Baseline Characteristics of the TOPaZ Study: Randomised Trial of Teriparatide and Zoledronic Acid Compared with Standard Care in Adults with Osteogenesis Imperfecta.

English summary Osteogenesis imperfecta - oral implications 690-7 Osteogenesis imperfecta (OI) is an inherited, rare connective tissue disorder leading to bone fragility and hence an increased risk of bone fractures and a number of other symptoms related to the connective tissue, including risk of dentinogenesis imperfecta (DI). The diagnosis DI is based on clinical findings and radiographic characteristics as a consequence of defective dentine. DI can appear as isolated DI or as a part of OI. OI is a clinical diagnosis, however both OI and DI can be confirmed by genetic analyses. Follow-up and treatment of OI and DI take place at specialized centers with special knowledge and expertise on rare inherited disorders. This article describes investigations, follow-up and treatment of DI and OI in a field where special attention and increased cooperation between medical physicians and dentists are of major importance.

Osteogenesis imperfecta is an inherited clinically heterogeneous disorder of bone metabolism characterized by bone and skeletal fragility and an increased risk of fractures. Pamidronate infusion was the standard treatment, but zoledronic acid is increasingly used to treat children with osteogenesis imperfecta. We conducted a systematic literature review to evaluate the efficacy and safety of intravenous zoledronic acid in the treatment of osteogenesis imperfecta in pediatric patients. A systematic review of the published literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Eligible articles were clinical trials and observational studies including pediatric patients (<16 years) with osteogenesis imperfecta treated with zoledronic acid. We selected articles published during the 20 past years. The selected languages were English and French. We included articles with a minimum sample size of five patients. Six articles fulfilled the selection criteria. The majority of patients were Chinese (58%). The predominant sex was male (65%), and the age of included patients ranged from 2.5 weeks to 16.8 years. For all patients, zoledronic infusions were administrated intravenously. The zoledronic treatment duration ranged from 1 to 3 years. Densitometry parameters before and after zoledronic treatment were evaluated and showed significant improvement both in lumbar spine-bone mineral density Z -score and femoral neck-bone mineral density Z -scores. A significant decrease in fracture rate has also been noted both in vertebral and nonvertebral fracture incidence. The two most common side effects were fever and flu-like reactions. None of the patients presented severe adverse events. Zoledronic acid appeared to be well-tolerated and effective in the treatment of pediatric osteogenesis imperfecta.

Background: Osteogenesis imperfecta (OI) and transplantation (TP) are independently associated with fractures. Yet reports regarding the skeletal effects of organ TP in OI are limited. We report the early skeletal outcomes in an OI patient with osteoporosis who underwent lung TP.Clinical Case: A 35-year-old man with moderate/severe OI and severe bronchiectasis was admitted for progressive respiratory failure and expedited lung TP evaluation. OI was diagnosed at age 10 after sustaining a hairline coccyx fracture when falling off a stool; scoliosis was diagnosed at age 14; additional fractures included ankle (18 y), toes (28 y) and rib (34 y). He had dentogenesis imperfecta, but no hearing loss, easy bruising or OI family history. Bronchiectasis also began at age 10 and progressed, with multiple drug resistant infections and glucocorticoid (GC) treatments. At admission, he was on 6L oxygen and bed-bound from dyspnea. Notably, he had been rejected twice for TP because of his bone disease. Admission medications included calcium, D3, famotidine, inhaled fluticasone, tobramycin, and tiotropium bromide. His exam was notable for height 5’5”, BMI 16.5 kg/m2, kyphoscoliosis, blue sclera and joint laxity. Labs were notable for (mg/dl): serum calcium 9.4, magnesium 2.4, phosphate 4.4; albumin 4.2 g/dl, alkaline phosphatase 75 U/L, 25(OH)D 34 ng/ml, sCTX 535 pg/ml, urinary calcium 370 mg/24 hr. DXA showed T-scores of -4.7 (lumbar spine), -3.3 (femoral neck), -3.2 (total hip), -2.6 (1/3 radius). Endocrinology was consulted about the skeletal risk of lung transplantation.Discussion and Follow-up:The patient’s manifestations of OI increased the risk of adverse skeletal outcomes. His high CTX suggested increased bone resorption, often seen with OI; bone formation was not directly measured but in OI is frequently reduced. Notably, his bronchiectasis was likely related to the OI: in addition to restrictive lung disease in OI, the abnormal type 1 collagen likely alters alveolar structure and elasticity. His risk for post-TP fractures was high given that the expected post-TP bone loss would likely be exacerbated by high dose GCs further increasing bone resorption and reducing presumed low bone formation. Nevertheless, because he had never sustained a major fracture even without OI treatment, the decision was made to proceed. He received zoledronate (ZOL) 5 mg IV and underwent an uncomplicated double lung transplant; initial high dose GCs were tapered to prednisone 10 mg/d. Three months later, he has steadily rising lung function, excellent functional status, and is working full time. A current sCTX of 73 pg/ml suggests that bone loss is not increased. Admittedly, the patient remains within the early high-risk fracture window. Yet this case is the first report to our knowledge which suggests that lung TP in an OI patient treated with ZOL did not lead to fracture in the early post-TP period.

