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. 2024 Aug 8;35(11):1897–1907. doi: 10.1007/s00198-024-07191-5

The Healing and therapeutic effects of perioperative bisphosphonate use in patients with fragility fractures: meta-analysis of 19 clinical trials

Yuhong Zeng 1,#, Yuan Yang 2,#, Jue Wang 2, Guolin Meng 3,✉
PMCID: PMC11499321  PMID: 39115687

Abstract

Objectives

Previous evidence suggests that bisphosphonates (BPs) may lower the risk of recurrent fractures and enhance functional recovery in patients with fractures. However, there has been controversy regarding the optimal timing of treatment initiation for patients with fragility fractures. We conducted a meta-analysis to evaluate the available evidence on the use of BPs during the perioperative period and compared it to both non-perioperative periods and non-usage.

Methods

Electronic searches were performed using PubMed, EMBASE, Web of Science and the Cochrane Library published before February 2023, without any language restrictions. The primary outcomes included fracture healing rate, healing time, and new fractures. We also examined a wide range of secondary outcomes. Random effects meta-analysis was used.

Results

A total of 19 clinical trials involving 2543 patients were included in this meta-analysis. When comparing patients with non-perioperative BPs use in 4-6 weeks and approximately 10-12 weeks post-surgically, the overall risk ratios (RRs) of perioperative BPs use for healing rate were 1.06 (95% CI: 0.81, 1.38, p=0.69) and 1.02 (95% CI: 0.94, 1.11, p=0.65), respectively, suggesting no difference in healing rate between perioperative and non-perioperative BP initiation. For healing time, the overall mean difference between perioperative and non-perioperative periods was -0.19 week (95% CI: -1.03, 0.64, p=0.65) at approximately 10-12 weeks, indicating no significant impact of perioperative BP initiation on healing time. In terms of new fractures, the overall RR with BP use was 0.35 (95% CI: 0.17-0.73, p=0.005), when compared to patients without BPs use. This suggests a protective impact of BP use against new fractures compared to patients without BP use. Perioperative BP use was associated with a markedly higher likelihood of having adverse experiences, including fever (RR: 23.78, 95% CI: 8.29, 68.21, p< 0.001), arthralgia (RR: 10.20, 95% CI: 2.41, 43.16, p=0.002), and myalgia (RR: 9.42, 95% CI: 2.54, 34.87, p< 0.001), compared with non-BPs use.

Conclusions

Treatment with BP during the perioperative period does not affect the healing process and has positive effects on therapy for patients with fragility fractures. These compelling findings underscore the potential efficacy of BP use during the perioperative period as a viable treatment option for patients with fragility fractures.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00198-024-07191-5.

Keywords: Bisphosphonates, Clinical trials, Fragility fractures, Healing, Meta-analysis, Perioperative

Introduction

Fragility fractures caused by osteoporosis impose a substantial healthcare burden worldwide, particularly affecting the elderly population [1]. Osteoporosis is a progressive skeletal disorder characterized by decreased bone density and structural deterioration. This leads to an increased susceptibility to fractures, notably in weight-bearing bones such as the hip, spine, and wrist. These fractures not only impair an individual’s physical function but also reduce the overall quality of life, even result in disability and mortality [1]. Despite the severity of the problem, there is debate regarding the most suitable timing for the treatment of fragility fractures post-surgery, and orthopedic surgeons are often unclear about the optimal approach. This leads to limited diagnoses, evaluations, and standardized treatments. As the aging population continues to grow, managing and treating fragility fractures becomes increasingly crucial to maintaining the overall health and well-being of affected individuals [2].

To combat the detrimental impact of fragility fractures, various anti-osteoporotic agents have been developed and utilized in fracture treatment regimens [3, 4]. Among these agents, bisphosphonates (BPs) have gained significant attention for their potential to enhance bone density, inhibit bone resorption, and improve bone microarchitecture. Consequently, incorporating BPs into the perioperative care of patients with fragility fracture has become a topic of active research.

