Adefovir-induced osteomalacia and hypophosphatemia

López Medina, José Antonio; Simón Frapolli, Víctor José; Tinahones Madueño, Francisco José

doi:10.1016/j.medcle.2021.05.018

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During childhood, this disorder is known by the name of rickets and also causes cartilage growth alterations. Calcium and phosphate salts are necessary for the proper formation of the bone architecture. Because calcium absorption is very closely linked to vitamin D, an alteration in the function of either of these factors results in an accumulation of unmineralized osteoid matrix and a decrease in bone strength. Osteomalacia has multiple known causes, including vitamin D alterations, phosphorus metabolism alterations, certain drugs, oncological diseases, and genetic causes.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>Adefovir is an antiretroviral drug indicated for the treatment of chronic hepatitis B in adults with a compensated liver disease with evidence of viral replication. One of its adverse effects is renal tubule involvement, which results in hypophosphatemia, hypouricemia, proteinuria, and glycosuria. Hypophosphatemia can cause osteomalacia by inhibiting bone mineralization.<a class="elsevierStyleCrossRefs" href="#bib0010">2,3</a>In his paper we describe the clinical case of a 53-year-old man who was referred to our Endocrinology Department for a phosphorus-calcium metabolism study due to presenting with multiple pathological bone fractures within the last year, pain in his lower limbs, and hypophosphatemia. His personal medical history included arterial hypertension under treatment with candesartan 16 mg/day, as well as chronic hepatitis B under treatment with adefovir 10 mg/day for 5 years. Physical examination revealed a weight of 75 kg, a height of 170 cm, and a body mass index (BMI) of 25.9 kg/m2. He had normal vital signs and no neurological focalities, but he complained of pain on palpation of the dorsal spine and multiple ribs of the right costal curvature.Blood tests revealed the following: normal complete blood count and erythrocyte sedimentation rate, creatinine levels of 1.13 mg/dl, estimated glomerular filtration rate of 64 ml/min, serum calcium levels of 9 mg/dl (normal range: 8.5–10.5), phosphorus levels of 1.8 mg/dl (normal range: 2.2–4.7), vitamin D levels of 16 ng/mL (normal range: 20–50), alkaline phosphatase levels of 218 U/L (normal range: 45–129), intact parathyroid hormone levels (PTHi) of 38 pg/mL (normal range: 10–65), normal transaminase levels, uric acid levels of 2.5 mg/dl (normal range: 3.4–7), and a tubular phosphate reabsorption rate of 47% (normal >80%). A urine analysis yielded the below figures: microalbuminuria 152 mg/day (normal figure: <30 mg/day) and glycosuria (>100 mg/day). In addition, he had a normal protein panel and thyroid stimulating hormone (TSH) levels of 1.36 IU/mL (normal range: 0.35–5.50), negativity for antinuclear antibodies and the HLA-B27 antigen, and a C-terminal fibroblast growth factor 23 (cFGF-23) concentration of 72 kRU/L (normal range: 26–110).A chest X-ray showed non-displaced fractures in the posterior, proximal segments of the sixth and eighth ribs of the right costal curvature. A bone scan showed multiple foci of radiopharmaceutical uptake in the rib cages, the sacroiliac joint, and chondromalacia patellae. In addition, a compression fracture in the upper endplates of vertebral bodies T5–T6 and T7, as well as traces of rib fractures in the areas described earlier, were identified in a magnetic resonance imaging (MRI) scan of the dorsal spine. A scintigram with octreotide-IN 111 revealed no alterations.In view of these findings, and given the suspected diagnosis of adefovir-induced hypophosphatemic osteomalacia, we decided to discontinue this drug, observing a progressive improvement of the patient’s symptoms and laboratory parameters thereafter. A follow-up examination performed three months later revealed serum phosphorus levels of 2.7 mg/dl (without oral supplementation) and normalization of the phosphate tubular reabsorption parameters.Adefovir is a drug indicated for the treatment of chronic hepatitis B, as it inhibits reverse transcriptase and DNA synthetase, thereby preventing the proliferation of the hepatitis B virus. It is a well-known fact that this drug can cause nephrotoxicity when used at high doses and for prolonged periods of time due to causing damage to the proximal renal tubule, which results in deficient tubular phosphate reabsorption and hypophosphatemic osteomalacia.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> However, these effects have also been described in patients taking a lower dose of adefovir of 10 mg/day.