Hip load capacity cut-points for Astronaut Skeletal Health NASA Finite Element Strength Task Group Recommendations.

Concerns raised at a 2010 Bone Summit held for National Aeronautics and Space Administration Johnson Space Center led experts in finite element (FE) modeling for hip fracture prediction to propose including hip load capacity in the standards for astronaut skeletal health. The current standards for bone are based upon areal bone mineral density (aBMD) measurements by dual X-ray absorptiometry (DXA) and an adaptation of aBMD cut-points for fragility fractures. Task Group members recommended (i) a minimum permissible outcome limit (POL) for post-mission hip bone load capacity, (ii) use of FE hip load capacity to further screen applicants to astronaut corps, (iii) a minimum pre-flight standard for a second long-duration mission, and (iv) a method for assessing which post-mission physical activities might increase an astronaut's risk for fracture after return. QCT-FE models of eight astronaut were analyzed using nonlinear single-limb stance (NLS) and posterolateral fall (NLF) loading configurations. QCT data from the Age Gene/Environment Susceptibility (AGES) Reykjavik cohort and the Rochester Epidemiology Project were analyzed using identical modeling procedures. The 75th percentile of NLS hip load capacity for fractured elderly males of the AGES cohort (9537N) was selected as a post-mission POL. The NLF model, in combination with a Probabilistic Risk Assessment tool, was used to assess the likelihood of exceeding the hip load capacity during post-flight activities. There was no recommendation to replace the current DXA-based standards. However, FE estimation of hip load capacity appeared more meaningful for younger, physically active astronauts and was recommended to supplement aBMD cut-points.

The Association Between Protein Intake by Source and Osteoporotic Fracture in Older Men: A Prospective Cohort Study.

Dietary protein is a potentially modifiable risk factor for fracture. Our objectives were to assess the association of protein intake with incident fracture among older men and whether these associations varied by protein source or by skeletal site. We studied a longitudinal cohort of 5875 men (mean age 73.6 ± 5.9 years) in the Osteoporotic Fractures in Men (MrOS) study. At baseline, protein intake was assessed as percent of total energy intake (TEI) with mean intake from all sources = 16.1%TEI. Incident clinical fractures were confirmed by physician review of medical records. There were 612 major osteoporotic fractures, 806 low-trauma fractures, 270 hip fractures, 193 spine fractures, and 919 non-hip non-spine fractures during 15 years of follow-up. We used Cox proportional hazards models with age, race, height, clinical site, TEI, physical activity, marital status, osteoporosis, gastrointestinal surgery, smoking, oral corticosteroids use, alcohol consumption, and calcium and vitamin D supplements as covariates to compute hazard ratios (HRs) with 95% confidence intervals (CIs), all expressed per unit (SD = 2.9%TEI) increase. Higher protein intake was associated with a decreased risk of major osteoporotic fracture (HR = 0.92; 95% CI, 0.84 to 1.00) with a similar association found for low-trauma fracture. The association between protein and fracture varied by protein source; eg, increased dairy protein and non-dairy animal protein were associated with a decreased risk of hip fracture (HR = 0.80 [95% CI, 0.65 to 0.98] and HR = 0.84 [95% CI, 0.72 to 0.97], respectively), whereas plant-source protein was not (HR = 0.99 [95% CI, 0.78 to 1.24]). The association between protein and fracture varied by fracture site; total protein was associated with a decreased risk of hip fracture (HR = 0.84 [95% CI, 0.73 to 0.95]), but not clinical spine fracture (HR = 1.06 [95% CI, 0.92 to 1.22]). In conclusion, those with high protein intake (particularly high animal protein intake) as a percentage of TEI have a lower risk of major osteoporotic fracture. © 2016 American Society for Bone and Mineral Research.

What Proportion of Incident Radiographic Vertebral Fractures in Older Men Is Clinically Diagnosed and Vice Versa: A Prospective Study.

To determine the proportion of incident radiographic vertebral fractures (vfx) also diagnosed as incident clinical vfx in older men and vice-versa, we used data from 4398 community-dwelling men age ≥65 years enrolled in the Osteoporotic Fractures in Men (MrOS) study. Incident radiographic vfx were identified by comparing baseline and follow-up lateral thoracic and lumbar spine study films (average 4.6 years between films) using a semiquantitative (SQ) method and defined as a change in SQ reading of ≥1 at a given vertebral level from baseline to follow-up study radiograph. Participants were contacted triannually to ascertain incident clinical vfx; community spinal imaging studies were obtained and clinical vfx were confirmed when the study radiologist determined that the community imaging study showed a new deformity of higher grade than was present in the same vertebra on the baseline study radiograph. A total of 237 incident radiographic vfx were identified in 197 men, whereas 31 men experienced 37 confirmed incident clinical vfx. Of incident radiographic vfx, 13.5% were also clinically diagnosed as incident fractures, with clinical diagnoses made for 16.3% of the radiographic vfx with SQ grade change ≥2. Of incident clinical vfx, 86.5% were identified as incident radiographic vfx, most of them with SQ grade change ≥2. In summary, less than 15% of incident radiographic vfx were also clinically diagnosed, whereas the majority of incident clinical vfx were identified as severe radiographic vfx. These results in men supplement those previously published for women and suggest a complex relationship between clinical and radiographic vfx in older adults. Published 2016.(†) American Society for Bone and Mineral Research.

Higher 25(OH)D2 is associated with lower 25(OH)D3 and 1,25(OH)2D3.

CONTEXT: Despite common use of supplemental vitamin D2 in clinical practice, the associations of serum vitamin D2 concentrations with other vitamin D metabolites and total vitamin D are unclear. OBJECTIVE: The aim of the study was to measure vitamin D2 and D3 levels and examine their associations with each other and with total vitamin D. DESIGN: We performed a cross-sectional analysis of 679 randomly selected participants from the Osteoporotic Fractures in Men Study. 25-Hydroxyvitamin D2 [25(OH)D2], 25(OH)D3, 1,25-dihydroxyvitamin D2 [1,25(OH)2D2], and 1,25(OH)2D3 were measured using liquid chromatography-tandem mass spectrometry and were summed to obtain total 25(OH)D and 1,25(OH)2D. Associations between all metabolites (D2, D3, and total levels) were examined using Wilcoxon rank-sum tests and Spearman correlations. RESULTS: 25(OH)D2 and 1,25(OH)2D2 were detectable in 189 (27.8%) and 178 (26.2%) of the men, respectively. Higher 25(OH)D2 levels did not correlate with higher total 25(OH)D (r = 0.10; P = .17), although median total 25(OH)D was slightly higher in those with detectable vs undetectable 25(OH)D2 (25.8 vs 24.3 ng/mL; P < .001). 25(OH)D2 was not positively associated with total 1,25(OH)2D levels (r = -0.11; P = .13), and median 1,25(OH)2D level was not higher in those with detectable vs undetectable 25(OH)D2. Higher 25(OH)D2 was associated with lower 25(OH)D3 (r = -0.35; P < .001) and 1,25(OH)2D3 (r = -0.32; P < .001), with median levels of both D3 metabolites 18-35% higher when D2 metabolites were undetectable. CONCLUSIONS: In a cohort of older men, 25(OH)D2 is associated with lower levels of 25(OH)D3 and 1,25(OH)2D3, suggesting that vitamin D2 may decrease the availability of D3 and may not increase calcitriol levels.

Circulating vitamin D, supplement use, and cardiovascular disease risk: the MrOS Sleep Study.

CONTEXT: Evidence suggests an inverse association between circulating 25(OH) vitamin D and cardiovascular disease (CVD). OBJECTIVE: To determine the association between serum 25(OH) vitamin D and risk for CVD events. SETTING AND DESIGN: From March 2000 to April 2002, participants were recruited for the Osteoporotic Fractures in Men (MrOS) study. Between December 2003 and March 2005, members of the MrOS cohort were invited to participate in the MrOS Sleep Study. Participants were recruited from 6 clinical centers across the United States and followed for a mean of 5.9 years. Three-thousand-one-hundred-thirty-five men ages 65 and older were included from the MrOS cohort, of whom 116 were excluded for missing vitamin D or CVD data. Participants were divided into two groups based on serum 25(OH) vitamin D levels, <20 ng/mL and ≥20 ng/mL. Participants were followed for CVD endpoints including coronary heart disease (CHD) and cerebrovascular events. Age- and multivariable-adjusted hazard ratios were calculated and stratified by use of vitamin D containing supplements. RESULTS: We observed no significant association between circulating 25(OH) vitamin D and risk of CVD event (HR, 0.91; 95% confidence interval (CI), 0.73-1.13) and CHD event (HR, 0.81; 95% CI, 0.61-1.07). For cerebrovascular events, men with vitamin D deficiency exhibited a higher risk (HR, 1.44; 95% CI, 1.00-2.08) using the minimally adjusted model and after excluding supplement users (HR, 1.70; 95% CI, 1.02-2.83). CONCLUSIONS: 25(OH) vitamin D was not associated with risk of CVD and CHD events. However, vitamin D deficiency may be associated with an increased risk of cerebrovascular events.

