Scandinavian Journal of Infectious Diseases, 2011; Early Online, 1–3
LETTER TO THE EDITOR
Adefovir induced hypophosphatemic osteomalacia
Scand J Infect Dis Downloaded from informahealthcare.com by Universita Studi di Perugia on 05/24/11 For personal use only.
GIANLUIGI FABBRICIANI1, GIUSEPPE VITTORIO L. DE SOCIO2, MARCO MASSAROTTI1, ROBERTO CERIANI3 & BIANCA MARASINI1 From the 1Rheumatology Unit, IRCCS Humanitas Clinical Institute, University of Milan, Rozzano, Milan, 2Department of Infectious Diseases, Hospital “Santa Maria della Misericordia”, Perugia, and 3Internal Medicine and Hepatology Unit, IRCCS Humanitas Clinical Institute, Rozzano, Milan, Italy
To the Editor, It is known that there is a high rate of nephrotoxicity with a dosage of 60–120 mg/day of adefovir-dipivoxil (Hepsera®). However, a dosage of 10 mg/day has been found to be safe [1,2]. Hypophosphatemic osteomalacia (OM) has recently been reported in patients treated with nucleotide analogues such as tenofovir [3] and adefovir [4–10], raising concerns about their long-term safety. Here we report a case of an incomplete adefovirinduced De Toni–Debré–Fanconi syndrome resulting in hypophosphatemic OM. A 68-y-old man came to our observation in July 2009 with 18-month history of severe bone pain, which had started in the left hip joint and had rapidly worsened, spreading to the rib cage, right hip, sacral region, left knee and left ankle. His family history was unremarkable. His past medical history included hepatitis B virus (HBV)related cirrhosis (Child’s score A). He had previously received treatment with interferon plus ribavirin, but as the hepatitis B e antigen (HBeAg)-positive hepatitis had relapsed after therapy discontinuation, adefovir-dipivoxil (10 mg/day) was started in May 2006. At the time of evaluation, medications also included acetaminophen, tramadol and aspirin 100 mg/day. At the first examination, his weight was 60 kg, for a height of 160 cm, giving a BMI of 23.4 kg/m2. He presented an antalgic gait and tenderness on palpation of the ribs, sternum and proximal areas of the tibias; the remainder of the physical examination was normal. Laboratory examinations during adefovir therapy showed hypophosphatemia (0.72 nM/l) over
several days, an increased level of alkaline phosphatase (ALP; 443 IU/l) with a significantly high bone fraction (bone-ALP 157 μg/l), high levels of osteocalcin (40 ng/ml), vitamin D insufficiency (25-hydroxy vitamin D 12 ng/ml), mildly elevated creatinine level (1.5 mg/dl), hypouricemia (2.2 mg/dl), normal ionized calcium (Ca2⫹ 1.18 nM/l), low–normal parathyroid hormone (20 ng/l), normal calciuria (7 nM/24-h), and unexpected normal levels of phosphaturia (20 nM/24-h), which should have been reduced in the face of the hypophosphatemia. Aspartate aminotransferase and alanine aminotransferase were 39 IU/l and 20 IU/l, respectively, and HBV-DNA was 25 IU/ml. Serum potassium, glycaemia, chloride, protein electrophoreses and urinalysis were normal. Dual-energy X-ray absorptiometry (DEXA) performed in July 2009 showed a bone mineral density (BMD) of 0.667 g/cm2 (T-score ⫽ ⫺4.8 SD, Z-score ⫽ ⫺3.7 SD) at the L2–L4 spine and a BMD of 0.470 g/cm2 (T-score ⫽ ⫺4.6 SD, Z-score ⫽ ⫺2.9 SD) at the femoral neck. A whole-body 99mTcmethylene diphosphonate bone scintigraphy showed increased uptake in the chest, both femoral heads, sacrum, left knee and left ankle, consistent with multiple pseudo-fractures (Figure 1, panel A). These data were consistent with the diagnosis of hypophosphatemic OM. Because of the temporal relationship between adefovir therapy and renal impairment and in view of the previous published cases [4–10], we considered that the hypophosphatemia was related to adefovir toxicity. Thus adefovir was replaced with entecavir 0.5 mg/day; moreover a single dose of oral cholecalciferol
Correspondence: G. V. L. De Socio, Clinica di Malattie Infettive, Università degli Studi di Perugia, Ospedale “Santa Maria della Misericordia”, piazzale Menghini, 1 – 06129 Perugia, Italy. Tel: ⫹39 075 5784319. Fax: ⫹39 075 5784346. E-mail:
[email protected] (Received 5 April 2011; accepted 7 April 2011) ISSN 0036-5548 print/ISSN 1651-1980 online © 2011 Informa Healthcare DOI: 10.3109/00365548.2011.581307
Scand J Infect Dis Downloaded from informahealthcare.com by Universita Studi di Perugia on 05/24/11 For personal use only.
