Owing to decreased sunlight exposure and the increased risk for colds and other illnesses during winter, people may be tempted to increase their vitamin D supplementation at this time of year. However, as is true for just about every vitamin and mineral, and even oxygen and water, just because we need some doesn’t mean more is always better. A study published last year in the Journal of the American Medical Association (JAMA) found that, contrary to expectations, supplementing with higher doses of vitamin D actually led to a slight decrease in bone mineral density compared to using lower doses. Let’s take a closer look.
The study involved three cohorts of healthy adults without osteoporosis, age 55 to 70. Baseline vitamin D levels (25-hydroxyvitamin D) were 30 to 125 nmol/L. The cohorts were supplemented with 400 IU, 4000 IU, or 10,000 IU of vitamin D daily for three years. Calcium supplements were provided to participants with a dietary calcium intake of less than 1200 mg/day. Co-primary outcomes were total volumetric bone mineral density (BMD) at the radius and tibia, and bone strength (failure load) at the radius and tibia.
At the end of the trial, radial volumetric BMD was lower for the 4000 and 10,000 IU groups compared to the 400 IU group. The mean percent change for the 400 IU group was -1.2%, compared to -2.4% and -3.5% for the 4000 and 10,000 IU groups, respectively. A similar pattern was seen for tibial volumetric BMD: -0.4% for the 400 IU group, and -1.0 and -1.7 for 4000 and 10,000 IU, respectively. Differences in failure load did not reach statistical significance, researchers wrote, “These findings do not support a benefit of high-dose vitamin D supplementation for bone health,” but they acknowledged that further research is needed to determine whether higher doses are actively harmful.
Although this finding appears to come as a surprise, perhaps it’s less paradoxical than it initially seems. Vitamin D is essential for the proper use of calcium in the body. When serum calcium level falls, the parathyroid hormone stimulates renal vitamin D synthesis, and vitamin D then increases intestinal calcium absorption, decreases urinary calcium excretion, and mobilizes calcium from the bones if dietary calcium is inadequate. Subjects in the JAMA study received calcium supplementation if reported calcium intake was insufficient, so assuming they were compliant in taking it, inadequate dietary calcium was not a factor here. However, calcium trafficking and homeostasis is a complex system modulated by more than just calcium and vitamin D.
More than Just Calcium
Studies that look at vitamin D and calcium while ignoring the crucial role of vitamin K2 may be missing a critical piece of the puzzle. Vitamin K1 is mostly known for its role in the clotting cascade, but the K2 form is needed for activation of proteins involved in depositing calcium in the bones and teeth, inhibiting the calcification of soft tissues, such as blood vessels and joints. Supplementing with high doses of vitamin D in the presence of inadequate K2 could potentially lead to a leaching of calcium from the bones with reduced trafficking back into the bones, and possibly increased risk for soft tissue calcification or kidney stone formation. It’s not inconceivable that supplemental calcium could make this even worse. A systematic review looking at vitamin D supplementation in adults found that, based on 4 trials involving nearly 43,000 subjects, combining vitamin D3 supplementation with calcium led to a small but significant increased risk for nephrolithiasis (relative risk 1.17; 95% CI 1.02 to 1.34; P = 0.02). Hypercalciuria is a risk factor for kidney stones. In the JAMA study, hypercalciuria occurred in 87 participants, with significant differences between the three supplementation levels: 17% in the 400 IU group, 22% in the 4000 IU group, and 31% in the 10,000 IU group. (If hypercalciuria was detected, calcium intake was decreased and follow-up testing showed the hypercalciuria to be resolved.)
Vitamin K2 isn’t the only nutrient needed to support the efficacy of vitamin D. A 2018 study determined that magnesium is instrumental in promoting the role of vitamin D in the body. According to that study, “the bioactivity of vitamin D is a magnesium-dependent process.” Magnesium is a cofactor for some of the enzymes involved in vitamin D synthesis and activation (hydroxylation). The study notes that, unfortunately, as much as 75 percent of the adult population in the US consumes a magnesium-deficient diet. Combine that with the nearly ubiquitous use of pharmaceutical drugs that interfere with magnesium absorption or increase its excretion (e.g., antacids, various diuretics), and there’s a recipe for magnesium deficiency. Under magnesium deficient conditions, supplementing with vitamin D may not have the intended effects. The study authors went so far as to say, “Consuming the RDA of magnesium may be more effective in preventing bone thinning than vitamin D, as magnesium potentiates vitamin D activities, possibly by increasing its absorption and endogenous activation.” (Emphasis added.)
Clearly, the use of vitamin D for supporting bone health is more complicated than simply adding more vitamin D to someone’s supplement regimen. Bone tissue is far more than just calcium, and it needs more than vitamin D for proper breakdown, turnover, and renewal. For individuals who have a clear-cut need for increased vitamin D, it’s important to ensure adequate magnesium and vitamin K2 status, and for those who are using vitamin D supplementation specifically for bone health, adequate dietary protein is also essential. Emma Billington, MD, one of the JAMA study authors, said that “large doses of vitamin D don't come with a benefit to the skeleton.” We can’t say for certain whether this is true across the board, or whether the confounding factors of suboptimal magnesium and/or K2 status may have played a role in the findings.