Journal of Bone and Mineral Research最新文献

{"title":"The effects of denosumab on osteoclast precursors in postmenopausal women: a possible explanation for the overshoot phenomenon after discontinuation.","authors":"Marian Schini, Fatma Gossiel, Tanya Saini, Peter Banda, Rachel Ward, Tatiane Vilaca, Richard Eastell, Andreas Fontalis","doi":"10.1093/jbmr/zjae170","DOIUrl":"https://doi.org/10.1093/jbmr/zjae170","url":null,"abstract":"<p><p>Upon denosumab discontinuation, an observed overshoot phenomenon in bone turnover may occur, potentially leading to a reduction in bone mineral density and the occurrence of vertebral fractures. Several theories have been proposed to explain this phenomenon, one of which is that osteoclast precursors might be accumulating during treatment. Our aim was to study the effects of denosumab on osteoclast precursors in postmenopausal women. This cross-sectional observational study included 30 postmenopausal women with osteopenia or osteoporosis, divided into two groups: 15 treated with denosumab (mean duration 4 years, range 6 months-9 years) and 15 treatment-naïve controls. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood and were stained for CD14, MCSFR, CD11b and TNFRII. Osteoclast precursors (CD14+/MCSFR+, CD14+/CD11b + OR CD14+/TNFRII+) were identified with fluorescent activated cell sorting (FACS). The proportion of osteoclasts was determined by calculating their percentage of the total cell population in each whole blood sample. To confirm the expected suppression of bone turnover in the subjects treated with denosumab, we measured serum PINP, CTX and TRACP5b. Denosumab-treated patients exhibited a significantly higher count of CD14+/CD11b + osteoclast precursors compared to controls (median 4% vs 0.75%, P=.011). There was no correlation with the duration of treatment. Bone turnover markers were significantly lower in the group treated with denosumab than controls. Our findings indicate an increase in osteoclast precursors, which could explain the overshoot phenomenon observed after discontinuing denosumab.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Changes in peripheral quantitative computed tomography measured bone density, size and strength in Zimbabwean children with and without HIV over one year: a cohort study.","authors":"Cynthia Kahari, Celia L Gregson, Mícheál Ó Breasail, Ruramayi Rukuni, Tafadzwa Madanhire, Victoria Simms, Joseph Chipanga, Lynda Stranix-Chibanda, Lisa K Micklesfield, Rashida A Ferrand, Kate A Ward, Andrea M Rehman","doi":"10.1093/jbmr/zjae169","DOIUrl":"https://doi.org/10.1093/jbmr/zjae169","url":null,"abstract":"<p><p>Understanding bone accrual in adolescents may inform approaches to improve skeletal health and reduce adult fracture risk. We investigated the effect of HIV on bone mineral accrual assessed by peripheral Quantitative Computed tomography (pQCT). Children with HIV (CWH) on ART for ≥2 years, and children without HIV (CWOH), aged 8-16 years (n = 609), had tibial pQCT scans at 0 and 12 months. Linear regression estimated sex stratified differences in change (∆) and mean pQCT bone density (trabecular and cortical), size (total cross-sectional area [CSA]) and strength (SSI) between CWH and CWOH, adjusting for socio-economic status (SES) and orphanhood and incorporating an interaction term for baseline pubertal status (Tanner 1-2[pre/early] vs 3-5[mid/late]). Structural equation modelling tested whether baseline height-for-age-Z-scores (HAZ) mediate the effect of HIV on ∆bone outcomes. CWH were more likely than CWOH to be orphans (44% vs 7%), of lower SES (43% vs 27%) and be stunted (30% vs 8%); but similar in age. At baseline and follow up, CWH had lower trabecular density, CSA and SSI than CWOH. After adjustment, bone density and strength increased similarly in CWH and CWOH. CWH in mid/late puberty at baseline had greater 12 months increases in CSA than CWOH, particularly males (mean difference [31.3(95%CI:-3.1, 65.6) mm2 in mid/late puberty vs. -2.04(-23.8, 19.7) mm2 in pre/early puberty; interaction P-value = 0.013]. HAZ mediated the effect of HIV on ∆bone outcomes only in females as follows: indirect pathways from HIV to ∆trabecular density [-1.85(-3.5, -0.2) mg/cm3], ∆cortical density [-2.01(-3.9, -0.01) mg/cm3], ∆CSA [-2.59(-4.7, -0.5) mm] and ∆SSI [-18.36(-29.6, -7.2) mm3]. In conclusion, CWH show bone deficits at follow up. Investigations of bone mineral accrual earlier in life and post-puberty to peak bone mass are needed.