Supplemental Vitamin D and Incident Fractures in Midlife and Older Adults.

BACKGROUND: Vitamin D supplements are widely recommended for bone health in the general population, but data on whether they prevent fractures have been inconsistent. METHODS: In an ancillary study of the Vitamin D and Omega-3 Trial (VITAL), we tested whether supplemental vitamin D3 would result in a lower risk of fractures than placebo. VITAL was a two-by-two factorial, randomized, controlled trial that investigated whether supplemental vitamin D3 (2000 IU per day), n-3 fatty acids (1 g per day), or both would prevent cancer and cardiovascular disease in men 50 years of age or older and women 55 years of age or older in the United States. Participants were not recruited on the basis of vitamin D deficiency, low bone mass, or osteoporosis. Incident fractures were reported by participants on annual questionnaires and adjudicated by centralized medical-record review. The primary end points were incident total, nonvertebral, and hip fractures. Proportional-hazards models were used to estimate the treatment effect in intention-to-treat analyses. RESULTS: Among 25,871 participants (50.6% women [13,085 of 25,871] and 20.2% Black [5106 of 25,304]), we confirmed 1991 incident fractures in 1551 participants over a median follow-up of 5.3 years. Supplemental vitamin D3, as compared with placebo, did not have a significant effect on total fractures (which occurred in 769 of 12,927 participants in the vitamin D group and in 782 of 12,944 participants in the placebo group; hazard ratio, 0.98; 95% confidence interval [CI], 0.89 to 1.08; P = 0.70), nonvertebral fractures (hazard ratio, 0.97; 95% CI, 0.87 to 1.07; P = 0.50), or hip fractures (hazard ratio, 1.01; 95% CI, 0.70 to 1.47; P = 0.96). There was no modification of the treatment effect according to baseline characteristics, including age, sex, race or ethnic group, body-mass index, or serum 25-hydroxyvitamin D levels. There were no substantial between-group differences in adverse events as assessed in the parent trial. CONCLUSIONS: Vitamin D3 supplementation did not result in a significantly lower risk of fractures than placebo among generally healthy midlife and older adults who were not selected for vitamin D deficiency, low bone mass, or osteoporosis. (Funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases; VITAL ClinicalTrials.gov number, NCT01704859.).

Accounting for Surgical Confounding Factors Affecting Dual-Energy X-ray Absorptiometry in a Large Clinical Trial.

Joint replacements are among the most common orthopedic procedures performed in the U.S. and will continue to increase with the aging population. It is therefore necessary to account for these and other confounding factors, such as breast implants, when performing dual-energy X-ray absorptiometry (DXA) measurements. Whole-body DXA scans were performed in 771 participants (men ≥50 yr and women ≥55 yr) to assess bone mineral density (BMD) and body composition (fat and lean mass). In the DXA scan analyses of participants with internal metal, these affected regions of interest were replaced with measures from the unaffected, contralateral side, consistent with recommendations of the International Society for Clinical Densitometry. T-scores and Z-scores were recalculated using default sex and ethnicity-matched databases. We also explored effects of breast implants on bone density and body composition analyses. Approximately 13.1% of participants had internal metal artifacts at baseline. Replacing metal artifacts with the unaffected, contralateral side decreased the whole-body BMD by an average of 8.1% (SEM 0.84%; n = 67). In participants with unilateral hip (n = 17) and knee replacements (n = 20), BMD was decreased by an average of 14.1% (SEM 1.7%) and 11.2% (SEM 1.1%), respectively. Fat and lean mass were not significantly affected by metal artifacts, as differences between values with and without metal were within 1%. Two participants had bilateral breast implants, and in a separate trial, one participant had a unilateral breast implant. Bone mineral content (BMC) in the region with the breast implant was 5.8 times higher than the contralateral side, and whole-body BMC was increased by 4.7%. Metal artifacts and breast implants can confound DXA whole-body bone but not fat and lean results. It is therefore important in clinical studies to account for these factors to detect physiologically relevant differences in bone measures.

Vertebral Imaging in the Diagnosis of Osteoporosis: a Clinician's Perspective.

