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Guideline

Pharmacologic approaches to prevention and treatment

Romosozumab

Romosozumab

Note: In Australia, romosozumab was only listed on the PBS in April 2021 and so these recommendations are based on current limited evidence.

Recommendation 27

Grade

Romosozumab is recommended as first-line therapy for the treatment of osteoporosis in postmenopausal women at very high risk of minimal trauma fracture.

A

Recommendation 28

Grade

Romosozumab is recommended as first-line therapy for the treatment of osteoporosis in men at very high risk of minimal trauma fracture.

C

Like denosumab, romosozumab is a ‘targeted therapy’ for the treatment of osteoporosis and is the most recent pharmacological therapeutic addition. Romosozumab, a monoclonal antibody, is a potent bone anabolic agent (builds bone) that specifically targets and binds sclerostin. Unlike bisphosphonates and denosumab, which predominantly reduce bone resorption, and teriparatide, which predominantly increases bone formation, romosozumab both increases bone formation and reduces bone resorption. This unique mechanism of action leads to a marked increase in BMD, greater than what is seen with oral alendronate or teriparatide.1,2

Romosozumab is administered as a subcutaneous injection (two 105-mg syringes) once a month. Two injections are given at the same time once a month for 12 months. Romosozumab has been shown to reduce vertebral and non-vertebral fractures in postmenopausal women with osteoporosis at high risk of fracture.3,4 Romosozumab has also been shown to reduce vertebral, non-vertebral, and hip fractures compared with the antiresorptive drug, alendronate. In a post hoc analysis of the FRActure study in postmenopausal woMen with ostEoporosis (FRAME), romosozumab had greater efficacy in reducing vertebral fractures than denosumab.3,4 These studies, and those of teriparatide compared with risedronate, indicate that bone anabolic agents are superior to antiresorptive drugs in reducing vertebral and clinical fractures.1–4 Although fracture reduction data in men are lacking, romosozumab was effective in increasing BMD and appeared safe in men with osteoporosis.5

Evidence Statement

In postmenopausal women

FRAME, an RCT of 7180 postmenopausal women with DXA T-scores of –2.5 to –3.5 at the total hip or FN, randomised participants to subcutaneous romosozumab 210 mg or placebo monthly for 12 months.3 Thereafter, patients received denosumab at the usual dose of 60 mg subcutaneously every six months for 12 months. At 12 months, new vertebral fractures had occurred in 16 of 3321 patients (0.5%) in the romosozumab group, compared with 59 of 3322 patients (1.8%) in the placebo group, a 73% lower risk with romosozumab (P<0.001). Clinical fractures occurred in 58 of 3589 patients (1.6%) in the romosozumab group, compared with 90 of 3591 patients (2.5%) in the placebo group, a 36% lower risk with romosozumab (P=0.008). Non-vertebral fractures occurred in 56 of 3589 patients (1.6%) in the romosozumab group and in 75 of 3591 (2.1%) in the placebo group (P=0.10). At 24 months, rates of vertebral fractures were significantly lower in the romosozumab than placebo group following transition to denosumab (0.6% [21/3325] versus 2.5% [84/3327] in the romosozumab and placebo groups, respectively; a 75% lower risk with romosozumab; P<0.001). Adverse events were balanced between groups. In postmenopausal women with osteoporosis, romosozumab was associated with a lower risk of vertebral fracture than placebo at 12 months and, after the transition to denosumab, at 24 months.3

The superior efficacy of romosozumab compared with an antiresorptive agent (alendronate) in patients at high risk of fracture was shown in the Active-Controlled Fracture Study in Postmenopausal Women with Osteoporosis at High Risk (ARCH) of 4093 postmenopausal women with osteoporosis and prevalent vertebral fractures.4 Participants were randomised to either romosozumab 210 mg monthly or alendronate 70 mg weekly for one year, followed by open-label treatment with alendronate for up to two years. Compared with alendronate, romosozumab increased BMD by approximately 2.5-fold at the spine and twofold at the hip in year 1, and vertebral fracture relative risk was 37% and 48% lower at year 1 and 2, respectively, compared with standard-of-care alendronate. At study completion (median exposure 33 months), relative risk reductions of 27% for clinical fractures, 19% for non-vertebral fractures and 38% for hip fractures were seen for the group initially treated with romosozumab relative to the group treated with alendronate alone.4 In postmenopausal women with osteoporosis at high risk of fracture, romosozumab treatment for 12 months followed by alendronate significantly reduced new vertebral, clinical and non-vertebral fractures compared with alendronate.

