The effects of intravenous pamidronate on the bone tissue of children and adolescents with osteogenesis imperfecta.

Cyclical pamidronate infusions increase bone mass in children suffering from osteogenesis imperfecta. The histological basis for these effects remains unknown. Therefore, we compared parameters of iliac bone histomorphometry from 45 patients before and after 2.4 +/- 0.6 years of pamidronate treatment (age at the time of the first biopsy, 1.4-17.5 years; 23 girls). Although biopsy size did not change significantly (P = 0.30), cortical width increased by 88%. Cancellous bone volume increased by 46%. This was due to a higher trabecular number, whereas trabecular thickness remained stable. Bone surface-based indicators of cancellous bone remodeling decreased by 26-75%. There was no evidence for a mineralization defect in any of the patients. These results suggest that, in the growing skeleton, pamidronate has a twofold effect. In remodeling, bone resorption and formation are coupled and consequently both processes are inhibited. However, osteoclasts and osteoblasts are active on different surfaces (and are thus uncoupled) during modeling of cortical bone. Therefore resorption is selectively targeted, and continuing bone formation can increase cortical width.

Intracortical remodeling during human bone development--a histomorphometric study.

Although intracortical bone remodeling is a key aspect of bone physiology, very little is known about this process during human bone development. In this study, we examined transiliac bone samples from 56 individuals between 1.5 and 22.9 years of age (31 female; tetracycline labeling present in 42 subjects) who did not have evidence of metabolic bone disease. Parameters of osteonal structure (osteon diameter, wall thickness, diameter of osteonal canals) and dynamic measures of intracortical remodeling were determined separately for the external and internal cortex. We found that measures of osteonal structure were independent of age. However, the percentage of osteons showing metabolic activity was lower in the older study subjects, corresponding to a slowdown in the turnover of cortical bone. Most dynamic parameters of bone metabolism were higher in the internal cortex than in the external cortex. Cortical porosity was negatively associated with age on the external, but not on the internal cortex. The bone forming activity that refills the remodeling cavities seemed to favor the side of the osteonal canal that faced towards the periosteum. In summary, intracortical remodeling activity varies markedly during bone development, and is slightly asymmetric between the two cortices of an iliac bone specimen. Remodeling during development is thus an age-dependent process that varies with location even within the same bone.

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.

Cellular activity on the seven surfaces of iliac bone: a histomorphometric study in children and adolescents.

UNLABELLED: Transiliac cortical bone histomorphometry was performed in 56 metabolic bone disease-free individuals 1.5-22.9 years of age. During the growing years, the two cortices of an iliac bone specimen differ with regard to bone cell activity on their surfaces, probably reflecting a modeling drift. INTRODUCTION: Standard bone histomorphometry in the clinical setting is typically limited to the analysis of cancellous bone. However, during the growth period, important changes occur also in the cortical compartment. MATERIALS AND METHODS: Transiliac bone samples from 56 individuals between 1.5 and 22.9 years of age (25 male; tetracycline labeling present in 42 subjects) and without evidence of metabolic bone disease were analyzed. Each of the three bone surface types (periosteal, intracortical, endocortical) of each cortex was evaluated separately. Results were expressed relative to those obtained in trabecular bone. RESULTS: A significant increase in cortical width with age was detected only for the internal cortex. Porosity of the external cortex was highest in the 7- to 10.9-year age group and decreased thereafter, whereas there was no clear trend with age for the porosity of the internal cortex. Intracortical remodeling activity decreased after 14 years of age. Periosteal bone formation was very active until 13 years of age, but was close to zero in subjects above that age. As to endocortical surfaces, all bone surface-based parameters of bone formation were higher on the internal cortex than on the external cortex, whereas bone resorption parameters were higher on the external cortex. CONCLUSIONS: In growing subjects, the two cortices of an iliac bone specimen differ with regard to bone cell activity on their surfaces. These data raise fundamental questions about the regulation of bone cell activity in children and adolescents.

