Treatment Of Osteogenesis Imperfecta Research Articles

Osteogenesis imperfecta: advancements in genetics and treatment.

The purpose of this review is to outline the current understanding of the molecular mechanisms and natural history of osteogenesis imperfecta, and to describe the development of new treatments for this disorder. The introduction of next-generation sequencing technology has led to better understanding of the genetic cause of osteogenesis imperfecta and enabled cost-effective and timely diagnosis via expanded gene panels and exome or genome sequencing. Clinically, despite genetic heterogeneity, different forms of osteogenesis imperfecta share similar features that include connective tissue and systemic manifestations in addition to bone fragility. Thus, the goals of treatment in osteogenesis imperfecta extend beyond decreasing the risk of fracture, to include the maximization of growth and mobility, and the management of extraskeletal complications. The standard of care in pediatric patients is bisphosphonates therapy. Ongoing preclinical studies in osteogenesis imperfecta mouse models and clinical studies in individuals with osteogenesis imperfecta have been instrumental in the development of new and targeted therapeutic approaches, such as sclerostin inhibition and transforming growth factor-β inhibition. Osteogenesis imperfecta is a skeletal dysplasia characterized by bone fragility and extraskeletal manifestations. Better understanding of the mechanisms of osteogenesis imperfecta will enable the development of much needed targeted therapies to improve the outcome in affected individuals.

Using a corkscrew-tipped telescopic nail in the treatment of osteogenesis imperfecta: a biomechanical study and preliminary results of 17 consecutive cases.

High complication rates were reported with the telescopic nail technique systems. To overcome such technical difficulties, we designed a corkscrew-tipped telescopic nail (CTTN). We biomechanically compared its pullout strength with that of two other tip designs. We used CTTN in 17 patients with osteogenesis imperfecta and reported their preliminary results. Average patient age was 82.6 months, and mean follow-up was 32.0±6 months. Telescoping and osteotomy site healing were assessed using radiological studies. Successful telescoping with event-free osteotomy site healing was achieved in 94.1% of patients; limited telescoping and delayed union were detected in one case each. Our results show that CTTN provides sufficient pullout strength and reduced complication rates compared with other designs.

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

Osteogenesis imperfecta (OI) is a genetic disease whose clinical phenotype and severity vary considerably. The increased risk of fractures due to bone fragility persists in adulthood, notably after 40 years of age, albeit at a lower level than during growth. Adults with OI require periodic evaluations of the other manifestations of OI including hearing loss, respiratory impairments, ocular and dental abnormalities, and cardiovascular disease. Follow-up should therefore be provided by a multidisciplinary team, at intervals tailored to disease severity. Currently used treatments for OI have not been proven to decrease the fracture risk but are consistently effective in increasing bone mineral density. Specific orthopedic expertise is often required to treat fractures in patients with OI. A combination of periodic evaluations, chronic pain control, and disability management is necessary to improve quality of life.

The Impact of Bisphosphonates on the Osteoclast Cells of Osteogenesis Imperfecta Patients

Bisphosphonates (BPs) are widely used for treatment of osteogenesis imperfecta (OI). However, prolonged use may be associated with suppression of bone turnover, the exact molecular mechanism of which is poorly understood. The objective of this study was to evaluate the effect of zoledronic acid (ZOL) on precursor osteoclasts by studying caspase 3 activity. A total of 15 children participated in the study (n = 10 OI patients, n= 5 controls). Out of the 10 OI children, 5 had received a cumulative dose of <30 mg and 5 received > 30 mg of ZOL. Isolated mononuclear cells were studied for caspase 3 activity from all study participants. The mean age of study participants was 7 ±1.5 years. Six of them had OI type IV, two had type III and one had types I & II each. Radiographs showed “zebra stripe sign” and dense metaphyses; suggestive of acquired osteosclerosis. Bone turnover markers (PINP and CTx) were suppressed in all OI patients compared to controls. Caspase-3 activity was significantly increased in precursor osteoclasts cells at higher doses of BPs (>30 mg). Overzealous use of ZOL in OI suppresses bone turnover markers (P1NP, CTx) causes osteosclerosis and increased expression of caspase 3 activity in precursor osteoclasts which results in adynamic bone.

