Clinical UM Guideline
This document addresses the use of Zoledronic acid, also known as Zoledronate, which is available under the brand names Reclast® and Zometa® , as well as in generic form. This drug is a member of bisphosphonate class of drugs which are calcium regulators. Zoledronic acid is specifically used to inhibit bone resorption.
Note: Please see the following for more information related to the treatment of pathologic bone loss:
The use of zoledronic acid is considered medically necessary for any of the following conditions:
Not Medically Necessary:
The use of zoledronic acid is considered not medically necessary when the criteria above have not been met and for all other indications.
The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.
|J3489||Injection, zoledronic acid, 1 mg [Reclast, Zometa]|
|C88.4||Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue [MALT-lymphoma]|
|C90.00-C90.32||Multiple myeloma and malignant plasma cell neoplasms|
|D00.00-D09.9||In situ neoplasms|
|M80.00XA-M80.88XS||Osteoporosis with current pathological fracture|
|M81.0-M81.8||Osteoporosis without current pathological fracture|
|M85.80-M85.9||Other specified disorders of bone density and structure [osteopenia]|
|M88.0-M88.9||Osteitis deformans [Paget's disease of bone]|
|Z79.52||Long term (current) use of systemic steroids|
|Z79.811||Long term (current) use of aromatase inhibitors|
|Z79.83||Long term (current) use of biphosphonates|
|Z85.00-Z85.9||Personal history of malignant neoplasm|
|Z92.241||Personal history of systemic steroid therapy|
Zoledronic acid, also known as Zoledronate, is available under the brand names Reclast and Zometa, as well as in generic form. This drug is a member of bisphosphonate class of drugs which are calcium regulators. Zoledronic acid is specifically used to inhibit bone resorption. In vitro, zoledronic acid inhibits osteoclastic activity and induces osteoclast apoptosis. Zoledronic acid also blocks the osteoclastic resorption of mineralized bone and cartilage through its binding to bone, including osteoclastic activity and skeletal calcium release induced by various stimulatory factors released by tumors. It is frequently used to treat individuals at risk for significant bone loss either due to a specific disease state or due to the result of another medical therapy.
Bone metastases from kidney cancer
Lipton and others (2003) reported on the results of a study investigating the use of zoledronic acid in 74 subjects with bone metastases from advanced renal cell carcinoma (RCC). This study was a retrospective subset analysis of a randomized controlled trial (RCT) involving 74 subjects with RCC. All subjects were originally randomized to receive zoledronic acid 4 mg, or 8 mg, or placebo every 3 weeks for 9 months along with concomitant antineoplastic therapy. Zoledronic acid (4 mg) was reported to significantly reduce the proportion of subjects with a skeletal-related event (SRE) compared with placebo (37% vs. 74%, p=0.015). In addition, zoledronic acid significantly reduced the mean skeletal morbidity rate compared with placebo (2.68 vs. 3.38, p=0.014) and extended the time to the first event (p=0.006). A multiple event analysis demonstrated that the risk of developing an SRE was reduced by 61% compared with placebo (hazard ratio [HR]=0.394, p=0.008). Finally, the median time to progression of bone lesions was significantly longer for subjects who were treated with zoledronic acid (p=0.014 vs. placebo).
Bone metastases from non-small cell lung cancer
Rosen (2003) published the results of a phase III, double-blind, randomized trial comparing zoledronic acid for the treatment of bone metastases from solid tumors other than breast and prostate cancer. In this study, 773 subjects were randomized to either 4 mg or 8 mg of zoledronic acid or placebo treatment. During the study, the 8 mg dose was eventually reduced to 4 mg due to concerns over renal safety. The proportion of subjects experiencing a SRE was 38% for the 4 mg zoledronic acid group, 35% for the zoledronic 8/4 mg group, and 44% in the placebo group (p=0.127 and p=0.025 for the 4 mg and 8/4 mg groups vs. placebo, respectively). The median time until the first SRE was 230 days and 163 days for the 4 mg zoledronic acid and placebo group, respectively (p=0.023). A multiple event analysis looking at the risk of developing skeletal events identified a significant benefit to the use of zoledronic acid. (HR=0.732, p=0.017).
Bone metastases from thyroid cancer
Orita (2011) reported on a nonrandomized controlled study involving 50 subjects with bone metastases from differentiated thyroid carcinoma. No bisphosphonate therapy was given to 28 subjects and 22 subjects received zoledronic acid. The authors reported that SREs occurred in significantly lower frequency in the zoledronic acid group (3/22 subjects, 14%) than the control group (14/28, 50%) (p=0.007). The use of zoledronic acid significantly retarded the onset of the first SRE (p=0.04). Two subjects in the zoledronic acid group developed bisphosphonate-related osteonecrosis of the jaw versus none in the control group.
A large double-blind, placebo-controlled trial by Rosen and colleagues (2004) involved 773 subjects with solid tumors (n=11 with thyroid carcinoma) who were randomized to receive either zoledronic acid (4 mg or 8 mg) or placebo via a 15-minute infusion every 3 weeks for 21 months. The 8 mg dose was later reduced to 4 mg (8/4 mg group). The reported results indicated that fewer subjects in the zoledronic acid group developed at least 1 SRE at 21 months vs. placebo group subjects (39% of those treated at the 4 mg dose [p=0.127] and 36% of those treated at the 8/4-mg dose [p=0.023], compared with 46% of those treated with placebo). Furthermore, 4 mg of zoledronic acid significantly delayed the median time to first SRE (236 days with 4 mg vs. 155 days with placebo; p=0.009) and significantly reduced the annual incidence of SREs (1.74 per year with the 4 mg dose vs. 2.71 per year with placebo; p=0.012). Moreover, the 4 mg dose of zoledronic acid was found to reduce the risk of developing a skeletal event by 31% (HR=0.693, p=0.003). Zoledronic acid was found to be well tolerated with long-term use; the most commonly reported adverse events in all treatment groups included bone pain and the transient, acute-phase reactions of nausea, anemia, and emesis.
