Updates on osteoporosis treatment: Addressing the unmet needs among high-risk postmenopausal osteoporosis patients
Until this year, parathyroid hormone and its related protein analogues were the only recommended anabolic agents for postmenopausal osteoporosis patients with multiple fractures.1 Patients who are contraindicated to the treatment or those who cannot tolerate frequent injections should be switched to antiresorptive agents. Romosozumab is a novel anabolic agent requiring fewer injections that may facilitate the acceptance of anabolicantiresorptive regimen.1-3 In a recent interview with Omnihealth Practice, Dr. Woo, Yu-Cho, Honorary Clinical Associate Professor, Department of Medicine, L i Ka Shing Faculty of Medicine, The University of Hong Kong, shared his insights on the updated management of postmenopausal osteoporosis and how the treatment update may address the unmet needs of postmenopausal osteoporosis patients.
The current landscape of postmenopausal osteoporosis management
In current clinical practice, treatment of osteoporosis is based on fracture risk assessments. Indeed, patients with fragility fracture at the hip or the vertebra, having low bone mineral density as assessed by dual-energy X-ray absorptiometry (DXA), or with fracture risk above treatment threshold as evaluated by the Fracture Risk Assessment Tool (FRAX) are considered high risk and should be treated by anti-osteoporosis agents.4
From the current clinical practice guideline for the pharmacological management of postmenopausal osteoporosis published by the Endocrine Society, the authors have recommended antiresorptive medications, such as bisphosphonates and denosumab, to treat highrisk patients (Figure 1).5 For very high-risk patients who have multiple fractures and low bone mineral density, the authors recommended anabolic treatment followed by antiresorptive regimen (anabolicantiresorptive sequential therapy).5 Regardless of patients’ risk level, the immediate timing after a recent fragility fracture remains a great window of opportunity to initiate anti-osteoporosis medications for postmenopausal osteoporosis patients.
Unmet needs and challenges in postmenopausal osteoporosis management
Despite the improvement in the awareness of osteoporosis among patients and healthcare practitioners, the initiation of anti-osteoporosis agent even after hip fracture had been low in the locality.6 Where some treatments are delayed due to the long waiting time for specialist clinics, some patients are reluctant to receive treatment due to misinformation, misconception, or fear of uncommon treatment side effects.
Multi-disciplinary fracture liaison services have been shown to enhance appropriate and timely treatment of patients with fragility fractures. Such services typically involve a designated case manager who is responsible for more structured and protocol-driven services or provision from various disciplines that can drive the improvement of the likelihood of bone mineral testing and treatment initiation.7 In addition, proper patient education can also help improve the acceptance and adherence to treatment. However, even among patients who are willing to initiate anti-osteoporosis treatment, the limited number of treatment options is still a major unmet need, especially in very high-risk patients in Hong Kong.1 The inconvenience resulting from daily injection has also caused problems in terms of treatment acceptance and adherence in some patients.1 Consequently, physicians may need to go for antiresorptive agents only, despite the known fracture reduction benefits of anabolic-antiresorptive sequential therapy in very high-risk postmenopausal osteoporosis patients.2,5
Romosozumab has been introduced to the updated treatment algorithm
Romosozumab, an anti-sclerostin antibody, is a novel anabolic agent that intervenes bone metabolism and increases bone formation. On a scheduled basis, romosozumab is administered subcutaneously monthly for 12 months and is recommended to be followed by a course of antiresorptive.3,5 The monthly dosing regimen allows healthcare professionals to give the romosozumab injection during their clinic visits if patients or caregivers cannot handle injections on their own. The introduction of romosozumab to the treatment algorithm has provided an additional treatment option and the convenience in drug administration to osteoporosis patients with very high fracture risk.
