ENGLISH
Introduction
Osteoporosis is a rare clinical entity in pediatric patients, typically secondary to chronic underlying conditions [1]. Secondary osteoporosis accounts for over 90% of cases and is commonly associated with disorders such as cerebral palsy, congenital myopathies, and thalassemia [2]. Primary osteoporosis is much less frequent (< 10%) and results from mutations in so-called “bone fragility genes” such as low-density lipoprotein receptor-related protein 5 (LRP5), protooncogene WNT1 and WNT3A, the plastin 3 gene (PLS3), and dickkopf-related protein 1 (DKK1) [3, 4]. In young patients, osteoporosis is often observed in the setting of necessary, intensive oncologic therapies. While current pediatric cancer treatments significantly increase survival – improving annually – they exert profound systemic stress on the developing child. One consequence of this therapeutic burden is the development of juvenile osteoporosis [5]. Although bone health may also be influenced by tumor biology, lifestyle, diet, and genetic predisposition, this study focuses primarily on mechanisms related to cancer treatment. Modern oncologic management in children primarily includes chemotherapy, radiotherapy, surgery, and hematopoietic stem cell transplantation (HSCT). Chemotherapy remains the most established method, but it is associated with high risk of endocrinopathies. It is estimated that 20–50% of treated patients will develop such complications, including obesity, metabolic syndrome, hypothalamic-pituitary axis dysfunction, gonadal impairment, osteopenia, and osteoporosis [6, 7]. At the molecular level, chemotherapy promotes inflammatory cytokine release, oxidative stress (via reactive oxygen species), and DNA damage, triggering immune activation and chronic low-grade inflammation – key contributors to bone loss. Additionally, hormone deficiencies (e.g., growth hormone, sex steroids) significantly impair bone mineral density (BMD), contributing to skeletal fragility [8]. Importantly, several other factors may also compromise bone integrity independently of oncologic treatment. Nutritional deficiencies, physical inactivity, and genetic predispositions may lead to fractures without cancer history. In adults, osteoporosis is diagnosed via bone densitometry using well-established criteria, but pediatric diagnosis is more complex and remains challenging due to variable radiologic and clinical manifestations [7]. Early diagnosis and intervention are essential to prevent life-threatening fractures. Though juvenile osteoporosis is multifactorial, understanding its relationship with oncologic treatment remains critical for long-term survivorship care [9].
Material and methods
A review of the available literature was conducted based on the PubMed database, Via Medica Journals, Google Scholar and Clinical Key, using the following key words: “osteoporosis,” “bone mineral density,” “cancer in pediatric population,” “chemotherapy,” “juvenile osteoporosis.” Out of 167,096 works from 2015–2025, 1,568 met the criteria. We included original papers, systematic reviews and case reports. The language criterion was English. Narrative reviews and works that did not meet the linguistic criteria were rejected. Only free articles were used to prepare the review. Two articles were included in the review regardless of the time criteria, because they constitute an integral part of the work and their contribution to the credibility of the work is indisputable. After the final selection of articles, 60 articles were selected.
Pathophysiological basis of osteoporosis and selected etiological factors
Osteoporosis remains the most prevalent skeletal disorder worldwide, currently affecting an estimated 200 million individuals [10]. The pathognomonic hallmark of this condition lies in the disruption of the tightly regulated equilibrium between osteoblasts – bone-forming cells – and osteoclasts – bone-resorbing counterparts [11]. A progressive dominance of osteoclastic activity results in pathological bone remodeling, culminating in accelerated bone resorption and structural weakening [12].