Hershman (2008) conducted a multicenter, randomized, double-blind, placebo-controlled, phase III study involving 101 premenopausal women receiving adjuvant chemotherapy for early-stage breast cancer. Subjects were selected to receive treatment with either placebo or zoledronic acid at baseline, 6 months, and at 12 months. The primary endpoint of change in lumbar spine bone mineral density (LS-BMD) was evaluated; secondary endpoints included change in femoral neck BMD (FN-BMD) and total hip BMD (TH-BMD). Overall, 96 subjects (95%) completed the 24 week evaluation, and 85 (84%) completed the final follow-up evaluation at 52 weeks. At 24 weeks and 52 weeks, the authors reported percentage change in LS-BMD, FN-BMD, and TH-BMD vs. baseline in the zoledronic acid group. In comparison, the placebo group had significant decreases in LS-BMD at 24 weeks (-2.98%) and at 52 weeks (-4.39%). Total hip BMD and FN-BMD were also significantly decreased vs. baseline (-2.08% and -1.5%, respectively, at 52 weeks). There were significant differences in measurements between the two groups at 24 and 52 weeks with regard to markers of bone resorption and formation, including serum C-telopeptide of type I collagen (CTX) and bone-specific alkaline phosphatase (BSAP), indicating favorable results for the zoledronic acid group (p<0.001). BSAP increased significantly between 24 and 36 weeks in the placebo arm (p<0.001); CTX increased significantly between 12 and 24 weeks in the placebo arm (p<0.001). The percentage of subjects who experienced adverse events was similar between the treatment arms, with the exception of eye discomfort, which was more common in the zoledronic acid arm vs placebo arm (47% vs 25%; p<0.01). There were no reports of renal function changes, osteonecrosis of the jaw, or cancer recurrence during the 52 week period.
In another study, the same group (Hershman, 2010) reported the results of a secondary analysis of a previously published multicenter, randomized, double-blind, placebo-controlled, phase III study. In the initial study, 101 premenopausal female subjects undergoing adjuvant chemotherapy for early-stage breast cancer were randomized to receive either zoledronic acid or placebo every 3 months for 12 months to assess effects on LS-BMD. At 24 months, 62 women (61%) completed evaluations to determine if effects persist after completion of therapy. In the zoledronic acid group, the percentage change in LS-BMD at 24 months was not significantly different when compared to baseline and 12 months (-0.6%). In contrast, when compared to baseline, the placebo group experienced a 6.3% decrease in LS-BMD at 24 months (p<0.05). Femoral neck BMD and TH-BMD measurements remained stable in the zoledronic acid arm at 24 months compared with baseline. In the placebo arm, FN-BMD changed by -2.4% (p<0.05), and TH-BMD changed by -2.6% (p<0.05). The authors concluded that their results indicated that premenopausal women treated with zoledronic acid for 12 months while receiving adjuvant chemotherapy for early-stage breast cancer experience stable BMD measurements at 24 months compared with significant BMD loss in subjects randomized to placebo.
Zoledronic acid in premenopausal women with early-stage breast cancer was shown to prevent bone loss during adjuvant goserelin plus tamoxifen or anastrazole therapy and improved bone mineral density at 5 years (Gnant, 2008). In a prospective substudy of a randomized, open-label, phase III study (n=1803) (Austrian Breast and Colorectal Cancer Study Group trial-12 [ABCSG-12]), 404 premenopausal women who underwent surgery for breast cancer and who were scheduled to receive goserelin for 3 years were randomized to endocrine therapy alone (goserelin and anastrozole or goserelin and tamoxifen; n=199) or endocrine therapy concurrent with zoledronic acid (goserelin, anastrozole, and zoledronic acid or goserelin, tamoxifen, and zoledronic acid; n=205). After 3 years of treatment, endocrine therapy alone caused significant loss of BMD at the lumbar spine (-11.3%, p<0.0001) and trochanter (-7.3%, p<0.0001). At 2 years following completion of treatment, subjects not receiving zoledronic acid still had decreased BMD at both sites compared with baseline (lumbar spine, -6.3%, p=0.001; trochanter, -4.1%, p=0.058). In contrast to these findings, subjects who received zoledronic acid had stable BMD at 36 months (lumbar spine, +0.4%; trochanter, +0.8%) and increased BMD at 60 months at both sites (lumbar spine, +4.0%, p=0.02; trochanter, +3.9%, p=0.07) compared with baseline.
The ZO-FAST trial, an open-label RCT published by Coleman (2013), involved 1065 postmenopausal women with hormone receptor-positive early-stage breast cancer receiving adjuvant letrozole randomly assigned to receive immediate zoledronic acid or delayed zoledronate (initiated for fracture or on-study BMD decrease). In the final analysis at 60 months, the authors reported significant improvement in LS-BMD in the immediate treatment groups vs. the delayed treatment group (mean change in LS-BMD, 4.3% vs -5.4%, respectively; p<0.0001). Furthermore, immediate treatment appeared to reduce the risk of disease-free survival (DFS) events by 34% (HR=0.66, p=0.0375) with fewer local (0.9% vs. 2.3%) and distant (5.5% vs. 7.7%) recurrences when compared to delayed treatment.
