Bone mass, size, and density in children and adolescents with osteogenesis imperfecta: effect of intravenous pamidronate therapy.

Cyclical intravenous therapy with pamidronate improves the clinical course in children and adolescents with osteogenesis imperfecta (OI). In this study, we evaluated the effect of this therapy on lumbar spine bone mass (bone mineral content [BMC]), size (bone volume [BV]), and density (volumetric bone mineral density [vBMD]). Results from 56 patients (age, 0.2-15.9 years; 25 girls) on long-term pamidronate treatment were compared with those of 167 patients who had not received pamidronate before densitometry. In all patients who received pamidronate, BMC, BV, and vBMD increased above levels expected for untreated patients (p < 0.001 in each case). After 4 years of treatment, BMC, BV, and vBMD were 154%, 44%, and 65% higher, respectively, in treated than in untreated patients who were matched for age and OI type. A multiple regression model showed that baseline BMC was negatively associated with the increase in BMC. In conclusion, the bone mass increase in pediatric OI patients receiving pamidronate is caused by increases in both bone size and density. Patients with larger deficits in bone mass at baseline have a more marked bone mass gain during therapy.     

Osteogenesis imperfecta type VI in childhood and adolescence: effects of cyclical intravenous pamidronate treatment

Cyclical intravenous treatment with pamidronate is of clinical benefit in children with moderate to severe osteogenesis imperfecta (OI) types I, III and IV, but there is no information on the effects of this treatment on the newly described OI type VI. Here, we report on the results of 3 years of pamidronate treatment in 10 children and adolescents with OI type VI (age range 0.8 to 14.5 years, three girls). Treatment effects were compared to those of 10 patients with OI types I, III, and IV, who were matched for age and disease severity (based on height and lumbar spine areal bone mineral density). During pamidronate therapy, lumbar spine areal bone mineral density z scores increased and lumbar spine vertebral bodies improved in shape. Iliac bone histomorphometry showed a tendency to higher cortical thickness (+53%, P=0.06) but the mineralization defect, a characteristic feature of OI type VI, did not change during pamidronate treatment. Annualized fracture incidence decreased from 3.1 per year before treatment to 1.4 fractures per year during treatment (P<0.05). Regarding mobility, the Pediatric Evaluation of Disability Inventory gross motor score increased by 42% during pamidronate treatment (P<0.005). Significant improvements were also found for age-related z scores of maximal isometric grip force. In comparison to the OI control group, the fracture incidence was higher and the gross motor scores were lower in OI type VI, both before and after pamidronate treatment (P<0.05 for each parameter). No differences were found between the groups for changes in densitometric measures and cortical thickness during pamidronate treatment. Our results suggest that 3 years of intravenous pamidronate therapy led to improvements in bone mineral mass, gross motor function, muscle force and fracture incidence in patients with OI type VI. However, the gains in mobility scores and reductions in fracture incidence during pamidronate treatment are less than in other OI types.     

Successful results of pamidronate treatment in children with osteogenesis imperfecta with emphasis on the interpretation of bone mineral density for local standards

AIM: To assess the long-term effect of pamidronate therapy on bone mineral metabolism and bone mineral density (BMD) in children with osteogenesis imperfecta (OI) and to evaluate BMD results with respect to national standards. METHODS: Pamidronate was administered intravenously on 3 consecutive days every 3 to 4 months at a dose of 1 mg/kg/d in 35 patients. Infusion cycles ranged from 4 to 17. Serum calcium, phosphorus, bone turnover markers, L1-L4 areal BMD (aBMD), and fracture rate were evaluated. Areal BMD Z scores were compared with national sex-specific reference data and volumetric BMD Z scores. RESULTS: In all children, linear growth continued along the same percentile during treatment. All parameters of bone turnover showed a decrease. L1 to L4 aBMD and Z score increased markedly, and fracture rate decreased in all patients during therapy. The mean annual percent gain in aBMD was highest in the first year and slowed down in subsequent years. Mean L1 to L4 aBMD Z scores according to Turkish reference data were higher than that of manufacturer values (P = 0.004). Correction of L1 to L4 vertebrae for bone size yielded to a decrease in osteoporosis in OI patients (41.5% vs 22.3%). CONCLUSIONS: Bone mineral density increased and fracture rate decreased in children and infants with OI during pamidronate treatment. Prevalence of osteoporosis decreased after correction for national standard and volumetric BMD. Use of an appropriate reference database and method of data analysis are very important for correct evaluation of osteoporosis.     

