Knee osteoarthritis (KOA) is a joint disease with chronic pain and walking disability that affects 37% of persons older than 60 years old (1, 2). KOA is thus regarded as a serious social issue with substantial economic burdens. KOA involves complex etiologies, such as degeneration of cartilage, abnormal metabolism of subchondral bone, and inflammation of the synovial membrane, caused by genetic, environmental, and biomechanical risk factors.

Subchondral bone is the bony component located distal to calcified cartilage (3, 4), and it has been demonstrated in recent studies to be related to the development and progression of KOA (4, 5). In early KOA, abnormal loading leads to microfractures within the osteochondral bone, and the subsequent healing response involves osteoblasts, osteoclasts, macrophages, mesenchymal stem cells, and complex chemical signals. At this stage, the subchondral remodeling rate increases, and the thickness of the subchondral plate decreases (4, 6). However, in the late stage of KOA, subchondral bone features decreased bone resorption, finally causing bone sclerosis (7). Subchondral sclerosis is one hallmark of KOA and is commonly considered to be accompanied by increased bone volume fraction (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), and decreased trabecular separation (Tb.Sp) (8). In brief, subchondral bone undergoes distinct pathophysiological processes in the initiation and progression of KOA.

Bisphosphonate has enormous potential for the treatment of KOA. Bisphosphonate can attach to the hydroxyapatite binding sites of bone surfaces. When bisphosphonate contacts the osteoclast, it impairs the ability of the osteoclasts to form the ruffled border that facilitates osteoclasts in adhering to the bony surface and producing the protons that are necessary for bone resorption (9, 10). Therefore, bisphosphonate decreases subchondral bone remodeling, possibly alleviating the increased bone turnover in early KOA. Animal studies have found that bisphosphonate increased BV/TV, Tb.N, and Tb.Th and was beneficial to early KOA (11–13). However, considering that the subchondral bone remodeling process in late KOA was inversely altered, bisphosphonate might negatively affect late KOA. In particular, increased BV/TV, Tb.N, and Tb.Th have been demonstrated to cause established KOA to deteriorate in humans (14–16). The effect of bisphosphonate on the BV/TV, Tb.N, and Tb.Th of subchondral bone in moderate to late KOA was decisive in the justification and safety of bisphosphonate use in these patients, but related studies have been lacking.

The present study aimed to check the safety of bisphosphonate use for subchondral bone in established patients with KOA, that is, whether bisphosphonate use aggravates subchondral bone sclerosis, just as in the theoretical deduction.

The effect of bisphosphonate on the subchondral bone morphometry of patients with KOA remains unclear. The concern about the possibility that bisphosphonate might increase the sclerosis of subchondral bone might discourage clinicians from using bisphosphonate for established KOA. The present study found that bisphosphonate use did not alter tibial subchondral bone morphometry, which indicates sclerosis.

Fernández-Martín's research (26) also revealed that bisphosphonate did not alter subchondral bone morphometry. However, there were enormous differences between the research settings. First, our results were from human data, which were different from previous studies using animal models. The mechanism of KOA in animal models could differ from that in humans; in particular, most animal models adopt traumatic KOA, which is not in accord with most cases of practical human KOA. Second, our study only enrolled established patients with KOA to investigate the effect of bisphosphonate on the late stage of KOA, while Fernández-Martín's research studied rabbits in the early stage.

The difference in the subchondral bone morphometry change was not significant between the two groups, but the hip BMD change in the current bisphosphonate-use group was significantly greater than that in the no current bisphosphonate-use group. There seems to be a contradiction between increased BMD and unchanged subchondral bone morphometry or sclerosis. This contradiction might be explained by the difference between increased trabecular volume and increased BMD. Li et al. (27) demonstrated that the subchondral bone of patients with OA contained greater bone volume but less mineralization than disease-free subchondral bone. In late KOA, bone volume (or sclerosis) increases due to decreased bone resorption and relatively increased bone formation. However, due to the lack of sufficient time for full mineralization in fast bone formation, the material density of subchondral bone will decrease (4).

The effect of bisphosphonate on patients with KOA has been widely investigated, but the results have been conflicting. In Maurizio Rossini et al.'s double-blind, phase III, randomized clinical trial (RCT) (28), intra-articular injection of 2 mg of clodronate was associated with a lower visual analogue scale (VAS) and less analgesic drug use in patients with KOA at the 5-week follow-up. Laslett et al. (29) reported a significant reduction in numeric rating scale pain in the first 3 years with bisphosphonate use in patients with KOA. Arti et al. (30) conducted a RCT of 130 patients, demonstrating that a combination therapy of glucosamine and alendronate significantly improved stiffness and function compared with glucosamine alone. Laslett et al. (31) revealed that zoledronic acid reduced knee pain and bone marrow lesion size over 6 months. One hypothesis was that the analgesic effect of bisphosphonate arose from the suppression of proton secretion by osteoclasts. In situations of high bone turnover with increased osteoclast activity, the acidification of the osteoclast environment was increased by the greater level of secreted protons, which would lead to the activation of acid-sensing receptors, such as transient receptor potential vanilloid subtype 1 (TRPV1) channels and acid-sensing ion channel 2 or 3 (ASIC2/3), which are located on bone-innervating primary afferents, producing nociceptive signaling (32). The effect of bisphosphonate on KOA structural progression might occur through bone remodeling (33). However, some studies have argued against the use of bisphosphonate in treating KOA. Cai et al. (34) detected no significant difference between the zoledronic acid and placebo groups regarding changes in cartilage volume, visual analog scale, or bone marrow lesion size. Ballal et al. (35) also reported that no benefit to bone marrow lesions (BML) volume was observed over a 12-month period. It is known that enlarging BMLs can lead to greater cartilage loss (36). Our study provided additional evidence on this issue from the perspective of morphometry.