Numerous meta-analyses have suggested that the use of BPs may lower the risk of recurrent fractures and improve functional recovery in patients with fractures [5–9]. One particular meta-analysis revealed that early administration of BPs after surgery did not significantly delay fracture healing time and effectively reduced subsequent fractures when compared to control groups [10]. Additionally, other meta-analyses have demonstrated improvements in bone mineral density, reduced pain scores, and a decreased risk of subsequent fractures in patients receiving BPs [5–9]. These findings provided preliminary support for the potential benefits of BPs use in fracture management. However, there have been controversy and uncertainty about the optimal timing of treatment for patients with fragility fractures. Furthermore, various consensus and guidelines advocate for the early and standardized initiation of anti-osteoporosis treatments following fragility fractures [10–15]. However, it is important to note that these meta-analyses and recommendations did not specifically focus on fragility fractures during the perioperative period.

To better understand the benefits of perioperative BPs use in patients with fragility fractures, we conducted a comprehensive meta-analysis of clinical trials. Our analysis involved comparing BPs use during the perioperative period to both non-perioperative periods and non-usage.

Methods

Study searches and selection

Following the PRISMA guidelines and the registered protocol (PROSPERO registration number: CRD42023405978), we conducted a comprehensive search for relevant studies up to February 16, 2023. Our electronic searches covered three databases: PubMed, EMBASE, and the Cochrane Library. No language restrictions were applied. The search terms encompassed various aspects, including types of bisphosphonates, fragility fractures, osteoporosis, and clinical trials. Detailed information about these search terms can be found in Supplementary Text.

After removing duplicate records, two authors (Yuhong Zeng and Yuan Yang) screened articles based on their titles and abstracts. Discrepancies that emerged were addressed through discussion and, if needed, resolved by a third reviewer. Additionally, we used the latest information involving multiple publications [16, 17]. Our inclusion criteria encompassed clinical trials that examined the use of BPs and assessed fragility fractures post-surgery in adults aged 18 years or older. For the healing rate with perioperative BP use, we also included cohort studies for further assessment [18–21].

The assessment of bias followed the revised Cochrane risk of bias assessment tool for randomized trials (RoB 2) [22]. Five domains were assessed: randomization process, deviations from intended interventions, missing outcome data, outcome measurement, and selection of reported results. Any discrepancies were resolved through discussion, with a third party consulted for judgment if necessary.

Outcomes

In this meta-analysis, we pursued two primary objectives: to assess the healing and therapeutic effects of BP use in patients with fragility fractures during the perioperative period. The perioperative period was defined as the seven days before and after fracture surgery.

The primary outcomes included fracture healing rate, healing time, and occurrence of new fractures. The secondary outcomes encompassed the evaluation of various factors: surgical effects (including the need for revision surgery, bone cement leakage, Cobb angle, fixation failure rate), effects of anti-osteoporosis treatments (including bone mineral density (BMD), bone turnover markers like procollagen type I N-propeptide (PINP) and C-terminal telopeptide of type I collagen (CTX)), assessment of functional recovery (including scores for shoulder joint function, Oswestry Disability Index, Harris joint function score), evaluation of pain relief (using the visual analogue scale (VAS) pain score), and monitoring of adverse events. Subgroup analyses were also conducted, considering different types of BPs used, treatment duration, and fracture locations.

Statistical analysis

For continuous outcomes, we calculated the mean difference (MD) and corresponding 95% confidence intervals (CIs) and p value for each study. For dichotomous outcomes, we evaluated the risk ratio (RR) along with 95% CIs. In cases where the study reported the odds ratio (OR), we converted it to RR using the formula: RR = OR / ((1 - P0) + (P0 * OR)), with P0 representing the incidence of the event in the control group.

Heterogeneity was assessed using the I2 statistic [23], with I2 values interpreted as follows: I2 ≤ 25% indicating no heterogeneity, 26% to 50% suggesting a low degree of heterogeneity, 51% to 75% indicating a moderate degree of heterogeneity, and ≥75% signifying a high degree of heterogeneity. To account for variations between studies, we applied a random effects model to calculate the summary RR and MD for each outcome. We used the GRADE approach to assess the overall quality of the synthesized evidence for various outcomes (https://gdt.gradepro.org/app).

All statistical analyses were performed using Review Manager Software (RevMan version 5.3; The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). Two-sided statistical tests were conducted, with significance levels set at P < 0.05 unless specified otherwise.

