Cross-sectional and longitudinal analysis of bone age maturation during peri-pubertal growth in children with type I, III and IV osteogenesis imperfecta.

Osteogenesis imperfecta (OI)is a rare genetically heterogeneous disorder caused by changes in the expression or processing of type I collagen. Clinical manifestations include bone fragility, decreased linear growth, and skeletal deformities that vary in severity. In typically growing children, skeletal maturation proceeds in a predictable pattern of changes in the size, shape, and mineralization on the hand and wrist bones that can be followed radiographically known at the bone age. Assessment of bone age can be clinically used to assess time remaining for linear growth, and the onset and duration of puberty, both of which can be useful in determining the timing of some surgeries or the interpretation of other imaging modalities such as bone densitometry. Additionally, deviations in the expected maturation process of the bone age may prompt or assist in the work up of a significant delay or advancement in a child's growth pattern. The primary aim of our study was to determine whether the bone age in children with a skeletal disorder such as OI follow the same pattern and rate of bone maturation compared to a control population. Using participants from the Natural History Study of the Brittle Bone Disorders Consortium, we analyzed 159 left hand and wrist radiographs (bone age) for a cross-sectional analysis and 55 bone ages repeated at approximately 24 months for a longitudinal analysis of skeletal maturation. Bone ages were read by a pediatric endocrinologist and by an automated analysis using a program called BoneXpert. Our results demonstrated that in children with mild-to-moderate OI (types I and IV), the skeletal maturation is comparable to chronological age-mated controls. For those with more severe forms of OI (type III), there is a delayed pattern of skeletal maturation of less than a year (10.5 months CI 5.1-16) P = 0.0012) at baseline and a delayed rate of maturation over the two-year follow up compared to type I (P = 0.06) and type III (P = 0.02). However, despite these parameters being statistically different, they may not be clinically significant. We conclude the bone age, with careful interpretation, can be used in the OI population in a way that is similar to the general pediatric population.

Alterations of a serum marker of collagen X in growing children with osteogenesis imperfecta.

Abnormalities in the structure and/or processing of type I collagen cause osteogenesis imperfecta and result in bone fragility, abnormal bone growth and short stature. Type I collagen is expressed in the growth plate but the mechanisms by which abnormalities in collagen I contribute to growth plate dysfunction and growth retardation are unknown. The non-collagenous domain (NC1) of type X collagen (CXM) is released from the hypertrophic zone of active growth plates and is a marker for new endochondral bone formation. Serum CXM levels are strongly correlated with the rate of growth in healthy children. We hypothesized that CXM levels in children with OI would be abnormal when compared to normally growing children. Using participants from the Brittle Bone Disease Consortium Natural History Study we analyzed the distribution of CXM over the ages of 8 months to 40 years in 187 subjects with OI (89 type I and 98 types III/IV) as well as analyzed the relationship between growth velocity and CXM levels in a subset of 100 children <16 years old with OI (44 type I and 56 types III/IV). CXM levels in both control and OI children demonstrated a similar pattern of variation by age with higher levels in early life and puberty followed by a post-pubertal drop. However, there was greater variability within the OI cohort and the relationship with growth velocity was weaker. The ratio of CXM level to growth velocity was elevated in children with type III/IV OI compared to controls. These results suggest that the relationship between hypertrophic zone function and the end point of skeletal growth is disrupted in OI.

Randomized, controlled trial to assess the safety and efficacy of odanacatib in the treatment of men with osteoporosis.

Odanacatib (ODN) was investigated as an osteoporosis treatment in 292 men. Compared with placebo, odanacatib improved bone mineral density and led to sustained bone resorption decreases while producing relatively little bone formation reduction that leveled off with time. However, increased risk of stroke in another study stopped further odanacatib development. INTRODUCTION: ODN, a selective oral cathepsin K inhibitor, was in development for osteoporosis treatment. This phase 3, double-blind, randomized, placebo-controlled, 24-month study investigated ODN safety and efficacy in men with osteoporosis. METHODS: Men with idiopathic osteoporosis or osteoporosis due to hypogonadism and a lumbar spine or hip (total hip [TH], femoral neck [FN], or trochanter) bone mineral density (BMD) T-score of ≤ - 2.5 to ≥ - 4.0 without prior vertebral fracture or ≤ - 1.5 to ≥ - 4.0 with one prior vertebral fracture were randomized (1:1) to once-weekly ODN 50 mg or placebo. All received 5600 IU vitamin D3 weekly and calcium supplementation as needed (≥ 1200 mg daily). The primary efficacy outcome was changed from baseline in lumbar spine BMD versus placebo. RESULTS: Overall, 292 men, mean age 68.8 years, were randomly assigned to ODN or placebo. Versus placebo, ODN increased BMD from baseline at the lumbar spine, TH, FN, and trochanter by 5.6%, 2.0%, 1.7%, and 2.1%, respectively (all p < 0.01), and decreased uNTx/Cr (68%, p < 0.001), sCTx (77%, p < 0.001), sP1NP (16%, p = 0.001), and sBSAP (8%, p = 0.019). The between-group bone formation marker decrease peaked at 3 months, then returned toward baseline. The safety profile, including cardiovascular events, was similar between groups. CONCLUSION: Though a promising osteoporosis therapy for men, ODN development was discontinued due to increased risk of stroke in the LOFT phase 3 trial. TRIAL REGISTRATION: Clinicaltrials.gov NCT01120600 (registered May 11, 2010).