Low Dose of Bisphosphonate Enhances Sclerostin Antibody-Induced Trabecular Bone Mass Gains in Brtl/+ Osteogenesis Imperfecta Mouse Model.

Osteogenesis imperfecta (OI) is a genetic disorder characterized by altered bone quality and imbalanced bone remodeling, leading to skeletal fractures that are most prominent during childhood. Treatments for OI have focused on restoring pediatric bone density and architecture to recover functional strength and consequently reduce fragility. Though antiresorptive agents like bisphosphonates (BPs) are currently the most common intervention for the treatment of OI, a number of studies have shown efficacy of sclerostin antibody (SclAb) in inducing gains in bone mass and reducing fragility in OI mouse models. In this study, the effects of the concurrent use of BP and SclAb were evaluated during bone growth in a mouse harboring an OI-causing Gly→Cys mutation on col1a1. A single dose of antiresorptive BP facilitated the anabolic action of SclAb by increasing availability of surfaces for new bone formation via retention of primary trabeculae that would otherwise be remodeled. Chronic effects of concurrent administration of BP and SclAb revealed that accumulating cycles conferred synergistic gains in trabecular mass and vertebral stiffness, suggesting a distinct advantage of both therapies combined. Cortical gains in mass and strength occurred through SclAb alone, independent of presence of BP. In conclusion, these preclinical results support the scientific hypothesis that minimal antiresorptive treatment can amplify the effects of SclAb during early stages of skeletal growth to further improve bone structure and rigidity, a beneficial outcome for children with OI. © 2018 American Society for Bone and Mineral Research.

Homeostasis and Disorder of Musculoskeletal System.Diagnosis and Treatment of Congenital Musculoskeletal Diseases.

Congenital skeletal dysplasias have been considered to be fundamentally untreatable diseases. However, molecular diagnosis by genetic testing has become more prevalent, and efforts are being made to develop novel therapies based on the pathogenesis. As treatments for osteogenesis imperfecta, in addition to anti-resorptive agents, neutralizing antibodies against sclerostin and transforming growth factor(TGF)-β and chemical chaperones can be beneficial. Enzyme replacement therapy using bone-targeting recombinant alkaline phosphatase has been recently developed to treat hypophosphatasia and has much improved the prognosis of the patients affected with severe forms of the disease. To treat the severe short stature in achondroplasia, drugs targeting the fibroblast growth factor receptor 3(FGFR3)-mediated signal are in development for clinical use.

Osteogenesis imperfecta: diagnosis and treatment.

Here we summarize the diagnosis of osteogenesis imperfecta, discuss newly discovered genes involved in osteogenesis imperfecta, and review the management of this disease in children and adults. Mutations in the two genes coding for collagen type I, COL1A1 and COL1A2, are the most common cause of osteogenesis imperfecta. In the past 10 years, defects in at least 17 other genes have been identified as responsible for osteogenesis imperfecta phenotypes, with either dominant or recessive transmission. Intravenous bisphosphonate infusions are the most widely used medical treatment. This has a marked effect on vertebra in growing children and can lead to vertebral reshaping after compression fractures. However, bisphosphonates are less effective for preventing long-bone fractures. At the moment, new therapies are under investigation. Despite advances in the diagnosis and treatment of osteogenesis imperfecta, more research is needed. Bisphosphonate treatment decreases long-bone fracture rates, but such fractures are still frequent. New antiresorptive and anabolic agents are being investigated but efficacy and safety of these drugs, especially in children, need to be better established before they can be used in clinical practice.

Long-Term Bisphosphonate Therapy in Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a genetic bone disorder resulting in bone fragility. It has a heterogeneous phenotype which typically includes reduced bone mass, multiple fractures, deformity, and chronic disability. Bisphosphonate treatment remains the first-line medical management, but there is still debate on aspects of its effectiveness. This review summarizes current knowledge about long-term bisphosphonate use in OI with recommendations on clinical application. Bisphosphonates increase bone mineral density, most notably of the vertebrae, and reduce fracture risk in the pediatric OI population. Gains in strength and mobility, together with the permissive effect on orthopedic surgery (e.g., in combination with intramedullary rodding) and physiotherapy, have resulted in improved quality of life for those with OI. As experience in its use continues, the risks and benefits of long-term bisphosphonate treatment in OI are slowly emerging. Patient registries containing data on genotype, phenotype, fractures, bisphosphonate treatment, orthopedic intervention, and functional outcomes are essential for systematic evaluation given the lack of large multi-centered randomized control trials.

