not available yet&#44; there is now more experience in the medical and surgical approach of these patients&#44; which varies depending on age&#44; location&#44; disease activity and associated complications&#46; Although the medical treatment of choice is bisphosphonates&#44; particularly in case of pain&#44; its effectiveness in controlling disease activity remains uncertain&#46; This review indicates the need to analyze the therapeutic strategy in FD and conduct standard controlled clinical trials that analyze the activity of the disease&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Funding</span><p id="par0175" class="elsevierStylePara elsevierViewall">There has been no funding&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conflict of interests</span><p id="par0180" class="elsevierStylePara elsevierViewall">The authors report no conflict of interest&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "identificador" => "sec0010"
          "titulo" => "Diagnosis and monitoring"
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          "identificador" => "sec0015"
          "titulo" => "Treatment"
          "secciones" => array:5 [
            0 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Antiresorptive drugs"
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            1 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Alendronate"
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            2 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Bisphosphonates of parenteral administration"
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            3 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Denosumab"
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            4 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Other therapies"
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        7 => array:2 [
          "identificador" => "sec0045"
          "titulo" => "Conclusions"
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        8 => array:2 [
          "identificador" => "sec0050"
          "titulo" => "Funding"
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        9 => array:2 [
          "identificador" => "sec0055"
          "titulo" => "Conflict of interests"
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        10 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2016-06-10"
    "fechaAceptado" => "2016-07-31"
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          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec795993"
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            0 => "Fibrous dysplasia"
            1 => "McCune&#8211;Albright syndrome"
            2 => "Bisphosphonates"
            3 => "Denosumab"
            4 => "FGF-23"
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          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec795994"
          "palabras" => array:5 [
            0 => "Displasia fibrosa"
            1 => "S&#237;ndrome de McCune-Albright"
            2 => "Bisfosfonatos"
            3 => "Denosumab"
            4 => "FGF-23"
          ]
        ]
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    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Fibrous dysplasia is a skeletal disorder that is associated with a wide spectrum of clinical manifestations&#44; including localized asymptomatic forms and extensive severe forms with severe bone deformities and endocrinological alterations&#44; depending on age&#44; location&#44; extent and associated processes&#46; Although the treatment of choice is based on bisphosphonates&#44; the therapeutic efficacy of these agents in the control of disease activity remains uncertain&#46; This article reviews the current data available on the treatment of this disease as well as the preliminary data on new therapeutic approaches&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La displasia fibrosa es un trastorno esquel&#233;tico que dependiendo de la edad&#44; la localizaci&#243;n&#44; la extensi&#243;n y los procesos asociados puede presentarse con un amplio espectro de manifestaciones cl&#237;nicas&#44; desde formas localizadas asintom&#225;ticas a formas extensas graves con deformidades &#243;seas importantes o incluso alteraciones endocrinol&#243;gicas&#46; Si bien el tratamiento de elecci&#243;n lo constituyen los bisfosfonato&#44; la eficacia en el control de la actividad de la enfermedad contin&#250;a siendo incierta&#46; En este art&#237;culo se revisan los datos sobre el tratamiento de esta entidad&#44; as&#237; como los resultados preliminares de nuevas dianas terap&#233;uticas&#46;</p></span>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Florez H&#44; Peris P&#44; Gua&#241;abens N&#46; Displasia fibrosa&#46; Revisi&#243;n cl&#237;nica y abordaje terap&#233;utico&#46; Med Clin &#40;Barc&#41;&#46; 2016&#59;147&#58;547&#8211;553&#46;</p>"
      ]
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      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Patient with McCune&#8211;Albright syndrome&#46; &#40;A&#41; &#8220;Coffee-with-milk&#8221; spots&#46; &#40;B&#41; The bone scintigraphy shows a hypercaptation in facial mass&#44; proximal and middle third of the right femur and right tibial diaphysis&#46; &#40;C&#41; Radiograph of the proximal third of the right femur with inflatable lesions in &#8220;dull glass&#8221; with sclerosing contours and slight thickening of the cortical&#44; with plate osteosynthesis&#46; &#40;D&#41; Computed tomography scan showing sclerotic and cystic changes at the base of the skull&#44; right orbit&#44; nasal fossa&#44; and right paranasal sinuses&#46; The superior orbital fissure and the optic canal on the right side have a reduced size&#46;</p>"
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        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">ALD&#44; alendronate&#59; APD&#44; pamidronate&#59; mFD&#44; monostotic fibrous dysplasia&#59; DFp&#44; polyostotic fibrous dysplasia&#59; DMAB&#44; denosumab&#59; BMD&#44; bone mineral density&#59; GMO&#44; bone scintigraphy&#59; Iv&#44; intravenous&#59; BRM&#44; markers of bone remodeling&#59; Rx&#44; radiologically assessed image&#59; MAS&#44; McCune&#8211;Albright syndrome&#59; TCZ&#44; tocilizumab&#59; ZOL&#44; zoledronic acid&#59; &#8594;&#44; the following treatment indicated&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Author&#44; year &#40;reference&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">n&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">mFD&#58;pFD &#40;MAS&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Sex&#44; M&#58;F&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Age&#44; years &#91;rank&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type of study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Dosage&#47;cadence &#40;cumulative dose&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Follow-up average time&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Parameters tested&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Evolution&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Liens et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">23</span></a> 1994&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#58;8 &#40;8 SMA&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#58;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">33 &#91;13&#8211;59&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">APD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">60<span class="elsevierStyleHsp" style=""></span>mg&#47;day<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>3<span class="elsevierStyleHsp" style=""></span>days&#47;6<span class="elsevierStyleHsp" style=""></span>months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">26 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain&#44; BRM and Rx&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain&#44; BRM and Rx improving&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Weinstein&#44;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">13</span></a> 1997&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#58;1 &#40;1 MAS&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#58;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case report&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">APD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">90<span class="elsevierStyleHsp" style=""></span>mg&#47;3&#8211;4 weeks<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>4 boluses &#40;360<span class="elsevierStyleHsp" style=""></span>mg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain&#44; BRM and BMD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain&#44; BRM and BMD improving&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ALD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10<span class="elsevierStyleHsp" style=""></span>mg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain&#44; BRM&#44; BMD and Rx&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain&#44; BRM&#44; BMD and Rx improving&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lane et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">21</span></a> 2001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">APD<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ALD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">60&#8211;90<span class="elsevierStyleHsp" style=""></span>mg&#47;3 month<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>mg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">28 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain and safety<br>APD<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ALD&#58; Rx and BRM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain improving&#44; preventing from fractures&#44; BRM and Rx&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ALD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10<span class="elsevierStyleHsp" style=""></span>mg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Kitagawa et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">22</span></a> 2001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#58;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#58;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">45&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case report&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ALD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5<span class="elsevierStyleHsp" style=""></span>mg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">24 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain&#44; Rx and BRM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain&#44; Rx and BRM improving&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Boyce et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">14</span></a> 2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#58;40 &#40;26 MAS&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11&#58;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">24&#46;5 &#91;8&#8211;52&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Randomized&#44; double-blind&#44; placebo-controlled study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ALD versus placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">40<span class="elsevierStyleHsp" style=""></span>mg&#47;day if &#62;50<span class="elsevierStyleHsp" style=""></span>kg<br>20<span class="elsevierStyleHsp" style=""></span>mg&#47;day if 30&#8211;50<span class="elsevierStyleHsp" style=""></span>kg<br>10<span class="elsevierStyleHsp" style=""></span>mg&#47;day if 20&#8211;30<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">24 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">APD&#58; pain&#44; BRM&#44; BMD&#44; BSC&#44; functional test and safety&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">BRM and BMD improving&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Chapurlat et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">15</span></a> 2004&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">58&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#58;36 PM &#40;7 MAS&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">28&#58;30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">28 &#91;5&#8211;63&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">APD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">60<span class="elsevierStyleHsp" style=""></span>mg&#47;day<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>3days&#47;6 months<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2 years&#46; If response is positive&#44; annual boluses<br>Children&#58; 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>3 days&#47;6 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">50 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain&#44; BRM&#44; Rx and BMD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain&#44; BRM&#44; Rx &#40;in 50&#37; patients&#41; and BMD improving&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Parisi et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">6</span></a> 2003&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#58;7 &#40;4 MAS&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#58;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">26 &#91;15&#8211;43&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">APD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">60<span class="elsevierStyleHsp" style=""></span>mg&#47;day<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>3 days&#47;6 months &#40;2 patients only 180<span class="elsevierStyleHsp" style=""></span>mg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain&#44; BRM&#44; Rx and BMD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain&#44; BRM and BMD improving&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Plotkin et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">25</span></a> 2003&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&#58;18 AM &#40;4 