Abstract
Childhood cancer survivors are at increased risk of developing (long-term) skeletal adverse effects, such as osteonecrosis, impaired bone mineral density, and fractures. This paper provides an overview of the current understanding of bone health in these survivors, examining whether it represents a significant concern. It focusses on the challenges of assessing and managing bone health in childhood cancer survivors, highlighting diagnostic pitfalls, methods for accurately identifying those at high risk, and suggested strategies for the surveillance and management of osteonecrosis and impaired bone mineral density. The need for improved surveillance strategies, particularly for high-risk survivors, alongside potential prevention and management options, including pharmacological and lifestyle interventions, is emphasised. Given the lack of consensus on optimal prevention and treatment strategies, the paper emphasises the need for further research to optimise care and improve long-term outcomes for childhood cancer survivors with bone health impairments.
Introduction
Over the past decades, numerous groups have published on the frequencies and risk factors associated with osteonecrosis, impaired bone mineral density (BMD), and fractures in children with cancer and in childhood cancer survivors. This research has provided a solid picture of the magnitude of these problems. However, several pressing issues have hampered the translation of these findings into daily clinical practice. These issues include the pitfalls of assessing BMD, uncertainty about which survivors are at high absolute risk of impaired BMD, questions regarding whether impaired BMD leads to fractures in this young population, the limited treatment options for osteonecrosis and impaired BMD, and the need for more insight into the long-term effects of osteonecrosis. In this perspective paper, we highlight recent advances that have been made regarding these issues.
Osteonecrosis
Osteonecrosis (also known as avascular bone necrosis) is a severe complication that mainly occurs during or shortly after treatment for acute lymphoblastic leukaemia (ALL) (1). Multiple mechanisms are thought to contribute to the development of osteonecrosis. These include intravascular microembolisms in the epiphysis and metaphysis of long bones, increased bone marrow pressure, and direct vascular injury, all of which can impair blood flow to the bones and lead to necrosis. In the context of ALL, glucocorticoids are major contributors to the development of osteonecrosis, particularly due to their role in inducing hyperlipidaemia (2), which may lead to the formation of lipid emboli that can obstruct blood vessels and cause ischemic necrosis (3). Moreover, dexamethasone promotes the differentiation of bone marrow stromal cells into adipocytes, leading to lipid accumulation in the marrow and ultimately inhibiting osteoblastogenesis (4, 5). Glucocorticoids may also affect antithrombin and protein S levels, an effect that is exacerbated by the concurrent administration of asparaginase, leading to an increased risk of hypercoagulability (6). The risk of developing osteonecrosis is strongly associated with the cumulative dose of glucocorticoids (7). However, since osteonecrosis can already be present in patients with ALL at the time of the initial diagnosis, leukaemia itself may contribute to the development of osteonecrosis (8).
Osteonecrosis can present as either asymptomatic or symptomatic. Symptomatic patients may experience severe pain, immobility, limitations in daily activities, and in some cases, articular collapse (9). Osteonecrosis is usually a multifocal disease, most frequently affecting weight-bearing joints, which consist of the hip, knee, and ankle joints (10). It is estimated that symptomatic osteonecrosis affects approximately 1–8% of children diagnosed with ALL (9, 11, 12). In our Dutch Childhood Oncology Group (DCOG) ALL-9 study, we found that after an average follow-up of 4.9 years, 60% of the participants continued to experience chronic pain, reduced joint mobility, physical disabilities, or ultimately needed surgical interventions such as joint replacements (9). A recent study found that adult survivors of childhood leukaemia and lymphoma, with a median age of 27, are more prone to long-term physical limitations than adults without cancer (13). Survivors with osteonecrosis had outcomes similar to those without it, except when hip surgery was required, which led to significantly greater challenges in strength, flexibility, and endurance compared to other survivors and healthy adults. However, studies on long-term functional outcomes are limited, making it challenging to provide current patients with osteonecrosis an accurate prognosis for the future. The limited availability of comprehensive data underscores the need for further research to better understand the long-term physical consequences of osteonecrosis. Recognising this gap, osteonecrosis was recently identified as a core outcome in a Delphi study initiated by the International Childhood Cancer Outcome Project, emphasising its significance as a crucial long-term effect of childhood cancer treatment and its importance in evaluating long-term outcomes (14).
