Calcium and Vitamin D Supplementation

Clinicians and patients are increasingly concerned about the prescription of the combination of calcium and vitamin D, despite a totality of evidence indicating efficacy and safety. Calcium is essential to build and maintain healthy bones and vitamin D for absorption and increased uptake. ^1,2 Lifelong adequate intakes of calcium and vitamin D are essential to prevent bone loss, osteoporosis, and skeletal fractures. Nonetheless, 90% of US women are deficient in calcium and 50% to 90% in vitamin D. Even among children, 30% to 40% are already deficient. Corresponding rates are likely to be even higher among minorities, including Hispanics and blacks. When dietary intakes are insufficient, supplements may be a necessary adjunct therapy to therapeutic lifestyle changes that should include increased exposure to sunlight. To decrease morbidity and mortality from osteoporosis, many guidelines recommend daily intakes of 1200 mg of calcium and 600 international units of vitamin D ² About 50% of women and 20% of men aged 50 and older will have a fracture consequent to osteoporosis leading to premature 1-year mortality rates of 17% in women and 30% in men. As regards drugs used to treat osteoporosis, the risks outweigh the benefits in patients with osteopenia and no history of fracture or additional risk factors. Although their long-term effects are not yet well known, alendronate therapy for 8 years has caused brittle bones, spontaneous femoral neck fractures, and rare but serious adverse effects including esophageal cancer and jaw osteonecrosis. In addition, before starting osteoporosis drugs in patients with severe disease or a related fracture, an initial evaluation should be performed followed by correction of any calcium and vitamin D deficiencies, in part, to avoid precipitating hypocalcemia. ¹ Although calcium is needed for proper bone mineralization, osteoporosis drugs strengthen bone and slow down loss. Thus, antiresorptive drugs serve as bricks, while adequate calcium and vitamin D serve as mortar. Without adequate intake of this combination, as recommended by most guidelines, healthy bone structure can neither be achieved nor be maintained. ² In addition, observational epidemiological studies and randomized trials of calcium alone show no significant increased risks of cardiovascular disease in women.

Nonetheless, concerns have arisen based largely on overreliance on subgroups and overinterpretation of results from a meta-analysis of 15 randomized trials not designed a priori to test the hypothesis which included 11 921 patients. In the subgroup analysis, calcium supplements in high doses without vitamin D showed a significant 27% increase in risk of myocardial infarction (MI) but no significant increases in either stroke or death from cardiovascular disease (CVD). The authors stated that any level of risk is unwarranted and judged that widespread use of calcium supplements is causing high mortality and morbidity. ³ These findings should be viewed as hypothesis formulating not hypothesis testing. In addition, there should be substantial differences between how trial evidence is interpreted for the prespecified main effects of treatments in contrast to somewhat unexpected side effects. Every side effect that reaches a level of statistical significance of P = .01, especially those generated from small trials not designed a priori to test a hypothesis or their meta-analyses, should not be accepted as real. If that were to occur, then many drugs of life-saving benefit would be mistakenly labeled as hazardous, and any real side effects might be obscured by a mass of unreal ones. As Professor Sir Austin Bradford Hill aptly stated, “the glitter of the t table diverts attention from the inadequacies of the fare.” ^{4 –6, p299}

The same authors expressed concerns about whether there is a need for calcium to prevent and treat bone loss and state it is of marginal efficacy against fracture. ³ In contrast, a Cochrane Review of 15 trials of 1806 postmenopausal women over 2 years showed statistically significant and potentially clinically important benefits on bone loss. They concluded that ensuring adequate calcium intake may be important for a variety of reasons, especially in combination with vitamin D and as an adjunct to bisphosphonates. ⁷

Calcium carbonate is the least expensive and most widely used formulation in the general population as well as in the trials included in the meta-analysis. In addition, however, over 90% of calcium carbonate is contaminated with lead which has been hypothesized to be associated with increased risk of CVD. Specifically, in the Third National Health and Nutrition Examination Survey (NHANES III), 2 µg/dL increases in lead were associated with increased risk of MI, stroke, and CVD death. In the United States, 40% of adults are estimated to have blood lead levels greater than 2 µg/dL. ⁸

We believe the evidence suggesting that there is a valid statistical association between calcium supplements and MI to be far from definite, so any causal inferences based on the totality of evidence are premature. In addition, the published meta-analyses of CVD did not include all patients ever randomized in the trials of calcium supplementation irrespective of their use of vitamin D or nontrial calcium supplements and did not make due allowance for the multiplicity of diseases that might by chance alone have appeared to be associated with treatment in the trial results. We believe strongly that there has been far too much emphasis on subgroups in the meta-analyses. The same authors who initially claimed the harm on CVD but were not involved in the Women’s Health Initiative (WHI) included only the calcium supplements alone patients while excluding the calcium and vitamin D patients as well as only women not on prerandomization supplements. ⁹ Interestingly, women on such supplements had apparently beneficial results on stroke. The WHI is the largest individual randomized trial of osteoporotic fractures, bone mineral density, and colorectal cancer. Among the 36 282 patients treated and followed for 7 years, there were no statistically significant associations between calcium supplements and MI, stroke, or CVD death. ¹⁰

Based on the current totality of evidence, which includes the prior rationale and results of the small trials not designed to test the hypothesis as well as their meta-analyses, the osteoporotic benefits of calcium supplements with vitamin D are definite, but the evidence that there are hazards on CVD is not. ^{4 –6,10} It would be unfortunate if clinicians failed to prescribe the combination of calcium and vitamin D supplements as adjuncts to therapeutic lifestyle changes of proven benefit, especially regular physical activity, to the very large number of patients in whom the benefit to risk ratio is clearly favorable.