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1 Ibandronate to treat skeletal-related events and bone pain in metastatic bone disease or multiple myeloma: a metaanalysis of randomized clinical trials Journal: BMJ Open Manuscript ID: bmjopen-0-00 Article Type: Research Date Submitted by the Author: -Nov-0 Complete List of Authors: Geng, Chun-Jing; Tumor Hospital of Guangxi Medical University, Department of Anesthesiology Liang, Qian; Guangxi Medical University, Postgraduate school Zhong, Jian-Hong; Tumor Hospital of Guangxi Medical University, Hepatobiliary Surgery Department Zhu, Min; Tumor Hospital of Guangxi Medical University, Department of Anesthesiology Meng, Fan-Ying; Hospital of Chifeng University, Inner Mongolia Autonomous Region, Department of Anesthesiology Wu, Ning; Tumor Hospital of Guangxi Medical University, Department of Anesthesiology Liang, Rui; Tumor Hospital of Guangxi Medical University, Department of Anesthesiology Yuan, Bin-Yi; Tumor Hospital of Guangxi Medical University, Out-patient Department <b>primary Subject Heading</b>: Oncology Secondary Subject Heading: Oncology Keywords: ONCOLOGY, Cancer pain < ONCOLOGY, Bone diseases < ORTHOPAEDIC & TRAUMA SURGERY BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright. -

2 Page of BMJ Open Ibandronate to treat skeletal-related events and bone pain in metastatic bone disease or multiple myeloma: a meta-analysis of randomized clinical trials Chun-Jing Geng *, Qian Liang *, Jian-Hong Zhong *, Min Zhu, Fan-Ying Meng, Ning Wu, Rui Liang, Bin-Yi Yuan. Department of Anesthesiology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 00, P.R. China. Postgraduate school of Guangxi Medical University, Nanning 00, P.R. China. Hepatobiliary Surgery Department, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 00, P.R. China. Department of Anesthesiology, Affiliated Hospital of Chifeng University, Inner Mongolia Autonomous Region. Out-patient Department, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 00, P.R. China *These authors contributed equally to this work. Correspondence to Professor Rui Liang, Department of Anesthesiology, Affiliated Tumor Hospital of Guangxi Medical University, and Doctor Bin-Yin Yuan, Out-patient Department, Affiliated Tumor Hospital of Guangxi Medical University, He Di Rd. #,Nanning 00, P.R. China - BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright.

3 Page of Phone: + -- (office). Fax: gxzlyyliangrui@.com or gxyuanbinyi@.com Running title: Ibandronate for MBD or multiple myeloma. - BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright.

4 Page of BMJ Open ABSTRACT Objectives: Randomized controlled trials (RCTs) have given contradictory results about the efficacy and safety of ibandronate in treating metastatic bone disease (MBD) or multiple myeloma. This review meta-analyzed the literature to gain a more comprehensive picture. Setting: PubMed, EMBASE, and the Cochrane Library databases were systematically searched to identify RCTs evaluating ibandronate to treat MBD or multiple myeloma. Participants: Ten RCTs involving, patients were included. Primary and secondary outcomes: The primary outcomes were the incidence of skeletal-related events and mean change in bone pain scores from baseline. Secondary outcomes were the incidence of adverse events. Results: Intravenous ibandronate ( mg) or oral drug (0 mg) decreased the risk of skeletal-related events compared to placebo (RR 0.0, % CI 0. to 0.0, P = 0.00). It also reduced the bone pain score below baseline significantly more than did placebo at weeks (WMD -0., % CI -0. to -0., P < 0.00).The incidence of diarrhea, nausea, and adverse renal events were similar between the ibandronate and placebo groups, but ibandronate was associated with greater risk of abdominal pain. Ibandronate was associated with similar risk of skeletal-related events as another bisphosphonate drug, zoledronate (RR.0, % CI 0. to., P = 0.). The incidence of fever or influenza-like sympotoms, jaw osteonecrosis, fatigue, and - BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright.

5 Page of nausea was similar for the two drugs, but the incidence of adverse renal events was significantly lower in the ibandronate group. Conclusion: Ibandronate significantly reduce the incidence of skeletal-related events and bone pain in patients with MBD or multiple myeloma relative to placebo. It is also associated with a similar incidence of skeletal-related events as zoledronate. Key words: bone pain; ibandronate; meta-analysis; skeletal-related events Strengths and limitations of this study It analyzes the largest randomized cohort of patients treated with ibandronate for metastatic cancer or multiple myeloma. It is the first review that directly compares ibandronate and zoledronate in treating patients with metastatic cancer. Three of the included studies have low Jadad scores. Two studies did not report the final number of patients allocated to the treatment and placebo groups, so we had to assume that patients were evenly distributed. The small number of included studies meant that we were unable to perform subgroup analysis based on patient demographics, drug delivery route, treatment duration, disease characteristics, or ethnicity. Publication bias may exist. - BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright.

