Context More than 3% of adults report vitamin D intakes of 4000 IU/day or more, but the safety of this practice is unknown. Objective The objective of this work is to establish whether vitamin D doses up to 10 000 IU/day are safe and well tolerated. Design The Calgary Vitamin D Study was a 3-year, double-blind, randomized controlled trial. Setting A single-center study was conducted at the University of Calgary, Canada. Participants Participants included healthy adults (n = 373) ages 55 to 70 years with serum 25-hydroxyvitamin D 30 to 125 nmol/L. Interventions Participants were randomly assigned 1:1:1 to vitamin D3 400, 40 000, or 10 000 IU/day. Calcium supplementation was initiated if dietary calcium intake was less than 1200 mg/day. Main Outcome Measures In these prespecified secondary analyses, changes in serum 25-hydroxyvitamin D, calcium, creatinine, 24-hour urine calcium excretion, and incidence of adverse events were assessed. Between-group differences in adverse events were examined using incident rate differences and logistic regression. Results Of 373 participants (400: 124, 4000: 125, 10 000: 124), 49% were male, mean (SD) age was 64 (4) years, and 25-hydroxyvitamin D 78.0 (19.5) nmol/L. Serum calcium, creatinine, and 24-hour urine calcium excretion did not differ between treatments. Mild hypercalcemia (2.56-2.64 mmol/L) occurred in 15 (4%) participants (400: 0%, 4000: 3%, 10 000: 9%, P = .002); all cases resolved on repeat testing. Hypercalciuria occurred in 87 (23%) participants (400: 17%, 4000: 22%, 10 000: 31%, P = .01). Clinical adverse events were experienced by 365 (97.9%) participants and were balanced across treatment arms. Conclusions The safety profile of vitamin D supplementation is similar for doses of 400, 4000, and 10 000 IU/day. Hypercalciuria was common and occurred more frequently with higher doses. Hypercalcemia occurred more frequently with higher doses but was rare, mild, and transient.

Athletes participating in sports characterized by specific loading modalities have exhibited different levels of augmentation of bone properties; however, the extent to which these loading environments affect bone micro-architecture and estimated bone strength (i.e., bone quality) remains unclear. Furthermore, the relative role of impact loading versus loading due to muscle forces in determining bone properties is confounded. The objectives of this study were 1) to examine the role of impact loading on bone quality of the distal radius and distal tibia in elite athletes, as determined by high resolution peripheral quantitative computed tomography (HR-pQCT) and finite element analysis (FEA), and 2) to investigate the relationship between bone quality and muscle strength in elite athletes. Ninety-five females (n=59) and males (n=36) between the ages of 16-30 years participated in the study. Participants included alpine skiers (high-impact), soccer players (moderate impact), swimmers (low-impact), and non-athletic controls. All group comparisons were made after accounting for age, height, and body mass. As expected, minimal differences in HR-pQCT parameters across groups were observed at the non weight-bearing distal radius. At the weight-bearing distal tibia, female alpine skiers and soccer players had significantly higher bone density, cortical thickness, and failure load (i.e., bone strength (N) in compression estimated by FEA) than swimmers (p<0.05). Female alpine skiers also had lower trabecular separation than swimmers and controls. Male alpine skiers had 20% higher trabecular bone mineral density than swimmers, and male soccer players exhibited 22% higher trabecular number than swimmers at the distal tibia (p<0.05). Male alpine skiers and soccer players had 28-38% higher failure load at the distal tibia than swimmers. No differences in bone parameters were observed between swimmers and controls for either sex at either site. Both muscle strength and sporting activity were predictors of failure load at the distal tibia in the female cohort. Sporting activity, but not muscle strength, was a significant predictor of failure load in the male cohort at both the radius and tibia. This data suggests that impact loading in sporting activity is highly associated with bone quality. Longitudinal and interventional studies are required to further clarify the muscle-bone interaction.

Like insulin, glucagon-like peptide 1 (GLP-1) may have direct trophic actions on the nervous system, but its potential role in supporting diabetic sensory neurons is uncertain. We identified wide expression of GLP-1 receptors on dorsal root ganglia sensory neurons of diabetic and nondiabetic mice. Exendin-4, a GLP-1 agonist, increased neurite outgrowth of adult sensory neurons in vitro. To determine the effects ofexendin-4 in comparison with continuous low- or high-dose insulin in vivo, we evaluated parallel cohorts of type 1 (streptozotocin-induced) and type 2 (db/db) mice of 2 months' diabetes duration with established neuropathy during an additional month of treatment. High-dose insulin alone reversed hyperglycemia in type 1 diabetic mice, partly reversed thermal sensory loss, improved epidermal innervation but failed to reverse electrophysiological abnormalities. Exendin-4 improved both sensory electrophysiology and behavioral sensory loss. Low-dose insulin was ineffective. In type 2 diabetes, hyperglycemia was uncorrected, and neither insulin nor exendin-4 reversed sensory electrophysiology, sensory behavior, or loss of epidermal axons. However, exendin-4 alone improved motor electrophysiology. Receptor for advanced glycosylated end products and nuclear factor-κB neuronal expression were not significantly altered by diabetes or treatment. Taken together, these results suggest that although GLP-1 agonists and insulin alone are insufficient to reverse all features of diabetic neuropathy, in combination, they might benefit some aspects of established diabetic neuropathy.

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Loss of cutaneous innervation from sensory neuropathy is included among mechanisms for impaired healing of diabetic skin wounds. The relationships between cutaneous axons and their local microenvironment during wound healing are challenged in diabetes. Here, we show that secondary wound closure of the hairy dorsal skin of mice is delayed by diabetes and is associated with not only a pre-existing loss of cutaneous axons but substantial retraction of axons around the wound. At 7d following a 3mm punch wound, a critical period of healing and reinnervation, both intact skin nearby the wound and skin directly at the wound margins had over 30-50% fewer axons and a larger deficit of ingrowing axons in diabetics. These findings contrasted with a pre-existing 10-15% deficit in axons. Moreover, new diabetic ingrowing axons had less evidence of plasticity. Unexpectedly, hair follicles adjacent to the wounds had a 70% reduction in their innervation associated with depleted expression of hair follicular stem cell markers. These impairments were associated with the local upregulation of two established axon regenerative ‘roadblocks’: PTEN and RHOA, potential but thus far unexplored mediators of these changes. The overall findings identify striking and unexpected superimposed cutaneous axon loss or retraction beyond that expected of diabetic neuropathy alone, associated with experimental diabetic skin wounding, a finding that prompts new considerations in diabetic wounds.

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