Results

Overview of studies included in the meta-analysis

After eliminating duplicates, a total of 1005 articles were initially identified and 963 articles were excluded. Following a comprehensive review of 42 articles in full text, 19 articles were selected for inclusion in this meta-analysis ultimately (Fig. 1). The details of these studies are summarized in Supplementary Table 1 [16, 24–41].

Fig. 1.

Fig. 1

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Systematic identification of published literature on the healing and therapeutic effects of perioperative BPs use in patients with fragility fractures. Search terms are described in Supplementary text

The quality assessment of the studies is shown in Supplementary Fig. 1. Most studies exhibited some concerns or were at high risk of bias in the randomization process, while only three were deemed to have a low risk of bias. Most of the studies were not randomized controlled trials (RCTs), resulting in the randomization process being identified as a potential bias in the clinical studies. Although other potential sources of bias were also detected, such as measurement bias and reporting bias, we determined that they did not significantly influence the overall bias within each study.

The comprehensive GRADE assessment of the synthesized evidence across various outcomes was presented in Supplementary Table 2. The overall quality of the evidence ranges from very low to high. Most outcome measures, such as fracture healing rates at different time points, new fracture incidence, and adverse events like muscle pain and fever, are rated as low to moderate quality due to serious concerns about risk of bias, imprecision, and, in some cases, inconsistency or indirectness. Specific outcomes like arthralgia and overall flu-like symptoms achieved a high certainty rating, indicating robust evidence despite the presence of high-risk studies in other areas.

Fracture healing rate

The fracture healing is determined by X-ray images, indicating the time required for the fracture to heal, which is defined as the formation of at least one bony bridge between cortical bone or bones. This can be observed on anterior-posterior or lateral X-ray images. The healing rate after fracture surgery was assessed in clinical studies over two follow-up periods: 4-6 weeks and approximately 10-12 weeks. In this meta-analysis, two studies investigated the healing rate after fracture surgery at the 4-6 weeks follow-up, encompassing a total of 52 events and 121 controls (Fig. 2). No significant heterogeneity was detected among these studies (I2 = 0%). Overall, when comparing perioperative BP initiation with non-perioperative initiation, the RR for healing rate was 1.06 (95% CI: 0.81-1.38; p = 0.69), indicating no notable difference in healing rate between the two initiation approaches.

Fig. 2.

Fig. 2

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Meta-analysis of perioperative bisphosphonates initiation for the healing rate after surgery at the follow-up of 4-6 weeks and approximately 10-12 weeks in the clinical studies

Similarly, four studies explored the healing rate after fracture surgery at the approximately 10-12 weeks follow-up, involving 221 events and 242 controls (Fig. 2). A moderate degree of heterogeneity was observed among these studies (I2 = 71%). Overall, compared to non-perioperative BP initiation, the RR for healing rate with perioperative initiation was 1.02 (95% CI: 0.94-1.11; p = 0.65), suggesting a lack of distinction in healing rate between perioperative and non-perioperative BP initiation.

This absence of differences was further validated by a meta-analysis of two cohort studies [18, 19], comprising a total of 215 events and 366 controls (Fig. 3). The overall RR for healing rate was 1.00 (95% CI: 0.95-1.05, p = 0.97) with little heterogeneity (I2 = 0%).

Fig. 3.

Fig. 3

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Meta-analysis of healing rates at the approximately 10-12 weeks between perioperative and non-perioperative bisphosphonates initiation in the cohort studies

Fracture healing time

Regarding healing time, two studies were identified, with a total of 48 patients in the perioperative period and 50 patients in the non-perioperative period (Fig. 4). No heterogeneity was noted among these studies (I2 = 0%). Overall, the mean difference between perioperative and non-perioperative periods was -0.19 week (95% CI: -1.03, 0.64, p = 0.65) at approximately 10-12 weeks, indicating no impact of perioperative BP initiation on healing time.

Fig. 4.

Fig. 4

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Meta-analysis of healing time at the approximately 10-12 weeks between perioperative and non-perioperative bisphosphonates initiation in the clinical studies

New fractures

In terms of new fractures after fracture surgery, seven studies were identified, including 132 events and 1942 controls (Fig. 5). A moderate degree of heterogeneity was evident across the studies (I2 = 62%). In total, the RR for new fractures with BP use was 0.35 (95% CI: 0.17-0.73; p = 0.005) compared to cases without BP use. This suggests a protective impact of BP use against new fractures in comparison to cases without BP use. When conducting subgroup analysis based on the timing of BP use, we observed more pronounced protective effects of BP use against new fractures at 12 months compared to 24 months (Supplementary Fig. 2). Their RRs were 0.18 (95% CI: 0.09-0.37) and 0.42 (95% CI: 0.14-1.20), respectively.

Fig. 5.

Fig. 5

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Meta-analysis of new fractures with and without the use of bisphosphonates

Three different sites were identified: osteoporotic vertebral compression fractures (OVCF), low-trauma hip fractures, and senile osteoporotic femoral intertrochanteric fractures (SOFIF) (Supplementary Fig. 3). Only one study assessed the low-trauma hip fractures and SOFIF, indicating no significant disparity in these fractures between individuals who used BPs and those who did not. In contrast, a substantial protective effect of BP use in OVCF was observed compared to cases without BP use, with an overall RR of 0.14 (95% CI: 0.07-0.30, p < 0.001). No heterogeneity was observed among the studies (I2 = 0%).

Impact on surgical outcomes

To further compare the effect of BPs use during the perioperative period to other time periods, the effects of BPs on surgery such as revision surgery, Cobb angle, bone cement leakage and fixation failure were assessed. Overall, the RR for revision surgery with perioperative BP initiation was 1.42 (95% CI: 0.38-5.25; p = 0.60, Supplementary Fig. 4). No significant heterogeneity was observed among two studies (I2 = 0%).

In terms of the Cobb angle, the mean differences were -0.18 degrees (95% CI: -0.80, 0.44, p = 0.57) and -0.58 degrees (95% CI: -2.25, 1.08, p = 0.49) at 1 and 12 months of follow-up, respectively (Supplementary Fig. 5). Meanwhile, the RR for bone cement leakage associated with the use of BPs was 1.06 (95% CI: 0.69-1.62; p = 0.79). These results indicate no significant difference between patients who received BPs and those who did not. Either no or a moderate level of heterogeneity was observed among these studies.

Anti-osteoporosis therapy

In the assessment of anti-osteoporosis therapy, we analysed bone mineral density (BMD), Procollagen type I N-pro-peptide (PINP), and cross-linked C-telopeptide of type I collagen (CTX). Overall, the mean difference in BMD between the perioperative and non-perioperative periods was 0.47 g/cm2 (95% CI: -0.23, 1.17, p = 0.19; Supplementary Fig. 7). A substantial degree of heterogeneity was observed among these studies (I2=89%).

For individuals with and without BPs use at 6 and 12 months, the overall mean difference in BMD was 0.06 g/cm2 (95% CI: 0.03-0.09, p < 0.001) and 0.09 g/cm2 (95% CI: 0.07-0.11, p < 0.001), respectively (Supplementary Fig. 8). The overall mean difference in PINP levels was -14.34 ng/mL (95% CI: -18.70, -9.99, p < 0.001) and -14.28 ng/mL (95% CI: -18.69, -9.86, p < 0.01), respectively (Supplementary Fig. 9). The overall mean difference in CTX levels was -0.28 ng/mL (95% CI: -0.39, -0.17, p < 0.001) and -0.25 ng/mL (95% CI: -0.35, -0.15, p < 0.01), respectively (Supplementary Fig. 10). These results suggest that the use of BPs has a favourable effect in anti-osteoporosis therapy compared to cases without BPs use.

Functional recovery

In terms of functional recovery, the Oswestry Disability Index (ODI) and the Harris joint function score were examined. Regarding ODI, three studies examined its impact following fracture surgery. Overall, the mean difference in ODI scores between individuals using and not using BPs was -5.31 (95% CI: -13.09, 2.46, p = 0.18; Supplementary Fig. 11). Similarly, two studies provided data on the Harris joint function score after fracture surgery. Overall, the mean difference in Harris joint function scores between individuals with and without BP use was -1.18 (95% CI: -3.51, 1.14; p = 0.32; Supplementary Fig. 11). These findings indicate that there is no significant difference in functional recovery between patients who received BPs and those who did not.

