Going beyond bone

Antiresorptive treatment alone may not reduce fractures among individuals 80 years and older in the presence of nonskeletal risk factors for fractures despite an improvement in bone metabolism. This is explained by a close relationship between fracture risk and muscle weakness and falling at an older age, and falls being the primary risk factor for hip fractures. Moreover, falling may affect bone density through increased immobility from self-restriction of activities. After their first fall, about 30% of persons develop a fear of falling resulting in self-restriction of activities and decreased quality of life. Based on new evidence, vitamin D reduces nonvertebral fractures, including those at the hip, irrespective of prevalent nonskeletal risk factors and offers an inexpensive and comprehensive primary fracture prevention strategy at higher age. Nonvertebral fracture prevention by vitamin D may be largely modulated by its effect on muscle strength and fall prevention. Thus, if antiresorptive treatment is initiated at an older age, it should be partnered with vitamin D in a dose of at least 700–1000 IU per day for fall prevention.

Vitamin D: its role in muscle health

In humans, 4 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. Vitamin D deficiency myopathy includes proximal muscle weakness, diffuse muscle pain, and gait impairments such as a waddling way of walking. Second, vitamin D receptor (VDR) is expressed in human muscle tissue, and VDR activation may promote de novo protein synthesis in muscle. Mice lacking VDR show a skeletal muscle phenotype with smaller and variable muscle fibers and persistence of immature muscle gene expression during adult life, which suggests a role of vitamin D in muscle development. These abnormalities persist after correction of systemic calcium metabolism by a rescue diet. Third, several observational studies suggest a positive association between 25-hydroxyvitamin D and muscle strength or lower extremity function in older persons. Four, in several double-blind RCTs, vitamin D supplementation increased muscle strength and balance, and reduced the risk of falling in community-dwelling individuals, as well as in institutionalized individuals. A study by Glerup and colleagues suggested that vitamin D deficiency may cause muscular impairment even before adverse effects on bone occur.

A dose-response relationship between vitamin D status and muscle health was examined in NHANES III (The Third National Health and Nutrition Examination Survey), which included 4100 ambulatory adults aged 60 years and older. Muscle function measured as the 8-ft walk test and the repeated sit-to-stand test was poorest in subjects with the lowest level of 25-hydroxyvitamin D (<20 nmol/L). Similar results were found in a Dutch cohort of older individuals. A threshold of 50 nmol/L has been suggested for optimal function from the smaller Dutch cohort. 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). 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 3 recent double-blind RCTs with 800 IU vitamin D ₃ resulting in a 4% to 11% gain in lower extremity strength or function, and up to 28% improvement in body sway in older adults aged 65+ years, within 2 to 12 months of treatment.

A dose-dependent benefit of vitamin D with regard to fall prevention was suggested by a 2004 meta-analysis and a recent multidose double-blind RCT among 124 nursing home residents receiving 200, 400, 600, or 800 IU vitamin D compared with placebo for a 5-month period. 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 [CI] 0.11–0.75). Including this trial, a most recent meta-analysis of 8 high-quality double-blind RCTs (n = 2426) found significant heterogeneity by dose (low dose <700 IU/d vs higher dose 700–1000 IU/d; P = .02) and achieved 25-hydroxyvitamin D level (<60 nmol/L vs ≥60 nmol/L; P = .005). Higher-dose supplemental vitamin D between 700 and 1000 IU per day reduced fall risk by 19% (pooled relative risk (RR) 0.81; 95% CI 0.71–0.92; n = 1921 from 7 trials) versus a lower dose that did not (pooled RR = 1.10, 95% CI 0.89–1.35 from 2 trials). 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). At the higher dose, this meta-analysis documented a 38% significant 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. Thus, the benefits of vitamin D on fall prevention are rapid and sustained provided a high enough dose is given. Subgroup analyses for the prevention of falls at a dose of 700 to 1000 IU per day suggested a benefit in all subgroups of the older population, and possibly better fall reduction with D ₃ compared with D ₂ .

Vitamin D: its role in muscle health

In humans, 4 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. Vitamin D deficiency myopathy includes proximal muscle weakness, diffuse muscle pain, and gait impairments such as a waddling way of walking. Second, vitamin D receptor (VDR) is expressed in human muscle tissue, and VDR activation may promote de novo protein synthesis in muscle. Mice lacking VDR show a skeletal muscle phenotype with smaller and variable muscle fibers and persistence of immature muscle gene expression during adult life, which suggests a role of vitamin D in muscle development. These abnormalities persist after correction of systemic calcium metabolism by a rescue diet. Third, several observational studies suggest a positive association between 25-hydroxyvitamin D and muscle strength or lower extremity function in older persons. Four, in several double-blind RCTs, vitamin D supplementation increased muscle strength and balance, and reduced the risk of falling in community-dwelling individuals, as well as in institutionalized individuals. A study by Glerup and colleagues suggested that vitamin D deficiency may cause muscular impairment even before adverse effects on bone occur.

A dose-response relationship between vitamin D status and muscle health was examined in NHANES III (The Third National Health and Nutrition Examination Survey), which included 4100 ambulatory adults aged 60 years and older. Muscle function measured as the 8-ft walk test and the repeated sit-to-stand test was poorest in subjects with the lowest level of 25-hydroxyvitamin D (<20 nmol/L). Similar results were found in a Dutch cohort of older individuals. A threshold of 50 nmol/L has been suggested for optimal function from the smaller Dutch cohort. 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). 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 3 recent double-blind RCTs with 800 IU vitamin D ₃ resulting in a 4% to 11% gain in lower extremity strength or function, and up to 28% improvement in body sway in older adults aged 65+ years, within 2 to 12 months of treatment.

A dose-dependent benefit of vitamin D with regard to fall prevention was suggested by a 2004 meta-analysis and a recent multidose double-blind RCT among 124 nursing home residents receiving 200, 400, 600, or 800 IU vitamin D compared with placebo for a 5-month period. 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 [CI] 0.11–0.75). Including this trial, a most recent meta-analysis of 8 high-quality double-blind RCTs (n = 2426) found significant heterogeneity by dose (low dose <700 IU/d vs higher dose 700–1000 IU/d; P = .02) and achieved 25-hydroxyvitamin D level (<60 nmol/L vs ≥60 nmol/L; P = .005). Higher-dose supplemental vitamin D between 700 and 1000 IU per day reduced fall risk by 19% (pooled relative risk (RR) 0.81; 95% CI 0.71–0.92; n = 1921 from 7 trials) versus a lower dose that did not (pooled RR = 1.10, 95% CI 0.89–1.35 from 2 trials). 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). At the higher dose, this meta-analysis documented a 38% significant 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. Thus, the benefits of vitamin D on fall prevention are rapid and sustained provided a high enough dose is given. Subgroup analyses for the prevention of falls at a dose of 700 to 1000 IU per day suggested a benefit in all subgroups of the older population, and possibly better fall reduction with D ₃ compared with D ₂ .