6 Page of BMJ Open INTRODUCTION Breast cancer, prostate cancer, and particularly multiple myeloma frequently metastasize to the skeleton. Patients with bone metastases often suffer fractures and severe pain, reducing their quality of life. Metastatic bone disease (MBD) often develops into skeletal-related events which define as hypercalcemia, pathologic fracture, radiotherapy or surgery to bone, and spinal cord compression., Treatment options for skeletal-related events and bone pain include chemotherapy, hormone therapy, radio therapy, radiopharmaceuticals, surgery, analgesics and bisphosphonates. Even though patients may achieve effective improvement with these treatments, some will continue to experience severe and refractory bone pain., Selection of the treatment method should base on the patient s symptoms, tumor size, location of metastases, patient s general health and life expectancy and also have to take the side effects of each method into consideration. Older patients often suffer from reduced renal function and other complicating medical conditions, which requires even more careful treatment selection. Bisphosphonates are the current standard of care for treating skeletal-related events or bone pain in patients with breast cancer, prostate cancer, or multiple myeloma. The action and activity of osteoclasts and osteoblasts keep a balance which also maintains bone strength and integrity. Bisphosphonates or receptor activator of nuclear factor-κβ ligand (RANKL) inhibitors like Denosumab (Xgeva) are the standard of care in either primary or metastatic bone cancers to fortify the skeleton. They also theoretically make the bones less receptive to neoplastic osteoclast - BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright.

7 Page of activation. Four bisphosphonates have been approved for clinical use: pamidronate, ibandronate, zoledronate and clodronate. These drugs are chemically and structurally different, which helps to explain their different clinical efficacies., Ibandronate, approved in 00 by the European Union for treating patients with metastatic breast cancer, inhibits osteoclast activity and osteoclast-mediated bone resorption, leading to osteoclast apoptosis. Pharmacokinetic data demonstrate that a 0-min fasting period would result in a bioavailability of 0.% for a 0 mg daily oral dose, and the resulting plasma concentration of the drug would match that achieved by monthly administration of intravenous ibandronate ( mg). However, clinical trials on using ibandronate to treat patients with bone metastases arising from breast cancer, colorectal cancer, and multiple myeloma have given conflicting results about efficacy and safety. - Zoledronate is widely used to treat MBD. Our previous study indicated that intravenous zoledronate ( mg) offers good clinical benefit in patients with MBD. However, several trials have reported that the drug can cause life-threatening renal toxicity. - This drug suffers several disadvantages compared to ibandronate, which is associated with lower nephrotoxicity, and which can be administered orally, making it well-suited to patients whose vascular problems preclude prolonged intravenous bisphosphonate therapy. Self-administered oral ibandronate therapy is also convenient for patients who would otherwise need to visit the hospital, and oral therapy is substantially less expensive than monthly intravenous treatment. Few studies have compared ibandronate with zoledronate for treating skeletal-related - BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright.

8 Page of BMJ Open events and bone pain. To address these questions, we conducted a systematic review and meta-analysis evaluating the efficacy and safety of ibandronate relative to placebo and zoledronate for treating skeletal-related events and bone pain in MBD or multiple myeloma. PATIENTS AND METHODS Study identification Literature searches were carried out to identify all relevant RCTs comparing ibandronate with placebo or zoledronate for treating patients with MBD or multiple myeloma. PubMed, EMBASE, and the Cochrane Library databases were systematically searched for relevant articles published up to March 0. The following search terms were used: (ibandronate OR zoledronate) AND (bone metastasis OR metastatic bone disease OR bone pain). We also manually searched references lists in each article to identify additional studies. Moreover, abstracts of official conferences and other previously unpublished data were also searched. Study selection Studies were included if they () involved patients at least years old with any type of MBD or multiple myeloma who had bone metastasis in at least one site; () assessed the clinical effects of ibandronate and reported at least one type of skeletal-related event, bone pain, or adverse event; and () included a placebo control - BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright.

9 Page of arm or a zoledronate as active control arm. Studies were included regardless of the dosage, delivery route (intravenous or oral) or duration of ibandronate or zoledronate therapy. Quality assessment The Jadad scale was used to assess the quality of the RCTs we selected. It is a five-point scale, with trials scoring or points considered low quality and points considered high quality. We assessed whether () the trial was randomized, () the authors provided a sufficiently detailed description of the randomization method, () the trial was double-blind, () the blinding method was described in sufficient detail, and () withdrawals were reported. Outcome measures Primary outcomes were the incidence of skeletal-related events and mean change in bone pain scores from baseline. Secondary outcomes were the incidence of adverse events such as abdominal pain, diarrhea, nausea, fever or influenza-like symptoms, renal toxicity and jaw osteonecrosis. Data extraction We used a standardized form to extract and combine data from all eligible studies that reported the number of patients with any type of skeletal-related event, the mean change in bone pain score from baseline, and adverse events. Bone pain was - BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright.