The Zometa-Femara Adjuvant Synergy Trial (Z-FAST), an open-label RCT involving 602 subjects treated with either immediate zoledronic acid or delayed administration in postmenopausal women with early breast cancer receiving adjuvant letrozole demonstrated that early treatment could prevent cancer treatment-induced bone loss (Brufsky, 2007). Subjects were randomized to receive letrozole with either upfront zoledronic acid (n=301) or delayed zoledronic acid (n=301) initiated when either lumbar spine or total hip T-scores decreased to less than -2 or a nontraumatic fracture occurred. At 12 months, only 25 (8.3%) of subjects in the delayed group had received treatment with zoledronic acid. At the same time point, there were 500 evaluable subjects (83%) in which a positive percent change in BMD occurred in the immediate group and a negative percent change in BMD was reported in the delayed group. An overall mean percent difference between the groups of 4.4% (p<0.0001) for LS-BMD and 3.3% (p<0.0001) for TH-BMD was reported at 12 months. In a subset of 212 subjects, the difference in percent change of serum bone turnover markers between the immediate and delayed groups was -35% for N-telopeptide (NTX) and -33% for BSAP at 12 months. Compared to baseline measurements, both NTX and BSAP significantly increased in the delayed group (NTX, p<0.0001; BSAP, p=0.0006) and significantly decreased in the immediate group (NTX, p=0.013; BSAP, p<0.0001). In another subset of 300 subjects used in a safety analysis, the incidence of adverse events and treatment-related withdrawals were similar between groups; however, bone pain occurred more frequently in the immediate group (11.3% vs 4%).
Gnant (2007) reported the results of a randomized, phase III, open-label study involving 401 premenopausal subjects with stage I to II, estrogen receptor (ER) and/or progesterone receptor (PR) positive breast cancer with no prior adjuvant therapy. Subjects were randomized into 4 groups: (1) treatment with goserelin and tamoxifen either with zoledronic acid (n=100), or (2) without zoledronic acid (n=103), or (3) treatment with goserelin and anastrozole either with zoledronic acid (n=104), or (4) without zoledronic acid (n=94). At 36 months, results from 114 subjects showed that the treatment groups without zoledronic acid had significant decreases in BMD compared with baseline (LS-BMD, -14.4%, p<0.0001; trochanter, -8.2%, p=0.0005) and T-scores (LS-BMD, -1.4, p<0.0001; trochanter, -0.6, p=0.0017). In the treatment groups containing zoledronic acid, BMD remained stable compared with baseline and T-scores significantly improved (p<0.0001) compared with adjuvant endocrine therapy alone. Adverse events were mild to moderate in severity and were consistent with known toxicities associated with each drug. Zoledronic acid use was not associated with renal dysfunction and the addition of zoledronic acid did not add significant toxicity to the other treatment groups. No subjects experienced bone fractures or jaw osteonecrosis.
Aside from the bone mineral density benefits derived from zoledronic acid for individuals who have undergone treatment for breast cancer, it has also been postulated that additional benefits may be possible in relation to the reduction in the rates of breast cancer recurrence. A meta-analysis published by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG, 2015) evaluated the impact of adjuvant bisphosphonate therapy on breast cancer recurrence. This report involved data from 26 trials encompassing 18,766 subjects with a median follow-up of 5.6 years. The authors stated that 3453 subjects experienced recurrence and 2106 had died during the study periods reported. Recurrence rates in the overall study population were not found to be significantly different. However, they found that bisphosphonates had a greater impact on preventing distant recurrence vs. local contralateral recurrence (p=0.01). This effect was attributed mainly to a reduction in bone metastases (10-year risk 7.8 vs. 9.0; relative risk [RR]=0.83, p=0.004). The effect of bisphosphonates in reducing bone recurrence in women 55 years of age and older was significant (p=0.02). Among the 4616 women 45 years of age and younger included in the study with bone recurrence, treatment group allocation had no significant impact (p=0.97). Alternatively, for women 55 years of age and older, the treatment group demonstrated a highly significant benefit from bisphosphonate therapy (p=0.002). Regarding the use of zoledronic acid specifically, their analysis showed significant benefits in such treatment, regardless of dose frequency (every 6 months vs. monthly) or duration of treatment (2 years vs. 3-5 years) (p=0.037). For pre-menopausal women, treatment with bisphosphonates appeared to provide little benefit with regard to bone metastases or breast cancer mortality. Conversely, in postmenopausal women, both were significantly improved (recurrence: RR=0.86, p=0.002; distant recurrence: RR=0.82, p=0.0003; bone recurrence: RR=0.72, p=0.0002; breast cancer mortality: RR=0.82, p=0.002). The absolute gain for bone recurrence was calculated to be 2.2%, and for breast cancer mortality 3.3%. This study also reported on bone fracture risk, with the use of bisphosphonates improving 5-year fracture rates from 6.3% to 5.1%, with little gain in the first year and the most benefit seen in years 2-4.
Gnant and colleagues in the Austrian Breast and Colorectal Cancer Study Group (ABCSG) have reported on the results of a long-term study of 1803 subjects with breast cancer assigned to one of 4 groups: (1) goserelin plus tamoxifen (n=451), (2) goserelin plus tamoxifen plus zoledronic acid (n=449), (3) goserelin plus anastrozole (n=453), and (4) goserelin plus anastrozole plus zoledronic acid (n=450) (Gnant, 2009, 2011, 2015). In their first report from 2009, after a median follow-up of 47.8 months, 137 events had occurred, with disease-free survival rates of 90.8% in the group that received endocrine therapy alone vs. 94.0% in the group that received endocrine therapy with zoledronic acid. They reported that the addition of zoledronic acid to endocrine therapy resulted in an absolute reduction of 3.2 % and a relative reduction of 36% in the risk of disease progression (p=0.01). However, the addition of zoledronic acid was not noted to significantly reduce the risk of death (p=0.11). The results of an interim analysis were reported in 2011, with a median follow-up of 62 months. They stated that zoledronic acid continued to reduce risk of disease-free survival events overall (p=0.009). However, this result was not found to be significant when the tamoxifen group arms and anastrozole arms were assessed separately (p=0.067 and p=0.061, respectively). They also noted that zoledronic acid did not significantly affect risk of death (p=0.09). Bone pain was reported in 601 patients (349 patients on zoledronic acid vs 252 not on zoledronic acid). Most recently, the results with a 94.4-month median follow-up was reported in 2015. The relative risks of disease progression and death were reported to continue to be reduced by zoledronic acid, although no longer significant at the predefined significance level (HR=0.77, p=0.042 for progression and HR=0.66, p=0.064 for death). The absolute risk reductions with zoledronic acid were 3.4% for disease free survival and 2.2% for overall survival.
In 2016, Kroep and colleagues reported the results of a meta-analysis of four studies assessing the impact of zoledronic acid in subjects with breast cancer receiving neoadjuvant chemotherapy or neoadjuvant chemotherapy plus zoledronic acid. Data was available for 735 subjects for measurement of pathological complete response in the breast (pCRb) and for 552 subjects for measurement of pathological complete response breast and lymph nodes (pCR). In the total study population of 750 subjects, the addition of zoledreonic acid to neoadjuvant chemotherapy did not increase pCRb or pCR rates. However, the authors reported that for postmenopausal subjects, the addition of zoledronic acid resulted in a significant, near doubling of the pCRb rate (10.8% for the chemotherapy only group vs. 17.7% for the chemotherapy plus zoledronic acid group; odds ratio [OR]=2.14). Their conclusions were that the addition of zoledronic acid to neoadjuvant chemotherapy had no impact on pCR. However, it may augment the effects of chemotherapy in postmenopausal individuals with breast cancer.
The Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) trial demonstrated that a single dose of zoledronic acid was noninferior to once daily oral risedronate for the prevention and treatment of glucocorticoid-induced osteoporosis in the multicenter, randomized, double-blind, double-placebo study involving 833 subjects who received treatment with prednisolone daily (Reid, 2009). Subjects were randomized in a 1:1 ratio to receive either a single dose of zoledronic plus a daily placebo, or daily oral risedronate plus a single IV placebo. The study groups were further divided into treatment and prevention subgroups. The primary outcome was the percent change from baseline in BMD of the lumbar spine (L1 to L4) at 12 months. Efficacy analysis was performed on the modified intent-to-treat (mITT) population, defined as subjects who received study medication and had baseline and at least one post-baseline BMD measurement. The mITT population included 568 women (68%), of whom, 373 (66%) were menopausal. While the number of baseline fractures was similar between groups in the treatment arm, more subjects in the zoledronic acid prevention group had baseline fractures. The mITT analysis revealed a single IV dose of zoledronic acid was noninferior to once daily oral risedronate 5 mg for the treatment and prevention of glucocorticoid-induced osteoporosis. In the treatment subgroup, the mean percent change from baseline in BMD at 12 months was 4.06% vs 2.71% in the zoledronic acid and risedronate groups, respectively. In the prevention subgroup, the mean percent change from baseline in BMD at 12 months was 2.6% vs 0.64% in the zoledronic acid and risedronate groups, respectively. Within the first 3 days of study drug administration, adverse events were significantly higher in the zoledronic acid treatment and prevention subgroups compared with risedronate. After 3 days, the incidence of events was similar between drug groups. Serious adverse events included worsening rheumatoid arthritis in the treatment subgroup (zoledronic acid, 8% vs risedronate, 6%) and pyrexia in the prevention subgroup (zoledronic acid, 15% vs risedronate, 2%).
In an unpublished pivotal trial data detailed in the Product Information for Reclast, zoledronic acid increased LS-BMD more than an oral bisphosphonate in a randomized, multicenter, double-blind, active controlled, 1-year study (n=833). Subjects treated with 7.5 mg/day or more of oral prednisone or its equivalent, were randomized to treatment for 1 year with either 1 dose of zoledronic acid or to an oral daily bisphosphonate. Subjects were stratified either to the treatment group defined as receiving 3 months or less of corticosteroid treatment prior to randomization, or the prophylaxis group, defined as greater than 3 months of corticosteroid treatment prior to randomization. For the treatment group, the mean increase in LS-BMD at 1 year for the zoledronic acid group was 4.1% vs. 2.7% for the bisphosphonate group. This was a treatment difference of 1.4% (p<0.001) for the treatment group. For prevention, the mean increase in the LS-BMD at 1 year was 2.6% in the zoledronic acid group vs. 0.6% for the bisphosphonate group. This was a treatment difference of 2% (p<0.001) for the prophylaxis group.
Hypercalcemia of malignancy
Major and colleagues (2001) conducted a pooled analysis of two concurrent, randomized, double-blind, double-dummy clinical trials, in which subjects with moderate to severe hypercalcemia of malignancy (HCM) were assigned to receive a single dose of zoledronic acid 4 mg via a 5 minute IV infusion (n=86), zoledronic acid 8 mg (n=98) via a 5 minute IV infusion, or pamidronate 90 mg (n=103) via 2 hour infusion. To maintain the blind, zoledronic acid therapy was administered simultaneously with IV hydration (500 mL of IV fluids over 4 hours). All subjects received 250 mL of IV fluids before infusion of study drug. The remaining portion of the required IV hydration was administered as part of a double-dummy infusion. Bone metastases at baseline existed in 144 subjects (52.4%). Assessment of corrected serum calcium (CSC) at day 10 revealed complete responses (CR) [defined as reduction in CSC to concentrations equal to or less than 10.8 mg/dL] in 88.4% (p=0.002) and 86.7% (p=0.015) of subjects receiving zoledronate 4 mg and 8 mg, respectively. By comparison, 69.7% of pamidronate-treated subjects attained CR status. The onset of CSC normalization occurred as early as 4 days after treatment in approximately 50% of subjects receiving zoledronate (4 mg, 45.3%; 8 mg, 55.6%) compared with 33.3% of pamidronate subjects. A total of 15 subjects were refractory to treatment with either agent. The median time to relapse in the zoledronate 4 mg group was 30 days (p=0.001) and 40 days in the zoledronate 8 mg (p=0.007). Both were significantly longer vs. the median time to relapse of 17 days in pamidronate subjects. A group of 70 subjects who were initially refractory to treatment or experiencing relapse after initial CR were re-treated with zoledronate 8 mg. Complete response was attained in 36 subjects (52%) by day 10, with a median response-duration of 15 days.
