Intravenous Pamidronate in Osteogenesis Imperfecta Type VII

Cyclical intravenous treatment with pamidronate is widely used to treat osteogenesis imperfecta (OI) types I, III, and IV, which are due to dominant mutations affecting collagen type I alpha chains. There is no information about the effects of pamidronate in children with OI type VII, an autosomal-recessive form of OI caused by a mutation in the cartilage-associated protein gene. In this retrospective single-center study, we compared the effects of pamidronate in four girls with OI type VII (age range 3.9–12.7 years) to those in eight girls with OI types caused by collagen type I mutations who were matched for age and disease severity. During 3 years of pamidronate therapy, lumbar spine areal bone mineral density increased and lumbar vertebral bodies improved in shape in patients with OI type VII. Other outcomes such as fracture rates and mobility scores did not show statistically significant changes in this small study cohort. There were no significant side effects noted during the time of follow-up. Thus, intravenous treatment with pamidronate seems to be safe and of some benefit in patients with OI type VII.     

The Interaction Between Sillence Type and BMD in Osteogenesis Imperfecta

Clinical studies with bisphosphonates in children with osteogenesis imperfecta (OI) show an increase in BMD and a decrease in fracture rate. Bone strength in children with OI is not only influenced by changes in BMD but also by changes in collagen I structure of the organic bone matrix. Therefore, we studied the interaction between these two factors in a cross-sectional, single center study including 54 children. We assumed that vertebral deformities in OI represent an unbalance between load and bone strength. Body weight was considered to be a well quantifiable load on vertebral bodies. BMD served as a marker, representing the amount of bone tissue available for vertebral load bearing, and the Sillence classification, either type I or III/IV, as a marker representing the quality of the organic bone matrix. Independent associations were observed between the prevalence of vertebral deformities and (1) Sillence type (OR: 5.7, 95%Cl:1.2–26.8), (2) BMD (OR: 0.003, 95%Cl: 0–0.25) and (3) body weight (OR: 1.15, 95%Cl: 1.05–1.25). Regarding the anthropometrical differences among the different types of OI, the BMD/body weight ratio was introduced to evaluate the BMD in relation to body size. Prevalent vertebral deformities were associated with low BMD/body weight ratios (OR: 0.04, 95%Cl: 0.008–0.2) in OI type I, but no association was found in type III/IV. It was concluded that BMD and Sillence type have independent relationships with vertebral deformities. The BMD/body weight ratio correlates with vertebral deformities in children with OI type I. Its meaning in types III/IV needs further research with larger samples because of the relatively high prevalence of vertebral deformities in this group.     

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.     

Risedronate in the Treatment of Mild Pediatric Osteogenesis Imperfecta: A Randomized Placebo‐Controlled Study

Intravenous pamidronate is the most widely used treatment for moderate to severe osteogenesis imperfecta (OI). Currently, there is no medical treatment for patients with mild OI. We conducted a single‐center randomized double‐blind placebo‐controlled trial to examine the efficacy and safety of oral risedronate in the treatment of pediatric patients with mild OI. A total of 26 children and adolescents (age, 6.1–17.7 yr; 11 girls) with OI type I were randomized to either placebo (N = 13) or risedronate (N = 13) for 2 yr. Risedronate doses were 15 mg once per week in patients weighing <40 kg and 30 mg once per week in patients weighing >40 kg. After 2 yr of treatment, risedronate decreased serum levels of the bone resorption marker collagen type I N‐telopeptide by 35% compared with a 6% reduction with placebo (p = 0.003). Risedronate increased lumbar spine areal BMD Z‐scores by 0.65, whereas patients receiving placebo experienced a decrease of 0.15 (p = 0.002). In contrast, no significant treatment differences in bone mass and density were found at the radial metaphysis and diaphysis, the hip, and the total body. Histomorphometric analysis of transiliac bone biopsies at the end of the study period did not show a significant treatment difference in cortical width, trabecular bone volume, or parameters of bone turnover. Similarly, there was no detectable treatment effect on vertebral morphometry, second metacarpal cortical width, grip force, bone pain, or number of new fractures. Regarding safety, risedronate was generally well tolerated, and the incidence of clinical or laboratory adverse experiences was similar among treatment groups. These results suggest that the skeletal effects of oral risedronate are weaker than those that are commonly observed with intravenous pamidronate treatment but still lead to an increase in lumbar spine areal BMD. Future studies should investigate whether oral risedronate is effective in reducing fracture rates in children and adolescents with mild OI type I.     