10 Page of BMJ Open self-assessed at each study visit using the patient-rated scoring system. Patients were asked to rate how severe their bone pain had been, on average, over the previous week using a scale of 0 (none), (mild), (moderate), (severe) or (intolerable). Data were extracted independently by two authors (CJG and Q-L) and discrepancies were resolved by discussion with a third reviewer (FYM). Intention-to-treat (ITT) analysis was used wherever possible. The ITT population was defined as participants who underwent randomization, took the assigned study medication and provided at least one post-baseline assessment. When the ITT population was not available, we planned to use a safety set population instead. The safety set population referred to participants who received at least one study medication. When data could not be pooled directly for meta-analysis, we transformed them using formulas recommended by the Cochrane Handbook for Systematic Reviews of Interventions. Statistical analysis RevMan. (Cochrane Collaboration) was used to meta-analyze the data. For dichotomous data, such as the incidence of skeletal-related events and adverse events, risk ratios (RRs) with % confidence intervals (CIs) were calculated. For continuous data, such as mean change in bone pain score from baseline, the weighted mean difference (WMD) was calculated as long as outcomes were measured in the same way between trials. The chi-squared test was used to analyze the heterogeneity of trial results and the I test to assess inconsistency among trials. Heterogeneity was defined - BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright.

11 Page of as significant if P < 0. for the chi-squared test. Pooled estimates were calculated using a fixed-effects model if substantial heterogeneity was not observed; otherwise, the estimate was calculated using a random-effects model. Unless otherwise noted, P < 0.0 served as the threshold for statistical significance. Outcomes that could not be meta-analyzed were presented descriptively. Sensitivity analysis We checked the reliability of our meta-analyses by comparing the outcomes obtained from a random-effects model and from a fixed-effects model. Robust pooled estimates should not depend on the choice of model. RESULTS Identification and characteristics of studies Ten RCTs -,- containing, patients met the inclusion criteria and were included in this meta-analysis (Fig. ). Six studies were placebo-controlled, -,- and the remaining four compared ibandronate with zoledronate. - Most studies were carried out in Greece, Russia, Kuwait, South Africa, Germany, UK, and the USA, and most patients were Caucasian. One study was carried out in India with Asian participants. Three studies involved only female patients,,, six studies involved both sexes,0-, and one study did not report the sex of participants. Six studies evaluated breast cancer involving bone metastases,,,,0,, two articles studied - BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright.

12 Page of BMJ Open several types of carcinoma,, one study evaluated non-small cell lung cancer, and one study evaluated multiple myeloma. Four studies involved a therapy regimen of oral ibandronate (0 mg) once daily;,,, one study, different doses of an oral formulation (,, 0, 0 mg); three studies, ibandronate ( mg) delivered intravenously every - weeks;,0, one study, ibandronate ( mg) delivered intravenously every weeks; and one study, ibandronate ( or mg) delivered intravenously every weeks. Other details of included studies are shown in Table. Quality assessment of the studies The mean Jadad score was. for the six placebo-controlled studies in the meta-analysis, and. for the four studies comparing ibandronate and zoledronate (Table ). The lower score for the two-drug studies was because all were open-label. All studies mentioned randomization, but only four described the randomization method.,,, Five of placebo-controlled trials stated that they were double-blind,,,- but only two reported the blinding method in detail., All studies reported the number of withdrawals. Therapy outcomes We did not perform subgroup analyses based on drug delivery route, treatment duration, ethnicity, or sex, because of the lack of studies reporting such comparisons. In the end, we performed subgroup analysis only for drug dose: intravenous ibandronate ( mg) vs intravenous ibandronate ( mg) or oral ibandronate (0 mg). - BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright.

13 Page of This subgroup analysis was performed for the primary outcomes of incidence of skeletal-related events and mean change in bone pain score from baseline. Incidence of skeletal-related events Five of placebo-controlled trials -,,0 reported data on the incidence of skeletal-related events. Both effect models indicated a significantly lower incidence with ibandronate than placebo (RR 0., % CI 0.0 to 0., P = 0.00, fixed-effects; I = %). Subgroup analysis showed no significant differences between intravenous ibandronate ( mg) and placebo (RR.0, P = 0.), while intravenous ibandroante ( mg) every - weeks or daily oral ibandronate (0 mg) was associated with significantly lower incidence than placebo was (RR 0.0, P = 0.00; Fig. ). Two of trials comparing ibandronate to zoledronate reported data on the incidence of skeletal-related events. 0, The two drugs were associated with similar incidence (RR.0, % CI 0. to., P = 0.), and this meta-analysis did not show significant heterogeneity (I = %; Fig. ). Mean change in bone pain score from baseline Two placebo-controlled studies reported data on the mean change in bone pain score from baseline., Bone pain used the patient-rated scoring system (Table ). Initial meta-analysis indicated a similar change from baseline for both ibandronate and placebo, but the pooled estimate showed significant heterogeneity (I = %). Therefore we performed a subgroup meta-analysis in which we eliminated data for - BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright.