Multiple myeloma and bone metastasis from solid tumors
Morgan et al. (2010) reported an open label, randomized controlled study involving 1960 subjects with newly diagnosed multiple myeloma comparing 4 mg zoledronic acid as an infusion every 3-4 weeks (n=981; 555 on intensive chemotherapy, 426 on non-intensive chemotherapy) vs. 1600 mg oral clodronic acid daily (n=979; 556 on intensive chemotherapy, 423 on non-intensive chemotherapy). All subjects also received intensive or non-intensive induction chemotherapy. The primary endpoints were overall survival (OS), progression-free survival PFS), and overall response rate. At the time of study cutoff, subjects received bisphosphonates for a median of 350 days before disease progression, with a median of 3.7 years follow-up. The authors reported that zoledronic acid reduced mortality by 16% vs. clodronic acid (HR=0.84, p=0.0118), and extended median OS by 5.5 months (50.0 months vs. 44.5 months; p=0.04). Zoledronic acid also significantly increased median PFS by 2.0 months (19.5 months vs. 17.5 months; p=0.07). Rates of complete, very good partial, or partial response did not differ significantly between the zoledronic acid and clodronic acid groups for subjects receiving intensive induction chemotherapy (432 subjects [78%] vs. 422 [76%]; p=0.43) or non-intensive induction chemotherapy (215 [50%] vs. 195 [46%]; p=0.18). Zoledronic acid was associated with higher rates of confirmed osteonecrosis of the jaw (35 [4%]) than was clodronic acid (3 [<1%]).
Additional results from the same study were reported in 2011 (Morgan, 2011). The researchers reported that at a median follow-up of 3.7 years, subjects in the zoledronic acid group had a lower incidence of SREs than did those in the clodronic acid group (265 [27%] vs. 346 [35%], respectively; HR=0.74, p=0.0004). Zoledronic acid was also associated with a lower risk of any SRE in the subsets of subjects with bone lesions (233 [35%] of 668 vs. 292 [43%] of 682 with clodronic acid; HR=0.77, p=0.0038) and without bone lesions at baseline (29 [10%] of 302 vs. 48 [17%] of 276 with clodronic acid; HR=0.53, p=0.0068). Fewer subjects in the zoledronic acid group had vertebral fractures than did those in the clodronic acid group (50 [5%] in the zoledronic acid group vs. 88 [9%] in the clodronic acid group; p=0.0008), other fractures (45 [5%] vs. 66 [7%]; p=0.04), and new osteolytic lesions (46 [5%] vs. 95 [10%]; p<0.0001). The authors concluded that the results of their study support the early use of zoledronic acid rather than clodronic acid in subjects with newly diagnosed multiple myeloma for the prevention of skeletal-related events, irrespective of bone disease status at baseline.
In another publication, the same group presented an analysis investigating the optimal therapy regimens for different subject populations in the MRC Myeloma IX trial. They examined traditional and thalidomide-based induction and maintenance regimens and IV zoledronic acid and oral clodronate in all enrolled subjects (Morgan, 2012). Zoledronic acid was reported to improve OS compared with clodronic acid independently of sex, stage, or myeloma subtype, most profoundly in subjects with baseline bone disease or other SREs. In subjects treated for ≥ 2 years, zoledronic acid improved OS vs. clodronic acid from randomization (p=0.02) and also from first on-study disease progression (median, 34 months for zoledronic acid vs 27 months for clodronate; p=0.03). The investigators concluded that zoledronic acid demonstrated greater benefits than clodronic acid.
Osteoporosis in men
Zoledronic acid significantly reduced the risk of vertebral fracture among men with osteoporosis in a 24 month, multicenter, double-blind, placebo-controlled, randomized trial involving 1199 male subjects with primary or hypogonadism-induced osteoporosis (Boonen, 2012). Subjects were allocated to receive two doses of zoledronic acid 5 mg (n=588) or placebo (n=611), infused at baseline and at 12 months. The primary outcome of the rate of new morphometric vertebral fractures over 24 months was reported as 1.6% in the zoledronic acid group vs. 4.9% in the placebo group, representing a 67% reduction in RR associated with zoledronic acid (RR, 0.33; 95% confidence interval [CI], 0.16 to 0.7; p=0.002). Additional clinical benefits in the zoledronic acid group compared with the placebo group at 24 months included fewer moderate to severe new vertebral fractures (RR reduction, 63%; p=0.03) and less height loss (-2.2 mm vs. -4.5 mm; p=0.002). Lumbar spine BMD, TH-BMD, and FN-BMD were all significantly greater in the zoledronic acid group over a 24-month period (all p<0.05 vs. placebo), and bone turnover markers were significantly lower in men who received zoledronic acid (p<0.05 vs. placebo). Subjects with low serum levels of total testosterone demonstrated similar results. Adverse events were reported more often in the zoledronic acid group and included arthralgia, extremity pain, pyrexia, or influenza-like symptoms. However, the incidence of serious adverse events were similar between groups (zoledronic acid group, 25.3%; the placebo group, 25.2%), with the exception of the incidence of myocardial infarction (MI), with 9 subjects in the zoledronic acid group having MIs vs. 2 men in the placebo group (p=0.03).
Osteoporosis, treatment and prevention in postmenopausal women
Data from an unpublished study submitted to the FDA for Reclast (see package insert) included 582 postmenopausal female subjects randomly assigned in a double-blind fashion into 1 of 3 treatment groups: (1) zoledronic acid at randomization and at 12 months (n=198); (2) zoledronic acid at randomization and placebo at 12 months (n=181); and (3) placebo at randomization and at 12 months (n=202). Subjects were further classified into 2 strata: (1) women less than 5 years from menopause (n=224); and (2) women 5 years or more from menopause (n=357). In treatment group 1, there were 77 subjects in stratum 1 and 121 in stratum 2; in group 2, there were 70 subjects in stratum 1 and 111 in stratum 2. No stratification data were provided for the control group. LS-BMD was significantly increased across both strata in comparison to placebo at month 24. In group 2, the increase was 4% in stratum 1 and 4.8% in stratum 2, in comparison to a decrease of 2.2% in stratum 2 and a 0.7% decrease in stratum 2 in the control group. Overall, treatment with zoledronic acid and placebo at month 12 resulted in an increase in LS-BMD of 6.3% in stratum 1 and 5.4% in stratum 2 over 24 months compared with placebo (both p<0.0001). Total hip BMD was also significantly increased across both strata compared with placebo at 24 months, with a 2.6% increase in stratum 2 and 2.1% in stratum 2 for group 2 vs. a 2.1% decrease in stratum 1 and 1% decrease in stratum 2 of control group subjects. Overall, treatment with zoledronic acid and placebo at month 12 resulted in an increase in TH-BMD of 4.7% in stratum 2 and 3.2% in stratum 2 over 24 months vs. placebo (both p<0.0001).