Pamidronate in children with osteogenesis imperfecta: histomorphometric effects of long-term therapy.

CONTEXT: Intravenous pamidronate treatment is beneficial to children and adolescents with osteogenesis imperfecta (OI), but the effects of prolonged therapy are not well characterized. OBJECTIVE: The objective of this study was to assess the effect of long-term pamidronate treatment on the bone tissue of children and adolescents with OI. DESIGN: This is an observational study on OI patients receiving iv pamidronate for more than 4 yr. SETTING: The study was carried out in a pediatric metabolic bone research unit. PATIENTS: Patients were 25 moderately to severely affected OI patients (seven girls) aged 1.4-15.3 yr at baseline. INTERVENTION: Intervention was cyclical iv pamidronate at a dose of 9 mg/kg.yr. MAIN OUTCOME MEASURES: Iliac bone biopsy and lumbar spine bone mineral density measures were obtained at treatment start, after 2.7 +/- 0.5 yr (mean +/- sd), and after 5.5 +/- 0.7 yr of therapy. RESULTS: Average areal bone mineral density increased by 72% in the first half of the observation period, but by only 24% in the second half. Mean cortical width and cancellous bone volume increased by 87 and 38%, respectively, between baseline and the first time point during treatment (P < 0.001 for all changes). Thereafter, cortical width did not change significantly, but there was a trend (P = 0.06) toward higher cancellous bone volume. Average bone formation rate on trabecular surfaces decreased by 70% after pamidronate treatment was initiated and showed a trend (P = 0.08) toward a further decline in the second part of the study interval. CONCLUSION: The gains that can be achieved with pamidronate treatment appear to be largely realized in the first 2-4 yr.

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.

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

UNLABELLED: 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.

Bone mineralization in polyostotic fibrous dysplasia: histomorphometric analysis.

Fibrous dysplasia (FD) of bone can be complicated by renal phosphate wasting. The effect of hypophosphatemia on normal and dysplastic bone of FD patients has not been well characterized. In this study, we compared serum phosphorus (sPi) levels to histomorphometric findings in 27 iliac bone samples from 23 children and adolescents (aged 4.2-16.4 years) with polyostotic FD. The samples were separated into two groups, based on the presence (n = 10) or absence (n = 17) of a dysplastic lesion within the specimen. Histomorphometric results were compared with those from 18 age-matched control subjects without metabolic bone disease. In dysplastic lesions, trabeculae were clearly thinner and increased in number. Osteoid indices, osteoblast surface per bone surface, and mineralization lag time were elevated in dysplastic areas, but there was no detectable effect of sPi concentrations on these indices. In nondysplastic bone tissue, low sPi levels were associated with mildly increased osteoid thickness and prolonged mineralization lag time. None of the 13 patients in whom hand X-rays were available at the time of biopsy had radiological signs of rickets. In conclusion, low sPi can cause a mild systemic mineralization defect in FD, but the more severe mineralization defect seen in dysplastic lesions is independent of sPi levels. It is debatable whether the mild systemic mineralization defect warrants treatment with oral phosphorus supplementation if signs of rickets are absent.

Osteogenesis imperfecta type VI: a form of brittle bone disease with a mineralization defect.

