Background
Osteoporosis affects an estimated 300,000 to 500,000 people in Ireland. Fragility fractures are a serious consequence with approximately 32,000 annually and are associated with significant morbidity, loss of independence and impaired quality of life. Furthermore, there is an approximate 24% one-year mortality in Irish adults following hip fracture. This fracture burden imposes significant economic costs estimated to be ¤1 billion in Ireland.
Romosozumab is a monoclonal antibody that targets sclerostin, a protein that inhibits bone formation and also promotes bone resorption through inhibition of the Wnt/βcatenin pathway. By blocking sclerostin, romosozumab is unique in having both anabolic (bone stimulating) and antiresorptive (inhibiting bone breakdown) effects, making it the most potent osteoporosis therapy developed to date.
While approved by the FDA and EMA in 2019, romosozumab was only made available in Ireland in November 2024 for postmenopausal females with severe osteoporosis who meet certain criteria. However, clinicians
in other countries (e.g. Japan) have extensive experience with its use where there is a growing body of real-world clinical evidence.
Which patients should be considered for romosozumab?
Osteoporosis guidelines (e.g. NOGG, IOF, AACE) increasingly advise on stratifying patient fracture risk into the categories of ‘high-risk’ or ‘very high-risk’ to guide decisions on optimal therapy. In general, anabolic or more potent antiresorptive agents are advised for those with the greatest fracture risk. The concept of “imminent fracture risk” is also core to this approach, as the highest risk for re-fracture (> 10%) occurs in the first two years after a fragility fracture. In Ireland, approximately 30% of older adults with a fragility fracture have a history of prior fracture, underscoring the need for prompt intervention.
“High risk” patients are typically defined as those meeting minimum intervention thresholds for treatment and where first line therapy is generally antiresorptives such as bisphosphonates. In contrast, “very high risk” includes patients with additional factors such as a recent major
osteoporotic fracture, very low T-scores (e.g. < –3.0) or multiple clinical risk factors. For these patients, most guidelines recommend an “anabolic-first approach” using agents like romosozumab to achieve a more rapid rise in BMD and reduction in fracture risk.
In Ireland, romosozumab is indicated for postmenopausal women with severe osteoporosis: (T-score ≤ –2.5 at hip, lumbar spine or distal forearm where latter not available) and who have sustained a recent major osteoporotic fracture (hip, vertebral, proximal humerus, or distal radius) within the past 24 months (see Table 1). It is available as a high-tech prescription under a HSE Managed Access Programme and can be prescribed by consultants in a specialism relevant to osteoporosis (e.g. geriatricians, endocrinologists, rheumatologists) who are registered and approved. How is it administered?
How is it administered?
Romosozumab is administered once monthly (dose of 210 mg) as two consecutive subcutaneous injections in the abdomen, thigh or upper arm for a total of 12 months. The drug is stable for up to one month at room temperature though longer storage requires refrigeration (2–8°C). If refrigerated, it should sit at room temperature for 30 minutes prior to use to avoid injection discomfort. Disposable prefilled autoinjector pens facilitate easy administration and the company provides training for patients and carers.
How effective is it and how does it compare to other treatment options?
Romosozumab is regarded as the most potent agent for increasing BMD and reducing fracture risk. In the FRAME trial, one year of romosozumab therapy resulted in a 13.3% gain in BMD at the lumbar spine and 6.8% at the total hip, with a 73% reduction in new vertebral fractures and a 36% reduction in clinical fractures. By contrast, potent bisphosphonates or denosumab typically yield around a 3% annual increase in lumbar spine BMD.9, 10 Romosozumab is not only superior at increasing BMD compared to bisphosphonates and denosumab, but also teriparatide, the only other bone-forming therapy available in Ireland.
When compared directly with alendronate in the ARCH trial, one year of romosozumab followed by alendronate for another year led to a 38% lower incidence of hip fractures and 48% reduction in vertebral fractures versus continuous alendronate. In the FRAME and FRAME Extension studies, romosozumab for 12 months followed by denosumab for 12 months was compared with 24 months of denosumab and resulted in a 9.3% greater improvement in BMD at the spine, 4.4% at the total hip and nearly 50% fewer vertebral fractures. In fact, the mean increase of T-score after one year of romosozumab followed by 12 months of denosumab was 1.1 at lumbar spine and 0.45 at total hip.
Studies also show its superiority over teriparatide. A meta-analysis of four small head-to-head trials comparing both agents found greater increases in spine and total hip BMD with romosozumab. In a recent observational study, romosozumab also resulted in greater 12-month rises in BMD than teriparatide (femoral neck: 4.8% vs. 0.2%, total hip: 5.7% vs. 0.3%, lumbar spine: 13.7% vs. 9.3%). Romosozumab’s greater effect on cortical bone versus teriparatide probably accounts for the larger hip BMD gains. Additionally, while pooled analysis of randomised trials suggests that teriparatide reduces hip fracture risk, this is not conclusively proven.
Romosozumab is not licensed for use in males in Europe or the US. While there is relatively little data on its use in men, the BRIDGE trial (n=245) demonstrated similar BMD gains. Further studies may pave the way for its future use in males, where it is currently permitted in Japan.
What treatment should follow are after completing a one-year course of romosozumab?