2
Letter to the Editor
Figure 1. Whole-body 99mTc-methylene diphosphonate bone scintigraphy. (A) At clinical presentation: increased uptake in the chest, both femoral heads, sacrum, left knee and left ankle, consistent with multiple stress fractures. (B) Eight months later: mildly increased uptake in the XI and XII right ribs.
300,000 IU and 10,000 IU/week, plus calcium 1 g/day and neutral phosphate 1.5 g/day were given. Bone pain and gait disturbances had significantly improved at 7 months after the discontinuation of adefovir, and 11 months later, bone and mineral parameters had reverted to normal and the patient was asymptomatic. A DEXA taken 7 months after the previous DEXA showed a BMD improvement of 18% at the L2–L4 spine (T-score ⫽ ⫺3.8 SD, Z-score ⫽ ⫺3.0 SD) and of 54% at the femoral neck (T-score ⫽ ⫺2.7 SD, Z-score ⫽ ⫺1.1 SD). A control whole-body 99mTc-methylene diphosphonate bone scintigraphy was compatible with near-complete resolution of the OM (Figure 1, panel B). The dramatic clinical and subsequent laboratory improvement observed with adefovir discontinuation further confirmed the diagnosis of drug-induced OM. De Toni–Debré–Fanconi syndrome arises from generalized proximal renal tubule dysfunction, leading to impaired reabsorption and wasting of phosphate, urate, amino acids, glucose and bicarbonate with the urine and subsequent hypophosphatemic OM and sometimes metabolic acidosis. It may be associated with a number of medications [11]. Adefovir is eliminated through the kidney, and active tubular secretion is responsible for approximately
60% of its catabolism. It may produce a dose-dependent kidney toxicity, characterized by a slight increase in serum creatinine and phosphate wasting. Rapid withdrawal of the drug usually reverses the renal damage, otherwise a permanent De Toni–Debré–Fanconi syndrome can ensue [2]. As bone is mostly composed of calcium and phosphate, hypophosphatemia may cause an inadequate mineralization of the bone matrix, with subsequent rickets or OM. The demineralized gelatinous matrix adsorbs water and expands, pushing outwards on the periosteum; this causes bone pain, which can be elicited by moderate pressure on the sternum [12]. The characteristic pseudo-fractures (Looser zone) of OM are linked to low osteoid tissue mineralization. They are usually multiple, symmetrical and mostly localized in areas of high mechanical stress (proximal femur, pubic rami, metatarsal bones). Radiographically they appear as translucent bands of decreased cortical density perpendicular to the bone surface, and on bone scintigraphy as hot spots [13], as in our case (Figure 1, panel A). Proximal muscle weakness is a characteristic feature of OM, probably due to a combination of vitamin D deficiency and hypophosphatemia. Three main types of OM exist: (1) vitamin D-related OM, (2) hypophosphatemic
Scand J Infect Dis Downloaded from informahealthcare.com by Universita Studi di Perugia on 05/24/11 For personal use only.