Differing Lumbar Vertebral Mineralization Rates in Ambulatory Pediatric Patients with Osteogenesis Imperfecta

The purpose of this study was to evaluate serial changes in bone mineral density (BMD) of the lumbar spine in individual children and adolescents with untreated osteogenesis imperfecta (OI) using dual X-ray absorptiometry (DXA). Twenty-seven pediatric patients with OI who had no historical or radiographic evidence of lumbar fracture, required no assistive device for mobility, and were taking no medications known to affect skeletal mineralization during the study period comprised the investigational group. Absolute BMD and age- and gender-matched BMD (Z-scores) were assessed relative to standard parameters of growth (height, weight, age, height adjusted for age and gender and body surface area) and severity of disease (lifetime fracture rate). The spinal mineralization rate (SMR) between examinations for 15 patients with more than one measurement (n= 20 intervals) was expressed as the magnitude of the change in BMD Z-score per year. Both BMD and BMD Z-score were closely correlated with height, height Z-score, weight and body surface area and were inversely related to fracture rate (P < 0.001 for all comparisons). BMD was also highly correlated with patient age (P < 0.001). Stepwise regression analysis showed that together height Z-score and lifetime fracture rate improved the prediction of BMD Z-score (r= 0.71; P < 0.001). SMRs ranged from −0.5 to 3.5. The average change in SMR between sequential measurements was 168% for the five children who had more than two DXA examinations. Linear regression showed a significant negative correlation between SMR and height Z-score (r=−0.79, P < 0.001). We conclude that vertebral body size is a critical determinant of BMD and BMD Z-score in OI because DXA results are expressed per unit area, not per unit volume. Pediatric patients with OI mineralize their lumbar vertebrae at rates similar to healthy children but tend to lag behind in overall mineralization. The rate of mineralization at any age appears to be related to the patient's height (adjusted for age- and gender-matched controls) and inversely related to the patient's lifetime rate of fractures. Our data suggest that vertebral mineralization in children with OI is related primarily to rapid increases in vertebral volume and only secondarily to increases in vertebral mineral density. Received: 2 March 1997 / Accepted: 5 June 1997     

Osteogenesis Imperfecta: Bone Turnover, Bone Density, and Ultrasound Parameters

We studied 21 patients (11 men and 10 women) with osteogenesis imperfecta (OI) and 21 age- and sex-matched controls. In all patients we measured serum levels of total alkaline phosphatase (ALP), type I procollagen carboxy-terminal propeptide (PICP), osteocalcin (BGP), urinary excretion of hydroxyproline (HOP/Cr), and pyridinoline crosslinks (Pyr/Cr). Bone mineral density was measured at the distal radius (BMD-R) and at the lumbar spine (BMD-LS) by dual X-ray absorptiometry (DXA). Ultrasound parameters were also performed at the calcaneous with the Achilles device and at the phalanxes with DBM Sonic 1200. A significant reduction (P < 0.001) in BMD and in ultrasound parameters was found in OI patients compared with normals. PICP was significantly reduced in the OI patients compared with controls (P < 0.001); other markers of bone turnover were higher in OI than in controls, but the difference did not reach the statistical significance. A significant correlation (P < 0.05) was found between PICP and BMD at the lumbar spine and between PICP and ultrasound parameters at the calcaneous. On the basis of our data, we conclude that patients with OI show low values of BMD and ultrasound parameters; therefore in these patients, not only is bone mass disturbed but also bone quality. The reduced levels of PICP in OI patients confirm that most OI patients have defects in collagen I biosynthesis. These defects may contribute to the fragility of OI bone by interfering with complete mineralization and/or normal tissue structure. PICP may be considered a useful marker in the clinical management of OI. Received: 26 March 1998 / Accepted: 15 January 1999     

Bone Density Measurements by Computed Tomography in Osteogenesis Imperfecta Type I

The objectives of this study were (1) to determine whether there are differences in bone density in children versus adults with osteogenesis imperfecta type I (OI-type I) using computed tomography (CT) bone density measurements, (2) to determine whether there are differences in bone density between normal infants and infants with OI-type I using CT bone density measurements and (3) to determine whether CT bone density measurements could be helpful in investigating the infant with unexplained fractures. CT bone density measurements determine both the cortical bone density (CBD) and the trabecular bone density (TBD). CT bone density was determined using the OsteoQuant in 14 individuals with OI-type I who ranged in ages from 8 months to 45 years. The control groups consisted of over 1000 normal individuals, mostly adults, and included 7 normal infants who ranged in age from 10 months to 27 months. One of the individuals with OI-type I was a 4-month-old infant with multiple, unexplained fractures who had no other features of OI-type I and whose parents were accused of child abuse. Infants and children with OI-type I had low CBD and low TBD compared with normal controls, whereas adults with OI-type I had low TBD and high CBD when compared with controls. The one infant with multiple unexplained fractures and no other features of OI-type I had a bone density profile suggesting OI-type I with a low TBD and low CBD. Subsequent collagen analysis showed biochemical evidence of OI-type I. Individuals with OI-type I have abnormal CT bone density profiles that evolve over time from a low CBD and low TBD during infancy and childhood to a high CBD and low TBD during adulthood. This may explain the decreased frequency of fractures in individuals with OI-type I in adulthood compared with childhood. Individuals with OI-type I can present with only multiple unexplained fractures and have no other clinical features to strongly suggest the diagnosis. CT bone density measurements can be helpful in these atypical cases of OI-type I and should be considered in the investigation of the infant with unexplained fractures to help distinguish intrinsic bone disease from child abuse. Received: 19 May 1998 / Accepted: 23 September 1998     

Morphometric Analysis of Type I Collagen Fibrils in the Osteoid of Osteogenesis Imperfecta

Electron microscopy and morphometric measurements of bone osteoid collagen diameter from 42 osteogenesis imperfecta (OI) patients and 25 age- and site-matched controls were carried out. Although the mean diameter did not correlate well with the severity of the disease, it related well with the clinical types and revealed collagen fibrils of reduced diameter in the osteoid of all OI types. Thus, OI type II (the severest type) demonstrated the smallest diameter (45 nm), followed by OI type I (the mildest form) with a mean diameter of 57 nm. The diameter obtained for type III (67 nm) and type IV (64 nm) was lower than the normal control mean diameter (73 nm) but did not show a statistical difference. The thinner fibrils observed in OI bone may be unable to provide nucleating and scaffolding sites for mineral propagation and may play a role in the fragility of bone in this disease. Received: 1 June 1998 / Accepted: 23 April 1999     

Evidence that Abnormal High Bone Mineralization in Growing Children with Osteogenesis Imperfecta is not Associated with Specific Collagen Mutations

Osteogenesis imperfecta type I (OI-I) represents the mildest form of OI. The collagen I mutations underlying the disorder can be classified as quantitative mutations that lead to formation of a decreased amount of normal collagen or qualitative mutations where structurally aberrant collagen chains are generated. However, the phenotypic consequences of a particular mutation are not well understood. Transiliac bone biopsies from 19 young OI-I patients (age range 2.0–14.1 years) and 19 age-matched controls were used to assess bone histomorphometric parameters and bone mineralization density distribution, measured by quantitative backscattered electron imaging. Thirteen of the OI-I patients were affected by quantitative and six patients by qualitative mutations. Compared to age-matched controls, iliac bone samples in the OI group were smaller and had thinner cortices and less trabecular bone. Resorption parameters were similar between groups, whereas surface-based parameters of bone formation were considerably higher in OI patients than in controls with the exception of bone formation rate per osteoblast surface, which was reduced in OI. Backscattered electron imaging revealed a higher mean mineralization density (+7%, P < 0.001) in OI-I patients than in age-matched controls, which was accompanied by a reduced heterogeneity of mineralization (−13%, P < 0.001). However, the increase of mean degree of mineralization in OI did not exceed the average level of normal adult bone. No differences were found between the two mutation types. In summary, the tissue- and material-level abnormalities found in OI-I (low bone mass and increased mineral content of the matrix) seem to be independent of the collagen mutations.     

The Microscopic Structure of Bone in Normal Children and Patients with Osteogenesis Imperfecta: A Survey Using Backscattered Electron Imaging

The microstructure of iliac crest biopsies from normal children or from those afflicted with osteogenesis imperfecta (OI) has not previously been studied to determine the tissue histology in the context of the degree of mineralization. The material in this study comprised 112 iliac crest biopsies from children aged 1.9–22.9 years. Fifty-eight were reference biopsies taken from children with no bone disease and the remainder were biopsies from children diagnosed as having OI (23 were Type I, 8 Type III, 18 Type IV, and 5 Type V). The specimens, which had been embedded in polymethylmethacrylate (PMMA), were micromilled and carbon coated to permit backscattered electron imaging. Reference biopsies from very young children often contained densely mineralized cartilage, and evidence of rapid cortical drift. Circumferential lamellae became a prominent feature after the toddler stage, and active remodeling and slower cortical drift continued through childhood. The biopsies from older teenagers and young adults were indistinguishable. Occasional mineralized osteocyte lacunae were detected in even the youngest children. Bone from children with OI Type I often appeared normal in microstructure and amount, but in some there was a dearth of bone and an abundance of osteocytes. Compared with age-matched controls, cortical and trabecular bone from children with OI Types III and IV were markedly sparse and very cellular, and primary osteonal systems continued to be formed later than expected. A distinguishing feature of the bone from OI Type V patients was the failure of patches of bone to mineralize, especially adjoining a reversal line. Packets of bone tissue exhibiting either considerably higher than normal or deficient mineralization would contribute to the characteristic trait of mechanical weakness. Received: 26 December 1997 / Accepted: 7 August 1998     

The Mineralization Density of Iliac Crest Bone from Children with Osteogenesis Imperfecta

We studied iliac crest biopsy cores taken from young individuals with osteogenesis imperfecta of several types, and from age-matched normals; the same samples had been used in prior studies using conventional light microscopic histomorphometric procedures. The PMMA blocks were micro-milled to a fine finish, carbon coated, and imaged using backscattered electrons (BSE) in an automated digital scanning electron microscope (SEM). For comparison of BSE signal levels between samples, microscope operation parameters were standardized by reference to halogenated dimethacrylate standards, and recording data from stereological arrays of 512*512 nonoverlapping pixels at 3.5 μm separation. All OI types showed higher average mineralization densities than age- and site-matched normals. This is interpreted as the result of the failure in matrix assembly, such that it has a higher water volume fraction available for mineral deposition. Added to the net deficit in bone quantity, the predicted higher stiffness of the more mineralized bone will account for much of the observed `brittleness' that characterizes this class of genetic disease. The mean mineralization density, which was higher in types III, IV, and V than in type I, appears to be correlated with disease severity. Received: 5 January 1998 / Accepted: 7 August 1998     

Total Hip Arthroplasty in Patients With Osteogenesis Imperfecta

BackgroundOsteogenesis imperfecta (OI) comprises a spectrum of disorders that result in bone fragility. This presents unique challenges when performing total joint arthroplasty in patients with OI. The purpose of this study is to determine the survivorship and clinical outcomes of total hip arthroplasty (THA) in patients with OI.MethodsWe retrospectively reviewed our institution’s total joint registry from 1969 to 2018 for all primary THAs in patients with a history of OI. There were 11 patients (13 hips) with a mean follow-up of 13 years (range 6-20). Survivorship free of component revision was determined using Kaplan-Meier analysis. Patient-reported clinical outcomes were assessed using Harris Hip Scores.ResultsAt final follow-up, the status of the implant was known in all 13 hips. One patient (1 hip) was deceased. Four hips (31%) underwent revision surgery at a mean of 9 years (range 5-17). Survivorship free of component revision was 52% at 20 years. Mean Harris Hip Scores at final follow-up were fair (75, 47-97), but significantly improved compared to available preoperative scores (P = .0015). No intraoperative complications occurred during the 13 primary THAs.ConclusionTHA in patients with OI is associated with high revision rates and low survivorship at long-term follow-up. Although this is a very challenging patient population, THA provided these patients with improved functional outcomes. To the authors’ knowledge, this is the largest series of primary THA in patients with OI reported in the literature and therefore provides surgeons with important data regarding the expected outcomes following THA in this unique patient population.Level of EvidenceLevel IV.     

