Decrease In Fracture Rate Research Articles

Romosozumab rescues impaired bone mass and strength in a murine model of diabetic kidney disease

As international incidence of diabetes and diabetes-driven comorbidities such as chronic kidney disease (CKD) continue to climb, interventions are needed that address the high-risk skeletal fragility of what is a complex disease state. Romosozumab (Romo) is an FDA-approved sclerostin inhibitor that has been shown to increase bone mineral density and decrease fracture rates in osteoporotic patients with mild to severe CKD, but its effect on diabetes-weakened bone is unknown. We aimed to test Romo's performance in a model of combined diabetes and CKD. 6-week old male C57BL/6 mice were randomly divided into control (CON) and disease model (STZ-Ad) groups, using a previously established streptozotocin- and adenine-diet-induced model. After 16 weeks of disease induction, both CON and STZ-Ad groups were subdivided into two treatment groups and given weekly subcutaneous injections of 100 μL vehicle (phosphorus buffered saline, PBS) or 10 mg/kg Romo. Mice were euthanized after 4 weeks of treatment via cardiac exsanguination and cervical dislocation. Hindlimb bones and L4 vertebrae were cleaned of soft tissue, wrapped in PBS-soaked gauze and stored at 20C. Right tibiae, femora, and L4s were scanned via microcomputed tomography; tibiae were then tested to failure in 4-pt bending while L4s were compression tested. Romo treatment significantly increased cortical and trabecular bone mass in both STZ-Ad and CON animals. These morphological improvements created corresponding increases in cortical bending strength and trabecular compression strength, with STZ-Ad treated mice surpassing vehicle CON mice in all trabecular mechanics measures. These results suggest that Romo retains its efficacy at increasing bone mass and strength in diabetic kidney disease.

THU455 Sclerostin Inhibitor Use In The Medical Management Of Osteogenesis Imperfecta Type III

Abstract Disclosure: M.D. Lundholm: None. A. Derkyi: None. S. Talvacchio: None. J.C. Marini: Other; Self; Ultragenyx, Amgen Inc. L.Z. Khan: None. Background: Osteogenesis imperfecta (OI) is a rare collagen-related hereditary skeletal disorder with an increased fracture risk from minimal trauma, short stature, and bone deformity. OI is associated with defects in collagen structure or synthesis, high bone turnover, and paradoxical bone hypermineralization. The optimal medical therapies for bone health in these patients are unknown. Clinical Case: A 27-year-old woman with OI presented to clinic for bone health. She was diagnosed with OI type III by phenotype, collagen biochemistry, and genetic analyses (heterozygous for a COL1A1 Gly187Ala substitution) following fractures at age 4 mos. She experienced dozens of fractures, has had orthopedic hardware in bilateral femora, left tibia, humerus, and radius, and right tibia, as well as spine fusion at age 7 yrs. She had not fractured in over 3 yrs which she attributed to the stability of her automatic wheelchair. She had no family history of OI and had been in studies at the NIH; from ages 6-9 yrs she received pamidronate (1 mg/kg/cycle q3m) with BMD improvement. Presently, her vitals were normal, with height of 3’6” (25-50th percentile for type III OI females) and weight of 64 lbs (BMI 25.5 kg/m2). On exam she had blue sclera, midface hypoplasia, dentinogenesis imperfecta, severe kyphosis and scoliosis, and a barrel chest. She had normal calcium, PTH, and 25-OH vitamin D levels. Skull CT showed 1 mm increase in basilar invagination (16 to 17 mm). DEXA demonstrated progressive decline in radial BMD from 0.671 g/cm2 to 0.625 g/cm2 over 3 yrs (z-score -0.4 to -1.1) into the osteopenic range. For worsening bone disease, she is starting romosozumab 210 mg monthly. Discussion: While several agents increase BMD in OI, there are no placebo-controlled studies to show an effect on fracture rate. Bisphosphonates including pamidronate are used most commonly, with increased areal BMD, decreased bone turnover, but also increased mineralization of already brittle bone. Overall, two Cochran reviews failed to support decreased fracture rates from bisphosphonates, and there is risk of adynamic bone with chronic use. There is even less evidence for use of denosumab which is additionally associated with a rebound effect upon discontinuation. Sclerostin inhibitors are the newest agents with both anabolic and antiresorptive effects and good results in OI mouse models. Phase 2 data with sestrusumab showed increased BMD and decreased bone turnover. Ongoing studies are looking at sclerostin inhibitor use in adults and adolescents. From a practical standpoint, romosozumab has a shorter effect with quicker offset than bisphosphonates if needed to stop for fracture healing. Conclusion: Sclerostin inhibitors are an option for the medical treatment of OI. Further investigation is needed to determine long-term safety, optimal duration, and use of sclerostin inhibitors in combination with antiresorptive agents in OI. Presentation: Thursday, June 15, 2023

"Osteogenesis Imperfecta Patients Wish Orthopedic Surgeons Had Better Strategies to Help with…"-Results of a Patient and Parent-Oriented Survey.