Detection and pitfalls of assessment
MRI is the gold standard for detecting osteonecrosis (15, 16, 17), as conventional radiographs lack sensitivity in the early stages, though they can diagnose severe cases once they progress (15). Over the years, several clinical and radiological staging methods have been developed to assess the severity of osteonecrosis (16). The Ponte di Legno Toxicity Working Group developed a clinical grading method based on the severity of symptoms and MRI findings (18). Additionally, Niinimäki and colleagues have developed the first non-joint-specific radiological grading system, allowing for broad applicability (17). This grading system includes the location of osteonecrosis and the extent of the lesions. The relationship between the clinical consequences of osteonecrosis and the classification systems, including the Ponte di Legno Toxicity Working Group and the Niinimäki radiological classification, requires further study to fully establish their clinical and prognostic value. The natural course of osteonecrosis, as detected by MRI screening, appears to be highly unpredictable (8). It will be helpful to identify (genetic) factors that can determine which patients have the most severe and clinically relevant lesions, as well as those who are at the highest risk for (long-term) complications.
Risk factors
Age is the most significant risk factor for osteonecrosis. Numerous studies have demonstrated that children older than 10 years are at increased risk of osteonecrosis compared to younger children (7). Our research showed that the most severe symptomatic osteonecrosis during or shortly after ALL treatment occurred in adolescents aged 15–18 years (19). In this age group, the absolute risk of osteonecrosis was high, with about one-third developing symptomatic osteonecrosis. Of these, more than half were classified as severe osteonecrosis (Ponte di Legno grade 4). This risk appears to decline in young adulthood, suggesting that puberty and the associated increase in growth velocity significantly contribute to the vulnerability to developing osteonecrosis (20). Female sex and high BMI have also been associated with osteonecrosis, though these findings have not always been consistently reported in the literature (9, 21). Recent studies have also identified hyperlipidaemia and hypertension as risk factors for osteonecrosis in this specific population (3, 22). Additionally, a recent review indicates that hypertriglyceridaemia, commonly observed during concomitant treatment with PEG-asparaginase and dexamethasone, significantly increases the risk of osteonecrosis (23). Osteonecrosis has also been shown to be associated with accelerated BMD decline during and shortly after ALL treatment (10, 24, 25), but the results on the direction of this association remain uncertain. Our group demonstrated that initial bone density at the diagnosis of ALL does not appear to affect the incidence of symptomatic osteonecrosis, but rather that bone density only starts to decline after osteonecrosis is diagnosed (24). However, another recent study observed that patients with osteonecrosis experienced significant decreases in spine and hip BMD Z-scores within the initial first and second years of treatment, prior to the development of osteonecrosis (26). Lower hip BMD Z-scores may be a significant predictor of osteonecrosis, aiding in the identification of children at higher risk for developing osteonecrosis (26). Genetic susceptibility may also contribute to the pathogenesis of osteonecrosis. Specific single-nucleotide polymorphisms (SNPs) in genes, such as those associated with the vitamin D receptor, thymidylate synthase, plasminogen activator inhibitor PAI-1, and the glutamate receptor GRIN3A, have been linked to its development (7, 27, 28).
Suggested surveillance
Routine MRI screening for osteonecrosis is generally not recommended, as there is insufficient evidence that asymptomatic lesions are clinically relevant, and because there are limited effective treatment options (29). Clinicians are advised to perform an MRI of affected joints at the first signs of persistent bone pain during or shortly after treatment, especially in adolescents aged 15–18 years. This proactive approach may enhance early identification of severe osteonecrosis, enabling timely intervention (e.g. weight-bearing restrictions) before potential collapse of the affected joint.
Prevention and management
There is currently no evidence-based guideline or consensus on the management of osteonecrosis in children with ALL (29, 30). Efforts to prevent osteonecrosis are crucial, given the limited availability of effective treatment options once symptomatic osteonecrosis develops (30) as well as the potential for severe associated morbidity. These efforts include adjusting treatment protocols, such as modifying the use of corticosteroids and exploring alternative therapies that reduce the risk of osteonecrosis while maintaining the efficacy of leukaemia treatment, as outlined below.
