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Case Report

Hypophosphatemic osteomalacia and renal Fanconi syndrome induced by low-dose adefovir dipivoxil: a case report and literature review suggesting ethnicpredisposition

C. Wu* MSc, H. Zhang† MD, Y. Qian* MSc, L. Wang* MSc, X. Gu‡ MD and Z. Dai* MSc*Department of Endocrinology, The Second Affiliated Hospital of Wenzhou Medical College, Wenzhou, †Department of Endocrinology, Key Laboratory ofEndocrinology, Ministy of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, and‡Department of Endocrine and Metabolic Diseases, The First Affiliated Hospital of Wenzhou Medical College, Wenzhou, China

Received 3 August 2012, Accepted 28 January 2013

Keywords: adefovir dipivoxil, hypophosphatemic osteomalacia, renal Fanconi syndrome, review

SUMMARY

What is known and Objective: Adefovir dipivoxil (ADV) is oneof the commonly used antiviral agents in the treatment ofchronic hepatitis B (CHB) infection. Safety of a daily dose of 10mg ADV is advocated by the registration trials. We report a caseof severe hypophosphatemic osteomalacia and renal Fanconisyndrome induced by low-dose ADV in a CHB-related cirrhosispatient, and discuss the case through a thorough review of othercases reported in the literature.Case summary: A 48-yr-old Chinese man with CHB-relatedcirrhosis developed severe progressive generalized bone painand muscle weakness after receiving ADV 10 mg daily for 54months. The laboratory results showed severe hypophosphate-mia and features of proximal renal tubule dysfunction. Imagingstudies were consistent with osteomalacia. After discontinuationof ADV, his symptoms resolved, laboratory abnormalitiesnormalized and imaging studies showed improvement. Inaddition to our case, 12 other patients have been reported tohave developed hypophosphatemic osteomalacia induced bylow-dose ADV. Most of the reported cases were of subjects ofEast-Asian ethnicity. After discontinuation or reduction of ADV,serum phosphate level increased and clinical symptoms sig-nificantly improved in all cases.What is new and Conclusion: Hypophosphatemic osteomalaciaand renal Fanconi syndrome can be associated with low-doseADV. Clinicians treating CHB patients with ADV 10 mg dailyover long periods of time should be aware of this infrequent butserious complication

WHAT IS KNOWN AND OBJECTIVES

Adefovir dipivoxil (ADV) is a nucleotide analogue of adenosinemonophosphate that is effective in viral suppression.1 ADV wasinitially assessed at higher doses for the treatment of humanimmunodeficiency virus (HIV) infection,2 but a daily dose of 60–

120 mg ADV was associated with significant rates of renaldysfunction 3–5 and ADV is no longer used for this indication. Adaily dose of 10 mg to treat patients infected with the hepatitis Bvirus (HBV) has been found to be safe.6, 7 Currently, its major roleis in the treatment of drug-na€õve or lamivudine-resistant HBVinfection.8–11 Adefovir has an elimination half-life of 7�5 h, whichis prolonged in renal impairment.12 Excretion of adefovir is mainlythrough urine (45% as active metabolite within 24 h).12

Here, we report a case of severe hypophosphatemia osteoma-lacia and renal Fanconi syndrome induced by low-dose ADV in apatient with CHB-related cirrhosis. All cases previously reportedin the literature are also reviewed.

DETAILS OF THE CASE

We report a case of a 48-year-old male with CHB-related cirrhosiswho developed severe hypophosphatemia osteomalacia and renalFanconi syndrome after the introduction of low-dose ADV. Then,we searched PubMed database for articles describing low-doseADV induced hypophosphatemia osteomalacia. We retrospec-tively review the published reports of 12 patients other than ourown.

A 48-year-old Chinese man was admitted to our hospital inDecember 2010. We obtained written informed consent from thepatient. He had a 14-month history of severe progressive general-ized bone pain involving the low back, sacrum, rib cage, bilateralhips and knees in the absence of antecedent trauma. The pain wasdull and persistent, and was accompanied by limitation of activityof both lumbar spine and hips. He began to experience weakness inhis leg muscles, with difficulty in walking and climbing stairs sinceJuly 2010, and could only ambulate with the assistance of a cane.Since September 2010 he had difficulty turning in bed and had beenbed-bound for most of the time. He had a history of CHB-relatedcirrhosis of Child-Pugh class A and had been on ADV (Hepsera�)10 mg daily since April 2005. He underwent splenectomy forsplenomegaly complicated by hypersplenism in March 2010. Hewas not on any medication or herbal remedy known to affectskeletal health or associated with nephrotoxicity. On admission, hewas 165 cm in height, 50 kg inweight and had a bodymass index of18�3 kg/m2. He presented with a waddling gait. Clinical examina-tion disclosed generalized bony tenderness, especially in the lumbarspine, sacrum, thoracic wall and bilateral hips. Laboratory profiling

