Vitamin D and calcium cannot reduce fractures

Relation

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.

Draft

A meta-analysis of 33 randomized clinical trials comparing calcium, vitamin D, or combined calcium and vitamin D supplements with placebo or no treatment on fracture incidence. The literature searches were conducted on December 24, 2016 and updated on July 16, 2017.

Participant

The 33 randomized trials included 51,145 community-dwelling adults aged >50 years.

Target parameters

Two independent reviewers performed 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.

Key insights

• Keine signifikante Assoziation von Kalzium (RR: 1,53; 95 % KI: 0,97–2,42) oder Vitamin D (RR: 1,21; 95 % KI: 0,99–1,47) mit dem Risiko einer Hüftfraktur im Vergleich zu Placebo oder keiner Behandlung.
• Keine signifikante Assoziation von kombiniertem Calcium und Vitamin D mit Hüftfrakturen im Vergleich zu Placebo oder keiner Behandlung (RR: 1,09; 95 % CI: 0,85-1,39).
• Keine signifikanten Zusammenhänge zwischen Kalzium, Vitamin D oder kombinierten Kalzium- und Vitamin-D-Ergänzungen und der Inzidenz von nichtvertebralen, vertebralen oder totalen Frakturen. Subgruppenanalysen zeigten, dass diese Ergebnisse im Allgemeinen unabhängig von der Calcium- oder Vitamin-D-Dosis, dem Geschlecht, der Frakturgeschichte, der diätetischen Calciumaufnahme oder der Ausgangskonzentration von 25-Hydroxyvitamin D im Serum konsistent waren.

In this meta-analysis of randomized clinical trials, use of dietary supplements containing calcium, vitamin D, or both was not associated with a lower risk of fracture in community-dwelling older adults compared with placebo or no treatment. These results do not support the routine use of these supplements in community-dwelling older adults.

Practice implications

Because of the high potential for these fractures in our patient populations and the significant associated morbidity, it is important for most of us in clinical practice to find ways to reduce the risk of osteoporotic fracture. Approximately 40% of 50-year-old women will suffer at least 1 major osteoporotic fracture during their lifetime.¹Hip fractures are generally considered the most severe type of osteoporotic fracture; In a cohort study conducted between 2000 and 2010, more than 20% of patients died within 1 year of a hip fracture.²

The results of this study are the opposite of what we have led the public to believe.

Over the years, we have strongly recommended patients take a combination of vitamin D and calcium because we believe these supplements would reduce the risk of fractures. The present study by Zhao et al. suggests that this prescription will provide relatively little benefit. Based on their systematic review and meta-analysis of 33 randomized trials, the authors found 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.

Previous 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, it seemed unlikely that vitamin D alone would prevent hip or other fractures. Below are some of the findings from Avenell's meta-analysis:

• Es ist unwahrscheinlich, dass Vitamin D allein eine Hüftfraktur verhindert (RR: 1,12; 95 % KI: 0,98-1,29); 11 Versuche (N=27.693).
• Es ist unwahrscheinlich, dass Vitamin D allein eine neue Fraktur verhindert (RR: 1,03; 95 % KI: 0,96–1,11); 15 Versuche (N=28.271).
• Vitamin D plus Calcium reduziert das Risiko jeder Art von Fraktur (RR: 0,95; 95 % CI: 0,90–0,99) um etwa 5 %; 10 Versuche (N=49.976).
• Vitamin D plus Kalzium führt zu einer 16 %igen Verringerung des Hüftfrakturrisikos (RR: 0,84; 95 % KI: 0,74–0,96; P=0,01); 9 Versuche (N=49.853).

They also found that neither vitamin D alone nor vitamin D plus calcium affected the risk of death (N = 71,032) and that vitamin D supplementation was associated with twice the risk of mild hypercalcemia (N = 17,124) and gastrointestinal symptoms (N = 47,761). .³

A meta-analysis published in April 2014 by Bolland et al. 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. Unfortunately, the results did not meet these minimal thresholds, which is why he described attempts to use vitamin D supplementation as futile.

