The Independent Role of Elevated Serum Calcium on Bone Metabolism

Blood sample for calcium test
Blood sample for calcium test
Elevated calcium levels may lead to suboptimal growth of bone, according to the study’s findings.

Serum calcium may have a negative effect on bone mineral density (BMD) independent of vitamin D, phosphate, and parathyroid hormone (PTH) levels, according to study results published in The Journal of Endocrinology & Metabolism. However, while this was true for life-long genetic exposure to increased serum calcium, insufficient data are available regarding the effect of calcium supplements.

Calcium plays an important part in bone metabolism and calcium supplementation is frequently supported to improve bone health. However, the independent effect of serum calcium on bone metabolism is difficult to evaluate. The goal of the current study was to assess the independent role of serum calcium in bone density maintenance.

The researchers used 2 independent epidemiologic studies of different genetic ancestries: the National Health and Nutrition Examination Survey (NHANES) conducted in 2003 to 2006, including 5478 participants from the United States aged ≥20 years with available data for BMD and biomarkers of mineral metabolism, and the Hong Kong Osteoporosis Study (HKOS), including 5556 participants aged ≥20 years recruited from Hong Kong from 1995 to 2010 with available data for BMD and biomarkers of mineral metabolism.

Mendelian randomization was used to allow assessment of unbiased independent role of serum calcium in bone metabolism. Initially, the association between serum calcium and BMD was investigated with adjustments for serum phosphate, vitamin D, and PTH; subsequently, causality was explored.

Data from a genome-wide association study and meta-analysis were used to identify 7 independent single nucleotide polymorphisms associated with serum calcium. The analysis of the association between these polymorphisms with BMD was based on 30 epidemiologic cohorts.

Each SD increase in serum calcium was significantly associated with a decrease in BMD at various sites: in the NHANES study, the decrease (β estimate) ranged between -0.036 at the pelvis and -0.092 in whole-body BMD; in HKOS, the change ranged between -0.039 at the femoral neck and -0.091 at the lumbar spine.

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In multivariable inverse-variance weighted mendelian randomization analysis, after adjustment for levels of PTH, vitamin D, and phosphate, there was an inverse association between genetic predisposition to higher serum calcium and whole-body BMD (-0.431 SD per SD increase in serum calcium; P =.014).

The study had several limitations, according to the researchers, including the possibility that calcium may affect BMD through extracalcium pathways. Furthermore, dual-energy x-ray absorptiometry-derived BMD was not used. There was also not sufficient power to detect genuine genetic loci for the traits in the genome-wide association study.

“These findings highlight that optimal calcium within a narrow range is required for optimal bone growth, while elevated calcium levels may lead to suboptimal growth of bone,” concluded the researchers.


Hoi-Yee G, Robinson-Cohen C, Sahni S, et al. Association of genetic variants related to serum calcium levels with reduced bone mineral density [published online October 25, 2019]. J Clin Endocrinol Metab. doi:10.1210/clinem/dgz088/5606940