Elsevier

Bone

Volume 41, Issue 1, Supplement 1, July 2007, Pages S13-S19
Bone

Where do we stand on vitamin D?

https://doi.org/10.1016/j.bone.2007.03.010Get rights and content

Abstract

A meta-analysis of primary prevention high-quality trials published in 2005 found that oral cholecalciferol (D3) in a daily dose of 700–800 IU or intermittently 100,000 IU every 4 months with or without calcium, should reduce both hip and non-vertebral fracture risk significantly compared to placebo. Trials that administered 400 IU vitamin D did not achieve fracture efficacy. Notably, there was a significant association between higher achieved 25-hydroxyvitamin D levels (25(OH)D) in the treatment groups and fracture efficacy: The minimal mean level where fracture efficacy was observed was 74 nmol/l (25(OH)D). Epidemiological data for bone density and lower extremity strength support this threshold, and high-quality trials that used 700 to 800 IU D3 suggested fall risk reduction by 35 to 65% in institutionalized and community-dwelling older individuals.

However, since the 2005 meta-analysis, benefits of vitamin D on fracture and fall reduction have been questioned by results from several recent trials. This review proposes that the interpretation of these recent trials is hindered by different doses of vitamin D, different types of supplemental vitamin D (D3 or ergocalciferol D2), low adherence, concurrent use of supplements outside the study protocol, open study design, short follow-up, and/or different patient risk profiles including primary and secondary fracture prevention. In most recent trials, low adherence, the use of the relatively less potent D2, or a too low dose of D3 (400 IU) may have prohibited a shift of (25(OH)D) levels in the treatment groups to the desirable range of at least 75 nmol/l. In summary, from recent trials, two lesson may be learned: (1) Adherence less than 60% is insufficient to achieve fracture efficacy with daily 800 IU D3 plus calcium, (2) D2 in any application or any previously studied dose may not reduce fractures in institutionalized or community-dwelling older individuals.

Section snippets

Available evidence from primary prevention high quality trials and rational of a proposed fracture efficacy threshold at 75 nmol/l 25-hydroxyvitamin D

In a recent quasi-consensus of vitamin D experts (5 out of 6), a threshold of 75 nmol/l was proposed as the serum 25(OH)D concentration at which older men and women will be at a lower risk of fracture [1]. This standard was supported by a recent meta-analysis of primary prevention high-quality trials (n = 9829) where 700–800 IU D3 per day (with or without calcium supplementation) reduced the relative risk (RR) of hip fracture by 26% (pooled RR = 0.74; 95% CI [0.61,0.88]) and any non-vertebral

Limitations of recent trials that used D3

Table 1 summarized details of recent trials. Two trials tested 800 IU D3 with 1000 mg calcium per day [12], [13], 2 trials tested 400 IU D3 plus 1000 mg calcium [14], [15], and 2 trials tested D2 in high intermittent doses (300,000 IU by intra-muscular injection [16], [17], or oral 100,000 IU every 3 months) [18]. All but one trial [17] showed negative results in the intent-to-treat analysis. And the one trial with positive findings does not qualify as a high-quality trial due to its

Limitations of recent pragmatic trials that used D2

There is increasing literature on the relative disproportionate potency of supplemental D2 compared to D3 as summarized in a recent review by Drs. Houghton and Vieth [21]. Although still regarded as equivalent, several recent studies indicate that their abilities to raise serum 25(OH)D serum levels differ significantly, especially if applied in large intermittent doses. Armas et al. demonstrated that 50,000 IU oral D2 produce a similar rise in serum 25(OH)D levels at Day 3 after the application

Summary and future research in vitamin D

Based on findings from recent trials discussed in this review, two questions appear important to be addressed in future trials with D3: (1) What is the optimal dose of D3 that will bring most individuals up to 75 nmol/l 25-hydroxyvitamin D where optimal bone density, optimal lower extremity strength, fall prevention, and fracture efficacy is expected, and (2) what are alternative dosing strategies that could improve adherence to supplementation with D3. Due to the relatively lower potency of D2

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