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Bisphosphonates for osteoporosis in nonmetastatic prostate cancer patients receiving androgen-deprivation therapy: a systematic review and meta-analysis |
Ding H, Yang L, Du W, Teng Y, Fu SJ, Tao Y, Lu JZ, Wang ZP |
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CRD summary The review concluded that bisphosphonates caused a rapid increase in spine and hip or thigh bone mineral density in men with non-metastatic prostate cancer receiving androgen-deprivation therapy, but did not reduce fracture incidence. Considering the risk of bias in the included trials and the possibility of publication bias affecting results, the authors' conclusions should be interpreted with caution. Authors' objectives To assess the efficacy and safety of bisphosphonates for prevention and treatment of osteoporosis in men with non-metastatic prostate cancer receiving androgen deprivation therapy. Searching PubMed, EMBASE, The Cochrane Library, Science Citation Index, and Chinese Biomedicine Database were searched up to October 2012 with no language restrictions. Google was searched for related references. Reference lists of relevant studies were also searched and experts in the field contacted. Only published studies were sought. Study selection Randomised controlled trials (RCTs) of bisphosphonates for patients with (histologically diagnosed) non-metastatic prostate cancer receiving androgen-deprivation therapy were eligible. Treatment periods had to be at least six months. Patients with metabolic bone disease were not eligible. Placebo, no treatment, or other therapies were all eligible comparators. The primary outcomes were percentage change in baseline bone mineral density of the lumbar spine, and incidence of newly diagnosed or worsening fractures. Most trials used the bisphosphonate zoledronic acid (4mg); other treatments included pamidronate, neridronate or alendronate. In most trials, all patients received calcium and vitamin D. The planned duration of treatment was one year in all trials. Mean patient ages ranged from 65 to 75 years. Trials were published from 2001 to 2010. Two reviewers independently selected studies for inclusion, with disagreements resolved by a third reviewer. Assessment of study quality Trial quality was assessed by evaluating methods and details for randomisation, allocation concealment, blinding (participants, investigators, outcome assessors, and data analysis), selective outcome reporting, incomplete outcome data, and other bias. Use of intention-to-treat analysis was separately assessed. An overall risk of bias assessment was made. The authors did not state how many reviewers performed the quality assessment. Data extraction Data were extracted to calculate odds ratios or weighted mean differences with 95% confidence intervals (CI). Two reviewers independently extracted data. Methods of synthesis Meta-analyses were performed to calculate pooled effect estimates with 95% confidence intervals. A random-effects model was used when important statistical heterogeneity was detected; otherwise a fixed-effect model was used. Heterogeneity was assessed using the Χ² test and Ι². Results of the review Ten RCTs were included (1,017 men). The risk of bias was reported as being moderate in seven trials and low in three trials; the trials were later described of being of moderate to poor quality. Methods for concealing treatment allocation were unclear in seven trials, adequate in two trials and inadequate in one trial. Blinding was reported in only two trials (it was unclear who was blinded, as only the description 'double blinding' was used in the review). It appeared that selective outcome reporting was a source of bias in all trials. After one year, there was greater improvement in bone mineral density of the lumbar spine for patients on bisphosphonates compared with those on placebo or other treatments (WMD 6.02, 95% CI 5.39 to 6.65; 10 RCTs; Ι²=20%). Smaller statistically significant effects were observed for total hip (eight RCTs; Ι²=59%), trochanter (three RCTs; Ι²=20%) or femoral neck (seven RCTs; Ι²=0%) bone mineral density. There was no significant difference between treatments for incidence of fractures (four RCTs), withdrawals due to adverse events (six RCTs), or withdrawals due to severe adverse events (six RCTs). The risk of fever (two RCTs) and of gastrointestinal symptoms (three RCTs) was significantly higher for patients taking bisphosphonates. Sensitivity analyses exploring mode of delivery (oral versus intravenous) produced similar results to the main analyses. Authors' conclusions Bisphosphonates caused a rapid increase in spine and hip or femoral bone mineral density in men with non-metastatic prostate cancer receiving androgen-deprivation therapy. Fever and gastrointestinal symptoms were common with the use of bisphosphonates. These short-term trials (maximum of 12 months) did not show fracture reduction or survival benefit. CRD commentary The review addressed a clear question and was supported by reproducible eligibility criteria. Although several relevant databases were searched, the restriction to searching only for published studies meant that some relevant studies may have been missed; the review may have been subject to publication bias, although no assessment was made to explore this possibility. Duplicate processes were employed to reduce the risks of reviewer error and bias during study selection and data extraction, but no relevant process details were reported for the quality assessment. The three trials reported as being at low risk of bias appeared likely to have a high risk of bias based on the review quality assessment results table. Appropriate methods were used to pool data and to assess heterogeneity. The authors noted the lack of any effect on the most clinically-important outcome (fractures), and that this was assessed in only four trials. In light of the risk of bias in the included trials and the possibility of publication bias affecting the pooled results, the authors' conclusions (particularly regarding bone mineral density) should be interpreted with some caution. Implications of the review for practice and research Practice: The authors did not state any implications for practice. Research: The authors stated that better quality long-term RCTs (longer than 12 months) were needed, where the outcomes were described in detail. Funding Lanzhou University Scholarship Award, China. Bibliographic details Ding H, Yang L, Du W, Teng Y, Fu SJ, Tao Y, Lu JZ, Wang ZP. Bisphosphonates for osteoporosis in nonmetastatic prostate cancer patients receiving androgen-deprivation therapy: a systematic review and meta-analysis. Asian Pacific Journal of Cancer Prevention 2013; 14(5): 3337-3343 Indexing Status Subject indexing assigned by NLM MeSH Aged; Androgen Antagonists /therapeutic use; Bone Density /drug effects; Bone Density Conservation Agents /adverse effects /therapeutic use; Bone Diseases, Metabolic /drug therapy /prevention & Diphosphonates /adverse effects /therapeutic use; Femur /physiology; Fractures, Bone /epidemiology /pathology; Hip /physiology; Humans; Lumbar Vertebrae /physiology; Male; Osteoporosis /drug therapy /prevention & Prostatic Neoplasms /drug therapy; Treatment Outcome; control; control AccessionNumber 12013035898 Date bibliographic record published 31/07/2013 Date abstract record published 29/01/2014 Record Status This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn. |
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