No Significant Differences between Bisphosphonates and Placebo for the Treatment of Bone Marrow Lesions of the Knee: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Objectives: The purpose of the present systematic review and meta-analysis is to summarize the current evidence on the role of bisphosphonates in the treatment of knee bone marrow lesions (BMLs), to understand whether they are truly effective in improving symptoms and restoring the subchondral bone status at imaging evaluation. Methods: A literature search was carried out on PubMed, Cochrane, and Google Scholar databases in accordance with the PRISMA guidelines. Potential risk of bias was evaluated using the Cochrane Risk of Bias 2 tool for randomized controlled trials (RCTs) and the ROBINS-I tool for non-randomized studies. Results: A total of 15 studies were included in the present systematic review and meta-analysis. Seven studies were RCTs, two were prospective cohort studies, three were retrospective, and three were case series. Our meta-analysis revealed that bisphosphonates did not significantly improve clinical scores or reduce BML size compared to placebo. Accordingly, the rate of adverse events was also non-significantly higher among bisphosphonate users versus placebo users. Conclusions: The main finding of the present meta-analysis and systematic review is that bisphosphonates show neither significant benefits nor significant adverse events when compared to placebo in the treatment of BMLs of the knee. Level of Evidence: Level IV systematic review of level II–III–IV studies. Level I meta-analysis of level I studies.

The clinical relevance of BMLs lies in the fact that these lesions are strongly associated with symptom onset and progression, and their persisting presence negatively affects the patient's prognosis in many diseases, above all knee OA [7,8].Hence, it has been hypothesized that initiating specific treatments targeting BMLs could improve a patient's pain and, therefore, activity levels, in an attempt to delay or even reverse further progression of the disease [9].
In terms of diagnostic features, BMLs can be detected at MRI using fluid-sensitive sequences, e.g., fat-suppressed T2-weighted, proton density-weighted, or intermediateweighted fast spin echo or short tau inversion recovery (STIR) sequences.The most representative imaging findings of BMLs are a high signal intensity within the bone marrow region on fat-suppressed T2-weighted images and a low signal intensity on T1-weighted images [10][11][12].
In selected cases, BMLs may resolve spontaneously over a period of 6-12 months; however most patients tend to experience intense or prolonged pain, thus requiring treatment [13][14][15].Currently, there is no established treatment algorithm for BMLs, and the available options mainly address symptoms, including restricted weight bearing, pharmacotherapy, extra-corporeal shock-wave therapy, and, eventually, surgery [6,16].Pharmacotherapy is based on anti-inflammatory and analgesic use dictated by the patient's pain and, more recently, intravenous prostacyclin or bisphosphonates [6,13].
Bisphosphonates are a class of anti-resorptive medications used in the treatment of osteoporosis that inhibit bone resorption and, consequently, bone remodeling by inducing apoptosis in osteoclasts and preventing apoptosis in osteocytes and osteoblasts [17,18].In the past two decades, bisphosphonates have gained significant attention as a potential therapeutic intervention in the treatment of knee BMLs to achieve both clinical improvement and prevent disease progression [19][20][21].Indeed, given their positive effects on bone metabolism, their use for knee BMLs has shown a reduction in lesion size with normalization of MRI, suggesting that these drugs might have a disease-modifying effect [22,23].
The purpose of the present systematic review and meta-analysis is to summarize the current evidence on the role of bisphosphonates in the treatment of knee BMLs, to understand whether they are truly effective in improving symptoms and restoring the subchondral bone status at imaging evaluation.

