Hypophosphatemic osteomalacia induced by prolonged low-dose adefovir dipivoxil therapy for CHB : two cases report and literature review

Background: Adefovir dipivoxil (ADV) is a nucleotide used as a long-term therapy for chronic hepatitis B (CHB). Low-dose ADV therapy (daily dose of 10 mg) to treat patients with CHB has been reported to be safe. However, there are cumulative reports describing that the long-term use of low-dose ADV triggers proximal renal tubular dysfunction and causes hypophosphatemic osteomalacia. Methods: We reported two CHB cases of low-dose ADV-induced hypophosphatemic osteomalacia who presented initially with bone pain. Literature review revealed other 33 cases of hypophosphatemic osteomalacia induced by low-dose (10 mg daily) ADV and we also performed the literature review of the main characteristics from all the included 35 cases. Results: The first patient was a 46-year-old man with a 3-year history of bone pain involving low back, lumbar spine, rib cage, cervical vertebra, both knees, ankles without antecedent trauma. The patient had been receiving adefovir for 10 years before the confirmation of hypophosphatemia. Bone scintigraphy revealed multiple ribs, cervical vertebra, clavicle, humerus, sacrum, both posterior iliac bones, ankles and calcaneus, which were suggestive of metabolic bone disorder. Laboratory investigations showed hypophosphatemia, hypocalcemia, hypouricemia, increased level of alkaline phosphatase (ALP) and decreased 25-hydroxyvitamin D level. After ADV was replaced with entecavir, with supplementation of phosphate, calcium carbonate, calcitriol, bone pain was significantly reduced within 7 months. The second patient was a 62-year-old man who presented with a 4-year history of bone pain of the heel bone, knee and breast bone. The patient had been taking ADV for approximately 24 months before the development of bone pain. Laboratory data revealed hypophosphatemia, hypouricemia, hyperglycemia, increased level of ALP and vitamin D deficiency. Bone scintigraphy showed increased uptake in cervical vertebra, clavicle, sacrum, posterior iliac bones, lateral condyle and upper tibia. The symptoms improved by changing the antiviral agent from adefovir to entecavir within 6 months. Follow-up examination after 14 months showed his serum level of phosphate and bone densitometry to be normal. Conclusion: Hypophosphatemic osteomalacia and renal Fanconi syndrome can be induced by long-term low-dose ADV therapies. The symptoms and the hypophosphatemia improved after discontinuation of ADV coupled with supplementation with phosphate in most cases and replacing ADV with entecavir may be a better alternative. CHB patients taking long-term ADV therapy (daily dose of 10 mg) daily should receive regular monitor of the renal function and serum phosphate level. Clinicians prescribing ADV over a long period of time should be aware of the late onset of hypophosphatemic osteomalacia and renal Fanconi syndrome.