Two-year clinical trial of oral alendronate versus intravenous pamidronate in children with osteogenesis imperfecta.

A 2-year prospective, partially randomized open-label trial comparing oral alendronate with intravenous pamidronate therapy in children with OI showed equivalence in increasing total body BMD, spine BMD, and linear growth, and decreasing bone turnover and fracture incidence. Children with mild OI had greater responses than severe OI in BMD and growth. INTRODUCTION: Bisphosphonate therapies increase BMD and may reduce fractures in children with osteogenesis imperfecta (OI). A study directly comparing oral with intravenous bisphosphonate has not been published. This clinical trial compares oral alendronate with intravenous pamidronate in children with OI using an open-label, prospective, 2-year, randomized design. MATERIALS AND METHODS: Children over the age of 3 years were stratified by bone age, pubertal stage, and type of OI and then randomized to receive oral alendronate 1 mg/kg/day in tablet form or intravenous pamidronate, 3 mg/kg/4 months. One child was assigned to pamidronate. One child randomized to intravenous pamidronate changed to oral alendronate. Eighteen children completed 12 months of therapy: nine on oral alendronate and nine on intravenous pamidronate. Primary outcome efficacy was increase in BMD. Secondary outcomes included changes in bone turnover biomarkers, fracture incidence, and growth. RESULTS: Total body and lumbar spine BMD increased, turnover markers decreased, and linear growth increased equivalently with oral and intravenous therapy. Fracture incidence showed a trend to decrease in both groups, with a significant decrease in fracture rates when the oral and intravenous groups were pooled. There were greater responses in BMD and growth in children with milder OI (type I) than those with more severe disease (types III and IV), but there were no significant effects of age or pubertal stage. CONCLUSIONS: Oral and intravenous bisphosphonate therapies are equally effective in children with OI and are particularly effective in milder forms. The oral route is highly acceptable in children and has practical advantages over the intravenous route.     

Growth hormone injections improve bone quality in a mouse model of osteogenesis imperfecta.

Systemic growth hormone injections increased spine and femur length in a mouse model of OI. Femur BMC, cross-sectional area, and BMD were increased. Smaller gains were produced in vertebral BMC and cross-sectional area. Biomechanical testing showed improvements to structural and material properties in the femur midshaft, supporting expanded testing of growth hormone therapy in children with OI. INTRODUCTION: Osteoblasts in heterozygous Cola2oim mutant mice produce one-half the normal amounts of the alpha2 strand of type I procollagen. The mice experience a mild osteogenesis imperfecta (OI) phenotype, with femurs and vertebrae that require less force than normal to break in a biomechanical test. MATERIALS AND METHODS: Subcutaneous injections of recombinant human growth hormone (rhGH) or saline were given 6 days per week to oim/+ mice between 3 and 12 weeks of age, in a protocol designed to simulate a trial on OI children. RESULTS: rhGH injections promoted significant weight gain and skeletal growth compared with saline-treated control animals. Femur and spine lengths were increased significantly. Significant increases at the femur midshaft in cortical BMD (2.2%), BMC (15.5%), and cross-sectional area (13%) were produced by rhGH treatment. Increases in the same cortical bone parameters were measured in the metaphyseal region of the femur and in tail vertebrae, but lumbar vertebrae showed significant increases in BMC (9.6%) and cross-sectional area (10.1%) of trabecular bone. Three-point bending testing documented functional improvements to the femur mid-shafts. GH treatment produced significant increases in bone stiffness (23.7%), maximum load (30.8%), the energy absorbed by the femurs to the point of maximum load (44.5%), and the energy to actual fracture (40.4%). The ultimate stress endured by the bone material was increased by 14.1%. CONCLUSIONS: Gains in bone length, cross-sectional area, BMD, BMC, structural biomechanical properties, and strength were achieved without directly addressing the genetic collagen defect in the mice. Results support expanded clinical testing of GH injections in children with OI.     