MAS&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#58;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#91;6&#46;2&#8211;17&#46;5&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">APD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">First bolus&#58; day 1 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#44; and day 2 and 3 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day<br>Following boluses&#58; 1&#8211;1&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>3 days&#47;4 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">120 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain and safety&#44; BRM&#44; histomorphometry and growth&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain and BRM improving&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Chapurlat&#44;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">26</span></a> 2006&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#58;9 &#40;3 MAS&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#58;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">39 &#91;22&#8211;63&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">APD<span class="elsevierStyleHsp" style=""></span>&#8594;<span class="elsevierStyleHsp" style=""></span>ZOL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">180<span class="elsevierStyleHsp" style=""></span>mg&#47;6 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4<span class="elsevierStyleHsp" style=""></span>mg&#47;6 months &#40;1&#8211;5 boluses&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain&#44; BRM and Rx&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Non-significant pain&#44; BRM improvement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Mansoori et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">27</span></a> 2010&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#58;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#58;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">39&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case report&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">APD<span class="elsevierStyleHsp" style=""></span>&#8594;<span class="elsevierStyleHsp" style=""></span>ZOL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">60<span class="elsevierStyleHsp" style=""></span>mg&#47;5 months<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2 boluses &#40;120<span class="elsevierStyleHsp" style=""></span>mg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5<span class="elsevierStyleHsp" style=""></span>mg &#40;one bolus&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 months after bolus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain&#44; BRM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain and BRM improving&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ozdemir Kutbay et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">28</span></a> 2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#58;2 &#40;1 MAS&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#58;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">39&#46;6 &#91;30&#8211;53&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">APD &#40;4 patients&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">60<span class="elsevierStyleHsp" style=""></span>mg&#47;day<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>3 days&#47;6 months &#40;one patient 360<span class="elsevierStyleHsp" style=""></span>mg&#44; 3 patients&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 to 24 months after treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain and BRM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain and BRM improving&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ZOL &#40;one patient&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5<span class="elsevierStyleHsp" style=""></span>mg &#40;one bolus&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain and BRM improving&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Thomsen and Rejnmark&#44;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">29</span></a> 2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9&#58;17 &#40;4 MAS&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#58;16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">29 &#91;4&#8211;70&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Biphosfonates &#40;23&#47;26 patients&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">48 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain&#44; BRM&#44; Rx and fractures&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain &#40;in 3 patients&#41;&#44; BRM and Rx &#40;in 2 patients&#41; improving&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Wu et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">30</span></a> 2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#58;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#58;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case report&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ZOL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5<span class="elsevierStyleHsp" style=""></span>mg&#47;year &#40;20<span class="elsevierStyleHsp" style=""></span>mg in 4 years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">48 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain&#44; BRM and Rx&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain&#44; BRM and Rx improving&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Boyce et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">31</span></a> 2012&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#58;1 &#40;1 MAS&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#58;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case report&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">DMAB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;month from first to third month&#44; 1&#46;25<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;month from fourth to sixth month&#44; 1&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg seventh month &#40;825<span class="elsevierStyleHsp" style=""></span>mg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lesion extension&#46; BRM&#44; pain&#44; dental development&#44; growth&#44; histomorphometry&#44; immunohistochemistry&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">DEcreased lesion extension&#46; Pain and BRM improving&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ganda and Seibel&#44;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">33</span></a> 2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#58;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#58;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">48 and 44&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case report&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ZOL<span class="elsevierStyleHsp" style=""></span>&#8594;<span class="elsevierStyleHsp" style=""></span>DMAB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4<span class="elsevierStyleHsp" style=""></span>mg&#47;6 months<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>5 boluses &#40;20<span class="elsevierStyleHsp" style=""></span>mg&#41; &#40;patient 