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

Phase 2

Completed

• Conditions: Osteoporosis; Leukemia; Ovarian Cancer; Lymphoma; Myelodysplastic Syndromes
• Interventions: Dietary Supplement: calcium; Dietary Supplement: cholecalciferol; Drug: zoledronic acid

• Registration Number: NCT00321932
• Lead Sponsor: University of Minnesota

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.

Study Timeline

• Study Start: 2005-07
• Study First Submitted: 2006-05-02
• Study First Submitted QC: 2006-05-02
• Study First Posted: 2006-05-04
• Primary Completion: 2011-03
• Study Completion: 2012-03
• Results First Submitted: 2012-05-04
• Results First Submitted QC: 2012-09-26
• Results First Posted: 2012-10-26
• Status Verified: 2017-01
• Last Update Submitted: 2017-01-26
• Last Update Posted: 2017-03-09

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 61

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (control)	calcium	Patients receive oral cholecalciferol (vitamin D) and oral calcium once a day for 12 months.
Arm I (control)	cholecalciferol	Patients receive oral cholecalciferol (vitamin D) and oral calcium once a day for 12 months.
Arm II (treatment)	zoledronic acid	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.
Arm II (treatment)	calcium	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.
Arm II (treatment)	cholecalciferol	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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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 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 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.
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 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 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.

Trial Locations

Locations (2)

Masonic Cancer Center at University of Minnesota; 🇺🇸 Minneapolis, Minnesota, United States

University of Wisconsin Paul P. Carbone Comprehensive Cancer Center; 🇺🇸 Madison, Wisconsin, United States