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Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine
Director, Editorial Development, Medscape, LLC
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Tang BMP, Eslick GD, Nowson C, Smith C, Bensoussan A
Use of Calcium in Combination With Vitamin D Supplementation to Prevent Fractures and Bone Loss in People Aged 50 or Older
Lancet. 2007;370:657-666
Autier P, Gandini S
Vitamin D Supplementation and Total Mortality: A Meta-analysis of Randomized Controlled Trials
Arch Intern Med. 2007;167:1730-1737
Calcium plus vitamin D supplements are routinely prescribed for the prevention of osteoporosis and fracture. Although a major study from 2006 questioned this practice,[1] a new meta-analysis reaffirms the usefulness of calcium plus vitamin D in the prevention of fracture, and another suggests that these supplements may protect against overall mortality. The role of vitamin D in cancer remains unclear, but some research suggests a benefit in cancer outcomes with higher levels of plasma biomarkers of vitamin D.
These studies were selected from Medscape Best Evidence, which uses the McMaster Online Rating of Evidence System. Of a possible top score of 7, both studies were ranked as 6 for both newsworthiness and relevance by clinicians who used this system.
Calcium with vitamin D is among the most commonly prescribed supplements, and the main indication for these prescriptions
is the prevention of osteoporosis and osteoporotic fracture. However, a study published in the New England Journal of Medicine in 2006 provided some disturbing news regarding the efficacy of calcium plus vitamin D in the prevention of fractures.[1] This study focused on subjects in the Women's Health Initiative (WHI), who had a mean age of
62 years at the outset of the study. Subjects received 1000 mg of elemental calcium carbonate plus 400 IU of vitamin D3 daily,
or matching placebo, and the mean follow-up period was 7 years.
Although calcium plus vitamin D improved preservation of bone density of the hip, the 12% relative reduction in the rate of hip fracture in the active treatment vs placebo groups failed to achieve statistical significance. Reductions in symptomatic spine fractures and total fractures were also nonsignificant comparing active treatment vs placebo. Moreover, the use of calcium plus vitamin D increased the risk for the development of renal calculi by 17% vs placebo, a statistically significant result.
The negative findings in the WHI cohort did not dismiss the possibility that supplementation with calcium and vitamin D could reduce the risk for fracture. The dose of vitamin D was lower than that used in previous studies. Also, only 59% of women were taking the intended dose of supplement by the end of the trial, and a subgroup analysis that focused exclusively on subjects who adhered to treatment demonstrated a significant benefit in the risk for fracture.
In 2005, a meta-analysis that focused on the effects of vitamin D supplementation with or without concomitant treatment with
calcium suggested that the dose of vitamin D was important in terms of fracture prevention at nonvertebral sites.[2] Researchers compiled data from 12 randomized, controlled trials and found that vitamin D at a dose of 700 to 800 IU per day
reduced the risk of hip fracture by 26% and any nonvertebral fracture by 23%. Both of these results were statistically significant.
However, the pool of data from randomized studies of vitamin D at a dose of 400 IU per day failed to demonstrate any fracture
benefit. In this study, higher levels of achieved
25-hydroxyvitamin D [25(OH)D] were associated with a reduced risk for fracture.
The current meta-analysis expands on previous collective research in including a larger number of trials, including studies like WHI. The authors searched for randomized trials of supplementation with calcium alone or calcium with vitamin D among adults at age 50 or older. The outcomes of the meta-analysis included both bone mineral density studies and risk for fracture.
Of 267 abstracts assessed, 29 studies were included in the analysis;13 of these studies focused on treatment with calcium plus vitamin D, whereas 16 trials examined calcium alone. A total of 63,897 subjects were examined in these trials, with a mean age of 67.8 years for all subjects; 92% were women.
The overall rate of fracture reduction associated with calcium or calcium plus vitamin D supplementation vs placebo was 12% (P = .0004). The active intervention was associated with a reduced bone loss of 0.54% at the hip and 1.19% at the spine. Greater treatment adherence strengthened the positive outcomes associated with active treatment, but results were generally unchanged when examining subgroups based on individual fracture sites and participant gender. The addition of vitamin D to calcium did not appear to alter the protective effects of supplementation, and patients with lower baseline levels of 25(OH)D and those who were institutionalized were more likely to benefit from active treatment. Finally, individuals over the age of 70 were particularly likely to benefit from supplementation with calcium alone or calcium plus vitamin D.
The strengths of this meta-analysis include its significant power to detect differences in relatively infrequent clinical events and its control of potential confounding variables. Based on this analysis of available data, physicians should certainly consider supplementation with calcium plus vitamin D among patients (women, in particular) over the age of 50. The minimum dose of calcium which appears effective is 1200 mg daily, and the intervention with calcium alone may be sufficient to reduce the risk for fracture.
