Efficacy of Zoledronic Acid to Prevent Bone Loss Following Denosumab Discontinuation

Efficacy of a Single Infusion of Zoledronic Acid to Mitigate the Rebound Effect of Rapid Bone Loss Following Denosumab Treatment Discontinuation

This two-year observational, open-label clinical trial will evaluate the efficacy of a once-yearly infusion of zoledronic acid after denosumab discontinuation to maintain tissue mineral density and bone microarchitecture using high-resolution peripheral quantitative computed tomography (HR-pQCT) among post-menopausal women with osteoporosis.

Study Overview

• Status: Active, not recruiting
• Conditions: Osteoporosis; Bone Loss; Osteopenia; Osteoporosis, Postmenopausal
• Intervention / Treatment: Drug: Zoledronic acid

Detailed Description

As part of an observational study, twenty female osteoporosis patients looking to transition off denosumab therapy will be recruited from the David Hanley Osteoporosis Centre and affiliated primary care physicians in Calgary. The decision to stop denosumab will be made in accordance with standard clinical care and fully separate from the present study. Approximately 6-8 months after the patients' final denosumab injection, patients will receive a single infusion of zoledronic acid (5 mg/100mL) as part of their routine standard of care. The 6-8 month time frame corresponds with the recommended duration between subsequent denosumab injections. Concurrent with zoledronic acid treatment (within one month before or after infusion), patients will visit to the McCaig Institute for Bone and Joint Health to receive a baseline dual X-ray absorptiometry scan (lumbar spine, lateral vertebral assessment, and hip) and a high-resolution peripheral computed tomography scan (radius and tibia) to quantify areal BMD and volumetric BMD/bone microarchitecture, respectively. They will also complete the MoJo Fracture Risk Questionnaire. Patients will return for repeat scanning and questionnaire administrations to monitor potential changes to bone at 6 and 12 months after baseline. Any fracture events during the 12-month time frame will be logged in consultation with the patients' physician as documented through routine clinical follow-up. Researchers may contact participants to repeat scanning and questionnaire administration at the 24-month time point, if participants agree to this contact within the informed consent.

• Study Type: Observational
• Enrollment (Estimated): 20

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
      • University of Calgary, McCaig Institute for Bone and Joint Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The study focuses on post-menopausal, osteoporotic females, anticipating or preparing to transition off active denosumab treatment, for which they have received at least 2 prior injections, via a transition to once-yearly infusion of zoledronic acid.

Description

Inclusion Criteria:

• Post-menopausal females with osteoporosis
• Anticipating or preparing to transition off active denosumab treatment for osteoporosis with the use of a once-yearly infusion of zoledronic acid
• Received at least 2 injections of denosumab treatment
• Had a recent test (within 6 months) of serum creatine, calcium and phosphate

Exclusion Criteria:

• Any person for whom zoledronic acid would be considered contraindicated
• Pre-menopausal females
• Any person with significant chronic kidney disease (eGFR < 50 ml/m2 at time of osteoporosis clinical assessment)
• Any person with previous adverse reactions or allergy to bisphosphonate therapies
• Any person with non-corrected hypocalcaemia
• Any person currently taking, and unable to discontinue the use of, prohibited medications including: ZOMETA, other bisphosphonate therapies, calcitonin, aminoglycosides, loop diuretics and agiogenesis inhibitors
• Any person with other history, condition, therapy, or uncontrolled intercurrent illness, which could in the opinion of the Qualified Medical Investigator affect compliance with study requirements or which would make the participant unsuitable for this study
• Any person with simultaneous participation in another interventional clinical study (e.g., Phase 1-3 clinical studies) or treatment with any investigational medicinal product within 30 days prior to screening visit

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in volumetric Bone Mineral Density (BMD)/bone microarchitecture from baseline	High-resolution peripheral computed tomography scan (radius and tibia) will be used to quantify volumetric BMD/bone microarchitecture	Change from Baseline (within 1-month of infusion) to 6-months and 12-months
Change in areal Bone Mineral Density (BMD) from baseline	Dual X-ray absorptiometry scan (lumbar spine, lateral vertebral assessment, and hip) will be used to quantify areal BMD	Change from Baseline (within 1-month of infusion) to 6-months and 12-months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fractures	Any clinically diagnosed fractures will be reported by treating physician	1 year
MoJo Fracture Risk Questionnaire	An assessment of fracture risk	1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Optional further assessment of change in volumetric Bone Mineral Density (BMD)/bone microarchitecture from baseline	High-resolution peripheral computed tomography scan (radius and tibia) will be used to quantify volumetric BMD/bone microarchitecture	Change from Baseline to 24-months
Optional further assessment of change in areal Bone Mineral Density (BMD) from baseline	Dual X-ray absorptiometry scan (lumbar spine, lateral vertebral assessment, and hip) will be used to quantify areal BMD	Change from Baseline to 24-months

Collaborators and Investigators

• Sponsor: University of Calgary
• Investigators: Principal Investigator: William Brent Edwards, PhD, University of Calgary

Publications and helpful links

General Publications

• Anastasilakis AD, Polyzos SA, Makras P, Aubry-Rozier B, Kaouri S, Lamy O. Clinical Features of 24 Patients With Rebound-Associated Vertebral Fractures After Denosumab Discontinuation: Systematic Review and Additional Cases. J Bone Miner Res. 2017 Jun;32(6):1291-1296. doi: 10.1002/jbmr.3110. Epub 2017 Mar 13.
• Solling AS, Harslof T, Langdahl B. Treatment with Zoledronate Subsequent to Denosumab in Osteoporosis: a Randomized Trial. J Bone Miner Res. 2020 Oct;35(10):1858-1870. doi: 10.1002/jbmr.4098. Epub 2020 Jul 12.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2022
• Primary Completion (Estimated): July 1, 2024
• Study Completion (Estimated): July 1, 2025

Study Registration Dates

• First Submitted: May 27, 2022
• First Submitted That Met QC Criteria: June 1, 2022
• First Posted (Actual): June 6, 2022

Study Record Updates

• Last Update Posted (Actual): May 14, 2024
• Last Update Submitted That Met QC Criteria: May 13, 2024
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Musculoskeletal Diseases; Bone Diseases; Osteoporosis; Bone Diseases, Metabolic; Osteoporosis, Postmenopausal; Physiological Effects of Drugs; Bone Density Conservation Agents; Zoledronic Acid
• Other Study ID Numbers: REB21-1898

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No