After the introduction of denosumab few years ago, another monoclonal antibody is making its way in the market for osteoporosis treatment – romosozumab. While denosumab is a RANKL inhibitor which inhibits osteoclast activity and bone resorption, romosozumab targets and inhibits sclerotin, thereby increasing the osteoblast activities and bone formation. The ARCH study was recently published in the New England Journal of Medicine; this study has highlighted both the benefits of romosozumab in the treatment of osteoporosis as well as its potential safety concerns in cardiovascular health.
Here’s a quick summary of the ARCH Trial:
Objective: To compare the effectiveness of the following treatment regimens:
- Regimen starting with romosozumab and transitioning to alendronate or,
- Regimen starting with alendronate treatment alone
Patients randomized to these treatment arms were followed up to determine their reduction in fracture risks.
- Ambulatory postmenopausal women 55 to 90 years who meet one of the following criteria:
- BMD T score of -2.5 or less at the total hip or femoral neck and one or more moderate or severe vertebral fractures or two or more mild vertebral fractures
- BMD T score of -2.0 or less at the total hip or femoral neck and either two or more moderate or severe vertebral fractures or a fracture of the proximal femur sustained 3 to 24 months before randomization
- Women who were unable to take oral alendronate tablets or contraindications to alendronate, including a GFR below 35mL/min/1.73m2 of BSA
Primary End Points:
- Cumulative incidence of new vertebral fracture at 24 months
- Cumulative incidence of clinical fracture (non-vertebral and symptomatic vertebral fracture) at time of primary analysis
Secondary End Points:
- Incidences of non-vertebral and hip fracture at the time of the primary analysis
Over 24 months, 4093 patients were enrolled into the study with:
- 2047 enrolled into the alendronate-to-alendronate group and
- 2046 enrolled into the romosozumab-to-alendronate group:
- A 48% lower risk of new vertebral fractures was observed in the romosozumab-to-alendronate group (6.2% [127 of 2046 patients]) than in the alendronate-to-alendronate group (11.9% [243 of 2047 patients]) (p<0.001).
- Clinical fractures occurred in 198 of 2046 patients (9.7%) in the romosozumab-to-alendronate group vs. 266 of 2047 patients (13.0%) in the alendronate-to-alendronate group, representing a 27% lower risk with romosozumab (p<0.001).
- The risk of nonvertebral fractures was lower by 19% in the romosozumab-to-alendronate group than in the alendronate-to-alendronate group (178 of 2046 patients [8.7%] vs. 217 of 2047 patients [10.6%]; p=0.04), and the risk of hip fracture was lower by 38% (41 of 2046 patients [2.0%] vs. 66 of 2047 patients [3.2%]; p=0.02).
While the primary efficacy outcomes from the romosozumab-alendronate group appear more promising as compared to the alendronate-alendronate group in reducing fracture risks, the results from the adjudicated serious cardiovascular adverse events has raised some safety red flags. Particularly, more cardiac ischemic events, cerebrovascular events, and deaths were observed in the romosozumab-alendronate group, prompting more investigations and questions from the FDA.
There are some speculations that sclerostin may have a role in regulating vascular smooth muscle and the inhibition of sclerostin by romosozumab may be upsetting the regulation and potentially causing changes in the vascular remodeling.
Nonetheless, the results from the ARCH study has established the efficacy results in reducing fracture risks in post-menopausal women with osteoporosis. The results from the same study has also shed some safety concerns that has prompted further investigations.
My after thoughts…
The management in osteoporosis and bone health has gone through some significant changes over the last twenty years. Below are some of my personal observations:
- We used to recommend hormone replacement therapy ……but it’s no longer recommended due to long term safety concerns with cancer risks.
- We used to recommend calcium supplementation up to 1500mg/day… but we now recommend dietary intake of calcium up to 1500mg/day and only consider supplementation for individuals at high risk for falls and fractures to a maximum of 500mg/day.
- While calcitonin was never considered first line therapy in osteoporosis, it is not recommended anymore due to recent concerns with cancer risks associated with the nasal spray formulation.
- We are still debating on the long term use of bisphosphonates given there are some concerns with atypical fractures and osteonecrosis of the jaw. Drug holidays may be implemented but the guidelines on the duration of drug holidays are not well established.
- Denosumab is one of the latest agents available for osteoporosis. So far, the main concern may be related to hypocalcemia that may require routine monitoring.
- As for romosozumab, there are cardiovascular safety concerns from the latest ARCH study that warrant further investigations.
Do we know what we are doing?
I understand practice needs to evolve based on new evidence. But over the span of 20 years, we have created more controversies with little consolidation in our management of osteoporosis.
I wonder if we should focus more on keeping things simple – telling patients to keep moving and active, engage in weight bearing exercises, expose to some sunshine for vitamin D intake and eat healthy and food that is rich in calcium. There is a role in using medication for prevention and treatment of osteoporosis, especially for individuals unable to adopt these lifestyle changes. But for the majority, prevention may be safer if implemented early on with as much lifestyle modifications as possible! I also wonder for a wheel chair bound lady with osteoporosis, should we be actively treating the osteoporosis when she cannot engage in some weight bearing exercises to improve bone and muscle strength?
What are your thoughts with the latest romosozumab? How do you feel about the current approach in the management of osteoporosis?
Thank you for reading my post and I look forward to hearing your thoughts.