Challenges to the Possible Use of Bisphosphonates in Early-Stage Osteoarthritis.

Abstract

To the Editor: In a recent issue of the Journal of Bone Mineral Research (JBMR), Hayes and colleagues(1) showed that the use of bisphosphonates is protective against 2-year radiographic-progression of knee osteoarthritis (OA) in Osteoarthritis Initiative (OAI) participants who were in early-stage OA, stratified by baseline radiographic disease status. In addition, they also stratified BMI for a subgroup analysis and found that bisphosphonates had a stronger protective effect on 2-year radiological progression in early-stage patients with OA who are non-overweight. Finally, they showed that the duration of bisphosphonate use had no effect on progression. Their study provides valuable information for the use of bisphosphonates to prevent radiological progression of knee OA. However, several important issues should be further discussed to better interpret the results. First, it is essential to assess baseline bone metabolism, not only bone density, but also bone microstructure and bone metabolism indicators. There may be different bone metabolism in patients with knee arthritis at the same baseline radiographic disease status. The worse the bone metabolism is, the more likely it will lead to hyperosteogeny and osteophyte formation, which will affect the status of radiographic OA and directly affect the main results of the study. The same was true between groups that used or did not use bisphosphonates. Patients who used bisphosphonates had better health condition, younger age, less smoking, less diabetes, and more vitamins, all of which may affect bone metabolism, so baseline bone metabolism should be evaluated to reduce intergroup heterogeneity. Second, use of bisphosphonates was self-reported by patients. Bisphosphonates are commonly used to treat osteoporosis, but there are various of drugs to treat osteoporosis. Many patients take multiple medications at the same time, such as calcium tablets and vitamin D. Whether patients mixed bisphosphonates with other osteoporosis drugs, resulting in biased results. In addition, the adherence of patients with bisphosphonates is still unknown. Diez-Perez and colleagues(2) concluded that adherence to oral bisphosphonates is low. It has been observed that the adherence to oral bisphosphonates is as low as 59%(3) or 43%(4) at 1 year and appears to be worse with generic medications.(5) This is related to the characteristics of oral bisphosphonates. In this study, 69% of the patients used alendronate, which needs to be taken once a week with long drug intervals and gastrointestinal adverse reactions. This may greatly affect adherence and lead to inaccurate evaluation of duration of medication. Furthermore, the use and adherence of bisphosphonates during the follow-up period, which is unknown, may also still affect the radiological progression of knee OA. Third, the follow-up time of this study was 2 years. The authors did not conduct a subgroup analysis to examine the correlation between bisphosphonate use and relative short-term and long-term radiological progression. The authors chose a 2-year follow-up because OA typically either progresses rapidly or remains stable for long periods of time. However, the effect of common oral bisphosphonates on bone metabolism is short, which may be as short as 6 months or 1 year. Therefore, it may be of certain significance to explore the radiological progression of 1 year, so as to provide some basis for future research. In conclusion, bisphosphonate therapy may be protective against radiographic knee OA progression in early-stage patients, particularly those who are non-overweight. However, further well-designed investigations are urgently needed to confirm the relationship. The authors have no conflicts of interest or relationships to disclose. Authors’ roles: JZ, QZ, and XL all put forward some questions and suggestions. JZ and QZ wrote the manuscript. XL critically revised the manuscript, finally approved the version to be published, and agreed to be accountable for all aspects of the work. Author Contributions: JZ: Conceptualization; validation; writing-original draft. QZ: Conceptualization; validation; writing-original draft. XL: Conceptualization; resources; validation; writing-review and editing.