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.

Plasma proteomics identifies CRTAC1 as a biomarker for osteoarthritis severity and progression.

OBJECTIVES: The aim of this study was to identify biomarkers for radiographic OA severity and progression acting within the inflammation and metabolic pathways. METHODS: For 3517 Rotterdam Study participants, 184 plasma protein levels were measured using Olink inflammation and cardiometabolic panels. We studied associations with severity and progression of knee, hip and hand OA and a composite overall OA burden score by multivariable regression models, adjusting for age, sex, cell counts and BMI. RESULTS: We found 18 significantly associated proteins for overall OA burden, of which 5 stayed significant after multiple testing correction: circulating cartilage acidic protein 1 (CRTAC1), cartilage oligomeric matrix protein (COMP), thrombospondin 4, IL-18 receptor 1 (IL-18R1) and TNF ligand superfamily member 14. These proteins were also associated with progression of knee OA, with the exception of IL-18R1. The strongest association was found for the level of CRTAC1, with 1 s.d. increase in protein level resulting in an increase of 0.09 (95% CI 0.06, 0.12) in the overall OA Kellgren-Lawrence sum score (P = 2.9 × 10-8) in the model adjusted for age, sex, BMI and cell counts. This association was also present with the severity of OA in all three joints and progression of knee OA and was independent of BMI. We observed a stronger association for CRTAC1 with OA than for the well-known OA biomarker COMP. CONCLUSION: We identified several compelling biomarkers reflecting the overall OA burden and the increased risk for OA progression. CRTAC1 was the most compelling and robust biomarker for OA severity and progression. Such a biomarker may be used for disease monitoring.

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.

Phenome-wide investigation of health outcomes associated with genetic predisposition to loneliness.

Humans are social animals that experience intense suffering when they perceive a lack of social connection. Modern societies are experiencing an epidemic of loneliness. Although the experience of loneliness is universally human, some people report experiencing greater loneliness than others. Loneliness is more strongly associated with mortality than obesity, emphasizing the need to understand the nature of the relationship between loneliness and health. Although it is intuitive that circumstantial factors such as marital status and age influence loneliness, there is also compelling evidence of a genetic predisposition toward loneliness. To better understand the genetic architecture of loneliness and its relationship with associated outcomes, we extended the genome-wide association study meta-analysis of loneliness to 511 280 subjects, and detect 19 significant genetic variants from 16 loci, including four novel loci, as well as 58 significantly associated genes. We investigated the genetic overlap with a wide range of physical and mental health traits by computing genetic correlations and by building loneliness polygenic scores in an independent sample of 18 498 individuals with EHR data to conduct a PheWAS with. A genetic predisposition toward loneliness was associated with cardiovascular, psychiatric, and metabolic disorders and triglycerides and high-density lipoproteins. Mendelian randomization analyses showed evidence of a causal, increasing, the effect of both BMI and body fat on loneliness. Our results provide a framework for future studies of the genetic basis of loneliness and its relationship to mental and physical health.

Vitamin K antagonist anticoagulant usage is associated with increased incidence and progression of osteoarthritis.

OBJECTIVES: Vitamin K is hypothesised to play a role in osteoarthritis (OA) pathogenesis through effects on vitamin K-dependent bone and cartilage proteins, and therefore may represent a modifiable risk factor. A genetic variant in a vitamin K-dependent protein that is an essential inhibitor for cartilage calcification, matrix Gla protein (MGP), was associated with an increased risk for OA. Vitamin K antagonist anticoagulants (VKAs), such as warfarin and acenocoumarol, act as anticoagulants through inhibition of vitamin K-dependent blood coagulation proteins. VKAs likely also affect the functioning of other vitamin K-dependent proteins such as MGP. METHODS: We investigated the effect of acenocoumarol usage on progression and incidence of radiographic OA in 3494 participants of the Rotterdam Study cohort. We also examined the effect of MGP and VKORC1 single nucleotide variants on this association. RESULTS: Acenocoumarol usage was associated with an increased risk of OA incidence and progression (OR=2.50, 95% CI=1.94-3.20), both for knee (OR=2.34, 95% CI=1.67-3.22) and hip OA (OR=2.74, 95% CI=1.82-4.11). Among acenocoumarol users, carriers of the high VKORC1(BB) expression haplotype together with the MGP OA risk allele (rs1800801-T) had an increased risk of OA incidence and progression (OR=4.18, 95% CI=2.69-6.50), while this relationship was not present in non-users of that group (OR=1.01, 95% CI=0.78-1.33). CONCLUSIONS: These findings support the importance of vitamin K and vitamin K-dependent proteins, as MGP, in the pathogenesis of OA. Additionally, these results may have direct implications for the clinical prevention of OA, supporting the consideration of direct oral anticoagulants in favour of VKAs.

Weight-Bearing Physical Activity, Lower-Limb Muscle Mass, and Risk of Knee Osteoarthritis.

Importance: It has been demonstrated that total physical activity is not associated with risk of osteoarthritis. However, the association of different types of physical activity with incident knee osteoarthritis remains unclear. Objective: To determine whether weight-bearing recreational physical activities are associated with increased risk of incident knee osteoarthritis. Design, Setting, and Participants: This prospective cohort study used data from the Rotterdam Study (1996 to 2009), including participants with knee x-ray measurements at baseline and follow-up examinations. Participants with knee osteoarthritis at baseline were excluded. Residents aged 45 years and older of the Ommoord district in the city of Rotterdam in The Netherlands were invited to join the Rotterdam Study (78% response rate). Analysis was conducted in June 2023. Exposure: Total, weight-bearing, and non-weight-bearing recreational physical activities collected by questionnaires at baseline. Main Outcomes and Measures: Incident radiographic knee osteoarthritis measured by knee x-ray was the primary outcome, and incident symptomatic knee osteoarthritis defined by x-ray and knee pain questionnaire was the secondary outcome. The association of different types of recreational physical activity with radiographic knee osteoarthritis was examined using logistic regression within generalized estimating equation framework after adjusting for potential confounders. A prespecified stratification analysis was planned on the basis of lower-limb muscle mass index (LMI) tertiles, measured by dual-energy x-ray absorptiometry. Results: A total of 5003 individuals (2804 women [56.0%]; mean [SD] age, 64.5 [7.9] years) were included. The knee osteoarthritis incident rate was 8.4% (793 of 9483 knees) for a mean (SD) follow-up time of 6.33 (2.46) years. Higher weight-bearing activity was associated with increased odds of incident knee osteoarthritis (odds ratio [OR], 1.22; 95% CI, 1.10-1.35; P < .001), but non-weight-bearing activity was not (OR, 1.04; 95% CI, 0.95-1.15; P = .37). In the analysis stratified by LMI tertiles, the association of weight-bearing activity with incident osteoarthritis was found only among 431 patients in the lowest LMI tertile (OR, 1.53; 95% CI, 1.15-2.04; P = .003), but not among patients in the middle or high LMI tertile. Conclusions and Relevance: The findings of this study suggest that weight-bearing activity is associated with incident knee osteoarthritis in people with low levels of lower-limb muscle mass, which might be a promising avenue for tailored advice for physical activity.