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>Osteomalacia is a difficult clinical entity to diagnose, as its symptoms are often non-specific. It usually manifests with pain, proximal muscle weakness, and, at advanced stages, bone fractures, which are very common in the ribs. The most prevalent cause of osteomalacia is a vitamin D deficiency, which usually presents with normal calcium and phosphorus levels, a low renal calcium excretion, a high renal phosphate excretion, increased PTH levels, and low vitamin D levels. However, hypophosphatemic osteomalacia caused by certain drugs presents with low phosphorus levels, elevated alkaline phosphatase, and normal calcium, PTH, and vitamin D levels. The most characteristic radiological alterations found in cases of osteomalacia are pseudofractures or the presence of Looser-Milkman lines, which are more frequently detected in the ribs, hips, scapulae, and lower limbs, can be seen in a plain X-ray, and can evolve into complete fractures. Bone scans are very useful and sensitive in locating these alterations.<a class="elsevierStyleCrossRef" href="#bib0025">5</a>Ethical responsibilitiesProtection of people and animals. The authors of this paper declare that no experiments were carried out on humans or animals for the conduct of this research.Data confidentiality. The authors of this paper declare that they followed their site’s protocols regarding the publication of patient data and that all patients included in the study received sufficient information and provided their written informed consent to participate in the study.Right to privacy and informed consent. The authors declare that no patient data appear in this article.Conflicts of interestThe authors declare no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Ethical responsibilities" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Conflicts of interest" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: López Medina JA, Simón Frapolli VJ, Tinahones Madueño FJ. Osteomalacia e hipofosfatemia inducida por adefovir. Med Clin (Barc). 2022;158:245." ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Senabre-Gallego JM, Salas E, Rosas J, Santos-Soler G, Santos-Ramírez C, Barber X, et al. Capítulo 40: Osteomalacia. Svreumatologia.com. [Accessed 18 March 2021]. Available at: <a target="_blank" href="https://svreumatologia.com/wp-content/uploads/2013/10/Cap-40-Osteomalacia.pdf">https://svreumatologia.com/wp-content/uploads/2013/10/Cap-40-Osteomalacia.pdf</a>." ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Two cases of hypophosphatemic osteomalacia after long-term low dose adefovir therapy in chronic hepatitis B and literature review" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "H. Jeong" 1 => "J. Lee" 2 => "T. Lee" 3 => "J. Lee" 4 => "H. Kim" 5 => "M. Heo" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.11005/jbm.2014.21.1.76" "Revista" => array:6 [ "tituloSerie" => "J Bone Metab" "fecha" => "2014" "volumen" => "21" "paginaInicial" => "76" "paginaFinal" => "83" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24707470" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Osteomalacia inducida por adefovir en paciente con hepatitis B" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "M. Nathali Rivas Zavaleta" 1 => "S. Guayambuco Romero" 2 => "M. Calabozo Raluy" 3 => "F. Pérez Ruiz" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.reuma.2013.01.006" "Revista" => array:6 [ "tituloSerie" => "Reumatol Clin" "fecha" => "2014" "volumen" => "10" "paginaInicial" => "120" "paginaFinal" => "121" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23664308" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A case of severe hypophosphatemia related to adefovir dipivoxil treatment in a patient with liver cirrhosis related to hepatitis B virus" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "H.J. Lee" 1 => "J.W. Choi" 2 => "T.N. Kim" 3 => "J.R. Eun" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3350/kjhep.2008.14.3.381" "Revista" => array:6 [ "tituloSerie" => "Korean J Hepatol" "fecha" => "2008" "volumen" => "14" "paginaInicial" => "381" "paginaFinal" => "386" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18815461" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Déficit de vitamina D en el adulto: clínica, diagnóstico y tratamiento" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "M. Zarazuela" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S1575-0922(05)71018-4" "Revista" => array:5 [ "tituloSerie" => "Endocrinol Nutr" "fecha" => "2005" "volumen" => "52" "paginaInicial" => "215" "paginaFinal" => "223" ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/23870206/0000015800000005/v1_202203050916/S2387020622000638/v1_202203050916/en/main.assets" "Apartado" => array:4 [ "identificador" => "43309" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Letters to the Editor" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/23870206/0000015800000005/v1_202203050916/S2387020622000638/v1_202203050916/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020622000638?idApp=UINPBA00004N"]

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Vol. 158. Issue 5.