Relationships between serum and urine phosphorus with all-cause and cardiovascular mortality: the Osteoporotic Fractures in Men (MrOS) Study.

BACKGROUND: Serum phosphorus is associated with cardiovascular disease (CVD) in the general population, but may not comprehensively reflect phosphorus homeostasis. Whether urine phosphorus-creatinine ratio (a marker of intestinal absorption) or urine fractional excretion of phosphorus (FEPi; a marker of urinary phosphorus handling) is associated with risk of mortality or CVD is uncertain. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: 1,325 community-dwelling men 65 years or older participating in the MrOS Study. PREDICTOR: Serum phosphorus, urine phosphorus-creatinine ratio, and FEPi. OUTCOMES: All-cause and CVD death. RESULTS: Mean age was 74 ± 6 (SD) years, estimated glomerular filtration rate was 75 ± 16 mL/min/1.73 m(2), and serum phosphorus level was 3.2 ± 0.4 mg/dL. During a median follow-up of 9.3 years, there were 364 (120 CVD) deaths. After adjustment for demographics, CVD risk factors, and kidney function, the risks of all-cause death in the highest quartiles of serum phosphorus (≥3.6 mg/dL), urine phosphorus-creatinine ratio (≥0.55), and FEPi (≥18%) were 1.63 (95% CI, 1.23-2.17), 1.22 (95% CI, 0.90-1.65), and 0.88 (95% CI, 0.64-1.23), respectively, compared to the lowest quartiles of each. Results were similar for CVD death. Results also were similar in those with estimated glomerular filtration rate ≥60 and <60 mL/min/1.73 m(2). LIMITATIONS: Older all-male cohort. Few had advanced chronic kidney disease. Spot urine specimens were used. CONCLUSIONS: In community-living older men, higher serum phosphorus concentrations are associated with all-cause and CVD death. In contrast, urine phosphorus-creatinine ratio and FEPi are not. These findings do not support using urine phosphorus-creatinine ratio or FEPi as adjuvant measures to predict risk of mortality or CVD in the general population.

Fracture risk and zoledronic acid therapy in men with osteoporosis.

BACKGROUND: Fractures in men are a major health issue, and data on the antifracture efficacy of therapies for osteoporosis in men are limited. We studied the effect of zoledronic acid on fracture risk among men with osteoporosis. METHODS: In this multicenter, double-blind, placebo-controlled trial, we randomly assigned 1199 men with primary or hypogonadism-associated osteoporosis who were 50 to 85 years of age to receive an intravenous infusion of zoledronic acid (5 mg) or placebo at baseline and at 12 months. Participants received daily calcium and vitamin D supplementation. The primary end point was the proportion of participants with one or more new morphometric vertebral fractures over a period of 24 months. RESULTS: The rate of any new morphometric vertebral fracture was 1.6% in the zoledronic acid group and 4.9% in the placebo group over the 24-month period, representing a 67% risk reduction with zoledronic acid (relative risk, 0.33; 95% confidence interval, 0.16 to 0.70; P=0.002). As compared with men who received placebo, men who received zoledronic acid had fewer moderate-to-severe vertebral fractures (P=0.03) and less height loss (P=0.002). Fewer participants who received zoledronic acid had clinical vertebral or nonvertebral fractures, although this difference did not reach significance because of the small number of fractures. Bone mineral density was higher and bone-turnover markers were lower in the men who received zoledronic acid (P<0.05 for both comparisons). Results were similar in men with low serum levels of total testosterone. The zoledronic acid and placebo groups did not differ significantly with respect to the incidence of death (2.6% and 2.9%, respectively) or serious adverse events (25.3% and 25.2%). CONCLUSIONS: Zoledronic acid treatment was associated with a significantly reduced risk of vertebral fracture among men with osteoporosis. (Funded by Novartis Pharma; ClinicalTrials.gov number, NCT00439647.).

