Clinical trial NCT02753283
Conditions: Osteoporosis, Postmenopausal Osteoporosis Osteoporotic Fractures
Keywords: Bone loss Frail Geriatric Patients Nursing Home Patients Long-term Care Patients Osteoporosis Osteoporotic Fractures
Sponsor: Susan L. Greenspan
Start date: 2016-06-01; Completion date: 2023-08-01
Enrollment: 201 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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.

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.

Arms: arm 1: Semi-annual dose for women: denosumab 60 mg semi-annual injection; Vitamin D 800-1000 IU/daily and Calcium approximately 1200 mg/daily (dietary + supplements). arm 2: Semi-annual for women: placebo saline injection; Vitamin D 800-1000 IU/daily and Calcium approximately1200 mg/daily (dietary + supplements). arm 3: Semi-annual dose for men: denosumab 60 mg semi-annual injection; Vitamin D 800-1000 IU/daily and Calcium approximately 1200 mg/daily (dietary + supplements). arm 4: Semi-annual for men: placebo saline injection; Vitamin D 800-1000 IU/daily and Calcium approximately1200 mg/daily (dietary + supplements)
Interventions: intervention 1: denosumab intervention 2: Placebo intervention 3: Calcium and Vitamin D
Intervention descriptions: intervention 1: Semi-annual dose: 60 mg injection; Vitamin D 800-1000 IU/daily and Calcium approximately 1200 mg/daily (dietary + supplement) intervention 2: Semi-annual saline injection intervention 3: Dietary supplement: Vitamin D 800-1000 IU/daily and Calcium approximately 1200 mg/daily (dietary + supplement)

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
Sustaining Skeletal Health in Frail Elderly 
NCT02753283 
21 AUG 2024 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study Protocol PROUD 
 
Overall summary: We propose to conduct a 2-year, randomized, double-blind, calcium-
vitamin-D controlled trial to test the efficacy of the antiresorptive RANK ligand inhibitor, 
denosumab, among a cohort of 201 institutionalized, overlooked, under-served, frail men 
and women ≥65 years old in long-term care (LTC). 
Our co-primary outcomes are percent changes in bone mineral density (BMD) of the total 
hip and spine over 24 months. 
 
Informed consent: All participants or their responsible party will provide written informed 
consent for screening and then randomized if eligible. 
 
Inclusion/Exclusion Criteria: Ambulatory male and female residents with osteoporosis or 
low bone mass (at risk for fracture) age 65 and older will be considered if: 
 
1) They reside in long-term care (LTC) including Managed Senior Communities. 
 
2) They have a) osteoporosis by bone density (spine, hip or forearm BMD T-score ≤ 
-2.5 SD) (108,109), b) a previous adult fragility fracture of the spine or hip, or c) 
would be treated based on FRAX and the NOF treatment thresholds of a 10-year 
risk of ≥ 20% for a major fracture or ≥ 3% for hip fracture using femoral neck BMD  
 
We will exclude 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) will be 
excluded. We will exclude those currently on therapy (including a bisphosphonate, 
denosumab or teriparatide) or who have been on a bisphosphonate for greater than 1 year 
during the previous 2 years because some bisphosphonates are long acting We will 
exclude subjects with a history of hypocalcemia or contraindication for treatment. 
 
Intervention: Participants will receive denosumab 60 mg subcutaneous injection or 
matching placebo every 6 months for 2 years. Participants, study personnel and 
investigators are blinded to the treatment assignments. All participants will receive 
appropriate calcium and vitamin D supplementation based on the Bone Health 
Osteoporosis Foundation guidelines. 
  
Assessments: The visits will be conducted in the participant’s LTC facility and participants 
will be assessed every 6 months for 2 years. 


Primary outcomes:  The 24-month percent change in bone mineral density (BMD) of the 
spine and hip.  
 
Randomization and Masking: We will use the high quality pseudo-random deviate generator 
in SAS® (SAS Institute, Inc., Cary, North Carolina) to randomize women and men separately to 
the two treatment groups in a 1:1 ratio. Within each gender, ambulatory status may play a role 
in a participant’s bone integrity, and confound the comparison between groups. Therefore, we 
will further stratify the randomization scheme for each gender with respect to the level of 
assistance required for ambulation (with/without assistance except cane) to force a balance, by 
design, between the arms. Those non-ambulatory will be excluded. We will use a blocked 
randomization scheme to force a within-stratum balance between the numbers of subjects in 
each arm at any point during the recruitment period, and employ a blocking strategy with 
random block sizes. Study statistician will create schedules which link the gender-specific 
randomization sequence number, and treatment arm, and the study research nurses will call in 
all prescriptions thereafter by the randomization sequence number. The independent research 
pharmacist at the institutional Investigational Drug Service will package drugs/placebos to be 
similar in appearance effectively keeping all involved masked to treatment assignment.  
 
Statistical analysis plan: 
 
Main Analysis: 
All analyses will be conducted separately for men and women based on intention-to-treat. 
First, we will perform a true multivariate Hotelling t-test to simultaneously compare baseline 
to 24-month percent change in two primary outcomes (spine and hip BMD) between the 
arms to protect the type I error rate from outcome multiplicity. If significant, subsequent 
analyses will be performed without further adjustment for multiplicity. If not, primary 
outcomes at the primary endpoint will be compared with a conservative Bonferroni 
correction at α=0.05/2=0.025 level. Second, we will fit a series of linear mixed models 
(SAS® MIXED procedure) with (percent) change from baseline in each of the continuous 
outcomes as the dependent variable; treatment arm, follow-up time point (6-/12-/18-/24-
month or as applicable) and their interaction as the fixed effects of interest; baseline value of 
the outcome as the sole and a catch-all covariate as an additional fixed effect to preserve 
the predictability of the primary analytic strategy; and a subject random effect to account for 
multiple measures from the same patients over time and resulting stochastic non-
independence of observations. We will construct contrasts to make between-arm 
comparisons at each time point. Statistical significance of between arm difference in 24-
month change in spine and hip BMD will serve as the formal test of the primary hypothesis. 
Multiple imputation will be used to handle missing data.