Functional significance of bone density measurements in children with osteogenesis imperfecta

BACKGROUND: The treatment of osteogenesis imperfecta has been directed at improvement of bone mineral density, yet the importance of bone mineral density in predicting functional and clinical outcome in this patient population has not been demonstrated. We used a validated functional outcome measure to identify the relationship between bone mineral density and physical function in children with osteogenesis imperfecta, and we also evaluated the relationship of bone mineral density to the rate of surgery and fracture in patients with osteogenesis imperfecta. METHODS: Twenty patients (age range, four to seventeen years) with osteogenesis imperfecta who had undergone bone mineral densitometry as measured by dual x-ray absorptiometry of the lumbar spine, wrist, and proximal aspect of the femur between November 1999 and April 2001 were retrospectively analyzed. Functional outcome was measured with use of the Pediatric Outcomes Data Collection Instrument. These questionnaires were completed by the parents of all twenty patients and, in addition, by fifteen patients in the study who were between the ages of eleven and eighteen years. Fracture and surgery rates were calculated on the basis of the number of documented fractures and surgical procedures that the patient had had from the time of the initial presentation until the time of the latest follow-up visit. RESULTS: There were significant relationships between the bone mineral density of the lumbar spine and the scores obtained on the parent-completed questionnaires with regard to upper-extremity functioning (r = 0.57, p < 0.01), transfers and basic mobility (r = 0.55, p = 0.01), sports and physical functioning (r = 0.55, p = 0.01), and global functioning (r = 0.60, p < 0.004). There were also significant relationships between the bone mineral density of the wrist and the scores obtained on the child-completed questionnaires with regard to upper-extremity functioning (r = 0.82, p < 0.01), sports and physical functioning (r = 0.76, p < 0.01), and global functioning (r = 0.83, p = 0.001). There were significant negative relationships between the bone mineral density of the lumbar spine and the rate of fractures (r = -0.69, p < 0.001) and the bone mineral density of the lumbar spine and the rate of surgery (r = -0.60, p < 0.01). CONCLUSIONS: There is a relationship between bone mineral density and the functional outcome, rate of fracture, and rate of surgery in patients with osteogenesis imperfecta. Bone mineral density appears to be an indicator of disease severity and may be predictive of long-term functional outcome. To establish specific guidelines for treatment, more data on normative bone-mineral density in children with osteogenesis imperfecta will be needed.     

Reduced bone volumetric density and weak correlation between infection and bone markers in cystic fibrosis adult patients

Summary

In our current adult CF population, low BMD prevalence was only 20 %, lower than that historically described. We found a mild increase of serum RANK-L levels, independent from the bone resorption level. The increased fracture risk in CF may be explained by a lower tibial cortical thickness and total vBMD.

Introduction

Bone disease is now well described in cystic fibrosis (CF) adult patients. CF bone disease is multifactorial but many studies suggested the crucial role of inflammation. The objectives of this study were, in a current adult CF population, to assess the prevalence of bone disease, to examine its relationship with infections and inflammation, and to characterize the bone microarchitecture using high resolution peripheral scanner (HR-pQCT).

Methods

Fifty-six patients (52 % men, 26?±?7 years) were assessed in clinically stable period, during a respiratory infection, and finally 14 days after the end of antibiotic therapy. At each time points, we performed a clinical evaluation, lung function tests, and biochemical tests. Absorptiometry and dorso-lumbar radiographs were also performed. A subgroup of 40 CF patients (63 % men, 29?±?6 years) underwent bone microarchitecture assessment and was age- and gender-matched with 80 healthy controls.

Results

Among the 56 CF patients, the prevalence of low areal BMD (T-score?<??2 at any site), was 20 % (95 % CI: [10.2 %; 32.4 %]). After infections, serum RANK-L (+24 %, p?=?0.08) and OPG (+13 %, p?=?0.04) were increased with a stable ratio. Microarchitectural differences were mostly observed at the distal tibia, with lower total and cortical vBMD and trabecular thickness (respectively ?9.9, ?3.0, and ?5 %, p?<?0.05) in CF patients compared to controls, after adjustment for age, gender, weight, and height.

Conclusions

In this study, bone disease among adult CF patients was less severe than that previously described with only 20 % of CF patients with low BMD. We found a mild increase of biological marker levels and an impaired volumetric density of the tibia that may explain the increased fracture risk in CF population.