Pain relief

For pain relief assessment, we evaluated the visual analogue scale (VAS) pain score. Overall, the mean difference in VAS pain scores between the perioperative and non-perioperative periods was -0.46 score (95% CI: -1.29, 0.37, p = 0.28; Supplementary Fig. 12). A notable degree of heterogeneity was evident among these studies (I2=76%).

The VAS pain scores across three different follow-up periods were also examined: one week, six months, and twelve months (Supplementary Fig. 13). Overall, the mean difference in VAS pain scores between individuals using and not using BPs was -0.06 score (95% CI: -0.29, 0.17, p = 0.59), -0.46 score (95% CI: -1.01, 0.09, p = 0.10), and -0.90 score (95% CI: -1.35, -0.45, p<0.001) for the one-week, six-month, and twelve-month follow-ups, respectively. This suggests that BPs use may potentially alleviate pain intensity after fracture surgery during the twelve-month follow-up period compared to cases where BPs were not used, but there is no significant effect at one week and six months.

Adverse effects

In the present meta-analysis, the adverse events of muscle-related pain were also assessed. Three studies provided data on such occurrences. However, only two studies documented adverse events of muscle-related pain within the intervention groups (Supplementary Fig. 14). A moderate degree of heterogeneity was noted among these studies (I2 = 42%). Overall, the RR for muscle-related pain was 1.22 (0.10, 14.76, p = 0.87), suggesting that BPs use did not increase muscle-related pain compared to non-operative BPs initiation.

In the context of BPs use during the perioperative period and non-usage, the occurrences of adverse effects were also investigated, including fever, arthralgia, flu-like symptoms, and myalgia (Supplementary Fig. 15). Overall, the RRs for developing these adverse effects associated with BPs use, as compared to cases without BPs use, were as follows: 23.78 (95% CI: 8.29-68.21, p < 0.001for fever, 10.20 (95% CI: 2.41-43.16, p = 0.002) for arthralgia, 10.38 (95% CI: 0.66-162.38, p = 0.10) for flu-like symptoms, and 9.42 (95% CI: 2.54-34.87, p < 0.001) for myalgia. This suggests a higher likelihood of experiencing these adverse effects in cases with BPs use than cases without BPs use, except for flu-like symptoms.

Subgroup analysis

To further assess the impact of perioperative BPs use on patients with fragility fractures, subgroup analyses were also conducted involving various factors, including different types of BPs used for healing rate, treatment time, and fracture locations. For healing rate, five studies were identified to have data on distinct types of BPs following fracture surgery. These studies involved a total of 221 events and 242 controls (Supplementary Fig. 16). The intervention involved three types of BPs: alendronate, risedronate, and zoledronic acid. A moderate degree of heterogeneity was observed among these studies (I2 = 71%). Overall, compared to non-perioperative BP initiation, the RR for the healing rate with perioperative BP initiation was 1.02 (95% CI: 0.94-1.11; p = 0.65). These findings indicate no significant distinction in healing rate when comparing perioperative and non-perioperative initiation of different types of BPs. Furthermore, no difference was also observed for different treatment time (Supplementary Fig. 17). Overall, the RR of two studies was 1.11 (95% CI: 0.69-1.79; p = 0.66) within less than one month, while the RR of four studies was 1.03(95% CI: 0.91-1.17, p = 0.66) at more than three months.

In the present meta-analysis, fracture sites included distal radial, intertrochanteric, proximal humerus and unilateral osteoporotic fracture. For each fracture site, only one or two studies reported (Supplementary Fig. 18). There was no significant difference between perioperative and non-perioperative BPs initiation across the various fracture sites. When combining all five studies, the RR was 1.02 (95% CI: 0.94-1.11, p = 0.65), involving a total of 221 events and 242 controls. Notably, little heterogeneity was evident among these studies (I2 = 71%). A moderate degree of heterogeneity was observed among these studies.

