In May 2021, the Health Sciences Authority (HSA) approved the use of Romosozumab (Evenity), a novel biologic, for the treatment osteoporosis in postmenopausal women at high risk of fractures. Fragility fractures are common amongst postmenopausal women with osteoporosis, and often result in limitation of ambulation, physical deformity, chronic pain, disability, loss of independence and decreased quality of life. Osteoporotic hip fractures are especially devastating, contributing to 5% of all-cause mortality globally. In Singapore, absolute fracture numbers in women increase by 3.3% annually, leading to an average increase of 46.3 fractures per year. The registry approval of Evenity augments the clinician’s armamentarium of strategies for arresting alarming trends associated with the burden of osteoporosis, and its related complications.
Drug Profile
Evenity is a human monoclonal antibody that blocks the effects of sclerostin, a protein that inhibits osteoblast differentiation and function. Its unique mechanism of action supports bone formation and restores skeletal architecture in patients with osteoporosis. A single 210mg dose of Evenity consists of two consecutive subcutaneous injections, administered once a month. The bone forming effect of Evenity wanes after 12 doses and patients should switch to an alternative treatment thereafter.
Place in Therapy
Efficacy
The safety and efficacy of Evenity were demonstrated in two clinical trials involving over 11,000 women with postmenopausal osteoporosis.
- The Fracture Study in Postmenopausal Women with Osteoporosis (FRAME) was an international, randomized, double-blind study of 7,180 women with an average age of 71 years. FRAME demonstrated that one year of treatment with Evenity reduced the overall clinical fracture risk by 36% at 12 months and non-vertebral fracture risk by 25% compared to placebo. Notably, the reduction in non-vertebral fractures was not statistically significant (adjusted p=0.10). The risk benefit with vertebral fractures was maintained over the second year of the trial when the Evenity and placebo arms were switched to Denosumab. During the year of open label Denosumab therapy, 80% (5 vs 25) fewer women who received Evenity had vertebral fractures compared to the placebo group.
- The Active-Controlled Fracture Study in Postmenopausal Women with Osteoporosis at High Risk (ARCH) trial compared the effects of Evenity with oral Alendronate for 12 months, followed by open label Alendronate therapy in both treatment groups for up to an additional 2 years. A total of 4,093 women were enrolled in the study. Notably, ARCH selected women at a much higher fracture risk than the placebo-controlled FRAME study. In the primary analysis, vertebral fracture risk was reduced by 19% with Evenity followed by Alendronate, compared to Alendronate alone. Similarly, non-vertebral fracture risk was 26% lower with Evenity at 12 months, but this did not achieve statistical significance (p=0.06).
Safety
Evenity was generally well tolerated in the clinical trials. Common side effects included joint pain and headache. Mild injection site reactions were also reported. Of note, although no important vascular safety signals with Evenity were noted in FRAME, the ARCH study found a higher rate of major adverse cardiovascular events (MACE) in patients treated with Evenity compared to those treated with Alendronate (0.8% vs 0.3%). Evenity use in patients with previous myocardial infarction or stroke it thus an explicit contraindication in the manufacturer’s labelling. Clinicians should also take precautions when initiating Evenity treatment in individuals with risk factors for cardiovascular disease.
Guidelines
Briefly, the 2020 American Association of Clinical Endocrinologists (AACE)/ American College of Endocrinology (ACE) Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis recommend the use of:
- Alendronate, Risedronate, Denosumab and Zoledronate as appropriate initial therapy for most osteoporotic women with a high fracture risk. These agents have proven “broad-spectrum” anti-fracture efficacy, reducing the risk of hip, non-vertebral and spine fractures.
- Denosumab, Zoledronate, Romosozumab, Teriparatide and Abaloparatide (not registered in Singapore) should be considered in patients unable to use oral therapy and as initial therapy for the same indication.
- Ibandronate or Raloxifene may be appropriate initial therapy in some cases for patients requiring drugs with spine-specific efficacy.
In Singapore, drug therapies approved by the HSA for the prevention and treatment of post-menopausal osteoporosis are outlined in the table below. Information is accurate as of September 2021.
| Drug Class | Mechanism of Action | HSA-Registered Therapeutics | Place in Therapy and Treatment Considerations |
| Bisphosphonate | Inhibits bone resorption, reducing vertebral and non-vertebral fracture risk
*Oral Ibandronate has not demonstrated effects on non-vertebral and hip fracture risks |
Oral Alendronate (Fosamax and generics)
Oral Risedronate (Actonel and generics) Intravenous Zoledronate (Aclasta and generics) * Oral Ibandronate (Bonviva) |
First-line for the prevention and treatment of post-menopausal osteoporosis;
Biological half-lives persist for years due to incorporation into bones and drug holidays are recommended |
| RANK ligand inhibitor | Inhibits osteoclast formation and increases osteoclast apoptosis, reducing vertebral and non-vertebral fracture risk | Subcutaneous Denosumab (Prolia) | Advantage in renal impairment; Skeletal effects wear off after treatment disruption and patients should be transitioned to alternative therapy |
| Parathyroid hormone analogue | Stimulates bone formation, reducing vertebral and non-vertebral fracture risk | Subcutaneous Teriparatide (Forteo) | Efficacy and safety not investigated beyond 2 years, follow with a drug intended for long-term use e.g. bisphosphonate |
| Sclerostin inhibitor | Inhibits sclerostin, increasing bone formation and decreasing bone resorption; reduces the risk of vertebral fractures | Subcutaneous Romosozumab (Evenity) | Uncertain effects on continuous bone formation on the skeletal system; Limit treatment to 1 year and follow with a drug intended for long-term use e.g. bisphosphonate or Denosumab |
| Selective oestrogen receptor modulator (SERM) | Oestrogen agonist in bone reducing bone loss; reduces the risk of vertebral fractures | Oral Raloxifene (Evista) | Acceptable in patients with low BMD in the spine but not the hip (discordance); An attractive option in patients at high risk of breast cancer |
| Oestrogen/ Hormonal therapy | Oestrogen receptors exist on osteoblasts, osteoclasts, macrophage cells and intestinal cells; reduces the risk of vertebral and hip fractures | Oral oestrogen (Premarin) | If used solely for the prevention of osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and for whom non-oestrogen medications are not considered to be appropriate |
The studies to date provide convincing evidence for Evenity’s utility in clinical practice for reducing the risk of vertebral fractures in high risk patients. Notwithstanding the absence of long-term data, its mechanistic dual effect (increasing bone formation and decreasing bone resorption) is a novel treatment strategy. Of note, Evenity has been studied in men but is not yet approved for male osteoporosis. Clinicians are encouraged to undertake a shared risk benefit assessment in consideration of the patient-specific fracture profile, costs and adverse events when evaluating the use of Evenity in the near term.