An effective strategy for preventing osteonecrosis in children with ALL involves the administration of dexamethasone in short pulses (11). A randomised controlled trial conducted in American children aged 10–21 years with high-risk ALL compared a new alternate-week dexamethasone regimen (10 mg/m2 per day on days 0–6 and 14–20) with the conventional continuous dexamethasone schedule (10 mg/m2 per day on days 0–20). This alternate-week approach significantly reduced the risk of osteonecrosis compared to continuous dexamethasone, despite the higher cumulative dose (11). In the Netherlands, children with ALL have been treated according to national DCOG protocols. Our research indicated no significant difference in the cumulative incidence of symptomatic osteonecrosis between children treated under more recent Dutch ALL protocols (i.e. DCOG ALL-10 and ALL-11), which involved short pulses of dexamethasone, and those treated under the earlier protocol (DCOG ALL-9; 1997–2004), which utilised long pulses of dexamethasone during maintenance (19). This suggests that the beneficial effect of shorter pulses of dexamethasone may be hampered by the intensification of other treatment components, such as the increased administration of (PEG-)asparaginase (31). Other studies have supported this finding, increasingly highlighting the role of asparaginase in the development of osteonecrosis. Patients treated with more recent Dana-Farber Cancer Institute ALL Consortium protocols including PEG-asparaginase showed a significantly higher incidence of osteonecrosis compared to those treated in earlier trials with native Escherichia coli asparaginase (20). The increased risk may result from a pharmacokinetic interaction between PEG-asparaginase and dexamethasone, causing higher dexamethasone exposure. A better understanding of the combined impact of dexamethasone and asparaginase on bone health may offer opportunities for the primary prevention of osteonecrosis. Randomised studies in mice and humans are needed to assess how regimen modifications, such as alternating these chemotherapeutic agents, affect osteonecrosis risk. This could help mitigate the risk associated with these agents.
In addition, ongoing efforts are exploring other strategies to reduce osteonecrosis in children with ALL. One such approach involves the use of antihypertensive drugs, which have shown promise in reducing the incidence of chemotherapy-induced osteonecrosis in mice (22). The impact of intensive versus conventional antihypertensive therapy on the incidence of extensive radiographic osteonecrosis in children and young adults with ALL is currently being evaluated in a randomised study at St. Jude Children’s Research Hospital (Memphis, TN, USA) (ClinicalTrials.gov Identifier: NCT04401267). Since hyperlipidaemia has been identified as a risk factor for osteonecrosis (3), research has also focused on managing lipid levels to mitigate the risk. A preclinical study reported that hypertriglyceridaemia in mice was successfully managed with fenofibrate, which was associated with a reduction in osteonecrosis frequencies (32). Currently, a trial has been initiated in Denmark to investigate the effect of lipid-lowering agents (i.e. fish oil) on children with ALL (ClinicalTrials.gov Identifier: NCT04209244).
Despite these preventive efforts, once osteonecrosis has developed, managing osteonecrosis remains challenging. Osteonecrosis symptoms resolved in only 40% of paediatric ALL patients treated conservatively within 5 years (9). Conservative treatment of osteonecrosis usually includes weight-bearing restrictions, but continuous non-weight-bearing activities are recommended as they potentially enhance bone formation and improve muscle strength while minimising stress on weight-bearing joints (24, 25). Pharmacologic therapies, such as bisphosphonates, prostacyclin analogs, or statins, are currently under investigation (30, 33). While some of these interventions appear to reduce pain, it is unclear whether they effectively prohibit the progression of osteonecrosis and improve functional performance. To date, there is no consensus on the efficacy and safety of bisphosphonates, and it has been concluded that there is insufficient evidence to recommend their use for preventing osteonecrosis (or impaired BMD) (34). A preclinical study from St. Jude Children’s Research Hospital (Memphis, TN, USA) evaluated the effects of bisphosphonates administration during ALL chemotherapy using xenograft models. The study found that initiating bisphosphonates at the start of chemotherapy might reduce the risk of osteonecrosis. However, they were found to be ineffective in preventing osteonecrosis once vascular damage has already occurred. Additionally, the study suggested that zoledronic acid could potentially diminish the antileukaemic effectiveness of chemotherapy in these models (35). As antileukaemic efficacy remains the key priority, we investigated the oncological safety of the use of bisphosphonates and recombinant human parathyroid hormone (rhPTH) by assessing their influence on in vitro chemotherapy sensitivity of ALL cells. No direct cytotoxic effect of zoledronic acid, pamidronic acid, or rhPTH was observed on leukaemia cell lines. Additionally, these agents did not affect leukaemia cell sensitivity to various chemotherapeutic agents. However, at higher concentrations, these bisphosphonates showed slight to moderate antagonistic effects on dexamethasone-induced leukaemia cell death. Caution is advised when using bisphosphonates during dexamethasone treatment in ALL patients, highlighting the need for the careful use of bisphosphonates and rhPTH, limited to highly selected cases (36). In light of recent discussions concerning the efficacy of prophylactic bisphosphonate therapy in reducing osteonecrosis without compromising cure rates, a call for a randomised clinical trial has emerged (37).
