Vitamin D: What is an adequate vitamin D level and how much supplementation is necessary?

Best Practice & Research Clinical Rheumatology 23 (2009) 789–795
Heike Bischoff-Ferrari, Director, Professor a,b,*
a Centre on Aging and Mobility, University of Zurich, Zurich, Switzerland
b Department of Rheumatology and Institute of Physical Medicine, University Hospital Zurich, Zurich, Switzerland

Strong evidence indicates that many or most adults in the United States and Europe would benefit from vitamin D supplements with respect to fracture and fall prevention, and possibly other public health targets, such as cardiovascular health, diabetes and cancer. This review discusses the amount of vitamin D supplementation needed and a desirable 25-hydroxyvitamin D level to be achieved for optimal musculoskeletal health.

Vitamin D modulates fracture risk in two ways: by decreasing falls and increasing bone density. Two most recent meta-analyses of double-blind randomised controlled trials came to the conclusion that vitamin D reduces the risk of falls by 19%, the risk of hip fracture by 18% and the risk of any non-vertebral fracture by 20%; however, this benefit was dose dependent. Fall prevention was only observed in a trial 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. Anti-fall efficacy started with achieved 25-hydroxyvitamin D levels of at least 60 nmol l_(24 ng ml_) and anti-fracture efficacy started with achieved 25-hydroxyvitamin D levels of at least 75 nmol l_1 (30 ng ml_) and both endpoints improved further with higher achieved 25-hydroxyvitamin D levels.

Founded on these evidence-based data derived from the general older population, vitamin D supplementation should be at least 700–1000 IU per day and taken with good adherence to cover the needs for both fall and fracture prevention. Ideally, the target range for 25-hydroxyvitamin D should be at least 75 nmol l_, which may need more than 700–1000 IU vitamin D in individuals with severe vitamin D deficiency or those overweight.

© 2009 Elsevier Ltd. All rights reserved.

• University Hospital Zurich, Centre on Aging and Mobility, Department of Rheumatology and Institute of Physical Medicine, Zurich, Switzerland.

E-mail address:heike.bischoff@usz.ch
1521-6942/$ – see front matter © 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.berh.2009.09.005

Target both muscle and bone

Critical for the understanding and prevention of fractures, especially at older age, is their close relationship with muscle weakness [1]and falling [2,3]. Over 90% of fractures occur after a fall and fall rates increase with age[4]and poor muscle strength or function[4]. Mechanistically, the circumstances [5] and the direction [6]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 individual who falls lands on a certain bone[7]. Moreover, falling may affect bone density through increased immobility from self-restriction of activities[8].It is well known that falls may lead to psychological trauma known as fear of falling[9]. After their first fall, about 30% of persons develop fear of falling resulting in self-restriction of activities, and decreased quality of life [8].

Notably, anti-resorptive treatment alone may not reduce fractures among individuals 80 years and older in the presence of non-skeletal risk factors for fractures, such as muscle weakness and falling, despite an improvement in bone metabolism [10].

Vitamin D: its role in muscle health

In humans, four 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[11].Vitamin D deficiency myopathy includes proximal muscle weakness, diffuse muscle pain and gait impairments such as a waddling way of walking[12].Second, receptor for vitamin D (VDR) is expressed in human muscle tissue[13],and VDR activation may promote de novo protein synthesis in muscle[14].Suggesting a role of vitamin D in muscle development, mice lacking the VDR show a skeletal muscle phenotype with smaller and variable muscle fibres and persistence of immature muscle gene expression during adult life[15,16].These abnormalities persist after correction of systemic calcium metabolism by a rescue diet[16].

Third, several observational studies suggest a positive association between 25-hydroxyvitamin D and muscle strength or lower extremity function in older persons[17,18].Finally, in several double-blind randomised controlled trials, vitamin D supplementation increased muscle strength and balance [19,20],and reduced the risk of falling in community-dwelling individuals[20–22],as well as in institutionalised individuals[19,23].Notably, a study by Glerup and colleagues suggest that vitamin D deficiency may cause muscular impairment even before adverse effects on bone occur[11].

Importance of 25-hydroxyvitamin D status and dose of vitamin D with respect to function, strength and risk of falling

A dose–response relationship between vitamin D status and muscle health was examined in The Third National Health and Nutrition Examination Survey(NHANES III) including 4100 ambulatory adults aged 60 years and older. Muscle function measured as the 8-foot walk test and the repeated sit-to-stand test was poorest in subjects with the lowest 25-hydroxyvitamin D (below 20 nmol l_) levels. Similar results were found in a Dutch cohort of older individuals[17].Notably, while from the smaller Dutch cohort, a threshold of 50 nmol l_has been suggested for optimal function[17],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_)[18].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.

These associations between higher 25-hydroxyvitamin D status and better function observed in epidemiologic studies in the United States and Europe were confirmed by three recent double-blind randomised controlled trials (RCTs) with 800 IU vitamin D3 resulting in a 4–11% gain in lower extremity strength or function[19,20],and in an up to 28% improvement in body sway [20,22]in older adults 65þ years of age, within 2–12 months of treatment.

