Zoledronic Acid in Preventing Osteoporosis in Patients Undergoing Donor Stem Cell Transplant

A Randomized Phase II of Zoledronic Acid (Zometa) in the Prevention of Osteoporosis in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00321932

Enrollment

Registered

2006-05-04

Start date

2005-07-31

Completion date

2012-03-31

Last updated

2017-03-09

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Leukemia, Lymphoma, Myelodysplastic Syndromes, Osteoporosis, Ovarian Cancer

Brief summary

RATIONALE: Zoledronic acid, vitamin D, and calcium may prevent bone loss in patients who are undergoing donor stem cell transplant. PURPOSE: This randomized phase II trial is studying how well zoledronic acid works in preventing osteoporosis in patients undergoing donor stem cell transplant.

Detailed description

OBJECTIVES: Primary * Evaluate whether prophylactic administration of zoledronic acid can reduce the severity of bone mineral loss in patients undergoing allogeneic hematopoietic stem cell transplantation. Secondary * Determine the safety of zoledronic acid in these patients. OUTLINE: This is a multicenter, open-label, prospective, randomized, controlled study. Patients are stratified according to participating center and type of transplant (myeloablative vs nonmyeloablative). Patients are randomized to 1 of 2 treatment arms. * Arm I (control): Patients receive oral cholecalciferol (vitamin D) and oral calcium once a day for 12 months. * Arm II (treatment): Patients receive vitamin D and calcium as in arm I. Patients also receive zoledronic acid intravenously (IV) over 15-30 minutes at 28 days prior to stem cell transplantation and at 3 and 6 months after transplantation. In both arms, treatment continues in the absence of unacceptable toxicity. After completion of study treatment, patients are followed periodically for up to 12 months.

Interventions

DRUGzoledronic acid

Zoledronic acid (Zometa®) will be administered after randomization (but within 28 days prior to transplant) and at 3 and 6 months after the transplant for a total of 3 doses. The dose of Zometa will be 4 mg intravenous in 100 ml of sterile 0.9% sodium chloride, United States Pharmacopeia (USP), or 5% dextrose, USP infused over a minimum of 15 minutes for patients with a calculated creatinine clearance of ≥60 mL/min. The drug may be administered through a peripheral or a central intravenous line.

DIETARY_SUPPLEMENTcalcium

All randomized patients (control and study drug) will take 1000 mg of calcium and 400 - 500 International Units (IU) of vitamin D orally each day, beginning as soon as possible after study enrollment. These supplements may be taken either in the morning or in the evening with food. Participants will continue taking the supplements on a daily basis until the final study visit (approximately 12 months after the transplant date).

DIETARY_SUPPLEMENTcholecalciferol

Given orally

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Patient age ≥18 years * Undergoing allogeneic hematopoietic stem cell transplantation (HCT) from any stem cell source with either a myeloablative or non-myeloablative conditioning regimen * Bone mineral density measured by baseline pre-transplant DEXA scan in the osteopenic range (defined as a T-score between -1 and -2.5 standard deviation (SD) at either the lumbar spine or the proximal femur or both) * Adequate renal function defined as: Calculated creatinine clearance of ≥ 60 ml/min using the Cockcroft-Gault formula: * Serum calcium (corrected) of ≤ 10.5 mg/dl * Patients (male or female) of reproductive potential are required to use a medically acceptable contraception while receiving zoledronic acid (if assigned study drug). * Normal dental exam within the year prior to study registration * Informed signed consent to participate in the study

Exclusion criteria

* Pre-existing metabolic bone disease including osteomalacia, hyperparathyroid bone disease, osteogenesis imperfecta, Paget's disease, rickets, or hypoparathyroidism. * Multiple myeloma * History of nontraumatic vertebral compression fractures * History of the following endocrine disorders - hyperparathyroidism, hyperthyroidism. * Malabsorption syndrome including Crohn's disease. * Chronic liver disease * Concomitant regular use of phenytoin. * Known hypersensitivity to zoledronic acid (Zometa) or other biphosphonates * Biphosphonate therapy within the preceding six months. * Current active dental problems including infection of the teeth or jawbone (maxilla or mandibular); dental or fixture trauma, or a current or prior diagnosis of osteonecrosis of the jaw (ONJ), of exposed bone in the mouth, or of slow healing after dental procedures. * Recent (within 6 weeks) or planned dental or jaw surgery (e.g. extraction, implants) * Not pregnant or breastfeeding since zoledronic acid is classified as Pregnancy Category C: risk in pregnancy cannot be ruled out. A negative pregnancy test is required within 7 days of registration if pre- or perimenopausal (i.e., last menstrual period within one year of registration). Because it is not known whether zoledronic acid is excreted in breast milk, breastfeeding is not permitted while receiving study drug.

