Preventing Osteoporosis Using Denosumab (PROUD)

Sustaining Skeletal Health in Frail Elderly

The purpose of this research study is to find out if denosumab (Prolia®), an injection given in the arm under the skin every 6 months, works to treat bone loss and prevent it from worsening in older men and women (ages 65 and older) who have osteoporosis and reside in long-term care (LTC) facilities.

Study Overview

• Status: Completed
• Conditions: Osteoporosis; Osteoporosis, Postmenopausal; Osteoporotic Fractures
• Intervention / Treatment: Drug: denosumab; Dietary supplement: Calcium and Vitamin D; Drug: Zoledronic Acid; Drug: Placebo

Detailed Description

Objective:

The long term goal is to improve health, well-being and quality of life in the frail long-term care (LTC) elderly population by reducing fractures. The short term goal is to demonstrate efficacy of the non-bisphosphonate denosumab to improve bone mineral density (BMD), a necessary (but not sufficient) pre-condition of a large fracture reduction trial. The investigators propose to conduct a 2-year, randomized, double-blind, calcium-vitamin D controlled trial to test the efficacy and predictability of the antiresorptive RANK ligand inhibitor, denosumab (60 mg), among a cohort of 212 institutionalized, under-served, frail men and women ≥65 years old in LTC.

Specific Aims:

Aim 1: To evaluate efficacy of denosumab in improving/maintaining bone mineral density. The investigators will measure conventional hip and spine bone mineral density (BMD).

Primary Hypothesis: After 2 years, women and men on denosumab will have greater hip and spine BMD increases.

Zoledronic Acid Infusion Safety Treatment and Follow-up Extension:

After the trial was started, case reports suggested a potential increase in fracture risk with disuse. A post hoc analysis that combined the pivotal denosumab trial and extension trial data suggested there was an increase in multiple vertebral fractures when patients discontinued therapy. Following discontinuation of denosumab/placebo, all patients will be offered treatment with 1 dose of intravenous zoledronic acid 5 mg. For those consenting to receive end of study treatment, the zoledronic acid will be given at month 27 for an individual patient.

Zoledronic Acid Safety Infusion Extension Specific Aims:

Aim 1: To evaluate maintenance of bone mineral density (BMD). Zoledronic acid will be administered intravenously at 9 months post-denosumab (month 27) and assess BMD by DXA at months 33 and 39 (6 months and 12 months after zoledronic acid infusion).

Primary Hypothesis: Zoledronic acid will prevent BMD loss at the spine and hip following denosumab discontinuation.

• Study Type: Interventional
• Enrollment (Actual): 201
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • UPMC Senior Communities

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years and older (Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Ambulatory male and female residents with osteoporosis or low bone mass (at risk for fracture) ages 65 and older will be considered if:

• Reside in long-term care institution (nursing home or assisted living facility); and
• HaveOsteoporosis: (1) by bone density [spine, hip or forearm Bone Mineral Density (BMD) T-score ≤ -2.5]; (2) A previous adult fragility fracture of the spine or hip; or (3) Would be treated based on FRAX® and the National Osteoporosis Foundation (NOF) treatment thresholds of a 10 year risk of ≥ 20% for a major fracture or ≥ 3% for hip fracture suing femoral neck BMD.

Exclusion Criteria:

• Institutionalized residents with subacute illnesses who are not expected to survive or who will be discharged in < 2 years.
• Non-ambulatory residents (those who cannot stand and pivot with assistance in order to transfer to the DXA table).
• Those currently on therapy (including bisphosphonate, denosumab, or teriparatide) or who have been on a bisphosphonate for > 1year during the previous 2 years because some bisphosphonates are long acting.
• Those with a history of hypocalcemia or contraindication for treatment. We will screen for these conditions by detailed history, chart review, and baseline laboratory analyses.
• Those with vitamin D levels < 25ng/mL will be treated with vitamin D 50,000 IU/wk for 8 weeks; they will be enrolled if the follow-up vitamin D level is 25 ng/mL or more (if after 2 rounds of vitamin D repletion their vitamin D level is not at least 25 ng/mL, they will not be eligible to be randomized into the study).
• Those on dialysis or with stage 5 chronic kidney disease (eGFR<15ml/min) will be excluded at screening.
• Those requiring tooth extraction or oral surgery will not be enrolled until cleared by a dentist.
• Patients will be allowed to continue on glucocorticoids and anticonvulsants because their use is common in this population.
• Those on glucocorticoids and anticonvulsants will be allowed to continue in the study because their use is common in this population.
• Those on hormone replacement therapy (HRT), raloxifene, or prescribed protective hip pads by their Primary Care Physician (PCP) will be allowed to participate and continue on these therapies.
• We will suggest that participants stop long-term calcitonin as it has been discontinued in Europe due to cancer concerns.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Denosumab, then Zoledronic Acid; Semi-annual dose: denosumab 60 mg semi-annual injection; Vitamin D 800-1000 IU/daily and Calcium approximately 1200 mg/daily (dietary + supplements); Zoledronic acid will be offered to all study participants upon completing the course of Denosumab.	Drug: denosumab; Semi-annual dose: 60 mg injection; Vitamin D 800-1000 IU/daily and Calcium approximately 1200 mg/daily (dietary + supplement); Other Names: Prolia; Dietary supplement: Calcium and Vitamin D; Dietary supplement: Vitamin D 800-1000 IU/daily and Calcium approximately 1200 mg/daily (dietary + supplement); Drug: Zoledronic Acid; One time safety treatment dose: 5 mg infusion; Other Names: Reclast
Placebo Comparator: Placebo Group, then Zoledronic Acid; Semi-annual: placebo saline injection; Vitamin D 800-1000 IU/daily and Calcium approximately1200 mg/daily (dietary + supplements); Zoledronic acid will be offered to all study participants upon completing the course of placebo.	Dietary supplement: Calcium and Vitamin D; Dietary supplement: Vitamin D 800-1000 IU/daily and Calcium approximately 1200 mg/daily (dietary + supplement); Drug: Zoledronic Acid; One time safety treatment dose: 5 mg infusion; Other Names: Reclast; Drug: Placebo; Semi-annual saline injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bone density of the total hip	Bone Mineral Density (BMD) of the total hip at 24 months as assessed by dual-energy x-ray absorptiometry (DXA)	24 months
Bone density of the spine	Bone Mineral Density (BMD) of the spine at 24 months as assessed by dual-energy x-ray absorptiometry (DXA)	24 months
Extension - Zoledronic Acid Infusion Safety Treatment: Bone density of the total hip	Bone Mineral Density (BMD) of the total hip at 33 months as assessed by dual-energy x-ray absorptiometry (DXA)	33 months
Extension - Zoledronic Acid Infusion Safety Treatment: Bone density of the total hip	Bone Mineral Density (BMD) of the total hip at 39 months as assessed by dual-energy x-ray absorptiometry (DXA)	39 months
Extension - Zoledronic Acid Infusion Safety Treatment: Bone density of the spine	Bone Mineral Density (BMD) of the spine at 33 months as assessed by dual-energy x-ray absorptiometry (DXA)	33 months
Extension - Zoledronic Acid Infusion Safety Treatment: Bone density of the spine	Bone Mineral Density (BMD) of the spine at 39 months as assessed by dual-energy x-ray absorptiometry (DXA)	39 months

Collaborators and Investigators

• Sponsor: Susan L. Greenspan
• Collaborators: National Institutes of Health (NIH); National Institute on Aging (NIA)
• Investigators: Principal Investigator: Susan L Greenspan, MD, University of Pittsburgh

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2016
• Primary Completion (Actual): August 1, 2023
• Study Completion (Actual): August 1, 2023

Study Registration Dates

• First Submitted: April 25, 2016
• First Submitted That Met QC Criteria: April 25, 2016
• First Posted (Estimated): April 27, 2016

Study Record Updates

• Last Update Posted (Estimated): October 10, 2023
• Last Update Submitted That Met QC Criteria: October 9, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Osteoporosis; Bone loss; Osteoporotic Fractures; Nursing Home Patients; Long-term Care Patients; Frail Geriatric Patients
• Additional Relevant MeSH Terms: Metabolic Diseases; Fractures, Bone; Wounds and Injuries; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Metabolic; Osteoporosis; Osteoporosis, Postmenopausal; Osteoporotic Fractures; Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Calcium; Zoledronic Acid; Denosumab
• Other Study ID Numbers: STUDY19050268; 1R01AG052123-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

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