Cohort profile: Worldwide Collaboration on OsteoArthritis prediCtion for the Hip (World COACH) - an international consortium of prospective cohort studies with individual participant data on hip osteoarthritis.

PURPOSE: Hip osteoarthritis (OA) is a major cause of pain and disability worldwide. Lack of effective therapies may reflect poor knowledge on its aetiology and risk factors, and result in the management of end-stage hip OA with costly joint replacement. The Worldwide Collaboration on OsteoArthritis prediCtion for the Hip (World COACH) consortium was established to pool and harmonise individual participant data from prospective cohort studies. The consortium aims to better understand determinants and risk factors for the development and progression of hip OA, to optimise and automate methods for (imaging) analysis, and to develop a personalised prediction model for hip OA. PARTICIPANTS: World COACH aimed to include participants of prospective cohort studies with ≥200 participants, that have hip imaging data available from at least 2 time points at least 4 years apart. All individual participant data, including clinical data, imaging (data), biochemical markers, questionnaires and genetic data, were collected and pooled into a single, individual-level database. FINDINGS TO DATE: World COACH currently consists of 9 cohorts, with 38 021 participants aged 18-80 years at baseline. Overall, 71% of the participants were women and mean baseline age was 65.3±8.6 years. Over 34 000 participants had baseline pelvic radiographs available, and over 22 000 had an additional pelvic radiograph after 8-12 years of follow-up. Even longer radiographic follow-up (15-25 years) is available for over 6000 of these participants. FUTURE PLANS: The World COACH consortium offers unique opportunities for studies on the relationship between determinants/risk factors and the development or progression of hip OA, by using harmonised data on clinical findings, imaging, biomarkers, genetics and lifestyle. This provides a unique opportunity to develop a personalised hip OA risk prediction model and to optimise methods for imaging analysis of the hip.

Effect of weight loss on knee joint synovitis over 48 months and mediation by subcutaneous fat around the knee: data from the Osteoarthritis Initiative.

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.

Age Is Associated With Dampened Circadian Patterns of Rest and Activity: The Study of Muscle, Mobility, and Aging (SOMMA).

BACKGROUND: The effects of aging on circadian patterns of behavior are insufficiently described. To address this, we characterized age-specific features of rest-activity rhythms (RAR) in community-dwelling older adults both overall, and in relation, to sociodemographic characteristics. METHODS: We examined cross-sectional associations between RAR and age, sex, race, education, multimorbidity burden, financial, work, martial, health, and smoking status using assessments of older adults with wrist-worn free-living actigraphy data (N = 820, age = 76.4 years, 58.2% women) participating in the Study of Muscle, Mobility, and Aging (SOMMA). RAR parameters were determined by mapping an extension to the traditional cosine curve to activity data. Functional principal component analysis determined variables accounting for variance. RESULTS: Age was associated with several metrics of dampened RAR; women had stronger and more robust RAR versus men (all p < .05). Total activity (56%) and time of activity (20%) accounted for most of the RAR variance. Compared to the latest decile of acrophase, those in the earliest decile had higher average amplitude (p < .001). Compared to the latest decile of acrophase, those in the earliest and midrange categories had more total activity (p = .02). Being in a married-like relationship and a more stable financial situation were associated with stronger rhythms; higher education was associated with less rhythm strength (all p < .05). CONCLUSIONS: Older age was associated with dampened circadian behavior; behaviors were sexually dimorphic. Some sociodemographic characteristics were associated with circadian behavior. We identified a behavioral phenotype characterized by early time of day of peak activity, high rhythmic amplitude, and more total activity.

The Association of Skeletal Muscle Energetics With Recurrent Falls in Older Adults Within the Study of Muscle, Mobility and Aging.

BACKGROUND: Falls in the older population are a major public health concern. While many physiological and environmental factors have been associated with fall risk, muscle mitochondrial energetics has not yet been investigated. METHODS: In this analysis, 835 Study of Muscle, Mobility and Aging (SOMMA) participants aged 70-94 were surveyed for number of falls (total), recurrent falls (2+), and fall-related injuries over the past 12 months at baseline and again after 1 year. Skeletal muscle energetics were assessed at baseline in vivo using 31P Magnetic Resonance Spectroscopy for the maximal rate of adenosine triphosphate recovery (ATPmax) after an acute bout of exercise, and ex vivo by High-Resolution Respirometry for the maximal rate of complex I and II supported oxygen consumption (MaxOXPHOS) in permeabilized muscle fibers from the vastus lateralis. RESULTS: At least 1 fall was reported in 28.7% of SOMMA participants in the first year of the study, with 12% of older adults reporting recurrent falls (2+). Individuals who experienced recurrent falls had a slower 400-m walk gait speed (1.0 ± 0.2 vs 1.1 ± 0.2, p < .001), reported fewer alcoholic drinks per week in the past year (2.4 ± 4.3 vs 2.8 ± 4.4, p = .054), and took a significantly greater number of medication in the 30 days before their baseline visit (5.6 ± 4.4 vs 4.2 ± 3.4, p < .05). A history of falls was reported in 63% of individuals who experienced recurrent falls in the first year of the study compared to 22.8% who experienced 1 or fewer falls. MaxOXPHOS was significantly lower in those who reported recurrent falls (p = .008) compared to those with 1 or fewer falls, but there was no significant difference in ATPmax (p = .369). Neither muscle energetics measure was significantly associated with total number of falls or injurious falls, but recurrent falls were significantly higher with lower MaxOXPHOS (risk ratio = 1.33, 95% confidence interval = 1.02-1.73, p = .033). However, covariates accounted for the increased risk. CONCLUSIONS: Mitochondrial energetics were largely unrelated to fall risk in older adults when accounting for variables, suggesting that the complex etiology of falls may not be related to a single "hallmark of aging" biological pathway.

Impact of Upadacitinib on Laboratory Parameters and Related Adverse Events in Patients with RA: Integrated Data Up to 6.5 Years.

INTRODUCTION: Upadacitinib (UPA) is a Janus kinase inhibitor that has demonstrated efficacy in moderate-to-severe rheumatoid arthritis (RA) with an acceptable safety profile. We investigated laboratory parameter changes in UPA RA clinical trials. METHODS: Pooled data from six randomized trials in the SELECT phase 3 program were included. Key laboratory parameters and safety data were measured for UPA 15 and 30 mg once daily (QD), adalimumab (ADA) 40 mg every other week + methotrexate (MTX), and MTX monotherapy. Exposure-adjusted event rates (EAERs) of adverse events were calculated. RESULTS: A total of 3209 patients receiving UPA 15 mg QD (10 782.7 patient-years [PY]), 1204 patients receiving UPA 30 mg QD (3162.5 PY), 579 patients receiving ADA + MTX (1573.2 PY), and 314 patients receiving MTX monotherapy (865.1 PY) were included, representing up to 6.5 years of total exposure. Decreases in mean levels of hemoglobin, neutrophils, and lymphocytes, and increases in mean levels of liver enzymes and creatinine phosphokinase were observed with UPA, with grade 3 or 4 changes observed in some patients. Mean low- and high-density lipoprotein cholesterol ratios remained stable for patients receiving UPA 15 mg QD. EAERs of anemia and neutropenia occurred at generally consistent rates between UPA and active comparators (3.1-4.3 and 1.7-5.0 events [E]/100 PY across treatment groups, respectively). Rates of hepatic disorder were higher with MTX monotherapy, UPA 15 mg and UPA 30 mg (10.8, 9.7, and 11.0 E/100 PY, respectively) versus ADA + MTX (6.4 E/100 PY). Rates of lymphopenia were highest with MTX monotherapy (3.2 E/100 PY). Treatment discontinuations due to laboratory-related events were rare, occurring in 1.1% and 2.2% of patients treated with UPA 15 and 30 mg QD, respectively. CONCLUSIONS: The results of this integrated long-term analysis of laboratory parameters continue to support an acceptable safety profile of UPA 15 mg QD for moderate-to-severe RA.

Perceived Neighborhood Characteristics and Later-Life Pain Outcomes: Evidence From the Health and Retirement Study.

Objectives: This study examines whether perceived neighborhood characteristics relate to pain outcomes among middle-aged and older adults. Methods: Data were from the Health and Retirement Study (2006-2014; n = 18,814). Perceived neighborhood characteristics were physical disorder, social cohesion, safety, and social ties. We fitted adjusted generalized estimating equation models to evaluate prevalence, incidence, and recovery of moderate-to-severe limiting pain 2 years later. Results: The mean age of our sample was 65.3 years; 54.6% were female and 24.2% reported moderate-to-severe limiting pain at baseline. Positive neighborhood characteristics were associated with low prevalence (e.g., prevalence ratio [PR]: .71 for disorder) and reduced incidence (e.g., PR: .63 for disorder) of moderate-to-severe limiting pain. Positive neighborhood characteristics were associated with a high recovery rate from moderate-to-severe limiting pain (e.g., PR = 1.15 for safety), though the 95% CIs for disorder and cohesion crossed the null. Discussion: Neighborhood characteristics may be important determinants in predicting pain in later life.

Weight Loss Induced by Antiobesity Medications and All-Cause Mortality Among Patients With Knee or Hip Osteoarthritis.

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.

Effect of Romosozumab Treatment in Postmenopausal Women With Osteoporosis and Knee Osteoarthritis: Results From a Substudy of a Phase 3 Clinical Trial.

OBJECTIVE: Romosozumab is a bone-forming agent approved for osteoporosis treatment. Here we report results of the protocol-specified, noninferiority osteoarthritis substudy of the fracture study in postmenopausal women with osteoporosis (FRAME), which evaluated the effect of romosozumab versus placebo on knee osteoarthritis in patients with a clinical history of osteoarthritis. METHODS: Women in FRAME with a history of knee osteoarthritis were eligible for enrollment in the osteoarthritis substudy; key inclusion criteria were osteoarthritis-related signal knee pain, morning stiffness lasting less than 30 minutes, knee crepitus, and knee osteoarthritis confirmed by x-ray within 12 months. The protocol-specified outcomes were change from baseline through month 12 in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, incidence of worsening knee osteoarthritis, and treatment-emergent adverse events (TEAEs) with romosozumab versus placebo. In a post hoc analysis, percentage change from baseline to month 12 in bone mineral density (BMD) was assessed. RESULTS: Of 7180 women in FRAME, 347 participated in the osteoarthritis substudy (placebo, 177; romosozumab, 170). At month 12, no significant difference in progression of knee osteoarthritis was observed with romosozumab versus placebo (least squares mean total WOMAC score: -2.2 vs. -1.3; P = 0.71). Incidence of worsening symptoms of knee osteoarthritis was comparable between romosozumab (17.1%) and placebo (20.5%) (odds ratio 0.9 [95% confidence interval: 0.5, 1.7]; P = 0.69). Incidence of TEAEs of osteoarthritis was numerically lower with romosozumab (13 [7.7%]) versus placebo (21 [12.0%]). BMD gains were higher with romosozumab. CONCLUSION: Romosozumab treatment did not impact knee pain or function in postmenopausal women with osteoporosis and knee osteoarthritis and resulted in significant BMD gains in these women.

Higher Expression of Denervation-responsive Genes is Negatively Associated with Muscle Volume and Performance Traits in the Study of Muscle, Mobility and Aging (SOMMA).

With aging skeletal muscle fibers undergo repeating cycles of denervation and reinnervation. In approximately the 8 th decade of life reinnervation no longer keeps pace, resulting in the accumulation of persistently denervated muscle fibers that in turn cause an acceleration of muscle dysfunction. The significance of denervation in important clinical outcomes with aging is poorly studied. The Study of Muscle, Mobility and Aging (SOMMA) is a large cohort study with the primary objective to assess how aging muscle biology impacts clinically important traits. Using transcriptomics data from vastus lateralis muscle biopsies in 575 participants we have selected 49 denervation-responsive genes to provide insights to the burden of denervation in SOMMA, to test the hypothesis that greater expression of denervation-responsive genes negatively associates with SOMMA participant traits that included time to walk 400 meters, fitness (VO 2peak ), maximal mitochondrial respiration, muscle mass and volume, and leg muscle strength and power. Consistent with our hypothesis, increased transcript levels of: a calcium-dependent intercellular adhesion glycoprotein (CDH15), acetylcholine receptor subunits (Chrna1, Chrnd, Chrne), a glycoprotein promoting reinnervation (NCAM1), a transcription factor regulating aspects of muscle organization (RUNX1), and a sodium channel (SCN5A) were each negatively associated with at least 3 of these traits. VO 2peak and maximal respiration had the strongest negative associations with 15 and 19 denervation-responsive genes, respectively. In conclusion, the abundance of denervation-responsive gene transcripts is a significant determinant of muscle and mobility outcomes in aging humans, supporting the imperative to identify new treatment strategies to restore innervation in advanced age.

The association of skeletal muscle energetics with recurrent falls in older adults within the Study of Muscle, Mobility and Aging (SOMMA).

Background: Falls in the older population are a major public health concern. While many physiological and environmental factors have been associated with fall risk, muscle mitochondrial energetics has not yet been investigated. Methods: In this analysis, 835 Study of Muscle, Mobility and Aging (SOMMA) participants aged 70-94 were surveyed for recurrent falls (2+) after one year. Skeletal muscle energetics were assessed at baseline in vivo using 31 P Magnetic Resonance Spectroscopy (MRS) (ATPmax) and ex vivo by High Resolution Respirometry (HRR) of permeabilized muscle fibers from the vastus lateralis (MaxOXPHOS). Results: SOMMA participants who reported recurrent falls (12%) had a slower 400m walk gait speed compared to those with 0-1 falls (1.0 +/-0.2 vs. 1.1 +/-0.2, p<.001) and took a greater number of medication in the 30 days before their baseline visit (5.6 +/-4.4 vs. 4.2 +/-3.4, p<0.05). MaxOXPHOS was significantly lower in those who reported recurrent falls (p=0.008) compared to those with one or fewer falls, but there was no significant difference in ATPmax (p=0.369). Neither muscle energetics measure was significantly associated with total number of falls or injurious falls, but recurrent falls were significantly higher with lower MaxOXPHOS (RR=1.33, 95% CI= 1.02-1.73, p=0.033). However, covariates accounted for the increased risk. Conclusions: Ex vivo maximal muscle mitochondrial energetics were lower in older adults who experienced recurrent falls, but covariates accounted for its association with recurrent fall risk, suggesting this "hallmark of aging" may not be directly implicated in the complex etiology of falls.

Age is Associated with Dampened Circadian Patterns of Rest and Activity: The Study of Muscle, Mobility and Aging (SOMMA).

Background: Aging is associated with declines in circadian functions. The effects of aging on circadian patterns of behavior are insufficiently described. We characterized age-specific features of rest-activity rhythms (RAR) in community dwelling older adults, both overall, and in relation, to sociodemographic characteristics. Methods: We analyzed baseline assessments of older adults with wrist-worn free-living wrist-worn actigraphy data (N=820, Age=76.4 yrs, 58.2% women) participating in the Study of Muscle, Mobility and Aging (SOMMA). We applied an extension to the traditional cosine curve to map RAR to activity data, calculating the parameters: rhythmic strength (amplitude); robustness (pseudo-F statistic); and timing of peak activity (acrophase). We also used function principal component analysis to determine 4 components describing underlying patterns of activity accounting for RAR variance. Linear models were used to examine associations between RAR and sociodemographic variables. Results: Age was associated with several metrics of dampened RAR; women had stronger and more robust RAR metrics vs. men (all P < 0.05). Total activity (56%) and time of activity (20%) accounted for most the RAR variance. Compared to the latest decile of acrophase, those in the earliest decile had higher average amplitude (P <0.001). Compared to the latest decile of acrophase, those is the earliest and midrange categories had more total activity (P=0.02). RAR was associated with some sociodemographic variables. Conclusions: Older age was associated with dampened circadian behavior; and behaviors were sexually dimorphic. We identified a behavioral phenotype characterized by early time-of-day of peak activity, high rhythmic amplitude, and more total activity.

Arthritis Foundation/HSS Workshop on Hip Osteoarthritis, Part 1: Epidemiology, Early Development, and Cohorts From Around the World.

Far more publications are available for osteoarthritis of the knee than of the hip. Recognizing this research gap, the Arthritis Foundation, in partnership with the Hospital for Special Surgery, convened an in-person meeting of thought leaders to review the state of the science of and clinical approaches to hip osteoarthritis. This article summarizes the recommendations and clinical research gaps gleaned from 5 presentations given in the "how hip osteoarthritis begins" session of the 2023 Hip Osteoarthritis Clinical Studies Conference, which took place on February 17 and 18, 2023, in New York City.

We Challenged the Kellgren and Lawrence Radiographic Scoring Method and Came Up With Some Interesting Epidemiology for Osteoarthritis of the Hip.

The study of hip osteoarthritis (OA) was slowed due to a lack of a good definition of radiographic hip OA (RHOA). The radiographic changes that occur in hip OA include both joint space narrowing and femoral head osteophytes in the early stages of the disease. This differs from OA of the knee, in which radiographic OA changes initially include osteophytes and only much later is joint space narrowing considered. The modified Croft Score is a novel scoring method for the hip that includes an equal weighting of femoral osteophytes and joint space narrowing. It is used to evaluate the epidemiology of prevalent, incident, and progressive RHOA. Use of the Croft Score found that mild changes in the femoral head or acetabulum could increase the risk of incident RHOA. Pioneering research on active shape modeling was undertaken to provide a more comprehensive assessment of hip shape and define actual femoral head shapes that increased the risk of RHOA. After defining RHOA, investigators found several risk factors, which included higher total hip bone mineral density and polymorphisms of the wnt/ß-catenin signaling pathway, to be significant predictors of RHOA in elderly white women. Recently, it was found that RHOA was a strong risk factor for both all-cause mortality and cardiovascular disease mortality in elderly women.

2022 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis.

OBJECTIVE: The objective is to update recommendations for prevention and treatment of glucocorticoid-induced osteoporosis (GIOP) for patients with rheumatic or nonrheumatic conditions receiving >3 months treatment with glucocorticoids (GCs) ≥2.5 mg daily. METHODS: An updated systematic literature review was performed for clinical questions on nonpharmacologic, pharmacologic treatments, discontinuation of medications, and sequential therapy. Grading of Recommendations Assessment, Development and Evaluation approach was used to rate the certainty of evidence. A Voting Panel achieved ≥70% consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS: For adults beginning or continuing >3 months of GC treatment, we strongly recommend as soon as possible after initiation of GCs, initial assessment of fracture risks with clinical fracture assessment, bone mineral density with vertebral fracture assessment or spinal x-ray, and Fracture Risk Assessment Tool if ≥40 years old. For adults at medium, high, or very high fracture risk, we strongly recommend pharmacologic treatment. Choice of oral or intravenous bisphosphonates, denosumab, or parathyroid hormone analogs should be made by shared decision-making. Anabolic agents are conditionally recommended as initial therapy for those with high and very high fracture risk. Recommendations are made for special populations, including children, people with organ transplants, people who may become pregnant, and people receiving very high-dose GC treatment. New recommendations for both discontinuation of osteoporosis therapy and sequential therapies are included. CONCLUSION: This guideline provides direction for clinicians and patients making treatment decisions for management of GIOP. These recommendations should not be used to limit or deny access to therapies.

2022 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis.

OBJECTIVE: The objective is to update recommendations for prevention and treatment of glucocorticoid-induced osteoporosis (GIOP) for patients with rheumatic or nonrheumatic conditions receiving >3 months treatment with glucocorticoids (GCs) ≥2.5 mg daily. METHODS: An updated systematic literature review was performed for clinical questions on nonpharmacologic, pharmacologic treatments, discontinuation of medications, and sequential therapy. Grading of Recommendations Assessment, Development and Evaluation approach was used to rate the certainty of evidence. A Voting Panel achieved ≥70% consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS: For adults beginning or continuing >3 months of GC treatment, we strongly recommend as soon as possible after initiation of GCs, initial assessment of fracture risks with clinical fracture assessment, bone mineral density with vertebral fracture assessment or spinal x-ray, and Fracture Risk Assessment Tool if ≥40 years old. For adults at medium, high, or very high fracture risk, we strongly recommend pharmacologic treatment. Choice of oral or intravenous bisphosphonates, denosumab, or parathyroid hormone analogs should be made by shared decision-making. Anabolic agents are conditionally recommended as initial therapy for those with high and very high fracture risk. Recommendations are made for special populations, including children, people with organ transplants, people who may become pregnant, and people receiving very high-dose GC treatment. New recommendations for both discontinuation of osteoporosis therapy and sequential therapies are included. CONCLUSION: This guideline provides direction for clinicians and patients making treatment decisions for management of GIOP. These recommendations should not be used to limit or deny access to therapies.

Brain-Derived CCN3 Is An Osteoanabolic Hormone That Sustains Bone in Lactating Females.

In lactating mothers, the high calcium (Ca 2+ ) demand for milk production triggers significant bone resorption. While estrogen would normally counteract excessive bone loss and maintain sufficient bone formation during this postpartum period, this sex steroid drops precipitously after giving birth. Here, we report that brain-derived CCN3 (Cellular Communication Network factor 3) secreted from KISS1 neurons of the arcuate nucleus (ARC KISS1 ) fills this void and functions as a potent osteoanabolic factor to promote bone mass in lactating females. Using parabiosis and bone transplant methods, we first established that a humoral factor accounts for the female-specific, high bone mass previously observed by our group after deleting estrogen receptor alpha (ER α ) from ARC KISS1 neurons 1 . This exceptional bone phenotype in mutant females can be traced back to skeletal stem cells (SSCs), as reflected by their increased frequency and osteochondrogenic potential. Based on multiple assays, CCN3 emerged as the most promising secreted pro-osteogenic factor from ARC KISS1 neurons, acting on mouse and human SSCs at low subnanomolar concentrations independent of age or sex. That brain-derived CCN3 promotes bone formation was further confirmed by in vivo gain- and loss-of-function studies. Notably, a transient rise in CCN3 appears in ARC KISS1 neurons in estrogen-depleted lactating females coincident with increased bone remodeling and high calcium demand. Our findings establish CCN3 as a potentially new therapeutic osteoanabolic hormone that defines a novel female-specific brain-bone axis for ensuring mammalian species survival.

The identification of distinct protective and susceptibility mechanisms for hip osteoarthritis: findings from a genome-wide association study meta-analysis of minimum joint space width and Mendelian randomisation cluster analyses.

BACKGROUND: Hip minimum joint space width (mJSW) provides a proxy for cartilage thickness. This study aimed to conduct a genome-wide association study (GWAS) of mJSW to (i) identify new genetic determinants of mJSW and (ii) identify which mJSW loci convey hip osteoarthritis (HOA) risk and would therefore be of therapeutic interest. METHODS: GWAS meta-analysis of hip mJSW derived from plain X-rays and DXA was performed, stratified by sex and adjusted for age and ancestry principal components. Mendelian randomisation (MR) and cluster analyses were used to examine causal effect of mJSW on HOA. FINDINGS: 50,745 individuals were included in the meta-analysis. 42 SNPs, which mapped to 39 loci, were identified. Mendelian randomisation (MR) revealed little evidence of a causal effect of mJSW on HOA (ORIVW 0.98 [95% CI 0.82-1.18]). However, MR-Clust analysis suggested the null MR estimates reflected the net effect of two distinct causal mechanisms cancelling each other out, one of which was protective, whereas the other increased HOA susceptibility. For the latter mechanism, all loci were positively associated with height, suggesting mechanisms leading to greater height and mJSW increase the risk of HOA in later life. INTERPRETATIONS: One group of mJSW loci reduce HOA risk via increased mJSW, suggesting possible utility as targets for chondroprotective therapies. The second group of mJSW loci increased HOA risk, despite increasing mJSW, but were also positively related to height, suggesting they contribute to HOA risk via a growth-related mechanism. FUNDING: Primarily funded by the Medical Research Council and Wellcome Trust.

Genetic Variants, Serum 25-Hydroxyvitamin D Levels, and Sarcopenia: A Mendelian Randomization Analysis.

Importance: Vitamin D deficiency is commonly associated with sarcopenia; however, the latest International Clinical Practice Guidelines for Sarcopenia do not recommend vitamin D supplementation for sarcopenia owing to a lack of an apparent therapeutic effect on the indices of sarcopenia among participants with replete vitamin D concentration (ie, 25-hydroxyvitamin D [25(OH)D] level >20 ng/mL) from randomized clinical trials. While there is consensus in all vitamin D guidelines that serum levels of 25(OH)D less than 10 ng/mL should be corrected, approximately 30% of the world population's 25(OH)D levels range from 10 to 20 ng/mL, and it remains unclear whether such suboptimal levels can maintain optimal health, including sarcopenia risk. Objective: To investigate the association of serum 25(OH)D level, especially suboptimal levels, with sarcopenia risk. Design, Setting, and Participants: This genome-wide genetic association study was performed from August 2022 to February 2023 among the 295 489 unrelated European participants from the UK Biobank (2006-2010). Nonlinear and standard mendelian randomization analyses were used to examine the association of serum 25(OH)D concentration with sarcopenia risk. Exposures: A weighted genetic risk score using 35 unrelated single-nucleotide variants from the UK Biobank and weights from the SUNLIGHT Consortium was selected as an instrumental variable for serum 25(OH)D concentration. Main Outcomes and Measures: The primary outcome was sarcopenia, and the secondary outcomes consisted of grip strength, appendicular lean mass index, and gait speed. Results: The final genetic analyses included 295 489 participants (mean [SD] age, 56.3 [8.1] years; 139 216 female [52.9%]). There was an L-shaped association between genetically predicted serum 25(OH)D concentration and sarcopenia risk. The risk of sarcopenia decreased rapidly as 25(OH)D concentration increased until 20 ng/mL and then leveled off. The odds ratio of sarcopenia for serum 25(OH)D level of 10 vs 20 ng/mL was 1.74 (95% CI, 1.17-2.59). Similar patterns were also observed when the association between serum 25(OH)D concentration and risks of each of the sarcopenia indices were evaluated. Conclusions and Relevance: In this mendelian randomization genetic association study of adults in the UK Biobank, the findings supported a nonlinear association between suboptimal 25(OH)D levels and sarcopenia risk. Randomized clinical trials among participants with suboptimal 25(OH)D levels are required to verify the potential causality.

Associations between weight change, knee subcutaneous fat and cartilage thickness in overweight and obese individuals: 4-Year data from the osteoarthritis initiative.

OBJECTIVE: To assess (i) the impact of changes in body weight on changes in joint-adjacent subcutaneous fat (SCF) and cartilage thickness over 4 years and (ii) the relation between changes in joint-adjacent SCF and knee cartilage thickness. DESIGN: Individuals from the Osteoarthritis Initiative (total=399) with > 10% weight gain (n=100) and > 10% weight loss (n=100) over 4 years were compared to a matched control cohort with less than 3% change in weight (n=199). 3.0T Magnetic Resonance Imaging (MRI) of the right knee was performed at baseline and after 4 years to quantify joint-adjacent SCF and cartilage thickness. Linear regression models were used to evaluate the associations between the (i) weight change group and 4-year changes in both knee SCF and cartilage thickness, and (ii) 4-year changes in knee SCF and in cartilage thickness. Analyses were adjusted for age, sex, baseline body mass index (BMI), tibial diameter (and weight change group in analysis (ii)). RESULTS: Individuals who lost weight over 4-years had significantly less joint-adjacent SCF (beta range, medial/lateral joint sides: 2.2-4.2 mm, p < 0.001) than controls; individuals who gained weight had significantly greater joint-adjacent SCF than controls (beta range: -1.4 to -3.9 mm, p < 0.001). No statistically significant associations were found between weight change and cartilage thickness change. However, increases in joint-adjacent SCF over 4 years were significantly associated with decreases in cartilage thickness (p = 0.04). CONCLUSIONS: Weight change was associated with joint-adjacent SCF, but not with change in cartilage thickness. However, 4-year increases in joint-adjacent SCF were associated with decreases in cartilage thickness independent of baseline BMI and weight change group.

Generalizability of Deep Learning Classification of Spinal Osteoporotic Compression Fractures on Radiographs Using an Adaptation of the Modified-2 Algorithm-Based Qualitative Criteria.

RATIONALE AND OBJECTIVES: Spinal osteoporotic compression fractures (OCFs) can be an early biomarker for osteoporosis but are often subtle, incidental, and underreported. To ensure early diagnosis and treatment of osteoporosis, we aimed to build a deep learning vertebral body classifier for OCFs as a critical component of our future automated opportunistic screening tool. MATERIALS AND METHODS: We retrospectively assembled a local dataset, including 1790 subjects and 15,050 vertebral bodies (thoracic and lumbar). Each vertebral body was annotated using an adaption of the modified-2 algorithm-based qualitative criteria. The Osteoporotic Fractures in Men (MrOS) Study dataset provided thoracic and lumbar spine radiographs of 5994 men from six clinical centers. Using both datasets, five deep learning algorithms were trained to classify each individual vertebral body of the spine radiographs. Classification performance was compared for these models using multiple metrics, including the area under the receiver operating characteristic curve (AUC-ROC), sensitivity, specificity, and positive predictive value (PPV). RESULTS: Our best model, built with ensemble averaging, achieved an AUC-ROC of 0.948 and 0.936 on the local dataset's test set and the MrOS dataset's test set, respectively. After setting the cutoff threshold to prioritize PPV, this model achieved a sensitivity of 54.5% and 47.8%, a specificity of 99.7% and 99.6%, and a PPV of 89.8% and 94.8%. CONCLUSION: Our model achieved an AUC-ROC>0.90 on both datasets. This testing shows some generalizability to real-world clinical datasets and a suitable performance for a future opportunistic osteoporosis screening tool.