Black (2007) reported the results of a 3 year, double-blind, placebo-controlled study of postmenopausal women with evidence of osteoporosis from the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly - Pivotal Fracture Trial (HORIZON-PFT) (n=7765). This study involved 768 subjects randomized to receive either zoledronic acid (n=3889) or placebo (n=3876) at baseline, 12 months, and 24 months. The investigators reported that the 3 year incidence of new vertebral fractures was reduced for the zoledronic acid group (3.3%, n=92) vs. the placebo group (10.9%, n=310) (RR=0.3, p=0.001). The incidence of hip fractures was also reduced in the zoledronic acid group (1.4%, n=52) vs. placebo (2.5%, n=88) (HR=0.59, p=0.002). They also reported significant reductions in the zoledronic acid group vs. the placebo group in the incidence of nonvertebral fractures (8% vs. 10.7%; HR=0.75), all clinical fractures (8.4% vs. 12.8%; HR=0.67) and clinical vertebral fractures (0.5% vs. 2.6%; HR=0.23) (p<0.001 for all comparisons). Significant increases in the zoledronic acid group vs. placebo were reported for TH-BMD (+6.02%), LS-BMD (+6.71%), and FN-BMD (+5.06%) (p<0.001). At 12 months, the biochemical markers of bone resorption and formation (CTX and NTX) were all significantly reduced for the zoledronic acid group vs. placebo (p<0.001 for all comparisons). The number of subjects reporting any adverse event was higher for the zoledronic acid group compared with placebo (95.5% vs 93.9%; p=0.002). However, the difference between groups for serious adverse events was not statistically significant.
A randomized, double-blind, dose-ranging study over 1 year involving postmenopausal women was conducted by Reid and colleagues (2002). Subjects were assigned to receive either placebo (n=59) or IV infusions of zoledronic acid in one of the following dose regimens: a single infusion every 3 months of zoledronic acid at the following dose strengths: (1) 0.25 mg (n=60); (2) 0.5 mg (n=58); (3) 1 mg (n=53); or (4) 2 mg every 6 months (n=61); or (5) 4 mg zoledronic acid given once at baseline (n=60). Throughout the duration of the study, all groups receiving zoledronic acid showed progressive increases from baseline in mean BMD of the lumbar spine vs. the placebo group (p<0.001). No significant differences between the five zoledronic acid dosing groups were noted with regard to post-treatment BMD. Subjects treated with zoledronic acid also showed progressive improvements in FN-BMD compared with the placebo group, with improvements in the treatment groups ranging between 3.1% and 3.5% at 12 months vs. a mean decline of 0.4% in the placebo group (p< 0.001). With the exception of the 4-dose regimen of zoledronic acid 0.25 mg, all other dosing regimens of zoledronic acid provoked significant increases in BMD of the distal radius compared with radius BMD in the placebo group (p<0.05, all comparisons). Subjects treated with zoledronic acid showed notable decreases in serum markers of bone turnover (CTX and NTX: creatinine ratio). Treatment-related adverse events occurred with significantly greater frequency in the zoledronic acid treatment groups, with musculoskeletal pain, nausea, and fever reported most frequently; most of these events were rated as mild in severity. Finally, serum calcium concentrations declined significantly from baseline to 1 month in all zoledronic acid groups subjects (mean reduction of 0.08 mmol/L; p<0.05). No significant changes in serum calcium concentrations were noted in the placebo groups at 3 months or thereafter.
In 2015, Greenspan and others reported the results of a double-blind, placebo-controlled RCT involving 181 frail women over the age of 65 years old with a history of vertebral or hip fracture or a measured bone BMD below the treatment cutoff for osteoporosis. Subjects were randomly assigned in a 1:1 fashion to undergo a single IV infusion with either 5 mg of zoledronic acid or placebo. Subjects were evaluated at 12 and 24 months. The primary outcome was percent change in BMD of the hip and spine at 12 months. Secondary outcomes included adverse events and bone turnover markers. In the intent-to-treat analysis, 89 subjects were in the experimental group and 92 were included in the control group. However, in the experimental group, 75 (84.3%) subjects completed DEXA scans at 12 months and 60 (67.4%) at 24 months. In the control group, these numbers were 83 (90.2%) and 72 (78.3%), respectively. The authors reported that mean total hip BMD increased significantly more in the experimental group vs. controls at both 12 and 24 months (2.8% vs. -0.5%, and 2.6% vs. -1.5%, respectively; p<0.001 for both). Similar findings were reported for mean spine BMD (3.0% vs. 1.1% at 12 months, 4.5% vs. 0.7% at 24 months, respectively; p<0.001 for both). Bone resorption, as measured by C-telopeptide cross-links type 1 collagen, decreased in the experimental group at both 12 and 24 months (p=0.01) whereas it was increased in the control group at both time points (p<0.05). A total adverse event rate of 97% was reported, with a serious adverse event rate of 64%. No between group differences were reported, including the number of deaths, fractures, or cardiac events (p=0.68 for total adverse events and p=0.29 for serious adverse events, respectively).