In an effort to mitigate the risk of joint collapse in patients with osteonecrosis, surgical interventions such as core decompression have been suggested, though their effectiveness remains uncertain (29, 38). During treatment, surgical interventions are generally not recommended, given that 40% of osteonecrosis cases are self-limiting. A joint replacement may be indicated for patients with grade IV (Ponte di Legno grading) or grade V (Niinimäki classification) osteonecrosis who experience persistent pain and functional limitations, resulting in significant functional improvements (29, 30, 33). However, the relatively short lifespan of prostheses compared to the life expectancy of children remains a concern.
Given the complexities and challenges in managing osteonecrosis in children and adolescents with ALL, further research is needed to improve early diagnosis, prevention, and treatment. As current management options have shown mixed results, there is a need for randomised clinical trials to provide clearer guidance. Additionally, since osteonecrosis is associated with declining BMD (10, 24, 25), advancements in its understanding and treatment could improve overall bone health and reduce morbidity from this debilitating condition.
Impairment of BMD
Childhood malignancies and their treatments are known to have negative effects on BMD (39). In particular, children with leukaemia may have low BMD (i.e. osteoporosis) at the time of cancer diagnosis (40), which can be attributed to leukaemic cells occupying the bone marrow and enhancing osteoclast activity through cytokines (41). In addition, many treatment components such as corticosteroids and (cranial) irradiation have detrimental effects on BMD. Corticosteroids affect bone tissue directly by inhibiting mesenchymal stem cell differentiation into osteoblasts and by increasing osteoblast apoptosis, which results in decreased bone formation (42). At the same time, bone resorption is transiently increased through enhanced osteoclastogenesis. Moreover, corticosteroids impact calcium homeostasis by reducing the absorption of calcium in the intestines and enhancing its excretion from the kidneys (43). Asparaginase and methotrexate can also directly contribute to BMD decline by inhibiting osteoblast activity. This impact is reflected in reduced BMD and the increased fracture risk observed in children undergoing treatment for ALL (40, 44, 45, 46). In the DCOG ALL-9 cohort, very low lumbar spine BMD (Z-score ≤−2) was observed in 24.1% of ALL patients at diagnosis and 35.7% at the end of treatment, while in the Canadian Steroid-Associated Osteoporosis in the Pediatric Population (STOPP) cohort, the percentages were 27.3% and 16.2%, respectively (47).
These detrimental effects on bone health do not only manifest during childhood; adult survivors of childhood cancer are also at risk, as treatment can affect BMD even years after the completion of therapy. Previous studies have shown that adult childhood cancer survivors are vulnerable to musculoskeletal long-term effects, including impaired BMD and fractures. Low BMD (Z-score ≤−1) is found in approximately 40–50% of long-term childhood cancer survivors, and very low BMD (Z-score ≤−2) in about 10–20%, respectively (48, 49, 50). A recent meta-analysis showed significant reductions in BMD Z-scores across all skeletal sites, with pooled mean Z-scores of −0.57 for whole body, −0.84 for lumbar spine, −0.79 for femoral neck, and −0.14 for total hip BMD. Additionally, compared to age- and sex-matched healthy controls, BMD was significantly lower at all sites (51). The decrease in BMD in survivors may be linked to the cancer itself, its treatment, or subsequent risk factors, such as endocrine and lifestyle-related factors, which will be discussed in more detail later (48, 52). These factors can impair bone mass formation, resulting in a lower peak bone mass, which is generally achieved between the ages of 20–30 years and is crucial for maintaining bone health later in life (53, 54). The long-term consequences of lower peak bone mass in childhood cancer survivors remain uncertain, as the mean age in our recent study was 33 years (50). As survivors age, particularly over the next two decades, the impact of lower peak bone mass will become clearer, as they reach the age at which impaired BMD and its sequelae are more common in the general population.
Detection and pitfalls of assessment
Osteoporosis is a systemic skeletal disease characterised by reduced bone mass and the degradation of bone microarchitecture, resulting in diminished biomechanical competence of the skeleton and susceptibility to fractures from low-trauma or non-traumatic events (55). For adults over the age of 40, the World Health Organization defines osteoporosis based on areal BMD as measured by dual-energy X-ray absorptiometry (DXA) with a T-score less than −2.5 s.d. (56). Vertebral compression fractures, whether symptomatic or not and without a local disease or high-energy trauma, are key radiographic markers of osteoporosis in children and adults (57, 58). In children and adolescents, diagnosing osteoporosis requires evidence of skeletal fragility, indicated by the presence of a vertebral fracture or a clinically significant fracture history (i.e. two or more long bone fractures by the age of 10 years, or three or more long bone fractures at any time up to age 19) (57). To diagnose osteoporosis in children and adolescents without a vertebral fracture, a BMD Z-score below −2 s.d. is required, along with a history of clinically significant fractures. In this age group, Z-scores are used because peak bone mass has not yet been achieved. For individuals with delayed puberty, often resulting from chronic childhood diseases, peak bone mass is typically reached later. Areal BMD measured by DXA can be misleading in these cases, as size artefacts may cause artificially low BMD Z-scores in children with short stature or delayed puberty when compared to healthy reference data. To address this, size-adjustment techniques like bone mineral apparent density and height Z-score-adjusted BMD Z-scores have been developed to provide a more accurate estimate of BMD in these children. In addition, the paediatric definition of osteoporosis can still be applied (59). The International Society of Clinical Densitometry recommends continuing to use Z-scores to define low BMD in all young adults (57). On the other hand, the International Osteoporosis Foundation advocates for using the T-score-based definition from the World Health Organization, which is also used for older adults (59).
