Contribution of vitamin D to bone health: fall and fracture prevention



Heike A. BISCHOFF-FERRARI
MD, DrPH
Director, Center on Aging and Mobility, University of Zurich
Swiss National Foundations
Professor, Department of Rheumatology and Institute of Physical Medicine
University Hospital Zurich
Zurich, SWITZERLAND

Contribution of vitamin D to bone health: fall and fracture prevention

by H. A. Bischof f – Ferrari ,Switzerland

The overwhelming majority of fractures occur after a fall, and fall rates increase with age and poor muscle strength or function. Furthermore, after a first fall, about 30% of persons develop a fear of falling, and as a result restrict their activities and suffer from decreased quality of life. Thus, the benefit of vitamin D in terms of fall and fracture prevention has significant clinical implications, all the more so as there is a growing number of epidemiologic studies linking low vitamin D status with an increase in the risk of colon and possibly other cancers, as well as in the risk of hypertension, myocardial infarction, cardiovascular and overall mortality, infections, and diabetes. Several recent meta-analyses have addressed the benefit of vitamin D on fracture reduction, with conflicting findings. This article will first summarize the findings from double-blind randomized trials of oral vitamin D supplementation with respect to antifracture efficacy. It will then address why meta-analyses using alternative approaches, including open-design trials and trials that tested intramuscular vitamin D, have reported discordant findings. Finally, as vitamin D modulates fracture risk in two ways, by decreasing falls and increasing bone density, the efficacy of vitamin D on fall prevention will be reviewed, and the optimal 25-hydroxyvitamin D level to achieve these benefits will be discussed.

Medicographia. 2010;32:384-390 (see French abstract on page 390)

Falls and fractures

Over 90% of fractures occur after a fall and fall rates increase with age and poor muscle strength or function.1 Mechanistically, the circumstances2 and the direction3 of a fall determine the type of fracture, whereas bone density and factors that attenuate a fall, such as better strength or better padding, critically determine whether a fracture will take place when the person who falls lands on a certain bone.4 Moreover, falling may affect bone density through increased immobility due to self-restriction of activities.5 After their first fall, about 30% of persons develop fear of falling resulting in self-restriction of activities and decreased quality of life.5

In this context, the benefit of vitamin D in terms of fall and fracture prevention has significant clinical importance. In humans, several lines of evidence support a role of vitamin D in muscle health. First, proximal muscle weakness is a prominent feature of the clinical syndrome of vitamin D deficiency.6 Vitamin D deficiency myopathy is characterized by proximal muscle weakness, diffuse muscle pain, and gait impair- ment with a waddling way of walking.7 Second, the vitamin D receptor gene (VDR) is expressed in human muscle tissue,8 and VDR activation may promote de novo protein synthesis in muscle.9 Mice lacking the VDR gene show a skeletal muscle phenotype with smaller and variable muscle fibers and persistence of immature muscle gene expression during adult life, suggesting a role of vitamin D in muscle development.10,11 These abnormalities persist after correction of systemic calcium metabolism by a rescue diet.11

Vitamin D supplementation in seniors aged 65 and above

We now look at the available evidence from double-blind randomized controlled trials of oral vitamin D supplementation in seniors aged 65 and older, and its efficacy in terms of fall and fracture prevention. Two 2009 meta-analyses of double-blind randomized controlled trials came to the conclusion that vitamin D reduces the risk of falls by 19%,12 the risk of hip fracture by 18%,13 and the risk of any nonvertebral fracture by 20%.13 However, this benefit was dose-dependent. Fall prevention was only observed in trials with a treatment dose of at least 700 IU vitamin D per day, and fracture prevention required a received dose (treatment dose*adherence) of more than 400 IU vitamin D per day. Lower doses failed to reduce fracture or fall risk, while the benefit of fall prevention and fracture prevention was present in all subgroups of the senior population at the higher dose of vitamin D. Primary prevention based on received dose (dose*adherence) as opposed to treatment dose in double-blind randomized controlled trials (RCTs), made it possible to assess antifracture efficacy using a dose that accounted for the low adherence in several recent large trials.14,15

_ 2009 meta-analysis on fall prevention
The 2009 meta-analysis on fall prevention included 8 doubleblind RCTs with predefined fall assessment throughout the trial period (n=2426) and found significant heterogeneity by dose (low-dose: <700 IU/day versus higher dose: 700 to 1000 IU/ day; P-value 0.02) and achieved 25-hydroxyvitamin D level (<60 nmol/L versus ≥60 nmol/L; P-value = 0.005).12 Higher-dose supplemental vitamin D reduced fall risk by 19% (pooled relative risk [RR], 0.81; 95% confidence interval [CI], 0.71-0.92; n=1921 from 7 trials) versus a lower dose did not (pooled RR=1.10, 95% CI, 0.89-1.35 from 2 trials), also achieved serum 25-hydroxyvitamin D concentrations less than 60 nmol/L did not reduce the risk of falling (pooled RR=1.35, 95% CI, 0.98-1.84). Notably, at the higher dose of 700 to 1000 IU vitamin D, this meta-analysis documented a 38% reduction in the risk of falling with treatment duration of 2 to 5 months and a sustained significant effect of 17% fall reduction with treatment duration of 12 to 36 months, and the benefit was independent of type of dwelling and age. Thus, benefits of 700 to 1000 IU vitamin D per day on fall prevention are rapid and sustained and include all subgroups of the senior population.

Further support for a dose-response relationship of vitamin D and fall reduction comes from a multidose double-blind RCT in 124 nursing home residents receiving 200, 400, 600, or 800 IU vitamin D compared with placebo over a 5-month period.16 Participants in the 800 IU group had a 72% lower rate of falls than those taking placebo or a lower dose of vitamin D (rate ratio, 0.28; 95% CI, 0.11-0.75).16

_ 2009 meta-analysis on fracture prevention
This meta-analysis on fracture prevention included 12 doubleblind RCTs for nonvertebral fractures (n=42 279) and 8 RCTs for hip fractures (n=40 886), and, similar to the meta-analysis on fall prevention, it found significant heterogeneity for received dose of vitamin D and achieved level of 25-hydroxyvitamin D in the treatment group for hip and any nonvertebral fractures (Figures 1 and 2, page 386).13-15,17-26 No fracture reduction was observed for a received dose of 400 IU or less per day or achieved 25-hydroxyvitamin D levels of less than 75 nmol/L. Conversely, a higher received dose of 482 to 770 IU supplemental vitamin D per day reduced nonvertebral fractures by 20% (pooled RR, 0.80; 95% CI, 0.72-0.89; n=33 265 from 9 trials) and hip fractures by 18% (pooled RR, 0.82; 95% CI, 0.69-0.97; n=31 872 from 5 trials). Notably, subgroup analyses for the prevention of nonvertebral fractures with the higher received dose suggested a benefit in all subgroups of the older population, and possibly better fracture reduction with vitamin D3 compared with vitamin D2, while additional calcium did not further improve antifracture efficacy (Table I, page 386).13

Results from meta-analyses having included double-blind and open-design trials in their primary analysis

In August 2007, a review and meta-analysis commissioned by the US Department of Health and Human Services (HHS) addressed the effect of vitamin D supplementation on all fractures in postmenopausal women and men ages 50 and older.27 The pooled results for all fractures included 10 doubleblinded and 3 open-design trials (n=58 712) and did not support a significant reduction of fractures with vitamin D (pooled odds ratio [OR], 0.90; 95% CI, 0.81-1.02). The report suggested that the benefit of vitamin D may depend on additional calcium and be primarily seen in institutionalized individuals, which is consistent with the meta-analysis of Boonen et al.28

Figure 1
Figure 1. Nonvertebral fracture prevention by received daily dose of 25(OH)D.

Triangles indicate trials with D3, circles trials with D2. Line = Trend line. All 12 high-quality trials were included for the received dose metaregression (n=42279 individuals).14,26 For any nonvertebral fractures, antifracture efficacy increased significantly with higher received dose (meta-regression: Beta = –0.0007; P=0.003).
Modified from reference 13: Bischoff-Ferrari et al. Arch Intern Med. 2009;169:551-561. © 2009, American Medical Association.

Figure 2
Figure 2. Nonvertebral Antifracture efficacy by achieved serum 25(OH)D fracture prevention by achieved 25(OH)D levels.

Triangles indicate trials with D3, circles trials with D2. Line = Trend line. For achieved 25(OH)D levels, 2 trials (out of the 12 trials) did not provide serum 25(OH)D levels measured in the study population during the trial period.14,26 For any nonvertebral fractures, antifracture efficacy increased significantly higher with higher achieved 25-hydroxyvitamin D levels (meta-regression: Beta = –0.005; P=0.04)
Modified from reference 13: Bischoff-Ferrari et al. Arch Intern Med. 2009;169:551-561. © 2009, American Medical Association.

Table I
Table I. Nonvertebral fracture reduction with vitamin D based on
evidence from double-blind RCTs.

Modified from reference 13: Bischoff-Ferrari et al. Arch Intern Med. 2009;169: 551-561. © 2009, American Medical Association.

A 2010 patient-based meta-analysis of a subgroup of 7 large trials of vitamin D included 68 500 individuals age 47 and older.29 The authors defined alternative criteria that permitted the inclusion of two open-design trials,30,31 one trial with intramuscular vitamin D,32 and 4 of the 12 double-blind RCTs of oral vitamin D included in the 2009 meta-analysis described above (one RCT using intermittent vitamin D2 without calcium,20 one RCT with 400 IU vitamin D3 without calcium,18 one trial with 800 IU vitamin D3 per day with and without calcium and less than 50% adherence,15 and one trial with 400 IU vitamin D with calcium14). The authors did not account for adherence to treatment. Based on these criteria, their findings showed a reduced overall risk of fracture (hazard ratio [HR], 0.92; 95% CI, 0.86 to 0.99) and a nonsignificant reduction of hip fractures (HR, 0.84; 95% CI, 0.70 to 1.01) for trials that used vitamin D plus calcium. Vitamin D alone, irrespective of dose, did not reduce fracture risk. The authors concluded that vitamin D, even in a dose of 400 IU vitamin D per day, reduces the risk of fracture if combined with calcium. Notably, this regimen was tested in 36 282 postmenopausal women in theWomen’s Health Initiative (WHI) trial over a treatment period of 7 years and did not reduce the risk of fracture.

In all three reports reviewed under this section, heterogeneity by dose may have been missed due to the inclusion of opendesign trials plus a dose evaluation that did not incorporate adherence. Biologically, the exclusion of heterogeneity by dose seems implausible even if a formal test of heterogeneity is not statistically significant. A dose-response relationship between vitamin D and fracture reduction is supported by epidemiologic data showing a significant positive trend between serum 25(OH)D concentrations and hip bone density,33 lower extremity strength,34,35 and trial data for fall prevention.12

In addition, greater antifracture efficacy with higher achieved 25(OH)D levels was documented in an earlier meta-analysis of high-quality primary prevention trials with supplemental vitamin D.36 Factors that may obscure a benefit of vitamin D are low adherence to treatment,15 low dose of vitamin D, or the use of less potent D2.37,38 Furthermore, open-design trials31 may bias results toward nil, because vitamin D is available over the counter.

Notably, the 2009 meta-analyses on fall12 and fracture13 prevention from double-blind RCTs performed sensitivity analyses that included 4 open-design trials for fracture prevention and 3 open-design trials for fall prevention. Both analyses found significant variation in results between open-design and double-blind trials at any dose of vitamin D, the lower and the higher dose suggesting that trial quality introduces heterogeneity.

