As the survival rates of childhood cancer increase, there has been a substantial increase in the number of children and adolescents with chronic complications. Survivors of childhood cancer are at risk for late adverse effects of cancer treatment. Endocrine and metabolic and skeletal sequelae are described in 50% of childhood cancer survivors (CCS) [1]. CCS have increased risk of low bone mineral density (BMD) because cancer treatments interfere with gains in BMD. Previous studies have included small numbers of cases, various age groups, heterogeneous treatments, different sites of BMD measurement, and different definitions of low BMD [2-4]. The terminology and definitions of low BMD in CCS are diverse. The World Health Organization’s (WHO) definitions of osteopenia and osteoporosis are based on T-scores, which are used to compare patient BMD with the maximum BMD of young adults, applying only to postmenopausal women. Some have defined a z-score < -1.0 as osteopenia (low BMD) and <-2.5 as osteoporosis (significantly low BMD) [5,6]. The International Society for Clinical Densitometry (ISCD) recommends the use of "low BMD for chronological age" when the BMD z-score is lower than -2.0 [7]. Last updated in 2019, diagnosis of osteoporosis in children and adolescents requires the presence of both a clinically significant fracture history and BMD z-score less than or equal to -2.0. Vertebral compression fractures without local disease or high-energy trauma are also indicative of osteoporosis [8]. Osteoporosis in adulthood has its origins in childhood and adolescence, which is an important period for optimizing peak bone mass (PBM) [9], which is the maximum amount of bone a person has during their lifetime and a crucial determinant of osteoporotic fracture risk [10]. A considerable part of PBM is determined by genetic factors. CCS fail to achieve PBM due to cancer itself, chemotherapy, malnutrition, and decreased activity. Low BMD in childhood and adolescents is a risk factor for fractures in youth and osteoporosis later in life [11]. In this article, we address the causes, prevalence, and management of low BMD in children and adolescents with cancer.

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Cancer itself causes BMD deficits. Low BMD at the time of diagnosis of pediatric cancer was primarily reported in patients with acute lymphoblastic leukemia (ALL) [12,13] and neuroblastoma [14]. Leukemic cell proliferation in the bone marrow and cytokine-mediated osteoclast activity are suggested as causes of low BMD [12]. Patients with primary bone tumors, including osteosarcoma and Ewing sarcoma, have low BMD in the affected sites [15-17].

Effects of chemotherapeutic agents on bone metabolism have been widely studied. The agents most frequently used to treat pediatric cancer are corticosteroids, alkylating agents, antimetabolites, and antibiotics. Corticosteroids inhibit the activity of osteoblasts and osteocytes, resulting in decreased bone formation and repair of microdamaged bones. Moreover, corticosteroids increase osteoclastic bone resorption and inhibit 1α-hydroxylation of vitamin D [18]. In patients with ALL, those receiving a total corticosteroid dose greater than 9 g/m² were more likely to have decreased BMD that did not recover after completing chemotherapy [19]. In patients with malignant lymphoma, prednisone dose greater than 20 g/m² is a risk factor for osteopenia [5].

Patients with ovary or testis tumors are at risk of primary hypogonadism, affecting BMD. Alkylating agents, such as cyclophosphamide and ifosfamide, also cause primary hypogonadism and result in BMD deficits [20]. Estrogen and androgens influence the growth and maintenance of bone [21]. Estrogen has a role in attaining PBM in both sexes [21]. Androgens enlarge the cross-sectional area of long bones and increase mechanical strength [21]. Doses of alkylating agents are closely related to degree of gonadal impairment. A CCS study developed a method to combine and compare cumulative doses of different alkylating agents using cyclophosphamide equivalent dose (CED) [22]. The St. Jude Lifetime Cohort study reported that high-dose alkylating agents (CED≥80 g/m²) and ovarian radiotherapy at any dose are associated with premature ovarian insufficiency [23]. For males, testicular radiotherapy at any dose and exposure to alkylating agents (CED≥40 g/m²) were independent risk factors for Leydig cell failure, defined as testosterone <250 ng/dL and luteinizing hormone >9.85 IU/L [24]. Methotrexate has a cytotoxic effect on the activity of osteoblasts and stimulates osteoclasts recruitment. It has been reported that a total cumulative dose greater than 4 g/m² was associated with failure to recover to a normal BMD after completion of chemotherapy [15,19]. In contrast, a recent study demonstrated that methotrexate exposure is not an independent risk factor for a significant decrease in BMD (z-score ≤-2). It is suggested that methotrexate lowers BMD but does not present a significant risk for z-score ≤-2 [25].