Materials and Methods
A literature review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [24].The literature search was conducted on PubMed, Embase, and Google Scholar databases up to 16 February 2024, by using the following search string: "bisphosphonates" OR "alendronate" OR "ibandronate" OR "zoledronic acid" OR "zoledronate" AND "bone marrow edema" OR "bone marrow oedema" OR "bone marrow lesion" OR "algodystrophy" OR "transient osteoporosis" OR "BME" OR "BML" OR "osteonecrosis".Two reviewers (GA and FÖ) independently carried out the screening process.Initially, the articles underwent title and abstract screening, considering the following inclusion criteria: (1) randomized controlled trials (RCTs); retrospective or prospective studies on humans; (2) written in English language; and (3) analyzing the effect of bisphosphonates in the management of BMLs of the knee.Exclusion criteria were articles written in other languages, in vitro studies, animal studies, reviews, and studies on the use of bisphosphonates for BMLs not located in the knee.
Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia) was utilized to screen citations and full-text articles, resolve conflicts, and extract data using customizable forms.Concluding the initial screening phase, full texts of included articles were evaluated and the reference list of all the retrieved articles was further screened for identification of potentially relevant studies.A PRISMA flowchart of the selection process is provided in Figure 1.
Senior investigators were responsible for consensus when discrepancies between the two reviewers were encountered.Included full texts underwent data extraction and subsequent collection, for the purposes of the present manuscript.
The quality of RCTs was assessed through the Cochrane Risk of Bias tool for Randomized Controlled Trials (ROB-2) [25].Conversely, the risk of bias for prospective and retrospective studies was performed according to the ROBINS-I tool for non-randomized studies [26].Senior investigators were responsible for consensus when discrepancies between the two reviewers were encountered.Included full texts underwent data extraction and subsequent collection, for the purposes of the present manuscript.
The quality of RCTs was assessed through the Cochrane Risk of Bias tool for Randomized Controlled Trials (ROB-2) [25].Conversely, the risk of bias for prospective and retrospective studies was performed according to the ROBINS-I tool for non-randomized studies [26].
For the meta-analysis, the statistical methodology employed was the inverse variance method, with the effect measure represented as the standardized mean difference.A random effects analysis model was applied to assess the overall effect.No subgroups or filters were implemented in this analysis.For adverse events analysis, we examined the occurrence of any complications, presented in a dichotomous format.The Mantel-Haenszel method was adopted, employing the odds ratio as the effect measure.We then implemented a random effects analysis model to gauge the overall impact.For the meta-analysis, the statistical methodology employed was the inverse variance method, with the effect measure represented as the standardized mean difference.A random effects analysis model was applied to assess the overall effect.No subgroups or filters were implemented in this analysis.For adverse events analysis, we examined the occurrence of any complications, presented in a dichotomous format.The Mantel-Haenszel method was adopted, employing the odds ratio as the effect measure.We then implemented a random effects analysis model to gauge the overall impact.

Results
Fifteen studies that met the inclusion criteria were included in the present review (Table 1).The included studies examined the effects of bisphosphonates on BMLs and pain in various conditions such as OA, bone marrow edema syndrome, complex regional pain syndrome, and osteonecrosis.Study designs were as follows: seven RCTs, two prospective cohort studies, three retrospective cohort studies, and three case series.Sample sizes ranged from 12 to 290 participants.The bisphosphonates evaluated were ibandronate, zoledronic acid (ZA), neridronate, and alendronate.

Risk of Bias Assessment
The seven different types of bias analyzed in ROB-2 were classified into "low risk", "high risk", or "unclear risk".Afterwards, the results of this assessment were converted to Agency for Healthcare Research and Quality standards, which ultimately rank the RCTs as "good quality", "fair quality", and "poor quality".Based on this, one study was categorized as good quality, five as fair quality, and one as poor quality.The ROBINS-I tool assesses seven different types of bias across seven domains: confounding, selection of participants, classification of interventions, deviations from intended interventions, missing data, measurement of outcomes, and selection of reported results.For each domain, the risk of bias is classified as "low risk", "moderate risk", "serious risk", or "critical risk" based on signaling questions.Afterwards, these domain-level risk judgments are synthesized into an overall risk of bias judgment for the study.The key criteria are: "low risk of bias" if all domains are low risk, "moderate risk of bias" if at least one domain is moderate risk, "serious risk of bias" if at least one domain is serious risk but none are critical risk, and "critical risk of bias" if any domain is critical risk.This ultimately categorizes the nonrandomized interventional studies into four tiers of quality: "low risk of bias", "moderate risk of bias", "serious risk of bias", and "critical risk of bias".Among the studies assessed, one study demonstrated a low risk of bias, four studies had a moderate risk of bias, and one study was judged to have a serious risk of bias (Figure 2       showing that administration of a single-dose intravenous zoledronic acid (ZA) significantly reduced BML volume at 12 weeks compared to placebo (p = 0.009).Accordingly, visual analog scale (VAS) reduction was significantly greater in the ZA group (p = 0.042).Other PROMs did not reach statistical significance.The biochemical analysis revealed a statistically significant decrease in serum calcium levels in the ZA treatment group compared to placebo (p = 0.011).No statistically significant differences were observed between the ZA and placebo groups for the other biochemical measures including alkaline phosphatase, creatinine, C-reactive protein, and phosphate [36].
Vasiliadis et al. demonstrated a significant decrease in VAS at 6 months (7.25 ± 7.25 at baseline compared to 4.25 ± 1.84 at 6 months, p < 0.001) with a single-dose ZA in 54 patients affected by bone marrow edema syndrome of the knee in their case series.No major adverse events were reported [2].
In a retrospective cohort study, Müller et al. evaluated various antiresorptive medications including ibandronate, ZA, denosumab, and alendronate in 34 patients with symptomatic knee BMLs.None of the reported variables reached significant differences, probably due to the small sample size [34].
Bartl et al. performed a prospective cohort study of 50 patients with knee or ankle bone marrow edema syndrome (BMES).They found that 12 months of ibandronate significantly improved pain; VAS improved from 8.5 to 1.2 in the knee ibandronate group vs. 8.1 to 4 in the control groups.Larson knee scores improved from 54 to 89 and 51 to 70 respectively.BME Stage decreased from stage 2.9 to 0.8 in ibandronate at 6 months compared to Stage 2.8 to 2.2 in the diclofenac group [29].

Bisphosphonates in Osteoarthritis
Looking at RCTs, Cai et al. performed a multicenter, double-blind RCT involving 223 OA patients with BMLs.The study revealed no significant difference in cartilage loss reduction, WOMAC, VAS, or BME after 2 years of yearly administration of ZA versus placebo [30].Similarly, the same group previously performed a single-center, double-blind RCT in 117 OA patients and found that a ZA infusion did not lead to a significant higher incidence of adverse events compared with 5 mg ZA and 10 mg methylprednisolone (VOLT01).Lesion size at 6 months between ZA compared to VOLT01 and placebo showed no significant difference between the respective groups.However, VOLT01 showed statistically significant improvements in WOMAC score compared to both placebo and ZA, as well as statistically significant improvements in VAS compared with ZA [31].
Conversely, a single-center, double-blind RCT by Laslett et al. on 59 OA patients demonstrated that a single intravenous ZA infusion significantly reduced pain at 6 but not at 12 months, whereas the KOOS score trend showed no significant difference between groups.Similarly, BML size was significantly less than in the placebo group only at 6 months.Adverse events were more common in the ZA group (p = 0.001) [32].
Varenna et al. conducted a double-blind RCT of 68 OA patients that showed a significantly greater VAS decrease in patients receiving intravenous neridronate (p < 0.001) compared to placebo.Similarly, WOMAC (p = 0.001), McGill (p = 0.001), and WORMS (p = 0.002) showed also significant improvement vs. placebo, and only the overall SF-36 score showed no inter-group difference [37].
Ballal et al. carried out a retrospective cohort study on 290 matched individuals treated with and without bisphosphonates.Bisphosphonates did not clearly reduce BML size at 12 months compared to controls (difference in the mean change in total BML volume was 98.8 mm 3 , (95% CI: 156.6 to +354.2), p = 0.4).However, bisphosphonate users underwent a higher BML volume reduction rate (48%) compared to non-users (41%) [28].