Sleep duration and bone health measures in older men.

The associations between objective measures of sleep duration and bone outcomes in older men are unknown. No consistent, significant association was identified between sleep duration and bone mineral density (BMD) in the current analysis. However, future research should determine if vitamin D status modifies this relationship. INTRODUCTION: Prior studies, predominantly in women, reported that long and short self-reported sleep duration are associated with lower BMD. Associations between actigraphy-determined sleep duration and BMD or bone turnover markers (BTMs) in older men are unknown. METHODS: Men in The Osteoporotic Fractures in Men (MrOS) Study with wrist actigraphy and concurrent BMD assessment but without comorbidities affecting bone health were included. Sleep duration was considered as a continuous (N = 1926) and dichotomized variable where men were classified as getting the recommended (7-8 h/night; N = 478) or short (< 6 h/night; N = 577) sleep. The cross-sectional association between BMD, BTMs, and sleep duration was examined using a t test or linear regression, where appropriate, in unadjusted and adjusted models. RESULTS: There were no clinically or statistically significant differences in BMD at the L-spine, total hip, or femoral neck between men getting the recommended vs. short sleep duration, using actigraphy or self-reported sleep duration (all p ≥ 0.07). When sleep duration was considered as a continuous variable, femoral neck BMD was higher in men with longer self-reported sleep duration (ß = 0.006 ±0.003, p = 0.02), but this was not significant after further adjustment. In men with low 25OHD (< 20 ng/mL), longer actigraphy-determined sleep duration was associated with higher total hip BMD (ß = 0.016 ± 0.008; p = 0.04). Sleep duration and BTMs were not associated. CONCLUSION: Sleep duration was not associated with hip or L-spine BMD or BTMs in older men. Future research should determine if vitamin D status or other factors modify this relationship.

Subregional statistical shape modelling identifies lesser trochanter size as a possible risk factor for radiographic hip osteoarthritis, a cross-sectional analysis from the Osteoporotic Fractures in Men Study.

OBJECTIVE: Statistical shape modelling (SSM) of hip dual-energy X-ray absorptiometry (DXA) scans has identified relationships between hip shape and radiographic hip OA (rHOA). We aimed to further elucidate shape characteristics related to rHOA by focusing on subregions identified from whole-hip shape models. METHOD: SSM was applied to hip DXAs obtained in the Osteoporotic Fractures in Men Study. Whole-hip shape modes (HSMs) associated with rHOA were combined to form a composite at-risk-shape. Subsequently, subregional HSMs (cam-type and lesser trochanter modes) were built, and associations with rHOA were examined by logistic regression. Subregional HSMs were further characterised, by examining associations with 3D-HSMs derived from concurrent hip CT scans. RESULTS: 4,098 participants were identified with hip DXAs and radiographs. Composite shapes from whole-hip HSMs revealed that lesser trochanter size and cam-type femoral head are related to rHOA. From sub-regional models, lesser trochanter mode (LTM)1 [OR 0.74; 95%CI 0.63.0.87] and cam-type mode (CTM)3 [OR 1.27; 1.13.1.42] were associated with rHOA, associations being similar to those for whole hip HSMs. 515 MrOS participants had hip DXAs and 3D-HSMs derived from hip CT scans. LTM1 was associated with 3D-HSMs that also represented a larger lesser trochanter [3D-HSM7 (beta (ß)-0.23;-0.33,-0.14) and 3D-HSM9 (ß0.36; 0.27.0.45)], and CTM3 with 3D-HSMs describing cam morphology [3D-HSM3 (ß-0.16;-0.25,-0.07) and 3D-HSM6 (ß 0.19; 0.10.0.28)]. CONCLUSION: Subregional SSM of hip DXA scans suggested larger lesser trochanter and cam morphology underlie associations between overall hip shape and rHOA. 3D hip modelling suggests our subregional SSMs represent true anatomical variations in hip shape, warranting further investigation.

Investigation of the Diet-Gut-Muscle Axis in the Osteoporotic Fractures in Men Study.

