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

• Sponsor: University of Minnesota (Other)
• Overall Status: Completed
• CT.gov ID: NCT00321932
• Collaborator: (none)
• Enrollment: 61
• Locations: 2
• Arms: 2
• Duration (Months): 80
• Patients Per Site: 30.5
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia; Lymphoma; Myelodysplastic Syndromes; Osteoporosis; Ovarian Cancer	Dietary Supplement: calcium; Dietary Supplement: cholecalciferol; Drug: zoledronic acid	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 61 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase II of Zoledronic Acid (Zometa) in the Prevention of Osteoporosis in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
• Study Start Date: Jul 1, 2005
• Actual Primary Completion Date: Mar 1, 2011
• Actual Study Completion Date: Mar 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm I (control) Patients receive oral cholecalciferol (vitamin D) and oral calcium once a day for 12 months.	Dietary Supplement: calcium; 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).; Other Names: calcium carbonate calcium citrate calcium gluconate ; Dietary Supplement: cholecalciferol; Given orally
Experimental: 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.	Dietary Supplement: calcium; 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).; Other Names: calcium carbonate calcium citrate calcium gluconate ; Dietary Supplement: cholecalciferol; Given orally; Drug: zoledronic 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.; Other Names: Zometa(R)

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Masonic Cancer Center at University of Minnesota	Minneapolis	Minnesota	United States	55455
2	University of Wisconsin Paul P. Carbone Comprehensive Cancer Center	Madison	Wisconsin	United States	53792-6164

Sponsors and Collaborators

• University of Minnesota

Investigators

• Study Chair: Linda J. Burns, MD, Masonic Cancer Center, University of Minnesota

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Minnesota
• ClinicalTrials.gov Identifier: NCT00321932
• Other Study ID Numbers: 2005NT018; UMN-0506M70866; UMN-MT2005-06; NOVARTIS-CZOL446EUS29
• First Posted: May 4, 2006
• Last Update Posted: Mar 9, 2017
• Last Verified: Jan 1, 2017

• Additional relevant MeSH terms: Osteoporosis; Myelodysplastic Syndromes; Calcium, Dietary; Cholecalciferol; Zoledronic Acid; Calcium Carbonate; Calcium

Study Results

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.

Arm/Group Title	Arm I (Standard of Care)	Arm II (Treatment With Zometa)
Arm/Group Description	Patients receive oral cholecalciferol (vitamin D) and oral calcium once a day for 12 months.	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.
Period Title: Overall Study
STARTED	29	32
COMPLETED	19	11
NOT COMPLETED	10	21

Baseline Characteristics

Arm/Group Title	Arm I (Standard of Care)	Arm II (Treatment With Zometa)	Total
Arm/Group Description	Patients receive oral cholecalciferol (vitamin D) and oral calcium once a day for 12 months.	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.	Total of all reporting groups
Overall Participants	29	32	61
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	29 100%	32 100%	61 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51 (10)	51 (12)	51 (11)
Sex: Female, Male (Count of Participants)
Female	13 44.8%	9 28.1%	22 36.1%
Male	16 55.2%	23 71.9%	39 63.9%
Region of Enrollment (participants) [Number]
United States	29 100%	32 100%	61 100%

Outcome Measures

1. Primary Outcome

Title	Mean Change in Bone Mineral Density
Description	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.
Time Frame	From Time of Transplant to 12 Months Post-Transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Standard of Care)	Arm II (Treatment With Zometa)
Arm/Group Description	Patients receive oral cholecalciferol (vitamin D) and oral calcium once a day for 12 months.	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.
Measure Participants	29	32
Mean (Standard Deviation) [percent]	-0.0714 (0.101)	-0.0036 (0.089)

2. Secondary Outcome

Title	Mean Change in Serum Osteocalcin
Description	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.
Time Frame	From Time of Transplant to 12 Months Post-Transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Standard of Care)	Arm II (Treatment With Zometa)
Arm/Group Description	Patients receive oral cholecalciferol (vitamin D) and oral calcium once a day for 12 months.	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.
Measure Participants	29	32
Mean (Standard Deviation) [ng/ml]	-3.6 (24.1)	-11.3 (7.6)

3. Secondary Outcome

Title	Mean Change in Serum Bone Specific Alkaline Phosphate
Description	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.
Time Frame	From Time of Transplant to 12 Months Post-Transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Standard of Care)	Arm II (Treatment With Zometa)
Arm/Group Description	Patients receive oral cholecalciferol (vitamin D) and oral calcium once a day for 12 months.	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.
Measure Participants	29	32
Mean (Standard Deviation) [U/L]	-3.0 (5.7)	-4.3 (5.6)

