Oral daily PTH(1-34) tablets (EB613) in postmenopausal women with low BMD or osteoporosis: a randomized, placebo-controlled, six-month, phase 2 study.

Anabolic treatment is indicated for high and very-high risk patients with osteoporosis, but acceptance is limited because current anabolic medications require subcutaneous injections. The purpose of this study was to assess the effects of a novel orally administered parathyroid hormone (PTH) tablet on serum markers of bone formation [N-terminal propeptide of Type I procollagen (PINP) and osteocalcin (OC)] and bone resorption [crosslinked C-telopeptide (CTX)], bone mineral density (BMD) and safety in postmenopausal women with low BMD or osteoporosis. In this 6-month, double-blind, placebo-controlled study, 161 patients were randomized to oral PTH tablets containing 0.5, 1.0, 1.5, or 2.5 mg or placebo daily. Biochemical markers were assessed at 1, 2, 3 and 6 months and BMD of lumbar spine, total hip and femoral neck was measured at 6 months. Biochemical marker changes were dose dependent with minimal or no effect at the two lowest doses. At the highest dose (2.5 mg once daily), serum PINP and OC levels increased 30% within 1 month after oral PTH initiation (p < 0.0001), remained elevated through 3 months and were back to baseline at 6 months. In contrast, serum CTX levels declined 16% and 21% below baseline at 3 and 6 months respectively (both p ≤ 0.02). At 6 months, 2.5 mg tablets increased mean BMD vs placebo of the lumbar spine by 2.7%, total hip by 1.8%, and femoral neck by 2.8% (all p ≤ 0.01). There were no drug-related serious adverse events. The most common adverse events were headache, nausea, and dizziness. In contrast to subcutaneous PTH, the oral PTH tablet appears to increase BMD rapidly by the dual mechanism of stimulating formation and inhibiting bone resorption. This might be the first effective oral anabolic alternative to subcutaneous administration for the treatment of low BMD or osteoporosis.

Despite the superior benefits of bone building (anabolic) agents and guidelines supporting their use, these medications are used in a minority of patients for whom they are appropriate, in part because they require daily or monthly injections, which limit patient acceptance. An oral anabolic tablet has potential to address this substantial treatment gap. In this double-blind, placebo controlled, dose-finding randomized study, 161 postmenopausal women with low bone mineral density or osteoporosis were treated with varying doses of the active part of parathyroid hormone [PTH(1-34)] or placebo given in daily oral tablets for 6 months. The highest oral PTH tablet dose (2.5 mg), produced an increase in markers of bone formation while simultaneously decreasing the markers of bone breakdown. Significant gains in bone mineral density of the spine and hip were observed at the end of the 6-month study and there were no significant safety concerns. The 2.5 mg oral PTH tablet dose was well tolerated when patients were instructed to titrate up to the full dose. We conclude that this PTH tablet might be the first effective orally administered bone building medication and should be studied further in treatment of women with osteoporosis.

Zoledronic acid sequential to teriparatide may promote greater inhibition of bone resorption than zoledronic acid alone.

Background: Teriparatide (TPTD) should be followed by an antiresorptive to maximize bone mineral density gain and anti-fracture protection. Infrequent zoledronic acid (ZOL) administration has demonstrated effectiveness. The duration of ZOL effect following TPTD is unknown. Objective: To evaluate the effect of ZOL on bone resorption marker in a post-TPTD versus ZOL-alone scenario in osteoporotic patients. Design: Retrospective cohort study. Methods: Patients treated with TPTD followed by ZOL (TPTD-ZOL) or with a single ZOL infusion were identified in the database of a tertiary referral center. Clinical and laboratory data, including C-terminal telopeptide of type I collagen (CTX) following ZOL treatment, were compared. Results: Twenty-six patients (93% women) treated with TPTD-ZOL and 41 with ZOL were comparable in age (median 70.1 versus 69.6 years, p = 0.6) and sex. Timing of CTX measurement post-ZOL was the same, median 1.0 year. CTX was lower following TPTD-ZOL (median 142.1 versus 184.2 pg/mL, p = 0.005). In a multivariable regression model (controlled for baseline characteristics), pretreatment with TPTD strongly predicted CTX <150 pg/mL, 1 year following ZOL (odds ratio = 7.5, 95% CI 1.3-58.1, p = 0.03). In a subgroup with sequential CTX measurements following one ZOL, significantly lower levels persisted in the TPTD-ZOL group for a median of 4.4 years follow-up. Conclusion: ZOL-administered sequential to TPTD yielded deeper and more prolonged bone resorption suppression than ZOL alone. Prospective data are needed to confirm whether in a sequential treatment scenario, subsequent ZOL dosing interval should be less frequent.