Osteogenesis Imperfecta (OI) is a rare genetic disorder in Type I collagen characterized by bone fractures, fragility, and deformity. Current treatments are focused on decreasing fracture rates, improving bone strength, and improving overall global function. Recent research has focused primarily on fracture fixation and outcomes of intramedullary rodding of long bones. While surgical techniques continue to evolve, recent trends in OI research are focusing on patient quality of life and patient-reported outcomes. We created a 12-question survey seeking information regarding aspects of orthopedic care that OI patients and families feel are the most pressing to improve. The survey was electronically administered, and 341 individuals participated. A total of 75% of respondents who answered the age question (254/335) were adults. Regarding surgical intervention for long bones, only 16% of respondents recall being told they could not have surgery because they were too young. Of the 16%, 37.8% were told that <5 years was too young, 13.4% <4 years was too young, and 48.8% <3 years of age was too young for surgical intervention for fractures or deformities. Nearly 22% of respondents were told that their bones were too small for intramedullary fixation. The patient and family responses help elucidate the topics requiring focus for the improvement of OI orthopedic care. Patient concerns and insights should drive the research questions we ask to advance the orthopedic care of OI patients.

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 1.4years of age; however, a year later he transitioned to denosumab 1mg/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 (1.62mmol/L, N 1.16-1.36), elevated serum creatinine due to hypercalcemia-induced muscle catabolism (83µmol/L, N 9-55), and suppressed parathyroid hormone (PTH) (< 0.7pmol/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 10days. To benefit from the powerful, albeit short-term, anti-resorptive effect of denosumab without further rebound episodes, he was treated thereafter with denosumab 1mg/kg alternating every three months with IV ZA 0.025mg/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.

“O.I. Wish Orthopaedic Surgeons Had Better Strategies to Help with …” Results of a Patient- and Parent-Based Survey

Purpose: Osteogenesis Imperfecta (OI) is a rare genetic disorder caused by a mutation in type I collagen, characterized by bone fragility and deformity. Current treatment methods aim to decrease fracture rates and improve bone density and mobility. Recent orthopaedic surgery research has focused primarily on fracture fixation and outcomes of intramedullary rodding procedures. While surgical techniques continue to evolve, recent trends are focusing on patient-reported outcomes measures (PROMs). Methods: The authors created a 12-question survey in conjunction with the OI Foundation (OIF). The survey was titled, “O.I. Wish Orthopaedic Surgeons Had Better Strategies to Help with . . .” and sought to gather information regarding the aspects of orthopaedic care OI patients and families would most like to see improved. The survey was electronically administrated to members of the OIF and the OI Federation Europe (OIFE). 341 individuals completed the survey. The final question of the survey indicated, “Please include any comments you would like to pass along.” To report on the responses for this question, the answers were grouped into themes. Results: Many of the survey questions we asked were related to childhood orthopaedic surgical interventions. However, 75% of the respondents who answered the age question (254/335) were adults. Regarding surgical intervention for long bones, 16% of respondents recall that they have been told that they could not have surgery because they were too young. Of the 16%, 37.8% were told that &lt;5 years was too young, 13.4% &lt;4 years was too young, and 48.8% &lt;3 years of age was too young for surgical intervention for fractures or deformity. Nearly 22% of respondents were told that their bones were too small to have intramedullary fixation. For the free text response, the most frequent comments were to focus future research on OI adults (14.9%), focus on pain management (11.8%), and focus on improving rodding surgery techniques (11.3%). Conclusion: The information collected helps reveal trends of the typical orthopaedic advice patients and families with OI are receiving. The patient and family responses help elucidate the topics requiring focus for the improvement of OI orthopaedic care. Patient concerns and insights most powerfully drive the research questions we should ask to advance the orthopaedic care of OI patients. Significance: This survey highlights variability in OI treatment for patients of all ages. The responses guide future OI research with a focus on patient-reported areas for improvement of care.

