Low Bone Mineral Density and High Bone Turnover In Patients with Non-Hodgkin's Lymphoma (NHL) Who Receive Frontline Therapy: Results of a Multicenter Prospective Study

Abstract 5071

Chemotherapy-associated bone loss is a severe problem in patients with malignancies as it increases the risk for fractures and deteriorates quality of life. However, there are very limited reports in the literature describing the effects of chemotherapy on bone metabolism of adult patients with NHL. To elucidate this issue we scheduled a prospective study in which patients with newly-diagnosed non-Hodgkin's lymphoma (NHL) had a thorough evaluation of bone remodeling, pre- and post- frontline chemotherapy. As of June 2009, 53 patients (33M/20F, median age 59 years, range: 18–90 years) had completed their first-line treatment: 36 patients (67.9%) had diffuse large B-cell lymphoma, 5 (9.4%) follicular lymphoma (grade III), 4 (7.5%) mantle-cell lymphoma, 6 (11.3%) marginal-zone lymphoma and 2 (3.8%) T-cell NHL. Nineteen patients (35.8%) had stage IV disease and B-symptoms before therapy initiation. Forty-seven patients (88.7%) received R-CHOP (40 every 21 days and 7 every 14 days), 4 received R-COP and 2 received CHOP as first-line therapy for their disease. Bone mineral density (BMD) of the lumbar spine (L1-L4, antero-posterior view), and femoral neck (FN) was measured by dual energy X-ray absorptiometry (DXA) on day 1 of cycle 1 (baseline) and on day 30 of the last cycle of chemotherapy. The following serum indices of bone metabolism were measured on the days of DXA: i) osteoclast stimulators [sRANKL and osteoprotegerin (OPG)], ii) osteoblast regulators [parathyroid hormone, vitamin-D, and dickkopf-1 (Dkk-1)], iii) bone resorption markers [C-telopeptide of collagen type-I (CTX) and tartrate-resistant acid phosphatase-5b (TRACP-5b)], and iv) bone formation markers [bone alkaline phosphatase (bALP) and osteocalcin (OC)]. The above markers were also evaluated in 30 healthy controls of similar gender and age. Patients were assessed for skeletal-related events (SREs) throughout the period of the study. At baseline, NHL patients had a median T-score of L1-L4 BMD of -0.63 (range -4.27 to +3.68) and of FN BMD of -0.875 (-4.01 to +2.07). The median T-score of the lumbar vertebra with the major bone loss was -1.425 (-4.6 to +3.03). At baseline patients had reduced levels of OC (p=0.01) compared to controls, while CTX, TRACP-5b and sRANKL/OPG ratio did not differ between patients and controls. There was a strong correlation between L1-L4 and FN BMD (r=0.64, p<0.0001) as well as between CTX with TRACP-5b (r=0.467, p=0.001), sRANKL (r=0.479, p=0.001) and Dkk-1 (r=0.442, p=0.003). Strong correlations were also observed between bALP and sRANKL/OPG ratio (r=0.406, p=0.006), Dkk-1 and TRACP-5b, (r=0.421, p=0.004), sRANKL and CTX (r=0.479, p=0.001). There was no correlation between BMD and NHL stage. The administration of chemotherapy resulted in a dramatic reduction of BMD in L1-L4 (median T-score: -1.12; range -4.49 to +3.04; p<0.001 and median T-score of the lumbar vertebra with the major loss: -1.45; range: -4.84 to +2.72; p=0.001) and in FN BMD (median T-score: -1.115; range: -3.68 to +1.12; p<0.001) compared to baseline values. The reduction of L1-L4 and FN BMD post-chemotherapy was more profound in males (p=0.003 and p=0.001 respectively) than in females (p=0.011 and p=0.01) and in patients of >55 years (p=0.001 and p<0.001 respectively) compared to all others (p=0.037 and p=0.014). This reduction was irrespective of the NHL stage (I/II vs. III/IV), while patients who received 8 cycles of chemotherapy had a greater reduction of L1-L4 (p<0.001) and FN (p=0.001) BMD compared to all others. The administration of chemotherapy also resulted in a dramatic increase of CTX (p=0.017), TRACP-5b (p<0.001), bALP (p<0.001), OC (p<0.001) and Dkk-1 (p=0.022) compared to baseline values. All studied markers of bone remodeling, with the exception of OPG and sRANKL, were significantly increased in NHL patients post-chemotherapy compared to controls (p=0.05 for CTX, p<0.001 for TRACP-5b and Dkk-1, p=0.01 for bALP, p=0.015 for OC). During study period, one male patient had a pathological fracture in his right FN. We conclude that frontline treatment with the combination of chemotherapy and/or rituximab results in high bone turnover, which leads to increased bone loss and reduced BMD of L1-L4 and FN in NHL patients. The prophylactic use of anti-resorptive agents, such as bisphosphonates, or the administration of agents with anti-Dkk-1 activity may be useful for preventing bone loss in these patients.