A Cochrane review [Abstract] 1 included 24 studies with a total of 7293 subjects. 20 studies compared bisphosphonates with either placebo or no treatment and 4 studies with a different bisphosphonate.
Pooled results showed that there was a reduction in mortality with overall survival (OS) from 41% to 31%, but the confidence interval is consistent with a larger reduction and small increase in mortality compared with placebo or no treatment (HR 0.90, 95% CI 0.76 to 1.07; 14 studies; 2706 participants). There was substantial heterogeneity among the included RCTs (I2 = 65%) for OS. A meta-regression was performed assessing the relationship between bisphosphonate potency and improvement in OS, which found an OS benefit with zoledronate but limited evidence of an effect on PFS. This provided a further rationale for performing a network meta-analyses of the various types of bisphosphonates that were not compared head-to-head in RCTs. Results from network meta-analyses showed evidence of a benefit for OS with zoledronate compared with etidronate (HR 0.56, 95% CI 0.29 to 0.87) and placebo (HR 0.67, 95% CI 0.46 to 0.91). However, there was no evidence for a difference between zoledronate and other bisphosphonates.
The effect of bisphosphonates on disease progression (PFS) is uncertain. Based on the HR of 0.75 (95% CI 0.57 to 1.00; seven studies; 908 participants), 47% participants would experience disease progression without treatment compared with between 30% and 47% with bisphosphonates. There is probably a similar risk of non-vertebral fractures between treatment groups (RR 1.03, 95% CI 0.68 to 1.56; six studies; 1389 participants). Pooled analysis demonstrated evidence for a difference favoring bisphosphonates compared with placebo or no treatment on prevention of pathological vertebral fractures (RR 0.74, 95% CI 0.62 to 0.89; seven studies; 1116 participants) and skeletal-related events (SREs) (RR 0.74, 95% CI 0.63 to 0.88; 10 studies; 2141 participants). The evidence for less pain with bisphosphonates was of very low quality (RR 0.75, 95% CI 0.60 to 0.95; eight studies; 1281 participants).
Bisphosphonates may increase osteonecrosis of jaw (ONJ) compared with placebo but the confidence interval is very wide (RR 4.61, 95% CI 0.99 to 21.35; P = 0.05; six studies; 1284 participants). The results from the network meta-analysis did not show any evidence for a difference in the incidence of ONJ (eight RCTs, 3746 participants) between bisphosphonates. Data from nine observational studies (1400 participants) reported an incidence of 5% to 51% with combination of pamidronate and zoledronate, 3% to 11% with zoledronate alone, and 0% to 18% with pamidronate alone.
The pooled results showed no evidence for a difference in increase in frequency of gastrointestinal symptoms with the use of bisphosphonates compared with placebo or no treatment (RR 1.23, 95% CI 0.95 to 1.59; seven studies; 1829 participants).The pooled results showed no evidence for a difference in increase in frequency of hypocalcemia with the use of bisphosphonates compared with placebo or no treatment (RR 2.19, 95% CI 0.49 to 9.74; three studies; 1090 participants). The results from network meta-analysis did not show any evidence for differences in the incidence of hypocalcemia, renal dysfunction and gastrointestinal toxicity between the bisphosphonates used.
Comment: The quality of evidence is downgraded by study quality (unclear allocation concealment).
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