A case-driven hypothesis for multi-stage crack growth mechanism in fourth-generation ceramic head fracture

BackgroundCeramic bearings are used in total hip arthroplasty due to their excellent wear behaviour and biocompatibility. The major concern related to their use is material brittleness, which significantly impacts on the risk of fracture of ceramic components. Fracture toughness improvement has contributed to the decrease in fracture rate, at least of the prosthetic head. However, the root cause behind these rare events is not fully understood. This study evaluated head fracture occurrence in a sizeable cohort of patients with fourth-generation ceramic-on-ceramic implants and described the circumstances reported by patients in the rare cases of head fracture.MethodsThe clinical survivorship of 29,495 hip prostheses, with fourth-generation ceramic bearings, was determined using data from a joint replacement registry. The average follow-up period was 5.2 years (range 0.1–15.6). Retrieval analysis was performed in one case for which the ceramic components were available.ResultsClinical outcomes confirmed the extremely low fracture rate of fourth-generation ceramic heads: only two out of 29,495 heads fractured. The two fractures, both involving 36 mm heads, occurred without a concurrent or previous remarkable trauma. Considering the feature of the fractured head, a multi-stage crack growth mechanism has been hypothesized to occur following damage at the head–neck taper interface.ConclusionsSurgeons must continue to pay attention to the assembly of the femoral head: achieving a proper head seating on a clean taper is a prerequisite to decrease the risk of occurrence of any damage process within head–neck junction, which may cause high stress concentration at the contact surface, promoting crack nucleation and propagation even in toughened ceramics.

Pediatric CKD-MBD: existing and emerging treatment approaches

The effects of bone and mineral metabolism on skeletal formation, as well as vascular and soft tissue calcifications, define chronic kidney disease-metabolic bone disease (CKD-MBD). Treatment recommendations center on establishing adequate vitamin D status, phosphate control through diet restriction and phosphate binders, and the use of vitamin D analogs for specific indications. Several emerging bone-promoting therapies have now been studied in adults with CKD, including bisphosphonates and denosumab. These approaches are associated with improved bone mass and, in some cases, decreased fracture rates in adults with CKD-MBD and are of potential interest for some children with CKD-MBD. In children with CKD and immobilization and/or muscle weakness, bisphosphonates appear to be an effective treatment to increase bone mass; baseline assessment and careful monitoring of bone density and/or bone biopsy findings are important in consideration of any new bone therapies for children with CKD-MBD.

Decreases in pediatric fractures during the COVID-19 pandemic - a nationwide epidemiological cohort study.

The COVID-19 pandemic led to fundamental changes in daily routines of children. Our aim was to evaluate the incidence and characteristics of fractures among Israeli children during 2020 compared with 2015–2019. Demographic, clinical data, and incidence rates of fractures in individuals aged < 18 years were derived from the electronic database of Meuhedet Health Services, which provides healthcare services to 1.2 million people in Israel. We further subdivided the year to five periods according to government regulations of lockdown and isolation at each period. Fracture sites were determined according to ICD9 definitions. During 2020, 10,701 fractures occurred compared with 12,574 ± 599 fractures per year during 2015–2019 (p-value < 0.001). Fracture rates were lower during all periods in 2020. The largest decline was observed during the first lockdown for both boys (56% decline, 95% confidence interval [CI] 52–60%) and girls (47% decline CI 41–53%). While the fracture rate declined for most age groups, the largest decline was recorded for the age group 11–14 years, with significant reduction rates of 66% (CI 59–71%) for boys and 65% (CI 54–73%) for girls. The most prominent declines were of fractures of the hand bones of both boys and girls (64% and 59%, respectively). Conclusions: Our data showed a significant decrease in fracture rate in 2020 compared to the previous 5 years, as well as differences between periods within that year.What is New:•The COVID-19 pandemic led to fundamental change in daily routines of children with significant decrease in school attendance and sport activities.•Consequent to these public health measures, the incidence rate of pediatric fractures decreased significantly.What is New:•This study demonstrates declines in fracture rates during lockdown periods, with only partial reversing of the trends between the lockdown periods.•The most pronounced decline was observed during the first lockdown period.•The decline was most prominent in children aged 11-14 years; there was no significant change in fracture incidence of children aged <3 years.

Decreased fracture rate by mandating bone protecting agents in the EORTC 1333/PEACEIII trial combining Ra223 with enzalutamide versus enzalutamide alone: An updated safety analysis.

