Osteoporosis/Osteopenia (OP) and Osteonecrosis (ON) in Survivors of Pediatric Stem Cell Transplantation Has a High Assiciation with Graft Versus Host Disease (GVHD)

Background: With improved survival following pediatric stem cell transplantation (SCT), long term effects of the therapy including OP and ON need to be addressed.  These problems are known to occur in adult solid organ transplantation and adult SCT but little is reported in the pediatric literature.  High-risk features associated with diminished bone density include hypothyroidism, hypogonadism, glucocorticoid steroid use, hypercholesterolemia, 25 hydroxy-vitamin D deficiency, total body irradiation, and growth hormone deficiencies.  This report is a single institutions retrospective analysis of bone density evaluation and incidence of OP/ON following pediatric SCT.

Method: From 2003 to 2012, 17 patients undergoing allogeneic stem cell transplantation (5 AML, 8 ALL, 1 CML, 1 NHL, 2 aplastic anemia) received lipid profile evaluation performed at Loma Linda University Medical Center by a Roche Modular System Photometric Assay and 25-OH vitamin D analysis at Mayo Clinic, Rochester Minnesota.   15 of these patients also had bone density testing by a dual-energy x-ray absorptiometry (DEXA) scan.  With osteoporosis and osteopenia defined as Z score <-1 and <-2.5 respectively.  9 patients received stem cells from HLA matched unrelated donors (MUD) and 8 HLA matched related sibling donors (MRD).  Patients were treated with: (14 ) 1200cGy total body irradiation, 1500mg/m2 etoposide, 120mg/kg cyclophosphamide; (1 ) busulfan (16 doses), 200mg/kg cyclophosphamide; (2) ATG, 200mg/kg cyclophosphamide, 200cGy total body irradiation. GVHD prophylaxis was cyclosporine for MRD or tacrolimus for MUD and short course methotrexate.  Patient’s age at testing ranged from 7 to 23 years, mean 13.5 years.

Result:  OP was extremely common after SCT with bone density Z score of lower then -1 in 13/15 tested.  25-OH Vit D was low in 15 /17 tested.  Elevated cholesterol was present in 8/17 and cholesterol/HDL ratio (>3.5%) in 12/15 tested.  Stratification of patients by history of chronic GVHD or moderate to severe acute GVHD showed that while metabolic abnormality was present in both groups, symptomatic OP/ON were confined to the chronic GVHD group.  Among 4 patients with no history of GVHD, 2/4 had normal bone density, 2/4 had normal lipids, and none had symptomatic OP/ON.  In contrast, among 13 patients with GVHD all 10/10 tested had diminished bone density, 9/10 tested had elevated lipid ratios, and 5/13 had symptomatic OP/ON with 4 requiring surgery.  Symptomatic OP/ON events resulted in the need for joint replacement of the knees, hips and shoulders. In addition, patients had fractures of the long bones needing internal fixation devices to help with the repair.

Conclusion: These results suggest that lipid metabolism abnormalities and low Vit D levels are common after SCT and interventions to normalize these abnormalities may have the greatest impact on symptomatic ON/OP in patients with GVHD.