First-Line Chemotherapy Leads to High Bone Turnover and Reduced Bone Mass in Patients with Non-Hodgkin's Lymphoma (NHL).

Abstract 1951

Poster Board I-974

Chemotherapy associated osteoporosis is a severe problem in patients with malignant diseases as it increases the risk for fractures and deteriorates quality of life. There are very limited data in the literature for the effect 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 NHL had a thorough evaluation of bone remodeling pre- and post- first-line chemotherapy. As of June 2009, 33 (20M/13F, median age 61 years, range: 28-90 years) of 52 patients, who were entered into this study, had completed their chemotherapeutic scheme: 19 patients (57%) had diffuse large B-cell lymphoma, 5 (15%) follicular lymphoma (grade III), 4 (12%) mantle-cell lymphoma, 4 marginal-zone lymphoma and one T-cell NHL. Twelve (36%) of those had stage IV disease and 17 (51%) had B-symptoms before therapy. Twenty-six patients (78%) received R-CHOP (25 every 21 days and 5 every 14 days), 2 received R-COP and one 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) using a Hologic QDR-1000 scanner on day 1 of cycle 1 (baseline) and on day 30 post 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 inhibitor 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 24 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 -0.65 (range -4.27 to +3.68) and of FN BMD of -1.1 (-4.01 to +0.2). The median T-score of the lumbar vertebra with the major bone loss was -1.44 (-4.6 to +3.03). At baseline patients had increased levels of Dkk-1 (p=0.036) and reduced levels of OC (p<0.001) compared to controls. In terms of bone resorption, 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 L1-L4 BMD and Dkk-1 (r=-0.617, p<0.0001) and between CTX with TRACP-5b (r=0.65, p<0.0001) and sRANKL (r=0.413, p=0.036). 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: -1.32; range -4.6 to +3.04; p=0.001 and median T-score of the lumbar vertebra with the major loss: -1.95; range: -4.84 to +2.72; p=0.002) and in a less impressive reduction in FN BMD (median T-score: -1.2; range: -3.68 to +0.38; p=0.022) compared to baseline values. The reduction of L1-L4 BMD post-chemotherapy was more profound in males (p=0.01) than in females (p=0.05) and in patients of >55 years (p=0.007) compared to all others (p=0.059). 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<0.0001) and FN (p=0.044) BMD compared to all others. The administration of chemotherapy also resulted in a dramatic increase of CTX (p=0.019) which was mainly due to a similar increase of sRANKL/OPG ratio (p=0.005). Both markers of bone formation, bALP (p=0.001) and OC (p<0.0001) were increased, while Dkk-1 showed a borderline increase post-therapy (p=0.1). All studied markers of bone remodeling were increased in NHL patients post-chemotherapy compared to controls (p<0.01 for CTX, TRACP-5b, bALP, Dkk-1, sRANKL and OPG; p=0.04 for OC and sRANKL/OPG ratio). There was a greater increase of CTX (p=0.04), sRANKL/OPG (p=0.015), TRACP-5b (p=0-.03), bALP (p=0.003) and OC (p<0.0001) in patients who received 8 cycles of chemotherapy compared to all others. During study period, one patient had a pathological fracture in his right FN. Our on-going study suggests that first-line chemotherapy results in high bone turnover, which leads to increased bone loss and reduced BMD of L1-L4 and FN in NHL patients. The confirmation of these results in a larger cohort of patients may lead to the prophylactic use of anti-resorptive agents, such as bisphosphonates in these patients.