Discussion

This meta-analysis includes 19 clinical trials involving a total of over 2500 participants, providing the most comprehensive assessment of BPs in patients with fragility fractures to date. Our analyses have demonstrated that perioperative BP initiation does not significantly delay the healing rate or time for patients with fragility fractures. Furthermore, compared to patients not using BPs, the use of BPs reduced the risk of new fractures and, in particular, lowered the risk of new fractures at 12 months post-surgically. Further analysis reveals that using BPs reduced the risk of osteoporotic vertebral compression fractures by 86%.

While the severity of fragility fractures has been widely recognized, uncertainty has persisted regarding the optimal timing for initiating BPs and managing fragility fractures during the perioperative period. In this meta-analysis, we have systematically synthesized and summarized all available evidence. Our findings indicate that early administration of BPs after surgery does not significantly delay fracture healing time. Moreover, it effectively reduces subsequent fractures when compared to patients not using BPs. Furthermore, it could improve the BMD, markers of bone turnover and pain after using BPs. These findings extend beyond the academic insight, holding significant clinical implications. They will prove invaluable for clinicians and patients, enabling informed decision-making in the management of fragility fractures.

In our evaluation of other outcomes, such as surgical effectiveness, anti-osteoporosis therapy, functional recovery, and pain relief, our findings indicate that perioperative BPs use generally has a positive impact on anti-osteoporosis therapy, including BMD, PINP, and CTX, when compared to both other time periods and non-usage. For the remaining outcomes, no significant differences in BPs use between the perioperative period and other time periods were observed, nor notable distinctions between patients with and without BPs use. This means that there was no evidence of any detrimental effects on these outcomes with perioperative BPs initiation. Regarding adverse effects, patients using BPs were more prone to experiencing fever, arthralgia, and myalgia when compared to patients not using BPs. Previous studies showed that some patients may have transient "influenza-like" symptoms such as fever, bone pain, and myalgia after the first oral or intravenous infusion of BPs, which are mostly relieved spontaneously within 3 days of treatment, and those with obvious symptoms can be treated symptomatically with non-steroidal antipyretic analgesics [42]. It is important to acknowledge that the benefits of perioperative BPs use following fragility fractures far outweigh its adverse effects.

In comparison to previous studies evaluating the effectiveness of other anti-osteoporotic agents for fragility fractures, BPs have shown better efficacy than other anti-osteoporotic agents such as raloxifene, and bazedoxifene [43]. Although early use of teriparatide may outperform BPs in terms of radiographic healing [43–46], a previous study reported no significant difference in fracture healing time [47]. It is important to note that the certainty of these comparisons in the pooled results and individual studies on fragility fractures remains uncertain due to the small sample sizes of the studies. Furthermore, the differences in efficacy among these drugs are relatively small. Therefore, clinicians and patients need to consider other factors such as costs, potential side effects, mode of administration, patient profile and preferences when selecting an anti-osteoporotic agent.

Given the instability and fragmentation associated with osteoporotic fractures, there exists a heightened risk of reduced screw fixation, implant loosening, and fixation failure. Therefore, it is recommended that individuals receive fracture liaison services (FLS) following such fractures. These services encompass confirming fragility fractures, conducting personalized assessments of bone health, implementing tailored management strategies, providing follow-up care and long-term treatment, and monitoring patient treatment outcomes [48]. Moreover, patients who suffer from osteoporotic fractures should undergo standardized anti-osteoporotic drug therapy during the perioperative period to minimize the risk of new or recurrent fractures [49, 50]. A systematic review of 37 studies underscored the effectiveness of FLS interventions in decreasing the risk of recurrent fractures among individuals aged 50 years and older who had experienced fragility fractures [51]. The most frequently used anti-osteoporotic medications included bisphosphonates (23 studies; 62.2% of studies), denosumab (10 studies; 27.0%), and teriparatide (10 studies; 27.0%).

