Guidance to Bone Morbidity in Children and Adolescents Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

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Guidance to Bone Morbidity in Children and Adolescents Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

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284X XMichaela XD KuhlenD285X X *, D286X XMarina KunstreichD287X X , D28X XRiitta NiinimakiD289X X , D290X XDesiree DunstheimerD291X X ,
WillaschD6297X X , D298X XPeter BaderD629X X , D30X XWolfgang Ho € glerD5301X X , D29X XAnita LawitschkaD293X4X , D294X XEdit BarditD5295X X , D296X XAndre 4 7 D302X XChristina PetersD30X X , D304X XAdriana BalduzziD305X X

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University Children's Hospital Augsburg, Swabian Children's Cancer Center, Augsburg, Germany Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Medical Faculty, Heinrich Heine University, € sseldorf, Germany Du 3 Department of Children and Adolescents, Oulu University Hospital and University of Oulu, Oulu, Finland 4 Department of Pediatrics, Medical University Vienna, St. Anna Children's Hospital, Vienna, Austria 5 Department of Pediatrics and Adolescent Medicine, Johannes Kepler University Linz, Linz, Austria 6 University Hospital Frankfurt/Main, Goethe University, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt/Main, Germany 7  degli Studi di Milano Bicocca, Ospedale San Gerardo, Monza, Italy Clinica Pediatrica Universita

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Article history: Received 10 May 2019 Accepted 8 October 2019

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Keywords: Bone morbidity Children and adolescents Allogeneic HSCT Leukemia

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A B S T R A C T Allogeneic hematopoietic stem cell XX transplantation (HSCT) is widely performed in children and adolescents with hematologic diseases, including very high-risk leukemia. With increasing success and survival rates, the longterm sequelae of HSCT have become important. Here, we provide guidance to the prevention and treatment of the most common bone morbiditiesD—osteoporosis 310X X and osteonecrosisD—emerging 31X X in the context of HSCT in children and adolescents. We give an overview on definitions, symptoms, and diagnostics and propose an algorithm for clinical practice based on discussions within the International BFM X XStem Cell TransplantationD312X XCommittee and the Pediatric Disease Working Party of the European Society for Blood and Marrow Transplantation, our expert knowledge, and a literature review. © 2019 Published by Elsevier Inc. on behalf of the American Society for Transplantation and Cellular Therapy

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INTRODUCTION Allogeneic hematopoietic stem cell transplantation (HSCT) is the standard of care in children with very high-risk acute leukemia [D1
3]. 31X X Through advances in donor selection and supportive care strategies, cure rates in patients with high-risk acute lymphoblastic leukemia (ALL) are approaching 70% in large multi-institutional trials [D4]. 314X X However, this success comes at the cost of complications and sequelae from chemotherapy and HSCT with a negative impact on quality of life (QoL). These complications are increasingly being recognized and become the focus of research in childhood leukemia survivors [D5,D 315X X 6]. 316X X Although D317X X little is known on complications specifically attributable to allogeneic HSCT in children with high-risk leukemia compared with D318X X chemotherapy alone, their overall greater number and severity are uncontroversial [D7
9]. 319X X Notably, sideD320X X effects vary between conditioning

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Financial disclosure: See Acknowledgments on page XX. *Correspondence and reprint requests: Michaela Kuhlen, University Children's Hospital Augsburg, Swabian Children's Cancer Center, Stenglinstr 2, 86156 Augsburg, Germany .X X E-mail address: [email protected] (M. Kuhlen).

regimensD321X X (e.g., depending on the use of total body irradiation [TBI] and the drugs administered). One of the most prevalent and debilitating complications from ALL therapy and HSCT is bone morbidity, including osteoporosis (OP) and osteonecrosis (ON) [D7]. 32X X Reported incidences range between 20% and 60% D32X X for reduced bone mass accrual, including OP, and 4% to 40% D324X X for ON, respectively. However, these estimates are mostly based on retrospective studies using dual-Denergy 325X X X-ray absorptiometry (DXA) for bone mineral density (BMD) assessmentD326X X and include several HSCT approaches and heterogeneous underlying diseases [D10
15]. 327X X In the setting of leukemia, clinically relevant fractures are associated with low BMD. A prospective surveillance study in children (STOPP)X X confirmed a vertebral fracture prevalence of Q5 16% at D328X X diagnosis of ALL [D16]. 329X X The proportion of children with fractures at any skeletal site over the 6
year observation period was 36%, with 71% of all incident fractures occurring in the first 2 years of chemotherapy [D17]. 30X X Other studies reported a 2D31X X to 6D32X X fold increase in the fracture rates during chemotherapy compared with healthy controls [D18-20]. 3X X Due to lack of vertebral fractures assessment (VFA) and only DXA-Dbased 34X X studies, it is difficult to determine the real extent of bone morbidity in older

