Introduction to vitamin D
Vitamin D deficiency remains prevalent in the population as a whole. Recent data suggest that children and younger adults present with vitamin D deficiency in about 50% of cases (25-hydroxyvitamin D levels <20 ng/ml or <50 nmol/l). The highest vitamin D deficiency prevalence however has been documented in senior hip fracture patients around the world, with about 80% being affected. This may be best explained with their frailty limiting their sun exposure, but also the fact that ageing reduces skin production of vitamin D 4-fold compared with younger adults.
In this chapter, we focus on the translation of the new intake recommendations of vitamin D for the senior population aiming at a 30% reduction of falls and hip fractures based on evidence from double-blind randomized controlled trials. We also discuss other health benefits of vitamin D and recent findings from meta-analyses suggesting that based on clinical trial findings, vitamin D supplementation may reduce mortality between 4–7%.
Falls and fractures
Over 90% of fractures occur after a fall and fall rates increase with age and poor muscle strength or function (Tinetti, 1988). Mechanistically, the circumstances (Cummings & Nevitt, 1994) and the direction (Nguyen et al., 2007) 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 faller lands on a certain bone (Nevitt & Cummings, 1993). Moreover, falling may affect bone density through increased immobility from self-restriction of activities (Vellas et al., 1997). After their first fall, about 30% of persons develop a fear of falling resulting in self-restriction of activities, and decreased quality of life (Vellas et al., 1997). Thus, a benefit of vitamin D on both fall and fracture prevention is of significant clinical importance.
Risk factors for vitamin D deficiency and its prevalence
Most vulnerable to vitamin D deficiency are older adults (McKenna, 1992; Theiler et al., 1999), individuals living in northern latitudes with prolonged winters and thus low UVB exposure (Webb et al., 1988; Dawson-Hughes et al., 1997b), obese individuals (Parikh et al., 2004), and individuals of all ages with a dark skin tone (Looker et al., 2002; Bischoff-Ferrari et al., 2004d; Nesby-O’Dell et al., 2002). Other risk factors include medical conditions such as malabsorption and the use of antiepileptic drugs (Holick et al., 2011). The prevalence of vitamin D deficiency (serum levels below 20 ng/ml or 50 nmol/l) among children (Hintzpeter et al., 2008), and younger and older adults has been found to be about 50% in many countries around the world (van Schoor & Lips, 2011), with the highest prevalence (80%) in older men and women with hip fractures (Bischoff-Ferrari et al., 2008; LeBoff et al., 1999).
Naturally high 25-hydroxyvitamin D levels observed in healthy outdoor workers are 135 nmol/l (Haddock et al., 1982) in farmers and 163 nmol/l (Haddad & Chyu, 1971) in lifeguards. As a first sign of toxicity, only serum 25(OH)D levels of above 220 nmol/l have been associated with hypercalcaemia (Gertner & Domenech, 1977; Vieth, 1999).
Four lines of evidence that link vitamin D to muscle health
Vitamin D deficiency may cause muscular impairment even before adverse effects on bone occur (Glerup et al., 2000). Four lines of evidence support a role for vitamin D in muscle health in humans.
First, proximal muscle weakness is a prominent feature of the clinical syndrome of vitamin D deficiency (Al-Shoha et al., 2009). Clinical findings in vitamin D deficiency myopathy include proximal muscle weakness, diffuse muscle pain, and gait impairments such as a waddling way of walking (Schott & Wills, 1976).
Second, the vitamin D receptor (VDR) is expressed (Bischoff-Ferrari et al., 2009a) in human muscle tissue, as documented in all (Bischoff et al., 2001; Bischoff-Ferrari et al., 2004b; Simpson et al., 1985; Boland, 1986; Costa et al., 1986; Ceglia et al., 2010) but one investigation (Wang & DeLuca, 2011). Further, several studies among older individuals suggest that VDR activation in muscle promotes de novo protein synthesis preferentially in type II fast-twitch muscle fibres relevant for fall prevention (Sorensen et al., 1979; Freedman, 1999; Ceglia et al., 2013) (see next section, ‘Type II fast-twitch muscle fibres and vitamin D’). 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 (Bouillon et al., 2008; Endo et al., 2003). Third, several observational studies suggest a positive association between 25(OH)D and muscle strength or lower extremity function in older persons (Wicherts et al., 2007; Bischoff-Ferrari et al., 2004c). Fourth, vitamin D supplementation in vitamin D-deficient seniors increased muscle strength and balance (Bischoff et al., 2003; Pfeifer et al., 2008), and reduced the risk of falling in community-dwelling individuals (Pfeifer et al., 2008; Bischoff-Ferrari et al., 2006; Pfeifer et al., 2000), as well as in institutionalized individuals (Bischoff et al., 2003; Broe et al., 2007).
Type II fast-twitch muscle fibres and vitamin D
Type II muscle atrophy in profound vitamin D deficiency, and the observed increase of type II fast-twitch muscle fibres with vitamin D treatment from the three small trials among older adults (Sorensen et al., 1979; Sato et al., 2005; Ceglia et al., 2013) fit well with the findings that standard vitamin D supplementation (700–1000 IU per day) reduces the risk of falling by 34% in a meta-analysis of eight double-blind randomized controlled trials (Bischoff-Ferrari et al., 2011) (see section ‘Fall prevention with vitamin D supplementation’, next). Type II muscle fibres are fast-twitch fibres and therefore are the first to be recruited when fast reaction is needed, such as in the prevention of a fall. Notably, ageing itself has been associated with a decrease in type II fast-twitch relative to type I slow-twitch muscle fibres (Grimby & Saltin, 1983). Given the high prevalence of vitamin D deficiency in senior adults, it is possible that the age-related decline in type II muscle fibres is in part explained by vitamin D deficiency, which may be accompanied by a decrease in muscular VDR expression with age (Bischoff-Ferrari et al., 2004b).