Background: The majority of osteogenesis imperfecta (OI) cases have an autosomal dominant pattern of inheritance and are usually caused by mutations in genes encoding type I collagen. Patients with OI may have blue sclerae, dentinogenesis imperfecta, and growth deficiency. Zoledronic acid is a third-generation bisphosphonate which was reported to inhibit osteoclast-mediated bone resorption, improve bone density, and reduce incidence of fractures. Aim: To describe the radiographic features of cyclic Zoledronic acid administration on the growing skeleton in children with OI and to report the efficacy of Zoledronic acid on bone mineral density. Methods: We retrospectively reviewed the radiographs of 11 children treated with Zoledronic acid. The age of these children ranged from one to 13 years. Zoledronic acid was administrated intravenously at 6 months intervals at the Pediatric Endocrinology Day Medical Unit, King Faisal Specialist Hospital and Research Centre, and Security Forces Hospital, Riyadh, Kingdom of Saudi Arabia for 2 years. Results: During the course of treatment, a gradual increase in bone density was observed. The baseline mean lumbar BMDz score was -4.9SD + 1.3, which improved to a mean score of -2.7SD + 1.1, and a mean whole body BMDz score was -2SD +1.2 and improved to a mean score of -1.1SD + 1.3 by the end of therapy. Post treatment, there were multiple sclerotic metaphyseal bands seen in all children in the long bones paralleling to the growth plates and corresponding to the number of treatment cycles. Conclusion: Intravenous Zoledronic acid in children with osteogenesis imperfecta improved the bone mineral density and resulted in permanent sclerotic metaphyseal bands.

Dentinogenesis imperfecta (DI) is the main orodental manifestation of osteogenesis imperfecta (OI) caused by COL1A1 or COL1A2 heterozygous pathogenic variants. Its prevalence varies according to the studied population. Here, we report the molecular analysis of 81 patients with OI followed at reference centers in Brazil and France presenting COL1A1 or COL1A2 variants. Patients were submitted to clinical and radiographic dental examinations to diagnose the presence of DI. In addition, a systematic literature search and a descriptive statistical analysis were performed to investigate OI/DI phenotype–genotype correlation in a worldwide sample. In our cohort, 50 patients had COL1A1 pathogenic variants, and 31 patients had COL1A2 variants. A total of 25 novel variants were identified. Overall, data from a total of 906 individuals with OI were assessed. Results show that DI was more frequent in severe and moderate OI cases. DI prevalence was also more often associated with COL1A2 (67.6%) than with COL1A1 variants (45.4%) because COL1A2 variants mainly lead to qualitative defects that predispose to DI more than quantitative defects. For the first time, 4 DI hotspots were identified. In addition, we showed that 1) glycine substitution by branched and charged amino acids in the α2(I) chain and 2) substitutions occurring in major ligand binding regions—MLRB2 in α1(I) and MLBR 3 in α2(I)—could significantly predict DI (P < 0.05). The accumulated variant data analysis in this study provides a further basis for increasing our comprehension to better predict the occurrence and severity of DI and appropriate OI patient management.

