Severe Forms Of Osteogenesis Imperfecta Research Articles

Cross-sectional and longitudinal analysis of bone age maturation during peri-pubertal growth in children with type I, III and IV osteogenesis imperfecta

Osteogenesis imperfecta (OI)is a rare genetically heterogeneous disorder caused by changes in the expression or processing of type I collagen. Clinical manifestations include bone fragility, decreased linear growth, and skeletal deformities that vary in severity. In typically growing children, skeletal maturation proceeds in a predictable pattern of changes in the size, shape, and mineralization on the hand and wrist bones that can be followed radiographically known at the bone age. Assessment of bone age can be clinically used to assess time remaining for linear growth, and the onset and duration of puberty, both of which can be useful in determining the timing of some surgeries or the interpretation of other imaging modalities such as bone densitometry. Additionally, deviations in the expected maturation process of the bone age may prompt or assist in the work up of a significant delay or advancement in a child's growth pattern. The primary aim of our study was to determine whether the bone age in children with a skeletal disorder such as OI follow the same pattern and rate of bone maturation compared to a control population. Using participants from the Natural History Study of the Brittle Bone Disorders Consortium, we analyzed 159 left hand and wrist radiographs (bone age) for a cross-sectional analysis and 55 bone ages repeated at approximately 24 months for a longitudinal analysis of skeletal maturation. Bone ages were read by a pediatric endocrinologist and by an automated analysis using a program called BoneXpert. Our results demonstrated that in children with mild-to-moderate OI (types I and IV), the skeletal maturation is comparable to chronological age-mated controls. For those with more severe forms of OI (type III), there is a delayed pattern of skeletal maturation of less than a year (10.5 months CI 5.1–16) P = 0.0012) at baseline and a delayed rate of maturation over the two-year follow up compared to type I (P = 0.06) and type III (P = 0.02). However, despite these parameters being statistically different, they may not be clinically significant. We conclude the bone age, with careful interpretation, can be used in the OI population in a way that is similar to the general pediatric population.

Non-collagen pathogenic variants resulting in the osteogenesis imperfecta phenotype in children: a single-country observational cohort study

Background/ObjectivesIn England, children (0–18 years) with severe, complex and atypical osteogenesis imperfecta (OI) are managed by four centres (Birmingham, Bristol, London, Sheffield) in a ‘Highly Specialised Service’ (HSS OI); affected...

Pamidronate Therapy Increases Trabecular Bone Complexity of Mandibular Condyles in Individuals with Osteogenesis Imperfecta.

Patients with Osteogenesis Imperfecta (OI) present extra-skeletal manifestations, including important orodental and craniofacial features as dentinogenesis imperfecta, dental agenesis, failure of maxilla growth and hypotonia of masticatory muscles. These features may compromise vital functions speech and mastication. Studies have demonstrated that cyclic pamidronate infusion, the standard therapy for patients with moderate to severe OI, influences the histomorphometric pattern of different body bones. The present study aimed to investigate the condyle trabecular bone pattern in OI patients. We used fractal dimension (FD) analysis on dental panoramic radiographic images to characterize the mandibular condyle trabecular bone in adolescents diagnosed with OI and treated with pamidronate. Imaging exam of 33 adolescents of both sexes, aged between 12 and 17years, were analyzed and compared with 99 age- and sex-matched healthy adolescents. FD in patients was significantly lower (1.23 ± 0.15) than in healthy controls (1.29 ± 0.11; p < 0.01). Type of OI, age at treatment onset, and the duration of therapy were variables that showed a statistically significant effect on the FD results. This study demonstrated that the bone architecture of mandibular condyles may be altered in pediatric patients with moderate and severe forms of OI. Also, pamidronate treatment seems to have a positive effect on condyle trabecular bone in these patients. This is supported by our finding that FD values were positively influenced by the length of cyclic pamidronate treatment at the time of imaging, as well as by the age of the individual at treatment onset.

SUN-530 Tri-ponderal Mass Index As A Parameter For Fat Mass Assessment In Children And Adolescents With Osteogenesis Imperfecta

Background. The negative metabolic impact of overweight and obesity (OW-OB) on bone health is a matter of concern in pediatrics. This situation is even more delicate in individuals with osteogenesis imperfecta (OI), who already have a compromised skeletal health. Assessing body fat through anthropometric indices in patients with OI is a challenge, mainly in the moderate and severe types, once skeletal deformities disrupt the expected proportionality between weight and height squared as obtained by the classical body mass index (BMI). So, it is asked whether the tri-ponderal mass index -TMI [mas divided by height cubed] would be a better surrogate parameter for adiposity index assessment in this group of patients. Aim. To compare the frequency of OW-OB among patients with moderate and severe forms of OI using both BMI and TMI methods and evaluate impact of each classification on bone fracture rates. Methods. Retrospective study comprised of 32 patients with OI followed at a tertiary level hospital in Brasilia, Brazil. All patients were being treated with intravenous cyclic infusion of disodium pamidronate at the time of evaluation. TMI absolute values and BMI Z-scores were used as indirect measures of adiposity index of patients. OW and OB frequencies in patients with OI were compared with a control group (CG) of 154 non-syndromic children and adolescents. The used TMI thresholds to diagnose OW and OB status were according to: boys, 16.0 kg/m3 and 18.8 kg/m3; girls 16.8 kg/m3 and 19.7 kg/m3, respectively.(1) Results. Thirty-two consecutive individuals (15 females) with OI were studied; mean age at evaluation was 13.4 ± 3.3 years (ranged 7 to 22 years), being 8 patients with OI type I; 11 type III: and 13 type IV. The proportion of OW-OB in OI group (43.8%) was higher than in CG (24.7%) [p = 0.029; Z-score = 2.19]. Using BMI Z-scores, 13 patients (7 females) were classified as overweight and 1 (male) as obese. Using TMI, 2 out of 15 females were classified as OW, and 3 as OB; seven out of 17 males were classified as OW, and 2 as OB. There was no difference in the bone fracture rate observed during the last previous year of follow up when comparing OW-OB and non-OW/OB patients classified according to BMI Z-score (p = 0.13). Nevertheless, after using TMI for classification, a higher fracture rate was observed in the OW-OB group (1.1 per patient-year) compared with the non-OW-OB group (0.4 per patient-year), p = 0.04. Conclusion. Although the proportion of OW-OB patients with OI detected by TMI and BMI were similar, the distribution of OW and OB subgroups was distinct. The finding of a higher fracture rate among the TMI-derived OW-OB individuals in this small sample sized study may suggest that this index would sustain a better characterization than BMI concerning the negative metabolic effect of OW-OB on bone quality among patients with OI. (1) Peterson CM et al. JAMA Pediatr. 2017;171(7):629-636.

Cyclic pamidronate treatment for osteogenesis imperfecta: Report from a Brazilian reference center.

Treatment of moderate and severe forms of osteogenesis imperfecta (OI) with cyclic pamidronate at the Reference Center for OI Treatment in Southern Brazil was studied. A retrospective cohort study was conducted from 2002 to 2012. Data were obtained during inpatient (drug infusion) and outpatient care. Clinical data, including the presence of blue sclerae, dentinogenesis imperfecta, history and site of the fractures, biochemical data, including calcium, phosphorus, and alkaline phosphatase levels, were systematically collected. Bone mineral density (BMD) was measured using dual energy X-ray absorptiometry (DXA). Forty-five patients (26 females) were included in the study, and the age of the patients at the time of diagnosis ranged from 1 to 144 months, with a median age (p25-p75) of 38 (5-96) months. Most cases presented OI-4 (51.1%), and the median age of the patients at the start of treatment was 3.3 years (25-75 percentiles: 0.5 - 8.7 years). Twenty-four patients (54.5%) had some adverse events or intercurrences during treatment, and the treatment compliance mean was 92.3% (± 10.7). The treatment with intravenous pamidronate has shown to be safe, well-tolerated, and effective in regard to the improvement of BMD and the reduction of the number of fractures in children and adolescents with OI.

Behavioral signs of pain and functional impairment in a mouse model of osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a congenital disorder caused most often by dominant mutations in the COL1A1 or COL1A2 genes that encode the alpha chains of type I collagen. Severe forms of OI are associated with skeletal deformities and frequent fractures. Skeletal pain can occur acutely after fracture, but also arises chronically without preceding fractures. In this study we assessed OI-associated pain in the Col1a1Jrt/+ mouse, a recently developed model of severe dominant OI. Similar to severe OI in humans, this mouse has significant skeletal abnormalities and develops spontaneous fractures, joint dislocations and vertebral deformities. In this model, we investigated behavioral measures of pain and functional impairment. Significant hypersensitivity to mechanical, heat and cold stimuli, assessed by von Frey filaments, radiant heat paw withdrawal and the acetone tests, respectively, were observed in OI compared to control wildtype littermates. OI mice also displayed reduced motor activity in the running wheel and open field assays. Immunocytochemical analysis revealed no changes between OI and WT mice in innervation of the glabrous skin of the hindpaw or in expression of the pain-related neuropeptide calcitonin gene-related protein in sensory neurons. In contrast, increased sensitivity to mechanical and cold stimulation strongly correlated with the extent of skeletal deformities in OI mice. Thus, we demonstrated that the Col1a1Jrt/+ mouse model of severe OI has hypersensitivity to mechanical and thermal stimuli, consistent with a state of chronic pain.

Structure-Function Relationships of the Collagen-Specific Chaperone Hsp47

Hsp47 is an essential collagen specific chaperone that is crucial for proper formation of the collagen triple helix. KO-mice die at an early emybronic state and missense mutations are linked to severe forms of osteogenesis imperfecta (Ishida &amp; Nagata, 2011). On the other hand, Hsp47 is strongly upregulated in fibrotic pathogenies and has in proof-of-principle studies been successfully targeted . It is a very unusual chaperone as it specifically recognises the folded conformation and releases ist client upon changes in pH and not in an ATP-cycle dependent manner. We have deterined the crystal structure of Hsp47 alone and in complex with homotrimeric collagen model peptides (Widmer et al., 2012), revealing a 2:1 stoichiometry Hsp47:collagen-trimer. The specific recognition of an arginine at the Y-position of the triple helix is explained by a saltbridge to an aspartic acid of Hsp47. Based on these structures we have undergone further investigation in order to shed light on the pH-triggered client release and to gain further insight into client recognition. We have undergone a systematic site-directed mutagenesis study of histidine residues in the binding interface. Interestingly, only few side-chains are predicted to change significantly their protonation state by a pH change from 7 to 6. We have furthermore investigated the influence of the reactive center loop, which is disordered in most crystal structures. An open question is how many binding sites for Hsp47 exist in procollagen. EM studies reveal a large number of specific binding sites, explaining how Hsp47 clamps and stabilises the triple helix and prevents lateral aggregation.

Evaluation of teriparatide treatment in adults with osteogenesis imperfecta

Adults with osteogenesis imperfecta (OI) have a high risk of fracture. Currently, few treatment options are available, and bone anabolic therapies have not been tested in clinical trials for OI treatment. 79 adults with OI were randomized to receive 20 μg recombinant human parathyroid hormone (teriparatide) or placebo for 18 months in a double-blind, placebo-controlled trial. The primary endpoint was the percent change in areal bone mineral density (aBMD) of the lumbar spine (LS), as determined by dual-energy X-ray absorptiometry. Secondary endpoints included percent change in bone remodeling markers and vertebral volumetric BMD (vBMD) by quantitative computed tomography, estimated vertebral strength by finite element analysis, and self-reported fractures. Compared with the placebo group, the teriparatide group showed increased LS aBMD (6.1% ± 1.0% vs. 2.8% ± 1.0% change from baseline; P < 0.05) and total hip aBMD (2.6% ± 1.0% vs. -2.4% ± 1.0% change; P < 0.001). Vertebral vBMD and strength improved with teriparatide therapy (18% ± 6% and 15% ± 3% change, respectively), but declined with placebo (-5.0% ± 6% and -2.0% ± 3% change; P < 0.05 for both comparisons). Serum procollagen type 1 N-terminal propeptide (P1NP) and urine collagen N-telopeptide (NTx) levels increased with teriparatide therapy (135% ± 14% and 64% ± 10% change, respectively). Teriparatide-induced elevation of P1NP levels was less pronounced in severe forms of OI (type III/IV) compared with the milder form (type I). Type I OI patients exhibited robust BMD increases with teriparatide; however, there was no observed benefit for those with type III/IV OI. There was no difference in self-reported fractures between the 2 groups. Adults with OI, particularly those with less severe disease (type I), displayed a teriparatide-induced anabolic response, as well as increased hip and spine aBMD, vertebral vBMD, and estimated vertebral strength. Trial registration. Clinicaltrials.gov NCT00131469. Funding. The Osteoporosis Imperfecta Foundation, Eli Lilly and Co., the National Center for Advancing Translational Science (NCATS) at the NIH (grant no. UL1RR024140), and the Baylor College of Medicine General Clinical Research Center (grant no. RR00188).

Muscle Strength, Joint Range of Motion, and Gait in Children and Adolescents With Osteogenesis Imperfecta

To analyze clinical and functional features of children and adolescents with osteogenesis imperfecta (OI). A cross-sectional study of 62 participants examined clinical, body structure and function and activity features. A total of 31 participants had OI type I, 9 had type III, and 22 had type IV. Mild (type I) and moderate/severe (types III and IV) OI differed significantly in occurrence of fractures, presence of bone deformities, the use of intramedullary rods, bone mineral density, and bisphosphonate therapy. Age of gait acquisition showed an association with overall joint range of motion and an inverse relationship with overall muscle strength. Level of ambulation was associated with overall muscle strength and inversely associated with overall joint range of motion. Features vary according to OI type. Moderate and severe forms of OI are associated with greater functional limitation, influenced by fracture history, which negatively affects the acquisition and level of ambulation.