Although DXA is widely used and considered the gold standard for measuring BMD, it has several limitations as a surveillance modality. As just mentioned, DXA measures the BMD of a 3D bone two-dimensionally (60). Consequently, DXA provides areal BMD (in g/cm2) and not volumetric BMD (in g/cm3), leading to a systematic underestimation of BMD in smaller individuals. In addition, DXA only measures BMD, without providing information on other crucial aspects of bone strength, such as bone geometry and microarchitecture. Alternative diagnostic methods, like quantitative computed tomography, offer insights into bone geometry and microarchitecture along with bone mass (61). These techniques are mainly utilised in research settings due to their own limitations (57). A benefit of DXA scans is their ability to measure body composition in addition to BMD, which can reliably assess overweight (62).
Risk factors and calculating risk for low and very low BMD
Over the years, research has identified multiple risk factors for reduced BMD in children with cancer and survivors. These factors include demographic, treatment-related, endocrine, lifestyle-related, and (pharmaco)genetic risk factors.
In children with ALL, various risk factors contribute to impaired BMD, including specific treatment components, such as cranial irradiation, corticosteroids, methotrexate, and asparaginase, along with reduced physical activity (especially weight-bearing activities) and nutritional deficiencies (39, 40, 44, 63). Recently, a validated risk prediction model for bone fragility in children with ALL has been developed, which demonstrates that patients’ low lumbar spine BMD can be accurately predicted using weight Z-scores and age at diagnosis (47). This model may assist clinicians in identifying children at high risk of bone fragility during and after therapy, potentially aiding in osteoporosis prevention and intervention.
Within the framework of the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG), internationally harmonised BMD surveillance recommendations for childhood, adolescent, and young adult cancer survivors were developed by 36 experts from 10 different countries. This endeavour involved a comprehensive review of existing literature to understand the risk factors that significantly increase the relative risk of developing low or very low BMD (64). Treatment with cranial irradiation may result in several endocrine deficiencies such as hypogonadism and growth hormone deficiency (GHD), which are known to impair bone density (39). These deficiencies may manifest shortly after treatment, especially after high-dose cranial irradiation, but also arise many years later even after lower doses (65). In addition, as in the general population, several indirect consequences of childhood cancer such as malnutrition, low body mass index, and physical inactivity may affect and reduce BMD (54, 66). Subsequently, several novel risk factors for reduced BMD were identified in our national cohort of Dutch childhood cancer survivors (Dutch Childhood Cancer Survivor Study (DCCSS) LATER cohort), which included individuals who had survived at least five years after being treated for childhood cancer between 1963 and 2001. This study confirmed previously identified risk factors in childhood cancer survivors, which included male sex, underweight, shorter follow-up time, total body irradiation, cranial irradiation, carboplatin, alkylating agents, hypogonadism, GHD, hyperthyroidism, low physical activity, severe vitamin D deficiency, vitamin B12 deficiency, and folic acid deficiency. Vitamin B12 and folic acid deficiencies emerged as potential modifiable risk factors. Future prospective or interventional studies are needed to evaluate the efficacy of addressing these vitamin deficiencies, along with interventions for the assessed endocrine disorders, in preventing or improving reduced BMD.
Although these risk factors had been identified, it was unclear for a long time which individual survivors faced the highest absolute risk of reduced BMD. In collaboration with St. Jude Children’s Research Hospital, we developed validated prediction models for low and very low BMD in two large cohorts of childhood cancer survivors (67). The prediction of low and very low BMD was found to be achievable by considering the clinical factors of sex, height, weight, age, cranial or abdominal irradiation, and smoking. This approach encourages healthcare professionals to assess multiple risk factors together rather than focussing on a single treatment-related factor. Several known risk factors for low and very low BMD, such as total body irradiation (TBI), hypogonadism, and GHD, could not be incorporated into this prediction model. Further enhancement of the prediction models’ discriminative capacity may be achieved by evaluating the impact of several well-established and novel risk factors, i.e. endocrine disorders and vitamin deficiencies. This initiative is currently being pursued.
