OBJECTIVE To compare the incidence of type 1 diabetes (T1D) before and during the coronavirus disease 2019 (COVID-19) pandemic and determine whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with T1D development. RESEARCH DESIGN AND METHODS All Danish residents age <30 years free of diabetes from 2015 to 2021 were included. Individuals were followed from 1 January 2015 or birth until the development of T1D, the age of 30, the end of the study (31 December 2021), emigration, development of type 2 diabetes, onset of any cancer, initiation of immunomodulating therapy, or development of any autoimmune disease. We compared the incidence rate ratio (IRR) of T1D using Poisson regression models. We matched each person with a SARS-CoV-2 infection with three control persons and used a cause-specific Cox regression model to estimate the hazard ratio (HR). RESULTS Among 2,381,348 individuals, 3,579 cases of T1D occurred. The adjusted IRRs for T1D in each quarter of 2020 and 2021 compared with 2015-2019 were as follows: January-March 2020, 1.03 (95% CI 0.86; 1.23); January-March 2021, 1.01 (0.84; 1.22), April-June 2020, 0.98 (0.80; 1.20); April-June 2021, 1.34 (1.12; 1.61); July-September 2020, 1.13 (0.94; 1.35); July-September 2021, 1.21 (1.01; 1.45); October-December 2020, 1.09 (0.91; 1.31); and October-December 2021, 1.18 (0.99; 1.41). We identified 338,670 individuals with a positive SARS-CoV-2 test result and matched them with 1,004,688 control individuals. A SARS-2-CoV infection was not significantly associated with the risk of T1D development (HR 0.90 [95% CI 0.60; 1.35]). CONCLUSIONS There was an increase in T1D incidence during April-June 2021 compared with April-June 2015-2019, but this could not be attributed to SARS-CoV-2 infection.

Anti-resorptive osteoporosis treatment might be more effective in patients with high bone turnover. In this registry study including clinical data, high pre-treatment bone turnover measured with biochemical markers was correlated with higher bone mineral density increases. Bone turnover markers may be useful tools to identify patients benefitting most from anti-resorptive treatment. In randomized, controlled trials of bisphosphonates, high pre-treatment levels of bone turnover markers (BTM) were associated with a larger increase in bone mineral density (BMD). The purpose of this study was to examine this correlation in a real-world setting. In this registry-based cohort study of osteoporosis patients (n = 158) receiving antiresorptive therapy, the association between pre-treatment levels of plasma C-telopeptide of type I Collagen (CTX) and/or N-terminal propeptide of type I procollagen (PINP) and change in bone mineral density (BMD) at lumbar spine, total hip, and femoral neck upon treatment was examined. Patients were grouped according to their pre-treatment BTM levels, defined as values above and below the geometric mean for premenopausal women. Pre-treatment CTX correlated with annual increase in total hip BMD, where patients with CTX above the geometric mean experienced a larger annual increase in BMD (p = 0.008) than patients with CTX below the geometric mean. The numerical pre-treatment level of CTX showed a similar correlation at all three skeletal sites (total hip (p = 0.03), femoral neck (p = 0.04), and lumbar spine (p = 0.0003)). A similar association was found for PINP where pre-treatment levels of PINP above the geometric mean correlated with a larger annual increase in BMD for total hip (p = 0.02) and lumbar spine (p = 0.006). Measurement of pre-treatment BTM levels predicts osteoporosis patients’ response to antiresorptive treatment. Patients with high pre-treatment levels of CTX and/or PINP benefit more from antiresorptive treatment with larger increases in BMD than patients with lower pre-treatment levels.

Background:Genomic aberrations have been identified in metastatic castration-resistant prostate cancer (mCRPC), but molecular predictors of resistance to abiraterone acetate/prednisone (AA/P) treatment are not known.Patients and methods:In a prospective clinical trial, mCRPC patients underwent whole-exome sequencing (n = 82) and RNA sequencing (n = 75) of metastatic biopsies before initiating AA/P with the objective of identifying genomic alterations associated with resistance to AA/P. Primary resistance was determined at 12 weeks of treatment using criteria for progression that included serum prostate-specific antigen measurement, bone and computerized tomography imaging and symptom assessments. Acquired resistance was determined using the end point of time to treatment change (TTTC), defined as time from enrollment until change in treatment from progressive disease. Associations of genomic and transcriptomic alterations with primary resistance were determined using logistic regression, Fisher's exact test, single and multivariate analyses. Cox regression models were utilized for determining association of genomic and transcriptomic alterations with TTTC.Results:At 12 weeks, 32 patients in the cohort had progressed (nonresponders). Median study follow-up was 32.1 months by which time 58 patients had switched treatments due to progression. Median TTTC was 10.1 months (interquartile range: 4.4-24.1). Genes in the Wnt/β-catenin pathway were more frequently mutated and negative regulators of Wnt/β-catenin signaling were more frequently deleted or displayed reduced mRNA expression in nonresponders. Additionally, mRNA expression of cell cycle regulatory genes was increased in nonresponders. In multivariate models, increased cell cycle proliferation scores (≥ 50) were associated with shorter TTTC (hazard ratio = 2.11, 95% confidence interval: 1.17-3.80; P = 0.01).Conclusions:Wnt/β-catenin pathway activation and increased cell cycle progression scores can serve as molecular markers for predicting resistance to AA/P therapy.

There is an increasing awareness of sarcopenia in older people. We applied machine learning principles to predict mortality and incident immobility in older Belgian men through sarcopenia and frailty characteristics. Mortality could be predicted with good accuracy. Serum 25-hydroxyvitamin D and bone mineral density scores were the most important predictors. Machine learning principles were used to predict 5-year mortality and 3-year incident severe immobility in a population of older men by frailty and sarcopenia characteristics. Using prospective data from 1997 on 264 older Belgian men (n = 152 predictors), 29 statistical models were developed and tuned on 75% of data points then validated on the remaining 25%. The model with the highest test area under the curve (AUC) was chosen as the best. From these, ranked predictor importance was extracted. Five-year mortality could be predicted with good accuracy (test AUC of .85 [.73; .97], sensitivity 78%, specificity 89% at a probability cut-off of 22.3%) using a Bayesian generalized linear model. Three-year incident severe immobility could be predicted with fair accuracy (test AUC .74 [.57; .91], sensitivity 67%, specificity 78% at a probability cut-off of 14.2%) using a multivariate adaptive regression splines model. Serum 25-hydroxyvitamin D levels and hip bone mineral density scores were the most important predictors of mortality, while biochemical androgen markers and Short-Form 36 Physical Domain questions were the most important predictors of immobility. Sarcopenia assessed by lean mass estimates was relevant to mortality prediction but not immobility prediction. Using advanced statistical models and a machine learning approach 5-year mortality can be predicted with good accuracy using a Bayesian generalized linear model and 3-year incident severe immobility with fair accuracy using a multivariate adaptive regression splines model.

Some antihyperglycemic medications have been found to affect bone metabolism. We assessed the long-term effects of metformin compared with placebo on bone mineral density (BMD) and trabecular bone score (TBS) in patients with type 2 diabetes. Metformin had no significant effect on BMD in the spine and hip or TBS compared with a placebo.

Osteonecrosis of the jaw (ONJ) is rare (2.53/10,000 person-years) among alendronate users, but long-term and compliant use are associated with an increased risk of surgically treated ONJ. Risk of surgically treated ONJ is higher in patients with rheumatoid diseases and use of proton pump inhibitors.

Clustering analysis can identify subgroups of patients based on similarities of traits. From data on 10,775 subjects, we document nine patient clusters of different fracture risks. Differences emerged after age 60 and treatment compliance differed by hip and lumbar spine bone mineral density profiles.

L’étude observationnelle européenne Forsteo a évalué l’incidence des fractures, des maux de dos, de la qualité de vie (QV) et de la persistance du traitement chez les femmes post-ménopausées traitées par du tériparatide en routine dans 8 pays européens. Nous présentons les résultats pour la France, où les critères de remboursement du tériparatide par l’assurance maladie sont réservés aux femmes ayant une maladie sévère et avec traitement limité à 18 mois.Un échantillon représentatif de femmes débutant un traitement par du tériparatide en France a été suivi en routine pendant 36 mois. Nous avons pris en compte les caractéristiques des patientes à l’inclusion, la prise en continu de tériparatide (Kaplan-Meier analyse), l’incidence des fractures, des maux de dos, et la qualité de vie (EQ-5D) à l’inclusion, puis après 18 et 36 mois de suivi (dernière observation reportée).Cent seize rhumatologues ont inclus 309 patients, dont 290 (93,9 %) ont eu au moins une visite de suivi. L’âge moyen des femmes (écart-type) était de 74,5 (7,4) ans et 296 (95,8 %) avaient eu au moins 2 fractures vertébrales avant traitement par tériparatide. L’incidence des fractures cliniques, principalement vertébrales, diminuait 6 mois environ après le début du traitement par tériparatide, et duraient jusqu’à 36 mois (p = 0,013). La plupart des patients étaient traités par antirésorptifs. Les maux de dos et les mesures EQ-5D étaient améliorés de façon significative à 18 et 36 mois (p < 0,0001) dans les analyses de DOR, mais pas l’échelle visuelle EQ-5D après ajustement de la covariable dans le modèle RMMR. La durée médiane de traitement était de 17,4 mois.Les femmes françaises débutant un traitement par tériparatide en routine avaient une ostéoporose sévère et il existait une bonne observance du traitement, en accord avec les critères de remboursement de l’assurance en France. L’amélioration du risque de fracture et des maux de dos commençait peu après le traitement et était maintenue après 36 mois de suivi.

A study of national Danish patient data with regard to thiazide diuretics vs. non-treatment. We find that after age 83 years, thiazides increase the 10-year risk of major fractures. We also find that thiazides can be stopped after 63 years old to possibly protect against fracture occurrence.

BackgroundData from observational studies have suggested that thiazide diuretics protect against fractures. Few studies have investigated time frames from initiation of treatment to fracture occurrence.ObjectiveTo evaluate the time to spinal, hip, femur, wrist and upper extremity fracture occurrence before and after thiazide exposure.MethodsA matched retrospective cohort study of patient information from national Danish patient databases was conducted. Patients with reimbursed prescriptions for noncompounded thiazide diuretics with potassium supplementation (Anatomical Therapeutic Chemical classification system code C03AB) between 1996 and 2011 were matched with nonexposed control subjects by date of birth and gender. Weekly odds ratios (ORs) of fracture occurrence and total incidence rates (IRs) and incidence rate ratios (IRRs) of fracture risk were calculated for the periods before treatment initiation, weeks 1-42 and weeks 43-780.ResultsA total of 1602141 thiazide exposure periods' (468271 individuals) and 1530233 nonexposure periods' (655399 individuals) were included in the analysis. Thiazide use was associated with factors of increased de novo fracture risk. Weekly adjusted fracture risk between exposure and nonexposure was increased prior to commencing thiazide therapy, further increasing from weeks 1-42weeks and then decreasing gradually from weeks 43-780. There was a decreasing trend in total age-adjusted risk during these periods: IRR [95% confidence interval 1.44 [1.42; 1.47], 1.27 [1.24; 1.29] and 1.14 [1.11; 1.18], respectively. Prescription patterns showed several treatment breaks amongst thiazide users.ConclusionsIt appears that thiazides reduce the background risk of fracture that is increased prior to commencing therapy. Long duration and continuity of thiazide exposure seems to be important to obtain this protective effect on fracture risk, but we have found in this study that this approach is not always used in clinical practice.

Cystic fibrosis (CF) is a serious autosomal recessive genetic disorder associated with chronic lung disease, malabsorption, malnutrition, pancreatic insufficiency and premature respiratory failure. Recent advances in medical science and technology have increased the lifespan of patients with CF, albeit with long-term consequences of the disease, such as osteoporosis, becoming of increasing significance. The medical treatment of osteoporosis in patients with CF or after organ transplantation is still being explored, and no clear guidelines regarding the best choice of bisphosphonate exist. We report a case of a young woman with CF, lung transplantation and low bone mass developing long-term leukopenia after treatment with zoledronic acid. The leukopenia, with a strong affection of the neutrocytes, lasted for 4 months and the condition only went into remission after granulocyte-colony stimulating factor (G-CSF) treatment. It is important to be aware of symptomatic leukopenia in immunosuppressive patients after treatment with zoledronic acid.

249 Background: Evaluating tumor specific pathologic and genetic profiles in mCRPC stage is difficult due to the limited availability of mCRPC tissue. We describe findings from a prospective cohort study performed to obtain concomitant histopathology and genetic information in mCRPC. Methods: Patients with mCRPC initiating abiraterone acetate therapy underwent 2 serial (3 months apart) metastatic (met) site needle core biopsies (NCB1/2). Bone lesions were biopsied using 11-13G core needles and 18G core biopsy devices were used for non-osseous masses. Up to 4 cores were obtained at each biopsy with the 1st core (S1) sent for DNA sequencing, the 2nd (S2) for RNA sequencing, and the 3rd/4th (X3, X4) submitted for xenograft implantation. From each, 1-2 mm segments were separated and formalin-fixed for histopathologic examination (HPE). Results: A total of 54 patients, enrolled between June 2013 and July 2014, underwent 94 NCB (54 NCB1, 40 NCB2), rendering a total of 259 samples (94 S1; 75 S2; 59 X3 and 31 X4) of which 85 (32%) were positive (pos) for tumor by HPE. Positivity for tumor in S1, S2, X3, and X4 cores was 42%, 33%, 22%, and 19%, respectively. At least one core pos for met tumor was observed in 62% NCB1 and 52% NCB2 (overall 52/94; 56%). Met sites biopsied include bone (71), lymph nodes (18), liver (3), penile (1) and pelvic (1) soft tissues. HPE revealed met adenocarcinoma in 44/52, and poorly differentiated carcinoma in 8/52. Gleason grade applied to the met ranged from 3+4 to 5+5. 45/85 pos samples (53%) had > 50% tumor cellularity. Pos NCB in bone lesions was observed in 23/71 (32%), compared to 17/23 (73%) of non-bone sites (p=.0004). 85 S1 samples yielded DNA material, of which 66 (77%) had ≥10% tumoral DNA. 24 cases with negative HPE had ≥10% tumoral DNA; 7 cases with pos HPE had <10 tumoral DNA. In all, 76/94 (81%) NCB yielded tumor material either by HPE or DNA analysis. Conclusions: NCB of mCRPC is feasible and provides adequate tissue for pursuing HPE and sequencing studies. HPE of extracted material correlates with DNA sequencing data and provides complementary information on tumor features. Bone lesions yield significantly less tumoral material than non-osseous sites.

Alendronate (ALN) and risedronate (RIS) are ideal as first-choice therapy options in the treatment of postmenopausal osteoporosis. What to do for patients who do not respond adequately to bisphosphonates has not been conclusively determined, but transitioning to other therapies should be considered. The aim of this article is to describe potential alternatives for patients switching from ALN or RIS to other therapies for osteoporosis. A systematic search of PubMed was conducted to find papers that evaluate the effects of switching therapies on fractures, bone mineral density (BMD), or bone turnover markers. Results from 11 studies that prospectively assessed treatment after ALN or RIS in women with postmenopausal osteoporosis were reviewed. All studies are of short duration (all 24 months or less) and assess the topic of transitioning therapy from ALN or RIS. None of the studies had the statistical power to assess fracture-reduction efficacy. Transitioning from ALN to zoledronic acid maintains therapeutic effects for 12 months. Switching to strontium ranelate, denosumab, or teriparatide causes further increases in BMD. Specifically, transitioning to teriparatide could be used for a limited time for select patients but needs to be followed up with anti-resorptive treatment to prevent a loss of the bone gained. There are only few studies-of short duration-that assess the topic of transitioning therapy from ALN or RIS, although this is a very frequent occurrence in clinical practice. This is especially true if the patient has not reached his/her therapy goal. Further long-term studies are needed.

The association between hyponatremia and osteoporosis was evaluated in humans. A significant association was found between low sodium levels, lower bone mineralization in the hip, and with several common conditions. Hyponatremia could be used as a marker of osteoporosis and systemic disease.

Fractures after the age of 50 are frequently observed in Denmark, and many of these may be osteoporotic. This study examined the incidence of all and subsequent fractures in a 10-year period from 2001 to 2011. The incidence of subsequent fractures was high, especially following hip fracture.

Long-term treatment with bisphosphonates against osteoporosis may cause atypical femur fractures and osteonecrosis of the jaw. Eight cases of bisphosphonate-associated osteonecrosis of the external auditory canal area are published. Based on Danish national registers, we report a time- and dose-dependent increased risk of cholesteatoma in osteoporosis patients treated with bisphosphonates.