Hip Bone Density Deficits Persist in High-Risk ALL Survivors

Survivors of childhood and young adult acute lymphoblastic leukemia (ALL) treated with modern regimens had lower hip bone mineral density (BMD) than matched controls, with the largest deficits among those who received high-risk (HR) treatment, according to a study published in Pediatric Blood & Cancer.¹

Among HR-treated survivors, adjusted BMD was about 90% of control values at the total hip, femoral neck, and trochanter areas, while lumbar spine BMD did not significantly differ from controls. Longer time since diagnosis was associated with partial normalization of BMD relative to controls among survivors treated in the standard- and intermediate-risk groups. However, this pattern was not seen in HR-treated survivors, which the authors said underscores the need for long-term skeletal monitoring in this subgroup.

“In recent years, increasing attention has been directed towards long-term effects when evaluating treatment success,” the authors explained. “Research in this area is essential to monitor and prevent treatment-related toxicities, inform patients and families, and optimize long-term follow-up. They noted that while stepwise therapy modifications have improved survival for patients with ALL, long-term effects among survivors have remained similar.

Why Bone Density Matters for Leukemia Survivors

More than 90% of patients diagnosed with childhood ALL today survive, but about half of survivors are expected to experience chronic or late-occurring adverse effects of therapy.² The Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol, used in Nordic and Baltic centers for patients aged 1 to 45 years with Philadelphia chromosome–negative ALL, was delivered without cranial irradiation.³ Bone health is a known concern during ALL therapy; a previous Canadian prospective cohort study found that 36% of children had fractures at any skeletal site over 6 years.⁴ Data on BMD in survivors treated under contemporary protocols and compared against matched community controls remain limited, the authors noted.¹

The study used data from the Danish ALL-STAR cohort, which included survivors diagnosed between 2008 and 2019 at ages 1 to 45 years who were treated according to NOPHO ALL2008 and had been off therapy for at least 1 year. Of 437 eligible survivors invited, 298 underwent dual-energy x-ray absorptiometry between 2019 and 2024, along with 346 controls who were frequency-matched by age and sex. Median age at examination was 14.1 years among survivors and 14.5 years among controls, and median time since diagnosis was 6.9 years. BMD was adjusted for sex, age, and height to account for treatment-related growth impairment.

Hip BMD Deficits Concentrated in High-Risk Leukemia Survivors

After excluding survivors who experienced a relapse or second malignant neoplasm, adjusted mean BMD was 95.9% (95% CI, 94.0%-97.9%) of control values at the femoral neck, 95.3% (95% CI, 93.4%-97.3%) at the total hip, and 94.9% (95% CI, 92.8%-97.0%) at the trochanter. Lumbar spine BMD did not differ between groups (99.2%; 95% CI, 97.2%-101.3%).

Among the 58 HR-treated survivors, adjusted BMD was 91.2% (95% CI, 88.2%-94.4%) of control values at the femoral neck, 90.1% (95% CI, 86.9%-93.3%) at the total hip, and 90.3% (95% CI, 87.0%-93.7%) at the trochanter. Survivors who underwent hematopoietic stem cell transplantation, with or without total body irradiation, showed a similar pattern of reduced hip BMD. The largest point estimates were seen in HR-treated survivors diagnosed at ages 10 to 17.9 years, although these subgroups were small and confidence intervals overlapped between age groups.

Patients in the HR group received dexamethasone during induction, whereas standard- and intermediate-risk patients received prednisolone. Total glucocorticoid exposure expressed as prednisolone-equivalent dose, however, was not higher in the HR group than in the intermediate-risk group.

“Although causal inferences cannot be drawn from the present study, our findings suggest that glucocorticoid type, rather than cumulative glucocorticoid exposure alone, may contribute to the observed differences in BMD,” the authors wrote.

Z-Scores, Fractures, and Study Limitations

Mean BMD Z-scores were lower among survivors than controls at all sites, with the largest differences at the trochanter (mean difference, –0.68 SD; 95% CI, –0.91 to –0.44; P < .001). Lifetime fracture distribution was similar between groups, with approximately 75% in each reporting no fractures. Among survivors, 55 (18.7%) reported 1 to 5 fractures after diagnosis, and more fractures were associated with lower hip BMD Z-scores.

The study was limited by its cross-sectional design, which prevents assessment of longitudinal recovery in BMD. Selection bias is another potential limitation, as controls were recruited partly through survivors’ social networks and partly via public announcements. Residual confounding is also possible despite adjustment for age, sex, and height. The authors also noted that the young age of the cohort and limited follow-up may mean differences in fracture risk have not yet emerged.

“The persistent hip deficits observed among HR-treated survivors may be clinically relevant if sustained into adulthood because impaired attainment of peak bone mass is associated with an increased risk of osteoporosis and fragility fractures later in life,” the authors concluded. “These findings support the need for long-term monitoring of skeletal health, particularly in the high-risk subgroup.”

References

1. Jensen KS, Skipper MT, Birkebæk NH, et al. Bone mineral density after contemporary treatment for acute lymphoblastic leukaemia: a matched cross-sectional study. Pediatr Blood Cancer. Published online October 5, 2026. doi:10.1002/1545-5017.70727

2. Andrés-Jensen L, Skipper MT, Mielke Christensen K, et al. National, clinical cohort study of late effects among survivors of acute lymphoblastic leukaemia: the ALL-STAR study protocol. BMJ Open. 2021;11(2):e045543. doi:10.1136/bmjopen-2020-045543

3. Toft N, Birgens H, Abrahamsson J, et al. Results of NOPHO ALL2008 treatment for patients aged 1-45 years with acute lymphoblastic leukemia. Leukemia. 2018;32(3):606-615. doi:10.1038/leu.2017.265

4. Rodriguez A. Study evaluates bone health in children with acute lymphoblastic leukemia. AJMC^®. July 10, 2018. Accessed October 5, 2026. https://www.ajmc.com/view/study-evaluates-bone-health-in-children-with-acute-lymphoblastic-leukemia-