Osteogenesis imperfecta (OI) is a rare genetic disorder that causes frequent fractures. Bisphosphonates play a key role in managing OI. This manuscript examines the comparative effectiveness of alendronate, neridronate, olpadronate, pamidronate, risedronate, and zoledronic acid on fracture rate reduction, increases in lumbar spine (LS) bone mineral density (BMD), and adverse effects compared to placebos and each other. A PubMed search using specific keywords for bisphosphonates and OI yielded 21 sources, from which data about fracture rates, fracture risk, and/or LS BMD were collected. The inclusion criteria consisted of randomized controlled trials involving bisphosphonates to treat OI with data regarding fracture rates, fracture risk, and/or BMD, and the exclusion criteria were any sources that did not meet such standards. A one-way analysis of variance (ANOVA) was conducted to assess the significance of differences among bisphosphonates. Neridronate, olpadronate, and risedronate had a lower fracture risk and fracture rate than their placebo counterparts. Olpadronate demonstrated a markedly lower fracture rate compared to its placebo, and neridronate similarly showed a substantially reduced fracture risk relative to its placebo. Risedronate was effective but less so than the other two. Pamidronate showed the largest overall increase in LS BMD, while alendronate demonstrated the highest placebo-adjusted ratio. Despite ANOVA testing finding insignificant differences between drugs, except for fracture risk, limited data constrained the analysis. Adverse effects varied: alendronate caused the most gastrointestinal distress, zoledronic acid and neridronate caused illness-like symptoms, risedronate had illness-like and gastrointestinal symptoms, and pamidronate was linked to severe effects, including death. This analysis highlighted the efficacy and safety profiles of bisphosphonates in the treatment of OI. Neridronate and olpadronate were highly effective in reducing fracture risk and rates, and olpadronate demonstrated superior efficacy in reducing fracture rates. Future research should focus on large, diverse samples, detailed fracture and BMD data, and comparisons across multiple bisphosphonates to refine treatment strategies.

Background:Osteogenesis imperfecta (OI) is an inherited clinically heterogenous disorder of bone metabolism characterized by bone and skeletal fragility and an increased risk of fractures. Pamidronate infusion was the standard treatment,...

Growth hormone treatment in osteogenesis imperfecta with quantitative defect of type I collagen synthesis

Treatment with zoledronic acid (ZA) over 2 years, among 33 children with osteogenesis imperfecta (OI) and five Bruck syndrome cases, showed reduction in fracture rates, pain, and improvement in bone mineral density (BMD) and motor milestones of development. This is the first study reporting the use of bisphosphonates in patients with Bruck syndrome (BS). OI and BS are genetic disorders that result in bone fragility and reduced BMD. There is little literature describing the efficacy and safety of ZA in this population. In this study, we assess the response to treatment with ZA at six monthly intervals in Egyptian children with OI and BS for a period of 2 years. Thirty-three patients with OI and five patients with BS were treated with 0.1 mg/kg ZA intravenously every 6 months for 2 years during which they were followed up using different parameters. A clinical severity score (CSS) was applied to the patients before and 2 years after the start of therapy. Comparison of disease severity and response to ZA treatment between autosomal-dominant (AD) and autosomal-recessive (AR) OI patients was also done. After 6 months of treatment, OI and BS patients showed a significant increase in BMD Z-scores (P < 0.003 in the spine and P < 0.004 in the hip), together with a significant drop in fracture rate (P < 0.001), relief of pain (P < 0.001), and improvement in ambulation (P < 0.001). CSS was significantly reduced after 2 years of treatment in both OI and BS patients. AR-OI patients were more severely affected than AD-OI patients and showed more significant improvement. Zoledronic acid proved to be safe and effective in the treatment of OI and BS. The biannual infusion protocol was convenient to patients. There was a positive correlation between disease severity and benefits of the treatment. The use of the CSS proved to be of value in the assessment of the degree of severity in OI, and with some modifications, it was a valuable tool for the assessment of response to treatment.

