Rose Travers

Cyclic administration of pamidronate in children with severe osteogenesis imperfecta.

BACKGROUND Severe osteogenesis imperfecta is a disorder characterized by osteopenia, frequent fractures, progressive deformity, loss of mobility, and chronic bone pain. There is no effective therapy for the disorder. We assessed the effects of treatment with a bisphosphonate on bone resorption. METHODS In an uncontrolled observational study involving 30 children who were 3 to 16 years old and had severe osteogenesis imperfecta, we administered pamidronate intravenously (mean [+/-SD] dose, 6.8+/-1.1 mg per kilogram of body weight per year) at 4-to-6-month intervals for 1.3 to 5.0 years. Clinical status, biochemical characteristics reflecting bone turnover, the bone mineral density of the lumbar spine, and radiologic changes were assessed regularly during treatment. RESULTS Administration of pamidronate resulted in sustained reductions in serum alkaline phosphatase concentrations and in the urinary excretion of calcium and type I collagen N-telopeptide. There was a mean annualized increase of 41.9+/-29.0 percent in bone mineral density, and the deviation of bone mineral density from normal, as indicated by the z score, improved from -5.3+/-1.2 to -3.4+/-1.5. The cortical width of the metacarpals increased by 27+/-20.2 percent per year. The increases in the size of the vertebral bodies suggested that new bone had formed. The mean incidence of radiologically confirmed fractures decreased by 1.7 per year (P<0.001). Treatment with pamidronate did not alter the rate of fracture healing, the growth rate, or the appearance of the growth plates. Mobility and ambulation improved in 16 children and remained unchanged in the other 14. All the children reported substantial relief of chronic pain and fatigue. CONCLUSIONS In children with severe osteogenesis imperfecta, cyclic administration of intravenous pamidronate improved clinical outcomes, reduced bone resorption, and increased bone density.

Type V Osteogenesis Imperfecta: A New Form of Brittle Bone Disease

Osteogenesis imperfecta (OI) is commonly subdivided into four clinical types. Among these, OI type IV clearly represents a heterogeneous group of disorders. Here we describe 7 OI patients (3 girls), who would typically be classified as having OI type IV but who can be distinguished from other type IV patients. We propose to call this disease entity OI type V. These children had a history of moderate to severe increased fragility of long bones and vertebral bodies. Four patients had experienced at least one episode of hyperplastic callus formation. The family history was positive for OI in 3 patients, with an autosomal dominant pattern of inheritance. All type V patients had limitations in the range of pronation/supination in one or both forearms, associated with a radiologically apparent calcification of the interosseous membrane. Three patients had anterior dislocation of the radial head. A radiodense metaphyseal band immediately adjacent to the growth plate was a constant feature in growing patients. Lumbar spine bone mineral density was low and similar to age‐matched patients with OI type IV. None of the type V patients presented blue sclerae or dentinogenesis imperfecta, but ligamentous laxity was similar to that in patients with OI type IV. Levels of biochemical markers of bone metabolism generally were within the reference range, but serum alkaline phosphatase and urinary collagen type I N‐telopeptide excretion increased markedly during periods of active hyperplastic callus formation. Qualitative histology of iliac biopsy specimens showed that lamellae were arranged in an irregular fashion or had a meshlike appearance. Quantitative histomorphometry revealed decreased amounts of cortical and cancellous bone, like in OI type IV. However, in contrast to OI type IV, parameters that reflect remodeling activation on cancellous bone were mostly normal in OI type V, while parameters reflecting bone formation processes in individual remodeling sites were clearly decreased. Mutation screening of the coding regions and exon/intron boundaries of both collagen type I genes did not reveal any mutations affecting glycine codons or splice sites. In conclusion, OI type V is a new form of autosomal dominant OI, which does not appear to be associated with collagen type I mutations. The genetic defect underlying this disease remains to be elucidated.

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.

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.

Normative data for iliac bone histomorphometry in growing children.

