Bone Loss in Lymphoma Patients Receiving Frontline Therapy: Urine NTx and Bone Specific Alkaline Phosphatase Provide Early Evidence of Zoledronic Acid Response.
Authors: Westin Jason R. , Thompson Michael A. , Cataldo Vince D. , Toth Bela B. , Sanjorjo Perpetua , Bourgeois Scott , Jimenez Camilo , Murphy William A. , Fanale Michelle , Fayad Luis , Fowler Nathan , Kwak Larry , McLaughlin Peter , Neelapu Sattva , Pro Barbara , Rodriguez Alma , Shah Jatin , Hagemeister Fredrick B. 
Published: October 2019

Abstract
Abstract 3922
Poster Board III-858
Abstract:
Patients diagnosed with lymphoma are at high risk of developing osteoporosis. We have shown previously that the majority of newly diagnosed patients are osteopenic or osteoporotic prior to receiving chemotherapy. 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. Pamidronate can reduce the risk of bone loss and vertebral fractures in lymphoma patients receiving chemotherapy. Zoledronic acid, a bisphosphonate approximately 100-fold more potent than pamidronate, has not been evaluated in lymphoma patients. 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.
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 report the change in urine NTx and bone specific AP levels in lymphoma patients treated with zoledronic acid.

Methods
All newly diagnosed lymphoma patients seen at our institution from 2005 – 2009 were evaluated for protocol eligibility. Exclusion criteria included bone fractures, BMD T-scores worse than –2.0, creatinine clearance less than 60 mL/min, dental problems, and recent steroid or bisphosphonate use. Patients on study were stratified as male, pre-menopausal female, or post-menopausal female. Accrued patients were randomized to receive either: 1) oral calcium and vitamin D (Ca+D) or 2) Ca+D and 4 mg zoledronic acid IV at baseline and at 6 months. Urine NTx and bone specific AP levels were measured at baseline, 3, 6, 9, and 12 months.

Results
To date, 33 patients have completed the study and have evaluable data. Patient characteristics include: 17 male, 4 pre-menopausal female, 12 post-menopausal female, median age 62 (range 33 – 80). Seventeen patients had osteopenia upon enrollment. Patients that received zoledronic acid had stable median T-scores at all locations during the 12 month observation, whereas the T-scores of the control group decreased at every location evaluated (Location: L1-4, p=0.004; L Neck, p= 0.001; L Hip, p=0.118; R Neck, p=0.009; R Hip, p=0.040). Each group had a similar baseline level of urine NTx and bone specific AP. At 6 months, the urine NTx decreased significantly in the zoledronic acid-treated group compared to urine NTx levels in the control group which increased (p<0.001). The separation between groups remained constant throughout the evaluation period (12 months, p<0.001). The bone specific AP level decreased in the zoledronic acid group by 3 months, and remained below baseline levels at 12 months. The control group had increases in bone specific AP levels throughout the 12 month period (6 months, p=0.001; 12 months, p<0.001).

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. The ability to predict response to bisphosphonates at 6 months may allow for early intervention, potentially preventing further bone loss. Our study demonstrates the bone markers urine NTx and bone specific AP are significantly associated with bone health in lymphoma patients receiving chemotherapy.

Disclosures:
Thompson: Novartis: Research Funding. Toth:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hagemeister:Novartis: Research Funding.