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studies [D16,D 35X X 21,D 36X X 22]. 37X X Noteworthy, studies exploring bone health in children and adolescents before D38X X and following allogeneic HSCT for high-risk ALL are very sparse. In the STOPP study, only 4.8% of 186 patients with ALL underwent D39X X HSCT. Across all patients D340X X with ALL, predictors for incident fractures were cumulative corticosteroid dose and vertebral fractures at diagnosis [D17]. 341X X Hence, it remains unclear whether allogeneic HSCT adds additional risk to bone health compared with D342X X standard ALL treatment. Notwithstanding, a number of studies reporting on quantitative computed tomography measures D34X X in long-term survivors of allogeneic HSCT in childhood demonstrated significant deficits, including growth, spine and tibia trabecular volumetric BMD, cortical dimensions, and muscle cross-sectional area at a median of 5 years after HSCT [D12,D 34X X 23]. 345X X Timely recognition of bone disease is crucial for initiation of treatment and for prevention of fractures, pain, loss of mobility, and deformity andD346X X thusD347X Xreducing long-term morbidity and adverse consequences on QoL. Therefore, assessment of bone health is indicated at diagnosis of leukemia and regularly after allogeneic HSCT. Here, we present guidance to the most important bone morbidities—Dreduced 348X X bone mass accrualD/D349X X OPD 350 X 351X X and OND D352X X 35X X in children and adolescents undergoing allogeneic HSCT—Dand 354X X recommendations for clinical practice. For patients affected by sickle cell disease, specific guidelines should be consideredD35X X D356XbecauseD X ,357X X compared with D358X X other HSCT patientsD,359X X further mechanisms add to their bone disease [D24
26]. 360X X

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METHODS D361X X improve the outcome of allogeneic HSCT in children and adolescents, To the International BFMX X Stem Cell Transplantation (I-BFM SCT) Committee and the Pediatric Disease Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) address and discuss various topics associated with allogeneic HSCT in working groups aiming at providing guidance for care. As bone D362X X morbidityD36X iX s a complex topic requiring particular consideration, a pediatric bone specialist and member of the European Society for Pediatric Endocrinology working D364X X group on bone and growth plate was involved in this process to approach this topic as an interdisciplinary team. To search for evidence in the field of acute leukemia/HSCT and low BMD/ OP/ON, a PubMed-based literature search was conducted using the MeSH terms children/adolescents, acute leukemia (ALL, AML, leukemia), HSCT, low D365X X BMD, reduced bone mass accrual, osteoporosis, vertebral fractures, and osteonecrosisD.36X X The titles and abstracts of identified articles were checked against the cohort and conditions reported (only those studies that D367X X primarily reported on children and adolescents, leukemia, and allogeneic HSCT were kept). Preference was given to articles written in English. One author (MK) prepared an evidence-based summary of the literature relating to the topics of bone mass deficits and ON D368X X and circulated it among all authors. The best available evidence was used to develop recommendations. Recommendations and evidence are described as follows: level D369X X of evidence (LoE) 1D,370X X evidence D371X X from at least 1 D372X X randomized trialD;37X X level D374X X D375X X ,376X X evidence 2D D37X X from cohort studies, case-Dcontrol 378X X studies, and time seriesD;379X X and level D380X X D381X X ,382X X opinions 3D D38X X of respected authoritiesD384X b X ased on clinical experience, descriptive studies, or reports of expert committees), and provide our practice whenever no evidence is available.X X Authors presented the revised summaries to the group for discussion at 3 D385X X consecutive rounds. All authors approved the recommendations of this guidance. This guidance includes the cumulative evidence up to the end of 2018. As OP and ON are 2 D386X X completely different conditions with regard to the underlying pathophysiology, risk factors, diagnostic steps, and treatment, we subsequently summarize our guidance in 2 D387X X paragraphs. The paragraphs are consistently structured in a brief overview on definitions, symptoms, diagnostics, and a summary of published evidence, including incidence and risk factors (supplemented by an overview of studies) followed by our suggestion for clinical practice (including a diagnostic workflow). In addition, references on treatment recommendations are givenD38X w X henever available.

RECOMMENDATIONS X X Low Bone Mass Accrual and Osteoporosis Definition According to the International Society for Clinical Densitometry (ISCD), low BMD is defined as a low bone mineral content or areal BMD ZD389X XscoreX Xthat is less than or equal to
2.0, D390X X adjusted for

age, sex, D391X X and body size, as appropriate. The diagnosis of OP requires at least 1 D392X X vertebral compression fracture or a combination of low BMD and a clinically significant fracture history. The latter is defined as at least 2 D39X X long-Dbone 394X X fractures before the age of 10 yearsD395X X or 3 D396X X or more long-bone fractures before the age of 19 years, in the absence of high-energy trauma [D27]. 397X X

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Symptoms Vertebral fractures often remain asymptomatic andD398X X thusD39X X will be missed and OP not diagnosed unless imaging is performed. However, back pain is a well-known sign of vertebral fractures.

