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BackgroundOne of the strongest predictors for osteoporosis is peak bone mass. Interventions to augment peak bone mass have yet to be developed. β-Ecdysone (βEcd), a natural steroid-like compound produced by arthropods to initiate metamorphosis, is believed to have androgenic effects and so may be used to augment bone mass.Questions/purposesThe purpose of this study was to use both male and female (1) gonadal-sufficient; and (2) -insufficient mice to investigate sex differences in terms of bone development and structure after βEcd administration.MethodsTwo-month-old male and female Swiss-Webster mice were randomized to receive either vehicle or βEcd (0.5 mg/kg) for 3 weeks. In a separate experiment to evaluate the effects of βEcd on sex hormone-deficient mice, gonadectomy was performed in male (orchiectomy [ORX]) and female mice (ovariectomy [OVX]). Sham-operated and the ORX/OVX mice were then treated for 3 weeks with βEcd. Primary endpoints for the study were trabecular bone structure and bone strength.ResultsIn male mice, the trabecular bone volume was 0.18±0.02 in the placebo-treated (PL) and 0.23±0.02 in the βEcd-treated group (p

BackgroundWomen are at a greater risk for knee osteoarthritis (OA), but reasons for this greater risk in women are not well understood. It may be possible that differences in cartilage composition and walking mechanics are related to greater OA risk in women.Questions/purposes(1) Do women have higher knee cartilage and meniscus T1ρ than men in young healthy, middle-aged non-OA and OA populations? (2) Do women exhibit greater static and dynamic (during walking) knee loading than men in young healthy, middle-aged non-OA and OA populations?MethodsData were collected from three cohorts: (1) young active (1) (18 men, 25 women). T1ρ and T2 relaxation times for cartilage in the medial knee, lateral knee, and patellofemoral compartments and medial and lateral menisci were quantified with 3.0-T MRI. A subset of the participants underwent three-dimensional motion capture during walking for calculation of peak knee flexion and adduction moments, flexion and adduction impulses, and peak adduction angle. Differences in MR, radiograph, and gait parameters between men and women were compared in the three groups separately using multivariate analysis of variance.ResultsWomen had higher lateral articular cartilage T1ρ (men=40.5 [95% confidence interval {CI}, 38.8-42.3] ms; women=43.3 [95% CI, 41.9-44.7] ms; p=0.017) and patellofemoral T1ρ (men=44.4 [95% CI, 42.6-46.3] ms; women=48.4 [95% CI, 46.9-50.0] ms; p=0.002) in the OA group; and higher lateral meniscus T1ρ in the young group (men=15.3 [95% CI, 14.7-16.0] ms; women=16.4 [95% CI, 15.6-17.2] ms; p=0.045). The peak adduction moment in the second half of stance was lower in women in the middle-aged (men=2.05 [95% CI, 1.76-2.34] %BW*Ht; women=1.66 [95% CI, 1.44-1.89] %BW*Ht; p=0.037) and OA (men=2.34 [95% CI, 1.76-2.91] %BW*Ht; women=1.42 [95% CI, 0.89-1.94] %BW*Ht; p=0.022) groups. Static varus from radiographs was lower in women in the middle-aged (men=178° [95% CI, 177°-179°]; women=180° [95% CI, 179°-181°]; p=0.002) and OA (men=176° [95% CI, 175°-178°]; women=180° [95% CI, 179°-181°]; p

BackgroundThe epidemiology of femoroacetabular impingement (FAI) is important but incompletely understood, because most reports arise from symptomatic populations. Investigating the prevalence of FAI in a community-based cohort could help us better understand its epidemiology and in particular the degree to which it might or might not be associated with hip pain.Questions/purposesThe purposes of this study were (1) to evaluate the proportion of older (≥65 years of age) men with morphologic abnormalities consistent with FAI; and (2) to assess the association of the morphologic abnormalities with prevalent radiographic hip osteoarthritis (OA) and hip pain.MethodsAnteroposterior radiographs were obtained in 4140 subjects (mean age±SD, 77±5 years) from the Osteoporotic Fractures in Men study. We assessed each hip for cam, pincer, and mixed FAI types using validated radiographic definitions. Both intra- and interobserver reproducibility were >0.9. Radiographic hip OA was assessed by an expert reader (intraobserver reproducibility, 0.7-0.8) using validated methods, and summary grades of 2 or greater (on a scale from 0 to 4) were used to define radiographic hip OA. Covariates including hip pain in the last 30 days were collected by questionnaires that were answered by all patients included in this report. Logistic regressions with generalized estimating equations were performed to evaluate the association of radiographic features of FAI and arthrosis.ResultsPincer, cam, or mixed types of radiographic FAI had a prevalence of 57% (1748 of 3053), 29% (886 of 3053), and 14% (419 of 3053), respectively, in this group of older men. Both pincer and mixed types of FAI were associated with arthrosis but not with hip pain (odds ratio [OR], 1.63; 95% confidence interval [CI], 1.25-2.13; p39° and a caput-collum-diaphyseal angle