PURPOSE OF REVIEW: Vertebral fractures are the most common osteoporotic fracture and result in functional decline and excess mortality. Dual-energy x-ray absorptiometry (DXA) is the gold standard for the diagnosis of osteoporosis to identify patients at risk for fragility fractures; however, advances in imaging have expanded the role of computed tomography (CT) and magnetic resonance imaging (MRI) in evaluating bone health. RECENT FINDINGS: The utility of CT and MRI in the assessment of bone density is starting to gain traction, particularly when used opportunistically. DXA, conventional radiography, CT, and MRI can all be used to assess for vertebral fractures, and MRI can determine the acuity of fractures. Finally, advances in imaging allow for non-invasive assessment of measures of bone quality, including microarchitecture, bone strength, and bone turnover, to help identify and treat at-risk patients prior to sustaining a vertebral fracture. CT and MRI techniques remain primarily research tools to assess metabolic bone dysfunction, while use of DXA can be clinically expanded beyond measurement of bone density to assess for vertebral fractures and bone architecture to improve fracture risk assessment and guide treatment.

Vertebral Morphometry.

There is as yet no agreement about the criteria by which to arrive at an imaging diagnosis of a vertebral fracture. Because high-grade fractures result in alterations in vertebral shape, 1 possible avenue of diagnosis has been to quantitate changes in vertebral shape. The result has been a variety of methods for the relative and absolute measurements of vertebral dimensions. Such measurements have also lent themselves to automated computed analysis. The number of techniques reflects the absence of any consensus about the best. The semiquantitative technique proposed by Genant has become the most widely used and has served the field well for comparative purposes. Its use in higher grade fractures has been widely endorsed, if some concepts (e.g., short vertebral height-vertebrae) are at variance with lower grades of fracturing. Vertebral morphometry may be the only recourse in high volume epidemiological and interventional studies.

Utility of heel dual-energy X-ray absorptiometry in diagnosing osteoporosis.

Although peripheral dual-energy X-ray absorptiometry measurements have been found to predict fractures in population studies of white subjects, little is known about their utility in other races and in patients with greater risk of fracture. In a cross-sectional study of 874 women referred for bone mineral density (BMD) testing, we examined the utility of heel BMD in African-American (AA) compared with Caucasian (CA) women and in women using glucocorticoids. The ability of heel T-score to predict central osteoporosis was similar in AA and CA women (odds ratio [OR] per 1 unit decrease in T-score of 2.79 [95% confidence interval {CI} 2.16-3.60] and 3.15 [95% CI 2.53-3.92], respectively). The association between heel T-score and prevalent vertebral fractures was also similar in the 2 groups (OR 1.46 [95% CI 1.15-1.85] in AA and 1.42 [95% CI 1.16-1.74] in CA). In women using glucocorticoids heel T-score was better than central T-score in predicting vertebral fractures (OR 1.38 [95% CI 1.03-1.85] and 1.22 [95% CI 0.86-1.73], respectively). We conclude that in a multiracial referral population heel BMD predicts central osteoporosis and prevalent vertebral fractures equally well in AA as in CA women and may be better than central BMD in assessing fragility in glucocorticoid users.

Simplified criteria for selecting patients for vertebral fracture assessment.

The 2013 Position Development Conference of the International Society for Clinical Densitometry (ISCD) has adopted simplified indications for vertebral fracture assessment (VFA) based on an analysis of the Study of Osteoporotic Fractures (SOF). This showed that a simpler regression model, which included only age, bone mineral density (BMD), and height loss, was able to differentiate women with vertebral fractures from those without vertebral fractures almost as well as more complex models. We aimed to verify these findings in 1228 women referred for BMD testing and determine if the 2013 ISCD indications for VFA would perform as well the 2007 indications. The simple and complex SOF-based models were similar in terms of sensitivity (88.4% vs 89.4%), specificity (44.4% vs 45.5%), positive (25.9% vs 26.5%) and negative (94.5% vs 95.1%) predictive values, and area under the receiver operating characteristics curve (AUROC) (0.664 vs 0.674). The 2013 and 2007 ISCD VFA indications did not differ significantly in terms of sensitivity (88.2% vs 91.3%), specificity (41.3% vs 37.5%), positive (25.3% vs 22.9%) and negative (93.9% vs 95.5%) predictive values, and AUROC (0.648 vs 0.644). Our study provides support for the use of the simplified 2013 ISCD VFA indications as a practical approach to VFA testing.

