Bisphosphonates in multiple myeloma: a network meta-analysis
ABSTRACT Bisphosphonates are specific inhibitors of osteoclastic activity and used in the treatment of patients with multiple myeloma (MM). While bisphosphonates are shown to be effective in reducing vertebral fractures and pain, their role in improving overall survival (OS) remains unclear. This is an update of a Cochrane review first published in 2002 and previously updated in 2010.
To assess the evidence related to benefits and harms associated with use of various types of bisphosphonates (aminobisphosphonates versus nonamino bisphosphonates) in the management of patients with MM. Our primary objective was to determine whether adding bisphosphonates to standard therapy in MM improves OS and progression-free survival (PFS), and decreases skeletal-related morbidity. Our secondary objectives were to determine the effects of bisphosphonates on pain, quality of life, incidence of hypercalcemia, incidence of bisphosphonate-related gastrointestinal toxicities, osteonecrosis of jaw and hypocalcemia.
We searched MEDLINE, LILACS, EMBASE (December 2009 to October 2011) and the Cochrane Controlled Trials Register (all years, latest Issue September 2011) to identify all randomized trials in MM up to October 2011 using a combination of text and MeSH terms. We also handsearched relevant meeting proceedings (December 2009 to October 2011).
Any randomized controlled trial (RCT) assessing the role of bisphosphonates and observational studies or case reports examining bisphosphonate-related osteonecrosis of the jaw in patients with MM were eligible for inclusion.
Two review authors extracted the data. Data were pooled and reported as hazard ratio (HR) or risk ratio (RR) under a random-effects model. Statistical heterogeneity was explored using metaregression.
In this update, we included 2 studies (2464 patients) that were not part of our last Cochrane review published in 2010. In this review we included 16 RCTs comparing bisphosphonates with either placebo or no treatment and 4 RCTs with a different bisphosphonate as a comparator. The 20 included RCTs enrolled 6692 patients. Overall methodological quality of reporting was moderate. Thirty per cent (6/20) of trials reported the method of generating the randomization sequence. Forty per cent (8/20) of trials had adequate allocation concealment. Withdrawals and dropouts were described in 60% (12/20) of trials. Pooled results showed no direct effect of bisphosphonates on OS compared with placebo or no treatment (HR 0.96, 95% CI 0.82 to 1.13; P = 0.64). However, there was a statistically significant heterogeneity among the included RCTs (I(2) = 55%, P = 0.01) for OS. To explain this heterogeneity we performed a metaregression assessing the relationship between bisphosphonate potency and improvement in OS, which found indicating an OS benefit with zoledronate (P = 0.058). This provided a further rationale for performing network meta-analyses of the various types of bisphosphonates that were not compared head to head in RCTs. Results from network meta-analyses showed superior OS with zoledronate compared with etidronate (HR 0.43, 95% CI 0.16 to 0.86) and placebo (HR 0.61, 95% CI 0.28 to 0.98). However, there was no difference between zoledronate and other bisphosphonates. Pooled analysis did not demonstrate a beneficial effect of bisphosphonates compared with placebo or no treatment in improving PFS (HR 0.70, 95% CI 0.41 to 1.19; P = 0.18) There was no heterogeneity among trials reporting PFS estimates (I(2) = 35%, P = 0.20).Pooled analysis demonstrated a beneficial effect of bisphosphonates compared with placebo or no treatment on prevention of pathological vertebral fractures (RR 0.74, 95% CI 0.62 to 0.89; I(2) = 7%), skeletal-related events (SRE) (RR 0.80, 95% CI 0.72 to 0.89; I(2) = 2%) and amelioration of pain (RR 0.75, 95% CI 0.60 to 0.95; I(2) = 63%). The network meta-analysis did not show any difference in the incidence of osteonecrosis of the jaw (5 RCTs, 3198 patients) between bisphosphonates. Rates of osteonecrosis of the jaw in observational studies (9 studies, 1400 patients) ranged from 0% to 51%. The pooled results (6 RCTs, 1689 patients) showed no statistically significant 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 1.60; P = 0.11).The pooled results (3 RCTs, 1002 patients) showed no statistically significant 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). The network meta-analysis did not show any differences in the incidence of hypocalcemia, renal dysfunction and gastrointestinal toxicity between the bisphosphonates used.
Use of bisphosphonates in patients with MM reduces pathological vertebral fractures, SREs and pain. Assuming a baseline risk of 20% to 50% for vertebral fracture without treatment, between 8 and 20 MM patients should be treated to prevent vertebral fracture(s) in one patient. Assuming a baseline risk of 31% to 76% for pain amelioration without treatment, between 5 and 13 MM patients should be treated to reduce pain in one patient. With a baseline risk of 35% to 86% for SREs without treatment, between 6 and 15 MM patients should be treated to prevent SRE(s) in one patient. Overall, there were no significant adverse effects associated with the administration of bisphosphonates identified in the included RCTs. We found no evidence of superiority of any specific aminobisphosphonate (zoledronate, pamidronate or ibandronate) or nonaminobisphosphonate (etidronate or clodronate) for any outcome. However, zoledronate appears to be superior to placebo and etidronate in improving OS.