Bisphosphonates in Osteonecrosis of the Knee
Meier et al. performed a double-blind RCT on 30 patients with spontaneous osteonecrosis of the knee, which did not demonstrate significant benefits of ibandronate over anti-inflammatory medications in VAS, WOMAC, or IKDC-subjective scores up to 48 weeks.At 12 weeks, the biomarker of bone turnover, CTX, was significantly lower in the ibandronate group (p < 0.01), whereas other markers (PINP and ALP) presented similar concentrations (p = 0.06 and p = 0.71 respectively) [33].
Agarwala et al. conducted a prospective case series showing that a combination of a single intravenous ZA administration with weekly oral alendronate led to faster recovery in 16 patients with spontaneous osteonecrosis of the knee (SPONK).Pain evaluated by the VAS significantly improved at 16 weeks (p = 0.03), and the area of bone marrow involvement also significantly decreased at 16 weeks (p = 0.03) [27].

Bisphosphonates in Transient Osteoporosis
Ringe et al. published a case series including 12 patients affected by localized transient osteoporosis and found ibandronate provided significant pain relief at 6 months compared to baseline VAS, although the increase in subchondral bone density did not reach statistical significance.No adverse events related to ibandronate were reported [35].

Bisphosphonates in Complex Regional Pain Syndrome of the Knee
Transitioning to complex regional pain syndrome (CRPS), a double-blind RCT of 78 patients by Varenna et al. revealed that the neridronate group had significantly greater VAS reduction (p = 0.0003) and smaller BML (p = 0.03) at 1 month compared to placebo.SF-36 and McGill did not reach statistical significance.Adverse event incidence was not significantly different between groups [38].
After unblinding the groups, patients previously randomized to placebo received intravenous neridronate and both groups (previous IV neridronate and cross-over patients) were then evaluated up to 12 months.Each domain of SF-36 form reached statistically significant amelioration, except for the 'General Health' domain.No difference between the two treatment arms were observed [39].

Meta-Analysis
Three studies (Cai et al., 2019 [31], Cai et al., 2020 [30], and Seefried et al., 2022 [36]) reported sufficient data to perform meta-analysis on effects of bisphosphonates on BML size.The analysis focused on BML size at the end of the follow-up period (6, 24, and 1 month, respectively), using a comparison between two intervention groups.The analysis demonstrated that bisphosphonates were not able to significantly reduce BML size compared to placebo (Figure 3).
After unblinding the groups, patients previously randomized to placebo received intravenous neridronate and both groups (previous IV neridronate and cross-over patients) were then evaluated up to 12 months.Each domain of SF-36 form reached statistically significant amelioration, except for the General Health' domain.No difference between the two treatment arms were observed [39].
Four studies (Cai et al. 2019 [31], Cai et al. 2020 [30], Meier et al. 2014 [33], and Varenna et al. 2015 [37]) reported sufficient data to perform meta-analysis on WOMAC.The analysis focused on WOMAC at the final follow-up evaluation (6, 24, 3, and 1 month, respectively).The results indicated a non-significant advantage of bisphosphonates compared to placebo (Std.mean difference [95%CI] −0.28 [−0.9, 0.34]) (Figure 5).In the context of this meta-analysis, we scrutinized data from five distinct studies (Cai et al. 2019 [31], Cai et al. 2020 [30], Laslett et al. 2012 [32], Seefried et al. 2022 [36], and Varenna et al. 2021 [38]) that provided sufficient information for the evaluation of adverse events (AEs).The primary objective was to discern any AE linked to the administration of bisphosphonates compared to placebo.Our findings demonstrated no statistically In the context of this meta-analysis, we scrutinized data from five distinct studies (Cai et al., 2019 [31], Cai et al., 2020 [30], Laslett et al., 2012 [32], Seefried et al., 2022 [36], and Varenna et al., 2021 [38]) that provided sufficient information for the evaluation of adverse events (AEs).The primary objective was to discern any AE linked to the administration of bisphosphonates compared to placebo.Our findings demonstrated no statistically significant association between AEs and the use of bisphosphonates in contrast to placebo.Notably, no subgroup analyses or supplementary filters were applied during this analysis (odds ratio [95% CI] 4. 35 [0.74, 25.65]) (Figure 6).The most commonly observed side effects were flu-like symptoms and arthralgia; none of the patients reported atypical fracture of the jaw.