One of the principal modulators of this dysregulation is chronic inflammation. The inflammatory milieu leads to upregulation of macrophage colony-stimulating factor (M-CSF), which promotes monocyte differentiation into osteoclasts, while concurrently enhancing the expression of RANKL (receptor activator of nuclear factor κB ligand), a pivotal cytokine that activates osteoclastogenesis [11]. This imbalance critically impairs osteogenesis, resulting in a substantial loss of bone mass and a marked increase in susceptibility to fragility fractures—some of which may be life-threatening [12]. A prototypical etiology of secondary osteoporosis is prolonged exposure to glucocorticoids. Between 30% and 50% of patients undergoing chronic glucocorticoid therapy manifest clinically significant skeletal complications. It has been conclusively demonstrated that such therapy induces apoptosis of osteoblasts, leading to a quantitative depletion of osteocytes and profound architectural deterioration of bone tissue. The fracture risk in this population is consistently elevated and correlates strongly with cumulative glucocorticoid dose and duration [13].
Another critical and frequently underrecognized contributor to osteoporotic pathology is iron overload. Excess iron disrupts trabecular and cortical bone microarchitecture and reduces overall bone mass. This phenomenon is particularly evident in conditions necessitating recurrent blood transfusions or characterized by chronic hemolysis, such as β-thalassemia or sickle cell anemia. Additionally, elevated systemic iron levels have been linked to increased concentrations of pro-inflammatory cytokines – namely IL-1, IL-6, and IL-7 – which further potentiate RANKL-mediated osteoclast activation, thereby accelerating bone resorption [14].
Juvenile osteoporosis
During the first two decades of life, approximately 94% of individuals reach their peak bone mass (PBM), a critical determinant of skeletal mineralization and a well-established predictor of future osteoporosis risk (15). The attainment of PBM is influenced by a complex interplay of endogenous and exogenous factors, including lifestyle behaviors, nutritional quality, calcium and vitamin D intake, chronic comorbidities, pharmacological interventions, biological sex, ethnic background, and hereditary predispositions [16].
Failure to attain optimal PBM during adolescence is unequivocally recognized as a major risk factor for the development of osteoporosis in adulthood. Pediatric oncology patients, in particular, often exhibit suboptimal bone accretion due to both the underlying malignancy and its treatment, thereby rendering them highly susceptible to osteoporosis [17]. The risk and severity of such skeletal sequelae depend on the type of neoplasm, its anatomical location, and a multitude of modifying factors, including genetic susceptibility and patient-specific lifestyle parameters [7].
Neoplastic disease itself may induce osteoporotic changes through direct tumor effects and the secretion of osteolytic mediators. For instance, primary bone malignancies such as osteosarcoma and Ewing sarcoma are known to disrupt local bone architecture prior to the initiation of any therapeutic intervention. Nevertheless, anticancer treatments themselves play a pivotal role in the pathogenesis of secondary osteoporosis [17]. Chemotherapeutic regimens, particularly those incorporating glucocorticoids, contribute to significant bone mass loss by inhibiting osteoblastic activity, reducing osteocalcin synthesis, and promoting osteoclastic bone resorption [18]. Furthermore, corticosteroids impair vitamin D hydroxylation, disrupt intestinal calcium absorption, and reduce muscle tone, all of which synergistically impair bone remodeling and skeletal loading [13]. Endocrinopathies resulting from oncologic therapies further exacerbate skeletal fragility. Treatment-induced gonadal dysfunction or deficiencies in anabolic hormones, such as growth hormone (GH), negatively impact bone mass acquisition [17]. Cyclophosphamide-induced hypogonadism, for instance, leads to decreased bone mineral content, given the fundamental role of sex steroids in promoting bone accrual and mechanical resistance [18].
Following completion of cancer therapy, many pediatric survivors fail to meet recommended nutritional requirements, exhibiting inadequate intake of macro- and micronutrients, while simultaneously avoiding regular physical activity [19]. Although such behavioral adaptations may be understandable given the psychological aftermath of intensive therapy, they substantially compromise skeletal health. Furthermore, oncologic treatments predispose survivors to obesity and metabolic derangements. Following chemotherapy, approximately 25% of patients present with vitamin D3 deficiency, often accompanied by hypomagnesemia and hypocalcemia. These deficits represent critical threats to adequate bone mineralization and cellular differentiation within the osteoblastic lineage [7, 17].
