A systematic review of the sex differences in risk factors for knee osteoarthritis.

OBJECTIVES: Previous systematic reviews focused on the evidence of common risk factors for knee OA (KOA); however, the effect and strength of association between risk factors and KOA might be different between the two sexes. The aim of the present systematic review was to determine the current evidence on sex differences in the association between risk factors and KOA and their prevalence. METHODS: We searched the following electronic bibliographic databases: MEDLINE (PubMed), EMBASE and Web of Science. A methodological quality assessment was conducted independently by two researchers according to an adapted version of the standardized set of criteria known as the Newcastle-Ottawa Quality Assessment Scale (NOS). The NOS, a star system, was converted to three categories of quality. RESULTS: In total, 27 studies reported sex-specific risk estimates on several risk factors for KOA. Out of the 22 longitudinal cohort studies (except one nested case-control), 12 were of good quality and 10 were of fair quality. The five cross-sectional studies consisted of one of good, three of fair and one of poor quality. There was an indication of sex differences in risk factors leading to higher risk of KOA: high BMI, alcohol consumption, atherosclerosis and high vitamin E levels in women, and high physical activity, soft drink consumption and abdominal obesity in men. Knee injury, high blood pressure and low step rate seem to affect both women and men. CONCLUSION: More good quality studies are needed to assess sex differences in risk factors for KOA, especially for symptomatic/clinical OA.

Towards sex-specific osteoarthritis risk models: evaluation of risk factors for knee osteoarthritis in males and females.

OBJECTIVES: The aim of this study was to identify sex-specific prevalence and strength of risk factors for the incidence of radiographic knee OA (incRKOA). METHODS: Our study population consisted of 10 958 Rotterdam Study participants free of knee OA in one or both knees at baseline. One thousand and sixty-four participants developed RKOA after a median follow-up time of 9.6 years. We estimated the association between each available risk factor and incRKOA using sex stratified multivariate regression models with generalized estimating equations. Subsequently, we statistically tested sex differences between risk estimates and calculated the population attributable fractions (PAFs) for modifiable risk factors. RESULTS: The prevalence of the investigated risk factors was, in general, higher in women compared with men, except that alcohol intake and smoking were higher in men and high BMI showed equal prevalence. We found significantly different risk estimates between men and women: high level of physical activity [relative risk (RR) 1.76 (95% CI: 1.29-2.40)] or a Kellgren and Lawrence score 1 at baseline [RR 5.48 (95% CI: 4.51-6.65)] was higher in men. Among borderline significantly different risk estimates was BMI ≥27, associated with higher risk for incRKOA in women [RR 2.00 (95% CI: 1.74-2.31)]. The PAF for higher BMI was 25.6% in women and 19.3% in men. CONCLUSION: We found sex-specific differences in both presence and relative risk of several risk factors for incRKOA. Especially BMI, a modifiable risk factor, impacts women more strongly than men. These risk factors can be used in the development of personalized prevention strategies and in building sex-specific prediction tools to identify high risk profile patients.

Course of pain and fluctuations in pain related to suspected early hip osteoarthritis: the CHECK study.

OBJECTIVES: To evaluate the prevalence during a 10-year follow-up of clinically relevant fluctuations in pain and the course of hip pain in participants with hip complaints suspected to be early stage hip osteoarthritis (OA). To distinguish between participants with relevant fluctuations in pain and those without based on baseline characteristics. METHODS: Data were collected at baseline and after 2, 5, 8, and 10 years on 495 participants from the Cohort Hip and Cohort Knee Study (CHECK) with hip pain at baseline. Baseline demographic, anamnestic, and physical-examination characteristics were assessed. The primary outcome was levels of pain in the past week (scored using 0-10 Numeric Rating Scale) at follow-up assessments. Relevant fluctuation was defined as average absolute residuals greater than 1 after fitting a straight line to the participant's pain scores over time. RESULTS: The majority of the participants (76%) had stable or decreasing pain. Relevant fluctuations were found in 37% of the participants. The following baseline variables were positively associated with the presence of relevant fluctuations: higher levels of pain in the past week, use of pain transformation as a coping style, higher number of comorbidities, use of pain medication, and higher levels of high-sensitivity C-reactive protein. No associations were found for baseline radiographic hip OA or clinical hip OA. CONCLUSION: During a 10-year follow-up, the majority of participants had stable or decreasing pain levels. In those participants with relevant fluctuation (37%), a limited number of baseline variables were associated with increased odds of having relevant fluctuations in pain.