Correspondence: Huabing Zhang, Department of Endocrinology,Key Laboratory of Endocrinology, Ministy of Health, PekingUnion Medical College Hospital, Peking Union Medical College,Chinese Academy of Medical Sciences, Beijing 100730, China.Tel.: +86-010-8719-7173; fax: +86-010-8719-7173; e-mail: [email protected]

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revealed severe hypophosphataemia, hypouricemia, massive nor-moglycemic glycosuria, massive aminoaciduria and proteinuria.Serum protein electrophoresis was normal. Laboratory data aresummarized in Table 1. Ultrasound of the abdomen revealed thatthe liver was cirrhotic. X-rays revealed ground-glass-like changeof the lumbar vertebrae. Awhole-body 99mTc-methylene diphosph-onate bone scintigraphy showed diffuse increased uptake inmultiple ribs, cervical spine, bilateral sacroiliac joints, left pubicramus, bilateral knees, bilateral proximal tibiae and bilateral ankles(Fig. 1a). Bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DEXA) revealed severe decreases at the lumbarspine and hip (Table 2). On the basis of history and laboratoryexamination, a clinical diagnosis of ADV-induced hypophospha-temic osteomalacia due to acquired renal Fanconi syndrome wassuspected.ADVwas discontinued and entecavirwas commenced ata daily dose of 0�5 mg in December 2010. Three weeks after thediscontinuation of ADV, his serum phosphate level increased,glycosuria disappeared and aminoaciduria improved (Table 1).Seven weeks later, his symptoms and general status improved.This paralleled an improvement in serum phosphate and reduc-tion of proteinuria and aminoaciduria. Thirteen weeks later, hereported that bone pain and his walking ability had improvedsignificantly and no longer needed a cane for ambulation. Thelaboratory parameters further improved, including normalizationof proteinuria and aminoaciduria. DEXA showed a BMD improve-ment in the lumbar spine and hip (Table 2). Forty-eight weeksafter the discontinuation of ADV, he no longer reported bone painand was asymptomatic. DEXA showed further improvement inthe BMD at the lumbar spine and hip (Table 2). Accompanyingthese changes was a significant reduction in isotope uptake on arepeat whole-body bone scintigraphy carried out in December

2011 (Fig. 1b). Our patient had received ADV for 54 monthsbefore the development of generalized bone pain. The dramaticclinical, laboratory and subsequent imaging improvementobserved after ADV discontinuation further supported the diag-nosis of ADV-induced renal Fanconi syndrome and hypophos-phatemic osteomalacia.

Literature review revealed only 12 other cases of hypophospha-temic osteomalacia induced by low-dose (10 mg daily) ADV 13–25

(see Table 3). The age of these patients varied from 22 to 74 years,with a median of 51�6 years. Male: female ratio was 10:3. Mostcases (11/13) involved subjects of East-Asian ethnicity, includingKorean, Cambodian, Chinese and Japanese.13, 15–23, 25 The othertwo cases did not specify ethnicity.14, 24 Symptoms becameclinically evident after a median 30�5 months (range 6–89 months)of ADV treatment. Major symptoms included muscle-weakness,generalized bone-pain and gait difficulties. Diagnosis of hypo-phosphatemia often takes longer (median 40�7 months of ADVtreatment, range 8–95 months). The reported serum phosphate ondiagnosis ranged from 0�30 to 0�77 mmol/L. Most of these caseshad several characteristics of renal Fanconi syndrome, includingnormoglycemic glycosuria (12/13), aminoaciduria (9/10) andproteinuria (11/12). Renal biopsy was done in three cases.Microscopical examination in one case with a history of renaltransplantation revealed acute tubular injury characterized byswelling and vacuolization of proximal tubular cells,14 the othercase revealed mild glomerular lesions but normal appearance ofrenal tubule.23 The third case revealed lesions in the proximalrenal tubule with loss of brush borders in some of the renaltubules.25 After discontinuation or reduction of ADV, serumphosphate level increased (after 4–8 weeks) and clinical symptomssignificantly improved (after 1–7 months) in all cases. This was

Table 1. Baseline and follow-up laboratory data after discontinuation of (ADV).