The package insert for Reclast describes the results of two unpublished identical, 6 month, randomized, double-blind trials addressing the treatment of Paget's disease of the bone. These studies involved 347 subjects with serum alkaline phosphatase (SAP) levels at least twice the age-specific upper limit who were randomized to a single 5 mg IV infusion of zoledronic acid (n=176) or daily oral risedronate 30 mg for 2 months (n=171). Therapeutic response was defined as either normalization of SAP or a reduction of at least 75% from baseline in total SAP excess at the end of 6 months. The zoledronic acid subjects achieved therapeutic response at a 96% rate, vs. 74% of risedronate subjects. Most zoledronic acid subjects achieved therapeutic response within 63 days of initiation of treatment. Additionally, 89% of the zoledronic acid group achieved normalization of SAP levels by 6 months vs. 58% of subjects receiving risedronate (p<0.0001). No differences were reported with regard to demographics or disease severity in the zoledronic acid group. In subjects who previously received oral bisphosphonate therapy, the therapeutic response rates were 96% in the zoledronic acid group and 55% in the risedronate group. The response rates in subjects who did not receive previous treatment were 98% and 86% for zoledronic acid and risedronate, respectively.
Prevention of skeletal-related events in men with prostate cancer
In 2004, Saad and others published the results of a placebo-controlled randomized clinical trial involving 122 subjects with hormone-refractory metastatic prostate cancer. At 24 months follow-up, fewer subjects in the zoledronic acid group had at least one SRE vs. the placebo group (38% vs. 49%, p=0.028) and the annual incidence of SREs was 0.77 for the zoledronic acid group versus 1.47 for the placebo group (p=0.005). The median time to the first SRE was significantly longer in the zoledronic acid group vs. the placebo group (488 days vs. 321 days, p=0.009). Finally, compared with placebo, treatment with zoledronic acid reduced the ongoing risk of SREs by 36% (RR=0.64, p=0.002). The authors concluded that treatment with zoledronic acid resulted in significantly lower incidence of SREs when compared to placebo, regardless of whether subjects had a previous SRE.
The same group reported the results of a randomized, placebo-controlled, phase III trial in 422 men with hormone-refractory prostate cancer and bone metastases (Saad, 2005). This study enrolled 422 subjects who were randomized to receive zoledronic acid or placebo. Subjects received zoledronic acid or placebo for a 15 month core phase, with the option to continue therapy for 9 more months in the extension phase of the study. Among all subjects, zoledronic acid significantly reduced the incidence of a second on-study SRE (p=0.017) and significantly delayed the median time to second SRE compared with placebo at 15 months (p=0.006). Among 144 subjects with a history of SREs before study entry (34%), zoledronic acid significantly reduced the skeletal morbidity rate by 65% (p=0.036) and reduced the overall risk of developing an SRE by 40% (p=0.028) compared with placebo at 24 months.
In an additional report of retrospective exploratory analyses to determine whether long-term treatment with zoledronic acid provides continuing efficacy, Saad (2007) looked at the data collected from 132 subjects involved in an extension phase of the study. For these subjects, it was reported that zoledronic acid significantly delayed the onset of first SRE (p=0.009) and decreased the risk of developing an SRE by 53% compared with placebo (p=0.022). The authors concluded that their analysis confirmed their previously reported results that suggest long-term treatment with zoledronic acid provides continuing clinical benefit in subjects with advanced prostate cancer, even after the occurrence of SREs.
Prevention or treatment of osteoporosis during androgen deprivation therapy
Smith and other (2003) conducted a randomized, double-blind, placebo-controlled, multicenter trial in 106 men with non-metastatic prostate cancer (stage M0). Subjects were randomized to receive 1 year of treatment with either zoledronic (n=55) or placebo (n=51). The authors designed the study to include the analysis of primary efficacy variables in 4 subgroups; (1) subjects receiving a gonadotropin-releasing hormone (Gn-RH) agonist alone, (2) receiving a Gn-RH agonist and antiandrogen, (3) baseline BMD T-score -1 or greater, and (4) baseline BMD T-score -2 or lower. Completion of the trial was reported for 47 subjects in the zoledronic acid group and 43 in the placebo group. At 1 year, LS-BMD in the zoledronic group was increased vs. a decrease of BMD in the placebo group (mean percent change 7.8%, p<0.001). The authors noted that antiandrogen had no impact on zoledronic acid efficacy. Lumbar spine BMD in the zoledronic group increased 5.6% from baseline (p<0.001) vs. a decrease of 2.2% from baseline in the placebo group (p=0.0012). Significant increases in BMD in the zoledronic acid group were reported in the femoral neck, trochanter, and total hip with corresponding decreases seen in the placebo group (p<0.001 for all comparisons). Grade 3 or 4 toxicities were reported in both groups; 24% in the zoledronic group and 39% in the placebo group. The most common toxicities reported in the zoledronic and placebo groups, respectively, were hot flushes (58% vs 51%), fatigue (38% vs 35%), arthralgias (22% vs 14%), constipation (16% in each group), and urinary frequency (15% vs 22%).
A randomized, placebo-controlled, double-blind clinical trial comparing zoledronic acid with placebo in subjects with bone metastases associated with hormone-refractory prostate cancer was published by Saad and others (2002). Subjects were randomized to receive either zoledronic acid 4 mg (n=214) or 8 mg (subsequently reduced to 4 mg due to renal function deterioration, 8/4 group) (n=221), or placebo (n=208) every 3 weeks for 15 months. There were significantly fewer SREs in the 4 mg zoledronic acid group vs. the placebo group (33% and 44% respectively, p=0.021). The proportion of subjects receiving 8/4 mg zoledronic acid who experienced a SRE was 38% (p=0.222). The median time to the first SRE was reported as being 321 days in the placebo group vs. 363 days the group receiving 8/4 mg zoledronic acid (p=0.491). In 4 mg zoledronic acid median SRE was not reached during the study period due to low numbers of subjects experiencing SREs (p=0.011). Urinary markers of bone resorption were significantly decreased in subjects receiving either dose of zoledronic acid (p=0.001). In addition, pain and analgesic scores increased more in subjects receiving placebo compared with subjects receiving zoledronic acid.