     

Vertebral bone mineral content in osteogenesis imperfecta

Summary Quantitative computed tomography of the lumbar spine was carried out in 28 patients with osteogenesis imperfecta (OI) in order to measure vertebral trabecular bone mineral concentration (BMC). The patients ranged in age from 6–73 years, and included 3 of the 4 major clinical subtypes of the disease. The findings underscore the heterogeneity of osteogenesis imperfecta even among family members with the same disease type. In addition, cross-sectional analysis of Type I OI patients suggests that BMC during young adulthood averages about 70% of normal, and subsequently falls more rapidly than in normal patients. BMC tends to be lower in the more severe forms of OI. Decreased BMC was not found in a few otherwise normal relatives with scoliosis or joint laxity.     

The functional muscle–bone unit in patients with osteogenesis imperfecta type I

ContextOsteogenesis imperfecta (OI) type I is a heritable bone fragility disorder that is caused by mutations affecting collagen type I. We recently showed that patients with OI type I frequently have muscle weakness. As muscle force and bone mass are usually closely related, we hypothesized that muscle weakness in OI type I could contribute to increase bone mass deficit in the lower extremities.ObjectiveTo assess the muscle–bone relationship in the lower extremities of children and adolescents with OI type I.SettingThe study was carried out in the outpatients department of a pediatric orthopedic hospital.Patients and other participantsThirty children and adolescents with OI type I (20 females; mean age [SD]: 11.2 years [3.9]) were compared with 30 healthy age- and sex-matched controls (mean age [SD]: 11.1 years [4.5]).Main outcome measuresTibia bone mineral content (BMC; mg/mm) was measured by peripheral quantitative computed tomography to estimate bone strength at the 4% and 14% sites. Lower extremity peak force (kN) was measured by mechanography using the multiple two-legged hopping test.ResultsCompared with age- and sex-matched controls, patients with OI type I had 17% lower peak force (1.3 kN vs. 1.7 kN; p = 0.002) as well as a 22% lower BMC (128 mg/mm vs. 165 mg/mm; p < 0.001). Stepwise regression analysis showed that muscle force and tibia length were positively related to bone strength (r² = 0.90, p < 0.001) whereas there was no effect of the disease status (OI vs. control).ConclusionsThese results suggest that the muscle–bone relationship is similar between children and adolescents with OI type I and healthy age and sex-matched controls. It also suggests that muscle weakness may contribute to decreased bone strength in individuals with OI type I.     

Cochlear implantation in patients with osteogenesis imperfecta.

OBJECTIVE: Hearing loss has been shown to occur in 42% to 58% of patients with osteogenesis imperfecta (OI), with deafness arising in 25% to 60% of the patients. Implantation in patients with OI is relatively rare, with only 4 prior single case reports published in the English-language literature. The goal of this study was to evaluate the feasibility and functional outcome of cochlear implantation in 2 patients with OI tarda type I with profound sensorineural hearing loss. STUDY DESIGN: Case series. SETTING: The implantations were performed in a tertiary academic referral center (Johns Hopkins University). RESULTS: Though promontory vascularity was encountered, full insertion of a normal cochlear implant array could be achieved in both cases. One-year postimplant scores demonstrated 20 to 40 dB hearing thresholds, Consonant-Nucleus-Consonant Test word scores of 54% and 70%, Consonant-Nucleus-Consonant Test phoneme scores of 75% and 83%, Hearing in Noise Test scores of 76% and 99%, and Central Institute of the Deaf Sentence Score sentence scores of 99% and 100%, for patients 1 and 2, respectively. CONCLUSIONS: Cochlear implantation in patients with OI is not only technically possible but the results are similar to implant outcomes for patients with sensorineural hearing loss from a variety of other causes. EBM rating: C.     

Skewfoot in patients with osteogenesis imperfecta

We report skewfoot deformities in two patients who have osteogenesis imperfecta. A discussion will follow proposing etiologies of skewfoot, speculating that the ligamentous laxity often present in children who have osteogenesis imperfecta may predispose the development of skewfoot.     

Musculoskeletal manifestations of mild osteogenesis imperfecta in the adult

The musculoskeletal manifestations of mild forms of osteogenesis imperfecta are not well defined in the adult. The aim of this study was to characterize the musculoskeletal manifestations and resulting impairments reported by adults with mild osteogenesis imperfecta. For this task a survey of musculoskeletal symptoms and impairments was hosted on the Osteogenesis Imperfecta Foundation web site for 6 weeks. Survey responses are reported herein. There were 111 unduplicated, adult respondents (78 female). Mean age was 40.8 years. More than one-quarter of 3,410 lifetime fractures occurred in adulthood. Nearly half of respondents reported an established diagnosis of arthritis (usually osteoarthritis), and the majority of these reported some degree of impairment attributable to arthritis. Articular pain, stiffness and instability were dominant in the large, weight-bearing joints of the lower extremities. Back pain and scoliosis were common. Of the respondents, 15% required assistance with light physical tasks and personal care. Two-thirds reported joint hyper-mobility, and one-third reported a previous tendon rupture. Complex regional pain syndrome was rare. Respondents reported frequent use of medications known to have potential adverse skeletal effects. In spite of these concerns the majority rated their overall physical health as good or excellent. Adults with mild osteogenesis imperfecta continue to sustain fractures into adulthood, and the majority reports some functional impairment due to musculoskeletal issues. Significant impairment is not rare.     

The spine in osteogenesis imperfecta

The natural history and treatment of spinal deformity is presented in light of the radiographic severity of the disease. The radiographic findings are grouped according to the changes over time and are prognostically significant for ambulation, spinal deformity, and life span.     

Extracellular matrix formation by osteoblasts from patients with osteogenesis imperfecta.

Extracellular matrix proteins synthesized by bone cells isolated from 16 patients with different forms of osteogenesis imperfecta (OI) were analyzed in vitro. Specific components of the extracellular matrix by OI and age-matched cultures were investigated by steady-state radiolabeling followed by quantitation of label into specific proteins and comparison of OI cultures to those of age-matched controls. The in vitro proliferation of OI bone cells was found to be lower than that of control cells. In seven patients, abnormalities of the alpha 1(I) and/or alpha 2(I) chains of type I collagen were detected by gel electrophoresis. In two of these patients, the mutations in the COLIA1 and COLIA2 genes have been previously identified. Although the amount of total protein synthesized by the cells in culture was the same for OI bone cells and age-matched control cells, OI bone cells showed a significantly reduced synthesis of not only collagen but also other bone matrix glycoproteins. The synthesis of osteonectin (SPARC/BM40) and three proteoglycans [a large chondroitin sulfate proteoglycan, biglycan (PGI), and decorin (PGII)] was found to be decreased in OI cells. The reduction was most pronounced at the developmental age at which these macromolecules reach maximal levels during normal development.     

Gender-specific pubertal changes in volumetric cortical bone mineral density at the proximal radius

It is well established that puberty affects the geometry of cortical bone differently in females and males. In the present study we investigated whether there are also gender differences in the volumetric bone mineral density of the cortical compartment (BMDcort). BMDcort was determined at the proximal radial diaphysis in 362 healthy children and adolescents (age 6-23 years; 185 females, 177 males) and in 107 adults (age 29-40 years; 88 women, 19 men) using peripheral quantitative computed tomography (pQCT). The densitometric result for BMDcort was similar in prepubertal girls and boys, but was significantly higher in females after pubertal stage 3. pQCT results for BMDcort are influenced by cortical thickness due to the partial volume effect. Therefore, these gender differences were reanalyzed in groups of subjects of the same developmental stage who were matched for cortical thickness. Thus calculated, no gender difference in BMDcort was detected in prepubertal children. However, adolescent females after pubertal stage 3 and adult women had a 3%-4% higher BMDcort than males at the same developmental stage. BMDcort is an integrated measure of both cortical porosity and mean material density of cortical bone. The metabolic activity of cortical bone (intracortical remodeling) increases cortical porosity and decreases the mean material density of cortical bone. Our results therefore suggest that intracortical remodeling is lower in postpubertal females than in males.     

Static and dynamic bone histomorphometry in children with osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a genetic disorder characterized by increased bone fragility and low bone mass. Four clinical types are commonly distinguished. Schematically, type I is the mildest phenotype, type II is usually lethal, type III is the most severe form compatible with postnatal survival, and type IV is moderately severe. Although mutations affecting collagen type I are responsible for the disease in most patients, the mechanisms by which the genetic defects cause abnormal bone development have not been well characterized. Therefore, we evaluated quantitative static and dynamic histomorphometric parameters in tetracycline-labeled iliac bone biopsies from 70 children, aged 1.5 to 13.5 years, with OI types I (n = 32), III (n = 11), and IV (n = 27). Results were compared with those of 27 age-matched controls without metabolic bone disease. Biopsy core width, cortical width, and cancellous bone volume were clearly decreased in all OI types. Decreased cancellous bone volume was due to a 41%–57% reduction in trabecular number and a 15%–27% lower trabecular thickness. Regression analyses revealed that trabecular number did not vary with age in either controls or OI patients, indicating that no trabecular loss occurred. The annual increase in trabecular thickness was 5.8 μm in controls and 3.6 μm in type I OI, whereas no trabecular thickening was evident in type III and IV OI. Wall thickness, which reflects the amount of bone formed during a remodeling cycle, was decreased by 14% in a subgroup of 17 type I OI patients, but was not determined in the other OI types. The remodeling balance was less positive in type I OI than in controls, and probably close to zero in types III and IV. Surface-based parameters of bone remodeling were increased in all OI types, indicating increased recruitment of remodeling units. No defect in matrix mineralization was found. In conclusion, there was evidence of defects in all three mechanisms, which normally lead to an increase in bone mass during childhood; that is, modeling of external bone size and shape, production of secondary trabeculae by endochondral ossification, and thickening of secondary trabeculae by remodeling. Thus, OI might be regarded as a disease in which a single genetic defect in the osteoblast interferes with multiple mechanisms that normally ensure adaptation of the skeleton to the increasing mechanical needs during growth.     