OBJECTIVES: To investigate the association between dietary fiber density (grams of fiber consumed per 100 kcal) with the gut-muscle axis in older adult men. DESIGN: Cross-sectional study. SETTING: Osteoporotic Fractures in Men (MrOS) cohort participants at Visit 4 (2014-16). PARTICIPANTS: Older adult men (average age, 85y) from the MrOS study. MEASUREMENTS: Men who were in the highest tertiles for dietary fiber density and the percentage of whole body lean mass were defined as T3T3 (n=42), whereas men who were in the lowest and intermediate tertiles for these variables were defined as T1T1 (n=32), T1T3 (n=24), and T3T1 (n=13), respectively. Additionally, measures of physical function, including the short physical performance battery (SPPB) score and grip strength were higher in T3T3 when compared with T1T1. Gut bacterial abundance was quantified with use of 16S v4 rRNA sequencing, and the bacterial functional potential was derived from the 16S data with PICRUSt. Chao1, ACE, Shannon, Simpson, and Fisher indices were used as measures of α-diversity. Weighted and unweighted Unifrac, and Bray-Curtis were used as measures of ß-diversity. Age, physical activity score, smoking, and number of medications-adjusted DESeq2 models were used to identify bacteria and functions that were different when comparing T3T3 with T1T1, but that were not also different when comparing T3T3 with T1T3 or T3T1. RESULTS: α-diversity was not different, but significant differences for ß-diversity (unweighted UniFrac, Bray-Curtis) were identified when comparing T3T3 with T1T1. Known butyrate-producing bacteria, including Ruminococcus, Lachnospira, and Clostridia, and gene counts for butyrate production (KEGG IDs: K01034, K01035) were higher in T3T3, when compared with T1T1. CONCLUSION: These data suggest that a high-fiber diet may positively impact butyrate-producing genera and gene counts, which collectively may be involved in mechanisms related to the percentage of whole body lean mass and physical functioning in older adult men. Future studies aimed at testing the causative role of this hypothesis are of interest.

Biomechanical Computed Tomography analysis (BCT) for clinical assessment of osteoporosis.

The surgeon general of the USA defines osteoporosis as "a skeletal disorder characterized by compromised bone strength, predisposing to an increased risk of fracture." Measuring bone strength, Biomechanical Computed Tomography analysis (BCT), namely, finite element analysis of a patient's clinical-resolution computed tomography (CT) scan, is now available in the USA as a Medicare screening benefit for osteoporosis diagnostic testing. Helping to address under-diagnosis of osteoporosis, BCT can be applied "opportunistically" to most existing CT scans that include the spine or hip regions and were previously obtained for an unrelated medical indication. For the BCT test, no modifications are required to standard clinical CT imaging protocols. The analysis provides measurements of bone strength as well as a dual-energy X-ray absorptiometry (DXA)-equivalent bone mineral density (BMD) T-score at the hip and a volumetric BMD of trabecular bone at the spine. Based on both the bone strength and BMD measurements, a physician can identify osteoporosis and assess fracture risk (high, increased, not increased), without needing confirmation by DXA. To help introduce BCT to clinicians and health care professionals, we describe in this review the currently available clinical implementation of the test (VirtuOst), its application for managing patients, and the underlying supporting evidence; we also discuss its main limitations and how its results can be interpreted clinically. Together, this body of evidence supports BCT as an accurate and convenient diagnostic test for osteoporosis in both sexes, particularly when used opportunistically for patients already with CT. Biomechanical Computed Tomography analysis (BCT) uses a patient's CT scan to measure both bone strength and bone mineral density at the hip or spine. Performing at least as well as DXA for both diagnosing osteoporosis and assessing fracture risk, BCT is particularly well-suited to "opportunistic" use for the patient without a recent DXA who is undergoing or has previously undergone CT testing (including hip or spine regions) for an unrelated medical condition.

Rapid suppression of bone formation marker in response to sleep restriction and circadian disruption in men.