An unexpected imbalance in adjudicated serious cardiovascular adverse events was observed in ARCH, with 50 (2.5%) patients in the romosozumab group and 38 (1.9%) in the alendronate group reporting these events (OR 1.31; 95% CI: 0.85–2.00).4 This was not observed in the larger FRAME study, which enrolled slightly younger patients with less severe osteoporosis.3 The mechanisms and implications for this observation remain uncertain, with the possibility of a cardioprotective effect of alendronate raised.

Romosozumab was compared to the other anabolic bone agent, teriparatide, in the STudy evaluating effect of RomosozUmab Compared with Teriparatide in postmenopaUsal women with osteoporosis at high risk for fracture previously treated with bisphosphonatE therapy (STRUCTURE).1 Subjects with prior bisphosphonate therapy and a DXA T-score ≤–2.5 at the total hip, lumbar spine or FN and a history of non-vertebral fracture after the age of 50 years or vertebral fracture were randomised to either subcutaneous romosozumab 210 mg once monthly (n=218) or subcutaneous teriparatide at the standard dose of 20 mcg once daily (n=218). There was significantly greater mean percentage change from baseline in favour of romosozumab at the total hip at month 12 compared with teriparatide (2.6% versus –0.6%, respectively; P<0.0001), for a mean difference between the two groups of 3.2% (P<0.0001).1 The relatively small increment in BMD even with romosozumab may have been due to ‘blunting’ of bone anabolism from prior bisphosphonate use. Although the study was too small to look at fracture outcomes, in postmenopausal women with osteoporosis at high risk of fracture previously treated with bisphosphonate therapy, 12 months of romosozumab resulted in statistically significant increases in BMD at the total hip, femoral neck and lumbar spine compared with teriparatide.

In men

Romosozumab was studied in men with osteoporosis in the placeBo-contRolled study evaluatIng the efficacy anD safety of romosozumab in treatinG mEn with osteoporosis (BRIDGE), which included men (n=245) aged 55–90 years with a DXA T-score at the lumbar spine, total hip, or FN of ≤–2.5, or ≤–1.5 with a history of fragility fracture.5 Patients were randomised to either romosozumab 210 mg (n=163) or placebo (n=82) subcutaneously once a month for 12 months.5

After 12 months, a significantly greater mean increase from baseline in lumbar spine BMD was seen in those on romosozumab compared with placebo (12.1% vs 1.2%; P<0.001). Lesser, but still significant, BMD increments were seen at the total hip and FN with romosozumab.5 Romosozumab appeared effective and safe in men with osteoporosis. There are no intervention studies evaluating fracture outcomes in men.

  • Monthly romosozumab subcutaneous injection is more convenient than the daily subcutaneous injections of the other bone anabolic agent (teriparatide).
  • The absolute risk reduction with romosozumab over bisphosphonate treatment is in the order of 1–1.3% fewer fractures per year.
  • A possible increase in cardiovascular risk with romosozumab4 means it should be avoided in those with a history of myocardial infarction or stroke. More data are needed to guide clinical practice in this area. At the time of writing (7 December 2023), the Therapeutic Goods Administration (TGA) had posted a safety update on their website about this (https://www.tga.gov.au/news/safety-updates/new-warnings-romosozumab-evenity-cardiovascular-risks).
  • Although current PBS criteria to access romosozumab are identical to those for teriparatide and limit the use of romosozumab to individuals with severe osteoporosis (T-score ≤–3.0) who have sustained fractures despite an antiresorptive therapy, increasing evidence suggests romosozumab is best used as initial therapy in those with severe osteoporosis for its potent anabolic effect, followed by an antiresorptive (ie sequential) therapy.1,4,6 (As of 1 February 2023, the PBS mandates romosozumab needs to be initiated by a consultant physician.)
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