5002 Background: The randomized phase III EORTC-1333-GUCG (NCT02194842) trial compares enzalutamide vs. a combination of Radium 223 and enzalutamide in asymptomatic or mildly symptomatic metastatic castration resistant prostate cancer (mCRPC) patients. The premature unblinding of ERA223 (NCT02043678) in Nov 2017 due to a significant increase in the rate of fractures in the combination of abiraterone and Ra223 arm led to the implementation of the mandatory use of bone protecting agents (BPA) in the EORTC-1333-GUCG trial. Skeletal fractures, pathological or not, are a frequent and underestimated adverse event of systemic treatment of advanced prostate cancer. Whether this mandated use of BPA (zoledronic acid or denosumab) would mitigate the risk of fractures in this patient population was unclear. An early safety analysis (Tombal, ASCO, 2019) suggested that the risk of fractures was well controlled in both arms when patients receive BPA. We present here an updated analysis of fracture incidence with longer follow-up. Methods: As of 28/01/2021, a total of 253 patients (134 after making BPA mandatory) were randomized between enzalutamide/Ra223 and enzalutamide. The fracture rate was estimated with the cumulative incidence method in the safety population of 237 (122 after making BPA mandatory) treated patients. Death in absence of fracture was analyzed as competing risk and censoring was applied at last follow-up. Results: Overall, 69.5% of enzalutamide/Ra223 patients (95.2% after making BPA mandatory) and 73.1% of enzalutamide patients (95% after making BPA mandatory) received BPA on treatment: 13.6% in the enzalutamide/Ra223 arm and 21.8% in the enzalutamide arm did not use BPA at registration, but started during protocol treatment and 55.9% and 51.3% respectively, received BPA since entry. At 36.7 months median follow-up in patients without BPA and 23.1 months median follow-up in patients receiving BPA, a total of 39 patients reported a fracture. Among them, 30 patients (20 in enzalutamide/Ra223 arm) did not receive BPA and 9 (4 in the enzalutamide/Ra223 arm) received BPA (see table). Conclusions: The updated safety analysis confirms the early fracture rate results. In the absence of BPA, the risk of fracture is increased when RA223 is added to enzalutamide. Strikingly, in both arms, the risk remains almost abolished by a preventive continuous administration of BPA, thus stressing the importance of complying to international recommendations in terms of giving BPA to mCRPC patients. This study is sponsored by EORTC and supported by Bayer and Astellas. Clinical trial information: NCT02194842. [Table: see text]

Effects of treatment with a bone-targeted prostaglandin E2 receptor 4 agonist C3 (Mes-1007) in a mouse model of severe osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a heritable bone fragility disorder that is usually caused by mutations affecting collagen type I synthesis in osteoblasts. Bisphosphonates are widely used to decrease fracture rate but are only partially effective. Bone anabolic compounds, such as prostaglandin E2 receptor 4 (EP4) agonists may be an alternative treatment approach. Here we assessed the effect of Mes-1007, a novel bone-targeted EP4 agonist in Jrt mice, a model of severe OI. Experimental study. Male 8-week old wild type (WT) and OI mice were randomly assigned to 4weeks of three intraperitoneal injections per week with Mes-1007 (25mg per kg body mass), phosphate-buffered saline, zoledronate (5μg per kg), or a combination treatment of zoledronate and Mes-1007. Treatment with Mes-1007 alone did not lead to higher trabecular bone volume per tissue volume (BV/TV) in the distal femur or lumbar vertebra 4 in either WT or OI mice. Treatment with zoledronate alone was associated with a significant increase in distal femur and vertebra BV/TV in both genotypes. In zoledronate-treated WT and OI mice, Mes-1007 increased bone formation rate in vertebral trabecular bone and had an additive effect on BV/TV. Vertebral BV/TV in OI mice that received zoledronate or Mes-1007/zoledronate combination treatment was similar to untreated WT mice (p=0.25). At the femoral midshaft, Mes-1007/zoledronate combination treatment increased cortical thickness in both genotypes and led to higher periosteal diameter in OI mice. Three-point bending tests of femurs showed that Mes-1007/zoledronate combination treatment increased the stiffness, load at yield and maximal load in WT but not in OI mice. Dosing Mes-1007 in combination with zoledronate improved the bone properties in a manner that is consistent with a mechanism of action of EP4 agonists on bone and additive to effects of anti-resorptives typified by zoledronate.

SUN-LB66 Oral Risedronate Treatment in Children With Osteogenesis Imperfecta

Introduction: To date, there are no approved pharmaceutical therapies for children with OI. Intravenous bisphosphonates have been used for years to treat children with OI with variable efficacy and tolerability. However, a few studies have evaluated the effects and tolerability of oral risedronate in children with OI (1)(2). In this study, we aimed to present our experience with oral risedronate treatment in children with OI. Methods: A retrospective chart review of patients with OI and history of multiple fragility fractures, who were treated with oral risedronate and followed in our bone clinic between the years of 2013 and 2019. Primary outcomes included changes in fracture rate, urinary N-terminal telopeptide (uNTX), height z-scores, and lumbar and femur BMD z-scores. Safety and tolerability of risedronate were reviewed. Wilcoxon matched-pairs sign-ranks test was used to assess the medians (IQR) between pre- and post-treatment with p value of < 0.05 set as statistically significant.Results: A total of 17 patients ages 5—19 ys were reviewed (11 males, 65% type I OI, 12% type III, 18% type XI, and 5% unknown). At the time of the review, 69% were on weekly, 19% on daily, and 12% on monthly risedronate treatment. Mean duration of therapy was 2.7 y ± 2.3 y, ranging 0.5 to 8 ys. The bone resorption marker, uNTX, decreased > 30% from baseline in 93% of subjects within the first year of treatment, and was statistically lower by the end of treatment period [245 (159, 393) to 170 (39, 261), p=0.02]. Height z-score did not change with treatment, -0.80 (-1.20, 0.10) pre- and -0.85 (-1.60, -0.40) post-treatment, p = 0.2 in patients with Type I OI. There was a clinically significant reduction in the rate of fractures from baseline 0.6 per y (0.4, 0.8) to 0.24 (0, 0.5) by the end of the treatment period, though it did not reach statistical significance. Within a year of treatment, 80% of children were fracture free with improvement in bone pain and mobility. BMD pre- and on treatment for lumbar and femur were -2.5 (-3.43, -1.94) and -2.36 (-3.25, -1.35), and -2.05 (-2.95, 0.3) and -1.18 (-1.73, 2.13), respectively. However, there was no statistical significance. There was one case of reflux without erosive esophagitis, which resolved with reflux treatment. Overall, risedronate was well tolerated with no cases of clinically significant acute phase reaction, hypocalcemia, erosive esophagitis, or osteonecrosis of the jaw.Conclusion: Based on our experience, oral risedronate effectively decreased bone resorption, showed a trend towards decrease in fracture rate with improvement in symptoms, and was well tolerated in children with OI. More data are needed to systematically evaluate its long-term effects on growth, bone mineral density, fracture frequency, and quality of life in children with different types of OI. Reference: (1) Rauch et al., J Bone Miner Res. 2009; 24: 1282-1289 (2) Bishop et al., Lancet. 2013;382(9902):1424-32.