Survivors who received the same treatment exhibit differences in BMD, indicating that genetic susceptibility may play a role in the development of reduced BMD. Numerous SNPs have been shown to be associated with BMD in the general population (68, 69). Also in childhood cancer survivors, several studies have identified SNPs associated with BMD, located in genes such as CDH2, VDR, ESR1, LRP5, RAPGEF5, and CRHR1. Currently available studies in survivors used a candidate gene or whole exome sequencing approach, were hampered by small sample sizes, lacked replication or functional validation, or mainly included ALL survivors (70, 71, 72). The genetic susceptibility to reduced BMD is currently under evaluation in a collaborative effort of the St. Jude Lifetime Cohort and DCCSS-LATER cohort. Moreover, the development of polygenic risk scores for BMD could potentially improve the diagnostic performance of the prediction models by incorporating replicated SNPs into them. Recently, a study on childhood ALL survivors demonstrated that a polygenic score based on heel quantitative ultrasound speed of sound (an established indicator of osteoporotic fracture risk) derived from imputed genotype data, combined with clinical risk factors, may serve as a valuable tool for stratifying the risk of treatment-related bone morbidity (73). Studies on genetic susceptibility may also identify novel (therapy-specific) SNPs and associated genes, offering deeper insights into the mechanisms of therapy-related bone loss and the underlying pharmacokinetic processes. This could ultimately improve the diagnostic performance of prediction models and enhance our understanding of how genetic factors contribute to reduced BMD in childhood cancer survivors.
Risk and risk factors of fractures
The fracture rate in children with ALL was found to be six times higher than in healthy controls (44). Additionally, another study (STOPP cohort) found that 16% of children with ALL had vertebral fractures at diagnosis, and over a 6-year period, the cumulative incidence increased to 33% for vertebral fractures and 23% for nonvertebral fractures (45). However, the association between reduced BMD and fractures in children, adolescents, and young adults with and without a history of childhood cancer is less clearly established, especially among those who had survived childhood cancer. It is also unclear whether interventions aimed at increasing BMD can effectively lower the risk of fractures in these age groups. In children with ALL, it has been shown that low BMD is significantly associated with both vertebral and non-vertebral fractures during and shortly after treatment (40, 45). The increased fracture risk, with a 3-year cumulative incidence of 17.8%, is more strongly associated with low lumbar spine BMD values at diagnosis and during treatment rather than with treatment-related declines in lumbar spine BMD (40).
A study on childhood cancer survivors showed that the lifetime fracture rate among survivors was similar to that of their siblings (74). However, an increased risk of long-term fractures was indicated in a population-based study, with higher hazard ratios for hospitalisation due to fractures in childhood cancer survivors who had survived at least 5 years (75). Recent findings indicate that long-term adult childhood cancer survivors are at increased risk of experiencing any first clinical vertebral and non-vertebral fracture (50). By taking into account sex- and age-adjusted person-years at risk, the risk of any first fracture was 3.5 times higher for male survivors and 5.4 times for female survivors compared with the general population. Only a few studies have assessed risk factors for fractures in childhood cancer survivors using multivariable models and observed that male sex, treatment with methotrexate, former and current smoking, as well as obesity, significantly increased fracture risk (74, 76). In addition, it is suggested that being underweight could also be an independent risk factor for fractures (77). However, survivors with low BMI are at an increased risk of developing low BMD, which may subsequently heighten their risk of fractures. A cross-sectional study of childhood leukaemia and lymphoma survivors 6 years post-therapy found that those with low BMD had significantly higher odds of long-bone fractures (77). Additionally, we recently showed that fractures – including any fracture, long bone, and fragility fractures – occurring more than 5 years after therapy cessation were significantly associated with reduced BMD in adult survivors of childhood cancer, with a median follow-up of 25 years. Moreover, very low lumbar spine (Z-score ≤−2) was identified as the most important risk factor for long bone and fragility fractures (50). These findings underscore the relevance of a prediction model for reduced BMD (67) and recommendations for BMD surveillance (64), as it now seems more likely that treatment of reduced BMD may prevent fractures in survivors. Due to the lack of evidence in other studies, the impact of reduced BMD on future fracture incidence needs validation in a longitudinal study.