14 Page of BMJ Open patients who received intravenous ibandronate ( mg). The resulting meta-analysis showed that intravenous ibandronate ( mg) every - weeks or daily oral ibandronate (0 mg) was associated with significantly greater reduction in bone pain score from baseline than was placebo at weeks (WMD = -0., %CI -0. to -0., P < 0.00, fixed-effects; heterogeneity: I = %; Fig. ). One placebo-controlled study did not report the bone pain data, but final evolution revealed ibandronate significantly decreased bone pain scores compared with baseline (Wilcoxon rank sum test; P < 0.). Other studies did not report bone pain.,0, Two studies comparing ibandronate and zoledronate reported data on the mean change in bone pain score from baseline., The other two trials which reported the effect of ibandronate and zoledronate on pain relief were tabulated described., The studies compared bone pain relief in different pain scoring system like McGill pain questionnaire (MPQ), brief pain inventory (BPI),, and patient-rating scoring system. We were unable to pool the data on this outcome because bone pain was not measured in comparable ways. Three RCTs,, showed no significant difference between the two drugs in reducing bone pain. One RCT with the number of patients in ibandronate group and 0 in zoledronate group, found that zoledronate was superior to ibandronate at months with a P-value of 0.0. However, the two drugs showed no significant difference at months or the end of the study. Adverse events - BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright.

15 Page of Adverse events were analyzed in placebo-controlled trials without adjusting for median duration of therapy (Table ). Incidence of abdominal pain was significantly higher in the ibandronate group (.0%) than in the placebo group (.%) based on fixed-effects meta-analysis (RR., % CI.0 to.0, P = 0.0; I = %), although random-effects analysis indicated no significant difference (P = 0.). Meta-analysis using fixed- or random-effects models showed similar incidence between the two groups for the following adverse events (only fixed-effects meta-analysis shown): diarrhea,.0% in the drug group vs 0.% in the placebo group, RR., % CI 0. to., P = 0.0; nausea,.% vs.0%, RR.0, % CI 0. to., P = 0.; and renal toxicity,.% vs.%, RR., % CI 0. to., P = 0.. No significant heterogeneity was detected among the trials (I < 0%). Adverse events were also analyzed in trials comparing ibandronate and zoledronate without adjusting for median duration of therapy (Table ). Incidence of renal toxicity was lower in the ibandronate group (.%) than zoledronate group (.%) based on fixed-effects meta-analysis (RR 0., % CI 0. to 0., P = 0.00; I = %), although random-effects meta-analysis indicated no significant different (P = 0.). Similar results were obtained for the incidence of fever or influenza-like symptoms (.% vs.%), which was significantly lower for ibandronate base on fixed-effects meta-analysis (RR 0., % CI 0. to 0., P < 0.00; heterogeneity: I = 0%) but which was similar for the two groups based on random-effects meta-analysis (P = 0.0). Meta-analysis using fixed- or random-effects models showed similar incidence between the two groups for the - BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright.

16 Page of BMJ Open following adverse events (only fixed-effects meta-analysis shown): anorexia,.% in the ibandronate group vs.% in the zoledronate group, RR 0., % CI 0. to., P = 0.; nausea,.% vs.%, RR 0., % CI 0. to.0, P = 0.; fatigue,.% vs.0%, RR 0., % CI 0. to.0, P = 0.; and jaw osteonecrosis, 0.% vs.%, RR 0., % CI 0. to., P = 0.. No significant heterogeneity was detected among the trials (I < 0%). DISCUSSION This meta-analysis suggests that intravenous ibandronate ( mg) every - weeks or daily oral medication (0 mg) is more effective than placebo for patients with MBD or multiple myeloma. In addition, ibandronate is well-tolerated for at least weeks, with risk of diarrhea, nausea, or renal toxicity similar between the drug and placebo. On the other hand, ibandronate was associated with significantly higher risk of abdominal pain compared to placebo. Our meta-analysis also suggests that ibandronate and zoledronate reduce the incidence of skeletal-related events to a similar extent and are associated with similar risk of anorexia, fatigue, nausea, fever or influenza-like symptoms, or jaw osteonecrosis. Ibandronate was associated with significantly lower incidence of renal toxicity than zoledronate. The quality of the placebo-controlled studies in our review was high (Jadad score ), with only one study earning two points because it failed to report the randomization method in detail and it did not clearly indicate whether it was - BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright.