Osteogenesis imperfecta (OI) is a genetically inherited metabolic bone disorder that results in multiple fractures and deformities in children. The treatment of OI has undergone tremendous improvement in the last two decades worldwide. AIMS: To review the clinical presentation and management of fractures in children with OI. METHODS: A retrospective audit of patients treated for OI at Chris Hani Baragwanath Academic Hospital. (CHBAH), from January 2000 to December 2011 was performed. RESULTS: Seventy-eight patients with OI were reviewed. The male to female ratio was 1:1.1. The median age at presentation was 20 months. The patients were classified according to the Sillence classification. Thirty-four patients were type III and 22 were type IV. Twenty patients (26%) had a first degree relative with OI The majority of patients received bisphosphonate (88%) and of these patients, 69 (93%) received intravenous bisphosphonate therapy; the remaining 7% received oral bisphosphonates. The most common long bone fractures were of the femur (93 fractures) and tibia (60 fractures). Sixty-six long bones (49 patients) received intramedullary rodding (IM). The mean age at time of surgery was 7 years. The indication for osteotomy and IM rodding was fracture of the long bones. Fifty-one long bones out of the 66 long bones rodded (77%) underwent revision surgery for complications - 49% (25/51) had rod migration, 39% (20/51) had peri-implant fractures and 12% (6/51) had rod breakage. Of 27 patients with type III OI, 14 (52%) were walking at final follow-up - eight were walking with assistive devices and six (22%) were walking independently. Of 19 patients with type IV OI, 16 (84%) were walking at final follow-up - four were walking with an assistive device and 12 (63%) were walking independently. CONCLUSION: An ongoing multidisciplinary approach to the management of children with OI is of paramount importance. There is an urgent need to improve the level of awareness of this rare condition among health professionals in order to facilitate prompt diagnosis and early referral.

