Acute lymphoblastic leukemia (ALL) is the most common cancer among pediatric and adolescent patients, and it accounts for major cancer-related deaths in childhood [1]. Various factors, including exogenous (e.g., infection) or endogenous exposures (e.g., inflammation, oxidative stress) and genetic background, contribute to disease onset; ALL occurs in roughly 1:2,000 children aged <15 years [2]. After successful evolution of chemotherapy and clinical trials spanning 5 decades, the current curability rate of ALL is approximately 90% in resource-rich countries [3].

Endocrine disorders are highly prevalent among cancer survivors; recent data indicate that 40%–50% of survivors will develop at least one endocrinopathy once in their lifetime [4]. Endocrine dysfunction is encountered in pediatric patients with ALL during and after therapy and might arise in the long term. Endocrine complications in children during and after ALL treatment include compromised growth, hyperglycemia, thyroid dysfunction, adrenocortical insufficiency, gonadal dysfunction, syndrome of inappropriate secretion of antidiuretic hormone, and bone demineralization [5].

Growing bone is vulnerable to the leukemic process and chemotherapeutic drugs. ALL is a classic malignancy for developing skeletal morbidities[6] such as pain, fractures, decreased bone mineral density (BMD), and chronic impairment of bone function, which may be present not only during ALL diagnosis, but also as long-term sequelae following therapy [7]. Osteoporosis originating from ALL is triggered by multiple factors, including leukemic infiltration of bone, reduced bone strength due to immobility, poor growth induced by nutritional deficiency, and the use of various osteotoxic drugs [8]. This review addresses bone morbidity after pediatric ALL treatment and provides an overview of bone pathology based on skeletal outcomes to increase awareness among pediatric hemato-oncologists and endocrinologists.

Lengthwise bone growth in children with ALL is not different from that in healthy children, whereas bone density is reduced by lower bone turnover [9]. Defective mineralization and reduced bone formation are recognized in most children with ALL prior to treatment initiation [9]. Cytokines released by leukemic cells trigger osteoclast-mediated bone resorption, which causes bone pain and osteopenia, and bone turnover marker levels are diminished before treatment [10]. This indicates that the leukemic process itself is a predominant risk factor for decreased bone formation.

Juxta-metaphyseal lucent bands and osteolytic lesions on plain radiography are present in 70% of ALL cases at initial diagnosis and occur as part of the leukemic process [11]. Tumor-associated factors upregulate receptor activator of nuclear factor kappa-β ligand, resulting in activation of osteoclasts, triggering of osteolytic lesions, and destruction of endochondrons [12]. Bone pain is a common presenting symptom of childhood ALL that occurs in over 40% of cases, and it is the most common sign of undermineralized bone. Bone pain mainly occurs due to uncontrolled osteoclastic activity causing altered sympathetic nerve fiber regulation and neuropeptide release [13,14]. Periosteal reaction (<19%), low bone mass (<40%), and fractures (<10%) are consecutive results due to infiltration of leukemic cells in bone [9].

The definition of osteoporosis remains too controversial to be applied to children and adolescents, and densitometric outcome does not fully confirm diagnosis. The International Society of Clinical Densitometry (ISCD) defines osteoporotic children based on the presence of fracture and lowered densitometric standard deviation score for age and sex. The ISCD definition for osteoporosis in children is based on a clinically significant fracture history and a BMD z-score ≤-2.0 (Table 1) at preferred sites [15]. A clinically significant fracture history indicates 1 or more of the following: (1) ≥2 long bone fractures by age 10 years or (2) ≥3 long bone fractures at any age up to 19 years [15]. The presence of ≥1 nontraumatic vertebral compression (crush) fracture is indicative of osteoporosis in children [15].