A dose-dependent benefit of vitamin D in regard to fall prevention was suggested by a 2004 meta­analysis[24] and a recent multi-dose double-blind RCT among 124 nursing home residents receiving 200, 400, 600 or 800 IU vitamin D compared with a placebo over a 5-month period[23].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% confidence interval=0.11–0.75)[23].Including this trial, a most recent meta-analysis of eight high-quality double-blind RCTs (n=2426) found significant heterogeneity by dose(low-dose:<700 IU/day vs. higher dose: 700–1000 IU per day; p-value 0.02) and achieved 25- hydroxyvitamin D level (<60 nmol l^-vs.> 60 nmol l^-; p-value=0.005)[25].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 seven trials) versus a lower dose that did not (pooled relative risk (RR)=1.10,95% CI, 0.89–1.35 from two trials), also achieved serum 25-hydroxyvitamin D concentrations less than60 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 700–1000 IU vitamin D, this meta-analysis documented a 38% reduction in the risk of falling with treatment duration of 2–5 months and a sustained significant effect of 17% fall reduction with treatment duration of 12–36 months. Thus, the benefits of vitamin D on fall prevention are rapid and sustained, provided a high enough dose is provided.

Importance of 25-hydroxyvitamin D status and dose of vitamin D with respect to bone density and fracture prevention

A threshold for optimal 25-hydroxyvitamin D and hip BMD has been addressed among 13 432individuals of NHANES III, including both younger (20–49 years) and older (50+years) individuals with different ethnic racial background[26].In the regression plots, higher serum 25- hydrox­yvitaminvitamin D levels were associated with higher bone mineral density (BMD) throughout the reference range of 22.5–94 nmol l^-in all subgroups. In younger whites and younger MexicanAmericans, higher 25-hydroxyvitamin D was associated with higher BMD even beyond 100 nmol l^-.

Consistently, a 2009 meta-analysis of 12 double-blind RCTs for non-vertebral fractures (n=42 279)and eight RCTs for hip fractures (n=40 886) found that anti-fracture efficacy of vitamin D is dose dependent and increases significantly with a higher achieved level of 25-hydroxyvitamin D in the treatment group starting at 75 nmol l^-[27].No fracture reduction was observed for a received dose of400 IU or less per day, while a higher received dose of 482–770 IU supplemental vitamin D per day reduced non-vertebral fractures by 20% (pooled RR=0.80; 95% CI, 0.72–0.89; n=33 265 from nine trials) and hip fractures by 18% (pooled RR=0.82; 95% CI, 0.69–0.97; n=31872 from five trials). Notably,subgroup analyses for the prevention of non-vertebral fractures with the higher received dose sug­gested a benefit in all subgroups of the older population, and possibly better fracture reduction with D3compared with D2, while additional calcium did not further improve anti-fracture efficacy (seeTable1).

Adding calcium to vitamin D

The observed calcium-independent benefit of vitamin D on non-vertebral fracture prevention at a vitamin D dose greater than 400 IU per day may be explained by a calcium-sparing effect of vitamin D[28,29],which is supported by two recent epidemiologic studies suggesting that both PTH suppres­sion[29] and hip bone density[30] may only depend on a higher calcium intake if serum 25-hydrox­yvitamin D levels are very low.

Thus, as calcium absorption is improved with higher serum 25-hydroxyvitamin D levels[29,31],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[31].If dietary calcium is a threshold nutrient, as suggested by Dr. Heaney[32],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 colon[33] and possibly other cancers[34],increases the risk of hypertension[35],myocardial infarction[36],cardiovascular[37] and overall mortality[38],infections[39] and diabetes[40].The development of mice lacking VDR provided insight into the global physiologic role of vitamin D. These mice express phenotypes that are consistent with epidemiologic studies of 25-hydroxyvitamin D deficiency in humans[41].

Table 1

Non-vertebral fracture reduction with vitamin D based on evidence from double-blind RCTs.

Subgroups by received dose of vitamin D Fracture reduction

Pooled analysis from 3 trials with low-dose vitamin D (340–380 IU/day) +2% Ø
Pooled analysis from 9 trials with higher dose vitamin D (482–770 IU/day): -20% Sig.
Pooled subgroup analysis from trials with higher dose vitamin D (482–770 IU/day):
Vitamin D2 -10% Ø
Vitamin D3 -23% Sig.
age 65–74 -33% Sig.
age 75 þ -17% Sig.
institutionalized 65þ -15% Sig.
community-dwelling 65þ -29% Sig.
Vitamin D plus Calcium -21% Sig.
Vitamin D main effects -21% Sig.

Legend: Adapted from Bischoff-Ferrari et al. Prevention of non-vertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Arch Intern Med. 2009 Mar 23;169(6):551–61., Copyright© (2009), American Medical Association[27].

The desirable threshold of 25-hydroxyvitamin D for other end points appears to range from 75 nmol l_to 150 nmol l_, similar and maybe somewhat higher than suggested for musculoskeletal health. Therefore, a large part of the human population may benefit from vitamin D supplementation with potentially major health implications.