Design outcomes

Primary

Measure	Time frame	Description
Mean Change in Bone Mineral Density	From Time of Transplant to 12 Months Post-Transplant	Change in bone mineral density of the femoral neck measured from baseline to 12 months after transplant utilizing Dual-energy X-ray absorptiometry (DEXA) scan. Comparison of difference between the standard of care group (receiving calcium and vitamin D)and the Zometa group. The measurement consists of baseline bone mineral density measurements with followup measurements at 12 months. This will be analyzed as a continuous variable. Percent change in bone mineral density (BMD) will be calculated as (BMD change) x 100/BMD baseline.

Secondary

Measure	Time frame	Description
Mean Change in Serum Bone Specific Alkaline Phosphate	From Time of Transplant to 12 Months Post-Transplant	Change in bone resorption markers of bone metabolism measured at baseline and 12 months post transplant for all enrolled patients. The decrease in serum bone-specific alkaline phosphatase predicts bone mineral density response to hormone replacement therapy in early postmenopausal women.
Mean Change in Urinary N-terminal Telopeptide	From Time of Transplant to 12 Months Post-Transplant	Change in bone resorption markers of bone metabolism measured at baseline and 12 months post transplant for all enrolled patients. In bone physiology, the N-terminal telopeptide is a biomarker used to measure the rate of bone turnover.
Mean Change in Luteinizing Hormone	From Time of Transplant to 12 Months Post-Transplant	Change in bone resorption markers of bone metabolism measured at baseline and 12 months post transplant for all enrolled patients. Luteinizing hormone is a hormone produced by the anterior pituitary gland.
Mean Change in Serum Osteocalcin	From Time of Transplant to 12 Months Post-Transplant	Change in bone resorption markers of bone metabolism measured at baseline and 12 months post transplant for all enrolled patients. As osteocalcin is produced by osteoblasts, it is often used as a marker for the bone formation process.
Mean Change in Thyroid Function Test 4	From Time of Transplant to 12 Months Post-Transplant	Change in bone resorption markers of bone metabolism measured at baseline and 12 months post transplant for all enrolled patients. Individuals who have hyperthyroidism will have an elevated thyroxine (FT4). Low serum thyroxine can also indicate a pituitary problem.
Mean Change in Ultrasensitive Estradiol	From Time of Transplant to 12 Months Post-Transplant	Change in bone resorption markers of bone metabolism measured at baseline and 12 months post transplant for all enrolled patients. In women estradiol is responsible for growth of the breast and reproductive epithelia, maturation of long bones and development of the secondary sexual characteristics.
Mean Change in Total Testosterone	From Time of Transplant to 12 Months Post-Transplant	Change in bone resorption markers of bone metabolism measured at baseline and 12 months post transplant for all enrolled patients. Testosterone affects the brain, bone and muscle mass, fat distribution, the vascular system, energy levels, genital tissues, and sexual functioning.
Mean Change in Follicle-Stimulating Hormone	From Time of Transplant to 12 Months Post-Transplant	Change in bone resorption markers of bone metabolism measured at baseline and 12 months post transplant for all enrolled patients. Follicle-stimulating hormone is a hormone produced by the anterior pituitary gland.

Countries

United States

Participant flow

Recruitment details

Patients undergoing allogeneic hematopoietic stem cell transplantation (HCT) at participating institutions were offered this trial. If the patient met study requirements, the patient was registered and randomized.

Participants by arm

Arm	Count
Arm I (Standard of Care) Patients receive oral cholecalciferol (vitamin D) and oral calcium once a day for 12 months.	29
Arm II (Treatment With Zometa) Patients receive vitamin D and calcium as in arm I. Patients also receive zoledronic acid IV over 15-30 minutes at 28 days prior to stem cell transplantation and at 3 and 6 months after transplantation.	32
Total	61

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Death	3	6
Overall Study	Early relapse	2	8
Overall Study	Missing data	2	1
Overall Study	Withdrawal by Subject	3	6

Baseline characteristics

Characteristic	Arm II (Treatment With Zometa)	Arm I (Standard of Care)	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	32 Participants	29 Participants	61 Participants
Age, Continuous	51 years STANDARD_DEVIATION 12	51 years STANDARD_DEVIATION 10	51 years STANDARD_DEVIATION 11
Region of Enrollment United States	32 participants	29 participants	61 participants
Sex: Female, Male Female	9 Participants	13 Participants	22 Participants
Sex: Female, Male Male	23 Participants	16 Participants	39 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	0 / 0	0 / 0
serious Total, serious adverse events	8 / 29	21 / 32

Outcome results

Primary

Mean Change in Bone Mineral Density

Change in bone mineral density of the femoral neck measured from baseline to 12 months after transplant utilizing Dual-energy X-ray absorptiometry (DEXA) scan. Comparison of difference between the standard of care group (receiving calcium and vitamin D)and the Zometa group. The measurement consists of baseline bone mineral density measurements with followup measurements at 12 months. This will be analyzed as a continuous variable. Percent change in bone mineral density (BMD) will be calculated as (BMD change) x 100/BMD baseline.