The International X-Linked Hypophosphatemia (XLH) Registry: first interim analysis of baseline demographic, genetic and clinical data.

BACKGROUND: X-linked hypophosphatemia (XLH) is a rare, hereditary, progressive, renal phosphate-wasting disorder characterized by a pathological increase in FGF23 concentration and activity. Due to its rarity, diagnosis may be delayed, which can adversely affect outcomes. As a chronic disease resulting in progressive accumulation of musculoskeletal manifestations, it is important to understand the natural history of XLH over the patient's lifetime and the impact of drug treatments and other interventions. This multicentre, international patient registry (International XLH Registry) was established to address the paucity of these data. Here we present the findings of the first interim analysis of the registry. RESULTS: The International XLH Registry was initiated in August 2017 and includes participants of all ages diagnosed with XLH, regardless of their treatment and management. At the database lock for this first interim analysis (29 March 2021), 579 participants had entered the registry before 30 November 2020 and are included in the analysis (360 children [62.2%], 217 adults [37.5%] and 2 whose ages were not recorded [0.3%]; 64.2% were female). Family history data were available for 319/345 (92.5%) children and 145/187 (77.5%) adults; 62.1% had biological parents affected by XLH. Genetic testing data were available for 341 (94.7%) children and 203 (93.5%) adults; 370/546 (67.8%) had genetic test results; 331/370 (89.5%) had a confirmed PHEX mutation. A notably longer time to diagnosis was observed in adults ≥ 50 years of age (mean [median] duration 9.4 [2.0] years) versus all adults (3.7 [0.1] years) and children (1.0 [0.2] years). Participants presented with normal weight, shorter length or height and elevated body mass index (approximately - 2 and + 2 Z-scores, respectively) versus the general population. Clinical histories were collected for 349 participants (239 children and 110 adults). General data trends for prevalence of bone, dental, renal and joint conditions in all participants were aligned with expectations for a typical population of people with XLH. CONCLUSION: The data collected within the International XLH Registry, the largest XLH registry to date, provide substantial information to address the paucity of natural history data, starting with demographic, family history, genetic testing, diagnosis, auxology and baseline data on clinical presentation.

Trabecular Bone Score Change Is Not Predicted by Bone Turnover: Short-term Sequential Follow-up.

BACKGROUND: Trabecular bone score (TBS) reflects vertebrae microarchitecture and assists in fracture risk assessment. The International Society of Clinical Densitometry postulates that the role of TBS in monitoring antiresorptive therapy is unclear. Whether changes in TBS correlate with bone resorption measured by bone turnover markers is not known. OBJECTIVES: To determine whether longitudinal changes in TBS correlate with C-terminal telopeptide (CTX) of type I collagen. METHODS: Examinees with two bone mineral density (BMD) measurements were detected via the institutional database. Over 5.8% change in TBS was considered least significant and patients were grouped accordingly (increment, decrement, or unchanged). CTX, BMD, co-morbidities, incident fractures, and medication exposure were compared between the groups by Kruskal-Wallis. The correlation between TBS and BMD change and CTX in a continuous model was analyzed by Pearson's correlation coefficient. RESULTS: In total, 110 patients had detailed medical records. In 74.5%, TBS change was below least significant change. Two other TBS categories, fracture incidence or medication exposure, did not differ by CTX. In the continuous model, BMD and TBS change was positively correlated (r = 0.225, P = 0.018). A negative correlation was observed between BMD change and CTX. The decrease in BMD level was associated with higher CTX (r = -0.335, P = 0.004). No correlation was observed between CTX and TBS. CONCLUSIONS: No correlation between TBS dynamics and bone resorption marker was found. Clinical interpretation and implication of longitudinal TBS changes should be further explored.

