(HRT) for children with clinically significant low BMD, and lack of data regarding the portfolio of bone‐strengthening agents used to treat adults. Adult definitions of osteopenia or osteoporosis based on T‐scores should not be used for children because T‐scores report the number of standard deviations below the BMD of an average 30‐year old. In children, Z‐scores are used for reporting BMD status because they consider age‐ and sex‐matched comparisons. However, Z‐scores per se are insufficient to define osteopenia or osteoporosis. In pediatric DXA reports; “low BMD” (instead of osteopenia) is the term used when BMD Z‐scores are ≤ ‐2.0. The International Society of Clinical Densitometry guidelines defines “osteoporosis” in children by the presence of both a clinically significant fracture history and BMD Z‐score ≤ ‐2.0 (must be adjusted for height‐age in short children to avoid BMD underestimation or tall children to avoid overestimation). A clinically significant fracture history is one or more of the following: ≥2 long bone fractures by age 10 years, or ≥3 long‐bone fractures at any age up to age 19 years. Low BMD occurs commonly in children after HCT with up to 21% having BMD Z‐scores below ‐2.0 and up to 33% below ‐1.0 before reaching adulthood, so that monitoring and potential management approaches are needed [73,74].

      BMD monitoring, vitamin D and calcium supplementation and lifestyle modifications parallels the approach taken for adults. When treating osteoporosis or low BMD, the emphasis is on growth hormone and/or gonadal HRT if clinically appropriate and supervised by a pediatric endocrinologist to avoid compromising final adult height. Growth hormone therapy after HCT does not appear to be associated with an excess of second malignancies or recurrent leukemia [75]. There is less emphasis on bone strengthening agents like bisphosphonate or calcitonin and almost no pediatric data for newer agents like denosumab, teriparatide, romosozumab, and raloxifene (reviewed elsewhere) [76] Bisphosphonate therapy is reserved for osteoporosis not responding to other measures. One retrospective study showed that pamidronate can improve BMD in children after HCT [77].

      AVN occurs in 3–10% by 5 years post‐HCT [78] and pediatric risk factors include age >5 years, TBI‐based conditioning, cGVHD, duration of steroids and female gender [79]. Femoral head is the commonest site, followed by knee, vertebral column and ankle [79]. The exact pathogenesis is poorly understood but a final common pathway is bone ischemia due to any combination of obliterative arteritis, thrombophilia, hyperlipidemia, fat embolism, repeated microinfarcts of weight‐bearing bone, and increased intramedullary pressure, possibly secondary to increased intramedullary fat (possibly glucocorticoid‐induced [80]). Plain X‐rays or MRI are appropriate next steps when AVN is suspected, based on the presence of risk factors or functional pain in the involved joints, later progressing to pain at rest when AVN severity increases. Plain X‐rays do not rule out occult radiographic lesions, making MRI the modality of choice for staging and early diagnosis. No formal staging system is applicable to all joints but a simplified staging system is used to describe joint involvement in relation to sub‐chondral collapse as: (A) “pre‐collapse”, (B) “early collapse” with depression of <2 mm, and (C) “late collapse” with >2 mm of joint depression or secondary joint changes [81–84]. Pre‐collapse lesions allow for conservative management versus advanced (post‐collapse) lesions which tend to be managed surgically and referral to orthopedics is always advised.

