Basal Metabolic Rate Versus Dietary Vitamin D and Calcium Intakes and the Association With Body Composition and Bone Health After Chronic Spinal Cord Injury.

We examined the association among basal metabolic rate (BMR) as well as dietary intakes of vitamin D (Vit D) and calcium on body composition and bone mineral density (BMD) after spinal cord injury (SCI). Cross-sectional design. Veterans Affairs Medical Center, Richmond, VA. About 33 individuals with chronic SCI who recorded their food consumption 3 days per week for 2 weeks. BMR was measured after 10 to 12 h of overnight fast. Average daily vit D and calcium intakes, and total caloric intake were recorded and analyzed using the Nutrition Data System for Research (NDSR) software. Fasting blood analysis for 25-hydroxyvitamin D (25[OH]D) status and Triiodothyronine (T3) status was performed (n = 10). Total and regional BMD, % fat mass (FM), and % lean mass (LM) were measured by dual X-ray absorptiometry scans. Participants consumed less than the Institute of Medicine (IOM) recommended daily allowances (RDA) for vit D (600-800 IU) and calcium (1000-1200 mg) for adults. BMR was positively related to total-lean mass (r = .62, P = .0001; n = 32) and leg-lean mass (r = .51, P = .003; n = 32). Adjusted BMR was negatively related to BMD of the left (r = -.38, P = .047; n = 28) and the right (r = -.41, P = .032; n = 28) proximal tibia. Vit D intake was negatively related to percentage total-FM (r = -.33, P = .07; n = 29) and legs-%FM (r = -.37, P = .047; n = 29). Multivariate regression models indicated that adjusted BMR explained the variance in leg fat mass (34%; P = .002) and percentage fat mass (44%; P < .0001). Persons with SCI are likely to consume less than the RDAs for vit D and calcium. BMR may explain the changes in body composition and bone metabolism. Dietary vit D should be considered as a prophylactic intervention in maintenance of bone health after SCI.

Consensus Statement on Vitamin D Status Assessment and Supplementation: Whys, Whens, and Hows.

The 6th International Conference, "Controversies in Vitamin D," was convened to discuss controversial topics, such as vitamin D metabolism, assessment, actions, and supplementation. Novel insights into vitamin D mechanisms of action suggest links with conditions that do not depend only on reduced solar exposure or diet intake and that can be detected with distinctive noncanonical vitamin D metabolites. Optimal 25-hydroxyvitamin D (25(OH)D) levels remain debated. Varying recommendations from different societies arise from evaluating different clinical or public health approaches. The lack of assay standardization also poses challenges in interpreting data from available studies, hindering rational data pooling and meta-analyses. Beyond the well-known skeletal features, interest in vitamin D's extraskeletal effects has led to clinical trials on cancer, cardiovascular risk, respiratory effects, autoimmune diseases, diabetes, and mortality. The initial negative results are likely due to enrollment of vitamin D-replete individuals. Subsequent post hoc analyses have suggested, nevertheless, potential benefits in reducing cancer incidence, autoimmune diseases, cardiovascular events, and diabetes. Oral administration of vitamin D is the preferred route. Parenteral administration is reserved for specific clinical situations. Cholecalciferol is favored due to safety and minimal monitoring requirements. Calcifediol may be used in certain conditions, while calcitriol should be limited to specific disorders in which the active metabolite is not readily produced in vivo. Further studies are needed to investigate vitamin D effects in relation to the different recommended 25(OH)D levels and the efficacy of the different supplementary formulations in achieving biochemical and clinical outcomes within the multifaced skeletal and extraskeletal potential effects of vitamin D.

Vitamin D status and supplementation before and after Bariatric Surgery: Recommendations based on a systematic review and meta-analysis.