A full-term male newborn presents with respiratory distress soon after delivery.Soon after delivery, the neonate developed shallow breathing and increased work of breathing, for which high-flow nasal cannula was initiated at 3 L/min with fraction of inspired oxygen (Fio2) of 0.21. Empiric treatment with ampicillin and gentamicin was started for clinical pneumonia.Chest radiography showed fracture of the left rib and slender “gracile” appearance of ribs. There was no lung opacity, pneumothorax, or pleural effusion (Fig 2).Skeletal survey showed minimally displaced distal right clavicle fracture, transverse fracture of the right radius and ulna, transverse fracture of the left radius, mild displaced segmental fracture of the left ninth rib, angulated fractures involving the distal tibias and fibulas, and coxa varus deformity of the left femur. There was diffuse osteopenia and thin cortices of the long bones and ribs. No wormian bones in the skull, vertebral body compression fracture, or spinal malalignment were evident (Fig 3).Osteogenesis Imperfecta Type IV (Moderately Deforming Type)The neonate received oral acetaminophen and morphine for pain. Respiratory support with high-flow nasal cannula at 3 L/min with Fio2 of 0.21 was continued because of increased work of breathing. Formula feedings were initiated via nasogastric tube. The pediatric genetics team was consulted and provided recommendations for general management as well as for treatment initiation with intravenous zoledronate. The neonate received 1 intravenous infusion of zoledronate (0.0125 mg/kg, in 10-mL saline at 12.5 mL/h) at 6 days of age. Serum ionized calcium levels were monitored every 8 hours for the first 2 days after infusion and subsequently once a day. Serum ionized calcium levels decreased over time, reaching a nadir of 0.77 mmol/L on the 5th day after zoledronate infusion. Oral calcium carbonate (50 mg/kg per day of elemental calcium divided every 6 hours) was started and the dose was later increased to up to 200 mg/kg per day of elemental calcium. He also received cholecalciferol 400 IU daily (vitamin D3) along with calcitriol 0.06 μg/kg per day. His ionized calcium improved gradually, and later calcitriol was discontinued at 18 days of age. He was jittery for the first few days after birth but later improved. He did not have any seizurelike activity during his hospital stay.Extreme care was taken while positioning, feeding, and movements as per physical medicine and rehabilitation recommendations to prevent further fractures. He was slowly weaned off morphine while his Finnegan scores were monitored for any withdrawal symptoms. He was weaned off nasal cannula at 18 days of age. He started oral feedings and gradually reached goal feedings by 20 days of age. He was discharged from the hospital at 1 month of age.Genetic testing for osteogenesis imperfecta (OI) using a multigene panel revealed a heterozygous pathogenic mutation in exon 31 of COL1A2, c.1801G>A (p.Gly601Ser).OI describes a clinically and genetically heterogeneous group of connective tissue syndromes, sometimes called “brittle bone disease,” characterized by osteopenia, bone deformity, and predisposition to fractures. OI most often results from mutations in 1 of the type 1 procollagen genes (COL1A1 or COL1A2). The underlying genetic heterogeneity results in a spectrum of disease that has been classified into several overlapping phenotypes ranging in severity from a perinatally lethal form, to a neonatal-onset progressively deforming form, to nondeforming forms that may have fewer fractures in a lifetime. (1)Among the forms that present in the neonatal period, typical radiographic features included diffuse osteopenia, thin cortices, multiple fractures with exuberant callus formation resembling a “pseudotumor,” gracile appearance of ribs, wormian bone in skull and biconcave “cod-fish” vertebrae. (2) Depending on the type of OI, extraskeletal manifestations include macrocephaly, characteristic facial features (flat midface and triangular facies), blue sclera (scleral thinning revealing the underlying uveal pigmentation), progressive hearing loss (conductive, sensorineural, or mixed), dentinogenesis imperfecta (a defect in mineralized dental tissues), and cardiovascular disease (aortic root dilation, valvular heart disease). (3) Pulmonary complications arising from rib fractures, congenital rib anomalies, scoliosis, and muscle weakness are an important cause of morbidity and mortality. (4) The neonate in this case presented with respiratory distress (caused by the rib fracture), blue sclerae, and multiple long bone fractures.The specific type of OI is determined by the features at clinical presentation, but the clinical course can be highly variable, depending on type, gene mutation, and degree of penetrance. (5) Neonatal forms of OI are often thought to include OI type II (perinatal lethal) and type III (progressively deforming). However, in this case, DNA sequencing revealed a heterozygous mutation in COL1A2 (c.1801G>A), which has been previously reported as a pathological variant described as classic nondeforming (OI type I) and moderately deforming phenotype (OI type IV) (Osteogenesis Imperfecta Variant Database; http://www.le.ac.uk/ge/collagen). This case highlights the clinical overlap among different phenotypic forms of OI and the variability of the phenotype among individuals harboring the same variant. (6) OI type IV is often described as a moderately deforming form that is known to have variable phenotypic expression with a range of severity. Because of this variability, it may be difficult to establish a specific clinical phenotype in the neonatal period.Management requires a multidisciplinary team of neonatologists, geneticists, endocrinologists, orthopedists, occupational therapists, and physiotherapists experienced in the care of OI. The ultimate goal is to minimize fractures, deformity, and associated disabilities. Bisphosphonates are often used in the treatment for moderate to severe cases of OI presenting in the neonatal period. Early studies suggested that administration of cyclic intravenous pamidronate increased bone mineral density, and perhaps reduced fracture risk in infants with severe OI types III and IV. However, their long-term effects on growth, bone pain, deformity, fractures, lung function, and overall functional status are less conclusive. (7) More recently, intravenous zoledronic acid has been used for its ease of administration and longer-lasting effects. (8) The most common adverse effects include an acute-phase infusion reaction (hyperpyrexia, myalgia, and weakness) and hypocalcemia. Monitoring serum calcium and phosphorous during treatment is essential.A broad differential is essential in evaluating newborns with multiple fractures, including a range of skeletal dysplasias, congenital rickets, syphilis, and various metabolic conditions such as hypophosphatasia, Menkes disease, and mucolipidosis type 2. (9) For an infant suspected to have constitutional disorder of bone, a skeletal survey is essential to distinguish among these conditions. Many of these conditions may share features of reduced bone density, deficient skull ossification, bowed long bones, fractures, gracile ribs, and narrow thorax. However, each disorder may have characteristic features. Perinatal hypophosphatasia manifests with characteristic metaphyseal abnormalities. Congenital rickets may demonstrate widened zones of provisional calcification and wide costochondral junctions, including widening along the anterior ends of the ribs (ie, rachitic rosary). Laboratory evaluation, including serum calcium, phosphorous, alkaline phosphatase, parathyroid hormone, and vitamin D levels may also help distinguish these disorders. Hypophosphatasia is characterized by low serum alkaline phosphatase, and congenital rickets shows abnormalities of calcium and phosphorous. An evaluation for extraskeletal manifestations may suggest specific disorders, including vesicobullous or maculopapular rash, generalized lymphadenopathy, hepatosplenomegaly (congenital syphilis); loose skin, kinky hair, hypotonia, seizures (Menkes disease); hypotonia, contractures, and characteristic facial features (mucolipidosis type 2). Family history and evaluation of affected relatives is critical for heritable diagnoses. However, many of these differentiating features may not be evident in the newborn period. Therefore, molecular genetic testing is an essential tool to diagnose these patients.