1&#41;<br>4<span class="elsevierStyleHsp" style=""></span>mg&#47;6 months<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10 boluses<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>5<span class="elsevierStyleHsp" style=""></span>mg in one bolus &#40;45<span class="elsevierStyleHsp" style=""></span>mg&#41; &#40;patient 2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9&#46;5 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">60<span class="elsevierStyleHsp" style=""></span>mg&#47;9 months<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2 doses<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>third dose at 6 months &#40;180<span class="elsevierStyleHsp" style=""></span>mg&#41; &#40;patient 1&#41;<br>60<span class="elsevierStyleHsp" style=""></span>mg&#47;4 months<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2 doses &#40;120<span class="elsevierStyleHsp" style=""></span>mg&#41; &#40;patient 2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain&#44; BRM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain and BRM improving&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Benhamou et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">32</span></a> 2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#58;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#58;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case report&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">APD<span class="elsevierStyleHsp" style=""></span>&#8594;<span class="elsevierStyleHsp" style=""></span>ZOL<span class="elsevierStyleHsp" style=""></span>&#8594;<span class="elsevierStyleHsp" style=""></span>DMAB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;3600<span class="elsevierStyleHsp" style=""></span>mg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10 years with APD<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>36 months after ZOL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5<span class="elsevierStyleHsp" style=""></span>mg<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>1 bolus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">60<span class="elsevierStyleHsp" style=""></span>mg&#47;6 months<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2 doses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain&#44; BRM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain and BRM improving&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">De Boysson et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">34</span></a> 2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#58;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#58;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">35&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case report&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">iv Biphosphonate<span class="elsevierStyleHsp" style=""></span>&#8594;<span class="elsevierStyleHsp" style=""></span>TCZ&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bisphosphonate monthly<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>6 boluses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">22 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain&#44; BSC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pain and BSC improving&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">600<span class="elsevierStyleHsp" style=""></span>mg&#47;month<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>4<span class="elsevierStyleHsp" style=""></span>&#8594;<span class="elsevierStyleHsp" style=""></span>400<span class="elsevierStyleHsp" style=""></span>mg&#47;2 months<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>3<span class="elsevierStyleHsp" style=""></span>&#8594;<span class="elsevierStyleHsp" style=""></span>200<span class="elsevierStyleHsp" style=""></span>mg&#47;3 months<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>&#8594;<span class="elsevierStyleHsp" style=""></span>80<span class="elsevierStyleHsp" style=""></span>mg&#47;3 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1338489.png"
              ]
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Treatments and characteristics of previous studies conducted in patients with fibrous dysplasia&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:34 [
            0 => array:3 [
              "identificador" => "bib0175"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fibrous dysplasia of bone"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "R&#46;D&#46; Chapurlat"
                            1 => "P&#46;J&#46; Meunier"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/berh.1999.0071"
                      "Revista" => array:6 [
                        "tituloSerie" => "Baillieres Best Pract Res Clin Rheumatol"
                        "fecha" => "2000"
                        "volumen" => "14"
                        "paginaInicial" => "385"
                        "paginaFinal" => "398"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10925751"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0180"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Riminucci"
                            1 => "M&#46;T&#46; Collins"
                            2 => "N&#46;S&#46; Fedarko"
                            3 => "N&#46; Cherman"
                            4 => "A&#46; Corsi"
                            5 => "K&#46;E&#46; White"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1172/JCI18399"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Invest"
                        "fecha" => "2003"
                        "volumen" => "112"
                        "paginaInicial" => "683"
                        "paginaFinal" => "692"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12952917"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0185"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Expression of FGF23 is correlated with serum phosphate level in isolated fibrous dysplasia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "K&#46; Kobayashi"
                            1 => "Y&#46; Imanishi"
                            2 => "H&#46; Koshiyama"
                          ]
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                    0 => array:2 [
                      "doi" => "10.1016/j.lfs.2005.09.052"
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                        "tituloSerie" => "Life Sci"
                        "fecha" => "2006"
                        "volumen" => "78"
                        "paginaInicial" => "2295"
                        "paginaFinal" => "2301"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16337659"
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                0 => array:2 [
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                      "titulo" => "Fibrous dysplasia and fibroblast growth factor-23 regulation"
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                          "autores" => array:3 [
                            0 => "A&#46;M&#46; Boyce"