Parameters Baseline After 3 weeks After 7 weeks After 13 weeks After 48 weeks Normal range

SerumPhosphate(mmol/L) 0�32 0�67 0�88 0�79 0�78 0�80–1�50Calcium (mmol/L) 2�09 2�48 2�41 2�41 2�24 2�08–2�60AKP (U/L) 297 239 278 327 324 40–150Potassium (mmol/L) 3�50 3�62 3�97 4�48 4�23 3�50–5�50Creatinine (lmol/L) 91�1 91�6 102�2 96�4 94�5 50–133Glucose (mmol/L) 4�81 5�37 5�26 5�03 5�37 3�90–5�60Uric acid (lmol/L) 130 171 181 208 216 149–416b2-MG (mg/L) 1�52 1�79 2�06 2�29 1�32 0�67–1�50Bicarbonate (mmol/L) 20�3 22�5 22�2 21�6 23�0 22�0–26�0PTH (pg/ml) 74�4 NA NA 41�9 47�1 12–88CK (U/L) 59 45 56 62 43 38–171ALT (U/L) 24 27 25 30 28 10–56c-GT (U/L) 96 98 96 91 112 11–50Albumin (g/L) 34�6 43�4 42 39�9 37�0 35–5025-Hydroxyvitamin D3 (ng/ml) 19�6 NA 20�2 NA 19�4 4�92–44�7

UrinePhosphorus (mmol/24 h) 32�42 NA 28�84 25�02 26�1 15–30Calcium (mmol/24 h) 6�2 NA 5�9 6�1 5�8 2�5–7�5Glucose Diffusely positive Negative Negative Negative Negative NegativeProtein Positive Positive Suspicious Negative Negative NegativeAmino acids Diffusely positive Positive Suspicious Negative Negative Negativeb2-MG (mg/L) 16�92 NA 15�87 7�11 12�28 <0�30

ADV, adefovir dipivoxil; AKP, alkaline phosphatase; ALT, alanine aminotransferase; CK, creatinine kinase; NA, not available; PTH, parathyroid hormone;b2-MG, b2-microglobulin; c-GT, c-glutamyl transpeptidase.

© 2013 John Wiley & Sons Ltd Journal of Clinical Pharmacy and Therapeutics, 2013, 38, 321–326322

Osteomalacia and renal Fanconi syndrome induced by ADV C. Wu et al.

associated with marked improvement in other serum and urineparameters.

The mechanisms of proximal renal tubule damage induced byADV are not fully understood. ADV is excretedmainly by proximalrenal tubule, and the human renal organic anion transporter-1(hOAT-1) on membrane of renal tubular epithelial cells has a highaffinity for ADV. Large doses or prolonged application of ADV canresult in significant increase of ADV concentration within renaltubular epithelial cells. The high concentration of ADV can inhibitmitochondrial DNA synthesis and cause cytochrome oxidasedeficiency, which will significantly inhibit mitochondrial function.Mitochondria in renal tubular epithelial cell may become swollenand deformed. If severe enough, apoptosis of the renal tubularepithelial cell will occur.26, 27 Consequently, the reabsorption abilityof the proximal renal tubule will decrease and urinary excretion ofphosphorus and other solutes will increase resulting in renalFanconi syndrome and hypophosphatemic ostemalacia. The vari-able susceptibility in developing nephrotoxicity at low-dose ADVmay be determined by genetic effects on the activity and density ofthe hOAT-1 expression in renal tubular cells.22

Renal Fanconi syndrome is a recognized complication of highdose ADV therapy in the treatment of HIV.28 Proximal tubulartoxicity has been documented in 22–50% of patients treated ADVfor 72 weeks with more than 30 mg daily.14 A daily dose of 60–120 mg has been associated with significant rates of renaldysfunction.3–5 The incidence appears to be dose related. Althoughclinical studies have shown that ADV at 10 mg daily is welltolerated with a side effect profile similar to placebo and noevidence of renal dysfunction,6, 8, 29, 30 our case suggests that renaldysfunction may be an underappreciated effect of ADV therapy.The symptoms and laboratory findings are delayed for months toyears after the start of ADV treatment leading clinicians not toassociate ADV with the abnormal findings. We believe that theactual incidence of ADV-induced hypophosphatemic ostemalaciaand renal Fanconi syndrome due to low-dose ADV is higher thanpreviously thought.

