Influence of zoledronic acid and pamidronate on tooth eruption in children with osteogenesis imperfecta.

INTRODUCTION: Osteogenesis imperfecta (OI) is a congenital disease comprising a heterogeneous group of inherited connective tissue disorders. The main treatment in children is bisphosphonate therapy. Previous animal studies have shown that bisphosphonates delay tooth eruption. The aim of this study is to determine whether patients with OI treated with pamidronate and/or zoledronic acid have a delayed eruption age compared to a control group of healthy children. METHODS: An ambispective longitudinal cohort study evaluating the age of eruption of the first stage mixed dentition in a group of children with OI (n = 37) all treated with intravenous bisphosphonates compared with a group of healthy children (n = 89). Within the study group, the correlation (Pearson correlation test) between the type of medication administered (pamidronate and/or zoledronic acid) and the chronology of tooth eruption is established, as well as the relationship between the amount of cumulative dose received and tooth eruption. RESULTS: The age of eruption of the study group was significantly delayed compared to the age of eruption of the control group for molars and lateral incisors (p < 0.05). Patients who received higher cumulative doses had a delayed eruption age compared to those with lower cumulative doses (p < 0.05). There is a high positive correlation between age of delayed tooth eruption and Zoledronic acid administration. CONCLUSION: Patients with OI have a delayed eruption of the 1st stage mixed dentition compared to a control group of healthy children. This delayed eruption is directly related to the cumulative dose of bisphosphonates and the administration of zoledronic ac.

Efficacy of Bisphosphonate for Urolithiasis Complicated by Osteogenesis Imperfecta.

A 44-year-old man with osteogenesis imperfecta presented with left renal colic. Non-contrast computed tomography revealed a stone (10×9 mm) in the left upper ureter. Ureteroscopic lithotripsy was performed twice and stone-free status was achieved. An analysis of the stone revealed a mixed composition including calcium oxalate and calcium phosphate. Postoperatively, we administered bisphosphonates to prevent recurrence of urolithiasis, as 24-hour urine collection revealed marked hypercalciuria. Eighteen months after surgery, the urinary calcium levels had normalized, and there was no recurrence of urolithiasis. Osteogenesis imperfecta can be complicated by urolithiasis, but bisphosphonates may be useful in preventing recurrence of this disease.

Assessing the Safety and Efficacy of Tranexamic Acid Usage in Osteogenesis Imperfecta Patients.

BACKGROUND: Osteogenesis Imperfecta (OI) usually causes an increased fracture burden and bone deformity, with subsequent operations common. In addition to skeletal manifestations, there is a potential increase in bleeding susceptibility due to the increased frequency of orthopedic procedures, warranting investigation into methods to mitigate this risk. This study aims to evaluate the safety and efficacy of tranexamic acid (TXA) usage to reduce intraoperative blood loss in children with OI. We want to assess the potential benefits, risks, and complications involved with TXA use in this patient population. METHODS: TXA-receiving patients (cases) were matched 1:1 with non-TXA-receiving controls on the following criteria: age within 2 years, bone category, and OI Type. Descriptive statistics were used to summarize the data. Fisher Exact Test was performed to compare transfusion status between groups. A Wilcoxon Rank Sum test was performed to assess differences between the groups in days of stay, length of surgery, and estimated blood loss (EBL). All analyses were conducted using SAS version 9.4. P <0.05 was considered statistically significant. RESULTS: Our TXA-receiving population of 30 patients consisted of 11 females and 19 males. One patient was OI type I, 13 were OI type III, 14 were OI type IV, and 2 were categorized as Other (not Type I through Type IV). We found a significant difference in transfusion status ( P =0.02), with zero TXA patients requiring a transfusion compared with 20% of the control cases. There is also a significant difference in median EBL ( P =0.0004) between groups, with TXA patients having decreased intraoperative EBL (20 vs. 62.5 mL). There was also a difference in median days of postoperative stay between TXA-receiving and non-TXA-receiving patients ( P =0.001; 2.6 vs. 4 d). CONCLUSIONS: Our study concluded that TXA use in OI patients is associated with lower perioperative transfusions and intraoperative blood loss rates. These results support the standard usage of TXA in these patients to reduce intraoperative blood loss. LEVEL OF EVIDENCE: Level III.