We describe the time course of bone formation marker (P1NP) decline in men exposed to ~ 3 weeks of sleep restriction with concurrent circadian disruption. P1NP declined within 10 days and remained lower with ongoing exposure. These data suggest even brief exposure to sleep and circadian disruptions may disrupt bone metabolism. INTRODUCTION: A serum bone formation marker (procollagen type 1 N-terminal, P1NP) was lower after ~ 3 weeks of sleep restriction combined with circadian disruption. We now describe the time course of decline. METHODS: The ~ 3-week protocol included two segments: "baseline," ≥ 10-h sleep opportunity/day × 5 days; "forced desynchrony" (FD), recurring 28 h day (circadian disruption) with sleep restriction (~ 5.6-h sleep per 24 h). Fasted plasma P1NP was measured throughout the protocol in nine men (20-59 years old). We tested the hypothesis that PINP would steadily decline across the FD intervention because the magnitude of sleep loss and circadian misalignment accrued as the protocol progressed. A piecewise linear regression model was used to estimate the slope (ß) as ΔP1NP per 24 h with a change point mid-protocol to estimate the initial vs. prolonged effects of FD exposure. RESULTS: Plasma P1NP levels declined significantly within the first 10 days of FD ([Formula: see text] = - 1.33 µg/L per 24 h, p < 0.0001) and remained lower than baseline with prolonged exposure out to 3 weeks ([Formula: see text] = - 0.18 µg/L per 24 h, p = 0.67). As previously reported, levels of a bone resorption marker (C-telopeptide (CTX)) were unchanged. CONCLUSION: Sleep restriction with concurrent circadian disruption induced a relatively rapid decline in P1NP (despite no change in CTX) and levels remained lower with ongoing exposure. These data suggest (1) even brief sleep restriction and circadian disruption can adversely affect bone metabolism, and (2) there is no P1NP recovery with ongoing exposure that, taken together, could lead to lower bone density over time.

The Association between Objectively Measured Physical Activity and the Gut Microbiome among Older Community Dwelling Men.

OBJECTIVES: To determine the relationship between objectively measured physical activity (PA) and the gut microbiome among community-dwelling older men. DESIGN: Cross-sectional study. SETTING: Osteoporotic Fractures in Men (MrOS) cohort participants at Visit 4 (2014-16). PARTICIPANTS: Eligible men (n=373, mean age 84 y) included participants with 5-day activity assessment with at least 90% wear time and analyzed stool samples. MEASUREMENTS: PA was measured with the SenseWear Pro3 Armband and stool samples analyzed for 16S v4 rRNA marker genes using Illumina MiSeq technology. Armband data together with sex, height, and weight were used to estimate total steps, total energy expenditure, and level of activity. 16S data was analyzed using standard UPARSE workflow. Shannon and Inverse Simpson indices were measures of (within-participant) α-diversity. Weighted and unweighted Unifrac were measures of (between-participant) ß-diversity. We used linear regression analysis, principal coordinate analysis, zero-inflated Gaussian models to assess association between PA and α-diversity, ß-diversity, and specific taxa, respectively, with adjustments for age, race, BMI, clinical center, library size, and number of chronic conditions. RESULTS: PA was not associated with α-diversity. There was a slight association between PA and ß-diversity (in particular the second principal coordinate). Compared to those who were less active, those who had higher step counts had higher relative abundance of Cetobacterium and lower relative abundance of taxa from the genera Coprobacillus, Adlercreutzia, Erysipelotrichaceae CC-115 after multivariable adjustment including age, BMI, and chronic conditions. There was no consistent pattern by phylum. CONCLUSION: There was a modest association between levels of PA and specific gut microbes among community-dwelling older men. The observed associations are consistent with the hypothesis that underlying health status and composition of the host microbiome are related.

Association between objective sleep duration and bone mineral density in older postmenopausal women from the Study of Osteoporotic Fractures (SOF).

Methodological limitations preclude determination of the association between sleep duration and bone mineral density (BMD) from existing literature. This was the first study to use objective sleep duration to determine its association with BMD. Nocturnal sleep duration, assessed objectively (actigraphy) or subjectively (questionnaire), was not independently associated with BMD in postmenopausal women. INTRODUCTION: Both long and short self-reported sleep durations are associated with low bone mineral density (BMD) in men and women. The association between sleep duration measured by actigraphy and BMD in postmenopausal women is unknown. METHODS: The Study of Osteoporotic Fractures (SOF) ancillary sleep study was used to determine the association between sleep duration and BMD at the total hip and femoral neck in postmenopausal women ≥ 75 years old. Sleep duration was assessed by wrist actigraphy (average 4 nights) and questionnaire. BMD was compared between postmenopausal women with short (< 6 h/night) vs. NIH-recommended (7-8 h/night) sleep durations. Data were analyzed using a 2-sample t test (unadjusted) and multivariate regression model (adjusted). Simple linear regression was used to estimate the difference in BMD per additional hour of sleep when sleep duration was considered as a continuous, rather than dichotomized, variable. RESULTS: Total hip BMD was higher in women with actigraphically assessed shorter sleep duration in unadjusted models only. No clinically or statistically significant differences in total hip or femoral neck BMD were observed according to nocturnal sleep duration after adjusting for body mass index (BMI) in dichotomized (N = 874) or continuous (N = 1624) sleep duration models or when subjective sleep duration was used. When sleep duration included daytime naps, longer sleep duration was associated with lower total hip BMD (ß = - 0.005, p = 0.04). CONCLUSIONS: Nocturnal sleep duration, whether assessed objectively (actigraphy) or subjectively (questionnaire), was not independently associated with BMD in older postmenopausal women.