Pain appears to be an important reason for consulting the general practitioner (GP) for hip osteoarthritis (OA) complaints. We know that hip pain remained quite stable over 10 years. Also is known that there is considerable variety between patients in pain. In this study, we found relevant pain fluctuations in 37% of primary care patients with hip complaints over a period of 10 years. The pain fluctuation was not associated with having osteoarthritis, neither radiographic hip OA (diagnosed based on a X-ray) or clinical hip OA (determined according to the American College of Rheumatology (ACR) criteria) at baseline. More research is needed to discover why some people experience fluctuations in time than others.

10-Year natural course of early hip osteoarthritis in middle-aged persons with hip pain: a CHECK study.

OBJECTIVE: To explore the natural course of hip osteoarthritis (OA) in a population of first-time presenters with hip complaints. METHODS: Data were collected at baseline and after 2, 5, 8 and 10 years on participants from the Cohort Hip and Cohort Knee study with early symptomatic hip OA. Descriptive statistics were used to analyse the natural course of the hip complaints with respect to clinical signs and symptoms, physical functioning and radiographic osteoarthritis (ROA) features. RESULTS: In total, 588 participants were included with hip complaints and 86% completed the 10-year follow-up. The 10-year follow-up showed that 12% (69 participants) underwent hip replacement (HR), an increase of ROA of the hip (Kellgren and Lawrence score≥2) from 19% to 49%, and an increase in clinical hip OA according to the American College of Rheumatology criteria from 27% to 43%. All Western Ontario and McMaster Osteoarthritis Index subscales and physical activity remained on average constant during the 10-year follow-up for those who did not undergo an HR. The use of pain medication increased from 43% at baseline to 50% after 10 years. CONCLUSION: One out of nine participants with early hip problems received an HR during the 10-year follow-up. Prevalence of clinical hip OA and hip ROA increased steadily during the 10-year follow-up. Overall, we observed more hip OA, but fewer or stable complaints with respect to clinical signs and symptoms, and physical functioning. So it could be cautiously concluded that after 10 years, first-time presenters with hip complaints either received an HR or their symptoms remained stable.

Characteristics associated between the incidence of hip osteoarthritis and early hip complaints (CHECK study) within 10 years.

OBJECTIVE: To determine which baseline characteristics, especially clinically variables like pain, stiffness, physical functioning and disease variables, are associated with incident hip OA within 10 years in first presenters with hip complaints. Rheumatology key messages History taking and not physical exam variables are associated with incident hip osteoarthritis. Specific questions about daily life activities are associated with incident hip OA. These questions are about pain while walking/shopping, difficulties putting socks on/off and rising from bed. METHODS: Data were obtained from the nationwide prospective Cohort Hip and Cohort Knee (CHECK) study (n = 1002). Incident hip OA was defined as fulfilling the clinical ACR criteria for hip OA, a Kellgren and Lawrence score ≥2 with hip pain, or received a hip replacement during follow-up. Baseline measurements were used of participants with hip complaints and without hip OA. Principal component analysis (PCA) was used to reduce the number of correlated variables. Associations between baseline characteristics (including PCA components) and incident hip OA were investigated using logistic regression analysis, adjusted for age, sex and BMI. RESULTS: In total, 312 participants (85% female and 98% Caucasian) were included, 181 developed hip OA. PCA resulted in four components. Incident hip OA was associated with (i) component 1 (general presence of pain and symptoms) [odds ratio (OR) = 1.46 (95%CI: 1.08, 1.98)], (ii) component 3 (relatively high levels of pain during shopping/walking combined with less difficulty with putting socks on/off and rising from bed) [OR = 1.58 (95%CI: 1.18, 2.12)] and (iii) knee pain [OR = 0.34 (95% CI: 0.17, 0.66)]. CONCLUSION: In first presenters with hip complaints, use of a few history-taking variables might allow better recognition of those at higher odds for incident hip OA within 10 years.

The relationship between cam morphology and hip and groin symptoms and signs in young male football players.