17 Page of double-blinded or not. The quality of the trials comparing ibandronate and zoledronate was lower because the studies were open-label. All studies used a parallel design for the ibandronate and placebo or zoledronate arms. Sensitivity analysis, which we performed by comparing the RRs using fixed- or random-effects models, showed that most pooled risk estimates were robust except for meta-analysis of the incidence of abdominal pain between ibandronate and placebo groups, and the incidence of fever or influenza-like symptoms and incidence of renal toxicity between ibandronate and zoledronate groups. In all three cases, the random-effects model showed no significant difference between the two groups, while the fixed-effects model showed a significantly lower incidence of abdominal pain in the placebo group, and a significantly lower incidence of fever or influenza-like symptoms and incidence of renal toxicity in the ibandronate group. We identified meta-analyses evaluating bisphosphonates in patients with breast cancer, prostate cancer, lung cancer, multiple myeloma or various cancers. 0 These analyses all focused on skeletal-related events and very few related to the treatment effects of bone pain. They also pooled data for different bisphosphonates, even though different members of this synthetic drug family vary in clinical activity and potency; thus, findings from those meta-analyses, should be treated with caution. Our meta-analysis focused specifically on ibandronate, commonly used to prevent skeletal-related events in cancer patients with MBD or multiple myeloma. Our meta-analysis showed that ibandronate is more effective than placebo at preventing skeletal-related events in the long term suggests that prolonged clinical use of this - BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright.

18 Page of BMJ Open drug is justified. Our meta-analysis also suggests that ibandronate and zoledronate show equivalent ability to prevent skeletal-related events. This gives clinicians another option if either drug is deemed unsuitable for a patient. Our meta-analysis of adverse events suggests that ibandronate is well-tolerated for at least weeks of treatment, and that the incidences of nausea and renal toxicity with the drug are similar to that with placebo. Ibandronate and zoledronate were associated with similar rates of fatigue, fever or influenza-like symptoms, nausea, and jaw osteonecrosis. In addition, ibandronate was associated with significantly lower risk of adverse renal events than zoledronate. In fact, one study examined -year oral ibandronate therapy and reported no adverse renal effects, with serum creatinine levels remaining stable. Similar results were reported for intravenous ibandronate therapy lasting years, suggesting that this class of bisphosphonates does not cause significant renal toxicity. Therefore, if renal function is a concern, it may be safer to use ibandronate than zoledronate. Even so, serum creatinine levels should be monitored in patients on ibandronate therapy. The risk of jaw osteonecrosis with either drug suggests the need for caution, though no cases of serious jaw osteonecrosis were reported for patients on either ibandronate or zoledronate in our meta-analysis. One strength of our study is that it analyzes the largest randomized cohort of patients treated with ibandronate for metastatic cancer or multiple myeloma. It is also the first review, to our knowledge, that directly compares ibandronate and zoledronate in treating patients with metastatic cancer. - BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright.

19 Page of Despite these strengths, our meta-analysis does have limitations. First, three of the included studies have low Jadad scores.,, Second, two studies did not report the final number of patients allocated to the treatment and placebo groups, so we had to assume that patients were evenly distributed.,0 Third, the small number of included studies meant that we were unable to perform subgroup analysis based on patient demographics, drug delivery route, treatment duration, disease characteristics, or ethnicity. And finally, publication bias may exist. Our review suggests that ibandronate can significantly prevent skeletal-related events and reduce bone pain with good tolerability in patients with MBD or multiple myeloma. Further studies on ibandronate should examine its efficacy and safety in patients of different ethnicities and different types of cancer. The efficacy and safety of the drug administered orally or intravenously for different treatment durations should also be rigorously examined. - BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright.

20 Page of BMJ Open Acknowledgement: The authors thank A. Rodríguez Chapin for his language editing and other suggestions, which helped improve the manuscript. Contributors: CJG conceived the study, and CJG and JHZ designed the search strategy and statistical analysis. CJG, QL, NW, BYY, and MZ collected the data, while JHZ checked the data against the original publications. CJG and JHZ drafted and revised the manuscript. CJG and RL are guarantors of the study. All authors had full access to all the data in the study and can take responsibility for data integrity and accuracy of the data analysis. All authors approved the final version of the article. Competing interests: None. Funding: N/A Data sharing: No additional data available. - BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright.

