In a Japanese female cohort without radiographic KOA, we evaluated the longitudinal relationship between the BMD of the distal radius at baseline and change in BML area during a 2-year follow-up. As for the most important finding of this study, converting the BMD to %YAM value, linear regression analysis clarified that the YAM at baseline was negatively associated with the change in BML area. Based on the ROC curves, the lower YAM was significant in predicting the risk of enlarging the BML area, while this value was not significant in predicting the risk of regressing the BML area. Finally, logistic regression analysis in the current study clarified that a cut-off YAM value of ≤85% could significantly predict the risk of enlarging the BML area.
Previous epidemiological studies have already discussed the relationship between systemic BMD and incidence or progression of radiographic KOA. In particular, several previous studies clarified how systemic BMDs of the lumbar spine and proximal femur were associated with the incidence of radiographic KOA.[23–29] For participants without definitive radiographic KOA, such as KLG 0 or 1, the majority of previous cohort studies have clarified that higher systemic BMD had increased the risk of incidence of radiographic KOA, compared to lower systemic BMD.[23–29] In other words, those with lower systemic BMD were less likely to develop radiographic KOA than those with higher systemic BMD. Therefore, the current results conflict with those of previous cohort studies. As for the disadvantages of previous epidemiological studies, three points should be considered. First, both male and female populations were included in the analyses. Middle-aged and elderly female patients who are likely to develop KOA are in a period of pre-, peri-, and post-menopause. Accordingly, there is a deficiency of female hormones due to follicular dysfunction; in particular, reducing the secretion of estrogen, which directly suppresses the activity of osteoclasts, overcomes the bone formation derived from osteoblasts.[30,31] Additionally, perimenopausal females are at risk of oxidative stress to induce osteoclast-dominant bone remodeling.[32,33] In short, the epidemiological study of KOA, which considers the relationship between bone metabolism and subchondral bone damage, should divide males and females based on sex-hormone differences to regulate bone metabolism. Second, previous studies reported by Kamil et al. and Bergink et al.[26,27] provided us with demographic data, according to the BMD quartile. Notably, those with a higher quartile of systemic BMD demonstrated a higher BMI compared to those with a lower quartile of systemic BMD. This finding has a potential confounding of higher systemic BMD in which knee articular cartilage is in danger of mechanical stress due to its higher BMI. Additionally, previous evidence has shown that those with higher BMD were associated with higher physical activity; therefore, weight-bearing site BMD, such as the spine and proximal femur are likely to be higher.[34–38] Those with higher physical activity have the potential to stress the articular cartilage of the knee joint to develop KOA. As for the unique point of this study, we evaluated the BMD of the non-weight-bearing site and forearm. Previous female-cohort studies reported that physical activity had little effect on the change in distal-radius BMD in cross-sectional[39,40] and longitudinal designs. Therefore, the BMD of the non-weight-bearing site may demonstrate a novel specificity of bone metabolism, compared to that of the weight-bearing sites, such as the spine and proximal femoral BMD. Future research would have the potential to clarify the detailed mechanism of non-weight-bearing BMD on articular cartilage degeneration of the knee joint. Third, only plain radiographs of the knee joint were evaluated in previous cohort studies that elucidated the relationship between systemic BMD and the incidence of KOA. Basically, the osteoarthritic changes on plain radiographs of the knee joint are relatively slow. In the general population with KOA, Mazzuka et al. reported that the medial femorotibial joint space narrows to less than 0.10 mm/year, and a more recent systematic review concluded that the annual rate of medial femorotibial joint space narrowing was 0.13 ± 0.15 mm/year. Additionally, it is difficult to detect a more detailed mechanism of periarticular bone damage, such as BML; MRI has an advantage of evaluating real-time bony pathology in comparison to plain radiography. Notably, the current data could longitudinally evaluate the alteration of BML in the female cohort with pre-radiographic KOA. Moreover, we could clarify the longitudinal relationship between the alteration of periarticular bone damage during the 2-year follow-up and the baseline BMD of the forearm. In line with more recent basic studies[1,3] to elucidate the pathological mechanism of subchondral bone porosity in the early stage of KOA, the current epidemiological study warns of the risk of enlarging BML in the non-radiographic-KOA female population with lower systemic BMD, indicating systemic bone fragility. Therefore, maintaining higher systemic BMD in females in the early stage of KOA has the potential to prevent the enlargement of further BML in the knee joint, which is a potential risk factor for cartilage degeneration and KOA.[8,10–16]