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Osteoclastic ATP6AP2 maintains β-catenin levels to prevent hyper-osteoclastic activation and trabecular bone-loss.","authors":"Li Chen, Lei Xiong, Haohan Guo, Xu Feng, Xiaojuan Zhu, Wen-Cheng Xiong","doi":"10.1093/jbmr/zjae164","DOIUrl":"https://doi.org/10.1093/jbmr/zjae164","url":null,"abstract":"<p><p>Osteoclast (OC) formation and bone resorption are regulated by several factors, including V-ATPase, Wnt/β-Catenin, and RANKL/RANK signaling. ATP6AP2, also known as the prorenin receptor (PRR), is an accessory subunit of V-ATPase and a regulator of Wnt/β-Catenin signaling. While the V-ATPase subunit ATP6AP1 is essential for osteoclast formation and function, the role of ATP6AP2 in OC-lineage cells is less clear. Here, we provide evidence that ATP6AP2 plays a negative role in osteoclastogenesis and function, contrasting with the positive role of ATP6AP1. Mice with conditional knockout (cKO) of ATP6AP2 in OCs (Atp6ap2LysM) exhibit trabecular bone loss, likely due to the increased osteoclastogenesis and activity, since bone formation rates are comparable to control mice. In vitro assays using bone marrow macrophages (BMMs) show that Atp6ap2LysM cultures have more RANKL-induced TRAP+ OC-like cells and increased bone resorptive activity. Further studies reveal that while RANKL signaling and V-ATPase activity are normal, in ATP6AP2 KO OCs, but not BMMs, have reduced basal levels of Wnt/β-Catenin pathway proteins, such as LRP5/6 and β-Catenin, compared to controls. Wnt3A treatment induces β-Catenin and suppresses osteoclast formation in both control and ATP6AP2 KO OC-lineage cells, indicating that Wnt/β-Catenin signaling negatively regulates OC-formation and operates independently of ATP6AP2. Overall, these results suggest that ATP6AP2 is critical for maintaining basal levels of LRP5/6 receptors and β-Catenin in osteoclasts, thus acting as a negative regulator of osteoclastogenesis and activation.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Patella Fractures are Associated with Bone Fragility - A Retrospective Study.","authors":"Isabella Rosillo, Carmen Germosen, Sanchita Agarwal, Ragyie Rawal, Ivelisse Colon, Mariana Bucovsky, Nayoung Kil, Elizabeth Shane, Marcella Walker","doi":"10.1093/jbmr/zjae165","DOIUrl":"10.1093/jbmr/zjae165","url":null,"abstract":"<p><p>Patella fractures are not typically considered osteoporotic fractures. We compared bone mineral density (BMD) and microstructure in elderly women from a multiethnic population-based study in New York City with any history of a patella fracture (n = 27) to those without historical fracture (n = 384) and those with an adult fragility forearm fracture (n = 28) using dual energy x-ray absorptiometry (DXA) and high resolution peripheral quantitative computed tomography (HR-pQCT). Compared to those without fracture, women with patella fracture had 6.5% lower areal BMD (aBMD) by DXA only at the total hip (P=.007), while women with forearm fracture had lower aBMD at multiple sites and lower trabecular bone score (TBS), adjusted for age, body mass index (BMI), race and ethnicity (all P<.05). By HR-pQCT, adjusted radial total and trabecular (Tb) volumetric BMD (vBMD) and Tb number were 10-24% lower while Tb spacing was 12-23% higher (all P<.05) in the fracture groups versus women without fracture. Women with a forearm, but not a patella, fracture also had lower adjusted radial cortical (Ct) area and vBMD and 21.8% (P<.0001) lower stiffness vs. women without fracture. At the