BACKGROUND: Conflicting and limited high-quality prospective data are available on the associations between cam morphology and hip and groin symptoms and range of motion (ROM). OBJECTIVES: This cross-sectional cohort study investigated associations between cam morphology presence, size and duration and symptoms and ROM. METHODS: Academy male football players (n = 49, 17-24 years) were included. Standardized antero-posterior pelvic and frog-leg lateral radiographs were obtained at baseline, 2.5- and 5-year follow-up. The femoral head-neck junction was quantified by: Visual score. Cam morphology (flattening or prominence), large cam (prominence). Alpha angle. Cam morphology (≥60°), large cam (≥78°). Cam morphology duration was defined as long (first present at baseline) or short (only from 2.5- to 5-year follow-up). Current symptoms at 5-year follow-up were assessed using a hip and groin pain question and by the "Hip and Groin Outcome Score" (HAGOS). HAGOS scores were categorized into: most symptoms (≥2 domains in lowest interquartile range [IQR]), least symptoms (≥2 domains in highest IQR). Hip ROM was measured by goniometry at 5-year follow-up. RESULTS: Large cam morphology based on visual score was associated with hip and groin pain (23.8% vs. 7.1%, OR: 3.17, CI: [1.15-8.70], P = .026), but not with HAGOS scores. Cam morphology presence, size, and duration were associated with limited flexion of around 6° and/or 3° to 6° for internal rotation. CONCLUSION: Cam morphology presence, size, and duration were associated with limited hip flexion and/or internal rotation, but differences might not exceed the minimal clinical important difference. Whether cam morphology results in symptoms is uncertain.

Cam morphology in young male football players mostly develops before proximal femoral growth plate closure: a prospective study with 5-yearfollow-up.

OBJECTIVES: Cam morphology is not completely understood. The aim of this study was threefold: (1) to investigate if cam morphology development is associated with growth plate status; (2) to examine whether cam morphology continues to develop after growth plate closure; and (3) to qualitatively describe cam morphology development over 5-year follow-up. METHODS: Academy male football players (n=49) participated in this prospective 5-year follow-up study (baseline 12-19 years old). Anteroposterior and frog-leg lateral views were obtained at baseline (142 hips), 2.5-year (126 hips) and 5-year follow-up (98 hips). Cam morphology on these time points was defined as: (A) visual scores of the anterior head-neck junction, classified as: (1) normal, (2) flattening, and (3) prominence; and (B) alpha angle ≥60°. Proximal femoral growth plates were classified as open or closed. Cam morphology development was defined as every increase in visual score and/or increase in alpha angle from <60° to ≥60°, between two time points. This resulted in 224 measurements for cam morphology development analysis. RESULTS: Cam morphology development was significantly associated with open growth plates based on visual score (OR: 10.03, 95% CI 3.49 to 28.84, p<0.001) and alpha angle (OR: 2.85, 95% CI 1.18 to 6.88, p=0.020). With both definitions combined, cam developed in 104 of 142 hips during follow-up. Of these 104 hips, cam developed in 86 hips (82.7%) with open growth plate and in 18 hips (17.3%) with a closed growth plate. Cam morphology developed from 12 to 13 years of age until growth plate closure around 18 years. CONCLUSION: Cam morphology of the hip is more likely to develop with an open growth plate.

Identification of receptor-type protein tyrosine phosphatase µ as a new marker for osteocytes.

Osteocytes are the predominant cells in bone, where they form a cellular network and display important functions in bone homeostasis, phosphate metabolism and mechanical transduction. Several proteins strongly expressed by osteocytes are involved in these processes, e.g., sclerostin, DMP-1, PHEX, FGF23 and MEPE, while others are upregulated during differentiation of osteoblasts into osteocytes, e.g., osteocalcin and E11. The receptor-type protein tyrosine phosphatase µ (RPTPµ) has been described to be expressed in cells which display a cellular network, e.g., endothelial and neuronal cells, and is implied in mechanotransduction. In a capillary outgrowth assay using metatarsals derived from RPTPµ-knock-out/LacZ knock-in mice, we observed that the capillary structures grown out of the metatarsals were stained blue, as expected. Surprisingly, cells within the metatarsal bone tissue were positive for LacZ activity as well, indicating that RPTPµ is also expressed by osteocytes. Subsequent histochemical analysis showed that within bone, RPTPµ is expressed exclusively in early-stage osteocytes. Analysis of bone marrow cell cultures revealed that osteocytes are present in the nodules and an enzymatic assay enabled the quantification of the amount of osteocytes. No apparent bone phenotype was observed when tibiae of RPTPµ-knock-out/LacZ knock-in mice were analyzed by µCT at several time points during aging, although a significant reduction in cortical bone was observed in RPTPµ-knock-out/LacZ knock-in mice at 20 weeks. Changes in trabecular bone were more subtle. Our data show that RPTPµ is a new marker for osteocytes.

