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Childhood, adolescent, and young adult cancer survivors are at increased risk of reduced bone mineral density. Clinical practice surveillance guidelines are important for timely diagnosis and treatment of these survivors, which could improve bone mineral density parameters and prevent fragility fractures. Discordances across current late effects guidelines necessitated international harmonisation of recommendations for bone mineral density surveillance. The International Late Effects of Childhood Cancer Guideline Harmonization Group therefore established a panel of 36 experts from ten countries, representing a range of relevant medical specialties. The evidence of risk factors for very low and low bone mineral density and fractures, surveillance modality, timing of bone mineral density surveillance, and treatment of very low and low bone mineral density were evaluated and critically appraised, and harmonised recommendations for childhood, adolescent, and young adult cancer survivors were formulated. We graded the recommendations based on the quality of evidence and balance between potential benefits and harms. Bone mineral density surveillance is recommended for survivors treated with cranial or craniospinal radiotherapy and is reasonable for survivors treated with total body irradiation. Due to insufficient evidence, no recommendation can be formulated for or against bone mineral density surveillance for survivors treated with corticosteroids. This surveillance decision should be made by the survivor and health-care provider together, after careful consideration of the potential harms and benefits and additional risk factors. We recommend to carry out bone mineral density surveillance using dual-energy x-ray absorptiometry at entry into long-term follow-up, and if normal (Z-score > -1), repeat when the survivor is aged 25 years. Between these measurements and thereafter, surveillance should be done as clinically indicated. These recommendations facilitate evidence-based care for childhood, adolescent, and young adult cancer survivors internationally., Competing Interests: Declaration of interests LMW received grants and personal fees from Novartis and Amgen (with funds to the Children's Hospital of Eastern Ontario Research Institute). KKN received grants from the National Institutes of Health and the American Lebanese Syrian Associated Charities. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Osteonecrosis and decline of bone density are serious side effects during and after treatment of childhood acute lymphoblastic leukemia. It is unknown whether osteonecrosis and low bone density occur together in the same patients, or whether these two osteogenic side-effects can mutually influence each other's development. Bone density and the incidence of symptomatic osteonecrosis were prospectively assessed in a national cohort of 466 patients with acute lymphoblastic leukemia (4-18 years of age) who were treated according to the dexamethasone-based Dutch Child Oncology Group-ALL9 protocol. Bone mineral density of the lumbar spine (BMDLS) (n=466) and of the total body (BMDTB) (n=106) was measured by dual X-ray absorptiometry. Bone density was expressed as age- and gender-matched standard deviation scores. Thirty patients (6.4%) suffered from symptomatic osteonecrosis. At baseline, BMDLS and BMDTB did not differ between patients who did or did not develop osteonecrosis. At cessation of treatment, patients with osteonecrosis had lower mean BMDLS and BMDTB than patients without osteonecrosis (respectively, with osteonecrosis: -2.16 versus without osteonecrosis: -1.21, P<0.01 and with osteonecrosis: -1.73 versus without osteonecrosis: -0.57, P<0.01). Multivariate linear models showed that patients with osteonecrosis had steeper BMDLS and BMDTB declines during follow-up than patients without osteonecrosis (interaction group time, P<0.01 and P<0.01). We conclude that bone density status at the diagnosis of acute lymphoblastic leukemia does not seem to influence the occurrence of symptomatic osteonecrosis. Bone density declines from the time that osteonecrosis is diagnosed; this suggests that the already existing decrease in bone density during acute lymphoblastic leukemia therapy is further aggravated by factors such as restriction of weight-bearing activities and destruction of bone architecture due to osteonecrosis. Osteonecrosis can, therefore, be considered a risk factor for low bone density in children with acute lymphoblastic leukemia., (Copyright© Ferrata Storti Foundation.)

