Journal of Bone and Mineral Research最新文献

{"title":"Non-invasive quantification of bone (re) modeling dynamics in adults with osteogenesis imperfecta treated with Setrusumab using timelapse HR-pQCT.","authors":"Seyedmahdi Hosseinitabatabaei, Isabela Vitienes, Maximillian Rummler, Annette Birkhold, Frank Rauch, Bettina M Willie","doi":"10.1093/jbmr/zjaf013","DOIUrl":"https://doi.org/10.1093/jbmr/zjaf013","url":null,"abstract":"<p><p>Timelapse imaging using high-resolution peripheral quantitative computed tomography (HR-pQCT) has emerged as a noninvasive method to quantify bone (re)modelling. However, there is no consensus on how to perform the procedure. As part of the ASTEROID phase-2b multicenter trial, we used 29 same-day repeated scans from adults with osteogenesis imperfecta (OI) to identify a method that minimized measurement error. We evaluated input image type, registration method, segmentation mask, and for grayscale images various values for the voxel density difference considered formed or resorbed, minimum formation/resorption cluster size, and Gaussian smoothing sigma. We verified the accuracy of our method and then used it on longitudinal scans (baseline, 6, 12, 18 and 24 month) from 78 participants to assess bone formation and resorption induced by an anabolic (setrusumab) and anti-catabolic (zoledronic acid) treatments as part of the ASTEROID trial. Regardless of image registration method, binary input images resulted in large errors ~13% and ~ 8% for first- and second-generation scanners, respectively. For the grayscale input images, errors were smaller for 3D compared to matched angle registration. For both scanner generations, a density threshold of 200mgHA/cm3 combined with Gaussian noise reduction resulted in errors <1%. We verified the method was accurate by showing that similar regions of bone formation and resorption were identified when comparing each scan from the same-day repeated scans with a scan from another timepoint. Timelapse analysis revealed a dose-dependent increase in bone formation and resorption with setrusumab treatment. Zoledronic acid altered bone changes in favor of formation, although no changes reached statistical significance. This study identifies a timelapse method that minimizes measurement error, which can be used in future studies to improve the uniformity of results. This noninvasive imaging biomarker revealed dose dependent bone (re) modeling outcomes from one year of setrusumab treatment in adults with OI.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143027702","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":"Assessing the Effects of Immune Checkpoint Inhibitors on Bone Utilizing Machine Learning-assisted Opportunistic Quantitative Computed Tomography.","authors":"Bryn E Matheson, Jacob L Jaremko, Alexandra Dowhanik, Jasmine Gill, Cassandra Gallant, John Walker, Nathan Armani, William D Leslie, Michael Kolinsky, Steven K Boyd, Carrie Ye","doi":"10.1093/jbmr/zjaf009","DOIUrl":"https://doi.org/10.1093/jbmr/zjaf009","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICI) are widely used in cancer treatment, yet their impact on bone health remains unclear. This study aimed to perform a retrospective cohort study utilizing routine computed tomography (CT) scans from patients with melanoma to perform opportunistic quantitative CT (QCT) analysis to investigate the effects of ICI treatment on skeletal health, including volumetric bone mineral density (vBMD) measurements and osteoarthritis (OA) parameters. A previously established machine-learning assisted opportunistic QCT pipeline was used to estimate lumbar spine vBMD from baseline and 12-month follow-up CT scans in patients with melanoma treated with ICI therapy and those not treated with ICI therapy. Facet joint OA, osteophyte formation and endplate sclerosis was also graded. Independent and paired t tests were used to determine any differences in vBMD and OA parameters between ICI users and non-ICI users. Multivariable linear regression models were used to control for confounding variables. Non-ICI users had a significant decrease in vBMD of -6.96 mg/cm3 from baseline to follow-up, whereas the ICI users had no significant change. There was a significant difference in change in vBMD from baseline to follow-up between the two groups, with the non-ICI users experiencing a 11.22 mg/cm3 larger decrease in vBMD. After adjusting for baseline age, sex, baseline vBMD and change in OA parameters, this difference remained significant at -13.04 mg/cm3. Among the ICI users, those who had a decline in vBMD had a lower baseline vBMD compared to those who increased vBMD. Neither group showed a significant change in OA parameters over the follow-up period, nor a difference in change between ICI and non-ICI users, even after adjusting for sex, age and baseline OA parameters. While the effects of ICI treatment on vBMD may vary based on baseline bone health, ICIs do not significantly impact OA parameters in the short term.