Principal Investigator

Kyriakie
Sarafoglou
Awardee Organization

University Of Minnesota
United States

Fiscal Year
2019
Activity Code
R01
Project End Date

Prevention of bone loss after pediatric hematopoietic cell transplantation

Childhood and adolescence are critical time periods for establishing peak bone mass for the rest of the adult life. Low bone mineral density (BMD) in childhood increases the risk of early osteoporosis and bone fracture later in life, which has serious individual and societal implications due to the impaired mobility, the associated morbidity and even mortality in older adults. Our long-term goal is to identify vulnerable pediatri populations at risk for bone loss in order to improve their bone health through an early intervention. This study focuses on the prevention of bone loss that occurs in children and adolescents treated with hematopoietic cell transplantation (HCT) for hematologic malignancies. An increase in bone resorption that occurs after HCT in these patients offers an opportunity for intervention with an anti-resorptive agent, yet no prospective studies have been performed that examine the effectiveness of any bisphosphonate or other anti-resorptive agent in pediatric HCT recipients. Therefore, we propose to conduct a prospective, randomized controlled clinical trial of calcium and vitamin D plus pamidronate versus calcium and vitamin D alone to prevent bone loss after pediatric HCT. The central hypothesis is that subjects treated with pamidronate and calcium and vitamin D (Pamidronate Group) will have higher bone mineral content (BMC) and BMD measured by dual-energy x-ray absorptiometry and by peripheral quantitative CT, respectively, at 1 year post-HCT than subjects receiving calcium and vitamin D alone (Control Group). The rationale for this study is that treatment with pamidronate at the time of peak bone resorption can prevent/reverse bone loss and have a positive long-term impact on bone health in pediatric HCT recipients. We will pursue three specific aims: 1) To determine the impact of calcium and vitamin D plus pamidronate versus calcium and vitamin D alone on BMC and BMD following HCT in 60 recipients aged 1-18 years at HCT; 2) To characterize the time course of changes in cytokine levels (IL-6, IL-7, TNF-a) associated with the activation of osteoclasts after HCT and their association with BMC and BMD; 3) To examine the sequence of changes in markers of bone turnover after HCT and their response to pamidronate treatment. The current study is innovative in that it is the first to prospectively evaluate the effects of an anti- resortive agent administered shortly after HCT on BMC and BMD in children. This study is expected to have an important positive impact on bone health in children and the field of pediatric endocrinology by providing much needed prospective data on the effectiveness of an anti-resorptive agent after pediatric HCT. The preventive intervention that this project seeks to examine is likely to have an impact on current clinical practice. While biomarkers of bone turnover have been used in adult studies, there is a striking paucity of data on the clinical applicability of these markers in children and adolescents. Evaluating changes in these markers and cytokines after HCT will provide insight into the underlying mechanisms of bone loss.

Publications

  • Bar M, Ott SM, Lewiecki EM, Sarafoglou K, Wu JY, Thompson MJ, Vaux JJ, Dean DR, Saag KG, Hashmi SK, Inamoto Y, Dholaria BR, Kharfan-Dabaja MA, Nagler A, Rodriguez C, Hamilton BK, Shah N, Flowers MED, Savani BN, Carpenter PA. Bone Health Management After Hematopoietic Cell Transplantation: An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020 Oct;26(10):1784-1802. Epub 2020 Jul 9. PMID: 32653624
  • Harindhanavudhi T, Petryk A, Jones R, Regodón Wallin A, Hodges JS, Nortwick SV, Miller BS, Holm TL, Sarafoglou K. Lumbar spine bone mineral density Z-score discrepancies by dual X-ray absorptiometry do not predict vertebral fractures in children. Journal of investigative medicine : the official publication of the American Federation for Clinical Research. 2018 Aug;66(6):980-985. Epub 2018 Apr 4. PMID: 29622758
  • Petryk A, Kanakatti Shankar R, Giri N, Hollenberg AN, Rutter MM, Nathan B, Lodish M, Alter BP, Stratakis CA, Rose SR. Endocrine disorders in Fanconi anemia: recommendations for screening and treatment. The Journal of clinical endocrinology and metabolism. 2015 Mar;100(3):803-11. Epub 2015 Jan 9. PMID: 25575015