The recombinant BMP-2 loaded silk fibroin microspheres improved the bone phenotype of mild osteogenesis imperfecta mice.

Osteogenesis imperfecta (OI) is an inherited congenital disorder, characterized primarily by decreased bone mass and increased bone fragility. Bone morphogenetic protein-2 (BMP-2) is a potent cytokine capable of stimulating bone formation, however, its rapid degradation and unanticipated in vivo effects restrict its application. The sustained release characteristic of silk fibroin (SF) microspheres may potentially address the aforementioned challenges, nevertheless they have not previously been tested in OI treatment. In the current investigation, recombinant BMP-2 (rBMP-2) loaded SF (rBMP-2/SF) microspheres-based release carriers were prepared by physical adsorption. The SF microparticles were characterized by scanning electron microscopy (SEM) and were investigated for their cytotoxicity behavior as well as the release profile of rBMP-2. The rBMP-2/SF microspheres were administered via femoral intramedullary injection to two genotypes of OI-modeled mice daily for two weeks. The femoral microstructure and histological performance of OI mice were evaluated 2 weeks later. The findings suggested that rBMP-2/SF spheres with a rough surface and excellent cytocompatibility demonstrated an initial rapid release within the first three days (22.15 ± 2.88% of the loaded factor), followed by a transition to a slower and more consistent release rate, that persisted until the 15th day in an in vitro setting. The factor released from rBMP-2/SF particles exhibited favorable osteoinductive activity. Infusion of rBMP-2/SF microspheres, as opposed to blank SF spheres or rBMP-2 monotherapy, resulted in a noteworthy enhancement of femoral microstructure and promoted bone formation in OI-modeled mice. This research may offer a new therapeutic approach and insight into the management of OI. However, further investigation is required to determine the systematic safety and efficacy of rBMP-2/SF microspheres therapy for OI.

Protocol of a randomised trial of teriparatide followed by zoledronic acid to reduce fracture risk in adults with osteogenesis imperfecta.

INTRODUCTION: Osteogenesis imperfecta (OI) is a rare genetic disease associated with multiple fractures throughout life. It is often treated with osteoporosis medications but their effectiveness at preventing fractures is unknown. The Treatment of Osteogenesis Imperfecta with Parathyroid Hormone and Zoledronic Acid trial will determine if therapy with teriparatide (TPTD) followed by zoledronic acid (ZA) can reduce the risk of clinical fractures in OI. METHODS AND ANALYSIS: Individuals aged ≥18 years with a clinical diagnosis of OI are eligible to take part. At baseline, participants will undergo a spine X-ray, and have bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) at the spine and hip. Information on previous fractures and previous bone targeted treatments will be collected. Questionnaires will be completed to assess pain and other aspects of health-related quality of life (HRQoL). Participants will be randomised to receive a 2-year course of TPTD injections 20 µg daily followed by a single intravenous infusion of 5 mg ZA, or to receive standard care, which will exclude the use of bone anabolic drugs. Participants will be followed up annually, have a repeat DXA at 2 years and at the end of study. Spine X-rays will be repeated at the end of study. The duration of follow-up will range between 2 and 8 years. The primary endpoint will be new clinical fractures confirmed by X-ray or other imaging. Secondary endpoints will include participant reported fractures, BMD and changes in pain and HRQoL. ETHICS AND DISSEMINATION: The study received ethical approval in December 2016. Following completion of the trial, a manuscript will be submitted to a peer-reviewed journal. The results will inform clinical practice by determining if TPTD/ZA can reduce the risk of fractures in OI compared with standard care. TRIAL REGISTRATION NUMBER: ISRCTN15313991.

Combination of osteogenesis imperfecta and hypophosphatasia in three children with multiple fractures, low bone mass and severe osteomalacia, a challenge for therapeutic management.

Osteogenesis imperfecta (OI) and hypophosphatasia (HPP) are rare skeletal disorders caused by mutations in the genes encoding collagen type I (COL1A, COL1A2) and tissue-non-specific isoenzyme of alkaline phosphatase (ALPL), respectively. Both conditions result in skeletal deformities and bone fragility although bone tissue abnormalities differ considerably. Children with OI have low bone mass and hypermineralized matrix, whereas HPP children develop rickets and osteomalacia. We report a family, father and three children, affected with growth retardation, low bone mass and recurrent fractures. None of them had rickets, blue sclera or dentinogenesis imperfecta. ALP serum levels were low and genetics revealed in the four probands heterozygous pathogenic mutations in COL1A2 c.838G > A (p.Gly280Ser) and in ALPL c.1333T > C (p.Ser445Pro). After multidisciplinary meeting, a diagnostic transiliac bone biopsy was indicated for each sibling for therapeutic decision. Bone histology and histomorphometry, as compared to reference values of children with OI type I as well as, to a control pediatric patient harboring the same COL1A2 mutation, revealed similarly decreased trabecular bone volume, increased osteocyte lacunae, but additionally severe osteomalacia. Quantitative backscattered electron imaging demonstrated that bone matrix mineralization was not as decreased as expected for osteomalacia. In summary, we observed within each biopsy samples classical features of OI and classical features of HPP. The apparent nearly normal bone mineralization density distribution results presumably from divergent effects of OI and HPP on matrix mineralization. A combination therapy was initiated with ALP enzyme-replacement and one month later with bisphosphonates. The ongoing treatment led to improved skeletal growth, increased BMD and markedly reduced fracture incidence.

Vitamin D and Bone fragility in Individuals with Osteogenesis Imperfecta: A Scoping Review.

Vitamin D affects several body functions, and thus general health, due to its pleiotropic activity. It plays a key role in bone metabolism, and its deficiency impacts bone development, leading to bone fragility. In osteogenesis imperfecta (OI), a group of hereditary connective tissue disorders characterized by bone fragility, additional factors, such as vitamin D deficiency, can affect the expression of the phenotype and aggravate the disorder. The aim of this scoping review was to assess the incidence of vitamin D deficit in OI patients and the association between vitamin D status and supplementation in individuals affected by OI. We searched the PubMed Central and Embase databases and included studies published between January/2000 and October/2022 evaluating vitamin D measurement and status (normal, insufficiency, deficiency) and supplementation for OI. A total of 263 articles were identified, of which 45 were screened by title and abstract, and 10 were included after a full-text review. The review showed that low levels of vitamin D was a frequent finding in OI patients. Vitamin D supplementation was mainly indicated along with drug therapy and calcium intake. Even if widely used in clinical practice, vitamin D supplementation for OI individuals still needs a better characterization and harmonized frame for its use in the clinical setting, as well as further studies focusing on its effect on bone fragility.

Pediatric Hand and Wrist Fractures in Osteogenesis Imperfecta: An Analysis of Incidence, Patient-specific Risk Factors, and Fracture-specific Characteristics.

BACKGROUND: Children with osteogenesis imperfecta (OI) frequently present with fractures; however, hand and wrist fractures (HWFs), those distal to the radial and ulnar diaphysis, are seldom observed. Yet, HWFs remain among the most common fractures in children with non-OI. The objective of this study was to identify the incidence of OI HWFs. Secondary objectives aimed at identifying patient-specific risk factors for HWFs in OI and comparing clinical courses to non-OI HWFs. METHODS: A retrospective cohort study was conducted. Database query by ICD-10 codes identified 18 patients with OI HWF, 451 patients with OI without HWFs, and 26,183 patients with non-OI HWF. Power analysis estimated appropriate sample sizes and random sampling was utilized to collect patients. Patient demographics, OI-specific variables, fracture morphology, and fracture clinical courses were recorded. Data were analyzed for patient-specific and fracture-specific factors affecting OI HWF incidence. RESULTS: Of patients with OI, 3.8% (18/469) sustained HWFs. Patients with OI HWF were significantly older than patients with OI without HWFs ( P = 0.002) with no differences in height, weight, ethnicity, sex, or ambulatory status. Compared with non-OI HWFs, patients with OI HWF were significantly shorter ( P < 0.001), weighed less ( P = 0.002), and were less likely to be ambulatory ( P < 0.001). OI HWFs were more commonly on the side of hand dominance ( P < 0.001) with transverse patterns ( P = 0.001). OI HWFs were less frequent in the thumb ( P = 0.048) and trended towards significance in the metacarpals ( P = 0.054). All OI HWFs were treated nonoperatively with similar union rates and refracture rates to non-OI HWFs. Multivariate regression showed that older patient age (odds ratio: 1.079, 95% CI: 1.005,1.159, P = 0.037) and OI type I (odds ratio: 5.535, 95% CI: 1.069, 26.795, P = 0.041) were significant prognosticators for HWFs in patients with OI. CONCLUSION: OI HWFs are uncommon (3.8%, 18/469) but specific HWF morphologies and locations are more common in patients with OI; however, these are not pathognomonic. Older patients with mild penetrance of type I OI are at the highest risk for HWFs. OI HWFs do well when managed nonoperatively with noninferior clinical courses compared with non-OI HWFs. LEVEL OF EVIDENCE: Level III.

