Unbroken. Does Romosozumab Build Better Bone than Alendronate for the Fracture-Prone?

It’s been 20 years since alendronate was approved to treat osteoporosis.  Although effective, bisphosphonates aren’t ideal — they have been associated with osteonecrosis of the jaw and atypical femoral fracture.^1,2  Rare events, to be sure, but troubling serious adverse events that weigh on the minds of many patients and clinicians. The 2016 AACE/ACE clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis recommend the use of bisphosphonates (both oral and IV) for the initial treatment of most patients at high risk of fractures.³

Romosozumab is an investigational monoclonal antibody that increases bone formation and decreases bone resorption by binding and inhibiting sclerostin. Romosozumab, given subcutaneously once a month at 210 mg, reduces bone resorption in postmenopausal women with low bone mass.⁴  See Table 1.  In the Fracture Study in Postmenopausal Women (FRAME) published in September 2016, romosozumab lowered the risk of new vertebral fractures by 73% and the risk of clinical fractures (nonvertebral and symptomatic vertebral fracture) by 36%. The incidences of osteonecrosis and atypical fractures were negligible.⁵ Is romosozumab a potentially better alternative to bisphosphonate therapy?  That’s what the ARCH study attempted to answer.

Table 1: Placebo-Controlled Romosozumab Studies

^{*Unless otherwise stated, the adverse events were reported to be similar between both intervention and control groups in the above three studies}

^{Abbreviations: BMD: bone mineral density, DXA: dual x-ray absorptiometry, CVS: cardiovascular}

The Active-Controlled Fracture Study in Postmenopausal Women with Osteoporosis at High Risk (ARCH) was a phase 3, multicenter, international, randomized, double-blind superiority trial.⁶   It enrolled 4,093 postmenopausal women with osteoporosis at high risk for fracture based on previous fracture history.  This was a comparative effectiveness study randomizing the study subjects to in a 1:1 ratio to either romosozumab or alendronate.  In the control group, patients took alendronate 70 mg orally every week for 24 months.  The intervention group was initially treated with romosozumab 210 mg administered subcutaneously once a month for 12 months followed by alendronate 70 mg taken orally every week for another 12 months.  Both groups received calcium and vitamin D throughout the study.

The primary endpoints of the ARCH study were the cumulative incidence of new vertebral fracture and clinical fracture at 24 months. The secondary endpoints included changes in bone mineral densities (BMD) at the lumbar spine, total hip and femoral neck at 12 and 24 months as well as the incidence of nonvertebral and hip fractures at 24 months.

The ARCH study was powered to show superiority, with 94% power to detect a 30% lower risk of clinical fracture in the intervention group when compared to the control, and 95% power to detect a 50% lower risk of new vertebral fracture over a period of 24 months. All analysis of treatment effect used an intention-to-treat approach. A safety analysis examining the risk of osteonecrosis and atypical fractures as well as cardiovascular adverse events was also performed in all randomly assigned patients who received at least one dose of study medication.

Over the 24-month treatment period, the intervention group had a 48% lower risk of new vertebral fractures and 27% lower risk of clinical fracture when compared to the control.  Gains in BMD at all measured sites and time points from baseline were superior in the intervention group. The intervention group also had a 19% lower rate of non-vertebral fractures and 38% lower rate of hip fractures.

The incidences of adverse events such as back pain (intervention=393, control=329), nasopharyngitis (intervention=373, control=363), osteonecrosis (intervention=1, control=1), and atypical femoral (intervention=4, control=2) fracture were similar in the two treatment groups.  However, there was a greater risk of adjudicated serious cardiovascular events in the romosozumab group (odds ratio, 2.65; 95% CI, 1.03 to 6.77). 

The strengths of the ARCH study was the inclusion of an active comparator, alendronate, which is considered a first-line treatment for osteoporosis. This study also focused on high-risk patients with prior fractures. However, this study was not designed to evaluate cardiovascular outcomes as one of its main objectives and did not include a placebo group. Baseline demographics regarding cardiovascular risk factors in the two treatment groups were not reported.

In 2017, the United States FDA rejected the application for approval of romosozumab for the treatment for postmenopausal women with osteoporosis.⁷ The FDA has asked Amgen and UCB Pharma to submit more information on cardiovascular safety outcomes.  The original license application only included the findings from the FRAME study⁵, which did not address the cardiac adverse effects associated with romosozumab.  The mechanism by which romosozumab may negatively impact the cardiovascular system is not yet understood.  More research is needed to determine if the cardiovascular safety signals are real and what patient populations should avoid its use.  Thus, the approval of romosozumab as a treatment option for postmenopausal women with osteoporosis has been put on hold until more safety data is made available.  Stay tuned!