Subchondral bone damage, such as BML is one of the pathological factors that emerged, not only in cartilage degeneration[10,11,14] but also in patients with both early and late stages of KOA[6–9]. Previous epidemiological studies have reported that knee symptoms in patients with KOA worsened in accordance with the severity of BML.[6,9] Interestingly, previous research in the recent decade has argued that knee symptoms derived from OA were significantly improved by administering bisphosphonate, which suppresses bone absorption and restores the systemic BMD in patients with osteoporosis.[44,45] In particular, it is notable that administering bisphosphonate reduced BML area concomitant with the improvement of knee pain[46–51]; moreover, in a more recent epidemiological study, Hayes et al. reported that bisphosphonate demonstrated the possibility of a disease-modifying drug in terms of preventing radiographic OA progression in a population with KLG <2. For middle-aged women, menopause linked to the hormonal reduction of estrogen causes a systemic bone turnover hyper; accordingly, they are likely to have a risk of fragility or porosity in the subchondral bone of the knee joint. Therefore, the current data would support that bisphosphonate can improve the knee symptoms derived from subchondral bone damage by alternating the systemic and periarticular bone microenvironment. Especially in middle-aged or elderly women without definitive radiographic KOA, preventing lower systemic BMD has the potential to reduce the risk of periarticular bone damage in the knee joint, which contributes to further development of KOA.
Another interesting finding of this study is that the optimal cut-off value to determine the risk of enlarging the BML area was 85% YAM of BMD, which is substantially higher than the 70% of YAM to determine the risk of fracture relative to osteoporosis.[52,53] In other words, the threshold of systemic bone strength to induce periarticular bone damage would be higher than that required to induce osteoporotic fracture. Accordingly, future studies should focus on the relationship between systemic bone strength and periarticular bone damage of the knee joint to distinguish the outcome to induce periarticular bone damage from that to induce osteoporotic fracture. The pathologies of bone metabolism between the periarticular damage of the knee joint and osteoporotic fracture are likely to be different.
The current study had several limitations. First, the participants in this study consisted of only women with non-radiographic KOA. Therefore, the relationship between BMD and the amount of change in the BML area is still unclear in the male population, and definitive radiographic KOA. Second, the sample size of the symptomatic group was relatively small, and it was difficult to conduct further multi-variable analysis for this group. Third, BMD was measured at the forearm, which is a non-weight-bearing site. Although the spinal and proximal femoral BMDs are the gold standard for evaluating systemic bone fragility, it was difficult to measure the spinal and proximal femoral BMD, which requires a large facility to shield radioactive materials, since this study was conducted as a part of a community-based general health check project in a limited space of a public hall. Therefore, the forearm was eligible for the substitutional measurement of systemic BMD in this study. However, the BMD of the non-weight-bearing site would show the different pathological meaning of the weight-bearing site, such as the spinal or proximal femur in terms of the alteration of periarticular bone damage. Despite these limitations, the current data can be variable for patients with early-stage KOA who have the potential to progress to definitive KOA. For these patients, lower systemic BMD is the risk of enlarging the area of BML, and maintaining a higher systemic BMD would prevent further deterioration of periarticular bone damage, which is linked to further osteoarthritic change and knee symptoms. Future studies will clarify the more detailed mechanisms of systemic BMD to control periarticular bone damage in the knee joint.