BOOSTB4: Boost Brittle Bones Before Birth A clinical trial on pre- and/or postnatal stem cell transplantation for treatment of osteogenesis imperfecta

BOOSTB4: Boost Brittle Bones Before Birth A clinical trial on pre- and/or postnatal stem cell transplantation for treatment of osteogenesis imperfecta

Long-term Effects of Neridronate in Adults with Osteogenesis Imperfecta: An Observational Three-Year Italian Study.

The aim of this study was to assess the long-term efficacy and safety of i.v. neridronate in the treatment of osteogenesis imperfecta (OI). One hundred and fourteen patients affected by OI were included in the study. Neridronate was administered by i.v. infusion at the dosage of 2mg/kg, up to a maximum of 100mg at three-month intervals for 3years. Dual X-ray absorptiometry of the lumbar spine, hip, and ultradistal and proximal radius were evaluated every 6months. Blood calcium, phosphate, albumin, fasting urinary calcium/creatinine ratio, total serum alkaline phosphatase, and bone alkaline phosphatase were obtained at baseline and every 3months. The mean lumbar spine and total hip BMD significantly increased from baseline to any time point (p < 0.001). The mean ultradistal radius BMD significantly increased from baseline only at month 18 (p = 0.026), 30 (p = 0.046), and 36 (p = 0.013), respectively. The mean proximal radius BMD did not change during the whole observation. The levels of bone turnover markers significantly decreased from baseline to any post-baseline observation time. The study was not able to find any statistically significant effect on fracture risk (p = 0.185). The percentage of patients with fractures was unaltered during treatment as compared to the 3-year period before treatment. The most common AEs were fragility fractures, back pain, arthralgia, fever, and joint sprain. An acute phase reaction was reported in 26 (22.8%) patients. None of the reported SAEs were considered as treatment-related. Long-term treatment with i.v. neridronate has positive effects on BMD and bone turnover markers with a good safety profile, although no significant effect on the risk of fracture was observed.

Clinical and Molecular Heterogeneity of Osteogenesis Imperfecta

Abstract Osteogenesis imperfecta (OI) is a disease encompassing a group of disorders mainly characterized by bone fragility and is the commonest form of heritable bone fragility. In this book, the clinical presentations with particular emphasis on rare phenotypes associated with OI are discussed together with molecular advances in diagnosis and treatment of OI. There is a broad spectrum of clinical severity in OI, ranging from multiple fractures in utero and perinatal death, to near-normal adult stature and low fracture incidence. Facial dysmorphism has been noted, but is not well described, nor is it an invariable feature. Sillence et al., in 1979, provided the clinical classification, which has been further expanded. Genetic defects in type 1 collagen can be identified in 85% of patients with a clinical diagnosis of OI, that is, mutations in COL1A1/COL1A2, which follows an autosomal dominant pattern of inheritance. Several genes have now been implicated in autosomal recessive forms of OI and X-linked os...

Сomplications in using different types of intramedullar telescopic fixators in children with osteogenesis imperfecta

