JBMR Plus最新文献

{"title":"Obese-diabetic female <i>Ksr2</i> knockout mice develop brittle bones near end of life.","authors":"Gustavo A Gomez, Sasidhar Uppuganti, Sheila Pourteymoor, Jillian Bray, Jeffry S Nyman, Subburaman Mohan","doi":"10.1093/jbmrpl/ziaf052","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziaf052","url":null,"abstract":"<p><p>The influence of obesity and type 2 diabetes (T2D) on the skeleton is complex, with affected individuals having higher fracture risk despite having higher BMD. To evaluate how obesity and T2D affect skeletal health, we studied mice with disruption of a gene that regulates energy intake and expenditure, <i>Ksr2</i>, which results in reduced metabolic rate and severe insulin resistance in both mice and a subpopulation of humans. Relative to 28-wk-old littermate sibling controls, <i>Ksr2</i> mutants weighed more than double the body and fat weight. Moreover, leptin and insulin were elevated by 20- and 10-fold in <i>Ksr2</i> mutant serum, consistent with prior reports of a T2D state. Micro-computed tomography analysis revealed increased trabecular bone volume (BV) per total volume (TV) in the mutant's distal femur, proximal tibia, and vertebrae. While the bone size (cortical (Ct) cross-sectional bone area) was increased by 7%-11% at the mid-diaphysis of femurs and tibiae, Ct BV adjusted for TV was unaffected. Three-point bending tests revealed increased ultimate force to failure and ultimate bending stress at the mid-diaphysis of femurs by 13% and 8%, respectively in <i>Ksr2</i> mutants. However, bone toughness, a measure of bone quality that assesses how well Ct bone resists fracture, was reduced by 25%. To determine the cause of reduced bone quality in <i>Ksr2</i> mutants, we evaluated femurs for bone hydration by nuclear magnetic resonance relaxometry and found reduced pore water (20%) in <i>Ksr2</i> mutant femurs relative to controls. Moreover, analysis of hydrolysates from femurs for advanced glycation end products revealed a 14% increase in <i>Ksr2</i> mutants. Based on our data, we conclude that while bone density and strength are increased in mice with obesity-induced insulin resistance, bone toughness is compromised due to reduced bone tissue quality, thus suggesting therapeutics focused on improving bone tissue are needed to reduce fracture risk in obese patients.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"9 5","pages":"ziaf052"},"PeriodicalIF":3.4,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12035690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calcium isotope ratio in patients with monogenic bone diseases: a prospective, cross-sectional, single-center pilot study.","authors":"Robert Munzinger, Felix N von Brackel, Mikolaj Bartosik, Florian Barvencik, Michael Amling, Ralf Oheim","doi":"10.1093/jbmrpl/ziaf032","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziaf032","url":null,"abstract":"<p><p>Stable calcium isotope fractions have long been related to the calcium metabolism in living organisms. The blood and urine proportions of calcium isotopes ⁴⁴Ca and ⁴²Ca (δ^44/42Ca) have recently again attracted attention as a potential diagnostic tool in metabolic bone diseases, in particular osteoporosis. The hypothesis is that the lighter isotopes (Ca⁴²) get incorporated into bone more quickly; hence, δ^44/42Ca ratios in urine and serum are higher for bone formation and lower for resorption phases. Therefore, δ^44/42Ca in blood and urine may serve as an indicator of bone metabolism, potentially reflecting bone density in general. We have conducted clinical characterization by means of laboratory assessment, bone densitometry, HRpQCT, and isotope analysis to test for the hypothesis in patients with monogenic bone diseases. We included 40 adult subjects with hereditary bone diseases, such as early-onset osteoporosis (<i>n</i> = 7), osteogenesis imperfecta (<i>n</i> = 12), hypophosphatasia (<i>n</i> = 12), and X-linked hypophosphatemia (XLH, <i>n</i> = 9), and controls (<i>n</i> = 17). Regression analyses revealed significant correlations of δ^44/42Ca with Ca/creatinine_urine (<i>R</i> ² = 0.6200, <i>p</i> < .0001), and bone densitometric parameters were significantly correlated with δ^44/42Ca (BMD: δ^44/42Ca_serum  <i>R</i> ² = 0.2685, <i>p</i> ≤ .001; δ^44/42Ca_urine  <i>R</i> ² = 0.3554; <i>p</i> < .0002). XLH differed significantly from the other diseases and controls by means of higher δ^44/42Ca_urine. Our results suggest that δ^44/42Ca is strongly coupled to urinary calcium excretion in patients with hereditary bone diseases. Significant correlations with BMD suggest an interaction of δ^44/42Ca and bone mass though it lacks discriminative power. Further studies are needed to evaluate the utility of δ^44/42Ca in clinical practice.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"9 5","pages":"ziaf032"},"PeriodicalIF":3.