Mapping the risk factors of impaired bone health in childhood cancer survivors: A protocol for a scoping review

Advancements in childhood cancer therapy have led to significant improvement in overall survival rates. Progress in treatment has contributed to an increased focus on treatment-related late effects. Of these late effects, impaired bone health is observed among survivors within the first 6 years after therapy (van der Sluis et al, 2002; Velentza et al, 2021). Impaired bone health includes declining bone mineral density, osteoporosis and fragility fractures. DXA measurement is standard of care in a comprehensive skeletal health assessment in pediatric patients with increased fracture risk as recommended by the 2019 International Society of Clinical Densitometry (ISCD, 2019). Current Children’s Oncology Group (COG) Long Term Follow-up Guidelines and International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) recommend any childhood cancer survivor with prior exposure to corticosteroids have a baseline BMD using a dual-energy X-ray absorptiometry (DXA) scan upon entry into the long term follow-up, which is 2 to 5 years after completion of treatment (Ward, 2020; van Atteveld et al, 2021; COG, 2023). Cohort studies have identified several risk factors leading to poor bone health among childhood cancer survivors (CCS): (1) chronic glucocorticoid exposure, (2) history of radiation therapy, (3) history of receiving hematopoeitic stem cell transplant, (4) low physical activity and muscle in extremities, (5) growth hormone and sex hormone deficiency, and (6) lifestyle habits including smoking and alcohol consumption (Kaste et al, 2001; Strauss et al, 2001; Gurney et al, 2014; van Atteveld et al., 2021). Two validated prediction models were developed using the SJLIFE, Dutch and STOPP cohorts to identify childhood cancer survivors with low BMD. The first model published in 2019 included the these factors after therapy: male sex, height, weight, age, current smoking status and history of cranial irradiation (van Atteveld et al, 2019). The second model published in 2021 included prognostic factors identified at diagnosis: age, weight, BMI and DXA (Verwaaijen et al, 2021). However, there are no available fracture prediction models or tools for childhood cancer survivors such as used in the adult population. While bone density screening methods and interpretation are well developed among adults, there remains several key challenges in children. First, the relationship between bone density and fracture risk in children is altered in growing bones (Johnell & Kanis, 2006; Ferrari et al, 2012). Second, presence of an asymptomatic vertebral fracture is a key element of adult skeletal health assessment but not yet in children (Nayak et al, 2011; Yang et al, 2020). The main challenge of skeletal health assessment among children is the lack of expertise in DXA-based vertebral fracture assessment in children and the potential downsides of unnecessary radiation exposure among routine plain films of the spine (Ward et al, 2018; Weber et al, 2019). There remains limited evidence on safe and effective measures in prevention and treatment of declining bone mineral density among childhood cancer survivors. Understanding the prognostic factors of deteriorating bone health and fragility fractures among childhood cancer survivors will be helpful in identifying those who will benefit from a timely diagnosis and intervention. Identifying those at high risk for deteriorating bone health and fracture helps prevent associated morbidities and substantial impairment of quality of life. The most recent comprehensive review of literature (1990 to 2021) on bone health in childhood cancer survivors was conducted in 2021 for the purpose of developing bone mineral density surveillance guidelines recommended by the IGHG (van Atteveld et al, 2021). No scoping review has been done on prognostic factors for impaired bone health among childhood cancer survivors. This research will compile and analyze existing literature impaired bone health in all CCS through a scoping review of prognostic studies and a formal cost-effective analysis of screening strategies, to be done as a separate study, will lead to a development of an evidence-based cost-effective method in bone health management among CCS of ALL – since most data on low BMD are focused on survivors of ALL.