138. Can dual-headed pedicle screws simplify use of dual rods and without sacrificing biomechanical stability?

BACKGROUND CONTEXT Long-segment fixation exposes instrumentation to substantial stresses and rod strain (RS), which result in high fracture rates. Supplemental rods provide greater stability, reduced posterior rod strain, and decreased fracture rates. Use of supplemental rods leads to reduced RS and decreased fracture risk; however the ideal method of supplemental rod attachment is unknown. Traditional methods of attachment include side connectors, which complicate intraoperative technique, and may increase duration of surgery and intraoperative contouring. Novel dual-tulip-headed screws have been developed to facilitate supplemental rod fixation for long segment constructs. PURPOSE The goal of this study was to evaluate a novel connector design and compare with traditional side-connectors such as a fixed angle connector (FAC) or variable angle connector (VAC). We hypothesized that dual-tulip-headed (DTH) screws would provide similar reduction in rod strain compared to fixed (FAC) or variable angled connectors (VAC). STUDY DESIGN/SETTING In vitro biomechanical study using human cadaveric specimens. PATIENT SAMPLE Seven fresh-frozen lumbar spine cadaveric specimens (L1–Ilium) were selected for this study (3F/4M, 48±7yrs, DEXA 0.9±0.1g/cm2). OUTCOME MEASURES Primary outcome measures of interest were range of motion (ROM) stability, posterior rod strain (RS) at L5/S1, and sacral screw bending moments (SM). METHODS Standard nondestructive flexibility tests (7.5 Nm) and compression tests (400 N) were performed (L1-ilium) to compare range of motion stability (ROM), posterior rod strain at L5-S1 (RS), and S1 screw bending moment (SM) between several supplemental 4-rod constructs (4R) vs standard 2-rod construction (2R). Directions of motion included: flexion (FL), extension (EX), left and right lateral bending (LLB, RLB), left and right axial rotation (LAR, RAR), and compression (C). Transforaminal lumbar interbody fusion (TLIF) was performed at L5/S1. Conditions included: (1) 2R, (2) dual tulip head with 4R (DTH), (3) fixed-angle connector with 4R (FAC), and (4) variable-angle connectors with 4R (VAC). Data were analyzed using RM-ANOVA. RESULTS Overall, there were no significant differences in ROM across the lumbosacral junction between conditions (p >.068). Compared to 2R, DTH and FAC significantly reduced RS in extension, LAR, and compression (p ≤.031). VAC significantly decreased RS compared to 2R in flexion, extension, LAR, RAR and compression (p ≤.033), and significantly decreased RS compared to DTH in extension (p=.024). DTH resulted in mildly increased SM compared to 2R in LAR and RAR (p ≤.003), and in LLB, RLB, LAR, RAR compared to FAC and VAC (p ≤.016). FAC and FAC resulted in decreased SM compared to 2R in RLB and LLB (p ≤.025). CONCLUSIONS Strain across the lumbosacral junction is high. Supplemental rod fixation with DTH is an effective strategy for reducing RS across the lumbosacral junction. However, the greatest reduction in RS and SM was achieved with variable connectors, likely due to their ability to allow for differential rod bending. FDA DEVICE/DRUG STATUS Unavailable from authors at time of publication.

Decreased fracture rate by mandating bone-protecting agents in the EORTC 1333/PEACE III trial comparing enzalutamide and Ra223 versus enzalutamide alone: An interim safety analysis.

5007 Background: Skeletal fractures, pathological or not, are a frequent and underestimated side-effect of systemic treatment of metastatic castration resistant prostate cancer (mCRPC). The ERA223 trial (NCT02043678) was recently unblinded following the report of a significant increase in the fracture rates when abiraterone is combined with Ra223. Hence, FDA and EMA advised against this combination. The question whether mandated use of bone protecting agents (BPA), zoledronic acid or denosumab, would have mitigated the fracture risk and whether this risk also exists in the enzalutamide/Ra223 combination is presently unknown. Methods: The phase III EORTC-1333-GUCG/PEACEIII (NCT02194842) trial compares enzalutamide vs. a combination of Ra223 and enzalutamide in asymptomatic or mildly symptomatic mCRPC patients (https://www.eortc.org/research_field/clinical-detail/1333/). After the unblinding of ERA223, the trial was amended (v4.0, April 19, 2018) to mandate that all patients must start a BPA. We report the fracture rate in the safety population of 146 treated patients as of 28/01/2019. Results: Overall, 54.2% of the patients in the enza/Ra223 arm and 51.4% of the enza arm did not receive BPA; 18.0% in the enza/Ra223 arm and 27.0% in the enza arm did not use BPA at randomization, but started during protocol treatment according to the v4.0 amendment. 27.8% and 21.6% respectively, received BPA as of randomization. In total, 45.8% of enza/Ra223 patients and 48.6% of enza only patients receive bone protection on treatment. The fracture rate is reported in the table. Conclusions: There is a 13% risk of fracture with enzalutamide in asymptomatic mCRPC, in line with previous reports. This risk is significantly increased to 33% when Ra223 is added to enzalutamide. Strikingly, the risk is almost abolished by mandatory continuous administration of BPA starting at least 6 weeks before the first injection of Ra223, thus emphasizing the importance of treating mCRPC patients with BPA. Clinical trial information: NCT02194842. [Table: see text]

Prenatal use of medications for gastroesophageal reflux disease and early childhood fracture risk.