Without subsequent therapy after romosozumab, BMD gains dissipate so it must be followed by an antiresorptive agent such as a bisphosphonate or denosumab. A potent intravenous bisphosphonate (e.g. zoledronic acid) is generally considered prudent in this setting though alendronate and ibandronate are also shown to further increase BMD. Transitioning to denosumab is an alternative option and results in even greater BMD gains of up to 5.6% at the lumbar spine and 3.9% at the total hip. Indeed, in the FRAME study, one year of romosozumab followed by denosumab for 12 months achieved BMD gains at the total hip and spine equivalent to nearly 7 years of denosumab in the FREEDOM study. However, the decision to use denosumab needs to be carefully considered, as if stopped at a future point, bisphosphonates may not prevent subsequent bone loss.
Do other prior osteoporosis therapies affect its response?
Romosozumab results in the greatest BMD gains in treatment-naïve patients, with prior antiresorptive therapy partially blunting its anabolic effect. This is relevant as in clinical practise, patients with severe osteoporosis are those most likely to be considered for romosozumab, though often have had prior bisphosphonate or denosumab therapy.
However, studies show that romosozumab after bisphosphonates still results in substantial rises in BMD at the spine (7.5 – 10.2%) and total hip (up to 4.3%). In the most recent Swiss study, improvements of 10.1% at the lumbar spine and 2.9% at the total hip were identified compared to 14.6% and 5.0% in treatment naïve patients. Longer bisphosphonate exposure though was correlated with a diminished romosozumab response. Data also suggests that romosozumab as opposed to teriparatide is a better option after bisphosphonate therapy. In the STRUCTURE trial, women switching from bisphosphonates (mean of 5.6 years) to romosozumab achieved greater BMD gains at the lumbar spine (+9.8%) and total hip (+2.6%) compared to those switching to teriparatide (+5.4% and –0.6%, respectively).
The use of romosozumab after denosumab is more questionable, with evidence showing that this results in a greater attenuation of its effect (by up to 50% or more). This appears to occur as the rebound increase in bone resorption on stopping denosumab is only partially mitigated by romosozumab.
A recent study of patients on denosumab for a median of two years found that switching to romosozumab still increased lumbar spine BMD by 6.8%, compared to 3.3% for those continuing denosumab. However, there was no increase in total hip BMD.
While there is almost no data on switching directly from long-term denosumab to romosozumab, case reports suggest an even larger blunting of its effect and in some patients a decline in BMD.
For patients who remain at high fracture risk despite denosumab therapy, adding romosozumab has been suggested. In a small case control study this was found to produce greater increases in lumbar spine, but not hip BMD after 6 months compared to continuing denosumab only therapy. However, more studies are needed to investigate this.
Some patients who may have completed teriparatide therapy may also remain at high risk of fracture. While data is limited, in four observational studies switching from teriparatide to romosozumab was still associated with significant increases in BMD at the spine (9.1 – 13.3%) and total hip (1.9 – 7.5%) though with gains less than seen in treatment naïve patients.
What are the adverse effects?
Romosozumab is well tolerated with only about 5% discontinuing the drug due to adverse effects. These include injection site reactions (5.0%), nasopharyngitis (10%) and arthralgia (10%). The main concern around use is a possible increase in cardiovascular events which were identified in one of the pivotal trials. The potential mechanism is unclear and may involve sclerostin mediated pathways, that might increase the risk of vascular calcification. However, studies on the effect of sclerostin on cardiovascular risk are conflicting and it remains to be seen whether the drug is implicated.
In the ARCH trial, 2.5% of romosozumab-treated patients had major adverse cardiovascular events in the first 12 months of use compared to 1.9% of thoseon alendronate. In con trast, the larger FRAME trial did not detect any significant signal for cardiovascular events. However, it included patients who were marginally younger, had a slightly lower prevalence of hypertension and less severe osteoporosis. Reassuringly, a recent study (n=11,220) using real-world data that compared romosozumab and teriparatide/abalopartide reported fewer cardiovascular events with romosozumab.
In Europe, the EMA contraindicates romosozumab in any patient with a history of myocardial infarction or stroke. Clinicians must balance the benefits of fracture risk reduction against cardiovascular risk before using it. Caution should be exercised in those with established cardiovascular disease and in other patients, clinical risk factors such as hypertension, diabetes, hyperlipidaemia, smoking and family history need to be considered.
MRONJ and AFF are very rare with romosozumab treatment. In the FRAME and ARCH trials, three AFFs were reported (two in prior bisphosphonate users) and three MRONJ cases (one each in prior alendronate and denosumab users). Hypocalcaemia was also rare (<0.1%) and patients are advised to have adequate calcium and vitamin D intake.
Conclusion
Romosozumab represents a significant advancement in osteoporosis treatment, uniquely combining potent anabolic and mild antiresorptive effects. By targeting patients at the highest risk of fracture, romosozumab has the potential to interrupt the cycle of repeated fractures, and associated morbidity. However, its use warrants caution in individuals with high cardiovascular risk and longer-term safety data remain necessary.
At present, strict eligibility criteria prevents many patients who are at very high fracture risk (e.g. very low T-scores but no recent fracture) from accessing romosozumab. However, in the pivotal FRAME trial, similar antifracture efficacy and BMD increases were observed in patients at high risk who had no prior fragility fracture.
Fracture liaison services (FLS) play a critical role in identifying patients at the highest fracture risk who may benefit from anabolic therapies such as romosozumab. The development of a national osteoporosis strategy could help in delivering timely, effective treatment to all at-risk individuals.
References available on request
Written by Dr Donal Fitzpatrick, Consultant Physician & Geriatrician, Mater Misericordiae Hospital, Dublin,
Dr Kevin McCarroll, Consultant Physician & Geriatrician, Bone Health Unit, St James’s Hospital, Dublin.
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