21 Page 0 of References:. Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 00; : -.. Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res 00; : s-s.. Janjan N. Bone metastases: approaches to management. Semin Oncol 00; : -.. Serafini AN. Therapy of metastatic bone pain. J Nucl Med 00; : -0.. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials ; : -.. Body JJ, Bartl R, Burckhardt P, et al. Current use of bisphosphonates in oncology. International Bone and Cancer Study Group. J Clin Oncol ; : 0-.. Bloomfield DJ. Should bisphosphonates be part of the standard therapy of patients with multiple myeloma or bone metastases from other cancers? An evidence-based review. J Clin Oncol ; : -.. Hitron A, Adams V. The pharmacological management of skeletal-related events from metastatic tumors. Orthopedics 00; :.. Leyland-Jones B. Pharmacokinetic and clinical equivalence of oral and intravenous ibandronate for metastatic bone disease. EJC Supplements 00; : -.. Body JJ, Diel IJ, Lichinitzer M, et al. Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies. Br J Cancer 00; 0: -.. Heras P, Karagiannis S, Kritikos K, Hatzopoulos A, Mitsibounas D. Ibandronate is effective in preventing skeletal events in patients with bone metastases from colorectal cancer. Eur J Cancer Care (Engl) 00; : -.. Menssen HD, Sakalova A, Fontana A, et al. Effects of long-term intravenous ibandronate therapy on skeletal-related events, survival, and bone resorption markers in patients with advanced multiple myeloma. J Clin Oncol 00; 0: -.. Zhu M, Liang R, Pan LH, et al. Zoledronate for metastatic bone disease and pain: a meta-analysis of randomized clinical trials. Pain medicine 0; : -.. McDermott RS, Kloth DD, Wang H, Hudes GR, Langer CJ. Impact of zoledronic acid on renal function in patients with cancer: Clinical significance and development of a predictive model. J Support Oncol 00; : -.. Cha YJ, Lee YJ. Risk factors for renal impairment in patients with solid tumors or multiple myeloma treated with zoledronic acid. Int J Clin Pharmacol Ther 0; : -.. Joensuu TK. Renal toxicity following zoledronic acid reversed with ibandronate in a prostate cancer patient with bone metastases. Urol Int 00; 0: -0.. Pecherstorfer M, Rivkin S, Body JJ, Diel I, Bergstrom B. Long-term safety of intravenous ibandronic acid for up to years in metastatic breast cancer: an open-label trial. Clin Drug Investig 00; : -.. Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions version..0 (updated March 0) BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright.

22 Page of BMJ Open Diel IJ, Body JJ, Lichinitser MR, et al. Improved quality of life after long-term treatment with the bisphosphonate ibandronate in patients with metastatic bone disease due to breast cancer. Eur J Cancer 00; 0: Heras P, Kritikos K, Hatzopoulos A, Georgopoulou AP. Efficacy of ibandronate for the treatment of skeletal events in patients with metastatic breast cancer. Eur J Cancer Care (Engl) 00; : -.. Coleman RE, Purohit OP, Black C, et al. Double-blind, randomised, placebo-controlled, dose-finding study of oral ibandronate in patients with metastatic bone disease. Ann Oncol ; : -.. Francini F, Pascucci A, Bargagli G, et al. Effects of intravenous zoledronic acid and oral ibandronate on early changes in markers of bone turnover in patients with bone metastases from non-small cell lung cancer. Int J Clin Oncol 0; : -.. Choudhury KB, Mallik C, Sharma S, Choudhury DB, Maiti S, Roy C. A randomized controlled trial to compare the efficacy of bisphosphonates in the management of painful bone metastasis. Indian J Palliat Care 0; : -.. Body JJ, Lichinitser M, Tjulandin S, Garnero P, Bergstrom B. Oral ibandronate is as active as intravenous zoledronic acid for reducing bone turnover markers in women with breast cancer and bone metastases. Ann Oncol 00; : -.. Barrett-Lee P, Casbard A, Abraham J, et al. Oral ibandronic acid versus intravenous zoledronic acid in treatment of bone metastases from breast cancer: a randomised, open label, non-inferiority phase trial. Lancet Oncol 0; : -.. Wong MH, Stockler MR, Pavlakis N. Bisphosphonates and other bone agents for breast cancer. Cochrane Database Syst Rev 0; : CD00.. Yuen KK, Shelley M, Sze WM, Wilt T, Mason MD. Bisphosphonates for advanced prostate cancer. Cochrane Database Syst Rev 00; : CD000.. Lopez-Olivo MA, Shah NA, Pratt G, Risser JM, Symanski E, Suarez-Almazor ME. Bisphosphonates in the treatment of patients with lung cancer and metastatic bone disease: a systematic review and meta-analysis. Support Care Cancer 0; 0: -.. Mhaskar R, Redzepovic J, Wheatley K, et al. Bisphosphonates in multiple myeloma: a network meta-analysis. Cochrane Database Syst Rev 0; : CD Palmieri C, Fullarton JR, Brown J. Comparative efficacy of bisphosphonates in metastatic breast and prostate cancer and multiple myeloma: a mixed-treatment meta-analysis. Clin Cancer Res 0; : -.. Sue-Ann M, David C, Robin M. Safety of oral ibandronate in the trement of bone metastases from breast cancer long-term follow-up experience. Clin Drug Invest 00; : BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright.