An interesting finding from literature review is that hypophos-phatemic osteomalacia and renal Fanconi syndrome induced bylow-dose ADV might have racial specificity, with 11/13 cases inpatients of East Asian ethnicity. Additional systematic evaluation

Table 2. The bone mineral density measurement of baseline and follow-up after discontinuation of ADV.

Region

Baseline After 7 weeks After 48 weeks

BMD(g/cm2) T–score Z–score BMD(g/cm2) Z–score BMD(g/cm2) T–score Z–score

L1–4 spine 0�649 –4�8 –3�7 0�731 –4�1 –3�1 0�823 –3�3 –2�4Femoral neck 0�398 –5�2 –4�0 0�443 –4�8 –3�6 0�572 –3�8 –2�7Total hip 0�355 –5�7 –4�6 0�423 –5�1 –4�1 0�580 –3�9 –3�0Trochanter 0�308 –5�7 –4�6 0�357 –5�2 –4�2 0�508 –3�8 –2�9

ADV, adefovir dipivoxil; BMD, Bone mineral density.

(a) (b)

Anteroir Posteroir Anteroir Posteroir

Fig. 1. Whole-body 99mTc-methylene diphosphonate bone scintigraphy. (a) An initial bone scan showed diffusely increased uptakethroughout the skeleton including multiple ribs, cervical spine, bilateral sacroiliac joints, left pubic ramus, bilateral knees, bilateral proximaltibiae and bilateral ankles. (b) Forty-eight weeks later, only mildly increased isotope uptake in the VIII left rib.



Table 3. Main characteristics of the 13 patients with hypophosphatemic osteomalacia and renal Fanconi syndrome induced by low-doseADV.

EthnicitySex/age(yr)

BMI(kg/m2) Underlying diseases

Durationof ADVuse toonsetsymptoms(mos)

Durationof ADVuse tofindhypophosphatemia(mos)

Baselineserumphosphate(mmol/L)

Follow-upserumphosphate(mmol/L)

Korean M/42 NA CHB-related cirrhosis 6 18 0�38 0�74Korean M/66 NA CHB infection 36 36 0�54 0�64Korean M/47 NA CHB infection 32 38 0�42 0�77Cambodian Chinese M/40 NA CHB-related cirrhosis 24 29 0�64 0�96Chinese Cambodian F /53 NA CHB-related cirrhosis 89 95 0�49 0�96Chinese (Hong Kong) F /74 NA CHB-related cirrhosis 48 48 0�49 Normal (data NA)Chinese (Mainland) M/48 24�7 CHB infection 12 37 0�77 0�98Chinese (Mainland) M/22 NA CHB infection 38 48 0�37 NAChinese (our case) M/48 18�3 CHB-related cirrhosis 54 68 0�32 0�78Japanese F /57 NA CHB-related cirrhosis 9 14 0�61 Normal (data NA)Japanese M/48 NA CHB-related cirrhosis, liver transplant 20 50 0�45 0�96Unspecified M/58 NA CHB infection,renal transplant 8 8 0�30 NAUnspecified M/68 23�4 CHB-related cirrhosis 20 38 0�72 NA

Baseline serumcalcium (mmol/L)

Baseline serumAKP (U/L)

Follow-upserum AKP (U/L)

Baselinecreatinine(lmol/L)

Follow-upcreatinine(lmol/L)

BaselineGFR (ml/min)

Follow-upGFR (ml/min)

Baseline serumuric acid(lmol/L)

Follow-upserum uric acid(lmol/L)

2�51 1722 770 88�4 NA NA NA 55 NA2�08 157 NA 106�1 NA NA NA NA NA2�10 321 NA 119�4 81�34 NA NA NA NA2�20 271 NA NA NA NA NA NA NA1�94 NA NA NA NA 58�8 NA NA NA2�29 698 Normal (data NA) 80�0 NA 61 NA NA NA2�21 195 NA 118�0 NA NA NA NA NA2�14 492 NA NA NA NA NA NA NA2�09 297 324 91�1 94�5 NA NA 130 216NA 800 NA 77�8 NA NA NA NA NA1�98 3410 300 97�3 114�9 37�9 NA 29 NANA NA NA 166�4 NA 39�5 31 145 525NA 443 NA 132�6 NA NA NA 37�6 NA

Baseline serumBicarbonate(mmol/L)

Follow-upserumBicarbonate(mmol/L)

BaselineserumPTH(pg/ml)

Baseline TmP/GFR(or TmP or% TRP)

Follow-upTmP/GFR(or TmP or% TRP)