Hematopoietic stem cell transplantation (HSCT) also affects BMD. Bone loss occurred and continued frequently in the first year following allogeneic HSCT [26]. At 6 months after HSCT, nearly 50% of patients had osteopenia (T-score ≤ -1) at the femoral neck or lumbar spine [27]. Approximately 1/3 of patients who had undergone allogeneic HSCT in childhood had reduced BMD before reaching adulthood, with a high prevalence of asymptomatic vertebral compression fractures [28]. Pediatric patients with solid tumors (osteosarcoma, Ewing sarcoma, neuroblastoma) who underwent autologous HSCT showed a significant decrease in whole-body BMD z-score [29]. Multiple factors are involved in the pathogenesis of bone loss following HSCT, including impairment of gonadal and pituitary hormone secretion by high-dose chemotherapy, immobilization, poor oral intake, vitamin D deficiency, and use of calcineurin inhibitors and corticosteroids for graft-versus-host disease [26]. High-dose chemotherapy for HSCT shows dose-dependent toxicity on bone marrow stromal osteoprogenitors [30]. Patients who underwent HSCT at a younger age and allogeneic HSCT had a significantly higher risk of low BMD of the spine [31,32].

Endocrine sequelae resulting from radiotherapy cause a significant decrease in BMD. Negative effects of radiotherapy on BMD have been frequently reported in children with brain tumors. Patients with a tumor in the sellar or suprasellar region such as craniopharyngioma, germinoma, or low-grade glioma are highly likely to develop growth hormone (GH) deficiency or central hypogonadism [20]. Radiation at the hypothalamic-pituitary axis and total body irradiation (TBI) can lead to GH deficiency, affecting bone growth and BMD [1,2,33]. GH and insulin-like growth factor I are important for maintaining bone mass because both independently contribute to bone remodeling and apposition [34]. The severity of GH deficiency depends on patient age, dose, and fraction of radiation. A young age, higher radiation dose (≥18 Gy), pretransplant radiation, TBI ≥10 Gy in a single fraction, and TBI ≥12 Gy fractionated increase the risk of GH deficiency [35]. Gonadotropin deficiency occurs in patients who received TBI ≥30 Gy at the brain and may occur in those who received lower radiation doses with longer follow-up [35]. In addition to hormonal effects, radiation directly affects bone health at the local site of exposure and results in abnormalities in bone growth and an increased risk of fractures [36,37].

Nutrition and physical activity are essential to obtaining PBM [38]. In childhood cancer patients, physical activities are decreased due to prolonged periods of hospitalization and surgery, causing bone resorption and negatively affecting BMD [39]. In a study with survivors of ALL, reduced exercise capacity was associated with reduced spine BMD [39].

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The prevalence of low BMD among CCS ranges from 9%–51% [2-4]. Multiple factors contribute to development of low BMD in patients with cancer, as described above. In a collaborative cohort study of St. Jude and Dutch CCS, shorter height, lower weight, younger attained age, use of alkylating agent, and prior exposure to cranial and abdominal irradiation were closely related with low BMD (z-score≤-1) [4]. In children with cancer, treatments affect bone health during the first year, causing a significant decrease in BMD. BMD decreased during the first 6 months in patients with leukemia or lymphoma and during the latter 6 months of therapy for those with solid tumors [29]. Thus, the prevalence of low BMD depends on subject risk factors and assessment timing of BMD. Nevertheless, decreased BMD is a common finding in survivors of leukemia, lymphoma, brain tumors, solid tumors, and those who undergo HSCT (Table 1).

