Bisphosphonates in a number of myeloma: an up to date community meta-analysis.
Cochrane Database Syst Rev. 2017 12 18;12:CD003188
Authors: Mhaskar R, Kumar A, Miladinovic B, Djulbegovic B
BACKGROUND: Bisphosphonates are particular inhibitors of osteoclastic exercise and are used within the therapy of sufferers with a number of myeloma (MM). Whereas bisphosphonates are proven to be efficient in decreasing vertebral fractures and ache, their position in bettering general survival (OS) stays unclear. That is an replace of a Cochrane evaluate first revealed in 2002 and beforehand up to date in 2010 and 2012.
OBJECTIVES: To evaluate the proof associated to advantages and harms related to use of assorted kinds of bisphosphonates (aminobisphosphonates versus non-aminobisphosphonates) within the administration of sufferers with MM. Our major goal was to find out whether or not including bisphosphonates to straightforward remedy in MM improves OS and progression-free survival (PFS), and reduces skeletal-related morbidity. Our secondary targets have been to find out the consequences of bisphosphonates on ache, high quality of life, incidence of hypercalcemia, incidence of bisphosphonate-related gastrointestinal toxicities, osteonecrosis of jaw (ONJ) and hypocalcemia.
SEARCH METHODS: We searched MEDLINE, Embase (September 2011 to July 2017) and the CENTRAL (2017, Situation 7) to establish all randomized managed trial (RCT) in MM as much as July 2017 utilizing a mixture of textual content and MeSH phrases.
SELECTION CRITERIA: Any randomized managed trial (RCT) evaluating bisphosphonates versus placebo/no therapy/bisphosphonates and observational research or case reviews analyzing bisphosphonate-related ONJ in sufferers with MM have been eligible for inclusion.
DATA COLLECTION AND ANALYSIS: Two evaluate authors extracted the information. Information have been pooled and reported as hazard ratio (HR) or threat ratio (RR) utilizing a random-effects mannequin. We used meta-regression to discover statistical heterogeneity. Community meta-analysis utilizing Bayesian method was carried out.
MAIN RESULTS: On this replace, we included 4 new research (601 contributors), leading to a complete of 24 included research.Twenty RCTs in contrast bisphosphonates with both placebo or no therapy and 4 RCTs concerned one other bisphosphonate as a comparator. The 24 included RCTs enrolled 7293 contributors. Pooled outcomes confirmed that there was moderate-quality proof of a discount in mortality with on OS from 41% to 31%, however the confidence interval is in line with a bigger discount and small improve in mortality in contrast with placebo or no therapy (HR zero.90, 95% CI zero.76 to 1.07; 14 research; 2706 contributors). There was substantial heterogeneity among the many included RCTs (I2 = 65%) for OS. To clarify this heterogeneity we carried out a meta-regression assessing the connection between bisphosphonate efficiency and enchancment in OS, which discovered an OS profit with zoledronate however restricted proof of an impact on PFS. This offered an extra rationale for performing a community meta-analyses of the varied kinds of bisphosphonates that weren’t in contrast head-to-head in RCTs. Outcomes from community meta-analyses confirmed proof of a profit for OS with zoledronate in contrast with etidronate (HR zero.56, 95% CI zero.29 to zero.87) and placebo (HR zero.67, 95% CI zero.46 to zero.91). Nevertheless, there was no proof for a distinction between zoledronate and different bisphosphonates.The impact of bisphosphonates on illness development (PFS) is unsure. Based mostly on the HR of zero.75 (95% CI zero.57 to 1.00; seven research; 908 contributors), 47% contributors would expertise illness development with out therapy in contrast with between 30% and 47% with bisphosphonates (low-quality proof). There’s in all probability an identical threat of non-vertebral fractures between therapy teams (RR 1.03, 95% CI zero.68 to 1.56; six research; 1389 contributors; moderate-quality proof). Pooled evaluation demonstrated proof for a distinction favoring bisphosphonates in contrast with placebo or no therapy on prevention of pathological vertebral fractures (RR zero.74, 95% CI zero.62 to zero.89; seven research; 1116 contributors; moderate-quality proof) and skeletal-related occasions (SREs) (RR zero.74, 95% CI zero.63 to zero.88; 10 research; 2141 contributors; moderate-quality proof). The proof for much less ache with bisphosphonates was of very low high quality (RR zero.75, 95% CI zero.60 to zero.95; eight research; 1281 contributors).Bisphosphonates could improve ONJ in contrast with placebo however the confidence interval may be very huge (RR four.61, 95% CI zero.99 to 21.35; P = zero.05; six research; 1284 contributors; low-quality proof). The outcomes from the community meta-analysis didn’t present any proof for a distinction within the incidence of ONJ (eight RCTs, 3746 contributors) between bisphosphonates. Information from 9 observational research (1400 contributors) reported an incidence of 5% to 51% with mixture of pamidronate and zoledronate, three% to 11% with zoledronate alone, and zero% to 18% with pamidronate alone.The pooled outcomes confirmed no proof for a distinction in improve in frequency of gastrointestinal signs with using bisphosphonates in contrast with placebo or no therapy (RR 1.23, 95% CI zero.95 to 1.59; seven research; 1829 contributors; low-quality proof).The pooled outcomes confirmed no proof for a distinction in improve in frequency of hypocalcemia with using bisphosphonates in contrast with placebo or no therapy (RR 2.19, 95% CI zero.49 to 9.74; three research; 1090 contributors; low-quality proof). The outcomes from community meta-analysis didn’t present any proof for variations within the incidence of hypocalcemia, renal dysfunction and gastrointestinal toxicity between the bisphosphonates used.
AUTHORS’ CONCLUSIONS: Use of bisphosphonates in contributors with MM reduces pathological vertebral fractures, SREs and ache. Bisphosphonates have been related to an elevated threat of growing ONJ. For each 1000 contributors handled with bisphosphonates, about one affected person will endure from the ONJ. We discovered no proof of superiority of any particular aminobisphosphonate (zoledronate, pamidronate or ibandronate) or non-aminobisphosphonate (etidronate or clodronate) for any end result. Nevertheless, zoledronate was discovered to be higher than placebo and first-generation bisposphonate (etidronate) in pooled direct and oblique analyses for bettering OS and different outcomes similar to vertebral fractures. Direct head-to-head trials of the second-generation bisphosphonates are wanted to settle the problem if zoledronate is actually essentially the most efficacious bisphosphonate presently utilized in follow.
PMID: 29253322 [PubMed – indexed for MEDLINE]