BaselineurinePhosphorus(mmol/24 h)

Follow-upurinePhosphorus(mmol/24 h)

Baseline urineglucose

Follow-upurineglucose

32�5 NA 3�7 NA NA 21�5 NA Diffusely positive NA23�0 NA 24�2 NA NA 15�4 NA Positive NA22�7 25�0 20�0 NA NA 14�2 NA Positive NANA NA 39�0 TmP 0�3% (0�8–1�3%) Normal (data NA) 34�0 NA Positive NegativeNA NA 86�5 TmP 0�13% (0�8–1�3%) NA 39�0 NA Positive NegativeNA NA 30�0 TmP/GFR 0�62 (0�8–1�35) NA NA NA Positive NANA NA 25�9 NA NA 14�4 NA Positive NAMA (data NA) NA 50�9 NA NA NA NA 56 mmol/L NA20�3 23�0 74�4 NA NA 32�4 26�1 Diffusely positive NegativeNA NA NA NA NA NA NA Positive Negative21�2 NA 85�0 TRP 53�7% NA 13�9 NA 143 mmol/24 h NA17�0 28�0 NA NA NA NA NA 21�8 mmol/24 h NegativeNA NA 20�0 NA NA 20�0 NA Negative NA



of patients on low-dose ADV is needed to confirm this observa-tion. Possible explanations for this observation might include ahigher incidence of HBV infection, and hence more frequent use ofadefovir in East Asian populations, a lower BMI in East Asianpopulation and polymorphism of the hOAT-1 gene.31 We were notable to get comparative data on use of adefovir worldwide.

We noted that although serum phosphate level increased in ourpatient after discontinuation of ADV, it remained outside thenormal range after 48 weeks of ADV withdrawal. A similarobservation has been seen in other cases.13, 17, 18 Proximal renaltubule damage induced by low-dose ADV may be irreversible tosome extent in some patients. Despite improvement of BMD onDEXA, our patient’s T/Z-score remained low at 48 weeks. Long-term follow-up of bone health after discontinuation of ADV needsfurther study.

Discontinuation of ADV offers the best chance of recovery fromADV-induced renal Fanconi syndrome. Alternative therapies toreplace adefovir include tenofovir and entecavir. However, ADVand tenofovir are both nucleoside analogues and there have beenseveral cases of renal Fanconi syndrome and osteomalacia inpatients with HIV treated with tenofovir.32 Replacing ADV with

an agent in a different class, such as entecavir, may be a betteralternative.

WHAT IS NEW AND CONCLUSION

Clinicians treating CHB patients with ADV 10 mg daily over along period of time should be aware of hypophosphatemicosteomalacia and renal Fanconi syndrome. To minimize this risk,patients on long-term ADV therapy should have periodic screen-ing of serum phosphate, urine glucose and protein. Early diagnosisis important as the disorder may completely or partially reverseafter discontinuation of ADV.

FUNDING

None of the authors received funding from any source in relationto this study.

CONFLICT OF INTEREST STATEMENT

None of the authors have any conflict of interest to declare.

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NA NA Positive NA ADV cessation, phosphorus supplement 12Positive NA NA NA ADV cessation, phosphorus supplement 16Positive NA NA NA ADV cessation, phosphorus supplement 17Positive Negative Significant positive NA ADV cessation, phosphorus supplement calcium, vitamin D3 14, 211�30 g/24 h Negative Significant positive NA ADV cessation, phosphorus supplement vitamin D3, calcitriol 210�41 g/24 h NA Positive NA ADV cessation, phosphorus supplement calcitriol 19, 201�91 g/24 h NA Positive NA ADV cessation, phosphorus supplement calcitriol 221�40 g/24 h NA NA NA ADV cessation, phosphorus supplement 24Positive Negative Diffused positive Negative ADV cessationPositive Negative Generalized positive Negative ADV reduction, phosphorus supplement 151�44 g/24 h NA Positive NA ADV reduction, phosphorus supplement 181�99 g/24 h Progressive

reductionPositive NA ADV cessation 13

Negative NA Negative NA ADV cessation, phosphorus supplement calcium, vitamin D3 23

ADV, adefovir dipivoxil; AKP, alkaline phosphatase; BMI, body mass index; CHB, chronic hepatitis B; MA, metabolic acidosis; NA, not available; OM,hypophosphatemic osteomalacia; PTH, parathyroid hormone; TmP, maximal tubular phosphate reabsorption; TRP, tublar reabsorption of phosphate.

Table 3. (Continued)



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