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1.  Association of Serum Uric Acid and Incident Nonspine Fractures in Elderly Men: The Osteoporotic Fractures in Men (MrOS) Study 
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.
doi:10.1002/jbmr.2164
PMCID: PMC4351860  PMID: 24347506
AGING; DXA < ANALYSIS/QUANTITATION OF BONE; EPIDEMIOLOGY
2.  Effects of Sequential Osteoporosis Treatments on Trabecular Bone Mass and Strength in Osteopenic Rats 
Introduction
Individual agents used to treat human osteoporosis reduce fracture risk by ~50-60%. Since agents that act with complementary mechanisms are available, sequential therapies that mix anti-resorptive and anabolic agents could improve fracture risk reduction, when compared to monotherapies.
Methods
We evaluated bone mass, bone microarchitecture, and bone strength in adult ovariectomized (OVX), osteopenic rats, during different sequences of vehicle (Veh), parathyroid hormone (PTH), alendronate (Aln), or raloxifene (Ral) in three 90 day treatment periods, over nine months. Differences among groups were evaluated. The interrelationships of bone mass and microarchitecture endpoints, and their relationship to bone strength were studied.
Results
Estrogen deficiency caused bone loss. OVX rats treated with Aln monotherapy had significantly better bone mass, microarchitecture, and bone strength than untreated OVX rats. Rats treated with an Aln drug holiday had bone mass and microarchitecture similar to the Aln monotherapy group, but with significantly lower bone strength. PTH-treated rats had markedly higher bone endpoints, but all were lost after PTH withdrawal without follow-up treatment. Rats treated with PTH followed by Aln had better bone endpoints than those treated with Aln monotherapy, PTH monotherapy, or an Aln holiday. Rats treated initially with Aln or Ral, then switched to PTH, also had better bone endpoints, than monotherapy treatment. Rats treated with Aln, then PTH, and returned to Aln had the highest values for all endpoints.
Conclusion
Our data indicate that anti-resorptive therapy can be coupled with an anabolic agent, to produce and maintain better bone mass, microarchitecture, and strength than can be achieved with any monotherapy.
doi:10.1007/s00198-014-2678-5
PMCID: PMC4394748  PMID: 24722767
parathyroid hormone; raloxifene; alendronate; trabecular bone; microarchitecture; ovariectomy
3.  Glucocorticoids and Osteocyte Autophagy 
Bone  2013;54(2):279-284.
Glucocorticoids are used for the treatment of inflammatory and autoimmune diseases. While they are effective therapy, bone loss and incident fracture risk is high. While previous studies have found GC effects on both osteoclasts and oteoblasts, our work has focused on the effects of GCs on osteocytes. Osteocytes exposed to low dose GCs undergo autophagy while osteocytes exposed to high doses of GCs or for a prolonged period of time undergo apoptosis. This paper will review the data to support the role of GCs in osteocyte autophagy.
doi:10.1016/j.bone.2013.01.034
PMCID: PMC3784314  PMID: 23356984
Glucocorticoids; autophagy; bone fragility
4.  Targeting the Wnt Signaling Pathway to Augment Bone Formation 
Current osteoporosis reports  2008;6(4):142-148.
Recent discoveries in humans and mice have revealed that the Wnt (Wingless and Int-1) signaling pathway is responsible for a complex array of functions in maintaining bone homeostasis. The Wnt proteins are key modulators of mesenchymal lineage specification and regulate most aspects of osteoblast physiology and post-natal bone acquisition by controlling the differentiation and activity of osteoblasts and osteoclasts. Initial reports have indicated that activators of Wnt signaling are potent promoters of osteogenesis; however, systemic hyperactivation of the canonical Wnt pathway could potentially accelerate neoplastic transformation and subsequent tumor growth. Alternatively, recent investigations of natural soluble antagonists of Wnt signaling in bone suggest the possibilities of bone-specific therapies targeting the negative regulators of Wnt pathway, especially sclerostin. With this new knowledge, novel pharmacologic interventions that alter Wnt signaling are being evaluated for the management of osteoporosis. In this article, we briefly describe the Wnt signaling elements, their characterized role in bone, and summarize the current knowledge on the potential to enhance bone formation through the manipulation of Wnt signaling antagonists.
PMCID: PMC3891875  PMID: 19032924
5.  Glucocorticoid Excess in Mice Results in Early Activation of Osteoclastogenesis and Adipogenesis and Prolonged Suppression of Osteogenesis 
Arthritis and rheumatism  2008;58(6):1674-1686.
Objective
Glucocorticoid (GC) excess induces alterations in bone metabolism that weaken bone structure and increase fracture risk. The aim of this study was to identify genes associated with bone metabolism in GC-treated mice, by performing a microarray analysis.
Methods
Long bones from mice exposed to GC excess were collected after 0, 7, 28, and 56 days of treatment, to measure bone microarchitecture and extract RNA for microarray analyses.
Results
Bone loss in this animal model was confirmed by changes in bone turnover markers as well as bone architecture, as measured by microfocal computed tomography. GC excess induced an early up-regulation of genes involved in osteoclast activation, function, and adipogenesis, which peaked on day 7. The expression of genes associated with osteoclast cytoskeletal reorganization and genes associated with matrix degradation peaked on day 28. On day 28 and day 56, the expression of genes associated with osteoblast activation and maturation was decreased from baseline, while the expression of Wnt antagonists was increased. In addition, the expression of genes expressed in osteocytes associated with bone mineralization was significantly higher at the later time points, day 28 and day 56. Reverse transcription–polymerase chain reaction confirmed the results of microarray analysis in selected genes.
Conclusion
GC excess is associated with early activation of genes associated with osteoclastogenesis and adipogenesis and a later suppression of genes associated with osteogenesis and mineralization. Novel interventions with agents that modulate either Wnt signaling or mineralization may be effective in GC-induced osteoporosis.
doi:10.1002/art.23454
PMCID: PMC3892702  PMID: 18512788
6.  The Degree of Bone Mineralization is Maintained with Single Intravenous Bisphosphonates in Aged Estrogen Deficient Rats and is a Strong Predictor of Bone Strength 
Bone  2007;41(5):10.1016/j.bone.2007.06.021.
The treatment of osteoporotic women with bisphosphonates significantly reduces the incidence of bone fractures to a degree greater than can be explained by an increase in bone mineral density. In this Study, 18 month Fischer 344 rats were ovariectomized and treated with a single dose of risedronate (intravenous, iv, 500μg), zoledronic acid (iv, 100μg) or continuous raloxifene (2mg/kg, po., 3x/wk). High resolution microCT was used to measure lumbar vertebral bone microarchitecture, the degree of bone mineralization (DBM) and the distribution of mineral. Small angle x-ray scattering was used to investigate mineral crystallinity. We found prolonged estrogen deficiency, reduced trabecular bone volume, and increased micro architecture bone compression strength. lowered the degree of mineralization. Treatment with resorptive agents (bisphosphonates > raloxifene) prevented the loss of mineralization, trabecular bone volume and bone compression strength. Crystal size was not changed with OVX or with anti-resorptive treatments. In conclusion, in the aged estrogen deficient rat model, single intravenous doses of two bisphosphonates were effective in maintaining the compressive bone strength for 180 days by reducing bone turnover, and maintaining the DBM to a greater degree than with raloxifene.
doi:10.1016/j.bone.2007.06.021
PMCID: PMC3883569  PMID: 17825637
intravenous bisphosphonates; bone mineralization; compression strength; rat; OVX
7.  Prolonged Alendronate Treatment Prevents The Decline In Serum TGF-β1 Levels And Reduces Cortical Bone Strength In Long-Term Estrogen Deficiency Rat Model 
Bone  2012;52(1):424-432.
Introduction
While 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.
Methods
TGF-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.
Results
Ale 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.
Conclusions
The 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.
doi:10.1016/j.bone.2012.10.017
PMCID: PMC3804116  PMID: 23088940
Alendronate; TGF- β1; cortical bone; bone quality
8.  Hip Osteoarthritis and the Risk of All-Cause and Disease-Specific Mortality in Older Women: Population-Based Cohort Study 
Objectives
Determine the risk of all-cause and disease-specific mortality among older women with hip OA and identify mediators in the causal pathway.
Methods
Data were from the Study of Osteoporotic Fractures, a US population-based cohort study of 9704 white women, aged ≥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 having Croft grade ≥2 in at least 1 hip (definite joint space narrowing or osteophytes plus 1 other radiographic feature).
Results
Mean follow-up time was 16.1 ±6.2 years. Baseline and year 8 prevalence of RHOA was 8.0% and 11.0%, respectively. Cumulative incidence (proportion of deaths during 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 (hazard ratio [HR], 1.14; 95% confidence interval [CI], 1.05–1.24), and CVD (HR, 1.24; 95% CI, 1.09–1.41) mortality adjusted for age, body mass index, education, smoking, health status, diabetes, and stroke. These associations were partially explained by physical function (mediating variable).
Conclusion
RHOA was associated with an increased risk of all-cause and CVD mortality among older white women followed 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.
doi:10.1002/art.39113
PMCID: PMC4521765  PMID: 25778744
Cardiovascular Disease; Epidemiology; Mortality; Osteoarthritis; Physical Function
9.  Variant Alleles of the WNT Antagonist FRZB Are Determinants of Hip Shape and Modify the Relationship between Hip Shape and Osteoarthritis 
Arthritis and Rheumatism  2012;64(5):1457-1465.
Objectives
(1) To test whether single nucleotide polymorphisms (SNPs) of the FRZB gene are associated with hip shape. (2) To determine whether FRZB variant alleles affect the relationship between hip shape and radiographic hip osteoarthritis (RHOA).
Methods
A nested case-control study of Caucasian women aged ≥ 65 years in the Study of Osteoporotic Fractures (SOF) was performed. Cases (n = 451) demonstrated incident RHOA during follow-up (mean 8.0 ± 0.4 years). Controls (n = 601) had no RHOA at baseline or follow-up. Statistical shape modeling (SSM) of digitized hip radiographs was used to assess proximal femur shape, and center-edge angle and acetabular depth were used to assess acetabular shape. The association of the rs288326 and rs7775 FRZB variant alleles with hip shape was analyzed using linear regression. The effect of these alleles on the relationship between hip shape and RHOA was analyzed using logistic regression with and without interaction terms.
Results
The rs288326 and rs7775 alleles were associated with shape of the proximal femur (SSM Mode 2). There was a significant interaction between the rs288326 SNP and proximal femur shape (Mode 2) in predicting RHOA (p for interaction = 0.022). Among subjects with the rs288326 variant allele, there were increasing odds of RHOA with increasing quartiles of proximal femur shape Mode 2 (OR for 4th quartile of Mode 2 = 2.5, 95% confidence interval 1.2–5.3; p for linear trend = 0.02).
Conclusions
The rs288326 and rs7775 FRZB SNPs are associated with the shape of the proximal femur. The presence of the rs288326 SNP alters the relationship between proximal femur shape and incident RHOA. Together, these findings suggest that FRZB may serve an important role in determining hip shape and may modify the relationship between hip shape and OA.
doi:10.1002/art.34526
PMCID: PMC3340442  PMID: 22544526
FRZB; WNT pathway; osteoarthritis; joint shape; active shape modeling; bone
10.  Frailty and Hip Osteoarthritis in Men in the MrOS Cohort 
Background.
Frailty 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.
Methods.
Participants (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.
Results.
Prevalence 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).
Conclusions.
RHOA 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.
doi:10.1093/gerona/glt126
PMCID: PMC3991147  PMID: 24253535
Osteoarthritis; Hip; Frailty; Older men.
11.  Inflammation, sleep disturbances, and depressed mood among community-dwelling older men 
Journal of psychosomatic research  2014;76(5):368-373.
Objective
High 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.
Methods
Cross-sectional associations of a panel of serum inflammatory markers with probable depression (measured with the Geriatric Depression Scale) were assessed among 2,560 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.
Results
Inflammatory 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).
Conclusions
In 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.
doi:10.1016/j.jpsychores.2014.02.005
PMCID: PMC3997106  PMID: 24745777
Aging; depression; epidemiology; inflammation; late-life; sleep
12.  Large-Scale Analysis of Association Between GDF5 and FRZB Variants and Osteoarthritis of the Hip, Knee, and Hand 
Arthritis and rheumatism  2009;60(6):1710-1721.
Objective
GDF5 and FRZB have been proposed as genetic loci conferring susceptibility to osteoarthritis (OA); however, the results of several studies investigating the association of OA with the rs143383 polymorphism of the GDF5 gene or the rs7775 and rs288326 polymorphisms of the FRZB gene have been conflicting or inconclusive. To examine these associations, we performed a large-scale meta-analysis of individual-level data.
Methods
Fourteen teams contributed data on polymorphisms and knee, hip, and hand OA. For rs143383, the total number of cases and controls, respectively, was 5,789 and 7,850 for hip OA, 5,085 and 8,135 for knee OA, and 4,040 and 4,792 for hand OA. For rs7775, the respective sample sizes were 4,352 and 10,843 for hip OA, 3,545 and 6,085 for knee OA, and 4,010 and 5,151 for hand OA, and for rs288326, they were 4,346 and 8,034 for hip OA, 3,595 and 6,106 for knee OA, and 3,982 and 5,152 for hand OA. For each individual study, sex-specific odds ratios (ORs) were calculated for each OA phenotype that had been investigated. The ORs for each phenotype were synthesized using both fixed-effects and random-effects models for allele-based effects, and also for haplotype effects for FRZB.
Results
A significant random-effects summary OR for knee OA was demonstrated for rs143383 (1.15 [95% confidence interval 1.09–1.22]) (P = 9.4 × 10−7), with no significant between-study heterogeneity. Estimates of effect sizes for hip and hand OA were similar, but a large between-study heterogeneity was observed, and statistical significance was borderline (for OA of the hip [P = 0.016]) or absent (for OA of the hand [P = 0.19]). Analyses for FRZB polymorphisms and haplotypes did not reveal any statistically significant signals, except for a borderline association of rs288326 with hip OA (P = 0.019).
Conclusion
Evidence of an association between the GDF5 rs143383 polymorphism and OA is substantially strong, but the genetic effects are consistent across different populations only for knee OA. Findings of this collaborative analysis do not support the notion that FRZB rs7775 or rs288326 has any sizable genetic effect on OA phenotypes.
doi:10.1002/art.24524
PMCID: PMC4412885  PMID: 19479880
13.  Osteoporosis: yesterday, today and tomorrow 
Rheumatology (Oxford, England)  2011;50(7):1181-1183.
doi:10.1093/rheumatology/ker147
PMCID: PMC3116213  PMID: 21680613
14.  High hip fracture risk in men with severe aortic calcification - MrOS study 
A significant link between cardiovascular disease and osteoporosis is established in postmenopausal women, but data in men are scarce. We tested the hypothesis that greater severity of abdominal aortic calcification (AAC) was associated with an increased risk of non-spine fracture in 5994 men aged ≥65 years. AAC wasassessed on 5400 baseline lateral thoraco-lumbar radiographs using a validated visual semi-quantitative score. Total hip bone mineral density (BMD) was measured using dual energy X-ray absorptiometry. Incident non-spine fractures were centrally adjudicated. After adjustment for age, BMI, total hip BMD, fall history, prior fracture, smoking status, co-morbidities, race and clinical center, the risk of non-spine fracture (n=805) was increased among men with higher AAC (HR Q4 (AAC score ≥9) vs Q1 (0-1): 1.36, 96%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 vs Q1: 2.33, 95%CI: 1.41-3.87). By contrast, the association between AAC and the risk of non-spine-non-hip fracture was weaker and not significant (HR Q4 vs 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 non-spine fractures. These findings suggest that AAC assessment may be a useful method for identification of older men at high risk of hip fracture.
doi:10.1002/jbmr.2085
PMCID: PMC3935989  PMID: 23983224
abdominal aortic calcification; hip fracture; men
15.  Differential Maintenance of Cortical and Cancellous Bone Strength Following Discontinuation of Bone-Active Agents 
Osteoporotic patients treated with antiresorptive or anabolic agents experience an increase in bone mass and a reduction in incident fractures. However, the effects of these medications on bone quality and strength after a prolonged discontinuation of treatment are not known. We evaluated these effects in an osteoporotic rat model. Six-month-old ovariectomized (OVX) rats were treated with placebo, alendronate (ALN, 2 µg/kg), parathyroid hormone [PTH(1–34); 20 µg/kg], or raloxifene (RAL, 2 mg/kg) three times a week for 4 months and withdrawn from the treatments for 8 months. Treatment with ALN, PTH, and RAL increased the vertebral trabecular bone volume (BV/TV) by 47%, 53%, and 31%, with corresponding increases in vertebral compression load by 27%, 51%, and 31%, respectively (p < .001). The resulting bone strength was similar to that of the sham-OVX control group with ALN and RAL and higher (p < .001) with PTH treatment. After 4 months of withdrawal, bone turnover (BFR/BS) remained suppressed in the ALN group versus the OVX controls (p < .001). The vertebral strength was higher than in the OVX group only in ALN-treated group (p < .05), whereas only the PTH-treated animals showed a higher maximum load in tibial bending versus the OVX controls (p < .05). The vertebral BV/TV returned to the OVX group level in both the PTH and RAL groups 4 months after withdrawal but remained 25% higher than the OVX controls up to 8 months after withdrawal of ALN (p < .05). Interestingly, cortical bone mineral density increased only with PTH treatment (p < .05) but was not different among the experimental groups after withdrawal. At 8 months after treatment withdrawal, none of the treatment groups was different from the OVX control group for cortical or cancellous bone strength. In summary, both ALN and PTH maintained bone strength (maximum load) 4 months after discontinuation of treatment despite changes in bone mass and bone turnover; however, PTH maintained cortical bone strength, whereas ALN maintained cancellous bone strength. Additional studies on the long-term effects on bone strength after discontinuation and with combination of osteoporosis medications are needed to improve our treatment of osteoporosis. © 2011 American Society for Bone and Mineral Research.
doi:10.1002/jbmr.249
PMCID: PMC3179292  PMID: 20839286
BONE STRENGTH; TREATMENT WITHDRAWAL; ALENDRONATE; PTH; RALOXIFENE
16.  Active Shape Modeling of the Hip in the Prediction of Incident Hip Fracture 
The objective of this study was to evaluate right proximal femur shape as a risk factor for incident hip fracture using active shape modeling (ASM). A nested case-control study of white women 65 years of age and older enrolled in the Study of Osteoporotic Fractures (SOF) was performed. Subjects (n = 168) were randomly selected from study participants who experienced hip fracture during the follow-up period (mean 8.3 years). Controls (n = 231) had no fracture during follow-up. Subjects with baseline radiographic hip osteoarthritis were excluded. ASM of digitized right hip radiographs generated 10 independent modes of variation in proximal femur shape that together accounted for 95% of the variance in proximal femur shape. The association of ASM modes with incident hip fracture was analyzed by logistic regression. Together, the 10 ASM modes demonstrated good discrimination of incident hip fracture. In models controlling for age and body mass index (BMI), the area under receiver operating characteristic (AUROC) curve for hip shape was 0.813, 95% confidence interval (CI) 0.771–0.854 compared with models containing femoral neck bone mineral density (AUROC = 0.675, 95% CI 0.620–0.730), intertrochanteric bone mineral density (AUROC = 0.645, 95% CI 0.589–0.701), femoral neck length (AUROC = 0.631, 95% CI 0.573–0.690), or femoral neck width (AUROC = 0.633, 95% CI 0.574–0.691). The accuracy of fracture discrimination was improved by combining ASM modes with femoral neck bone mineral density (AUROC = 0.835, 95% CI 0.795–0.875) or with intertrochanteric bone mineral density (AUROC = 0.834, 95% CI 0.794–0.875). Hips with positive standard deviations of ASM mode 4 had the highest risk of incident hip fracture (odds ratio = 2.48, 95% CI 1.68–3.31, p < .001). We conclude that variations in the relative size of the femoral head and neck are important determinants of incident hip fracture. The addition of hip shape to fracture-prediction tools may improve the risk assessment for osteoporotic hip fractures. © 2011 American Society for Bone and Mineral Research.
doi:10.1002/jbmr.254
PMCID: PMC3179295  PMID: 20878772
ACTIVE SHAPE MODELING; HIP SHAPE; HIP FRACTURE; OSTEOPOROSIS; BONE
17.  Higher Doses of Bisphosphonates Further Improve Bone Mass, Architecture, and Strength but Not the Tissue Material Properties in Aged Rats 
Bone  2009;46(5):1267-1274.
We report the results of a series of experiments designed to determine the effects of ibandronate (Ibn) and risedronate (Ris) on a number of bone quality parameters in aged osteopenic rats to explain how bone material and bone mass may be affected by the dose of bisphosphonates (BP) and contribute to their anti-fracture efficacy.
Eighteen-month old female rats underwent either ovariectomy or sham surgery. The ovariectomized (OVX) groups were left untreated for 2 months to develop osteopenia. Treatments started at 20 months of age as follows: sham and OVX control (treated with saline), OVX+risedronate 30 and 90 (30 or 90 μg/kg/dose), and OVX+ibandronate 30 and 90 (30 or 90 μg/kg/dose). The treatments were given monthly for four months by subcutaneous injection. At sacrifice at 24 months of age the 4th lumbar vertebra was used for μCT scans (bone mass, architecture, and degree of mineralization of bone, DMB) and histomorphometry, and the 6th lumbar vertebra, tibia, and femur were collected for biomechanical testing to determine bone structural and material strength, cortical fracture toughness, and tissue elastic modulus. The compression testing of the vertebral bodies (LVB6) was simulated using finite-element analysis (FEA) to also estimate the bone structural stiffness.
Both Ibn and Ris dose-dependently increased bone mass and improved vertebral bone microarchitecture and mechanical properties compared to OVX control. Estimates of vertebral maximum stress from FEA were correlated with vertebral maximum load (r=0.5, p<0.001) and maximum stress (r=0.4, p<0.005) measured experimentally. Tibial bone bending modulus and cortical strength increased compared to OVX with both BP but no dose-dependent effect was observed. DMB and elastic modulus of trabecular bone were improved with Ibn30 compared to OVX but were not affected in other BP-treated groups. DMB of tibial cortical bone showed no change with BP treatments. The fracture toughness examined in midshaft femurs did not change with BP even with the higher doses. In summary, the anti fracture efficacy of BP is largely due to their preservation of bone mass and while the higher doses further improve the bone structural properties do not improve the localized bone material characteristics such as tissue strength, elastic modulus, and cortical toughness.
doi:10.1016/j.bone.2009.11.019
PMCID: PMC3003226  PMID: 19931661
bisphosphonate; bisphosphonate dose; structural properties; material properties; bone mineralization
18.  Incident symptomatic hip osteoarthritis is associated with differences in hip shape by active shape modeling 
Arthritis care & research  2014;66(1):74-81.
Objective
To investigate hip shape by active shape modeling (ASM) as a potential predictor of incident radiographic and symptomatic hip OA (rHOA and srHOA).
Methods
All hips developing rHOA from baseline (Kellgren-Lawrence [KL] grade 0/1) to mean 6 year follow up (KL ≥2, 190 hips), and 1:1 control hips (KLG 0/1 at both times, 192 hips) were included. Proximal femur shape was defined on baseline AP 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 intra-person correlations, sex, race, body mass index (BMI), baseline KL and/or symptoms.
Results
We evaluated 382 hips from 342 individuals: 61% women, 83% white, with mean age 62 years and BMI 29 kg/m2. 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, OR 1.7 [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%.
Conclusion
This 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.
doi:10.1002/acr.22094
PMCID: PMC3959908  PMID: 23926053
19.  The association of parity with osteoarthritis and knee replacement in the Multicenter Osteoarthritis Study 
Objective
We evaluated the association of parity to both risk of knee replacement (KR) and knee osteoarthritis (OA).
Design
The NIH-funded Multicenter Osteoarthritis Study (MOST) is a longitudinal observational study of persons age 50 to 79 years with either symptomatic knee OA or at elevated risk of disease. Baseline and 30-month knee radiographic OA (ROA) was defined as Kellgren/Lawrence (K/L) grade≥2 or KR. Women were grouped based by number of births: 0; 1 (reference group); 2; 3; 4; and 5 or more. We examined the relation of parity to the incidence over 30 months of ROA and KR using a Poisson regression model. Generalized estimating equations were used to control for correlation between two knees within a subject. We adjusted for age, BMI, race, education, occupation, baseline estrogen use, clinical site, injury, and for KR analyses WOMAC pain and use of pain medication.
Results
Among 1618 women who reported parity information, mean age was 62.6 years, mean BMI 30.7 kg/m2, mean WOMAC pain subscale score 3.7 at baseline. There were 115 KRs and 134 cases of incident knee ROA over 30 months. The relative risk of incident KR was 2.7 times as high (95% CI: 1.0, 7.3) and relative risk of incident knee ROA was 2.6 times as high (95% CI: 1.2, 5.3) among women with 5–12 children compared with those with one birth.
Conclusion
Parity in women at risk for OA is associated with both incident ROA and KR, particularly for those with more than 4 children.
doi:10.1016/j.joca.2013.08.025
PMCID: PMC3855897  PMID: 24029601
parity; knee; osteoarthritis; joint replacement
20.  Prolonged Treatments With Antiresorptive Agents and PTH Have Different Effects on Bone Strength and the Degree of Mineralization in Old Estrogen-Deficient Osteoporotic Rats 
Current approved medical treatments for osteoporosis reduce fracture risk to a greater degree than predicted from change in BMD in women with postmenopausal osteoporosis. We hypothesize that bone active agents improve bone strength in osteoporotic bone by altering different material properties of the bone. Eighteen-month-old female Fischer rats were ovariectomized (OVX) or sham-operated and left untreated for 60 days to induce osteopenia before they were treated with single doses of either risedronate (500 μg/kg, IV), zoledronic acid (100 μg/kg, IV), raloxifene (2 mg/kg, PO, three times per week), hPTH(1-34) (25 μg/kg, SC, three times per week), or vehicle (NS; 1 ml/kg, three times per week). Groups of animals were killed after days 60 and 180 of treatment, and either the proximal tibial metaphysis or lumbar vertebral body were studied. Bone volume and architecture were assessed by μCT and histomorphometry. Measurements of bone quality included the degree of bone mineralization (DBM), localized elastic modulus, bone turnover by histomorphometry, compression testing of the LVB, and three-point bending testing of the femur. The trabecular bone volume, DBM, elastic modulus, and compressive bone strength were all significantly lower at day 60 post-OVX (pretreatment, day 0 study) than at baseline. After 60 days of all of the bone active treatments, bone mass and material measurements agent were restored. However, after 180 days of treatment, the OVX + PTH group further increased BV/TV (+30% from day 60, p < 0.05 within group and between groups). In addition, after 180 days of treatment, there was more highly mineralized cortical and trabecular bone and increased cortical bone size and whole bone strength in OVX + PTH compared with other OVX + antiresorptives. Treatment of estrogen-deficient aged rats with either antiresorptive agents or PTH rapidly improved many aspects of bone quality including microarchitecture, bone mineralization, turnover, and bone strength. However, prolonged treatment for 180 days with PTH resulted in additional gains in bone quality and bone strength, suggesting that the maximal gains in bone strength in cortical and trabecular bone sites may require a longer treatment period with PTH.
doi:10.1359/jbmr.81005
PMCID: PMC3276355  PMID: 18847326
PTH(1-34); intravenous bisphosphonates; bone mineralization; compression and bending strengths; bone mineral homogeneity
21.  Glucocorticoid-induced bone loss can be reversed by the actions of PTH and Risedronate on different pathways for bone formation and mineralization 
Arthritis and rheumatism  2008;58(11):3485-3497.
Glucocorticoid (GC) excess decreases bone mineralization and microarchitecture and lead to reduced bone strength. Both anabolic (PTH) and anti-resorptive agents are used to prevent and treat GC-induced bone loss, yet these bone active agents alter bone turnover by very different mechanisms. Our study objective was to determine how PTH and risedronate (Ris) alter bone quality following GC excess. Five-month-old Swiss-Webster male mice were treated with the glucocorticoid (GC) prednisolone (5 mg/kg 60-day slow-release pellet) or placebo (PL)]. At day 28−56, two groups of GC-treated animals had either PTH (5μg/kg, 5x/wk) or Ris (5μg/kg, 5x/wk) intervention. Bone quality and quantity measurements include x-ray tomography microscopy (XTM) for the degree of bone mineralization (DBM), microCT for bone microarchitecture, compression testing for trabecular bone strength, biochemistry and histomorphometry for bone turnover. In addition, real-time PCR and immunohistochemistry were performed to monitor the expression of several key genes regulating Wnt signaling (bone formation) and mineralization.
Results
Compared to the placebo treated mice, GC treatment decreased trabecular bone volume (BV/TV) and serum osteocalcin, but increased serum CTX and osteoclast surface with a peak at day 28. GC+PTH increased and GC+Ris restored BV/TV to the PL levels after a 28 day treatment period. Average DBM was lowered after GC treatment (−27%), and it was restored to PL level with GC+Ris and GC+PTH. At day 56, RT-PCR revealed that continuous exposure to GC and GC+PTH increased, while GC+Ris decreased the expression of genes that inhibit bone mineralization (Dmp1 and Phex), compared to the PL group. Wnt signaling antagonists Dkk1, Sost and Wif1 were up-regulated by GC treatment but were down-regulated after GC+PTH treatment. Immunohistochemistry of bone sections found GC increased N terminal dmp-1 while PTH treatment increased both N and C terminal dmp-1 staining around osteocytes.
Summary
GC excess reduced expression of genes that regulate mineralization and increased expression of genes that inhibit Wnt signaling which were associated with reduced bone formation and bone volume over a 60 day treatment period. The addition of both PTH and Ris improved bone mass, DBM and bone strength during concurrent GC treatment, with PTH lowering expression of Wnt inhibitors and increasing bone formation; while Ris lowered the expression of mineralization inhibitors and reversed the deterioration of bone mineralization induced by GC excess.
doi:10.1002/art.23954
PMCID: PMC2597521  PMID: 18975341
Glucocorticoid; bone mineralization; risedronate; PTH; gene
22.  Subchondral Bone Trabecular Integrity Predicts and Changes Concurrently with Radiographic and MRI Determined Knee Osteoarthritis Progression 
Arthritis and rheumatism  2013;65(7):1812-1821.
Objective
To evaluate subchondral bone trabecular integrity (BTI) from a radiograph as a predictor of knee osteoarthritis (OA) progression.
Methods
Longitudinal (baseline, 12- and 24-month) knee radiographs were available from 60 female subjects with knee OA. OA progression was defined by 12- and 24-month change in radiographic medial compartment minimal joint space width (JSW) and medial joint space area (JSA), and medial tibial and femoral cartilage volume from magnetic resonance imaging. Bone Trabecular Integrity (BTI) of the medial tibial plateau was analyzed by fractal signature analysis with a commercially available software. Receiver Operating Characteristic curves of BTI were used to predict 5% change in OA progression parameters.
Results
Individual terms (linear and quadratic) of baseline BTI of vertical trabeculae predicted knee OA progression based on 12- and 24-month change in JSA (p<0.01 for 24 months), 24-month change in tibial (p<0.05) but not femoral cartilage volume, and 24-month change in JSW (p=0.05). ROC utilizing both terms of baseline BTI predicted 5% change in the OA progression parameters over 24 months with high accuracy as reflected by the area under the curve (AUC) measures: JSW 81%, JSA 85%, tibial 75% and femoral 85% cartilage volume. Change in BTI was also significantly associated (p<0.05) with concurrent change in JSA over 12 and 24 months and change in tibial cartilage volume over 24 months.
Conclusions
BTI predicts structural OA progression as determined by radiographic and MRI outcomes. BTI may therefore be worthy of study as an outcome measure for OA studies and clinical trials.
doi:10.1002/art.37970
PMCID: PMC4152231  PMID: 23576116
23.  Kyphosis and Decline in Physical Function Over 15 Years in Older Community-Dwelling Women: The Study of Osteoporotic Fractures 
Background
Maintaining 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.
Methods.
We 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.
Results.
In cross-sectional multivariate analyses, with each 10-degree increment of kyphosis, grip strength was 0.24kg 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.
Conclusions.
Greater 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.
doi:10.1093/gerona/glt009
PMCID: PMC3712361  PMID: 23633167
Normative aging; Physical function; Imaging
24.  Global point signature for shape analysis of carpal bones 
Physics in medicine and biology  2014;59(4):961-973.
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 (ℓ2) 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.
doi:10.1088/0031-9155/59/4/961
PMCID: PMC3966902  PMID: 24503490
carpal bone; shape comparison; global point signature; morphometry; eigenfunctions; wrist
25.  IL-23 Is Critical for Induction of Arthritis, Osteoclast Formation, and Maintenance of Bone Mass 
The role of IL-23 in the development of arthritis and bone metabolism was studied using systemic IL-23 exposure in adult mice via hydrodynamic delivery of IL-23 minicircle DNA in vivo and in mice genetically deficient in IL-23. Systemic IL-23 exposure induced chronic arthritis, severe bone loss, and myelopoiesis in the bone marrow and spleen, which resulted in increased osteoclast differentiation and systemic bone loss. The effect of IL-23 was partly dependent on CD4+ T cells, IL-17A, and TNF, but could not be reproduced by overexpression of IL-17A in vivo. A key role in the IL-23–induced arthritis was made by the expansion and activity of myeloid cells. Bone marrow macrophages derived from IL-23p19−/− mice showed a slower maturation into osteoclasts with reduced tartrate-resistant acid phosphatase-positive cells and dentine resorption capacity in in vitro osteoclastogenesis assays. This correlated with fewer multinucleated osteoclast-like cells and more trabecular bone volume and number in 26-wk-old male IL-23p19−/− mice compared with control animals. Collectively, our data suggest that systemic IL-23 exposure induces the expansion of a myeloid lineage osteoclast precursor, and targeting IL-23 pathway may combat inflammation-driven bone destruction as observed in rheumatoid arthritis and other autoimmune arthritides. The Journal of Immunology, 2011, 187: 951–959.
doi:10.4049/jimmunol.1003986
PMCID: PMC3896980  PMID: 21670317

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