Pregnancy- and lactation-induced osteoporosis: a social-media-based survey.

BACKGROUND: Pregnancy- and lactation-induced osteoporosis (PLO) presenting as spinal fractures is rare, and the spectrum of clinical presentation, risk factors and pathophysiology are incompletely understood. The aim of this study was to delineate clinical parameters, risk factors and osteoporosis-related quality of life (QOL) of women with PLO. METHODS: Participants of a social-media (WhatsApp) PLO group and mothers of a parents' WhatsApp group (control group) were offered to fill a questionnaire, including an osteoporosis-related QOL section. The groups were compared using the independent Students t test for numerical variables, and the Chi-square test or Fisher's exact test for categorical variables. RESULTS: Twenty-seven women with PLO and 43 in the control group (aged 36.2 ± 4.7 and 38.8 ± 4.3 years, respectively, p = 0.04) participated. Among women with PLO, more than 5 vertebrae were involved in 13 (48%), 4 vertebrae in 6 (22%), and 3 or fewer vertebrae in 8 (30%). Among the 24 women with relevant data, 21 (88%) had nontraumatic fractures; 3 (13%) women had fractures during pregnancy, and the remaining during the early postpartum period. Diagnosis was delayed for over 16 weeks for 11 (41%) women; 16 (67%) received teriparatide. Significantly lower proportions of women in the PLO group engaged in physical activity over 2 hours/week, before and during pregnancy (37 vs. 67%, p < 0.015 and 11 vs. 44%, p < 0.003, respectively). A lower proportion of the PLO than the control group reported calcium supplementation during pregnancy (7% vs. 30%, p = 0.03) and a higher proportion reported treatment with low-molecular-weight-heparin during pregnancy (p = 0.03). Eighteen (67%) of the PLO group expressed fear of fractures and 15 (56%) fear of falls, compared to none and 2%, respectively, of the control group (p < 0.00001 for both). CONCLUSIONS: Most of the women with PLO who responded to our survey reported spinal fractures involving multiple vertebrae, delayed diagnosis, and treatment with teriparatide. Compared to a control group, they reported less physical activity and impaired QOL. For this uncommon yet severe condition, a multidisciplinary effort should be exerted for early identification and treatment, to alleviate back pain, prevent subsequent fractures and improve QOL.

Hip Fracture Risk Assessment in Elderly and Diabetic Patients: Combining Autonomous Finite Element Analysis and Machine Learning.

Autonomous finite element analyses (AFE) based on CT scans predict the biomechanical response of femurs during stance and sidewise fall positions. We combine AFE with patient data via a machine learning (ML) algorithm to predict the risk of hip fracture. An opportunistic retrospective clinical study of CT scans is presented, aimed at developing a ML algorithm with AFE for hip fracture risk assessment in type 2 diabetic mellitus (T2DM) and non-T2DM patients. Abdominal/pelvis CT scans of patients who experienced a hip fracture within 2 years after an index CT scan were retrieved from a tertiary medical center database. A control group of patients without a known hip fracture for at least 5 years after an index CT scan was retrieved. Scans belonging to patients with/without T2DM were identified from coded diagnoses. All femurs underwent an AFE under three physiological loads. AFE results, patient's age, weight, and height were input to the ML algorithm (support vector machine [SVM]), trained by 80% of the known fracture outcomes, with cross-validation, and verified by the other 20%. In total, 45% of available abdominal/pelvic CT scans were appropriate for AFE (at least 1/4 of the proximal femur was visible in the scan). The AFE success rate in automatically analyzing CT scans was 91%: 836 femurs we successfully analyzed, and the results were processed by the SVM algorithm. A total of 282 T2DM femurs (118 intact and 164 fractured) and 554 non-T2DM (314 intact and 240 fractured) were identified. Among T2DM patients, the outcome was: Sensitivity 92%, Specificity 88% (cross-validation area under the curve [AUC] 0.92) and for the non-T2DM patients: Sensitivity 83%, Specificity 84% (cross-validation AUC 0.84). Combining AFE data with a ML algorithm provides an unprecedented prediction accuracy for the risk of hip fracture in T2DM and non-T2DM populations. The fully autonomous algorithm can be applied as an opportunistic process for hip fracture risk assessment. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Bone mineral density of the ultra-distal radius: are we ignoring valuable information?

The current study explored the possible utilization in dual-X-ray-absorptiometry scanning (DXA) of the ultra-distal radius (UDR). This region of interest is currently unused and mostly unstudied in this context. The study findings suggest UDR as potential useful region of interest in DXA scanning and warrant further study of the site. PURPOSE: Bone mineral density (BMD) measurement of a non-dominant arm is not routinely performed during dual-X-ray-absorptiometry (DXA) test, and the possible utility of ultra-distal (UDR) radius BMD is not well-studied. We evaluated in women, correlations of UDR BMD with fracture prevalence, fracture risk prediction by the fracture risk assessment tool (FRAX), and osteoporosis diagnosed by traditional sites. METHODS: Women who underwent a routine DXA (including their non-dominant forearm and including UDR BMD) in a tertiary medical center were included. Risk factors relevant to FRAX calculation were assessed via a self-administered questionnaire. Spearman correlations of UDR BMD to 10-year risks of major osteoporotic and hip fractures (assessed by FRAX) were explored. The possible added value of UDR BMD in explaining prevalent osteoporotic fractures was assessed using a multivariable regression model incorporating age and traditional osteoporosis diagnosis. RESULTS: The study included 1245 women with a median age of 66 years (interquartile range: 59-73), of whom 298 (24%) had UDR T-score ≤ - 2.5 and 154 (12%) reported prior fractures. UDR BMD was significantly negatively correlated with FRAX risk score for hip and major osteoporotic fractures (R = - 0.5 and R = - 0.41, respectively; P < 0.001). UDR T-score ≤ - 2.5 was associated with higher fracture prevalence (19% vs 10%; P < 0.001) and remained significant after adjusting for traditional BMD and age (OR 1.49, 1.01-2.19; P = 0.043). CONCLUSION: UDR BMD correlates both with prior fractures and with predicted fracture risks and might pose added value over traditional DXA sites.

Post-authorisation safety study of burosumab use in paediatric, adolescent and adult patients with X-linked hypophosphataemia: rationale and description.

Background: X-linked hypophosphataemia (XLH) is a rare, inherited, phosphate-wasting disorder that elevates fibroblast growth factor 23 (FGF23), causing renal phosphate-wasting and impaired active vitamin D (1,25(OH)2D) synthesis. Disease characteristics include rickets, osteomalacia, odontomalacia, and short stature. Historically, treatment has been oral phosphate and 1,25(OH)2D supplements. However, these treatments do not correct the primary pathogenic mechanism or treat all symptoms and can be associated with adverse effects. Burosumab is a recombinant human immunoglobulin G1 monoclonal antibody against FGF23, approved for treating XLH in several geographical regions, including Europe and Israel. Burosumab restores normal serum phosphate levels, minimising the clinical consequences of XLH. Safety data on long-term treatment with burosumab are lacking owing to the rarity of XLH. This post-authorisation safety study (PASS) aims to evaluate the safety outcomes in patients aged >1 year. Methods: The PASS is a 10-year retrospective and prospective cohort study utilising data from the International XLH Registry (NCT03193476), which includes standard diagnostic and monitoring practice data at participating centres. The PASS aims to evaluate frequency and severity of safety outcomes, frequency and outcomes of pregnancies in female patients, and safety outcomes in patients with mild to moderate kidney disease at baseline, in children, adolescents and adults treated with burosumab for XLH. It is expected that there will be at least 400 patients who will be administered burosumab. Results: Data collection started on 24 April 2019. The expected date of the final study report is 31 December 2028, with two interim reports. Conclusion: This PASS will provide data on the long-term safety of burosumab treatment for XLH patients and describe safety outcomes for patients receiving burosumab contrasted with those patients receiving other XLH treatments, to help inform the future management of XLH patients. The PASS will be the largest real-world safety study of burosumab. Registry identification: The International XLH Registry is registered with clinicaltrials.gov as NCT03193476 (https://clinicaltrials.gov/ct2/show/NCT03193476), and the PASS is registered with the European Union electronic Register of Post-Authorisation Studies as EUPAS32190 (http://www.encepp.eu/encepp/viewResource.htm?id=32191).

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.

Changes in trabecular bone score and bone density in female adolescents with anorexia nervosa: a longitudinal study.

Impaired bone health is a common complication of anorexia nervosa (AN). We aimed to assess longitudinal changes in bone mineral density (BMD) and trabecular bone score (TBS), a measure of bone quality, in female adolescents with anorexia nervosa (AN). We conducted a retrospective longitudinal study of 41 female adolescents with AN who underwent two dual-energy X-ray absorptiometry (DXA) scans. Clinical data, including age, weight, height, body mass index (BMI), and DXA measurements were retrieved from the medical charts. Lumbar bone mineral apparent density (BMAD) was calculated to correct for size. Changes (Δ) in BMD, BMAD, and TBS were examined for correlations with clinical characteristics. Mean ages at the time of DXA scans were 14.8±1.9 and 16.8±2.0 years. There was a significant improvement in anthropometric parameters and DXA measurements at the second DXA scan. However, these values were still significantly lower than expected in the general population. The Δlumbar BMD Z-score was 0.3±0.7, the Δlumbar BMAD Z-score was 0.2±0.7 and the ΔTBS Z-score was 0.5±0.7. ΔTBS Z-score was positively correlated with Δheight Z-score, Δweight Z-score and ΔBMI Z-scores, and negatively correlated height Z-score, weight Z-score and TBS Z-scores at the first DXA scan (p<0.05). Δheight Z-score, ΔBMI Z-score and the progression from early to late puberty were identified as significant independent predictors of Δlumbar BMAD Z-score (p<0.05). During two years of treatment, both BMD and TBS increased significantly. Improvement in height and in weight status, and progression in puberty are predictors of improvement in BMD and TBS.

Bisphosphonates Related Ocular Side Effects: A Case Series and Review of Literature.

OBJECTIVE: To describe the clinical features of patients with bisphosphonate related ocular side effects (BROSE). METHODS: The medical records of all patients with BROSE between January 2009 and December 2019 were reviewed. RESULTS: Nine cases with BROSE were identified. All subjects were female. Median age at diagnosis was of 69 years. The leading indication for bisphosphonate treatment was osteoporosis (n=7), Paget's disease of bone (n=1) and breast cancer (n=1). Six (66.67%) patients presented with uveitis, one (11%) episcleritis and two (22%) with orbital inflammation. Five events (55.5%) occurred within 10 days of initiating the bisphosphonate and the rest (44.44%) developed within 2 weeks to 3 years later. Four (44.44%) patients had concurrent thyroid disease. An association was found between underlying thyroid disease or autoimmunity. CONCLUSION: BROSE is an uncommon complication of bisphosphonate therapy occurring more frequently in patients with an autoimmune predisposition.

Epidemiology of childhood fractures in Israel during 2000-2019.

BACKGROUND: Differences have been reported in incidence rates of fractures in the pediatric population, between countries and over time. The aim of this study was to evaluate the incidence and characteristics of fractures over 20 years among Israeli children. METHODS: Incidence rates of fractures were derived from the electronic database of Meuhedet Health Services, a health maintenance organization providing healthcare services to 1.2 million people in Israel. Demographic and clinical data were extracted of all the fractures in individuals aged <18 years during 2000-2019. Fracture sites were determined according to ICD9 definitions. Fracture data were analyzed by age, sex, season and sector (general Jewish population, ultra-orthodox Jews and Arabs). RESULTS: During the study period 188,283 fractures occurred in 142,049 individuals. The most common were fractures of the upper limb (65%), followed by fractures of the lower limb [20%]. The overall fracture rate was 251 per 10,000 person- years (PY), and was higher for boys than girls (319 vs. 180 per 10,000 PY, p < 0.001). During 20 years, standardized fracture rates decreased significantly in the general Jewish population, among both boys (from 457 to 325 per 10,000 PY, p < 0.001) and girls (from 244 to 196 per 10,000 PY, p < 0.001); increased among ultra-orthodox Jewish boys (from 249 to 285 per 10,000 PY, p = 0.002) and girls (from 147 to 194 per 10,000 PY, p < 0.001); and did not change significantly among Arab boys and girls. The fracture rate peaked among girls aged 10-11 years and among boys aged 12-13 years. Seasonal variation showed a bimodal distribution with peaks during spring and autumn. CONCLUSIONS: The incidence of pediatric fractures is affected by age, gender, sector and season. Recognition of fracture characteristics may help identify specific populations and conditions for targeted prevention strategies.

Bone Mineral Density of the 1/3 Radius Refines Osteoporosis Diagnosis, Correlates With Prevalent Fractures, and Enhances Fracture Risk Estimates.

OBJECTIVE: To investigate the added value of 1/3 radius (1/3R) for the diagnosis of osteoporosis by spine and hip sites and its correlation with prevalent fractures and predicted fracture risk. METHODS: Fracture Risk Assessment Tool (FRAX) scores for hip and major osteoporotic fractures (MOF) with/without trabecular bone score were considered proxy for fracture risk. The contribution of 1/3R to risk prediction was depicted via linear regression models with FRAX score as the dependent variable-first only with central and then with radius T-score as an additional covariate. Significance of change in the explained variance was compared by F-test. RESULTS: The study included 1453 patients, 86% women, aged 66 ± 10 years. A total of 32% (n = 471) were osteoporotic by spine/hip and 8% (n = 115) by radius only, constituting a 24.4% increase in the number of subjects defined as osteoporotic (n = 586, 40%). Prior fracture prevalence was similar among patients with osteoporosis by spine/hip (17.4%) and radius only (19.1%) (P = .77). FRAX prediction by a regression model using spine/hip T-score yielded explained variance of 51.8% and 49.9% for MOF and 39.8% and 36.4% for hip (with/without trabecular bone score adjustment, respectively). The contribution of 1/3R was statistically significant (P < .001) and slightly increased the explained variance to 52.3% and 50.4% for MOF and 40.9% and 37.4% for hip, respectively. CONCLUSION: Reclassification of BMD results according to radius measurements results in higher diagnostic output. Prior fractures were equally prevalent among patients with radius-only and classic-site osteoporosis. FRAX tool performance slightly improved by incorporating radius BMD. Whether this approach may lead to a better fracture prediction warrants further prospective evaluation.

Long-Term Follow-Up of Denosumab Discontinuers with Multiple Vertebral Fractures in the Real-World: A Case Series.

Denosumab discontinuation is associated with rapid reversal of bone turnover suppression and with a considerable increase in fracture risk, including a risk for multiple vertebral fractures (MVF). Long-term follow-up of patients who sustained MVF after denosumab discontinuation has not been reported. This case-series was aimed to provide a long-term follow-up on the management and outcome of denosumab discontinuers who initially presented with multiple vertebral fractures. Denosumab discontinuers were identified from a computerized database of a large healthcare provider. Baseline and follow-up clinical, laboratory, and imaging data were obtained from the computerized database and electronic medical records. The post-denosumab discontinuers MVF patients consisted of 12 women aged 71±12. Osteoporotic fractures were prevalent before denosumab discontinuation in 6 of the patients. The majority received bisphosphonates before denosumab. MVF occurred 134±76 days after denosumab discontinuation. The patients were followed for a median of 36.5 (IQR 28.2, 42.5) months after MVF. Two patients passed-away. Two patients suffered recurrent vertebral fractures. Following MVF, patients were treated inconsistently with denosumab, teriparatide, oral, and intravenous bisphosphonates, in various sequences. Two patients underwent vertebroplasty/kyphoplasty. This long-term follow-up of real-world patients with MVF following denosumab discontinuation reveals that management is inconsistent, and recurrent fractures are not uncommon. It calls for clear management guidelines for patients with MVF after denosumab discontinuation and for special attention to this high-risk group.

Trabecular Bone Score in Children and Adolescents With Inflammatory Bowel Diseases.

INTRODUCTION: Trabecular bone score (TBS) is a textural index that evaluates bone microarchitecture of the lumbar spine. Our aim was to assess TBS in children with inflammatory bowel diseases and to evaluate correlations with clinical, laboratory and densitometric variables. METHODS: A retrospective study of TBS and areal bone mineral density measurements by dual-energy X-ray absorptiometry (DXA) of children with either Crohn's disease (CD) or ulcerative colitis (UC). Bone mineral apparent density was calculated for size adjustment. TBS Z-score for each child were calculated based on data from a healthy population of similar age and gender distribution. Variables significantly associated with TBS were included in stepwise linear regression models to examine independent predictors of TBS. RESULTS: Fifty patients (age at DXA scan 13.8 ± 3.0 years, 29 males) were included. No significant differences were observed between the patients with CD and UC, in age at diagnosis, age at DXA scan and disease duration. The mean TBS of patients with CD (n = 35) was lower than of patients with UC (n = 15): 1.340 ± 0.080 vs 1.395 ± 0.092, p = 0.040. The mean TBS Z-score of patients with CD, -0.443 ± 0.788, was significantly lower than expected in healthy children (p = 0.002), while the mean TBS Z-score of patients with UC, 0.231 ± 0.685, was similar to that of healthy children (p = 0.212). In the stepwise linear regression analysis, BMI Z-score at diagnosis, phosphorus level at diagnosis and age at the time of the DXA scan were significant independent predictors of TBS (r²â€¯= 0.604; ß = 0.037, 95% confidence interval (CI) for ß 0.022-0.051, p < 0.001; ß = 0.045, 95% CI: 0.017-0.073, p = 0.002; and ß = 0.031, 95% CI: 0.005-0.021, p < 0.002, respectively). CONCLUSIONS: TBS is significantly reduced in pediatric patients with CD but not in patients with UC. This finding likely reflects the effect of CD on bone microarchitecture.

SEIZURES ASSOCIATED WITH ZOLEDRONIC ACID (ZA) THERAPY: A CASE REPORT AND REVIEW OF THE LITERATURE.

OBJECTIVE: Seizures following administration of potent bisphosphonates have been reported only sporadically in the medical literature. The rare cases described were often attributed to other precipitating factors such as hypoglycemia, acute infection, or predisposition to post-bisphosphonate hypocalcemia. We review the previous cases and present a new case of suspected seizure episode following zoledronic acid therapy. METHODS: We describe a case of a 63-year-old woman with a history of well-controlled epileptic disorder with no seizure activity in recent years. She was treated with intravenous zoledronic acid due to osteoporosis. Twelve hours after treatment, she suffered an episode of loss of consciousness with urinary incontinence suspected to be seizure-related. RESULTS: Unlike previously reported cases, our patient had a low risk for postinfusion hypocalcemia as her creati-nine, calcium, parathyroid hormone, and vitamin D were all within normal limits prior to the infusion. CONCLUSION: Our interpretation of the scenario described is based on clinical judgment and not supported by ancillary studies. Nevertheless, our case, along with the limitations described, joins other reports, and raises questions about possible interaction between a convulsion disorder and a potent bone resorption inhibition administration, leading to a relative hypocalcemia and possible seizure threshold reduction. This question should be further explored by other studies.

Paediatricians' attitudes and beliefs towards transgender people: a cross-sectional survey in Israel.

OBJECTIVE: The number of transgender and gender non-conforming children is on the rise. For these children, the timing of medical intervention is crucial, yet transgender children report poorer overall physical and mental health outcomes compared with their cisgender peers. We aim to describe how paediatricians perceive transgender people. SETTING: The 'Transgender Attitudes and Beliefs Scale', which consists of 29 items in three domains-human value, interpersonal comfort and sex/gender beliefs-was administered to 391 senior and resident paediatricians in Israel. The responses on a 7-point Likert scale were collapsed into two categories: a mean score of ≥6 for each domain was a 'Favourable' perception and <6 'Unfavourable'. RESULTS: Of 355 respondents (91% response rate), 221 (62%) were females, 132 (37%) were males and 2 identified as 'other'; 290 (82%) were born in 'trans-respect countries', 274 (77%) identified as secular, 223 (63%) were senior physicians and 132 (27%) were residents. Overall, 90% of the cohort scored favourably on the 'Human value' domain, 68% on 'Interpersonal comfort' and 40% on 'Sex/gender beliefs'. In the 'Interpersonal comfort' domain, being a man, birthplace in a transphobic country, identification as religious and being a senior physician were all associated with increased ORs for an unfavourable score: 2.1 (95% CI 1.3 to 3.4), 3.4 (95% CI 1.9 to 6.3), 2.4 (95% CI 1.4 to 4.2) and 1.8 (95% CI 1.1 to 3.0), respectively. In the 'Sex/gender beliefs' domain, being a man and identifying as religious had significantly increased ORs for unfavourable scores: 2.2 (95% CI 1.3 to 3.5) and 10.6 (95% CI 4.7 to 24.1), respectively. CONCLUSIONS: Negative attitudes towards transgender people are still widespread among paediatricians. Interventions are warranted to positively impact these attitudes.

Fracture incidence after denosumab discontinuation: Real-world data from a large healthcare provider.

BACKGROUND: Vertebral fractures (VF) upon Denosumab (DMAB) discontinuation were first described as a distinct phenomenon in 2015, yet the magnitude of this event remains undetermined. OBJECTIVES: To estimate fracture risk after DMAB discontinuation, in a real-world setting. METHODS: The computerized database of a 2.3-million members' state-mandated health organization was utilized to detect osteoporotic patients with at least two DMAB dispenses. Treatment discontinuation was defined as a refill gap of 3 months or more, while the discontinuation date was defined as an anticipated missed purchase date. Fractures were identified by an osteoporosis registry and individually adjudicated by an expert's review. Fractures occurring within one year from discontinuation among DMAB discontinuers (DD) and from the 2nd year of treatment onwards for persistent users (PU) were included. RESULTS: A total of 1500 DD (92% females, mean ±â€¯SD age = 71.8 ±â€¯9.5y), and 1610 PU (91%, 71.7 ±â€¯8.8) were identified. At baseline, the groups were comparable in fracture- history, bisphosphonate exposure, smoking, and bone density. Multiple VF occurred in 12 (0.8%) DD vs. 2 (0.1%) PU (p = 0.006). The overall rate of fractures per 100 patient-years of follow-up was significantly higher in DD than PU (RR 3.2, 95% CI 2.2-4.8), as well as the rate of VF (RR 4.7, 95% CI 2.3-9.6) and multiple VF (RR 14.6, 95% CI 3.3-65.3, effect size 1.06). CONCLUSIONS: Patients who discontinue DMAB are at greater risk of major OP fractures than those who persist with treatment. Same is true for clinical multiple vertebral fractures, yet the incidence of the latter was low. These findings demonstrate a need for greater awareness and thoughtful management of DMAB discontinuation.