Pamidronate preserves bone mass for at least 2 years following acute administration for pediatric burn injury

We have previously shown that pamidronate, when given within 10 days of burn injury, preserves lumbar spine bone mineral content from admission to discharge in 6-8 weeks and at 6 months increases both lumbar spine and total body bone mineral content (BMC) over placebo. We followed patients unblinded after 6 months every 3 months up to 2 years post-burn to see if the effects of pamidronate were sustained. Additionally, we assessed bone remodeling at 1 year post-burn by iliac crest bone biopsy. We enrolled 57 subjects who were initially randomized to pamidronate (n=32) and placebo (n=25). After 2 years, 21 subjects (pamidronate=8, placebo=13) remained. Analysis of bone densitometry by dual energy X-ray absorptiometry revealed an effect of both treatment (p<0.012 for total body BMC, p<0.001 for lumbar spine BMC, p<0.014 for lumbar spine bone area and p<0.003 for lumbar spine bone density (BMD)) and time (p<0.0003 on total body BMC, p<0.001 on lumbar spine BMC, p<0.001 on lumbar spine bone area, and no significant difference on lumbar spine BMD). There was no interaction between treatment and time. Results for bone histomorphometry revealed no effect of treatment on either static or dynamic parameters but did show an effect of time on osteoid area (p=0.004, surface p<0.001, and width, p<0.001). We conclude that acute administration of pamidronate resulted in sustained therapeutic effect on bone and that this type of administration may serve as a useful adjunct to other therapies in the preservation and augmentation of bone mass following severe burns.     

Interpretation of whole body dual energy X-ray absorptiometry measures in children: comparison with peripheral quantitative computed tomography

The assessment of bone health in children requires strategies to minimize the confounding effects of bone size on dual energy X-ray absorptiometry (DXA) areal bone mineral density (BMD) results. Cortical bone composes 80% of the total skeletal bone mass. The objective of this study was to develop analytic strategies for the assessment of whole body DXA that describe the biomechanical characteristics of cortical bone across a wide range of body sizes using peripheral quantitative computed tomography (pQCT) measures of cortical geometry, density (mg/mm³), and strength as the gold standard. Whole body DXA (Hologic QDR 4500) and pQCT (Stratec XCT-2000) of the tibia diaphysis were completed in 150 healthy children 6–21 years of age. To assess DXA and pQCT measures relative to age, body size, and bone size, gender-specific regression models were used to establish z scores for DXA bone mineral content (BMC) for age, areal BMD for age, bone area for height, bone area for lean mass, BMC for height, BMC for lean mass, and BMC for bone area; and for pQCT, bone cross-sectional area (CSA) for tibia length and bone strength (stress-strain index, SSI) for tibia length. DXA bone area for height and BMC for height were both strongly and positively associated with pQCT CSA for length and with SSI for length (all P < 0.0001), suggesting that decreases in DXA bone area for height or DXA BMC for height represent narrower bones with less resistance to bending. DXA BMC for age (P < 0.01) and areal BMD (P < 0.05) for age were moderately correlated with strength. Neither DXA bone area for lean mass nor BMC for lean mass correlated with pQCT CSA for length or SSI for length. DXA BMC for bone area was weakly associated with pQCT SSI for length, in females only. Therefore, normalizing whole body DXA bone area for height and BMC for height provided the best measures of bone dimensions and strength. DXA BMC normalized for bone area and lean mass were poor indicators of bone strength.     