Osteogenesis imperfecta in children: Indosesian experiences

Medical management of osteogenesis imperfecta (OI), a genetic disorder of connective tissue characterized by reduced bone mass and frequent fractures, is focused on maximizing patients’ mobility and function. Many methods of pharmacological treatment have been introduced for the severe forms of OI, including calcium, anabolic steroids, growth hormone, and calcitonin, without consistent benefit. Recent studies reported beneficial effect of intravenous and oral bisphosphonates on moderate to severe form of OI in children. This report is to review OI cases in Indonesian children and to know the effect of bisphosphonate treatment for them. Data on age, gender, age at diagnosis, availability of bisphosphonate treatment, and its effects were collected from Indonesian OI children registry, which documented from April to June 2012. Fourteen centers which have members of pediatric endocrinology chapter, Indonesian Pediatric society, were involved in obtaining data for the registry. Forty-six OI cases (17 female), who were diagnosed at the age of 7 days-11 years old and mostly categorized as type 3 of OI, were recorded. Two patients were died before commencing treatment. There were twenty-seven (27/46) patients received bisphosphonates, which were administered to moderate to severe cases. Two patients,who were treated, were died due to hyperthermia after the first day of pamidronate infusion, and pneumonia aspiration. Twenty-five patients received intravenous pamidronate and 3 oral alendronate. Liver and renal function test, and serum electrolyte were evaluated before and after treatment. Most patients reported decreased irritability, increased muscle tone and mobility. In addition, despite hyperthermia in one case, no serious adverse effects documented. Although some patients had government health insurance for the poor, unfortunately, the medicine, which is considered expensive for the patients, is not yet included in the drug list of government insurance. Most of registered OI cases in Indonesian children were type 3. More than half of the cases underwent treatment with bisphosphonates with beneficial effects, although long-term follow up and well-documented data are required.

Challenges in managing osteogenesis imperfecta patients in H. Adam Malik hospital, North Sumatera, Indonesia

Background Osteogenesis imperfecta (OI) is a genetic disorder with increased bone fragility and low bone mass, the incidence has been estimated at 1 in per 10000-20000 births, however milder forms of OI are probably under recognized. Cyclical intravenous therapy with the biphosphonate pamidronate has been reported to be beneficial in children and adolescents with moderate to severe forms of OI.

1829 Severe Forms of Osteogenesis Imper.Fecta (OI) In Infants and the Role of Respiratory Syncitial Virus (RSV) Immunoprophylaxis with Palivizumab

Background and AimsRespiratory illnesses could be serious, even life threatening among infants with severe forms of osteogenesis imperfecta (OI). Respiratory syncitial virus (RSV) bronchiolitis could deteriorate the respiratory status of...

Bone and joint diseases in children. Bisphosphonates in osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a genetic disorder characterized by fragile bone and reduced bone mineral density. Cyclic intravenous pamidronate is now the most widely used treatment for moderate to severe forms of OI. Oral bisphosphonates provide clinical benefit and convenience to the patients with mild form of OI. Recently, some studies demonstrated that intravenous zolendronate in children with OI is safe in short-term and similarly effective to parmidronate. Optimal dose, duration of treatment and long-term safety of newer bisphosphonates require further investigations.

Bigger, faster, stronger — Improvement in early outcomes following use of zoledronic acid in neonates with severe forms of Osteogenesis Imperfecta

Bigger, faster, stronger — Improvement in early outcomes following use of zoledronic acid in neonates with severe forms of Osteogenesis Imperfecta

Bigger, faster, stronger — Improvement in early outcomes following use of zoledronic acid in neonates with severe forms of osteogenesis imperfecta

Bigger, faster, stronger — Improvement in early outcomes following use of zoledronic acid in neonates with severe forms of osteogenesis imperfecta

Bisphosphonates and other new therapeutic agents for the treatmednt of osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a genetic disorder characterized by fragile bone and reduced bone mineral density. Cyclic intravenous pamidronate is now the standard treatment for moderate to severe forms of OI, however clinical studies are not yet sufficient to conclude appropriate annual doze and ideal duration of therapy at present time. Oral alendronate is also effective in milder forms of OI. Zoledronic acid has undergone international multicentric clinical trials to examine efficiency and long-term side effects including osteonecrosis of the jaw. Teriparatide (rhPTH1-34) and denosumab (monoclonal antibody against RANK ligand) have the potential for management of OI. Stem cell and gene therapy are currently being actively investigated and may become clinically applicable in the near future.

