Bone Resorption, Heart Transplantation, Liver Transplantation
Conditions
Keywords
Heart Transplantation, Liver Transplantation, Immunosuppression, Bone Density/drug effects, Alendronate, Zoledronic acid, Comparative study, Humans
Brief summary
The purpose of this study is to compare the effectiveness and safety of zoledronic acid with alendronate in the prevention of bone loss after organ transplantation. Zoledronic acid is given as a single intravenous infusion. Alendronate is given as a weekly pill. Both are expected to be very effective, but it is not known which one will work best.
Detailed description
Patients who have undergone heart or liver transplantation are usually required to remain on medications, such as Prednisone and Cyclosporine A or Tacrolimus, that prevent the body from rejecting the transplanted organ. These medications may cause bone loss which leads to thinning of the bones (osteoporosis) and therefore greatly increase the risk of having broken bones (fractures) after transplantation. Several published studies have shown that 14% to 35% of heart transplant patients develop fractures (spine, ribs and hip) during the first year after transplantation. We have previously shown that alendronate (Fosamax), a drug approved by the FDA for prevention and treatment of postmenopausal osteoporosis and prednisone-induced osteoporosis, prevents bone loss after heart transplantation. We are conducting this study to determine whether a newer drug, zoledronic acid, is as effective as alendronate. This study is a randomized, double-blind, placebo-controlled 2-year study. Participants will receive one dose of active zoledronic acid during the first month after heart or liver transplantation and weekly placebo alendronate pills or one dose of placebo zoledronic acid and weekly active alendronate pills for the first year after transplant. Over 2 years, participants will provide blood samples on nine occasions. Bone density will be performed 4-5 times and spine xrays will be performed twice.
Interventions
DRUGZoledronic acid
Drug is administered through 5 mg intravenous infusion over 20 minutes
DRUGAlendronate
Alendronate 70 mg will be taken once a week in the morning at least 30-60 minutes before first meal
OTHERPlacebo Zoledronic Acid
Infusion of placebo zoledronic acid during the first 5 weeks after transplantation
OTHERPlacebo Alendronate
Placebo alendronate 70 mg once weekly
Sponsors
Novartis Pharmaceuticals
Columbia University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* A man or woman, aged 20 to 70, of any race who has had a heart or liver transplant
Exclusion criteria
* hyperparathyroidism * Paget's disease * hyperthyroidism * cancer * severe kidney disease, * intestinal disease * active peptic ulcer disease * current or past treatment for osteoporosis * pregnancy or lactation * severe oral/dental disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From Baseline in Total Hip Bone Mineral Density (BMD) at 12 Months | Baseline, 12 months | BMD was measured by dual-energy x-ray absorptiometry (QDR-4500 densitometer; Hologic, Inc., Bedford, MA); short-term in vivo coefficient of variation is 0.68% (spine) and 1.36% (femoral neck). T scores were generated using gender-specific databases provided by the manufacturer. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) at 12 Months | Baseline, 12 months | BMD was measured by dual-energy x-ray absorptiometry (QDR-4500 densitometer; Hologic, Inc., Bedford, MA); short-term in vivo coefficient of variation is 0.68% (spine) and 1.36% (femoral neck). T scores were generated using gender-specific databases provided by the manufacturer. |
| Percentage Change From Baseline in Femoral Neck Bone Mineral Density (BMD) at 12 Months | Baseline, 12 months | BMD was measured by dual-energy x-ray absorptiometry (QDR-4500 densitometer; Hologic, Inc., Bedford, MA); short-term in vivo coefficient of variation is 0.68% (spine) and 1.36% (femoral neck). T scores were generated using gender-specific databases provided by the manufacturer. |
| Serum N-telopeplide Percent Change | 24 months | — |
Countries
United States
Participant flow
Recruitment details
Men and women, aged 20 to 70 yr, who had undergone heart or liver transplantation at CUMC were eligible. Of 495 patients transplanted between 3/2006 and 7/2009, 235 were ineligible. 149 patients declined or were not approached. 84 were randomized, 43 to alendronate and 41 to zoledronate. 27 were the reference group since they refused randomization.
