The most important finding of this study was that bone fragility and high turnover bone metabolism with menopause correlated with EKOA and DKOA in middle-aged Japanese females. Furthermore, AMH reduction below 0.08 ng/ml during menopausal transition indicated the presence of KOA from the early stage of this disease. On the other hand, reduction of the AMH and estradiol, which were proof of menopause, indicated lower BMD, high turnover bone metabolisms, and increased inflammation. These results suggested that the decline of female hormone would track KOA from the early stages. Bone fragility and inflammations based on menopause influenced the KOA even in early phase of this disease, which is a target of treatment or preventive interventions for KOA.
Females are at a higher risk of knee OA, and many previous epidemiological studies revealed that the prevalence of OA in females were higher than in males7,26. A systematic review estimated that the total odds ratio of females was up to 1.68 (95%CI: 1.37–2.07)27. Framingham study showed that the prevalence of OA in females was 36% and 1.2 times higher than that in males11. In Japan, the prevalence of OA in females were 1.5 to 2.8 times higher than males5,8−9; the prevalence was higher than that of Caucasians. Considering the role played by menopause, a longitudinal study from Melbourne Women’s Midlife Health Project showed that those who have never undergone hormone therapy were at a higher risk of developing knee OA28. Further, representative therapy decreased the incidence of knee OA29. Although one systematic review concluded that there was no clear association between female hormonal aspects and knee OA30, the relationship between DKOA and menopause shown in this study is supported by previous studies.
Firstly, this study revealed the application of AMH as a serum biomarker to detect EKOA and DKOA, especially at an early phase of the disease. AMH indicated the presence of EKOA, which proved that the initiation of KOA is in line with the menopausal transition stage. AMH is a glycoprotein dimer, only expressed in growing follicles, and has been identified as a marker of ovarian aging31–32. AHM decreases during menopausal transition, as previous reports found that the AMH reduces three years before menopause17. Another advantage of AMH is that it is not affected by menstrual cycles like estradiol, LH, and FSH. AMH helps to detect KOA in its early stages and aids in early intervention.
The influences of bone fragility on OA incidence or progression are controversial19. However, this study showed that lower BMD and high turnover bone metabolism of middle-aged females were correlated with the presence of KOA. In the 90 s, several studies have reported that higher BMD is related to the incidence of KOA33. On the contrary, from the basis of evidences in the most recent decade, Ota et al. revealed that symptomatic BMLs on MRI were related to bone fragility, including lower BMD and high turnover of bone metabolism in middle-aged females without radiographic abnormalities21. Furthermore, others also reported a pathogenic mechanism since excessive bone resorption takes place in the early phase of OA34–35.
Currently, the etiology and pathology of EKOA remain unclear. Our study was important because reduced AMH was associated with the presence of female EKOA, which suggested that initiation of degenerative change was in line with the menopausal transition stage. In the early stages of KOA, the Framingham study, including 710 knees with KL grade 0/1, showed the featured MRI findings in those with knee pain as having BMLs, attrition, and subchondral bone cysts36. Further, the CHECK study, a 5 year longitudinal cohort of general population, showed that the incidence risk factors for knee OA from KL grade 0/1 were BMLs, effusion, and meniscal lesion on MRI37. Bone abnormalities in the early stage of KL are likely to occur in the middle-aged female population36–37. During menopausal transition, bone metabolism changes dramatically, corresponding to the intrinsic hormonal changes in females. Based on this evidence, the current data indicates that such abrupt transitions in menopause predicts not only systemic bone metabolism turbulence but also focal bone abnormalities, which could induce osteoarthritic changes in knee joints.
Another interesting result in this study was that serum AMH concentration in the female population having KOA was associated with serum inflammation markers. Systemic and focal inflammation in synovium play an important role. Inflammation is generally induced by microfragments of cartilages or danger-associated molecular pattern (DAMPS) in synovial fluids and releases several proteases and cytokines, which accelerate the degeneration of articular tissues38–40. The infrapatellar fat pad is a major source of adiponectin in synovial fluid; adiponectins are closely related to the metabolic syndrome and degenerative pathological changes in the cartilage and bone during OA41. In this study, the presence of EKOA and DKOA correlated with an increasing serum hyaluronan concentration, which indicated synovitis, severity of knee OA, and degree of pain23,42; this predicts future joint space narrowing over 5 years43. AMH was a valuable and predictive biomarker for EKOA, which indicated bone fragility and inflammation. However, the utility and reliability of systemic biomarkers in OA diagnosis was not validated; further studies are needed.
This study has several limitations besides the selection bias focusing only on middle- to old-aged females. First, the study sample was the general Japanese population; their background information and confounding factors were not completely evaluated. Second, the imaging examination was limited to the radiographs. Although the MRI and ultrasonographic imaging detected minute structural changes and inflammation of the knee joint22,37 especially in EKOA, we could not use these modalities. However, by measuring many inflammation biomarkers, we could evaluate the minute changes of osteoarthritis. Furthermore, regarding radiographic examination, patellofemoral joint OA was not fully examined. Although crepitus was evaluated as one of the symptoms of patellofemoral OA, an imaging analysis was not performed. Imaging of patellofemoral joints could not be performed as a result of time constraints. However, patellofemoral OA should be assessed because of its significant effect on ADL and QOL44–45. Third, this study was a cross sectional study; basal causes of the incidence of knee OA were not determined. Further, a longitudinal observation was conducted in our cohort to estimate the real incidence of knee OA after AMH reduction and to certify its predictive values. Despite these limitations, this cohort study revealed the association of AMH to predict EKOA during menopausal transition, in addition to the relationship between menopause and osteoporotic knee OA in middle-aged females. In considering the etiology of OA, AMH reduction occurs three years before menopause, which leads to high turnover of bone metabolism and bone fragility. Bone fragility and inflammation at menopause influences knee OA even in the early phase of this disease. Therefore, AMH reduction could detect the EKOA without radiographic abnormalities via bone fragility and synovitis.