Chronic nausea and suboptimal dietary practices, common among cancer survivors, further deteriorate nutritional status. Many pediatric patients, upon completing oncologic treatment, revert to high-fat, low-mineral-density diets as a form of psychological compensation. This maladaptive pattern stems from insufficient nutritional counseling and awareness. Survivors should ideally receive comprehensive dietary guidance emphasizing low-sodium, low-fat regimens enriched in protein, minerals, and dietary fiber [20].
Physical rehabilitation poses an additional challenge [21]. The long-term burden of cancer therapies, invasive medical procedures, and diminished patient motivation hinder the resumption of adequate physical activity. A predominantly sedentary or bedbound lifestyle accelerates bone mass depletion and muscular deconditioning, perpetuating a deleterious cycle of musculoskeletal decline [22].
In summary, pediatric cancer survivors are frequently left in a state of physical and psychological depletion that predisposes them to skeletal complications, including secondary osteoporosis [22]. Emerging evidence suggests that structured, preference-tailored physical activity can significantly ameliorate these outcomes [23]. In oncologic patients aged 6–18 years, regular physical exercise has been associated with reduced anxiety, improved physical fitness, and enhanced psychological well-being [22]. Notably, these benefits appear largely independent of the specific type of physical activity pursued. Furthermore, physical rehabilitation is often accompanied by improved dietary habits, with patients demonstrating more regular and nutrient-dense meal patterns [20].
It is also imperative to recognize that juvenile osteoporosis in the context of chemotherapy may arise from underlying genetic vulnerabilities. To date, approximately 16 genes have been implicated in increased bone fragility [24]. Recent studies have identified a negative impact of folate metabolism disturbances on bone mineral density. Notably, polymorphisms of the corticotropin-releasing hormone receptor 1 gene (CRHR1) in patients with acute lymphoblastic leukemia (ALL) have been consistently associated with decreased bone density [25]. Current research is increasingly focused on the estrogen receptor gene ESR1 and the low-density lipoprotein receptor-related protein 5 gene (LRP5), whose mutations may serve as valuable early predictive markers for osteoporosis. Genetic testing – and even clinical suspicion of relevant mutations – may, in the future, facilitate early identification of pediatric patients at heightened risk for skeletal complications in the setting of oncologic treatment [26]. Table I shows genes associated with susceptibility to osteoporosis in pediatric oncology.
Table I
Genes associated with susceptibility to osteoporosis in pediatric oncology [25, 26]
Chemotherapy and skeletal health
Chemotherapeutic agents, akin to all currently available modalities of oncologic treatment, exert a deleterious influence on bone mineralization [27]. Skeletal complications following chemotherapy are observed in approximately 20% to 50% of cancer survivors [28]. Among the agents most implicated in chemotherapy-induced osteopathy are methotrexate and glucocorticoids, particularly when administered in high cumulative doses [27].This deleterious impact is especially pronounced in the treatment of pediatric leukemias, where both aforementioned drugs have been shown to inhibit osteoblastic proliferation, augment osteoclastic activity, and ultimately lead to a decrease in peak bone mass (PBM) during critical periods of skeletal development [24, 27]. The adverse skeletal effects of chemotherapy have been recognized and scrutinized for several decades. These agents are commonly employed in the treatment of leukemias and lymphomas, both to directly target malignant cells and to mitigate systemic complications such as gastrointestinal inflammation [27]. Glucocorticoids, in particular, remain indispensable in the context of hematopoietic stem cell transplantation (HSCT), where they serve to prevent graft-versus-host disease (GvHD) and other transplant-related complications. Nevertheless, their extensive systemic effects indirectly and profoundly impair skeletal integrity [13].
Mechanistically, glucocorticoids contribute to muscle mass reduction, thereby increasing mechanical vulnerability of bones and predisposing to fractures, reduced gastrointestinal absorption of calcium and vitamin D, leading to progressive demineralization and suppression of gonadal steroidogenesis, eliminating the protective effects of sex steroids on bone homeostasis [13, 29, 30].
Following chemotherapeutic regimens, vertebral fractures, particularly in the lumbar spine, are the most frequently observed osseous complications in pediatric patients, with femoral neck fractures ranking second [31]. Clinical evidence supports a dose- and duration-dependent relationship between glucocorticoid exposure and the severity of skeletal complications. Notably, studies in survivors of acute myeloid leukemia (AML) have consistently demonstrated vertebral deformities in all participants, accompanied by persistent dorsolumbar pain [32, 33]. Methotrexate, another cornerstone of pediatric cancer therapy, has also been directly associated with juvenile osteoporosis. Its cytotoxic properties, while therapeutically effective against malignant cells, are likewise detrimental to osteoblasts [27]. Methotrexate impairs bone formation, fosters structural skeletal abnormalities, and reduces overall bone mass [34]. Concurrently, it stimulates osteoclastic differentiation and activity, compounding the resultant bone loss. Importantly, methotrexate’s skeletal toxicity appears to be modulated by genetic determinants, including Runx2, a pivotal transcription factor in osteogenesis. Empirical data confirm that increasing doses of methotrexate correlate inversely with maximal bone mass accrual in the pediatric population, potentially compromising long-term skeletal health [35]. Table II shows the endocrinopathies associated with cancer treatment.
Table II
Endocrinopathies associated with oncological treatment [27, 36, 37]
Prevention of osteoporosis in childhood cancer survivors is particularly critical during the phase of intensive skeletal growth, when bone mass accrual is most dynamic. The PanCare and IGHG recommendations emphasize early identification of high-risk groups, especially patients exposed to prolonged corticosteroid therapy, hematopoietic stem cell transplantation with graft-versus-host disease, or high-dose skeletal irradiation. Central to the preventive strategy is optimization of nutritional status and supplementation [38]. Vitamin D, as a key regulator of calcium and phosphate metabolism, remains the cornerstone of prophylaxis. Current evidence-based guidelines advocate maintaining serum 25-hydroxyvitamin D levels above 20–30 ng/ml, with supplementation in children typically ranging from 600 to 1,000 IU/day, and in adolescents up to 2,000 IU/day in cases of deficiency, always tailored to body weight and serum monitoring [39]. Adequate calcium intake is equally crucial, with daily requirements of 1,000–1,300 mg during adolescence, the period of peak bone mass accrual. Beyond these fundamental measures, growing evidence supports the role of folate and vitamin B12 in modulating bone metabolism through regulation of homocysteine pathways; folate supplementation in the range of 264–569 µg/day has been associated with improved bone mineral density in population-based studies, while ensuring sufficient vitamin B12 intake (2.4 µg/day in adolescents) prevents functional folate deficiency and mitigates skeletal fragility [40]. Collectively, these interventions, alongside lifestyle measures such as regular weight-bearing exercise, abstinence from smoking and alcohol, and maintaining adequate body mass, form an integrated preventive framework. Early implementation of these strategies in pediatric oncology survivors fosters optimal attainment of peak bone mass and reduces the lifelong burden of osteoporosis and fracture risk [38].
Management of pediatric oncology-associated osteoporosis: a multidisciplinary approach
The management of osteoporosis in pediatric oncology patients necessitates a multifaceted therapeutic strategy, encompassing pharmacological interventions, non-pharmacological support, and psychological care [41]. The pathogenesis of bone fragility in this population is multifactorial – resulting from both the direct effects of malignancy and the deleterious impact of oncologic therapies. A thorough diagnostic workup aimed at identifying reversible contributors to bone metabolism impairment is imperative [27]. Bisphosphonates remain the cornerstone of pharmacologic treatment. Intravenous zoledronic acid is typically administered at a dose of 0.05 mg/kg every six months, whereas pamidronate is dosed at 1 mg/kg daily for three consecutive days every four months. Though therapeutically equivalent, zoledronic acid is generally preferred due to superior cost-effectiveness and a more favorable side effect profile [42]. These agents mitigate bone resorption and are indicated in children with pathologic vertebral fractures or a BMD Z-score below –2.0, even in the absence of fractures. Intravenous administration is favored over the oral route due to superior skeletal bioavailability and the avoidance of gastrointestinal toxicity, particularly mucosal injury in pediatric patients [12].
