Author(s): Pei-ran Zhou aff1 , Xiao-jie Xu aff1 , Zhen-lin Zhang aff2 , Er-yuan Liao aff3 , De-cai Chen aff4 , Jian Liu aff5 , Wen Wu aff6 , Yan Jiang aff1 , Ou Wang aff1 , Wei-bo Xia aff1 , Xiao-ping Xing aff1 , Ling Xu aff7 , Mei Li [*] aff1
osteoporosis; polymorphisms; response to alendronate; SOST gene
Postmenopausal osteoporosis is a systemic skeletal disorder characterized by progressive bone loss, which results in deteriorated bone microstructure, compromised bone strength and increased risk of fracture [1 ]. A genetic contribution to osteoporosis is well established, of which linkage and genome-wide association studies have identified several loci which influence bone mineral density (BMD) variation or fracture risk [ 2-5 ].
As we know, bisphosphonates (BPs) are appropriate first-line therapy for osteoporosis, which is characterized by differing clinical responses. In terms of BMD, about 26-53% of patients do not respond to BPs therapy [ 6 ]. Identification of the factors that predict responsiveness to BPs may contribute to the avoidance of unnecessary BPs treatment and result in a significant decrease in medical costs. Sequence variants in the human genome are now considered as important causes of differences in drug responses [ 7 ]. To date, there are few, small sampled studies on pharmacogenetics of osteoporosis, in which polymorphisms of VDR [8 ], ER[beta] [9 ], LRP5 [10 ], FDPS [11 ], DKK1 [12 ] have been investigated with regard to response to antiosteoporotic agents, such as hormone-replacement therapy, raloxifene or BPs. However, the genes that may determine bone response to BPs have not yet been precisely defined.
The effects of antiosteoporotic treatment are determined by status of the remodeling process, which involves both bone resorption by osteoclasts and bone formation by osteoblasts. Stimulation of bone formation is necessary to achieve improvements in bone mass, architecture and strength. The wingless integration (Wnt) signaling pathway has been well known as a key regulatory component of bone formation [13 ]. Sclerostin, an osteocyte-derived inhibitor of osteoblast activity, antagonizes Wnt signaling in both osteocytes and osteoblasts by binding to the lipoprotein receptor-related protein (LRP5/6 ) coreceptor [14,15 ]. Sclerostin is encoded by SOST gene, which locates on chromosome 17q12-q21 [13 ]. Loss-of-function mutations of SOST lead to rare genetic skeletal disorders such as sclerosteosis and Van Buchem disease, associating with a high BMD phenotype and low risk of fractures [ 16 ]. Antisclerostin antibodies were associated with increased BMD and bone formation [17,18 ]. As one of the most crucial regulators of Wnt pathway and a new treatment target of osteoporosis, it is valuable to assess the possible relevance of SOST variance and bone response to antiosteoporotic agents. The polymorphisms of SOST gene were demonstrated to be strongly associated with BMD of postmenopausal Chinese women [19 ], and were correlated to body composition and BMD in young and elderly Men [ 20 ]. However, correlation between genetic variance of SOST and the response to BPs treatment are still scanty.
As we know, alendronate is a nitrogen-containing bisphosphonate, and the most widely used in the treatment of postmenopausal osteoporosis, with a proven...