Real-life effects of pharmacological osteoporosis treatments on bone mineral density by quantitative computed tomography.

Monitoring of bone mineral density (BMD) is used to assess pharmacological osteoporosis therapy. This study examined the real-life effects of antiresorptive and osteoanabolic treatments on volumetric BMD (vBMD) of the spine by quantitative computed tomography (QCT). Patients aged ≥ 50 years with a vBMD < 120 mg/ml had ≥ 2 QCT. For analysis of therapy effects, the pharmacological treatment and the duration of each therapy were considered. Identical vertebrae were evaluated in all vBMD measurements for each patient. A linear mixed model with random intercepts was used to estimate the effects of pharmacological treatments on vBMD. A total of 1145 vBMD measurements from 402 patients were analyzed. Considering potential confounders such as sex, age, and prior treatment, a reduction in trabecular vBMD was estimated for oral bisphosphonates (- 1.01 mg/ml per year; p < 0.001), intravenous bisphosphonates (- 0.93 mg/ml per year; p = 0.015) and drug holiday (- 1.58 mg/ml per year; p < 0.001). Teriparatide was estimated to increase trabecular vBMD by 4.27 mg/ml per year (p = 0.018). Patients receiving denosumab showed a statistically non-significant decrease in trabecular vBMD (- 0.44 mg/ml per year; p = 0.099). Compared to non-treated patients, pharmacological therapy had positive effects on trabecular vBMD (1.35 mg/ml; p = 0.001, 1.43 mg/ml; p = 0.004, 1.91 mg/ml; p < 0.001, and 6.63 mg/ml; p < 0.001 per year for oral bisphosphonates, intravenous bisphosphonates, denosumab, and teriparatide, respectively). An increase in trabecular vBMD by QCT was not detected with antiresorptive agents. Patients treated with teriparatide showed increasing trabecular vBMD. Non-treatment led to a larger decrease in trabecular vBMD than pharmacological therapy.

Boehm E ，Sauer C ，Baur-Melnyk A ，Biebl JT ，Harada S ，Wegener B ，Kraft E ，Stahl R ，Feist-Pagenstert I ... -  《-》

Safety, pharmacokinetics, and pharmacodynamics of LBP-EC01, a CRISPR-Cas3-enhanced bacteriophage cocktail, in uncomplicated urinary tract infections due to Escherichia coli (ELIMINATE): the randomised, open-label, first part of a two-part phase 2 trial.

The rate of antibiotic resistance continues to grow, outpacing small-molecule-drug development efforts. Novel therapies are needed to combat this growing threat, particularly for the treatment of urinary tract infections (UTIs), which are one of the largest contributors to antibiotic use and associated antibiotic resistance. LBP-EC01 is a novel, genetically enhanced, six-bacteriophage cocktail developed by Locus Biosciences (Morrisville, NC, USA) to address UTIs caused by Escherichia coli, regardless of antibiotic resistance status. In this first part of the two-part phase 2 ELIMINATE trial, we aimed to define a dosing regimen of LBP-EC01 for the treatment of uncomplicated UTIs that could advance to the second, randomised, controlled, double-blinded portion of the study. This first part of ELIMINATE is a randomised, uncontrolled, open-label, phase 2 trial that took place in six private clinical sites in the USA. Eligible participants were female by self-identification, aged between 18 years and 70 years, and had an uncomplicated UTI at the time of enrolment, as well as a history of at least one drug-resistant UTI caused by E coli within the 12 months before enrolment. Participants were initially randomised in a 1:1:1 ratio into three treatment groups, but this part of the trial was terminated on the recommendation of the safety review committee after a non-serious tolerability signal was observed based on systemic drug exposure. A protocol update was then implemented, comprised of three new treatment groups. Groups A to C were dosed with intraurethral 2 × 1012 plaque-forming units (PFU) of LBP-EC01 on days 1 and 2 by catheter, plus one of three intravenous doses daily on days 1-3 of LBP-EC01 (1 mL of 1 × 1010 PFU intravenous bolus in group A, 1 mL of 1 × 109 PFU intravenous bolus in group B, and a 2 h 1 × 1011 PFU intravenous infusion in 100 mL of sodium lactate solution in group C). In all groups, oral trimethoprim-sulfamethoxazole (TMP-SMX; 160 mg and 800 mg) was given twice daily on days 1-3. The primary outcome was the level of LBP-EC01 in urine and blood across the treatment period and over 48 h after the last dose and was assessed in patients in the intention-to-treat (ITT) population who received at least one dose of LBP-EC01 and had concentration-time data available throughout the days 1-3 dosing period (pharmacokinetic population). Safety, a secondary endpoint, was assessed in enrolled patients who received at least one dose of study drug (safety population). As exploratory pharmacodynamic endpoints, we assessed E coli levels in urine and clinical symptoms of UTI in patients with at least 1·0 × 105 colony-forming units per mL E coli in urine at baseline who took at least one dose of study drug and completed their day 10 test-of-cure assessment (pharmacodynamic-evaluable population). This trial is registered with ClinicalTrials.gov, NCT05488340, and is ongoing. Between Aug 22, 2022, and Aug 28, 2023, 44 patients were screened for eligibility, and 39 were randomly assigned (ITT population). Initially, eight participants were assigned to the first three groups. After the protocol was updated, 31 participants were allocated into groups A (11 patients), B (ten patients), and C (ten patients). One patient in group C withdrew consent on day 2 for personal reasons, but as she had received the first dose of the study drug was included in the modified ITT population. Maximum urine drug concentrations were consistent across intraurethral dosing, with a maximum mean concentration of 6·3 × 108 PFU per mL (geometric mean 8·8 log10 PFU per mL and geometric SD [gSD] 0·3). Blood plasma level of bacteriophages was intravenous dose-dependent, with maximum mean concentrations of 4·0 × 103 (geometric mean 3·6 log10 PFU per mL [gSD 1·5]) in group A, 2·5 × 103 (3·4 log10 PFU per mL [1·7]) in group B, and 8·0 × 105 (5·9 log10 PFU per mL [1·4]) in group C. No serious adverse events were observed. 44 adverse events were reported across 18 (46%) of the 39 participants in the safety population, with more adverse events seen with higher intravenous doses. Three patients in groups 1 to 3 and one patient in group C, all of whom received 1 × 1011 LBP-EC01 intravenously, had non-serious tachycardia and afebrile chills after the second intravenous dose. A rapid reduction of E coli in urine was observed by 4 h after the first treatment and maintained at day 10 in all 16 evaluable patients; these individuals had complete resolution of UTI symptoms by day 10. A regimen consisting of 2 days of intraurethral LBP-EC01 and 3 days of concurrent intravenous LBP-EC01 (1 × 1010 PFU) and oral TMP-SMX twice a day was well tolerated, with consistent pharmacokinetic profiles in urine and blood. LBP-EC01 and TMP-SMX dosing resulted in a rapid and durable reduction of E coli, with corresponding elimination of clinical symptoms in evaluable patients. LBP-EC01 holds promise in providing an alternative therapy for uncomplicated UTIs, with further testing of the group A dosing regimen planned in the controlled, double-blind, second part of ELIMINATE. Federal funds from the US Department of Health and Human Services, Administration for Strategic Preparedness and Response, and Biomedical Advanced Research and Development Authority (BARDA).

Kim P ，Sanchez AM ，Penke TJR ，Tuson HH ，Kime JC ，McKee RW ，Slone WL ，Conley NR ，McMillan LJ ，Prybol CJ ，Garofolo PM ... -  《-》

Bone properties in persons with type 1 diabetes and healthy controls - A cross-sectional study.

The risk of fractures is increased in persons with type 1 diabetes (T1D) and assessment of bone health has been included in the 2024 updated Standards of Care by The American Diabetes Association (ADA). Previous studies have found that in T1D bone metabolism, mineral content, microstructure, and strength diverge from that of persons without diabetes. However, a clear description of a T1D bone phenotype has not yet been established. We investigated bone mechanical properties and microstructure in T1D compared with healthy controls. For the potential future introduction of additional bone measures in the clinical fracture risk assessment, we aimed to assess any potential associations between various measures related to bone indices in subjects with T1D. We studied human bone indices in a clinical cross-sectional setup including 111 persons with early-onset T1D and 37 sex- and age-matched control persons. Participants underwent hip and spine DXA scans for bone mineral density (BMD) of the femoral neck (FN), total hip (TH), and lumbar spine (LS), and TBS evaluation, microindentation of the tibial shaft for Bone Material Strength index (BMSi), and high-resolution periphery quantitative computed tomography (HRpQCT) of the distal radius and tibia for volumetric BMD (vBMD) and structural measures of trabecular and cortical bone. Results are reported as means with (standard deviation) or (95% confidence intervals (CI)), medians with [interquartile range], and differences are reported with (95% CI). The study included 148 persons aged 20 to 75 years with a median age of 43.2 years. The T1D group who had all been diagnosed with T1D before the age of 18 years demonstrated values of HbA1c ranging from 39 to 107 mmol/mol and a median HbA1c of 57 mmol/mol. The BMD did not differ between groups (the mean difference in FN-BMD was 0.026 g/cm2 (-0.026; 0.079), p = 0.319) and the median BMSi was comparable in the two groups (79.2 [73.6; 83.8] in the T1D group compared with 77.9 [70.5, 86.1] in the control group). Total and trabecular vBMD (Tb.vBMD), cortical thickness (Ct.Th), and trabecular thickness (Tb.Th) of both radius and tibia were lower in participants with T1D. The mean Tb.vBMD at the radius was 143.6 (38.5) mg/cm3 in the T1D group and 171.5 (37.7) mg/cm3 in the control group, p < 0.001. The mean Ct. Thd of the radius was 0.739 mm (0.172) in the T1D group and 0.813 (0.188) in the control group, p = 0.044. Crude linear regressions revealed limited agreement between BMSi and Tb.vBMD (p = 0.010, r2 = 0.040 at the radius and p = 0.008, r2 = 0.040 at the tibia and between BMSi and the estimated failure load (FL) at the tibia (p < 0.001, r2 = 0.090). There were no significant correlations between BMSi and Ct.Th. TBS correlated with Tb.vBMD at the radius (p = 0.008, r2 = 0.044) and the tibia (p = 0.001, r2 = 0.069), and with the estimated FL at the distal tibia (p = 0.038, r2 = 0.026). In this study, we examined the bones of persons with well-controlled, early-onset T1D. Compared with sex- and age-matched healthy control persons, we found reduced total and trabecular vBMD, as well as decreased trabecular and cortical thickness. These results suggest that a debut of T1D before reaching peak bone mass negatively impacts bone microarchitecture. No differences in areal BMD or BMSi were observed. Although the variations in total hip BMD reflect some variation in the vBMD, the reduction in trabecular bone mineral density was not captured by the DXA scan. Consequently, fracture risk may be underestimated when relying on DXA, and further research into fracture risk assessment in T1D is warranted.

Brandt IAG ，Viggers R ，Harsløf T ，Frost M ，Vestergaard P ... -  《-》

Abrocitinib, tralokinumab and upadacitinib for treating moderate-to-severe atopic dermatitis.

Edwards SJ ，Karner C ，Jhita T ，Barton S ，Marceniuk G ，Yiu ZZN ，Wittmann M ... -  《-》

Comparison of Two Modern Survival Prediction Tools, SORG-MLA and METSSS, in Patients With Symptomatic Long-bone Metastases Who Underwent Local Treatment With Surgery Followed by Radiotherapy and With Radiotherapy Alone.

Survival estimation for patients with symptomatic skeletal metastases ideally should be made before a type of local treatment has already been determined. Currently available survival prediction tools, however, were generated using data from patients treated either operatively or with local radiation alone, raising concerns about whether they would generalize well to all patients presenting for assessment. The Skeletal Oncology Research Group machine-learning algorithm (SORG-MLA), trained with institution-based data of surgically treated patients, and the Metastases location, Elderly, Tumor primary, Sex, Sickness/comorbidity, and Site of radiotherapy model (METSSS), trained with registry-based data of patients treated with radiotherapy alone, are two of the most recently developed survival prediction models, but they have not been tested on patients whose local treatment strategy is not yet decided. (1) Which of these two survival prediction models performed better in a mixed cohort made up both of patients who received local treatment with surgery followed by radiotherapy and who had radiation alone for symptomatic bone metastases? (2) Which model performed better among patients whose local treatment consisted of only palliative radiotherapy? (3) Are laboratory values used by SORG-MLA, which are not included in METSSS, independently associated with survival after controlling for predictions made by METSSS? Between 2010 and 2018, we provided local treatment for 2113 adult patients with skeletal metastases in the extremities at an urban tertiary referral academic medical center using one of two strategies: (1) surgery followed by postoperative radiotherapy or (2) palliative radiotherapy alone. Every patient's survivorship status was ascertained either by their medical records or the national death registry from the Taiwanese National Health Insurance Administration. After applying a priori designated exclusion criteria, 91% (1920) were analyzed here. Among them, 48% (920) of the patients were female, and the median (IQR) age was 62 years (53 to 70 years). Lung was the most common primary tumor site (41% [782]), and 59% (1128) of patients had other skeletal metastases in addition to the treated lesion(s). In general, the indications for surgery were the presence of a complete pathologic fracture or an impending pathologic fracture, defined as having a Mirels score of ≥ 9, in patients with an American Society of Anesthesiologists (ASA) classification of less than or equal to IV and who were considered fit for surgery. The indications for radiotherapy were relief of pain, local tumor control, prevention of skeletal-related events, and any combination of the above. In all, 84% (1610) of the patients received palliative radiotherapy alone as local treatment for the target lesion(s), and 16% (310) underwent surgery followed by postoperative radiotherapy. Neither METSSS nor SORG-MLA was used at the point of care to aid clinical decision-making during the treatment period. Survival was retrospectively estimated by these two models to test their potential for providing survival probabilities. We first compared SORG to METSSS in the entire population. Then, we repeated the comparison in patients who received local treatment with palliative radiation alone. We assessed model performance by area under the receiver operating characteristic curve (AUROC), calibration analysis, Brier score, and decision curve analysis (DCA). The AUROC measures discrimination, which is the ability to distinguish patients with the event of interest (such as death at a particular time point) from those without. AUROC typically ranges from 0.5 to 1.0, with 0.5 indicating random guessing and 1.0 a perfect prediction, and in general, an AUROC of ≥ 0.7 indicates adequate discrimination for clinical use. Calibration refers to the agreement between the predicted outcomes (in this case, survival probabilities) and the actual outcomes, with a perfect calibration curve having an intercept of 0 and a slope of 1. A positive intercept indicates that the actual survival is generally underestimated by the prediction model, and a negative intercept suggests the opposite (overestimation). When comparing models, an intercept closer to 0 typically indicates better calibration. Calibration can also be summarized as log(O:E), the logarithm scale of the ratio of observed (O) to expected (E) survivors. A log(O:E) > 0 signals an underestimation (the observed survival is greater than the predicted survival); and a log(O:E) < 0 indicates the opposite (the observed survival is lower than the predicted survival). A model with a log(O:E) closer to 0 is generally considered better calibrated. The Brier score is the mean squared difference between the model predictions and the observed outcomes, and it ranges from 0 (best prediction) to 1 (worst prediction). The Brier score captures both discrimination and calibration, and it is considered a measure of overall model performance. In Brier score analysis, the "null model" assigns a predicted probability equal to the prevalence of the outcome and represents a model that adds no new information. A prediction model should achieve a Brier score at least lower than the null-model Brier score to be considered as useful. The DCA was developed as a method to determine whether using a model to inform treatment decisions would do more good than harm. It plots the net benefit of making decisions based on the model's predictions across all possible risk thresholds (or cost-to-benefit ratios) in relation to the two default strategies of treating all or no patients. The care provider can decide on an acceptable risk threshold for the proposed treatment in an individual and assess the corresponding net benefit to determine whether consulting with the model is superior to adopting the default strategies. Finally, we examined whether laboratory data, which were not included in the METSSS model, would have been independently associated with survival after controlling for the METSSS model's predictions by using the multivariable logistic and Cox proportional hazards regression analyses. Between the two models, only SORG-MLA achieved adequate discrimination (an AUROC of > 0.7) in the entire cohort (of patients treated operatively or with radiation alone) and in the subgroup of patients treated with palliative radiotherapy alone. SORG-MLA outperformed METSSS by a wide margin on discrimination, calibration, and Brier score analyses in not only the entire cohort but also the subgroup of patients whose local treatment consisted of radiotherapy alone. In both the entire cohort and the subgroup, DCA demonstrated that SORG-MLA provided more net benefit compared with the two default strategies (of treating all or no patients) and compared with METSSS when risk thresholds ranged from 0.2 to 0.9 at both 90 days and 1 year, indicating that using SORG-MLA as a decision-making aid was beneficial when a patient's individualized risk threshold for opting for treatment was 0.2 to 0.9. Higher albumin, lower alkaline phosphatase, lower calcium, higher hemoglobin, lower international normalized ratio, higher lymphocytes, lower neutrophils, lower neutrophil-to-lymphocyte ratio, lower platelet-to-lymphocyte ratio, higher sodium, and lower white blood cells were independently associated with better 1-year and overall survival after adjusting for the predictions made by METSSS. Based on these discoveries, clinicians might choose to consult SORG-MLA instead of METSSS for survival estimation in patients with long-bone metastases presenting for evaluation of local treatment. Basing a treatment decision on the predictions of SORG-MLA could be beneficial when a patient's individualized risk threshold for opting to undergo a particular treatment strategy ranged from 0.2 to 0.9. Future studies might investigate relevant laboratory items when constructing or refining a survival estimation model because these data demonstrated prognostic value independent of the predictions of the METSSS model, and future studies might also seek to keep these models up to date using data from diverse, contemporary patients undergoing both modern operative and nonoperative treatments. Level III, diagnostic study.

Lee CC ，Chen CW ，Yen HK ，Lin YP ，Lai CY ，Wang JL ，Groot OQ ，Janssen SJ ，Schwab JH ，Hsu FM ，Lin WH ... -  《-》