Osteoporosis, Postmenopausal, Osteoporosis, Osteoporotic Fractures
Conditions
Keywords
Bone loss, Frail Geriatric Patients, Nursing Home Patients, Long-term Care Patients, Osteoporosis, Osteoporotic Fractures
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.
Interventions
DRUGdenosumab
Semi-annual dose: 60 mg injection; Vitamin D 800-1000 IU/daily and Calcium approximately 1200 mg/daily (dietary + supplement)
DRUGPlacebo
Semi-annual saline injection
DIETARY_SUPPLEMENTCalcium and Vitamin D
Dietary supplement: Vitamin D 800-1000 IU/daily and Calcium approximately 1200 mg/daily (dietary + supplement)
Sponsors
National Institutes of Health (NIH)
National Institute on Aging (NIA)
Susan L. Greenspan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Bone Density of the Total Hip | 24 months | Bone Mineral Density (BMD) of the total hip percent change over 24 months as assessed by dual-energy x-ray absorptiometry (DXA) |
| Bone Density of the Spine | 24 months | Bone Mineral Density (BMD) of the spine percent change over 24 months as assessed by dual-energy x-ray absorptiometry (DXA) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| TBS | 24 Months | Trabecular Bone Score (TBS) Percent change over 24 months. This not a scale. Higher values are better. |
| Femoral Neck BMD | 24 Months | Percent change over 24 months |
| Distal Radius BMD | 24 Months | Percent change over 24 months |
Other
| Measure | Time frame | Description |
|---|---|---|
| CTX | 12 Months | Bone Turnover Marker change from Baseline |
| P1NP | 12 Months | Bone Turnover Marker Change from Baseline |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Women Denosumab 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).
denosumab: Semi-annual dose: 60 mg injection; Vitamin D 800-1000 IU/daily and Calcium approximately 1200 mg/daily (dietary + supplement)
Calcium and Vitamin D: Dietary supplement: Vitamin D 800-1000 IU/daily and Calcium approximately 1200 mg/daily (dietary + supplement) | 62 |
| Women Placebo Group Semi-annual for women: placebo saline injection; Vitamin D 800-1000 IU/daily and Calcium approximately1200 mg/daily (dietary + supplements).
Placebo: Semi-annual saline injection
Calcium and Vitamin D: Dietary supplement: Vitamin D 800-1000 IU/daily and Calcium approximately 1200 mg/daily (dietary + supplement) | 61 |
| Men Denosumab 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).
denosumab: Semi-annual dose: 60 mg injection; Vitamin D 800-1000 IU/daily and Calcium approximately 1200 mg/daily (dietary + supplement)
Calcium and Vitamin D: Dietary supplement: Vitamin D 800-1000 IU/daily and Calcium approximately 1200 mg/daily (dietary + supplement) | 40 |
| Men Placebo Group Semi-annual for men: placebo saline injection; Vitamin D 800-1000 IU/daily and Calcium approximately1200 mg/daily (dietary + supplements).
Placebo: Semi-annual saline injection
Calcium and Vitamin D: Dietary supplement: Vitamin D 800-1000 IU/daily and Calcium approximately 1200 mg/daily (dietary + supplement) | 38 |
| Total | 201 |
Baseline characteristics
| Characteristic | Women Denosumab | Women Placebo Group | Men Denosumab | Men Placebo Group | Total |
|---|---|---|---|---|---|
| Age, Continuous | 81.5 Years STANDARD_DEVIATION 7.6 | 80.0 Years STANDARD_DEVIATION 9 | 82.6 Years STANDARD_DEVIATION 8.9 | 82.7 Years STANDARD_DEVIATION 7.6 | 81.5 Years STANDARD_DEVIATION 8.3 |
| Bone Density of Spine | 1.038 g/cm^2 STANDARD_DEVIATION 0.178 | 1.044 g/cm^2 STANDARD_DEVIATION 0.187 | 1.221 g/cm^2 STANDARD_DEVIATION 0.217 | 1.204 g/cm^2 STANDARD_DEVIATION 0.205 | 1.108 g/cm^2 STANDARD_DEVIATION 0.21 |
| Bone Density of the Hip | .783 g/cm^2 STANDARD_DEVIATION 0.114 | .748 g/cm^2 STANDARD_DEVIATION 0.142 | .923 g/cm^2 STANDARD_DEVIATION 0.163 | .884 g/cm^2 STANDARD_DEVIATION 0.143 | .821 g/cm^2 STANDARD_DEVIATION 0.154 |
| Race/Ethnicity, Customized Black | 4 participants | 6 participants | 1 participants | 1 participants | 12 participants |
| Race/Ethnicity, Customized Other | 0 participants | 0 participants | 2 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized White | 58 participants | 55 participants | 37 participants | 37 participants | 187 participants |
| Sex: Female, Male Female | 62 Participants | 61 Participants | 0 Participants | 0 Participants | 123 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 40 Participants | 38 Participants | 78 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 62 | 4 / 61 | 4 / 40 | 2 / 38 |