Bone mineral density in prepubertal obese and control children: relation to body weight,lean mass,and fat mass

The aim of the study was to determine the influence of obesity on bone status in prepubertal children. This study included 20 obese prepubertal children (10.7 +/- 1.2 years old) and 23 maturation-matched controls (10.9 +/- 1.1 years old). Bone mineral area, bone mineral content (BMC), bone mineral density (BMD), and calculation of bone mineral apparent density (BMAD) at the whole body and lumbar spine (L1-L4) and body composition (lean mass and fat mass) were assessed by DXA. Broadband ultrasound attenuation (BUA) and speed of sound (SOS) at the calcaneus were measured with a BUA imaging device. Expressed as crude values, DXA measurements of BMD at all bone sites and BUA (69.30 versus 59.63 dB/MHz, P < 0.01) were higher in obese children. After adjustment for body weight and lean mass, obese children displayed lower values of whole-body BMD (0.88 versus 0.96 g/cm2, P < 0.05) and BMC (1190.98 versus 1510.24 g, P < 0.01) in comparison to controls. When results were adjusted for fat mass, there was no statistical difference between obese and control children for DXA and ultrasound results. Moreover, whole-body BMAD was lower (0.086 versus 0.099 g/cm3, P < 0.0001), whereas lumbar spine BMAD was greater (0.117 versus 0.100 g/cm3, P < 0.001) in obese children. Thus, it was observed that, in obese children, cortical and trabecular bone displayed different adaptation patterns to their higher body weight. Cortical bone seems to enhance both size and BMC and trabecular bone to enhance BMC. Finally, considering total body weight and lean mass of obese children, these skeletal responses were not sufficient to compensate for the excess load on the whole body.     

Impact of alendronate on quality of life in children with osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a debilitating clinical condition characterized by fragile bone and skeletal deformity. Over the past decade frequent reports have suggested that the cyclical administration of intravenous pamidronate has a positive impact on bone density and skeletal fractures; however, the impact of such therapy on the quality of life (QOL) has rarely been reported. Alendronate, an oral bisphosphonate, is widely used to treat osteoporosis. The purpose of this study was to evaluate the impact of daily alendronate on QOL and bone parameters in children with OI. A prospective double-blind crossover study was designed in which placebo was alternated with daily alendronate. Twenty children with types I, III, and IV OI were recruited. Seventeen patients completed the study. Markers of QOL were measured in children with type III and IV OI (n = 15) using total mobility (PEDI), self-care (WeeFIM), well-being, pain, and use of analgesic scores. After 1 year of alendronate therapy, vertebral bone mineral density (BMD) improved from a change in standard deviation score (z-score) of 0.89 +/- 0.19 to -0.12 +/- 0.14 after 1 year of placebo (P < 0.001). All QOL markers, except for mobility score, improved in response to alendronate therapy. Change in height z-score also improved in response to 1 year of alendronate therapy (0.41 +/- 0.21 vs. -0.09 +/- 0.11, P < 0.05). Alendronate therapy did not alter serum levels of calcium, osteocalcin, parathyroid hormone (PTH), 1, 5 (OH)2 vitamin D, cholesterol, or urinary hydroxyproline or any other biochemical marker evaluated. Alendronate decreased by 56% urinary cross-linked N-telopeptide of type 1 collagen divided by urinary creatinine (uNTX/uCr). Daily alendronate therapy was well tolerated. Only two patients had mild gastrointestinal discomfort, responding to minor adjustments in alendronate intake. Daily alendronate therapy is safe and effective in improving QOL in children with OI.     