Treatment of patients with osteogenesis imperfecta (OI) is a com­plex problem in orthopedics. The most effective method of surgi­cal correction of long bone deformities in OI is the use of Fassi­er-Duval rod. However, a significant number (35 %) of its as­sociated complications (instability, migration and lock eruption, no extension during bone growth, bone deformity and fractures in terms of loading, bone fractures) leads to development of the new approaches. In Sytenko Institute of Spine and Joint Pathol­ogy designed intramedullary telescopic fiction device (ITF), which combines the principles of rotational and axial stability. Objective:to analyze the complications of treatment in OI chil­dren after fixation of long bones by means of rotary ITF stability and without it. Methods: we performed 28 surgeries in 9 patients with combined deformations of the bones of the lower limbs, us­ing ITF (5 rotary unstable, made of stainless steel and 23 rotary-stable — rods in 2 cases made of stainless steel, 21 — with tita­nium alloy). Results: after the use of rotary unstable ITF, eternal immobilization was longer for 10– 14 days, and recovery time range of motion in adjacent joints were longer by 7 days on av­erage compared with the group of patients who used stable rota­ry ITF. There was the following symptoms: violation of blocking wires, deformation and limb segment with ITF migration, ab­sence of ITF lengthening, limb fracture with ITF. Complications from the use of rotary unstable ITF was 60 %, and after rotary-stable — 17.4 %. Conclusions:the use of rotary stable ITF cor­recting deformities of long bones of the extremities in patients with OI is more efficient and leads to less (17.4 %) complica­tions.

Management of osteogenesis imperfecta at the Chris Hani Baragwanath Hospital

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.

Pharmacological and biological therapeutic strategies for osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility, low bone mass, and bone deformities. The majority of cases are caused by autosomal dominant pathogenic variants in the COL1A1 and COL1A2 genes that encode type I collagen, the major component of the bone matrix. The remaining cases are caused by autosomal recessively or dominantly inherited mutations in genes that are involved in the post-translational modification of type I collagen, act as type I collagen chaperones, or are members of the signaling pathways that regulate bone homeostasis. The main goals of treatment in OI are to decrease fracture incidence, relieve bone pain, and promote mobility and growth. This requires a multi-disciplinary approach, utilizing pharmacological interventions, physical therapy, orthopedic surgery, and monitoring nutrition with appropriate calcium and vitamin D supplementation. Bisphosphonate therapy, which has become the mainstay of treatment in OI, has proven beneficial in increasing bone mass, and to some extent reducing fracture risk. However, the response to treatment is not as robust as is seen in osteoporosis, and it seems less effective in certain types of OI, and in adult OI patients as compared to most pediatric cases. New pharmacological treatments are currently being developed, including anti-resorptive agents, anabolic treatment, and gene- and cell-therapy approaches. These therapies are under different stages of investigation from the bench-side, to pre-clinical and clinical trials. In this review, we will summarize the recent findings regarding the pharmacological and biological strategies for the treatment of patients with OI. © 2016 Wiley Periodicals, Inc.

Correlations Between Bone Mechanical Properties and Bone Composition Parameters in Mouse Models of Dominant and Recessive Osteogenesis Imperfecta and the Response to Anti-TGF-β Treatment.

Osteogenesis imperfecta (OI) is a group of genetic disorders characterized by brittle bones that are prone to fracture. Although previous studies in animal models investigated the mechanical properties and material composition of OI bone, little work has been conducted to statistically correlate these parameters to identify key compositional contributors to the impaired bone mechanical behaviors in OI. Further, although increased TGF-β signaling has been demonstrated as a contributing mechanism to the bone pathology in OI models, the relationship between mechanical properties and bone composition after anti-TGF-β treatment in OI has not been studied. Here, we performed follow-up analyses of femurs collected in an earlier study from OI mice with and without anti-TGF-β treatment from both recessive (Crtap-/- ) and dominant (Col1a2+/P.G610C ) OI mouse models and WT mice. Mechanical properties were determined using three-point bending tests and evaluated for statistical correlation with molecular composition in bone tissue assessed by Raman spectroscopy. Statistical regression analysis was conducted to determine significant compositional determinants of mechanical integrity. Interestingly, we found differences in the relationships between bone composition and mechanical properties and in the response to anti-TGF-β treatment. Femurs of both OI models exhibited increased brittleness, which was associated with reduced collagen content and carbonate substitution. In the Col1a2+/P.G610C femurs, reduced hydroxyapatite crystallinity was also found to be associated with increased brittleness, and increased mineral-to-collagen ratio was correlated with increased ultimate strength, elastic modulus, and bone brittleness. In both models of OI, regression analysis demonstrated that collagen content was an important predictor of the increased brittleness. In summary, this work provides new insights into the relationships between bone composition and material properties in models of OI, identifies key bone compositional parameters that correlate with the impaired mechanical integrity of OI bone, and explores the effects of anti-TGF-β treatment on bone-quality parameters in these models. © 2016 American Society for Bone and Mineral Research.