Pharmacological options in the treatment of osteogenesis imperfecta: A comprehensive review of clinical and potential alternatives.

Osteogenesis imperfecta (OI) is a genetically heterogeneous connective tissue disorder characterized by bone fragility and different extra-skeletal manifestations. The severity of these manifestations makes it possible to classify OI into different subtypes based on the main clinical features. This review aims to outline and describe the current pharmacological alternatives for treating OI, grounded on clinical and preclinical reports, such as antiresorptive agents, anabolic agents, growth hormone, and anti-TGFß antibody, among other less used agents. The different options and their pharmacokinetic and pharmacodynamic properties will be reviewed and discussed, focusing on the variability of their response and the molecular mechanisms involved to attain the main clinical goals, which include decreasing fracture incidence, improving pain, and promoting growth, mobility, and functional independence.

Cyclic intravenous pamidronate for an infant with osteogenesis imperfecta type II.

A woman in her 30s underwent a 17-week ultrasound which revealed short bowed long bones. Fetal CT at 28 weeks' gestation showed decreased ossification of the skull, a small bell-shaped thorax, hypoplastic vertebrae, and shortening and bowing of the long bones, leading to the diagnosis of osteogenesis imperfecta (OI) type II. The newborn was delivered via caesarean delivery, and tracheal intubation was performed due to the respiratory distress. A heterozygous variant in COL1A1 (c.1679G>T, p. Gly358Val) was ascertained, confirming the diagnosis of OI type II.Cyclic intravenous pamidronate was started at 41 days old with dose modification and was successfully administered every month. Currently, the infant is 8 months old without any new bone fracture. He was extubated successfully at 7 months of age and is now stable using high flow nasal cannula. The efficacy, safety, and optimal dose and timing of cyclic pamidronate for OI type II remain undefined. We report our experience of successful cyclic intravenous pamidronate treatment for an infant with OI type II.

Mitigating the Denosumab-Induced Rebound Phenomenon with Alternating Short- and Long-Acting Anti-resorptive Therapy in a Young Boy with Severe OI Type VI.

Osteogenesis imperfecta (OI) type VI, a recessively inherited form of OI caused by mutations in SERPINF1, is a severe form distinguished by osteomalacia on bone histomorphometry. We describe a boy with severe OI type VI who was initially treated with intravenous (IV) zoledronic acid (ZA) at 1.4 years of age; however, a year later he transitioned to denosumab 1 mg/kg sub-cutaneously every three months in an effort to decrease fracture rates. After two years on denosumab, he presented with symptomatic hypercalcemia due to the denosumab-induced, hyper-resorptive rebound phenomenon. Laboratory parameters at the time of the rebound were as follows: elevated serum ionized calcium (1.62 mmol/L, N 1.16-1.36), elevated serum creatinine due to hypercalcemia-induced muscle catabolism (83 µmol/L, N 9-55), and suppressed parathyroid hormone (PTH) (< 0.7 pmol/L, N 1.3-5.8). The hypercalcemia was responsive to low-dose IV pamidronate, with a rapid decline in serum ionized calcium, and otherwise normalization of the aforementioned parameters within 10 days. To benefit from the powerful, albeit short-term, anti-resorptive effect of denosumab without further rebound episodes, he was treated thereafter with denosumab 1 mg/kg alternating every three months with IV ZA 0.025 mg/kg. Five years later, he remained on dual alternating anti-resorptive therapy without further rebound episodes, and an overall improvement in his clinical status. This novel pharmacological approach of alternating short- and long-term anti-resorptive therapy every three months has not previously been described. Our report suggests this strategy may be an effective method for prevention of the rebound phenomenon in select children for whom denosumab may be beneficial.