At a clinical level, this is supported by findings of three small trials in older adults, which documented an increase in type II fast muscle fibres after treatment with 1-alpha-calcidiol (Sorensen et al., 1979), vitamin D2 (Sato et al., 2005), or vitamin D3 (Ceglia et al., 2013). Notably, a recent randomized controlled trial supports that VDR expression and type II fibre atrophy may be reversed with vitamin D supplementation in postmenopausal women (Ceglia et al., 2013). Also, muscle biopsy studies in humans suggest a potentially selective effect of vitamin D on type II muscle fibres. Patients with osteomalacic myopathy reveal type II muscle atrophy in muscle histology investigations (Yoshikawa et al., 1979).
Fall prevention with vitamin D supplementation
Consistent with the mechanistic evidence on how vitamin D is linked to muscle health, it is not surprising that most meta-analyses of clinical trials suggest a reduction in falls (Bischoff-Ferrari et al., 2004a; 2009a; Jackson et al., 2006; 2007; Kalyani et al., 2010; O’Donnell et al., 2008; Richy et al., 2008; Michael et al., 2011a; 2011b; Cameron et al., 2010) with vitamin D supplementation, although conclusions have varied by the selection of trials and quality of fall assessment (Bischoff-Ferrari et al., 2009a; IOM, 2011; Cameron et al., 2012; Gillespie et al., 2009). In two meta-analyses, low-dose vitamin D did not appear effective compared with a standard recommended dose of 800 IU/day, and data on higher doses are limited (Bischoff-Ferrari et al., 2004a; 2009a; 2011). Notably, one large bolus dose of vitamin D (500,000 IU vitamin D3 annually; see Sanders et al., 2010) increased the risk of falling in the three months following the bolus dose and larger monthly doses of 60'000 IU vitamin D3 or a combination with calcifediol therefore daily dosing of 800 IU or equivalent monthly doses of 24,000 IU are therefore preferred in clinical care (Bischoff-Ferrari HA et al., 2016).
Why one recent meta-analysis may have missed fall efficacy with vitamin D
In a recent comprehensive meta-analysis, Bolland and colleagues documented a neutral effect of vitamin D on fall prevention (Bolland et al., 2014a). The authors included 20 randomized controlled trials (n = 29,535) irrespective of blinding and quality of fall assessment. Many studies included by Bolland and colleagues applied a low dose vitamin D (Graafmans et al., 1996), had less than 50% adherence (Grant et al., 2005), had a low-quality fall assessment (Trivedi et al., 2003) or used one large bolus dose of vitamin D among seniors (Latham et al., 2003) provided as an annual intramuscular injection with limited impact on serum 25(OH)D levels (Smith et al., 2007). Therefore, the pooled effect assessed by the authors cannot be considered a reliable indicator of true treatment efficacy of vitamin D on falls.
As an alternative approach, treatment efficacy of vitamin D may need to be based on double-blinded randomized controlled trials with a high-quality prospective fall assessment.
This approach was chosen in another recent meta-analysis (Bischoff-Ferrari et al., 2009a; 2011), where the benefit of fall prevention was present in all subgroups of the senior population at the higher dose of vitamin D (700 to 1000 IU vitamin D per day). At this dose of vitamin D, there was a 38% reduction in the risk of falling with treatment duration of two to five months and a sustained significant effect of 17% fall reduction with treatment duration of 12 to 36 months. The benefit was independent of type of dwelling and age. There was a suggestion that vitamin D3 was superior to vitamin D2 for fall prevention. Although the number of studies for active vitamin D and fall prevention was small, the authors pooled these trials separately and found a significant benefit on fall prevention (-22%), which adds to the evidence that improved vitamin D status will reduce the risk of falling in older individuals.
Vitamin D and function and strength
In several trials of older adults at risk for vitamin D deficiency, vitamin D supplementation improved strength, function, gait speed, and balance (Bischoff et al., 2003; Pfeifer et al., 2000; 2008; Meyer et al., 2014). Most importantly, these benefits translated into a reduction in falls in some of the same trials (Bischoff et al., 2003; Pfeifer et al., 2000; 2008). In three recent double-blind randomized clinical trials (RCTs), supplementation with 800 IU vitamin D3 resulted in a 4–11% gain in lower extremity strength or function (Bischoff et al., 2003; Pfeifer et al., 2008), and an up to 28% improvement in body sway (Pfeifer et al., 2000; 2008) in older adults age 65+ within 2 to 12 months of treatment. Extending to individuals with better vitamin D status, a 2014 meta-analysis by Beaudart et al. included 30 randomized controlled trials (5615 individuals with mean age 61.1 years) and found a small but significant positive effect of vitamin D supplementation with or without calcium on global muscle strength with a standardized mean difference (SMD) of 0.17 (P = 0.02), while no significant effect was found on muscle mass and muscle power (Beaudart et al., 2014). Results on muscle strength were most pronounced in individuals with 25-hydroxyvitamin D level below 30 nmol/L and was more effective in seniors age 65 years or older compared to younger subjects (SMD 0.25; 95% CI 0.01–0.48 vs. SMD 0.03; 95% CI -0.08–0.14) (Beaudart et al., 2014).