Leptin is an effective treatment for hypothalamic amenorrhea.

Hypothalamic amenorrhea (HA) is associated with dysfunction of the hypothalamic-pituitary-peripheral endocrine axes, leading to infertility and bone loss, and usually is caused by chronic energy deficiency secondary to strenuous exercise and/or decreased food intake. Energy deficiency also leads to hypoleptinemia, which has been proposed, on the basis of observational studies as well as an open-label study, to mediate the neuroendocrine abnormalities associated with this condition. To prove definitively a causal role of leptin in the pathogenesis of HA, we performed a randomized, double-blinded, placebo-controlled trial of human recombinant leptin (metreleptin) in replacement doses over 36 wk in women with HA. We assessed its effects on reproductive outcomes, neuroendocrine function, and bone metabolism. Leptin replacement resulted in recovery of menstruation and corrected the abnormalities in the gonadal, thyroid, growth hormone, and adrenal axes. We also demonstrated changes in markers of bone metabolism suggestive of bone formation, but no changes in bone mineral density were detected over the short duration of this study. If these data are confirmed, metreleptin administration in replacement doses to normalize circulating leptin levels may prove to be a safe and effective therapy for women with HA.

Effects of Supplemental Vitamin D3, Omega-3 Fatty Acids on Physical Performance Measures in VITamin D and OmegA-3 TriaL.

CONTEXT: Declining muscle strength and performance in older adults are associated with falls, fractures, and premature death. OBJECTIVE: To determine whether supplementation with vitamin D3 or omega-3 fatty acids vs. placebo for 2 years improves physical performance measures. DESIGN: VITamin D and OmegA-3 TriaL (VITAL) was a double-blinded, placebo-controlled randomized trial of supplemental vitamin D3 and/or omega-3 fatty acids vs. placebo in the prevention of cancer and cardiovascular disease in 25,871 U.S. adults. This ancillary study was completed in a New England sub-cohort that had in-person evaluations at baseline and 2-year follow-up. SETTING: Center for Clinical Investigations in Boston. PARTICIPANTS: 1,054 participants (men ≥50 and women ≥55 years). INTERVENTIONS: 2x2 factorial design of supplemental vitamin D3 (cholecalciferol, 2000 IU/day) and/or marine omega-3 fatty acids (1 g/day). MAIN OUTCOME MEASURES: 2-year changes in physical performance measures of grip strength, walking speed, standing balance, repeated chair stands, and Timed-up and Go (TUG). RESULTS: At 2 years, all randomized groups showed worsening walking speeds and TUG. There were no differences in changes in grip strength, walking speeds, Short Physical Performance Battery (composite of walking speed, balance, and chair stands), and TUG between the vitamin D3-treated and the placebo-treated groups and between the omega-3-treated and the placebo-treated groups. Effects overall did not vary by sex, age, body mass index, or baseline measures of total or free 25-hydroxyvitamin D (25[OH]D) or plasma n-3 index; TUG slightly worsened with vitamin D supplementation, compared to placebo, in participants with baseline total 25(OH)D levels above the median (p=0.01, p for interaction=0.04). CONCLUSIONS: Neither supplemental vitamin D3 nor marine omega-3 fatty acids for 2 years improved physical performance in this generally healthy adult population.

Relative Energy Deficiency in sport (REDs): Endocrine manifestations, pathophysiology and treatments.

Research on lean, energy-deficient athletic and military cohorts has broadened the concept of the Female Athlete Triad into the Relative Energy Deficiency in Sport (REDs) syndrome. REDs represents a spectrum of abnormalities induced by low energy availability (LEA), which serves as the underlying cause of all symptoms described within the REDs concept, affecting exercising populations of either biological sex. Both short- and long-term LEA, in conjunction with other moderating factors, may produce a multitude of maladaptive changes that impair various physiological systems and adversely affect health, well-being, and sport performance. Consequently, the comprehensive definition of REDs encompasses a broad spectrum of physiological sequelae and adverse clinical outcomes related to LEA, such as neuroendocrine, bone, immune, and hematological effects, ultimately resulting in compromised health and performance. In this review, we discuss the pathophysiology of REDs and associated disorders. We briefly examine current treatment recommendations for REDs, primarily focusing on non-pharmacological, behavioral, and lifestyle modifications that target its underlying cause - energy deficit. We also discuss treatment approaches aimed at managing symptoms, such as menstrual dysfunction and bone stress injuries, and explore potential novel treatments that target the underlying physiology, emphasizing the roles of leptin and the activin-follistatin-inhibin axis, the roles of which remain to be fully elucidated, in the pathophysiology and management of REDs. In the near future, novel therapies leveraging our emerging understanding of molecules and physiological axes underlying energy availability or lack thereof may restore LEA-related abnormalities, thus preventing and/or treating REDs-related health complications, such as stress fractures, and improving performance.