Correlation between hand and total body bone density in normal Chinese children

Hand bone mineral density (BMD) in adults was found to be significantly correlated with various skeletal sites, including the total body. However, the relationships between hand and total body bone measurements have yet to be explored for children. We conducted a cross-sectional study of 892 normal Chinese children (511 males, 381 females) aged 5-14 years by measuring the BMD and bone mineral content (BMC) at the total hand, upper limb, subtotal body, and total body using dual-energy X-ray absorptiometry (DXA). We found that hand BMD and BMC increased with age for both genders. Female children had significantly higher hand BMD and BMC than males. Age explained more variance in hand BMD for females (R2=0.727) than for males (R2=0.596). For both genders, hand BMD and BMC correlated highly with age, weight, height, total body lean mass, and BMD and BMC at the upper limb, subtotal body, and total body (r=0.730-0.965, p<0.001) and moderately with body mass index and total body fat mass (r=0.525-0.701, p<0.001). Therefore, the hand DXA scan can potentially be a new tool for the clinical assessment of bone health in children.     

Benefits of pamidronate in children with osteogenesis imperfecta: an open prospective study

OBJECTIVES: To study the efficacy of pamidronate in children with osteogenesis imperfecta (OI). PATIENTS AND METHODS: Twenty-nine patients (median age 8.7 years), were given pamidronate in cyclic infusions of 3 days. Patients received 3-13 cycles (median 6), at a dose of 0.5 mg/kg/day in infants (below 2 years of age) and 1 mg/kg/day in children (2 years and older). The interval time between cycles was 2 months in infants and 4 months in children. The median follow-up was 16 months. All patients received daily supplementation of calcium, vitamin D and physical rehabilitation. Assessments were performed at baseline and before each cycle. Fracture rate under treatment was compared to the one in the pre-treatment period. RESULTS: Pain decreased after the first infusion cycle (P < 0.0001). The median of fracture incidence decreased from 15 to 0.5 per year in infants and from 2.0 to 1 per year in children (P = 0.04). Alkaline phosphatase decreased by 31.2% and N-telopeptide collagen cross-links decreased by 61.8% (P < 0.001). Bone mineral density (BMD) of the spine increased by a median of 55.4% (P < 0.001). Z-scores increased from a median of -4.7 to -2.6 (P < 0.001). The femoral neck, BMD increased by a median of 16%. The area of the first four lumbar vertebrae increased by a median of 21.5% (P < 0.001). No adverse effect on growth or on fracture healing was observed. Side effects were symptomatic hypocalcemia in one infant, and the transient acute phase reaction. CONCLUSION: Pamidronate increases BMD, decreases bone remodeling markers, pain and fracture rate in infants and children with OI.     

Short-term and long-term site-specific effects of tennis playing on trabecular and cortical bone at the distal radius

Mechanical loading during growth magnifies the normal increase in bone diameter occurring in long bone shafts, but the response to loading in long bone ends remains unclear. The aim of the study was to investigate the effects of tennis playing during growth at the distal radius, comparing the bone response at trabecular and cortical skeletal sites. The influence of training duration was examined by studying bone response in short-term (children) and long-term (young adults) perspectives. Bone area, bone mineral content (BMC), and bone mineral density (BMD) of the radius were measured by DXA in 28 young (11.6 ± 1.4 years old) and 47 adult tennis players (22.3 ± 2.7 years old), and 70 age-matched controls (12 children, 58 adults) at three sites: the ultradistal region (trabecular), the mid-distal region, and the third-distal region (cortical). At the ultradistal radius, young and adult tennis players displayed similar side-to-side differences, the asymmetry in BMC reaching 16.3% and 13.8%, respectively (P < 0.0001). At the mid- and third-distal radius, the asymmetry was much greater in adults than in children (P < 0.0001) for all the bone parameters (mid-distal radius, +6.6% versus +15.6%; third-distal radius, +6.9% versus +13.3%, for BMC). Epiphyseal bone enduring longitudinal growth showed a great capacity to respond to mechanical loading in children. Prolonging tennis playing into adulthood was associated with further increase in bone mineralization at diaphyseal skeletal sites. These findings illustrate the benefits of practicing impact-loading sports during growth and maintaining physical activity into adulthood to enhance bone mass accrual and prevent fractures later in life.     

Whole body bone mass and body composition in a girl with achondroplasia, at ages 9 through 12.

A 9-yr-old white female with achondroplasia was one of a group of 773 children who were recruited for a study of the accumulation of whole body skeletal mass during four annual measurements. Measurements of bone, fat, and lean mass were obtained with a Hologic 1000W instrument. The following variables are used to compare the subject with the 130 healthy white girls who participated in the study: bone mineral content (BMC), bone mineral density (BMD), and bone mineral apparent density (BMAD). Ratios of BMC to weight or BMC to height, and BMD to weight or height, were also calculated. We found that the BMC of the subject was lower when compared to the reference group, but the ratios of BMC to weight or BMC to height were similar in both. BMD was also lower in the patient, but, when expressed in relation to height and weight, the ratios were similar or slightly higher in the case. BMAD was higher in the subject with achondroplasia at all ages. The subject had a lower percentage fat and higher percentage lean mass than the reference children. We conclude that the accumulation of bone mass in this subject with achondroplasia is appropriate for her reduced body size.     

Effects of intravenous pamidronate treatment in infants with osteogenesis imperfecta: clinical and histomorphometric outcome.

Clinical and histomorphometric outcome was compared between children with OI who had received pamidronate since infancy and age-matched patients who had never received pamidronate. Pamidronate was associated with improved vertebral shape and mass, higher cortical width, increased cancellous bone volume, and suppressed bone turnover. INTRODUCTION: Observations in small patient series indicate that infants with severe osteogenesis imperfecta (OI) benefit from treatment with cyclical intravenous pamidronate. However, detailed analyses of outcome are lacking for this age group. MATERIALS AND METHODS: Clinical outcome was evaluated in 29 children with OI types I (n = 3), III (n = 14), or IV (n = 12) who started pamidronate therapy before 2 years of age (age at treatment onset: median, 6 months; range, 2 weeks to 23 months) and who had completed 3 years of treatment (total annual pamidronate dose, 9 mg/kg). They were compared with a historical control group of 29 untreated children with severe OI who were matched for OI type and age at the 3-year treatment time-point. In addition, iliac bone histomorphometry was compared between 24 pamidronate-treated patients and 24 age-matched OI patients who had not received pamidronate. RESULTS: Morphometric evaluation of lumbar vertebrae (L(1)-L(4)) showed that the shape of vertebral bodies was better preserved in pamidronate-treated patients. This was accompanied by significantly higher lumbar spine areal and volumetric BMD (+110 and +96%, respectively) and a larger vertebral bone volume (+26%) on densitometry. Regarding mobility function, the Pediatric Evaluation of Disability Inventory gross motor score was 50% greater in the pamidronate group (p < 0.001). Iliac bone histomorphometry showed 61% higher cortical width and 89% higher cancellous bone volume in pamidronate-treated patients. Bone formation rate per bone surface in the pamidronate group was only 17% that of untreated patients. CONCLUSIONS: In conclusion, this study suggests that cyclical pamidronate treatment started in infancy leads to improved bone strength and better gross motor function but also suppresses bone turnover markedly. It is therefore prudent to reserve pamidronate treatment to infant OI patients who present with a moderate to severe phenotype.     