Fracture prevention with vitamin D supplementation
Regarding the effect of vitamin D supplementation on fracture risk, data from several study-level meta-analyses and two pooled individual participant-level (IPD) analyses are conflicting. While one trial-level meta-analysis of RCTs suggested an 18% reduction of hip and 20% reduction of any non-vertebral fractures at a received dose of no less than 482 IU vitamin D per day (Bischoff-Ferrari et al., 2009b), three study-level meta-analyses (Cranney et al., 2007; Boonen et al., 2007; Avenell et al., 2009) and one pooled analysis of IPD (DIPART, 2010) from open design and blinded trials, suggested that vitamin D may have a neutral effect on total fractures (Cranney et al., 2007), or may reduce hip fractures by 7–16%, independent of its dose if combined with calcium supplementation (Cranney et al., 2007; Boonen et al., 2007; Avenell et al., 2009). Finally, in the most recent 2012 pooled IPD analysis of 31,022 primarily postmenopausal women enrolled in double-blind RCTs of vitamin D, only an actual intake of 792–2000 IU per day reduced the risk of fracture with no benefit at any lower dose (Bischoff-Ferrari et al., 2012). At the high-intake range (median 800 IU per day) hip fracture risk was reduced by 30% (Bischoff-Ferrari et al., 2012). The discordant findings may in part be explained by different inclusion criteria of trials with respect to blinding and intake form (oral, injectable), or different accommodations for adherence. A dose-response relationship between vitamin D and fracture reduction as documented in the 2009 meta-analyses of double-blind RCTs (Bischoff-Ferrari et al., 2009b) and the 2012 IPD pooled analysis (Bischoff-Ferrari et al., 2012) is supported by epidemiologic data showing a significant positive trend between serum 25(OH)D concentrations and hip bone density (Bischoff-Ferrari et al., 2004d) falls and lower extremity strength (Wicherts et al., 2007; Bischoff-Ferrari et al., 2004c).
Factors that may obscure a benefit of vitamin D on fracture prevention
Factors that may obscure a benefit of vitamin D on fall and fracture prevention are low adherence to treatment (Grant et al., 2005), low dose of vitamin D, or the use of less potent vitamin D2 (Armas et al., 2004; Houghton & Vieth, 2006). Furthermore, open design trials (Porthouse et al., 2005) may bias results towards the null, because participants who know that they have been randomized to the control group may purchase vitamin D themselves as it is available without prescription.
The inclusion of mixed quality studies may explain the recent findings and conclusion of the 2014 sequential meta-analysis by Bolland and colleagues (Bolland et al., 2014b; Bischoff-Ferrari et al., 2014) that vitamin D may not be effective in fall or fracture reduction. The authors included many studies that had little chance to demonstrate the true potential benefits of vitamin D. In particular, their analysis was based on a great mix of trials with blinded and open designs, follow-up periods that were often too short, administered doses that ranged widely, compliance that ranged widely, and endpoints that ranged from primary to secondary to unprespecified, and consequently were adjudicated and non-adjudicated. The authors also chose to carry out their sequential meta-analysis with the goal of detecting a 15% effect threshold for most outcomes and 5% for mortality. One must question this approach, as even small effects carry an enormous benefit if an inexpensive intervention such as vitamin D is implemented broadly. In fact, for vitamin D plus calcium, the authors themselves document a significant 8% reduction for total and a significant 16% reduction for hip fractures. Further, the authors document a significant 4% reduction in overall mortality with vitamin D alone or in combination with calcium, which is particularly notable in the context of the limitations of the studies included. A fair question of a clinician may be, based on the assessment of Bolland et al. including trials of any quality: ‘Do I really stop supplementation with vitamin D when it has a significant reduction of hip fracture by 16% (in conjunction with calcium) and mortality of 4% but not 5%?’ Notably, on a public health level, a 4% reduction of mortality generates an enormous population benefit.
Recent guidelines on vitamin D and fracture prevention
Vitamin D supplementation in a dose of 800 IU per day as a primary prevention strategy in maintaining bone health and reducing fracture risk in the senior population is in line with Institute of Medicine (IOM, 2011), the 2010 American Geriatrics Society/British Geriatrics Society Clinical Practice Guideline (AGS/BGS, 2011), the 2010 assessment by the International Osteoporosis Foundation (IOF) (Dawson-Hughes et al., 2010), and the 2011 Endocrine Society Recommendations.
Vitamin D effect on fall prevention may modulate hip fracture prevention
Falls are the primary risk factor for hip fractures in seniors (Cummings & Nevitt, 1994) and vitamin D deficiency may cause muscular impairment even before adverse effects on bone occur (Glerup et al., 2000). Thus, the beneficial effect of vitamin D on calcium absorption and small benefit on bone mineral density (Bischoff-Ferrari et al., 2004d; Reid et al., 2014) may not be the only explanation for its protective effect against hip fractures (Bischoff-Ferrari et al., 2009b; 2012). Most likely the early (within two to five months) (Bischoff et al., 2003; Broe et al., 2007) and sustained (Bischoff-Ferrari et al., 2006; Flicker et al., 2005; Prince et al., 2006; Pfeifer et al., 2009) effect of vitamin D on falls (Bischoff-Ferrari et al., 2009a) may explain a large part of hip fracture prevention with vitamin D. Notably, the early effect of vitamin D supplementation on fall prevention (Bischoff-Ferrari et al., 2009a) may explain a fracture reduction that was apparent within six months of treatment in the Boston STOP-IT (Dawson-Hughes et al., 1997a) and the Decalyos I studies (Chapuy et al., 1992). Finally, antifracture efficacy of pharmacological therapy for bone health alone is insufficient in seniors with non-skeletal risk factors for fractures (McClung et al., 2001; Bischoff-Ferrari & Meyer, 2014). Thus, vitamin D is an integral partner also in the treatment of seniors with osteoporosis.
