In medicine, lessons from rare genetic disorders can sometimes be turned into treatment for a common disease. Since the discovery that patients with sclerostin deficiency have surprisingly high bone mass,[1,2,3] inhibiting sclerostin has been an appealing strategy to treat osteoporosis. Romosozumab is a humanized monoclonal antibody against sclerostin, and its approval by the US Food and Drug Administration (FDA) makes it the first in its class for the treatment of osteoporosis.
The approval of romosozumab comes as welcome news after concerns about cardiovascular adverse events derailed the initial biologics license application almost 2 years ago. Romosozumab joins the parathyroid hormone (PTH) analog teriparatide and the PTH-related peptide analog abaloparatide as FDA-approved anabolic medications for osteoporosis. Here, I will discuss how romosozumab fits into the treatment options for osteoporosis.
Rapid Reduction of Fracture Risk
Romosozumab has rapid and substantial effects on bone density and fracture risk. In the phase 3 FRAME study, romosozumab reduced new vertebral fractures by 73% at 12 months. This is a greater reduction in only 12 months than has been reported for any other medication, although the FDA does not mandate reporting of 12-month fracture data.
A second phase 3 study, ARCH, confirmed the clinical efficacy of romosozumab in women with postmenopausal osteoporosis and a fragility fracture, demonstrating that romosozumab for 12 months followed by alendronate for another 12 months decreased new vertebral and nonvertebral (including hip) fractures compared with alendronate alone.
Compared with the other anabolic osteoporosis medications, teriparatide and abaloparatide, romosozumab offers several potential advantages:
- No concern for increased risk for osteosarcoma. Both teriparatide and abaloparatide were associated with an increased incidence of osteosarcoma in rodent toxicology studies. As a result, these medications carry a boxed warning that lifetime cumulative use is not recommended to exceed 2 years. In contrast, romosozumab did not increase osteosarcoma incidence in toxicology studies.
- Different dosing schedule. Teriparatide and abaloparatide are administered as daily subcutaneous injections over 18-24 months, and many patients are deterred by the need for self-injection. In contrast, romosozumab is administered as a monthly subcutaneous injection (by a medical provider) over 12 months. For patients who are unable or unwilling to perform self-injections, romosozumab may be a more appealing alternative.
- No lifetime limit. Osteoporosis is a chronic disease that may require treatment over decades, but the lifetime combined use of teriparatide and abaloparatide is limited to 2 years. Romosozumab now provides another option for those who have exhausted their exposure to teriparatide or abaloparatide. The treatment duration for romosozumab is limited to 12 months, after which the effect on bone mineral density (BMD) wanes. However, if future studies demonstrate that romosozumab regains its effectiveness after a period of time, repeated courses of treatment could be a valuable option in the long-term management of osteoporosis.
Warning: Cardiovascular Risk
Although the clinical effectiveness of romosozumab was clearly established, concern arose over a potential cardiovascular safety signal in ARCH. During the first year, a higher incidence of positively adjudicated serious cardiovascular events were observed with romosozumab (2.5%) than with alendronate (1.9%). On the basis of this finding, the FDA rejected the initial biologics license application for romosozumab in July 2017.
The FDA conducted a meta-analysis of major adverse cardiovascular events (MACE)—a composite endpoint of cardiovascular death, nonfatal myocardial infarction (MI), and nonfatal stroke—of the 12-month data from FRAME and ARCH. There were 51 (0.9%) persons with MACE in the control group and 71 (1.3%) in the romosozumab group, with a hazard ratio (95% confidence interval) of 1.38 (0.96–1.99). However, there were too few events overall to distinguish whether this imbalance was attributable to drug effect, chance, or perhaps even a cardioprotective effect of alendronate (the control group treatment in ARCH).
Because these were not cardiovascular outcomes trials, additional risk factors such as lipid levels were not available to estimate cardiovascular risk.
Questions remain regarding whether these cardiovascular safety outcomes are generalizable to the United States, given that US patients accounted for only 1.8% of participants in FRAME and 1.4% in ARCH. Therefore, the risk for cardiovascular adverse events as well as the potential underlying mechanisms associated with romosozumab treatment remain unclear.
The possibility of cardiovascular adverse events is concerning because cardiovascular disease is the leading cause of death in women, and this risk increases after menopause. Therefore, those who are at greatest risk for fracture may also be at increased risk for cardiovascular disease.
The participants in ARCH were older and had a significantly higher risk for fracture than those in FRAME, and epidemiologic studies have shown that low BMD and a history of fragility fracture are associated with higher risks for major cardiovascular events. The indication for romosozumab was narrowed to osteoporosis in postmenopausal women at high risk for fracture, and a boxed warning for the potential risk for MI, stroke, and cardiovascular death was included. Romosozumab should not be initiated in patients who have had an MI or stroke within the preceding year.
Definitive clarity on cardiovascular safety may prove elusive. Both fractures and potential cardiovascular adverse events were rare in the phase 3 trials. The FDA estimated that at month 12 in ARCH, the risk difference per 1000 patients was 18 fewer morphometric vertebral fractures, 14 fewer nonvertebral fractures, three fewer hip fractures, and nine major adverse cardiovascular events.
Other adverse events. Bisphosphonates and denosumab are rarely associated with osteonecrosis of the jaw and atypical femoral fracture, adverse events that are attributed to their antiresorptive effects. Despite the predominantly anabolic action of romosozumab, it is noteworthy that three cases each of osteonecrosis of the jaw and atypical femoral fracture were observed in the combined romosozumab groups from FRAME and ARCH. More investigation will be needed to understand the underlying etiology.
Who Can Use Romosozumab?
The FDA-approved indication for romosozumab is treatment of osteoporosis in postmenopausal women at high risk for fracture. There is no consensus definition of high fracture risk, but it would be reasonable to consider romosozumab for patients with a T score < -2.5 and a previous vertebral fracture, those with multiple fragility fractures or a hip fracture, or those with no fracture history but extremely low BMD (T < -3.5).
Among the anabolic medications, romosozumab may be preferable for those who have already received 2 years of teriparatide and/or abaloparatide; those who have a contraindication to teriparatide or abaloparatide, such as skeletal irradiation; or those who prefer the monthly dosing schedule of romosozumab.
Uncertainty remains regarding its use in men and premenopausal women with osteoporosis. Men are generally at higher risk for cardiovascular disease, warranting caution. In younger adults with severe osteoporosis, romosozumab could potentially be a useful option to dramatically increase bone mass at a time of lower cardiovascular risk while avoiding a long horizon for potential osteosarcoma risk associated with teriparatide or abaloparatide, but data are lacking.
Similarly, patients with diabetes are at increased risk for both fractures and cardiovascular disease, but the relative risks versus benefits of romosozumab in these individuals are unknown.
Romosozumab is administered as subcutaneous monthly injections of 210 mg. Extrapolating from studies suggesting that bisphosphonate treatment may blunt the subsequent effects of anabolic therapies, patients starting on romosozumab ideally should not have received bisphosphonates in the previous 12 months.
Patients should also not be transitioned directly from denosumab to romosozumab, given the potential for accelerated bone remodeling. After 12 months of romosozumab, patients should be transitioned to antiresorptive treatment.
Both denosumab (FRAME) and alendronate (ARCH) have been demonstrated to sustain the fracture risk reduction for an additional 12 months after romosozumab. The duration of subsequent antiresorptive treatment should be governed by ongoing monitoring of bone density and fracture risk.
Overall, a new class of medication for the treatment of osteoporosis is very welcome, especially one with such promising clinical effectiveness as romosozumab. For patients with extremely low BMD, previous fragility fractures, or who are otherwise at high risk for impending fracture, romosozumab offers the most rapid fracture risk reduction reported to date.
More generally, accumulating evidence suggests that anabolic followed by antiresorptive therapy can yield rapid, substantial, and sustained increases in BMD. The choice of initial anabolic treatments has now been widened, providing physicians with greater opportunity to tailor osteoporosis treatment on the basis of patients’ risks and preferences.
Patient selection will be crucial, with romosozumab ideally used in patients who are at high risk for fracture but not cardiovascular disease, although there may be significant overlap between these two populations, and patients should be carefully counseled on the risks versus benefits of romosozumab.