Adefovir induced hypophosphatemic osteomalacia OM and (3) OM with normal calcium/phosphorus metabolism (fibrogenesis imperfecta ossium and hypophosphatasia). Increased ALP is a constant laboratory finding in hypophosphatemic and vitamin D-related OM, and is due to the increase of osteoid tissue and of the mineralization lag time [13]. Because of the bone demineralization, BMD assessed by DEXA is markedly reduced in patients with OM. A tetracycline-labelled bone biopsy is required only in patients with atypical clinical, laboratory and radiological features or in those non-responsive to therapy [12,13]. At the time of writing, 7 cases of hypophosphatemic OM induced by adefovir at a low dose (10 mg daily) have been reported [4–10]. All of them had several features of the De Toni–Debré–Fanconi syndrome; the hypophosphatemia had become clinically evident after 6–43 months of treatment [6–8] and all cases recovered after withdrawal of adefovir. In conclusion, this report illustrates that hypophosphatemic OM is a potentially relevant problem in the management of patients with HBV-related cirrhosis on long-term adefovir and suggests the importance of monitoring the levels of phosphate, creatinine and ALP during treatment, since the disorder can be resolved with drug withdrawal.
[2] [3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
Acknowledgement We thank Ms Jackie Iraci for her revision of the English translation. Declaration of interest: None of the authors has a conflict of interest.
[11]
[12] [13]
References [1] Izzedine H, Hulot JS, Launay-Vacher V, Marcellini P, Hadziyannis SJ, Currie G, et al. Renal safety of adefovir
3
dipivoxil in patients with chronic hepatitis B: two doubleblind, randomized, placebo-controlled studies. Kidney Int 2004;66:1153–8. Fontana RJ. Side effects of long-term oral antiviral therapy for hepatitis B. Hepatology 2009;49(Suppl):185–95. Fux CA, Rauch A, Simcock M, Bucher HC, Hirschel B, Opravil M, et al. Tenofovir use is associated with an increase in serum alkaline phosphatase in the Swiss HIV Cohort Study. Antivir Ther 2008;13:1077–82. 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. Korean J Hepatol 2008;14:381–6. 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 2009;23:544–5. Wong T, Girgis CM, Ngu MC, Chen RC, Emmett L, Archer KA, et al. Hypophosphatemic osteomalacia after low-dose adefovir dipivoxil therapy for hepatitis B. J Clin Endocrinol Metab 2010;95:479–80. Girgis CM, Wong T, Ngu MC, Emmett L, Archer KA, Chen RC, et al. Hypophosphataemic osteomalacia in patients on adefovir dipivoxil. J Clin Gastroenterol 2011;45:468–73. Minemura M, Tokimitsu Y, Tajiri K, Nakayama Y, Kawai K, Kudo H, et al. Development of osteomalacia in a post-liver transplant patient receiving adefovir dipivoxil. World J Hepatol 2010;2:442–6. Jung YK, Yeon JE, Choi JH, Kim CH, Jung ES, Kim JH, et al. Fanconi’s syndrome associated with prolonged adefovir dipivoxil therapy in a hepatitis B virus patient. Gut Liver 2010;4:389–93. Kwon SY, Ahn SY, Ko SY, Jang YM, Choi YH, Kim BK, et al. A case of osteomalacia related to adefovir in a patient with chronic hepatitis B. Korean J Gastroenterol 2010;56: 117–20. Santer R, Schneppenheim R, Suter D, Schaub J, Steinmann B. Fanconi–Bickel syndrome—the original patient and his natural history, historical steps leading to the primary defect, and a review of the literature. Eur J Pediatr 1998;157: 783–97. Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357:266–81. Lips P, van Schoor NM, Bravenboer N. Vitamin D-related disorders. In: Rosen CJ, editor. Primer of the metabolic bone diseases and disorders of mineral metabolism. Scarborough, ME: American Society for Bone and Mineral Research; 2008 pp 329–35.
