Pathological femoral fractures due to osteomalacia associated with adefovir dipivoxil treatment for hepatitis B: a case report
© Tanaka et al.; licensee BioMed Central Ltd. 2012
Received: 30 May 2012
Accepted: 28 June 2012
Published: 20 August 2012
We present a case of a 62-year-old man who underwent total hip arthroplasty for treatment of pathologic femoral neck fracture associated with adefovir dipivoxil-induced osteomalacia. He had a 13-month history of bone pain involving his shoulders, hips, and knee. He received adefovir dipivoxil for treatment of lamivudine-resistant hepatitis B virus infection for 5 years before the occurrence of femoral neck fracture. Orthopedic surgeons should be aware of osteomalacia and pathological hip fracture caused by drug-induced renal dysfunction, which results in Fanconi’s syndrome.
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KeywordsOsteomalacia Pathological femoral neck fracture Adefovir dipivoxil Hepatitis B Fanconi’s syndrome
Hypophosphatemic osteomalacia caused by proximal renal tubule dysfunction induces Fanconi’s syndrome, which leads to impaired reabsorption of amino acids, glucose, urate, and phosphate . The chronic loss of phosphate and impaired synthesis of 1,25-dihydroxyvitamin D3 may lead to failure of bone mineralization. Recently, osteomalacia was reported in cases in which hepatitis B virus and human immunodeficiency virus (HIV) infections were treated using high-dose adefovir dipivoxil [2–6]. We report a case of a patient who underwent total hip arthroplasty for pathological femoral neck fracture associated with osteomalacia induced by low-dose adefovir dipivoxil treatment.
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Adefovir dipivoxil is a commonly used antiviral agent in the treatment of chronic hepatitis B or HIV infection . Fanconi’s syndrome has been recognized as a complication of high-dose adefovir dipivoxil therapy (dose, 60–120 mg/day) in the treatment of HIV infection . Few studies have reported severe hypophosphatemia with 10 mg/day adefovir dipivoxil therapy [11–14]. In addition, to our knowledge, this is the first report of pathological femoral neck fracture associated with adefovir dipivoxil-induced osteomalacia treated by total hip arthroplasty. When orthopaedic surgeons encounter adefovir dipivoxil–treated chronic hepatitis B patients with pathological hip fractures, the patients’ renal function and levels of electrolytes, including calcium and phosphorus, should be carefully monitored.
Fanconi’s syndrome results from dysfunction of the proximal renal tubule, causing impaired reabsorption of amino acids, urate, bicarbonate, and phosphate and increased excretion of these solutes into the urine. The pathophysiology of proximal renal tubule dysfunction is thought to be an increase in the adefovir dipivoxil concentration in the mitochondria mediated by inhibition of several ATP-dependent transporters [15, 16]. Patients with Fanconi’s syndrome show low phosphate levels (because of renal phosphate loss) and normal levels of calcium, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and PTH and increased ALP levels. Radiography and bone scan showed multiple patterns of osteomalacia. Our findings were consistent with those in previous reports .
Entecavir is more effective than adefovir dipivoxil, with a favorable safety profile and low incidence of resistance . We switched adefovir dipivoxil with entecavir hydrate as previously reported [19, 20]. Entecavir may be a good treatment choice. In addition to adefovir dipivoxil, the patient received oral administration of lamivudine, rebamipide, rabeprazole sodium, and methylprednisolone. These drugs may have caused Fanconi’s syndrome. After the patient’s condition was diagnosed as Fanconi’s syndrome, adefovir dipivoxil was replaced with entecavir hydrate. Thereafter, the symptoms of Fanconi’s syndrome improved. These findings suggested that adefovir dipivoxil caused Fanconi’s syndrome and osteomalacia.
In conclusion, orthopaedic surgeons should be aware of osteomalacia and pathologic fractures caused by adefovir dipivoxil administered as anti-hepatitis B virus therapy. In addition to the above-mentioned antiviral agent, ifosfamide, valproic acid, aminoglycosides, methyl-3-chromone, paraquat, l-lysine, calcineurin-inhibitor, or tetracycline may cause hypophosphatemic osteomalacia; therefore, serum ALP and phosphorus levels of patients receiving these drugs should be monitored [21–28].