The sagittal balance of the spine in children and adolescents with osteogenesis imperfecta

In severe forms of osteogenesis imperfecta, multiple compression fractures of the spine, as well as vertebral height shortening could be responsible for an increased thoracic kyphosis or a diminished lumbar lordosis. Theses progressive changes in sagittal shapes of the trunk could be responsible for a global sagittal trunk imbalance. We compare the parameters of sagittal spinopelvic balance in young patients with OI to those parameters in a control group of healthy volunteers. Eighteen patients with osteogenesis imperfecta were compared to a cohort of 300 healthy volunteers. A standing lateral radiograph of the spine was obtained in a standardized fashion. The sacral slope, pelvic tilt, pelvic incidence, lumbar lordosis, thoracic kyphosis, T1 and T9 sagittal offset were measured using a computer-assisted method. The variations and reciprocal correlations of all parameters in both groups according to each other were studied. Comparison of angular parameters between OI patients and control group showed an increased T1T12 kyphosis in OI patients. T1 and T9 sagittal offset was positive in OI patients and negative in control group. This statistically significant difference among sagittal offsets in both groups indicated that OI patients had a global sagittal balance of the trunk displaced anteriorly when compared to the normal population. Reciprocal correlations between angular parameters in OI patients showed a strong correlation between lumbar lordosis (L1L5 and L1S1) and sacral slope. The T9 sagittal offset was also strongly correlated with pelvic tilt. Pelvic incidence was correlated with L1S1 lordosis, T1 sagittal offset and pelvic tilt. In OI patients, the T1T12 thoracic kyphosis was statistically higher than in control group and was not correlated with other shape (LL) or pelvic (SS, PT or PI) parameters. Because isolated T1T12 kyphosis increase without T4T12 significant modification, we suggest that vertebral deformations worsen in OI patients at the upper part of thoracic spine. Further studies are needed to precise the exact location of most frequent vertebral deformities.

Treatment of children with osteogenesis imperfecta

Children with moderate to severe forms of osteogenesis imperfecta (OI) require adequate physiotherapy, rehabilitation and orthopedic surgery. Supportive treatment with bisphosphonates can improve the effects of these nonmedicinal treatment modalities. Benefits of bisphosphonate treatment include decreased pain, lower fracture incidence, and better mobility. Among the various bisphosphonates, intravenous pamidronate has been studied in most detail. However, the optimal treatment regimen and the long-term consequences of pamidronate treatment in children are currently unknown. Given these uncertainties, treatment with bisphosphonates during growth should be reserved for patients who have significant clinical problems, such as vertebral compression fractures or long-bone deformities. Medical therapies other than bisphosphonates play a minor role at present. Gene-based therapy currently remains in the realm of preclinical research.

Intravenous pamidronate treatment of infants with severe osteogenesis imperfecta

Objective: Children with the severe forms of osteogenesis imperfecta have in several studies been treated with intravenous pamidronate, but there are only few reports of the effect of early treatment....

Early bisphosphonate treatment in infants with severe osteogenesis imperfecta

To evaluate prospectively the efficacy of bisphosphonate treatment in infants with severe forms of osteogenesis imperfecta (OI). Of 10 children (6 females) with OI type III, 5 (group A) started treatment (2 mg/kg neridronate administered intravenously for 2 consecutive days, every 3 months) just after diagnosis at birth and 5 (group B) after 6 months. Ten untreated children, matched for sex, age, and clinical severity of OI, constituted a historical control group (group C). We measured weight, length, and number of fractures every 3 months and serum and urinary levels of calcium, phosphorus, creatinine, serum alkaline phosphatase, 25-hydroxyvitamin D, insulin-like growth factor I, parathyroid hormone, and osteocalcin, urinary type I collagen N-terminal telopeptide, and lateral radiography of vertebral column every 6 months. Group A had better growth and a lower incidence of fractures than groups B and C in the first 6 months of treatment. In the second 6 months, both groups A and B had lower fracture rates than group C. After 12 months of therapy, osteocalcin and insulin-like growth factor I levels significantly increased only in group A. The urinary Ca/Cr ratio and N-terminal telopeptide/Cr ratio significantly declined only in treated patients. Vertebral body area and the structure of vertebral bodies improved in all treated patients, but especially in group A. Cyclical neridronate treatment, started just after diagnosis at birth, had positive effects on growth and fracture rate.