Nontraumatic vertebral fracture (VF) is a commonly encountered skeletal manifestation in children and adolescents with newly diagnosed ALL that occurs in as many as 16% of cases [9]. Cummings et al. reported a 4-year cumulative incidence of VF following ALL diagnosis of 26%, with T5–7 as the most severely fractured levels [16]. Back pain can occur in <55% of children at ALL diagnosis, and most fractures occur at thoracolumbar (31%, T12–L2) and midthoracic (24%, T6–T7) levels [17]. Because most children do not manifest with back pain at initial presentation, this is under-recognized [18]. Moderate or severe VF can also occur asymptomatically; therefore, routine vertebral assessment as systematic surveillance on ALL diagnosis is fundamental [16]. VF can be diagnosed by conventional radiograph, and its assessment is useful as VF severity correlates with the degree of lumbar spine BMD.

Conventional radiology, hand examination, and morphometric study of the spine are used to examine trabecular thickness and cortical thinning [19]. VF can be recognized by measuring the heights of vertebral bodies on a conventional radiograph. To visualize radiologic signs of reduction in bone density, a 30%–40% loss of mineralized bone is necessary [19]. In 1993, a "semiquantitative method" grading system was proposed to assess VF based on vertebral shape and reduction in height by qualitatively and quantitatively assessing osteoporotic vertebral deformity [20]. Depending on the degree of reduction in vertebral body height, grading reflects the severity of VF. Other scoring systems for assessment of VF through conventional radiography, such as an algorithm-based quantitative method, Koerber’s technique, and a semiautomated technique, are used in clinical practice [21,22]. Yet, there is no reliable method available specifically designed for pediatric use that encompasses normal physiologic variation and observer variability. Thus, current techniques need further improvement to develop software tools to diagnose VF in the pediatric population [23].

Quantitative computed tomography (QCT) is beneficial because it measures bone volume and computes volumetric BMD, unlike planar images generated by dual-energy X-ray absorptiometry (DXA); it also differentiates dense cortical bone from metabolically active trabecular bone [24]. With good accuracy and precision, QCT causes exposure to low radiation dose (approximately 3 microsievert per scan) and enables functional evaluation of pediatric bone disease [25]. QCT can measure both axial and appendicular sites, and a tabletop peripheral QCT device can measure the radius, tibia, or femur in children [26]. However, pitfalls of QCT include limited evaluation of appendicular bone with low turnover, low spatial resolution, and exact reposition of the extremity required for follow-up [25].

DXA remains the most commonly used imaging modality for measuring BMD because it confirms low bone mass. DXA determines the amount of bone mineral in a specific region by differential absorption of X-rays of 2 different energies and calculates the depth and composition of adjacent soft tissue to generate measurements of fat and lean mass [27]. Measurable sites in adults are the posterior-anterior spine and hip, and posterior-anterior spine and total body without head are the preferred sites for performing bone mineral content and areal BMD (aBMD) [15]. DXA only measures the 2 dimensional density of bone and not 3 dimensional volumetric density [28]. Hence, because the depth of bone is not considered, DXA is size-dependent and overestimates aBMD in large bones and underestimates aBMD in small bones. This is challenging for children in whom chronic disease stunts skeletal growth [29]. Furthermore, height and bone age-adjusted aBMD z-scores are more reliable values as they avoid pitfalls such as low aBMD z-scores due to short stature [30,31]. BMD differs according to age, sex, race, ethnicity, and lifestyle, requiring appropriate references for the pediatric population. Lim et al. [31] released BMD reference values in healthy Korean children and adolescents were released in 2010.

Administration of chemotherapeutic agents also destroys bone formation, and the adverse effects of therapy, rather than the antileukemia response, should be addressed during treatment. ALL treatment usually spans 3 years and comprises 3 phases of chemotherapy (remission-induction, consolidation, and maintenance), whereas hematopoietic stem cell transplantation (HSCT) with or without irradiation remains an option for patients at very high risk [2]. Among current regimens of chemotherapy against ALL, osteotoxic drugs such as glucocorticoids, methotrexate, L-asparaginase, daunorubicin, and vincristine, as well as irradiation treatment, are predominant risk factors that equally cause deficient BMD. The accumulated dosage and duration of therapy result in bone destruction (Table 2).