Discussion
The main finding of the present meta-analysis is that bisphosphonates are not able to significantly reduce BML size compared to placebo, and even in terms of clinical response, evaluated by pain and subjective scores, no significant benefit emerged over the control group.Accordingly, a non-significant higher rate of AEs was documented after bisphosphonate administration.The heterogeneity tests reveal some important insights about the variability across the included studies.For the meta-analysis on bone marrow edema size, there was no significant heterogeneity (I² = 0%), indicating consistent effects across studies.However, substantial heterogeneity was observed in the meta-analyses for clinical outcomes like VAS pain scores (I² = 93%), WOMAC scores (I² = 86%), and other subjective measures (I² = 80%).The high degree of heterogeneity for these patient-reported outcomes suggests considerable variability in the effects reported across studies, which could be attributable to differences in patient populations, study designs, or other clinical factors.While bisphosphonates did not demonstrate significant benefits over placebo in reducing BML size or improving clinical outcomes, the presence of substantial The most commonly observed side effects were flu-like symptoms and arthralgia; none of the patients reported atypical fracture of the jaw.

Discussion
The main finding of the present meta-analysis is that bisphosphonates are not able to significantly reduce BML size compared to placebo, and even in terms of clinical response, evaluated by pain and subjective scores, no significant benefit emerged over the control group.Accordingly, a non-significant higher rate of AEs was documented after bisphosphonate administration.The heterogeneity tests reveal some important insights about the variability across the included studies.For the meta-analysis on bone marrow edema size, there was no significant heterogeneity (I² = 0%), indicating consistent effects across studies.However, substantial heterogeneity was observed in the meta-analyses for clinical outcomes like VAS pain scores (I² = 93%), WOMAC scores (I² = 86%), and other subjective measures (I² = 80%).The high degree of heterogeneity for these patient-reported outcomes suggests considerable variability in the effects reported across studies, which could be attributable to differences in patient populations, study designs, or other clinical factors.While bisphosphonates did not demonstrate significant benefits over placebo in reducing BML size or improving clinical outcomes, the presence of substantial heterogeneity, particularly for patient-reported measures, warrants cautious interpretation.
Bisphosphonates are anti-resorptive drugs borrowed from the treatment regimen for osteoporosis [40][41][42], but they also demonstrated a particular "reconstructive" effect on the periarticular bone [43].Given the strong correlation between articular cartilage and subchondral bone [44,45], the first application was therefore the treatment of the subchondral pathology in knee OA.Encouraging preclinical studies [46][47][48] were followed by human application [23,43,49] which, however, did not show such exciting results.One of the major reasons for this discordance lies in the nature of OA itself, which entails a wide spectrum of alterations, and therefore the evaluation of response is likely to be influenced by the concomitant cartilage and synovial tissue damage [50,51].However, BMLs are not only observed in cases of OA, but they are also a common MRI finding in a variety of pathologies which are sometimes difficult to distinguish.In fact, the previously called 'bone marrow edema' has nothing to do with fluid extravasation in the subchondral bone, but rather englobes peculiar ultrastructural and histological changes [52].The modern concept of subchondral bone alterations includes a continuum of pathologies where posttraumatic and OA-related BMLs are at the extremities [12]: transient osteoporosis, regional migratory osteoporosis, complex regional pain syndrome (CRPS), and algodystrophy are considered reversible conditions, [53] whereas spontaneous osteonecrosis of the knee, avascular necrosis, and insufficiency fractures are mostly considered irreversible [22].Despite the wide range of diseases grouped under the definition of "bone marrow lesions", the pathological changes seen in each of the above are sustained by similar mechanisms, which are targeted by