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Diagnostics Bone mass is measured using a DXAD D40X X 401X X scan of the lumbar spine (L1D402X X to L4) and/or whole body and expressed relative to age- and body size-matched (ZD403X X score) norms [D28]. 40X X Low bone mass is defined as a BMD ZD405X Xscore at or below
2.0. D406X X For children under the age of 5 years, DXA reference values are lacking as children have to lie 407XD X still during measurement. Because D408X X BMD is underestimated in children with short stature and chronically D409X X ill children are frequently short, adjustments for height and bone volume are necessary. Typical adjustments used are the calculation of lumbar spine bone mineral apparent density (Din 410X X g/cm3) or BMD adjustments for height Z score D41X X at the lumbar spine and removing the head from the total body scan (total body less head BMD) [D27, 412X X 29]. Suspected (extremity) fractures should be confirmed using conventional X-ray. D413X X Particular attention is needed for D41X X vertebral compression fractures. These are usually not recognized clinically at the time of their occurrence. However, their detection confirms the presence of OP and poses a substantial risk for subsequent fractures independent of BMD [D30] 415X X Noteworthy, a BMD ZD416X X score D417X X >
2.0 does not preclude the possibility of skeletal fragility and increased fracture risk. Thus, screening for vertebral fractures using VFAD D418X X 419X X by DXA, lateral spine X-rays, D420X X or magnetic resonance imaging (MRI) at regular intervals is necessary [D30,D 421X X 31]. 42X X

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Summary of Published Evidence It was long believed that adolescents who fail to appropriately accrue bone mass and/or lose part of it as after HSCT are at risk for lifeDlong 423X X osteopenia, early onset OP, and fractures [D5,D 42X X 425 X X 12,D 7,D 426X X 14,D 427X X 18,D 428X X 32,D 429X X 33]. 430X X However, this D431Xpeak X bone massD432X X concept has been heavily disputed [D34]. 43X X Moreover, a number of studies demonstratedD43X X that children with ALL have the potential to recover from the leukemia- and treatment-related skeletal morbiditiesD435X o X nce the skeleton regains its adaptive biomechanical competence [D23,D 436X X 35,D 437X X 36]. 438X X The development of bone mass deficits in children and adolescents with leukemia undergoing allogeneic HSCT is multifactorial in origin, including the underlying (malignant) disease, osteotoxic chemoDtherapy 439X X and particularly glucocorticoid therapy, prolonged reduced physical activity and poor muscle mass, poor nutrition, TBI, D40X X immunosuppressive therapies, and cytokine activation such as graft versus host disease (DGVHD) 41X X [D37
40]. 42X X In addition, cranial and spinal radiation, untreated hypogonadism, growth hormone deficiency, vitamin D deficiency, and hypophosphatemia are risk factors for incomplete bone mass accrual and accelerated bone resorption [D35,D 43X X 41]. 4X X D45X X Furthermore, various studies demonstrated that myeloablative treatment regimens directly damage osteoprogenitor D46X X cells, thereby negatively affecting the receptor activator of nuclear factor kB ligandD-osteoprogenitor 47X X D48X X system and bone formation [D42,D 49X X 43]. 450X X D451X X GVHD and dysregulation of the immune system activate osteoclasts and reduce the number and function of osteoblasts [D23,D 452X X 44]. 453X X

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The STOPP prospective trial has demonstrated that vertebral fractures are most frequent and severe in the first 2 years of ALL therapy [D16]. 45X X In survivors of childhood HSCT, who are at potentially greater risk for inadequate bone accrual and metabolismD45X X because they have D456X X had more osteotoxic therapy, the incidence of clinically asymptomatic and symptomatic fractures still needs to be studied [D22,D 457X X 45,D 458X X 46]. 459X X An overview on studies reporting on BMD deficits and fractures in children, adolescents, and young adults following HSCT is given in Table 1. Q10 Table 2 X X

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radiographs or MRI should be conducted to check for vertebral fracturesD504X (X LoE 2) [17].

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A diagnostic workflow for low BMD and fractures is depicted in figure 1.

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Suggestions for Clinical Practice (Treatment)D50X X Principally, assessment of treatment indication and OP treatment should be performed in consultation with the pediatric endocrinologist or metabolic bone specialist.

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Suggestions for Clinical Practice (Prevention)D460X X To date, there is no evidence that shows a benefit for the prevention of fractures or bone mass deficits in ALLD461X X or in the context of HSCT. The first biochemical signD462X X of osteomalacia is an increasing parathyroid hormoneD463X X and indicates low dietary calcium, low vitamin D status, or malabsorption [D47]. 46X X Osteoporosis, in contrast to osteomalacia and rickets, cannot be prevented by giving vitamin D. We therefore only provide general recommendations: ! Measurement of calcium, phosphorus, alkaline phosphatase (ALP), parathyroid hormoneD,465X X and 25-hydroxy vitamin D (25 (OH)D) on a regular basis (e.g., every 6 D46X X months during the first year, afterwardD467X X yearly; adapted in patients with chronic GVHD D468X X D469X X (LoE 2) [17,D35,D 470X X 48]. 471X X ! Adequate calcium and vitamin D intake are important for preventing osteomalacia and rickets but will not prevent or treat OP D472X X [D49]. 473X X The minimum intakes known to prevent rickets are D500 47X X mg/dD475X Xof calcium and 10 mg (400 IU)/dD476X Xof vitamin D; higher vitamin D intakes (12.5D47X X to 25 mg or 500D478X X to 1D000 479X X IU) have been recommended for children and adolescents atD480X Xrisk of vitamin D deficiency due to factors and conditions that reduce synthesis or intake (De.g., 481X X restricted exposure to sun, high latitude during winter/spring season, and low dietary calcium intake). Target 25(OH)D levels should be above 50 nmol/L. There is no benefit in higher 25(OH)D levels from vitamin D supplementationD482X X (LoE 1) [50,D51]. 483X X The regular use of dairy products and vitamin D supplements should be taken into account especially in countries in which this is common practice (De.g., 48X X in Scandinavia) [D52,D 485X X 53]. 486X X ! Linear growth should be evaluated before D487X X and on a regular basis after HSCTD48X (X LoE 2) [12,D17,D 489X X 18,D 490X X 54-56]. 491X X ! Pubertal delay due to hypogonadism and other endocrinopathies need to be assessed on a regular basis and if necessary pediatric endocrinologists consultedD492X (X LoE 2) [35,D42,D 493X X 48,D 49X X 57
63]. 495X X ! Muscle force enhances bone accrual. Thus, promoting physical activity and exercise during and after HSCT is of particular importance, within the limits of illnessD496X X (LoE 2) [62]. Regular age-adapted work programs should be established. ! Yearly screening by DXA scan of the lumbar spine (L1D497X Xto L4) and whole body should be performed before D498X X and 12 months after HSCTD49X X(LoE 2) [17,D64]. 50X X In the D501X X presence of vertebral fractures, age, and taking into consideration growth potential and future health, the endocrine team should be consulted for consideration of bisphosphonate (BP) therapy. ! Yearly screening for vertebral fractures using either DXA VFA or lateral spine X-rays should be performed and assessed by a pediatric radiologist using the Genant scoreD502X X (LoE 2) [17,D65]. 503X X For stable patients without new risk factors and no vertebral fractures, spine X-ray screening for vertebral fractures can be stopped 2 years after HSCT. ! In patients with back pain at any time, lateral spine

! Basically, diagnosis and treatment of OP in children and adolescents should follow the ISCD guidance of pediatric OPD506X X (LoE 2) [27]. Therein, BP treatment is reserved for older patients with overt bone fragility and low potential for BMD restitution and vertebral body reshaping. ! In case of significant functional impairment limiting QoL, age becomes less important and treatment may be initiatedD507X X (LoE 2) [27]. ! However, the ISCD guidance only provides recommendations for children with standard ALL. As in children and adolescents with ALL undergoing HSCT, more complications and poor outcome are probably more likelyD.508X X BP therapy may be used in younger patients with serious complications, bone pain, and therefore less potential for recovery, as long as ISCD criteria of OP are fulfilledD509X (X LoE 3) [17,D23,D 510X X 60]. 51X X

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References on Prevention and Treatment Recommendations By mineral ion supplementation according to the general consensus, osteomalacia and rickets can be prevented [D49]. 512X X In marked contrast to that, low BMD and OP cannot be prevented by dietary or supplemental calcium and vitamin D therapy. Only few studies have assessed the efficacy of BPs in increasing BMD and reducing pain due to vertebral fractures in children with ALL [D66,D 513X X 67]. 514X X To date, there is no evidence supporting the routine use of bone-targeted therapy such as BPs in the absence of fractures in children with ALL undergoing HSCT and low BMD. Hence, attention is needed for D51X X secondary prevention in children with less potential to recover spontaneously from low BMD and/or fractures and therefore increased risk of disease progression and disability [D48]. 516X X In children and adolescents, the potential to recover from bone fragility depends on the severity of bone morbidity, the remaining growth potential, and the persistence of risk factors. Consequently, children with limited or no potential of recovery including children of older age with restricted linear growth potential qualify for bone-targeted therapy. Furthermore, younger children with potential for spontaneous recovery may warrant BP treatment if OP due to pain and functional limitation significantly impacts their QoL [D27,D 517X X 48]. 518X X The treatment of leukemia- and HSCT-related osteoporotic fractures should follow these general principles of bone-targeted treatment of OP in children. For the future, alternative agents may become further treatment options. For example, the receptor activator of nuclear factor kB ligand inhibitor D519X X denosumab operates by inhibiting bone resorption and, to a lesser degree, bone formationD520X X and is commonly used in postmenopausal women [D68]. 521X X Efficacy and particularly safety in children need prospective studies. Under development but far from routine use are other promising therapies that D52X X target bone formation pathways (anti-transforming growth factor bD523X Xantibody and antiDsclerostin 524X X antibody) [D69
71]. 52X X

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Table 1 Overview of Studies on Bone Mass Deficits and Fractures in Children and Adolescents after HSCT D25X X Study Design

Study D26XPopuD X 27X X lation

HSCT

Disease

Age at HSCT, D28XyDX r29X X

Ward et al. [8]

2018

D34XProspective, X multicenter cohort study

186 patients D35X X

D36XIncluded X 4.8% recipients of allogeneic HSCT

ALL

Bechard et al. [1]

2015

D45XProspective, X multicenter cohort study

26 patients D46X X

allogeneic (12 D47Xpatients X sibling related)

Mostoufi-Moab et al. [4]

2012

D61X X Cross-sectional

55 patients D62X X HSCT recipientsD/63X X 985 healthy controls

Petryk et al. [6]

2006

D81X X Longitudinal

Petryk et al. [7]

2014

D103X X Cross-sectional

Incidence of OP D30X X y D31X X

Follow-Dup, 32X X yrD3X X

Methods

D37X X NA

6 yr D38X X

D39XSpine X radiographs, spine BMDD D40X X 41X X

7 patients D48X X ALL 7 patients D49X X AML 3 patients D50X X MDS 3 patients D51X X CML 2 patients D52X X lymphoma 4 patients D53X X nonD54Xmalignant X

