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Romosozumab or Alendronate for Fracture
Prevention in Women with Osteoporosis
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NEJM September 18, 2017
Background
Romosozumab is a monoclonal antibody that binds to and inhibits sclerostin, increases bone formation, and decreases bone resorption.
Methods
We enrolled 4093 postmenopausal women with osteoporosis and a fragility fracture and randomly assigned them in a 1:1 ratio to receive monthly subcutaneous romosozumab (210 mg) or weekly oral alendronate (70 mg) in a blinded fashion for 12 months, followed by open-label alendronate in both groups. The primary end points were the cumulative incidence of new vertebral fracture at 24 months and the cumulative incidence of clinical fracture (nonvertebral and symptomatic vertebral fracture) at the time of the primary analysis (after clinical fractures had been confirmed in ≥330 patients). Secondary end points included the incidences of nonvertebral and hip fracture at the time of the primary analysis. Serious cardiovascular adverse events, osteonecrosis of the jaw, and atypical femoral fractures were adjudicated.
Results
Over a period of 24 months, a 48% lower risk of new vertebral fractures was observed in the romosozumab-to-alendronate group (6.2% [127 of 2046 patients]) than in the alendronate-to-alendronate group (11.9% [243 of 2047 patients]) (P<0.001). Clinical fractures occurred in 198 of 2046 patients (9.7%) in the romosozumab-to-alendronate group versus 266 of 2047 patients (13.0%) in the alendronate-to-alendronate group, representing a 27% lower risk with romosozumab (P<0.001). The risk of nonvertebral fractures was lower by 19% in the romosozumab-to-alendronate group than in the alendronate-to-alendronate group (178 of 2046 patients [8.7%] vs. 217 of 2047 patients [10.6%]; P=0.04), and the risk of hip fracture was lower by 38% (41 of 2046 patients [2.0%] vs. 66 of 2047 patients [3.2%]; P=0.02). Overall adverse events and serious adverse events were balanced between the two groups. During year 1, positively adjudicated serious cardiovascular adverse events were observed more often with romosozumab than with alendronate (50 of 2040 patients [2.5%] vs. 38 of 2014 patients [1.9%]). During the open-label alendronate period, adjudicated events of osteonecrosis of the jaw (1 event each in the romosozumab-to-alendronate and alendronate-to-alendronate groups) and atypical femoral fracture (2 events and 4 events, respectively) were observed.
Conclusions
In postmenopausal women with osteoporosis who were at high risk for fracture, romosozumab treatment for 12 months followed by alendronate resulted in a significantly lower risk of fracture than alendronate alone. (Funded by Amgen and others; ARCH ClinicalTrials.gov number, NCT01631214.)
Fragility fractures are common and increase morbidity and mortality.1,2 Romosozumab (Amgen and UCB Pharma) is a new bone-forming monoclonal antibody that binds to and inhibits sclerostin, with a dual effect of increasing bone formation and decreasing bone resorption.3,4
In a randomized, controlled trial,5 1 year of romosozumab treatment was associated with significantly lower risks of new vertebral fracture and clinical fracture (a composite of nonvertebral fracture and symptomatic vertebral fracture) than placebo among postmenopausal women with osteoporosis. That trial excluded patients with severe osteoporosis and thus enrolled a relatively low-risk population.6-10 In that context, the risk of nonvertebral fracture was not significantly lower with romosozumab than with placebo.
Alendronate is an antiresorptive agent commonly used as first-line therapy for osteoporosis. In a trial involving postmenopausal women with prevalent fractures, the risks of vertebral and clinical (in particular, hip) fractures were lower with alendronate than with placebo.10
There are few head-to-head studies of osteoporosis therapy with fracture end points, and only one trial evaluating bone-building versus antiresorptive therapy was designed with fracture as the primary end point.11 In the Active-Controlled Fracture Study in Postmenopausal Women with Osteoporosis at High Risk (ARCH), we compared the effectiveness of a treatment regimen starting with romosozumab and transitioning to alendronate with alendronate treatment alone in reducing the risk of fracture among postmenopausal women with osteoporosis and a previous fracture.
Discussion
In this phase 3 trial involving postmenopausal women with osteoporosis and a previous fracture, treatment with romosozumab for 12 months before alendronate was superior to alendronate alone with respect to the risks of a new vertebral, clinical, nonvertebral, and hip fracture. It is worth noting that romosozumab outperformed an effective drug; in large meta-analyses, alendronate has been shown to consistently reduce vertebral, nonvertebral, and hip fractures by up to 50%13,14 among patients with osteoporosis. In our trial, the effect of romosozumab on the risk of fracture was rapid: the risks of new vertebral fracture and clinical fracture were significantly lower with romosozumab than with alendronate at 12 months, findings that imply both a near-term and persistent reduction in fracture risk with the initiation of romosozumab before antiresorptive therapy in patients at high risk for fracture. Although the placebo-controlled Fracture Study in Postmenopausal Women with Osteoporosis (FRAME) showed that 12 months of romosozumab had preventive effects with respect to vertebral and clinical but not nonvertebral fractures (potentially influenced by the lower baseline fracture risk),5 the present trial assessed efficacy in a higher-risk population and showed broad beneficial effects on fracture risk as compared with a commonly used active drug.