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ABSTRACT: The mechanical properties of cortical and trabecular bones from beagles treated with the bisphosphonate pamidronate (administered intermittently 1 week every month for 3 months, at a dosage of 0.45 mumol/kg/day) were assessed. The mechanical properties of cortical bone were measured by four-point bending tests on femoral quadrants, in order to measure their elastic modulus and ultimate stress. The structural properties of whole tibias were measured in torsion to determine the torsional stiffness and failure torque. The elastic modulus and maximum compressive stress of the trabecular bone samples were measured by compression tests of trabecular cores. Intermittent treatment with pamidronate did not change the pattern of mechanical properties that occurs naturally around the femur or the torsional stiffness and failure torque of the tibias. By contrast, pamidronate did significantly increase the modulus of elasticity (by 19%) and maximum compressive stress (by 33%) of vertically aligned cylindrical trabecular specimens taken from the vertebrae of the beagles.Journal of Orthopaedic Research 09/1994; 12(5):742-6. DOI:10.1002/jor.1100120518 · 2.97 Impact Factor
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ABSTRACT: In a double blind randomized study, the bisphosphonate drug Pamidronate (Aredia) significantly protected Durie-Salmon stage III multiple myeloma patients from osteolytic bone disease. In the patient sub-group on salvage chemotherapy. Pamidronate treatment was also significantly associated with prolonged survival. To test if this drug could induce direct antitumor effects, we exposed myeloma cells to increasing concentrations of Pamidronate or a more potent bisphosphonate, Zoledronate. A concentration- and time-dependent cytotoxic effect was detected on four of five myeloma cell lines as well as three specimens obtained directly from myeloma patients. Zoledronate-induced cytotoxicity was significantly greater than that of Pamidronate. Cytotoxicity could not be explained by bisphosphonate-induced chelation of extracellular calcium or secondary decrease in production of the myeloma growth factor interleukin-6. Morphological examination, DNA electrophoresis and cell cycle analysis indicated that the bisphosphonate-induced cytotoxic effect consisted of a combination of cytostasis and apoptotic myeloma cell death. Enforced expression of BCL-2 protected against the apoptotic death but not against cytostasis. Most cytotoxic effects were seen between 10 and 100 microM of drug. The results suggest a possible direct anti-tumor effect in myeloma patients treated with bisphosphonates which may participate in their significantly increased survival. This hypothesis should now be further tested in clinical trials.Leukemia 02/1998; 12(2):220-9. DOI:10.1038/sj.leu.2400892 · 9.38 Impact Factor
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ABSTRACT: Long-term safety and tolerance is paramount when treating women who are otherwise healthy after the primary adjuvant therapy of breast cancer. Efficacy and limited safety results of a large-scale clinical trial, using adjuvant oral clodronate to prevent bone metastases in primary breast cancer patients, have been reported previously, demonstrating a reduction in the rate of bone metastases during treatment. Here we present expanded safety and tolerability results for clodronate treatment from this trial (cut-off date extended from June 1997 to June 2000). For this randomised, double-blind, placebocontrolled, multicentre study, patients were enrolled and randomised to receive oral clodronate (Bonefos) 1600 mg/day or placebo for 2 years. The total median treatment period plus follow-up was 5.5 years. Adverse events (AEs) and laboratory parameters were followed up regularly for the total study period. The 95% CIs were estimated for the difference in the rate of AEs between the treatment groups. A total of 1079 women with primary operable breast cancer were enrolled to the study; 538 received clodronate and 541 received placebo. Overall incidence of AEs (96.5% of the patients) was the same in both treatment groups, although gastrointestinal disorders were significantly more frequent in the clodronate group during the total study period (66% vs 56.2%; 95% CI 4.0-15.6; p < 0.05). This was mainly due to an increase in non-severe diarrhoea beginning 3-4 months after treatment start. Serious AEs (SAEs) were reported for 39.4% of the patients receiving clodronate and 44.5% of those receiving placebo; no drug-related (clodronate or placebo) SAEs were identified. Clodronate significantly lowered mortality (98 deaths vs 129 deaths; hazard ratio 0.77; 95% CI 0.59-1.00; p = 0.047) reducing the risk of death over the total study period by 23%. AEs caused 58 early discontinuations (five drug-related events) in the clodronate group and 43 discontinuations (three drug-related events) in the placebo group. These results indicate that in women with early breast cancer receiving adjuvant systemic therapy, oral clodronate for 2 years is generally well tolerated with no serious long-term sequelae, providing a safe, long-term therapy in the adjuvant setting.Drug Safety 01/2003; 26(9):661-71. DOI:10.2165/00002018-200326090-00005 · 2.62 Impact Factor