Therapeutic duration and intensity should be tailored to disease severity. Treatment may be discontinued following normalization of BMD, absence of fractures, and exclusion of asymptomatic vertebral deformities on imaging. While pamidronate and zoledronic acid have shown comparable efficacy, emerging evidence suggests that zoledronic acid offers enhanced safety monitoring, particularly in children with osteosarcoma receiving concomitant cisplatin therapy – where a synergistic anti-osteolytic effect has been observed via osteoclastogenesis suppression [42].
Neridronate has demonstrated favorable tolerability in the pediatric population and was associated with a 50% increase in lumbar spine BMD over a three-year course. Nevertheless, bisphosphonate therapy is not devoid of adverse effects, including metaphyseal sclerosis, hypocalcemic episodes, osteonecrosis of the jaw, and paradoxical femoral fractures [43]. Table III shows a comparison of bisphosphonates.
Table III
Comparison of bisphosphonates [41, 42, 44]
Recent studies have investigated denosumab, a monoclonal antibody targeting RANKL [45]. While mechanistically promising through osteoclast suppression, its safety and efficacy remain unestablished in pediatric oncology. Concerns include dosing uncertainties, potential interference with longitudinal growth, and the risk of prolonged hypocalcemia and cardiotoxicity [46]. Consequently, denosumab is not currently recommended outside of clinical trials. Similarly, emerging agents such as anti-sclerostin antibodies – currently used in adult giant cell tumors – are under investigation in pediatric osteoporosis [47].
Nutritional optimization is a crucial adjunct to medical therapy. Up to 60% of pediatric cancer survivors exhibit dietary imbalances, notably fiber deficiency, excessive intake of ultra-processed and high-fat foods, and inadequate protein consumption [48]. Given that protein constitutes up to 30% of bone mass in healthy children, insufficient intake is an independent risk factor for skeletal fragility [49]. However, high-protein diets may exacerbate nephrotoxicity when administered alongside methotrexate or other nephrotoxic chemotherapeutics, necessitating individualized dietary planning guided by renal function indicators such as eGFR [50].
Vitamin D insufficiency is prevalent, driven by photosensitivity, limited sunlight exposure, corticosteroid therapy, and intestinal malabsorption – particularly in patients treated for hematologic malignancies. Monitoring of serum calcium, 25(OH)D, and active vitamin D metabolites is essential [51]. While there is no conclusive evidence that supplementation alters the disease course, daily intake of at least 500 mg of calcium and 400 IU of vitamin D is generally recommended to maintain physiological levels. Nevertheless, clinicians should remain vigilant regarding gastrointestinal intolerance to supplementation, especially in patients experiencing chemotherapy-induced nausea or constipation [52]. Promising nutraceuticals under investigation include resveratrol, which exerts anti-inflammatory effects on bone tissue by attenuating reactive oxygen species and osteoclastogenesis [53]. Other compounds such as genistein and icariin have shown potential in preclinical models through modulation of Wnt/β-catenin signaling and inhibition of bone resorption following chemotherapy. Though interactions with agents such as methotrexate may confer marrow-protective effects, robust human data are lacking, and pediatric use remains investigational [54]. The endocannabinoid system has emerged as a novel regulator of bone metabolism. CB1 receptor activation stimulates osteoclast activity, while CB2 promotes osteoblastogenesis and inhibits osteoclastic bone resorption [55]. Reduced CB2 expression has been observed in pediatric patients with osteosarcoma undergoing chemotherapy and correlates with heightened osteoclastogenic potential. Notably, mifamurtide – a macrophage-activating immunomodulator– may reverse chemotherapy-induced osteoclastic activity, suggesting a potential anti-resorptive role [56].
