Toward personalized calcium and vitamin D supplementation.

Calcium and vitamin D (CaD) are essential components for building and maintaining strong bones throughout life. Although calcium is present in many food products and vitamin D can be synthesized in the skin by sunlight irradiation, for many people, especially elderly, frail, and institutionalized individuals, these sources are not sufficient to provide the necessary daily requirements. Chronic deficiency of CaD results in defective bone mineralization, secondary hyperparathyroidism, bone loss, and increased risk of falls and fractures (1). A beneficial effect of CaD supplementation on fracture risk has emerged from meta-analysis of large fracture trials (2, 3), and dietary CaD supplements and fortified food products are readily available and inexpensive. Hence, one would think that this aspect of bone health management is settled. Yet, it is hard to imagine any other topic in the bone metabolism field that has generated more animated and prolonged controversy. There is still disagreement on what constitutes vitamin D deficiency and on the recommended daily requirements of CaD, and whether calcium (not vitamin D) supplements increase cardiovascular disease risk is still hotly debated (4, 5). The heterogeneity of the populations studied in the different trials in terms of genetic and environmental risk factors might contribute to explain these inconsistencies. Therefore, a better understanding of who may most benefit from CaD supplementation would allow a more targeted approach, possibly resulting in improved outcomes. The study by Wang et al. (6), published in this issue of the Journal, represents a new step in this direction. The authors analyzed genome-wide association study data from the CaD trial in the Women’s Health Initiative database to determine genetic risk scores (GRSs) for fractures (Fx-GRS) and for bone mineral density (BMD-GRS) in relation to CaD intake. Their main finding was that there was no interaction between Fx-GRS and CaD on fracture risk; however, there was a significant multiplicative interaction between BMD-GRS and CaD assignment. Further analysis showed that the significant effects of CaD intake on fracture risk occurred only in women with the lowest genetic predisposition to low BMD. On first look, these results are somewhat counterintuitive, because in drug-effectiveness trials the higher the incidence (or prevalence) of the risk one tries to prevent, the higher the likelihood that the intervention may show an effect. For example, alendronate reduces the risk of hip fracture in women with osteoporosis, but not in those with higher bone density (7); likewise, statins have a greater effect in patients with higher cardiovascular disease risk (8). On more careful analysis, these results become clearer when considering the possibility that high-risk patients might not benefit from CaD supplementation if they have alterations in genetic factors that are involved in CaD responsiveness. The authors argue that possible variants in genes contributing to calcium, vitamin D, or other aspects of bone metabolism included in the genetic risk analysismight havemade subjects whowere at higher risk partially “resistant” to the effect of CaD. A corollary to this conclusion is that CaD is not a generalizable “one-size-fits-all” therapy for fracture risk prevention, but rather a risk modifier in genetically defined populations of postmenopausal women, hence supporting the rationale for personalized therapeutic interventions. In a way, the results of Wang et al. are reminiscent of the reality cable companies now face in the unbundling of their monolithic services. In increasingly more human population genetics studies, patient groups need to be “unbundled” to extract trends. To this end, it would be important to understand the pathobiological bases of CaD effects on low-risk subjects. One way of looking at the variants that confer low risk is that they confer hypersensitivity to CaD. In single nucleotide polymorphism (SNP) analysis, SNPs associated with 2 genes, dynamin 3 (DNM3) and osteoprotegerin (OPG/TNFRSF11B), were identified. Because osteoprotegerin is a major regulator of osteoclastogenesis, it should not be too surprising that OPG has emerged as a genetic factor for bone density and fracture risk (9, 10). However, if and how CaD regulates OPG remains to be determined. The role of DNM3 is intriguing considering that it has been linked to the regulation of the vitamin D receptor (11) and to skeletal development (12). Another interesting result is that the greatest risk reduction was seen in subjects taking not more than 1200 mg Ca. Although low power might explain the lack of effect of CaD in women taking higher amounts of supplemental calcium, this result supports the view that there are no extra benefits in taking calcium in excess of what is recommended for daily intake. There are some limitations to this study, as pointed out by the authors. First, most of the participants were not calciumand/or