Inge M. van der Sluis

Reference data for bone density and body composition measured with dual energy x ray absorptiometry in white children and young adults

Aims: To obtain normative data on bone mineral density and body composition measured with dual energy x ray absorptiometry (DXA) from early childhood to young adulthood. Methods: Cross sectional results from 444 healthy white volunteers (4–20 years) in the Netherlands were combined with the results from 198 children who agreed to participate in the follow up study approximately four years later. DXA (Lunar, DPXL) of lumbar spine and total body was performed to assess bone density and body composition. Results: Bone density and lean body mass (LBM) increased with age. Maximal increase in bone density and LBM occurred around the age of 13 years in girls and approximately two years later in boys. Bone density of total body and lumbar spine showed an ongoing slight increase in the third decade. Mean fat percentage in boys remained at 10.5% throughout childhood, but increased in girls. Conclusions: Most of the skeletal mass in lumbar spine and total body is reached before the end of the second decade, with a slight increase thereafter. This study provides reference values for bone density and body composition measured with DXA for children and young adults.

Bone mineral density, body composition, and height in long‐term survivors of acute lymphoblastic leukemia in childhood

BACKGROUND Childhood leukemia has increasing numbers of survivors, so more emphasis is being placed on long-term effects. The ALL-6 protocol of the Dutch Childhood Leukemia Study Group involved high-dose dexamethasone and methotrexate and no cranial irradiation. Therefore, we studied the long-term effects on bone mineral density (BMD), body composition, and growth in survivors of non-high-risk ALL treated with the ALL-6 protocol. PROCEDURE Twenty-three subjects (12.2-25.4 years) participated in this cross-sectional study. Mean follow-up was 9.6 years (range 7.9-11.4 years). BMD of lumbar spine (LS) and total body (TB) and body composition were measured by dual energy X-ray absorptiometry; results are expressed as standard deviation scores (SDS). Bone mineral apparent density (BMAD(LS)) was calculated to correct for bone size. A questionnaire was administered to determine physical activity, calcium intake, and medical history. RESULTS Mean SDS for BMD(LS), BMD(TB), and BMAD(LS) were normal. None of the subjects had BMD below -2 SDS; one subject had BMAD(LS) below -2 SDS. Mean SDS for lean body mass, percentage fat, and height were not significantly different from zero. Calcium intake correlated positively with BMD. Nine subjects reported traumatic fractures (eight during or shortly after therapy). CONCLUSIONS Ten years after ALL-6 treatment, no long-term side effects on height, BMD, or body composition were found in this small group of patients, despite high-dose dexamethasone and methotrexate. This study suggests that ALL treatment without cranial irradiation might not be associated with long-term side effects on growth and BMD.

Peak bone mineral density, lean body mass and fractures

BACKGROUND During childhood and adolescence, bone mass and lean body mass (LBM) increase till a plateau is reached. In this longitudinal and cross-sectional study, the age of reaching the plateau was evaluated for lumbar spine and total body bone mass measurements and lean body mass. The association between fractures and bone mineral density (BMD) was studied. PATIENTS AND METHODS We included 501 healthy participants, 141 males and 360 females, aged 13-29 years. Of these 90 had participated in a previous longitudinal study of 444 participants, aged 4-20 years (for the first measurement) and 198 participants, aged 8-25 years (for a second measurement). BMD and body composition were measured with dual energy X-ray absorptiometry (DXA). Volumetric BMD (bone mineral apparent density, BMAD) was calculated. All the data were used to determine the age of reaching the plateau. RESULTS The plateau for lumbar spine BMD, BMAD, total body BMD, bone mineral content and LBM was reached between 18 and 20 years of age in females and between 18 and 23 years in males. The prevalence of fractures was 37% in males and 28% in females. Total body BMD Z-score was significantly lower in all participants who had had a fracture (p<0.05), whereas lumbar spine BMD and BMAD was only significantly lower in females who had had fractures (p=0.007 and p<0.001, respectively). Mean lumbar spine BMAD Z-score at the previous measurement was significantly lower in the participants who had a first fracture between the last two measurements (p=0.04). CONCLUSION Peak BMD and peak LBM were attained between 18 and 20 years in females and between 18 and 23 years in males in this study using longitudinal and cross sectional data in the age range of 4 to 30 years. A significantly lower total body BMD was seen in participants who had had a fracture and a lower lumbar spine BMD and BMAD in females who had had a fracture. Lumbar spine BMAD Z-score seems to be a good predictor for future fractures.

Prospective Study on Incidence, Risk Factors, and Long-Term Outcome of Osteonecrosis in Pediatric Acute Lymphoblastic Leukemia

PURPOSE We studied cumulative incidence, risk factors, therapeutic strategies, and outcome of symptomatic osteonecrosis in pediatric patients with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS Cumulative incidence of osteonecrosis was assessed prospectively in 694 patients treated with the dexamethasone-based Dutch Child Oncology Group-ALL9 protocol. Osteonecrosis was defined by development of symptoms (National Cancer Institute grade 2 to 4) during treatment or within 1 year after treatment discontinuation, confirmed by magnetic resonance imaging. We evaluated risk factors for osteonecrosis using logistic multivariate regression. To describe outcome, we reviewed clinical and radiologic information after antileukemic treatment 1 year or more after osteonecrosis diagnosis. RESULTS Cumulative incidence of osteonecrosis at 3 years was 6.1%. After adjustment for treatment center, logistic multivariate regression identified age (odds ratio [OR], 1.47; P < .01) and female sex (OR, 2.23; P = .04) as independent risk factors. Median age at diagnosis of ALL in patients with osteonecrosis was 13.5 years, compared with 4.7 years in those without. In 21 (55%) of 38 patients with osteonecrosis, chemotherapy was adjusted. Seven patients (18%) underwent surgery: five joint-preserving procedures and two total-hip arthroplasties. Clinical follow-up of 35 patients was evaluated; median follow-up was 4.9 years. In 14 patients (40%), symptoms completely resolved; 14 (40%) had symptoms interfering with function but not with activities of daily living (ADLs; grade 2); seven (20%) had symptoms interfering with ADLs (grade 3). In 24 patients, radiologic follow-up was available; in six (25%), lesions improved/disappeared; in 13 (54%), lesions remained stable; five (21%) had progressive lesions. CONCLUSION Six percent of pediatric patients with ALL developed symptomatic osteonecrosis during or shortly after treatment. Older age and female sex were risk factors. After a median follow-up of 5 years, 60% of patients had persistent symptoms.

Body Composition Abnormalities in Children with Prader-Willi Syndrome and Long-Term Effects of Growth Hormone Therapy

Obesity and hypothalamic GH deficiency contribute in different ways to the disturbances of body composition in Prader-Willi syndrome (PWS); while both increase the fat compartment, the reduction of lean tissue mass has been attributed mainly to GH deficiency. Therefore, body composition measured by dual-energy X-ray absorptiometry was prospectively studied in 12 overweight children with PWS and weight for height (WfH) SDS >0 before and during 3.5 years of treatment with hGH (0.037 mg/kg/day) on average. In the long term, there is a net reduction of body fat from 3.1 to 1.2 SD, with a minimum at the end of the second year of treatment. WfH SDS correctly reflects body fat mass and its changes. The initial deficit of lean mass (–1.6 SD) is counteracted by GH only during the first year of therapy (increase to –1.25 SD). But in the long term, GH therapy does not further compensate for this deficit, when lean mass is corrected for its growth-related increase. In conclusion, exogenous GH changes the phenotype of children with PWS: fat mass becomes normal, but, at least in the setting studied, GH is not sufficient to normalize lean tissue mass.

A prospective study on drug monitoring of PEGasparaginase and Erwinia asparaginase and asparaginase antibodies in pediatric acute lymphoblastic leukemia.

This study prospectively analyzed the efficacy of very prolonged courses of pegylated Escherichia coli asparaginase (PEGasparaginase) and Erwinia asparaginase in pediatric acute lymphoblastic leukemia (ALL) patients. Patients received 15 PEGasparaginase infusions (2500 IU/m(2) every 2 weeks) in intensification after receiving native E coli asparaginase in induction. In case of allergy to or silent inactivation of PEGasparaginase, Erwinia asparaginase (20 000 IU/m(2) 2-3 times weekly) was given. Eighty-nine patients were enrolled in the PEGasparaginase study. Twenty (22%) of the PEGasparaginase-treated patients developed an allergy; 7 (8%) showed silent inactivation. The PEGasparaginase level was 0 in all allergic patients (grade 1-4). Patients without hypersensitivity to PEGasparaginase had serum mean trough levels of 899 U/L. Fifty-nine patients were included in the Erwinia asparaginase study; 2 (3%) developed an allergy and none silent inactivation. Ninety-six percent had at least 1 trough level ≥100 U/L. The serum asparagine level was not always completely depleted with Erwinia asparaginase in contrast to PEGasparaginase. The presence of asparaginase antibodies was related to allergies and silent inactivation, but with low specificity (64%). Use of native E coli asparaginase in induction leads to high hypersensitivity rates to PEGasparaginase in intensification. Therefore, PEGasparaginase should be used upfront in induction, and we suggest that the dose could be lowered. Switching to Erwinia asparaginase leads to effective asparaginase levels in most patients. Therapeutic drug monitoring has been added to our ALL-11 protocol to individualize asparaginase therapy.