Distinct subtypes of knee osteoarthritis: data from the Osteoarthritis Initiative.

OBJECTIVE: OA is suspected to be a collection of distinct subtypes, each with different aetiology and clinical characteristics. We aimed to explore the existence of different subtypes of knee OA, using cluster analysis of the data of the OA Initiative. METHODS: We used latent class cluster analysis (LCA) to cluster baseline data of 518 subjects of the OA Initiative progression cohort. Data included radiographic scores of OA features per compartment, regional quantitative MRI measures of cartilage quantity and denuded bone, and self-reported clinical scores on knee symptoms. To ensure that the clusters were found independently of OA severity, the LCA model was corrected with a measure of OA severity. The resulting clusters were compared with respect to the presence of risk factors and progression. RESULTS: LCA resulted in four clusters containing 47%, 27%, 15% and 12% of the subjects. Clusters 1, 2 and 4 showed OA features at the medial compartment, while cluster 3 only showed lateral OA features. Clusters 3 and 4 showed severe increases in areas of denuded bone, whereas no denuded bone was present in cluster 1. Prevalence of OA progression over 24 months was highest in clusters 3 and 4 and lowest in cluster 1. The clusters also differed significantly in BMI, knee alignment and prevalence of reported trauma. CONCLUSION: LCA confirmed the existence of distinct subtypes of knee OA with clear differences in structural degradation and symptoms. The fact that subtypes also differed in risk factors suggests that different causes lead to different types of knee OA.

Validation of statistical shape modelling to predict hip osteoarthritis in females: data from two prospective cohort studies (Cohort Hip and Cohort Knee and Chingford).

OBJECTIVES: To prospectively investigate whether hip shape variants at baseline are associated with the need for future total hip replacement (THR) in women and to validate the resulting associated shape variants of the Cohort Hip and Cohort Knee (CHECK) cohort and the Chingford cohort. METHODS: Female participants from the CHECK cohort without radiographic OA (Kellgren-Lawrence score <2) at baseline were included (1100 hips); 22 hips had a THR within 5 years of follow-up. For the Chingford cohort, with only female participants, hips without radiographic OA at baseline were selected and a nested case-control design was used, with 19 THR cases within 19 years of follow-up and 95 controls matched 5 to 1 for age and BMI. Hip shape on baseline anteroposterior pelvic radiographs was assessed by statistical shape modelling (SSM) using the same model for both cohorts. RESULTS: In the CHECK and Chingford cohorts, the respective mean age was 55.8 (s.d. 5.1) and 53.6 (s.d. 5.4) and the BMI was 26.14 (s.d. 4.3) and 25.7 (s.d. 3.3), respectively. Multiple shape variants of the hip were significantly (P < 0.05) associated with future THR in both the CHECK (modes 4, 11, 15, 17 and 22) and Chingford (modes 2 and 17) cohorts. Mode 17 [odds ratio (OR) 0.51 (95% CI 0.33, 0.80) in the CHECK cohort], representing a flattened head-neck junction and flat greater trochanter, could be confirmed in the Chingford cohort [OR 0.41 (95% CI 0.23, 0.82)]. Modes 4 and 15 of the CHECK cohort also showed non-significant trends in the Chingford cohort. CONCLUSION: Several baseline shape variants are associated with the future need for THR within a cohort. Despite differences in participant characteristics, radiographic protocol and follow-up time, we could validate at least one shape variant, suggesting that SSM is reasonably transferable between cohorts.

Hsp90 inhibition protects against biomechanically induced osteoarthritis in rats.