According to Bolland, vitamin D supplementation with or without calcium in myocardial infarction or ischemic heart disease (9 studies; N = 48,647), stroke or cerebrovascular disease (8 studies; N = 46,431), cancer (7 studies; N = 48,167), and total rupture (22 studies; N = 76,497) were within the Futility limit, which by definition means that vitamin D does not change the relative risk for any of these endpoints by 15% or more. Vitamin D supplementation alone did not reduce hip fracture by 15% or more (12 studies; N = 27,834).⁴

A second one by Bolland et al. Meta-analysis published in July 2014 only looked at vitamin D given for fall prevention. Bolland again set a threshold of 15% risk reduction. Data from 20 randomized controlled trials (N = 29,535) did not meet this threshold of benefit, and therefore vitamin D supplementation was described as futile.⁵Bolland et al. however, reported in a 2015 publication that calcium supplementation was significantly associated with a lower incidence of total fractures in community-dwelling participants.⁶

Data from the Women's Health Initiative (WHI) studies published in 2014 indicate a significant interaction between hormone therapy, calcium and vitamin D. In these studies, supplementation in combination with hormonal therapies significantly reduced the risk of hip fracture.⁷

Vitamin D supplementation may not be risk-free as we once thought. Recent reports actually suggest that high bolus doses of vitamin D increase the risk of falls in older people. Due to concerns about an increased risk of falls, a warning was issued in November 2016 that vitamin D bolus doses or daily doses should not exceed 3,000 IU and serum levels of 25-hydroxyvitamin D should not exceed 40-45 ng/ml in older individuals.⁸

The other popular belief about vitamin D is that taking it reduces the risk of cancer. A Cochrane review published in June 2014 by Bjelakovic et al. analyzed data from 18 randomized clinical trials (N=50,623) on cancer prevention in adults. The participants, who came from high-income countries and were mostly older women (47-97 years old), were supplemented with vitamin D for an average of 6 years. In the end, 7.6% of women who received vitamin D developed cancer versus 7.7% of women who did not.⁹

We should note that in the recent meta-analysis by Zhao et al. Hip fracture risk tended to increase with calcium or vitamin D supplementation, although this did not reach statistical significance. It was a significant enough trend for the authors to consider the possibility of a significant association between nutritional supplementation and increased fracture incidence. Perhaps this can be explained by an increased risk of falls. It should certainly give us pause as we have long thought vitamin D was harmless.

Reducing the risk of fracture is of great clinical importance in older women. It appears that vitamin D and calcium are not quite as beneficial as we once thought, and taking these supplements may potentially pose risks.

In clinical practice, it appears that women respond well to our proposed osteoporosis treatments, with clearly noticeable improvement. But the meager benefits reported in these studies appear to be too small to be clinically noticeable. However, we should recognize that we rarely, if ever, prescribe calcium or vitamin D alone. Patients often receive vitamin K₂and strontium citrate in addition to calcium and vitamin D. We also encourage daily one-legged standing. Perhaps these more complex protocols are more effective, either because they enhance the effects of vitamin D and calcium or have greater impact as stand-alone therapies.

Our patients believe in vitamin D and calcium to increase bone density, and we would be hard-pressed to convince them that these pills are unnecessary. Aside from the balance problems associated with large bolus doses of vitamin D, the risk of harm from taking it still appears to be low. The data suggests that mortality rates are not adversely affected. In the Cochrane review by Bjelakovic et al. from 2014 is vitamin D₃was associated with a small but significant decrease in mortality and cancer deaths. In the composite study data from 38 studies (N = 75,927), those taking vitamin D had a mortality rate of 11% compared to 11.4% in the control group (RR: 0.94; 95% CI: 0.91-0.98;P=0.002); in 4 studies (N=44,492), cancer deaths decreased significantly in the vitamin D group (RR: 0.88; 95% CI: 0.78–0.98;P=0.02). The combination of vitamin D₃and calcium was associated with an increased risk of nephrolithiasis (RR: 1.17; 95% CI: 1.02-1.34;P=0.02) in 4 studies (N=42,876).⁹

Of note, the conclusions of the current supplementation study were made without consideration of laboratory values ​​for circulating vitamin D or calcium levels. Replenishing those who are deficient in these nutrients can alter the associated results.