Determinants of Low Bone Mineral Density after Childhood Cancer

Purpose: Osteopenia is a potential complication of childhood cancer treatment, but the magnitude of this problem in survivors is unknown. We examined (determinants of) bone mineral density (BMD) status in long-term survivors of adult childhood cancer (CCS).

Methods: This retrospective single-center cohort study included 346 subjects with the most common types of childhood cancer. Acute leukemia or lymphoma was diagnosed in 273 (81%) of the patients. All subjects had a median age at diagnosis of 7.0 years (range: 0.1-16.8 years) and a median follow-up time of 16.7 years (range 5.6-39.9 years). Total body BMD (BMD_TB) and BMD of the lumbar spine (BMD_LS) were measured by dual-X-ray absorptiometry. Osteopenia was defined as BMD standardized deviation score (SDS) below -1. Twelve candidate single nucleotide polymorphisms (SNPs) in 11 genes (COL1A1, TNFSF11, TNFRSF11, TNRFSA11B, VDR, ESR1,WLS, LRP5, MTHFR, MTRR, IL6) were investigated.

Results: Survivors had a lower BMD_TB and BMD_LS (mean SDS: -0.55, p<0.001; and -0.30, p<0.001, respectively) as compared to healthy peers. This was similar in cancer survivors of leukemia and lymphoma (mean SDS: -0.49, p<0.001; and -0.32, p<0.001, respectively). Osteopenia (BMD_TB and/or BMD_LS) was present in 45% of the survivors (46% of the leukemia and lymphoma survivors). Multivariate logistic regression analyses identified age at diagnosis <12 years, age >30 years at follow-up, male gender, underweight at follow-up, carriers of the minor allele of rs2504063 (LRP5), treatment with cranial-spinal radiotherapy and prednisone as independent prognostic factors for osteopenia. In survivors of leukemia and lymphoma, we identified low BMI at follow-up, carriers the minor allele of rs2504063 (LRP5), treatment with cranial-spinal radiotherapy and cyclophosphamide use as prognostic factors for osteopenia.

Conclusions: This large cohort of childhood cancer survivors with the long follow-up identified osteopenia in 45% of CCS. This indicates that greater awareness for low BMD is warranted, especially in survivors who are older than 30 years, male, have underweight, have a genetic predisposition, and who were treated with cranial-spinal radiotherapy and/or steroids.