Clinical trial NCT04091243: Romosozumab Versus Denosumab for Osteoporosis in Long-term Glucocorticoid Users
Official title: Romosozumab Versus Denosumab for Osteoporosis in Long-term Glucocorticoid Users: an Open Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Glucocorticoid-induced Osteoporosis
Keywords: glucocorticoid
osteoporosis
rheumatic diseases
Lead sponsor: Tuen Mun Hospital
Sponsor class: OTHER_GOV
First posted: 2019-09-16
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: An open randomized parallel group controlled trial
Primary purpose: TREATMENT

Brief summary: Glucocorticoid (GC) is the main stay of treatment of many rheumatic diseases but is also an important cause of secondary osteoporosis. The long-term use of GCs increases the risk of fragility fracture at a much higher bone mineral density (BMD) than postmenopausal osteoporosis, indicating an additional deleterious effect of GC on bone quality. An increased relative risk of vertebral and hip fractures is demonstrated in chronic GC users, with fracture risk proportional to the daily dose of GC. Other studies have also confirmed that intermittent use of high-dose GC and the cumulative GC dose was associated with an augmented risk of osteoporotic fracture.

Romosozumab (ROMO) is a humanized monoclonal antibody against sclerostin. The landmark RCT has demonstrated efficacy of ROMO (210mg subcutaneously monthly) over placebo in reducing vertebral fractures by 73% at 12 months in 7180 postmenopausal women with osteoporosis of the hip at entry. Another RCT has demonstrated efficacy of ROMO in reducing vertebral and hip fractures in 4093 post-menopausal women at month 24.

There are no data regarding the efficacy of ROMO in GC-induced osteoporosis. Comparative study on the efficacy of ROMO and denosumab in post-menopausal osteoporosis is also not yet available in the literature. This prompts the current pilot study to compare the efficacy of ROMO with denosumab in high-risk patients receiving long-term GCs.

Detailed description: Glucocorticoid (GC) is the main stay of treatment of many rheumatic diseases but is also an important cause of secondary osteoporosis. The long-term use of GCs increases the risk of fragility fracture at a much higher bone mineral density (BMD) than postmenopausal osteoporosis, indicating an additional deleterious effect of GC on bone quality. More than one-third of postmenopausal women receiving GC therapy developed asymptomatic vertebral fractures. A study in general practice reported an increased relative risk of vertebral and hip fractures in chronic GC users, with fracture risk proportional to the daily dose of GC. Another study also confirmed that intermittent use of high-dose GC and the cumulative GC dose was associated with an augmented risk of osteoporotic fracture.

The glycoprotein sclerostin, secreted by the osteocytes under the influence of mechanical loading, inhibits activation of the canonical Wnt pathway involved in osteoblastogenesis and hence suppresses 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. The landmark RCT has demonstrated efficacy of ROMO (210mg subcutaneously monthly) over placebo in reducing vertebral fractures by 73% at 12 months in 7180 postmenopausal women with osteoporosis of the hip at entry. The suppression of markers of bone resorption and enhancement of markers of bone formation indicates that ROMO has a dual mode of action on the bones. The efficacy of ROMO has also been tested against oral bisphosphonates. A RCT was conducted in 4093 post-menopausal women who were assigned to receive either ROMO (201mg subcutaneously monthly) or oral alendronate (70mg weekly) for 12 months, followed by open-label alendronate for another 12 months. At month 24, a 48% lower risk of new vertebral fractures was observed in the ROMO (6.2%) than the alendronate group (11.9%; p\<0.001). The risk of incident hip fractures was also significantly lower in the ROMO (2%) than alendronate treated patients (3.2%; p=0.02). The frequencies of adverse events and serious adverse events, however, were similar in the two treatment arms.

There are no data regarding the efficacy of ROMO in GC-induced osteoporosis. Comparative study on the efficacy of ROMO and denosumab in post-menopausal osteoporosis is also not yet available in the literature. This prompts the current pilot study to compare the efficacy of ROMO with denosumab in high-risk patients receiving long-term GCs.

Eligibility criteria: Inclusion Criteria:

1. Adults (women or men) \>18 years of age
2. Receiving long-term prednisolone treatment for various medical illnesses, defined as a daily prednisolone dose of ≥5mg/day for ≥12 months.
3. High risk of osteoporotic fracture (in subjects \<40 years, personal history of fragility/vertebral fracture, bone mineral density \[BMD\] of the hip/spine Z score ≤ -3.0, loss of BMD \>10% per year or new fracture; in subjects aged ≥40 years, personal history of fragility/vertebral fracture, BMD of the hip/spine T score ≤ -2.5, GC-adjusted 10-year major osteoporotic fracture risk ≥20% or hip fracture risk ≥3% by FRAX \[ie. multiplying risk by 1.15 for the former and 1.20 for the latter when prednisolone ≥7.5mg/day\], or new fracture development).

5. Informed consent from patients. 6. Willing to comply with all study procedures

Exclusion Criteria:

1. Patients with previous use of denosumab, teriparatide, intravenous bisphosphonates, strontium or other experimental anti-osteoporotic agents within 24 months of study entry.
2. Premenopausal women who plan for pregnancy within 24 months of study entry.
3. Patients with a known past history of atherosclerotic cardiovascular or cerebrovascular disease.
4. Patients with known bone disorders such as osteomalacia, renal osteodystrophy, and hyperparathyroidism.
5. Patients with unexplained hypocalcemia.
6. Patients with serum creatinine level of \>=200umol/L.

Primary outcomes:
measure: Bone mineral density (BMD)
timeFrame: month 12
Secondary outcomes:
measure: Bone mineral density (BMD)
timeFrame: month 12
measure: bone turnover markers
timeFrame: months 6,12,18 and 24
Other outcomes:
Locations:
city: Hong Kong
country: China
facility: Tuen Mun Hospital
Study officials:
affiliation: Tuen Mun Hospital
name: Chi Chiu Mok, MD, FRCP
role: PRINCIPAL_INVESTIGATOR
References: