Bone Loss and High Bone Turnover in Patients with Non-Hodgkin's Lymphoma Who Receive Frontline Chemotherapy: Final Results of a Multicenter Prospective Study
Authors: Terpos Evangelos , Fotiou Despina , Anargyrou Konstantinos , Vassilakopoulos Theodoros P. , Christoulas Dimitrios , Makras Polyzois , Dimou Maria , Ntanasis-Stathopoulos Ioannis , Masouridou Stavroula , Angelopoulou Maria K. , Papatheodorou Athanasios , Tsionos Konstantinos , Panayiotidis Panayiotis , Dimopoulos Meletios A. 
Published: November 2019

Introduction: 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 Non-Hodgkin Lymphoma (NHL). Thus, there is lack of formal recommendation regarding bone investigations at baseline or prophylactic bone management during treatment administration. The aim of this study was to perform a thorough assessment of bone remodeling in newly diagnosed patients with NHL, prior and post chemotherapy administration, to provide insight on the mechanisms of bone loss in these patients.
Methods : Patients with NHL who received frontline treatment were eligible for participation in this study. Exclusion criteria included patients with lymphoma bone-involvement or with known osteoporosis under medication, previous bone fractures, BMD T-scores <-2.0, creatinine clearance <60 mL/min, prior bisphosphonate or significant steroid use for other medical reasons, dental and endocrine problems, metabolic bone diseases and previous radiotherapy to lumbar spine. Bone Mineral Density (BMD) of the lumbar spine (L1-L4, antero-posterior view), and femoral neck (FN) was measured on day 1 of cycle 1 (baseline) and on day 30 post the last cycle of chemotherapy. The following serum markers of bone remodeling were measured on samples collected on the days of DXA in NHL patients and in 44 healthy controls of similar age and gender, using ELISA methodology: (i) osteoclast regulators [sRANKL, osteoprotegerin (OPG)]; (ii) osteoblast regulators [dickkopf-1 (Dkk-1), parathyroid hormone (PTH) and vitamin-D]; (iii) bone resorption markers: NTX, CTX, and TRACP-5b; and (iii) bone formation markers [bone-specific alkaline phosphatase (bALP) and osteocalcin (OC)].
Results: Sixty-one newly diagnosed patients with NHL were prospectively enrolled: 42 (68.9%) patients had diffuse large B-cell lymphoma, 6 (9.8 %) follicular lymphoma (grade III), 4 (6.6%) mantle-cell lymphoma, 7 (11.5%) marginal-zone lymphoma and 2 (3.3%) T-cell NHL. Fifty-four patients (88.5%) received R-CHOP (47 every 21 days and 7 every 14 days), 4 (6.6%) received R-CVP and 3 (4.9%) CHOP as first-line therapy. At baseline, NHL patients had a median T-score of L1-L4 BMD of -0.71 (range -4.27 to +4.36) and of FN BMD of -0.79 (-4.01 to +2.49). The administration of chemotherapy resulted in a dramatic reduction of BMD in L1-L4 (median T-score: -1.12; range -4.49 to +4.34; p=0.001 and median T-score of the lumbar vertebra with the major loss: median T score -1.45; range: -4.84 to +29; p=0.001) and in FN BMD (median T-score: -0.95; range: -3.68 to +2.12; p=0.0001) compared to baseline values. The reduction of L1-L4 BMD post-chemotherapy and of vertebrae BMD with major loss was more profound in males than in females (p=0.001) and in patients of >55 years compared to all others (p=0.0001). Patients who received 8 cycles of chemotherapy had a greater reduction of L1-L4 (p=0.0001), of vertebra with major loss (p=0.003) and of FN (p=0.0001) BMD compared to patients who received 6 cycles of chemotherapy. This reduction was irrespective of the NHL stage (I/II vs. III/IV). At baseline, patients had decreased levels of OC (0.6 vs. 10.4 ng/ml in controls; p=0.001) and increased levels of TRACP-5b (1.82 vs. 1.52 U/L in controls; p=0.005), with no other alterations in bone markers studied. The administration of chemotherapy resulted in a dramatic increase of markers of bone resorption, CTX (6.93 vs. 0.6 ng/ml, p=0.008) and TRACP-5b (2.78 vs. 1.82 U/L; p=0.0001). Markers of bone formation and Dkk-1 were also increased: bALP (26.2 vs. 19.0 U/L; p=0.0001), OC (18.6 vs. 0.6 ng/mL; p=0.0001) and Dkk-1 (192.2 vs. 166.5 pg/mL, p=0.005 and), respectively. 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.
Conclusions : Our study suggests that first-line chemotherapy (immuno-chemotherapy for the vast majority of patients) results in high bone turnover, which leads to increased bone loss and reduced BMD of L1-L4 and FN in NHL patients. These patients should benefit from the prophylactic use of bone-targeted agents, i.e. bisphosphonates, denosumab or romosozumab.

Disclosures
Terpos: Amgen: Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Genesis: Honoraria, Research Funding; Janssen: Honoraria, Other: Travel expenses, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria. Vassilakopoulos:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; WinMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees. Makras:Amgen: Honoraria, Research Funding; Glaxo: Honoraria; Eli-Lilly: Honoraria; Pfizer: Honoraria; Leo: Honoraria; Genesis: Honoraria; UCB: Honoraria. Angelopoulou:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene / GenesiaPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Panayiotidis:Bayer: Other: Support of clinical trial. Dimopoulos:Sanofi Oncology: Research Funding.