Background: In recent years interest in bone densitometry in children has increased., Objective: To evaluate the clinical application of digital X-ray radiogrammetry (DXR) and compare the results with those of dual-energy X-ray absorptiometry (DXA)., Materials and Methods: A total of 41 children with acute lymphoblastic leukaemia (ALL) and 26 children with growth hormone deficiency (GHD) were included in this longitudinal study. Radiographs of the left hand were obtained and used for DXR. DXA of the total body and of the lumbar spine was performed., Results: In both study populations significant correlations between DXR and DXA were found, and, with the exception of the correlation between DXR bone mineral density (DXR-BMD) and bone mineral apparent density in the GHD population, all correlations had a P-value of <0.001. During treatment a change in DXR-BMD was found in children with GHD., Conclusions: Our study showed that DXR in a paediatric population shows a strong correlation with DXA of the lumbar spine and total body and that it is able to detect a change in BMD during treatment.

We have evaluated the applicability of a new Digital X-ray Radiogrammetry (DXR) system in a Dutch Caucasian pediatric population. For this study we enrolled 535 healthy participants who all signed an informed consent form. In addition, 20 children suffering from inflammatory bowel disease (IBD) and juvenile chronic arthritis (JCA) were enrolled. Radiographs of the left hand were obtained from all participants. From the healthy population a subset of children with a history of forearm fractures were separately analyzed. Measurements consisted of DXR (X-posure; Pronosco-Sectra, Linköping, Sweden). Five hundred thirty-five subjects were enrolled in the study. Twenty-two subjects (4.3%) were discontinued (age 3-10 years), all because of a nonrecognizable radiograph by the DXR system. The short-term coefficient of variation of DXR in this population was 0.59%. Significant differences in DXR-BMD between boys and girls for the ages of 11, 12, 16, 17, and 18 years were found. There were also significant differences in DXR-BMD between the sequential Tanner stages. For 88 subjects repeat radiographs were available (mean interval 1.8 years). In all cases an increase in DXR-BMD was seen. Girls with IBD, JCA, or a history of forearm fractures and boys with IBD showed a significantly lower DXR-BMD compared with healthy controls. We show that DXR is an applicable technique in children. Also, in a small subpopulation it is possible to discriminate children with a high risk of low BMD.

Background: Several longitudinal studies have shown contradictory results regarding the change in bone status in children with acute lymphoblastic leukaemia (ALL) using dual-energy X-ray absorptiometry as the bone assessment technique., Objective: To determine whether a more recently developed bone assessment technique which does not use radiation, tibial ultrasonometry, can be used for the detection of short-term changes., Patients and Methods: From January 1997 to February 2001, 37 patients (25 boys, 12 girls, mean age 9.0 years, range 3.0-16.8 years) were included in a longitudinal study to assess changes in bone status induced by the disease itself and/or treatment. Of these 37 patients, 35 had a measurement at the start of therapy (t0), 26 at 6 months (t6), 24 at 12 months (t12), 11 at 24 months (t24) and 9 at 36 months (t36). For assessment of bone mass, the tibial ultrasound (US) device SoundScan Compact was used, which measures the speed of sound (SOS) along the cortex of the tibia over a fixed length of 5 cm at the mid-tibial point. RESULTS. The SOS standard deviation (SD) scores were significantly lower at t6, t12, t24 and t36 than at baseline (t0). The biggest change was found between t0 and t6. During follow-up, no significant correlation was found between changes from baseline of height SD scores and SOS SD scores, indicating that tibial ultrasonometry was not measuring growth. After ending therapy (t36), no further growth retardation was found., Conclusions: Short-term changes of SOS SD scores in children with ALL can be detected by tibial ultrasonometry. Tibial ultrasonometry measures a change in bone status, not growth.

A large proportion of the variation in bone mass can be explained by genetic factors. We analyzed the G to T substitution in the Sp1 binding site in the first intron of the collagen type Ialpha1 (COLIA1) gene in relation to bone mass. The genotypes GG, GT, and TT were determined in 148 Caucasian children and young adults. We performed dual energy X-ray absorptiometry twice (mean follow-up time 4.4 years), and speed of sound (SOS) was assessed by tibial ultrasonometry at follow-up. Genotype distribution was 104 (70%) GG, 40 (27%) GT and 4 (3%) TT. Carriers of the T-allele had a 0.5 SDS (standard deviation score) decreased bone mineral content (BMC) of total body (P = 0.001), and a 0.4 SDS decreased bone mineral density (BMD) for both lumbar spine (P = 0.04) and total body (P = 0.05). The genotype effect on BMD and BMC decreased after adjustment for height or body mass index. When we calculated apparent BMD, these differences diminished to 0.1 SDS and were no longer significant. T-allele carriers had shorter stature (0.4 SDS; P = 0.04) and smaller bones (0.5 SDS lower width of the lumbar vertebral body; P = 0.01). The T-allele was also associated with lower SOS (P = 0.03), independent of BMD and BMC, and lower lean body mass. Similar associations were found at follow-up. The change in BMD and BMC SDS between the first and second measurement did not differ between the GG and GT&TT group. In conclusion, the COLIA1 polymorphism in children and young adults is associated with several bone characteristics. However, at least a part of the COLIA1 effect on bone mass may be related to differences in frame size.