Gastroesophageal reflux disease is a common condition in pregnancy and is often managed with medications. Specific medications have been linked to osteoporosis and fragility fracture in older adults. This study assessed whether maternal use of antireflux medications is associated with early childhood fracture. TRICARE beneficiaries during pregnancy were retrospectively identified using the Military Health System Data Repository and pharmacy data. Mother and infant data were linked; children with continuous enrollment for the first 5years of life were included. Differences in the children's fracture risk were analyzed through multivariate analysis, adjusting for region, rank, and military branch of service. A total of 378150 patients comprised the final cohort with 3.3% (n=12479) prescribed antireflux medications during pregnancy. A significant decrease in fracture rate was found among children of women who were prescribed antireflux medications during pregnancy compared with those who were not (0.8% vs 1.2%, RR=0.70, 95% CI 0.58-0.85). There was no difference in fracture risk between histamine type 2 receptor antagonists and proton pump inhibitors. A significantly increased fracture incidence was seen in pregnancies with multiple gestations (RR=1.38, 95% CI 1.04-1.85). There was no identified difference in fracture risk for women with gestational diabetes, preeclampsia, preterm or low birthweight, chronic hypertension, induction, or breech presentation when compared to women without these conditions. We found no increase in early childhood fracture risk with maternal antireflux medication use. This suggests that prenatal exposure to antireflux medications does not affect fetal bones to a clinically significant extent.

Bone and calcium metabolism associated with malignancy. Clinical Characteristics and Treatment of Cancer Treatment Induced Bone Loss(CTIBL)in Breast Cancer.

Breast cancer is a typical hormone-dependent tumor and at the time of diagnosis more than 60% of breast cancers are positive for estrogen receptors and estrogen(E)is required for proliferation. Since breast cancer is a tumor easily to cause micrometastasis, adjuvant hormonal therapy(HT)for 5 to 10 years after surgery that suppresses the action of estrogen actively prevents recurrence is very popular. However, HT with aromatase inhibitor(AI)for postoperative postmenopausal breast cancer markedly reduces the E concentration in the body, leading to significant bone loss and fracture as known as aromatase inhibitor-induced bone loss(AIBL), a typical example of CTIBL. Under these circumstances, the usefulness of bone modifying agents as a supportive therapy to increase bone density and decrease fracture rate without interrupting the treatment of breast cancer became clear, mainly in Europe and the United States. And recently, our study revealed even in Japanese breast cancer patients denosumab injection every 6 months showed significant increase in bone density. The number of women suffering from breast cancer in Japan reaches approximately 90,000 per year, a considerable number is estimated as a preliminary group of CTIBL, so early appropriate measures are desired.

Osteocyte-specific WNT1 regulates osteoblast function during bone homeostasis.

Mutations in WNT1 cause osteogenesis imperfecta (OI) and early-onset osteoporosis, identifying it as a key Wnt ligand in human bone homeostasis. However, how and where WNT1 acts in bone are unclear. To address this mechanism, we generated late-osteoblast-specific and osteocyte-specific WNT1 loss- and gain-of-function mouse models. Deletion of Wnt1 in osteocytes resulted in low bone mass with spontaneous fractures similar to that observed in OI patients. Conversely, Wnt1 overexpression from osteocytes stimulated bone formation by increasing osteoblast number and activity, which was due in part to activation of mTORC1 signaling. While antiresorptive therapy is the mainstay of OI treatment, it has limited efficacy in WNT1-related OI. In this study, anti-sclerostin antibody (Scl-Ab) treatment effectively improved bone mass and dramatically decreased fracture rate in swaying mice, a model of global Wnt1 loss. Collectively, our data suggest that WNT1-related OI and osteoporosis are caused in part by decreased mTORC1-dependent osteoblast function resulting from loss of WNT1 signaling in osteocytes. As such, this work identifies an anabolic function of osteocytes as a source of Wnt in bone development and homoeostasis, complementing their known function as targets of Wnt signaling in regulating osteoclastogenesis. Finally, this study suggests that Scl-Ab is an effective genotype-specific treatment option for WNT1-related OI and osteoporosis.

Lifetime prediction of zirconia and metal ceramic crowns loaded on marginal ridges

ObjectiveTo evaluate the fatigue life of zirconia-veneered and metal-ceramic crowns comprised by an even thickness or a modified framework design when loaded on marginal ridges. MethodsEighty marginal ridges were present after fabrication of forty molar crowns cemented onto composite-resin replicas and divided (n=20/each), in the following groups: metal-ceramic with even thickness (MCev) or with a modified framework design (MCm, lingual collar with proximal struts); porcelain-fused to zirconia with even thickness (PFZev) or with the modified framework design (PFZm). Each marginal ridge (mesial and distal) was subjected to cyclic loading separately with a lithium disilicate indenter for 106 cycles or until fracture. Kruskal–Wallis and Wilcoxon matched pair test (p<0.05) evaluated both marginal ridges. Every 125,000 cycles, the test was interrupted for damage inspection. Weibull distribution (90% confidence bounds) determined the probability of survival (reliability). ResultsWeibull 2-parameter contour-plot showed significantly higher fatigue life for PFZev compared to MC, and comparable with PFZm. A significant decrease in reliability was observed between groups from 625,000 until 106 cycles. Metal-ceramic groups presented significantly lower probability of survival at 106 cycles (MCev=0.66% and MCm=4.73%) compared to PFZm (23.41%) and PFZev (36.68%). Fractographic marks showed a consistent fracture origin and direction of crack propagation. Reliability was higher for porcelain-fused to zirconia than for metal ceramic crowns, regardless of framework design. SignificanceZirconia-veneered crowns presented decreased fracture rates compared to metal ceramics, even when loaded at marginal ridges, regardless of framework design.