Long-Term Effects of Growth Hormone Therapy on Bone Mineral Density, Body Composition, and Serum Lipid Levels in Growth Hormone Deficient Children: A 6-Year Follow-Up Study

Aim: To study the effects of growth hormone (GH) deficiency (GHD) and GH replacement therapy (GHRx) on bone mineral density (BMD) and body composition. Methods: 59 GHD children participated (age range 0.4–16.9 years); the follow-up period was 6 years. Lumbar spine BMD (BMD_LS), total-body BMD (BMD_TB), and body composition were measured prospectively using dual-energy X-ray absorptiometry. Results: Mean BMD_LSand BMD_TB were significantly reduced at the time of the diagnosis. The bone mineral apparent density of the lumbar spine (BMAD_LS) was reduced to a lesser degree. The BMAD_LS increased to normal values after 1 year; BMD_LS and BMD_TB normalized 1 year later. At the time of the diagnosis, the lean body mass was reduced and steadily increased during GHRx. Percentage of body fat was increased at baseline and normalized within 6 months. The severity of GHD was not associated with the BMD at diagnosis or the response to GHRx. Conclusion: Areal BMD_LS and BMD_TB and, to a lesser extent, BMAD_LS are decreased in GHD children, but normalize within 1–2 years.

Idiopathic infantile arterial calcification: clinical presentation, therapy and long-term follow-up

Idiopathic infantile arterial calcification (IIAC) is a rare disease characterised by extensive depositions of hydroxyapatite in the internal elastic lamina of medium-sized and large arteries, frequently accompanied by periarticular calcifications. We report on three patients with various presenting signs and symptoms. Diagnostic imaging techniques and therapy with bisphosphonates will be discussed. For the first time long-term follow-up of up to 25 years will be reported.

A Cross-Sectional Study on Biochemical Parameters of Bone Turnover and Vitamin D Metabolites in Healthy Dutch Children and Young Adults

Aim: To provide reference data of biochemical markers of bone turnover and vitamin D metabolites for children and young adults. Methods: Blood samples were taken from 176 healthy Dutch children and young adults (age range 7.6–25.3 years) to assess serum calcium, alkaline phosphatase, inorganic phosphate, osteocalcin, collagen type I cross-linked N-telopeptide, N-terminal propeptide of type I procollagen , 25-hydroxyvitamin D3, and 1,25-dihydroxyvitamin D3 levels. Cross-linked telopeptide of type I collagen and carboxy-terminal propeptide of type I procollagen were assessed in 286 subjects (age range 1.4–25.3 years). Results: Calcium and vitamin D levels were independent of age. The peak concentrations for collagen type I cross-linked N-telopeptide, cross-linked telopeptide of type I collagen, carboxy-terminal propeptide of type I procollagen, N-terminal propeptide of type I procollagen, alkaline phosphatase, and osteocalcin were found during puberty, in girls approximately 2.5 years earlier than in boys. Strong correlations were found between the markers of bone turnover, while no correlation was found between the markers of bone turnover and bone mineral density measured by dual-energy X-ray absorptiometry. Conclusions: Single measurements of bone markers cannot predict bone density. Reference data according to gender, age, and Tanner stage are given which allow calculating standard deviation scores adjusted for age and gender.

Osteoporosis in children with cancer.

As increasing numbers of childhood cancer patients are surviving, the long‐term complications of the disease and its treatment have become ever more increasingly important. Reduced bone mineral density and increased fracture risk have been reported during and after treatment of children with cancer. The causes of osteoporosis are multifactorial. Among others, the disease itself, chemotherapy, irradiation and genetic susceptibility play a role. Bone mineral density in later life depends largely on the peak bone mass achieved in adolescence or young adulthood. Therefore, optimizing peak bone mass is of clinical importance. Preventive and therapeutic strategies, such as calcium and vitamin D supplementation, physical activity and bisphosphonates, are considered. Pediatr Blood Cancer 2008;50:474–478.