Acute lymphoblastic leukemia (ALL) in childhood is a serious disease that can affect growth and the attainment of maximal peak bone mass. The latter has recently been recognized as a risk factor for the development of osteoporosis later in life. To determine long-term effects of the disease itself and its treatment, we assessed the bone status of a group of long-term survivors of childhood ALL, all treated with high doses of steroids (dexamethasone) and methotrexate and without cranial irradiation. All 21 subjects enrolled in this cross-sectional study were diagnosed to have non-high-risk precursors acute lymphoblastic leukemia (12 boys and 9 girls, mean age 16.5 yr, range 12.2-25.4 yr). Standard deviation (SD) scores were calculated using a tibial ultrasound device and spinal dual-energy X-ray absorptiometry (DXA) device as bone assessment techniques. SD scores of those two different bone assessment techniques were compared. The mean SOS (speed of sound) SD scores (SDS) of the tibia (mean 0.26, standard deviation [sd] 1.00) were not significantly different from our reference value of 0. There was no significant difference between the SOS SDS in boys and girls. With DXA, no significant difference was seen between the mean BMD SDS and the reference data and no significant difference in BMD between boys and girls was found. The individual mean SDS for bone mineral density (BMD) of lumbar spine are 0.24 (sd 1.02), total body 0.17 (sd 1.00), and apparent BMD (BMAD) 0.07 (sd 1.09). Spearman's correlation between mean SOS SDS and mean BMD of lumbar spine was 0.47, mean SOS SDS and mean BMAD SDS was 0.43, and mean SOS SDS and mean BMD of total body was 0.49. These correlations were significant at the 0.05 level (two tailed). Despite high-dose dexamethasone and methotrexate used for treatment of these children with ALL, no long-term side effects on the bone mineral status of the subjects, measured with DXA or tibial ultrasonometry, could be determined.

There is a need for a reliable bone assessment technique in children. In this study, we compare an existing technique used in children, radiographic absorptiometry (RA), with a relatively novel technique, quantitative tibial ultrasonometry (QUS). In a prospective cohort study, we enrolled 290 girls (mean age 12.7 years) and 273 boys (mean age 12.4 years). Radiographs of the left hand and the left index finger were taken with an aluminium reference wedge within the field of exposure. Radiographic absorptiometry on the second middle phalanx at the mid-level (BMD50%) and proximal quarter (BMD25%) was performed with interactive software. Tibial QUS was performed using the SoundScan Compact. Multiple regression analysis showed that SOS correlated significantly with BMD25% for both boys (r = 0.65, P < 0.001) and girls (r = 0.59, P < 0.001), taking into account age and gender. The same applied for the correlation between speed of sound (SOS) and BMD50% in boys (r = 0.62, P < 0.001) and girls (r = 0.67, P < 0.001). Cubic regression between calendar age and BMD25% showed the best fit for both boys (r2 = 0.60) and girls (r2 = 0.60). For BMD50% a difference in regression was found between boys and girls. Quadratic regression gave a satisfactory fit for boys (r2 = 0.61 ) whereas for girls, a cubic relation was best (r2 = 0.59). Overall, there was a significant correlation between BMD25% and BMD50% for boys r = 0.89 and for girls r = 0.91 (both P < 0.001). Our data show a significant correlation between two different bone assessment techniques. In addition, these data suggest that both tibial ultrasonometry and RA are useful techniques in children.

In the field of bone densitometry, attention has recently been focused on the pediatric population. Quantitative ultrasound (QUS) as bone assessment technique has many advantages for children in comparison with bone assessment techniques that use ionizing radiation. In this pilot study, we investigated the use of calcaneal and tibial QUS systems in a healthy Caucasian pediatric population. We studied 120 healthy Caucasian Dutch children between ages 7 and 19 yr: 53 boys (mean age of 12.5 yr, range 4.5-18) and 67 girls (mean age of 13.5 yr; range 7.1-19). We recruited children from a large population who previously had participated in a bone assessment study performed at our hospital. Two operators performed calcaneal QUS of the right calcaneus and tibial QUS of the right tibia. The correlation between calcaneal and tibial ultrasound was modest but significant (r = 0.29; p < 0.01). Using the calcaneal device, we found in girls a weak positive correlation between skeletal age and speed of sound (SOS) (r = 0.38), broadband ultrasound attenuation (r = 0.57), and quantitative ultrasound index (r = 0.46), all with a value of p < 0.01. For boys all parameters failed to reach significance. Using the tibial device, we found a good correlation between skeletal age and SOS in girls (r = 0.76) and modest correlation in boys (r = 0.50), both with a value of p < 0.01. This is one of the first studies to present a comparison between two ultrasound techniques in children. At present we feel that, in light of the poor correlation with skeletal age, calcaneal ultrasound has yet to prove its efficacy in children. Tibial ultrasound seems to be a good bone assessment technique in children.

Rationale and Objectives: To understand normal bone development, studies in healthy children and adolescents are important. To assess the applicability of tibial quantitative ultrasound measurements (QUS) in children, we performed a study that compared dual-energy x-ray absorptiometry (DXA) of the lumbar spine and whole body with tibial QUS., Methods: For this study we recruited 146 Dutch children and adolescents, 58 boys (median age, 14.1 years; range, 7.6-23.4 years) and 88 girls (median age, 18.0 years; range, 7.6-23.5 years). Tanner stage, weight, and height were assessed for all participants. Bone mineral density (BMD; g x cm(-2)) of the whole body and lumbar spine (L2-L4) and bone mineral apparent density (BMAD) of the lumbar spine (g x cm(-3)) were assessed by using the Lunar DPXL. For tibial QUS, the Soundscan compact system was used., Results: Both lumbar as well as whole-body BMD showed a strong, significant correlation with tibial QUS in boys and girls: rtotal body boys = 0.81, rtotal body girls = 0.77, rlumbar spine boys = 0.79, and rlumbar spine girls = 0.72. Lumbar spine BMAD also showed significant correlations with tibial QUS: rboys= 0.63 and rgirls = 0.63 (for all correlations, P < 0.001)., Conclusions: Our study showing strong, significant correlations between DXA and tibial QUS measurements suggests that tibial QUS is a technique that may be applicable in children and adolescents.

The availability of improved therapies for children with diseases affecting bone growth and/or metabolism has caused increased interest in bone mineral density (BMD) assessment. The purpose of this study was to determine normal values for phalangeal radiographic absorptiometry (RA) in a Caucasian pediatric population. Five hundred and seventy-two healthy Caucasian children and adolescents (aged 5-19 years) were enrolled in this study. For RA one posteroanterior exposure of the left hand and one lateral exposure of the left index finger were taken. All films were analyzed, yielding BMD (mg Al/mm3) values for two phalangeal sites: one at the proximal quarter of the phalangeal length (BMD25%) and the second at the midpoint of the phalangeal length (BMD50%). Also skeletal age (SA) was assessed, as data normalized for SA can be used in populations which show a dissociation between SA and calendar age. We found that the BMD25% was significantly higher in girls than in boys for the SA group 11-14 years. The BMD50% was significantly higher in girls than in boys for the SA group 11-15 years. Our data show that BMD25% remains fairly constant until the SA of 12.0 years in boys and 10.1 years in girls; after these skeletal ages BMD shows a sharp increase. The same applies to BMD50%, which remains fairly constant until the SA of 12.4 years in boys and 10.7 years in girls. In this paper we present normative data for RA in a pediatric population. These data normalized for skeletal age could be implemented in a clinical setting.