      Non‐surgical, pre‐collapse therapies have included: medication, hyperbaric oxygen and extracorporeal shock‐waves [82,84], but reported benefits have been mixed, with no consensus on the standard of care [85]. Bisphosphonates may reduce the incidence of collapse and early studies showed improved function for up to 10 years posttreatment but recent meta‐analyses in femoral head AVN failed to demonstrate improvement in hip dysfunction, progression‐free interval, or need for hip replacement [86]. Likewise statin [55,87] and enoxaparin [88] therapies have not been proven to change AVN outcomes [84]. Core decompression (CD) is a surgery for pre‐collapse AVN that involves removing the necrotic segment and reducing intraosseous pressure to allow healing. CD is usually more successful in younger patients with lower BMI [82] and can be combined with non‐vascularized or vascularized bone grafting to provide structural support while the necrotic lesion heals and remodels. A recent meta‐analysis of CD, or equivalent procedures, found an overall success rate to be 65%. In practice, these procedures are effective at relieving acute pain but it is unclear if natural progression of AVN is altered [83,89]. Once collapse occurs, surgical options are osteotomy [90,91], designed to rotate necrotic bone away from the weight‐bearing surface and allow for healing of the involved segment; total hip resurfacing (metal‐on‐metal cup); or total joint replacement for skeletally mature patients [84]. Advancements in artificial bearing surfaces and porous ingrowth implants has reduced concerns about implant survivorship for younger patients [82,83] Contraindications to AVN surgery after HCT include active infection and relevant medical comorbidities. Medications like high‐dose glucocorticoids or sirolimus can impede wound healing. While there is no consensus as to a safe dose of glucocorticoids, sirolimus may be held peri‐operatively or switched to another agent. Risks for impaired wound healing, fractures, and friability of connective tissues must be weighed against benefits of surgery.

      Skin

      Late effects in the skin are similar to those seen in adults and the key problems can be permanent sequelae of cGVHD or high‐dose TBI/cranial irradiation. The former may cause sclerosis ± contractures, alopecia, nail dystrophy and disfiguring skin manifestations that include poikiloderma, ichthyosis, keratosis pilaris, vitiligo or hyperpigmentation, and patches of morphea through confluent superficial and/or deep tissue sclerosis. Alopecia may be a sequela of TBI/cranial irradiation. See also “cGVHD” and “Subsequent neoplasm” sections.

      Endocrinopathies

      In children, these include disturbances of the hypothalamic‐pituitary adrenal axis, and end‐organ damage to thyroid and/or gonads mainly from alkylating agents and radiation exposures but are often multifactorial.

      Growth Hormone deficiency

Growth in children and the attainment of normal adult height is a complex process that requires balanced nutritional, genetic, endocrine, and other physical and psychosocial factors. During infancy, growth is highly dependent on nutrition and thyroid hormone. During childhood, hGH predominates and, in puberty, the synergistic interplay of hGH and sex steroids is critical for attainment of final adult height. During all stages, any prolonged disturbance of physical or psychosocial well‐being may adversely impact growth and development [93,94]. For the child with cGVHD such disturbances may include delayed hormonal and direct skeletal effects of pretransplant TBI ± cranial irradiation, chronic glucocorticoid therapy >5mg/m²/day [95,96] and phases when GVHD activity is inadequately controlled. Excessive glucocorticoid doses may cause pubertal delay by inhibiting release of gonadotropins or directly inhibiting secretion of sex steroids, but primary gonadal failure can also occur secondary to conditioning.

      The monitoring approach is to, at least annually, plot height, height‐velocity, weight annually on age/gender‐appropriate (and sometimes disease‐specific) growth charts, along with Tanner staging to assess pubertal status. Bone age is followed in growing children to assess skeletal maturity and growth potential while children progress towards final adult height. Referral to pediatric endocrinology is advised if a child is falling off their height percentile channel and/or not entering puberty at the usual time. Coordination of testosterone or estrogen therapy for pubertal delay must be carefully coordinated with hGH therapy so that premature closure of epiphyses and compromise of final adult height is avoided. Issues to note are that there is no threshold dose of glucorticoids above which response to hGH clearly and predictably declines. However, the best growth responses to hGH appear to occur when prednisone is dosed at ≤0.5 mg/kg/once daily on alternate‐days [97,98]. A reasonable approach is to wait until prednisone therapy is at every‐other‐day dosing or at least <5 mg/m²/day before hGH testing and/or replacement therapy are undertaken. HCT survivors who received TBI ± CNS radiation showed an unfavorable profile of inflammation (higher IL‐6), adipokines (higher leptin and lower adiponectin), and sarcopenic obesity (higher percent fat mass and lower