bisphosphonates.Indeed, from a qualitative evaluation of the articles retrieved, the use of bisphosphonates offers significant amelioration in terms of clinical response for the treatment of isolated BMLs.Accordingly, the potential of these drugs is also evident when BMLs are associated with OA.In fact, two [30,31] out of three RCTs analyzing the reduction in BML size are on knee OA and documented a "borderline" significant reduction in BML size when bisphosphonates were used, hence raising hopes on the potential benefits of these drugs in OA-associated BMLs.Moreover, although our meta-analysis yielded no statistically significant clinical benefits from bisphosphonate use, none of the studies reported information on the Minimal Clinically Important Difference (MCID) [54], which appears to be a much more prominent approach to critically present the effects of an intervention rather than a mere statistical test.Furthermore, when focusing on the type of bisphosphonate used, seven out of 15 studies reviewed here adopted ZA and, more interestingly, the only results close to statistical significance in terms of BML size were documented in studies employing ZA [30,31,36], thus supporting the thought of its potential superiority over other drugs of the same class.Nonetheless, we feel that the peculiar characteristics and the potential harms and benefits of specific bisphosphonates for the treatment of BMLs still needs to be clearly elucidated.Indeed, although the adverse events related to bisphosphonates are not truly a major concern, since they are well-known following their extensive use in the treatment of osteoporotic patients, orthopedic surgeons are usually more cautious when prescribing molecules whose first indication is a bone metabolism disease such osteoporosis: this is due to the fact that osteoporosis is a systemic disease, whereas BMLs are always localized and therefore, from the perspective of a surgeon, a "systemic" drug may fail to sufficiently reach the injured site, thereby exposing the patient to the risk of undesired adverse events of such drugs.This demands further investigations to identify the right dosages and timing of bisphosphonate application in BMLs in order to maximize their efficacy.To date, some significant results have been achieved: in fact, the trials on neridronate published by Varenna et al. [37][38][39] reported such brilliant results for the treatment of CRPS that this drug has received approval, in some countries, as the only labeled drug for the treatment of CRPS.
The present systematic review and meta-analysis is not free from limitations.Firstly, we analyzed studies that evaluated the effectiveness of bisphosphonates in the different pathologies of BML spectrum.However, the differential diagnosis among the abovementioned diseases is often difficult to apply in clinical practice due to the lack of standardized diagnostic criteria for each of them.Hence, we preferred to evaluate the impact of bisphosphonates in the treatment of BMLs irrespective of any clinical classification and also because to our knowledge, there is no evidence that any clinical entity has higher or lower chances of response following its administration.One further burden is represented by the different timing of administration from symptom onset, which may itself impact the results.One further limitation is given by publication bias, as studies with significant or positive results are more likely to be published and included, which may overestimate the true effect size.Going into the specifics of the single studies included, the overall risk of bias for the majority of the included articles is still far from high-level evidence.Furthermore, the different molecules used, the variable dosage and diverse ways of administration, represent adding confounding variables preventing us from standardizing the available results.Lastly, we included multiple studies by the same authors that adopted similar inclusion criteria, which could suggest that the same patient population was utilized for multiple studies.

Conclusions
Bisphosphonates show neither significant benefits nor significant adverse events when compared to placebo in the treatment of BMLs of the knee.

Figure 1 .
Figure 1.Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) flowchart of the systematic literature review.

Figure 1 .
Figure 1.Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) flowchart of the systematic literature review.