Intraoperative hyperpyrexia in patients with osteogenesis imperfecta

The aim of this study was to evaluate the influence of different types of anesthesia upon the intra- and postoperative body temperature in osteogenesis imperfecta patients. The development of an intraoperative hyperpyrexia of unknown origin is a typical phenomenon in patients with osteogenesis imperfecta. Body temperatures of up to 40 degrees C are known to complicate the operation. Therefore, in a retrospective study, the pre-, intra- and postoperative body temperature curves of 45 operations under different anaesthesias were measured. Group A underwent a common balanced anaesthesia with the volatile anaesthetic Enfluran in combination with Fentanyl, while group B was operated on under total intravenous anaesthesia (TIVA) with Propofol and Alfentanil. The preoperative temperatures were not different in the two groups. The intraoperative curves showed a constant body core temperature or even an increase under Enfluran, while the temperature always decreased under TIVA. This could be confirmed by intraindividual studies in 5 patients.     

A morphological and ultrastructural study of bone in osteogenesis imperfecta

A morphological and electron microscopic study of bone from patients with osteogenesis imperfecta (OI) has been performed. Bone from OI patients from various anatomical sites has been compared with that from normal, age-, site-, and sex-matched controls. The morphology of OI bone appeared variable among patients and sites of bone examined. Immature woven bone and a poor lamellar pattern were the significant morphological features and demonstrated that OI could not be characterized on the basis of a single histological pattern. At the ultrastructural level, a number of previously unreported features were evident. Abnormal collagen fibers and an altered mineral composition were found in many OI patients, however, the panoramic heterogeneity between clinical types and indeed within a single clinical type made it difficult to classify OI in this manner. The presence of intermitochondrial inclusions containing calcium and phosphorus and the presence of a stromal calcification in the bone in some OI patients suggested an abnormal mineral formation. Qualitatively, no obvious difference in the number of osteoblasts or osteoclasts was observed. The morphology and ultrastructure of OI bone were good indicators of the disease and serve a role in assessing the progress of a patient through diagnosis and treatment. This report presents new ultrastructural findings in collagen and in mineral formation in OI compared with normal human bone.     

Increased intra-cortical porosity reduces bone stiffness and strength in pediatric patients with osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a heritable disease occurring in one out of every 20,000 births. Although it is known that Type I collagen mutation in OI leads to increased bone fragility, the mechanism of this increased susceptibility to fracture is not clear. The aim of this study was to assess the microstructure of cortical bone fragments from patients with osteogenesis imperfecta (OI) using polarized light microscopy, and to correlate microstructural observations with the results of previously performed mechanical compression tests on bone from the same source. Specimens of cortical bone were harvested from the lower limbs of three (3) OI patients at the time of surgery, and were divided into two groups. Group 1 had been subjected to previous micro-mechanical compression testing, while Group 2 had not been subjected to any prior testing. Polarized light microscopy revealed disorganized bone collagen architecture as has been previously observed, as well as a large increase in the areal porosity of the bone compared to typical values for healthy cortical bone, with large (several hundred micron sized), asymmetrical pores. Importantly, the areal porosity of the OI bone samples in Group 1 appears to correlate strongly with their previously measured apparent Young's modulus and compressive strength. Taken together with prior nanoindentation studies on OI bone tissue, the results of this study suggest that increased intra-cortical porosity is responsible for the reduction in macroscopic mechanical properties of OI cortical bone, and therefore that in vivo imaging modalities with resolutions of ~ 100 μm or less could potentially be used to non-invasively assess bone strength in OI patients. Although the number of subjects in this study is small, these results highlight the importance of further studies in OI bone by groups with access to human OI tissue in order to clarify the relationship between increased porosity and reduced macroscopic mechanical integrity.