Palmitate-derivatized human IL-2: a potential anticancer immunotherapeutic of low systemic toxicity.

PURPOSE AND EXPERIMENTAL DESIGN: Recombinant human IL-2 (rhIL-2) is a potent cytokine and FDA-approved anticancer drug. However, its clinical use has been limited by severe toxicity, associated primarily with systemic administration with excess protein distributing freely throughout the body. We hypothesized that rhIL-2 in alternate forms permitting more restricted localization may exert stronger antitumor efficacy and less toxicity. Here, we have tested the utility of palmitate-derivatized rhIL-2. rhIL-2 was reacted with N-hydroxysuccinimide palmitate ester. The resultant lipidated rhIL-2 (pIL-2), when mixed with cells, could spontaneously transfer from solution to cell surfaces. Next, anticancer efficacy of pIL-2 was assessed in two modalities. For adoptive T cell therapy, antitumor cytotoxic T cells (CTLs) were protein transferred ("painted") with pIL-2 and injected into mice bearing lymphoma. For in situ therapy, pIL-2 was injected intratumorally into mice bearing melanoma. Tumor growth and IL-2-associated toxicity were determined. RESULTS: In the lymphoma model, painting of the antitumor CTLs with pIL-2 markedly increased their viability and titer. In the melanoma model, intratumoral injection of pIL-2, but not rhIL-2, increased the number of activated CD8(+) T cells (IFN-γ(+)) in the spleen, reduced lung metastasis and prolonged the survival of treated mice. Moreover, while repeated intratumoral injection of rhIL-2 at an excessively high dose (10 injections of 10,000 IU/mouse) caused marked vascular leakage syndrome, the same regimen using pIL-2 caused no detectable toxicity. CONCLUSIONS: Transferring spontaneously from solution to cell surfaces, pIL-2 may bypass the current limitations of rhIL-2 and, thus, serve as a more effective and tolerable anticancer drug.

Thermionic current densities from first principles.

We present a density functional theory-based method for calculating thermionic emission currents from a cathode into vacuum using a non-equilibrium Green's function approach. It does not require semi-classical approximations or crude simplifications of the electronic structure used in previous methods and thus provides quantitative predictions of thermionic emission for adsorbate-coated surfaces. The obtained results match well with experimental measurements of temperature-dependent current densities. Our approach can thus enable computational design of composite electrode materials.

Rationale and design of an ancillary study evaluating the effects of the cocoa flavanol and/or multivitamin interventions on falls and physical performance outcomes in the COcoa Supplement and Multivitamin Outcomes Study (COSMOS).

BACKGROUND: Falls and decreased physical function increase markedly with age and result in injury, hospitalization, and premature death. Emerging studies show potential benefits of supplemental cocoa extract on physical performance, including grip strength and walking speed in older adults. However, there are no large, long-term randomized controlled trials of effects of supplemental cocoa extract on falls, muscle performance, and/or fall-related injuries. METHODS: The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) is a double-blind, placebo-controlled, 2 × 2 factorial trial investigating effects of supplementation with cocoa extract (500 mg/d, including 80 mg (-)-epicatechin) and/or a multivitamin on prevention of cardiovascular disease and cancer in 21,442 women (≥65 years) and men (≥60 years). COSMOS: Effects on Falls and Physical Performance is an ancillary study to COSMOS that will clarify effects of cocoa extract and/or multivitamin supplementation on falls, physical performance, and incident fracture outcomes in older adults. Injurious fall(s) resulting in healthcare utilization and recurrent falls were regularly assessed by follow-up questionnaires in the overall cohort. Incident fractures were also assessed by annual questionnaires. Circumstances surrounding falls and any fall-related injuries will be confirmed by medical record review. Effects of the interventions on 2-year changes in physical performance measures (grip strength, walking speed, and the Short Physical Performance Battery) will be tested in a clinic sub-cohort (n = 603). CONCLUSION: Results from this ancillary study will determine whether supplemental cocoa extract slows age-related declines in physical performance and decrease injurious and recurrent falls and fall-related injuries and fractures that are major public health problems in older adults.