Written informed consent was obtained from the patient and his family for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of the journal.
Human immunodeficiency virus
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- Clarke BL, Wynne AG, Wilson DM, Fitzpatrick LA: Osteomalacia associated with adult Fanconi's syndrome: clinical and diagnostic features. Clin Endocrinol. 1995, 43: 479-490. 10.1111/j.1365-2265.1995.tb02621.x.View Article
- Verhelst D, Monge M, Meynard JL, Fouqueray B, Mougenot B, Girard PM, Ronco P, Rossert J: Fanconi syndrome and renal failure induced by tenofovir: a first case report. Am J Kidney Dis. 2002, 40: 1331-1333. 10.1053/ajkd.2002.36924.View ArticlePubMed
- Earle KE, Seneviratne T, Shaker J, Shoback D: Fanconi's syndrome in HIV + adults: report of three cases and literature review. J Bone Miner Res. 2004, 19: 714-721. 10.1359/jbmr.2004.19.5.714.View ArticlePubMed
- Parsonage MJ, Wilkins EG, Snowden N, Issa BG, Savage MW: The development of hypophosphataemic osteomalacia with myopathy in two patients with HIV infection receiving tenofovir therapy. HIV Med. 2005, 6: 341-346. 10.1111/j.1468-1293.2005.00318.x.View ArticlePubMed
- Zimmermann AE, Pizzoferrato T, Bedford J, Morris A, Hoffman R, Braden G: Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2006, 42: 283-290. 10.1086/499048.View Article
- Malik A, Abraham P, Malik N: Acute renal failure and Fanconi syndrome in an AIDS patient on tenofovir treatment–case report and review of literature. J Infect. 2005, 51: E61-E65. 10.1016/j.jinf.2004.08.031.View ArticlePubMed
- Garden RS: LOW-ANGLE FIXATION IN FRACTURES OF THE FEMORAL NECK. J Bone Joint Surg Br. 1961, 43-B: 647-663.
- Ott SM: Bone histomorphometry in renal osteodystrophy. Semin Nephrol. 2009, 29: 122-132. 10.1016/j.semnephrol.2009.01.005.View ArticlePubMed
- Wong T, Girgis CM, Ngu MC, Chen RC, Emmett L, Archer KA, Seibel MJ: Hypophosphatemic osteomalacia after low-dose adefovir dipivoxil therapy for hepatitis B. J Clin Endocrinol Metab. 2010, 95: 479-480. 10.1210/jc.2009-2051.View ArticlePubMed
- Kahn J, Lagakos S, Wulfsohn M, Cherng D, Miller M, Cherrington J, Hardy D, Beall G, Cooper R, Murphy R, et al.: Efficacy and safety of adefovir dipivoxil with antiretroviral therapy: a randomized controlled trial. Jama. 1999, 282: 2305-2312. 10.1001/jama.282.24.2305.View ArticlePubMed
- Izzedine H, Kheder-Elfekih R, Housset P, Sarkozy C, Brocheriou I, Deray G: Adefovir dipivoxil-induced acute tubular necrosis and Fanconi syndrome in a renal transplant patient. AIDS (London, England). 2009, 23: 544-545. 10.1097/QAD.0b013e32832407f7.View Article
- Jung YK, Yeon JE, Choi JH, Kim CH, Jung ES, Kim JH, Park JJ, Kim JS, Bak YT, Byun KS: Fanconi's syndrome associated with prolonged adefovir dipivoxil therapy in a hepatitis B virus patient. Gut and Liver. 2010, 4: 389-393. 10.5009/gnl.2010.4.3.389.PubMed CentralView ArticlePubMed
- Minemura M, Tokimitsu Y, Tajiri K, Nakayama Y, Kawai K, Kudo H, Hirano K, Atarashi Y, Yata Y, Yasumura S, et al.: Development of osteomalacia in a post-liver transplant patient receiving adefovir dipivoxil. World J Hepatol. 2010, 2: 442-446. 10.4254/wjh.v2.i12.442.PubMed CentralView ArticlePubMed