OBJECTIVE: Although articular cartilage has evolved to facilitate joint mobilization, severe loading can induce chondrocyte apoptosis, which is related to the progression of osteoarthritis (OA). To avoid apoptosis, chondrocytes synthesize heat-shock proteins (HSPs). This study was undertaken to examine the roles of Hsp70 and Hsp90 in biomechanically induced OA, and the possibility of using Hsp90 inhibition as an intervention strategy for OA management. METHODS: OA was biomechanically induced in rats by means of strenuous running. Disease progression was compared between running rats treated with Hsp90 inhibitor and untreated running controls. Hsp70 and Hsp90 protein levels in articular cartilage were determined by Western blotting. OA progression was monitored using contrast-enhanced micro-computed tomography to measure cartilage degradation and subchondral bone changes and single-photon-emission computed tomography to examine synovial macrophage activation and histologic features. RESULTS: Chronic cartilage loading led to early OA development, characterized by degeneration of cartilage extracellular matrix. In vivo Hsp90 inhibition resulted in increased Hsp70 synthesis, which suggests that Hsp90 activity limits Hsp70 production. Hsp90 inhibitor treatment increased cartilage sulfated glycosaminoglycan levels to concentrations even beyond baseline and protected against cartilage degradation, stimulated subchondral bone thickness, and suppressed macrophage activation. CONCLUSION: Our findings indicate that Hsp90 plays a pivotal role in biomechanically induced chondrocyte stress responses. Intervention strategies that inhibit Hsp90 can potentially protect or improve cartilage health and might prevent OA development.

Stimulation of fibrotic processes by the infrapatellar fat pad in cultured synoviocytes from patients with osteoarthritis: a possible role for prostaglandin f2α.

OBJECTIVE: Stiffening of the joint is a feature of knee osteoarthritis (OA) that can be caused by fibrosis of the synovium. The infrapatellar fat pad (IPFP) present in the knee joint produces immune-modulatory and angiogenic factors. The goal of the present study was to investigate whether the IPFP can influence fibrotic processes in synovial fibroblasts, and to determine the role of transforming growth factor ß (TGFß) and prostaglandin F2α (PGF2α ) in these processes. METHODS: Batches of fat-conditioned medium (FCM) were made by culturing pieces of IPFP obtained from the knees of 13 patients with OA. Human OA fibroblast-like synoviocytes (FLS) (from passage 3) were cultured in FCM with or without inhibitors of TGFß/activin receptor-like kinase 5 or PGF2α for 4 days. The FLS were analyzed for production of collagen and expression of the gene for procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2; encoding lysyl hydroxylase 2b, an enzyme involved in collagen crosslinking) as well as the genes encoding α-smooth muscle actin and type I collagen α1 chain. In parallel, proliferation and migration of the synoviocytes were analyzed. RESULTS: Collagen production and PLOD2 gene expression by the FLS were increased 1.8-fold (P < 0.05) and 6.0-fold (P < 0.01), respectively, in the presence of FCM, relative to control cultures without FCM. Moreover, the migration and proliferation of synoviocytes were stimulated by FCM. Collagen production was positively associated with PGF2α levels in the FCM (R = 0.89, P < 0.05), and inhibition of PGF2α levels reduced the extent of FCM-induced collagen production and PLOD2 expression. Inhibition of TGFß signaling had no effect on the profibrotic changes. CONCLUSION: These results indicate that the IPFP can contribute to the development of synovial fibrosis in the knee joint by increasing collagen production, PLOD2 expression, cell proliferation, and cell migration. In addition, whereas the findings showed that TGFß is not involved, the more recently discovered profibrotic factor PGF2α appears to be partially involved in the regulation of profibrotic changes.

Cam impingement causes osteoarthritis of the hip: a nationwide prospective cohort study (CHECK).