Leptin in human physiology and therapeutics.

Leptin regulates energy homeostasis and reproductive, neuroendocrine, immune, and metabolic functions. In this review, we describe the role of leptin in human physiology and review evidence from recent "proof of concept" clinical trials using recombinant human leptin in subjects with congenital leptin deficiency, hypoleptinemia associated with energy-deficient states, and hyperleptinemia associated with garden-variety obesity. Since most obese individuals are largely leptin-tolerant or -resistant, therapeutic uses of leptin are currently limited to patients with complete or partial leptin deficiency, including hypothalamic amenorrhea and lipoatrophy. Leptin administration in these energy-deficient states may help restore associated neuroendocrine, metabolic, and immune function and bone metabolism. Leptin treatment is currently available for individuals with congenital leptin deficiency and congenital lipoatrophy. The long-term efficacy and safety of leptin treatment in hypothalamic amenorrhea and acquired lipoatrophy are currently under investigation. Whether combination therapy with leptin and potential leptin sensitizers will prove effective in the treatment of garden-variety obesity and whether leptin may have a role in weight loss maintenance is being greatly anticipated.

Team Approach: Preoperative Management of Metabolic Conditions in Total Joint Replacement.

¼: Total joint arthroplasties (TJAs) of the knee and hip have been considered 2 of the most successful surgical procedures performed to date. ¼: Frailty is defined as increased vulnerability to adverse outcomes with physiologic stress. ¼: Preoperative optimization of frailty and metabolic bone conditions, including osteoporosis, vitamin D deficiency, and diabetes, through a multidisciplinary approach can help improve outcomes and minimize costs after TJA.

Effects of Vitamin D3 Supplementation on Body Composition in the VITamin D and OmegA-3 TriaL (VITAL).

CONTEXT: Although observational studies show inverse associations between vitamin D status and body weight/adiposity, there are few large randomized controlled trials (RCTs) investigating this relationship. OBJECTIVE: To determine whether vitamin D3 supplementation lowers weight or improves body composition. DESIGN: The VITamin D and OmegA-3 TriaL (VITAL) was a double-blinded, placebo-controlled RCT including 25 871 US adults. This ancillary study was completed in a sub-cohort that underwent body composition assessments at baseline and 2-year follow-up (89% retention). SETTING: Harvard Clinical and Translational Science Center in Boston. PARTICIPANTS: 771 participants (men ≥ 50 and women ≥ 55 years). INTERVENTIONS: 2 × 2 factorial design of supplemental vitamin D3 (2000 IU/day) and/or omega-3 fatty acids (1 g/day). MAIN OUTCOME MEASURES: Endpoints were 2-year changes in weight, body mass index (BMI), waist circumference, and total and/or regional fat and lean tissue measures determined by dual-energy X-ray absorptiometry. Effect modification by clinical variables and total and free 25-hydroxyvitamin D (25[OH]D) levels was explored. RESULTS: There were no effects of supplemental vitamin D3vs placebo on weight, BMI, or measures of adiposity and lean tissue. Effects did not vary by sex, race/ethnicity, fat mass index, or baseline total or free 25(OH)D levels. Vitamin D3 supplementation did slightly improve body fat percentage in participants with normal BMI at baseline, but not in the overweight or obese (P for interaction = 0.04). CONCLUSIONS: Daily vitamin D3 supplementation vs placebo in the general older population did not improve weight or body composition. Whether supplemental vitamin D3 may benefit individuals with normal BMI warrants further study.

VITamin D and OmegA-3 TriaL (VITAL): Effects of Vitamin D Supplements on Risk of Falls in the US Population.

