Genetically Elevated Serum Calcium Linked to Lower Whole-Body BMD


Increased serum calcium levels are associated with a reduction in whole-body bone mineral density, according to analyses of data from 2 independent epidemiologic studies published in The Journal of Clinical Endocrinology & Metabolism.

Calcium supplements have long been recommended to improve bone health in older adults. Although these supplements have been shown to increase serum calcium levels, there are inconsistent associations between serum calcium and bone mineral density (BMD). It is important to evaluate the effect of serum calcium, independent of other factors, to determine the efficacy of dietary calcium supplements.

The relationship between serum calcium levels and whole-body BMD was examined in 2 independent epidemiologic studies using data from the National Health and Nutrition Examination Survey (NHANES) and the Hong Kong Osteoporosis Study (HKOS). Individuals ≥20 years of age who had whole-body BMD and biomarkers of mineral metabolism measured from 2003 to 2006 were included. Additional BMD site measurements were used from HKOS for further specificity. From NHANES, 5478 participants (50.1% women) with an average age of 44.15±14.96 years were included. Most individuals included from NHANES were non-Hispanic white (73.1%) with the next largest race/ethnicity groups being non-Hispanic blacks (10.0%) and Mexican Americans (8.1%). From HKOS, 5556 participants (68.9% women) with an average age of 54.57±16.34 years were included.

In the NHANES group, models adjusting for confounders including relevant hormone levels showed that each standard deviation (SD) increase in serum calcium correlated with a decrease in whole-body BMD of -0.092 SD (95% CI, -0.125 to -0.059; P <.0001). In the HKOS group, models adjusting for confounding factors showed that each SD increase in serum calcium correlated with a decrease in total hip BMD of -0.041 SD (95% CI, -0.068 to -0.014; P =.003), as well as decreases at the lumbar spine, femoral neck, and trochanter.

To infer causality of serum calcium levels on whole-body BMD, a Mendelian randomization analysis approach was used, allowing unbiased causal effects to be estimated. Seven independent single nucleotide polymorphisms associated with serum calcium were selected to account for genetic predisposition to elevated serum calcium levels. After adjusting for confounding factors, higher genetically predicted serum calcium levels (0.35 ng/dL per 1 SD) were associated with lower whole-body BMD (full model: -0.431 SD; 95% CI, -0.773 to -0.089; P =.014), indicating an association between lifelong genetic exposure to increased serum calcium and decreased whole-body BMD (sensitivity analysis: -0.348 SD; 95% CI, -0.613 to -0.082; P =.01).

This study showed a consistent, inverse, and independent association of serum calcium with BMD. Because cross-sectional analyses cannot satisfactorily predict causation, Mendelian randomization analysis was used to clarify the independent and causal role of serum calcium on BMD. Further research is needed to determine whether the increased serum calcium level caused by supplementation would have the same effect on BMD levels.

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Li GHY, Robinson-Cohen C, Sahni S, et al. Association of genetic variants related to serum calcium levels with reduced bone mineral density. J Clin Endocrinol Metab. 2020;105(3):1-9.


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