However, based on other new evidence, clinicians should strongly consider the addition of at least 800 IU of vitamin D on a daily basis. Vitamin D has been hypothesized to play a role in cell dysplasia and cancer because it can reduce cell proliferation while stimulating apoptosis and cell differentiation. Epidemiologic research supports a possible role of vitamin D in mortality related to cancer. In one study, greater exposure to sunlight was associated with an independent effect in reducing the rate of mortality from ovarian, prostate, breast, and colon cancer.[3]
Colorectal cancer has been particularly scrutinized for its interaction with vitamin D. In an analysis of the Nurses' Health Study, researchers found an inverse linear relationship between plasma levels of 25(OH)D and the risk for incident colorectal cancer.[4] Comparing women in the highest quintile for 25(OH)D vs the lowest quintile, the odds ratio for the development of colorectal cancer was 0.53. Higher levels of vitamin D were particularly effective in preventing colorectal cancer among women at age 60 or older.
A new study of the Third National Health and Nutrition Examination Survey reinforces the relationship between 25(OH)D levels
and colorectal cancer mortality.[5] The authors followed 16,818 participants and found that 25(OH)D levels of 80 nmol/L or more were associated with an 18% reduction
in the risk for mortality from colorectal cancer compared with levels of less than
50 nmol/L. Higher levels of 25(OH)D failed to reduce the rates of mortality related to other forms of cancer.)
The improvement in colorectal cancer outcomes associated with higher serum markers of vitamin D levels is most clinically meaningful if a simple intervention such as vitamin D supplementation can be demonstrated to reduce the risk of colorectal cancer or its resultant complications. However, data from the WHI suggest that the intervention with calcium plus vitamin D is not effective in preventing colorectal cancer.[6] The hazard ratio for incident colorectal cancer in the active calcium plus vitamin D vs placebo groups was 1.08 (P = .51), and tumor characteristics were similar regardless of study therapy.
The relationship between vitamin D and cancer is confusing and has not been completely settled. It is very possible that higher serum markers for vitamin D levels are beneficial for colorectal cancer outcomes, and vitamin D may have a greater effect on overall levels of mortality related to colorectal cancer as opposed to the incidence of cancer. Further research is required to determine whether supplementation with vitamin D at the higher doses indicated for fracture prevention can improve outcomes related to colorectal cancer.
In general, the most critical outcome related to any intervention is mortality, and one more recently published meta-analysis examining the effects of vitamin D on mortality deserves comment. The authors of this study evaluated 18 randomized, controlled trials of vitamin D supplementation for any indication. The mean daily dose of vitamin D was 528 IU, and the mean follow-up period was 5.7 years. Vitamin D supplementation was associated with a significant reduction in all-cause mortality compared with placebo (relative risk = 0.93). The concomitant use of calcium supplementation did not affect this main study outcome. The main point of caution in interpreting these results is that only one of the included trials focused on mortality as its main endpoint, meaning that study design and methodology might have been lacking in the examination of mortality.
The balance of this evidence argues for the routine use of calcium plus vitamin D at minimum daily doses of 1200 mg and 800 IU, respectively, among postmenopausal women, as this is the subgroup of patients most represented in the randomized trials of supplementation. This relatively simple, safe, and inexpensive intervention can improve the risk for fracture and may improve the overall risk for mortality. Further study is needed to determine whether vitamin D supplementation can improve outcomes related to colorectal cancer, but this remains a possibility. The use of these supplements would be in line with the current recommendations from the American Association of Clinical Endocrinologists, as most women do not receive their recommended daily calcium intake through diet alone.[7] Calcium and vitamin D may be the rare intervention with supplements that leads to significant improvement in important clinical outcomes.
A new study by Bolland and colleagues,[8] published first online in the January 15, 2008, issue of the British Medical Journal, adds further intrigue into the effects of calcium supplementation. The authors found an increased risk for self-reported
myocardial infarction associated with the use of calcium citrate 1 gm daily vs placebo, and this association just achieved
statistical significance (relative risk = 2.24; P = .001). In addition, a composite endpoint of reported myocardial infarction, stroke, and mortality was elevated in the calcium
vs placebo groups (relative risk = 1.66;
P = .0075).
These data are certainly concerning and unexpected. However, there are a number of reasons that lead the study authors to state that their results are not conclusive regarding an increased cardiovascular risk associated with calcium. First, this study was a secondary analysis of data from a trial of calcium to prevent osteoporosis and fractures. Cardiovascular events were not a primary endpoint of the research. Second, when reported cardiovascular events were adjudicated with medical records, the risk for myocardial infarction associated with calcium was attenuated, and the risk for the composite cardiovascular outcome was no longer statistically significant. Finally, there were some differences in study methodology, including older age of the patient cohort, the use of calcium citrate vs calcium carbonate, and the nonuse of vitamin D supplementation, which make these findings, even if statistically significant, potentially less relevant to clinical practice.
Nonetheless, the results by Bolland and colleagues are concerning and should certainly prompt further studies. Research examining the role of calcium plus vitamin D supplementation could include cancer incidence and outcomes as well as cardiovascular events as primary goals. This research might also identify women who might particularly benefit or be harmed by calcium/vitamin D supplementation.