Once-yearly zoledronic acid in older men compared with women with recent hip fracture.

OBJECTIVES: To assess the efficacy of once-yearly zoledronic acid (ZOL) 5 mg in increasing bone mineral density (BMD) in men with a recent hip fracture participating in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once- Yearly Recurrent Fracture Trial and to compare the efficacy with that in women from the same study. DESIGN: Randomized, placebo-controlled, double-blind trial. SETTING: International multicenter. PARTICIPANTS: Five hundred and eight men and 1,619 women within 90 days of surgical repair of low-trauma hip fracture in the same study (for comparison). INTERVENTION: Once-yearly intravenous (IV) ZOL 5 mg (n = 248) or placebo (n = 260), loading dose of vitamin D, daily calcium, and vitamin D supplements. MEASUREMENT: Changes in BMD. RESULTS: Percentage change from baseline in total hip BMD at Months 12 and 24 was significantly higher with ZOL than with placebo (between-group difference, 2.0%, P = .003, and 3.8%, P = .002, respectively). Percentage change from baseline in femoral neck BMD at Month 24 was significantly higher with ZOL than with placebo (3.8%, P = .003). The BMD benefit was comparable with that observed in women in this study. New clinical fractures occurred in 36 (7.1%) participants (ZOL, n = 16; placebo, n = 20; P = .64). The ZOL safety profile was comparable with that of placebo, with no significant differences in cardiovascular or long-term renal function and a trend toward lower mortality in ZOL-treated men. CONCLUSION: Once-yearly IV ZOL 5 mg increases bone mass at the hip and femoral neck in men within 90 days of repair of a low-trauma hip fracture. Increases were of a similar magnitude to those observed in women in the same study.

Associations of estradiol and testosterone with serum phosphorus in older men: the Osteoporotic Fractures in Men study.

Postmenopausal women consistently have higher phosphorus levels than similarly aged men. As it is known that estradiol induces phosphaturia in rodents, we evaluated the cross-sectional association of sex hormones with serum phosphorus in 1346 community-living older men (mean age 76) of which 18% had moderate (stage 3) kidney disease. Using linear regression with serum phosphorus levels as the dependent variable, we found that for each 10 pg/ml higher total estradiol level there was a statistically significant 0.05 mg/dl lower serum phosphorus when adjusted for age, ethnicity, testosterone, sex hormone-binding globulin, calcium, estimated glomerular filtration rate, intact parathyroid hormone, 25(OH) vitamin D, bone mineral density, and alkaline phosphatase. These results were similar in individuals with or without chronic kidney disease. Serum testosterone concentrations were also statistically significantly associated with lower serum phosphorus levels. We confirmed these results in an independent sample of 2555 older men, wherein these associations were not attenuated when adjusted for fibroblast growth factor-23 levels. Hence, our study of community-living older men suggests that estradiol may directly or indirectly induce phosphaturia in humans. The mechanism responsible for the association of testosterone with serum phosphorus remains to be determined.

Vitamin D deficiency in older men.

CONTEXT: Vitamin D deficiency is not adequately evaluated in older men. OBJECTIVE: The aim of the study was to determine the prevalence of vitamin D deficiency and identify risk factors for its occurrence. DESIGN AND SETTING: We conducted a cross-sectional evaluation of 1606 older men in the general community who were enrolled in the Osteoporotic Fractures in Men Study. PARTICIPANTS: A randomly selected subcohort of a large population of men from six U.S. communities participated in the study. MAIN OUTCOME MEASURES: Serum concentrations of 25-hydroxyvitamin D(2) [25(OH)D(2)] and 25(OH)D(3) were measured using mass spectrometry. RESULTS: Deficiency [25(OH)D <20 ng/ml] was present in 26%, and insufficiency (<30 ng/ml) was present in 72%. Deficiency was particularly common among men during the winter and spring (especially in the northern communities) and in the oldest and more obese men. For instance, in Caucasian men in winter or spring who were >80 yr old, did not engage in lawn/garden work, and had a body mass index greater than 25 kg/m(2) and vitamin D intake below 400 IU/d, the prevalence of vitamin D deficiency was 86%. 25(OH)D(2) levels were present in a small fraction of men and accounted for a low proportion of total 25(OH)D levels. The use of vitamin D supplements was reported by 58% of men, but supplement use had a small effect on total 25(OH)D levels and, despite supplement use, low levels remained frequent. CONCLUSIONS: Vitamin D deficiency is common in older men and is especially prevalent in obese, sedentary men living at higher latitudes. Use of vitamin D supplements at levels reported here did not result in adequate vitamin D nutrition.