Skeletal differences in bone mineral area and content before and after cure of endogenous Cushing’s syndrome

SUMMARY: We examined bone densitometric data in a four-year follow-up period before and after the cure of CS. Plasma cortisol concentrations were similar, but the duration of estimated glucocorticoid excess was longer in patients with prevalent bone fractures compared to those without fractures. After therapy of CS, bone area, BMC and BMD increased significantly at the LS and femur during follow-up, but they decreased at the forearm, suggesting redistribution of bone minerals from the peripheral to the axial skeleton. INTRODUCTION: Only a few studies report the changes in bone mineral density (BMD) after the cure of Cushing's syndrome (CS). METHODS: Forty-one patients with Cushing's disease, 21 patients with adrenal CS and 6 patients with ectopic CS were prospectively enrolled. BMD, bone mineral content (BMC) and bone area were measured by DXA. RESULTS: No significant correlations were found between serum cortisol concentrations and baseline bone densitometric data. After successful therapy of CS, bone area and BMD increased significantly at the lumbar spine (LS) and femur during follow-up, but they decreased at the forearm. The progressive increase in BMC at the LS had a significant negative correlation with the change of the BMC of radius in the first and second follow-up years. The change in the body mass index was an independent predictor for changes in BMC both at the LS and at the forearm at the second year of remission. CONCLUSIONS: The regional differences and the time-dependent changes of BMC suggest that the source of marked increase in axial BMC after the cure of CS is, at least partly, due to the redistribution of bone minerals from the peripheral to the axial skeleton.     

Intravenous neridronate in adults with osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a heritable disease of connective tissue, characterized by increased bone fragility. Bisphosphonates currently seems to be the most promising therapy, at least in children. We tested IV neridronate, an amino-bisphosphonate structurally similar to alendronate and pamidronate in adults with OI. Twenty-three men and 23 premenopausal women with OI were randomized to either iv neridronate (100 mg infused intravenously for 30 minutes every 3 months) or no treatment with a ratio of 2 to 1. Control patients were given the same bisphosphonate therapy at the end of the first year. Clinical evaluation included bone densitometry measurements using dual energy X-ray absorptiometry (DXA), fasting serum and urinary biochemistry every 6 months, and radiographs of the spine taken at baseline and after 12 and 24 months of follow-up. Spine and hip bone mineral density rose by 3.0 +/- 4.6% (SD) and by 4.3 +/- 3.9%, respectively, within the first 12 months of treatment, whereas small insignificant changes were observed in the control group. During the second year of follow-up, additional 3.91% and 1.49% increases were observed at the spine and hip, respectively. Markers of skeletal turnover significantly fell during neridronate treatment. Fracture incidence during neridronate treatment was significantly lower than before therapy and compared with controls. Neridronate iv infusions, administered quarterly, significantly increase bone mineral density and lowered the risk of clinical fracture in adults with OI. Bisphosphonate therapy seems to provide clinical benefits, not only to children with OI, but also to adult patients.     

A clinical study evaluating bone mineral mass in the radius during skeletal growth--single photon absorptiometry

Using 125-I single photon absorptiometry, bone mineral measurements were performed on 206 healthy Japanese children (2 to 19 years of age). Bone mineral content (BMC), bone width (BW) and BMC/BW values were determined for the radius at distal 1/6 site (metaphysis) and distal 1/3 site (diaphysis). BMC/BW values at both sites correlated well with body height and weight. Bone mass in the diaphysis (distal 1/3 site) increased linearly during the 2-19 years of skeletal growth, but bone mass in the metaphysis (1/6 site) increased steeply during the pubertal period. In children receiving glucocorticoid therapy, bone mass was reduced in proportion to the duration of drug administration. In children under anticonvulsant therapy, the yearly increase in bone mass was significantly low especially in those patients with poor physical activity levels. Bone mineral decrease in the radius occurred in the children with hypopituitalism, hypothyroidism (cretinism), hyperthyroidism and Turner's syndrome.     