How does alendronate affect orthodontic tooth movement in osteogenesis imperfecta: an in vivo study on a mice model.

OBJECTIVES: The purpose of this study was to evaluate the effects of alendronate on orthodontic tooth movement (OTM) and bone modelling/remodelling in an osteogenesis imperfecta (OI) mice model. MATERIALS AND METHODS: Ten-week-old male and female OI mice (Col1a2oim, n = 32) were divided into four groups: 1. Alendronate male (AM, n = 8), 2. Alendronate female (AF, n = 8), 3. saline male (SM, n = 8), and 4. saline female (SF, n = 8). The mice in all four groups received either Alendronate (0.05 mg/kg) or vehicle (saline 0.05 mg/kg) subcutaneously for 2 weeks prior to the placement of orthodontic spring. A nickel-titanium spring applying 3-5 cN of force was used to perform the OTM for 1 week. After 7 days of OTM, the OI mice were euthanized with CO2 inhalation and microfocus computed tomography and histological analyses were performed. RESULTS: AM and AF mice showed a significant decrease (P < 0.05) in the rate of OTM compared with SM and SF mice, respectively. In addition, AM and AF mice showed a significant increase (P < 0.05) in the bone volume fraction (BVF) and tissue density (TD) compared with SM and SF mice. Histological analysis of haematoxylin-eosin staining revealed a hyalinization zone in AM and AF mice compared with SM and SF mice. Furthermore, tartrate-resistant acid phosphatase staining indicated decreased number of osteoclasts in AM and AF mice compared with SM and SF mice. Picrosirius red staining showed, Alendronate treatment led to thick uniform and smooth morphology of collagen fibres as compared with saline group. Similarly, second harmony generation images also revealed thicker collagen fibres at the periodontal ligament (PDL)-cementum entheses and PDL-alveolar bone entheses in AM and AF mice compared with SM and SF mice. CONCLUSIONS: Alendronate led to a decrease in the rate of OTM, increase in BVF and TD, decrease in the number of osteoclasts, and smooth and thick collagen fibres compared with saline in both male and female OI mice.

Genotypic and Phenotypic Spectrum and Pathogenesis of WNT1 Variants in a Large Cohort of Patients With OI/Osteoporosis.

CONTEXT: Mutations in WNT1 can cause rare inherited disorders such as osteogenesis imperfecta (OI) and early-onset osteoporosis (EOOP). Owing to its rarity, the clinical characteristics and pathogenic mechanism of WNT1 mutations remain unclear. OBJECTIVE: We aimed to explore the phenotypic and genotypic spectrum and treatment responses of a large cohort of patients with WNT1-related OI/OP and the molecular mechanisms of WNT1 variants. METHODS: The phenotypes and genotypes of patients and their responses to bisphosphonates or denosumab were evaluated. Western blot analysis, quantitative polymerase chain reaction, and immunofluorescence staining were used to evaluate the expression levels of WNT1, total ß-catenin, and type I collagen in the tibial bone or skin from one patient. RESULTS: We included 16 patients with 16 mutations identified in WNT1, including a novel mutation. The types of WNT1 mutations were related to skeletal phenotypes, and biallelic nonsense mutations or frameshift mutations could lead to an earlier occurrence of fragility fractures and more severe skeletal phenotypes. Some rare comorbidities were identified in this cohort, including cerebral abnormalities, hematologic diseases, and pituitary adenoma. Bisphosphonates and denosumab significantly increased the spine and proximal hip BMD of patients with WNT1 mutations and reshaped the compressed vertebrae. We report for the first time a decreased ß-catenin level in the bone of patient 10 with c.677C > T and c.502G > A compared to the healthy control, which revealed the potential mechanisms of WNT1-induced skeletal phenotypes. CONCLUSION: Biallelic nonsense mutations or frameshift mutations of WNT1 could lead to an earlier occurrence of fragility fractures and a more severe skeletal phenotype in OI and EOOP induced by WNT1 mutations. The reduced osteogenic activity caused by WNT pathway downregulation could be a potential pathogenic mechanism of WNT1-related OI and EOOP.

Approach to the Patient: Pharmacological Therapies for Fracture Risk Reduction in Adults With Osteogenesis Imperfecta.

CONTEXT: Osteogenesis imperfecta (OI) is a genetic disorder characterized by increased bone fragility largely caused by defects in structure, synthesis, or post-translational processing of type I collagen. The effectiveness of medications used for fracture reduction in adults with OI is understudied and practice recommendations are not well established. Drugs currently used to improve skeletal health in OI were initially developed to treat osteoporosis. Oral and intravenous bisphosphonates have been shown to improve bone mineral density (BMD) in adults with OI and are commonly used; however, conclusive data confirming fracture protection are lacking. Similarly, teriparatide appears to increase BMD, an effect that seems to be limited to individuals with type I OI. The role of denosumab, abaloparatide, romosozumab, and estradiol/testosterone in adult OI have not been systematically studied. Anti-sclerostin agents and transforming growth factor-beta antagonists are under investigation in clinical trials. OBJECTIVE: This review summarizes current knowledge on pharmacologic treatment options for reducing fracture risk in adults with OI. METHODS: A PubMed online database search of all study types published in the English language using the terms "osteogenesis imperfecta," "OI," and "brittle bone disease" was performed in June 2022. Articles screened were restricted to adults. Additional sources were identified through manual searches of reference lists. CONCLUSION: Fracture rates are elevated in adults with OI. Although clinical trial data are limited, bisphosphonates and teriparatide may be useful in improving BMD. Further research is needed to develop medications for adults with OI that will lead to definite fracture rate reduction.

Modeling anabolic and antiresorptive therapies for fracture healing in a mouse model of osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a genetic bone fragility disorder that features frequent fractures. Bone healing outcomes are contingent on a proper balance between bone formation and resorption, and drugs such as bone morphogenetic proteins (BMPs) and bisphosphonates (BPs) have shown to have utility in modulating fracture repair. While BPs are used for OI to increase BMD and reduce pain and fracture rates, there is little evidence for using BMPs as local agents for fracture healing (alone or with BPs). In this study, we examined wild-type and OI mice (Col1a2+/G610C ) in a murine tibial open fracture model with (i) surgery only/no treatment, (ii) local BMP-2 (10 µg), or (iii) local BMP-2 and postoperative zoledronic acid (ZA; 0.1 mg/kg total dose). Microcomputed tomography reconstructions of healing fractures indicated BMP-2 was less effective in an OI setting, however, BMP-2 +ZA led to considerable increases in bone volume (+193% WT, p < 0.001; +154% OI, p < 0.001) and polar moment of inertia (+125% WT, p < 0.01; +248% OI, p < 0.05). Tissue histology revealed a thinning of the neocortex of the callus in BMP-2 treated OI bone, but considerable retention of woven bone in the healing callus with BMP + ZA specimens. These data suggest a cautious approach may be warranted with the sole application of BMP-2 in an OI surgical setting as a bone graft substitute. However, this may be overcome by off-label BP administration.

Retrospective analyses of clinical features in 28 Chinese patients with type V osteogenesis imperfecta: new perspectives in an old issue.