Acid-suppressive medications and risk of bone loss and fracture in older adults.

Recent studies have suggested an increased fracture risk with acid-suppressive medication use. We studied two cohorts of men and women over age 65 who were enrolled in the Osteoporotic Fractures in Men Study (MrOS) and the Study of Osteoporotic Fractures (SOF), respectively. We used dual-energy X-ray absorptiometry and assessed baseline use of proton pump inhibitors (PPIs) and/or H2 receptor antagonists (H2RAs) in 5,755 men and 5,339 women. Medication use and bone mineral density (BMD) were assessed, and hip and other nonspine fractures were documented. On multivariate analysis, men using either PPIs or H2RAs had lower cross-sectional bone mass. No significant BMD differences were observed among women. However, there was an increased risk of nonspine fracture among women using PPIs (relative hazard [RH] = 1.34, 95% confidence interval [CI] 1.10-1.64). PPI use was also associated with an increased risk of nonspine fracture in men but only among those who were not taking calcium supplements (RH = 1.49, 95% CI 1.04-2.14). H2RA use was not associated with nonspine fractures, and neither H2RA use nor PPI use was associated with incident hip fractures in men or women. The use of PPIs in older women, and perhaps older men with low calcium intake, may be associated with a modestly increased risk of nonspine fracture.

Osteoporosis in men.

With the aging of the population, there is a growing recognition that osteoporosis and fractures in men are a significant public health problem, and both hip and vertebral fractures are associated with increased morbidity and mortality in men. Osteoporosis in men is a heterogeneous clinical entity: whereas most men experience bone loss with aging, some men develop osteoporosis at a relatively young age, often for unexplained reasons (idiopathic osteoporosis). Declining sex steroid levels and other hormonal changes likely contribute to age-related bone loss, as do impairments in osteoblast number and/or activity. Secondary causes of osteoporosis also play a significant role in pathogenesis. Although there is ongoing controversy regarding whether osteoporosis in men should be diagnosed based on female- or male-specific reference ranges (because some evidence indicates that the risk of fracture is similar in women and men for a given level of bone mineral density), a diagnosis of osteoporosis in men is generally made based on male-specific reference ranges. Treatment consists both of nonpharmacological (lifestyle factors, calcium and vitamin D supplementation) and pharmacological (most commonly bisphosphonates or PTH) approaches, with efficacy similar to that seen in women. Increasing awareness of osteoporosis in men among physicians and the lay public is critical for the prevention of fractures in our aging male population.

Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use.

All therapies currently recommended for the management of osteoporosis act mainly to inhibit bone resorption and reduce bone remodeling. PTH and its analog, teriparatide [recombinant human PTH(1-34)], represent a new class of anabolic therapies for the treatment of severe osteoporosis, having the potential to improve skeletal microarchitecture. Significant reductions in both vertebral and appendicular fracture rates have been demonstrated in the phase III trial of teriparatide, involving elderly women with at least one prevalent vertebral fracture before the onset of therapy. However, there is as yet no evidence that the antifracture efficacy of PTH will be superior to the bisphosphonates, whereas cost-utility estimates suggest that teriparatide is significantly more expensive. Teriparatide should be considered as treatment for postmenopausal women and men with severe osteoporosis, as well as for patients with established glucocorticoid-induced osteoporosis who require long-term steroid treatment. Teriparatide should also be considered for the management of individuals at particularly high risk for fractures, including subjects who are younger than age 65 and who have particularly low bone mineral density measurements (T scores < or = 3.5). Teriparatide therapy is not recommended for more than 2 yr, based, in part, on the induction of osteosarcoma in a rat model of carcinogenicity. Total daily calcium intake from both supplements and dietary sources should be limited to 1500 mg together with adequate vitamin D intake (< or =1000 U/d). Monitoring of serum calcium may be safely limited to measurement after 1 month of treatment; mild hypercalcemia may be treated by withdrawing dietary calcium supplements, reducing the dosing frequency of PTH, or both. At present, concurrent therapy with antiresorptive therapy, particularly bisphosphonates, should be avoided, although sequential therapy with such agents may consolidate the beneficial effects upon the skeleton after PTH is discontinued.