Bent Telescopic Rods in Patients With Osteogenesis Imperfecta.

Telescopic rods require alignment of 2 rods to enable lengthening. A telescopic rod converts functionally into a solid rod if either rod bends, preventing proper engagement. Our goal was to characterize implant bending as a mode of failure of telescopic rods used in the treatment of osteogenesis imperfecta in children. We conducted a retrospective review of our osteogenesis imperfecta database for patients treated with intramedullary telescopic rods at our institution from 1992 through 2010 and identified 12 patients with bent rods. The 6 boys and 6 girls had an average age at the time of initial surgery of 3.1 years (range, 1.8 to 8.3 y) and a total of 51 telescoping rods. Clinic notes, operative reports, and radiographs were reviewed. The rods were analyzed for amount of lengthening, characteristics of bending, presence of cut out, or disengagement from an anchor point. Bends in the rods were characterized by their location on the implant component. The bent and straight rods were compared. Data were analyzed with the Mann-Whitney test (statistical significance set at P≤0.05). Of the 51 telescoping rods, 17 constructs (33%) bent. The average interval between surgery and rod bending was 4.0 years (range, 0.9 to 8.2 y). Before bending, 11 of 17 telescoping rods had routine follow-up radiographs for review. In 10 of the rods, bending was present when early signs of rod failure were first detected. Rod bending did not seem to be related to rod size. There was no area on the rod itself that seemed more susceptible to bending. Rod bending can be an early sign of impending rod failure. When rod bending is first noted, it may predispose the rod to other subsequent failures such as loss of proximal and distal fixation and cut out. Rod bending should be viewed as an indicator for closer monitoring of the patient and discussions regarding future need for rod exchange. Level III-retrospective review.

Advances in the Classification and Treatment of Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a rare disorder of type 1 collagen with 13 currently identified types attributable to inherited abnormalities in type 1 collagen amount, structure, or processing. The disease is characterized by an increased susceptibility to bony fracture. In addition to the skeletal phenotype, common additional extraskeletal manifestations include blue sclerae, dentinogenesis imperfecta, vascular fragility, and hearing loss. Medical management is focused on minimizing the morbidity of fractures, pain, and bone deformities by maximizing bone health. Along with optimizing Vitamin D status and calcium intake and physical/occupational therapy, individualized surgical treatment may be indicated. Pharmacological therapy with bisphosphonate medications is now routinely utilized for moderate to severe forms and appears to have a good safety profile and bone health benefits. New therapies with other anti-resorptives as well as anabolic agents and transforming growth factor (TGF)β antibodies are in development. Other potential treatment modalities could include gene therapy or mesenchymal cell transplant. In the future, treatment choices will be further individualized in order to reduce disease morbidity and mortality.

New Aspects of Genetic Basis, Classification and Treatment of Osteogenesis Imperfecta: Literature Review

Osteogenesis imperfecta is characterized by increased congenital brittleness of bones with a broad spectrum of clinical manifestations — from perinatal/lethal form and severe bone deformities to the mildest forms. In most cases, the disease is caused by autosomaldominant mutation in the collagen 1 gene. At present, the approach to patients with osteogenesis imperfecta is multidisciplinary. Bisphosphonate drug therapy is conducted to reduce the incidence of fractures in the process of treatment, which also involves active rehabilitation and surgical correction of bone deformities. A more profound understanding of pathogenesis of osteogenesis imperfecta may lead to a development of new and effective therapeutic approaches capable of improving functional outcomes in patients.

Risedronate in the treatment of Osteogenesis Imperfecta: Retrospective review of practice and outcomes in a large paediatric metabolic bone unit

Risedronate in the treatment of Osteogenesis Imperfecta: Retrospective review of practice and outcomes in a large paediatric metabolic bone unit

Zoledronic acid in children with osteogenesis imperfecta and Bruck syndrome: a 2-year prospective observational study.

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.