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                    0 => array:2 [
                      "doi" => "10.1007/s11914-013-0144-5"
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                        "tituloSerie" => "Curr Osteoporos Rep"
                        "fecha" => "2013"
                        "volumen" => "11"
                        "paginaInicial" => "65"
                        "paginaFinal" => "71"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23532406"
                            "web" => "Medline"
                          ]
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              "identificador" => "bib0195"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Displasia fibrosa&#46; Condrodisplasias"
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                          "etal" => false
                          "autores" => array:1 [
                            0 => "G&#46; Sal&#243; Bru"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Fibrous dysplasia of bone and McCune&#8211;Albright syndrome"
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                          "autores" => array:2 [
                            0 => "R&#46;D&#46; Chapurlat"
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                    0 => array:2 [
                      "doi" => "10.1016/j.berh.2007.11.004"
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                        "tituloSerie" => "Best Pract Res Clin Rheumatol"
                        "fecha" => "2008"
                        "volumen" => "22"
                        "paginaInicial" => "55"
                        "paginaFinal" => "69"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18328981"
                            "web" => "Medline"
                          ]
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                ]
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                    0 => array:2 [
                      "titulo" => "McCune&#8211;Albright syndrome and the extraskeletal manifestations of fibrous dysplasia"
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                          "autores" => array:3 [
                            0 => "M&#46;T&#46; Collins"
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                            2 => "E&#46; Eugster"
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
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                        "tituloSerie" => "Orphanet J Rare Dis"
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                        "link" => array:1 [
                          0 => array:2 [
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                            "web" => "Medline"
                          ]
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                    0 => array:2 [
                      "titulo" => "Fibrous dysplasia of bone&#58; a clinicopathologic review"
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                            0 => "H&#46; Mohan"
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                            3 => "S&#46; Kumar"
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                    ]
                  ]
                  "host" => array:1 [
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                      "Revista" => array:5 [
                        "tituloSerie" => "Pathol Lab Med Int"
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                        "paginaInicial" => "31"
                        "paginaFinal" => "42"
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                    ]
                  ]
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "The histopathology of fibrous dysplasia of bone in patients with activating mutations of the Gs alpha gene&#58; site-specific patterns and recurrent histological hallmarks"
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                        0 => array:2 [
                          "etal" => true
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                            3 => "A&#46; Shenker"
                            4 => "A&#46;M&#46; Spiegel"
                            5 => "P&#46;G&#46; Robey"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/(SICI)1096-9896(199901)187:2<249::AID-PATH222>3.0.CO;2-J"
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                        "tituloSerie" => "J Pathol"
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                        "paginaInicial" => "249"
                        "paginaFinal" => "258"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10365102"
                            "web" => "Medline"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Diagnostic value of investigating GNAS mutations in fibro-osseous lesions&#58; a retrospective study of 91 cases of fibrous dysplasia and 40 other fibro-osseous lesions"
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                            3 => "A&#46;V&#46; Decouvelaere"
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                            5 => "F&#46; Larousserie"
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                    0 => array:2 [
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                        "tituloSerie" => "Mod Pathol"
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                        "volumen" => "26"
                        "paginaInicial" => "911"
                        "paginaFinal" => "921"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23370769"
                            "web" => "Medline"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Pathophysiology and medical treatment of pain in fibrous dysplasia of bone"
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                            3 => "J&#46;R&#46; Ghilardi"
                            4 => "M&#46; Kelly"
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                    ]
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                        "tituloSerie" => "Orphanet J Rare Dis"
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                        "link" => array:1 [
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "An instrument to measure skeletal burden and predict functional outcome in fibrous dysplasia of bone"
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                            3 => "C&#46; Chebli"
                            4 => "M&#46;H&#46; Kelly"
                            5 => "A&#46; Gupta"
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                    ]
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                    0 => array:2 [
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                        "tituloSerie" => "J Bone Miner Res"
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                        "paginaInicial" => "219"
                        "paginaFinal" => "226"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15647815"
                            "web" => "Medline"
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              ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Long-term aminobisphosphonate treatment of fibrous dysplasia&#58; spectacular increase in bone density"
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                          "etal" => false
                          "autores" => array:1 [
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                        "tituloSerie" => "J Bone Miner Res"
                        "fecha" => "1997"
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                        "paginaInicial" => "1314"
                        "paginaFinal" => "1315"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9258763"
                            "web" => "Medline"
                          ]
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                    ]
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                ]
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              "identificador" => "bib0240"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "A randomized&#44; double blind&#44; placebo-controlled trial of alendronate treatment for fibrous dysplasia of bone"
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                          "etal" => true
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                            2 => "B&#46;A&#46; Brillante"
                            3 => "H&#46; Kushner"
                            4 => "S&#46; Wientroub"
                            5 => "M&#46; Riminucci"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
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                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "2014"
                        "volumen" => "99"
                        "paginaInicial" => "4133"
                        "paginaFinal" => "4140"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25033066"
                            "web" => "Medline"
                          ]
                        ]
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                  ]
                ]
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Treatment of fibrous dysplasia of bone with intravenous pamidronate&#58; predictors of response to treatment and long-term effectiveness"
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                          "etal" => false
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                        "fecha" => "2004"
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                        "paginaInicial" => "235"
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                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15207763"
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                ]
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Effect of intravenous pamidronate on bone markers and local bone mineral density in fibrous dysplasia of bone"
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                        "paginaFinal" => "588"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14555262"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Clinical guidelines for the management of craniofacial fibrous dysplasia"
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                            3 => "H&#46;J&#46; Kim"
                            4 => "L&#46;R&#46; Lustig"
                            5 => "S&#46;O&#46; Akintoye"
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                      ]
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              "identificador" => "bib0260"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "The surgical management of fibrous dysplasia of bone"
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                        "link" => array:1 [
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22640754"
                            "web" => "Medline"
                          ]
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              ]
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              "identificador" => "bib0265"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The nonsurgical treatment of fibrous dysplasia"
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                            0 => "R&#46;D&#46; Chapurlat"
                            1 => "P&#46;J&#46; Meunier"
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                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Rev Rhum Engl Ed"
                        "fecha" => "1999"
                        "volumen" => "66"
                        "paginaInicial" => "1"
                        "paginaFinal" => "3"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10036690"
                            "web" => "Medline"
                          ]
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                      ]
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                  ]
                ]
              ]
            ]
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              "identificador" => "bib0270"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fibrous dysplasia"
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                        0 => array:2 [
                          "etal" => false
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                  ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Bisphosphonate therapy in fibrous dysplasia"
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                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;M&#46; Lane"
                            1 => "S&#46;N&#46; Khan"
                            2 => "W&#46;J&#46; O&#8217;Connor"
                            3 => "M&#46; Nydick"
                            4 => "J&#46;P&#46; Hommen"
                            5 => "R&#46; Schneider"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Clin Orthop Relat Res"
                        "fecha" => "2001"
                        "volumen" => "382"
                        "paginaInicial" => "6"
                        "paginaFinal" => "12"
                      ]
                    ]
                  ]
                ]
              ]
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            21 => array:3 [
              "identificador" => "bib0280"
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                0 => array:2 [
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                          "autores" => array:3 [
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                        "tituloSerie" => "J Orthop Sci"
                        "fecha" => "2001"
                        "volumen" => "9"
                        "paginaInicial" => "521"
                        "paginaFinal" => "525"
                        "link" => array:1 [
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                      "titulo" => "Long-term effects of intravenous pamidronate in fibrous dysplasia of bone"