Correlates of T50 and relationships with bone mineral density in community-living older men: the osteoporotic fractures in men (MrOS) study.

PURPOSE: T50 is a novel serum-based marker that assesses the propensity of calcification in serum. Shorter T50 indicates greater propensity to calcify and it has been associated to cardiovascular disease (CVD) and mortality among patients with kidney disease. In the general population, neither the correlates of T50 nor the relationships of T50 with bone mineral density (BMD) are known. METHODS: We performed a nested cross-sectional study selecting 150 individuals at random among participants from the Osteoporotic Fractures in Men (MrOS) Study, a study of community-living older men. We categorized individuals into tertiles of T50 and compared demographics and disease indicators across tertiles. We utilized linear regression to evaluate the cross-sectional association between T50 and hip and spine BMD in multivariable models. RESULTS: Older age was associated with shorter T50. Kidney function tended to be lower in those with shorter T50 and the prevalence of CVD and peripheral arterial disease in those with shorter T50, albeit these findings did not achieve statistical significance. We found no statistically significant associations between T50 and total hip or total spine BMD in either unadjusted or multivariable adjusted models. CONCLUSIONS: T50, a novel indicator of serum calcification propensity, is not associated with BMD in community-living older men. Future larger studies should determine if T50 may give insights to CVD in the general population above and beyond traditional risk factors.

Radiological criteria for atypical features of femur fractures: what we can learn when applied in a clinical study setting.

The paper focuses on the identification of atypical fractures (AFFs). This paper examines the concordance between objective classification and expert subjective review. We believe the paper adds critical information about how to apply the American Society of Bone and Mineral Research (ASBMR) criteria to diagnose AFFs and is of high interest to the field. INTRODUCTION: Assess American Society of Bone and Mineral Research (ASBMR) criteria for identifying atypical femoral fractures (AFFs). METHODS: Two orthopedic surgeons independently evaluated radiographs of 372 fractures, applying ASBMR criteria. We assessed ease of applying ASBMR criteria and whether criteria-based assessment matched qualitative expert assessment. RESULTS: There was up to 27% uncertainty about how to classify specific features. 84% of films were classified similarly for the presence of AFF according to ASBMR criteria; agreement increased to 94% after consensus meeting. Of 37 fractures categorized as AFFs based on ASBMR criteria, 23 (62.2%) were considered AFFs according to expert assessment (not relying on criteria). Only one (0.5%) femoral shaft fracture that did not meet ASBMR criteria was considered an AFF per expert assessment. The number of major ASBMR features present (four vs five) and whether there was periosteal or endosteal thickening ("beaking" or "flaring") played major roles in the discrepancies between ASBMR criteria-based and expert-based determinations. CONCLUSIONS: ASBMR AFF criteria were useful for reviewers but several features were difficult to interpret. Expert assessments did not agree with the ASBMR classification in almost one-third of cases, but rarely identified an AFF when a femoral shaft fracture did not meet ASBMR AFF criteria. Experts identified lateral cortical transverse fracture line and associated new-bone formation along with no or minimal comminution as crucial features necessary for the definition of atypical femoral fractures.

Normative Values of Muscle Power using Force Plate Jump Tests in Men Aged 77-101 Years: The Osteoporotic Fractures in Men (MrOS) Study.

OBJECTIVE: To determine normative values for weight-bearing, countermovement leg extension ("jump") tests in the oldest men and characteristics of those not completing vs. completing tests. DESIGN: 2014-16 cross-sectional exam. SETTING: Six U.S. sites from the Osteoporotic Fractures in Men (MrOS) Study. PARTICIPANTS: Community-dwelling men (N=1,841) aged 84.5±4.2 (range: 77-101) years. INTERVENTIONS: N/A. MEASUREMENTS: Jump tests on a force plate measured lower-extremity muscle peak power/kg, velocity and force/kg at peak power, with normative values for 5-year age groups and by limitations in moderate-intensity activities of daily living (ADLs) and climbing several flights of stairs. RESULTS: Jump completion was 68.9% (N=1,268/1,841) and 98% (1,242/1,268) had ≥1 analyzable trial/participant. Exclusions primarily were due to poor mobility and/or balance: 24.8% (456/1,841) prior to and 6.4% (N=117/1,841) after attempting testing. Peak power was 20.8±5.3 W/kg, with 1.2±0.3 m/s for velocity, and 16.7±1.9 N/kg for force at peak power. Each 5-year age group >80 years had subsequently 10% lower power/kg, with 30% lower power/kg at >90 vs. ≤80 years (all p<0.05). Velocity and force/kg at peak power were 24% and 9% lower respectively, at >90 vs. ≤80 years (all p<0.05). Limitations in both moderate ADLs and climbing several flights of stairs were associated with 16% lower age-adjusted power/kg, equivalent to 5-10 years of aging, with 11% and 6% lower age-adjusted velocity and force/kg respectively, vs. those without limitation (all p<0.05). Men not completing vs. completing jumps had older age, higher BMI, lower physical activity, more comorbidities, worse cognition, more IADLs/ADLs and more falls in the past year (all p<0.05). Post-jump pain occurred in 4.6% (58/1,268), with 2 participants stopping testing due to pain. Only 24/1,242 (2%) had all trials/participant without flight (i.e., inability to lift feet), with 323/1,242 having ≥1 trial/participant without flight (total of 28%). No serious adverse safety events (e.g., injury) occurred. CONCLUSIONS: A multicenter cohort of oldest men with a range of function had higher declines in jump power/kg and velocity vs. force/kg across each 5-year age group >80 years. Future research should examine age- and functional-related declines in jump measures related to physical performance decline, falls, fractures, and disability.

Weight loss in men in late life and bone strength and microarchitecture: a prospective study.

Weight loss in men in late life was associated with lower bone strength. In contrast, weight gain was not associated with a commensurate increase in bone strength. Future studies should measure concurrent changes in weight and parameters of bone strength and microarchitecture and evaluate potential causal pathways underlying these associations. INTRODUCTION: Our aim was to determine associations of weight loss with bone strength and microarchitecture. METHODS: We used data from 1723 community-dwelling men (mean age 84.5 years) who attended the MrOS study Year (Y) 14 exam and had high-resolution peripheral quantitative computed tomography (HR-pQCT) scans at ≥ 1 skeletal sites (distal tibia, distal radius, or diaphyseal tibia). Weight change from Y7 to Y14 exams (mean 7.3 years between exams) was classified as moderate weight loss (loss ≥ 10%), mild weight loss (loss 5 to < 10%), stable weight (< 5% change), or weight gain (gain ≥ 5%). Mean HR-pQCT parameters (95%CI) were calculated by weight change category using linear regression models adjusted for age, race, site, health status, body mass index, limb length, and physical activity. The primary outcome measure was estimated failure load. RESULTS: There was a nonlinear association of weight change with failure load at each skeletal site with different associations for weight loss vs. weight gain (p < 0.03). Failure load and total bone mineral density (BMD) at distal sites were lower with greater weight loss with 7.0-7.6% lower failure loads and 4.3-5.8% lower BMDs among men with moderate weight loss compared to those with stable weight (p < 0.01, both comparisons). Cortical, but not trabecular, BMDs at distal sites were lower with greater weight loss. Greater weight loss was associated with lower cortical thickness at all three skeletal sites. CONCLUSION: Weight loss in men in late life is associated with lower peripheral bone strength and total BMD with global measures reflecting cortical but not trabecular parameters.

Dietary patterns and longitudinal change in hip bone mineral density among older men.

Studying dietary patterns is often more informative than individual nutrients or foods. We found that a Prudent dietary pattern (rich in vegetables and fish) was associated with reduced loss of total hip BMD in older men. A Prudent dietary pattern may be a potential lifestyle strategy for minimizing bone loss. INTRODUCTION: This study aimed to identify baseline dietary patterns using factor analysis in a cohort of older men and to evaluate whether the dietary patterns were associated with bone mineral density change (%ΔBMD) at the total hip and femoral neck over time. METHODS: Participants (n = 4379; mean age 72.9 ± 5.5 years) were from the Osteoporotic Fractures in Men (MrOS) prospective cohort study and had dietary data collected at baseline (March 2000-April 2002) and BMD measured at baseline and Visit 2 (March 2005-May 2006). Dietary intake was assessed with a brief Block food frequency questionnaire (FFQ); factor analysis was used to derive dietary patterns. BMD was measured by dual-energy x-ray absorptiometry (DXA); %ΔBMD was calculated from baseline to Visit 2. We used generalized linear regression to estimate least square (LS) means of %ΔBMD in quartiles of the dietary pattern scores adjusted for potential confounding factors. RESULTS: Two major dietary patterns were derived: Prudent (abundant in vegetables, salad, and non-fried fish) and Western (rich in hamburger, fries, processed meats, cheese, and sweets/desserts). There was an inverse association between adherence to the Prudent pattern and total hip %ΔBMD (p-trend = 0.028 after adjusting for age and clinical site; p-trend = 0.033 after further adjustment for smoking, calcium supplement use, diabetes, hypertension, and total energy intake). No other consistent associations between dietary patterns and %ΔBMD were observed. CONCLUSIONS: Greater adherence to a Prudent dietary pattern may attenuate total hip BMD loss (%ΔBMD) in older men.

The epidemiology of wrist fractures in older men: the Osteoporotic Fractures in Men (MrOS) study.

There is limited wrist fracture information on men. Our goal was to calculate frequency and identify risk factors for wrist fracture in the Osteoporotic Fractures in Men (MrOS) study. We confirmed that fracture history and certain medications are predictors, and identified novel predictors including markers of kidney function and physical performance. INTRODUCTION: To calculate the incidence of wrist fractures and their risk factors in older community-dwelling men from the US Osteoporotic Fractures in Men (MrOS) study. METHODS: Using triannual postcards, we identified incident wrist fractures (centrally confirmed by radiology) in men aged ≥ 65. Potential risk factors included the following: demographics, lifestyle, bone mineral density (BMD), selected medications, biomarkers, and physical function and performance measures. Both baseline and time-varying models were adjusted for age, race/ethnicity, MrOS geographic location, and competing mortality risks. RESULTS: We observed 97 incident wrist fractures among 5875 men followed for an average of 10.8 years. The incidence of wrist fracture was 1.6 per 1000 person-years overall and ranged from 1.0 among men aged 65-69 to 2.4 among men age ≥ 80. Significant predictors included the following: fracture history after age 50 [hazard ratio (95% CI): 2.48 (1.65, 3.73)], high serum phosphate [1.25 (1.02, 1.53)], use of selective serotonin receptor inhibitor (SSRI) [3.60 (1.96, 6.63), decreased right arm BMD [0.49 (0.37, 0.65) per SD increase], and inability to perform the grip strength test [3.38 (1.24, 9.25)]. We did not find associations with factors commonly associated with wrist and other osteoporosis fractures like falls, diabetes, calcium and vitamin D intake, and alcohol intake. CONCLUSIONS: Among these older, community-dwelling men, we confirmed that fracture history is a strong predictor of wrist fractures in men. Medications such as SSRIs and corticosteroids also play a role in wrist fracture risk. We identified novel risk factors including kidney function and the inability to perform the grip strength test.

High dairy protein intake is associated with greater bone strength parameters at the distal radius and tibia in older men: a cross-sectional study.

Dairy protein but not plant protein was associated with bone strength of the radius and tibia in older men. These results are consistent with previous results in women and support similar findings related to fracture outcomes. Bone strength differences were largely due to thickness and area of the bone cortex. INTRODUCTION: Our objective was to determine the association of protein intake by source (dairy, non-dairy animal, plant) with bone strength and bone microarchitecture among older men. METHODS: We used data from 1016 men (mean 84.3 years) who attended the Year 14 exam of the Osteoporotic Fractures in Men (MrOS) study, completed a food frequency questionnaire (500-5000 kcal/day), were not taking androgen or androgen agonists, and had high-resolution peripheral quantitative computed tomography (HR-pQCT) scans of the distal radius and distal or diaphyseal tibia. Protein was expressed as percentage of total energy intake (TEI); mean ± SD for TEI = 1548 ± 607 kcal/day and for total protein = 16.2 ± 2.9%TEI. We used linear regression with standardized HR-pQCT parameters as dependent variables and adjusted for age, limb length, center, education, race/ethnicity, marital status, smoking, alcohol intake, physical activity level, corticosteroids use, supplement use (calcium and vitamin D), and osteoporosis medications. RESULTS: Higher dairy protein intake was associated with higher estimated failure load at the distal radius and distal tibia [radius effect size = 0.17 (95% CI 0.07, 0.27), tibia effect size = 0.13 (95% CI 0.03, 0.23)], while higher non-dairy animal protein was associated with higher failure load at only the distal radius. Plant protein intake was not associated with failure load at any site. CONCLUSION: The association between protein intake and bone strength varied by source of protein. These results support a link between dairy protein intake and skeletal health, but an intervention study is needed to evaluate causality.

Association of incident hip fracture with the estimated femoral strength by finite element analysis of DXA scans in the Osteoporotic Fractures in Men (MrOS) study.

Finite element model can estimate bone strength better than BMD. This study used such a model to determine its association with hip fracture risk and found that the strength estimate provided limited improvement over the hip BMDs in predicting femoral neck (FN) fracture risk only. INTRODUCTION: Bone fractures occur only when it is loaded beyond its ultimate strength. The goal of this study was to determine the association of femoral strength, as estimated by finite element (FE) analysis of DXA scans, with incident hip fracture as a single condition or with femoral neck (FN) and trochanter (TR) fractures separately in older men. METHODS: This prospective case-cohort study included 91 FN and 64 TR fracture cases and a random sample of 500 men (14 had a hip fracture) from the Osteoporotic Fractures in Men study during a mean ± SD follow-up of 7.7 ± 2.2 years. We analysed the baseline DXA scans of the hip using a validated plane-stress, linear-elastic FE model of the proximal femur and estimated the femoral strength during a sideways fall. RESULTS: The estimated strength was significantly (P < 0.05) associated with hip fracture independent of the TR and total hip (TH) BMDs but not FN BMD, and combining the strength with BMD did not improve the hip fracture prediction. The strength estimate was associated with FN fractures independent of the FN, TR and TH BMDs; the age-BMI-BMD adjusted hazard ratio (95% CI) per SD decrease of the strength was 1.68 (1.07-2.64), 2.38 (1.57, 3.61) and 2.04 (1.34, 3.11), respectively. This association with FN fracture was as strong as FN BMD (Harrell's C index for the strength 0.81 vs. FN BMD 0.81) and stronger than TR and TH BMDs (0.8 vs. 0.78 and 0.81 vs. 0.79). The strength's association with TR fracture was not independent of hip BMD. CONCLUSIONS: Although the strength estimate provided additional information over the hip BMDs, its improvement in predictive ability over the hip BMDs was confined to FN fracture only and limited.

DXA-derived hip shape is related to osteoarthritis: findings from in the MrOS cohort.

OBJECTIVE: Statistical shape modelling (SSM) of radiographs has been used to explore relationships between altered joint shape and hip osteoarthritis (OA). We aimed to apply SSM to Dual-energy X-ray Absorptiometry (DXA) hip scans, and examine associations between resultant hip shape modes (HSMs), radiographic hip OA (RHOA), and hip pain, in a large population based cohort. METHOD: SSM was performed on baseline hip DXA scans from the Osteoporotic Fractures in Men (MrOS) Study. Associations between the top ten HSMs, and prevalent RHOA from pelvic radiographs obtained 4.6 years later, were analysed in 4100 participants. RHOA was defined as Croft score ≥2. Hip pain was based on pain on walking, hip pain on examination, and Western Ontario and McMaster Universities Arthritis Index (WOMAC). RESULTS: The five HSMs associated with RHOA showed features of either pincer- or cam-type deformities. HSM 1 (increased pincer-type deformity) was positively associated with RHOA [1.23 (1.09, 1.39)] [odds ratio (OR) and 95% CI]. HSM 8 (reduced pincer-type deformity) was inversely associated with RHOA [0.79 (0.70, 0.89)]. HSM 10 (increased cam-type deformity) was positively associated with RHOA [1.21 (1.07, 1.37)]. HSM 3 and HSM 4 (reduced cam-type deformity) were inversely associated with RHOA [0.73 (0.65, 0.83) and 0.82 (0.73, 0.93), respectively]. HSM 3 was inversely related to pain on examination [0.84 (0.76, 0.92)] and walking [0.88, (0.81, 0.95)], and to WOMAC score [0.87 (0.80, 0.93)]. CONCLUSIONS: DXA-derived measures of hip shape are associated with RHOA, and to a lesser extent hip pain, possibly reflecting their role in the pathogenesis of hip OA.

24-hour profile of serum sclerostin and its association with bone biomarkers in men.

The osteocyte's role in orchestrating diurnal variations in bone turnover markers (BTMs) is unclear. We identified no rhythm in serum sclerostin (osteocyte protein). These results suggest that serum sclerostin can be measured at any time of day and the osteocyte does not direct the rhythmicity of other BTMs in men. INTRODUCTION: The osteocyte exerts important effects on bone remodeling, but its rhythmicity and effect on the rhythms of other bone cells are not fully characterized. The purpose of this study was to determine if serum sclerostin displays rhythmicity over a 24-h interval, similar to that of other bone biomarkers. METHODS: Serum sclerostin, FGF-23, CTX, and P1NP were measured every 2 h over a 24-h interval in ten healthy men aged 20-65 years. Maximum likelihood estimates of the parameters in a repeated measures model were used to determine if these biomarkers displayed a diurnal, sinusoidal rhythm. RESULTS: No discernible 24-h rhythm was identified for sclerostin (p = 0.99) or P1NP (p = 0.65). CTX rhythmicity was confirmed (p < 0.001), peaking at 05:30 (range 01:30-07:30). FGF-23 levels were also rhythmic (p < 0.001), but time of peak was variable (range 02:30-11:30). The only significant association identified between these four bone biomarkers was for CTX and P1NP mean 24-h metabolite levels (r = 0.65, p = 0.04). CONCLUSIONS: Sclerostin levels do not appear to be rhythmic in men. This suggests that in contrast to CTX, serum sclerostin could be measured at any time of day. The 24-h profiles of FGF-23 suggest that a component of osteocyte function is rhythmic, but its timing is variable. Our results do not support the hypothesis that osteocytes direct the rhythmicity of other bone turnover markers (CTX), at least not via a sclerostin-mediated mechanism.