ObjectiveTo determine the risk of all-cause and disease-specific mortality among older women with hip osteoarthritis (OA) and to identify mediators in the causal pathway.MethodsData were from the Study of Osteoporotic Fractures, a US population-based cohort study of 9,704 white women age ≥65 years. The analytic sample included women with hip radiographs at baseline (n = 7,889) and year 8 (n = 5,749). Mortality was confirmed through October 2013 by death certificates and hospital discharge summaries. Radiographic hip OA (RHOA) was defined as a Croft grade of ≥2 in at least 1 hip (definite joint space narrowing or osteophytes plus 1 other radiographic feature).ResultsThe mean ± SD followup time was 16.1 ± 6.2 years. The baseline and year 8 prevalence of RHOA were 8.0% and 11.0%, respectively. The cumulative incidence (proportion of deaths during the study period) was 67.7% for all-cause mortality, 26.3% for cardiovascular disease (CVD) mortality, 11.7% for cancer mortality, 1.9% for gastrointestinal disease mortality, and 27.8% for all other mortality causes. RHOA was associated with an increased risk of all-cause mortality (hazard ratio 1.14 [95% confidence interval 1.05-1.24]) and CVD mortality (hazard ratio 1.24 [95% confidence interval 1.09-1.41]) adjusted for age, body mass index, education, smoking, health status, diabetes, and stroke. These associations were partially explained by the mediating variable of physical function.ConclusionRHOA was associated with an increased risk of all-cause and CVD mortality among older white women followed up for 16 years. Dissemination of evidence-based physical activity and self-management interventions for hip OA in community and clinical settings can improve physical function and might also contribute to lower mortality.

ObjectiveTo evaluate whether T2 relaxation time measurements obtained at 3 T MRI predict the onset of radiographic knee osteoarthritis (OA).Materials and methodsWe performed a nested case-control study of incident radiographic knee OA in the Osteoarthritis Initiative cohort. Cases were 50 knees with baseline Kellgren-Lawrence (KL) grade of 0 that developed KL grade of 2 or more over a 4-year period. Controls were 80 knees with KL grade of 0 after 4 years of follow-up. Baseline T2 relaxation time measurements and laminar analysis of T2 in deep and superficial layers were performed in all knee compartments. The association of T2 values with incident OA was assessed with logistic regression and differences in T2 values by case-control status with linear regression, adjusting for age, sex, body mass index (BMI) and other covariates.ResultsBaseline T2 values in all compartments except the medial tibia were significantly higher in knees that developed OA compared with controls and were particularly elevated in the superficial cartilage layers in all compartments. There was an increased likelihood of incident knee OA associated with higher baseline T2 values, particularly in the patella, adjusted OR per 1 SD increase in T2 (3.37 (95% CI 1.72 to 6.62)), but also in the medial femur (1.90 (1.07 to 3.39)), lateral femur (2.17 (1.11 to 4.25)) and lateral tibia (2.23 (1.16 to 4.31)).ConclusionsThese findings suggest that T2 values assessed when radiographic changes are not yet apparent may be useful in predicting the development of radiological tibiofemoral OA.

BackgroundTo develop a semi-quantitative MR-based hip osteoarthritis (OA) evaluation system (Scoring hip osteoarthritis with MRI, SHOMRI), and to test its reproducibility and face validity.MethodsThe study involved 98 subjects with informed consent. Three-Tesla MR imaging of hip was performed in three planes with intermediate-weighted fat saturated FSE sequences. Two radiologists assessed cartilage loss, bone marrow edema pattern, subchondral cyst in 10 subregions, and assessed labrum in 4 subregions. In addition, presence or absence of ligamentum teres integrity, paralabral cysts, intra-articular body, and effusion in the hip joint were analyzed using the SHOMRI system. The reproducibility was assessed with intra-class correlation coefficient (ICC), Cohen's Kappa values and percent agreement. SHOMRI scores were correlated with radiographic Kellgren-Lawrence (KL) and OARSI atlas gradings, and clinical parameters, the hip osteoarthritis outcome score (HOOS) and hip range of motion (ROM), using Spearman's rank correlation and ordinal logistic regression.ResultsICC values were in the excellent range, 0.91 to 0.97. Cohen's Kappa values and percent agreement ranged from 0.55 to 0.79 and 66 to 99%, respectively. SHOMRI demonstrated significant correlations with KL and OARSI gradings as well as with clinical parameters, HOOS and ROM (P < 0.05). Among the SHOMRI features, subchondral cyst and bone marrow edema pattern showed the highest correlation with HOOS and ROM.ConclusionSHOMRI demonstrated moderate to excellent reproducibility and significant correlation with radiographic gradings and clinical parameters.

RationaleFormer smoking history and chronic obstructive pulmonary disease (COPD) are potential risk factors for osteoporosis and fractures. Under existing guidelines for osteoporosis screening, women are included but men are not, and only current smoking is considered.ObjectivesTo demonstrate the impact of COPD and smoking history on the risk of osteoporosis and vertebral fracture in men and women.MethodsCharacteristics of participants with low volumetric bone mineral density (vBMD) were identified and related to COPD and other risk factors. We tested associations of sex and COPD with both vBMD and fractures adjusting for age, race, body mass index (BMI), smoking, and glucocorticoid use.Measurements and main resultsvBMD by calibrated quantitative computed tomography (QCT), visually scored vertebral fractures, and severity of lung disease were determined from chest CT scans of 3,321 current and ex-smokers in the COPDGene study. Low vBMD as a surrogate for osteoporosis was calculated from young adult normal values. Male smokers had a small but significantly greater risk of low vBMD (2.5 SD below young adult mean by calibrated QCT) and more fractures than female smokers. Low vBMD was present in 58% of all subjects, was more frequent in those with worse COPD, and rose to 84% among subjects with very severe COPD. Vertebral fractures were present in 37% of all subjects and were associated with lower vBMD at each Global Initiative for Chronic Obstructive Lung Disease stage of severity. Vertebral fractures were most common in the midthoracic region. COPD and especially emphysema were associated with both low vBMD and vertebral fractures after adjustment for steroid use, age, pack-years of smoking, current smoking, and exacerbations. Airway disease was associated with higher bone density after adjustment for other variables. Calibrated QCT identified more subjects with abnormal values than the standard dual-energy X-ray absorptiometry in a subset of subjects and correlated well with prevalent fractures.ConclusionsMale smokers, with or without COPD, have a significant risk of low vBMD and vertebral fractures. COPD was associated with low vBMD after adjusting for race, sex, BMI, smoking, steroid use, exacerbations, and age. Screening for low vBMD by using QCT in men and women who are smokers will increase opportunities to identify and treat osteoporosis in this at-risk population.

Beta-ecdysone (βEcd) is a phytoecdysteroid found in the dry roots and seeds of the asteraceae and achyranthes plants, and is reported to increase osteogenesis in vitro. Since glucocorticoid (GC) excess is associated with a decrease in bone formation, the purpose of this study was to determine if treatment with βEcd could prevent GC-induced osteoporosis. Two-month-old male Swiss-Webster mice (n=8-10/group) were randomized to either placebo or slow release prednisolone pellets (3.3mg/kg/day) and treated with vehicle control or βEcd (0.5mg/kg/day) for 21days. GC treatment inhibited age-dependent trabecular gain and cortical bone expansion and this was accompanied by a 30-50% lower bone formation rate (BFR) at both the endosteal and periosteal surfaces. Mice treated with only βEcd significantly increased bone formation on the endosteal and periosteal bone surfaces, and increased cortical bone mass were their controls to compare to GC alone. Concurrent treatment of βEcd and GC completely prevented the GC-induced reduction in BFR, trabecular bone volume and partially prevented cortical bone loss. In vitro studies determined that βEcd prevented the GC increase in autophagy of the bone marrow stromal cells as well as in whole bone. In summary, βEcd prevented GC induced changes in bone formation, bone cell viability and bone mass. Additional studies are warranted of βEcd for the treatment of GC induced bone loss.

Osteoporosis is a disease of excess skeletal fragility that results from estrogen loss and aging. Age related bone loss has been attributed to both elevated bone resorption and insufficient bone formation. We developed a hybrid compound, LLP2A-Ale in which LLP2A has high affinity for the α4β1 integrin on mesenchymal stem cells (MSCs) and alendronate has high affinity for bone. When LLP2A-Ale was injected into mice, the compound directed MSCs to both trabecular and cortical bone surfaces and increased bone mass and bone strength. Additional studies are underway to further characterize this hybrid compound, LLP2A-Ale, and how it can be utilized for the treatment of bone loss resulting from hormone deficiency, aging, and inflammation and to augment bone fracture healing. This article is part of a Special Issue entitled "Stem Cells and Bone".

The effect of progesterone on bone remains elusive. We previously reported that global progesterone receptor (PR) knockout mice displayed high bone mass phenotype, suggesting that PR influences bone growth and modeling. Recently, Mx1+ cells were characterized to be mesenchymal stem cell-like pluripotent Cells. The aim of this study was to evaluate whether the PR in Mx1+ cells regulates osteogenesis. Using the Mx1-Cre;mT/mG reporter mouse model, we found that the calvarial cells exhibited minimal background Mx1-Cre activity prior to Cre activation by IFNα treatment as compared to the bone marrow stromal cells. IFNα treatment significantly activated Mx1-Cre in the calvarial cells. When the PR gene was deleted in the Mx1-Cre;PR-flox calvarial cells in vitro, significantly higher levels of expression of osteoblast maturation marker genes (RUNX2, Osteocalcin, and Dmp1) and osteogenic potential were detected. The PR-deficient calvariae exhibited greater bone volume, especially in the males. Although Mx1-Cre activity could be induced on the bone surface in vivo, the Mx1+ cells did not differentiate into osteocytes in long bones. Bone volumes at the distal femurs and the bone turnover marker serum Osteocalcin were similar between the Mx1-Cre;PR-flox mutant mice and the corresponding wild types in both sexes. In conclusion, our data demonstrates that blocking progesterone signaling via PRs in calvarial Mx1+ cells promoted osteoblast differentiation in the calvaria. Mx1+ was expressed by heterogeneous cells in bone marrow and did not differentiate into osteocyte during long bone development in vivo. Selectively inactivating the PR gene in Mx1+ cells affected the membrane bone formation but did not affect peripheral skeletal homeostasis.

BackgroundThe prevalence of hyperkyphosis is increased in older men; however, risk factors other than age and vertebral fractures are not well established. We previously reported that poor paraspinal muscle composition contributes to more severe kyphosis in a cohort of both older men and women.MethodsTo specifically evaluate this association in older men, we conducted a cross-sectional study to evaluate the association of paraspinal muscle composition and degree of thoracic kyphosis in an analytic cohort of 475 randomly selected participants from the Osteoporotic Fractures in Men (MrOS) study with baseline abdominal quantitative computed tomography (QCT) scans and plain thoracic radiographs. Baseline abdominal QCT scans were used to obtain abdominal body composition measurements of paraspinal muscle and adipose tissue distribution. Supine lateral spine radiographs were used to measure Cobb angle of kyphosis. We examined the linear association of muscle volume, fat volume and kyphosis using loess plots. Multivariate linear models were used to investigate the association between muscle and kyphosis using total muscle volume, as well as individual components of the total muscle volume, including adipose and muscle compartments alone, controlling for age, height, vertebral fractures, and total hip bone mineral density (BMD). We examined these associations among those with no prevalent vertebral fracture and those with BMI < 30 kg/m2.ResultsAmong men in the analytic cohort, means (SD) were 74 (SD = 5.9) years for age, and 37.5 (SD = 11.9) degrees for Cobb angle of kyphosis. Men in the lowest tertile of total paraspinal muscle volume had greater mean Cobb angle than men in the highest tertile, although test of linear trend across tertiles did not reach statistical significance. Neither lower paraspinal skeletal muscle volume (p-trend = 0.08), or IMAT (p-trend = 0.96) was associated with greater kyphosis. Results were similar among those with no prevalent vertebral fractures. However, among men with BMI < 30 kg/m2, those in the lowest tertile of paraspinal muscle volume had greater adjusted mean kyphosis (40.0, 95% CI: 37.8 - 42.1) compared to the highest tertile (36.3, 95% CI: 34.2 - 38.4).ConclusionsThese results suggest that differences in body composition may potentially influence kyphosis.

ObjectivesOsteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects.MethodsWe performed a two-stage meta-analysis on more than 78,000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for 'in silico' or 'de novo' replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used.ResultsWe accumulated 11,277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9×10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p=5.6×10(-8)) and follow-up studies (p=7.3×10(-4)). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9×10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2×10(-6), OR=1.27 in male specific analysis).ConclusionsNovel genetic loci for hip OA were found in this meta-analysis of GWAS.

Study designA descriptive study of the association between diffuse idiopathic skeletal hyperostosis (DISH) and kyphosis.ObjectiveTo investigate the association of DISH with Cobb angle of kyphosis in a large cohort of older subjects from the Health Aging and Body Composition Study.Summary of background dataDISH and thoracic kyphosis are well-defined radiographical findings in spines of older individuals. Characteristics of DISH (ossifications between vertebral segments) reflect changes of spine anatomy and physiology that may be associated with Cobb angle of kyphosis.MethodsUsing data from 1172 subjects aged 70 to 79 years, we measured DISH and Cobb angle of kyphosis from computed tomographic lateral scout scans. Characteristics of participants with and without DISH were assessed using the χ² and t tests. Association between DISH and Cobb angle was analyzed using linear regression. Cobb angle and DISH relationship was assessed at different spine levels (thoracic and lumbar).ResultsDISH was identified on computed tomographic scout scan in 152 subjects with 101 cases in only the thoracic spine and 51 in both thoracic and lumbar spine segments. The mean Cobb angle of kyphosis in the analytic sample was 31.3° (standard deviation = 11.2). The presence of DISH was associated with a greater Cobb angle of 9.1° and 95% confidence interval (95% CI) (5.6-12.6) among African Americans and a Cobb angle of 2.9° and 95% CI (0.5-5.2) among Caucasians compared with those with no DISH. DISH in the thoracic spine alone was associated with a greater Cobb angle of 10.6° and 95% CI (6.5-14.7) in African Americans and a Cobb angle of 3.8° and 95% CI (1.0-6.5) in Caucasians compared with those with no DISH.ConclusionDISH is associated with greater Cobb angle of kyphosis, especially when present in the thoracic spine alone. The association of DISH with Cobb angle is stronger within the African American population.

Our aim was to examine the impact of TLR5 ligation in rheumatoid arthritis (RA) and experimental arthritis pathology. Studies were conducted to investigate the role of TLR5 ligation on RA and mouse myeloid cell chemotaxis or osteoclast formation, and in addition, to uncover the significance of TNF-α function in TLR5-mediated pathogenesis. Next, the in vivo mechanism of action was determined in collagen-induced arthritis (CIA) and local joint TLR5 ligation models. Last, to evaluate the importance of TLR5 function in RA, we used anti-TLR5 Ab therapy in CIA mice. We show that TLR5 agonist, flagellin, can promote monocyte infiltration and osteoclast maturation directly through myeloid TLR5 ligation and indirectly via TNF-α production from RA and mouse cells. These two identified TLR5 functions are potentiated by TNF-α, because inhibition of both pathways can more strongly impair RA synovial fluid-driven monocyte migration and osteoclast differentiation compared with each factor alone. In preclinical studies, flagellin postonset treatment in CIA and local TLR5 ligation in vivo provoke homing and osteoclastic development of myeloid cells, which are associated with the TNF-α cascade. Conversely, CIA joint inflammation and bone erosion are alleviated when TLR5 function is blocked. We found that TLR5 and TNF-α pathways are interconnected, because TNF-α is produced by TLR5 ligation in RA myeloid cells, and anti-TNF-α therapy can markedly suppress TLR5 expression in RA monocytes. Our novel findings demonstrate that a direct and an indirect mechanism are involved in TLR5-driven RA inflammation and bone destruction.

UnlabelledAnti-resorptive and anabolic agents are often prescribed for the treatment of osteoporosis continuously or sequentially for many years. However their impact on cortical bone quality and bone strength is not clear.MethodsSix-month old female rats were either sham operated or ovariectomized (OVX). OVX rats were left untreated for two months and then were treated with vehicle (Veh), hPTH (1-34) (PTH), alendronate (Aln), or raloxifene (Ral) sequentially for three month intervals, for a total of three periods. Mid-tibial cortical bone architecture, mass, mineralization, and strength were measured on necropsy samples obtained after each period. Bone indentation properties were measured on proximal femur necropsy samples.ResultsEight or more months of estrogen deficiency in rats resulted in decreased cortical bone area and thickness. Treatment with PTH for 3months caused the deposition of endocortical lamellar bone that increased cortical bone area, thickness, and strength. These improvements were lost when PTH was withdrawn without followup treatment, but were maintained for the maximum times tested, six months with Ral and three months with Aln. Pre-treatment with anti-resorptives was also somewhat successful in ultimately preserving the additional endocortical lamellar bone formed under PTH treatment. These treatments did not affect bone indentation properties.SummarySequential therapy that involved both PTH and anti-resorptive agents was required to achieve lasting improvements in cortical area, thickness, and strength in OVX rats. Anti-resorptive therapy, either prior to or following PTH, was required to preserve gains attributable to an anabolic agent.

A few clinical studies have reported that elderly male participants with hypertensive disease frequently have higher bone mineral density (BMD) than the normotensive participants at several skeletal sites. The detailed mechanism is still unknown; therefore, a study of bone structure and density using the hypertensive animal models could be informative. We used micro-computed tomography to quantitatively evaluate the tibial and 3rd lumbar vertebral bones in the 20-month-old male spontaneous hypertensive rat (SHR). The BMD, volume fraction, and the microarchitecture changes of the SHR were compared to those of same-age normotensive controls (Wistar-Kyoto rat, WKY). We found that in the very old (20 month) male rats, the trabecular bone fraction and microstructure were higher than those in the same-age normotensive controls. The observation of the association of hypertension with BMD and bone strength in hypertensive rats warrants further investigations of bone mass and strength in elderly males with hypertension.

Uric acid (UA) is produced from purines by the enzyme xanthine oxidase, and elevated levels may cause arthritis and kidney stones. Conversely, UA also appears to function as an antioxidant and may protect against the oxidative stress associated with aging and disease. We performed a prospective fracture case-cohort study to understand the relation of UA and fracture risk in older men enrolled in the Osteoporotic Fractures in Men (MrOS) study. In the cohort of 5994 men aged 65 years and older attending the baseline MrOS examination, we evaluated a subgroup 1680 men in a case-cohort study design. The analytic group included 387 men with incident nonspine fractures (73 hip) and a random sample of 1383. Serum UA was measured in baseline serum samples. Modified proportional hazards models that account for case-cohort study design were used to estimate the relative hazards (RH) of hip and nonspine fracture in men for serum UA. Models were adjusted for age, race, clinic site, body mass index, vitamin D, parathyroid hormone, walking speed, Physical Activity Scale for the Elderly (PASE) score, frailty, and total. Subjects with incident nonspine fractures were older, had lower total hip bone mineral density (BMD), and higher serum phosphorus. There was an 18% decreased risk of nonspine fractures (95% confidence interval [CI] 0.71-0.93; p = 0.003) per 1 SD increase of baseline serum and 34% decreased risk of nonspine fractures in quartile 4 of UA versus quartiles 1, 2, and 3 (95% CI 0.49-0.89; p = 0.028) compared with nonfracture cases after multivariate adjustment. Hip fractures were not significantly associated with UA. Total hip BMD was significantly higher in the group of men with high UA levels compared with lower UA levels and increased linearly across quartiles of UA after multivariate adjustment (p for trend = 0.002). In summary, higher serum UA levels were associated with a reduction in risk of incident nonspine fractures but not hip fractures and higher hip BMD.

BackgroundFrailty has been associated in previous studies with increased mortality and morbidity, but little has been published on its association with arthritis. This study examined the association of hip osteoarthritis to frailty status in a longitudinal observational cohort of older men in the Osteoporotic Fractures in Men Study.MethodsParticipants (N = 4,130) were men aged 65 years and older with complete frailty status and hip radiographs. We defined frailty as three or more of the following components: unintentional weight loss, weakness, self-reported exhaustion, low activity level, and slow walking speed. Men with intermediate stage status met one or two criteria while robust men had none. We defined radiographic hip osteoarthritis (RHOA) as a modified Croft score greater than or equal to 2 on hip radiograph. The relation of RHOA or total hip replacement (THR) to frailty status was examined in cross-sectional and incident analyses using logistic regression.ResultsPrevalence of robust, intermediate, and frail status was 50%, 42%, and 8%, respectively. RHOA or THR was associated with increased odds of being frail or intermediate compared with robust (adjusted odds ratio = 1.45, 95% confidence interval [CI] 1.18, 1.78). Men with RHOA or THR were 1.27 times more likely to have incident frail or intermediate status compared with robust (95% CI: 1.19, 1.38).ConclusionsRHOA and THR are associated with greater frailty status in older men, suggesting that interventions to reduce frailty should be evaluated in older men with either RHOA or THR.

ObjectiveHigh rates of sleep disturbances occur in depression. Sleep disturbances are linked to heightened inflammation. We sought to determine if sleep disturbances explain a portion of the putative inflammation - depression association among older adults. In late life, age-related immunoregulation changes may modify the inflammation-depression relationship.MethodsCross-sectional associations of a panel of serum inflammatory markers with probable depression (measured with the Geriatric Depression Scale) were assessed among 2560 community-dwelling older men. We tested whether inflammatory marker - probable depression associations were independent of chronic diseases, as well as objective and subjectively measured sleep disturbances. We also tested whether inflammation-probable depression associations were moderated by age.ResultsInflammatory markers were not independently associated with higher odds of probable depression. A significant age by C-reactive protein (CRP) interaction (p=0.01) was detected such that the strength of the CRP-probable depression association decreased with age. When stratifying by the median age of 76, elevated odds of probable depression were found for men with CRP levels above the median only among the younger group (OR=2.08, 95% CI 1.18-3.69). In the final adjusted model, independent effects of chronic diseases and subjective sleep disturbances contributed to a total of 37% attenuation of the original OR (adjusted OR=1.68, 95% CI 0.911-3.10, p=.09).ConclusionsIn late-life, associations between inflammatory markers and mood may be explained by both chronic diseases and subjectively reported sleep disturbances. Our findings indicate that the association of CRP with probable depression diminishes in strength with age.

A significant link between cardiovascular disease and osteoporosis is established in postmenopausal women, but data for men are scarce. We tested the hypothesis that greater severity of abdominal aortic calcification (AAC) was associated with an increased risk of nonspine fracture in 5994 men aged ≥ 65 years. AAC was assessed on 5400 baseline lateral thoracolumbar radiographs using a validated visual semiquantitative score. Total hip bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry. Incident nonspine fractures were centrally adjudicated. After adjustment for age, body mass index (BMI), total hip BMD, fall history, prior fracture, smoking status, comorbidities, race, and clinical center, the risk of nonspine fracture (n=805) was increased among men with higher AAC (hazard ratio [HR] quartile 4 [Q4] [AAC score ≥ 9] versus quartile 1 [Q1] [0-1], 1.36; 96% confidence interval [CI], 1.10-1.68). This association was due to an increased risk of hip fracture (n=178) among men with higher AAC (HR Q4 versus Q1, 2.33; 95% CI, 1.41-3.87). By contrast, the association between AAC and the risk of nonspine, nonhip fracture was weaker and not significant (HR Q4 versus Q1, 1.22; 95% CI, 0.96-1.55). The findings regarding higher AAC and increased risk of fracture were not altered in additional analyses accounting for degree of trauma, estimated glomerular filtration rate, presence of lumbar vertebral fractures (which may bias AAC assessment), preexisting cardiovascular disease, ankle brachial index, or competing risk of death. Thus, in this large cohort of elderly men, greater AAC was independently associated with an increased risk of hip fracture, but not with other nonspine fractures. These findings suggest that AAC assessment may be a useful method for identification of older men at high risk of hip fracture.

We present a method based on spectral theory for the shape analysis of carpal bones of the human wrist. We represent the cortical surface of the carpal bone in a coordinate system based on the eigensystem of the two-dimensional Helmholtz equation. We employ a metric--global point signature (GPS)--that exploits the scale and isometric invariance of eigenfunctions to quantify overall bone shape. We use a fast finite-element-method to compute the GPS metric. We capitalize upon the properties of GPS representation--such as stability, a standard Euclidean (ℓ(2)) metric definition, and invariance to scaling, translation and rotation--to perform shape analysis of the carpal bones of ten women and ten men from a publicly-available database. We demonstrate the utility of the proposed GPS representation to provide a means for comparing shapes of the carpal bones across populations.

ObjectiveTo investigate hip shape by active shape modeling (ASM) as a potential predictor of incident radiographic hip osteoarthritis (RHOA) and symptomatic hip osteoarthritis (SRHOA).MethodsAll hips developing RHOA from baseline (Kellgren/Lawrence [K/L] grade 0/1) to mean 6-year followup (K/L grade ≥2, 190 hips) and 1:1 control hips (K/L grade 0/1 at both times, 192 hips) were included. Proximal femur shape was defined on baseline anteroposterior pelvis radiographs and submitted to ASM, producing a mean shape and continuous variables representing independent modes of shape variation. Mode scores (n = 14, explaining 95% of shape variance) were simultaneously included in logistic regression models with incident RHOA and SRHOA as dependent variables, adjusted for intraperson correlations, sex, race, body mass index (BMI), baseline K/L grade, and/or symptoms.ResultsWe evaluated 382 hips from 342 individuals: 61% women and 83% white, with mean age 62 years and mean BMI 29 kg/m(2) . Several modes differed by sex and race, but no modes were associated with incident RHOA overall. Among men only, modes 1 and 2 were significantly associated (for a 1-SD decrease in mode 1 score: odds ratio [OR] 1.7 [95% confidence interval (95% CI) 1.1-2.5] and for a 1-SD increase in mode 2 score: OR 1.5 [95% CI 1.0-2.2]) with incident RHOA. A 1-SD decrease in mode 2 or 3 score increased the odds of SRHOA by 50%.ConclusionThis study confirms other reports that variations in proximal femur shape have a modest association with incident hip OA. The observation of proximal femur shape associations with hip symptoms requires further investigation.

Objective: While risk factors for osteoarthritis (OA) are well known, it is not well understood why certain individuals maintain high mobility and joint health throughout their life while others demonstrate OA at older ages. The purpose of this study was to assess which demographic, clinical and MRI quantitative and semi-quantitative factors are associated with preserving healthy knees in older individuals. Methods: This study analyzed data from the OA Initiative (OAI) cohort of individuals at the age of 65 years or above. Participants without OA at baseline (BL) (Kellgren-Lawrence (KL) ≤ 1) were followed and classified as incident cases (KL ≥ 2 during follow-up; n = 115) and as non-incident (KL ≤ 1 over 96-month; n = 391). Associations between the predictor-variables sex, age, BMI, race, clinical scoring systems, T2 relaxation times and Whole-Organ Magnetic Resonance Imaging-Score (WORMS) readings at BL and the preservation of healthy knees (KL ≤ 1) during a 96-month follow-up period were assessed using logistic regression models. Results: Obesity and presence of pain showed a significant inverse association with maintaining radiographically normal joints in patients aged 65 and above. T2 relaxation times of the lateral femur and tibia as well as the medial femur were also significantly associated with maintaining radiographically normal knee joints. Additionally, absence of lesions of the lateral meniscus and absence of cartilage lesions in the medial and patellofemoral compartments were significantly associated with maintaining healthy knee joints. Conclusion: Overall, this study provides protective clinical parameters as well as quantitative and semi-quantitative MR-imaging parameters associated with maintaining radiographically normal knee joints in an older population over 8 years. Significance and innovations: Most protective parameters for osteoarthritis seem to be similar in the elderly as compared to mixed age cohorts. Nevertheless, some risk factors may be different in the elderly, especially regarding quantitative imaging parameters. [ABSTRACT FROM AUTHOR]

Background: Obesity influences the development of osteoarthritis via low-grade inflammation. Progression of local inflammation (= synovitis) increased with weight gain in overweight and obese women compared to stable weight. Synovitis could be associated with subcutaneous fat (SCF) around the knee. Purpose of the study was to investigate the effect of weight loss on synovitis progression and to assess whether SCF around the knee mediates the relationship between weight loss and synovitis progression. Methods: We included 234 overweight and obese participants (body mass index [BMI] ≥ 25 kg/m2) from the Osteoarthritis Initiative (OAI) with > 10% weight loss (n = 117) or stable overweight (< ± 3% change, n = 117) over 48 months matched for age and sex. In magnetic resonance imaging (MRI) at baseline and 48 months, effusion-synovitis and Hoffa-synovitis using the MRI Osteoarthritis Knee Score (MOAKS) and average joint-adjacent SCF (ajSCF) were assessed. Odds-ratios (ORs) for synovitis progression over 48 months (≥ 1 score increase) were calculated in logistic regression models adjusting for age, sex, baseline BMI, Physical Activity Scale for the Elderly (PASE), and baseline SCF measurements. Mediation of the effect of weight loss on synovitis progression by local SCF change was assessed. Results: Odds for effusion-synovitis progression decreased with weight loss and ajSCF decrease (odds ratio [OR] = 0.61 and 0.56 per standard deviation [SD] change, 95% confidence interval [CI] 0.44, 0.83 and 0.40, 0.79, p = 0.002 and 0.001, respectively), whereas odds for Hoffa-synovitis progression increased with weight loss and ajSCF decrease (OR = 1.47 and 1.48, CI 1.05, 2.04 and 1.02, 2.13, p = 0.024 and 0.038, respectively). AjSCF decrease mediated 39% of the effect of weight loss on effusion-synovitis progression. Conclusions: Effusion-synovitis progression was slowed by weight loss and decrease in local subcutaneous fat. Hoffa-synovitis characterized by fluid in the infrapatellar fat pad increased at the same time, suggesting a decreasing fat pad rather than active synovitis. Decrease in local subcutaneous fat partially mediated the systemic effect of weight loss on synovitis. [ABSTRACT FROM AUTHOR]

Objective: The current guidelines recommend weight loss for patients with overweight or obesity and knee or hip osteoarthritis (OA); however, there is a paucity of data on the relation of weight loss to death among patients with OA. We aimed to examine the relation of the rate of weight loss induced by antiobesity medications over one year to all‐cause mortality among patients with overweight or obesity and knee or hip OA. Methods: Using the IQVIA Medical Research Database, we identified people with overweight or obesity and knee or hip OA. We emulated analyses of a hypothetical target trial to assess the effect of slow‐to‐moderate (2%–10%) or fast (≥10%) weight loss induced by the initiation of antiobesity medications within one year on all‐cause mortality and secondary outcomes over five years' follow‐up. Results: Among 6,524 participants, the five‐year all‐cause mortality rates were 5.3%, 4.0%, and 5.4% for weight gain or stable, slow‐to‐moderate weight loss, and fast weight loss arms, respectively. Compared with the weight gain or stable arm, hazard ratios of all‐cause mortality were 0.72 (95% confidence interval [CI] 0.56–0.92) for the slow‐to‐moderate weight loss arm and 0.99 (95% CI 0.67–1.44) for the fast weight loss arm. We found dose–response protective effects of weight loss on incident hypertension, type 2 diabetes, and venous thromboembolism but a slightly higher risk of cardiovascular disease, albeit not statistically significant, in the fast rate of weight loss arm than in the weight gain or stable arm and no significant relations of weight loss to the risk of cancer. Conclusion: In this population‐based study, a slow‐to‐moderate, but not fast, rate of weight loss induced by antiobesity medications is associated with a lower risk of all‐cause mortality in people with overweight or obesity and knee or hip OA. [ABSTRACT FROM AUTHOR]

Normal mineral metabolism is critical for skeletal integrity, and recently serum fibroblast growth factor 23 (FGF23) levels were found to be directly related to overall fracture risk in elderly Swedish men. To confirm this association, we performed a prospective case-cohort study to understand the relation of FGF23 and fracture risk in older white men enrolled in the Osteoporotic Fractures in Men (MrOS) study. In the cohort of 5994 men attending the baseline MrOS examination, we evaluated a subgroup of 387 men with incident nonvertebral fracture including 73 hip fractures and a sample of 1385 men randomly selected from the cohort with baseline mineral and calcium hormone measurements. FGF23 was measured in baseline serum samples by ELISA (Millipore, Billerica, MA, USA). Modified Cox proportional hazards models that account for case-cohort study design were used to estimate the relative hazards (RH) of fracture in men across quartiles of FGF23. Subjects were also stratified by renal function, and RH per strata was estimated in men with the highest quartile of FGF23 compared with quartiles 3, 2, and 1. Overall, there was no difference in risk of nonspine or hip fracture by baseline FGF23. However, associations differed by strata of eGFRCrCy . Among men with eGFRCrCys 60 mL/min/1.73 m2 (304/1370 fractures) the RH was 0.91 (95% CI 0.66-1.25) after adjustment for age, clinic site, body mass index, race, total hip bone mineral density, vitamin D, parathyroid hormone, alcohol use, physical activity, fracture history, and serum phosphorus. Serum FGF23 levels are not associated with incident fractures in elderly men overall. However, higher levels of serum FGF23 are associated with fracture risk in those with poor renal function.

Bone regeneration by systemic transplantation of mesenchymal stem cells (MSCs) is problematic due to the inability to control the MSCs' commitment, growth, and differentiation into functional osteoblasts on the bone surface. Our research group has developed a method to direct the MSCs to the bone surface by conjugating a synthetic peptidomimetic ligand (LLP2A) that has high affinity for activated α4β1 integrin on the MSC surface, with a bisphosphonates (alendronate) that has high affinity for bone (LLP2A-Ale), to direct the transplanted MSCs to bone. Our in vitro experiments demonstrated that mobilization of LLP2A-Ale to hydroxyapatite accelerated MSC migration that was associated with an increase in the phosphorylation of Akt kinase and osteoblastogenesis. LLP2A-Ale increased the homing of the transplanted MSCs to bone as well as the osteoblast surface, significantly increased the rate of bone formation and restored both trabecular and cortical bone loss induced by estrogen deficiency or advanced age in mice. These results support LLP2A-Ale as a novel therapeutic option to direct the transplanted MSCs to bone for the treatment of established bone loss related to hormone deficiency and aging.

BackgroundMaintaining physical function is an important prerequisite for preserving independence in later life. Greater degrees of kyphosis in the thoracic spine are prevalent in older persons and accompanied by reduced physical function in multiple cross-sectional studies. It is unknown whether kyphosis predicts worse physical function over time.MethodsWe retrospectively assessed whether greater magnitude of kyphosis is associated with decline in self-reported and objectively measured physical function over 15 years. Digitized Cobb angle kyphosis (T4-T12) was derived from supine lateral thoracic spine radiographs in a cohort of 1,196 women aged 65 and older (mean = 69.3 years [SD = 4.0]). Using regression models, we evaluated associations of baseline kyphosis with both self-reported functional status and objectively measured gait speed, grip strength, and timed chair stands cross-sectionally and as change assessed over 15 years.ResultsIn cross-sectional multivariate analyses, with each 10-degree increment of kyphosis, grip strength was 0.24 kg lower (p = .02), but there were no significant associations between kyphosis and functional status, gait speed, or timed chair stand, likely reflecting the high functioning study participants. In multivariate longitudinal analysis, with each 10-degree increment in baseline kyphosis, there was 0.07 point additional decline in functional status (p = .09), 0.01 m/s more decline in gait speed (p = .07), and 0.32 s greater decline in time to complete five chair stands (p = .004), but no association with decline in grip strength.ConclusionsGreater magnitude of kyphosis may predict worsening lower extremity function over time in older women. Early recognition and preventative measures against kyphosis progression may help preserve physical function over the long term.

IntroductionWhile the anti-resorptive effects of the bisphosphonates (BPs) are well documented, many questions remain about their mechanisms of action, particularly following long-term use. This study evaluated the effects of alendronate (Ale) treatment on TGF-β1 signaling in mesenchymal stem cells (MSCs) and osteocytes, and the relationship between prolonged alendronate treatment on systemic TGF-β1 levels and bone strength.MethodsTGF-β1 expression and signaling were evaluated in MSCs and osteocytic MLO-Y4 cells following Ale treatment. Serum total TGF-β1 levels, a bone resorption marker (DPD/Cr), three-dimensional microCT scans and biomechanical tests from both the trabecular and cortical bone were measured in ovariectomized rats that either received continuous Ale treatment for 360 days or Ale treatment for 120 days followed by 240 days of vehicle. Linear regression tests were performed to determine the association of serum total TGF-β1 levels and both the trabecular (vertebrae) and cortical (tibiae) bone strength.ResultsAle increased TGF-β1 signaling in the MSCs but not in the MLO-Y4 cells. Ale treatment increased serum TGF-β1 levels and the numbers of TGF-β1-positive osteocytes and periosteal cells in cortical bone. Serum TGF-β1 levels were not associated with vertebral maximum load and strength but was negatively associated with cortical bone maximum load and ultimate strength.ConclusionsThe increase of serum TGF-β1 levels during acute phase of estrogen deficiency is likely due to increased osteoclast-mediated release of matrix-derived latent TGF-β1. Long-term estrogen-deficiency generally results in a decline in serum TGF-β1 levels that are maintained by Ale treatment. Measuring serum total TGF-β1 levels may help to determine cortical bone quality following alendronate treatment.