14D.9 5X X (SD 4D.2) 56X X

100 days

D57XWholeX body DXA

D58X X .94
0D 59X X (0D.24) 60X X

Vitamin D deficiency

D64X X Allogeneic

Leukemia Bone marrow failure syndrome

5-26

>3 yDears 65X X after HSCT

D6X X Tibia pQCT

D67XLower X height Z scoreDs68X X (D
1.21 69X X § 1.25; P D70X X < D71X.001), X lower trabecular vBMD (D
1.05; 72X X D73X X < P D74X.001), X muscle (D
1.01; 75X X 76XD X < P D7X.001) X Z scoreDs78X X and greater fat (0.82; P D79X X < .001) D80X X

TBI growth hormone deficiency

49 patients D82X X

47 patients D83X X allogeneic 2 patients D84X X autologous

12 patients D85X X Fanconi anemia 10 patients D86X X ALL 8 patients D87X X AML 6 patients D8X X adrenoleukodystrophy 3 patients D89X X AA 3 patients D90X X CML 3 patients D91X X metachromatic leukodystrophy 4 patients D92X X others

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At 1 yr: 19% patients D93X X D94X X OP 33.3% patients D95X X osteopenia

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DXA of lumbar spine BMD, areal D96X X LBMDA L2L4

D97X X 0.84
D 98X X (D
1.29 9X X to D10X
0.39) X

D10XOsteocalcin X possible biomarker for vulnerable patients D102X X

151 HSCT recipientsD/92 104X X healthy siblings

116 D105Xpatients X allogeneic 35 patients D106X X autologous

56 patients D107X X lymphoid malignancy 78 patients D108X X myeloid malignancy

24D.7 109X X § 8D.6 10X X

26 patients D1X X (TBMD Z scoreD)12X X 33 patients D13X X (LBMD Z scoreD)14X X D
1 15X X = osteopenia (17%-22%)

12D.2D 16X X
15D 17X X 18X X .0

DXA of lumbar spine BMD, areal D19X X LBMDA L2L4 and TBMD

0D.5 120X X lower than controls

D12XYoung X age
Z Score

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D42XAcross X all D43Xpatients: X cumulative corticosteroid dose D4XVertebral X fractures at diagnosis

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Risk Factors and Other Important Findings

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Table 1 (Continued)

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Reference*

Year

Study Design

Study D26XPopuD X 27X X lation

HSCT

Disease

Age at HSCT, yD D28X X r29X X

Incidence of OP D30X X y D31X X

Follow-Dup, 32X X yrD3X X

Methods

Z Score

Perkins et al. [5]

2007

D124X X Cross-sectional

17 patients D125X X

13 patients D126X X allogeneic 4 patients D127X X autologous

14 patients D128X X AML 3 patients D129X X ALL

1D.67 130X X (0D.58-2D 13X X 132X X .97)

1 patient D13X X D134X X OP 3 patients D135X X osteopenia

11D.55 136X X (3D.25137X X 22D.33) 138X X

DXA of lumbar spine BMD, areal D139X X LBMDA L2L4

D140X X
0.34 § 1.09 (D
2.4 14X X to +0.7)

Campos et al. [2]

2014

D142XRetrospective X case-Dcontrol 143X X study

50 patients/D 14XD X 145X X 25 controls

25 patients D146X X related allogeneic 25 patients D147X X unrelated allogeneic

5 patients D148X X ALL 3 patients D149X X AML 3 patients D150X X MDS 2 patients D15X X CML 17 patients D152X X Fanconi anemia 5 patients D153X X adrenoleukodystrophy 10 patients D154X X severe aplastic anemia 3 patients D15X X CML 5 patients D156X X Wiskott-Aldrich syndrome

10D.4 157X X §D158X 4 X .6 D159X X

6 moD160X X

D16XWholeX body and lumbar spine DXA

D162X
1D X .12 163X X (D
3D 164X X .73 165X X to + 1D.12) 16X X (TBD167X B X MD (g/ cm2) 0D.750 168X X §D169X 0 X .D167 170X X LS BMD 0D.664 17X X §D172X 0 X .176) D173X X

D174XGVHD X D175XCorticosteroid X treatment duration 25(OH)D level D176XFamily X history of OP D17X X

Kaste et al. [3]

2004

D178X X Retrospective

48 patients D179X X

D180X X Allogeneic

10 patients D18X X ALL 10 patients D182X X AML 9 patients D183X X MDS 9 patients D184X X CML 1 patient D185X X other leukemia 7 patients D186X X nonDmalignant 187X X

10D.3 18X X (1D.6-20D 189X X 190X X .4)

5D.1 194X X (1D.0-10D 195X X 196X X .2)

QCT/ MRI

QCT ZDscore 197X X D198X
0D X .88 19X X (D
3D 20X X .3 201X X to +2D.33) 20X X

D203XDecreased X BMD risk factor for ON

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21% patients D19X X D192X X OP 26% patients D193X X osteopenia