Optimal 25-hydroxyvitamin D level for fracture prevention in seniors
A threshold for optimal serum 25-hydroxyvitamin D concentration and fracture prevention has been addressed in a recent benefit-risk analysis (Bischoff-Ferrari et al., 2010). Based on data from RCTs and their achieved 25-hydroxyvitamin D levels in the treatment group, 75 nmol/l (30 ng/ml) is suggested as the best point estimate for an optimal threshold of 25-hydroxyvitamin D for fracture prevention. This threshold is further supported by epidemiologic data for hip bone density in younger and older adults (Bischoff-Ferrari et al., 2004d), as well as a large bone biopsy study where with serum levels of at least 75 nmol/l, mineralization defects were absent (Priemel et al., 2011). Also, the most recent pooled IPD analysis of double-blind RCTs found that among over 4000 primarily postmenopausal women, fracture risk declined significantly with higher baseline 25-hydroxyvitamin D levels (Bischoff-Ferrari et al., 2012). Comparing individuals with starting levels of less than 30 nmol/l to those with starting levels of 61 nmol/l and above, the latter had a 37% lower risk of hip fracture and a 31% lower risk of any non-vertebral fracture (Bischoff-Ferrari et al., 2012).
Current guidelines put into practice
All current guidelines agree that vitamin D deficiency should be corrected for better bone health at all ages. Current intake recommendations of 600 IU vitamin D per day in children and adults up to age 60 and 800 IU vitamin D per day in seniors will shift over 97% of the population to at least 50 nmol/l (20 ng/ml) and about 50% to 75 nmol/l (IOM, 2011; Bischoff-Ferrari et al., 2010) (30 ng/ml). All guidelines agree that a 25-hydroxyvitamin D test prior to supplementation is only needed in individuals at high risk for severe vitamin D deficiency (i.e. individuals with osteoporosis, low-trauma fractures, low-trauma falls, obesity, malabsorption).
The 25(OH)D threshold of at least 75 nmol/l (30 ng/ml) for optimal fracture prevention is supported by the 2010 IOF position statement on vitamin D (Dawson-Hughes et al., 2010) and the 2011 US Endocrine Society Task Force on Vitamin D (Holick et al., 2011). In contrast, the 2010 Institute of Medicine recommendations suggest that 50 nmol/l (20 ng/ml) may be sufficient for bone health in the population.
Notably, half-live of 25-hydroxyvitamin D is three to six weeks, thus daily (800 IU), weekly (5600 IU), and monthly (24,000 IU) dose intervals reach similar 25-hydroxyvitamin D thresholds (Ish-Shalom et al., 2008). Large bolus (Sanders et al., 2010; Smith et al., 2007) applications beyond 100,000 IU every four months are not recommended based on the current literature (Trivedi et al., 2003). Among seniors with a prior fall, monthly bolus doses of 24,000 IU are safe and effective, while bolus doses of monthly 60,000 IU vitamin D3 or a combination with monthly calcifediol may increase the risk of falling (Bischoff-Ferrari, HA et al.; JAMA Internal Medicine, 2016).
Are there general health benefits of vitamin D?
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 (Bouillon et al., 2008) including mineralization defects in bone, small and variable muscle fibres, impaired insulin secretion, and hypertension.
At the human level, data from large cohort studies suggest that low vitamin D status increases the risk of colon (Feskanich et al., 2004) and possibly other cancers (Giovannucci et al., 2006), increases the risk of hypertension (Forman et al., 2007), myocardial infarction (Giovannucci et al., 2008), cardiovascular (Dobnig et al., 2008) and overall mortality (Autier & Gandini, 2007), infections (Liu et al., 2006) and diabetes (Chiu et al., 2004). However, data from large clinical trials with a sufficiently high dose of vitamin D are lacking. Two ongoing trials (VITAL in the US and DO-HEALTH in Europe) have been designed to clarify the role of vitamin D supplementation in improving multiple endpoints of health and will provide important opportunities to verify such benefits.
Vitamin D supplementation and mortality risk
25-hydroxyvitamin D levels have been associated with mortality in several epidemiologic studies (Dobnig et al., 2008; Visser et al., 2006; Ginde et al., 2009; Melamed et al., 2008; Zittermann et al., 2009), most of which suggested a continuous inverse relationship between increasing values of 25-hydroxyvitamin D and a lower risk of mortality. In two studies, however, a U-shaped relationship has been described with an increased risk of mortality both at low and higher levels of 25(OH)D (Melamed et al., 2008; Michaelsson et al., 2010). Furthermore, one trial-level meta-analysis of 18 randomized trials suggested a significant 7% reduction of mortality with vitamin D supplementation irrespective of dose (daily doses of vitamin D supplements varied from 300 to 2000 IU) (Autier & Gandini, 2007). This was confirmed in a recent sequential meta-analysis including any quality clinical trial suggesting that vitamin D reduces mortality risk significantly by 4% (Bolland et al., 2014b). Clearly, such a benefit is of public health importance but needs confirmation in a large clinical trial.
Based on evidence from double-blind randomized controlled trials, vitamin D supplementation reduces both falls and non-vertebral fractures, including those at the hip. Current guidelines therefore support supplementation with 800 IU vitamin D per day among seniors age 60 years and older. This supplementation dose will replete vitamin D deficiency in over 97% of seniors and can be implemented without prior testing of blood levels. Additional health benefits of vitamin D have been proposed in observational studies and need confirmation in a large clinical trial (Fig. 61.1).
AGS/BGS (2011). AGS/BGS Guidelines on Fall Prevention in older Persons. Available at: http://www.medcats.com/FALLS/frameset.htm (accessed 25 Februay 2017) [Online].
