Zhao JG, Zeng XT, Wang J, Liu L. Association between calcium or vitamin D supplementation and fracture incidence in community-dwelling older adults: a systematic review and meta-analysis. JAMA. 2017;318(24):2466-2482.
A meta-analysis of 33 randomized clinical trials comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment for fracture incidence. Literature searches were performed on December 24, 2016 and then updated on July 16, 2017.
The 33 randomized trials included 51,145 community-dwelling adults aged >50 years.
Two independent reviewers performed the data extraction and assessed study quality. A meta-analysis was performed to calculate risk ratios (RRs), absolute risk differences (ARDs), and 95% confidence intervals (CIs) using random-effects models.
- No significant association of calcium (RR: 1.53; 95% CI: 0.97-2.42) or vitamin D (RR: 1.21; 95% CI: 0.99-1.47) with risk of hip fracture compared with placebo or no treatment.
- No significant association of combined calcium and vitamin D with hip fracture compared with placebo or no treatment (RR: 1.09; 95% CI: 0.85-1.39).
- No significant associations between calcium, vitamin D, or combined calcium and vitamin D supplements and the incidence of nonvertebral, vertebral, or total fractures. Subgroup analyses showed that these results were generally consistent regardless of the calcium or vitamin D dose, sex, fracture history, dietary calcium intake, or baseline serum 25-hydroxyvitamin D concentration.
In this meta-analysis of randomized clinical trials, the use of supplements that included calcium, vitamin D, or both compared with placebo or no treatment was not associated with a lower risk of fractures among community-dwelling older adults. These findings do not support the routine use of these supplements in community-dwelling older people.
Finding ways to reduce osteoporotic fracture risk is important to most of us in clinical practice because of the high potential for these fractures in our patient populations and the considerable associated morbidity. Approximately 40% of 50-year-old women will have at least 1 major osteoporotic fracture during the remainder of their lifetimes.1 Hip fractures are generally considered the most serious type of osteoporotic fracture; in a cohort study conducted between 2000 to 2010, more than 20% of patients died within a year after a hip fracture.2
The results of this study are the opposite of what we have been encouraging the public to believe.
Over the years we have urged patients to take a combination of vitamin D and calcium, believing these supplements would reduce fracture risk. The present study by Zhao et al suggests this prescription will have relatively little benefit. Based on their systematic review and meta-analysis of 33 randomized trials, the authors determined that neither calcium alone, calcium plus vitamin D, nor vitamin D alone significantly reduced the incidence of hip, nonvertebral, vertebral, or total fractures in community-dwelling older adults.
Earlier meta-analyses have reported slight benefits from supplementation. Avenell’s 2014 Cochrane review combined data from 54 clinical trials (N=91,281) in which vitamin D was given in the hope of reducing bone fractures. Based on this review vitamin D taken alone appeared unlikely to prevent hip or other fractures. The following are some of the findings from Avenell’s meta-analysis:
- Vitamin D alone is unlikely to prevent hip fracture (RR: 1.12; 95% CI: 0.98-1.29); 11 trials (N=27,693).
- Vitamin D alone is unlikely to prevent any new fracture (RR: 1.03; 95% CI: 0.96-1.11); 15 trials (N=28,271).
- Vitamin D plus calcium reduces the risk of any type of fracture (RR: 0.95; 95% CI: 0.90-0.99) by about 5%; 10 trials (N=49,976).
- Vitamin D plus calcium results in a 16% reduction in hip fracture risk (RR: 0.84; 95% CI: 0.74-0.96; P=0.01); 9 trials (N=49,853).
They also found that neither vitamin D alone or vitamin D plus calcium affected risk of dying (N=71,032), and that vitamin D supplementation was associated with double the risk for mild hypercalcemia (N=17,124) and gastrointestinal symptoms (N=47,761).3
A meta-analysis by Bolland et al published in April 2014 examined the effects of vitamin D supplementation on skeletal, vascular, and cancer outcomes. Bolland defined clinical outcomes using a risk reduction threshold of 5% for mortality and 15% for other endpoints. Results unfortunately did not meet these minimal thresholds so he described attempts to use vitamin D supplementation as futile.
According to Bolland, vitamin D supplementation with or without calcium for myocardial infarction or ischemic heart disease (9 trials; N=48,647), stroke or cerebrovascular disease (8 trials; N=46,431), cancer (7 trials; N=48,167), and total fracture (22 trials; N=76,497) lay within the futility boundary, which, by definition, means that vitamin D does not alter the relative risk of any of these endpoints by 15% or more. Vitamin D supplementation alone did not reduce hip fracture by 15% or more (12 trials; N=27, 834).4
A second meta-analysis published by Bolland et al in July 2014 looked only at vitamin D given to prevent falls. Bolland again set a threshold of a 15% risk reduction. Data from 20 randomized controlled trials (N=29,535) failed to reach this benefit threshold and so vitamin D supplementation was described as futile.5 However, Bolland et al did report in a 2015 publication that calcium supplementation was significantly associated with a lower incidence of total fracture in community-dwelling participants.6
Data from the Women’s Health Initiative (WHI) trials published in 2014 suggested a significant interaction between hormone therapy, calcium, and vitamin D. In these trials, supplementation in combination with hormonal therapies significantly reduced risk of hip fracture.7
Vitamin D supplementation may not come risk-free as we once thought. Recent reports actually suggest high bolus doses of vitamin D increase risk of falls in the elderly. Out of concern for increased fall risk, a warning was published in November 2016 that vitamin D bolus dosing or daily doses should not exceed 3,000 IU and serum levels of 25-hydroxyvitamin D should not exceed 40-45 ng/mL in elderly individuals.8
The other common belief about vitamin D is that taking it will lower risk of cancer. A Cochrane review by Bjelakovic et al published in June 2014 analyzed data from 18 randomized clinical trials (N=50,623) on cancer prevention in adults. Participants, who were from high-income countries and were mostly older women (47-97 years old), were supplemented with vitamin D for a mean of 6 years. In the end, 7.6% of the women who received vitamin D developed cancer vs 7.7% of the women who did not.9
We should note that in the current meta-analysis by Zhao et al, hip fracture risk tended to increase with calcium or vitamin D supplementation, though this did not reach statistical significance. It was a noticeable enough trend for the authors to consider the possibility of a significant association between supplementation and increased fracture incidence. Perhaps this might be explained by an increased risk of falling. It certainly should give us pause as we have long thought of vitamin D as harmless.
Reducing fracture risk is of great clinical importance in older women. It appears that vitamin D and calcium may not be quite as beneficial as we once thought and taking these supplements may possibly pose risks.
In clinical practice it seems that women respond well to our suggested osteoporosis treatments with clearly noticeable improvement. Yet the meager benefits described in these studies seem to be too small to be clinically noticeable. We should acknowledge though that we rarely if ever prescribe calcium or vitamin D alone. Often patients receive vitamin K2 and strontium citrate in addition to the calcium and vitamin D. We also encourage daily unipedal standing. Perhaps these more complex protocols are more effective, either because they augment the impact of vitamin D and calcium or as stand-alone therapies they have greater impact.
Our patients believe in vitamin D and calcium for increasing bone density, and we would be hard-pressed to convince them that these pills are unnecessary. Aside from the balance issues associated with large bolus doses of vitamin D, there still seems to be little risk of harm from taking it. Data suggests that mortality rates are not adversely affected. In Bjelakovic et al’s 2014 Cochrane Review, vitamin D3 was associated with a small but significant decrease in mortality and cancer deaths. In the composite trial data from 38 trials (N=75,927), those taking vitamin D had an 11% mortality rate compared to 11.4% in the control group (RR: 0.94; 95% CI: 0.91-0.98; P=0.002); in 4 trials (N=44,492) deaths from cancer decreased significantly in the vitamin D group (RR: 0.88; 95% CI: 0.78-0.98; P=0.02). The combination of vitamin D3 and calcium was associated with an increased risk for nephrolithiasis (RR: 1.17; 95% CI: 1.02-1.34; P=0.02) in 4 trials (N=42,876).9
It should be noted that the current study's conclusions were drawn on supplementation without regard to laboratory values for circulating vitamin D or calcium levels. Repleting those who are deficient in these nutrients may change associated outcomes.
- Si L, Winzenberg TM, Chen M, Jiang Q, Palmer AJ. Residual lifetime and 10 year absolute risks of osteoporotic fractures in Chinese men and women. Curr Med Res Opin. 2015;31(6):1149-1156.
- Lo JC, Srinivasan S, ChandraM, et al. Trends in mortality following hip fracture in older women. Am J Manag Care. 2015;21(3):e206-e214.
- Avenell A, Mak JC, O'Connell D. Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men. Cochrane Database Syst Rev. 2014;(4):CD000227.
- Bolland MJ, Grey A, Gamble GD, Reid IR. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes Endocrinol. 2014;2(4):307-320.
- Bolland MJ, Grey A, Gamble GD, Reid IR. Vitamin D supplementation and falls: a trial sequential meta-analysis. Lancet Diabetes Endocrinol. 2014;2(7):573-580.
- Bolland MJ, Leung W, Tai V, et al. Calcium intake and risk of fracture: systematic review. BMJ. 2015;351:h4580.
- Robbins JA, Aragaki A, Crandall CJ, et al. Women’s Health Initiative clinical trials: interaction of calcium and vitamin D with hormone therapy. Menopause. 2014;21(2):116-123.
- Gallagher JC. Vitamin D and falls - the dosage conundrum. Nat Rev Endocrinol. 2016;12(11):680-684.
- Bjelakovic G, Gluud LL, Nikolova D, et al. Vitamin D supplementation for prevention of cancer in adults. Cochrane Database Syst Rev. 2014;(6):CD007469.