Bariatric surgery is associated with a postoperative reduction of 25(OH) vitamin D levels (25(OH)D) and with skeletal complications. Currently, guidelines for 25(OH)D assessment and vitamin D supplementation in bariatric patients, pre- and post-surgery, are still lacking. The aim of this work is to analyse systematically the published experience on 25(OH)D status and vitamin D supplementation, pre- and post-surgery, and to propose, on this basis, recommendations for management. Preoperatively, 18 studies including 2,869 patients were evaluated. Prevalence of vitamin D insufficiency as defined by 25(OH)D < 30 ng/mL (75 nmol/L) was 85%, whereas when defined by 25(OH)D < 20 ng/mL (50 nmol/L) was 57%. The median preoperative 25(OH)D level was 19.75 ng/mL. After surgery, 39 studies including 5,296 patients were analysed and among those undergoing either malabsorptive or restrictive procedures, a lower rate of vitamin D insufficiency and higher 25(OH)D levels postoperatively were observed in patients treated with high-dose oral vitamin D supplementation, defined as ≥ 2,000 IU/daily (mostly D3-formulation), compared with low-doses (< 2,000 IU/daily). Our recommendations based on this systematic review and meta-analysis should help clinical practice in the assessment and management of vitamin D status before and after bariatric surgery. Assessment of vitamin D should be performed pre- and postoperatively in all patients undergoing bariatric surgery. Regardless of the type of procedure, high-dose supplementation is recommended in patients after bariatric surgery.

Predictors of muscle hypertrophy responsiveness to electrically evoked resistance training after spinal cord injury.

The purpose of the study was to identify potential predictors of muscle hypertrophy responsiveness following neuromuscular electrical stimulation resistance training (NMES-RT) in persons with chronic spinal cord injury (SCI). Data for twenty individuals with motor complete SCI who completed twice weekly NMES-RT lasting 12-16 weeks as part of their participation in one of two separate clinical trials were pooled and retrospectively analyzed. Magnetic resonance imaging (MRI) was used to measure muscle cross-sectional area (CSA) of the whole thigh and knee extensor muscle before and after NMES-RT. Muscle biopsies and fasting biomarkers were also measured. Following the completion of the respective NMES-RT trials, participants were classified into either high-responders (n = 8; muscle CSA > 20%) or low-responders (n = 12; muscle CSA < 20%) based on whole thigh muscle CSA hypertrophy. Whole thigh muscle and knee extensors CSAs were significantly greater (P < 0.0001) in high-responders (29 ± 7% and 47 ± 15%, respectively) compared to low-responders (12 ± 3% and 19 ± 6%, respectively). There were no differences in total caloric intake or macronutrient intake between groups. Extensor spasticity was lower in the high-responders compared to the low-responders as was the dosage of baclofen. Prior to the intervention, the high-responders had greater body mass compared to the low-responders with SCI (87.8 ± 13.7 vs. 70.4 ± 15.8 kg; P = 0.012), body mass index (BMI: 27.6 ± 2.7 vs. 22.9 ± 6.0 kg/m2; P = 0.04), as well as greater percentage in whole body and regional fat mass (P < 0.05). Furthermore, high-responders had a 69% greater increase (P = 0.086) in total Akt protein expression than low-responders. High-responders also exhibited reduced circulating IGF-1 with a concomitant increase in IGFBP-3. Exploratory analyses revealed upregulation of mRNAs for muscle hypertrophy markers [IRS-1, Akt, mTOR] and downregulation of protein degradation markers [myostatin, MurF-1, and PDK4] in the high-responders compared to low-responders. The findings indicate that body composition, spasticity, baclofen usage, and multiple signaling pathways (anabolic and catabolic) are involved in the differential muscle hypertrophy response to NMES-RT in persons with chronic SCI.

Testosterone and long pulse width stimulation (TLPS) for denervated muscles after spinal cord injury: a study protocol of randomised clinical trial.

INTRODUCTION: Long pulse width stimulation (LPWS; 120-150 ms) has the potential to stimulate denervated muscles and to restore muscle size in denervated people with spinal cord injury (SCI). We will determine if testosterone treatment (TT)+LPWS would increase skeletal muscle size, leg lean mass and improve overall metabolic health in persons with SCI with denervation. We hypothesise that the 1-year TT+LPWS will upregulate protein synthesis pathways, downregulate protein degradation pathways and increase overall mitochondrial health. METHODS AND ANALYSIS: Twenty-four male participants (aged 18-70 years with chronic SCI) with denervation of both knee extensor muscles and tolerance to the LPWS paradigm will be randomised into either TT+neuromuscular electrical stimulation via telehealth or TT+LPWS. The training sessions will be twice weekly for 1 year. Measurements will be conducted 1 week prior training (baseline; week 0), 6 months following training (postintervention 1) and 1 week after the end of 1 year of training (postintervention 2). Measurements will include body composition assessment using anthropometry, dual X-ray absorptiometry and MRI to measure size of different muscle groups. Metabolic profile will include measuring of basal metabolic rate, followed by blood drawn to measure fasting biomarkers similar to hemoglobin A1c, lipid panels, C reactive protein, interleukin-6 and free fatty acids and then intravenous glucose tolerance test to test for insulin sensitivity and glucose effectiveness. Finally, muscle biopsy will be captured to measure protein expression and intracellular signalling; and mitochondrial electron transport chain function. The participants will fill out 3 days dietary record to monitor their energy intake on a weekly basis. ETHICS AND DISSEMINATION: The study was approved by Institutional Review Board of the McGuire Research Institute (ID # 02189). Dissemination plans will include the Veteran Health Administration and its practitioners, the national SCI/D services office, the general healthcare community and the veteran population, as well as the entire SCI community via submitting quarterly letters or peer-review articles. TRIAL REGISTRATION NUMBER: NCT03345576.

Protocol for the models of primary osteoporosis screening in men (MOPS) cluster randomized trial.

Current guidelines recommend primary osteoporosis screening for at-risk men to reduce the morbidity, mortality, and cost associated with osteoporotic fractures. However, analyses in a national Veterans Health Administration cohort of over 4,000,000 men demonstrated that primary osteoporosis screening as it is currently operationalized does not benefit most older Veterans due to inefficient targeting and low subsequent treatment and adherence rates. The overall objective of this study is to determine whether a new model of primary osteoporosis screening reduces fracture risk compared to usual care. We are conducting a pragmatic group randomized trial of 38 primary care teams assigned to usual care or a Bone Health Service (BHS) screening model in which screening and adherence activities are managed by a centralized expert team. The study will: 1) compare the impact of the BHS model on patient-level outcomes strongly associated with fracture rates (eligible proportion screened, proportion meeting treatment criteria who receive osteoporosis medications, medication adherence, and femoral neck bone mineral density); 2) quantify the impact on provider and facility-level outcomes including change in DXA volume, change in metabolic bone disease clinic volume, and PACT provider time and satisfaction; and 3) estimate the impact on health system and policy outcomes using Markov models of screening program cost per quality adjusted life year based from health system and societal perspectives.

Vitamin D: Dosing, levels, form, and route of administration: Does one approach fit all?

The 4th International Conference on Controversies in Vitamin D was held as a virtual meeting in September, 2020, gathering together leading international scientific and medical experts in vitamin D. Since vitamin D has a crucial role in skeletal and extra-skeletal systems, the aim of the Conference was to discuss improved management of vitamin D dosing, therapeutic levels and form or route of administration in the general population and in different clinical conditions. A tailored approach, based on the specific mechanisms underlying vitamin D deficiency in different diseases that were discussed, was recommended. Specifically, in comparison to healthy populations, higher levels of vitamin D and greater amounts of vitamin D were deemed necessary in osteoporosis, diabetes mellitus, obesity (particularly after bariatric surgery), and in those treated with glucocorticoids. Emerging and still open issues were related to target vitamin D levels and the role of vitamin D supplementation in COVID-19 since low vitamin D may predispose to SARS-CoV-2 infection and to worse COVID-19 outcomes. Finally, whereas oral daily cholecalciferol appears to be the preferred choice for vitamin D supplementation in the general population, and in most clinical conditions, active vitamin D analogs may be indicated in patients with hypoparathyroidism and severe kidney and liver insufficiency. Parenteral vitamin D administration could be helpful in malabsorption syndromes or in states of vitamin D resistance.Specific guidelines for desired levels of vitamin D should be tailored to the different conditions affecting vitamin D metabolism with the goal to define disease-specific normative values.