Bone metabolism and the muscle–bone relationship in children,adolescents and young adults with phenylketonuria

The aim of the study was to assess body composition in subjects with phenylketonuria (PKU). Forty-five patients aged 13.8 ± 5.2 years were evaluated. Among them, 15 patients had not reached sexual maturity, showing normal serum values of phenylalanine (Phe) (subgroup 1), and 30 subjects were sexually mature (Tanner 5 stage), showing either normal serum Phe (18 cases; subgroup 2a) or increased serum Phe (12 cases; subgroup 2b). DXA-assessed spine and total body (TB) measurements [bone mineral density (BMD), bone mineral content (BMC), lean body mass (LBM) and the calculated ratios BMC/LBM] as well as laboratory parameters (serum carboxyterminal telopeptide of type I collagen, bone alkaline phosphatase, osteocalcin, parathormone, calcitonin, total and ionized calcium) were analyzed. Statistically significant differences were revealed between subgroup 1 versus 2a for TB BMC/LBM ratio SD scores and between subgroup 2a versus 2b for TB BMD, spine BMD, TB BMC/LBM ratio and spine BMC/LBM ratio SD scores. Stepwise multiple regression analysis revealed that serum Phe negatively affected bone status. The skeletal status in children with PKU is impaired by the disease. Applying body composition parameters instead of BMD alone may reflect the level of impairment in a new, different way.     

The effect of cyclical intravenous pamidronate in children and adolescents with osteogenesis imperfecta type V

Intravenous treatment with pamidronate is beneficial in children and adolescents with moderate to severe forms of osteogenesis imperfecta (OI) types I, III and IV, but there is little information on the effects of this treatment on the newly described OI type V. Here, we describe the results of 2 years of pamidronate treatment in 11 children and adolescents with OI type V (age at start of therapy 1.8 to 15.0 years; 6 girls). Pamidronate was given in intravenous cycles at a cumulative yearly dose of 9 mg/kg. The first infusion cycle was associated with fever and mild hypocalcemia in most patients, but no other short-term side effects were noted. Two years of pamidronate treatment led to a decrease in the urinary excretion of N-terminal telopeptide of type I collagen to 50% of baseline levels. Both the size and volumetric bone mineral density of lumbar vertebrae increased compared to age- and sex-matched reference data (P < 0.05 in both cases). Histomorphometry of transiliac bone samples showed an average increase of 86% in cortical thickness (N = 7; P = 0.005). No significant changes with treatment were observed in the age-related z scores of isometric maximal grip force and height. Fracture incidence decreased from 1.5 fractures per year before treatment to 0.5 fractures per year during the fist 2 years of treatment. Ambulation status improved in four patients and remained unchanged in the others. In conclusion, the intravenous pamidronate therapy has a similar effect in OI type V as it has in the other OI types.     

Large Osteoclasts in Pediatric Osteogenesis Imperfecta Patients Receiving Intravenous Pamidronate

Intravenous pamidronate is widely used to treat children with moderate to severe osteogenesis imperfecta (OI). Changes in the appearance of osteoclasts have previously been noted in children receiving pamidronate and have been interpreted as signs of toxicity. In this study, we analyzed osteoclast parameters in paired iliac bone specimens before and after 2–4 yr of cyclical intravenous pamidronate therapy in 44 pediatric OI patients (age range: 1.4–17.5 yr; 21 girls). During pamidronate treatment, average osteoclast diameter and the mean number of nuclei present per osteoclast increased by 18% (p = 0.02) and 43% (p < 0.001), respectively. The number of samples containing large osteoclasts (LOcs, diameter > 50 μm) increased from 6 (14%) before treatment to 23 (52%) after pamidronate therapy (p < 0.001 by χ² test). Post‐treatment samples containing LOcs had a greater core width (p = 0.04) and a higher cancellous bone volume per tissue volume (p < 0.001), because cancellous bone volume had increased more during pamidronate treatment (p < 0.001). Osteoclast number and surface were higher in samples with LOcs, but there was no difference in cancellous bone formation parameters. The presence of LOcs was independent of OI type, type of collagen type I mutation, lumbar spine BMD, and other clinical or biochemical measures. In conclusion, this study did not show any indication that LOcs during pamidronate treatment are indicative of toxicity. It seems more likely that the observed abnormalities in osteoclast morphology are part of the mechanism of action of this drug.