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25-Hydroxyvitamin D and Risk of Osteoporotic Fractures: Mendelian Randomization Analysis in 2 Large Population-Based Cohorts.
Clin Chem. 2020 05 01; 66(5):676-685.CC

Abstract

BACKGROUND

Whether low plasma 25-hydroxyvitamin D concentrations cause osteoporotic fractures is unclear. We tested the hypothesis that low plasma 25-hydroxyvitamin D concentrations are associated with increased risk of osteoporotic fractures using a Mendelian randomization analysis.

METHODS

We genotyped 116 335 randomly chosen white Danish persons aged 20-100 years in 2 population-based cohort studies for plasma 25-hydroxyvitamin D decreasing genotypes in CYP2R1 (rs117913124 and rs12794714), DHCR7 (rs7944926 and rs11234027), GEMIN2 (rs2277458), and HAL (rs3819817); 35 833 had information on plasma 25-hydroxyvitamin D. We assessed risk of total, osteoporotic, and anatomically localized fractures from 1981 through 2017. Information on fractures and vital status was obtained from nationwide registries.

RESULTS

During up to 36 years of follow-up, we observed 17 820 total fractures, 10 861 osteoporotic fractures, and 3472 fractures of hip or femur. Compared with individuals with 25-hydroxyvitamin D ≥ 50nmol/L, multivariable adjusted hazard ratios (95% CIs) for total fractures were 1.03 (0.97-1.09) for individuals with 25-49.9 nmol/L, 1.19 (1.10-1.28) for individuals with 12.5-24.9 nmol/L, and 1.39 (1.21-1.60) for individuals with 25-hydroxyvitamin D < 12.5 nmol/L. Corresponding hazard ratios were 1.07 (1.00-1.15), 1.25 (1.13-1.37), and 1.49 (1.25-1.77) for osteoporotic fractures and 1.09 (0.98-1.22), 1.37 (1.18-1.57), and 1.41 (1.09-1.81) for fractures of hip or femur, respectively. Hazard ratios per 1 increase in vitamin D allele score, corresponding to 3.0% (approximately 1.6 nmol/L) lower 25-hydroxyvitamin D concentrations, were 0.99 (0.98-1.00) for total fractures, 0.99 (0.97-1.00) for osteoporotic fractures, and 0.98 (0.95-1.00) for fractures of hip or femur.

CONCLUSIONS

Low plasma 25-hydroxyvitamin D concentrations were associated with osteoporotic fractures; however, Mendelian randomization analysis provided no evidence supporting a causal role for vitamin D in the risk for osteoporotic fractures.

Authors+Show Affiliations

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark. The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark. The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark. The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32255480

Citation

Çolak, Yunus, et al. "25-Hydroxyvitamin D and Risk of Osteoporotic Fractures: Mendelian Randomization Analysis in 2 Large Population-Based Cohorts." Clinical Chemistry, vol. 66, no. 5, 2020, pp. 676-685.
Çolak Y, Afzal S, Nordestgaard BG. 25-Hydroxyvitamin D and Risk of Osteoporotic Fractures: Mendelian Randomization Analysis in 2 Large Population-Based Cohorts. Clin Chem. 2020;66(5):676-685.
Çolak, Y., Afzal, S., & Nordestgaard, B. G. (2020). 25-Hydroxyvitamin D and Risk of Osteoporotic Fractures: Mendelian Randomization Analysis in 2 Large Population-Based Cohorts. Clinical Chemistry, 66(5), 676-685. https://doi.org/10.1093/clinchem/hvaa049
Çolak Y, Afzal S, Nordestgaard BG. 25-Hydroxyvitamin D and Risk of Osteoporotic Fractures: Mendelian Randomization Analysis in 2 Large Population-Based Cohorts. Clin Chem. 2020 05 1;66(5):676-685. PubMed PMID: 32255480.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 25-Hydroxyvitamin D and Risk of Osteoporotic Fractures: Mendelian Randomization Analysis in 2 Large Population-Based Cohorts. AU - Çolak,Yunus, AU - Afzal,Shoaib, AU - Nordestgaard,Børge G, PY - 2019/12/02/received PY - 2020/01/24/accepted PY - 2020/4/8/pubmed PY - 2020/11/11/medline PY - 2020/4/8/entrez KW - Bone KW - Calcium KW - Dietary Supplements KW - Endocrine System KW - Epidemiology KW - Fractures KW - Genetic Polymorphism KW - Metabolism KW - Osteoporosis KW - Vitamin D SP - 676 EP - 685 JF - Clinical chemistry JO - Clin Chem VL - 66 IS - 5 N2 - BACKGROUND: Whether low plasma 25-hydroxyvitamin D concentrations cause osteoporotic fractures is unclear. We tested the hypothesis that low plasma 25-hydroxyvitamin D concentrations are associated with increased risk of osteoporotic fractures using a Mendelian randomization analysis. METHODS: We genotyped 116 335 randomly chosen white Danish persons aged 20-100 years in 2 population-based cohort studies for plasma 25-hydroxyvitamin D decreasing genotypes in CYP2R1 (rs117913124 and rs12794714), DHCR7 (rs7944926 and rs11234027), GEMIN2 (rs2277458), and HAL (rs3819817); 35 833 had information on plasma 25-hydroxyvitamin D. We assessed risk of total, osteoporotic, and anatomically localized fractures from 1981 through 2017. Information on fractures and vital status was obtained from nationwide registries. RESULTS: During up to 36 years of follow-up, we observed 17 820 total fractures, 10 861 osteoporotic fractures, and 3472 fractures of hip or femur. Compared with individuals with 25-hydroxyvitamin D ≥ 50nmol/L, multivariable adjusted hazard ratios (95% CIs) for total fractures were 1.03 (0.97-1.09) for individuals with 25-49.9 nmol/L, 1.19 (1.10-1.28) for individuals with 12.5-24.9 nmol/L, and 1.39 (1.21-1.60) for individuals with 25-hydroxyvitamin D < 12.5 nmol/L. Corresponding hazard ratios were 1.07 (1.00-1.15), 1.25 (1.13-1.37), and 1.49 (1.25-1.77) for osteoporotic fractures and 1.09 (0.98-1.22), 1.37 (1.18-1.57), and 1.41 (1.09-1.81) for fractures of hip or femur, respectively. Hazard ratios per 1 increase in vitamin D allele score, corresponding to 3.0% (approximately 1.6 nmol/L) lower 25-hydroxyvitamin D concentrations, were 0.99 (0.98-1.00) for total fractures, 0.99 (0.97-1.00) for osteoporotic fractures, and 0.98 (0.95-1.00) for fractures of hip or femur. CONCLUSIONS: Low plasma 25-hydroxyvitamin D concentrations were associated with osteoporotic fractures; however, Mendelian randomization analysis provided no evidence supporting a causal role for vitamin D in the risk for osteoporotic fractures. SN - 1530-8561 UR - https://www.unboundmedicine.com/medline/citation/32255480/25_Hydroxyvitamin_D_and_Risk_of_Osteoporotic_Fractures:_Mendelian_Randomization_Analysis_in_2_Large_Population_Based_Cohorts_ L2 - https://academic.oup.com/clinchem/article-lookup/doi/10.1093/clinchem/hvaa049 DB - PRIME DP - Unbound Medicine ER -