Bone metabolism genes variation and response to bisphosphonate treatment in women with postmenopausal osteoporosis

Abstract

Introduction Long-term treatment is used in patients with osteoporosis, and bisphosphonates (BPs) are the most commonly prescribed medications. However, in some patients this therapy is not effective, cause different side effects and complications. Unfortunately, at least one year is needed to identify and confirm an ineffectiveness of BPs therapy on bone mineral density (BMD). Among other factors, a response to BPs therapy may also be explained by genetic factors. The aim of this study was to analyze the influence of SOST , PTH , FGF2 , FDPS , GGPS1 , and LRP5 gene variants on the response to treatment with aminobisphosphonates. Materials and methods Women with postmenopausal osteoporosis were included to this study if they used aminobisphosphonates for at least 12 months. Exclusion criteria were: persistence on BPs therapy less than 80%, bone metabolic diseases, diseases deemed to affect bone metabolism, malignant tumours, using of any medications influencing BMD. The study protocol was approved by the local ethics committee. The BMD at the lumbar spine and femoral neck were measured using dual x-ray absorptiometry (GE Lunar) before and at least 12 months after treatment with BPs. According to BMD change, patients were divided in two groups–responders and non-responders to BPs terapy. Polymorphic variants in SOST , PTH , FGF2 , FDPS , GGPS1 , and LRP5 genes were determined using PCR analysis with TaqMan probes (Thermo Scientific). Results In total, 201 women with BPs therapy were included in the study. No statistically significant differences were observed in age, age at menopause, weight, height, BMI and baseline BMD levels between responders (122 subjects) and non-responders (79 subjects). As single markers, the SOST rs1234612 T/T (OR = 2.3; P = 0.02), PTH rs7125774 T/T (OR = 2.8, P = 0.0009), FDPS rs2297480 G/G (OR = 29.3, P = 2.2×10 −7 ), and GGPS1 rs10925503 C/C+C/T (OR = 2.9; P = 0.003) gene variants were over-represented in non-responders group. No significant association between FGF2 rs6854081 and LRP5 rs3736228 gene variants and response to BPs treatment was observed. The carriers of T-T-G-C allelic combination (constructed from rs1234612, rs7125774, rs2297480, and rs10925503) were predisposed to negative response to BPs treatment (OR = 4.9, 95% CI 1.7–14.6, P = 0.005). The C-C-T-C combination was significantly over-represented in responders (OR = 0.1, 95% CI 0.1–0.5, P = 0.006). Conclusions ...

Zoledronic Acid Is Not Equally Potent on Osteoclasts Generated From Different Individuals

“…A recent study reported that single nucleotide polymorphisms in the FDPS gene correlate with the effect of bisphosphonates in women with postmenopausal osteoporosis. (60) Therefore, we were surprised that the FDPS levels had no detectable effect on OCs' sensitivity to Zol. A possible explanation could be that FDPS activity is more relevant for Zol sensitivity rather than gene expression levels.…”

Genomic Medicine: Lessons Learned From Monogenic and Complex Bone Disorders

“…For instance, VDR variants were suggested to modify the effect of alendronate ( 87 , 88 ) or of etidronate ( 89 ); the COL1A1 Sp1 polymorphism the effect of etidronate; and variants of genes belonging to the FDPS (mevalonate pathway) the response to amino-bisphosphonate treatment ( 90 – 92 ). Allelic combinations of SOST, PTH, FDPS , and GGPS1 gene variants may also have a role in the individual response to bisphosphonate treatment ( 93 ). From the other clinically-relevant perspective of side effects, several polymorphisms mapping within the cytochrome P450-2C ( CYP2C8) gene have been associated with increased risk of bisphosphonate-induced osteonecrosis of the jaw in patients with multiple myeloma ( 94 ).…”

Root canal treatment of compromised teeth as alternative treatment for patients receiving bisphosphonates: 60‐month results of a prospective clinical study

“…In addition, a potential genetic marker for this association has been considered (Marozik et al . 2019).…”

“…Osteoclastic inhibition of bone remodelling induced by BPs (Reid et al 2007), the anatomic vascularization of the oral region, angiogenesis process alteration, oral microbiome dysbiosis and sustained chronic inflammation may lead to this condition (Reid et al 2007, Hokugo et al 2010, Allen & Burr 2011. In addition, a potential genetic marker for this association has been considered (Marozik et al 2019).…”