Controversies in Vitamin D: A Statement From the Third International Conference.

The Third International Conference on Controversies in Vitamin D was held in Gubbio, Italy, September 10-13, 2019. The conference was held as a follow-up to previous meetings held in 2017 and 2018 to address topics of controversy in vitamin D research. The specific topics were selected by the steering committee of the conference and based upon areas that remain controversial from the preceding conferences. Other topics were selected anew that reflect specific topics that have surfaced since the last international conference. Consensus was achieved after formal presentations and open discussions among experts. As will be detailed in this article, consensus was achieved with regard to the following: the importance and prevalence of nutritional rickets, amounts of vitamin D that are typically generated by sun exposure, worldwide prevalence of vitamin D deficiency, the importance of circulating concentrations of 25OHD as the best index of vitamin D stores, definitions and thresholds of vitamin D deficiency, and efficacy of vitamin D analogues in the treatment of psoriasis. Areas of uncertainly and controversy include the following: daily doses of vitamin D needed to maintain a normal level of 25OHD in the general population, recommendations for supplementation in patients with metabolic bone diseases, cutaneous production of vitamin D by UVB exposure, hepatic regulation of 25OHD metabolites, definition of vitamin D excess, vitamin D deficiency in acute illness, vitamin D requirements during reproduction, potential for a broad spectrum of cellular and organ activities under the influence of the vitamin D receptor, and potential links between vitamin D and major human diseases. With specific regard to the latter area, the proceedings of the conference led to recommendations for areas in need of further investigation through appropriately designed intervention trials. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Secondary Fracture Prevention: Consensus Clinical Recommendations from a Multistakeholder Coalition.

Osteoporosis-related fractures are undertreated, due in part to misinformation about recommended approaches to patient care and discrepancies among treatment guidelines. To help bridge this gap and improve patient outcomes, the American Society for Bone and Mineral Research assembled a multistakeholder coalition to develop clinical recommendations for the optimal prevention of secondary fractureamong people aged 65 years and older with a hip or vertebral fracture. The coalition developed 13 recommendations (7 primary and 6 secondary) strongly supported by the empirical literature. The coalition recommends increased communication with patients regarding fracture risk, mortality and morbidity outcomes, and fracture risk reduction. Risk assessment (including fall history) should occur at regular intervals with referral to physical and/or occupational therapy as appropriate. Oral, intravenous, andsubcutaneous pharmacotherapies are efficaciousandcanreduce risk of future fracture.Patientsneededucation,however, about thebenefitsandrisks of both treatment and not receiving treatment. Oral bisphosphonates alendronate and risedronate are first-line options and are generally well tolerated; otherwise, intravenous zoledronic acid and subcutaneous denosumab can be considered. Anabolic agents are expensive butmay be beneficial for selected patients at high risk.Optimal duration of pharmacotherapy is unknown but because the risk for second fractures is highest in the earlypost-fractureperiod,prompt treatment is recommended.Adequate dietary or supplemental vitaminDand calciumintake shouldbe assured. Individuals beingtreatedfor osteoporosis shouldbe reevaluated for fracture risk routinely, includingvia patienteducationabout osteoporosisandfracturesandmonitoringfor adverse treatment effects.Patients shouldbestronglyencouraged to avoid tobacco, consume alcohol inmoderation atmost, and engage in regular exercise and fall prevention strategies. Finally, referral to endocrinologists or other osteoporosis specialists may be warranted for individuals who experience repeated fracture or bone loss and those with complicating comorbidities (eg, hyperparathyroidism, chronic kidney disease).

Secondary Fracture Prevention: Consensus Clinical Recommendations from a Multistakeholder Coalition.