Finally, the consistency of the results for both received dose and achieved 25(OH)D levels in the treatment group across all 12 masked trials lends support to the presence of a doseresponse relationship between supplemental vitamin D and fracture reduction (Figures 1 and 2).14,15,17-26

Optimal 25-hydroxyvitamin D levels for bone and muscle health

The threshold for optimal 25(OH)D and hip BMD was investigated in 13 432 individuals of NHANES III (Third National Health And Nutrition Examination Survey), including both younger (20 to 49 years) and older (50+ years) individuals of various ethnic backgrounds.33 In the regression plots, higher serum 25(OH)D levels were associated with higher BMD throughout the reference range of 22.5 to 94 nmol/L in all subgroups. In younger whites and younger Mexican-Americans, higher 25(OH)D was associated with higher BMD, even beyond 100 nmol/L.

The threshold for optimal 25(OH)D and lower-extremity function was evaluated in the same survey (NHANES III) in 4100 ambulatory adults age 60 years and older34 and a Dutch cohort of older individuals.35 Results from the smaller Dutch cohort suggested a threshold of 50 nmol/L for optimal function,35 while a threshold beyond which function would not further improve was not identified in the larger NHANES III survey, even beyond the upper end of the reference range (>100 nmol/L).34 In NHANES III, a similar benefit of higher 25- hydroxyvitamin D status was documented by gender, level of physical activity, and level of calcium intake.

The threshold for optimal 25(OH)D and fracture and fall prevention was assessed in a recent benefit-risk analysis and is illustrated in Figure 3.39 Based on these data, 75 or better 100 nmol/L (30 or better 40 ng/mL) is suggested as the optimal threshold of 25-hydroxyvitamin D for fall and fracture prevention.

Figure 3
Figure 3. Threshold for optimal fall and fracture prevention based
on double-blind randomized controlled trials.

Data points show the relative risk of falls and the relative risk of sustaining any nonvertebral fracture from double-blind RCTs, by achieved 25-hydroxyvitamin D levels in the treatment groups. Data were extracted from two 2009 meta-analyses12,13 and summarized in a recent benefit-risk analysis of vitamin D.39 Based on these data, 75 or better 100 nmol/L (30 or better 40 ng/mL) are suggested as an optimal threshold of 25-hydroxyvitamin D for fall and fracture prevention.
Modified from reference 39: Bischoff-Ferrari HA et al. Osteoporos Int. 2009. Dec 3. [Epub ahead of print]. © 2009, © Springer.

Adding calcium to vitamin D

The pooled RR reduction was 21% with or without additional calcium for the higher dose of vitamin D in the 2009 metaanalysis of double-blind RCTs.13 The observed calcium-independent benefit of vitamin D on nonvertebral fracture prevention at a vitamin D dose greater than 400 IU per day may be explained by a calcium-sparing effect of vitamin D.40,41 This is supported by two recent epidemiologic studies suggesting that both parathyroid hormone suppression41 and hip bone density42 may only depend on a higher calcium intake if serum 25-hydroxyvitamin D levels are very low. Other meta-analyses may have missed this finding due to their analyses including all doses of vitamin D.

As calcium absorption is improved with higher serum 25-hydroxyvitamin D levels,41,43 future studies may need to evaluate whether current calcium intake recommendations with higher doses of vitamin D beyond 2000 IU per day are safe or require downward adjustment.43 If dietary calcium is a threshold nutrient, as suggested by Heaney,44 then that threshold for optimal calcium absorption may be at a lower calcium intake when vitamin D supplementation is adequate.

Other potential benefits of vitamin D supplementation

Many lines of evidence also suggest that low vitamin D status increases the risk of colon45 and possibly other cancers,46 as well as the risk of hypertension,47 myocardial infarction,48 cardiovascular49 and overall mortality,50 infections51 and diabetes.52 The development of mice lacking the receptor for vitamin D (VDR) has provided insight into the physiological role of vitamin D. These mice express phenotypes that are consistent with epidemiologic studies of 25-hydroxyvitamin D deficiency in humans.10

Are current recommended vitamin D intakes sufficient for optimal bone and muscle health?

