Supportive care interventions in metastatic bone disease: scoping review.

BACKGROUND: Patients with secondary metastatic involvement of the musculoskeletal system due to primary cancers are a rapidly growing population with significant risks for health-related end-of-life morbidities. In particular, bone metastases or metastatic bone disease (MBD) imparts significant adversity to remaining quality of life. No rigorous review of clinical trials on the use of supportive care interventions for MBD has been conducted. The objective of this review was to examine the characteristics of supportive care interventions for MBD and critically appraise study designs, key findings, and quality of evidence of the research. METHODS: We searched for published clinical trials, systematic reviews and meta-analyses in PubMED, CINAHL and Google Scholar for articles published between September 2017 and September 2022. Some examples of Medical Subject Headings terms were: 'secondary neoplasm', 'metastatic bone disease', 'palliative care' and 'supportive care intervention'. Quality of published evidence was evaluated based on treatment types and study design. RESULTS: After reviewing 572 publications, 13 articles were included in the final review and evaluation including seven clinical trials, two trial protocols and four systematic reviews. Feasible interventions included enhanced palliative care consultation, palliative radiotherapy and alternative medicines. Interventions addressed primary endpoints of fatigue (N=4, 31%), pain (N=3, 23%) or cancer-related symptoms (N=3, 23%) with patient-reported outcome instruments. No interventions reported on fracture complications or endpoints, specifically. The quality of most studies was moderate to strong. CONCLUSION: Supportive care interventions for MBD are feasible and the impact is measurable via patient-reported outcome measures. While the evidence for interventions was moderate to strong, there are very few specific controlled trials for skeletal-related events and impacts of social determinants of health. Further clinical trials are needed to define supportive care interventions for MBD that demonstrate reduced risk of fracture and that mitigate the reduced quality of life when negative musculoskeletal outcomes arise.

The Benefit of an Umbrella Protocol: Reducing Challenges in Orthopedic Oncology Research.

Background: Orthopedic oncology research is hindered by the scarcity of musculoskeletal tumors and research administrative inefficiencies. This paper introduces observational research through an innovative institution-specific methodology-termed an umbrella protocol. This protocol outlines a comprehensive standard procedure to expedite ethical approval for future aligned studies, reducing administrative barriers to research. Methods: We developed an umbrella protocol at an academic center, involving meticulous methodological identification and coordination with the institutional review board (IRB) to adhere to local guidelines. The protocol encompasses identifying investigators, research objectives, study goals, and data and safety monitoring frameworks necessary for typical standards. Results: Implementation of the umbrella protocol took 110 days to achieve exemption status, following multiple discussions with the IRB and extensive revisions. At the authors institution, this protocol significantly reduces protocol review times from an average of six-to-eight weeks to nearly instantaneous, facilitating a streamlined research process. Additionally, we established a dedicated orthopedic oncology patient registry to enhance future research endeavors. Conclusions: The adoption of umbrella protocols represents a pioneering strategy in orthopedic oncology. This approach mitigates research administrative burdens and broadens research scope in the field. It underscores the necessity of IRB collaboration, methodological precision, and stringent data management. The article also reflects on the ethical implications and potential biases introduced by emerging technologies like artificial intelligence, advocating for diligent ethical oversight. The establishment of an umbrella protocol marks a significant step towards more efficient research methodologies, ultimately aiming to improve patient care and outcomes for individuals with rare musculoskeletal conditions.

Association of Parity and Previous Birth Outcome With Brachial Plexus Birth Injury Risk.

OBJECTIVE: To evaluate the association of maternal delivery history with a brachial plexus birth injury risk in subsequent deliveries and to estimate the effect of subsequent delivery method on brachial plexus birth injury risk. METHODS: We conducted a retrospective cohort study of all live-birth deliveries occurring in California-licensed hospitals from 1996 to 2012. The primary outcome was recurrent brachial plexus birth injury in a subsequent pregnancy. The exposure was delivery history (parity, shoulder dystocia in a previous delivery, or previously delivering a neonate with brachial plexus birth injury). Multiple logistic regression was used to model adjusted associations of delivery history with brachial plexus birth injury in a subsequent pregnancy. The adjusted risk and adjusted risk difference for brachial plexus birth injury between vaginal and cesarean deliveries in subsequent pregnancies were determined, stratified by delivery history, and the number of cesarean deliveries needed to prevent one brachial plexus birth injury was determined. RESULTS: Of 6,286,324 neonates delivered by 4,104,825 individuals, 7,762 (0.12%) were diagnosed with a brachial plexus birth injury. Higher parity was associated with a 5.7% decrease in brachial plexus birth injury risk with each subsequent delivery (adjusted odds ratio [aOR] 0.94, 95% CI 0.92-0.97). Shoulder dystocia or brachial plexus birth injury in a previous delivery was associated with fivefold (0.58% vs 0.11%, aOR 5.39, 95% CI 4.10-7.08) and 17-fold (1.58% vs 0.11%, aOR 17.22, 95% CI 13.31-22.27) increases in brachial plexus birth injury risk, respectively. Among individuals with a history of delivering a neonate with a brachial plexus birth injury, cesarean delivery was associated with a 73.0% decrease in brachial plexus birth injury risk (0.60% vs 2.21%, aOR 0.27, 95% CI 0.13-0.55) compared with an 87.9% decrease in brachial plexus birth injury risk (0.02% vs 0.15%, aOR 0.12, 95% CI 0.10-0.15) in individuals without this history. Among individuals with a history of brachial plexus birth injury, 48.1 cesarean deliveries are needed to prevent one brachial plexus birth injury. CONCLUSIONS: Parity, previous shoulder dystocia, and previously delivering a neonate with brachial plexus birth injury are associated with future brachial plexus birth injury risk. These factors are identifiable prenatally and can inform discussions with pregnant individuals regarding brachial plexus birth injury risk and planned mode of delivery.

Coccidioidomycosis Osteoarticular Dissemination.

Valley fever or coccidioidomycosis is a pulmonary infection caused by species of Coccidioides fungi that are endemic to California and Arizona. Skeletal coccidioidomycosis accounts for about half of disseminated infections, with the vertebral spine being the preferred site of dissemination. Most cases of skeletal coccidioidomycosis progress to bone destruction or spread to adjacent structures such as joints, tendons, and other soft tissues, causing significant pain and restricting mobility. Manifestations of such cases are usually nonspecific, making diagnosis very challenging, especially in non-endemic areas. The lack of basic knowledge and research data on the mechanisms defining susceptibility to extrapulmonary infection, especially when it involves bones and joints, prompted us to survey available clinical and animal data to establish specific research questions that remain to be investigated. In this review, we explore published literature reviews, case reports, and case series on the dissemination of coccidioidomycosis to bones and/or joints. We highlight key differential features with other conditions and opportunities for mechanistic and basic research studies that can help develop novel diagnostic, prognostic, and treatment strategies.

Impact of COVID-19 pandemic on pharmacologic treatment of patients newly diagnosed with osteoporosis.

PURPOSE: This study determined whether initiation of pharmacologic treatment was delayed for newly diagnosed osteoporosis patients during the COVID-19 pandemic. METHODS: 1,189 patients ≥50 years with newly diagnosed osteoporosis using dual-energy x-ray absorptiometry (DXA) screening at a single academic institution were included. Patients with previous osteoporosis were excluded. Patients diagnosed between March 1, 2018-January 31, 2020 (pre-pandemic cohort, n = 576) were compared to those diagnosed between March 1, 2020-January 31, 2022 (pandemic cohort, n = 613). Age, sex, race, ethnicity, ordering providers (primary vs specialty), and pharmacological agents were evaluated. Primary outcomes included proportion of patients prescribed therapy within 3 and 6-months of diagnosis, and mean time from diagnosis to treatment initiation. RESULTS: The pre-pandemic cohort had more White patients (74.3 vs 68.4%, p = .02) and no differences between remaining demographic variables. Only 40.5% of newly diagnosed patients initiated pharmacologic therapy within 6 months. Patients treated at 3-months (31.8 vs 35.4%, p = 0.19) and 6-months (37.8 vs 42.9, p = 0.08) were comparable between cohorts (47.2 vs 50.2% p = 0.30). Mean time from diagnosis to treatment initiation was similar (46 vs 45 days, p = 0.72). There were no treatment differences based on gender, race, or ethnicity or between ordering providers (65.1 vs 57.4% primary care, p = 0.08). Bisphosphonates were most often prescribed in both cohorts (89% vs 82.1%). CONCLUSIONS: This is the first study assessing COVID-19's impact on pharmacologic treatment of newly diagnosed osteoporosis. 40.5% of newly diagnosed patients were treated pharmacologically within six months of diagnosis, and the pandemic did not significantly affect treatment rates.

Maternal Epidemiology of Brachial Plexus Birth Injuries in California: 1996 to 2012.

OBJECTIVE: This study aimed to evaluate the incidence of brachial plexus birth injury (BPBI) and its associations with maternal demographic factors. Additionally, we sought to determine whether longitudinal changes in BPBI incidence differed by maternal demographics. STUDY DESIGN: We conducted a retrospective cohort study of over 8 million maternal-infant pairs using California's Office of Statewide Health Planning and Development Linked Birth Files from 1991 to 2012. Descriptive statistics were used to determine BPBI incidence and the prevalence of maternal demographic factors (race, ethnicity, age). Multivariable logistic regression was used to determine associations of year, maternal race, ethnicity, and age with BPBI. Excess population-level risk associated with these characteristics was determined by calculating population attributable fractions. RESULTS: The incidence of BPBI between 1991 and 2012 was 1.28 per 1,000 live births, with peak incidence of 1.84 per 1,000 in 1998 and low of 0.9 per 1,000 in 2008. Incidence varied by demographic group, with infants of Black (1.78 per 1,000) and Hispanic (1.34 per 1,000) mothers having higher incidences compared with White (1.25 per 1,000), Asian (0.8 per 1,000), Native American (1.29 per 1,000), other race (1.35 per 1,000), and non-Hispanic (1.15 per 1,000) mothers. After controlling for delivery method, macrosomia, shoulder dystocia, and year, infants of Black (adjusted odds ratio [AOR] = 1.88, 95% confidence interval [CI] = 1.70, 2.08), Hispanic (AOR = 1.25, 95% CI = 1.18, 1.32), and advanced-age mothers (AOR = 1.16, 95% CI = 1.09, 1.25) were at increased risk. Disparities in risk experienced by Black, Hispanic, and advanced-age mothers contributed to a 5, 10, and 2% excess risk at the population level, respectively. Longitudinal trends in incidence did not vary among demographic groups. Population-level changes in maternal demographics did not explain changes in incidence over time. CONCLUSION: Although BPBI incidence has decreased in California, demographic disparities exist. Infants of Black, Hispanic, and advanced-age mothers are at increased BPBI risk compared with White, non-Hispanic, and younger mothers. KEY POINTS: · The incidence of BPBI has decreased over time.. · Demographic disparities in BPBI incidence and risk exist.. · Infants of Black, Hispanic, and advanced age mothers are at greatest risk of BPBI..

Chondrocalcinosis and Osteoarthritis: A Literature Review.

OBJECTIVE: The objective of this study was to review the literature on associations between chondrocalcinosis (CC) and osteoarthritis (OA) and to examine the role of colchicine, previously established as effective for calcium pyrophosphate deposition disease, in the treatment of OA. METHODS: A literature search for mechanistic and clinical studies published between 1990 and 2021 listed in PubMed was performed and studies were included if they examined the associations between OA and CC or colchicine using relevant search terms. RESULTS: Published evidence suggests significant radiographic and mechanistic associations between knee OA and knee CC, but there are only a limited number of studies demonstrating associations between OA and CC in the hips, hands, and ankles. We examined three studies testing the efficacy of colchicine on treatment of pain in OA and found insufficient evidence to definitively establish that colchicine is effective to ameliorate symptoms of OA, although differences in study methodologies and inclusion criteria may explain inconsistent study findings. CONCLUSION: An association between CC and OA is supported at the knee joint in both radiographic and in-vitro studies, but is less definite when the relationship is evaluated at other joints, including at the hips, hands, and ankles. Further research is required to ascertain whether CC modifies symptoms in patients with osteoarthritis or is associated with OA progression. It may be worthwhile to further evaluate colchicine or other agents for potential symptom modifying roles in OA or in OA with CC.

Socioeconomic and insurance-related disparities in disease-specific survival among patients with metastatic bone disease.

BACKGROUND: Approximately 5% of cancer patients in the United States presented with metastatic bone disease (MBD) at diagnosis. Current study explores the disparities in survival for patients with MBD. METHODS: Patients with the diagnosis of MBD at presentation for the five most common primary anatomical sites were extracted from Surveillance, Epidemiology, and End Results Census tract-level dataset (2010-2016). Kaplan-Meier and Cox Proportional Hazard models were used to evaluate survival, and prognostic factors for each cohort. Prognostic significance of socioeconomic status (SES) and insurance status were ascertained. RESULTS: The five most common anatomical-sites with MBD at presentation included "lung" (n = 59 739), "prostate" (n = 19 732), "breast" (n = 16 244), "renal and urothelium" (n = 7718) and "colon" (n= 3068). Lower SES was an independent risk factor for worse disease-specific survival (DSS) for patients with MBD originating from lung, prostate, breast and colon. Lack of insurance was an independent risk factor for worse DSS for MBD patients with primary tumors in lung and breast. CONCLUSIONS: MBD patients from the five most common primary sites demonstrated SES and insurance-related disparities in disease-specific survival. This is the first and largest study to explore SES and insurance-related disparities among patients specifically afflicted with MBD. Our findings highlight vulnerability of patients with MBD across multiple primary sites to financial toxicity.

Sex, racial/ethnic and socioeconomic disparities in patients with metastatic bone disease.

BACKGROUND: We have analyzed sex, race/ethnicity or socioeconomic disparities in the incidence of metastatic bone disease (MBD). METHODS: Patients with the diagnosis of MBD at presentation for five most common primary anatomical sites was extracted from Surveillance, Epidemiology, and End Results Census tract-level dataset. Mean incidence of MBD for different sex, racial/ethnic and socioeconomic groups were compared. RESULTS: The five most common anatomical sites with MBD at presentation include "lung: (n = 59 739), "prostate" (n = 19 732), "breast" (n = 16 244), "renal" (n = 7718) and "colon" (n = 3068). There was an increase in incidence of MBD among cancers originating from prostate (annual percentage change [APC] 4.94), renal (APC 2.55), and colon (APC 3.21) (p < 0.05 for all). Non-Hispanic Blacks had higher incidence of MBD for prostate and breast primary sites (p < 0.001). Non-Hispanic American Indian Alaskan Native had higher incidence of MBD for cancers originating from renal (p < 0.001) and colon (p = 0.049). A higher incidence of MBD was seen in lower socioeconomic status (SES) groups for the selected sites (p < 0.001). CONCLUSIONS: These findings suggest that there are multiple sex-related, racial/ethnic and SES disparities in the incidence of MBD from the 5 most common primary sites. Higher incidence seen among lower SES suggests delay in diagnosis and limited access to screening modalities.

Longitudinal Relationship Between Physical Activity and Joint Space Narrowing: Forty-Eight-Month Follow-Up Data From the Osteoarthritis Initiative.

OBJECTIVE: To determine whether the amount of physical activity (PA) is a determinant of joint space narrowing (JSN) worsening over 48 months in participants with knee osteoarthritis. METHODS: Data were obtained from the Osteoarthritis Initiative. PA, measured using the Physical Activity Scale for the Elderly (PASE), was defined as the mean value of the annual measurements conducted prior to development of worsening JSN. Worsening JSN was defined as at least a partial grade increase in the Osteoarthritis Research Society International JSN score over 48 months, in comparison with baseline. Restricted cubic spline function was used to group participants based on the linear association between PA and JSN worsening. A pooled logistic regression model was used to evaluate the association between PA and JSN worsening adjusted for confounders. RESULTS: A total of 2,167 participants were included. In total, 625 participants (28.8%) had JSN worsening over 48 months. Compared with a PASE score of 141-180, PASE scores of 101-140 and >220 were associated with an increased risk of JSN worsening in men, with odds ratios (ORs) of 1.73 (95% confidence interval [95% CI] 1.07-2.81) and 1.83 (95% CI 1.14-2.93), respectively. Similarly, in participants with Kellgren/Lawrence (K/L) grade 2, compared with a PASE score of 141-180, PASE scores of ≤100 and >220 were associated with increased risks of JSN worsening, with an OR of 1.69 (95% CI 1.13-2.54) and 1.64 (95% CI 1.05-2.56), respectively. CONCLUSION: Compared to moderate PA, higher or lower amounts of PA are associated with an elevated risk for JSN worsening in men and in participants with K/L grade 2 knees.

Referrals for physical therapy for osteoarthritis during the COVID-19 pandemic: A retrospective analysis.

BACKGROUND: Osteoarthritis (OA) is a leading cause of musculoskeletal pain and disability among Americans. Physical therapy (PT) is recommended per the 2019 ACR /Arthritis Foundation Guideline for Treatment of OA of the Hand, Hip, and Knee. During COVID-19, access to healthcare has been altered in a variety of clinical settings, with the pandemic creating delays in healthcare, with an unknown impact on access to PT care for OA. OBJECTIVES: We sought to determine whether referrals to PT for OA were reduced in 2020 during the COVID-19 pandemic compared to 2019. METHODS: A retrospective analysis was done of 3586 PT referrals placed by the University of California, Davis for 206 OA ICD-10 codes from January to November 2019 and from January to November 2020. The numbers of PT referrals per month of each year were compared using both descriptive statistics and Poisson Regression analysis. RESULTS: A total of 1972 PT referrals for OA were placed from January to November 2019. Only 1614 referrals for OA were placed from January to November 2020, representing a significant decrease (p = 0.001). Month-by-month analysis of 2020 compared to 2019 revealed statistically significant drops in PT referrals for OA in April (p = 0.001), May (p = 0.001), and August (p = 0.001). CONCLUSIONS: These findings reveal a significant reduction in the number of referrals for PT for OA placed in 2020 during the first year of the COVID-19 pandemic. These reductions were particularly evident in the months following state-mandated actions and closures. Factors associated with this outcome may include decreased access to primary care providers, perceptions of PT availability by health care providers, decreased mobility limiting access to both clinic and PT appointments, and/or willingness to engage in PT by patients during the pandemic.

The Association of Parity with Greater Dynamic Pronation of the Feet.

BACKGROUND: Postpartum women are at increased risk for lower limb musculoskeletal disorders. Foot arch collapse following pregnancy has been reported as a mechanism for this increased risk. However, dynamic changes during gait in postpartum women have not been reported. Therefore, we assessed the association between parity and dynamic foot pronation during gait. OBJECTIVE: To determine (1) if there is an association between parity and dynamic foot pronation (center of pressure excursion index, CPEI) during gait; and (2) the extent to which there is a dose-effect of parity on foot pronation. DESIGN: The Multicenter Osteoarthritis Study (MOST) Study is a longitudinal cohort study of adults with or at risk for knee osteoarthritis (OA). SETTING: Two communities in the United States, Birmingham, Alabama and Iowa City, Iowa. INTERVENTIONS: Not applicable PARTICIPANTS: A population-based sample of 1177 MOST participants who were female, had complete CPEI and parity data and completed the baseline, 30- and 60-month visits. MAIN OUTCOME MEASURES: Odds of a one quintile decrease in CPEI by parity group and mean CPEI by parity group. RESULTS: In 1177 women, mean age was 67.7 years and mean body mass index (BMI) was 30.6 kg/m2 . As parity increased, there was significantly greater foot pronation, lower mean CPEI: 19.1 (18.2-20.1), 18.9 (18.4-19.4), 18 (17.5-18.6) to 17.5 (16.4-18.6) in the 0 to 4 and >5 children groups, respectively; (P = .002), which remained significant after adjusting for race and clinic site (P = .005). There was a positive linear trend (ß = 1.08, 1.03-1.14) in odds ratios of a one quintile decrease in CPEI (greater pronation) with increasing parity level (P = .004), which remained significant after adjusting for race and clinic site (P = .01). After adjusting for age and BMI, these two associations were no longer statistically significant. CONCLUSIONS: This study indicates a positive correlation between parity and greater dynamic pronation of the feet.

The evolution of nerve growth factor inhibition in clinical medicine.

Nerve growth factor (NGF) is a neurotrophin that activates nociceptive neurons to transmit pain signals from the peripheral to the central nervous system and that exerts its effects on neurons by signalling through tyrosine kinase receptors. Antibodies that inhibit the function of NGF and small molecule inhibitors of NGF receptors have been developed and tested in clinical studies to evaluate the efficacy of NGF inhibition as a form of analgesia in chronic pain states including osteoarthritis and chronic low back pain. Clinical studies in individuals with painful knee and hip osteoarthritis have revealed that NGF inhibitors substantially reduce joint pain and improve function compared with NSAIDs for a duration of up to 8 weeks. However, the higher tested doses of NGF inhibitors also increased the risk of rapidly progressive osteoarthritis in a small percentage of those treated. This Review recaps the biology of NGF and the studies that have been performed to evaluate the efficacy of NGF inhibition for chronic musculoskeletal pain states. The adverse events associated with NGF inhibition and the current state of knowledge about the mechanisms involved in rapidly progressive osteoarthritis are also discussed and future studies proposed to improve understanding of this rare but serious adverse event.

High susceptibility to collagen-induced arthritis in mice with progesterone receptors selectively inhibited in osteoprogenitor cells.

BACKGROUND: Progesterone receptor (PR) affects immunomodulation, and lack of PR in osteoprogenitor cells primarily affects pathways associated with immunomodulation, especially in males. In this study, we selectively deleted PR from osteoprogenitor cells using Prx1-Cre to evaluate the tissue-specific effects of PR on the pathegenesis of inflammatary arthritis (IA). METHODS: Collagen-induced arthritis (CIA) was used as an IA animal model. Both male and female PRΔPrx1 mice and their wild-type (WT) littermates were immunized with collagen II (CII) emulsified complete Freund's adjuvant (CFA). Joint erosion, inflammation, and cartilage damage were assessed using a semiquantitative histologic scoring system. Bone volume and erosions in knee and ankle joints were quantitated using microCT and histology. RESULTS: Bone erosions developed in both paw joints in 37.5% and 41.7% of the WT and PRΔPrx1 female mice and in 45.4 and 83.3% of the WT and PRΔPrx1 male mice, respectively. Also, both joint damage and subchondral bone erosions were significantly more severe in male PRcKO-CIA mice than in male WT-CIA mice. Female PRΔPrx1 mice also developed higher bone loss in the knee joints than the KO-normal or WT-CIA females although with less severity compared to the male mice. CONCLUSIONS: The presence of PR in osteoprogenitor cells decreased the development of collagen-induced arthritis and might help to explain the sex differences observed in human inflammatory arthritis.

Patterns of Change Over Time in Knee Bone Shape Are Associated with Sex.

BACKGROUND: Knee osteoarthritis (OA) is more common in females than in males; however, the biological mechanisms for the difference in sex in patients with knee OA are not well understood. Knee shape is associated with OA and with sex, but the patterns of change in the bone's shape over time and their relation to sex and OA are unknown and may help inform how sex is associated with shape and OA and whether the effect is exerted early or later in life.Questions/purposes (1) Does knee shape segregate stably into different groups of trajectories of change (groups of knees that share similar patterns of changes in bone shape over time)? (2) Do females and males have different trajectories of bone shape changes? (3) Is radiographic OA at baseline associated with trajectories of bone shape changes? METHODS: We used data collected from the NIH-funded Osteoarthritis Initiative (OAI) to evaluate a cohort of people aged 45 to 79 years at baseline who had either symptomatic knee OA or were at high risk of having it. The OAI cohort included 4796 participants (58% females; n = 2804) at baseline who either had symptomatic knee OA (defined as having radiographic tibiofemoral knee OA and answering positively to the question "have you had pain, aching or stiffness around the knee on most days for at least one month during the past 12 months") or were at high risk of symptomatic knee OA (defined as having knee symptoms during the prior 12 months along with any of the following: overweight; knee injury; knee surgery other than replacement; family history of total knee replacement for OA; presence of Heberden's nodes; daily knee bending activity) or were part of a small nonexposed subcohort. From these participants, we limited the eligible group to those with radiographs available and read at baseline, 2 years, and 4 years, and randomly selected participants from each OAI subcohort in a manner to enrich representation in the study of the progression and nonexposed subcohorts, which were smaller in number than the OA incidence subcohort. From these patients, we randomly sampled 473 knees with radiographs available at baseline, 2 years, and 4 years. We outlined the shape of the distal femur and proximal tibia on radiographs at all three timepoints using statistical shape modelling. Five modes (each mode represents a particular type of knee bone shape variation) were derived for the proximal tibia and distal femur's shape, accounting for 78% of the total variance in shape. Group-based trajectory modelling (a statistical approach to identify the clusters of participants following a similar progression of change of bone shape over time, that is, trajectory group) was used to identify distinctive patterns of change in the bone shape for each mode. We examined the association of sex and radiographic OA at baseline with the trajectories of each bone shape mode using a multivariable polytomous regression model while adjusting for age, BMI, and race. RESULTS: Knee bone shape change trajectories segregated stably into different groups. In all modes, three distinct trajectory groups were derived, with the mean posterior probabilities (a measure of an individual's probability of being in a particular group and often used to characterize how well the trajectory model is working to describe the population) ranging from 84% to 99%, indicating excellent model fitting. For most of the modes of both the femur and tibia, the intercepts for the three trajectory groups were different; however, the rates of change were generally similar in each mode. Females and males had different trajectories of bone shape change. For Mode 1 in the femur, females were more likely to be in trajectory Groups 3 (odds ratio 30.2 [95% CI 12.2 to 75.0]; p < 0.001) and 2 than males (OR 4.1 [95% CI 2.3 to 7.1]; p < 0.001); thus, females had increased depth of the intercondylar fossa and broader shaft width relative to epicondylar width compared with males. For Mode 1 in the tibia, females were less likely to be in trajectory Group 2 (OR 0.5 [95% CI 0.3 to 0.9]; p = 0.01) than males (that is, knees of females were less likely to display superior elevation of tibial plateau or decreased shaft width relative to head width). Radiographic OA at baseline was associated with specific shape-change trajectory groups. For Mode 1 in the femur, knees with OA were less likely to be in trajectory Groups 3 (OR 0.4 [95% CI 0.2 to 0.8]; p = 0.008) and 2 (OR 0.6 [95% CI 0.3 to 1.0]; p = 0.03) than knees without OA; thus, knees with OA had decreased depth of the intercondylar fossa and narrower shaft width relative to epicondylar width compared with knees without OA. For Mode 1 in the tibia, knees with OA were not associated with trajectory. CONCLUSIONS: The shapes of the distal femur and proximal tibia did not change much over time. Sex and baseline knee radiographic OA status are associated with the trajectory of change in the bone's shape, suggesting that both may contribute earlier in life to the associations among trajectories observed in older individuals. Future studies might explore sex-related bone shape change earlier in life to help determine when the sex-specific shapes arise and also the degree to which these sex-related shapes are alterable by injury or other events. LEVEL OF EVIDENCE: Level III, prognostic study.

Selective inhibition of progesterone receptor in osteochondral progenitor cells, but not in mature chondrocytes, modulated subchondral bone structures.

OBJECTIVE: The presence or relative proportion of progesterone nuclear receptors (PR) in different tissues may contribute to sexual dimorphism in these tissues. PR is expressed in chondrocytes, but its function is mostly unknown. We hypothesized that the PR may regulate chondrocyte metabolism and affect subchondral bone structure. METHODS: We utilized genetic fate mapping and immunohistochemistry to elucidate PR expression in and effect on cartilage. To define sex-dependent and chondrocyte-specific effects of the PR on subchondral bone, we selectively deleted PR in osteochondrogenic progenitor cells marked by Prx1 (Prx1; PRcKO) and Collagen 2 (Col2; PRcKO), or in matured chondrocytes marked by aggrecan (Acan; PRcKO) and evaluated subchondral bone structure at 4 months of age. Chondrocyte aging was monitored by anti-senescence marker p16INK4a, and MMP13, one of the Senescence-Associated Secretary Phenotype (SASP) components. RESULTS: Compared to wild-type (WT) mice, the female Prx1; PRcKO and the Col2; PRcKO mice had greater total subchondral bone volume and greater subchondral cortical bone thickness, with increased estimated subchondral bone stiffness and failure load in both female and male Col2; PRcKO mice. Moreover, Col2; PRcKO mice from both sexes had greater bone formation and bone strength at the femurs. In contrast, we did not observe any subchondral bone changes in Acan; PRcKO mice other than higher work-to-failure observed in the male Acan; PRcKO mice. Despite no detected difference in articular cartilage between the WT and the PR; chondrocyte conditional deletion mice, there were greater numbers of senescent chondrocytes and increased MMP13 expression, especially in the male mutant mice. CONCLUSION: These findings suggest that selective inhibition of PR in osteoprogenitor cells, but not in terminally differentiated chondrocytes, induced an increased subchondral bone phenotype and high estimated subchondral bone strength, which might be associated with the development of osteoarthritis in older age.

Bone shape mediates the relationship between sex and incident knee osteoarthritis.

BACKGROUND: Knee bone shape differs between men and women and the incidence of knee osteoarthritis (OA) is higher in women than in men. Therefore, the purpose of the present study was to determine whether the observed difference in the incidence of knee radiographic OA (ROA) between men and women is mediated by bone shape. METHODS: We randomly sampled 304 knees from the OAI with incident ROA (i.e., development of Kellgren/Lawrence grade ≥ 2 by month 48) and 304 knees without incident ROA. We characterized distal femur and proximal tibia shape on baseline radiographs using Statistical Shape Modeling. If a specific bone shape was associated with the risk of incident ROA, marginal structural models were generated to assess the mediation effect of that bone shape on the relation of sex and risk of incident knee ROA adjusting for baseline covariates. RESULTS: Case and control participants were similar by age, sex and race, but case knees were from higher body mass index (BMI) participants (29.4 vs. 27.0; p < 0.001). Women had 49% increased odds of incident knee ROA compared with men (adjusted odds ratio (OR) = 1.49, 95% Confidence Interval (C.I.): 1.04, 2.12). There was an inconsistent mediation effect for tibial mode 2 between sex and incident knee ROA, with an indirect effect OR of 0.96 (95% C.I.: 0.91-1.00) and a direct effect OR of 1.56 (95% C.I.: 1.08-2.27), suggesting a protective effect for this mode. Similar findings were also observed for the mediation effect of tibia mode 10 and femur mode 4. These shape modes primarily involved differences in the angular relation of the heads to the shafts of the femur and tibia. CONCLUSIONS: Distal femur and proximal tibia bone shapes partially and inconsistently mediated the relationship between sex and incident knee OA. Women had a higher risk of incident ROA, and specific bone shapes modestly protected them from even higher risk of ROA. The clinical significance of these findings warrant further investigation.

Lower Quadriceps Rate of Force Development Is Associated With Worsening Physical Function in Adults With or at Risk for Knee Osteoarthritis: 36-Month Follow-Up Data From the Osteoarthritis Initiative.

OBJECTIVE: To determine the association between quadriceps rate of force development (RFD) and decline in self-reported physical function and objective measures of physical performance. DESIGN: Longitudinal cohort study. SETTING: Community-based sample from 4 urban areas. PARTICIPANTS: Osteoarthritis Initiative participants with or at risk for knee osteoarthritis, who had no history of knee/hip replacement, knee injury, or rheumatoid arthritis (N=2630). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Quadriceps RFD (N/s) was measured during isometric strength testing. Worsening physical function was defined as the minimal clinically important difference for worsening self-reported Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) physical function subscale score, 20-m walk time, and repeated chair stand time over 36 months. RESULTS: Compared with the slowest tertile of RFD, the fastest tertile had a lower risk for worsening of WOMAC physical function subscale score at 36-month follow-up, with an odds ratio (OR) of .68 (95% confidence interval [CI], .51-.92) after adjustment for age, sex, body mass index, depression, history of chronic diseases, and knee pain. In women, in comparison with the slowest tertile of RFD, the fastest tertile had a lower risk for worsening of WOMAC physical function subscale score at 36-month follow-up, with an adjusted OR of .57 (95% CI, .38-.86). This decreased risk did not reach statistical significance in men (OR, 0.81; 95% CI, 0.52-1.27). No statistically significant associations were detected between baseline RFD and walk or chair stand times. CONCLUSIONS: Our results indicate that higher RFD is associated with decreased risk for worsening self-reported physical function but not with decreased risk for worsening of physical performance.

Valgus malalignment and prevalence of lateral compartmental radiographic knee osteoarthritis (OA): The Wuchuan OA study.

AIM: To evaluate whether knee alignment explains the higher prevalence of lateral compartment tibiofemoral radiographic osteoarthritis (TFROA) among rural Chinese compared with that among Whites. METHODS: The Wuchuan OA Study is a population-based longitudinal study of risk factors for knee OA. At baseline 1030 participants had home interviews, clinical examinations and weight-bearing posteroanterior semi-flexed radiographs of the tibiofemoral joints. Anatomic knee alignment was measured using an e-film workstation and divided into three categories: normal (182°-184°), valgus (> 184°), and varus (< 182°) alignment. A knee was defined as having medial or lateral compartmental ROA if its Kellgren and Lawrence grade was ≥ 2 and joint space narrowing ≥ 1 in the medial or lateral compartment, respectively. We examined the association between knee alignment with prevalent medial or lateral knee ROA separately using multiple logistic regression. RESULTS: Among 1030 participants, the proportions of knees with normal, valgus and varus alignment were 29.9%, 56.5% and 13.7%, respectively. The prevalence of medial and lateral ROA was 16.0% and 4.3%, respectively. Valgus alignment was associated with prevalence of lateral compartment ROA (odds ratio [OR] = 5.0, 95% CI: 2.4-10.5), while varus alignment was associated with medial compartment ROA (OR = 6.1, 95% CI: 4.4-8.6). The ratio of prevalence of lateral versus medial compartment TFROA was greater in Wuchuan than that in the Framingham OA Study and valgus malalignment was more common in Wuchuan than in the Rotterdam study. CONCLUSIONS: The prevalence of compartment-specific TFROA differs between rural Chinese and Whites. This difference is likely due to relatively high prevalence of valgus malalignment in rural Chinese compared with that in Whites.

Knee Pain and Structural Damage as Risk Factors for Incident Widespread Pain: Data From the Multicenter Osteoarthritis Study.

OBJECTIVE: To examine the longitudinal relationship of knee pain, radiographic osteoarthritis (OA), symptomatic knee OA, and knee pain severity to incident widespread pain. METHODS: The Multicenter Osteoarthritis Study is a longitudinal cohort of persons with or at risk of knee OA. Participants were characterized as having consistent frequent knee pain, radiographic OA (Kellgren/Lawrence scale grade ≥2), symptomatic OA, and knee pain severity at the 60-month visit (baseline). Widespread pain was categorized as pain above and below the waist, on both sides of the body and axially, using a standard homunculus, excluding knee pain. Incident widespread pain was defined as the presence of widespread pain at 84 months in those who were free of widespread pain at baseline. We assessed the relationship of baseline radiographic OA, symptomatic OA, consistent frequent knee pain, and knee pain severity, respectively, with incident widespread pain using logistic regression, adjusting for potential confounders, including models with and without pain severity. RESULTS: At baseline, 1,129 subjects were eligible for analysis (mean ± SD age 66.7 ± 7.8 years; mean ± SD body mass index 30.1 ± 5.8 kg/m2 ; 52% women). Radiographic OA in either knee (adjusted odds ratio [ORadj ] 0.90 [95% confidence interval (95% CI) 0.63-1.30]; P = 0.587) was not associated with incident widespread pain. Baseline bilateral consistent frequent knee pain (ORadj 2.35 [95% CI 1.37-4.03]), bilateral symptomatic OA (ORadj 2.11 [95% CI 1.04-4.24]), and knee pain severity (worst knee) (ORadj 1.11 [95% CI 1.05-1.17]; P < 0.001) were significantly associated with incident widespread pain. CONCLUSION: Consistent frequent knee pain, symptomatic OA, and knee pain severity increased the risk of developing widespread pain, independently of structural pathology. These results suggest that knee pain, and not structural pathology, contributes to the onset of widespread pain.