Recent perspectives on the association between osteonecrosis and bone mineral density decline in childhood acute lymphoblasticleukemia

The attention to treatment related toxicity has increased since the survival of children with acute lymphoblastic leukemia (ALL) has improved significantly over the past few decades. Intensive ALL treatment schedules including corticosteroids and asparaginase have been shown to give rise to skeletal abnormalities such as osteonecrosis and low bone mineral density (BMD), which may lead to debilitating sequelae in survivors. Although osteonecrosis and low BMD are different entities with suggested separate pathophysiological mechanisms, recent studies indicate that osteonecrosis is associated with accelerated BMD decline. Common underlying mechanisms for osteonecrosis and BMD decline are considered, such as an enhanced sensitivity to corticosteroids in children who suffer from both osteonecrosis and low BMD. In addition, restriction of weight-bearing activities, which is generally advised in patients with osteonecrosis, could aggravate BMD decline. This induces a clinical dilemma, since bone stimulation is important to maintain BMD but alternative interventions for osteonecrosis are limited. Furthermore, this recent finding of accelerated BMD decline in children with osteonecrosis emphasizes the need to develop effective preventive measures for osteonecrosis, which may include targeting BMD decline

Prevalence, risk factors, and optimal way to determine overweight, obesity, and morbid obesity in the first Dutch cohort of 2338 long-term survivors of childhood cancer:a DCCSS-LATER study

Background: Overweight and obesity are common challenges among childhood cancer survivors. Overweight may be disguised, as survivors can have normal weight but high fat percentage (fat%) on dual-energy X-ray absorptiometry (DXA). We aimed to assess prevalence, identify determinants and biomarkers, and assess which method captures overweight best, in a nationwide cohort. Methods: The prevalence of overweight and obesity, primarily defined by body mass index (BMI), was assessed in the DCCSS-LATER cohort of adult survivors treated from 1963-2002, with the LifeLines cohort as reference. The associations between risk factors and overweight metrics were investigated using logistic regression. Additional overweight metrics included DXA fat%, waist circumference (WC), waist/hip ratio (WHR), waist/height ratio (WHtR), and high-molecular-weight (HMW) adiponectin. Results: A total of 2338 (mean age 35.5 years, follow-up 28.3 years) survivors participated. The overweight prevalence was 46.3% in men and 44.3% in women (obesity 11.2% and 15.9%, morbid obesity 2.4% and 5.4%), with highest rates among brain tumor survivors. Compared to controls, there was no overall increased overweight rate, but this was higher in women &gt; 50 years, morbid obesity in men &gt; 50 years. Overweight at cancer diagnosis (adjusted odds ratio [aOR] = 3.83, 95% CI 2.19-6.69), cranial radiotherapy (aOR = 3.21, 95% CI 1.99-5.18), and growth hormone deficiency (separate model, aOR = 1.61, 95% CI 1.00-2.59) were associated with overweight. Using BMI, WC, WHR, and WHtR, overweight prevalence was similar. Low HMW adiponectin, present in only 4.5% of survivors, was an insensitive overweight marker. Dual-energy X-ray absorptiometry–based classification identified overweight in an additional 30%, particularly after abdominal radiotherapy, total body irradiation, anthracyclines, and platinum. Conclusions: Overweight occurs in almost half of long-term survivors. There was no overall increased incidence of overweight compared to controls. We identified factors associated with overweight, as well as subgroups of survivors in whom DXA can more reliably assess overweight.</p

Risk and determinants of low and very low bone mineral density and fractures in a national cohort of Dutch adult childhood cancer survivors (DCCSS-LATER): a cross-sectional study

Background: Childhood cancer survivors are at risk of developing skeletal comorbidities later in life. We aimed to assess risk factors for low and very low bone mineral density (BMD), and the risk of and risk factors for any fractures and vertebral fractures in a national cohort of Dutch adult childhood cancer survivors. Methods: In this cross-sectional study, we used data from the DCCSS LATER cohort, which comprised individuals who were alive for at least 5 years after diagnosis of childhood cancer (ie, histologically confirmed malignancies or Langerhans cell histiocytosis), were diagnosed before the age of 19 years, and who had been treated at one of seven Dutch paediatric oncology centres between 1963 and 2002 (hereafter referred to as survivors). For this study, we invited survivors aged 18–45 years, who were alive as of Oct 10, 2016, living in the Netherlands, and who were deemed eligible by their treating physician to participate. We assessed BMD using dual-energy x-ray absorptiometry (DXA). Self-reported fractures that occurred at least 5 years after cancer diagnosis were assessed using available medical history and compared with population-level data from the Swedish national registry. We assessed vertebral fractures in a subset of participants using a vertebral fracture assessment. We assessed associations between the occurrence of low (Z-score of ≤–1) or very low (Z-score of ≤–2) BMD, fractures, and vertebral fractures and demographic, treatment-related, endocrine, and lifestyle-related factors using logistic regression analysis. Findings: Between April 29, 2016, and Jan 22, 2020, 3996 (64·8%) of 6165 individuals from the DCCSS LATER cohort were invited to participate, of whom 2003 (50·1%) were enrolled (mean age at participation was 33·1 years [SD 7·2], 966 [48·2%] were female, and 1037 [51·8%] were male [data on ethnicity and race were not available due to national policies]). 1548 (77·3%) had evaluable DXA scans for assessment of BMD, 1892 (94·5%) provided medical history of fractures, and 249 (12·4%) were assessed for vertebral fractures. 559 (36·1%) of 1548 had low BMD at any site, and 149 (9·6%) had very low BMD at any site. The standardised incidence ratio of any first fracture was 3·53 (95% CI 3·06–4·06) for male participants and 5·35 (4·46–6·52) for female participants. 33 (13·3%) of 249 participants had vertebral fractures. Male sex, underweight, high carboplatin dose, any dose of cranial radiotherapy, hypogonadism, hyperthyroidism, low physical activity, and severe vitamin D deficiency were associated with low BMD at any site and male sex, underweight, cranial radiotherapy, growth hormone deficiency, and severe vitamin D deficiency were associated with very low BMD at any site. Additionally, male sex, former and current smoking, and very low lumbar spine BMD were associated with any fractures, whereas older age at follow-up, previous treatment with platinum compounds, growth hormone deficiency, and low physical activity were specifically associated with vertebral fractures. Interpretation: Survivors of childhood cancer are at increased risk of any first fracture. Very low lumbar spine BMD was associated with fractures, highlighting the importance of active BMD surveillance in high-risk survivors (ie, those treated with cranial, craniospinal, or total body irradiation). Moreover, our results indicate that intensive surveillance and timely interventions for endocrine disorders and vitamin deficiencies might improve bone health in childhood cancer survivors, but this needs to be assessed in future studies. Funding: Children Cancer-free Foundation (KiKa), KiKaRoW, and ODAS foundation