The Active-Controlled Fracture Study in Postmenopausal Women with Osteoporosis at High Risk (ARCH) trial is a phase 3, multicenter, international, randomized, double-blind clinical trial. The efficacy of romosozumab followed by alendronate was compared head-to-head against alendronate-only regimen in postmenopausal women with osteoporosis and a history of fragility fracture in the ARCH study.2 Individuals assigned to the romosozumab-to-alendronate group were given subcutaneous injections of romosozumab monthly for a year before the transition to weekly oral alendronate.2 For patients in the alendronate-to-alendronate arm, weekly oral alendronate was given instead.2 The results of the global study demonstrated that compared to patients receiving alendronate only, high-risk patients receiving romosozumab-based regimen had a 48% reduction in risk of new vertebral fractures (RR=0.52; 95% CI: 0.40-0.66; p<0.001) (Figure 2A) and a 27% reduction in risk of clinical fractures (HR=0.73; 95% CI: 0.61-0.88; p<0.001) (Figure 2B).2 Patients in the romosozumabto-alendronate group also achieved 19% lower risk of nonvertebral fracture than the alendronate-to-alendronate group (HR=0.81; 95% CI: 0.66-0.99; p=0.04).2
Additionally, patients receiving romosozumab followed by alendronate had a more significant gain in bone mineral density than those receiving only alendronate (Figure 3).2 This superiority in bone mineral density gain was maintained after the transition to alendronate (p<0.001).2 Together with the reduction of fracture risk, romosozumab-toalendronate regimen displayed the benefit of secondary fracture prevention in high-risk postmenopausal osteoporosis patients.
In a recently published sub-analysis of East Asian patients enrolled in the ARCH study, while not sufficiently powered to determine statistical significance, trends similar to the global study in terms of anti-fracture efficacy including fracture risk reduction and bone mineral density gain were observed.8 Patients recruited to the ARCH trial shares similar profiles to osteoporosis patients with very high fracture risk. Moreover, the design of the ARCH study visits is applicable to the current clinic-based visits in real-life practice. The clinical outcomes observed in the clinical trial should be well translated into clinical practice. In terms of safety, patients in both arms of the study had similar adverse event rate, and that the event rate leading to discontinuation of the trial was low.8 Although the imbalance in positively adjudicated severe cardiovascular adverse effects noted in the overall ARCH population was not observed in the East Asian subgroup, the sample size of this subgroup analysis is too small to draw any conclusion.8
In a previous study using data from 13 university hospitals in Japan, a monthly regimen was shown to have better adherence to treatment as compared with weekly and daily regimens in patients taking oral bisphosphonates.9 A similar effect of dosing regimens on drug compliance should also be applicable to injectables. As shown in the setting of the romosozumab clinical trials which is practical in both private and public settings in real-life practice, this visit-based treatment model suits the need of many patients who may have problems with handling the injections by themselves. The under-utilization of anabolic-antiresorptive sequential therapy may be a crucial unmet need in very high-risk osteoporosis patients, and the updated treatment option with romosozumab may provide an alternative to address the problem.
The incorporation of romosozumab in the current treatment landscape
According to the Endocrine Society guideline, postmenopausal osteoporosis patients with a history of fragility fracture and low bone mineral density are considered to have very high fracture risk and warrant the use of anabolic agents.5 While the option of anabolic agents was once limited, the inclusion of romosozumab in the management guideline has provided an alternative for physicians to tailor-make optimal treatment plans for patients according to their indications, preferences and acceptance.
Although an increase in cardiovascular adverse events was observed in the ARCH study in which romosozumab was compared to alendronate, the same observation has not been shown in the FRAME study in which romosozumab was compared to denosumab.2,10,11 That said, romosozumab is contraindicated in patients with a history of myocardial infarction and stroke and should be used cautiously in patients with multiple cardiovascular risk factors.10
In addition to the safety profile of romosozumab, the fear of treatment side effects remains to be a significant hurdle in treating patients with osteoporosis. In particular, patients are often concerned about the two uncommon side effects of antiresorptive agents, the osteonecrosis of jaw and atypical fracture of femur. Considering that antiresorptive agents are part of the sequential therapy, patients should be well informed and counseled before the initiation of treatment. It is essential to convey the message that with proper case selection and close monitoring, the benefits of fracture risk reduction significantly outweigh the risk of the uncommon adverse events.
An important message
Osteoporosis is a prevalent disease with the resulting fragility fractures leading to high morbidity and mortality in our aging population. We welcome the introduction of a novel treatment with encouraging anti-fracture efficacy to the management guideline for secondary fracture prevention in patients with very high fracture risk. In addition to secondary prevention, we should also stay alert on the proper management of osteoporosis patients with moderate-high fracture risk to prevent their first fracture. Hopefully, more patients will benefit from anabolic-antiresorptive sequential therapy in the future and reduce the risks of postmenopausal osteoporosis as a whole.