Osteogenesis imperfecta (OI) is a heritable disease of bone in which the hallmark is bone fragility. Usually, the disorder is divided into four groups on clinical grounds. We previously described a group of patients initially classified with OI type IV who had a discrete phenotype including hyperplastic callus formation without evidence of mutations in type I collagen. We called that disease entity OI type V. In this study, we describe another group of 8 patients initially diagnosed with OI type IV who share unique, common characteristics. We propose to name this disorder "OI type VI." Fractures were first documented between 4 and 18 months of age. Patients with OI type VI sustained more frequent fractures than patients with OI type IV. Sclerae were white or faintly blue and dentinogenesis imperfecta was uniformly absent. All patients had vertebral compression fractures. No patients showed radiological signs of rickets. Lumbar spine areal bone mineral density (aBMD) was low and similar to age-matched patients with OI type IV. Serum alkaline phosphatase levels were elevated compared with age-matched patients with type IV OI (409 +/- 145 U/liter vs. 295 +/- 95 U/liter; p < 0.03 by t-test). Other biochemical parameters of bone and mineral metabolism were within the reference range. Mutation screening of the coding regions and exon/intron boundaries of both collagen type I genes did not reveal any mutations, and type I collagen protein analyses were normal. Qualitative histology of iliac crest bone biopsy specimens showed an absence of the birefringent pattern of normal lamellar bone under polarized light, often with a "fish-scale" pattern. Quantitative histomorphometry revealed thin cortices, hyperosteoidosis, and a prolonged mineralization lag time in the presence of a decreased mineral apposition rate. We conclude that type VI OI is a moderate to severe form of brittle bone disease with accumulation of osteoid due to a mineralization defect, in the absence of a disturbance of mineral metabolism. The underlying genetic defect remains to be elucidated.

Osteogenesis imperfecta types I, III, and IV: effect of pamidronate therapy on bone and mineral metabolism.

Cyclical iv 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 bone and mineral metabolism in 165 patients with OI types I, III, and IV (age, 2 wk to 17.9 yr; 86 girls and 79 boys). All patients received iv pamidronate infusions on 3 successive days, administered at age-dependent intervals of 2-4 months. During the 3 d of the first infusion cycle, serum concentrations of ionized calcium dropped by 0.14 +/- 0.008 mmol (mean +/- SE; P < 0.001), and serum PTH levels transiently almost doubled (P < 0.001). At the same time, urinary excretion of the bone resorption marker type I collagen N-telopeptide related to creatinine (uNTX/uCr) decreased by 61-73% (P < 0.001). Two to 4 months later, ionized calcium had returned to pretreatment levels, and uNTX/uCr remained 30-35% lower than at baseline (P < 0.001). During 4 yr of pamidronate therapy (n = 40 patients), ionized calcium levels remained stable, but PTH levels increased by about 30% (P < 0.01). uNTX/uCr, expressed as a percentage of the age- and sex-specific mean value in healthy children, decreased from 132 +/- 13% (mean +/- SE) at baseline to 49 +/- 3% after 4 yr of therapy (P < 0.001). In conclusion, serum calcium levels can decrease considerably during and after pamidronate infusions, requiring close monitoring especially at the first infusion cycle. In long-term therapy, bone turnover is suppressed to levels lower than those in healthy children. The consequences of chronically low bone turnover in children with OI are unknown at present.

Effect of pamidronate treatment in children with polyostotic fibrous dysplasia of bone.

Intravenous infusions with the bisphosphonate compound pamidronate decrease bone pain and reportedly can lead to refilling of dysplastic lesions in adults with fibrous dysplasia (FD) of bone. Here we describe the effects of this treatment approach in 18 children and adolescents (age at start of therapy, 6.2-17.5 yr; eight girls) with polyostotic FD, who received pamidronate for 1.2-9.1 yr (median, 3.8 yr). Treatment cycles with pamidronate (1-1.5 mg/kg.d on 3 consecutive days) were given every 4 months. Levels of serum alkaline phosphatase and urinary collagen type I N-telopeptide were elevated at baseline and decreased continuously during the first 3 yr of therapy. There was no radiographic evidence of filling of lytic lesions or thickening of the bone cortex surrounding the lesions in any patient. Histomorphometric results in dysplastic bone tissue of patients receiving pamidronate (n = 7; time of therapy, 1.4-4.8 yr) were similar to those of patients without medical therapy (n = 9). No serious side effects were noted. In conclusion, pamidronate therapy appears to be safe in children and adolescents with polyostotic FD. However, we found no clear evidence that pamidronate has an effect on dysplastic lesions in such patients.

Three children with lower limb fractures and a mineralization defect: a novel bone fragility disorder?