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143027701","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":"Mechanisms to explain the overshoot in bone remodeling markers after denosumab discontinuation: Are we there yet?","authors":"Sabashini K Ramchand, Michelle M McDonald","doi":"10.1093/jbmr/zjaf007","DOIUrl":"https://doi.org/10.1093/jbmr/zjaf007","url":null,"abstract":"","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021372","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":"Early and multiple doses of zoledronate mitigates rebound bone loss following withdrawal of RANKL inhibition.","authors":"Albert S Kim, Victoria E Taylor, Ariel Castro-Martinez, Suraj Dhakal, Amjad Zamerli, Sindhu T Mohanty, Ya Xiao, Marija K Simic, Alyssa Pantalone, Julian Chu, Tegan L Cheng, Peter I Croucher, Jacqueline R Center, Christian M Girgis, Michelle M McDonald","doi":"10.1093/jbmr/zjaf008","DOIUrl":"https://doi.org/10.1093/jbmr/zjaf008","url":null,"abstract":"<p><p>Rebound bone loss following denosumab discontinuation is an important barrier in the effective long-term treatment of skeletal disorders. This is driven by increased osteoclastic bone resorption following the offset of RANKL inhibition, and sequential osteoclast-directed therapy has been utilised to mitigate this. However, current sequential treatment strategies intervene following the offset of RANKL inhibition and this approach fails to consistently prevent bone loss. Our previous work, using a mouse model of denosumab discontinuation, has shown that the processes that drive the rebound phenomenon occur earlier than when bone loss is detected, namely a rise and overshoot in serum TRAP. We identified that these changes in serum TRAP may provide an earlier window of opportunity to intervene with sequential therapy following RANKL inhibition withdrawal. Here, we show that early treatment with zoledronate (10 mg/kg, 3 weeks following the last dose of OPG:Fc), preceding the rise and overshoot in serum TRAP, effectively mitigates rebound bone density loss through preventing the overshoot in serum TRAP. Further, we show that multiple doses of zoledronate (early treatment and during anticipated BMD loss) is superior in consolidating bone density gains made with RANKL inhibition and preventing rebound BMD loss as measured by DXA. Importantly, we demonstrate the efficacy of early and multi-dose zoledronate strategy in preventing bone loss in both growing and skeletally mature mice. MicroCT analysis showed improved trabecular bone structure in both the femur and lumbar vertebrae with zoledronate treatment compared to control. These increases in bone mass translated to increased fracture resistance in skeletally mature mice. This work provides a novel approach of early and multi-dose sequential treatment strategy following withdrawal of RANKL inhibition, contributing valuable insight into the clinical management of patients who discontinue denosumab therapy.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021369","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":"Preterm birth and risk of bone fractures during childhood and early adulthood.","authors":"Suvi Alenius, Maija E Miettinen, Markku Nurhonen, Samuli Salmi, Pieta Näsänen-Gilmore, Peija Haaramo, Marjaana Tikanmäki, Marja Vääräsmäki, Mika Gissler, Outi Mäkitie, Petteri Hovi, Eero Kajantie","doi":"10.1093/jbmr/zjaf011","DOIUrl":"https://doi.org/10.1093/jbmr/zjaf011","url":null,"abstract":"<p><p>People born preterm have reduced bone mineral density, subnormal peak bone mass, and an increased risk of osteoporosis. Whether this translates to increased risk of bone fractures is uncertain. We assessed fracture risk from childhood to early adulthood in relation to gestational age and sex by conducting a nationwide register-linkage cohort study comprising all 223 615 liveborn (1/1987- 9/1990) singletons (9161, 4.1%, preterm) in Finland. Cox regression models provided hazard ratios (HR) for fracture diagnosis in public specialty healthcare in both first and recurrent event settings during the whole follow-up (0-29 yr), and during different age periods (0-4/5-9/10-29 yr). Gestational age was considered categorical (full-term, 39-41 weeks, reference). A total of 39 223 (17.5%) children or young adults had at least one fracture. In analyses not stratified by sex, only extremely preterm birth (<28 completed weeks' gestation) was associated with risk of bone fracture at 0-29 yr; adjusted HR (aHR) 0.46 (95% CI 0.28-0.74) compared with those born full-term. Among females, gestational age was unrelated to fracture risk at 0-29 yr. Among males, extremely and very preterm (28-31 weeks) birth was associated with lower risk of fracture at 0-29 yr compared with those born full-term: aHR 0.38 (CI 0.21-0.71) and 0.75 (CI 0.59-0.95) respectively. Restricting the analyses to the individuals without severe medical condition(s) attenuated the associations. However, the fracture risk varied according age and sex: at 10-29 yr moderately preterm (32-33wk) females, and extremely- and very preterm males had a lower risk: aHR 0.63 (0.43-0.94), 0.35 (0.17-0.69), and 0.74 (0.57-0.95) respectively, while late preterm birth (34-36wk) was associated to 1.6-fold higher risk among females at 0-5 yr, and 1.4-fold risk among males at 5-10 yr. Analyses on recurrent fractures showed similar pattern. Children and young adults, in particular males, born extremely or very preterm may have less bone fractures, this is partly explained by severe medical conditions in this group.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021385","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":"Comparative cardiovascular safety of romosozumab versus bisphosphonates in Japanese patients with osteoporosis: a new-user, active comparator design with instrumental variable analyses.","authors":"Ryoji Tominaga, Tatsuyoshi Ikenoue, Ryosuke Ishii, Kakuya Niihata, Tetsuro Aita, Tadahisa Okuda, Sayaka Shimizu, Masataka Taguri, Noriaki Kurita","doi":"10.1093/jbmr/zjaf010","DOIUrl":"https://doi.org/10.1093/jbmr/zjaf010","url":null,"abstract":"<p><p>This study analyzed the association of romosozumab, a human monoclonal antibody with bone-forming and bone resorption-inhibiting effects, and bisphosphonates with the development of cardiovascular disease among patients with osteoporosis. A new-user design was employed to address selection bias, and instrumental variable analysis was used to address confounding by indication. Japanese patients aged ≥40 years, diagnosed with osteoporosis or experienced a fragility fracture, were admitted to medical facilities covered by a commercial administrative claims database, and newly prescribed romosozumab or bisphosphonates after the commercialization of romosozumab in Japan (March 4, 2019) were included based on verification of a 180-day washout period. Cardiovascular disease (myocardial infarction or stroke) was identified based on information regarding diagnosis, medical procedures, and drug codes. Facility-level prescription preference for romosozumab was used as an instrumental variable, defined as the proportion of romosozumab prescribed at the patient's facility within 90 days prior to the index date. Of the 59 694 included prescriptions, 8808 were for romosozumab and 50 886 were for bisphosphonates. The mean age in the romosozumab group was higher than that in the bisphosphonates group (80.5 vs. 78.2 years, respectively), and most patients were females (85.3 vs. 80.2%, respectively). The incidence of cardiovascular disease within 1 year of prescription was 12.3 per 100 person-years for romosozumab versus 11.4 for bisphosphonates (unadjusted incidence rate ratio: 1.08, 95% confidence interval: 1.00-1.18). An instrumental variable analysis using the two-stage residual inclusion method yielded a hazard ratio of 1.30 (95% confidence interval: 0.88-1.90) for romosozumab compared with bisphosphonates over 1 year. Although possibly underpowered, this study showed that no definitive evidence of increased cardiovascular risk associated with romosozumab use compared with bisphosphonates was observed in patients with osteoporosis. These findings should be further validated by larger pharmacoepidemiological studies to alleviate clinicians' concerns about romosozumab's safety.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996720","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":"Time-lapse HR-pQCT reliably assesses and monitors local bone turnover in patients with chronic kidney disease.","authors":"Minhao Zhou, Saghi Sadoughi, Lauren Go, Gabriella Ramil, Isabel Yu, Isra Saeed, Bo Fan, Po-Hung Wu, Isidro B Salusky, Thomas L Nickolas, Joachim H Ix, Galateia J Kazakia","doi":"10.1093/jbmr/zjaf006","DOIUrl":"https://doi.org/10.1093/jbmr/zjaf006","url":null,"abstract":"<p><p>Bone turnover assessment and monitoring are essential for chronic kidney disease (CKD)-associated bone care. Patients with CKD suffer from significantly elevated fracture risk due to abnormally high or low bone turnover, which requires diametrically opposite treatments informed by patient-specific bone turnover data. However, a reliable, accessible, non-invasive bone turnover assessment and monitoring tool remains an unmet clinical need. Combining time-lapse (TL) analysis with high-resolution peripheral quantitative computed tomography (HR-pQCT) scans obtained over time allows for in vivo temporospatial bone remodeling assessment. This study aimed to evaluate the feasibility of applying TL HR-pQCT to assess and monitor local bone formation and resorption in patients with CKD. A customized TL HR-pQCT pipeline was developed on a second-generation HR-pQCT platform and optimized using ex vivo cadaveric phantom and in vivo scan-rescan HR-pQCT images. The annualized least significant change in bone formation and resorption were evaluated using in vivo longitudinal reproducibility images. Finally, the feasibility of the TL HR-pQCT pipeline in assessing and monitoring bone turnover was evaluated in patients with end stage kidney disease (ESKD; n = 9). We found that a 2-month time-lapse period was sufficient for the TL HR-pQCT pipeline to reliably assess and monitor local bone turnover in a cohort of patients with ESKD. We also demonstrated the importance of characterizing TL HR-pQCT precision metrics using longitudinal baseline/follow-up rather than short-term scan-rescan datasets. The TL HR-pQCT pipeline assessed a range of bone formation metrics consistent with the gold standard histomorphometric bone formation reported in the literature for patients with CKD and ESKD. Our findings highlight that TL HR-pQCT holds promise as a \"virtual bone biopsy\" that reliably assesses and monitors local bone turnover for CKD bone care. Subsequent work will focus on validating this TL HR-pQCT pipeline against the gold standard bone biopsy with quantitative histomorphometry.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982050","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":"Proteins and pathways involved in inflammation are longitudinally associated with total body bone mineral density among primarily hispanic overweight/obese adolescents and young adults.","authors":"Emily Beglarian, Jiawen Carmen Chen, Zhenjiang Li, Elizabeth Costello, Hongxu Wang, Hailey Hampson, Tanya L Alderete, Zhanghua Chen, Damaskini Valvi, Sarah Rock, Wu Chen, Nahid Rianon, Max T Aung, Frank D Gilliland, Michael I Goran, Rob McConnell, Sandrah P Eckel, Miryoung Lee, David V Conti, Jesse A Goodrich, Lida Chatzi","doi":"10.1093/jbmr/zjaf002","DOIUrl":"https://doi.org/10.1093/jbmr/zjaf002","url":null,"abstract":"<p><p>Bone mineral density (BMD), an important marker of bone health, is regulated by a complex interaction of proteins. Plasma proteomic analyses can contribute to identification of proteins associated with changes in BMD. This may be especially informative in stages of bone accrual and peak BMD achievement (i.e., adolescence and young adulthood), but existing research has focused on older adults. This analysis in the Study of Latino Adolescents at Risk for Type 2 Diabetes (SOLAR; n = 304; baseline age 8-13, 100% Hispanic) explored associations between baseline proteins (n = 653 proteins) measured with Olink® plasma protein profiling and repeated annual DXA measures of BMD (average of 3.2 visits per participant). Covariate-adjusted linear mixed effect regression models were applied to estimate longitudinal protein-BMD associations using an adjusted p-value cutoff (P < 0.00068). Identified proteins were imported into the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database to determine significantly enriched protein pathways. Forty-four proteins, many of which are involved in inflammatory processes, were associated with longitudinal changes in total body BMD, including several proteins previously linked to bone health such as osteopontin (SPP1) and microfibrillar-associated protein 5 (MFAP5; both P < 0.00068). These 44 proteins were associated with enrichment of pathways including PI3K-Akt Signaling Pathway and Cytokine-Cytokine Receptor Interaction, supporting results from existing proteomics analyses in older adults. To evaluate whether protein associations were consistent into young adulthood, linear mixed effect models were repeated in a young adult cohort (n = 169; baseline age 17-22; 62.1% Hispanic) with 346 available overlapping Olink® protein measures. While there were no significant overlapping longitudinal protein associations between the cohorts, these findings suggest differences in protein regulation at different ages and provide novel insight on longitudinal protein associations with BMD in overweight/obese adolescents and young adults of primarily Hispanic origin, which may inform the development of biomarkers for bone health in youth.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982045","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 effect of calcium supplementation on bone calcium balance and calcium and bone metabolism during load carriage in women: a randomised controlled crossover trial.","authors":"Charlotte V Coombs, Julie P Greeves, Christina D Young, Alice S Irving, Anton Eisenhauer, Ana Kolevica, Alexander Heuser, Jonathan C Y Tang, William D Fraser, Thomas J O'Leary","doi":"10.1093/jbmr/zjaf004","DOIUrl":"https://doi.org/10.1093/jbmr/zjaf004","url":null,"abstract":"<p><p>Calcium supplementation before exercise attenuates the decrease in serum calcium and increase in PTH and bone resorption. This study investigated the effect of calcium supplementation on calcium and bone metabolism during load carriage in women. Forty-eight women completed two load carriage sessions (load carriage 1 n = 48; load carriage 2 n = 40) (12.8 km in 120 min carrying 20 kg) 60 min after consuming either 1000 mg calcium (Calcium) or nothing (Control) in a randomised order. Pre- and post-exercise urine samples were analysed for calcium isotope ratio (δ44/42Ca). Fasted blood samples were taken before (pre-exercise), during (0, 20, 40, 60, 80, 100, 120 min), and after (+15, +30, +60, +90 min) exercise and analysed for markers of calcium and bone metabolism. There was no effect of load carriage or supplementation on urine δ44/42Ca (P≥.110). Serum δ44/42Ca did not change with load carriage in Control (P=.617) but increased in Calcium (P=.003) and was higher at 120 min in Calcium vs Control (P=.018). Ionised calcium (iCa) decreased from pre-exercise to all exercise time-points (P<.001); iCa was higher in Calcium than Control throughout (P<.001). PTH increased from pre-exercise to 120 min in Control (P<.001) but decreased from pre-exercise to all time-points in Calcium (P<.001). PTH was higher in Control than Calcium from 0 to +90 min (P<.001). βCTX decreased from pre-exercise to 20 to +15 min in Control (P≤.004); βCTX decreased from pre-exercise to 0 to +90 min in Calcium (P<.001). βCTX was lower in Calcium than Control from 20 to +90 min (P≤.036). A 1000 mg calcium supplement before load carriage promotes bone calcium balance and prevents disruptions to bone and calcium homeostasis.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969024","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":"Preclinical evaluation of the efficacy and safety of AAV8-TNAP-D10 in Alpl-/- and AlplPrx1/Prx1 mouse models for the treatment of early and late-onset hypophosphatasia.","authors":"Flavia Amadeu de Oliveira, Cintia Kazuko Tokuhara, Fatma F Mohamed, Sonoko Narisawa, Elis J Lira Dos Santos, Natalie L Andras, Mohammad Shadid, Koichi Miyake, Brian L Foster, José Luis Millán","doi":"10.1093/jbmr/zjaf005","DOIUrl":"https://doi.org/10.1093/jbmr/zjaf005","url":null,"abstract":"<p><p>We previously documented successful resolution of skeletal and dental disease in the infantile and late-onset murine models of hypophosphatasia (HPP), with a single injection of an adeno-associated serotype 8 vector encoding mineral-targeted TNAP (AAV8-TNAP-D10). Here, we conducted dosing studies in both HPP mouse models. A single escalating dose from 4x108 up to 4x1010 (vg/b) was intramuscularly injected into 4-day-old Alpl-/- mice (an infantile HPP model) and a single dose from 4x106 up to 4x109 (vg/b) was administered to 8-week-old AlplPrx1/Prx1 mice (a late-onset HPP model). Wild-type littermates were used as controls. Serum alkaline phosphatase activity was increased, and PPi levels were decreased in a dose-dependent manner in both the Alpl-/- and AlplPrx1/Prx1 models. Radiographic and μCT analysis of long bones of female and male Alpl-/- mice showed full correction of skeletal phenotype at 4x1010 vg/b. We observed full correction of the bone phenotype at 4x108 and 4x109 in female AlplPrx1/Prx1 mice, but bones remained hypomineralized with the 4x106 and 4x107 (vg/b) doses after 70 days of treatment. We observed skeletal improvements using the 4x109 (vg/b) dose, but the phenotype was not fully corrected in male AlplPrx1/Prx1. Immunohistochemistry using anti-TNAP and anti-D10 antibodies showed high immunolocalization in the femurs of female AlplPrx1/Prx1 mice, while D10 immunolocalization was high in the liver of male AlplPrx1/Prx1 mice at a dose of 4x109 (vg/b). This sex-dependent difference was not seen in the infantile HPP model. A serum proteome analysis showed enhanced inflammatory pathways in treated AlplPrx1/Prx1 males compared to treated female mice. We also found a few areas of ectopic calcification in soft organs at the highest tested dose of 4x1010 (vg/b) in Alpl-/- or 4x109 (vg/b) in the AlplPrx1/Prx1 model. This pre-clinical study will inform the design of clinical trials to develop gene therapy in early-onset and late-onset HPP patients.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969023","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}