Are current recommended intakes for vitamin D sufficient for optimal musculoskeletal health?

The recommended adequate 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 over. These recommendations are insufficient to meet the requirements for optimal fall and non-vertebral 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_[26].

Studies suggest that 700–1000 IU of vitamin D per day may bring 50% of younger and older adults up to 75–100 nmol l_[42–44].Thus, to bring majority of older adults to the desirable range of 75–100 nmol–l^~, vitamin D doses higher than 700–1000 IU would be needed. According to studies in younger adults, intakes of as high as 4000–10 000 IU are safe[45,46],and 4000 IU may bring 88% of healthy young men and women to at least 75 nmol l_[46].Heaney and colleagues, in a study of healthy men, estimated that 1000 IU cholecalciferol per day are needed during winter months in Nebraska to maintain a late summer starting level of 70 nmol l_, while baseline levels between 20 and 40 nmol l_1 may require a daily dose of 2200 IU vitamin D to reach and maintain 80 nmol l_[32,45].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.

Based on a dose–response calculation proposed by Dr. Heaney, about 1.0 nmol per 40 IU at the lower end of the distribution and 0.6 nmol per 40 IU at the upper end[32].Naturally high 25-hydroxyvitamin D levels observed in healthy outdoor workers are 135 nmol l_in farmers[47] and 163 nmol l_in lifeguards.[48]As a first sign of toxicity, only serum 25-hydroxyvitamin D levels of above 220 nmol l_1 have been associated with hypercalcaemia[49,50].

Due to seasonal fluctuations of 25-hydroxyvitamin D levels[51],some individuals may be in the desirable range during the summer months. However, these levels will not sustain during the winter months even in sunny latitudes[52,53].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-hydroxyvitamin D levels during the summer months suggesting that vitamin D supplementation should be independent of the season in older persons[53–55].Even among younger

persons, the use of sunscreen or sun-protective clothing may prevent a significant increase in 25- hydroxyvitamin D levels[55].

Most vulnerable to low vitamin D levels are older individuals[53,56],individuals living in northern latitudes with prolonged winters[51,57],obese individuals[58]and individuals of all ages with dark skin pigmentation living in northern latitudes[26,59,60].

In summary, based on evidence from RCTs, vitamin D supplementation reduces both falls and non-vertebral fractures, including those at the hip. However, this benefit is dose dependent. According to two 2009 meta-analysis of double-blind RCTs, no fall reduction was observed for a dose of less than 700 IU per day, while a higher dose of 700–1000 IU supplemental vitamin D per day reduced falls by 19%[25].Similarly, no fracture reduction was observed for a received dose of 400 IU or less per day, while a higher received dose of 482–770 IU supplemental vitamin D per day reduced non-vertebral fractures by 20% and hip fractures by 18%. The anti-fracture effect was present in all subgroups of the older population and was most pronounced among those community-dwelling (–29%) and those 65– 74 years of age (–33%).

Consistently, fall prevention and non-vertebral fracture prevention increased significantly with higher achieved 25-hydroxyvitamin D levels in the 2009 meta-analyses. Fall prevention occurred with 25-hydroxyvitamin D levels of 60 nmol l_up to 95 nmol l_[25],while 75–112 nmol l_were required for non-vertebral fracture prevention[27].Given the absence of data beyond this beneficial range, these recent meta-analyses do not preclude the possibility that higher doses or higher achieved 25-hydroxyvitamin D concentrations would have been even more efficient in reducing falls and non-vertebral fractures.

Practice points

1. Based on evidence from double-blind RCTs summarised in two 2009 meta-analyses, vitamin D supplementation should be a primary prevention strategy in the prevention of falls and fractures at older age – however, a sufficient dose is key!

• a. A dose of 400 IU of vitamin D or less is insufficient for fall or fracture prevention.
• b. For fall prevention, at least 700 IU vitamin D per day and a serum level of 60–95 nmol l_1 25-hydroxyvitamin D is required.
• c. For non-vertebral fracture prevention, more than 400 IU vitamin D per day and a serum level of 75–112 nmol l_is required.
• d. To ensure 25-hydroxyvitamin D concentrations of at least 75 nmol l_for fall þ non-vertebral fracture prevention, a daily intake of at least 1000 IU supplemental vitamin D per day is warranted in all individuals age 65 and older.

i. Individuals with severe vitamin D deficiency or obese individuals may need more vitamin D.
ii. A dose of 400 IU vitamin D may increase 25-hydroxyvitamin D levels by 10 nmol l_, 1000 IU vitamin D may increase 25-hydroxyvitamin D levels by 25 nmol l.
iii.With sufficient vitamin D supplementation, additional calcium supplementation for non-vertebral fracture prevention may not be needed as long as dietary calcium intake is about 700 mg per day.

2. Based on epidemiologic studies, desirable 25-hydroxyvitamin D levels for optimal bone health in younger and older adults are 75–100 nmol l_. Based on epidemiologic studies, desirable 25-hydroxyvitamin D levels for optimal lower extremity function for older adults are also 75–100 nmol l_.

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