Despite direct leukemic effects and exposure to multiple osteotoxic treatment regimens, which altogether induce demineralization, the most rapid skeletal development occurs during childhood and adolescence. Skeletal recovery after therapy completion in children with ALL is crucial, while bone metabolic status continues to change significantly in this age group.

Survivors begin to recover lost bone mass after ALL therapy, while those who do not reach their optimal bone mineral acquisition experience critical bone loss 2 years following therapy cessation [7]. Associated clinical factors include glucocorticoid exposure and baseline lumbar spine BMD z-scores, which are both associated with VF and non-VF [59]. The BMD z-score for the lumbar spine and femoral neck reaches osteoporotic range 6 years after therapy; despite BMD increase after treatment completion, changes in z-scores do not reveal full recovery [60]. Changes in cortical dimensions and BMD might depend on the interval after treatment cessation since early increase in cortical dimensions contributes to transient declines in cortical BMD, reflecting a longer time necessary to fully mineralize newly formed bone [61]. Yet, the extent of bone mass recovery in children after termination of therapy is unknown.

ALL survivors treated with cranial radiotherapy, craniospinal radiotherapy, and total body irradiation are prone to hypopituitary hormone deficiency and growth, and gonadal hormones predominantly act on bone mineral accrual. GH promotes bone formation via IGF-1 by stimulating osteoblastic activity [43]. Glucocorticoids alter bone health via decreasing the synthesis of IGF-1 and gonadotropins to result in deficiency of GH and sex steroid hormone [41,62]. Radiation directly affects the growth plate and causes GH deficiency and growth retardation. GH therapy is beneficial for BMD, bone geometry, and body composition and improves bone health [62]. Based on safety and efficacy, guidelines recommend GH replacement after a 1-year disease-free state in childhood cancer survivors with confirmed GH deficiency [4]. If not properly treated, primary or secondary hypogonadism compromises bone mineralization. Leydig cell failure is common if males are exposed to testicular radiation doses in excess of 20 Gy, whereas females older than 10 years of age who receive 10 Gy of fractionated total body irradiation may experience ovarian failure [43]. Androgen receptors are located in growth plate osteoblasts and exert the anabolic effects of testosterone on bone, while estrogen has more direct activity in skeletal maturation and mineralization [63]. Compared to those who completed treatment with standard chemotherapy regimens, HSCT recipients are at higher risk of treatment-associated GH deficiency and hypogonadism and subsequent poor bone acquisition.

Vertebral reshaping is a growth-dependent bone remodeling phenomenon that involves acquiring normal vertebral dimensions following VF, which does not occur beyond epiphyseal fusion [6]. Seventy-seven percent of ALL children with VF had complete reshaping at the last follow-visit, 18% had incomplete reshaping, and 4% were not reshaped over 6 years of follow-up [59]. Therefore, spontaneous vertebral reshaping is an opportunity for osteoporotic children to be conservatively observed, rather than to initiate pharmacologic intervention [64].

Although many clinicians recommend calcium and vitamin D supplementation to remediate osteoporotic change, their role is controversial [65]. Calcium- and calcitriol-retarded BMD loss in children receiving glucocorticoids was less in patients taking calcitriol and calcium compared to those taking placebo; this could be considered a preventive measure when supplementation begins simultaneously with glucocorticoid initiation [66]. Conversely, 2 years of vitamin D and calcium supplements in children with ALL after treatment completion did not significantly increase BMD compared to the placebo group [65]. There is no specific recommendation guideline for dosage of calcium and vitamin D supplements for children with ALL; therefore, 400 IU/day of vitamin D and 500–1,300 mg/day of calcium intake are recommended to prevent any deficiency [67,68]. Particularly, calcium and vitamin D should be adequate for effective pharmacologic treatment of osteoporosis since low calcium and cholecalciferol levels represent low bone mass [69]. Bone metabolic markers should be monitored throughout supplementation to avoid any episode of nephrolithiasis or urolithiasis from calcium excess.