Osteogenesis imperfecta (OI) consists of a group of phenotypically and genetically heterogeneous connective tissue disorders that share similar skeletal anomalies causing bone fragility and deformation. The aim was to investigate the molecular genetic etiology and determine the relationship between genotype and phenotype in OI patients using targeted next-generation sequencing (NGS). A targeted NGS analysis panel (Illumina TruSight One) containing genes involved in collagen/bone synthesis was performed on the Illumina Nextseq550 platform in patients with a confirmed diagnosis of OI. Fifty-six patients (female/male: 25/31) from 46 different families were included. Consanguinity was noted in 15 (32.6%) families. Based on Sillence classification 18 (33.1%) were type 1 OI, 1 (1.7%) type 2, 26 (46.4%) type 3 and 11 (19.6%) type 4. Median body weight was -1.1 (-6.8, - 2.5) standard deviation scores (SDS), and height was -2.3 (-7.6, - 1.2) SDS. Bone deformity affected 30 (53.5%), while 31 (55.4%) were evaluated as mobile. Thirty-six (60.7%) had blue sclera, 13 (23.2%) had scoliosis, 12 (21.4%) had dentinogenesis imperfecta (DI), and 2 (3.6%) had hearing loss. Disease-causing variants in COL1A1 and COL1A2 were found in 24 (52.1%) and 6 (13%) families, respectively. In 8 (17.3%) of the remaining 16 (34.7%) families, the NGS panel revealed disease-causing variants in three different genes (FKBP10, SERPINF1, and P3H1). Nine (23.6%) of the variants detected by NGS panel had not previously been reported and were also classified as pathogenic based on American College of Medical Genetics guidelines pathogenity scores. In ten (21.7%) families, a disease-related variant was not found in any of the 13 OI genes on the panel. Genetic etiology was found in 38 (82.6%) of 46 families by targeted NGS analysis. Furthermore, nine new variants were identified in known OI genes which were classified as pathogenic by standard guidelines.

The management of osteogenesis imperfecta in adults: state of the art.

Background/Objectives: Osteogenesis Imperfecta (OI) is a congenital disorder, in which the production of collagen, mainly type I, is altered, leading to a decrease in bone mineral density, increasing the risk of fracture with minimal trauma. Several studies have analyzed bone mineral density in osteoporotic patients based on linear measurements such as radiomorphometric indices measured with panoramic radiographs, although few studies have investigated bone trabeculation in children diagnosed with OI. Therefore, the aim of the present investigation was to analyze the dental panoramic indices in panoramic radiographs in the cortical and trabeculated bone of children with OI. Methods: Thus, 66 pediatric patients diagnosed with OI under antiresorptive treatment were compared with a sample of controls matched for sex and age. Using Image J software (version: 1.54d), three radiomorphometric indices were analyzed in orthopantomographies of the study and control groups, evaluating the influence of disease severity as well as the type of antiresorptive treatment administered. Results: Patients with OI had a higher presence of type C2 and C3 MCI (mandibular cortical index) than their matched controls (p < 0.05), although no differences were found for the visual estimation of cortical width (SVE) and mandibular cortical width (MCW). Treatment with zoledronic acid was associated with a higher number of cases of type C1 MCI, in terms of sample description, while patients treated with a combination of pamidronate and zoledronic acid had a higher rate of type C1 and C2 MCI, with no statistical differences. Conclusions: In the overall sample, most patients showed a thin SVE index (59.1%), a C2 or C1 type MCI (46.2% and 42.4%) and an MCW of 2.9 mm. Differences in bone mineral density were also observed throughout growth and the different antiresorptive treatments. Zoledronic acid has been associated with a higher percentage of C1 and C3 ICM, and pamidronate alone or in combination is associated with a C1 and C2 MCI index.

Sclerostin antibody improves skeletal parameters in a Brtl/+ mouse model of osteogenesis imperfecta