NA indicates XXX; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; CML, chronic myeloid leukemia; pQCT, peripheral quantitative computed tomography; vBMD, XXX; AA, XXX; LBMDA, areal lumbar BMD; TBMD, tibia BMD; LBMD, lumbar BMD; TB, XXX; LS, XXX; QCT, quantitative computed tomography. X X * References 1. Bechard LJ, Gordon C, Feldman HA, et al. Bone loss and vitamin D deficiency in children undergoing hematopoietic cell transplantation. Pediatr Blood Cancer. 2015;62:687-692. 2. Campos DJ, Boguszewski CL, Funke VA, et al. Bone mineral density, vitamin D, and nutritional status of children submitted to hematopoietic stem cell transplantation. Nutrition. 2014;30:654-659. 3. Kaste SC, Shidler TJ, Tong X, et al. Bone mineral density and osteonecrosis in survivors of childhood allogeneic bone marrow transplantation. Bone Marrow Transplant. 2004;33:435-441. 4. Mostoufi-Moab S, Ginsberg JP, Bunin N, et al. Bone density and structure in long-term survivors of pediatric allogeneic hematopoietic stem cell transplantation. J Bone Min Res. 2012;27:760-769. 5. Perkins JL, Kunin-Batson AS, Youngren NM, et al. Long-term follow-up of children who underwent hematopoeitic cell transplant (HCT) for AML or ALL at less than 3 years of age. Pediatr Blood Cancer. 2007;49:958-963. 6. Petryk A, Bergemann TL, Polga KM, et al. Prospective study of changes in bone mineral density and turnover in children after hematopoietic cell transplantation. J Clin Endocrinol Metab. 2006;91:899-905. 7. Petryk A, Polgreen LE, Zhang L, et al. Bone mineral deficits in recipients of hematopoietic cell transplantation: the impact of young age at transplant. Bone Marrow Transplant. 2014;49:258-263. 8. Ward LM, Ma J, Lang B, et al. Bone morbidity and recovery in children with acute lymphoblastic leukemia: results of a six-year prospective cohort study. J Bone Min Res. 2018;33:1435-1443. y Osteoporosis (Z score less than
2); osteopenia (Z scores between
1 and
2).

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Table 2 Overview of Studies D204X X on Osteonecrosis in Children and Adolescents after HSCT D205X X

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Study Design D206X X

HSCT

Disease

Study Population D207X X

Age

Incidence

Risk Factors D208X X

2007

Prospective

Allogeneic

84 patients D209X X myeloid malignancy 40 patients D210X X lymphoid malignancy 31 patients D21X X nonDmalignant 21X X

155 patients D213X X

D214X X Median 9.7 yr D215X X (0.5-21.4)

20 of 155 patients D216X X (13%)

 Female D217X X sex  Age D218X X >8 yr D219X X at HSCT

Faraci et al. [1]

2006

D20XRetrospective X case-Dcontrol 21X X study

D2X X Allogeneic

22 patients D23X X ALL 8 patients D24X X AML 2 patients D25X X CML 5 patients D26X X NHL 6 patients D27X X nonDmalignant 28X X

43 patients D29X X (ON, allogeneic HSCT) matched to 129 controls

D230X X Mean age 13.1 yr D231X X

Sharma et al. [5]

2012

D23XRetrospective X MRI control study

D234X X Allogeneic

116 patients D235X X malignant (ALL, NHL, D236X X and Hodgkin disease) 33 patients D237X X nonmalignant

149 patients D238X X

11 yr D239X X (0.5-21 yr) D240X X

44 (ON) D241X X of 149 patients D24X X (29.5%)

 Age D10 243X X yr D24X X at HSCT (DP 245X X = .051) D246X X  Preallogeneic D247X X HSCT MRI positive D248X X (DP 249X X = .001) D250X X

Kuhlen et al. [3]

2018

Retrospective

Allogeneic

ALL

557 patients D251X X

10.3 yr D25X X (0.5-26 yr) D253X X

Cumulative incidence of sON at 5 yr D254X X 9% (SD 1%)

 Age D25X X at HSCT (>D10 256X X yr) D257X X  Diagnosis D258X X of sON D259Xbefore X HSCT  cDGVHD 260X X

Girard et al. [2]

2013

D261X X Retrospective

191 patients D26X X allogeneicD263X X 65 patients D264X X autologous

177 patients D265X X ALL 79 patients D26X X AML

256 HSCT

8.65 (§ 0.30) D267X X

17 patients D268X X (ON) of 256 HSCT (CI 1.04- 7.09)

 Older D269X X age at HSCT (>D10 270X X yr) D271X X  Higher D27X X total steroid dose post-transplant 2 (>2D055mg/m 273X X ) (cGVHD)

Kaste et al.