OBJECTIVE: To determine the association between cam impingement, which is hip incongruity by a non-spherical femoral head and development of osteoarthritis. METHODS: A nationwide prospective cohort study of 1002 early symptomatic osteoarthritis patients (CHECK), of which standardised anteroposterior pelvic radiographs were obtained at baseline and at 2 and 5 years follow-up. Asphericity of the femoral head was measured by the α angle. Clinically, decreased internal hip rotation (≤20°) is suggestive of cam impingement. The strength of association between those parameters at baseline and development of incident osteoarthritis (K&L grade 2) or end-stage osteoarthritis (K&L grades 3, 4, or total hip replacement) within 5 years was expressed in OR using generalised estimating equations. RESULTS: At baseline, 76% of the included hips had no radiographic signs of osteoarthritis and 24% doubtful osteoarthritis. Within 5 years, 2.76% developed end-stage osteoarthritis. A moderate (α angle>60°) and severe (α angle>83°) cam-type deformity resulted in adjusted OR of 3.67 (95% CI 1.68 to 8.01) and 9.66 (95% CI 4.72 to 19.78), respectively, for end-stage osteoarthritis. The combination of severe cam-type deformity and decreased internal rotation at baseline resulted in an even more pronounced adjusted OR, and in a positive predictive value of 52.6% for end-stage osteoarthritis. For incident osteoarthritis, only a moderate cam-type deformity was predictive OR=2.42 (95% CI 1.15 to 5.06). CONCLUSIONS: Individuals with both severe cam-type deformity and reduced internal rotation are strongly predisposed to fast progression to end-stage osteoarthritis. As cam impingement might be a modifiable risk factor, early recognition of this condition is important.

Nocturnal pain and fatigue in middle-aged persons with hip symptoms suspected to be osteoarthritis, is there a link in 10-year follow-up of the CHECK study?

Objective: To explore the prevalence of nocturnal pain and fatigue in participants with hip symptoms suspected to be early osteoarthritis (OA) and to test the mediating effect of nocturnal pain on the association between hip OA pain and fatigue. Methods: We included participants with hip pain but no knee pain at baseline, from the Cohort Hip and Cohort Knee (CHECK)-study. Severity of hip OA pain was determined using the Numeric-Rating-Scale-pain-score last week. Fatigue was assessed using the SF-36 Fatigue subscale. Nocturnal pain was determined using the WOMAC-question: "How much pain have you experienced in the last 48 â€‹h at night while in bed?". Hip OA pain, nocturnal pain and fatigue were measured repeatedly during 10-year follow-up. Path analysis were used per time point to determine the direct effect of OA pain on fatigue and the indirect effect through nocturnal pain. Results: In 170 participants (female: 76%; mean age: 55.7 years; mean BMI: 25.5 â€‹kg/m2) the prevalence of nocturnal pain varied between 22 and 35% and the prevalence of fatigue ranged between 14 and 18%. Hip OA pain was associated with nocturnal pain and fatigue. The direct effect of hip OA pain on fatigue was significant at all-time points. No significant mediating effect of nocturnal pain was found. Conclusion: In this cohort of participants suspected to have early hip OA, the prevalence of fatigue remained stable and the prevalence of nocturnal pain decreased slightly over 10-year follow-up. We did not find a mediating effect of nocturnal pain in the pathway between hip OA pain and fatigue.

Defining discriminative pain trajectories in hip osteoarthritis over a 2-year time period.

BACKGROUND: Although pain due to osteoarthritis (OA) generally deteriorates over time, there is a large individual variation in the course of pain. This study examines the different longitudinal trajectories of patients with hip pain due to OA. METHODS: Data from a previously performed randomised controlled trial were used to investigate the course of pain over 2 years in 222 patients with clinically and radiographically determined hip OA. Pain was measured with a visual analogue scale (0-100). Latent class growth analysis was used to determine the number of trajectories of patients with hip pain due to OA. RESULTS: Analyses yielded five trajectories of pain due to hip OA. Trajectory 1 ('mild pain'; n=69) consists of patients with stable mild pain. Patients in trajectory 2 ('moderate pain'; n=31) fluctuated slightly between moderate and severe pain levels. Trajectory 3 ('always pain'; n=32) consists of patients with severe pain. Patients in trajectory 4 ('regularly progressing'; n=48) started with mild pain and progressed slowly to moderate pain. Trajectory 5 ('highly progressing'; n=42) patients also started with mild pain but quickly progressed to severe pain over 2 years. Compared with the 'mild pain' group, patients in the 'always pain' group had more severe radiographic hip OA, morning stiffness and decreased range of motion. The 'highly progressing' group had more severe radiographic hip OA and morning stiffness. CONCLUSIONS: Latent class growth analysis applied to longitudinal data of patients with hip OA identified five distinct trajectories of pain. More studies are needed to externally validate these findings.

Low-magnitude whole body vibration does not affect bone mass but does affect weight in ovariectomized rats.