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At the time of diagnosis, significantly reduced BMD (z-score: -0.60 ± 1.55) was observed at the lumbar spine [12]. Chemotherapy for ALL includes corticosteroids and methotrexate, and a decrease in BMD occurs during chemotherapy. In a study of childhood leukemia and lymphoma survivors, lumbar spine BMD was low (z-score <-1) in 17.2% of subjects [40]. Also, 10.8% of survivors aged 15–19 years at diagnosis had very low BMD (z-score <-2), indicating that those of an older age were at high risk for low BMD [40]. A pharmacogenetic study evaluated the influence of single nucleotide polymorphisms in 4 genes (i.e., vitamin D receptor, collagen type I alpha 1, estrogen receptor 1, and glucocorticoid receptor) on body composition, BMD, and fracture risk. The vitamin D receptor gene (VDR) 5'-end (Cdx2/GATA) haplotype 3 was a risk factor for lower lumbar spine BMD during treatment of pediatric ALL [41]. In children with ALL, skeletal complications, such as bone pain, osteonecrosis, fracture, loss of mobility, bone deformation, and osteopenia, have been frequently reported during or after treatment [42]. Osteonecrosis is the best known skeletal complication, but fractures and bone pain are also frequent. In a case series of 122 pediatric patients with ALL, the 5-year incidence of fractures and bone pain was 13.5% and 12.3%, respectively [42].

BMD was decreased in long-term survivors of Hodgkin disease and non-Hodgkin lymphoma. A BMD z-score<-1.0 was reported in 41% of patients with Hodgkin disease and 50% of patients with non-Hodgkin lymphoma at the lumbar spine after 24.1 and 14.1 years of follow-up, respectively [5,43]. In addition to high cumulative dose of corticosteroid, mechlorethamine, vincristine, and procarbazine for treating malignant lymphoma also cause low BMD [5].

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Low BMD is a common finding among brain tumor patients treated in childhood [33,44]. Causes of low BMD are multifactorial, including craniospinal irradiation, GH deficiency, massive corticosteroids doses, and use of alkylating agents. Researchers have found that 23.6%–33% of patients with brain tumors treated in childhood had reduced BMD, with a total body BMD z-score<-2.0 [33,44]. In a case series of 28 intracranial germ cell tumor survivors, the prevalence of osteoporosis and osteopenia was 25.0% and 42.9%, respectively. In addition to radiation, risk factors included male sex, a low lean mass, and adult GH replacement [45].

Low BMD was reported in survivors of various other solid tumors. Ten of 48 long-term survivors of highly malignant osteosarcoma were osteoporotic, and 21 of 48 were osteopenic, according to the WHO definition [15]. Reduced lumbar BMD (z-score<-1.0) was also reported in 28.3%–43.6% of survivors of osteosarcoma or Ewing sarcoma [16,17]. In a Korean study evaluating the BMD of 9 osteosarcoma patients before and after treatment, 44% showed decreased lumbar BMD and 78% showed decreased femur neck BMD after adjuvant chemotherapy, while all 8 healthy controls showed increased lumbar and femur BMD [46]. Young age at diagnosis, male sex, and decreased lean mass are risk factors of osteoporosis in long-term survivors of osteosarcoma [47]. In children with neuroblastoma, three of 27 patients showed low lumbar BMD (z-score<-2.0) at the time of diagnosis, necessitating BMD assessment during the early course of the disease [14]. The incidence of osteopenia (z-score<-1.0) was 27% in long-term survivors of Wilms tumor [48].

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Low BMD is prevalent among CCS diagnosed with different types of cancer. Therapeutic modalities affecting BMD are essential for treating cancer. Thus, periodic evaluations of BMD in CCS should be performed. We need to pay more attention to CCS with many risk factors for reduced BMD, and proper management is needed during therapy as well as after cessation of treatment. Moreover, long-term follow-up is necessary to maintain bone health after cancer treatment. Further studies are required to analyze the efficacy and safety of medication.

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