The recommended intake of vitamin D as defined by the Institute of Medicine in 1997 is 200 IU per day for adults up to 50 years of age, 400 IU per day for adults between age 51 and 70, and 600 IU per day for those aged 70 years and above. These recommendations are insufficient to meet the requirements for optimal fall and nonvertebral fracture prevention. The current intake recommendation for older persons (600 IU per day) may bring most individuals to 50-60 nmol/L, but not to 75-100 nmol/L.33

Studies suggest that 700 to 1000 IU of vitamin D per day may bring 50% of younger and older adults up to 75-100 nmol/L.53-55 Thus, to bring most older adults to the desirable range of 75-100 nmol/L, vitamin D doses higher than 700- 1000 IU would be needed. According to a recent benefit-risk analysis on vitamin D, mean levels of 75 to 110 nmol/L were reached in most RCTs with 1800 IU to 4000 IU vitamin D/d without risk.39 In a recent trial among acute hip fracture patients, 70% reached the 75 nmol/L threshold with 800 IU vitamin D3 per day, and 93% with 2000 IU vitamin D3 per day, at 12 months follow-up and with over 90% adherence.56

Heaney and colleagues, in a study of healthy men, consistently estimated that 1000 IU cholecalciferol per day is needed during the winter months in Nebraska to maintain a late summer starting level of 70 nmol/L, while baseline levels between 20 and 40 nmol/L may require a daily dose of 2200 IU vitamin D to achieve and maintain 80 nmol/L.44,57 These results indicate that individuals with a lower starting level may need a higher dose of vitamin D to achieve desirable levels, while relatively lower doses may be sufficient in individuals who start at higher baseline levels.

Due to seasonal fluctuations in 25(OH)D levels,58 some individuals may be in the desirable range during summer months. However, these levels will not be maintained during the winter months even in sunny latitudes.59,60 Thus, winter supplementation with vitamin D is needed even after a sunny summer.

Furthermore, several studies suggest that many older persons will not achieve optimal serum 25(OH)D levels during summer months, which suggests that vitamin D supplementation should be independent of season in older persons.60-62 Even in younger persons, the use of sunscreen or sun-protective clothing may prevent a significant increase in 25-hydroxyvitamin D levels.62

The persons most vulnerable to low vitamin D levels include older individuals,60,63 individuals living in northern latitudes with prolonged winters,58,64 obese individuals,65 and individuals of all ages with dark skin pigmentation living in northern latitudes.33,66,67 In healthy outdoor workers, naturally elevated 25- hydroxyvitamin D levels are observed: 135 nmol/L68 in farmers and 163 nmol/L69 in lifeguards. The first sign of toxicity, hypercalcemia, is only observed with serum levels of 25(OH)D above 220 nmol/L.70,71

In summary

Evidence fromdouble-blind randomized-controlled trials shows that vitamin D supplementation reduces both falls and nonvertebral fractures, including hip fractures. However, this benefit is dose-dependent. According to two 2009 meta-analyses of double-blind RCTs, no fall reduction was observed at doses of less than 700 IU per day, while a higher dose of 700 to 1000 IU vitamin D per day reduced falls by 19%.12 Similarly, no fracture reduction was observed for a received dose of 400 IU or less per day, while a higher received dose of 482 to 770 IU vitamin D per day reduced nonvertebral fractures by 20% and hip fractures by 18%. Of note, the antifracture benefit was present in all subgroups of the older population and was most pronounced among community dwellers (–29%) and those age 65 to 74 years (–33%).

Fall prevention and nonvertebral fracture prevention increased consistently and significantly with higher achieved 25-hydroxyvitamin D levels in the 2009 meta-analyses. Fall prevention started at 25-hydroxyvitamin D levels of 60 nmol/L,12 while at least 75 nmol/L is required for nonvertebral fracture prevention.13 Optimal fall and fracture prevention was observed with 25-hydroxyvitamin D levels of close to 100 nmol/L.39 Given the absence of available data beyond this beneficial range, these recent meta-analyses do not preclude the possibility that higher doses or higher achieved 25-hydroxyvitamin D concentrations may be even more effective in reducing falls and nonvertebral fractures. _

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Keywords: vitamin D; fracture; fall; optimal 25-hydroxyvitamin D level; meta-analysis