Mechanical loading has stimulating effects on bone architecture, which can potentially be used as a therapy for osteoporosis. We investigated the skeletal changes in the tibia of ovariectomized rats during treatment with whole body vibration (WBV). Different low-magnitude WBV treatment protocols were tested in a pilot experiment using ovariectomized rats with loading schemes of 2 × 8 min/day, 5 days/week (n = 2 rats per protocol). Bone volume and architecture were evaluated during a 10 week follow-up using in-vivo microcomputed tomography scanning. The loading protocol in which a 45 Hz sine wave was applied at 2 Hz with an acceleration of 0.5g showed an anabolic effect on bone and was therefore further analyzed in two groups of animals (n = 6 each group) with WBV starting directly after or 3 weeks after ovariectomy and compared to a control (non-WBV) group at 0, 3, 6 and 10 weeks' follow-up. In the follow-up experiment the WBV stimulus did not significantly affect trabecular volume fraction or cortical bone volume in any of the treatment groups during the 10 week follow-up. WBV did reduce weight gain that was induced as a consequence of ovariectomy. We could not demonstrate any significant effects of WBV on bone loss as a consequence of ovariectomy in rats; however, the weight gain that normally results after ovariectomy was partly prevented. Treatment with WBV was not able to prevent bone loss during induced osteoporosis.

Osteoarthritis induction leads to early and temporal subchondral plate porosity in the tibial plateau of mice: an in vivo microfocal computed tomography study.

OBJECTIVE: In osteoarthritis (OA), changes occur in both cartilage and subchondral bone. The subchondral bone plate facilitates normal cross-talk between articular cartilage and trabecular subchondral bone, and adaptive changes in the plate due to OA may therefore disturb cross-talk homeostasis. To investigate these changes over time, we examined the cartilage-subchondral bone interface using a combined approach of histologic analysis and in vivo microfocal computed tomography. METHODS: Sixteen-week-old male C57BL/6 mice (n=32) received intraarticular injections of collagenase in 1 joint to induce instability-related OA and received saline injections in the contralateral knee joint (control joint). At 2, 4, 6, 10, and 14 weeks after injection, changes in the tibial subchondral bone plate and subchondral trabeculae were analyzed. RESULTS: Two weeks after injection, collagenase-injected joints had significantly more cartilage damage and osteophytosis than did control joints. Osteoclast activity directly underneath the subchondral bone plate was significantly elevated in collagenase-injected joints compared to control joints (mean±SEM osteoclast surface/bone surface 11.07±0.79% versus 7.60±0.81%), causing the plate to become thinner and creating a large increase in subchondral bone plate porosity (mean±SEM cumulative porosity volume 0.05±0.04×10(-3) mm3 in control joints versus 2.52±0.69×10(-3) mm3 in collagenase-injected joints). Four weeks after injection, the previously formed perforations disappeared, coinciding with a significant rise in osteoblast activity in the subchondral trabecular bone in collagenase-injected joints compared to control joints (mean ± SEM bone formation rate/bone surface 0.62±0.13 µm3/µm2 per day versus 0.30±0.03 µm3/µm2 per day). CONCLUSION: The current study is the first to provide quantitative longitudinal data on the dynamic changes in the subchondral bone plate after OA induction. The development of plate perforations may enhance mutual interaction between subchondral trabeculae, bone marrow cells, and the articular cartilage in OA.

Systemic treatment with pulsed electromagnetic fields do not affect bone microarchitecture in osteoporotic rats.

PURPOSE: Pulsed electromagnetic fields (PEMF) are currently used in the treatment of spinal fusions and non-unions. There are indications that PEMF might also be effective in the treatment of osteoporosis. In this study we examined whether whole-body PEMF treatment affects the bone microarchitecture in an osteoporotic rat model. METHODS: Twenty-week-old female rats were ovariectomised (n=20). Four different PEMF treatment protocols based on previous experimental studies and based on clinically used PEMF signals were examined (2 h/day, 5 days/week). A control group did not receive PEMF. At zero, three and six weeks cancellous and cortical bone architectural changes at the proximal tibia were evaluated using in vivo microCT scanning. RESULTS: PEMF treatment did not induce any changes in cancellous or cortical bone compared to untreated controls. CONCLUSIONS: Although previous studies have shown strong effects of PEMF in osteoporosis we were unable to demonstrate this in any of the treatment protocols. Using in vivo microCT scanning we were able to identify small bone changes in time. Subtle differences in the experimental set-up might explain the differences in study outcomes in the literature. Since PEMF treatment is safe, future experimental studies on the effect of PEMF on bone can better be performed directly on humans, eliminating the potential translation issues between animals and humans. In this study we found no support for the use of PEMF in the treatment of osteoporosis.

A prospective cohort study on cam morphology and its role in progression of osteoarthritis.

BACKGROUND: Cam morphology contributes to the development of hip osteoarthritis (OA) but is less studied in the general population. This study describes its associations with clinical and imaging features of hip OA. METHODS: Anteroposterior hip radiographs of 1019 participants from the Tasmanian Older Adult Cohort (TASOAC) were scored at baseline for α angle (cam morphology) in both hips. Using the Altman's atlas, radiographic hip OA (ROA) was assessed at baseline. Hip pain and right hip structural changes were assessed on a subset of 245 magnetic resonance images (MRI) at 5 years. Joint registry data for total hip replacement (THR) was acquired 14 years from baseline. RESULTS: Of 1906 images, cam morphology was assessed in 1016 right and 890 left hips. Cross-sectionally, cam morphology modestly associated with age (prevalence ratio [PR]: 1.02 P = .03) and body mass index (BMI) (PR: 1.03-1.07, P = .03) and strongly related to male gender (PR: 2.96, P < .001). Radiographically, cam morphology was prevalent in those with decreased joint space (PR: 1.30 P = .03) and osteophytes (PR: 1.47, P = .03). Longitudinally, participants with right cam and high BMI had more hip pain (PR: 17.9, P = .02). At the end of 5 years of follow-up these participants were also more likely to have structural changes such as bone marrow lesions (BMLs) (PR: 1.90 P = .04), cartilage defects (PR: 1.26, P = .04) and effusion-synovitis at multiple sites (PR: 1.25 P = .02). Cam morphology at baseline in either hip predicted up to threefold risk of THR (PR: 3.19, P = .003) at the end of 14 years. CONCLUSION: At baseline, cam morphology was linked with age, higher weight, male gender, early signs of radiographic OA such as joint space narrowing (JSN) and osteophytes (OST). At follow-up, cam predicted development of hip BMLs, hip effusion-synovitis, cartilage damage and THR. These findings suggest that cam morphology plays a significant role in early OA and can be a precursor or contribute to hip OA in later life.

The peroxisome proliferator-activated receptor (PPAR) alpha agonist fenofibrate maintains bone mass, while the PPAR gamma agonist pioglitazone exaggerates bone loss, in ovariectomized rats.

BACKGROUND: Activation of peroxisome proliferator-activated receptor (PPAR)gamma is associated with bone loss and increased fracture risk, while PPARalpha activation seems to have positive skeletal effects. To further explore these effects we have examined the effect of the PPARalpha agonists fenofibrate and Wyeth 14643, and the PPARgamma agonist pioglitazone, on bone mineral density (BMD), bone architecture and biomechanical strength in ovariectomized rats. METHODS: Fifty-five female Sprague-Dawley rats were assigned to five groups. One group was sham-operated and given vehicle (methylcellulose), the other groups were ovariectomized and given vehicle, fenofibrate, Wyeth 14643 and pioglitazone, respectively, daily for four months. Whole body and femoral BMD were measured by dual X-ray absorptiometry (DXA), and biomechanical testing of femurs, and micro-computed tomography (microCT) of the femoral shaft and head, were performed. RESULTS: Whole body and femoral BMD were significantly higher in sham controls and ovariectomized animals given fenofibrate, compared to ovariectomized controls. Ovariectomized rats given Wyeth 14643, maintained whole body BMD at sham levels, while rats on pioglitazone had lower whole body and femoral BMD, impaired bone quality and less mechanical strength compared to sham and ovariectomized controls. In contrast, cortical volume, trabecular bone volume and thickness, and endocortical volume were maintained at sham levels in rats given fenofibrate. CONCLUSIONS: The PPARalpha agonist fenofibrate, and to a lesser extent the PPARaplha agonist Wyeth 14643, maintained BMD and bone architecture at sham levels, while the PPARgamma agonist pioglitazone exaggerated bone loss and negatively affected bone architecture, in ovariectomized rats.