Recent research has also expanded our understanding of the risk and risk factors for vertebral fractures in childhood cancer survivors. A study including survivors of childhood ALL reported a prevalence of vertebral deformities of 23% and identified male sex, prior treatment with a higher cumulative corticosteroid dose, and back pain as significant predictors of prevalent vertebral fractures (78). In our single-centre cohort, which included long-term survivors of all types of childhood cancer, 13.3% of individuals had a prevalent vertebral fracture identified through vertebral fracture assessment by DXA, with the majority being asymptomatic (50). Furthermore, univariable analysis revealed that older attained age, previous exposure to platinum compounds, GHD, and low physical activity were significantly associated with vertebral fractures. A higher prevalence of vertebral fractures was found in survivors treated with spinal radiotherapy (50). However, as these risk factors were identified in univariable models, the extent to which these factors independently increase the risk of vertebral fractures remains uncertain. Thus, further validation of these findings in larger cohorts is imperative to facilitate replication using multivariable models.
Suggested surveillance
Clinical practice guidelines play a crucial role in ensuring standardised and evidence-based healthcare. Several national guidelines for BMD surveillance in childhood cancer survivors have existed for some years, but these guidelines all lacked a systematic review of the literature (79, 80, 81, 82). As outlined previously, internationally harmonised recommendations for BMD surveillance in childhood, adolescent, and young adult cancer survivors have been recently developed (64). In this guideline, BMD surveillance is recommended for survivors treated with cranial/craniospinal or total body irradiation using DXA at entry into long-term follow-up (between 2 and 5 years after completion of therapy), and if normal (Z-score >−1), again at 25 years of age. After careful consideration of the benefits and harms of BMD surveillance, it was decided to only recommend BMD surveillance for treatment-related risk factors with at least moderate-quality evidence for very low BMD (Z-score ≤−2). For instance, corticosteroid treatment did not meet these stringent criteria. Hypogonadism and GHD, both of which have moderate-quality evidence for their association with low or very low BMD, warrant careful monitoring. It is recommended that BMD assessments in survivors with these deficiencies be performed as part of standard endocrine care, preferably under the guidance of a medical bone health specialist (64).
In addition, the externally validated prediction model is currently the only tool that enables physicians to calculate survivors’ absolute risk of low or very low BMD based on multiple risk factors (67). Identifying high-risk survivors is crucial for guiding clinicians in determining which individuals may benefit from BMD assessment by DXA, aiming to identify very low BMD early on and minimising unnecessary evaluations. However, the timing for surveillance is largely based on expert consensus. Decisions regarding surveillance should be made collaboratively between the survivor and their healthcare provider, considering potential risks, benefits, and additional risk factors. Despite the recommendations, challenges remain in accessing and interpreting DXA, particularly in lower-resource settings, where paediatric expertise and facilities are less available. This emphasises the need for tailored approaches to manage bone disorders, especially in these environments (83). Hence, vertebral imaging may be considered in survivors of childhood cancer, particularly in those with very low BMD. It is suggested that routine vertebral imaging might also be warranted for survivors who underwent spinal radiotherapy or received platinum drugs, individuals diagnosed with GHD, or those leading sedentary lifestyles (i.e. not physically active) (50).
Prevention and management
Preventing BMD decline during childhood cancer therapy would be ideal. Early interventions and tailored management strategies may help reduce the risk of impaired BMD in childhood cancer survivors. In the absence of an underlying condition, maintaining bone health will primarily focus on lifestyle interventions, i.e. diet and physical activity (60). This approach is also essential for all children with cancer and survivors, especially when low or very low BMD is expected or identified. Ensuring sufficient intake of dietary vitamin D and calcium is crucial for optimal bone mineralisation. To prevent BMD decline, some clinicians routinely prescribe vitamin D supplements during childhood cancer treatment. However, a recent systematic review of the literature on this subject found very low-quality evidence supporting the beneficial effect of vitamin D supplementation on BMD and fracture frequency during childhood cancer therapy (84). The authors recommend adhering to standard national guidelines for dietary vitamin D or calcium intake, along with periodic monitoring of 25OHD levels to identify deficiencies below 20 ng/mL. Vitamin D or calcium supplementation is advised only in children with deficient levels.
In childhood cancer survivors, it is also recommended to provide counseling on lifestyle habits to maintain or improve bone health (64). This includes engaging in regular physical activity, abstaining from smoking, limiting alcohol intake, ensuring adequate intake of dietary vitamin D (at least 400 IU/day) and calcium (at least 500 mg/day), supplementing with vitamin D for those with low levels (25OHD <20 ng/mL), and considering nutritional supplementation for those with low BMI or who are underweight. As previously discussed, several modifiable risk factors for low and very low BMD in survivors were identified, including hypogonadism, GHD, thyroid disorders, vitamin D and B12 deficiencies, and low physical activity (50). Addressing these factors through appropriate interventions could potentially prevent bone loss and ultimately reduce the risk of fractures. However, in light of these findings, there has been a growing call for well-conducted randomised controlled trials to determine the extent to which modifying these factors can effectively prevent bone loss and fractures among childhood cancer survivors (85).