Wirth and colleagues (2015) reported the results of an RCT of zoledronic in the prevention of bone metastases in patients with high-risk non-metastatic prostate cancer. A total of 1433 subjects were randomized to receive standardized localized prostate cancer therapy alone or standard therapy plus 4 mg of zoledronic acid IV every 3 months for ≤ 4 years. Of that population, 1393 subjects were used for intention-to-treat (ITT) efficacy analyses, with 1040 patients having available bone imaging studies. Bone imaging detected new bone metastases in 88 of 515 subjects (17.1%) in the zoledronic group and 89 of 525 subjects (17.0%) in the control group (p=0.95). In the ITT population (n=1393), the Kaplan-Meier estimated proportion of bone metastases after a median follow-up of 4.8 years was 14.7% in the zoledronic acid group versus 13.2% in the control group (p=0.65). The authors concluded that zoledronic acid was demonstrated to be ineffective for the prevention of bone metastases in high-risk individuals with localized prostate cancer.
In 2016, three studies were published addressing the efficacy of zoledronic acid in subjects with prostate cancer. The first, by Vale et al. was a meta-analyses of aggregate data from large RCTs combining docetaxel or bisphosphonates with standard of care in hormone-sensitive prostate cancer. They identified seven eligible trials involving bisphosphonates for men with M1 disease. The survival results from three of these trials (n=2740) demonstrated that addition of bisphosphonates improved survival (p=0.025). However, they found no evidence of a benefit from the addition of zoledronic acid (p=0.323). Of 17 trials of bisphosphonates for men with M0 disease, survival results from four trials (n=4079) demonstrated no evidence of benefit from the addition of zoledronic acid (p=0.782). They concluded that no evidence exists to suggest that zoledronic acid improves survival in men with M1 or M0 disease. James and others (2016b) reported the results of the STAMPEDE trial, involving 2962 subjects with high-risk, locally advanced, metastatic or recurrent prostate cancer who were starting first-line long-term hormone therapy. Subjects were stratified and randomized in a 2:1:1:1 fashion to: (1) standard of care only (SOC-only; control), (2) standard of care plus zoledronic acid (SOC + ZA), (3) standard of care plus docetaxel (SOC + Doc), or (4) standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Median follow-up was 43 months. The authors reported that the median overall survival was 71 months for SOC-only group, not reached for the SOC + ZA group (HR=0.94, p=0.450), 81 months for the SOC + Doc group (HR=0.78, p=0•006), and 76 months for SOC + ZA + Doc (HR=0.82, p=0.022). Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc. They concluded that zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. James (2016a) also reported the results of the TRAPEZE trial, which evaluated the clinical effectiveness and palliative benefits of combining docetaxel, zoledronic acid, and Sr89 on subjects with bony metastatic CRPC. Overall, 349 of 757 subjects (46%) completed docetaxel treatment. The clinical progression-free survival did not reach statistical significance for either Sr89 or zoledronic acid. However, zoledronic acid did have a significant effect on skeletal-related event-free interval (HR=0.78, p=0.01). Additionally, no impact on overall survival are noted for zoledronic acid (HR=0.99, p=0.91). They concluded that zoledronic acid did not improve clinical progression free survival or overall survival, but it did significantly improve median skeletal-related event-free interval and reduced total skeletal-related event-free by around one-third, suggesting a role as post-chemotherapy maintenance therapy.
Nationally recognized recommendations
The use of zoledronic acid has become widely accepted as a standard therapy for the prevention and treatment of conditions related to bone loss. Such use is recommended by both the National Comprehensive Cancer Network (NCCN, 2014) and the American Society of Clinical Oncology (ASCO) for cancer-related conditions (Angel, 2013; Kyle, 2007; Van Poznak, 2011). The American Association of Clinical Endocrinologists (Watts, 2010), the American College Physicians (ACP; Quaseem, 2008), and the American College of Obstetricians and Gynecologists (ACOG, 2012) all recommend the use of zoledronic acid for the treatment of osteoporosis.
Warnings and Adverse Events
The FDA-approved prescribing information provides the following warnings and adverse event information for
The FDA-approved prescribing information provides the following warnings and adverse event information for
Antineoplastic therapy: Any medical therapy intended to prevent, inhibit, or halt the development or growth of tumors.
Aromatase inhibitor: A class of drugs used in the treatment of breast cancer and ovarian cancer in postmenopausal women.
Glucocorticoid: A class of adrenal steroid hormones that bind to the glucocorticoid receptor, which are present in almost every human cell and which are essential for the utilization of carbohydrate, fat and protein by the body and for normal response to stress. Glucocorticoid drugs are widely used for the suppression of inflammation in chronic inflammatory diseases such as asthma, rheumatoid arthritis, and inflammatory bowel disease.
Hypercalcemia: A condition characterized by abnormally high blood levels of calcium. It is defined as an albumin-corrected calcium (cCa) of greater than or equal to 12 mg/dL [3.0 mmol/L] using the formula: cCa in mg/dL=Ca in mg/dL + 0.8 (4.0 g/dL - patient albumin [g/dL]).
Osteoporosis: A disease condition characterized by clinically significant loss of bone mass and/or bone density.
Peer Reviewed Publications:
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The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.
|Reviewed||05/04/2017||Medical Policy & Technology Assessment Committee (MPTAC) review.|
|Reviewed||05/03/2017||Hematology/Oncology Subcommittee review. Updated Discussion and References sections.|
|Reviewed||05/04/2016||Hematology/Oncology Subcommittee review. Defined abbreviation in clinical indications section. Updated Discussion and References sections. Removed ICD-9 codes from Coding section.|
|Reviewed||05/06/2015||Hematology/Oncology Subcommittee review. Updated Discussion and References sections.|
|New||11/13/2014||MPTAC review. Initial document development.|