Type V osteogenesis imperfecta (OI) is a form of OI characterized by radial head dislocation (RHD), calcification of interosseous membrane (CIM), and hyperplastic callus (HPC). In this study, we characterized the clinical features of 28 type V OI patients. We presented that dysfunctions of elbow, hip joint, and abnormal epiphyseal growth plate were associated with ectopic calcification and summarized the history of HPC progression and treatment. INTRODUCTION: The current study aims to systematically characterize the skeletal phenotypes of patients with type V OI and suggested possible surgical solutions. METHODS: A total of 28 patients were admitted for inpatient care at The Hong Kong University-Shenzhen Hospital diagnosed with type V OI (either clinically diagnosed or genetically confirmed with the IFITM5 c.-14C > T mutation). RESULTS: Prevalence of type V radiological features was comparable to previous literatures (RHD, 100%; CIM, 100%; HPC, 44%; and scoliosis, 50%). Novel skeletal phenotypes were presented including extension of coronoid process, acetabular labrum, acetabular protrusion, spontaneous autofusion of the hip, bulbous epiphysis, and popcorn calcification. Significant increase in BMD was observed in patients with bisphosphonate treatment. Twenty-five percent (3/12) of patients with preoperative use of indomethacin developed HPC postoperatively, and HPCs were absorbed in 2 young patients 2 years later. CONCLUSION: This retrospective study summarized the clinical features and highlighted the abnormalities in elbow, hip joint, and growth plate in type V OI patients. Our study contributed to a more comprehensive clinical spectrum of type V OI. We also characterized the natural progression of HPC formation and resorption in patients in different ages. The use of bisphosphonate treatment is effective in improving bone mineral density in type V OI patients, and whether indomethacin can reduce incidence of HPC formation deserves further investigation.

Macular neovascularisation in a patient with osteogenesis imperfecta exhibiting a novel COL1A1 mutation.

Osteogenesis imperfecta is a congenital disease that presents with varying degrees of connective tissue symptoms, including susceptibility to fracture, growth disorders and hearing loss. Here, we discuss a case in which macular neovascularisation (MNV) resulted in metamorphopsia and decreased visual acuity in a patient with osteogenesis imperfecta exhibiting a novel COL1A1 gene mutation (p.Tyr165*). The patient was a woman in her 30s who reported experiencing distorted vision and diminished visual acuity in her right eye for 1 month as well as a history of hearing loss. Rapid improvements in exudative changes and suppression of relapse were achieved after only two intravitreal injections of ranibizumab. Furthermore, since MNV occurred slightly inferior to the fovea centralis, improvements in visual acuity were better than previously reported. As fragility of Bruch's membrane represents the basis of onset, recurrence and relapse are likely in patients exhibiting MNV, highlighting the need for regular follow-up.

Skeletal outcomes of patients with osteogenesis imperfecta during drug holiday of bisphosphonates: a real-world study.

Purpose: This study aimed to investigate the skeletal outcomes of patients with osteogenesis imperfecta (OI) who received bisphosphonate (BP) treatment and entered drug holiday after achieving an age- and sex-specific bone mineral density (BMD) reference. Methods: Patients with OI receiving BP treatment were enrolled when they entered drug holidays of BPs. The skeletal outcomes were evaluated in detail during the drug holiday, including BMD, X-ray of the bone, bone fracture incidence, and bone turnover biomarkers. The pathogenic mutations of OI were identified by next-generation sequencing and confirmed by Sanger sequencing. Results: A total of 149 OI patients (127 juveniles and 22 adults) who entered drug holidays after nearly 4 years of BP treatment were included. Areal BMD at the lumbar spine increased from 0.934 ± 0.151 to 0.990 ± 0.142 g/cm2 and was stable in the second (1.029 ± 0.176 g/cm2) and third years (1.023 ± 0.174 g/cm2) of BP drug holidays, and BMD at the femoral neck, trochanter, and total hip had no significant change, but it was gradually inferior to that of the same-gender juveniles in the second and third years of the drug holiday. BMD at the lumbar spine and proximal hip did not change and was inferior to that of the same-gender adults. The average time of fractures fluctuated from 0.18 to 0.08 per year in juveniles, while only one adult suffered from a fracture during BP drug holidays. Bone turnover markers were in the normal range, except for a mildly high level of ß-carboxy-terminal cross-linked telopeptide of type 1 collagen in the juvenile group. A total of 17 (11.4%) patients received BP retreatment because of bone loss during the drug holiday. OI type III and type IV and COL1A2 mutation were correlated to a longer duration of BP treatment to enter drug holidays (all p < 0.05). Old age at initial treatment (OR, 1.056) and OI type III (OR, 10.880) were correlated to a higher risk of BP retreatment. Conclusions: OI patients will undergo nearly 4 years of BP treatment to achieve drug holidays. During the 3 years of the drug holiday, the patients' BMD is stable, and fracture incidence does not increase significantly. Patients are more inclined to need retreatment during drug holidays owing to the late start of BP treatment and more severe OI phenotypes.