Subchondral bone morphometry was demonstrated to be related to the severity and progression of KOA in humans. Chiba et al. (16) examined 60 patients with KOA with 3-T MRI and found that medial tibial subchondral BV/TV, Tb.N, and Tb.Th increased as the cartilage area decreased in the medial compartment. Lo et al. (14) demonstrated that BV/TV, Tb.N, and Tb.Th were positively related to medial JSN scores, and Tb.Sp was negatively related to medial JSN scores. Lo et al. (15) also reported that higher baseline BV/TV, Tb.N, and Tb.Th and lower baseline Tb.Sp were associated with more progression of JSN in the medial compartment at 12 months. Therefore, BV/TV, Tb.N, Tb.Th, and Tb.Sp are excellent indicators for both subchondral bone remodeling and KOA progression.

Our results of no significant improvement of morphometry in the bisphosphonate group could not conclude that bisphosphonate was useless for KOA because the molecular subtypes of KOA were not considered in the participants in this research. Vaysbrot's meta-analysis (37) proposed that bisphosphonate might be beneficial in certain subsets of patients who display high rates of subchondral bone turnover. Lv et al. (38) proposed that progressive KOA could be divided into four subtypes based on pathophysiology: cartilage degradation-driven, bone remodeling-driven, inflammation-driven, and pain-driven subtypes. Theoretically, bisphosphonate is most beneficial to the bone remodeling-driven KOA subtype. Therefore, future studies enrolling the corresponding subtype via strict inclusion criteria considering molecular biomarkers remain necessary. However, it might also be oversimplified to divide KOA into a high turnover subtype and other subtypes. Bone turnover in one person might change with the pathological state. Furthermore, it remains unknown whether subchondral bone changes are a trigger factor or a consequence of KOA. Lv et al.'s classification considered increased resorption to be a trigger factor and supported bisphosphonate therapy. However, when the bone turnover of patients with KOA changes from high to low, the role of bisphosphonates might also change from beneficial to detrimental. Decreased resorption could also be seen as a consequence of late KOA, and from this perspective, bisphosphonate might be harmful and cause sclerosis. Our research partially resolved this concern since we found that, in late-stage KOA, the use of bisphosphonates did not increase the sclerosis of subchondral bone. In brief, our results did not support the use of bisphosphonate in KOA therapy itself, but we considered that the use of bisphosphonate for patients with osteoporosis who also had KOA would not exacerbate KOA.

The significance of the present study was in two aspects. The concern about potential sclerosis of subchondral bone after bisphosphonate use was addressed to some extent. Since there is no applicable method in clinical practice to predict when and how bone remodeling is altered from increased resorption in the early stage to decreased resorption in the late stage, our results demonstrated that bisphosphonate did not increase the risk of subchondral bone sclerosis in moderate to late KOA, which might prolong the therapy window of bisphosphonate for its analgesic effect on KOA. The present study also revealed the difference in the effect of bisphosphonate on the subchondral bone between late KOA and animal KOA models, perhaps providing some insight into the different pharmacological mechanisms of bisphosphonate in KOA initiation and progression. The microenvironment alteration in late KOA, such as the cross talk between synovium inflammation and subchondral bone after fissure form in cartilage, might play a crucial role in the effect of bisphosphonate on subchondral bone.

There were several limitations to the present study. First, intraarticular injection of bisphosphonate might have greater potential than oral bisphosphonate for KOA therapy. The results of this study could not substitute for the change after intra-articular injection of bisphosphonate. Second, due to the limited sample size, no more detailed classification of bisphosphonates or analysis was conducted. Third, the pattern of decreased resorption in late KOA might not be identical in each patient, and different subtypes of KOA might exist. We failed to classify the participants by osteoclast function or molecular markers due to the absence of related data in the OAI project. Fourth, the exact regimen of bisphosphonate for each participant was unknown, and further RCTs are necessary.

The patients with KOA who used bisphosphonate did not experience greater sclerosis of tibial subchondral bone than patients who did not use bisphosphonate. Considering that previous studies found that bisphosphonate in early KOA significantly altered subchondral bone morphometry, this study suggests that the effect of bisphosphonate on tibial subchondral bone in the initiation and progression of KOA might be OA-stage dependent.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. All OAI project participants signed the informed consent.

ML, YN, and BS: study design and manuscript writing. YW, YZ, and JX: data extracting. LW and YL: statistical analysis. ML and BS: data checking. All authors contributed to the article and approved the submitted version.

This study was funded by National Natural Science Foundation of China (Program No. 81974347), National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University (No. Z20192003), and Science and Technology of Foundation of Sichuan province of China (2021YFH0094). Post-Doctor Research Project, West China Hospital, Sichuan University (No. 2020HXBH081). All authors declared that the funding did not have any effect on the results of this study.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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