tibia, the fracture groups had 9.3-15.7% lower total and Tb vBMD (all P<.05) compared to the non-fracture group. Women with a forearm fracture also had 10.9, and 14.7% lower tibial Ct area and thickness versus those without fracture. Compared to women without fracture, tibial stiffness was 9.9 and 12% lower in the patella and forearm fracture groups, respectively (all P<.05). By HR-pQCT, the patella vs. forearm fracture group had 36% higher radial Tb heterogeneity (P<.05). In summary, women with patella fracture had Tb deterioration by HR-pQCT associated with lower tibial mechanical competence that was similar to those with fragility forearm fracture, a more universally accepted \"osteoporotic\" fracture. These data suggest patella fractures are associated with skeletal fragility and warrant skeletal evaluation.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142386745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maternal loss of 24-hydroxylase causes increased intestinal calcium absorption and hypercalcemia during pregnancy but reduced skeletal resorption during lactation in mice.","authors":"Alexandre S Maekawa, David Bennin, Sarah A Hartery, Beth J Kirby, Ingrid J Poulton, René St-Arnaud, Natalie A Sims, Christopher S Kovacs","doi":"10.1093/jbmr/zjae166","DOIUrl":"https://doi.org/10.1093/jbmr/zjae166","url":null,"abstract":"<p><p>Inactivation of 24-hydroxylase (CYP24A1) causes mild hypercalcemia in humans that becomes severe and life-threatening during pregnancy through unclear mechanisms. We studied Cyp24a1 null mice during pregnancy, lactation, and post-weaning. We hypothesized that Cyp24a1 nulls have a much greater increase in calcitriol during pregnancy and lactation, leading to markedly increased intestinal calcium absorption and reduced lactational bone loss. WT and Cyp24a1 null sisters were mated to Cyp24a1+/- males. Timepoints included baseline (BL), late pregnancy (LP), mid-lactation (ML), late lactation (LL), and weekly x4 weeks of post-weaning recovery (R1-4). Assessments included intestinal calcium absorption (IntCaAbs) by gavage of 45Ca, bone mineral content (BMC) by DXA, microCT of femurs, 3-point bending tests of tibias, serum hormones, serum and urine minerals, milk analysis, and intestinal gene expression. At LP, whole body BMC increased equally by ~12% in null and WT. Calcitriol was 2.5-fold higher in nulls vs WT, accompanied by 3-fold increased IntCaAbs, hypercalcemia, hypercalciuria, and 6.5-fold higher FGF23. PTH was suppressed in both. Twenty percent of null dams died during delivery but their serum calcium at LP did not differ from Cyp24a1 nulls that survived. At ML, calcitriol, IntCaAbs, and FGF23 declined in both genotypes but remained higher than BL values in Cyp24a1 nulls. By LL, nulls were still hypercalcemic vs WT, and had lost less mean whole body BMC (11% vs. 21%, P<.02), but by micro-CT there were no differences from WT in cortical or trabecular bone mass. Lactational losses in BMC, cortical thickness, and trabecular number were restored by R4 in both genotypes. In summary, ablation of Cyp24a1 increased IntCaAbs and caused hypercalcemia during pregnancy and lactation, late gestational mortality in some nulls, and reduced lactational BMC loss. Treating women with gestational hypercalcemia from CYP24A1 mutations should focus on reducing calcitriol or IntCaAbs, since increased bone resorption is not the cause.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142386744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Quantification of Bone Mineral Density Using Photon Counting Computed Tomography and its Implications for Detecting Bone Remodelling.","authors":"Jilmen Quintiens, Walter Coudyzer, Melissa Bevers, Evie Vereecke, Joop P van den Bergh, Sarah L Manske, G Harry van Lenthe","doi":"10.1093/jbmr/zjae163","DOIUrl":"https://doi.org/10.1093/jbmr/zjae163","url":null,"abstract":"<p><p>High-Resolution peripheral quantitative CT (HR-pQCT) has become standard practice when quantifying volumetric bone mineral density (vBMD) in vivo. Yet, it is only accessible to peripheral sites, with small fields of view and lengthy scanning times. This limits general applicability in clinical workflows. The goal of this study was to assess the potential of Photon Counting CT (PCCT) in quantitative bone imaging. Using the European Forearm Phantom, PCCT was calibrated to hydroxy-apatite (HA) density. Eight cadaveric forearms were scanned twice with PCCT, and once with HR-pQCT. The dominant forearm of two volunteers was scanned twice with PCCT. In each scan the carpals were delineated. At bone-level, accuracy was assessed with a paired measurement of total vBMD (Tt.vBMD) calculated with PCCT and HR-pQCT. At voxel-level, repeatability was assessed by image registration and voxel-wise subtraction of the ex vivo PCCT scans. In an ideal scenario, this difference would be zero; any deviation was interpreted as falsely detected remodelling. For clinical usage, the least detectable remodelling was determined by finding a threshold in the PCCT difference image that resulted in a classification of bone formation and resorption below acceptable noise levels (<0.5%). The paired measurement of Tt.vBMD had a Pearson correlation of 0.986. Compared to HR-pQCT, PCCT showed a bias of 7.46 mgHA/cm3. At voxel-level, the repeated PCCT scans showed a bias of 17.66 mgHA/cm3 and standard error of 96.23 mgHA/cm3. Least detectable remodelling was found to be 250 mgHA/cm3, for which 0.37% of the voxels was incorrectly classified as newly added or resorbed bone. In vivo, this volume increased to 0.97%. Based on the cadaver data we conclude that PCCT can be used to quantify vBMD and bone turnover. We provided proof of principle that this technique is also accurate in vivo, hence, that it has high potential for clinical applications.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"24-Hour Activity Composition is Associated with Lower Fall and Fracture Risk in Older Men.","authors":"Lauren S Roe, Elsa S Strotmeyer, Peggy M Cawthon, Nancy W Glynn, Yan Ma, Sonia Ancoli-Israel, Kristine Ensrud, Susan Redline, Katie L Stone, Kelley Pettee Gabriel, Jane A Cauley","doi":"10.1093/jbmr/zjae160","DOIUrl":"https://doi.org/10.1093/jbmr/zjae160","url":null,"abstract":"<p><p>Physical activity (PA), sedentary behavior (SB), and sleep are each individually associated with falls and fractures, but often are not examined simultaneously. Compositional data analysis examined the combined prospective associations between the proportion of time in PA, SB, and sleep relative to the remaining behaviors with recurrent falls (2+ falls in any year), any fractures, and major osteoporotic fracture (MOF) from tri-annual questionnaires, with adjudication for fractures, in 2918 older men aged 78.9 ± 5.1 years in the Osteoporotic Fractures in Men (MrOS) Study. Accelerometers were worn on the right tricep for seven consecutive 24-hour periods and measured PA (>1.5 METs), SB (≤1.5 METs), and sleep. Generalized Estimating Equations evaluated associations with recurrent falls. Cox proportional hazards regression estimated any incident fracture and MOF risk separately. Over four years of follow-up 1025 (35.2%) experienced recurrent falls; over 10 ± 4 years of follow-up, 669 (22.9%) experienced incident fractures and 370 (12.7%) experienced a MOF. Higher proportions of PA relative to SB and sleep were associated with a lower odds of recurrent falls [Odds Ratio (OR): 0.87, 95% CI: 0.76-0.99]. Higher proportions of SB relative to PA and sleep were associated with a higher odds of recurrent falls (OR: 1.38, 95% CI: 1.06-1.81) and higher risk of any fracture [Hazard Ratio (HR): 1.42, 95% CI: 1.05-1.92]. Higher proportions of sleep relative to PA and SB were associated with a lower risk of fracture (HR: 0.74, 95% CI: 0.54-0.99). No associations of activity composition with MOF were observed. When accounting for the co-dependence of daily activities, higher proportions of SB relative to the proportion of PA and sleep were associated with higher odds of recurrent falls and fracture risk. Results suggest reducing SB (and increasing PA) may lower fall and fracture risk in older men, which could inform future interventions.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Atypical fractures at non-classical sites associated with anti-resorptive therapy: A Systematic Review.","authors":"Lucy Collins, Alec Ronan, Evelyn Hutcheon, Peter R Ebeling, Vivian Grill, Hanh H Nguyen","doi":"10.1093/jbmr/zjae159","DOIUrl":"https://doi.org/10.1093/jbmr/zjae159","url":null,"abstract":"<p><strong>Background: </strong>Osteoporosis is common, affecting more than 20% of women and 6% of men globally over the age of 50 (1). Anti-resorptive drugs, bisphosphonates and denosumab, have been effective treatments for osteoporosis for more than 30 years. Rare complications of anti-resorptive therapy include medication-related osteonecrosis of the jaw and atypical femur fractures (AFF). The American Society for Bone and Mineral Research (ASBMR) proposed a case definition for these atypical femoral fractures in 2010, which was updated in 2013. However, atypical fractures at non-classical sites have been increasingly described.</p><p><strong>Aims: </strong>We aimed to systematically identify atypical fracture cases, excluded from the ASBMR AFF case definition in patients receiving anti-resorptive medication for longer than three years.</p><p><strong>Methods: </strong>A structured search of electronic databases, including PubMed, Medline (Ovid), Embase (Ovid), Cochrane and Web of Sciences, and hand-searching of conference abstracts was undertaken. All full-text articles written in English describing an atypical fracture in patients (aged >18 years) and receiving anti-resorptive medication for >3 years were included, with data extracted and analysed by two independent reviewers.</p><p><strong>Results: </strong>Sixty-six articles were identified, describing 151 cases of atypical fractures in 114 individuals. The most frequent fracture site was the ulna, followed by the tibia. All patients were taking anti-resorptive treatment prior to or at the time of fracture, most frequently alendronate monotherapy (44%). Most commonly, fractures were transverse in nature (95%), following minimal or no trauma (96%), non-comminuted (98%) with cortical thickening of the surrounding bone (69%). Anti-resorptive treatment was ceased following atypical fracture in the majority (89%).</p><p><strong>Conclusions: </strong>Atypical fractures are rare and should not deter physicians from appropriate anti-resorptive therapy for osteoporosis. However, clinicians should be alert to their presence, at additional sites to the femur. An update of the current ASBMR AFF case definition to include other skeletal sites could be timely.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epidural Steroid Injections and Fracture Incidence Among Older Individuals with Radiculopathy.","authors":"Huifeng Yun, Ye Liu, Jeffrey R Curtis, Kenneth Saag, Gia D'Erasmo, Katherine Haseltine, Emily M Stein","doi":"10.1093/jbmr/zjae162","DOIUrl":"https://doi.org/10.1093/jbmr/zjae162","url":null,"abstract":"<p><p>Epidural steroid injections (ESIs) are a common and often effective treatment for radicular back pain. While oral glucocorticoids increase fracture incidence, little is known regarding fracture risk after ESI. This study investigated the incidence of fractures among individuals who received ESI and those who did not. We hypothesized that ESI exposure would be associated with an increased incidence of osteoporotic fracture and specifically vertebral fractures. Using 2005-2018 5% Medicare data, individuals with radicular pain who had ≥1 ESI and those who did not (non-ESI) were matched 1:10 by age, sex, and month of radicular pain diagnosis using exposure density sampling (EDS). Using a high-dimensional propensity score (HDPS) calculated based on the top 500 covariates across multiple data dimensions, ESI and non-ESI individuals were matched 1:1. Fractures were identified using validated ICD-9/10 diagnosis codes. Fracture incidence rate (IR) was calculated by group, and hazard ratios (HR) compared using Cox regression. 25 062 ESI patients and 221 735 non-ESI patients who met eligibility criteria were identified using EDS. Mean age was 76 years (74% female). Among ESI-treated individuals, there were 2296 fractures, IR 49.1 (95% CI: 47.2-51.2) per 1000 person years. For non-ESI individuals, there were 11 917 fractures, IR 35.2 (95% CI: 34.5-35.8). Individuals who received ESI had a greater hazard of fracture at typical osteoporotic sites, HR 1.39 (95% CI 1.33-1.46) by EDS and 1.32 (1.12-1.54) by HDPS, and greater hazard of vertebral fracture, 1.54 (1.45-1.64) by EDS and 1.69 (1.38-2.07) by HDPS. Patients who received greater cumulative ESI doses (≥3 in 1 year) had a higher risk of fractures within the first six months of follow-up. ESI exposure in older individuals is associated with an increased risk of fracture, suggesting there may be lasting detrimental skeletal effects of ESI. Further research into strategies to reduce fracture risk in this population is warranted.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety, pharmacokinetics, and pharmacodynamics of efzimfotase alfa, a second-generation enzyme replacement therapy: phase 1, dose-escalation study in adults with hypophosphatasia.","authors":"Kathryn M Dahir, Amy Shannon, Derek Dunn, Walter Voegtli, Qunming Dong, Jawad Hasan, Rajendra Pradhan, Ryan Pelto, Wei-Jian Pan","doi":"10.1093/jbmr/zjae128","DOIUrl":"10.1093/jbmr/zjae128","url":null,"abstract":"<p><p>Hypophosphatasia (HPP) is a rare, inherited metabolic disease caused by deficient activity of tissue-nonspecific alkaline phosphatase (TNSALP). Efzimfotase alfa (ALXN1850) is a second-generation TNSALP enzyme replacement therapy in development for HPP. This first-in-human open-label, dose-escalating phase 1 trial evaluated efzimfotase alfa safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity. Fifteen adults (5/cohort) with HPP received efzimfotase alfa in doses of 15 mg (cohort 1), 45 mg (cohort 2), or 90 mg (cohort 3) as one intravenous (i.v.) dose followed by 3 weekly subcutaneous (s.c.) doses. The primary objective was to assess safety and tolerability. Secondary objectives included pharmacokinetics, pharmacodynamics of ALP substrates known to be biomarkers of disease (inorganic pyrophosphate [PPi] and pyridoxal 5'-phosphate [PLP]) and immunogenicity. Treatment-emergent adverse events (TEAEs) occurred in 12 (80%) participants. Eight (53%) participants had injection site reactions (ISRs), observed after 10 of 41 (24%) s.c. injections. Most ISR TEAEs were mild and resolved within 1-2 d. Peak and total exposures of efzimfotase alfa increased in a greater-than-dose proportional manner over the range of 15-90 mg after i.v. and s.c. dosing. The arithmetic mean elimination half-life was approximately 6 d; absolute bioavailability was 28.6%-36.8% over the s.c. dose range of 15-90 mg. Dose-dependent reductions in plasma concentrations of PPi and PLP relative to baseline reached nadir in the first week after i.v. dosing and were sustained for 3-4 wk after the last s.c. dose. Four (27%) participants tested positive for antidrug antibodies (ADAs), 3 of whom were ADA positive before the first dose of efzimfotase alfa. ADAs had no apparent effect on efzimfotase alfa pharmacokinetics/pharmacodynamics. No participants had neutralizing antibodies. Efzimfotase alfa demonstrated acceptable safety, tolerability, and pharmacokinetic profiles and was associated with sustained reductions in biomarkers of disease in adults with HPP, supporting further evaluation in adult and pediatric patients. Registration: ClinicalTrials.gov NCT04980248 (https://clinicaltrials.gov/study/NCT04980248).</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"1412-1423"},"PeriodicalIF":5.1,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11425692/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}