CONTEXT: It is unclear whether vitamin D supplementation reduces risk of falls, and results from randomized controlled trials (RCTs) are conflicting. OBJECTIVE: The objective of this work is to determine whether 2000 IU/day of supplemental vitamin D3 decreases fall risk. DESIGN: VITamin D and OmegA-3 TriaL (VITAL) is a double-blind, placebo-controlled RCT including 25 871 adults, randomly assigned November 2011 to March 2014 and treated for 5.3 years (median). SETTING: This is a nationwide study. PARTICIPANTS: Men 50 years or older and women 55 years or older (mean age, 67.1 years) without cancer or cardiovascular disease at baseline participated in this study. INTERVENTIONS: Interventions included vitamin D3 (cholecalciferol; 2000 IU/day) and/or omega-3 fatty acids (1 g/day) or respective placebos in a 2 × 2 factorial design. MAIN OUTCOME MEASURES: Main outcome measures include 2 or more falls and falls resulting in a doctor or hospital visit. RESULTS: Baseline serum total 25-hydroxyvitamin D (25[OH]D) level was 77 nmol/L; characteristics were well-balanced between groups. Numbers of participants with 2 or more falls were similar between active and placebo groups (9.8% vs 9.4%). Over 5 years, there were no differences in the proportion having 2 or more falls (odds ratio [OR] = 0.97; 95% CI, 0.90-1.05, P = .50), falls resulting in a doctor visit (OR = 1.03; 95% CI, 0.94-1.13, P = .46), or resulting in a hospital visit (OR = 1.04; 95% CI, 0.90-1.19, P = .61) between groups. Results did not differ between those with baseline 25(OH)D less than 50 vs 50 nmol/L or greater or other cut points. CONCLUSION: Daily supplemental vitamin D3 vs placebo did not decrease fall risk in generally healthy adults not selected for vitamin D insufficiency. This large RCT does not indicate that supplemental vitamin D should be used for primary prevention of falls in the US population.

Effects of Supplemental Vitamin D on Bone Health Outcomes in Women and Men in the VITamin D and OmegA-3 TriaL (VITAL).

Although supplemental vitamin D is used to promote bone health in the general population, data from randomized controlled trials (RCTs) have been inconsistent. We determined whether daily, vitamin D3 supplementation improves bone mineral density (BMD) and/or structure. VITamin D and OmegA-3 TriaL (VITAL) is a double-blind, placebo-controlled RCT of supplemental vitamin D3 (2000 IU/d) and/or omega-3 fatty acids (1 g/d) in 25,871 adults nationwide. This ancillary study included a subcohort of 771 participants (men ≥50 and women ≥55 years; not taking bone active medications) evaluated at baseline and at 2-year follow-up (89% retention). Total 25(OH)D levels were measured by liquid chromatography tandem mass spectrometry (Quest Diagnostics, San Juan Capistrano, CA, USA). Free 25(OH)D (FVD) levels were measured using the ELISA assay by Future Diagnostics Solutions BV (Wijchen, Netherlands). Primary endpoints were 2-year changes in areal (a) BMD at the spine, hip, and whole body determined by dual-energy X-ray absorptiometry (DXA). Secondary endpoints were 2-year changes in volumetric (v) BMD and cortical thickness at the radius and tibia assessed by peripheral quantitative computed tomography. Supplemental vitamin D3 versus placebo had no effect on 2-year changes in aBMD at the spine (0.33% versus 0.17%; p = 0.55), femoral neck (-0.27% versus -0.68%; p = 0.16), total hip (-0.76% versus -0.95%; p = 0.23), or whole body (-0.22% versus -0.15%; p = 0.60), or on measures of bone structure. Effects did not vary by sex, race/ethnicity, body mass index, or 25(OH)D levels. Among participants with baseline FVD levels below the median (<14.2 pmol/L), there was a slight increase in spine aBMD (0.75% versus 0%; p = 0.043) and attenuation in loss of total hip aBMD (-0.42% versus -0.98%; p = 0.044) with vitamin D3 . Whether baseline FVD levels help to identify those more likely to benefit from supplementation warrants further study. Supplemental vitamin D3 versus placebo for 2 years in general healthy adults not selected for vitamin D insufficiency did not improve BMD or structure. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.