BETHESDA, MD—Avascular necrosis—usually at the site of the femoral head—is a common adverse event of bone marrow transplantation. So said Peter Ebeling, MD, Deputy Director of the Department of Diabetes and Endocrinology and Associate Professor at the University of Melbourne, Royal Melbourne Hospital, speaking here at the Skeletal Complications of Malignancy Symposium.
The problem, the most serious skeletal complication of bone marrow transplantation, develops in about 10% to 20% of patients undergoing the procedure, which is now the most common form of organ transplant, he said.
If the problem is going to develop, it typically occurs between about three months to one year after the bone marrow transplant. Efforts to combat the condition—especially in the hip—with bisphosphonate therapy have had mixed results, Dr. Ebeling said.
“Rapid bone loss occurs within six months of bone marrow transplantation and occurs preferentially from the femoral neck for reasons that aren't clear. Only part of the bone loss from the femoral neck is explained by glucocorticoid effects. Our current therapy has not been effective in preventing bone loss from the femoral neck. The femoral head is most often affected, but frequently more than one site per patient may be involved.”
However, while the avascular necrosis often occurs within a year after bone marrow transplantation, the bone marrow factors that contribute to normal bone production do not return to normal for as long as 12 years later.
At the meeting cosponsored by the National Cancer Institute, the University of Virginia Health System, and the Paget Foundation, Dr. Ebeling said that possible factors causing avascular necrosis might be related to the transplant procedure itself, to vitamin D deficiency, or to the use of steroids for immunosuppression to prevent graft-versus-host disease.
Growing Body of Literature
Philip McCarthy, Jr., MD, Chief of the Division of Blood and Marrow Transplantation at Roswell Park Cancer Institute, noted that there is a growing body of literature that links osteoporosis and avascular necrosis to bone marrow transplantation.
“We have unpublished data showing that nearly half of all our patients who are evaluated with bone density scans have developed osteoporosis early after bone marrow transplant. We are trying to determine if this is related to prior therapy and transplant or only to the transplant.”
In his presentation, Dr. Ebeling noted that avascular necrosis appears to be far more common in patients undergoing allogeneic rather than autologous transplants.
In allogeneic transplantation there is a greater need for the use of immunosuppressant therapy, including steroids, to prevent graft-versus-host disease rejection of the transplanted bone marrow, he explained.
“We need to think about strategies to prevent this bone loss after bone marrow transplantation,” he said, adding that a small study that used zoledronic acid as the bisphosphonate appeared to slow or prevent bone loss.
The hint of success with that study has prompted him and international colleagues to recruit patients into a protocol that will test whether zoledronic acid after bone marrow transplantation will reduce the incidence of osteoporosis or avascular necrosis.
“We are going to be testing dosing schedules with an abbreviated course of two infusions of 4 mg versus four infusions of 4 mg,” he said.
The study will not be blinded or placebo controlled. All patients will receive calcium and vitamin D. The primary study endpoint will be the effect on femoral neck bone density at 12 months, and the secondary endpoint will be changes in spinal and hip bone density at six and 12 months. The rates of avascular necrosis and fractures in patients from each study arm will be compared after five years.
Dr. Ebeling noted that several studies have investigated the use of other bisphosphonates in attempts to prevent bone loss and avascular necrosis in patients undergoing bone marrow transplantation. In one study, Dr. Ebeling and his team treated patients with pamidronate. The 116 patients were randomized to receive either pamidronate or no pamidronate following allogeneic bone marrow transplantation.
Patients received 90 mg of pamidronate a month for 12 months or no pamidronate. All the patients were given vitamin D and calcium carbonate supplementation daily.
“What we found was again this rapid and severe bone loss at the femoral neck in the control group and also at the total hip but less bone loss at the lumbar spine,” Dr. Ebeling said.
“There was a marked reduction in bone loss at the spine and actually an increase in spinal bone density in the pamidronate group. But we didn't prevent bone loss at the hip.”
Patients on moderate and high doses of prednisolone in the first six months after bone marrow transplantation benefited the most from pamidronate therapy to prevent bone loss, he said. “Perhaps more interestingly, pamidronate did not prevent bone loss from the femoral neck in the patients on low doses of prednisolone,” and other studies with pamidronate have shown similar results.
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