23 Page of potentially eligible trials identified in EMBASE (0), Zero additional records MEDLINE (0), and identified through other sources CENTRAL () Trials excluded based on title, abstract, and keywords (): Reviews () Not placebo or zoledronate controlled () Refer to other drugs () Refer to other diseases () Trials screened based on full text () Trails excluded because duplicate/overlapping () Trials included in Trials included in meta-analysis meta-analysis comparing ibandronate comparing ibandronate and placebo () and zoledronate () Selection process for trials included in this meta-analysis BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright. -

24 Page of BMJ Open xmm ( x DPI) - BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright.

25 Page of xmm ( x DPI) - BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright.

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27 Ibandronate to treat skeletal-related events and bone pain in metastatic bone disease or multiple myeloma: a metaanalysis of randomized clinical trials Journal: BMJ Open Manuscript ID: bmjopen-0-00.r Article Type: Research Date Submitted by the Author: -Mar-0 Complete List of Authors: Geng, Chun-Jing; Tumor Hospital of Guangxi Medical University, Department of Anesthesiology Liang, Qian; Guangxi Medical University, Postgraduate school Zhong, Jian-Hong; Tumor Hospital of Guangxi Medical University, Hepatobiliary Surgery Department Zhu, Min; Tumor Hospital of Guangxi Medical University, Department of Anesthesiology Meng, Fan-Ying; Hospital of Chifeng University, Inner Mongolia Autonomous Region, Department of Anesthesiology Wu, Ning; Tumor Hospital of Guangxi Medical University, Department of Anesthesiology Liang, Rui; Tumor Hospital of Guangxi Medical University, Department of Anesthesiology Yuan, Bin-Yi; Tumor Hospital of Guangxi Medical University, Out-patient Department <b>primary Subject Heading</b>: Oncology Secondary Subject Heading: Oncology Keywords: ONCOLOGY, Cancer pain < ONCOLOGY, Bone diseases < ORTHOPAEDIC & TRAUMA SURGERY BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright. -

28 Page of BMJ Open Ibandronate to treat skeletal-related events and bone pain in metastatic bone disease or multiple myeloma: a meta-analysis of randomized clinical trials Chun-Jing Geng *, Qian Liang *, Jian-Hong Zhong *, Min Zhu, Fan-Ying Meng, Ning Wu, Rui Liang, Bin-Yi Yuan. Department of Anesthesiology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 00, P.R. China. Postgraduate School of Guangxi Medical University, Nanning 00, P.R. China. Hepatobiliary Surgery Department, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 00, P.R. China. Department of Anesthesiology, Affiliated Hospital of Chifeng University, Inner Mongolia Autonomous Region. Out-patient Department, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 00, P.R. China *These authors contributed equally to this work. Correspondence to Professor Rui Liang, Department of Anesthesiology, Affiliated Tumor Hospital of Guangxi Medical University, and Doctor Bin-Yin Yuan, Out-patient Department, Affiliated Tumor Hospital of Guangxi Medical University, He Di Rd. #, Nanning 00, P.R. China. Phone: + -- (office). Fax: gxzlyyliangrui@.com or gxyuanbinyi@.com Running title: Ibandronate for MBD or multiple myeloma. Conflicts of interest: The authors declared no conflict of interest with respect to this manuscript. - BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright.

29 Page of ABSTRACT Objective: Randomized controlled trials (RCTs) have given contradictory results about the efficacy and safety of ibandronate in treating metastatic bone disease (MBD) or multiple myeloma. This review meta-analyzed the literature to gain a more comprehensive picture. Design: Systematic review and meta-analysis of ibandronate compared with placebo or zoledronate. Data sources: PubMed, EMBASE, and the Cochrane Library databases were systematically searched to identify RCTs published up to March 0 evaluating ibandronate to treat MBD or multiple myeloma. Review method: Ten RCTs involving, patients were included. Six RCTs were placebo-controlled and four compared ibandronate with zoledronate. The studies included in this review were majorly from European countries. Results: Intravenous ibandronate ( mg) or oral drug (0 mg) decreased the risk of skeletal-related events compared to placebo (RR 0.0, % CI 0. to 0.0, P = 0.00). It also reduced the bone pain score below baseline significantly more than placebo did at weeks (WMD -0., % CI -0. to -0., P < 0.00). The incidence of diarrhea, nausea, and adverse renal events was similar between the ibandronate and placebo groups, but ibandronate was associated with greater risk of abdominal pain. Ibandronate was associated with similar risk of skeletal-related events as another bisphosphonate drug, zoledronate (RR.0, % CI 0. to., P = 0.). The incidence of nausea, jaw osteonecrosis and fatigue was similar for the two drugs, but the incidence of adverse renal events was significantly lower in the ibandronate group. Conclusion: Ibandronate significantly reduces the incidence of skeletal-related events and bone pain in patients with MBD or multiple myeloma relative to placebo. It is associated with a similar incidence of skeletal-related events as zoledronate. - BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright.

30 Page of BMJ Open Key words: bone pain; ibandronate; meta-analysis; skeletal-related events Strengths and limitations of this study First meta-analysis on ibandronate for metastatic cancer or multiple myeloma. Compared the efficacy and adverse events of ibandronate and zoledronate directly. Limited by lacking subgroup analysis based on drug delivery route or treatment duration. - BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright.

