Bone Loss in Patients with Previously Untreated Lymphoma: The Effect of Periodontal Disease on the Use of Zoledronic Acid

Treatment of lymphoma with alkylating agents and steroids is known to cause bone loss and increased fracture risk. These effects result from multiple causes including systemic lymphoma-related cytokine activity, steroid-mediated bone loss, and therapy-induced hypogonadism. Furthermore, over half of all untreated lymphoma patients are either osteopenic or osteoporotic at the time of diagnosis.^1,2 Pamidronate is known to reduce bone loss and risk of vertebral fractures in lymphoma patients undergoing chemotherapy. However, the effects of the more potent bisphosphonate zoledronic acid in this setting are unknown. Therefore, we report on an ongoing phase III trial designed to evaluate the effect of zoledronic acid on the change in bone mineral density (BMD) in patients with newly-diagnosed lymphoma undergoing chemotherapy. In total, 72 patients will be randomized to either the control arm consisting of therapy with calcium carbonate (1200 mg orally per day) plus vitamin D (400 mg orally per day), or the bisphosphonate arm consisting of therapy with calcium carbonate and vitamin D as in the control arm plus zoledronic acid (4 mg IV given at baseline and at 6 months). The primary endpoint of the study is to compare the absolute change between the baseline and 12-month measures of BMD at the lumbar spine and femoral necks. Thus far, 97 patients have been screened for enrollment. Twenty-four patients (24.7%) failed screening due to periodontal disease, a predetermined exclusion criterion of the study. Twenty-three patients have been randomized to the control arm, and 18 patients have been randomized to the bisphosphonate arm. To date, 11 patients in the control arm and 7 patients in the bisphosphonate arm have completed the one-year follow up period including baseline and one-year BMD evaluations. In comparing the change in BMD at one year of patients in the control arm to that of patients in the bisphosphonate arm, the average change in T scores at the lumber spine was −0.482 vs. 0, at the left femoral neck was −0.218 vs. 0.057, and at the right femoral neck was −0.309 vs. 0.243, respectively. There have been no therapy-related serious adverse events in either arm of the study. In addition, no occurrences of osteonecrosis of the jaw have been noted. In conclusion, treatment with the bisphosphonate zoledronic acid in combination with calcium carbonate and vitamin D supplementation appears to provide prevention of bone loss or improvement in the BMD of patients with lymphoma undergoing chemotherapy. Given the large number of patients with below-average BMD prior to therapy and the known deleterious effects of lymphoma therapy on bone density, baseline BMD evaluation may be warranted in all lymphoma patients. In addition, the unexpectedly high rate of periodontal disease in this patient population further supports the need for careful dental evaluation prior to the consideration of bisphosphonate therapy given the well-described, albeit rare, risk of osteonecrosis of the jaw from zoledronic acid.