Role of Zoledronic Acid in Treating Osteoporosis in Post-Allogeneic Bone Marrow Transplant Patients - A Phase II Trial.

Introduction: Multiple risk factors exist for the development of osteoporosis in patients undergoing allogeneic hematopoietic stem cell transplant. Bone loss is greatest during the first year, predominantly the first 40 days. Bisphosphonate therapy combined with calcium and Vitamin D supplementation in allogeneic stem cell transplant patients may be one useful strategy to prevent the accelerated bone resorption.

Study Design: A Phase II clinical trial studying the role of zoledronic acid (Zometa, Novartis Pharmcaeutical Corporation) in treating post-allogeneic bone marrow transplant(BMT) osteoporosis was undertaken. The study included adult patients undergoing allogeneic BMT for malignant and non-malignant disorders. Patients with plasma cell dyscrasias, thyrotoxicosis, primary and secondary hyperparathyroidism were excluded. Patients received zoledronic acid (4 mg IV over 15 minutes) pre-transplant and every three months thereafter for a total of 4 doses. All patients concomitantly received daily calcium (1000mg) and Vitamin D (400IU) supplements (oral or intravenous). Serial bone density(BMD) measurements at lumbar spine, total hip and forearm using DEXA were scheduled to be done at baseline (pre-transplant), 6 weeks, 6 months, 12 months, and 24 months. Urine NTX was a measured as a surrogate marker for bone turnover.

Results: 22 patients were enrolled between January 2002 and August 2005. BMD data were available at baseline on 20 patients, at 6 weeks on 11 patients, at 6 months on 11 patients, at 1 year on 9, and on 5 patients on 2 years. Random coefficient analyses were performed. A statistically significant reduction in total hip BMD was observed (−3.6%, p<0.001). The reduction for the lumbar spine (−1.1%) was not significant (p=0.416). The observed BMD change was positive at the forearm (+2.4%) and statistically significant (p=0.047). Post-transplant urine N-telopeptide (NTX) measurements were higher than baseline. Severe hypocalcemia (12%) was the only adverse effect attributable to the study drug.

Discussion: Review of recent literature implies that the degree of increased bone resorption pre- and post-BMT is highest at the femoral neck/total hip and can be up to 7.8% in the absence of bisphosphonate therapy. Our data indicates that zoledronic acid helps curtail the expected reduction in bone loss. Bisphoshonate therapy may be needed more frequently and for longer duration. Calcium/Vitamin D supplementation may need replenished more rigorously. Using urine NTX measurements concurrently with BMD to monitor bone turnover and response to treatment is indicated until standards of therapy are established. In conclusion, bisphosphonate therapy with zoledronic acid does impact standard of care for patients after allogeneic stem cell transplantation.