Bone Mineral Density At Diagnosis Determines Fracture Rate in Children Treated According to the DCOG-ALL9 Protocol

As survival rates for pediatric acute lymphoblastic leukemia (ALL) have significantly improved, awareness of side effects such as skeletal toxicity becomes increasingly important. As BMD decrease over time might be associated with an increased risk of fractures, we performed repeated measurements of BMD in a large nation-wide study and studied the incidence of fractures in these children treated for ALL.

Prospectively, serial measurements (at diagnosis, after 32 weeks, after 2 years (at cessation of therapy) and after 3 years (1 year after cessation of therapy)) of bone mineral density of the lumbar spine (BMD_LS) were performed in 399 ALL patients using dual energy X-ray absorptiometry (DXA). Using logistic multivariate regression, we evaluated the following putative risk factors for a low BMD_LS:age at diagnosis, gender, risk group of ALL treatment, weight and height at diagnosis. Moreover, Kaplan-Meier survival analysis was used to assess the cumulative incidence of fractures in 672 patients treated with the dexamethasone-based DCOG-ALL9 protocol. All reported fractures were symptomatic, and confirmed by X-ray. Cumulative incidences of fractures for different subgroups were compared with the Log-Rank test.

At diagnosis, mean BMD_LS of ALL patients was lower than that of healthy peers (mean BMD_LS= −1.10 SDS, P< 0.001), and this remained significant lower during and after treatment (8 months: BMD_LS = −1.10 SDS, P< 0.001; 24 months: BMD_LS = −1,27 SDS, P< 0.001; 36 months: BMD_LS = −0.95 SDS, P< 0.001). Multivariate linear regression analysis showed that after correction for weight, height and gender, treatment according to the HR treatment arm and older age at diagnosis had a significant negative effect on the decline of BMD_LS during treatment (high-risk group: b = −0.50, P<0.001 and age at diagnosis: b = −0.15, P<0.001). The cumulative incidence of fractures at 3 years was 17.8%. Cumulative incidences of fractures between risk groups and age groups were not significantly different (NHR 18.8% vs. HR 15.7%, P = 0.18 and <10 years 17.7% vs. ≥10 years 17.6%, P = 0.85). Patients who developed fractures had a lower BMD_LS during treatment than those without fractures. Treatment-related bone loss was similar in patients without fractures and patients with fractures (respectively: Δ BMD_LS = −0.12 SDS vs. Δ BMD_LS= −0.36 SDS; interaction group time, P = 0.295).

This large prospective study shows that the low value of BMD_LS both at diagnosis and during treatment, rather than the treatment-related decline of BMD_LS, determines the markedly increased fracture risk of 17.8%.

No relevant conflicts of interest to declare.