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Bone problems in childhood cancer patients

Bone problems in childhood cancer patients
Literature review current through: Jan 2024.
This topic last updated: Dec 20, 2022.

INTRODUCTION — Children and adolescents may experience bone problems and endocrine problems during and after therapy for oncologic problems. The bone problems, which may be acute or chronic, and symptomatic or asymptomatic, will be discussed in this topic review.

The related endocrine problems will be discussed briefly here and in detail separately. (See "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood".)

PATHOPHYSIOLOGY

Normal bone formation — Bone forms by deposition of osteoid through osteoblast activity. Resorption of osteoid occurs through osteoclast activity. Resorption actively occurs even in growing children. This allows bone remodeling as bones increase in circumference and length. Length is added to bones in the epiphyseal plate, a metabolically active zone in which chondrocytes and cartilage are converted to osteocytes and calcified matrix. The relatively faster rate of bone formation compared with rate of bone resorption leads to growth in bone size and increase in bone mineral density (BMD). Bone strength and fracture risk are related to bone size, BMD, and microstructural architecture. (See "Normal skeletal development and regulation of bone formation and resorption".)

Both bone size and BMD increase gradually through the childhood years with more rapid increases during puberty [1]. Calcium is added to bone most rapidly between ages 9 and 15 years in girls and between ages 10 and 18 years in boys [2,3]. After adult height is achieved, bone size remains stable, but BMD continues to increase until age reaches the mid- to late 20s (peak bone mass). Subsequently, bone mass and BMD decline very gradually throughout the rest of adult life. If peak bone mass is lower, osteoporosis and fractures may occur earlier in adult life. Bone growth and remodeling are regulated by endogenous factors, including hormones such as growth hormone, sex steroids, and various growth factors; cytokines; and growth plate aging. Exogenous factors such as nutrition, including vitamin D, and weightbearing exercise also contribute [4,5].

Effects of cancer — Childhood cancer can affect bone metabolism and growth through a variety of mechanisms [6]. The relative contributions of these factors to bone disease in a particular patient, and the contribution of genetics, are often unclear [7].

Cancer itself can affect bone metabolism by interfering with nutrition, physical activity, and/or pubertal progression during critical periods of growth and bone accumulation. Cancer cells may contribute directly to bone pathology; leukemic cells may overexpress RANK ligand (RANKL), which is a regulator of osteoclast differentiation [8].

Cancer treatment can alter bone metabolism through several mechanisms [9,10]:

Local effects on bone (antimetabolites such as methotrexate, glucocorticoids, and/or regional radiation).

Central nervous system effects from chemotherapy and/or cranial radiation, causing pituitary hormone dysfunction (eg, growth hormone deficiency [GHD] or hypogonadotropic hypogonadism).

Peripheral effects of chemotherapy or radiation on endocrine organs associated with bone metabolism (gonads, thyroid, or kidneys).

Dietary modifications during and after cancer therapy. Studies have shown that cancer survivors are very likely to have vitamin D deficiency [11,12], but this is similar to the general population.

Children are particularly sensitive to the above effects because of their rapid bone growth and turnover.

AVASCULAR NECROSIS (OSTEONECROSIS) — Avascular necrosis (AVN), also known as aseptic osteonecrosis, is a serious complication of chemotherapy that can destroy the bone underlying the articular surface of the joint, especially the weightbearing joints of the lower extremities. AVN is usually associated with high-dose glucocorticoid treatment and bone marrow transplantation, but it has occasionally been reported in association with other types of chemotherapy [13-16]. Adolescent patients are disproportionately affected [13,15,16]. AVN commonly presents with pain upon weightbearing but may be asymptomatic.

Incidence — Between 2 and 10 percent of children treated for acute lymphoblastic leukemia (ALL) develop symptomatic AVN [17-19]. In one study, the rate of symptomatic AVN was 17 percent (10 percent in children younger than 10 years and 45 percent in children older than 10 years) and the overall rate of asymptomatic disease was 72 percent [17]. These rates are higher than in previous reports, probably because this study employed routine screening by magnetic resonance imaging (MRI) during re-induction therapy and identified symptomatic disease when minimal dysfunction was present. Most cases of AVN occur during or shortly after chemotherapy; onset of AVN ranges from 6 to 53 months after initiation of chemotherapy [13]. The five-year cumulative incidence of AVN was 21 percent in patients with ALL younger than 30 years [20]. One long-term study suggests that AVN can develop years after treatment [21].

AVN is a particularly common complication of treatment for ALL, but it also affects a substantial portion of patients undergoing hematopoietic cell transplant (HCT) who receive glucocorticoids as primary treatment or for graft-versus-host disease [16]. AVN is also seen in association with other malignancies that are treated with glucocorticoids, including non-Hodgkin lymphoma, Hodgkin disease, and other leukemias [13,15].

Risk factors — The patient's age and the dose and duration of glucocorticoid treatment are important risk factors [9,21-23]. Most cases of chemotherapy-associated AVN occur in children and adolescents over 10 years of age [13,15-17]. This is probably because rapid bone growth and bone turnover in this age group accelerate the pathologic effects of the glucocorticoids. Adults treated with the same regimens as adolescents have less risk for AVN [20,24]. Several studies have suggested that the use of dexamethasone rather than prednisone, and exposure to radiation therapy (particularly gonadal radiation), contribute to the risk [21]. Studies conflict in their conclusions about whether White race and female sex confer additional risk [17,21,25]. Genetic polymorphisms, elevated lipid levels, and obesity may also contribute to the risk [17,26-28].

Pathogenesis — Glucocorticoids are the main cause of AVN in children with malignancies [13,23]. Regimens including L-asparaginase also may increase risk for AVN [20]. The reasons for these associations and other contributing factors are not clear. Genetics, epigenetics, and inflammatory pathways play a role [29-32]. AVN probably begins with an interruption of the blood supply to the bone, possibly because of fat emboli. Subsequently, the adjacent area becomes hyperemic, resulting in demineralization and trabecular thinning. When subjected to physical stress (such as weightbearing), the bone collapses. The potential contribution from other components of chemotherapy (particularly antimetabolites such as methotrexate and mercaptopurine) has not been established. (See "Treatment of nontraumatic hip osteonecrosis (avascular necrosis of the femoral head) in adults".)

Assessment — AVN typically presents as a limp and bone or joint pain, usually occurring while the patient is receiving high-dose glucocorticoids. Most cases of symptomatic AVN involve weightbearing joints (eg, the femoral head and femoral and tibial condyles), but multiple joints are often affected in the same patient [13].

The joint is usually initially evaluated by plain radiograph, mostly to identify other potential sources of pain, such as fracture or bony metastasis. However, a normal plain radiograph does not exclude AVN, and any patient at risk for AVN with unexplained joint pain should be further evaluated by MRI, which is far more sensitive and specific than plain radiographs for detection of AVN [23,33]. The sensitivity and specificity of radionuclide bone scans is intermediate [34].

Treatment — Treatment for AVN usually depends on the severity of the lesion, but there are no established criteria for determining severity in this age group [34]. Most cases are treated with an initial trial of conservative therapy, with advancement to surgical intervention when necessary [23].

Conservative therapy includes restriction of weightbearing and avoidance of abduction; pendulum exercises may be helpful. If possible, a decrease or modification of glucocorticoid dose may improve the condition.

Conservative therapy is ineffective for many patients with chemotherapy-related AVN of the hip or knee. Among patients who developed chemotherapy-related AVN, 30 to 60 percent required surgical intervention, consisting of core decompression or joint replacement [13]. More extensive AVN is more likely to require surgical intervention. In one series, 80 percent of patients with lesions occupying more than 30 percent of the femoral head volume had joint collapse within two years of diagnosis and 50 percent required arthroplasty [35]. One report of two patients has shown benefit of locally implanted autologous stem cell therapy [36]. In a prospective randomized study in 51 patients who had 79 AVN sites, 37 ankle sites were treated with autologous stem cell injections, 37 sites underwent core decompression only, and 20 sites received no treatment [37]. The AVN sites that received stem cells had the best clinical outcomes.

Bisphosphonates are beneficial in this patient population in reducing pain and improving mobility but do not prevent joint destruction [38]. Other treatment approaches that have been explored include a prostacyclin analog (iloprost), electrical stimulation, and hyperbaric oxygen, but none of these interventions has been sufficiently studied to determine if they are useful [13,23,39,40]. (See "Treatment of nontraumatic hip osteonecrosis (avascular necrosis of the femoral head) in adults", section on 'Introduction' and 'Prevention and treatment' below.)

SLIPPED CAPITAL FEMORAL EPIPHYSIS — Slipped capital femoral epiphysis (SCFE) is a displacement of the proximal femur upwards through the epiphyseal growth plate, giving the appearance of downward displacement of the epiphysis itself.

The risk for SCFE may be raised by increased bone resorption or impaired development of bone. "Typical" SCFE occurs with increased frequency in overweight or actively growing children and adolescents, in patients after renal transplant or in renal failure, in girls with Turner syndrome, and in obese pubertal boys. "Atypical" SCFE occurs at a younger age, shorter height, and lower weight [41]. Among 22 children with atypical SCFE, 19 had neoplasia [41]. Atypical SCFE can occur in patients with growth hormone deficiency (GHD) or those receiving growth hormone therapy [42]. The latter is relevant for survivors of childhood cancer, some of whom develop GHD. (See 'Growth hormone deficiency' below.)

There appears to be a weak association between SCFE and radiation therapy and/or chemotherapy. Direct radiation to the hip appears to be the most consistent association [43]. Most of the reported cases underwent cancer treatment in early childhood and presented with SCFE during late childhood (mean 10 years), which is younger than the usual age of onset of SCFE in the absence of cancer treatment.

The evaluation, diagnosis, and management of SCFE are discussed in detail in a separate topic review. (See "Evaluation and management of slipped capital femoral epiphysis (SCFE)".)

ALTERED EPIPHYSEAL GROWTH — Epiphyseal growth is altered temporarily during cancer therapy but is altered also in a lasting manner after certain types of chemotherapy and after irradiation to epiphyses. Children undergoing intensive chemotherapy for acute lymphoblastic leukemia (ALL) typically display a marked deceleration in height velocity [44,45], generally followed by catch-up growth after chemotherapy is complete. Agents that directly alter bone growth include glucocorticoids, doxorubicin, actinomycin D, methotrexate, and cisplatin [46].

Direct irradiation to long bones and the vertebral column can retard bone growth. The risk is increased in younger patients and with regional radiation doses of more than 20 Gy [9,10,44].

Regional or cranial radiation and chemotherapy can also have indirect effects on bone growth by disrupting growth-promoting hormones, including growth hormone, insulin-like growth factor 1 (IGF-1), gonadal steroids, and thyroid hormones [44,47,48]. Hypothyroidism is an important consequence of radiotherapy and contributes to growth failure. Hyperthyroidism is less common, but, when present, it can impair bone mineralization. (See 'Reduced bone mineral density' below and "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood".)

Abnormality of each of these factors may disrupt epiphyseal growth. The effects on longitudinal growth may be seen only transiently during chemotherapy, or may persist and compromise adult height [10,47,49]. In most cases, trunk length (sitting height) is affected more than standing height because of additive effects on each of the many epiphyses in the vertebral column [10]. Patients undergoing treatment at an age when growth is normally rapid (early childhood or early puberty) are most likely to have measurable effects on linear growth.

REDUCED BONE MINERAL DENSITY — Reduced bone mineral density (BMD) is particularly common among survivors of hematologic malignancies and brain tumors [44]. Some of the risk seems to be related to the underlying cancer: bone mineral is already decreased, compared with normal for age, at the time of diagnosis of acute lymphoblastic leukemia (ALL) [50]. Chemotherapy and/or radiation therapy further increase these risks. However, it is important to adjust BMD results for height as one study has shown that uncorrected BMD was low but size-corrected BMD was normal after stem cell transplant [51].

Reduced BMD is often clinically invisible and unrecognized until a fracture occurs. Symptoms of fractures associated with osteoporosis may include bone pain, abnormal gait, vertebral collapse, back pain, or low-impact fractures.

Most survivors of childhood cancer will regain bone mass with increasing time after therapy [52-54]. However, BMD may be permanently reduced if the cancer or its treatment reduces peak bone mass, so children treated for cancer during puberty are particularly at risk. In addition, there may be progressive effects on BMD if the individual has a treatment-related endocrinopathy (eg, growth hormone deficiency [GHD] or hypogonadism) or nephropathy causing chronic renal phosphate loss (eg, Fanconi syndrome associated with ifosfamide) [55].

Definition — In adults, osteopenia is defined as BMD that is more than 1 standard deviation (SD) below the mean (expressed as a T-score <-1), and osteoporosis is defined as BMD that is more than 2.5 SD below the mean (with the mean based on the standard of young adults). BMD is most commonly measured by dual-energy x-ray absorptiometry (DXA) or, at some centers, by quantitative computed tomography (CT). (See 'Bone mineral density measurement' below.)

In children, comparison of BMD to adult standards is not a good predictor of current fracture risk [35]. Therefore, use of age- and sex-based standards (Z-scores) is recommended [34,56]. A Z-score <-2.0 defines reduced BMD. Correction for body size (for height age) is important [51]. In children, the term "osteoporosis" is not used unless there is a clinically significant fracture history, such as fracture of lower extremity long bone, two episodes of upper extremity long bone fractures, or vertebral compression fracture.

Primary osteoporosis results from the gradual losses of BMD resulting from aging and menopause. Secondary osteoporosis is caused by other medical disorders, including cancer and cancer treatments [57]. (See "Screening for osteoporosis in postmenopausal women and men".)

Incidence — A number of studies have reported reduced BMD in long-term survivors of cancer in pediatric patients, particularly those affected by brain tumors or leukemia [58-62]. Therapy for solid tumors can also lead to reduced BMD [63]. Reduced BMD (as measured in the lumbar spine) has been reported in 14.6 to 22 percent of leukemia survivors who received chemotherapy prior to epiphyseal closure and in 54 percent of survivors treated with cranial radiation [64,65]. In one study of 155 patients with ALL, 16 percent had vertebral fractures identified by MRI during the first 12 months of chemotherapy [66]. In another study of young adults who had been treated with chemotherapy for bone sarcoma, BMD reduction was observed in 58 percent of survivors during a mean follow-up period of seven to eight years [67]. However, other studies showed no decrease in bone mass, perhaps because these studies described longer-term outcomes and/or results of more recent treatment protocols [52,68].

Cancer treatment during adulthood appears to be less likely to reduce BMD. As an example, decreased BMD was seen in children, but not adults, two years after hematopoietic cell transplantation (HCT) for myeloid leukemia [69]. Similarly, among 25 individuals treated with HCT for leukemia or lymphoma during adulthood, decreased bone mass was not observed when measured by DXA eight years later [70].

Risk factors — Risk factors for decreased BMD include the following [44,48]:

Cranial irradiation [71-73]

HCT [74]

Glucocorticoids [71,75,76]

Methotrexate (high cumulative doses, eg, >40,000 mg/m2) [75,77]

Alkylating agents (cyclophosphamide, ifosfamide) [71]

Younger age at diagnosis (prior to puberty) [64,78]

Male sex, White race [59,62,71,78]

Vitamin D deficiency [11,12,67,79]

Pathogenesis — Cancer and cancer treatments can affect BMD through several mechanisms. In many cases, several factors will contribute to reduced BMD in the same individual.

Glucocorticoids — Glucocorticoids are an important component of chemotherapy for many childhood cancers. They contribute to bone loss through a variety of mechanisms, including direct inhibitory effects on osteoblasts and by inhibiting production of growth hormone, insulin-like growth factor 1 (IGF-1), androgens, and estrogens. These mechanisms are discussed in detail separately. (See "Clinical features and evaluation of glucocorticoid-induced osteoporosis".)

Glucocorticoids are more likely to cause reduced BMD in patients exposed to cumulative doses >9000 mg/m2 of prednisone equivalent (>36,000 mg/m2 of hydrocortisone equivalent). Patients treated with dexamethasone are more likely to have reduced BMD as compared with those treated with prednisone, even at doses that are considered equivalent for glucocorticoid replacement [75]. For comparison, physiologic doses of glucocorticoids are hydrocortisone 10 mg/m2 daily divided into two or three doses, prednisone 2.5 mg/m2 daily divided into two doses, or dexamethasone 0.125 mg/m2 once daily (table 1).

Other chemotherapeutic agents — Antimetabolite drugs, such as methotrexate, reduce BMD by directly inhibiting formation of new bone [77]. Reduced BMD has been noted with cumulative methotrexate doses exceeding 40,000 mg/m2 [75]. Alkylating agents, such as ifosfamide, can reduce BMD through toxicity to the gonads (thus reducing gonadal steroid production) or kidneys (causing renal phosphate loss); these effects may be acute or chronic [55]. (See "Drugs that affect bone metabolism".)

Growth hormone deficiency — Cancer treatment, particularly cranial radiation, can have permanent effects on the hypothalamic-pituitary axis, causing GHD [47,80]. The highest risk for GHD has been observed in patients exposed to radiation doses of 18 Gy or more to the cranium. Patients undergoing total body irradiation doses of more than 12 Gy for HCT are also at risk for GHD [81]. GHD is the most common pituitary hormone abnormality after cranial radiation and is almost universal among patients treated with doses above 35 Gy [55]. (See "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood".)

GHD inhibits bone formation both directly and indirectly by reducing serum 1,25-dihydroxyvitamin D concentrations [82]. In patients with reduced BMD because of GHD, treatment with growth hormone enhances BMD [83]. DXA tends to underestimate bone density in individuals with short stature. Thus, individuals with short stature and GHD may have falsely abnormal measurements of BMD, and it may be difficult to distinguish those with true deficits of bone density [84].

Hypogonadism — Cancer treatment may cause hypogonadism, either through direct effects on the gonads (primary hypogonadism) or indirect effects on hypothalamic-pituitary axis (secondary hypogonadism) [72]. Hypogonadism is the most prominent cause of bone loss following HCT in adults [72,74].

Primary hypogonadism may be caused by direct toxicity to the gonads from regional radiation or chemotherapy (eg, alkylating agents) [81]. Gonadal dysfunction may develop after radiation doses to the ovaries of 10 Gy or more in prepubertal age and 5 Gy or more during puberty. Radiation doses of 5 Gy to the testes may cause loss of sperm production, while doses of 20 Gy or more cause Leydig cell dysfunction and androgen deficiency [81].

Secondary hypogonadism may be caused by high-dose cranial irradiation, which causes gonadotropin-releasing hormone deficiency and hypogonadism in 2 to 5 percent of individuals receiving radiation doses at or above 40 Gy; this rate is considerably lower than that of GHD [47,80,85]. Paradoxically, lower doses of cranial irradiation have been associated with higher rates of early puberty due to loss of inhibitory influences controlling timing of puberty [80].

Either chemotherapy or irradiation can cause deficiencies of estrogen and/or androgens, which reduce BMD. These gonadal hormones inhibit bone resorption, and androgens also stimulate bone formation. (See "Pathogenesis of osteoporosis", section on 'Sex steroid deficiency'.)

Hyperthyroidism — High-dose irradiation to the thyroid gland commonly causes hypothyroidism. Hyperthyroidism is less common but was detected in 2.5 percent of individuals treated with radiation therapy [86]. When present, hyperthyroidism can lead to increased bone resorption and bone loss. (See "Bone disease with hyperthyroidism and thyroid hormone therapy".)

Other — Illness itself may result in reduced BMD because of prolonged immobilization, altered diet, and elevated immune cytokines. Habits of daily living, such as deficient intake of calcium or vitamin D, smoking, or decreased exercise, can also contribute to reduced BMD in cancer survivors, as in other individuals [87]. (See "Bone health and calcium requirements in adolescents".)

Additional factors that predispose to osteopenia include genetic variants in the vitamin D receptor and familial patterns in the timing of puberty. A family history of osteoporosis suggests the possibility of heritable factors [88].

Direct irradiation to bone can reduce bone strength and increase fracture risk even without affecting BMD. Clinically important effects are most often seen in long bones and the vertebral column in patients treated for solid tumors [55]. The risk is increased in younger patients and those receiving radiation therapy doses of more than 20 Gy.

Assessment — Assessment of BMD in the growing child presents a challenge for accuracy and consistency. BMD varies with age and sex and must be analyzed by comparing results to age- and sex-based normative data [56,89]. However, BMD also varies with height and pubertal stage, and these factors are rarely included in normative data sets [56,84]. Even comparison of longitudinal data in the same patient is complicated because of the process of growth, which prevents measurement of exactly the same part of the bone over time.

Bone mineral density measurement — Guidelines from the Children's Oncology Group recommend that all patients treated with agents that predispose to reduced BMD (including glucocorticoids, cranial radiation, methotrexate, or HCT) have a quantitative measure of BMD at the time of entry into long-term follow-up, which typically occurs two years after completion of cancer chemotherapy [90].

BMD should be measured with either DXA or quantitative CT. The methodology employed may influence the results, and the optimal approach has not been established [91-93].

DXA measures areal BMD, providing an estimate of bone mass at a specific site. The process involves x-ray beam attenuation across a cross-section of bone (g/cm2). Results must be interpreted using age- and sex-specific standards (Z-scores) and not adult standards (T-scores). Since DXA provides a two-dimensional measurement of BMD, test results are affected by bone size [56]. Adjustment for bone size discrepant from normal has been found to lead to fewer false-positives. No particular method of size adjustment is perfect (height age, bone age, or other method), but applying some adjustment for bone size improves accuracy of DXA interpretation. The clinician can adjust the result for bone size by interpretation of Z-score for height age [34,84,94], but the mathematical adjustment is not always sufficient. (See "Overview of dual-energy x-ray absorptiometry" and 'Definition' above.)

Quantitative CT measures volumetric BMD [34]. The result is expressed as g/cm3 and thus does not require adjustment for bone size of the patient. This technique provides distinct measures of trabecular and cortical bone dimension and density, and is thus more sensitive than DXA in detecting changes in BMD. However, the technique is not widely available and requires higher doses of radiation than DXA. Quantitative CT is primarily a research modality but is used clinically at some centers [94].

Results from the baseline evaluation and other clinical factors should determine the need for follow-up. In general, patients with normal BMD study results (eg, Z-score >-1) do not require follow-up examinations. Patients with significant BMD deficits (eg, Z-scores <-2), recurrent fractures, or medical risk factors for decreasing BMD such as GHD or hypogonadism, require endocrine evaluation and treatment, counseling to optimize lifestyle factors affecting bone health, and long-term follow-up of BMD. (See 'Prevention and treatment' below.)

Other tests — Quantitative bone ultrasound has been used to assess bone structure and elasticity, but this technique does not measure BMD. The amount of overlying soft tissue can influence the results.

Metabolic markers of bone formation and bone resorption (bone turnover markers), such as serum osteocalcin and pyridinoline cross-links or osteoprotegerin, can be measured [95]. These markers do not have a role in screening for osteoporosis or selection of candidates for therapy but might be useful in monitoring response to therapy. Visfatin is an adipokine that correlates with BMD and holds some promise as a serum marker for osteoporosis [96]. Evaluation of biochemical markers after ALL did not show an association with risk for osteopenia [97]. (See "Use of biochemical markers of bone turnover in osteoporosis".)

Prevention and treatment — Therapy of reduced BMD starts with prevention [98]. It is important to maintain recommended intakes of calcium (usually 1000 to 1500 mg daily, depending on age) and vitamin D. Recommended intake of vitamin D is 600 units daily for healthy children and adolescents, but many require doses of 1000 to 2000 units daily to achieve optimal serum vitamin D levels [99-101] or even higher doses during stem cell transplant [102]. The patient should be encouraged to adopt habits that promote bone health (weightbearing exercise and avoid smoking) [103-107]. (See "Bone health and calcium requirements in adolescents", section on 'Other factors' and "Vitamin D insufficiency and deficiency in children and adolescents".)

Early identification and therapy of hormone deficits have the potential to preserve BMD. In patients with established hypogonadism, it is important to provide replacement of gonadal steroids as appropriate to the patient's age, height, and pubertal status. Untreated hypogonadism and GHD are associated with lower BMD [72]. Patients with GHD should be treated with growth hormone, and, in this setting, growth hormone therapy can augment BMD [83,108]. In general, BMD improves with duration of follow-up after completion of therapy for ALL [109]. (See "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood", section on 'Gonadal dysfunction' and "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood", section on 'Growth hormone deficiency'.)

Bisphosphonates have been used in adults during active cancer and are generally safe and effective for increasing BMD [110]; they may also reduce bone metastases [111]. In a randomized double-blind study of adult patients undergoing chemotherapy for lymphoma, adjunctive treatment with oral alendronate reduced bone resorption compared with placebo [112]. Experience in use of bisphosphonates in children is limited [113-116]. The most extensive experience has been with children with osteogenesis imperfecta who show improved growth rate and decreased bone pain with bisphosphonate therapy [117]. (See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors" and "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy" and "Osteogenesis imperfecta: An overview".)

There are several important reasons for caution when considering bisphosphonates in children and adolescents [113]:

Bisphosphonates, which are anticatabolic agents that suppress bone remodeling, may have different effects when administered to patients during active bone growth as compared with adults.

The bone matrix created by bisphosphonates is more brittle than normal bone and is subject to atypical fractures [117], and bisphosphonates have extremely long half-lives (several years) [118].

Significant jaw osteonecrosis has been observed in adults and adolescents during bisphosphonate use [119-121].

Associations between measures of reduced BMD and fracture risk have not been clearly established for children, making it difficult to select pediatric patients who would benefit most from bisphosphonate treatment [122].

Thus, bisphosphonates should not be used as standard therapy for pediatric cancer patients with reduced BMD [53,123]. These drugs are generally reserved for pediatric patients with severe reductions in BMD (height-adjusted BMD Z-score lower than -2.0 SD) and pathologic extremity fractures or vertebral compression (eg, long bone fracture of the leg, vertebral compression fracture, or two or more long bone fractures of the arm).

Other treatments that have been used for patients with severe osteoporosis include calcitonin and selective estrogen receptor modulators, parathyroid hormone (teriparatide), denosumab (an anti-osteoclastic monoclonal antibody), and mechanical vibration [90,124,125]. However, minimal information is available on the safety or efficacy of these treatments/drugs in children [121]. (See "Prevention and treatment of glucocorticoid-induced osteoporosis".)

ENDOCRINE EVALUATION — All patients should be carefully monitored for growth rates and pubertal progression during and after cancer treatment. Patients with the following characteristics should be further evaluated for specific endocrine deficiencies (see "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood"):

Patients with growth failure or low height velocity should be evaluated for GHD and central and/or primary hypothyroidism. If GHD or central hypothyroidism is found, testing should also be undertaken for adrenocorticotrophic hormone (ACTH) deficiency. (See "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood", section on 'Disordered growth'.)

Patients with delayed or interrupted progression of puberty or accelerated puberty should be evaluated for abnormalities of the hypothalamic-pituitary-gonadal axis. (See "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood", section on 'Disorders of luteinizing and follicle-stimulating hormones'.)

Patients with significant BMD deficits (eg, Z-scores <-2) or those who have been exposed to high-risk treatments, including high-dose cranial radiation or gonadal radiation, should also be screened for the above endocrinopathies.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pediatric bone health".)

SUMMARY AND RECOMMENDATIONS

Overview – Children affected by cancer are at risk for several important skeletal problems during and after treatment, including osteonecrosis of the joints, reduced bone mineral density (BMD) and osteoporosis, and transient or permanent effects on linear growth. (See 'Introduction' above.)

In some cases, reductions in bone mineralization and linear growth are caused by disruption of growth hormone, gonadal hormones, or thyroid hormones. (See 'Reduced bone mineral density' above and 'Altered epiphyseal growth' above.)

Avascular necrosis (AVN) – AVN typically presents as a limp and pain in weightbearing joints, usually occurring while the patient is receiving high-dose glucocorticoids. A normal plain radiograph does not exclude AVN, and any patient at risk for AVN with unexplained joint pain should be further evaluated by MRI. (See 'Avascular necrosis (Osteonecrosis)' above.)

Reduced BMD:

Prevention – All childhood cancer patients should be counseled to maintain recommended intakes of calcium (usually 1000 to 1500 mg daily, depending on age) and vitamin D, even during cancer therapy. Recommended intake of vitamin D is 600 units daily for healthy children and adolescents, but many individuals require doses of 1000 to 2000 units daily to achieve optimal serum vitamin D levels. Patients should be encouraged to adopt habits supporting bone health (weightbearing exercise and avoid smoking). (See 'Prevention and treatment' above.)

Monitoring – All patients exposed to therapies expected to reduce BMD (including glucocorticoids, cranial radiation, methotrexate, or hematopoietic cell transplant [HCT]) should be evaluated with a quantitative measure of BMD. The initial assessment should be done at the time of entry into long-term follow-up, or when symptomatic bone-related disease develops, whichever comes first. (See 'Bone mineral density measurement' above.)

Other monitoring – All childhood cancer patients should be carefully monitored for growth rates and pubertal progression during and after cancer treatment [16,126]. Patients with growth failure or deceleration, or those with delayed or interrupted progression of puberty or accelerated puberty should be evaluated. Likewise, patients with significant BMD deficits (Z-scores <-2) should be evaluated for endocrinopathies. (See 'Endocrine evaluation' above and "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood".)

  1. Camacho-Hübner C. Normal Physiology of Growth Hormone and Insulin-Like Growth Factors in Childhood. In: Endotext [Internet], De Groot LJ, Beck-Peccoz P, Chrousos G, Dungan K, Grossman A (Eds), Dept of Endocrinology, St. Bartholomew's Hospital, London 2010.
  2. Abrams SA. Calcium turnover and nutrition through the life cycle. Proc Nutr Soc 2001; 60:283.
  3. O'Brien KO, Abrams SA. Using stable isotope tracers to study bone metabolism in children. J Physiol 2019; 597:1311.
  4. Lui JC, Nilsson O, Baron J. Recent research on the growth plate: Recent insights into the regulation of the growth plate. J Mol Endocrinol 2014; 53:T1.
  5. Lui JC, Jee YH, Garrison P, et al. Differential aging of growth plate cartilage underlies differences in bone length and thus helps determine skeletal proportions. PLoS Biol 2018; 16:e2005263.
  6. Fiscaletti M, Alos N, Ward LM. Beyond Bone Mineral Density: The Impact of Childhood Cancer and Its Treatment on Bone Structure and Strength. Front Horm Res 2021; 54:69.
  7. den Hoed MA, Pluijm SM, Stolk L, et al. Genetic variation and bone mineral density in long-term adult survivors of childhood cancer. Pediatr Blood Cancer 2016; 63:2212.
  8. Rajakumar SA, Papp E, Lee KK, et al. B cell acute lymphoblastic leukemia cells mediate RANK-RANKL-dependent bone destruction. Sci Transl Med 2020; 12.
  9. Latoch E, Zubowska M, Młynarski W, et al. Late effects of childhood cancer treatment in long-term survivors diagnosed before the age of 3 years - A multicenter, nationwide study. Cancer Epidemiol 2022; 80:102209.
  10. Hain BA, Waning DL. Bone-Muscle Crosstalk: Musculoskeletal Complications of Chemotherapy. Curr Osteoporos Rep 2022; 20:433.
  11. Choudhary A, Chou J, Heller G, Sklar C. Prevalence of vitamin D insufficiency in survivors of childhood cancer. Pediatr Blood Cancer 2013; 60:1237.
  12. Myers KC, Howell JC, Wallace G, et al. Poor growth, thyroid dysfunction and vitamin D deficiency remain prevalent despite reduced intensity chemotherapy for hematopoietic stem cell transplantation in children and young adults. Bone Marrow Transplant 2016; 51:980.
  13. Lackner H, Benesch M, Moser A, et al. Aseptic osteonecrosis in children and adolescents treated for hemato-oncologic diseases: a 13-year longitudinal observational study. J Pediatr Hematol Oncol 2005; 27:259.
  14. Fan C, Foster BK, Wallace WH, Xian CJ. Pathobiology and prevention of cancer chemotherapy-induced bone growth arrest, bone loss, and osteonecrosis. Curr Mol Med 2011; 11:140.
  15. Salem KH, Brockert AK, Mertens R, Drescher W. Avascular necrosis after chemotherapy for haematological malignancy in childhood. Bone Joint J 2013; 95-B:1708.
  16. Bar M, Ott SM, Lewiecki EM, et al. Bone Health Management After Hematopoietic Cell Transplantation: An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy. Biol Blood Marrow Transplant 2020; 26:1784.
  17. Kawedia JD, Kaste SC, Pei D, et al. Pharmacokinetic, pharmacodynamic, and pharmacogenetic determinants of osteonecrosis in children with acute lymphoblastic leukemia. Blood 2011; 117:2340.
  18. Chen SH, Chang TY, Jaing TH, et al. Incidence, risk factors, and treatment outcome of symptomatic osteonecrosis in Taiwanese children with acute lymphoblastic leukemia: a retrospective cohort study of 245 patients in a single institution. Int J Hematol 2015; 102:41.
  19. Padhye B, Dalla-Pozza L, Little D, Munns C. Incidence and outcome of osteonecrosis in children and adolescents after intensive therapy for acute lymphoblastic leukemia (ALL). Cancer Med 2016; 5:960.
  20. Valtis YK, Stevenson KE, Place AE, et al. Orthopedic toxicities among adolescents and young adults treated in DFCI ALL Consortium Trials. Blood Adv 2022; 6:72.
  21. Kadan-Lottick NS, Dinu I, Wasilewski-Masker K, et al. Osteonecrosis in adult survivors of childhood cancer: a report from the childhood cancer survivor study. J Clin Oncol 2008; 26:3038.
  22. Mattano LA Jr, Devidas M, Nachman JB, et al. Effect of alternate-week versus continuous dexamethasone scheduling on the risk of osteonecrosis in paediatric patients with acute lymphoblastic leukaemia: results from the CCG-1961 randomised cohort trial. Lancet Oncol 2012; 13:906.
  23. Rao SS, El Abiad JM, Puvanesarajah V, et al. Osteonecrosis in pediatric cancer survivors: Epidemiology, risk factors, and treatment. Surg Oncol 2019; 28:214.
  24. Valtis YK, Place AE, Silverman LB, et al. Orthopaedic adverse events among adolescents and adults treated with asparaginase for acute lymphoblastic leukaemia. Br J Haematol 2022; 198:421.
  25. Armstrong GT, Sklar CA, Hudson MM, Robison LL. Long-term health status among survivors of childhood cancer: does sex matter? J Clin Oncol 2007; 25:4477.
  26. Niinimäki RA, Harila-Saari AH, Jartti AE, et al. High body mass index increases the risk for osteonecrosis in children with acute lymphoblastic leukemia. J Clin Oncol 2007; 25:1498.
  27. Karol SE, Yang W, Van Driest SL, et al. Genetics of glucocorticoid-associated osteonecrosis in children with acute lymphoblastic leukemia. Blood 2015; 126:1770.
  28. Karol SE, Mattano LA Jr, Yang W, et al. Genetic risk factors for the development of osteonecrosis in children under age 10 treated for acute lymphoblastic leukemia. Blood 2016; 127:558.
  29. Chang C, Greenspan A, Gershwin ME. The pathogenesis, diagnosis and clinical manifestations of steroid-induced osteonecrosis. J Autoimmun 2020; 110:102460.
  30. Gagné V, Aubry-Morin A, Plesa M, et al. Genes identified through genome-wide association studies of osteonecrosis in childhood acute lymphoblastic leukemia patients. Pharmacogenomics 2019; 20:1189.
  31. Erdem M, Tüfekçi Ö, Kızıldağ S, et al. Investigation of the Relationship Between Fok1 and Col1A1 Gene Polymorphisms and Development of Treatment-Related Bone Complications in Children with Acute Lymphoblastic Leukemia. Turk J Haematol 2019; 36:12.
  32. Plesa M, Gagné V, Glisovic S, et al. Influence of BCL2L11 polymorphism on osteonecrosis during treatment of childhood acute lymphoblastic leukemia. Pharmacogenomics J 2019; 19:33.
  33. Jones LC, Kaste SC, Karol SE, et al. Team approach: Management of osteonecrosis in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 2020; 67:e28509.
  34. Kaste SC. Skeletal toxicities of treatment in children with cancer. Pediatr Blood Cancer 2008; 50:469.
  35. Karimova EJ, Rai SN, Howard SC, et al. Femoral head osteonecrosis in pediatric and young adult patients with leukemia or lymphoma. J Clin Oncol 2007; 25:1525.
  36. de Rojas T, Martínez-Álvarez S, Lerma-Lara S, et al. Outcome of childhood leukaemia survivors and necrosis of the femoral head treated with autologous mesenchymal stem cells. Clin Transl Oncol 2018; 20:584.
  37. Hernigou P, Auregan JC, Dubory A, et al. Ankle osteonecrosis in fifty-one children and adolescent's leukemia survivors: a prospective randomized study on percutaneous mesenchymal stem cells treatment. Int Orthop 2021; 45:2383.
  38. Daneshdoost SM, El Abiad JM, Ruble KJ, et al. Bisphosphonate Therapy for Treating Osteonecrosis in Pediatric Leukemia Patients: A Systematic Review. J Pediatr Hematol Oncol 2021; 43:e365.
  39. Niinimäki T, Harila-Saari A, Niinimäki R. The diagnosis and classification of osteonecrosis in patients with childhood leukemia. Pediatr Blood Cancer 2015; 62:198.
  40. DeFeo BM, Kaste SC, Li Z, et al. Long-Term Functional Outcomes Among Childhood Survivors of Cancer Who Have a History of Osteonecrosis. Phys Ther 2020; 100:509.
  41. Chung CH, Ko KR, Kim JH, Shim JS. Clinical and Radiographic Characteristics of Atypical Slipped Capital Femoral Epiphysis. J Pediatr Orthop 2019; 39:e742.
  42. Mostoufi-Moab S, Isaacoff EJ, Spiegel D, et al. Childhood cancer survivors exposed to total body irradiation are at significant risk for slipped capital femoral epiphysis during recombinant growth hormone therapy. Pediatr Blood Cancer 2013; 60:1766.
  43. Liu SC, Tsai CC, Huang CH. Atypical slipped capital femoral epiphysis after radiotherapy and chemotherapy. Clin Orthop Relat Res 2004; :212.
  44. Rose SR, Horne VE, Howell J, et al. Late endocrine effects of childhood cancer. Nat Rev Endocrinol 2016; 12:319.
  45. Antal Z, Balachandar S. Growth Disturbances in Childhood Cancer Survivors. Horm Res Paediatr 2019; 91:83.
  46. Xian CJ, Cool JC, Scherer MA, et al. Cellular mechanisms for methotrexate chemotherapy-induced bone growth defects. Bone 2007; 41:842.
  47. van Iersel L, van Santen HM, Potter B, et al. Clinical impact of hypothalamic-pituitary disorders after conformal radiation therapy for pediatric low-grade glioma or ependymoma. Pediatr Blood Cancer 2020; 67:e28723.
  48. van Iersel L, Mulder RL, Denzer C, et al. Hypothalamic-Pituitary and Other Endocrine Surveillance Among Childhood Cancer Survivors. Endocr Rev 2022; 43:794.
  49. Rodari G, Cattoni A, Albanese A. Final height in growth hormone-deficient childhood cancer survivors after growth hormone therapy. J Endocrinol Invest 2020; 43:209.
  50. te Winkel ML, Pieters R, Hop WC, et al. Bone mineral density at diagnosis determines fracture rate in children with acute lymphoblastic leukemia treated according to the DCOG-ALL9 protocol. Bone 2014; 59:223.
  51. Wei C, Candler T, Davis N, et al. Bone Mineral Density Corrected for Size in Childhood Leukaemia Survivors Treated with Haematopoietic Stem Cell Transplantation and Total Body Irradiation. Horm Res Paediatr 2018; 89:246.
  52. Seland M, Smeland KB, Bjøro T, et al. Bone mineral density is close to normal for age in long-term lymphoma survivors treated with high-dose therapy with autologous stem cell transplantation. Acta Oncol 2017; 56:590.
  53. Marcucci G, Beltrami G, Tamburini A, et al. Bone health in childhood cancer: review of the literature and recommendations for the management of bone health in childhood cancer survivors. Ann Oncol 2019; 30:908.
  54. Mostoufi-Moab S, Kelly A, Mitchell JA, et al. Changes in pediatric DXA measures of musculoskeletal outcomes and correlation with quantitative CT following treatment of acute lymphoblastic leukemia. Bone 2018; 112:128.
  55. van Leeuwen BL, Kamps WA, Jansen HW, Hoekstra HJ. The effect of chemotherapy on the growing skeleton. Cancer Treat Rev 2000; 26:363.
  56. Kindler JM, Lappe JM, Gilsanz V, et al. Lumbar Spine Bone Mineral Apparent Density in Children: Results From the Bone Mineral Density in Childhood Study. J Clin Endocrinol Metab 2019; 104:1283.
  57. Högler W, Ward L. Osteoporosis in Children with Chronic Disease. Endocr Dev 2015; 28:176.
  58. Latoch E, Muszyńska-Rosłan K, Panas A, et al. Bone mineral density, thyroid function, and gonadal status in young adult survivors of childhood cancer. Contemp Oncol (Pozn) 2015; 19:142.
  59. Siegel DA, Claridy M, Mertens A, et al. Risk factors and surveillance for reduced bone mineral density in pediatric cancer survivors. Pediatr Blood Cancer 2017.
  60. Pietilä S, Sievänen H, Ala-Houhala M, et al. Bone mineral density is reduced in brain tumour patients treated in childhood. Acta Paediatr 2006; 95:1291.
  61. Rohani F, Arjmandi Rafsanjani Kh, Bahoush G, et al. Bone Mineral Density in Survivors of Childhood Acute Lymphoblastic Leukemia. Asian Pac J Cancer Prev 2017; 18:535.
  62. Bloomhardt HM, Sint K, Ross WL, et al. Severity of reduced bone mineral density and risk of fractures in long-term survivors of childhood leukemia and lymphoma undergoing guideline-recommended surveillance for bone health. Cancer 2020; 126:202.
  63. Muszynska-Roslan K, Konstantynowicz J, Panasiuk A, Krawczuk-Rybak M. Is the treatment for childhood solid tumors associated with lower bone mass than that for leukemia and Hodgkin disease? Pediatr Hematol Oncol 2009; 26:36.
  64. Tabone MD, Kolta S, Auquier P, et al. Bone Mineral Density Evolution and Its Determinants in Long-term Survivors of Childhood Acute Leukemia: A Leucémies Enfants Adolescents Study. Hemasphere 2021; 5:e518.
  65. Isaksson S, Bogefors K, Åkesson K, et al. Low bone mineral density is associated with hypogonadism and cranial irradiation in male childhood cancer survivors. Osteoporos Int 2020; 31:1261.
  66. Alos N, Grant RM, Ramsay T, et al. High incidence of vertebral fractures in children with acute lymphoblastic leukemia 12 months after the initiation of therapy. J Clin Oncol 2012; 30:2760.
  67. Pirker-Frühauf UM, Friesenbichler J, Urban EC, et al. Osteoporosis in children and young adults: a late effect after chemotherapy for bone sarcoma. Clin Orthop Relat Res 2012; 470:2874.
  68. Molinari PCC, Lederman HM, Lee MLM, Caran EMM. ASSESSMENT OF THE LATE EFFECTS ON BONES AND ON BODY COMPOSITION OF CHILDREN AND ADOLESCENTS TREATED FOR ACUTE LYMPHOCYTIC LEUKEMIA ACCORDING TO BRAZILIAN PROTOCOLS. Rev Paul Pediatr 2017; 35:78.
  69. Bhatia S, Ramsay NK, Weisdorf D, et al. Bone mineral density in patients undergoing bone marrow transplantation for myeloid malignancies. Bone Marrow Transplant 1998; 22:87.
  70. Nysom K, Holm K, Michaelsen KF, et al. Bone mass after allogeneic BMT for childhood leukaemia or lymphoma. Bone Marrow Transplant 2000; 25:191.
  71. Benmiloud S, Steffens M, Beauloye V, et al. Long-term effects on bone mineral density of different therapeutic schemes for acute lymphoblastic leukemia or non-Hodgkin lymphoma during childhood. Horm Res Paediatr 2010; 74:241.
  72. Chemaitilly W, Li Z, Huang S, et al. Anterior hypopituitarism in adult survivors of childhood cancers treated with cranial radiotherapy: a report from the St Jude Lifetime Cohort study. J Clin Oncol 2015; 33:492.
  73. Chemaitilly W, Cohen LE. DIAGNOSIS OF ENDOCRINE DISEASE: Endocrine late-effects of childhood cancer and its treatments. Eur J Endocrinol 2017; 176:R183.
  74. Le Meignen M, Auquier P, Barlogis V, et al. Bone mineral density in adult survivors of childhood acute leukemia: impact of hematopoietic stem cell transplantation and other treatment modalities. Blood 2011; 118:1481.
  75. Mandel K, Atkinson S, Barr RD, Pencharz P. Skeletal morbidity in childhood acute lymphoblastic leukemia. J Clin Oncol 2004; 22:1215.
  76. Alikasifoglu A, Yetgin S, Cetin M, et al. Bone mineral density and serum bone turnover markers in survivors of childhood acute lymphoblastic leukemia: comparison of megadose methylprednisolone and conventional-dose prednisolone treatments. Am J Hematol 2005; 80:113.
  77. Fan C, Georgiou KR, King TJ, Xian CJ. Methotrexate toxicity in growing long bones of young rats: a model for studying cancer chemotherapy-induced bone growth defects in children. J Biomed Biotechnol 2011; 2011:903097.
  78. Lim JS, Kim DH, Lee JA, et al. Young age at diagnosis, male sex, and decreased lean mass are risk factors of osteoporosis in long-term survivors of osteosarcoma. J Pediatr Hematol Oncol 2013; 35:54.
  79. Frisk P, Arvidson J, Ljunggren O, Gustafsson J. Decreased bone mineral density in young adults treated with SCT in childhood: the role of 25-hydroxyvitamin D. Bone Marrow Transplant 2012; 47:657.
  80. Lawson SA, Horne VE, Golekoh MC, et al. Hypothalamic-pituitary function following childhood brain tumors: Analysis of prospective annual endocrine screening. Pediatr Blood Cancer 2019; 66:e27631.
  81. Shalitin S, Pertman L, Yackobovitch-Gavan M, et al. Endocrine and Metabolic Disturbances in Survivors of Hematopoietic Stem Cell Transplantation in Childhood and Adolescence. Horm Res Paediatr 2018; 89:108.
  82. Gómez JM. The role of insulin-like growth factor I components in the regulation of vitamin D. Curr Pharm Biotechnol 2006; 7:125.
  83. van den Heijkant S, Hoorweg-Nijman G, Huisman J, et al. Effects of growth hormone therapy on bone mass, metabolic balance, and well-being in young adult survivors of childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol 2011; 33:e231.
  84. Kelly A, Shults J, Mostoufi-Moab S, et al. Pediatric Bone Mineral Accrual Z-Score Calculation Equations and Their Application in Childhood Disease. J Bone Miner Res 2019; 34:195.
  85. van Iersel L, Li Z, Srivastava DK, et al. Hypothalamic-Pituitary Disorders in Childhood Cancer Survivors: Prevalence, Risk Factors and Long-Term Health Outcomes. J Clin Endocrinol Metab 2019; 104:6101.
  86. Inskip PD, Veiga LHS, Brenner AV, et al. Hyperthyroidism After Radiation Therapy for Childhood Cancer: A Report from the Childhood Cancer Survivor Study. Int J Radiat Oncol Biol Phys 2019; 104:415.
  87. Gurney JG, Kaste SC, Liu W, et al. Bone mineral density among long-term survivors of childhood acute lymphoblastic leukemia: results from the St. Jude Lifetime Cohort Study. Pediatr Blood Cancer 2014; 61:1270.
  88. Zgheib NK, El-Khoury H, Maamari D, et al. A GRIN3A polymorphism may be associated with glucocorticoid-induced symptomatic osteonecrosis in children with acute lymphoblastic leukemia. Per Med 2021; 18:431.
  89. Wren TA, Kalkwarf HJ, Zemel BS, et al. Longitudinal tracking of dual-energy X-ray absorptiometry bone measures over 6 years in children and adolescents: persistence of low bone mass to maturity. J Pediatr 2014; 164:1280.
  90. Children's Oncology Group. Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. Version 5.0 (October 2018). Available at: http://www.survivorshipguidelines.org/ (Accessed on November 11, 2022).
  91. Leonard MB. Assessment of bone health in children and adolescents with cancer: promises and pitfalls of current techniques. Med Pediatr Oncol 2003; 41:198.
  92. Wasserman H, O'Donnell JM, Gordon CM. Use of dual energy X-ray absorptiometry in pediatric patients. Bone 2016.
  93. Kaste SC, Tong X, Hendrick JM, et al. QCT versus DXA in 320 survivors of childhood cancer: association of BMD with fracture history. Pediatr Blood Cancer 2006; 47:936.
  94. International Society For Clinical Densitometry. Pediatric Positions: Skeletal Health Assessment In Children from Infancy to Adolescence. 2019. Available at: https://iscd.org/learn/official-positions/pediatric-positions/ (Accessed on November 11, 2022).
  95. Shetty S, Kapoor N, Bondu JD, et al. Bone turnover markers: Emerging tool in the management of osteoporosis. Indian J Endocrinol Metab 2016; 20:846.
  96. Siviero-Miachon AA, Spinola-Castro AM, de Martino Lee ML, et al. Visfatin is a positive predictor of bone mineral density in young survivors of acute lymphocytic leukemia. J Bone Miner Metab 2017; 35:73.
  97. Watsky MA, Carbone LD, An Q, et al. Bone turnover in long-term survivors of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 2014; 61:1451.
  98. Ahn MB, Suh BK. Bone morbidity in pediatric acute lymphoblastic leukemia. Ann Pediatr Endocrinol Metab 2020; 25:1.
  99. Zhang FF, Saltzman E, Kelly MJ, et al. Comparison of childhood cancer survivors' nutritional intake with US dietary guidelines. Pediatr Blood Cancer 2015; 62:1461.
  100. Golden NH, Abrams SA, Committee on Nutrition. Optimizing bone health in children and adolescents. Pediatrics 2014; 134:e1229.
  101. Cohen JE, Wakefield CE, Cohn RJ. Nutritional interventions for survivors of childhood cancer. Cochrane Database Syst Rev 2016; :CD009678.
  102. Wallace G, Jodele S, Myers KC, et al. Single Ultra-High-Dose Cholecalciferol to Prevent Vitamin D Deficiency in Pediatric Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant 2018; 24:1856.
  103. Joyce ED, Nolan VG, Ness KK, et al. Association of muscle strength and bone mineral density in adult survivors of childhood acute lymphoblastic leukemia. Arch Phys Med Rehabil 2011; 92:873.
  104. Braam KI, van der Torre P, Takken T, et al. Physical exercise training interventions for children and young adults during and after treatment for childhood cancer. Cochrane Database Syst Rev 2016; 3:CD008796.
  105. Dimitri P, Joshi K, Jones N, Moving Medicine for Children Working Group. Moving more: physical activity and its positive effects on long term conditions in children and young people. Arch Dis Child 2020; 105:1035.
  106. Bland VL, Heatherington-Rauth M, Howe C, et al. Association of objectively measured physical activity and bone health in children and adolescents: a systematic review and narrative synthesis. Osteoporos Int 2020; 31:1865.
  107. Jung R, Zürcher SJ, Schindera C, et al. Effect of a physical activity intervention on lower body bone health in childhood cancer survivors: A randomized controlled trial (SURfit). Int J Cancer 2023; 152:162.
  108. van Santen HM, Chemaitilly W, Meacham LR, et al. Endocrine Health in Childhood Cancer Survivors. Pediatr Clin North Am 2020; 67:1171.
  109. Pluijm S, den Hoed M, van den Heuvel-Eibrink MM. Catch-up of bone mineral density among long-term survivors of childhood cancer? Letter to the editor: Response to the article of Gurney et al. 2014. Pediatr Blood Cancer 2015; 62:369.
  110. Fujihara N, Fujihara Y, Hamada S, et al. Current practice patterns of osteoporosis treatment in cancer patients and effects of therapeutic interventions in a tertiary center. PLoS One 2021; 16:e0248188.
  111. Schwartz E, Reichert Z, Van Poznak C. Pharmacologic management of metastatic bone disease. Bone 2022; 158:115735.
  112. Jensen P, Jakobsen LH, Bøgsted M, et al. A randomized trial of alendronate as prophylaxis against loss in bone mineral density following lymphoma treatment. Blood Adv 2022; 6:2549.
  113. Wood CL, Ahmed SF. Bone protective agents in children. Arch Dis Child 2018; 103:503.
  114. Jin HY, Lee JA. Low bone mineral density in children and adolescents with cancer. Ann Pediatr Endocrinol Metab 2020; 25:137.
  115. Grover M, Bachrach LK. Osteoporosis in Children with Chronic Illnesses: Diagnosis, Monitoring, and Treatment. Curr Osteoporos Rep 2017; 15:271.
  116. Lemay V, Caru M, Samoilenko M, et al. Prevention of Long-term Adverse Health Outcomes With Cardiorespiratory Fitness and Physical Activity in Childhood Acute Lymphoblastic Leukemia Survivors. J Pediatr Hematol Oncol 2019; 41:e450.
  117. Shi CG, Zhang Y, Yuan W. Efficacy of Bisphosphonates on Bone Mineral Density and Fracture Rate in Patients With Osteogenesis Imperfecta: A Systematic Review and Meta-analysis. Am J Ther 2016; 23:e894.
  118. Papapoulos SE, Cremers SC. Prolonged bisphosphonate release after treatment in children. N Engl J Med 2007; 356:1075.
  119. Gadgaard NR, Olesen TB, Svane HML, et al. Osteonecrosis of the jaw among cancer patients in Denmark: risk and prognosis. Int J Oral Maxillofac Surg 2022; 51:1424.
  120. Jara MA, Varghese J, Hu MI. Adverse events associated with bone-directed therapies in patients with cancer. Bone 2022; 158:115901.
  121. Rachner TD, Coleman R, Hadji P, Hofbauer LC. Individualized Bone-Protective Management in Long-Term Cancer Survivors With Bone Metastases. J Bone Miner Res 2021; 36:1906.
  122. Harris AM, Lee AR, Wong SC. Systematic review of the effects of bisphosphonates on bone density and fracture incidence in childhood acute lymphoblastic leukaemia. Osteoporos Int 2020; 31:59.
  123. Bachrach LK, Ward LM. Clinical review 1: Bisphosphonate use in childhood osteoporosis. J Clin Endocrinol Metab 2009; 94:400.
  124. Mogil RJ, Kaste SC, Ferry RJ Jr, et al. Effect of Low-Magnitude, High-Frequency Mechanical Stimulation on BMD Among Young Childhood Cancer Survivors: A Randomized Clinical Trial. JAMA Oncol 2016; 2:908.
  125. Deligiorgi MV, Trafalis DT. The safety profile of denosumab in oncology beyond the safety of denosumab as an anti-osteoporotic agent: still more to learn. Expert Opin Drug Saf 2021; 20:191.
  126. Chow EJ, Anderson L, Baker KS, et al. Late Effects Surveillance Recommendations among Survivors of Childhood Hematopoietic Cell Transplantation: A Children's Oncology Group Report. Biol Blood Marrow Transplant 2016; 22:782.
Topic 5830 Version 32.0

References

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