4. Secondary Outcome

Title	Mean Change in Urinary N-terminal Telopeptide
Description	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.
Time Frame	From Time of Transplant to 12 Months Post-Transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Standard of Care)	Arm II (Treatment With Zometa)
Arm/Group Description	Patients receive oral cholecalciferol (vitamin D) and oral calcium once a day for 12 months.	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.
Measure Participants	29	32
Mean (Standard Deviation) [nM Bone Collagen Equivalents/mM creatini]	-22.5 (137.7)	-103.0 (137.7)

5. Secondary Outcome

Title	Mean Change in Luteinizing Hormone
Description	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.
Time Frame	From Time of Transplant to 12 Months Post-Transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Standard of Care)	Arm II (Treatment With Zometa)
Arm/Group Description	Patients receive oral cholecalciferol (vitamin D) and oral calcium once a day for 12 months.	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.
Measure Participants	29	32
Mean (Standard Deviation) [IU/L]	18.8 (21.6)	12.8 (16.8)

6. Secondary Outcome

Title	Mean Change in Follicle-Stimulating Hormone
Description	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.
Time Frame	From Time of Transplant to 12 Months Post-Transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Standard of Care)	Arm II (Treatment With Zometa)
Arm/Group Description	Patients receive oral cholecalciferol (vitamin D) and oral calcium once a day for 12 months.	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.
Measure Participants	29	32
Mean (Standard Deviation) [IU/L]	14.0 (46.7)	6.6 (6.5)

7. Secondary Outcome

Title	Mean Change in Thyroid Function Test 4
Description	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.
Time Frame	From Time of Transplant to 12 Months Post-Transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Standard of Care)	Arm II (Treatment With Zometa)
Arm/Group Description	Patients receive oral cholecalciferol (vitamin D) and oral calcium once a day for 12 months.	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.
Measure Participants	29	32
Mean (Standard Deviation) [ng/dL]	-0.6 (2.2)	-0.2 (0.9)

8. Secondary Outcome

Title	Mean Change in Ultrasensitive Estradiol
Description	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.
Time Frame	From Time of Transplant to 12 Months Post-Transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Standard of Care)	Arm II (Treatment With Zometa)
Arm/Group Description	Patients receive oral cholecalciferol (vitamin D) and oral calcium once a day for 12 months.	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.
Measure Participants	29	32
Mean (Standard Deviation) [pg/ml]	-3.6 (19.4)	-6.3 (21.0)

9. Secondary Outcome

Title	Mean Change in Total Testosterone
Description	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.
Time Frame	From Time of Transplant to 12 Months Post-Transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Standard of Care)	Arm II (Treatment With Zometa)
Arm/Group Description	Patients receive oral cholecalciferol (vitamin D) and oral calcium once a day for 12 months.	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.
Measure Participants	29	32
Mean (Standard Deviation) [ng/dL]	-65.4 (130.4)	-23.6 (140.0)

Adverse Events

Time Frame	Serious adverse events are collected from first dose of study medication through 30 days of the last dose of treatment. Any death that occured within one year of first treatment is also included.
Adverse Event Reporting Description	Adverse reactions to Zometa® (zoledronic acid for injection) are usually mild and transient and similar to those reported for other bisphosphonates. Therefore, only serious events were collected.
Arm/Group Title	Arm I (Standard of Care)		Arm II (Treatment With Zometa)
Arm/Group Description	Patients receive oral cholecalciferol (vitamin D) and oral calcium once a day for 12 months.		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.
All Cause Mortality
	Arm I (Standard of Care)		Arm II (Treatment With Zometa)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm I (Standard of Care)		Arm II (Treatment With Zometa)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/29 (27.6%)		21/32 (65.6%)
Blood and lymphatic system disorders
Graft-versus-host disease	0/29 (0%)	0	2/32 (6.3%)	2
Nosebleed	1/29 (3.4%)	1	0/32 (0%)	0
Pseudomonas sepsis	0/29 (0%)	0	1/32 (3.1%)	1
General disorders
Death	6/29 (20.7%)	6	15/32 (46.9%)	15
Infections and infestations
Infection with unknown absolute neutrophil count	0/29 (0%)	0	2/32 (6.3%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
New Malignancy	0/29 (0%)	0	1/32 (3.1%)	1
Respiratory, thoracic and mediastinal disorders
Idiopathic pulmonary syndrome	1/29 (3.4%)	1	0/32 (0%)	0
Other (Not Including Serious) Adverse Events
	Arm I (Standard of Care)		Arm II (Treatment With Zometa)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.