In this report, we describe three unrelated children with an apparently novel bone fragility disorder that is associated with an idiopathic mineralization defect. Recurrent lower limb fractures started with weight bearing. The patients had none of the phenotypic, radiological, or histomorphometric features classically associated with known bone fragility disorders such as osteogenesis imperfecta (OI), idiopathic juvenile osteoporosis (IJO), or mild autosomal dominant osteopetrosis. Radiologically, there was increased metaphyseal trabeculation, normal to increased cortical thickness, and no evidence of rickets or osteomalacia. Areal and volumetric bone mineral density (BMD) of the lumbar spine did not show any major alteration. Peripheral quantitative computed tomography of the radius showed elevated cortical thickness and total and trabecular volumetric bone mineral density in one patient. Qualitative histology of iliac bone biopsy specimens showed a paucity of the birefringent pattern of normal lamellar bone. Quantitative histomorphometric analysis demonstrated osteomalacia with a prolonged mineralization lag time in the presence of a decreased mineral apposition rate. There was no biochemical evidence of abnormal calcium or phosphate metabolism. Type I collagen mutation analysis was negative. We conclude that this is a bone fragility disorder of moderate severity that tends to cause fractures in the lower extremities and is associated with the accumulation of osteoid due to an intrinsic mineralization defect. The pathogenetic basis for this disorder remains to be elucidated.

Mutations in SERPINF1 cause osteogenesis imperfecta type VI.

Osteogenesis imperfecta (OI) is a spectrum of genetic disorders characterized by bone fragility. It is caused by dominant mutations affecting the synthesis and/or structure of type I procollagen or by recessively inherited mutations in genes responsible for the posttranslational processing/trafficking of type I procollagen. Recessive OI type VI is unique among OI types in that it is characterized by an increased amount of unmineralized osteoid, thereby suggesting a distinct disease mechanism. In a large consanguineous family with OI type VI, we performed homozygosity mapping and next-generation sequencing of the candidate gene region to isolate and identify the causative gene. We describe loss of function mutations in serpin peptidase inhibitor, clade F, member 1 (SERPINF1) in two affected members of this family and in an additional unrelated patient with OI type VI. SERPINF1 encodes pigment epithelium-derived factor. Hence, loss of pigment epithelium-derived factor function constitutes a novel mechanism for OI and shows its involvement in bone mineralization.

Urinary excretion of cross-linked N-telopeptides of type 1 collagen to assess bone resorption in infants from birth to 1 year of age.

OBJECTIVES: To evaluate noninvasively bone resorption in infants and more specifically, to assess the accuracy of urinary collagen type 1 cross-linked N-telopeptide (NTX) excretion normalized to creatinine (NTX/Cr) in a spot urine sample as a reflection of daily NTX production in infants and to compute normative values for NTX excretion from birth to 1 year of age. METHODS: NTX/Cr values obtained from a single spot urine sample were compared with daily urinary NTX excretion and NTX/Cr obtained in 24-hour urine collected from 8 hospitalized infants. Normative values for NTX excretion were collated with a cross-sectional study in 70 healthy French infants (42 boys, 28 girls) aged 0 to 374 days (weight: 2700-11 340 g; length: 46-76.5 cm) and free of diseases or treatments that could influence growth, bone mineralization, or renal function. RESULTS: NTX/Cr values from single spot urine sample were significantly and linearly correlated with both daily NTX excretion (r = 0.783) and daily NTX/Cr (r = 0.952). In healthy infants, NTX excretion is low at birth, increases dramatically and significantly during the first 10 days of life, remains significantly elevated for approximately 3 months, and then decreases progressively to return to values similar to that observed at birth by 1 year of age. CONCLUSIONS: These data provide new insights regarding the use of spot urine analysis for assessing NTX excretion during the first year of life. The normative data demonstrate significant age-related variations in this marker, which probably reflect adaptation to extrauterine life and accelerated bone turnover in infancy and which should be considered for the interpretation of this noninvasive bone resorption marker in the clinical setting.