Reviewed by Dr. Allexa Hammond
Saag KG, et al. N Engl J Med. 2017 Oct 12; 377(15):1417-1427
The ARCH (Active-Controlled Fracture Study in Postmenopausal Women with Osteoporosis at High Risk) trial was a phase 3, double-blinded, randomized trial powered to evaluate the superiority of romosozumab versus alendronate for fracture prevention in postmenopausal women with osteoporosis. 4,093 patients were randomized to receive either a monthly injection of romosozumab or weekly oral alendronate for 12 months. All patients then received another 12 months of weekly alendronate. All patients underwent baseline DEXA studies, which were repeated every 12 months. Measures of bone-turnover (such as ß-CTX, a bone-resorption marker, and P1NP, a bone formation marker) were also obtained from a subgroup of patients at baseline and at the conclusion of the study. The primary endpoints of the study included the cumulative incidence of new vertebral fracture at 24 months and the cumulative incidence of non-vertebral and symptomatic vertebral fractures. Secondary endpoints included bone mineral density at the lumbar spine, hip and femoral neck at 12 and 24 months.
Results were analyzed using an intention-to-treat approach. Patients in the romosozumab group suffered fewer fractures than the alendronate only group, with a 48% lower relative risk of new vertebral fractures (6.2% versus 11.9%, RR= 0.52, 95% CI= 0.40-0.66, P<0.001). There were also fewer new non-vertebral and hip fractures in the romosozumab group. Increased efficacy of romosozumab compared to alendronate alone was also inferred based on greater improvement in DEXA scores, increased levels of P1NP and decreased levels of ß-CTX. However, there were also a greater number of adjudicated cardiovascular adverse events observed in the first 12 months in the romosozumab group than in the alendronate group (2.5% versus 1.9%, OR=1.31, 95% CI= 0.85-2.00). In particular, there were more cardiac ischemic events in the romosozumab group (0.8% versus 0.3%, OR=2.65, 95% CI= 1.03-6.77). Ultimately, the authors conclude that romosozumab followed by alendronate is more efficacious than alendronate alone in reducing fracture risk in post-menopausal women affected by osteoporosis. The greater number of serious cardiovascular adverse events identified in the romosozumab group was unable to be explored further given the study design and small total number of events.
Osteoporosis is common in post-menopausal women, and if left untreated, can result in devastating consequences which increase morbidity, such as fractures. Although bisphosphonates are considered the first line treatment, concerns regarding compliance and fear of side effects, such as osteonecrosis of the jaw and atypical
fractures, are often reasons why both patients and providers may hesitate when discussing treatment options.1 Romosozumab, a monoclonal antibody against sclerostin, has been shown to reduce the risk of osteoporotic fractures by increasing bone formation and decreasing bone resorption. Even more striking, the ARCH trial provides evidence that romosozumab is more efficacious than bisphosphonates, which are currently considered the gold standard for the treatment of osteoporosis.
Although these findings have the potential to change the clinical approach to osteoporosis, one should also take notice of the potential downfalls associated with this novel agent. The increased number of adverse cardiovascular events associated with romosozumab compared to alendronate in the ARCH trial is concerning and warrants further investigation. Multiple hypotheses have been offered as possible explanations. For example, alendronate has been shown to have a cardio-protective benefit with long-term use, which may have contributed to the decreased incidence of adverse cardiovascular events reported in this group.2 In addition, sclerostin, through unclear mechanisms, has been speculated to play a role as a negative regulator of vascular calcification, particularly in the aorta where this molecule is widely expressed. By inhibiting sclerostin, one may expect to observe a greater incidence of cardiac ischemic events as witnessed in the romosozumab group.2 Further still, questions as to the study population itself have arisen, as ARCH’s sister trial, the FRAME study, yielded no significant differences in adverse cardiovascular events between those taking romosozumab versus placebo.2,3 Regardless of the cause, this observation has ultimately swayed the Food and Drug Administration to delay approval of the medication until further data is available to ensure its safety.4 Thus, although there is true promise in regards to the efficacy of romosozumab, it remains to be determined at what cost. More research is needed to investigate the potential adverse outcomes associated with its use and which populations may have the most benefit (and likewise, the least benefit) from use of this otherwise highly promising therapy.
1. Kolata, G. Fearing Drugs’ Rare Side Effects, Millions Take Their Chances with Osteoporosis. The New York Times. https://www.nytimes.com/2016/06/02/health/osteoporosis-drugs-bones.html. Published June 1, 2016. Accessed January 13, 2018.
2. Rosen, CJ. Romosozumab- Promising or Practice Changing? New England Journal of Medicine. 2017;377(15):1479-1480.
3. Khosla, S. Bone diseases: Romosozumab- On Track or Derailed? Nature Reviews Endocrinology. 2017;13(12):697-698.
4. Amgen and UCB Provide Update on Regulatory Status of EVENITYTM (romosozumab) In The US. http://wwwext.amgen.com/media/news-releases/2017/07/amgen-and-ucb-provide-update-on-regulatory-status-of-evenity-romosozumab-in-the-us/. Published July 16, 2017. Accessed January 13, 2018.