- Lee HJ, Choi JW, Kim TN, Eun JR: A case of severe hypophosphatemia related to adefovir dipivoxil treatment in a patient with liver cirrhosis related to hepatitis B virus. The Korean Journal of Hepatology. 2008, 14: 381-386. 10.3350/kjhep.2008.14.3.381.View ArticlePubMed
- Tanji N, Tanji K, Kambham N, Markowitz GS, Bell A, D’Agati VD: Adefovir nephrotoxicity: possible role of mitochondrial DNA depletion. Hum Pathol. 2001, 32: 734-740. 10.1053/hupa.2001.25586.View ArticlePubMed
- Cihlar T, Lin DC, Pritchard JB, Fuller MD, Mendel DB, Sweet DH: The antiviral nucleotide analogs cidofovir and adefovir are novel substrates for human and rat renal organic anion transporter 1. Mol Pharmacol. 1999, 56: 570-580.PubMed
- Izzedine H, Launay-Vacher V, Isnard-Bagnis C, Deray G: Drug-induced Fanconi's syndrome. Am J Kidney Dis. 2003, 41: 292-309. 10.1053/ajkd.2003.50037.View ArticlePubMed
- Asselah T, Lada O, Boyer N, Martinot M, Marcellin P: Treatment of chronic hepatitis B. Gastroenterol Clin Biol. 2008, 32: 749-768. 10.1016/j.gcb.2008.07.001.View ArticlePubMed
- Lai CL, Rosmawati M, Lao J, Van Vlierberghe H, Anderson FH, Thomas N, Dehertogh D: Entecavir is superior to lamivudine in reducing hepatitis B virus DNA in patients with chronic hepatitis B infection. Gastroenterology. 2002, 123: 1831-1838. 10.1053/gast.2002.37058.View ArticlePubMed
- Chang TT, Gish RG, Hadziyannis SJ, Cianciara J, Rizzetto M, Schiff ER, Pastore G, Bacon BR, Poynard T, Joshi S, et al.: A dose-ranging study of the efficacy and tolerability of entecavir in Lamivudine-refractory chronic hepatitis B patients. Gastroenterology. 2005, 129: 1198-1209. 10.1053/j.gastro.2005.06.055.View ArticlePubMed
- Melnick JZ, Baum M, Thompson JR: Aminoglycoside-induced Fanconi's syndrome. Am J Kidney Dis. 1994, 23: 118-122.View ArticlePubMed
- Yoshikawa H, Watanabe T, Abe T: Fanconi syndrome caused by sodium valproate: report of three severely disabled children. Eur J Paediatr Neurol. 2002, 6: 165-167. 10.1053/ejpn.2002.0585.View ArticlePubMed
- Otten J, Vis HL: Acute reversible renal tubular dysfunction following intoxication with methyl-3-chromone. J Pediatr. 1968, 73: 422-425. 10.1016/S0022-3476(68)80124-6.View ArticlePubMed
- Vaziri ND, Ness RL, Fairshter RD, Smith WR, Rosen SM: Nephrotoxicity of paraquat in man. Arch Intern Med. 1979, 139: 172-174. 10.1001/archinte.1979.03630390032014.View ArticlePubMed
- Lo JC, Chertow GM, Rennke H, Seifter JL: Fanconi's syndrome and tubulointerstitial nephritis in association with L-lysine ingestion. Am J Kidney Dis. 1996, 28: 614-617. 10.1016/S0272-6386(96)90476-X.View ArticlePubMed
- Varavithya W, Chulajata R, Ayudthya PS, Preeyasombat C: Fanconi syndrome caused by degraded tetracycline. J Med Assoc Thail= Chotmaihet thangphaet. 1971, 54: 62-67.
- Negro A, Regolisti G, Perazzoli F, Davoli S, Sani C, Rossi E: Ifosfamide-induced renal Fanconi syndrome with associated nephrogenic diabetes insipidus in an adult patient. Nephrol Dial Transplant. 1998, 13: 1547-1549. 10.1093/ndt/13.6.1547.View ArticlePubMed
- Morard I, Mentha G, Spahr L, Majno P, Hadengue A, Huber O, Morel P, Giostra E: Long-term renal function after liver transplantation is related to calcineurin inhibitors blood levels. Clin Transplant. 2006, 20: 96-101. 10.1111/j.1399-0012.2005.00447.x.View ArticlePubMed
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