Bone Loss in Lymphoma Patients Prior to Receiving Front-line Therapy

Abstract Introduction Patients diagnosed with lymphoma are at high risk of developing osteoporosis. When treated with alkylating agents or corticosteroids, especially if the patient develops hypogonadism, the risk is further increased. Osteoporotic bone cannot easily be restored to normal levels of strength; thus, prevention of bony loss is crucial. The percentage of healthy patients with osteoporosis dramatically increases with advanced age, suggesting that progressive bone loss is common, even without the above-mentioned cancer-related factors. Pamidronate can reduce the risk of bone loss and vertebral fractures in patients with lymphoma receiving chemotherapy. Zoledronic acid, a bisphosphonate approximately 100-fold more potent than pamidronate, has not been evaluated in patients with lymphoma. Urinary N -telopeptide cross-linked collagen type I (NTx), a marker of bone resorption, has early predictive value for long-term bony outcomes in patients treated with bisphosphonates. Bone-specific alkaline phosphatase (AP), a marker of bone formation, also correlates with response to bisphosphonate therapy. We have conducted a phase III trial to evaluate the effect of zoledronic acid on the change in bone mineral density (BMD) in patients with untreated lymphoma undergoing chemotherapy. We report the striking number of untreated lymphoma patients who present with osteopenia and thus would be at significant risk for future bone-related sequelae. Patients and Methods All patients with newly diagnosed lymphoma seen at our institution from 2005 to 2009 were evaluated for protocol eligibility. Exclusion criteria included bone fractures, BMD T-scores worse than −2.0, creatinine clearance Results To date, 46 patients have completed the study and have evaluable data. Patient characteristics include 27 male, 4 premenopausal female, 15 postmenopausal female, median age of 62 years (range, 33-80 years). Twenty-one patients had indolent lymphoma (18 follicular, 1 follicular center, 2 small lymphocytic), 19 had large B-cell lymphoma (17 diffuse large B-cell, 2 primary mediastinal B-cell lymphoma), 3 patients had Hodgkin lymphoma, 2 patients had mantle cell lymphoma, and 1 patient had Waldenstrom macroglobulinemia. Twenty-two patients (48% of all patients) had osteopenia at baseline enrollment in the trial, including 15 men (56% of men) and 7 women (37% of women). We have previously reported our significant findings of stable T scores in the zoledronic treatment group at all locations during the 12-month observation, and the T-scores of the control group decreased at every location evaluated (location: L1-4, P = .004; L neck, P = .001; L hip, P = .118; R neck, P = .009; R hip, P = .04). We have also reported our significant findings of the bone markers urine NTx and BSAP decreasing in the zoledronic acid treatment group and increasing in the control group. The bone makers were similar at baseline in both groups, and demonstrated early response at 3 months for BSAP and 6 months for urine NTx. Conclusions Treatment with zoledronic acid in newly-diagnosed lymphoma patients prevents the bone mineral density loss commonly seen in this population. Bone mass lost is difficult to restore, thus necessitating effective prevention strategies. Urine NTx and bone-specific AP levels demonstrate early response to bisphosphonate therapy, which may allow for early intervention and potentially prevention of further bone loss. With improving long-term survival for lymphoma patients, the need to address survivorship issues will prove more relevant to avoid preventable morbidity. We found a much-larger-than-expected portion of men with osteopenia at baseline. The etiology of the baseline low bone mass is unknown, but further evaluation of this finding in future trials is warranted to determine the significance. The portion of all lymphoma patients with baseline osteopenia in our trial, prior to any therapy, is striking and argues for baseline screening of all patients.