Al-Shoha, A., Qiu, S., Palnitkar, S., & Rao, D. S. (2009). Osteomalacia with bone marrow fibrosis due to severe vitamin D deficiency after a gastrointestinal bypass operation for severe obesity. Endocr Pract, 15, 528–33.Find this resource:
Autier, P. & Gandini, S. (2007). Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med, 167, 1730–7.Find this resource:
Avenell, A., Gillespie, W. J., Gillespie, L. D., & O’Connell, D. (2009). Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis. Cochrane Database Syst Rev, (3), CD000227.Find this resource:
Beaudart, C., Buckinx, F., Rabenda, V., et al. (2014). The effects of vitamin d on skeletal muscle strength, muscle mass, and muscle power: a systematic review and meta-analysis of randomized controlled trials. J Clin Endocrinol Metab, 99, 4336–45.Find this resource:
Bischoff, H. A., Borchers, M., Gudat, F., et al. (2001). In situ detection of 1,25-dihydroxyvitamin D3 receptor in human skeletal muscle tissue. Histochem J, 33, 19–24.Find this resource:
Bischoff, H. A., Stahelin, H. B., Dick, W., et al. (2003). Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial. J Bone Miner Res, 18, 343–51.Find this resource:
Bischoff-Ferrari, H. A., Dawson-Hughes, B., Willett, W. C., et al. (2004a). Effect of Vitamin D on falls: a meta-analysis. JAMA, 291, 1999–2006.Find this resource:
Bischoff-Ferrari, H. A., Borchers, M., Gudat, F., Durmuller, U., Stahelin, H. B., & Dick, W. (2004b). Vitamin D receptor expression in human muscle tissue decreases with age. J Bone Miner Res, 19, 265–9.Find this resource:
Bischoff-Ferrari, H. A., Dietrich, T., Orav, E. J., et al. (2004c). Higher 25-hydroxyvitamin D concentrations are associated with better lower-extremity function in both active and inactive persons aged >=60 y. Am J Clin Nutr, 80, 752–8.Find this resource:
Bischoff-Ferrari, H. A., Dietrich, T., Orav, E. J., & Dawson-Hughes, B. (2004d). Positive association between 25-hydroxy vitamin D levels and bone mineral density: a population-based study of younger and older adults. Am J Med, 116, 634–9.Find this resource:
Bischoff-Ferrari, H. A., Orav, E. J., & Dawson-Hughes, B. (2006). Effect of cholecalciferol plus calcium on falling in ambulatory older men and women: a 3-year randomized controlled trial. Arch Intern Med, 166, 424–30.Find this resource:
Bischoff-Ferrari, H. A., Can, U., Staehelin, H. B., et al. (2008). Severe vitamin D deficiency in Swiss hip fracture patients. Bone, 42, 597–602.Find this resource:
Bischoff-Ferrari, H. A., Dawson-Hughes, B., Staehelin, H. B., et al. (2009a). Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ, 339, b3692.Find this resource:
Bischoff-Ferrari, H. A., Willett, W. C., Wong, J. B., et al. (2009b). Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Arch Intern Med, 169, 551–61.Find this resource:
Bischoff-Ferrari, H. A., Shao, A., Dawson-Hughes, B., Hathcock, J., Giovannucci, E., & Willett, W. C. (2010). Benefit-risk assessment of vitamin D supplementation. Osteoporos Int, 21, 1121–32.Find this resource:
Bischoff-Ferrari, H. A., Willett, W. C., Orav, E. J., Kiel, D. P., & Dawson-Hughes, B. (2011). Re: Fall prevention with Vitamin D. Clarifications needed. Available at: http://www.bmj.com/rapid-response/2011/11/03/rerefall-prevention-vitamin-d-clarifications-needed (accessed 13 February 2012) [Online].
Bischoff-Ferrari, H. A., Orav, E. J., Willett, W. C., et al. (2012). A pooled analysis of vitamin D dose requirements for fracture prevention. N Engl J Med, 367, 40–9.Find this resource:
Bischoff-Ferrari, H. A., Orav, E. J., Willett, W. C., & Dawson-Hughes, B. (2014). The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes. Lancet Diabetes Endocrinol, 2, 63–4.Find this resource:
Bischoff-Ferrari, H. A. & Meyer, O. (2014). Comparative effectiveness of pharmacologic treatments to prevent fractures: is this all we need to know? Ann Intern Med, 161, 755–6.Find this resource:
Boland, R. (1986). Role of vitamin D in skeletal muscle function. Endocr Rev, 7, 434–48.Find this resource:
Bolland, M. J., Grey, A., Gamble, G. D., & Reid, I. R. (2014a). Vitamin D supplementation and falls: a trial sequential meta-analysis. Lancet Diabetes Endocrinol, 2, 573–80.Find this resource:
Bolland, M. J., Grey, A., Gamble, G. D., & Reid, I. R. (2014b). The effect of vitamin D on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes Endocrinol, 2, 307–20.Find this resource:
Boonen, S., Lips, P., Bouillon, R., Bischoff-Ferrari, H. A., Vanderschueren, D., & Haentjens, P. (2007). Need for additional calcium to reduce the risk of hip fracture with vitamin D supplementation: evidence from a comparative metaanalysis of randomized controlled trials. J Clin Endocrinol Metab, 92, 1415–23.Find this resource:
Bouillon, R., Bischoff-Ferrari, H., & Willett, W. (2008). Vitamin D and health: perspectives from mice and man. J Bone Miner Res, 23, 974–9.Find this resource:
Broe, K. E., Chen, T. C., Weinberg, J., Bischoff-Ferrari, H. A., Holick, M. F., & Kiel, D. P. (2007). A higher dose of vitamin d reduces the risk of falls in nursing home residents: a randomized, multiple-dose study. J Am Geriatr Soc, 55, 234–9.Find this resource:
Cameron, I. D., Gillespie, L. D., Robertson, M. C., et al. (2012). Interventions for preventing falls in older people in care facilities and hospitals. Cochrane Database Syst Rev, 12, CD005465.Find this resource:
Cameron, I. D., Murray, G. R., Gillespie, L. D., et al. (2010). Interventions for preventing falls in older people in nursing care facilities and hospitals. Cochrane Database Syst Rev, (1), CD005465.Find this resource:
Ceglia, L., da Silva Morais, M., Park, L. K., et al. (2010). Multi-step immunofluorescent analysis of vitamin D receptor loci and myosin heavy chain isoforms in human skeletal muscle. J Mol Histol, 41, 137–42.Find this resource:
Ceglia, L., Niramitmahapanya, S., da Silva Morais, M., et al. (2013). A randomized study on the effect of vitamin D3 supplementation on skeletal muscle morphology and vitamin D receptor concentration in older women. J Clin Endocrinol Metab, 98, E1927–35.Find this resource:
Chapuy, M. C., Arlot, M. E., Duboeuf, F., et al. (1992). Vitamin D3 and calcium to prevent hip fractures in the elderly women. N Engl J Med, 327, 1637–42.Find this resource:
Chiu, K. C., Chu, A., Go, V. L., & Saad, M. F. (2004). Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr, 79, 820–5.Find this resource:
Costa, E. M., Blau, H. M., & Feldman, D. (1986). 1,25-dihydroxyvitamin D3 receptors and hormonal responses in cloned human skeletal muscle cells. Endocrinology, 119, 2214–20.Find this resource:
Cranney, A., Horsley, T., O’Donnell, S., et al. (2007). Effectiveness and safety of vitamin D in relation to bone health. Evid Rep Technol Assess (Full Rep), (158), 1–235.Find this resource:
Cummings, S. R. & Nevitt, M. C. (1994). Non-skeletal determinants of fractures: the potential importance of the mechanics of falls. Study of Osteoporotic Fractures Research Group. Osteoporos Int, 4(Suppl 1), 67–70.Find this resource:
Dawson-Hughes, B., Harris, S. S., Krall, E. A., & Dallal, G. E. (1997a). Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med, 337, 670–6.Find this resource:
Dawson-Hughes, B., Harris, S. S., & Dallal, G. E. (1997b). Plasma calcidiol, season, and serum parathyroid hormone concentrations in healthy elderly men and women. Am J Clin Nutr, 65, 67–71.Find this resource:
Dawson-Hughes, B., Mithal, A., Bonjour, J. P., et al. (2010). IOF position statement: vitamin D recommendations for older adults. Osteoporos Int, 21, 1151–4.Find this resource:
DIPART (2010). Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe. BMJ, 340, b5463.Find this resource:
Dobnig, H., Pilz, S., Scharnagl, H., et al. (2008). Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality. Arch Intern Med, 168, 1340–9.Find this resource:
Endo, I., Inoue, D., Mitsui, T., et al. (2003). Deletion of vitamin D receptor gene in mice results in abnormal skeletal muscle development with deregulated expression of myoregulatory transcription factors. Endocrinology, 144, 5138–44.Find this resource:
Flicker, L., MacInnis, R. J., Stein, M. S., et al. (2005). Should all older people in residential care receive vitamin D to prevent falls? Results of a randomized trial. J Am Geriatr Soc, 53, 1881–8.Find this resource:
Forman, J. P., Giovannucci, E., Holmes, M. D., et al. (2007). Plasma 25-Hydroxyvitamin D Levels and Risk of Incident Hypertension. Hypertension, 19, 19.Find this resource:
Freedman, L. P. (1999). Transcriptional targets of the vitamin D3 receptor-mediating cell cycle arrest and differentiation. J Nutr, 129, 581S–6S.Find this resource:
Gertner, J. M., & Domenech, M. (1977). 25-Hydroxyvitamin D levels in patients treated with high-dosage ergo- and cholecalciferol. J Clin Pathol, 30, 144–50.Find this resource:
Gillespie, L. D., Robertson, M. C., Gillespie, W. J., et al. (2009). Interventions for preventing falls in older people living in the community. Cochrane Database Syst Rev, (2), CD007146.Find this resource:
Ginde, A. A., Scragg, R., Schwartz, R. S., & Camargo, C. A., Jr. (2009). Prospective study of serum 25-hydroxyvitamin d level, cardiovascular disease mortality, and all-cause mortality in older U.S. Adults. J Am Geriatr Soc, 57, 1595–603.Find this resource:
Giovannucci, E., Liu, Y., & Willett, W. C. (2006). Cancer incidence and mortality and vitamin D in black and white male health professionals. Cancer Epidemiol Biomarkers Prev, 15, 2467–72.Find this resource:
Giovannucci, E., Liu, Y., Hollis, B. W., & Rimm, E. B. (2008). 25-hydroxyvitamin D and risk of myocardial infarction in men: a prospective study. Arch Intern Med, 168, 1174–80.Find this resource:
Glerup, H., Mikkelsen, K., Poulsen, L., et al. (2000). Hypovitaminosis D myopathy without biochemical signs of osteomalacic bone involvement. Calcif Tissue Int, 66, 419–24.Find this resource:
Graafmans, W. C., Ooms, M. E., Hofstee, H. M., Bezemer, P. D., Bouter, L. M., & Lips, P. (1996). Falls in the elderly: a prospective study of risk factors and risk profiles. Am J Epidemiol, 143, 1129–36.Find this resource:
Grant, A. M., Avenell, A., Campbell, M. K., et al. (2005). Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet, 365, 1621–8.Find this resource:
Grimby, G. & Saltin, B. (1983). The ageing muscle. Clin Physiol, 3, :209–18.Find this resource:
Haddad, J. G. & Chyu, K. J. (1971). Competitive protein-binding radioassay for 25-hydroxycholecalciferol. J Clin Endocrinol Metab, 33, 992–5.Find this resource:
Haddock, L., Corcino, J., & Vazquez, M. D. (1982). 25(OH)D serum levels in the normal Puerto Rican population and in subjects with tropical sprue and paratyroid disease. Puerto Rico Health Sci J, 1, 85–91.Find this resource:
Hintzpeter, B., Scheidt-Nave, C., Muller, M. J., Schenk, L., & Mensink, G. B. (2008). Higher prevalence of vitamin D deficiency is associated with immigrant background among children and adolescents in Germany. J Nutr, 138, 1482–90.Find this resource:
Holick, M. F., Binkley, N. C., Bischoff-Ferrari, H. A., et al. (2011). Evaluation, treatment, and prevention of vitamin d deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab, 96, 1911–30.Find this resource:
Houghton, L. A. & Vieth, R. (2006). The case against ergocalciferol (vitamin D2) as a vitamin supplement. Am J Clin Nutr, 84, 694–7.Find this resource:
Institute of Medicine (IOM) (2011). Dietary Reference Ranges for Calcium and Vitamin D. Washington, DC: National Academies Press.Find this resource:
Ish-Shalom, S., Segal, E., Salganik, T., Raz, B., Bromberg, I. L., & Vieth, R. (2008). Comparison of daily, weekly, and monthly vitamin D3 in ethanol dosing protocols for two months in elderly hip fracture patients. J Clin Endocrinol Metab, 93, 3430–5.Find this resource:
Jackson, C., Gaugris, S., Sen, S. S., & Hosking, D. (2007). The effect of cholecalciferol (vitamin D3) on the risk of fall and fracture: a meta-analysis. QJM, 100, 185–92.Find this resource:
Jackson, R. D., LaCroix, A. Z., Gass, M., et al. (2006). Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med, 354, 669–83.Find this resource:
Kalyani, R. R., Stein, B., Valiyil, R., Manno, R., Maynard, J. W., & Crews, D. C. (2010). Vitamin D treatment for the prevention of falls in older adults: systematic review and meta-analysis. J Am Geriatr Soc, 58, 1299–310.Find this resource:
Latham, N. K., Anderson, C. S., Lee, A., Bennett, D. A., Moseley, A., & Cameron, I. D. (2003). A randomized, controlled trial of quadriceps resistance exercise and vitamin D in frail older people: the Frailty Interventions Trial in Elderly Subjects (FITNESS). J Am Geriatr Soc, 51, 291–9.Find this resource:
LeBoff, M. S., Kohlmeier, L., Hurwitz, S., Franklin, J., Wright, J., & Glowacki, J. (1999). Occult vitamin D deficiency in postmenopausal US women with acute hip fracture. JAMA, 281, 1505–11.Find this resource:
Liu, P. T., Stenger, S., Li, H., et al. (2006). Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science, 23, 23.Find this resource:
Looker, A. C., Dawson-Hughes, B., Calvo, M. S., Gunter, E. W., & Sahyoun, N. R. (2002). Serum 25-hydroxyvitamin D status of adolescents and adults in two seasonal subpopulations from NHANES III. Bone, 30, 771–7.Find this resource:
McClung, M. R., Geusens, P., Miller, P. D., et al. (2001). Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med, 344, 333–40.Find this resource:
McKenna, M. J. (1992). Differences in vitamin D status between countries in young adults and the elderly. Am J Med, 93, 69–77.Find this resource:
Melamed, M. L., Michos, E. D., Post, W., & Astor, B. (2008). 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med, 168, 1629–37.Find this resource:
Meyer, O., Dawson-Hughes, B., Sidelnikov, E., et al. (2014). Calcifediol versus vitamin D effects on gait speed and trunk sway in young postmenopausal women: a double-blind randomized controlled trial. Osteoporos Int, 26, 373–81.Find this resource:
Michael, Y. L., Lin, J. S., Whitlock, E. P., et al. (2011a). Interventions to prevent falls in older adults: an updated systematic review. US Preventive Services Task Force Evidence Syntheses, formerly Systematic Evidence Reviews, Report No.: 11-05150-EF-1.Find this resource:
Michael, Y. L., Whitlock, E. P., Lin, J. S., Fu, R., O’Connor, E. A., & Gold, R. (2011b). Primary care-relevant interventions to prevent falling in older adults: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med, 153, 815–25.Find this resource:
Michaelsson, K., Baron, J. A., Snellman, G., et al. (2010). Plasma vitamin D and mortality in older men: a community-based prospective cohort study. Am J Clin Nutr, 92, 841–8.Find this resource:
Nesby-O’Dell, S., Scanlon, K. S., Cogswell, M. E., et al. (2002). Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988–1994. Am J Clin Nutr, 76, 187–92.Find this resource:
Nevitt, M. C., Cummings, S. R. (1993). Type of fall and risk of hip and wrist fractures: the study of osteoporotic fractures. The Study of Osteoporotic Fractures Research Group. J Am Geriatr Soc, 41, 1226–34.Find this resource:
Nguyen, N. D., Frost, S. A., Center, J. R., Eisman, J. A., & Nguyen, T. V. (2007). Development of a nomogram for individualizing hip fracture risk in men and women. Osteoporos Int, 17, 17.Find this resource:
O’Donnell, S., Moher, D., Thomas, K., Hanley, D. A., & Cranney, A. (2008). Systematic review of the benefits and harms of calcitriol and alfacalcidol for fractures and falls. J Bone Miner Metab, 26, 531–42.Find this resource:
Parikh, S. J., Edelman, M., Uwaifo, G. I., et al. (2004). The relationship between obesity and serum 1,25-dihydroxy vitamin D concentrations in healthy adults. J Clin Endocrinol Metab, 89, 1196–9.Find this resource:
Pfeifer, M., Begerow, B., Minne, H. W., Abrams, C., Nachtigall, D., & Hansen, C. (2000). Effects of a short-term vitamin D and calcium supplementation on body sway and secondary hyperparathyroidism in elderly women. J Bone Miner Res, 15, 1113–8.Find this resource:
Pfeifer, M., Begerow, B., Minne, H. W., Suppan, K., Fahrleitner-Pammer, A., & Dobnig H. (2008). Effects of a long-term vitamin D and calcium supplementation on falls and parameters of muscle function in community-dwelling older individuals. Osteoporos Int, 16, 16.Find this resource:
Pfeifer, M., Begerow, B., Minne, H. W., Suppan, K., Fahrleitner-Pammer, A., & Dobnig, H. (2009). Effects of a long-term vitamin D and calcium supplementation on falls and parameters of muscle function in community-dwelling older individuals. Osteoporos Int, 20, 315–22.Find this resource:
Porthouse, J., Cockayne, S., King, C., et al. (2005). Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care. BMJ, 330, 1003.Find this resource:
Priemel, M., von Domarus, C., Klatte, T. O., et al. (2011). Bone mineralization defects and vitamin D deficiency: histomorphometric analysis of iliac crest bone biopsies and circulating 25-hydroxyvitamin D in 675 patients. J Bone Miner Res, 25, 305–12.Find this resource:
Prince, R. L., Devine, A., Dhaliwal, S. S., & Dick, I. M. (2006). Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women. Arch Intern Med, 166, 869–75.Find this resource:
Reid, I. R., Bolland, M. J., & Grey, A. (2014). Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis. Lancet, 383, 146–55.Find this resource:
Richy, F., Dukas, L., & Schacht, E. (2008). Differential effects of D-hormone analogs and native vitamin D on the risk of falls: a comparative meta-analysis. Calcif Tissue Int, 82, 102–7.Find this resource:
Sanders, K. M., Stuart, A. L., Williamson, E. J., et al. (2010). Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA, 303, 1815–22.Find this resource:
Sato, Y., Iwamoto, J., Kanoko, T., & Satoh, K. (2005). Low-dose vitamin D prevents muscular atrophy and reduces falls and hip fractures in women after stroke: a randomized controlled trial. Cerebrovasc Dis, 20, 187–92.Find this resource:
Schott, G. D. & Wills, M. R. (1976). Muscle weakness in osteomalacia. Lancet, 1, 626–9.Find this resource:
Simpson, R. U., Thomas, G. A., & Arnold, A. J. (1985). Identification of 1,25-dihydroxyvitamin D3 receptors and activities in muscle. J Biol Chem, 260, 8882–91.Find this resource:
Smith, H., Anderson, F., Raphael, H., Maslin, P., Crozier, S., & Cooper, C. (2007). Effect of annual intramuscular vitamin D on fracture risk in elderly men and women--a population-based, randomized, double-blind, placebo-controlled trial. Rheumatology (Oxford), 46, 1852–7.Find this resource:
Sorensen, O. H., Lund, B., Saltin, B., et al. (1979). Myopathy in bone loss of ageing: improvement by treatment with 1 alpha-hydroxycholecalciferol and calcium. Clin Sci (Lond), 56, 157–61.Find this resource:
Theiler, R., Stahelin, H. B., Tyndall, A., Binder, K., Somorjai, G., & Bischoff, H. A. (1999). Calcidiol, calcitriol and parathyroid hormone serum concentrations in institutionalized and ambulatory elderly in Switzerland. Int J Vitam Nutr Res, 69, 96–105.Find this resource:
Tinetti, M. E. (1988). Risk factors for falls among elderly persons living in the community. N Engl J Med, 319, 1701–7.Find this resource:
Trivedi, D. P., Doll, R., & Khaw, K. T. (2003). Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ, 326, 469.Find this resource:
van Schoor, N. M. & Lips, P. (2011). Worldwide vitamin D status. Best Pract Res Clin Endocrinol Metab, 25, 671–80.Find this resource:
Vellas, B. J., Wayne, S. J., Romero, L. J., Baumgartner, R. N., & Garry, P. J. (1997). Fear of falling and restriction of mobility in elderly fallers. Age Ageing, 26, 189–93.Find this resource:
Vieth, R. (1999). Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr, 69, 842–56.Find this resource:
Visser, M., Deeg, D. J., Puts, M. T., Seidell, J. C., Lips, P. (2006). Low serum concentrations of 25-hydroxyvitamin D in older persons and the risk of nursing home admission. Am J Clin Nutr, 84, 616–22; quiz 71–2.Find this resource:
Wang, Y. & DeLuca, H. F. (2011). Is the vitamin d receptor found in muscle? Endocrinology, 152, 354–63.Find this resource:
Webb, A. R., Kline, L., & Holick, M. F. (1988). Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. J Clin Endocrinol Metab, 67, 373–8.Find this resource:
Wicherts, I. S., van Schoor, N. M., Boeke, A. J., et al. (2007). Vitamin D status predicts physical performance and its decline in older persons. J Clin Endocrinol Metab, 6, 6.Find this resource:
Yoshikawa, S., Nakamura, T., Tanabe, H., & Imamura, T. (1979). Osteomalacic myopathy. Endocrinol Jpn, 26, 65–72.Find this resource: