Bone health in childhood cancer: review of the literature and recommendations for the management of bone health in childhood cancer survivors

      ABSTRACT

      In the past decades, new cancer treatment approaches for children and adolescents have led to a decrease in recurrence rates and an increase in long-term survival. Recent studies have focused on the evaluation of the late effects on bone of pediatric cancer-related treatments, such as chemotherapy, radiation and surgery. Treatment of childhood cancer can impair the attainment of peak bone mass, predisposing to premature onset of low bone mineral density, or causing other bone side-effects, such as bone quality impairment or avascular necrosis of bone. Lower bone mineral density and microarchitectural deterioration can persist during adulthood, thereby increasing fracture risk. Overall, long-term follow-up of childhood cancer survivors is essential to define specific groups at higher risk of long-term bone complications, identify unrecognized long-term adverse effects, and improve patient care. Children and adolescents with a cancer history should be carefully monitored, and patients should be informed of possible late complications of their previous medical treatment. The International Osteoporosis Foundation convened a working group to review the bone complications of pediatric cancer survivors, outlining recommendations for the management of bone health, in order to prevent and treat these complications.

      Key words

       Key Message

      New cancer treatments in children and adolescents have decreased recurrence rates and increased long-term survival. We review bone complications in pediatric cancers and childhood cancer survivors, and outline recommendations for their management, to prevent and treat these complications.

      Introduction

      During the past 30 years, changes in the treatment of children and adolescents with cancer have led to substantial improvements in survival, with a 5-year survival rate of childhood cancer close to 80% [
      • Gatta G.
      • Botta L.
      • Rossi S.
      • et al.
      Childhood cancer survival in Europe 1999-2007: results of EUROCARE-5—a population-based study.
      ]. This results in an increasing number of childhood cancer survivors (CCSs) who received cancer treatment during growth. On the other hand, CCSs are at substantial risk of late adverse effects of cancer treatment. The adverse events can systemically involve the whole organism, including the cardiac, gastrointestinal, genitourinary, musculoskeletal, neurological, and pulmonary systems, as well as the endocrine system, skeletal maturation and growth, sexual development, fertility, and reproduction. CCSs are also at an increased risk of secondary neoplasms, and cognitive and emotional impairments [
      • Robison L.L.
      • Hudson M.M.
      Survivors of childhood and adolescent cancer: life-long risks and responsibilities.
      ,
      • Poplack D.G.
      • Fordis M.
      • Landier W.
      • et al.
      Childhood cancer survivor care: development of the Passport for Care.
      ,
      • Kremer L.C.
      • van der Pal H.J.
      • Offringa M.
      • et al.
      Frequency and risk factors of subclinical cardiotoxicity after anthracycline therapy in children: a systematic review.
      ,
      • Travis L.B.
      The epidemiology of second primary cancers.
      ,
      • Oeffinger K.C.
      • Hudson M.M.
      Long-term complications following childhood and adolescent cancer: foundations for providing risk-based health care for survivors.
      ,
      • Oeffinger K.C.
      • Mertens A.C.
      • Sklar C.A.
      • et al.
      Chronic health conditions in adult survivors of childhood cancer.
      ,
      • Armstrong G.T.
      • Kawashima T.
      • Leisenring W.
      • et al.
      Aging and risk of severe, disabling, life-threatening, and fatal events in the childhood cancer survivor study.
      ]. Although childhood cancers and their treatments have been shown to impact bone health, there are limited data on this topic [
      • Kang M.J.
      • Lim J.S.
      Bone mineral density deficits in childhood cancer survivors: pathophysiology, prevalence, screening, and management.
      ]. Endocrine, metabolic, and skeletal sequelae are among the most frequently described complications, affecting between 20% and 50% of subjects [
      • Chemaitilly W.
      • Sklar C.A.
      Endocrine complications in longterm survivors of childhood cancers.
      ,
      • Wilson C.L.
      • Ness K.K.
      Bone mineral density deficits and fractures in survivors of childhood cancer.
      ,
      • Dickerman J.D.
      The late effects of childhood cancer therapy.
      ,
      • Pfeilschifter J.
      • Diel I.J.
      Osteoporosis due to cancer treatment: pathogenesis and management.
      ,
      • van der Sluis I.M.
      • van den Heuvel-Eibrink M.M.
      • Hahlen K.
      • et al.
      Bone mineral density, body composition, and height in long-term survivors of acute lymphoblastic leukemia in childhood.
      ]. All cancer therapies can decrease bone mineral density (BMD) through long-term endocrine alterations, such as gonadal dysfunction, growth hormone (GH) deficiency, and altered body composition [
      • Choi Y.J.
      • Park S.Y.
      • Cho W.K.
      • et al.
      Factors related to decreased bone mineral density in childhood cancer survivors.
      ,
      • Gurney J.G.
      • Kaste S.C.
      • Liu W.
      • et al.
      Bone mineral density among long-term survivors of childhood acute lymphoblastic leukemia: results from the St. Jude Lifetime Cohort Study.
      ,
      • Makitie O.
      • Heikkinen R.
      • Toiviainen-Salo S.
      • et al.
      Long-term skeletal consequences of childhood acute lymphoblastic leukemia in adult males: a cohort study.
      ,
      • Joyce E.D.
      • Nolan V.G.
      • Ness K.K.
      • et al.
      Association of muscle strength and bone mineral density in adult survivors of childhood acute lymphoblastic leukemia.
      ,
      • Marcucci G.
      • Brandi M.L.
      Rare causes of osteoporosis.
      ]. These therapies can also directly affect bone cells. Furthermore, modifiable factors, such as nutritional deficiency and less physical activity, can modify bone mass and quality.
      The aim of this study is to review bone complications in CCSs and propose recommendations for the management of bone health in these patients.

      Materials and methods

      The International Osteoporosis Foundation convened a working group to review the literature regarding bone health in childhood cancer and propose recommendations for the management of bone health in CCSs. As in previous initiatives and publications, the International Osteoporosis Foundation (IOF) working group consists of clinical scientists and experts in the field of bone metabolism and oncology.
      Randomized controlled studies, prospective–retrospective studies, case–control studies, cohort studies, systematic reviews, and meta-analyses published from 1992 to 2017 were searched on PubMed using the following search terms: (i) osteopenia, osteoporosis, fragility fracture, bone mineral density; (ii) acute lymphoblastic leukemia, Hodgkin and non-Hodgkin lymphomas, osteosarcoma, Ewing’s sarcoma, chondrosarcoma, brain tumors, and neuroblastoma; (iii) hormonal deprivation, glucocorticoids, physical activity, immobilization and limb surgery, radiotherapy, chemotherapy, hematopoietic stem-cell transplantation (HSCT), and calcineurin inhibitors; (iv) guidelines, survivors of childhood cancers. Case reports and case series were also included due to the limited evidence available in the current literature. Only English-language papers were reviewed. Letters, comments, editorials, expert opinions, and personal communications were excluded. The selection of studies was based on relevance to the broad scope of this study. A list of the most important papers based on their review of the literature was made, followed by a set of preliminary recommendations graded according to the strength of underlying evidence, based on the available guidelines, literature reviews, and the expert opinions of the working group. Subsequently, the plan of the manuscript, the recommendations, and the conclusions were further discussed. All positions were graded on quality of evidence as High, Moderate, Low, or Very low [Grading of Recommendations Assessment, Development and Evaluation (GRADE); http://www.gradeworkinggroup.org] [
      • Atkins D.
      • Best D.
      • Briss P.A.
      • et al.
      Grading quality of evidence and strength of recommendations.
      ].
      The review contains four sections:
      • Part I: Key points of peak bone mass and bone evaluation in children and teenagers
      • Part II: Bone health in CCSs
      • Part III: Contributing factors of bone mass impairment in CCSs
      • Part IV: Recommendations for bone health in CCSs

      Part I: Key points of peak bone mass and bone evaluation in children and teenagers

       Attainment of peak bone mass and assessment of BMD

      In young adults, BMD is dependent on peak bone mass (PBM) [
      • Rizzoli R.
      • Bianchi M.L.
      • Garabédian M.
      • et al.
      Maximizing bone mineral mass gain during growth for the prevention of fractures in the adolescents and the elderly.
      ,
      • Theintz G.
      • Buchs B.
      • Rizzoli R.
      • et al.
      Longitudinal monitoring of bone mass accumulation in healthy adolescents: evidence for a marked reduction after 16 years of age at the levels of lumbar spine and femoral neck in female subjects.
      ]. Patients treated for childhood or adolescent cancer may not undergo optimal bone growth at puberty [
      • Theintz G.
      • Buchs B.
      • Rizzoli R.
      • et al.
      Longitudinal monitoring of bone mass accumulation in healthy adolescents: evidence for a marked reduction after 16 years of age at the levels of lumbar spine and femoral neck in female subjects.
      ,
      • Weaver C.M.
      • Gordon C.M.
      • Janz K.F.
      • et al.
      The National Osteoporosis Foundation’s position statement on peak bone mass development and lifestyle factors: a systematic review and implementation recommendations.
      ]. An inadequate lean mass acquisition, weight-bearing physical activity, and diet might also impair the attainment of PBM [
      • Rizzoli R.
      • Bianchi M.L.
      • Garabédian M.
      • et al.
      Maximizing bone mineral mass gain during growth for the prevention of fractures in the adolescents and the elderly.
      ,
      • Theintz G.
      • Buchs B.
      • Rizzoli R.
      • et al.
      Longitudinal monitoring of bone mass accumulation in healthy adolescents: evidence for a marked reduction after 16 years of age at the levels of lumbar spine and femoral neck in female subjects.
      ,
      • Weaver C.M.
      • Gordon C.M.
      • Janz K.F.
      • et al.
      The National Osteoporosis Foundation’s position statement on peak bone mass development and lifestyle factors: a systematic review and implementation recommendations.
      ,
      • Rizzoli R.
      • Bonjour J.P.
      Determinants of peak bone mass and mechanisms of bone loss.
      ,
      • Muszynska-Roslan K.
      • Latoch E.
      • Konstantynowicz J.
      • et al.
      Bone mineral density in pediatric survivors of Hodgkin and non-Hodgkin lymphomas.
      ,
      • Jackowski S.A.
      • Faulkner R.A.
      • Farthing J.P.
      • et al.
      Peak lean tissue mass accrual precedes changes in bone strength indices at the proximal femur during the pubertal growth spurt.
      ].
      The World Health Organization (WHO) operational definition of osteoporosis on the basis of T-score is not applicable in children and adolescents, in whom a Z-score, derived from age- and sex-matched BMDs in a healthy population, should be used [
      • Gafni R.I.
      • Baron J.
      Overdiagnosis of osteoporosis in children due to misinterpretation of dual-energy x-ray absorptiometry (DEXA).
      ]. Juvenile osteoporosis, referring to a BMD less than expected for age in children and adolescents, has been defined as a BMD >2 SD below the age- and sex-appropriate reference population (Z-score < −2 SD) [
      • Gafni R.I.
      • Baron J.
      Overdiagnosis of osteoporosis in children due to misinterpretation of dual-energy x-ray absorptiometry (DEXA).
      ]. In 2013, the International Society for Clinical Densitometry (IS-CD) proposed that the diagnosis of osteoporosis in children and adolescents should not be made on the basis of densitometric criteria alone, but that an overall assessment of bone health, such as the presence of fractures due to low trauma, should also be considered (http://www.iscd.org/official-positions/2013-iscd-official-positions-pediatric/)[
      • Ferrari S.
      • Bianchi M.L.
      • Eisman J.A.
      • et al.
      Osteoporosis in young adults: pathophysiology, diagnosis, and management.
      ]. On the other hand, a BMD Z-score > −2.0 does not preclude the possibility of skeletal fragility and increased fracture risk (http://www.iscd.org/official-positions/2013-iscd-official-positions-pediatric/). Moreover, the Official Position stated that in children with short stature or growth delay, spine, and total body less head BMC and areal BMD (aBMD) results should be adjusted (for the spine, adjustment is recommended using either bone mineral apparent density or the height Z-score; for total body less head, adjusted using the height Z-score) [
      • Crabtree N.J.
      • Arabi A.
      • Bachrach L.K.
      • et al.
      Dual-energy X-ray absorptiometry interpretation and reporting in children and adolescents: the revised 2013 ISCD Pediatric Official Positions.
      ,
      • Bianchi M.L.
      • Leonard M.B.
      • Bechtold S.
      • et al.
      Bone health in children and adolescents with chronic diseases that may affect the skeleton: the 2013 ISCD Pediatric Official Positions.
      ]. Finally, in children for whom other sites are not measurable, lateral distal femur scans by dual-energy X-ray absorptiometry (DEXA) are often feasible, and the recent availability of reference data for lateral distal femur for use in children is an important advance [
      • Zemel B.S.
      • Stallings V.A.
      • Leonard M.B.
      • et al.
      Revised pediatric reference data for the lateral distal femur measured by Hologic Discovery/Delphi dual-energy X-ray absorptiometry.
      ].
      Quantitative computed tomography (QCT), evaluating volumetric BMD and trabecular and cortical bone compartments, requires much higher radiation doses than DEXA, and is therefore difficult to use in children. A more powerful tool is the high-resolution peripheral QCT, which evaluates, at the distal forearm and tibia, the cortical and trabecular microarchitecture and densities with a resolution up to 82 µm [
      • Wasilewski-Masker K.
      • Kaste S.C.
      • Hudson M.M.
      • et al.
      Bone mineral density deficits in survivors of childhood cancer: long-term follow-up guidelines and review of the literature.
      ]. The radiation is lower, but the technique is complex, particularly for growing bones, and it therefore remains a research tool.

       Role of sex hormones

      Estrogen has a role for attaining PBM in both sexes, as demonstrated by the lower BMD in young females with late menarche, as well as in males with loss-of-function mutations in the estrogen receptor α gene and aromatase gene [
      • Almeida M.
      • Laurent M.R.
      • Dubois V.
      • et al.
      Estrogens and androgens in skeletal physiology and pathophysiology.
      ,
      • Chevalley T.
      • Bonjour J.P.
      • Ferrari S.
      • Rizzoli R.
      Deleterious effect of late menarche on distal tibia microstructure in healthy 20-year-old and premenopausal middle-aged women.
      ,
      • Chevalley T.
      • Bonjour J.P.
      • Ferrari S.
      • Rizzoli R.
      Influence of age at menarche on forearm bone microstructure in healthy young women.
      ,
      • Zemel B.S.
      • Kalkwarf H.J.
      • Gilsanz V.
      • et al.
      Revised reference curves for bone mineral content and areal bone mineral density according to age and sex for black and non-black children: results of the bone mineral density in childhood study.
      ,
      • Karasik D.
      • Ferrari S.L.
      Contribution of gender-specific genetic factors to osteoporosis risk.
      ]. On the other hand, androgens enlarge the cross-sectional area of long bones that increase mechanical strength, may promote trabecular bone development and thickness in young adulthood, subsequently promote cortical consolidation in midlife, and maintain cortical thickness and trabecular bone volume in older men through the stimulation of periosteal apposition and trabecular bone formation [
      • Karasik D.
      • Ferrari S.L.
      Contribution of gender-specific genetic factors to osteoporosis risk.
      ,
      • Seeman E.
      • Delmas P.D.
      Bone quality—the material and structural basis of bone strength and fragility.
      ].

       Bone remodeling as assessed by bone turnover markers

      Morning fast serum procollagen type I N propeptide (s-PINP) and serum C-terminal telopeptide of type I collagen (s-CTX) are recommended by the IOF and the International Federation of Clinical Chemistry (IFCC) for the evaluation of bone turnover [
      • Vasikaran S.
      • Eastell R.
      • Bruyère O.
      • et al.
      Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards.
      ]. Current findings in cancer-treated children show decreased bone formation and increased bone resorption [
      • Atkinson S.A.
      Vitamin D status and bone biomarkers in childhood cancer.
      ]. However, the evaluation of biomarkers in these patients can be difficult because of the lack of reliable reference values and their large variations according to age, gender, or pubertal stage [
      • Atkinson S.A.
      Vitamin D status and bone biomarkers in childhood cancer.
      ]. Bone biomarker data from longitudinal prospective studies on cancer-treated children and long-term survivors are lacking. Alterations in bone metabolism markers and growth deficits during therapy may display a trend to recovery in the long term. These findings are confirmed in adults treated for childhood cancer, who showed reduced BMD and even asymptomatic vertebral fractures, but no evident differences in bone turnover between patients and a control group [
      • Hoorweg-Nijman J.J.
      • Kardos G.
      • Roos J.C.
      • et al.
      Bone mineral density and markers of bone turnover in young adult survivors of childhood lymphoblastic leukaemia.
      ,
      • van Leeuwen B.L.
      • Kamps W.A.
      • Jansen H.W.
      • Hoekstra H.J.
      The effect of chemotherapy on the growing skeleton.
      ].

      Part II: Bone health in CCSs

       Osteopenia/osteoporosis in CCSs

      The prevalence of osteopenia and osteoporosis in CCSs is not yet well documented. Moreover, the occurrence of fractures is still insufficiently characterized among CCSs [
      • Wilson C.L.
      • Ness K.K.
      Bone mineral density deficits and fractures in survivors of childhood cancer.
      ,
      • Han J.W.
      • Kim H.S.
      • Hahn S.M.
      • et al.
      Poor bone health at the end of puberty in childhood cancer survivors.
      ]. Supplementary Table S1, available at Annals of Oncology online, summarizes the main studies on CCSs and bone status. Some pediatric cancer treatments, listed below, are no longer used in current treatment protocols; however, it is important to report them for CCSs.

       Acute lymphoblastic leukemia

      Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood, and most data on low BMD in CCSs are focused on this type of cancer. The disease process per se and its treatments, such as high cumulative doses of steroids, methotrexate, HSCT, cranial and testicular radiation, are all potential risk factors for BMD deficits [
      • van der Sluis I.M.
      • van den Heuvel-Eibrink M.M.
      • Hahlen K.
      • et al.
      Bone mineral density, body composition, and height in long-term survivors of acute lymphoblastic leukemia in childhood.
      ]. In summary, during treatment of pediatric forms of ALL, low BMD is commonly described, as well as reduced levels of bone formation markers, and this may lead to an increase of fracture incidence [
      • Tillmann V.
      • Darlington A.S.
      • Eiser C.
      • et al.
      Male sex and low physical activity are associated with reduced spine bone mineral density in survivors of childhood acute lymphoblastic leukemia.
      ,
      • Arikoski P.
      • Komulainen J.
      • Riikonen P.
      • et al.
      Alterations in bone turnover and impaired development of bone mineral density in newly diagnosed children with cancer: a 1-year prospective study.
      ,
      • Rohani F.
      • Arjmandi Rafsanjani K.
      • Bahoush G.
      • et al.
      Bone mineral density in survivors of childhood acute lymphoblastic leukemia.
      ,
      • Högler W.
      • Wehl G.
      • van Staa T.
      • et al.
      Incidence of skeletal complications during treatment of childhood acute lymphoblastic leukemia: comparison of fracture risk with the General Practice Research Database.
      ]. A prospective cohort study, conducted within the STeroid-associated Osteoporosis in the Pediatric Population (STOPP) research program, showed that children with ALL had a high incidence of vertebral fractures after 12 months of chemotherapy, and the presence of vertebral fractures and reductions in spine BMD Z-scores at baseline were highly associated clinical features [
      • Alos N.
      • Grant R.M.
      • Ramsay T.
      • et al.
      High incidence of vertebral fractures in children with acute lymphoblastic leukemia 12 months after the initiation of therapy.
      ]. The STOPP research program showed that vertebral compression was an under-recognized complication of newly diagnosed ALL, and whether the fractures will resolve through bone growth during or after leukemia chemotherapy remains to be determined [
      • Halton J.
      • Gaboury I.
      • Grant R.
      • et al.
      Advanced vertebral fracture among newly diagnosed children with acute lymphoblastic leukemia: results of the Canadian Steroid-Associated Osteoporosis in the Pediatric Population (STOPP) research program.
      ].
      Rayar et al. enrolled children and adolescents with ALL at the time of the first clinical remission. Twenty-three (18.5%) patients developed fractures, but the fracture sites were not reported. Older age and lower LS-BMD at diagnosis were predictors of lower LS-BMD during continuation therapy, and dexamethasone and lower LS-BMD were associated with fractures. The authors concluded that using these variables could be feasible to develop a predictor model to define the risk of bony morbidity in children receiving ALL therapy [
      • Rayar M.S.
      • Nayiager T.
      • Webber C.E.
      • et al.
      Predictors of bony morbidity in children with acute lymphoblastic leukemia.
      ]. Mostoufi-Moab et al. [
      • Mostoufi-Moab S.
      • Brodsky J.
      • Isaacoff E.J.
      • et al.
      Longitudinal assessment of bone density and structure in childhood survivors of acute lymphoblastic leukemia without cranial radiation.
      ] conducted a longitudinal assessment of BMD and bone structure in childhood survivors of ALL without cranial radiation. Their findings suggested that ALL treatment in childhood without cranial radiation may not result in long-term detrimental effects on bone development. However, given the lack of complete normalization of trabecular and cortical BMD, future studies are needed to confirm complete BMD recovery, and additional investigations would be useful to find a connection between changes in bone outcomes to short- and long-term fracture risk [
      • Mostoufi-Moab S.
      • Brodsky J.
      • Isaacoff E.J.
      • et al.
      Longitudinal assessment of bone density and structure in childhood survivors of acute lymphoblastic leukemia without cranial radiation.
      ].
      Finally, regarding the long-term effects of allogeneic BMT (bone marrow transplant) on bone, the whole-body bone mass tends to be only marginally lower in BMT patients than in ALL survivors treated without BMT, and the size-adjusted bone mass (BMC for bone area) remains normal [
      • Nysom K.
      • Holm K.
      • Michaelsen K.F.
      • et al.
      Bone mass after allogeneic BMT for childhood leukaemia or lymphoma.
      ].

       Hodgkin and non-Hodgkin lymphomas

      Regarding bone health in childhood Hodgkin and non-Hodgkin lymphomas, most studies were conducted long after completion of therapy [
      • Rizzoli R.
      • Bonjour J.P.
      Determinants of peak bone mass and mechanisms of bone loss.
      ]. Most patients treated for childhood malignant lymphomas had no apparent deficits in bone mass and tended to maintain their normal BMD during follow-up [
      • Rizzoli R.
      • Bonjour J.P.
      Determinants of peak bone mass and mechanisms of bone loss.
      ]. Therefore, childhood lymphoma survivors appear to be only at negligible risk for lower BMD [
      • Nysom K.
      • Holm K.
      • Michaelsen K.F.
      • et al.
      Bone mass after allogeneic BMT for childhood leukaemia or lymphoma.
      ].

       Osteosarcoma

      Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. The introduction of neoadjuvant chemotherapy has improved the survival and limb-salvage rate by decreasing the tumor burden before surgery [
      • Luetke A.
      • Meyers P.A.
      • Lewis I.
      • Juergens H.
      Osteosarcoma treatment—where do we stand? A state of the art review.
      ]. The long-term survivors of osteosarcoma usually have lower PBM, with premature osteopenia/osteoporosis, and higher fracture risk [
      • Holzer G.
      • Krepler P.
      • Koschat M.A.
      • et al.
      Bone mineral density in long-term survivors of highly malignant osteosarcoma.
      ,
      • Pirker-Frühauf U.M.
      • Friesenbichler J.
      • Urban E.C.
      • et al.
      Osteoporosis in children and young adults: a late effect after chemotherapy for bone sarcoma.
      ,
      • Lim J.S.
      • Kim D.H.
      • Lee J.A.
      • et al.
      Young age at diagnosis, male sex, and decreased lean mass are risk factors of osteoporosis in long-term survivors of osteosarcoma.
      ]. Moreover, most young patients with osteosarcoma could fail to achieve optimal lean mass, because of chemotherapy, nutritional deficits, and reduced physical activity levels during and after treatment [
      • van Leeuwen B.L.
      • Kamps W.A.
      • Jansen H.W.
      • Hoekstra H.J.
      The effect of chemotherapy on the growing skeleton.
      ,
      • Holzer G.
      • Krepler P.
      • Koschat M.A.
      • et al.
      Bone mineral density in long-term survivors of highly malignant osteosarcoma.
      ,
      • Pirker-Frühauf U.M.
      • Friesenbichler J.
      • Urban E.C.
      • et al.
      Osteoporosis in children and young adults: a late effect after chemotherapy for bone sarcoma.
      ,
      • Lim J.S.
      • Kim D.H.
      • Lee J.A.
      • et al.
      Young age at diagnosis, male sex, and decreased lean mass are risk factors of osteoporosis in long-term survivors of osteosarcoma.
      ].

       Ewing’s sarcoma

      Ewing’s sarcoma is another common primary skeletal malignancy in childhood, usually treated with chemotherapy, surgery, and local radiation therapy [
      • Yaw K.M.
      Pediatric bone tumors.
      ]. Treatment regimens have led to survival rates approaching 70% of patients with no metastases at diagnosis. Low BMD and risk of fractures can occur due to chemotherapy and limited mobility. The risk of fractures could be associated with bone microarchitectural changes, but further studies should be conducted [
      • Lim J.S.
      • Kim D.H.
      • Lee J.A.
      • et al.
      Young age at diagnosis, male sex, and decreased lean mass are risk factors of osteoporosis in long-term survivors of osteosarcoma.
      ].

       Chondrosarcoma

      Chondrosarcoma is a malignant bone tumor but is uncommon in children. The standard treatment consists of a wide resection or aggressive curettage, only for selected low-grade extremity chondrosarcomas, and is usually not followed by conventional adjuvant treatment [
      • Hobusch G.M.
      • Tiefenboeck T.M.
      • Patsch J.
      • et al.
      Do patients after chondrosarcoma treatment have age-appropriate bone mineral density in the long term?.
      ]. Very little data exist on effects on bone health.

       Other childhood tumors: brain tumors and neuroblastoma

      BMD has been reported to be reduced in up to one-third of survivors of childhood brain tumors [
      • Pietila S.
      • Sievanen H.
      • Ala-Houhala M.
      • et al.
      Bone mineral density is reduced in brain tumour patients treated in childhood.
      ]. Children with brain tumors are subject to several risk factors, such as decreased physical activity, glucocorticoid treatment, GH deficiency, hypogonadotropic hypogonadism due to cranial–spinal irradiation. The latter is probably the most important risk factor [
      • Pietila S.
      • Sievanen H.
      • Ala-Houhala M.
      • et al.
      Bone mineral density is reduced in brain tumour patients treated in childhood.
      ,
      • Fletcher B.D.
      Effects of pediatric cancer therapy on the musculoskeletal system.
      ]; however, further studies are necessary.
      Finally, some data are also available on bone complications (short stature and osteopenia) in neuroblastoma, an embryonic malignancy of early childhood treated with high-dose therapy and HSCT [
      • Utriainen P.
      • Vatanen A.
      • Toiviainen-Salo S.
      • et al.
      Skeletal outcome in long-term survivors of childhood high-risk neuroblastoma treated with high-dose therapy and autologous stem cell rescue.
      ].

      Part III: Contributing factors of bone mass impairment in CCSs

      Figure 1 summarizes the main contributing factors of bone mass impairment in CCSs, which are described below.
      Figure 1
      Figure 1The main contributing factors of bone mass impairment in childhood cancer survivors. The following factors can negatively affect the bone health status of childhood cancer survivors: an inadequate diet, especially characterized by calcium and vitamin D deficiency, prolonged treatments with glucocorticoids, failure to achieve sufficient bone mass peak, hormone alterations involving growth hormone and/or gonadal hormones, reduced or absent physical activity, cancer treatments including chemotherapy, radiotherapy, stem-cell transplantation, and last, the inflammation and altered secretion of cytokines due to cancer cells. Furthermore, the achievement of the peak bone mass, a fundamental factor for bone mass in adulthood, can be negatively influenced by prolonged use of corticosteroids, hormonal deficits implicated in skeletal growth, and limitations of motor function.

       Hormonal deprivation

      In both sexes, the degree of gonadal impairment due to cancer treatment is related to the age, dose, and fractionation schedule for radiation therapy and chemotherapy, and it can negatively affect PBM and bone mass [
      • Chemaitilly W.
      • Sklar C.A.
      Endocrine complications in longterm survivors of childhood cancers.
      ,
      • Wilson C.L.
      • Ness K.K.
      Bone mineral density deficits and fractures in survivors of childhood cancer.
      ,
      • Ferrari S.
      • Bianchi M.L.
      • Eisman J.A.
      • et al.
      Osteoporosis in young adults: pathophysiology, diagnosis, and management.
      ,
      • Chevalley T.
      • Bonjour J.P.
      • Ferrari S.
      • Rizzoli R.
      Deleterious effect of late menarche on distal tibia microstructure in healthy 20-year-old and premenopausal middle-aged women.
      ,
      • Chevalley T.
      • Bonjour J.P.
      • Ferrari S.
      • Rizzoli R.
      Influence of age at menarche on forearm bone microstructure in healthy young women.
      ,
      • Skinner R.
      • Mulder R.L.
      • Kremer L.C.
      • et al.
      Recommendations for gonadotoxicity surveillance in male childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium.
      ,
      • Kantartzis K.L.
      • Sucato G.S.
      Menstrual suppression in the adolescent.
      ]. Moreover, in young females, GnRH agonists can be used for short-term use in patients with estrogen-dependent tumors. Overall, standard GnRH agonist treatment regimens of 6 months cause significant bone loss in both the trabecular and cortical bones [
      • Magon N.
      Gonadotropin releasing hormone agonists: expanding vistas.
      ]. After treatment discontinuation, bone loss recovers slowly, but may not be completely recovered in all women [
      • Magon N.
      Gonadotropin releasing hormone agonists: expanding vistas.
      ]. Specific future investigations on CCSs and the usefulness of treatment to prevent bone loss could be valuable.
      Moreover, GH deficiency (GHD) is a major side-effect of radiotherapy and has a negative effect on BMD. GHD can lead to decreased bone turnover, delayed growth in children, low PBM, and increased fracture risk in adults [
      • Chemaitilly W.
      • Sklar C.A.
      Endocrine complications in longterm survivors of childhood cancers.
      ,
      • Tritos N.A.
      • Klibanski A.
      Effects of growth hormone on bone.
      ,
      • Mazziotti G.
      • Bianchi A.
      • Bonadonna S.
      • et al.
      Increased prevalence of radiological spinal deformities in adult patients with GH deficiency: influence of GH replacement therapy.
      ].

       Glucocorticoids

      Glucocorticoids have a central role in the treatment of most childhood tumors. Their effects on bone metabolism have been widely studied, both in adults and in children [
      • Pfeilschifter J.
      • Diel I.J.
      Osteoporosis due to cancer treatment: pathogenesis and management.
      ,
      • Rizzoli R.
      • Biver E.
      Glucocorticoid-induced osteoporosis: who to treat with what agent?.
      ,
      • Mazziotti G.
      • Angeli A.
      • Bilezikian J.P.
      • et al.
      ] (Figure 2). In the cancer setting, the use of steroids is rarely continuous with chemotherapy programs, but a relatively high dose is common, either to prevent side-effects such as nausea and allergy or to potentiate anticancer drugs. Thus, the attributable part of bone quantity/quality reduction due to steroids is less easy to evaluate, and probably depends on the dose itself, but also time of exposure, cumulative dose, or compounds used [
      • Chemaitilly W.
      • Sklar C.A.
      Endocrine complications in longterm survivors of childhood cancers.
      ,
      • Rizzoli R.
      • Biver E.
      Glucocorticoid-induced osteoporosis: who to treat with what agent?.
      ].
      Figure 2
      Figure 2The effects of glucocorticoids on bone. The figure shows the effects of glucocorticoids on bone cells and other organs/systems. Bone cells: Glucocorticoids have mostly inhibitory effects on osteoblasts and osteocytes, inhibiting bone formation and decreasing the repair of microdamaged bone. Moreover, glucocorticoids have stimulatory effects on osteoclasts, with consequent increase of cell recruitment and differentiation, followed by bone reabsorption. However, the effects by glucocorticoids on osteoclasts are less evident compared with effects by osteoblasts on osteoclasts mediated by RANKL and M-CSF. Other organs: The increase of bone reabsorption due to glucocorticoids is also mediated by the effects of glucocorticoids on other organs, described below. In fact, glucocorticoids have catabolic effects on muscle, with the consequent reduction of bone load (in addition to an increased fracture risk due to muscle weakness); in the intestinal tract they reduce the absorption of vitamin D; in the renal tubule they decrease calcium reabsorption and increase 24-hydroxylase activity; and last, gonadotropin secretion can be reduced, leading to a loss of sex steroids. RANKL, receptor activator of nuclear factor kappa-B ligand; M-CSF, macrophage colony-stimulating factor; OPG, osteoprotegerin; ↑, increase; ↓, decrease; (−), inhibitory effect; (+), stimulatory effect [
      • Mazziotti G.
      • Angeli A.
      • Bilezikian J.P.
      • et al.
      ,
      • van der Sluis I.M.
      • van den Heuvel-Eibrink M.M.
      Osteoporosis in children with cancer.
      ].

       Physical activity, immobilization, and limb surgery

      Decreased physical activity or the immobilization in subjects with childhood cancer and CCSs increases bone resorption and negatively affects BMD [
      • Weaver C.M.
      • Gordon C.M.
      • Janz K.F.
      • et al.
      The National Osteoporosis Foundation’s position statement on peak bone mass development and lifestyle factors: a systematic review and implementation recommendations.
      ,
      • Rizzoli R.
      • Bonjour J.P.
      Determinants of peak bone mass and mechanisms of bone loss.
      ,
      • Ferrari S.
      • Bianchi M.L.
      • Eisman J.A.
      • et al.
      Osteoporosis in young adults: pathophysiology, diagnosis, and management.
      ,
      • Holzer G.
      • Krepler P.
      • Koschat M.A.
      • et al.
      Bone mineral density in long-term survivors of highly malignant osteosarcoma.
      ]. However, skeletal responses to disuse can be highly variable [
      • Weaver C.M.
      • Gordon C.M.
      • Janz K.F.
      • et al.
      The National Osteoporosis Foundation’s position statement on peak bone mass development and lifestyle factors: a systematic review and implementation recommendations.
      ].
      Depending on the sites where the surgery is carried out, its effects will, of course, be different [
      • Song A.
      • Fish J.D.
      Caring for survivors of childhood cancer: it takes a village.
      ]. Limb reconstructions in children usually have a long functional recovery. Patients must be immobilized with consequent disuse osteoporosis. This is a feared consequence that could cause implant failures and fractures. Moreover, as a consequence of immobilization, the stiffness of soft tissues and the poor compliance of sick children trigger a vicious circle that delays the healing of weight-bearing bones [
      • Pfeilschifter J.
      • Diel I.J.
      Osteoporosis due to cancer treatment: pathogenesis and management.
      ]. Care should be taken to ensure rapid healing of orthopedic reconstruction in an interdisciplinary fashion, even if the literature remains quite limited in this field.

       Radiotherapy

      Radiotherapy is an integral therapy to the treatment of several childhood cancers, including leukemia, lymphoma, brain tumors, sarcomas, neuroblastoma, and nephroblastoma (Wilms tumor) [
      • Song A.
      • Fish J.D.
      Caring for survivors of childhood cancer: it takes a village.
      ,
      • Armstrong G.T.
      • Stovall M.
      • Robison L.L.
      Long-term effects of radiation exposure among adult survivors of childhood cancer: results from the childhood cancer survivor study.
      ]. The risk of late effects from radiation treatments depends on the radiation source, field, cumulative dose, volume, and fractionation, as well as sex and age at the time of treatment [
      • Robison L.L.
      • Hudson M.M.
      Survivors of childhood and adolescent cancer: life-long risks and responsibilities.
      ,
      • Song A.
      • Fish J.D.
      Caring for survivors of childhood cancer: it takes a village.
      ]. It is mainly cranial, orbital, infratemporal, and nasopharyngeal irradiation that can cause radiation-induced hypothalamic-pituitary injury, leading to GHD and central hypogonadism [
      • Sklar C.
      • Constine L.S.
      Chronic neuroendocrinological sequelae of radiation therapy.
      ]. Alone or in combination with alkylating agent chemotherapy, it can also cause peripheral hypogonadism in case of pelvic, whole-abdomen, and lumbar/sacral spine radiation [
      • Warner J.T.
      • Evans W.D.
      • Webb D.K.
      • et al.
      Relative osteopenia after treatment for acute lymphoblastic leukemia.
      ]. These endocrine alterations can affect bone growth, bone mass acquisition, and low BMD [
      • Vassilopoulou-Sellin R.
      • Brosnan P.
      • Delpassand A.
      • et al.
      Osteopenia in young adult survivors of childhood cancer.
      ]. Local radiation doses of ≥40 Gy have been associated with hyperthyroidism [
      • Meacham L.
      Endocrine late effects of childhood cancer therapy.
      ], which can induce bone loss by activation of osteoclast activity [
      • Pfeilschifter J.
      • Diel I.J.
      Osteoporosis due to cancer treatment: pathogenesis and management.
      ]. Finally, some studies suggest that local and total body irradiation may affect BMD directly by damaging the bone marrow stroma, but others show conflicting findings [
      • Kaste S.C.
      • Shidler T.J.
      • Tong X.
      • et al.
      Bone mineral density and osteonecrosis in survivors of childhood allogeneic bone marrow transplantation.
      ,
      • Markbreiter L.A.
      • Pelker R.R.
      • Friedlaender G.E.
      • et al.
      The effect of radiation on the fracture repair process. A biomechanical evaluation of a closed fracture in a rat model.
      ,
      • Nyaruba M.M.
      • Yamamoto I.
      • Kimura H.
      • Morita R.
      Bone fragility induced by X-ray irradiation in relation to cortical bone-mineral content.
      ].
      In addition, other systemic dysfunctions involve cardiovascular, cerebrovascular, gastrointestinal, hepatic, pulmonary, reproductive, and urinary systems. Neurocognitive, neurosensory, and neurological deficits can occur [
      • Song A.
      • Fish J.D.
      Caring for survivors of childhood cancer: it takes a village.
      ]. The most common sites at risk of subsequent neoplasm include bone [
      • Song A.
      • Fish J.D.
      Caring for survivors of childhood cancer: it takes a village.
      ,
      • Fidler M.M.
      • Frobisher C.
      • Guha J.
      • et al.
      Long-term adverse outcomes in survivors of childhood bone sarcoma: the British Childhood Cancer Survivor Study.
      ], in addition to skin, breast, thyroid, and central nervous system [
      • Song A.
      • Fish J.D.
      Caring for survivors of childhood cancer: it takes a village.
      ].

       Chemotherapy

      The most commonly used chemotherapeutic agents in childhood cancer include alkylating agents, antibiotics, and antimetabolites [
      • Song A.
      • Fish J.D.
      Caring for survivors of childhood cancer: it takes a village.
      ,
      • Balis F.M.
      • Holcenberg J.S.
      • Poplack D.G.
      General principles of chemotherapy.
      ]. The risk for late effects depends on the cumulative dose, route of administration, treatment schedule, and the sex and age of the patient [
      • Song A.
      • Fish J.D.
      Caring for survivors of childhood cancer: it takes a village.
      ].
      BMD is usually low in children treated with different chemotherapeutic regimens [
      • Arikoski P.
      • Komulainen J.
      • Riikonen P.
      • et al.
      Alterations in bone turnover and impaired development of bone mineral density in newly diagnosed children with cancer: a 1-year prospective study.
      ,
      • Arikoski P.
      • Kröger H.
      • Riikonen P.
      • et al.
      Disturbance in bone turnover in children with a malignancy at completion of chemotherapy.
      ]. Methotrexate has been consistently associated with reduced BMD in children treated for childhood cancer [
      • Davies J.H.
      • Evans B.A.
      • Jenney M.E.
      • Gregory J.W.
      Skeletal morbidity in childhood acute lymphoblastic leukaemia.
      ]. Through a cytotoxic effect on osteoblasts, this drug has been associated with reduced bone volume and impaired bone formation. It is unclear whether there is a synergistic effect of methotrexate and steroids, as they are given together in the treatment of ALL [
      • Hesseling P.B.
      • Hough S.F.
      • Nel E.D.
      • et al.
      Bone mineral density in long-term survivors of childhood cancer.
      ]. In children treated for ALL, low doses of methotrexate suppress osteoblast activity and stimulate osteoclast recruitment [
      • Crofton P.M.
      • Ahmed S.F.
      • Wade J.C.
      • et al.
      Effects of intensive chemotherapy on bone and collagen turnover and the growth hormone axis in children with acute lymphoblastic leukemia.
      ]. Higher cumulative doses of methotrexate have been associated with a greater incidence of osteopenia [
      • Crofton P.M.
      • Ahmed S.F.
      • Wade J.C.
      • et al.
      Effects of intensive chemotherapy on bone and collagen turnover and the growth hormone axis in children with acute lymphoblastic leukemia.
      ]. In vitro studies with doxorubicin have described that it also has a toxic effect on osteoblasts [
      • Serafino A.
      • Sinibaldi-Vallebona P.
      • Pierimarchi P.
      • et al.
      Induction of apoptotsis in neoplastic cells by anthracycline antitumor drugs: nuclear and cytoplasmic triggering?.
      ]. Several chemotherapy regimens, such as methotrexate and cisplatin, are also nephrotoxic and may cause skeletal abnormalities [
      • Neglia J.P.
      • Nesbit Jr., M.E.
      Care and treatment of long-term survivors of childhood cancer.
      ]. Moreover, ifosfamide can damage renal tubular function and induce a Fanconi syndrome [
      • Womer R.B.
      Ifosfamide and paediatrics: should this marriage be saved?.
      ,
      • Loebstein R.
      • Atanackovic G.
      • Bishai R.
      • et al.
      Risk factors for long-term outcome of ifosfamide-induced nephrotoxicity in children.
      ,
      • Rossi R.
      • Pleyer J.
      • Schäfers P.
      • et al.
      Development of ifosfamideinduced nephrotoxicity: prospective follow-up in 75 patients.
      ]. In long-term survivors of ALL, ifosfamide has been found to negatively affect BMD [
      • Warner J.T.
      • Evans W.D.
      • Webb D.K.
      • et al.
      Relative osteopenia after treatment for acute lymphoblastic leukemia.
      ].
      In addition to musculoskeletal abnormalities, it is known that chemotherapy exposure has been associated with gonadal, urinary tract, hepatic, cardiovascular, and neurocognitive and neurosensory deficits, as well as pulmonary fibrosis. Finally, secondary myelodysplasia and acute myeloid leukemia are also potential late complications of chemotherapy [
      • Skinner R.
      • Mulder R.L.
      • Kremer L.C.
      • et al.
      Recommendations for gonadotoxicity surveillance in male childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium.
      ,
      • Song A.
      • Fish J.D.
      Caring for survivors of childhood cancer: it takes a village.
      ].

       Hematopoietic stem-cell transplantation

      Patients undergoing HSCT often receive multiple treatments (i.e. methotrexate, steroids, total body irradiation, and high dose of alkylating agents) and can display low BMD levels. It is unclear whether there is additional risk from the transplant itself [
      • Nysom K.
      • Holm K.
      • Michaelsen K.F.
      • et al.
      Bone mass after allogeneic BMT for childhood leukaemia or lymphoma.
      ,
      • Kaste S.C.
      • Shidler T.J.
      • Tong X.
      • et al.
      Bone mineral density and osteonecrosis in survivors of childhood allogeneic bone marrow transplantation.
      ,
      • Mattano L.
      The skeletal remains: porosis and necrosis of bone in the marrow transplantation setting.
      ]. Moreover, as patients who have had an HSCT tend to have more severe acute and chronic therapy-related complications, they usually have additional risk factors, including poor nutrition, decreased physical activity, and less exposure to sunshine. In adulthood, transplant studies have shown 2%–10% loss of BMD, with high risk of fracture [
      • Mattano L.
      The skeletal remains: porosis and necrosis of bone in the marrow transplantation setting.
      ].

      Part IV: Recommendations for bone health in CCSs

      In 2018, the Children’s Oncology Group (COG) published an update of long-term follow-up (LTFU) guidelines for survivors of childhood, adolescent, and young adult cancer surveillance and counseling recommendations (http://www.survivorshipguidelines.org/pdf/2018/COG_LTFU_Guidelines_v5.pdf) [

      Children’s Oncology Group. Children’s Oncology Group—The World’s Childhood Cancer Experts: About Us [online]. 2014; http://www.childrensoncologygroup.org/index.php/about.

      ,
      ,
      National Cancer Policy Board (US) Committee on Cancer Survivorship: Improving Care and Quality of Life.
      ,
      • Landier W.
      • Bhatia S.
      • Eshelman D.A.
      • et al.
      Development of risk-based guidelines for pediatric cancer survivors: the Children’s Oncology Group Long-Term Follow-Up Guidelines from the Children’s Oncology Group Late Effects Committee and Nursing Discipline.
      ,
      American Academy of Pediatrics Section on Hematology/Oncology Children’s Oncology Group
      Long-term follow-up care for pediatric cancer survivors.
      ]. The COG is the world’s largest organization devoted to clinical trials and research of childhood and adolescent cancer [

      Children’s Oncology Group. Children’s Oncology Group—The World’s Childhood Cancer Experts: About Us [online]. 2014; http://www.childrensoncologygroup.org/index.php/about.

      ]. In Europe, there are three LTFU guidelines (in the UK, Scotland, and Germany) [
      • Song A.
      • Fish J.D.
      Caring for survivors of childhood cancer: it takes a village.
      ].

       Recommendations

      Based on the literature review, the available guidelines, and our experience, we propose the following evidence-based recommendations for clinical practice regarding bone health in CCSs.
      Figure 3 shows a summary of the diagnostic-therapeutic algorithm of bone fragility for CCSs, which are explained and discussed in detail in the following paragraphs.
      Figure 3
      Figure 3The diagnostic–therapeutic algorithm of bone fragility for childhood cancer survivors. LTFU, long-term follow-up; BMD, bone mass density; DEXA, dual-energy X-ray absorptiometry; 25(OH)D, 25-hydroxyvitamin D; iPTH, intact parathyroid hormone; ALP, alkaline phosphatase; BTMs, bone turnover markers; s-PINP, serum-procollagen type I N propeptide; s-CTX, serum C-terminal telopeptide of type I collagen; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; GOT, glutamic oxaloacetic transaminase; GPT, alanine aminotransferase; gamma-GT, gamma glutamyl transferase; Hba1C, hemoglobin A1c; TSH, thyroid-stimulating hormone; SHBG, sex hormone-binding globulin; GH, growth hormone; IGF-1, insulin-like growth factor 1; LH, luteinizing hormone; FSH, follicle-stimulating hormone; BMI, body mass index.
      • The baseline assessment at entry into LTFU, which usually occurs 2 years after the end of cancer therapy, potentially damaging for bone health, should include a BMD evaluation (grade of evidence: moderate), followed by laboratory exams, in order to assess bone metabolism, renal function, and factors inducing secondary osteoporosis (grade of evidence: low). In case of young patients, BMD evaluation should be carried out at specialized centers capable of interpreting pediatric scans. Baseline anthropometric evaluations are useful to check for growth disorders, bone deformations, or BMI alterations that may have influenced bone health (grade of evidence: low).
      • Recommendations regarding adequate calcium (or diet intake) and vitamin D supplementations, in case of deficit, in addition to adequate physical activity, to avoid negative lifestyles, should always be given, irrespective of BMD, as recommended in the general population (quality of evidence: low). Further studies are needed to establish the exact levels of vitamin D and precise physical activity programs for this specific population that may have an influence on skeletal growth and maintenance of bone mass in adulthood.
      • When low BMD (juvenile osteoporosis) is reported, Z-score <−2 or T-score <−2.5 (based on age, pubertal development, and growth process), and/or fragility fractures, and/or chronic use of glucocorticoids, antiresorptive treatments (bisphosphonate) should be taken into consideration (grade of evidence in childhood/adolescent/young adult age: low; grade of evidence in adulthood: moderate). Also, if necessary, correction of endocrine alterations or other modifiable risk factors of impaired bone quantity/quality should be evaluated (grade of evidence: low). As, in most studies, BMDs in survivors improve with increasing time-off therapy, and if hormonal deficiencies are corrected, repeat measurements in case of normal results (BMD Z-score > −1) should not be necessary (grade of evidence: low).
      In the following paragraphs, the recommendations are further discussed, subdividing them into ‘Assessment and Monitoring’ and ‘Prevention and Treatment’.

       Assessment and monitoring

       Bone mineral density

      The frequency and severity of bone mineral deficits reported for CCSs suggest that specific diagnostic and treatment interventions during childhood and adulthood should be undertaken.
      Although reduced BMD after childhood cancer treatment might recover spontaneously following cessation of therapy, adults treated for childhood cancer frequently have reduced BMD and an increased risk of fractures [
      • Kang M.J.
      • Lim J.S.
      Bone mineral density deficits in childhood cancer survivors: pathophysiology, prevalence, screening, and management.
      ,
      • Wilson C.L.
      • Ness K.K.
      Bone mineral density deficits and fractures in survivors of childhood cancer.
      ,
      • Choi Y.J.
      • Park S.Y.
      • Cho W.K.
      • et al.
      Factors related to decreased bone mineral density in childhood cancer survivors.
      ]. COG LTFU guidelines recommend an initial evaluation of BMD by DEXA or QCT at entry into LTFU and 2 years after completion of cancer therapy for children treated with agents and or modalities predisposing to BMD decrease (i.e. methotrexate, corticosteroids, or HSCT), or in case of survivors with GHD, hypogonadism, delayed puberty, or hyperthyroidism.
      We recommend the use of DEXA at the spine and femur, based on age, to diagnose and monitor BMD changes in these patients. The number of aBMD revaluations depends on the magnitude of the ongoing risk of fracture, the magnitude of low aBMD, and periods when significant clinical changes are expected [
      • Bianchi M.L.
      • Leonard M.B.
      • Bechtold S.
      • et al.
      Bone health in children and adolescents with chronic diseases that may affect the skeleton: the 2013 ISCD Pediatric Official Positions.
      ]. Results from the baseline evaluation and possible treatment intervention should then determine the frequency of subsequent follow-ups (grade of evidence: moderate).
      The use of QCT should be avoided because of the higher radiation dose applied (grade of quality: very low).
      In the future, imaging methods based on magnetic resonance imaging or bone densitometer using ultrasound, such as the recent radiofrequency echography multi-spectrometry technique, may be considered, especially in the pediatric population, to closely monitor quantity and quality of the trabecular and cortical bone tissue. However, such techniques must still be validated and standardized in the pediatric population (grade of quality: very low).

       Bone turnover markers

      The interest of bone turnover marker (BTM) levels, such as s-PINP and s-CTX, during LTFU in survivors, should be further evaluated, and levels should be considered in relation to age, skeletal growth, or recent fractures [
      • Vasikaran S.
      • Eastell R.
      • Bruyère O.
      • et al.
      Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards.
      ,
      • Atkinson S.A.
      Vitamin D status and bone biomarkers in childhood cancer.
      ]. Evaluation and monitoring of BTM concentrations can show the bone turnover and effects of treatments on bone metabolism, but the prediction of fracture risk independently from BMD still needs stronger evidence on which to base practice (grade of quality: very low). Data demonstrating a predictive role of BTMs for fracture risk in secondary osteoporosis are lacking [
      • Ferrari S.
      • Bianchi M.L.
      • Eisman J.A.
      • et al.
      Osteoporosis in young adults: pathophysiology, diagnosis, and management.
      ,
      • Atkinson S.A.
      Vitamin D status and bone biomarkers in childhood cancer.
      ]. Moreover, BTM levels are influenced by several factors, such as vitamin D, IGF-1, physical activity, and nutrition, which should be taken into consideration [
      • Atkinson S.A.
      Vitamin D status and bone biomarkers in childhood cancer.
      ].
      Observational and intervention studies should still be carried out to evaluate the application of these BTMs in these patients.

       Prevention and treatment

       Calcium and vitamin D supplementations and other recommendations

      Vitamin D [25-hydroxyvitamin D (25(OH)D)] deficiency and insufficient calcium intake are common in pediatric patients affected by cancers, and in CCSs mean values for serum 25OHD result in the deficient or insufficient range in some, but not all studies [
      • Choudhary A.
      • Chou J.
      • Heller G.
      • Sklar C.
      Prevalence of vitamin D insufficiency in survivors of childhood cancer.
      ,
      • Othman F.
      • Guo C.Y.
      • Webber C.
      • et al.
      Osteopenia in survivors of Wilms tumor.
      ,
      • Marinovic D.
      • Dorgeret S.
      • Lescoeur B.
      • et al.
      Improvement in bone mineral density and body composition in survivors of childhood acute lymphoblastic leukemia: a 1-year prospective study.
      ,
      • 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.
      ,
      • Bilariki K.
      • Anagnostou E.
      • Masse V.
      • et al.
      Low bone mineral density and high incidences of fractures and vitamin D deficiency in 52 pediatric cancer survivors.
      ]. They may benefit from adequate dietary intake/supplementation of calcium and vitamin D (grade of quality: low), although the role of sub-optimal vitamin D and calcium status in delayed recovery of bone mass after completion of cancer therapy requires further investigation [
      • Atkinson S.A.
      Vitamin D status and bone biomarkers in childhood cancer.
      ,
      • Winzenberg T.
      • Shaw K.
      • Fryer J.
      • Jones G.
      Effects of calcium supplementation on bone density in healthy children: meta-analysis of randomised controlled trials.
      ,
      • Winzenberg T.M.
      • Shaw K.
      • Fryer J.
      • Jones G.
      Calcium supplementation for improving bone mineral density in children.
      ,
      • Weaver C.M.
      • Alexander D.D.
      • Boushey C.J.
      • et al.
      Calcium plus vitamin D supplementation and risk of fractures: an updated meta-analysis from the National Osteoporosis Foundation.
      ,
      • Rønne M.S.
      • Heidemann M.
      • Lylloff L.
      • et al.
      Bone mass development in childhood and its association with physical activity and vitamin D levels. The CHAMPS-Study DK.
      ,
      • Neville K.A.
      • Walker J.L.
      • Cohn R.J.
      • et al.
      The prevalence of Vitamin D deficiency is higher in adult survivors of childhood cancer.
      ,
      • Modan-Moses D.
      • Pinhas-Hamiel O.
      • Munitz-Shenkar D.
      • et al.
      Vitamin D status in pediatric patients with a history of malignancy.
      ,
      • Cohen J.E.
      • Wakefield C.E.
      • Cohn R.J.
      Nutritional interventions for survivors of childhood cancer.
      ]. Regarding this, the dietary intake of calcium and vitamin D and the dosages of eventual calcium and vitamin D supplementation should be evaluated according to national guidelines. Indeed, the wise and balanced choice of the recommendations to follow depends on one’s individual health outcome concerns, age, body weight, latitude of residence, dietary and cultural habits, making the regional or nationwide guidelines more applicable in clinical practice [
      • Pludowski P.
      • Holick M.F.
      • Grant W.B.
      • et al.
      Vitamin D supplementation guidelines.
      ].
      Long-term trials and intervention studies in these patients are needed to see whether supplementation of vitamin D and calcium can prevent increased morbidity from fractures not only in the period directly following treatment but also later in life.
      Moreover, it is important to counsel survivors to avoid smoking, alcohol, cannabis, and excessive use of caffeine.

       Physical activity

      Physical activity, such as weight-bearing exercise, is an important factor for BMD growth in children and BMD maintenance in adults; therefore, it is recommended for CCSs to perform regular physical activity, always taking into consideration the patient’s clinical situation (grade of evidence: low) [
      • Rizzoli R.
      • Bianchi M.L.
      • Garabédian M.
      • et al.
      Maximizing bone mineral mass gain during growth for the prevention of fractures in the adolescents and the elderly.
      ,
      • Rønne M.S.
      • Heidemann M.
      • Lylloff L.
      • et al.
      Bone mass development in childhood and its association with physical activity and vitamin D levels. The CHAMPS-Study DK.
      ,
      • Jarfelt M.
      • Fors H.
      • Lannering B.
      • et al.
      Bone mineral density and bone turnover in young adult survivors of childhood acute lymphoblastic leukaemia.
      ]. Although physical activity and exercise have become a cornerstone in the prevention and treatment of chronic diseases such as osteoporosis, there are no data on the effects of regular exercise from randomized controlled trials aiming to reduce cancer- and therapy-related sequelae in CCSs. Future prospective studies are necessary to elaborate adequate physical training programs in childhood and in subsequent periods for these patients [
      • Rueegg C.S.
      • Kriemler S.
      • Zuercher S.J.
      • et al.
      A partially supervised physical activity program for adult and adolescent survivors of childhood cancer (SURfit): study design of a randomized controlled trial [NCT02730767].
      ].

       Correction of endocrine alterations

      Treatment of low BMD in CCSs can also imply the correction of underlying diseases that may exacerbate BMD deficits [
      • Chemaitilly W.
      • Sklar C.A.
      Endocrine complications in longterm survivors of childhood cancers.
      ,
      • Wilson C.L.
      • Ness K.K.
      Bone mineral density deficits and fractures in survivors of childhood cancer.
      ].
      In case of childhood cancer treatment that can alter the GH–IGF-I axis, GH replacement in CCSs may be considered [
      • Dickerman J.D.
      The late effects of childhood cancer therapy.
      ,
      • Wasilewski-Masker K.
      • Kaste S.C.
      • Hudson M.M.
      • et al.
      Bone mineral density deficits in survivors of childhood cancer: long-term follow-up guidelines and review of the literature.
      ,

      MM Hudson, WLandier, S.Bhatia Long-Term Follow-up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. In Children’s Oncology Group (ed.), Version 2.0; www.survivorshipguidelines.org (24 December 2007, date last accessed).

      ]. However, in childhood, GH seems to be relatively weak as a bone-targeted anabolic treatment outside of the GHD setting. Therefore, considering the burden to children of multiple injections, the potential side-effects, and uncertainties about the longer-term safety, the benefits to prevent or treat osteoporosis outside of hormone replacement therapy for GHD do not justify its risks and costs [
      • Dickerman J.D.
      The late effects of childhood cancer therapy.
      ,
      • Ward L.M.
      • Rauch F.
      Anabolic therapy for the treatment of osteoporosis in childhood.
      ]. In adulthood, GHD may be associated with a decreased BMD, and BMC with an increased fracture risk. Recombinant human GH replacement induces a progressive increase in BMD for up to 5–7 years of treatment, but data on longer follow-ups are limited (grade of evidence: very low) [
      • Appelman-Dijkstra N.M.
      • Claessen K.M.
      • Hamdy N.A.
      • et al.
      Effects of up to 15 years of recombinant human GH (rhGH) replacement on bone metabolism in adults with growth hormone deficiency (GHD): the Leiden Cohort Study.
      ].
      In case of suspected testosterone deficiency in young age, it is advisable to seek specialist referral following no advancement in Tanner stage over a 6-month period in order to avoid delayed referral in a population of survivors at high risk of pubertal failure and consequent potential impairment of growth, metabolic health, bone mineral accretion, and quality of life as a result of testosterone deficiency [
      • Skinner R.
      • Mulder R.L.
      • Kremer L.C.
      • et al.
      Recommendations for gonadotoxicity surveillance in male childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium.
      ]. The effect of testosterone replacement therapy on bone health in boys with delayed puberty has not been described. There are only a few studies conducted on adult male subjects that have shown the benefits of testosterone as replacement treatment [
      • Ward L.M.
      • Rauch F.
      Anabolic therapy for the treatment of osteoporosis in childhood.
      ]. Among male CCSs, limited data exist on the influence of androgen insufficiency on BMD (grade of evidence: very low) [
      • Wilson C.L.
      • Ness K.K.
      Bone mineral density deficits and fractures in survivors of childhood cancer.
      ]. In case of testosterone deficiency, although testosterone replacement treatment may be appropriate in deficient patients following accepted endocrine guidelines, the potential benefits and risks of treatment need to be considered appropriately for each patient with cancer history [
      • Skinner R.
      • Mulder R.L.
      • Kremer L.C.
      • et al.
      Recommendations for gonadotoxicity surveillance in male childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium.
      ,
      • Bhasin S.
      • Cunningham G.R.
      • Hayes F.J.
      • et al.
      Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society Clinical Practice Guideline.
      ,
      • Dohle G.R.
      • Arver S.
      • Bettocchi C.
      • et al.
      ,
      • Dwyer A.D.
      • Phan-Hug F.
      • Hauschild M.
      • et al.
      Hypogonadism in adolescence.
      ,
      • Morales A.
      • Bebb R.A.
      • Manjoo P.
      • et al.
      Diagnosis and management of testosterone deficiency syndrome in men: clinical practice guideline.
      ,
      • Seftel A.D.
      • Kathrins M.
      • Niederberger C.
      Critical update of the 2010 Endocrine Society Clinical Practice Guidelines for Male Hypogonadism: a systematic analysis.
      ,
      • Watson S.
      • Fuqua J.S.
      • Lee P.A.
      Treatment of hypogonadism in males.
      ].
      Among female survivors, estrogen replacement may prevent sex hormone deprivation-dependent risk of low BMD, but findings are not yet consistent across all studies (grade of evidence: very low) [
      • Wilson C.L.
      • Ness K.K.
      Bone mineral density deficits and fractures in survivors of childhood cancer.
      ].
      Overall, survivors treated with one or more potentially gonadotoxic treatments, and their providers, should be aware of the risk of premature ovarian insufficiency or testosterone deficiency and its implications for future fertility. Regarding this, we refer to the recommendations of ‘International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) in collaboration with the PanCareSurFup Consortium’ [
      • Skinner R.
      • Mulder R.L.
      • Kremer L.C.
      • et al.
      Recommendations for gonadotoxicity surveillance in male childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium.
      ].

       Treatments to decrease bone fragility: bisphosphonates and others

      Bisphosphonates, inhibitors of bone resorption, are usually used in primary and secondary osteoporosis in adults, but in some cases are administered for low BMD in childhood, mostly in osteogenesis imperfecta [
      • Biggin A.
      • Munns C.F.
      Long-term bisphosphonate therapy in osteogenesis imperfecta.
      ]. Although bisphosphonates, such as alendronate and pamidronate, have not been evaluated in large groups of CCSs for safety and efficacy, several small studies, especially in children with ALL, have described that their use during and after the completion of chemotherapy can improve whole body BMD as well as BTMs (grade of quality: low) [
      • Barr R.D.
      • Guo C.Y.
      • Wiernikowski J.
      • et al.
      Osteopenia in children with acute lymphoblastic leukemia: a pilot study of amelioration with Pamidronate.
      ,
      • Lethaby C.
      • Wiernikowski J.
      • Sala A.
      • et al.
      Bisphosphonate therapy for reduced bone mineral density during treatment of acute lymphoblastic leukemia in childhood and adolescence: a report of preliminary experience.
      ,
      • Wiernikowski J.T.
      • Barr R.D.
      • Webber C.
      • et al.
      Alendronate for steroid-induced osteopenia in children with acute lymphoblastic leukaemia or non-Hodgkin’s lymphoma: results of a pilot study.
      ,
      • Lee J.M.
      • Kim J.E.
      • Bae S.H.
      • Hah J.O.
      Efficacy of pamidronate in children with low bone mineral density during and after chemotherapy for acute lymphoblastic leukemia and non-Hodgkin lymphoma.
      ,
      • Lim S.W.
      • Ahn J.H.
      • Choi A.
      • et al.
      Efficacy of pamidronate in pediatric osteosarcoma patients with low bone mineral density.
      ]. Supplementary Table S2, available at Annals of Oncology online, summarizes findings regarding the main published studies, based on expert opinion, on the use of bisphosphonates in pediatric cancer patients, the doses that have been used, and adverse events reported [
      • Barr R.D.
      • Guo C.Y.
      • Wiernikowski J.
      • et al.
      Osteopenia in children with acute lymphoblastic leukemia: a pilot study of amelioration with Pamidronate.
      ,
      • Lethaby C.
      • Wiernikowski J.
      • Sala A.
      • et al.
      Bisphosphonate therapy for reduced bone mineral density during treatment of acute lymphoblastic leukemia in childhood and adolescence: a report of preliminary experience.
      ,
      • Wiernikowski J.T.
      • Barr R.D.
      • Webber C.
      • et al.
      Alendronate for steroid-induced osteopenia in children with acute lymphoblastic leukaemia or non-Hodgkin’s lymphoma: results of a pilot study.
      ,
      • Lee J.M.
      • Kim J.E.
      • Bae S.H.
      • Hah J.O.
      Efficacy of pamidronate in children with low bone mineral density during and after chemotherapy for acute lymphoblastic leukemia and non-Hodgkin lymphoma.
      ,
      • Lim S.W.
      • Ahn J.H.
      • Choi A.
      • et al.
      Efficacy of pamidronate in pediatric osteosarcoma patients with low bone mineral density.
      ].
      Overall, evidence is limited for recommending bone-specific drugs such as bisphosphonates in young adults with secondary osteoporosis [
      • Ferrari S.
      • Bianchi M.L.
      • Eisman J.A.
      • et al.
      Osteoporosis in young adults: pathophysiology, diagnosis, and management.
      ]; the optimal duration of osteoporosis treatment is controversial and there are no specific dosages recommended for patients with pediatric cancers or CCSs. Regarding adult osteoporosis, the therapy should be reviewed after 3–5 years of treatment with bisphosphonates. Fracture risk should be reassessed after a new fracture, regardless of when it occurs. There is little evidence to guide decision making beyond 10 years of treatment, and management options in such patients should be considered on an individual basis [
      • Kanis J.A.
      • Cooper C.
      • Rizzoli R.
      • et al.
      Executive summary of European guidance for the diagnosis and management of osteoporosis in postmenopausal women.
      ,
      • Tarantino U.
      • Iolascon G.
      • Cianferotti L.
      • et al.
      Clinical guidelines for the prevention and treatment of osteoporosis: summary statements and recommendations from the Italian Society for Orthopaedics and Traumatology.
      ].
      Regarding side-effects, bisphosphonates may cause an acute phase reaction after intravenous administration, and gastrointestinal side-effects can occur with all orally administered bisphosphonates [
      • Shaw N.J.
      • Bishop N.J.
      Bisphosphonate treatment of bone disease.
      ]. In case of impaired renal function, an appropriate dose reduction should always be considered. Risk factors of bisphosphonate-related osteonecrosis of the jaw include duration of bisphosphonate treatment, intravenous administration, dental procedures (extraction/surgery), dental trauma/prosthesis, and an underlying diagnosis of cancer; however, this is rare and has not been described in the pediatric population to date [
      • Barr R.D.
      • Guo C.Y.
      • Wiernikowski J.
      • et al.
      Osteopenia in children with acute lymphoblastic leukemia: a pilot study of amelioration with Pamidronate.
      ,
      • Khan A.A.
      • Morrison A.
      • Kendler D.L.
      • et al.
      Case-based review of osteonecrosis of the jaw (ONJ) and application of the international recommendations for management from the International Task Force on ONJ.
      ]. As the half-life of bisphosphonates in bone may be several years, concerns regarding the potential for long-term effects in children have been raised, such as the risk of impaired mineralization of bone, linear growth, and delayed bone healing after orthopedic procedures [
      • Wilson C.L.
      • Ness K.K.
      Bone mineral density deficits and fractures in survivors of childhood cancer.
      ]. However, until now, few data exist supporting the risks of these adverse events in treated children. We are also reassured of the benign nature of bisphosphonates in the growing skeleton by patients with osteogenesis imperfecta who show normal bone growth but with slower remodeling of the metaphysis of long bones [
      • Barr R.D.
      • Guo C.Y.
      • Wiernikowski J.
      • et al.
      Osteopenia in children with acute lymphoblastic leukemia: a pilot study of amelioration with Pamidronate.
      ].
      Thus, in the case of children affected by cancer, and in CCSs with low BMD or fragility fractures, the use of bisphosphonates can be envisaged, as proposed in COG LTFU guidelines (grade of evidence in childhood/adolescent/young adult age: low; grade of evidence in adulthood: moderate). However, long-term controlled studies with larger samples are needed to assess the risks and benefits of bisphosphonates in children with low BMD, as well as the long-term outcomes in adulthood.
      Studies on the use of denosumab, a human monoclonal antibody that inhibits bone resorption by binding RANKL (receptor activator of nuclear factor kappa-B ligand), should also be carried out, in order to evaluate the effects on improvement of BMD and reduction of the risk of fragility fractures in these patients. Overall, pediatric data on safety and efficacy of denosumab are limited, unlike adult subjects with osteoporosis, bone metastases, or giant cell tumors. However, some evidence suggests that denosumab may also be beneficial in children in terms of increasing BMD, decreasing bone turnover, and preventing growth of certain skeletal neoplasms (grade of evidence: very low). As opposed to bisphosphonates, denosumab does not incorporate into bone matrix and bone turnover is not suppressed after its cessation. After drug discontinuation, denosumab’s effect on bone turnover is rapidly reversible, representing an important key difference from bisphosphonates. On the other hand, rebound increased bone turnover has led to severe hypercalcemia in several pediatric patients; therefore, further research is needed to clarify the use of denosumab in young patients [
      • Boyce A.M.
      Denosumab: an emerging therapy in pediatric bone disorders.
      ]. Moreover, this turnover rebound appears to be associated with a marked increase in vertebral fracture risk [
      • Cummings S.R.
      • Ferrari S.
      • Eastell R.
      • et al.
      Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension.
      ]. Recently, the European Calcified Tissue Society formed a working group to perform a systematic review of existing literature on the effects of stopping denosumab [
      • Tsourdi E.
      • Langdahl B.
      • Cohen-Solal M.
      • et al.
      Discontinuation of Denosumab therapy for osteoporosis: a systematic review and position statement by ECTS.
      ]. In adulthood, a re-evaluation should be carried out after 5 years of denosumab treatment, and bisphosphonate therapy should be considered to reduce or prevent the rebound increase in bone turnover. However, as the optimal bisphosphonate regimen post-denosumab is currently unknown, continuation of denosumab can also be considered until results from ongoing trials become available [
      • Tsourdi E.
      • Langdahl B.
      • Cohen-Solal M.
      • et al.
      Discontinuation of Denosumab therapy for osteoporosis: a systematic review and position statement by ECTS.
      ]. There are no data in pediatric populations, and further studies are needed in this regard.
      Finally, teriparatide [parathyroid hormone (1–34)], an anabolic hormonal therapy approved for the treatment of severe osteoporosis in adults, does not represent a possible therapeutic option in cancer patients (grade of evidence: high). Moreover, it has a black box warning against its use in children, due to risk of osteosarcoma [
      • Ward L.M.
      • Rauch F.
      Anabolic therapy for the treatment of osteoporosis in childhood.
      ].

       Avascular necrosis of bone in childhood cancer

      Childhood cancer patients are also at increased risk of avascular osteonecrosis of bone (AVN), which can be a bone devastating complication in some cases [
      • Geczova L.
      • Soltysova A.
      • Gecz J.
      • et al.
      Avascular necrosis of bone in childhood cancer patients: a possible role of genetic susceptibility.
      ]. It occurs more frequently after HSCT than after chemotherapy and/or radiotherapy [
      • Geczova L.
      • Soltysova A.
      • Gecz J.
      • et al.
      Avascular necrosis of bone in childhood cancer patients: a possible role of genetic susceptibility.
      ,
      • Girard P.
      • Auquier P.
      • Barlogis V.
      • et al.
      Symptomatic osteonecrosis in childhood leukemia survivors: prevalence, risk factors and impact on quality of life in adulthood.
      ,
      • Li X.
      • Brazauskas R.
      • Wang Z.
      • et al.
      Avascular necrosis of bone after allogeneic hematopoietic cell transplantation in children and adolescents.
      ,
      • Campbell S.
      • Sun C.L.
      • Kurian S.
      • et al.
      Predictors of avascular necrosis of bone in long-term survivors of hematopoietic cell transplantation.
      ]. Osteonecrosis is one of the most common therapy-related and debilitating side-effects of antileukemic treatment. An innovative approach to reduce osteonecrosis-associated morbidity might be systematic early screening for osteonecrosis by serial magnetic resonance images (grade of quality: very low) [
      • Kunstreich M.
      • Kummer S.
      • Laws H.J.
      • et al.
      Osteonecrosis in children with acute lymphoblastic leukemia.
      ]. This is probably not realistic in routine daily practice. More research is needed to determine whether genetic testing for patients at high risk for developing AVN would reduce the morbidity associated with this complication. There is no evidence-based consensus on how osteonecrosis needs to be managed in pediatric ALL patients [
      • Te Winkel M.L.
      • Pieters R.
      • Wind E.J.
      • et al.
      Management and treatment of osteonecrosis in children and adolescents with acute lymphoblastic leukemia.
      ].
      Osteonecrosis among long-term CCSs is rare. However, a retrospective cohort study described that CCSs had a significantly increased relative rate compared with the healthy population, especially those who were older at diagnosis and received dexamethasone or radiation therapy. Future investigations are needed to better delineate these results [
      • Kadan-Lottick N.S.
      • Dinu I.
      • Wasilewski-Masker K.
      • et al.
      Osteonecrosis in adult survivors of childhood cancer: a report from the childhood cancer survivor study.
      ].

      Discussion

       Conclusions

      CCSs have a multifactorial impact on bone fragility. Particular attention during cancer treatment should be paid to reduce the impact on future adult bone health. Once in remission or cured, patients should undergo prolonged follow-up for bone fragility to prevent fracture onset. More studies in large and homogenous patient groups are needed to better quantify the BMD loss, incidence of growth impairment, osteoporosis occurrence, fractures, relationship between DEXA parameters and fragility fractures, BTMs monitoring, and AVN in all childhood malignancies. A useful research axis would be to identity groups at higher risk of long-term bone complications, identify unrecognized long-term adverse effects, and improve patient care. Early detection of CCSs at high fracture risk should lead to adequate preventive or therapeutic measures, aiming to decrease morbidity and health costs, both at younger and older ages. For the multidisciplinary team taking care of CCSs, the overall target remains the reduction of cancer-related morbidity from treatment-induced bone loss in the increasing population of adolescents and young adults who have been adequately and successfully treated for childhood cancers.
      In the development of these recommendations, several substantial knowledge gaps for clinical research were revealed. Until now, there have been no large observational or randomized trials capable of determining whether improving bone health in CCSs differs from the management of the general population with bone disorders. Future research should be approached in a systematic manner by large single-institution studies, or international multicenter collaborative projects to fill the highlighted gaps.
      In response to USA recommendations to improve evidence-based follow-up care in these patients, a web-based support system for clinical decision making, called the Passport for Care (PFC), was recently developed [
      • Poplack D.G.
      • Fordis M.
      • Landier W.
      • et al.
      Childhood cancer survivor care: development of the Passport for Care.
      ]. The aim of the PFC is to foster clinician–survivor conversations and decision making, enhancing screening and long-term follow-up care, and ultimately to improve health outcomes, including bone health [
      • Poplack D.G.
      • Fordis M.
      • Landier W.
      • et al.
      Childhood cancer survivor care: development of the Passport for Care.
      ]. In some European centers, an electronic tool called ‘Survivorship Passport (SurPass)’ is used [
      • Haupt R.
      • Essiaf S.
      • Dellacasa C.
      • et al.
      The ‘Survivorship Passport’ for childhood cancer survivors.
      ]. SurPass provides a summary of each survivor’s clinical history, together with personalized follow-up and screening recommendations based on guidelines published by the IGHG and PanCareSurFup consortia [
      • Haupt R.
      • Essiaf S.
      • Dellacasa C.
      • et al.
      The ‘Survivorship Passport’ for childhood cancer survivors.
      ,
      • Kremer L.C.
      • Mulder R.L.
      • Oeffinger K.C.
      • et al.
      A worldwide collaboration to harmonize guidelines for the long-term follow-up of childhood and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group.
      ]. However, the ‘bone toxicity’ section of the IGHG is currently not available. Finally, optimal survivorship care should include an effective transition in care from pediatric to adult care; instead, transition to adulthood is currently suboptimal [
      • Tonorezos E.S.
      • Barnea D.
      • Cohn R.J.
      • et al.
      Models of care for survivors of childhood cancer from across the globe: advancing survivorship care in the next decade.
      ]. A well-coordinated transition of care is crucial for adherence to follow-up, because young adults are particularly at risk of loss for follow-ups, and adherence to late-effects screening decreases with age. Until now, despite the need to improve communication between pediatric oncology and primary care, only a few countries have existing national efforts to educate primary care physicians [
      • Tonorezos E.S.
      • Barnea D.
      • Cohn R.J.
      • et al.
      Models of care for survivors of childhood cancer from across the globe: advancing survivorship care in the next decade.
      ].

      Funding

      None declared.

      Disclosure

      CBC: Lilly, Amgen, Expansciences. DLK: research grants, speaker’s bureau, and/or consultancies from Amgen, Eli Lilly, AstraZeneca, Pfizer. DK has received research grants, speaker honoraria, and or consultant honoraria from Amgen, Eli Lilly, AstraZeneca, and Pfizer. MLB: is a consultant for Alexion, Bruno Farmaceutici, Shire, Servier, Kyowa Kirin; academic grants and/or speaker: Abiogen, Alexion, Amgen, Bruno Farmaceutici, Eli Lilly, Kyowa Kirin, MSD, NPS, Servier, Shire, SPA; she has received honoraria from: Amgen, Bruno Farmaceutici, Kyowa Kirin. RR: consultant or lecture fees for Radius Health, Nestlé, Danone, Effryx, CNIEL. All remaining authors have declared no conflicts of interest.

      References

        • Gatta G.
        • Botta L.
        • Rossi S.
        • et al.
        Childhood cancer survival in Europe 1999-2007: results of EUROCARE-5—a population-based study.
        Lancet Oncol. 2014; 15: 35-47
        • Robison L.L.
        • Hudson M.M.
        Survivors of childhood and adolescent cancer: life-long risks and responsibilities.
        Nat Rev Cancer. 2014; 14: 61-70
        • Poplack D.G.
        • Fordis M.
        • Landier W.
        • et al.
        Childhood cancer survivor care: development of the Passport for Care.
        Nat Rev Clin Oncol. 2014; 11: 740-750
        • Kremer L.C.
        • van der Pal H.J.
        • Offringa M.
        • et al.
        Frequency and risk factors of subclinical cardiotoxicity after anthracycline therapy in children: a systematic review.
        Ann Oncol. 2002; 13: 819-829
        • Travis L.B.
        The epidemiology of second primary cancers.
        Cancer Epidemiol Biomarkers Prev. 2006; 15: 2020-2026
        • Oeffinger K.C.
        • Hudson M.M.
        Long-term complications following childhood and adolescent cancer: foundations for providing risk-based health care for survivors.
        CA Cancer J Clin. 2004; 54: 208-236
        • Oeffinger K.C.
        • Mertens A.C.
        • Sklar C.A.
        • et al.
        Chronic health conditions in adult survivors of childhood cancer.
        N Engl J Med. 2006; 355: 1572-1582
        • Armstrong G.T.
        • Kawashima T.
        • Leisenring W.
        • et al.
        Aging and risk of severe, disabling, life-threatening, and fatal events in the childhood cancer survivor study.
        J Clin Oncol. 2014; 32: 1218-1227
        • Kang M.J.
        • Lim J.S.
        Bone mineral density deficits in childhood cancer survivors: pathophysiology, prevalence, screening, and management.
        Korean J Pediatr. 2013; 56: 60-67
        • Chemaitilly W.
        • Sklar C.A.
        Endocrine complications in longterm survivors of childhood cancers.
        Endocr Relat Cancer. 2010; 17: 141-159
        • Wilson C.L.
        • Ness K.K.
        Bone mineral density deficits and fractures in survivors of childhood cancer.
        Curr Osteoporos Rep. 2013; 11: 329-337
        • Dickerman J.D.
        The late effects of childhood cancer therapy.
        Pediatrics. 2007; 119: 554-568
        • Pfeilschifter J.
        • Diel I.J.
        Osteoporosis due to cancer treatment: pathogenesis and management.
        J Clin Oncol. 2000; 18: 1570-1593
        • van der Sluis I.M.
        • van den Heuvel-Eibrink M.M.
        • Hahlen K.
        • et al.
        Bone mineral density, body composition, and height in long-term survivors of acute lymphoblastic leukemia in childhood.
        Med Pediatr Oncol. 2000; 35: 415-420
        • Choi Y.J.
        • Park S.Y.
        • Cho W.K.
        • et al.
        Factors related to decreased bone mineral density in childhood cancer survivors.
        J Korean Med Sci. 2013; 28: 1632-1638
        • Gurney J.G.
        • Kaste S.C.
        • 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: 1270-1276
        • Makitie O.
        • Heikkinen R.
        • Toiviainen-Salo S.
        • et al.
        Long-term skeletal consequences of childhood acute lymphoblastic leukemia in adult males: a cohort study.
        Eur J Endocrinol. 2013; 168: 281-288
        • Joyce E.D.
        • Nolan V.G.
        • Ness K.K.
        • et al.
        Association of muscle strength and bone mineral density in adult survivors of childhood acute lymphoblastic leukemia.
        Arch Phys Med Rehabil. 2011; 92: 873-879
        • Marcucci G.
        • Brandi M.L.
        Rare causes of osteoporosis.
        Clin Cases Miner Bone Metab. 2015; 12: 151-156
        • Atkins D.
        • Best D.
        • Briss P.A.
        • et al.
        Grading quality of evidence and strength of recommendations.
        BMJ. 2004; 328: 1490
        • Rizzoli R.
        • Bianchi M.L.
        • Garabédian M.
        • et al.
        Maximizing bone mineral mass gain during growth for the prevention of fractures in the adolescents and the elderly.
        Bone. 2010; 46: 294-305
        • Theintz G.
        • Buchs B.
        • Rizzoli R.
        • et al.
        Longitudinal monitoring of bone mass accumulation in healthy adolescents: evidence for a marked reduction after 16 years of age at the levels of lumbar spine and femoral neck in female subjects.
        J Clin Endocrinol Metab. 1992; 75: 1060-1065
        • Weaver C.M.
        • Gordon C.M.
        • Janz K.F.
        • et al.
        The National Osteoporosis Foundation’s position statement on peak bone mass development and lifestyle factors: a systematic review and implementation recommendations.
        Osteoporos Int. 2016; 27: 1281-1386
        • Rizzoli R.
        • Bonjour J.P.
        Determinants of peak bone mass and mechanisms of bone loss.
        Osteoporos Int. 1999; 9: S17-S23
        • Muszynska-Roslan K.
        • Latoch E.
        • Konstantynowicz J.
        • et al.
        Bone mineral density in pediatric survivors of Hodgkin and non-Hodgkin lymphomas.
        Adv Med Sci. 2014; 59: 200-205
        • Jackowski S.A.
        • Faulkner R.A.
        • Farthing J.P.
        • et al.
        Peak lean tissue mass accrual precedes changes in bone strength indices at the proximal femur during the pubertal growth spurt.
        Bone. 2009; 44: 1186-1190
        • Gafni R.I.
        • Baron J.
        Overdiagnosis of osteoporosis in children due to misinterpretation of dual-energy x-ray absorptiometry (DEXA).
        J Pediatr. 2004; 144: 253-257
        • Ferrari S.
        • Bianchi M.L.
        • Eisman J.A.
        • et al.
        Osteoporosis in young adults: pathophysiology, diagnosis, and management.
        Osteoporos Int. 2012; 23: 2735-2748
        • Crabtree N.J.
        • Arabi A.
        • Bachrach L.K.
        • et al.
        Dual-energy X-ray absorptiometry interpretation and reporting in children and adolescents: the revised 2013 ISCD Pediatric Official Positions.
        J Clin Densitom. 2014; 17: 225-242
        • Bianchi M.L.
        • Leonard M.B.
        • Bechtold S.
        • et al.
        Bone health in children and adolescents with chronic diseases that may affect the skeleton: the 2013 ISCD Pediatric Official Positions.
        J Clin Densitom. 2014; 17: 281-294
        • Zemel B.S.
        • Stallings V.A.
        • Leonard M.B.
        • et al.
        Revised pediatric reference data for the lateral distal femur measured by Hologic Discovery/Delphi dual-energy X-ray absorptiometry.
        J Clin Densitom. 2009; 12: 207-218
        • Wasilewski-Masker K.
        • Kaste S.C.
        • Hudson M.M.
        • et al.
        Bone mineral density deficits in survivors of childhood cancer: long-term follow-up guidelines and review of the literature.
        Pediatrics. 2008; 121: e705-e713
        • Almeida M.
        • Laurent M.R.
        • Dubois V.
        • et al.
        Estrogens and androgens in skeletal physiology and pathophysiology.
        Physiol Rev. 2017; 97: 135-187
        • Chevalley T.
        • Bonjour J.P.
        • Ferrari S.
        • Rizzoli R.
        Deleterious effect of late menarche on distal tibia microstructure in healthy 20-year-old and premenopausal middle-aged women.
        J Bone Miner Res. 2009; 24: 144-152
        • Chevalley T.
        • Bonjour J.P.
        • Ferrari S.
        • Rizzoli R.
        Influence of age at menarche on forearm bone microstructure in healthy young women.
        J Clin Endocrinol Metab. 2008; 93: 2594-2601
        • Zemel B.S.
        • Kalkwarf H.J.
        • Gilsanz V.
        • et al.
        Revised reference curves for bone mineral content and areal bone mineral density according to age and sex for black and non-black children: results of the bone mineral density in childhood study.
        J Clin Endocrinol Metab. 2011; 96: 3160-3169
        • Karasik D.
        • Ferrari S.L.
        Contribution of gender-specific genetic factors to osteoporosis risk.
        Ann Hum Genet. 2008; 72: 696-714
        • Seeman E.
        • Delmas P.D.
        Bone quality—the material and structural basis of bone strength and fragility.
        N Engl J Med. 2006; 354: 2250-2261
        • Vasikaran S.
        • Eastell R.
        • Bruyère O.
        • et al.
        Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards.
        Osteoporos Int. 2011; 22: 391-420
        • Atkinson S.A.
        Vitamin D status and bone biomarkers in childhood cancer.
        Pediatr Blood Cancer. 2008; 50: 479-482
        • Hoorweg-Nijman J.J.
        • Kardos G.
        • Roos J.C.
        • et al.
        Bone mineral density and markers of bone turnover in young adult survivors of childhood lymphoblastic leukaemia.
        Clin Endocrinol (Oxf). 1999; 50: 237-244
        • van Leeuwen B.L.
        • Kamps W.A.
        • Jansen H.W.
        • Hoekstra H.J.
        The effect of chemotherapy on the growing skeleton.
        Cancer Treat Rev. 2000; 26: 363-376
        • Han J.W.
        • Kim H.S.
        • Hahn S.M.
        • et al.
        Poor bone health at the end of puberty in childhood cancer survivors.
        Pediatr Blood Cancer. 2015; 62: 1838-1843
        • Tillmann V.
        • Darlington A.S.
        • Eiser C.
        • et al.
        Male sex and low physical activity are associated with reduced spine bone mineral density in survivors of childhood acute lymphoblastic leukemia.
        J Bone Miner Res. 2002; 17: 1073-1080
        • Arikoski P.
        • Komulainen J.
        • Riikonen P.
        • et al.
        Alterations in bone turnover and impaired development of bone mineral density in newly diagnosed children with cancer: a 1-year prospective study.
        J Clin Endocrinol Metab. 1999; 84: 3174-3181
        • Rohani F.
        • Arjmandi Rafsanjani K.
        • Bahoush G.
        • et al.
        Bone mineral density in survivors of childhood acute lymphoblastic leukemia.
        Asian Pac J Cancer Prev. 2017; 18: 535-540
        • Högler W.
        • Wehl G.
        • van Staa T.
        • et al.
        Incidence of skeletal complications during treatment of childhood acute lymphoblastic leukemia: comparison of fracture risk with the General Practice Research Database.
        Pediatr Blood Cancer. 2007; 48: 21-27
        • Alos N.
        • Grant R.M.
        • Ramsay T.
        • et al.
        High incidence of vertebral fractures in children with acute lymphoblastic leukemia 12 months after the initiation of therapy.
        JCO. 2012; 30: 2760-2767
        • Halton J.
        • Gaboury I.
        • Grant R.
        • et al.
        Advanced vertebral fracture among newly diagnosed children with acute lymphoblastic leukemia: results of the Canadian Steroid-Associated Osteoporosis in the Pediatric Population (STOPP) research program.
        J Bone Miner Res. 2009; 24: 1326-1334
        • Rayar M.S.
        • Nayiager T.
        • Webber C.E.
        • et al.
        Predictors of bony morbidity in children with acute lymphoblastic leukemia.
        Pediatr Blood Cancer. 2012; 59: 77-82
        • Mostoufi-Moab S.
        • Brodsky J.
        • Isaacoff E.J.
        • et al.
        Longitudinal assessment of bone density and structure in childhood survivors of acute lymphoblastic leukemia without cranial radiation.
        J Clin Endocrinol Metab. 2012; 97: 3584-3592
        • Nysom K.
        • Holm K.
        • Michaelsen K.F.
        • et al.
        Bone mass after allogeneic BMT for childhood leukaemia or lymphoma.
        Bone Marrow Transplant. 2000; 25: 191-196
        • Luetke A.
        • Meyers P.A.
        • Lewis I.
        • Juergens H.
        Osteosarcoma treatment—where do we stand? A state of the art review.
        Cancer Treat Rev. 2014; 40: 523-532
        • Holzer G.
        • Krepler P.
        • Koschat M.A.
        • et al.
        Bone mineral density in long-term survivors of highly malignant osteosarcoma.
        J Bone Joint Surg Br. 2003; 85: 231-237
        • Pirker-Frühauf U.M.
        • Friesenbichler J.
        • Urban E.C.
        • et al.
        Osteoporosis in children and young adults: a late effect after chemotherapy for bone sarcoma.
        Clin Orthop Relat Res. 2012; 470: 2874-2885
        • Lim J.S.
        • Kim D.H.
        • Lee J.A.
        • 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: 54-60
        • Yaw K.M.
        Pediatric bone tumors.
        Semin Surg Oncol. 1999; 16: 173-183
        • Hobusch G.M.
        • Tiefenboeck T.M.
        • Patsch J.
        • et al.
        Do patients after chondrosarcoma treatment have age-appropriate bone mineral density in the long term?.
        Clin Orthop Relat Res. 2016; 474: 1508-1515
        • Pietila S.
        • Sievanen H.
        • Ala-Houhala M.
        • et al.
        Bone mineral density is reduced in brain tumour patients treated in childhood.
        Acta Paediatr. 2006; 95: 1291-1297
        • Fletcher B.D.
        Effects of pediatric cancer therapy on the musculoskeletal system.
        Pediatr Radiol. 1997; 27: 623-636
        • Utriainen P.
        • Vatanen A.
        • Toiviainen-Salo S.
        • et al.
        Skeletal outcome in long-term survivors of childhood high-risk neuroblastoma treated with high-dose therapy and autologous stem cell rescue.
        Bone Marrow Transplant. 2017; 52: 711-716
        • Skinner R.
        • Mulder R.L.
        • Kremer L.C.
        • et al.
        Recommendations for gonadotoxicity surveillance in male childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium.
        Lancet Oncol. 2017; 18: e75-e90
        • Kantartzis K.L.
        • Sucato G.S.
        Menstrual suppression in the adolescent.
        J Pediatr Adolesc Gynecol. 2013; 26: 132-137
        • Magon N.
        Gonadotropin releasing hormone agonists: expanding vistas.
        Indian J Endocrinol Metab. 2011; 15: 261-267
        • Tritos N.A.
        • Klibanski A.
        Effects of growth hormone on bone.
        Prog Mol Biol Transl Sci. 2016; 138: 193-211
        • Mazziotti G.
        • Bianchi A.
        • Bonadonna S.
        • et al.
        Increased prevalence of radiological spinal deformities in adult patients with GH deficiency: influence of GH replacement therapy.
        J Bone Miner Res. 2006; 21: 520-528
        • Rizzoli R.
        • Biver E.
        Glucocorticoid-induced osteoporosis: who to treat with what agent?.
        Nat Rev Rheumatol. 2015; 11: 98-109
        • Mazziotti G.
        • Angeli A.
        • Bilezikian J.P.
        • et al.
        Trends Endocrinol Metab. 2006; 17: 144-149
        • van der Sluis I.M.
        • van den Heuvel-Eibrink M.M.
        Osteoporosis in children with cancer.
        Pediatr Blood Cancer. 2008; 50: 474-478
        • Song A.
        • Fish J.D.
        Caring for survivors of childhood cancer: it takes a village.
        Curr Opin Pediatr. 2018; 30: 864-873
        • Armstrong G.T.
        • Stovall M.
        • Robison L.L.
        Long-term effects of radiation exposure among adult survivors of childhood cancer: results from the childhood cancer survivor study.
        Radiat Res. 2010; 174: 840-850
        • Sklar C.
        • Constine L.S.
        Chronic neuroendocrinological sequelae of radiation therapy.
        Int J Radiat Oncol Biol Phys. 1995; 31: 1113-1121
        • Warner J.T.
        • Evans W.D.
        • Webb D.K.
        • et al.
        Relative osteopenia after treatment for acute lymphoblastic leukemia.
        Pediatr Res. 1999; 45: 544-555.1
        • Vassilopoulou-Sellin R.
        • Brosnan P.
        • Delpassand A.
        • et al.
        Osteopenia in young adult survivors of childhood cancer.
        Med Pediatr Oncol. 1999; 32: 272-278
        • Meacham L.
        Endocrine late effects of childhood cancer therapy.
        Curr Probl Pediatr Adolesc Health Care. 2003; 33: 217-242
        • Kaste S.C.
        • Shidler T.J.
        • Tong X.
        • et al.
        Bone mineral density and osteonecrosis in survivors of childhood allogeneic bone marrow transplantation.
        Bone Marrow Transplant. 2004; 33: 435-441
        • Markbreiter L.A.
        • Pelker R.R.
        • Friedlaender G.E.
        • et al.
        The effect of radiation on the fracture repair process. A biomechanical evaluation of a closed fracture in a rat model.
        J Orthop Res. 1989; 7: 178-183
        • Nyaruba M.M.
        • Yamamoto I.
        • Kimura H.
        • Morita R.
        Bone fragility induced by X-ray irradiation in relation to cortical bone-mineral content.
        Acta Radiol. 1998; 39: 43-46
        • Fidler M.M.
        • Frobisher C.
        • Guha J.
        • et al.
        Long-term adverse outcomes in survivors of childhood bone sarcoma: the British Childhood Cancer Survivor Study.
        Br J Cancer. 2015; 112: 1857-1865
        • Balis F.M.
        • Holcenberg J.S.
        • Poplack D.G.
        General principles of chemotherapy.
        in: Pizzo P.A. Poplack D.G. Principles and Practice of Pediatric Oncology. Lippincott-Raven, Philadelphia, PA1997: 215-272
        • Arikoski P.
        • Kröger H.
        • Riikonen P.
        • et al.
        Disturbance in bone turnover in children with a malignancy at completion of chemotherapy.
        Med Pediatr Oncol. 1999; 33: 455-461
        • Davies J.H.
        • Evans B.A.
        • Jenney M.E.
        • Gregory J.W.
        Skeletal morbidity in childhood acute lymphoblastic leukaemia.
        Clin Endocrinol (Oxf). 2005; 63: 1-9
        • Hesseling P.B.
        • Hough S.F.
        • Nel E.D.
        • et al.
        Bone mineral density in long-term survivors of childhood cancer.
        Int J Cancer Suppl. 1998; 11: 44-47
        • Crofton P.M.
        • Ahmed S.F.
        • Wade J.C.
        • et al.
        Effects of intensive chemotherapy on bone and collagen turnover and the growth hormone axis in children with acute lymphoblastic leukemia.
        J Clin Endocrinol Metab. 1998; 83: 3121-3129
        • Serafino A.
        • Sinibaldi-Vallebona P.
        • Pierimarchi P.
        • et al.
        Induction of apoptotsis in neoplastic cells by anthracycline antitumor drugs: nuclear and cytoplasmic triggering?.
        Anticancer Res. 1999; 19: 1909-1918
        • Neglia J.P.
        • Nesbit Jr., M.E.
        Care and treatment of long-term survivors of childhood cancer.
        Cancer. 1993; 71: 3386-3391
        • Womer R.B.
        Ifosfamide and paediatrics: should this marriage be saved?.
        Eur J Cancer. 1996; 32A: 1100-1101
        • Loebstein R.
        • Atanackovic G.
        • Bishai R.
        • et al.
        Risk factors for long-term outcome of ifosfamide-induced nephrotoxicity in children.
        J Clin Pharmacol. 1999; 39: 454-461
        • Rossi R.
        • Pleyer J.
        • Schäfers P.
        • et al.
        Development of ifosfamideinduced nephrotoxicity: prospective follow-up in 75 patients.
        Med Pediatr Oncol. 1999; 32: 177-182
        • Mattano L.
        The skeletal remains: porosis and necrosis of bone in the marrow transplantation setting.
        Pediatr Transplant. 2003; 7: 71-75
      1. Children’s Oncology Group. Children’s Oncology Group—The World’s Childhood Cancer Experts: About Us [online]. 2014; http://www.childrensoncologygroup.org/index.php/about.

      2. Hewitt M. Weiner S.L. Simone J.V. Institute of Medicine (US) and National Research Council (US) National Cancer Policy Board. Childhood Cancer Survivorship: Improving Care and Quality of Life. National Academies Press, 2003
        • National Cancer Policy Board (US) Committee on Cancer Survivorship: Improving Care and Quality of Life.
        Hewitt M.E. Weiner S.L. Simone J.V. From Childhood Cancer Survivorship. National Academies Press, Washington2003
        • Landier W.
        • Bhatia S.
        • Eshelman D.A.
        • et al.
        Development of risk-based guidelines for pediatric cancer survivors: the Children’s Oncology Group Long-Term Follow-Up Guidelines from the Children’s Oncology Group Late Effects Committee and Nursing Discipline.
        JCO. 2004; 22: 4979-4990
        • American Academy of Pediatrics Section on Hematology/Oncology Children’s Oncology Group
        Long-term follow-up care for pediatric cancer survivors.
        Pediatrics. 2009; 123: 906-915
        • Choudhary A.
        • Chou J.
        • Heller G.
        • Sklar C.
        Prevalence of vitamin D insufficiency in survivors of childhood cancer.
        Pediatr Blood Cancer. 2013; 60: 1237-1239
        • Othman F.
        • Guo C.Y.
        • Webber C.
        • et al.
        Osteopenia in survivors of Wilms tumor.
        Int J Oncol. 2002; 20: 827-833
        • Marinovic D.
        • Dorgeret S.
        • Lescoeur B.
        • et al.
        Improvement in bone mineral density and body composition in survivors of childhood acute lymphoblastic leukemia: a 1-year prospective study.
        Pediatrics. 2005; 116: e102-e108
        • 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: 113-118
        • Bilariki K.
        • Anagnostou E.
        • Masse V.
        • et al.
        Low bone mineral density and high incidences of fractures and vitamin D deficiency in 52 pediatric cancer survivors.
        Horm Res Paediatr. 2010; 74: 319-327
        • Winzenberg T.
        • Shaw K.
        • Fryer J.
        • Jones G.
        Effects of calcium supplementation on bone density in healthy children: meta-analysis of randomised controlled trials.
        BMJ. 2006; 333: 775.
        • Winzenberg T.M.
        • Shaw K.
        • Fryer J.
        • Jones G.
        Calcium supplementation for improving bone mineral density in children.
        Cochrane Database Syst Rev. 2006; 19 (CD005119)
        • Weaver C.M.
        • Alexander D.D.
        • Boushey C.J.
        • et al.
        Calcium plus vitamin D supplementation and risk of fractures: an updated meta-analysis from the National Osteoporosis Foundation.
        Osteoporos Int. 2016; 27: 367-376
        • Rønne M.S.
        • Heidemann M.
        • Lylloff L.
        • et al.
        Bone mass development in childhood and its association with physical activity and vitamin D levels. The CHAMPS-Study DK.
        Calcif Tissue Int. 2019; 104: 1-13
        • Neville K.A.
        • Walker J.L.
        • Cohn R.J.
        • et al.
        The prevalence of Vitamin D deficiency is higher in adult survivors of childhood cancer.
        Clin Endocrinol (Oxf). 2015; 82: 657-662
        • Modan-Moses D.
        • Pinhas-Hamiel O.
        • Munitz-Shenkar D.
        • et al.
        Vitamin D status in pediatric patients with a history of malignancy.
        Pediatr Res. 2012; 72: 620-624
        • Cohen J.E.
        • Wakefield C.E.
        • Cohn R.J.
        Nutritional interventions for survivors of childhood cancer.
        Cochrane Database Syst Rev. 2016; 22 (CD009678)
        • Pludowski P.
        • Holick M.F.
        • Grant W.B.
        • et al.
        Vitamin D supplementation guidelines.
        J Steroid Biochem Mol Biol. 2018; 175: 125-135
        • Jarfelt M.
        • Fors H.
        • Lannering B.
        • et al.
        Bone mineral density and bone turnover in young adult survivors of childhood acute lymphoblastic leukaemia.
        Eur J Endocrinol. 2006; 154: 303-309
        • Rueegg C.S.
        • Kriemler S.
        • Zuercher S.J.
        • et al.
        A partially supervised physical activity program for adult and adolescent survivors of childhood cancer (SURfit): study design of a randomized controlled trial [NCT02730767].
        BMC Cancer. 2017; 5: 822.
      3. MM Hudson, WLandier, S.Bhatia Long-Term Follow-up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. In Children’s Oncology Group (ed.), Version 2.0; www.survivorshipguidelines.org (24 December 2007, date last accessed).

        • Ward L.M.
        • Rauch F.
        Anabolic therapy for the treatment of osteoporosis in childhood.
        Curr Osteoporos Rep. 2018; 16: 269-276
        • Appelman-Dijkstra N.M.
        • Claessen K.M.
        • Hamdy N.A.
        • et al.
        Effects of up to 15 years of recombinant human GH (rhGH) replacement on bone metabolism in adults with growth hormone deficiency (GHD): the Leiden Cohort Study.
        Clin Endocrinol. 2014; 81: 727-735
        • Bhasin S.
        • Cunningham G.R.
        • Hayes F.J.
        • et al.
        Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society Clinical Practice Guideline.
        J Clin Endocrinol Metab. 2010; 95: 2536-2559
        • Dohle G.R.
        • Arver S.
        • Bettocchi C.
        • et al.
        Guidelines on Male Hypogonadism. 2015 (13 May 2016 date last accessed)
        • Dwyer A.D.
        • Phan-Hug F.
        • Hauschild M.
        • et al.
        Hypogonadism in adolescence.
        Eur J Endocrinol. 2015; 173: R15-R24
        • Morales A.
        • Bebb R.A.
        • Manjoo P.
        • et al.
        Diagnosis and management of testosterone deficiency syndrome in men: clinical practice guideline.
        CMAJ. 2015; 187: 1369-1377
        • Seftel A.D.
        • Kathrins M.
        • Niederberger C.
        Critical update of the 2010 Endocrine Society Clinical Practice Guidelines for Male Hypogonadism: a systematic analysis.
        Mayo Clin Proc. 2015; 90: 1104-1115
        • Watson S.
        • Fuqua J.S.
        • Lee P.A.
        Treatment of hypogonadism in males.
        Pediatr Endocrinol Rev. 2014; 11: 230-239
        • Biggin A.
        • Munns C.F.
        Long-term bisphosphonate therapy in osteogenesis imperfecta.
        Curr Osteoporos Rep. 2017; 15: 412-418
        • Barr R.D.
        • Guo C.Y.
        • Wiernikowski J.
        • et al.
        Osteopenia in children with acute lymphoblastic leukemia: a pilot study of amelioration with Pamidronate.
        Med Pediatr Oncol. 2002; 39: 44-46
        • Lethaby C.
        • Wiernikowski J.
        • Sala A.
        • et al.
        Bisphosphonate therapy for reduced bone mineral density during treatment of acute lymphoblastic leukemia in childhood and adolescence: a report of preliminary experience.
        J Pediatr Hematol Oncol. 2007; 29: 613-616
        • Wiernikowski J.T.
        • Barr R.D.
        • Webber C.
        • et al.
        Alendronate for steroid-induced osteopenia in children with acute lymphoblastic leukaemia or non-Hodgkin’s lymphoma: results of a pilot study.
        J Oncol Pharm Pract. 2005; 11: 51-56
        • Lee J.M.
        • Kim J.E.
        • Bae S.H.
        • Hah J.O.
        Efficacy of pamidronate in children with low bone mineral density during and after chemotherapy for acute lymphoblastic leukemia and non-Hodgkin lymphoma.
        Blood Res. 2013; 48: 99-106
        • Lim S.W.
        • Ahn J.H.
        • Choi A.
        • et al.
        Efficacy of pamidronate in pediatric osteosarcoma patients with low bone mineral density.
        Ann Pediatr Endocrinol Metab. 2016; 21: 21-25
        • Kanis J.A.
        • Cooper C.
        • Rizzoli R.
        • et al.
        Executive summary of European guidance for the diagnosis and management of osteoporosis in postmenopausal women.
        Aging Clin Exp Res. 2019; 31: 15-17
        • Tarantino U.
        • Iolascon G.
        • Cianferotti L.
        • et al.
        Clinical guidelines for the prevention and treatment of osteoporosis: summary statements and recommendations from the Italian Society for Orthopaedics and Traumatology.
        J Orthop Traumatol. 2017; 18: 3-36
        • Shaw N.J.
        • Bishop N.J.
        Bisphosphonate treatment of bone disease.
        Arch Dis Child. 2005; 90: 494-499
        • Khan A.A.
        • Morrison A.
        • Kendler D.L.
        • et al.
        Case-based review of osteonecrosis of the jaw (ONJ) and application of the international recommendations for management from the International Task Force on ONJ.
        J Clin Densitom. 2017; 20: 8-24
        • Boyce A.M.
        Denosumab: an emerging therapy in pediatric bone disorders.
        Curr Osteoporos Rep. 2017; 15: 283-292
        • Cummings S.R.
        • Ferrari S.
        • Eastell R.
        • et al.
        Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension.
        J Bone Miner Res. 2018; 33: 190-198
        • Tsourdi E.
        • Langdahl B.
        • Cohen-Solal M.
        • et al.
        Discontinuation of Denosumab therapy for osteoporosis: a systematic review and position statement by ECTS.
        Bone. 2017; 105: 11-17
        • Geczova L.
        • Soltysova A.
        • Gecz J.
        • et al.
        Avascular necrosis of bone in childhood cancer patients: a possible role of genetic susceptibility.
        Bratisl Lek Listy. 2015; 116: 289-295
        • Girard P.
        • Auquier P.
        • Barlogis V.
        • et al.
        Symptomatic osteonecrosis in childhood leukemia survivors: prevalence, risk factors and impact on quality of life in adulthood.
        Haematologica. 2013; 98: 1089-1097
        • Li X.
        • Brazauskas R.
        • Wang Z.
        • et al.
        Avascular necrosis of bone after allogeneic hematopoietic cell transplantation in children and adolescents.
        Biol Blood Marrow Transplant. 2014; 20: 587-592
        • Campbell S.
        • Sun C.L.
        • Kurian S.
        • et al.
        Predictors of avascular necrosis of bone in long-term survivors of hematopoietic cell transplantation.
        Cancer. 2009; 115: 4127-4135
        • Kunstreich M.
        • Kummer S.
        • Laws H.J.
        • et al.
        Osteonecrosis in children with acute lymphoblastic leukemia.
        Haematologica. 2016; 101: 1295-1305
        • Te Winkel M.L.
        • Pieters R.
        • Wind E.J.
        • et al.
        Management and treatment of osteonecrosis in children and adolescents with acute lymphoblastic leukemia.
        Haematologica. 2014; 99: 430-436
        • Kadan-Lottick N.S.
        • 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: 3038-3045
        • Haupt R.
        • Essiaf S.
        • Dellacasa C.
        • et al.
        The ‘Survivorship Passport’ for childhood cancer survivors.
        Eur J Cancer. 2018; 102: 69-81
        • Kremer L.C.
        • Mulder R.L.
        • Oeffinger K.C.
        • et al.
        A worldwide collaboration to harmonize guidelines for the long-term follow-up of childhood and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group.
        Pediatr Blood Cancer. 2013; 60: 543
        • Tonorezos E.S.
        • Barnea D.
        • Cohn R.J.
        • et al.
        Models of care for survivors of childhood cancer from across the globe: advancing survivorship care in the next decade.
        J Clin Oncol. 2018; 36: 2223-2230