Moreover, in adults, pharmacological treatments such as bisphosphonates have been proven to prevent bone loss (86) and are administered prophylactically to those at high risk of fractures (87). Intravenous bisphosphonate therapy is also an important treatment option for osteoporosis in childhood and adolescence (88), and the publication of the first international randomised, placebo-controlled trial of zoledronic acid marks a milestone in osteoporosis therapy for this population. However, there has been caution in using bisphosphonate therapy due to potential long-term effects (89). Despite no reports of osteonecrosis of the jaw in children and adolescents on bisphosphonate therapy (90), and findings that femur fractures with atypical characteristics are linked to the severity of osteogenesis imperfecta rather than the therapy itself (91), a proactive approach to dental care and careful timing of bisphosphonate infusions are still advised. As previously mentioned, bisphosphonate administration has been suspected to interfere with the efficacy of leukaemia treatment (35, 36). A recent retrospective cohort study showed that in children with ALL undergoing active treatment, those who received weekly oral alendronate experienced a significant increase in lumbar spine BMD, with no observed increase in relapse frequency amongst those receiving alendronate (92).
Childhood cancer treatment can lead to several endocrine disorders, such as GHD and hypogonadism, which are associated with reduced BMD after treatment (52, 93, 94). Growth and sex hormone replacement therapies have been demonstrated to be effective in preventing bone loss in individuals with deficiencies (95, 96, 97, 98). For adult survivors with GHD, hormone replacement might be considered (99), but several factors need to be considered despite the potential benefits. Growth hormone replacement necessitates a daily subcutaneous injection (100), which may be challenging for survivors. Moreover, while earlier studies raised concerns about the potential risks of hormone replacement therapy, recent research indicates no association between growth hormone replacement in adults and the risk of secondary neoplasia (99, 101, 102, 103). Additionally, sex hormone replacement carries several risks, including a slight increase in the rates of breast cancer and strokes (104, 105). Shared decision-making is recommended when counseling patients about hormone replacement therapy, after thoroughly weighing the individual benefits and risks. This approach aligns with the IGHG recommendations for managing cancer treatment-related endocrine disorders (106).
Furthermore, there is a need for new bone-modifying agents tailored for children, adolescents, and young adults. Bone anabolics like human parathyroid hormone (107), Denosumab (a RANKL inhibitor) (108), sclerostin (a Wnt signaling pathway inhibitor) (109), and odanacatib (a cathepsin K inhibitor) (110) have shown promising effects on BMD in preclinical models and in adults with osteoporosis, but further research is required to assess their safety and efficacy in younger individuals.
Conclusion
This overview of recent advances in understanding and managing osteonecrosis and reduced BMD in childhood cancer survivors highlights several key areas of progress and ongoing challenges. The article outlines the complex interplay of risk factors contributing to osteonecrosis in patients treated for ALL, as well as potential advancements in management and their current limitations. Furthermore, it emphasises the need for further research to enhance the prognostic accuracy of the classifications of osteonecrosis and to develop more effective treatment strategies, considering the limited current effective options.
Additionally, we underscore the high prevalence of low and very low BMD amongst childhood cancer survivors and its association with fractures in adult survivors, highlighting the urgency of early detection and intervention. This emphasises the need for effective surveillance and management protocols, including tailored preventive and therapeutic strategies, to minimise the long-term effects of impaired BMD. Enhancing risk prediction models and exploring genetic factors that influence BMD variability are crucial steps toward improving early detection and intervention. Continued research is essential to identify therapy-specific SNPs and associated genes, with the ultimate goal of integrating these insights into the existing prediction models as well as standardised treatment strategies for these patients.
In conclusion, while significant progress has been made in understanding and managing osteonecrosis and BMD impairment in children with cancer and childhood cancer survivors, substantial gaps remain. The findings advocate for an approach that encompasses further refinement of diagnostic tools, exploration of new preventive and therapeutic measures, and more comprehensive integration of genetic and biochemical markers into clinical practice. Ultimately, enhancing our understanding of these long-term adverse effects and international collaboration to standardise treatment for these patients will lead to improved patient outcomes and quality of life for childhood cancer survivors.
Declaration of interests
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.
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