Romosozumab Versus Denosumab In Glucocorticoid-induced Osteoporosis: An Extended Observation Of a Clinical Trial at 6 Years

Sclerostin is a glycoprotein secreted by osteocytes under the influence of mechanical loading that inhibits activation of the canonical Wnt pathway involved in osteoblastogenesis, leading to suppression of bone formation. Moreover, sclerostin enhances resorption of the bone by stimulating the production of RANKL by the osteocytes. Romosozumab (ROMO) is a humanized monoclonal antibody against sclerostin. By having a dual mechanism on bone resorption and formation, ROMO has been shown by head-to-head RCTs to be more effective than oral alendronate in reducing vertebral and hip fractures in postmenopausal women. ROMO has also been demonstrated to be superior to teriparatide in raising the BMD and bone strength of the spine and hip at month 12 in postmenopausal women with low bone mass. In subjects transitioned from bisphosphonates, a phase 3 RCT showed that the use of ROMO was associated with a greater gain in the hip BMD after 12 months than teriparatide. However, there is little information on the comparative efficacy of ROMO and denosumab (DEN) in postmenopausal osteoporosis. There is also a paucity of data regarding the use of ROMO in patients with GIOP and long-term data on the BMD changes.

Recently, an open-label 24-month RCT comparing the efficacy of ROMO with DEN in high-risk adult patients using long-term GCs (daily prednisolone dose of ≥5mg/day for ≥12 months) was conducted. All patients had moderate to high risk of osteoporotic fracture as evidenced by at least one of the following: (1) a personal history of fragility/vertebral fracture; (2) dual energy X-ray absorptiometry (DXA) T score ≤-2.5 [age ≥40 years] or Z scores ≤-3.0 [age <40 years] at spine, hip or femoral neck; or (3) high risk of 10-year FRAX-estimated major fracture).

A total of 70 patients were enrolled and 63 completed the study. At month 12, the spine BMD at month 12 was significantly higher in the ROMO than DEN group after adjustment for baseline values and confounding factors. At month 24, the spine BMD continued to increase in both the ROMO and DEN groups, and the intergroup difference remained significantly different. P1NP increased significantly at month 3 after ROMO treatment but suppression of CTX was greater by DEN. Both treatments were well tolerated, with more frequent injection site reaction observed in the ROMO group. The results from this study suggested that ROMO was superior to DEN in raising the spinal BMD in high-risk patients with GIOP. On switching to DEN, the spinal BMD continued to improve in both treatment groups at month 24.

The participants of the original study were continued on denosumab (60mg SC every 6 months) and a DXA scan was repeated at month 48. Fifty-four patients (27 ROMO-DEN; 27 DEN) completed this extension phase. At month 48, the spine and hip BMD increased significantly from baseline in both the sequential ROMO-DEN and DEN alone groups. However, the absolute gain in BMD from baseline to month 48 at the spine and hip was significantly higher in the ROMO-DEN than DEN group of patients.

As there is a lack of data on the very long-term efficacy of sequential ROMO and DEN in the treatment of high risk patients using long-term GCs, the current extension study is carried out to look at the changes in BMD compared between the two treatment arms at year 6. This will provide useful information in the literature regarding the sequential ROMO/DEN regimen in long-term GC users.

Inclusion criteria

• patients who are continued on 6-monthly subcutaneous injection of DEN in either the ROMO or DEN arms after month 48; (2) those who are willing to have a repeat DXA assessment at the end of 6 years

Exclusion criteria

• patients who refuse to be maintained on denosumab after month 48
• patients who are maintained on other anti-osteoporotic drugs after month 48
• patients in whom prednisolone is planned to be tapered or discontinued after month 48.