2004

Retrospective

Allogeneic

10 patients D274X X ALL 10 patients D275X X AML 9 patients D276X X MDS 9 patients D27X X CML 1 patient D278X X other leukemia 7 patients D279X X nonDmalignant 280X X

48 patients D281X X

D28X X Median 10.3 (1.6-20.4)

19 of 43 patients D283X X (44%)

Female sex

474 475 476 477 478 479 480 481 482 483 484 485 486 487 488

Multivariate logistic regression analysis  cGVHD (OR 1.7-9.7)  TBI (OR 2.9-20.0)  Older age D23X X (OR 1.44)

489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511

NHL indicates non-Hodgkin lymphoma; cGVHD, chronic GVHD; OR, odds ratio; sON, symptomatic) osteonecrosis; CI, cumulative incidence. * References 1. Faraci M, Calevo MG, Lanino E et al. (2006) Osteonecrosis after allogeneic stem cell transplantation in childhood. A case-control study in Italy. Haematologica 91:1096-1099 2. Girard P, Auquier P, Barlogis V et al. (2013) Symptomatic osteonecrosis in childhood leukemia survivors: prevalence, risk factors and impact on quality of life in adulthood. Haematologica 98:1089-1097 3. Kuhlen M, Bader P, Sauer M et al. (2018) Low incidence of symptomatic osteonecrosis after allogeneic HSCT in children with high-risk or relapsed ALL - results of the ALL-SCT 2003 trial. British journal of haematology 183:104-109 4. Leung W, Ahn H, Rose SR et al. (2007) A prospective cohort study of late sequelae of pediatric allogeneic hematopoietic stem cell transplantation. Medicine (Baltimore) 86:215-224 5. Sharma S, Leung WH, Deqing P et al. (2012) Osteonecrosis in children after allogeneic hematopoietic cell transplantation: study of prevalence, risk factors and longitudinal changes using MR imaging. Bone marrow transplantation 47:1067-1074

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610 Figure 1. Workflow for prevention of osteomalacia and rickets and assessment of bone mass deficits and OP D1X X in children and adolescents undergoing hematopoietic stem cell transplantation. ALP, alkaline D2X X phosphataseD;3X X Ca, D4X X calciumD;5X X IGF-1, D6X X D7X X insulin-like growth factor 1D;8X X PTH, parathyroid D9X X hormoneD.10X X *Minimum intakes of vitamin D and dietary calcium are given.

Osteonecrosis (ON) Definition OND—also 526X X known as avascular necrosisD—is 527X X defined as the death of a bone segment due to an imbalance between the actual and required blood flow due to various reasons [D72]. 528X X

555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572

Symptoms The clinical picture of ON is multifaceted and usually depends on ON stage and location. Most commonly, ON occurs in the midshaft of long bones and remains asymptomatic and completely harmless. However, in ON affecting the major joints, this is frequently associated with pain. At first, the pain is mostly stressD529X X induced, caused by the pressure on the affected bone, typically on the lower limbs. Subsequently, it becomes more constant and appears also at rest. In case of further disease progression, including joint collapse, the joint surface loses its smooth shape, and severe pain interferes with daily life. Other symptoms include restrictions in activities of daily living such as climbing stairs and putting on shoes as well as gait abnormalities, whereas D530X X D531X X joint swelling, mobility restrictions, and stiffening and taking a relieving posture are generally symptoms of a far-Dprogressed 532X X joint disease. The time between first symptoms and collapse of the bone may vary from several months to more than a year.

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Diagnostics D53X X MRID 534X X is the only appropriate imaging to show osteonecrotic lesions and allowing their grading. Standard X-ray images may

look normal in early stages and become significant in advanced stages only.

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Summary of Published Evidence Risk factors for the development of ON include older age at HSCT, steroid treatment, cDGVHD, 53X X and ON before D536X X HSCT. Other factors such as sex, D537X X obesity, TBI, D538X X and other immunosuppressants have only inconsistently been reported to increase the incidence of ON [D11,D 539X X 13,D 540X X 73
75]. 541X X In addition, children already presenting with grade 1 ON at MRI screening within 6D542X X to 8 months of ALL therapy are at increased risk of developing symptomatic ON grades 2 to 4 [D76]. 543X X In an MRI-based single-Dcenter 54X X study, the prevalence of ON in children following HSCT is reported to be approximately 30% [D15]. 54X X In contrast, the cumulative incidence of symptomatic ON following HSCT in children and adolescents is reported to be 4% to 9% D546X X [D10,D 547X X 11,D 548X X 75]. 549X X Most cases of ON are diagnosed within D50X2X years following HSCT with hips and knees being most frequently affected [75], with lesion size being the best predictor of clinical outcome in hip ON [D77]. 51X X In the majority of symptomatic patients, the clinical course is multiDarticular 52X X and bilateral. Empirically, most commonly, ON in the hips and shoulders is D53X X diagnosed in D54X X an advanced stage and it is hard to impede further disease progression, whereas ON in the knees may improve over time. Typically, diaphyseal lesions evolve favorably, are not associated with fractures, and do not need MRI follow-up [D78]. 5X X

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An overview of studies reporting on ON in children, adolesQ13 cents, and young adults following HSCT is given in Table D56X X 3 .X X

644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668

Suggestions for Clinical PracticeD57X X ! Before D58X X and at each follow-up evaluation following HSCT, patients should be asked for pain. In addition, age-appropriate pain self-assessment scores, assessment of self-care D59X X activities of daily living, and monitoring of the gait pattern should be included in routine clinical evaluationD560X (X LoE 3). ! MRI screening of asymptomatic patients to identify (asymptomatic) ON before D561X X and/or following allogeneic HSCT should only be performed within studies, as no evidencebased interventions are available yetD562X (X LoE 3) [79]. ! In case of a pre-existing ON diagnosis before HSCT, the use of steroids might be limited and alternative immunosuppressants might be chosen for subsequent lines of treatment in multiple resistant GVHD. D563X X However, there are no studies supporting this recommendation, andD564X X hence, focus should be laid on best possible GVHD D56X X treatmentD56X (X LoE 3). ! Physicians in charge should be aware of ON as a frequent and debilitating complication, in order to accelerate the diagnostic process at the onset of the first symptoms. This becomes even more importantD567X X when patients are referred back to the referring centers and are not managed within the tertiary transplant centersD568X (X LoE 3).