Methotrexate (MTX), one of the most widely used pediatric chemotherapeutics, induces significant bone resorption and growth disturbances [27]. Experimental studies suggest that nutraceutical supplementation with flavonoids, resveratrol, and omega-3 fatty acids may attenuate MTX-induced skeletal damage by suppressing inflammatory cytokines, limiting osteoclast activity, and preserving osteoblastic function [57].
Diagnostic principles based on international recommendations
The recent consensus from the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) has provided an evidence-based framework for the surveillance of bone mineral density (BMD) in childhood, adolescent, and young adult cancer survivors. Individuals exposed to cranial or craniospinal irradiation or total body irradiation (TBI) constitute the highest-risk cohort and require structured monitoring. The cornerstone of diagnostic evaluation is dual-energy X-ray absorptiometry (DXA), which should be performed once at entry into long-term follow-up (typically two to five years after completion of therapy), with a subsequent examination at approximately 25 years of age, coinciding with the attainment of peak bone mass. Thereafter, DXA assessments are indicated on a clinical basis, particularly in the context of symptoms (e.g., vertebral pain, fragility fractures) or progressive decline in BMD. Comprehensive clinical history with emphasis on risk factors – including prior corticosteroid exposure, hypogonadism, growth hormone deficiency, low body mass index, sedentary lifestyle, smoking, or alcohol consumption – remains an integral component of the evaluation, to be repeated at least every five years. Importantly, a BMD Z-score ≤ –2 mandates referral to a bone health specialist for endocrine assessment and therapeutic intervention, whereas a Z-score between –1 and –2 necessitates closer monitoring and repeat DXA within two years. Beyond diagnostic imaging, preventive counseling addressing optimal calcium and vitamin D intake, sustained physical activity, and avoidance of tobacco and alcohol represents an essential adjunct to medical surveillance. Such a harmonized approach ensures timely recognition of osteopenia and osteoporosis in pediatric oncology survivors, enabling early intervention and mitigation of long-term skeletal morbidity [38].
Despite encouraging preclinical outcomes, randomized controlled trials in pediatric oncology patients are urgently needed to establish safety and efficacy. Table IV shows the current recommendations.
Table IV
Recommendations for monitoring and prevention [52, 58–60]
Conclusions
In summary, while modern oncologic therapies have dramatically improved survival among pediatric cancer patients, their long-term skeletal sequelae remain a formidable clinical challenge. As such, it is imperative to implement a personalized, mechanism-driven approach in every patient – balancing the imperatives of disease control with proactive efforts to prevent life-altering skeletal complications [7]. Antineoplastic therapies, though life-saving, predispose pediatric patients to a spectrum of long-term skeletal complications, including bone pain, growth disturbances, and increased fracture susceptibility – all of which may culminate in physical disability and diminished quality of life. Bone health should be a critical consideration not only during active oncologic treatment but also in post-therapy surveillance and long-term follow-up. Given the paucity of evidence-based treatment modalities for pediatric patients, early identification of at-risk individuals and elucidation of the pathomechanisms underlying bone loss remain the cornerstone of preventive strategies. Timely identification of children at high fracture risk may significantly reduce both morbidity and mortality. There is an urgent need for rigorous clinical research into both repurposed and novel therapeutic agents with osteoprotective potential. For pharmacologic agents already deemed safe, further studies are warranted to establish optimal dosing regimens capable of mitigating chemotherapy-induced bone damage without compromising antitumor efficacy. A parallel concern pertains to the broader, multidimensional consequences faced by childhood cancer survivors. These individuals often require comprehensive, long-term care extending beyond oncology – including psychosocial support, given the elevated incidence of psychiatric comorbidities. Expedited access to diagnostic modalities such as radiographic screening is imperative in this high-risk population. Importantly, childhood cancer survivors are disproportionately affected by socioeconomic sequelae, including stigmatization, barriers to employment, and limited access to health insurance. In an era of escalating treatment costs, financial toxicity represents a significant yet frequently overlooked determinant of adherence and clinical outcomes. As such, future oncologic frameworks must integrate medical, psychological, and socioeconomic dimensions to ensure equitable, holistic survivorship care [5, 12].
