Commentary

Calcium and vitamin D: To supplement or not?

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We live in the era of evidence-based medicine, so new interventions must meet criteria for both safety and efficacy before they are adopted. However, we have inherited many practices adopted before the current standards were in place, and we have not always been rigorous in reevaluating traditional remedies. A conservative belief in established practice or the influence of vested interests may account for this lack of rigor in reappraisal.1 Calcium and vitamin D supplements are possible examples of this phenomenon.

BONE METABOLISM IS TIGHTLY REGULATED

Bone is a connective tissue, its matrix composed principally of type 1 collagen, which provides tensile strength. Hydroxyapatite crystals, composed predominantly of calcium and phosphate, lie between the collagen fibers and provide compressive strength. In a tightly regulated process, osteoblasts lay down the collagenous matrix, and osteoclasts remove it. Mineralization of newly formed bone proceeds if normal levels of extracellular calcium and phosphate are present, in the absence of inhibitors of mineralization.

High calcium intake does not drive bone formation

The endocrine system is critical in maintaining normocalcemia. A decrease in calcium intake results in increased parathyroid hormone secretion, resulting in increased renal tubular calcium reabsorption, increased bone turnover (both formation and resorption), and increased activation of vitamin D leading to increased intestinal absorption of calcium. High calcium intake reverses these changes.

Absolute change in total body bone mineral content (BMC) over 5 years in normal postmenopausal women Reid IR, Bristow SM, Bolland MJ. Calcium supplements: benefits and risks. J Intern Med 2015; 278(4):354–368. Copyright 2015, The Association for the Publication of the Journal of Internal Medicine.

Figure 1. Absolute change in total body bone mineral content (BMC) over 5 years in normal postmenopausal women, as a function of each woman’s average calcium intake assessed at baseline and at year 5. The lines show the regression (with 95% confidence intervals) for this relationship (P = .53)

Thus, a normal serum calcium concentration can be maintained with calcium intake ranging from 200 to more than 2,000 mg/day, and rates of bone loss in postmenopausal women are unaffected by calcium intake (Figure 1).2

If calcium intake is very low, hypocalcemia and secondary hyperparathyroidism develop,3 and bone mineralization may be impaired. However, levels of calcium intake in Africa and in East and Southeast Asia are typically less than 400 mg/day,4 yet there is no evidence that these levels adversely affect skeletal health. In fact, fracture risk is lower in these regions than in North America, where calcium intake is several times greater.

Thus, some calcium intake is required to maintain circulating concentrations, but there is no mechanism by which high calcium intake can drive bone formation. Quite the opposite, in fact.

Vitamin D deficiency has little relationship with diet

Vitamin D is a biologically inactive secosteroid activated by hydroxylation in the liver and kidney to function as the key regulator of intestinal calcium absorption. As with calcium, its deficiency results in hypocalcemia and impaired bone mineralization.

Paradoxically, high levels of vitamin D stimulate bone resorption and inhibit bone mineralization in mice,5 and large doses increase bone resorption markers acutely in clinical studies.6 Thus, it is important to ensure an adequate vitamin D supply, but not an oversupply.

In the absence of supplements, most vitamin D is produced in the skin as a result of the action of ultraviolet light (from sunlight) on 7-dehydrocholesterol. Thus, vitamin D deficiency occurs in those deprived of skin exposure to sunlight (eg, due to veiling, living at high latitude, staying permanently indoors), but it has little relationship with diet.

ARE CALCIUM SUPPLEMENTS EFFECTIVE?

Calcium supplements are certainly biologically active. They transiently increase serum calcium concentrations, suppress parathyroid hormone, and reduce bone resorption.2 In the first year of use, they increase bone density by about 1% compared with placebo.7 However, longer use does not result in further bone density advantage over placebo,7 suggesting that the response simply reflects a decreased number of osteoclastic resorption sites and does not indicate a sustained change in bone balance.

A 1% difference in bone density would not be expected to reduce fracture risk, and a number of large, carefully conducted randomized controlled trials published over the last 15 years have failed to demonstrate anti­fracture efficacy for calcium.8–12 As a result, the US Preventive Services Task Force recommends against the routine use of calcium supplements in community-dwelling adults.13

In contrast, in a placebo-controlled trial published in 1992, Chapuy et al14 found that elderly women residing in nursing homes who received calcium and vitamin D supplements had fewer fractures. At 18 months, by intention-to-treat analysis, nonvertebral fractures had occurred in 160 (12%) of 1,387 women in the supplement group compared with 215 (15%) of 1,403 women in the placebo group (P < .001). However, these women were severely vitamin D-deficient (the mean serum 25-hydroxyvitamin D level at baseline in the placebo group was 13 ng/mL, normal range 15–50), to the extent that many must have had osteomalacia.

Thus, this study shows that calcium and vitamin D are effective in managing osteomalacia, but the subsequent trials8–12 did not observe any benefit in community-dwelling cohorts. Meta-analyses that pool the Chapuy study with community-based studies generally find that calcium with vitamin D is beneficial, but the heterogeneity of these populations means that such pooling is inappropriate.15

It is sometimes stated that calcium and vitamin D should always be given with osteoporosis medications because the efficacy of these drugs has only been demonstrated when coadministered with these supplements. This is incorrect. The addition of calcium to alendronate does not alter its effects on bone density,16 and the antifracture efficacy of both bisphosphonates17 and estrogen18,19 has been demonstrated in the absence of supplementation with calcium or vitamin D. The evidence that bisphosphonates prevent fractures in the absence of calcium supplements has recently been strengthened by the results of a randomized controlled trial comparing zoledronate with placebo in women over age 65 with osteopenia.20

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