! In symptomatic patients, ON should be investigated by MRID569X X (LoE 3) [79]. As ON in weight-bearing joints most commonly occurs in multiple locations, we would recommend to do lower limb MRI including hips, knees, and anklesD570X X(LoE 2) [80]. ! As evidence is lacking, the use of crutches is controversially discussed. In other ON conditions such as Perthes disease, reduced weight bearing is a regular part of care aiming at reducing pain and mechanic destruction. In case crutches are used, upper limb MRI including shoulders should be considered to exclude extended yet still asymptomatic OND571X X (LoE 3). ! In patients presenting with persisting symptoms suggestive of ON but without corresponding findings in a first MRI, other reasons for pain should be sought and MRI should be repeated after 3 monthsD572X (X LoE 3). ! For reasons of comparability, ON should be classified according to the radiologicD573X X classification system developed by Niinim€aki X X et al. [81] (LoE 2),D574X X which allows scorD D57X X 576X X ing all Q14 joints and districts. In addition, there are joint specific classification systems (Steinberg, Ficat, and ARCO )X X for grading Q15 ON of the hips. In addition, the Delphi consensus on ON by the Ponte Di Legno toxicity working group can be used for clinical classificationD57X (X LoE 3) [79]. A diagnostic workflow for ON is depicted in Figure 2.

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Figure 2. Diagnostic workflow for children and adolescents undergoing HSCTD D1X X 12X Xand/or being suspected D13X X of having ON D14X X following HSCT. ADL, D15Xactivities X of daily livingD;16X X D17X X TIRM, D18X X turbo inversion recovery magnitudeD;19X X T1, D20X X T1-weighted MRI scansD21X. X *Some preliminary data suggest that interventions including core decompression plus mesenchymal stem cells may provide improved outcome if patients are treated at an earlyD/D2X X precollapse 23 X stage. These data still need to be confirmed in children and adolescents with acute lymphoblastic leukemiaD24X (X reviewed in Kuhlen et al. [90]).

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References on Treatment Recommendations Management of ON in children and adolescents with ALL following HSCT is challenging, and evidence-based guidelines or consensus on management of these children are D578X X still lacking. Effective pain management is crucial. Beyond that, treatment should be decided on an individual basis, in close collaboration with orthopedic surgeons and the pain team. If possible, affected patients should be enrolled in prospective clinical trials evaluating treatment options. Previous studies in children and adolescents with ALL exploring pharmacologicD579X X interventions for ON including BPs and prostacyclin analogues lack sufficient quality evidence, as previously reviewed [D82D 580X X ]581X X studies in children with ON after allogeneic HSCT are completely missing. New therapies targeting pathways in bone metabolism such as antiDsclerostin 582X X antibody may deserve prospective clinical trials in children after allogeneic HSCT. In general, surgical management is based on patient factors and lesion characteristics. In late-Dstage 583X X ON with joint infarction, surgical interventions comprise arthroplasty and surface replacement. In precollapse lesions, joint-preserving procedures including core decompression may D584X X be attempted. In non-cancer-Drelated 58X X ON, data indicate that core decompressionD586X X combined with cellular therapies (autologous or allogeneic bone marrow cells, mesenchymal stem cells, human bone morphogenetic protein), vascularized bone grafts, avascular grafts, combinations of the aforementioned, or rotational osteotomies is beneficial [D83
89]. 587X X Therapeutic approaches in children and adolescents with ALL have been previously reviewed [D82,D 58X X 90,D 589X X 91]. 590X X

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SUMMARIZING REMARKS AND OUTLOOK Children and adolescents undergoing allogeneic HSCT are at increased risk of OP and ON. Bone health monitoring is therefore an important component of the care plan for these patients. The combination of international efforts and prospective intervention studies incorporating standardized diagnostic strategies and novel therapeutic treatment options will be necessary to determine the true scale of bone morbidity in those patients. Both the I-BFM SCT and the PDWP of EBMT provide a strong basis to establish prospective studies on bone morbidity in children and adolescents undergoing allogeneic HSCT. ACKNOWLEDGMENTS The authors thank all members of the I-BFM SCT Committee and the PDWP of the EBMT for their critical discussion of the topic within the framework meetings. Financial disclosure: M. Kuhlen is supported by the German Childhood Cancer Foundation (DKS 2011.11). Conflict of interest statement: There are no conflicts of interest to report. Authorship statement: M. Kuhlen screened the literature, collected data, and wrote the manuscript. M. Kunstreich screened the literature, collected the data, compiled the tables, and drafted the figures. RN, DD, AL, EB, AW, PB, and CP critically revised the manuscript for important intellectual content. WH and AB screened the literature and critically revised the manuscript for important intellectual content. All authors approved the final version of the manuscript.

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