Hypophosphataemic Osteomalacia in Patients on Adefovir Dipivoxil

Abstract

Fanconi syndrome results from generalised renal tubular toxicity and, owing to phosphate wasting can cause hypophosphataemic osteomalacia. Large clinical trials advocated the safety of adefovir dipivoxil at a daily dose of 10 mg, the standard dose given to patients with hepatitis B. We diagnosed Fanconi syndrome in conjunction with severe osteomalacia in 2 hepatitis B-positive patients on standard-dose adefovir therapy. The first patient was a 40-year-old male with a 5 month history of bone pain involving his knees, ankles, and ribs. He had been receiving adefovir dipivoxil for 27 months before the development of hypophosphataemia, urinary phosphate wasting, and aminoaciduria. These abnormalities resolved within weeks of discontinuation of adefovir dipivoxil and supplementation with elemental phosphate, calcium carbonate, and cholecalciferol. The second patient was a 53-year-old female with a 6 month history of lethargy, cachexia, and generalized bone pain. She had been receiving adefovir for 64 months before the development of these symptoms. She had hypophosphataemia, hypocalcaemia, metabolic acidosis, and severe vitamin D deficiency, but initially no urinary phosphate wasting. Four months of high-dose cholecalciferol supplementation unmasked her Fanconi syndrome including significant urinary phosphate wasting. The patient improved within weeks of discontinuation of adefovir and supplementation with elemental phosphate, calcium carbonate, and calcitriol. Despite large clinical trials advocating the safety of adefovir dipivoxil at 10-mg daily, long-term use of this agent may be nephrotoxic and in rare cases, cause Fanconi syndrome and severe hypophosphataemic osteomalacia. Clinicians prescribing this drug should be aware of this potential complication.

Adefovir-induced Fanconi syndrome: diagnostic pearls and perils of late or missed diagnosis

“…Nephrotoxicity associated with high-dose ADV typically has a late onset ([6 months) [15]. The time to onset of low-dose ADV-induced FS, based on case reports, ranges from a few months to [5 years [4][5][6][7][8][9][10][11][12]. In our patient, it took more than 2 years before the tubulopathy became apparent.…”

“…From the series of case reports so far, the time to resolution after cessation of ADV ranged from a few weeks to months [4][5][6][7][8][9][10][11][12]. A previous trial with high-dose ADV treatment showed a median time to resolution of renal dysfunction of 15 weeks, with the nephrotoxicity failing to resolve completely at 41 weeks after onset in 16 % of the patients [15].…”

“…The first report of ADV-associated hypophosphatemic osteomalacia was published in 2008 [4], with a number of reported cases of ADV-induced FS [5][6][7][8][9][10][11][12] since then. Most of the cases published were in East Asian subjects, which may either suggest a racial predilection, or an indication of the increased prevalence of hepatitis B infection requiring ADV treatment in East Asia.…”

Misdiagnosis of Bone Metastasis Cancer After Using Adefovir Dipivoxi in a Hepatitis B Patient with Fanconi Syndrome

“…Acquired forms of Fanconi syndrome are caused by paraproteinemia, Sjögren syndrome, primary biliary cirrhosis (PBC) and drugs such as cisplatin [4][5][6]. Osteomalacia is a metabolic bone disease that leads to softening of the bones and can be caused by hypophosphatemia [7]. The clinical features of hypophosphatemic osteomalacia were slowly progressive distal muscle weakness, bone pain or even fracture.…”

Adefovir dipivoxil-induced Fanconi syndrome and its predictive factors: A study of 28 cases

“…Compared with other nucleoside analogs, adefovir dipivoxil is characterized by low cost, low drug resistance and absence of cross-resistance, and has been applied widely in developing countries (4,5). However, renal toxicity is the most common adverse reaction associated with adefovir dipivoxil, and it has been reported to cause Fanconi syndrome (6)(7)(8), which is often misdiagnosed due to a dearth of knowledge among the majority of clinicians (9). In addition, some common manifestations of Fanconi syndrome, including systemic bone pain, osteoporosis and spontaneous fracture, are easily misdiagnosed as osteoarthrosis, osteoporosis and bone tumors in the early stages (9,10).…”