Osteoporosis-related fractures are undertreated, due in part to misinformation about recommended approaches to patient care and discrepancies among treatment guidelines. To help bridge this gap and improve patient outcomes, the American Society for Bone and Mineral Research assembled a multistakeholder coalition to develop clinical recommendations for the optimal prevention of secondary fracture among people aged 65 years and older with a hip or vertebral fracture. The coalition developed 13 recommendations (7 primary and 6 secondary) strongly supported by the empirical literature. The coalition recommends increased communication with patients regarding fracture risk, mortality and morbidity outcomes, and fracture risk reduction. Risk assessment (including fall history) should occur at regular intervals with referral to physical and/or occupational therapy as appropriate. Oral, intravenous, and subcutaneous pharmacotherapies are efficacious and can reduce risk of future fracture. Patients need education, however, about the benefits and risks of both treatment and not receiving treatment. Oral bisphosphonates alendronate and risedronate are first-line options and are generally well tolerated; otherwise, intravenous zoledronic acid and subcutaneous denosumab can be considered. Anabolic agents are expensive but may be beneficial for selected patients at high risk. Optimal duration of pharmacotherapy is unknown but because the risk for second fractures is highest in the early post-fracture period, prompt treatment is recommended. Adequate dietary or supplemental vitamin D and calcium intake should be assured. Individuals being treated for osteoporosis should be reevaluated for fracture risk routinely, including via patient education about osteoporosis and fractures and monitoring for adverse treatment effects. Patients should be strongly encouraged to avoid tobacco, consume alcohol in moderation at most, and engage in regular exercise and fall prevention strategies. Finally, referral to endocrinologists or other osteoporosis specialists may be warranted for individuals who experience repeated fracture or bone loss and those with complicating comorbidities (eg, hyperparathyroidism, chronic kidney disease). © 2019 American Society for Bone and Mineral Research.

Acetylcholinesterase Inhibitors Are Associated with Reduced Fracture Risk among Older Veterans with Dementia.

Acetylcholinesterase inhibitors (AChEIs) have been noted to increase bone density and quality in mice. Human studies are limited but suggest an association with improved bone healing after hip fracture. We examined the relationship between AChEI use and fracture risk in a national cohort of 360,015 male veterans aged 65 to 99 years with dementia but without prior fracture using Veterans Affairs (VA) hospital, Medicare, and pharmacy records from 2000 to 2010. Diagnosis of dementia, any clinical fracture (excluding facial and digital), comorbidities, and medications were identified using ICD-9 and drug class codes. Cox proportional hazard models considering AChEI use as a time-varying covariate and adjusting for fall and fracture risk factors compared the time-to-fracture in AChEI users versus non-AChEI users. Potential confounders included demographics (age, race, body mass index), comorbidities associated with fracture or falls (diabetes, lung disease, stroke, Parkinson's, seizures, etc.) and medications associated with fracture or falls (bisphosphonates, glucocorticoids, androgen deprivation therapy [ADT], proton pump inhibitors [PPIs], selective serotonin receptor inhibitors [SSRIs], etc.). Competing mortality risk was considered using the methods of Fine and Gray. To account for persistent effects on bone density or quality that might confer protection after stopping the medication, we completed a secondary analysis using the medication possession ratio (MPR) as a continuous variable in logistic regression models and also compared MPR increments of 10% to minimal/no use (MPR 0 to <0.10). Among older veterans with diagnosis of dementia, 20.1% suffered a fracture over an average of 4.6 years of follow-up. Overall, 42.3% of the cohort were prescribed AChEIs during the study period. The hazard of any fracture among AChEI users compared with those on other/no dementia medications was significantly lower in fully adjusted models (hazard ratio [HR] = 0.81; 95% confidence interval [CI] 0.75-0.88). After considering competing mortality risk, fracture risk remained 18% lower in veterans using AChEIs (HR = 0.82; 95% CI 0.76-0.89). © 2019 American Society for Bone and Mineral Research. Published 2019. This article is a U.S. Government work and is in the public domain in the USA.

Skeletal muscle hypertrophy and attenuation of cardio-metabolic risk factors (SHARC) using functional electrical stimulation-lower extremity cycling in persons with spinal cord injury: study protocol for a randomized clinical trial.