Decreased fracture rate, pharmacogenetics and BMD response in 79 Swedish children with osteogenesis imperfecta types I, III and IV treated with Pamidronate

BackgroundOsteogenesis imperfecta (OI) is an inherited heterogeneous bone fragility disorder, usually caused by collagen I mutations. It is well established that bisphosphonate treatment increases lumbar spine (LS) bone mineral density (BMD), as well as improves vertebral geometry in severe OI; however, fracture reduction has been difficult to prove, pharmacogenetic studies are scarce, and it is not known at which age, or severity of disease, treatment should be initiated. Materials and methodsCOL1A1 and COL1A2 were analyzed in 79 children with OI (type I n=33, type III n=25 and type IV n=21) treated with Pamidronate. Data on LS BMD, height, and radiologically confirmed non-vertebral and vertebral fractures were collected prior to, and at several time points during treatment. ResultsAn increase in LS BMD Z-score was observed for all types of OI, and a negative correlation to Δ LS BMD was observed for both age and LS BMD Z-score at treatment initiation. Supine height Z-scores were not affected by Pamidronate treatment, The fracture rate was reduced for all OI types at all time points during treatment (overall p<0.0003, <0.0001 and 0.0003 for all OI types I, III and IV respectively). The reduced fracture rate was maintained for types I and IV, while an additional decrease was observed over time for type III. The fracture rate was reduced also in individuals with continued low BMD after >4yrs Pamidronate. Twice as many boys as girls with OI type I were treated with Pamidronate, and the fracture rate the year prior treatment was 2.2 times higher for boys (p=0.0236). Greater Δ LS BMD, but smaller Δ fracture numbers were observed on Pamidronate for helical glycine mutations in COL1A1 vs. COL1A2. Vertebral compression fractures did not progress in any individual during treatment; however, they did not improve in 9%, and these individuals were all >11years of age at treatment initiation (p<0.0001). ConclusionPamidronate treatment in children with all types of OI increased LS BMD, decreased fracture rate, and improved vertebral compression fractures. Fracture reduction was prompt and maintained during treatment, irrespective of age at treatment initiation and collagen I mutation type.

Cesarean delivery is not associated with decreased at-birth fracture rates in osteogenesis imperfecta.

PurposeOsteogenesis imperfecta (OI) predisposes to recurrent fractures. The moderate-to-severe forms of OI present with antenatal fractures and the mode of delivery that would be safest for the fetus is not known.MethodsWe conducted systematic analyses on the largest cohort of individuals (n=540) with OI enrolled to-date in the OI Linked Clinical Research Centers. Self-reported at-birth fracture rates were compared in individuals with OI types I, III, and IV. Multivariate analyses utilizing backward-elimination logistic regression model building were performed to assess the effect of multiple covariates including method of delivery on fracture-related outcomes.ResultsWhen accounting for other covariates, at-birth fracture rates did not differ based on whether delivery was by vaginal route or by cesarean section (CS). Increased birth weight conferred higher risk for fractures irrespective of the delivery method. In utero fracture, maternal history of OI, and breech presentation were strong predictors for choosing CS for delivery.ConclusionOur study, the largest to analyze the effect of various factors on at-birth fracture rates in OI shows that delivery by CS is not associated with decreased fracture rate. With the limitation that the fracture data were self-reported in this cohort, these results suggest that CS should be performed only for other maternal or fetal indications, but not for the sole purpose of fracture prevention in OI.

THU0397 Efficacy of pamidronate in children with osteogenesis imperfecta: An open prospective study

BackgroundOsteogenesis imperfecta (O.I) is a disorder characterized by osteopenia, frequent fractures, progressive deformity, and chronic bone pain. Its severity depends mainly on the severity of the bone lesions. Treatment with...