Femurosteosynthesen mit dem Teleskopnagel nach Bailey-Dubow bei Osteogenesis imperfecta

Operationsprinzip Deformierungen des Femurs, Achsfehlstellungen oder Femurfrakturen bei Deformation des Knochens werden durch segmentale Osteotomien korrigiert und nach Aufbohren der Markh?hle mit dem Teleskopnagel nach Bailey u. Dubow [1] stabilisiert. Der mit dem Wachstum sich elongierende Nagel wird transartikul?r durch die interkondyl?re Grube des distalen Femurs verankert. T-f?rmige Verbreiterung der Nagelenden sorgen dafür, da? mit dem L?ngenwachstum des Knochens der Nagel auseinandergezogen wird.      

Serum Calcitonin and Bone Mineral Content in Patients with Osteogenesis Imperfecta

Serum calcitonin and bone mineral content in the forearm, measured by photon absorptiometry, were investigated in 21 patients with osteogenesis imperfecta tarda. The bone mineral content was significantly reduced as compared with normal controls, whereas the bone mineral content corrected for bone width was normal in adult patients but subnormal in children and young adults. Serum calcitonin did not differ significantly from that in normal individuals and no relation was found between serum calcitonin and bone mineral content.     

Gait characteristics and functional assessment of children with Type I Osteogenesis Imperfecta

The purpose of this study was to improve the evaluation process of children with type I Osteogenesis Imperfecta (OI) by providing a quantitative comparison of gait and selected functional assessments to age‐matched controls. A 14‐camera Vicon Motion Analysis System was used for gait analysis along with selected functional assessments (Pediatric Outcomes Data Collection Instrument [PODCI], Functional Assessment Questionnaire [FAQ], Faces Pain Scale‐Revised [FPS‐R]) conducted on 10 subjects with type I OI and 22 age‐matched healthy controls. The results of the OI group demonstrated abnormal gait parameters including increased double support, delayed foot off, reduced ankle range of motion and plantarflexion during third rocker, along with greater ankle power absorption during terminal stance and reduced ankle power generation during push off. The functional assessment scores of the OI group were similar to the control group for basic mobility and function, but were lower than their peers in the sports and physical function category. The evaluation of individuals with OI by means of gait analysis and selected functional assessments, along with an accurate biomechanical model of the lower extremities, is proposed to better understand and predict OI disability and improve quality of life. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res     

Abnormal Mineral Composition of Osteogenesis Imperfecta Bone as Determined by Electron Probe X-ray Microanalysis on Conventional and Cryosections

Osteogenesis imperfecta (OI) is a genetic disorder of the connective tissue characterized by frequent bone fractures. The cause of bone fragility is still unknown even though substantial work on collagen has been done. We measured the calcium to phosphorus ratio (Ca/P) of bone mineral from 35 OI bone samples and 25 age- and site-matched control specimens, using electron probe X-ray microanalysis in the transmission electron microscope. Ultra-thin cryosections and conventionally prepared resin sections were used. Cryo-ultramicrotomy avoids any possible artifactual demineralization that may occur in conventional aqueous media. The Ca/P ratio obtained by these two methods was compared and there was no statistical difference between them. The results were differentiated according to the clinical types of OI for the first time. The Ca/P ratio of OI bone mineral was lower than normal in both resin and cryosections, and mirrored the severity of the disease. OI type II had the lowest ratio (Ca/P = 1.49) compared with normal age- and site-matched controls (Ca/P = 1.69). This abnormal mineral composition in OI type II could be a contributory factor to bone fragility in OI bone. Received: 1 June 1998 / Accepted: 23 December 1998