1a. Objectives (from AD-416)
1. Conduct clinical studies to determine the effects of vitamin D in the prevention of physical dysfunction, oral disease, and diabetes, and other chronic diseases in older adults. 2. Conduct clinical studies to determine the effects of dietary protein and dietary acid-base balance on bone and muscle metabolism and function, respectively, in older adults. 3. Determine the role and mechanisms of action for calcium, magnesium, and other dietary components in the maintenance of bone health and the progression of related diseases.
1b. Approach (from AD-416)
The Bone Metabolism Laboratory uses a variety of approaches to carry out its clinical and translational research program. Observational studies such as the publicly available cross-sectional National Health and Nutrition Examination Survey Nutrition, Exercise Physiology and Sarcopenia Laboratory, and external. These collaborations allow us to expand our reach to examine the effect of vitamin D on risk of other chronic diseases such as periodontal disease and diabetes. They also allow us access to basic research technologies, such as gene array analysis, that enable us to identify mechanisms by which nutrients affect bone and muscle.
3. Progress Report
We recently found that short-term administration of potassium bicarbonate, a compound that neutralizes the acid load of the diet, had favorable effects on short-term indicators of bone and muscle health. A weaker response to the bicarbonate in the men suggests that men may need a higher dose than women. In the future, it will be important to conduct a large, long-term potassium bicarbonate intervention trial to determine whether the favorable bone and muscle effects persist over the long term. Before this is done, however, it is first necessary to identify the dose of potassium bicarbonate that is optimal for men and women. A dose-finding study is now underway. In this study we are evaluating doses up to twice the amount we administered previously and basing the doses on body weight. Once the dose that is most effective and safe over the short-term has been identified, we will seek funding to conduct a large, long-term trial to fully evaluate the effects of potassium bicarbonate on musculoskeletal health. Vitamin D is known to affect muscle tissue, but the mechanism(s) for its effect have not been delineated. Enrollment into this study is currently ongoing. At the same time we have been developing the methods needed to determine how vitamin D affects muscle. This method development work has been successful and we have recently had a manuscript describing the details of tissue staining and analysis accepted for publication. The method is being applied to the human muscle biopsy tissue specimens that are being collected in the study. The study to determine the association between serum 25-hydroxyvitamin D (25OHD) levels and risk of developing type 2 diabetes in the Harvard Nurses’ Health Study is underway. The cases and controls have been selected and the serum 25OHD levels in the baseline samples have been measured. Data analyses are currently in progress. On schedule, we have completed enrollment into the randomized, controlled trial in which we are examining the effects of calcium, vitamin D, and the combination, versus placebo on blood sugar levels and insulin sensitivity in adults with prediabetes, defined as fasting blood sugars between 100 and 120 mg/dl. The samples are currently being analyzed in the laboratory. Data analyses will follow. All subject visits have been completed on the randomized controlled trial to assess the effect of 2000 IU of supplemental vitamin D per day, compared with placebo, on progression of knee osteoarthritis. The blood samples collected during this trial are currently being analyzed. The randomized controlled trial of 4000 IU/d vitamin D to improve insulin sensitivity and glucose control in overweight, pre-diabetic African Americans is in the second of three study years. It is ahead of schedule in recruitment of subjects and completion of study visits. Laboratory measurements have been begun. Data analyses will begin next year. For publications related to project, see parent project #1950-51000-069-00D.
1. Vitamin D supplementation is associated with reduced risk of falling Vitamin D insufficiency increases risk of falling in older adults. ARS-funded researchers from Tufts University in Boston, MA recently completed and published a meta-analysis of the available data from randomized controlled trials that assessed the effect of supplemental vitamin D versus placebo on risk of falling in older men and women. Eight trials involving more than 2,426 subjects were included in the analysis. We found that doses of vitamin D in the range of 700 – 1000 IU/d lowered risk of falling by an average of 20%; lower doses in the range of 200-600 IU per day had no significant effect on risk of falling. This work suggests that correction of widespread vitamin D deficiency is likely to be an effective strategy to reduce falls in older adults.
2. Supplemental vitamin D and home-based exercise reduce falls in subjects with recent hip fracture Falls are a major cause of fractures and other injuries in the elderly. ARS-funded researchers from Tufts University in Boston, MA recently collaborated with scientists in Switzerland to complete a randomized controlled trial in 173 elders with recent hip fractures. The study revealed that supplementation with vitamin D (2000 compared with 800 IU) lowered the number of injurious falls and the numbers of hospital admissions for infection in the year following the hip fracture. A moderately vigorous home-based exercise program significantly lowered risk of falling in the same subjects, when compared with the standard of care, no exercise training or advice. It appears that the combination of 2000 IU per day of supplemental vitamin D and training in home-based exercises along with advice to exercise for 30 minutes per day have complementary effects on lowering risk of falling in the elderly. These interventions were safe and well tolerated and should be evaluated in other populations for their ability to lower risk of falling.
3. Poor vitamin D status is associated with poorer cognitive function Impaired cognitive function with aging is a serious and growing problem in the U.S. ARS-funded researchers from Tufts University in Boston, MA completed a study of the association of vitamin D status with mental function in a large group of homebound elders. They demonstrated that serum 25-hydroxyvitamin D levels are positively associated with several components of mental function, including executive function and mental processing speed. These findings provide preliminary data needed to design intervention studies of vitamin D supplementation to improve mental function in older adults.
4. Potassium bicarbonate enhances the impact of protein on muscle Dietary protein is essential for muscle health, but less is known about how the overall composition of the diet may influence the effect of protein on muscle. ARS-funded researchers from Tufts University in Boston, MA investigated the muscle effects of dietary protein in combination with potassium bicarbonate (to neutralize the acid load of the protein). They demonstrated that this combination increases serum insulin-like growth factor 1 (IGF-1) and reduces levels of nitrogen in the urine. These findings suggest that the favorable effects of dietary protein on muscle may be enhanced by neutralizing the acid load that accompanies high protein diets.
5. Poor Vitamin D status is associated with increased blood pressure Hypertension is a major health problem in the elderly and vitamin D insufficiency may be a contributing factor. ARS-funded researchers from Tufts University in Boston, MA, in collaboration with researchers at Michigan State University completed a cross-sectional study of the association of vitamin D deficiency with hypertension in uninsured women. The subjects were 18 to 64 years old and were patients at a County Free Clinic in urban Michigan. Vitamin D status, as indicated by serum 25OHD measurements, was inversely associated with hypertension prevalence and with both systolic and diastolic blood pressure. These findings suggest that improving vitamin D status may help to prevent hypertension in the vulnerable uninsured population.