Pre-assignment details
Serum creatinine levels above 2.0 mg/dl, or enrollment in another clinical trial
Participants by arm
| Arm | Count |
|---|---|
| Active Zoledronic Acid and Placebo Alendronate Group 1 will receive an infusion of active zoledronic acid 5 mg during the first 4 weeks after transplantation. Placebo alendronate 70 mg once weekly will be initiated at the same time as the first zoledronic acid infusion. | 41 |
| Placebo Infusion and Active Alendronate Group 2 will receive an infusion of placebo during the first 5 weeks after transplantation. Active alendronate 70 mg once weekly will be initiated at the same time as the placebo infusion. | 43 |
| Reference Group The reference group included concurrently transplanted patients with T scores of -1.5 or greater. | 27 |
| Total | 111 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| 12 Month Visit | Adverse Event | 0 | 3 | 0 |
| 12 Month Visit | Lost to Follow-up | 1 | 0 | 0 |
| 12 Month Visit | Withdrawal by Subject | 0 | 3 | 0 |
| 6 Month Visit | Adverse Event | 0 | 1 | 0 |
| 6 Month Visit | Death | 1 | 0 | 2 |
| 6 Month Visit | Withdrawal by Subject | 2 | 1 | 1 |
Baseline characteristics
| Characteristic | Active Zoledronic Acid and Placebo Alendronate | Placebo Infusion and Active Alendronate | Reference Group | Total |
|---|---|---|---|---|
| Age, Continuous | 55 years STANDARD_DEVIATION 8 | 54 years STANDARD_DEVIATION 10 | 48 years STANDARD_DEVIATION 15 | 52.9 years STANDARD_DEVIATION 11.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 12 Participants | 5 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 37 Participants | 31 Participants | 22 Participants | 90 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 11 Participants | 8 Participants | 7 Participants | 26 Participants |
| Sex: Female, Male Male | 30 Participants | 35 Participants | 20 Participants | 85 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 14 / 41 | 11 / 43 | 0 / 27 |
| serious Total, serious adverse events | 21 / 41 | 14 / 43 | 2 / 27 |
Outcome results
Primary
Percentage Change From Baseline in Total Hip Bone Mineral Density (BMD) at 12 Months
BMD was measured by dual-energy x-ray absorptiometry (QDR-4500 densitometer; Hologic, Inc., Bedford, MA); short-term in vivo coefficient of variation is 0.68% (spine) and 1.36% (femoral neck). T scores were generated using gender-specific databases provided by the manufacturer.
Time frame: Baseline, 12 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Active Zoledronic Acid and Placebo Alendronate | Percentage Change From Baseline in Total Hip Bone Mineral Density (BMD) at 12 Months | 0.39 percent change |
| Placebo Zoledronic Acid and Active Alendronate | Percentage Change From Baseline in Total Hip Bone Mineral Density (BMD) at 12 Months | -0.21 percent change |
| Reference Group | Percentage Change From Baseline in Total Hip Bone Mineral Density (BMD) at 12 Months | -2.2 percent change |
Secondary
Percentage Change From Baseline in Femoral Neck Bone Mineral Density (BMD) at 12 Months
BMD was measured by dual-energy x-ray absorptiometry (QDR-4500 densitometer; Hologic, Inc., Bedford, MA); short-term in vivo coefficient of variation is 0.68% (spine) and 1.36% (femoral neck). T scores were generated using gender-specific databases provided by the manufacturer.
Time frame: Baseline, 12 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Active Zoledronic Acid and Placebo Alendronate | Percentage Change From Baseline in Femoral Neck Bone Mineral Density (BMD) at 12 Months | 0.28 percent change |
| Placebo Zoledronic Acid and Active Alendronate | Percentage Change From Baseline in Femoral Neck Bone Mineral Density (BMD) at 12 Months | -0.57 percent change |
| Reference Group | Percentage Change From Baseline in Femoral Neck Bone Mineral Density (BMD) at 12 Months | -3.3 percent change |
Secondary
Percentage Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) at 12 Months
BMD was measured by dual-energy x-ray absorptiometry (QDR-4500 densitometer; Hologic, Inc., Bedford, MA); short-term in vivo coefficient of variation is 0.68% (spine) and 1.36% (femoral neck). T scores were generated using gender-specific databases provided by the manufacturer.
Time frame: Baseline, 12 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Active Zoledronic Acid and Placebo Alendronate | Percentage Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) at 12 Months | 1.98 percent change |
| Placebo Zoledronic Acid and Active Alendronate | Percentage Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) at 12 Months | -0.45 percent change |
| Reference Group | Percentage Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) at 12 Months | -2.6 percent change |
Secondary
Serum N-telopeplide Percent Change
Time frame: 24 months
Population: Serum n-telopeplide percent change was not collected.