BACKGROUND: Persons with spinal cord injury (SCI) are at heightened risks of developing unfavorable cardiometabolic consequences due to physical inactivity. Functional electrical stimulation (FES) and surface neuromuscular electrical stimulation (NMES)-resistance training (RT) have emerged as effective rehabilitation methods that can exercise muscles below the level of injury and attenuate cardio-metabolic risk factors. Our aims are to determine the impact of 12 weeks of NMES + 12 weeks of FES-lower extremity cycling (LEC) compared to 12 weeks of passive movement + 12 weeks of FES-LEC on: (1) oxygen uptake (VO2), insulin sensitivity, and glucose disposal in adults with SCI; (2) skeletal muscle size, intramuscular fat (IMF), and visceral adipose tissue (VAT); and (3) protein expression of energy metabolism, protein molecules involved in insulin signaling, muscle hypertrophy, and oxygen uptake and electron transport chain (ETC) activities. METHODS/DESIGN: Forty-eight persons aged 18-65 years with chronic (> 1 year) SCI/D (AIS A-C) at the C5-L2 levels, equally sub-grouped by cervical or sub-cervical injury levels and time since injury, will be randomized into either the NMES + FES group or Passive + FES (control group). The NMES + FES group will undergo 12 weeks of evoked RT using twice-weekly NMES and ankle weights followed by twice-weekly progressive FES-LEC for an additional 12 weeks. The control group will undergo 12 weeks of passive movement followed by 12 weeks of progressive FES-LEC. Measurements will be performed at baseline (B; week 0), post-intervention 1 (P1; week 13), and post-intervention 2 (P2; week 25), and will include: VO2 measurements, insulin sensitivity, and glucose effectiveness using intravenous glucose tolerance test; magnetic resonance imaging to measure muscle, IMF, and VAT areas; muscle biopsy to measure protein expression and intracellular signaling; and mitochondrial ETC function. DISCUSSION: Training through NMES + RT may evoke muscle hypertrophy and positively impact oxygen uptake, insulin sensitivity, and glucose effectiveness. This may result in beneficial outcomes on metabolic activity, body composition profile, mitochondrial ETC, and intracellular signaling related to insulin action and muscle hypertrophy. In the future, NMES-RT may be added to FES-LEC to improve the workloads achieved in the rehabilitation of persons with SCI and further decrease muscle wasting and cardio-metabolic risks. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02660073 . Registered on 21 Jan 2016.

Glycemic Control and Insulin Treatment Alter Fracture Risk in Older Men With Type 2 Diabetes Mellitus.

Diabetes mellitus among older men has been associated with increased bone mineral density but paradoxically increased fracture risk. Given the interactions among medication treatment, glycemic control, and diabetes-associated comorbidities, the relative effects of each factor remains unclear. This retrospective study includes 652,901 male veterans aged ≥65 years with diabetes and baseline hemoglobin A1c (HbA1c) value. All subjects received primary care in the Veterans Health Administration (VHA) from 2000 to 2010. Administrative data included ICD9 diagnoses and pharmacy records and was linked to Medicare fee-for-service data. Hazard ratios (HR) for any clinical fracture and hip fracture were calculated using competing risk hazards models, adjusted for fracture risk factors including age, race/ethnicity, body mass index (BMI), alcohol and tobacco use, rheumatoid arthritis, corticosteroid use, as well as diabetes-related comorbidities including cardiovascular disease, chronic kidney disease, and peripheral neuropathy. HbA1c <6.5% was associated with a higher risk of any clinical fracture (HR = 1.08, 95% confidence interval [CI] 1.06-1.11) compared with the reference HbA1c of 7.5% to 8.5%. Fracture risk was not increased among those with A1c ≥8.5%, nor among those with A1c 6.5% to 7.5%. Use of insulin was independently associated with greater risk of fracture (HR = 1.10, 95% CI 1.07-1.12). There was a significant interaction between insulin use and HbA1c level, (p < 0.001), such that those using insulin with HbA1c <6.5% had HR = 1.23 and those with HbA1c 6.5% to 7.5% had HR = 1.15. Metformin use was associated with decreased fracture risk (HR = 0.88, 95% CI 0.87-0.90). We conclude that among older men with diabetes, those with HbA1c lower than 6.5% are at increased risk for any clinical and hip fracture. Insulin use is associated with higher fracture risk, especially among those with tight glycemic control. Our findings demonstrate the importance of the treatment regimen and avoiding hypoglycemia for fracture prevention in older men with diabetes. © 2019 American Society for Bone and Mineral Research.

Limited Osteoporosis Screening Effectiveness Due to Low Treatment Rates in a National Sample of Older Men.

OBJECTIVE: To determine the association between dual-energy x-ray absorptiometry (DXA) testing for osteoporosis and subsequent fractures in US male veterans without a previous fracture. PATIENTS AND METHODS: This is a propensity score-matched observational study using Centers for Medicare and Medicaid Services and Veterans Affairs (VA) data from January 1, 2000, through December 31, 2010, with a mean follow-up time of 4.7 years (range, 0-10 years). Men receiving VA primary care aged 65 to 99 years without a previous fracture (N=2,539,812) were included. Men undergoing DXA testing were propensity score matched with untested controls in a 1:3 ratio, indicating the probability of DXA testing within the next year. Time to first clinical fracture was the primary outcome. Comorbidities, demographic characteristics, medications, DXA results, and osteoporosis treatment were defined using administrative data and natural language processing. A landmark analysis contingent on surviving to 12 months after screening was completed, accounting for competing risk of mortality. RESULTS: During follow-up of 153,311 men tested by DXA and 390,158 controls, 56,083 (10.3%) had sustained a fracture and 111,774 (20.6%) died. Overall, DXA testing was not associated with a decrease in fractures; conclusions are limited by unmeasured confounders and low medication initiation and adherence in those meeting treatment thresholds (12% of follow-up time). In contrast, DXA testing in prespecified subgroups was associated with a lower risk of fracture in comparison to the overall population who underwent DXA testing: androgen deprivation therapy (hazard ratio [HR], 0.77; 95% CI, 0.66-0.89), glucocorticoids (HR, 0.77; 95% CI, 0.72-0.84), age 80 years and older (HR, 0.85; 0.81-0.90), 1 or more VA guideline risk factors (HR, 0.91; 95% CI, 0.87-0.95), and high Fracture Risk Assessment Tool using body mass index score (HR, 0.90; 95% CI, 0.86-0.95). CONCLUSION: Current VA DXA testing practices are ineffective overall; interventions to improve treatment adherence are needed. Targeted DXA testing in higher-risk men was associated with a lower fracture risk.

Glucocorticoid Exposure and Fracture Risk in a Cohort of US Patients With Selected Conditions.

The purpose of this work was to evaluate systemic glucocorticoid exposure and fracture among patients with newly-diagnosed inflammatory and immune-modulated conditions. Using administrative data, inception cohorts of rheumatoid arthritis (RA), asthma/chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (IBD), multiple sclerosis (MS), lupus, and sarcoidosis patients age 18 to 64 years with benefits coverage ≥12 months before diagnosis (January 1, 2005 to December 31, 2012) were followed to clinical fracture, cancer diagnosis, or December 31, 2012. Glucocorticoid users were new to therapy. Fracture incidence rates (IRs) per 1000 person-years were stratified by prednisone equivalent doses. Cox's proportional hazards models assessed risk by daily and cumulative dose, and by time since discontinuation, adjusted for baseline characteristics. Most patients (72% of 403,337) had glucocorticoid exposure; 52% were under age 50. IR (95% confidence interval [CI]) of any osteoporotic fracture was elevated at doses <5 mg/day (IR 9.33; 95% CI, 7.29 to 11.77) versus 0 mg/day (IR 4.87 (95% CI, 4.72 to 5.02). Fracture rates were elevated at doses <5 mg/day in patients <50 years and those ≥50 years. In both age groups, fracture risk increased with increasing cumulative exposure, being approximately 2.5-fold higher at cumulative dose ≥5400 mg compared to <675 mg. At ≥5400 mg, IR values were 5.69 (95% CI, 4.32 to 7.35) in patients <50 years and 17.10 (95% CI, 14.97 to 19.46) in older patients. Fracture risk decreased significantly within months following glucocorticoid discontinuation. In patients with a variety of inflammatory conditions, fracture risk increased at doses as low as <5 mg/day. Risk increased with increasing cumulative exposure and decreased soon following glucocorticoid discontinuation. Trends were similar between patients older and younger than 50 years. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

