Efficacy and safety of denosumab administered at 6-monthly versus 9-monthly intervals in postmenopausal osteoporosis: Protocol for a randomized, open-label, blinded endpoint clinical trial
Ranvijay Singh, Rimesh Pal, Sanjay Kumar Bhadada, Pinaki Dutta, Urmila Yadav, Richa Rattan, Naresh Sachdeva, Snigdha Kumari, Tulika SinghBackground
Denosumab is widely used for postmenopausal osteoporosis and is conventionally administered at 6-month intervals. However, pharmacodynamic and pharmacokinetic evidence suggests that suppression of bone turnover may persist beyond this duration. In a prior prospective study from our group, bone turnover marker-guided delayed dosing was not associated with early skeletal harm. Whether a longer fixed dosing interval can maintain skeletal efficacy while reducing treatment burden remains uncertain.
Objectives
To compare the efficacy and safety of denosumab administered at fixed 6-monthly versus 9-monthly intervals in postmenopausal women with osteoporosis.
Design
Prospective, randomized, open-label, blinded endpoint (PROBE) clinical trial.
Methods
Postmenopausal women aged ≥50 years with DXA-defined osteoporosis and/or prior fragility fracture will be randomized (1:1) to receive denosumab 60 mg subcutaneously every 6 months or every 9 months for 18 months (four vs. three doses), along with calcium and cholecalciferol supplementation. Participants will be followed for an additional 12 months after treatment discontinuation, with predefined criteria for rescue therapy using zoledronic acid. The primary endpoint is percent change in areal bone mineral density at the lumbar spine at 24 months. Secondary outcomes include incident fragility fractures, changes in trabecular bone score, HR-pQCT-derived microarchitecture and bone strength, longitudinal changes in bone turnover markers, and requirement for rescue therapy. Safety outcomes include hypocalcemia, osteonecrosis of the jaw, atypical femoral fractures, incident vertebral fractures during the extended-interval treatment period, and post-discontinuation skeletal events.
Ethics
The study has received institutional ethics approval, and written informed consent will be obtained from all participants.
Discussion
This trial is designed to provide the first randomized evidence evaluating whether a fixed extended dosing interval of denosumab can preserve skeletal efficacy. The findings are expected to inform optimization of dosing strategies, with potential implications for treatment burden and cost.
Registration
Prospectively registered in Clinical Trial Registry of India (CTRI/2025/12/099664) dated 22-12-2025.