Safety and Efficacy of Zoledronic Acid in children with Osteogenesis Imperfecta.

OBJECTIVE: To evaluate the efficacy and safety of zoledronic acid in children with osteogenesis imperfecta (OI). STUDY DESIGN: Descriptive Study. PLACE AND DURATION OF STUDY: National Institute of Child Health, Department of Endocrine and Diabetes, Karachi, Pakistan, from January 2011 to December 2020. METHODOLOGY: Children, with OI registered for the treatment, were included. Zoledronic acid was given to them by intravenous infusion over 30 minutes with a dose of 0.05 mg/Kg/day for a median duration of 60 (24-96) months. To ensure safety, patients were kept for 24 hours after dose administration to monitor any short-term side effects. The patients were assessed after every 3-6 months for frequency of fracture, bone pain, and BMD. RESULT: Out of 82 children [40 females (48.8%) and 42 males (51.2%)], 11 patients (13.4%) had fever and 2 patients (2.4%) had flu-like illness. No other side effects were observed. The annual fracture rate decreased overall from 2.8±1.5 to 0.2±0.5 (˂0.001) in both males (2.6±1.3 to 0.1±0.4) and females (3.1±1.7 to 0.2±0.6). Z-score on DEXA scan showed improvement in BMD overall (-3.9±2.0 to 2.2 ±1.7), in males (-3.7±1.9 to -2.1±1.7) and in females (4.1±2.1 to -2.3±1.8). There were no other long-term side effects like ocular problems, osteonecrosis of the jaw, and delayed healing of the fractures. CONCLUSION: Zoledronate use in children is associated with minimal short-term and long-term side effects with a significant improvement in BMD and decline in fracture rate. KEY WORDS: Osteogenesis imperfecta (OI), Bisphosphonates (BPs), DEXA scan, Bone mineral density (BMD).

Therapeutic aptamer targeting sclerostin loop3 for promoting bone formation without increasing cardiovascular risk in osteogenesis imperfecta mice.

Rationale: Sclerostin inhibition demonstrated bone anabolic potential in osteogenesis imperfecta (OI) mice, whereas humanized therapeutic sclerostin antibody romosozumab for postmenopausal osteoporosis imposed clinically severe cardiac ischemic events. Therefore, it is desirable to develop the next generation sclerostin inhibitors to promote bone formation without increasing cardiovascular risk for OI. Methods and Results: Our data showed that sclerostin suppressed inflammatory responses, prevented aortic aneurysm (AA) and atherosclerosis progression in hSOSTki.Col1a2+/G610C.ApoE-/- mice. Either loop2&3 deficiency or inhibition attenuated sclerostin's suppressive effects on expression of inflammatory cytokines and chemokines in vitro, whilst loop3 deficiency maintained the protective effect of sclerostin on cardiovascular system both in vitro and in vivo. Moreover, loop3 was critical for sclerostin's antagonistic effect on bone formation in Col1a2+/G610C mice. Accordingly, a sclerostin loop3-specific aptamer aptscl56 was identified by our lab. It could recognize both recombinant sclerostin and sclerostin in the serum of OI patients via targeting loop3. PEG40k conjugated aptscl56 (Apc001PE) demonstrated to promote bone formation, increase bone mass and improve bone microarchitecture integrity in Col1a2+/G610C mice via targeting loop3, while did not show influence in inflammatory response, AA and atherosclerosis progression in Col1a2+/G610C.ApoE-/- mice with Angiotensin II infusion. Further, Apc001PE had no influence in the protective effect of sclerostin on cardiovascular system in hSOSTki.Col1a2+/G610C.ApoE-/- mice, while it inhibited the antagonistic effect of sclerostin on bone formation in hSOSTki.Col1a2+/G610C mice via targeting loop3. Apc001PE was non-toxic to healthy rodents, even at ultrahigh dose. Apc001PE for OI was granted orphan drug designation by US-FDA in 2019 (DRU-2019-6966). Conclusion: Sclerostin loop3-specific aptamer Apc001PE promoted bone formation without increasing cardiovascular risk in OI mice.