In Switzerland, every second woman aged 50 and over suffers an osteoporosis-related fracture during her lifetime [1]. In this context, the risk of a subsequent fracture immediately after the first fracture is particularly high [2,3]. Rapid and effective therapeutic intervention can reduce the risk of subsequent fractures and minimize the associated negative consequences for those affected [2].
Osteoporosis often brings serious consequences for those affected – about 400,000 in Switzerland alone – ranging from chronic pain and physical disability to depression and increased mortality [1, 4]. After a first osteoporosis-related fracture, the risk of suffering a subsequent fracture doubles. Almost a quarter of such subsequent fractures occur within one year and about half within five years after the first fracture [3]. The window of opportunity for effective therapeutic intervention is thus short.
Proven clinical efficacy of romosozumab
Romosozumab (Evenity®) can significantly reduce the risk of subsequent osteoporotic fracture and was approved in Switzerland for the treatment of severe osteoporosis in postmenopausal women at high risk of fracture as of July 1, 2020, based on the results of the randomized phase III ARCH study [5-7]. Other pivotal phase III trials include FRAME and STRUCTURE [8, 9]. Cash approval is currently being negotiated and is expected in 2021.
Dual mechanism of action: Romosozumab promotes bone formation and inhibits bone resorptionThe humanized monoclonal sclerostin antibody Romosozumab is the first representative of its drug class and is characterized by a unique dual mechanism of action: By inhibiting sclerostin, which is produced by osteocytes and inhibits the differentiation and activity of osteoblasts, it promotes bone formation on the one hand and counteracts bone resorption on the other. Romosozumab thus has a primary anabolic effect and also an antiresorptive effect. Romosozumab treatment can increase trabecular and cortical bone mass as well as improve bone structure and strength. Thus, it counteracts the degradation of bone substance and the deterioration of bone quality that underlie osteoporosis-related fractures [4, 5, 10, 11]. |
ARCH Study – Romosozumab vs. alendronate
The ARCH study included 4,093 postmenopausal women with osteoporosis and fragility fractures. Study participants were randomized to double-blind, 12-month treatment with monthly subcutaneous romosozumab injection (210 mg) or weekly oral alendronate (70 mg), followed by an open-label alendronate phase in both groups. Alendronate is an antiresorptive drug commonly used for first-line therapy in osteoporosis. At 24 months, vertebral fractures occurred significantly less frequently in the romosozumab arm than in the alendronate arm, which was also the case with respect to clinical fractures at the time of the primary analysis (Table 1). The incidence of hip fractures was also significantly reduced with romosozumab compared with alendronate (Table 1) [7]. The lower incidence of recurrent vertebral and nonvertebral fractures correlated with greater mean improvement in total hip T score after one year of treatment with romosozumab [12]. As with placebo, patients on romosozumab showed greater increases in BMD at the hip and lumbar spine compared with alendronate, and the difference between the two treatment groups also persisted throughout the study period (Table 1). During the first 12 months, the tolerability of romosozumab and alendronate was comparable, and neither osteonecrosis of the jaw nor atypical femoral fractures were observed. However, a dysbalance of major cardiovascular events occurred between the romosozumab and alendronate groups (2.5% vs. 1.9%, OR 1.31). This was not the case in the FRAME trial compared with placebo [7].
FRAME Study – Romosozumab vs. Placebo
In the double-blind FRAME study, 7,180 postmenopausal women with a T-score of -2.5 to -3.5 in total hip or femoral neck received either a subcutaneous injection of romosozumab (210 mg) or placebo for 12 months, followed by treatment with the antiresorptive drug denosumab for one year. At 12 and 24 months, the risk of new vertebral fractures was reduced by 73% and 75%, respectively, in the romosozumab group compared with placebo, and clinical fractures also occurred significantly less frequently at 12 months with romosozumab than with placebo (Table 2). In addition, a greater increase in bone mineral density (BMD) at the hip, femoral neck, and lumbar spine was observed in patients receiving romosozumab (Table 2). The beneficial effects of romosozumab persisted during the subsequent denosumab phase (Table 2). Tolerability was comparable for romosozumab and placebo [8].
STRUCTURE Study – Romosozumab vs. Teriparatide
The STRUCTURE open-label study evaluated the effects of romosozumab and teriparatide on BMD in postmenopausal women with osteoporosis who had previously taken an oral bisphosphonate for at least three years prior to screening and alendronate in the year immediately preceding screening. For this purpose, 436 study participants with BMD T-score ≤ -2.5 at the total hip, lumbar spine, or femoral neck and a history of fractures were injected subcutaneously with romosozumab (210 mg monthly) or teriparatide (20 µg daily) for 12 months, in addition to a baseline therapy with calcium and vitamin D. The romosozumab group, in contrast to the teriparatide group, showed a significant improvement in BMD at the total hip after 12 months (Table 3). Treatment tolerability was comparable in both groups [9].
Which patients benefit from treatment with romosozumab?
Which therapy is suitable for a patient depends primarily on her fracture risk [2]. According to current recommendations of the Swiss Association against Osteoporosis (SVGO), all patients with a very high or imminent risk of fracture, which is given by the previous occurrence of a fracture or a strongly reduced bone density, among other factors, can receive one year of therapy with romosozumab [13]. This may additionally promote bone formation as also shown by the clinical studies [5, 7-9]. Subsequently, antiresorptive therapy with bisphosphonates or denosumab should help to inhibit bone resorption and thus reduce the risk of fracture in the long term [2, 13]. In this regard, the beneficial effects achieved by one year of romosozumab treatment can be maintained during follow-up treatment with antiresorptive therapies [7, 8].
Conclusion
The sclerostin inhibitor romosozumab has been available since July 1, 2020, for the treatment of postmenopausal women with severe osteoporosis and high risk of fracture [5, 6]. The dual mechanism of action of the monoclonal antibody makes it possible to simultaneously support bone formation and inhibit bone resorption [5, 10, 11]. In direct comparison with the established antiresorptive drug alendronate or with placebo, romosozumab can thus significantly reduce the recurrence of vertebral fractures within one year with comparable tolerability and, compared with alendronate, also significantly reduce the risk of clinical fractures [7, 8]. In addition, romosozumab is shown to be advantageous over both alendronate and teriparatide in terms of BMD improvement [7, 9]. Overall, romosozumab in sequential combination with an antiresporptive agent offers a promising therapeutic approach for postmenopausal women who have already suffered an osteoporotic fracture and are thus at very high risk of fracture [5].
Table 1: Results of the ARCH study, adapted from [7]. BMD: bone mineral density; ∆: mean difference from baseline; primary endpoints shaded gray; *after clinical fractures were confirmed in ≥330 patients.
Table 2: Results of the FRAME study, adapted from [8]. BMD: bone mineral density; ∆: mean difference from baseline; primary endpoints grayed out.
Table 3: Results of the STRUCTURE study, adapted from [9]. BMD: bone mineral density; ∆: mean difference from baseline; primary endpoint shaded gray; * average month 6 and month 12.
CH-N-RM-OP-2000071
Brief technical information Evenity®
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