Romosozumab rapidly increased bone mineral density, a finding consistent with those of previous studies.5,15 We found significantly greater gains with romosozumab than with alendronate at the lumbar spine, total hip, and femoral neck by month 6. After the transition to alendronate, the significant difference between treatment groups was maintained. A plateau in bone mineral density was observed with ongoing alendronate therapy, a finding similar to results from other studies.10
Overall, adverse events and serious adverse events were balanced between the two groups. No cases of osteonecrosis of the jaw or atypical femoral fracture were identified during the period of romosozumab-alone treatment. Events were observed in the alendronate open-label period, with four events of atypical femoral fracture in the alendronate-to-alendronate group and two in the romosozumab-to-alendronate group. Adjudicated serious cardiovascular adverse events were more frequent in the romosozumab group than in the alendronate group during the double-blind period, with cardiac ischemic events and cerebrovascular events contributing to the imbalance.
There are theoretical considerations that sclerostin inhibition could be associated with cardiovascular risk. Sclerostin is constitutively expressed in the aorta16-18 and up-regulated in foci of vascular and valvular calcification.19-22 The function of sclerostin in the vasculature is unknown. Although sclerostin may function as a negative regulator of vascular calcification and sclerostin inhibition could promote vascular calcification, studies have shown conflicting results.22,23 In long-term toxicology studies in rats17 and monkeys,17,24 there was no histologic or radiographic evidence of the development or exacerbation of vascular mineralization. Vascular calcification, although not specifically examined, has not been reported in Sost knockout mice or patients with sclerosteosis or van Buchem’s disease.25-28
Further evaluation is needed to determine the cause of the observed imbalance in cardiovascular events. Such an imbalance was not seen in FRAME, a larger (7180 patients), placebo-controlled trial that enrolled a somewhat younger population with less advanced osteoporosis.5 Another important contrast is the comparison drug. Alendronate has been associated with a reduction in the risk of cardiovascular disease in some studies29 but not in two meta-analyses,30,31 perhaps related to differences in the patient populations studied or the dosing of alendronate.32
Strengths of this trial include an active-comparator design involving patients with osteoporosis and a high risk of fracture. Limitations include the facts that the trial was not designed as a cardiovascular-outcomes trial and that it did not include a placebo control. Investigation is ongoing, including evaluation of cardiovascular risk factors; however, the small number of events makes interpretation difficult.
In conclusion, rapid gains in bone mineral density from bone-forming therapy with romosozumab were associated with a lower risk of fracture than with alendronate within 1 year and over the course of romosozumab followed by alendronate. Hip fractures were less frequent with romosozumab followed by alendronate than with alendronate alone, suggesting an important benefit and challenging the common treatment practice of first-line use of alendronate in women who have had a previous fracture. An imbalance in serious cardiovascular adverse events in comparison with alendronate was also found, which was not observed in a previous large, placebo-controlled trial.
Results
Patients
A total of 4093 patients underwent randomization; 3654 patients (89.3%) completed 12 months of the trial (Fig. S2 in the Supplementary Appendix), and 3150 (77.0%) completed the primary analysis period. The reasons for discontinuation were similar in the two treatment groups (Fig. S2 in the Supplementary Appendix). The demographic and clinical characteristics of the patients at baseline were balanced between the two groups (Table 1). The mean age of the patients was 74.3 years, 99.0% had a previous osteoporotic fracture at 45 years of age or older, 96.1% had a prevalent vertebral fracture, and the mean bone mineral density T scores were –2.96 at the lumbar spine, –2.80 at the total hip, and –2.90 at the femoral neck.
Efficacy
Fracture
Over a period of 24 months, treatment with romosozumab followed by alendronate resulted in a 48% lower risk of new vertebral fractures than alendronate alone (6.2% [127 of 2046 patients] vs. 11.9% [243 of 2047 patients]; risk ratio, 0.52; 95% confidence interval [CI], 0.40 to 0.66; P<0.001) with the use of multiple imputation for missing fracture status (Figure 2A); similarly, a 50% lower risk with romosozumab was observed with the use of the last observation carried forward (Table S1 in the Supplementary Appendix). At the time of the primary analysis, romosozumab followed by alendronate resulted in a 27% lower risk of clinical fracture than alendronate alone (hazard ratio, 0.73; 95% CI, 0.61 to 0.88; P<0.001) (Figure 2B). The cumulative incidence of clinical fracture in the romosozumab-to-alendronate group was 9.7% (198 of 2046 patients) versus 13.0% (266 of 2047 patients) in the alendronate-to-alendronate group.
