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Variation in the Cox-2 Gene May Modify the Effect of Alendronate on Vertebral Fracture Prevention

Bisphosphonates such as alendronate, which are potent specific inhibitors of osteoclast-mediated bone resorption, are widely used for treatment of postmenopausal osteoporosis as well as other diseases related to bone remodeling. We evaluated whether the reportedly functional PTGS2 (prostaglandin-endoperoxide synthase 2/cyclooxygenase [COX] 2) genotypes influence the efficacy of alendronate on vertebral fracture prevention. Sixty postmenopausal osteoporotic women participated in this interventional study. The extent of vertebral fracture was evaluated in all participants before and after intervention using X-ray imaging. Alendronate (10mg/day), calcium (1gr/day) and vitamin D (400mg/day) were given to participants for 2 years. Laboratory measurements included circulating crosslaps, osteocalcin, PTH, osteoporotegrin, RANKL, vitamin D, TNF-α, IL-6, IL-1 levels. Hip and spine BMD (bone mass density) were measured using DEXA. Genotyping for cox-2 gene SNP (−765G/C) was performed using PCR- RFLP method. Genotype frequency of homozygous major allele (GG), heterozygous (GC) and homozygous minor allele (CC) were 61.7%, 33.3% and 5% respectively. Evaluation of vertebral fracture before alendronate therapy in participants demonstrated no significant difference between carriers of G and C alleles, although the difference appeared near to significant after alendronate therapy at the end of 2 years. Serum PTH level and L2-L4 BMD were significantly different between subjects with different alleles. Moreover, IL-1 had prominently higher concentration in C allele carries. Furthermore, there was a significant difference in terms of the extent of vertebral fracture between two allelic groups after two years of treatment. Since bone remodeling process has been proved to be affected by inflammatory factors; it appears that variation in COX-2 genotypes may influence alendronate efficacy in fracture prevention among postmenopausal osteoporotic women.