Osteomalacia induced by long-term low-dose adefovir dipivoxil: Clinical characteristics and genetic predictors.
Adefovir dipivoxil (ADV) was an important cause of adult-onset hypophosphatemic osteomalacia. However, its clinical characteristics and mechanisms have not been well defined.



The objective of the study was to summarize the clinical characteristics of ADV-induced osteomalacia and to explore the association between ADV-associated tubulopathy and polymorphisms in genes encoding drug transporters.



Seventy-six affected patients were clinically studied. The SLC22A6 and ABCC2 genes were screened and compared with healthy people from the HapMap.



Hypophosphatemia, high serum alkaline phosphatase (ALP) levels, hypouricemia, nondiabetic glycosuria, proteinuria, metabolic acidosis and high bone turnover markers were the main metabolic characteristics. Fractures and pseudofractures occurred in 39 patients. Stopping ADV administration, supplementing calcitriol and calcium was effective during the follow-up period. Single SNP analysis revealed a higher percentage of the G/A genotype at c.2934 in exon 22 of the ABCC2 gene (rs3740070) in patients than in healthy people (12% [7 of 58 patients] vs. 0% [0 of 45 patients]; P=0.017), while there was no subject with homozygosity for the A allele at c.2934.



ADV can be nephrotoxic at a conventional dosage. The G/A genotype at c.2934 of the ABCC2 gene may be a predictor of patients at greater risk for developing ADV-associated tubulopathy. Larger case-control studies are needed to further verify this finding.
Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
Zhe
Z
Wei
Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
Jin-Wei
JW
He
Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
Wen-Zhen
WZ
Fu
Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China. Electronic address: zzl2002@medmail.com.cn.
Zhen-Lin
ZL
Zhang
D000225:Adenine / Q000009:adverse effects / Q000031:analogs & derivatives*; D000595:Amino Acid Sequence; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000737:chemistry / Q000235:genetics; D027362:Organic Anion Transport Protein 1 / Q000737:chemistry / Q000235:genetics; D063065:Organophosphonates / Q000009:adverse effects*; D010018:Osteomalacia / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000235:genetics* / Q000628:therapy; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D017386:Sequence Homology, Amino Acid
D000225:Adenine; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027362:Organic Anion Transport Protein 1; D063065:Organophosphonates; C000715087:ABCC2 protein, human; C106812:adefovir dipivoxil
ABCC2; Adefovir dipivoxil; Clinical characteristic; Hypophosphatemic osteomalacia; Risk genotype; SLC22A6