At the time of the primary analysis, romosozumab followed by alendronate also resulted in a 19% lower risk of nonvertebral fracture than alendronate alone (hazard ratio, 0.81; 95% CI, 0.66 to 0.99; P=0.04) (Figure 2C), with fractures occurring in 178 of 2046 patients (8.7%) in the romosozumab-to-alendronate group versus 217 of 2047 patients (10.6%) in the alendronate-to-alendronate group (Table S1 in the Supplementary Appendix). Hip fractures occurred in 41 of 2046 patients (2.0%) in the romosozumab-to-alendronate group as compared with 66 of 2047 patients (3.2%) in the alendronate-to-alendronate group at the time of the primary analysis, representing a 38% lower risk with romosozumab (hazard ratio, 0.62; 95% CI, 0.42 to 0.92; P=0.02).
Between-group differences in favor of romosozumab were observed by month 12, including in new vertebral fractures (risk ratio, 0.63; 95% CI, 0.47 to 0.85) and clinical fractures (hazard ratio, 0.72; 95% CI, 0.54 to 0.96). The risk of nonvertebral fracture was 26% lower with romosozumab than with alendronate, but the difference was not significant (P=0.06). Table S1 in the Supplementary Appendix shows details of these and other fracture end points.
Bone Mineral Density
Patients who received romosozumab had greater gains in bone mineral density from baseline at all measured sites and at all time points than patients who received alendronate alone. The differential greater gains achieved by month 12 with romosozumab were maintained at month 36, after the transition to alendronate (P<0.001 for all comparisons) (Figure 3A and 3B, and Fig. S3 and Table S2 in the Supplementary Appendix). In a subgroup of patients assessed every 6 months, greater gains with romosozumab were observed beginning at month 6 (P<0.001 for all comparisons) (Table S3 in the Supplementary Appendix).
Bone-Turnover Markers
Romosozumab increased levels of the bone-formation marker P1NP and decreased levels of the bone-resorption marker β-CTX within 12 months (Figure 3C and 3D). After the transition to alendronate, levels of P1NP and β-CTX decreased and remained below baseline levels at 36 months. In patients receiving alendronate alone, levels of P1NP and β-CTX decreased within 1 month and remained below baseline levels at 36 months.
Safety
The incidences of adverse events and serious adverse events were similar overall between the two treatment groups during the 12-month double-blind period, and cumulative incidences were similar between the two groups during the primary analysis period (Table 2). In the first 12 months, injection-site reactions (mostly mild in severity) were reported in more patients receiving romosozumab (90 of 2040 patients [4.4%]) than in those receiving alendronate (53 of 2014 patients [2.6%]).
An imbalance in adjudicated serious cardiovascular adverse events was observed during the double-blind period, with 50 patients (2.5%) in the romosozumab group and 38 (1.9%) in the alendronate group reporting these events (odds ratio, 1.31; 95% CI, 0.85 to 2.00). A total of 16 patients (0.8%) in the romosozumab group and 6 (0.3%) in the alendronate group reported cardiac ischemic events (odds ratio, 2.65; 95% CI, 1.03 to 6.77), and 16 patients (0.8%) in the romosozumab group and 7 (0.3%) in the alendronate group reported cerebrovascular events (odds ratio, 2.27; 95% CI, 0.93 to 5.22), whereas heart failure, noncoronary revascularization, and peripheral vascular ischemic events not requiring revascularization were numerically lower in the romosozumab group (Table 2). Cardiovascular risk factors in patients with positively adjudicated cardiovascular events are shown in Table S4 in the Supplementary Appendix.
No adjudicated events of osteonecrosis of the jaw or atypical femoral fracture were reported in the 12-month double-blind period. During the open-label period, 2 events of osteonecrosis of the jaw (1 [<0.1%] in each treatment group) and 6 events of atypical femoral fracture (2 [<0.1%] in the romosozumab-to-alendronate group and 4 [0.2%] in the alendronate-to-alendronate group) were positively adjudicated.
During the first 18 months of the trial, binding anti-romosozumab antibodies were observed in 310 of 2028 patients (15.3%) in the romosozumab group; neutralizing antibodies were observed in 12 patients (0.6%), with no detectable effect on relevant efficacy or safety (Tables S5 and S6 in the Supplementary Appendix).
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