The current study has several strengths. We conducted an extensive systematic review and meta-analysis, encompassing a wide range of outcome measures, to compare the effects of BPs used during the perioperative period with other time periods and non-usage. Previous meta-analyses focused solely on the timing of BPs use [10] or the presence or absence of BPs use [5–9]. Our approach allows for a more comprehensive assessment of the initiation of perioperative BP treatment after fragility fractures than was previously possible. We assessed various outcomes, including healing time, surgical outcomes, anti-osteoporosis effects, functional recovery, pain relief, and adverse effects, with analyses of subgroups. This approach enhances our understanding of the healing and therapeutic effects of perioperative BPs use in patients with fragility fractures. These comprehensive evaluations of primary and secondary outcomes have provided clinical insights into the initiation of perioperative BPs treatment for patients with fragility fractures. Moreover, the methods employed in this meta-analysis were adhering to pre-defined criteria in accordance with established guidelines for scientific transparency and rigour. Furthermore, most studies included in the meta-analysis were randomized controlled trials (17 out of 19), which enhances the robustness of our findings by minimizing the influence of confounding factors.

This meta-analysis does have several notable limitations that should be considered. Firstly, the majority of studies included in the meta-analysis were small, which may result in the potential overestimation of effects and may not yield highly reliable conclusions. Large-scale studies are needed to provide more robust evidence. Secondly, some of the meta-analyses included in this study exhibit a high degree of heterogeneity. However, due to the limited number of studies available for inclusion, it was not feasible to explore the sources of heterogeneity. This could potentially impact the consistency and generalizability of the findings. Thirdly, the low-quality ratings in the GRADE assessment may be attributed to a high risk of bias in the included studies, small sample sizes, and serious imprecision. The assessment highlights the need for caution in interpreting these results and suggests that while some moderate-quality evidence supports perioperative bisphosphonate use, much of the evidence may be limited by methodological issues and variability in study designs. Lastly, in this meta-analysis, the focus was solely on the use of perioperative BPs, which restricts our ability to compare directly with other anti-osteoporotic agents in terms of fracture healing and other outcomes. Consequently, it becomes challenging to determine the relative efficacy of BPs compared to alternative treatment options, for example, denosumab or teriparatide. Despite these limitations, the study provides valuable insights and contributes to the existing body of knowledge regarding perioperative BP use for fragility fractures. Further research with larger, individual patient data from the clinical is warranted to advance our understanding.

In conclusion, this meta-analysis illustrates the beneficial effects of initiating BPs perioperatively to help the healing process in patients with fragility fractures. By evaluating diverse outcomes across 19 clinical trials, it provides substantial evidence in favour of considering perioperative BPs initiation as a valuable treatment strategy for patients with fragility fractures. However, further large-scale clinical trials are required to validate these findings and directly compare the efficacy and safety of BPs with other anti-osteoporotic agents. Nevertheless, the results from this meta-analysis support the initiation of perioperative BPs as a potentially valuable treatment option for patients with fragility fractures, which may potentially improve functional outcomes and enhance the quality of life for those experiencing such fractures.

Supplementary information

ESM 1 (1.4MB, docx)

(DOCX 1457 kb)

Acknowledgments

The study team acknowledged the contributions of all the investigators in collecting study data.

Abbreviations

BPs

bisphosphonates

RRs

risk ratios

BMD

bone mineral density

PINP

procollagen type I N-propeptide

CTX

C-terminal telopeptide of type I collagen

VAS

visual analogue scale

MD

mean difference

CIs

confidence intervals

OR

odds ratio

RCTs

randomized controlled trials

OVCF

osteoporotic vertebral compression fractures

SOFIF

senile osteoporotic femoral intertrochanteric fractures

ODI

Oswestry Disability Index

Author contribution

YHZ and YY conceived and designed research; JW and GLM collected data and conducted research; ZYH and YY analyzed and interpreted data; YY and JW wrote the initial paper; JW and GLM revised the paper. All the authors read and approved the final manuscript.

Funding

Funding was provided by Organon (Shanghai) Pharmaceutical Technology Co., Ltd.

Data availability

Included in the manuscript and appendix are tables with source data, and links to online data repositories with statistical code and source data are presented in the manuscript.

Declarations

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors. For this type of study, formal consent is not required.

Conflicts of interest

Yuhong Zeng, Yuan Yang, Jue Wang, and Guolin Meng declare that they have no conflict of interest.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Y. Zeng and Y. Yang are the co-first authors of this article.

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