Many insights into normal and pathologic bone development can only be gained by bone histomorphometry. However, the use of this technique in pediatrics has so far been hampered by the lack of reference data. Therefore, we obtained transfixing iliac bone samples from 58 individuals between 1.5 and 22.9 years of age (25 male; tetracycline labeling performed in 48 subjects), who underwent surgery for reasons independent of abnormalities in bone development and metabolism. The results of histomorphometric analyses of cancellous parameters and cortical width are presented as means and standard deviations, as well as medians and ranges in five age groups. In addition, the original data are available from the authors. There were significant age-dependent increases in both cortical width and cancellous bone volume, the latter being due to an increase in trabecular thickness. Osteoid thickness did not vary significantly with age. Bone surface-based indicators of bone formation showed an age-dependent decline, reflecting similar changes in activation frequency. Mineral apposition rate decreased continuously with age. Parameters of bone resorption did not vary significantly between age groups. Paired biopsies from adjacent sites, obtained in eight subjects, were used to examine the reproducibility of histomorphometric parameters in children. The lowest coefficients of variation (<10%) were found for structural measures, as well as mineral apposition rate and wall thickness. The highest variability was found for cellular parameters. The availability of reference material will greatly facilitate the use of histomorphometry in pediatrics.

Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease.

Osteogenesis imperfecta (OI) is a heritable disease of bone with low bone mass and bone fragility. The disease is generally classified into four types based on clinical features and disease severity, although recently fifth and sixth forms have also been reported. Most forms of OI are autosomal dominant. Rarely, autosomal recessive disease has been described. We report the clinical, radiological, and histological features of four children (age 3.9-8.6 years at last follow-up; all girls) and four adults (age 28-33 years; two women) with a novel form of autosomal recessive OI living in an isolated First Nations community in northern Quebec. In keeping with the established numeric classification for OI forms, we have called this form of the disease OI type VII. The phenotype is moderate to severe, characterized by fractures at birth, bluish sclerae, early deformity of the lower extremities, coxa vara, and osteopenia. Rhizomelia is a prominent clinical feature. Histomorphometric analyses of iliac crest bone samples revealed findings similar to OI type I, with decreased cortical width and trabecular number, increased bone turnover, and preservation of the birefringent pattern of lamellar bone. The disease has subsequently been localized to chromosome 3p22-24.1, which is outside the loci for type I collagen genes. The underlying genetic basis for the disease remains to be determined.

Temporal and spatial expression of bone morphogenetic protein-2, -4, and -7 during distraction osteogenesis in rabbits

The Ilizarov method of limb lengthening makes use of the fact that osteogenesis is induced at an osteotomy site when distraction is applied. It is unknown at present how the mechanical forces created by distraction are translated into biological signals. Because bone morphogenetic proteins (BMPs) are potent inducers of osteogenesis in many experimental systems, they are obvious candidates for playing a role in this process. In this study, we investigated the temporal and spatial expression of BMP-2, -4, and -7 proteins during distraction osteogenesis using immunohistochemistry. An osteotomy was performed on the right tibiae of white New Zealand rabbits. After a delay of 7 days, distraction was started at a rate of 0.25 mm/12 h for 3 weeks, followed by a 3 week consolidation phase. Each week after osteotomy one rabbit was killed for immunohistochemical studies. Staining for BMP-2, -4, and -7 was evident before distraction was applied and was mainly localized to mesenchymal cells and osteoblastic cells in the periosteal region. After distraction was started, the typical fibrous interzone developed between the osteotomy fragments, where both intramembranous and endochondral ossification were noted. In this area, cells resembling fibroblasts and chondrocytes, but not mature osteoblasts, showed intense staining for all three BMPs. This high level of expression was maintained during the entire distraction phase and then gradually disappeared during the consolidation phase. These results are compatible with the hypothesis that BMPs play an important role in the signaling pathways that link the mechanical forces created by distraction to biological responses.

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.

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.

Sclerotic metaphyseal lines in a child treated with pamidronate: histomorphometric analysis.

CYCLICAL INTRAVENOUS THERAPY with pamidronate is increasingly used to treat children and adolescents with osteogenesis imperfecta (OI) and other osteopenic disorders in children. In OI patients, histomorphometric studies of iliac bone samples have shown that this treatment increases cortical thickness and the amount of trabecular bone, but suppresses bone turnover. Typically pamidronate is given in intravenous infusion cycles that are repeated every month to every 4 months. As long as growth continues, each of these infusion cycles leaves a dense transverse line in the metaphysis. The histological nature of these metaphyseal lines has not been elucidated, but it has been speculated that they consist of calcified cartilage and might reduce biomechanical strength. For obvious reasons, it is difficult to obtain bone tissue from sites where these sclerotic lines are most conspicuous radiographically, i.e., in fast growing long bones. Nevertheless, sclerotic lines are also observed in the iliac wing, which has an apophyseal growth plate (Fig. 1A). This is close to the location where bone biopsy samples are typically obtained for histomorphometric analysis. Although our standard site for transiliac biopsy specimens is 2 cm distal from the apophyseal growth cartilage, growth plate tissue is sometimes inadvertently included in a biopsy specimen. This reduces the value of the specimen for histomorphometric analysis, but offers the opportunity to study sclerotic lines associated with pamidronate treatment. The present patient was a 12-year-old girl with OI type VII who had received cyclical intravenous pamidronate every 4 months for the past 6.9 years. A biopsy of the left iliac bone was performed after dual tetracycline labeling as part of a follow-up program of long-term pamidronate therapy. The sample was embedded in polymethylmetacrylate, sectioned, and stained with Goldner-Masson Trichrome, as described in detail previously. The entire cancellous bone compartment excluding the endocortical surfaces was analyzed histomorphometrically in three sections that were separated by at least 150 m, as described previously. Results were compared with age-matched reference data. Trabecular bone volume per tissue volume of the entire cancellous bone compartment was in the upper one-half of the reference range (30.9%; age-specific reference values: 24.4 4.3%), with normal trabecular thickness (132 m; reference, 148 23 m; Fig. 1B). An identically processed iliac bone sample obtained at the start of pamidronate therapy (6.9 years earlier) had revealed a trabecular bone volume of 12.2% (Fig. 1C). Thus, trabecular bone volume had increased about 2.5-fold during the treatment period. The bone obtained after pamidronate treatment was arranged in bands parallel to the growth plate (Fig. 1B). The distance between the bands was 1.0–1.3 mm. This was similar to the distance between sclerotic lines in the corresponding radiograph (Fig. 1A). In the band closest to the growth plate, about one-quarter of the mineralized tissue consisted of calcified cartilage (Table 1). The relative amount of cartilage decreased continuously with increasing distance from the growth plate. Averaged over the entire cancellous compartment, parameters of bone formation were within normal limits (e.g., bone formation rate per bone surface was 52 m/ m/year; reference, 37 17 m/ m/year), whereas resorption parameters were elevated (osteoclast surface per bone surface was 2.3%; reference, 0.94 0.38%; the number of osteoclasts per bone perimeter was 0.82/mm; reference, 0.29 0.14/mm). As noted in our previous studies, many of the osteoclasts were unusually large, with a high number of nuclei (compare Figs. 1D and 1E). The increased number of osteoclasts probably reflects the fact that bone turnover is usually elevated close to the growth plate. It is expected that bone formation parameters should be equally elevated at that location, but bone formation rate was within normal limits. This is in accordance with our earlier observation that pamidronate has a more pronounced suppressive effect on histomorphometric parameters of bone formation than on the number of osteoclasts. This lack of treatment effect on osteoclast number may seem paradoxical with an antiresorptive therapy, but pamidronate may exert its effect through interference with The authors have no conflict of interest.