Prevention of Osteoporosis in Bone Marrow Transplantation (BMT) Patients

A Randomized, Controlled Study of Ibandronate for the Prevention of Bone Loss in Patients Who Have Received Allogeneic Bone Marrow Transplantation for Hematological Malignancies

The goal of this clinical research study is to see if ibandronate can help to slow the rate of bone loss that may occur in patients who have received a bone marrow transplant for blood cancer.

This study plans to address the following hypotheses:

1. The addition of Ibandronate initiated immediately after the transplantation will prevent bone loss in patients undergoing allogenic bone marrow transplantation (BMT) with underlying hematologic malignancies or hematologic disorders.
2. BMT patients who require prolonged steroid and other immunosuppressive treatment for Graft versus Host Diseases(GVHD) have a higher rate of bone loss, which can be prevented or attenuated by Ibandronate.

Specific objectives to test these hypotheses are:

1. Primary Objective:

   1. To prospectively compare the bone mineral density changes of lumbar spine, femoral neck and total hip between patients randomly assigned to ibandronate and control group over 12 months post bone marrow transplantation at the University of Texas MD Anderson Cancer Center.

2. Secondary Objectives:

   1. To measure and compare the accumulated level of steroid used in both treatment and control groups.
   2. To collect and compare the level of serum C-terminal telopeptide (CTX) in both treatment and control groups to monitor the bone turnover rate for the duration of the study.
   3. To conduct a cost-effectiveness analysis of participating patients for both outcomes on bone mineral density (measured data) and skeletal-related events (modeled data).
   4. To record incidence of bone fractures and the graft rate in both treatment and control groups.

The Study Drug:

Ibandronate is designed to slow the rate of bone loss.

Screening Process:

Before you can receive the study drug, the study doctor will check the results of various tests that you recently had performed as part of standard care for the bone marrow transplant. These test results will help the doctor decide if you are eligible to take part in this study.

Study Groups:

If you are found to be eligible to take part in the study and you choose to take part, you will be randomly assigned (as in the toss of a coin) to 1 of 2 study groups. Group 1 (the "treatment" group) will receive ibandronate in addition to calcium and vitamin D supplements. Group 2 will only receive the calcium and vitamin D supplements. The chance of being in either group is equal.

Study Visits:

For both groups, you will be visited by a research team member during your hospital stay soon after the transplant (at Month Zero [0]), and during routine visits to your transplant doctor's office at Months 3, 6, and 9 after the transplant. At each of these study visits, you will be asked how you are feeling, as well as whether you have had any bone fractures (breakages).

At Months 0, 3, 6, and 9 after the transplant, blood (up to 1 tablespoon each time) will be drawn for routine tests for your transplant follow-up. As part of this same blood draw, an additional ½ tablespoon of blood will be drawn during each study visit (at Months 0, 3, 6, and 9). This blood will be tested for a "marker" in the bone that may help researchers predict who may respond to treatment.

If you are in the "treatment" group, you will receive a total of 4 ibandronate infusions by vein (over 15-30 seconds each time). These study drug infusions will take place in the hospital or at your routine visit to the transplant doctor's office at 3-6 weeks after the transplant, and at Months 3, 6, and 9 after the transplant.

At Month 6, all study participants will have a study-related (non-routine) bone density test (an x-ray) performed to check for bone loss. If the test results show that you have lost an abnormally large amount of bone mineral, you will be taken off study and also advised about treatment options.

Vitamin Supplements:

All study participants will receive a supply of calcium and vitamin D to take at home, for general bone health. These supplements should be taken by mouth, twice a day for 12 months. If you do not tolerate the supplements provided by the research study, you may take another brand of calcium/Vitamin D that you buy over-the-counter. The doses that you take each time (twice daily) should be 500 mg for calcium and 400 International Units (IU) for Vitamin D.

Cost Analysis:

Researchers on this study also want to look at how cost-effective the different procedures and treatments are on this study. To do this, they will use information from your patient records, pharmacy records, and other information of yours on M. D. Anderson databases. You will not be asked to actively participate in any interviews or procedures for these studies, but you should be aware that this research will take place while you are study.

End-of-Study Visit:

You will be visited by a research team member during your routine visit to your transplant doctor's office at Month 12 after the transplant. At this visit, you will be asked how you are feeling as well as whether you have had any bone fractures. Your doctor will check this by x-ray, if you do not have an outside x-ray film available. Blood (up to 1 tablespoon) will be drawn for routine tests. As part of this same blood draw, an additional ½ tablespoon of blood will be drawn to test for the same bone marker. You will have a routine bone density test (an x-ray) performed to check for bone loss. After these tests, your participation in this study will be over.

This is an investigational study. Ibandronate is commercially available and FDA approved for use in the prevention and treatment of bone loss in women who have been through menopause. However, its use in slowing the rate of bone loss in patients who have had a bone marrow transplant is considered experimental. For this purpose, the M. D. Anderson Institutional Review Board (IRB) has authorized the use of ibandronate for research only. The IRB is a committee made up of doctors, researchers, and members of the community. The IRB is responsible for protecting the participants involved in research studies and making sure all research is done in a safe and ethical manner.

Up to 200 patients will take part in this study. All will be enrolled at M. D. Anderson.

Inclusion Criteria:

1. Age greater than or equal to 18 years.
2. Patients with the diagnosis of hematologic malignancies or hematological disorders, who are immediately post- allogeneic bone marrow transplantation.
3. Female patients of childbearing potential (i.e. no hysterectomy, no loss of menses for 12 consecutive months), must be willing to use contraception.
4. Negative pregnancy test in premenopausal patients.
5. Patients with GVHD or infections can be entered only if they respond to treatment and become controlled.
6. Dental considerations: patients with negative dental screening for jaw osteonecrosis 0-3 months prior to their transplant and patients that do not have a plan for tooth extraction in the near future.

Exclusion Criteria:

1. Patients with documented relapsed malignancy or recurrence of the original hematological disorder after the transplant, uncontrolled acute GVHD, or uncontrolled infection.
2. Patients with hypocalcemia of less than 8.4 (corrected to account for the albumin level).
3. Patients with hypercalcemia >12.2, due to a cause not related to their hematological malignancy or hematological disorder (i.e. hyperparathyroidism, multiple myeloma).
4. Hypersensitivity to Ibandronate or other bisphosphonates.
5. Pre-existing osteoporosis, defined as a bone density T-score of -2.5 S.D. or less.
6. Renal insufficiency (calculated creatinine clearance < 30 ml/min).
7. Patients already on bisphosphonates (over the past two years), calcitonin, anabolic steroids, or daily oral fluoride supplement.
8. Myeloma patients who have previously been on bisphosphonates over the past two years and/or have active bone lesions.
9. If corrected calcium is above 10.3 and the immunoreactive parathyroid hormone (iPTH) is elevated or normal, the patient will be excluded from the study.
10. Patients with a 25-hydroxyvitamin D concentration <20 ng/ml and evidence of osteomalacia (low ionized calcium and elevated intact PTH).
11. Dental considerations: Patients with recent tooth extraction with signs of incomplete healing or significant infection will be excluded.