Figure 2 .
Figure 2. RoB2 tool for the risk of bias assessment of the included RCTs.

Figure 2 .
Figure 2. RoB2 tool for the risk of bias assessment of the included RCTs.

Figure 3 .
Figure 3. Forest plot of the individual studies and pooled mean difference for BML size, with a 95% confidence interval.The size of the squares shows the weight of the study.The random-effects model was used due to the inherent heterogeneity in the design and methodology of the included studies.Six studies (Cai et al., 2019 [31], Cai et al., 2020 [30], Meier et al., 2014 [33], Seefried et al., 2022 [36], Varenna et al., 2015 [37], and Varenna et al., 2021[38]) reported sufficient data to perform meta-analysis on VAS for pain.The analysis focused on VAS at the final follow-up evaluation (6, 24, 3, 1, 1 and 1 month respectively), comparing the two intervention groups.The results showed a slight no significant advantage of bisphosphonates compared to placebo (Std.mean difference [95% CI] −0.58 [−1.34, 0.18]) (Figure4).

Figure 3 .
Figure 3. Forest plot of the individual studies and pooled mean difference for BML size, with a 95% confidence interval.The size of the squares shows the weight of the study.The random-effects model was used due to the inherent heterogeneity in the design and methodology of the included studies.

Figure 4 .
Figure 4. Forest plot of the individual studies and pooled mean difference for Visual Analogue Scale (VAS) for pain improvement, with a 95% confidence interval.The size of the squares shows the weight of the study.The random-effects model was used due to the inherent heterogeneity in the design and methodology of the included studies.

Figure 4 .
Figure 4. Forest plot of the individual studies and pooled mean difference for Visual Analogue Scale (VAS) for pain improvement, with a 95% confidence interval.The size of the squares shows the weight of the study.The random-effects model was used due to the inherent heterogeneity in the design and methodology of the included studies.Four studies (Cai et al., 2019 [31], Cai et al., 2020 [30], Meier et al., 2014 [33], and Varenna et al., 2015[37]) reported sufficient data to perform meta-analysis on WOMAC.The analysis focused on WOMAC at the final follow-up evaluation (6, 24, 3, and 1 month, respectively).The results indicated a non-significant advantage of bisphosphonates compared to placebo (Std.mean difference [95% CI] −0.28 [−0.9, 0.34]) (Figure5).

Figure 5 .
Figure 5. Forest plot of the individual studies and pooled mean difference for WOMAC, with a 95% confidence interval.The size of the squares shows the weight of the study.The random-effects model was used due to the inherent heterogeneity in the design and methodology of the included studies.

Figure 5 .
Figure 5. Forest plot of the individual studies and pooled mean difference for WOMAC, with a 95% confidence interval.The size of the squares shows the weight of the study.The random-effects model was used due to the inherent heterogeneity in the design and methodology of the included studies.
J. Clin.Med.2024, 13, x FOR PEER REVIEW 14 of 18 significant association between AEs and the use of bisphosphonates in contrast to placebo.Notably, no subgroup analyses or supplementary filters were applied during this analysis (odds ratio [95%CI] 4.35 [0.74, 25.65]) (Figure 6).

Figure 6 .
Figure 6.Forest plot of the individual studies for adverse events, with a 95% confidence interval.The size of the squares shows the weight of the study.The random-effects model was used due to the inherent heterogeneity in the design and methodology of the included studies.

Figure 6 .
Figure 6.Forest plot of the individual studies for adverse events, with a 95% confidence interval.The size of the squares shows the weight of the study.The random-effects model was used due to the inherent heterogeneity in the design and methodology of the included studies.

Table 2 .
ROBINS-I tool for the risk of bias assessment of the included studies that were not RC

Table 1 .
List and main characteristics of the included studies.

Table 2 .
ROBINS-I tool for the risk of bias assessment of the included studies that were not RCTs.