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                        "paginaInicial" => "953"
                        "paginaFinal" => "954"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7909013"
                            "web" => "Medline"
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                      "titulo" => "Long-term effects of intravenous pamidronate in fibrous dysplasia of bone"
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                            0 => "R&#46;D&#46; Chapurlat"
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                            3 => "P&#46;J&#46; Meunier"
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                    0 => array:2 [
                      "doi" => "10.1359/jbmr.1997.12.10.1746"
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                        "tituloSerie" => "J Bone Miner Res"
                        "fecha" => "1997"
                        "volumen" => "12"
                        "paginaInicial" => "1746"
                        "paginaFinal" => "1752"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9333137"
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                            0 => "H&#46; Plotkin"
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                            2 => "L&#46; Zeitlin"
                            3 => "C&#46; Munns"
                            4 => "R&#46; Travers"
                            5 => "F&#46;H&#46; Glorieux"
                          ]
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                      ]
                    ]
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                  "host" => array:1 [
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                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "2003"
                        "volumen" => "88"
                        "paginaInicial" => "4569"
                        "paginaFinal" => "4575"
                        "link" => array:1 [
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14557424"
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                      "titulo" => "Medical therapy in adults with fibrous dysplasia of bone"
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                          "autores" => array:1 [
                            0 => "R&#46;D&#46; Chapurlat"
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                        "paginaInicial" => "114"
                        "paginaFinal" => "119"
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                      "titulo" => "Bisphosphonate treatment in polyostotic fibrous dysplasia of the cranium&#58; case report and literature review"
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                          "etal" => false
                          "autores" => array:3 [
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                            2 => "M&#46;S&#46; Rothman"
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                    0 => array:2 [
                      "doi" => "10.4158/EP10136.CR"
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                        "tituloSerie" => "Endocr Pract"
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                        "volumen" => "16"
                        "paginaInicial" => "851"
                        "paginaFinal" => "854"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20570808"
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                      "titulo" => "Characteristics and treatment results of 5 patients with fibrous dysplasia and review of the literature"
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                            4 => "F&#46; Saygili"
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                        "paginaInicial" => "670809"
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26171261"
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                    0 => array:2 [
                      "titulo" => "Clinical and radiological observations in a case series of 26 patients with fibrous fysplasia"
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                          "autores" => array:2 [
                            0 => "M&#46;D&#46; Thomsen"
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                        "tituloSerie" => "Calcif Tissue Int"
                        "fecha" => "2014"
                        "volumen" => "94"
                        "paginaInicial" => "384"
                        "paginaFinal" => "395"
                        "link" => array:1 [
                          0 => array:2 [
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                      "titulo" => "Continuous effect with long-term safety in zoledronic acid therapy for polyostitic fibrous displasia with severe bone destruction"
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                          "etal" => false
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                        "paginaFinal" => "772"
                        "link" => array:1 [
                          0 => array:2 [
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Denosumab treatment for fibrous dysplasia"
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                        "tituloSerie" => "J Bone Miner Res"
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                        "paginaInicial" => "1462"
                        "paginaFinal" => "1470"
                        "link" => array:1 [
                          0 => array:2 [
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                          "etal" => false
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                    ]
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                        "paginaFinal" => "551"
                        "link" => array:1 [
                          0 => array:2 [
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                        "paginaInicial" => "777"
                        "paginaFinal" => "782"
                        "link" => array:1 [
                          0 => array:2 [
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                      "titulo" => "Tocilizumab in the treatment of a polyostotic variant of fibrous dysplasia of bone"
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                          "autores" => array:6 [
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                            2 => "N&#46; Hablani"
                            3 => "W&#46; Hajlaoui"
                            4 => "C&#46; Auzary"
                            5 => "L&#46; Geffray"
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                  ]
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                        "tituloSerie" => "Rheumatology &#40;Oxford&#41;"
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