| other Total, other adverse events | 46 / 62 | 50 / 61 | 32 / 40 | 33 / 38 |
| serious Total, serious adverse events | 21 / 62 | 26 / 61 | 21 / 40 | 15 / 38 |
Outcome results
Primary
Bone Density of the Spine
Bone Mineral Density (BMD) of the spine percent change over 24 months as assessed by dual-energy x-ray absorptiometry (DXA)
Time frame: 24 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Women Denosumab | Bone Density of the Spine | 7.41 Percent change | Standard Error 0.93 |
| Women Placebo Group | Bone Density of the Spine | 2.15 Percent change | Standard Error 0.56 |
| Men Denosumab | Bone Density of the Spine | 7.91 Percent change | Standard Error 0.96 |
| Men Placebo Group | Bone Density of the Spine | 1.12 Percent change | Standard Error 1.13 |
p-value: 0.014Mixed Models Analysis
p-value: 0.002Mixed Models Analysis
Primary
Bone Density of the Total Hip
Bone Mineral Density (BMD) of the total hip percent change over 24 months as assessed by dual-energy x-ray absorptiometry (DXA)
Time frame: 24 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Women Denosumab | Bone Density of the Total Hip | 4.62 Percent change | Standard Error 0.62 |
| Women Placebo Group | Bone Density of the Total Hip | -0.19 Percent change | Standard Error 0.79 |
| Men Denosumab | Bone Density of the Total Hip | 3.74 Percent change | Standard Error 0.55 |
| Men Placebo Group | Bone Density of the Total Hip | 0.48 Percent change | Standard Error 0.74 |
p-value: 0.007Mixed Models Analysis
p-value: 0.018Mixed Models Analysis
Secondary
Distal Radius BMD
Percent change over 24 months
Time frame: 24 Months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Women Denosumab | Distal Radius BMD | 2.030 Percent change from baseline | Standard Deviation 3.322 |
| Women Placebo Group | Distal Radius BMD | -.376 Percent change from baseline | Standard Deviation 3.894 |
| Men Denosumab | Distal Radius BMD | 2.386 Percent change from baseline | Standard Deviation 4.187 |
| Men Placebo Group | Distal Radius BMD | -1.115 Percent change from baseline | Standard Deviation 3.455 |
p-value: 0.06Mixed Models Analysis
p-value: 0.055Mixed Models Analysis
Secondary
Femoral Neck BMD
Percent change over 24 months
Time frame: 24 Months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Women Denosumab | Femoral Neck BMD | 3.212 Percent change from baseline | Standard Deviation 5.207 |
| Women Placebo Group | Femoral Neck BMD | .185 Percent change from baseline | Standard Deviation 4.195 |
| Men Denosumab | Femoral Neck BMD | 2.932 Percent change from baseline | Standard Deviation 3.574 |
| Men Placebo Group | Femoral Neck BMD | -.958 Percent change from baseline | Standard Deviation 5.926 |
p-value: 0.112Mixed Models Analysis
p-value: 0.07Mixed Models Analysis
Secondary
TBS
Trabecular Bone Score (TBS) Percent change over 24 months. This not a scale. Higher values are better.
Time frame: 24 Months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Women Denosumab | TBS | 3.007 Percent change from baseline | Standard Deviation 5.99 |
| Women Placebo Group | TBS | 1.099 Percent change from baseline | Standard Deviation 5.498 |
| Men Denosumab | TBS | 2.370 Percent change from baseline | Standard Deviation 6.645 |
| Men Placebo Group | TBS | 3.318 Percent change from baseline | Standard Deviation 6.688 |
p-value: 0.904Mixed Models Analysis
p-value: 0.616Mixed Models Analysis
Other Pre-specified
CTX
Bone Turnover Marker change from Baseline
Time frame: 12 Months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Women Denosumab | CTX | -.190 nmol/L | Standard Deviation 0.206 |
| Women Placebo Group | CTX | -.078 nmol/L | Standard Deviation 0.181 |
| Men Denosumab | CTX | -.178 nmol/L | Standard Deviation 0.211 |
| Men Placebo Group | CTX | -.071 nmol/L | Standard Deviation 0.177 |
p-value: <0.001Mixed Models Analysis
p-value: 0.005Mixed Models Analysis
Other Pre-specified
P1NP
Bone Turnover Marker Change from Baseline
Time frame: 12 Months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Women Denosumab | P1NP | -25.345 ug/L | Standard Deviation 21.367 |
| Women Placebo Group | P1NP | -3.158 ug/L | Standard Deviation 22.633 |
| Men Denosumab | P1NP | -19.539 ug/L | Standard Deviation 28.219 |
| Men Placebo Group | P1NP | -10.731 ug/L | Standard Deviation 21.548 |
p-value: 0.001Mixed Models Analysis
p-value: 0.038Mixed Models Analysis