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. 2019 Aug 22;14(8):e0221511.
doi: 10.1371/journal.pone.0221511. eCollection 2019.

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

Pavel Marozik  1   2 , Vidmantas Alekna  3 , Ema Rudenko  4 , Marija Tamulaitiene  3 , Alena Rudenka  5 , Asta Mastaviciute  3 , Volha Samokhovec  5 , Andrejus Cernovas  3 , Katsiaryna Kobets  1 , Irma Mosse  1   2
Affiliations

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

Pavel Marozik et al. PLoS One. .

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: Our findings highlight the importance of identified single gene variants and their allelic combinations for pharmacogenetics of BPs therapy of osteoporosis. Complex screening of these genetic markers could be used as a new strategy for personalized antiresorptive therapy.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. The comparison of frequencies of estimated allelic combinations, constructed from SOST, PTH, FDPS, and GGPS1 gene variants, in responders and non-responders groups of patients with postmenopausal osteoporosis after 12 months to treatment with BPs.
(*)–compared with reference combination.
Fig 2
Fig 2. The comparison of frequencies of estimated allelic combinations, constructed from FDPS and GGPS1 gene variants, in responders and non-responders groups of patients with postmenopausal osteoporosis after 12 months to treatment with BPs.
(*)–compared with reference combination.
See this image and copyright information in PMC

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