Practical Issues in Vitamin D Replacement.

Practical clinical guidance for vitamin D assessment and management relies on a strong evidence base, but unfortunately there are many deficiencies in our current knowledge. For the general population the Institute of Medicine recommendations are likely to provide adequate vitamin D levels without harms. Thus, most adults should ingest 600-800 IU (international units) in diet and supplements with up to 4,000 IU daily likely to be safe. In certain populations, such as those with osteoporosis or after bariatric surgery, it is important to know the levels of circulating 25-hydroxyvitamin D, but general screening has not been shown to improve health. One expert group has recommended a "reasonable" level of 30 ng/mL in those individuals for whom testing is required.

Clinical Fractures Among Older Men With Diabetes Are Mediated by Diabetic Complications.

Introduction: Type 2 diabetes mellitus among older women has been associated with increased bone mineral density, but paradoxically with increased fracture risk. Findings among older men have varied, and potential mechanisms have not been fully elucidated. Methods: A retrospective study of male veterans 65 to 99 years of age who received primary care in the Veterans Health Administration from 2000 to 2010, using administrative data from all 146 Veterans Health Administration medical centers linked to Centers for Medicare and Medicaid Services Medicare fee-for-service data. Potential mediating factors of the diabetes-associated risk were evaluated using negative binomial regression models with the outcomes of any clinical fracture and hip fracture. Results: Of 2,798,309 Veterans included in the cohort, 900,402 (32.3%) had a diagnosis of diabetes. After adjusting for age, race, ethnicity, body mass index, alcohol and tobacco use, rheumatoid arthritis, and corticosteroid use, the risk of any clinical fracture associated with diabetes was 1.22 (95% confidence interval, 1.21 to 1.23) and that of hip fracture was 1.21 (95% confidence interval, 1.19 to 1.23). Significant mediating factors included peripheral neuropathy, cardiovascular disease, and congestive heart failure, with 45.5% of the diabetes-associated fracture risk explained by these diagnoses. Conclusions: Older male Veterans with diabetes have a 22% increased risk of incident clinical fracture compared with those without. A significant portion of this risk is explained by diabetes-related comorbidities, specifically peripheral neuropathy and congestive heart failure. Identification of these mediating factors suggests possible mechanisms, as well as potential interventions.

Disruption in bone marrow fat may attenuate testosterone action on muscle size after spinal cord injury: a case report.

BACKGROUND: Mesenchymal stem cells can be differentiated into muscle satellite cells. Testosterone replacement therapy (TRT) promotes the differentiation of satellite cells into muscle cells. CASE REPORT: A 31-year-old male with a T4 complete chronic spinal cord injury (SCI) had fixation for a mid-shaft fracture of the left femur. The participant received transdermal testosterone patches (4 mg/day) daily for 16 weeks. Skeletal muscle and yellow bone marrow adiposity cross-sectional areas (CSAs) of both thighs were measured using magnetic resonance imaging. CLINICAL REHABILITATION IMPACT: The yellow bone marrow CSA was 67-69% lower in the left femur compared to the right femur. Following intervention, a discrepancy was noted between the whole skeletal muscle CSAs of the right (+13%) and left (+6%) thighs. The right knee extensor CSA increased by 7% with no changes in the left CSA. Disruption in bone marrow fat may attenuate the systemic effects of TRT on muscle size.