31 Page of INTRODUCTION Breast cancer, prostate cancer, and particularly multiple myeloma frequently metastasize to the skeleton. Patients with bone metastases often suffer fractures and severe pain, reducing their quality of life. Metastatic bone disease (MBD) often develops into skeletal-related events, defined as hypercalcemia, pathologic fracture, radiotherapy or surgery involving bone, and spinal cord compression., Treatment options for skeletal-related events and bone pain include chemotherapy, hormone therapy, radiotherapy, radiopharmaceuticals, surgery, analgesics and bisphosphonates. Even though patients may achieve effective improvement with these treatments, some will continue to experience severe and refractory bone pain., Selection of the treatment method should be based on tumor size, location of metastases, patient s general health, symptoms and life expectancy; method selection should also take into account the possible side effects. Older patients often suffer from reduced renal function and other complicating medical conditions, which requires even more careful treatment selection. Bone metastases are classified as osteolytic, osteosclerotic or mixed lesions., Osteolytic metastases are believed to be caused by osteoclast-activating factors, the most important of which may be parathyroid hormone-related peptide. Osteoblastic metastases, in contrast, are believed to arise when cancer cells produce factors that stimulate osteoblast proliferation, differentiation and bone formation. The relative activity of osteoclasts and osteoblasts maintains a balance that ensures bone strength and integrity. A balance between levels of osteoprotegerin and of the receptor activator of nuclear factor-κβ ligand (RANKL) is important in bone pathophysiology and it is a drug target in the treatment of bone metastases and osteoarthritis. Bisphosphonates or RANKL inhibitors such as Denosumab are the current standard of care for treating skeletal-related events or bone pain in primary and metastatic bone cancers. These drugs strengthen the skeleton and may also make bones less receptive to activation by neoplastic osteoclasts. Four bisphosphonates have been approved for clinical use: pamidronate, ibandronate, zoledronate and clodronate. These drugs are - BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright.

32 Page of BMJ Open chemically and structurally different, which helps to explain their different clinical, efficacies. Ibandronate, approved in 00 by the European Union for treating patients with metastatic breast cancer, inhibits osteoclast activity and osteoclast-mediated bone resorption, leading to osteoclast apoptosis. Pharmacokinetic data demonstrate that a 0-min fasting period results in a bioavailability of 0.% for a 0 mg daily oral dose, and the resulting plasma concentration of the drug matches that achieved with monthly administration of intravenous ibandronate ( mg). However, clinical trials on ibandronate to treat patients with bone metastases arising from breast cancer, colorectal cancer, and multiple myeloma have given conflicting results about efficacy and safety. - Zoledronate is also widely used to treat MBD. Our previous study indicated that intravenous zoledronate ( mg) offers good clinical benefit in patients with MBD. Ibandronate and zoledronate are generally well-tolerated, triggering primarily transient side effects such as mild flu-like symptoms. However, all bisphosphonates have a potential for side effects such as jaw osteonecrosis and renal toxicity. Bisphosphonate-induced jaw osteonecrosis which is a potentially complication should be worth our highly valued. It is supposed that awareness and good knowledge of this disease by physicians are important factors of its early detection and management. As to renal adverse events, several trials have reported that zoledronate can cause life-threatening renal toxicity. - Ibandronate is associated with lower nephrotoxicity than zoledronate and can be administered orally, which can be more cost-effective than an intravenous approach and which makes the therapy well-suited to patients who have a phobia of needles. Self-administered oral ibandronate therapy is also convenient for patients who would otherwise require administration in hospital or during a home nursing visit. Whether one drug or the other is superior in the clinic, however, is poorly understood, since few studies have compared them for their safety and efficacy in treating skeletal-related events and bone pain. - BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright.

33 Page of To address these questions, we conducted a systematic review and meta-analysis evaluating the efficacy and safety of ibandronate relative to placebo or zoledronate for treating skeletal-related events and bone pain in MBD and multiple myeloma. PATIENTS AND METHODS Study identification Literature searches were carried out to identify all relevant RCTs comparing ibandronate with placebo or zoledronate for treating patients with MBD or multiple myeloma. The searches were performed by two authors (CJG and JHZ). PubMed, EMBASE, and the Cochrane Library databases were systematically searched for relevant articles published up to March 0. The following search terms were used: (ibandronate OR zoledronate) AND (bone metastasis OR metastatic bone disease OR bone pain). Detailed database search strategies are shown in Table. We also manually searched references lists in each article to identify additional studies. Moreover, abstracts of official conferences and other previously unpublished data were searched. Study selection Studies were included if they () involved patients at least years old with any type of MBD or multiple myeloma who had bone metastasis in at least one site; () assessed the clinical effects of ibandronate and reported at least one type of skeletal-related event, bone pain, or adverse event; and () included a placebo control arm or a zoledronate as active control arm. Studies were included regardless of the dosage, delivery route (intravenous or oral) or duration of ibandronate or zoledronate therapy. Quality assessment - BMJ Open: first published as./bmjopen-0-00 on June 0. Downloaded from on January 0 by guest. Protected by copyright.