Children with VF and/or low BMD and ≥2 long bone fractures are considered for intravenous bisphosphonate (BP) therapy using potent antiresorptive agents, which have shown promising outcomes for treating VF in pediatric ALL patients (Fig. 1) [6,8]. BPs are synthetic analogues of pyrophosphate widely used in primary and secondary osteoporosis management [70]. BPs prevent osteoclastic bone resorption and relieve bone pain, while their use in prevention remains limited [6]. An Australian group recommends serum calcidiol level should be >50 nmol/L prior to the first BP infusion and maintained postinfusion [8]. Increased BMD, reduced bone pain, and improved vertebral body shape were observed after BP use in patients with hematologic malignancy and in bone marrow transplant patients with graft-versus-host disease, although there is limited case-control data [8]. Optimal agents, dose, and duration remain controversial, although intravenous agents may be more effective than oral agents [64]. Pamidronate (9 mg/kg/yr, 4–6 divided doses) and zolendronate (0.05–0.1 mg/kg/ yr, 2–4 divided doses) are widely used BPs [8,64]. Adverse effects are generally well-tolerated, although transient myalgia, bone pain, fever, and nausea are common after the first infusion [64]. BP therapy is the first-line treatment option for adults with low bone mass who receive glucocorticoid therapy for >3 months; however, there are insufficient data to support the efficacy of BPs in children exposed to excess glucocorticoids [39]. Although the long-term beneficial effects of BP therapy are currently unknown, it remains the optimal drug of choice for children with ALL since BPs can be used during steroid dosing and improve bone health despite other treatments.

Both calcitonin and teriparatide are effective at delaying the progression of osteoporosis. Calcitonin inhibits osteoclastic activity in bones, while teriparatide enhances bone formation [69,71]. However, the use of calcitonin and teriparatide in osteoporotic patients with ALL is limited, and their benefits compared to oral calcium and vitamin D or BP therapy are questionable.

Mobility and exercise during and after ALL treatment may be beneficial to bone mass acquisition. Exercise programs or physical activity interventions include exercises to maintain hand and leg function, stretching exercises to maintain ankle dorsiflexion mobility, and short-burst high-intensity exercises; outcomes of these programs revealed a significant positive intervention effect on total body BMD [72]. Intrahospital supervised exercise may also considerably improve children’s quality of life (QoL) and overall health status during treatment periods [73].

ALL is the most commonly encountered cancer during the pediatric and adolescent period, and bones are vulnerable to the leukemic process. Treatment of various skeletal complications diminishes QoL. From diagnosis until several years posttreatment, ALL may threaten bone health by triggering bone demineralization and reducing bone formation. Routine screening and monitoring of skeletal conditions via radiographic and laboratory assessment can lead to prompt recognition and intervention to prevent adverse long-term sequalae. Factors contributing to bone morbidity include chemotherapeutic drugs, irradiation, malnutrition, and lack of physical activity, while accumulated dosage and prolonged exposure to these factors results in bone destruction. Although long-term outcomes such as pituitary hormone deficiency after cranial irradiation may be irreversible, spontaneous recovery of bone mass is a privilege of this age group. BP administration, supplementation with adequate vitamin D and calcium, and regular exercise are beneficial options for optimal bone mineral accrual in pediatric patients with ALL. There is no definitive method for bone morbidity assessment and treatment in children with ALL. Our goal to combine up-to-date diagnostic and therapeutic options to provide appropriate screening to any patient overcoming ALL. Healthcare-givers who are responsible for treating these patients should consider bone morbidity throughout the entire disease course.