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12009546/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fracture risk by cortisol excess status in patients with adrenal incidentalomas: a population-based cohort study.","authors":"Annette L Adams, In-Lu Amy Liu, Iris Anne C Reyes, Hina Chowdhry, Richard Contreras, Yuqian M Gu, Mackenzie Crawford, Bennett McDonald, Joshua I Barzilay, Tish Villanueva, David A Katz, Frank S Czerwiec, Wansu Chen","doi":"10.1093/jbmrpl/ziaf043","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziaf043","url":null,"abstract":"<p><p>Adrenal incidentalomas (AIs) may secrete excess cortisol, representing an elevated endogenous exposure to glucocorticoids, which could decrease bone mineral density and increase fracture risk. However, measurement of cortisol excess is not routinely done in patients with AI; thus, those with hormonally active AI at increased risk for fracture are under-identified. We sought to examine the association between excess cortisol levels and the incidence of fragility fracture in people with AI. This retrospective cohort study, conducted within two Kaiser Permanente regions (Southern California and Georgia), comprised women and men aged ≥50 yr with identified AI in the study period January 1, 2015-August 31, 2022. Patients' cortisol excess status was categorized by the type of test conducted (if any) and the test result. Fractures and relevant covariates were ascertained via International Classification of Diseases (ICD)-9/10 codes. Hazard ratios (HR) were estimated using Cox proportional hazard models with mortality as a competing risk. Among the cohort of 14 886 patients with AI, 273 (1.8%) had autonomous cortisol secretion (ACS) confirmed by dexamethasone suppression test (DST) results >1.8 μg/dL (>50 nmol/L), and another 201 (1.4%), tested with urine free or random cortisol tests, had results suggestive of excess cortisol production. Most of the cohort (<i>n</i> = 9353, 62.8%) were untested around AI diagnosis or during follow-up. Compared to patients with normal DST results (and adjusted for age, sex, race/ethnicity, and several other clinical characteristics), the estimated HR of fracture risk for patients with ACS (HR 1.42, CI 0.86-2.32), evidence of cortisol excess (1.41, 0.85-2.32), and untested patients (1.28, 0.88-1.87) were suggestive of elevated risk. However, none of the elevated hazard rates were statistically significant at the 95% significance level. The apparent elevated risk in the untested patients suggests that many untested patients may have hormonally active AI that puts them at risk for fracture from secondary osteoporosis.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"9 5","pages":"ziaf043"},"PeriodicalIF":3.4,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12036655/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Burosumab treatment of a child with McCune-Albright syndrome/polyostotic fibrous dysplasia: challenges and benefits.","authors":"Sophia D Sakka, Danai Georgakopoulou, Artemis Doulgeraki, Andreas H Krieg, John Anastasopoulos, Gabor Szinnai, Christina Kanaka-Gantenbein","doi":"10.1093/jbmrpl/ziaf042","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziaf042","url":null,"abstract":"<p><p>Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare condition caused by a mutation in the GNAS locus. Apart from endocrinopathies, some cases are characterized by excessive fibroblast growth factor 23 (FGF23) production from abnormal fibro-osseous tissue in FD lesions, resulting in increased renal phosphate excretion. We present a girl with FD/MAS and severe skeletal burden, evidenced by the presence of polyostotic fibrous dysplasia, which was complicated with bone fractures. She also had hyperthyroidism and GnRH-independent precocious puberty. She received zoledronic acid infusions in preparation for hip surgery. Despite optimal conventional management with oral phosphate and alphacalcidol, which was poorly tolerated, she presented persistent hypophosphatemia. To control hypophosphatemia and its deleterious effects on bone health, treatment with burosumab off-label at a dose of 0.66 mg/kg (20 mg) every 2 wk was initiated. Serum phosphate levels normalized within 2 wk of treatment. Laboratory results showed improvement in serum alkaline phosphatase (ALP) and PTH levels. After the second injection of burosumab, phosphate and PTH rose above the normal range with normal vitamin D levels; therefore, the interval between doses was increased to 3 wk, and calcium 500 mg daily was added. However, phosphate levels dropped again below normal range, so she had to return to 2-weekly injections of 20 mg. After 11 mo on burosumab, she remains with high normal phosphate levels and normal PTH and ALP values. Burosumab is well tolerated, with no adverse events to date. Burosumab is a human monoclonal antibody against FGF23 that reduces the risk of developing FGF23-mediated hypophosphatemia and its associated complications. Burosumab should be considered as an effective and safe alternative strategy for FGF23-mediated hypophosphatemia in FD/MAS for those who either cannot tolerate or do not respond to conventional therapy. To our knowledge, this is the fourth published case worldwide describing successful treatment with burosumab in FD/MAS.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"9 5","pages":"ziaf042"},"PeriodicalIF":3.4,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12035695/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gallium-68-DOTATATE PET/CT for phosphaturic mesenchymal tumor localization in suspected tumor-induced osteomalacia.","authors":"Caroline W S Hoong, Jad G Sfeir, Matthew T Drake, Stephen M Broski","doi":"10.1093/jbmrpl/ziaf040","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziaf040","url":null,"abstract":"<p><p>Gallium-68-DOTA-Tyr3-Octreotate (Ga-68-DOTATATE) positron emission tomography/computed tomography (PET/CT) has recently been shown to have utility for the localization of phosphaturic mesenchymal tumors (PMT) that cause tumor-induced osteomalacia (TIO), a rare renal phosphate-wasting disorder. The aim of this study was to evaluate the accuracy of Ga-68-DOTATATE PET/CT in localizing PMTs causing TIO and to compare its performance with other functional imaging modalities. Prospective recruitment and retrospective chart review of 30 patients with suspected TIO and evaluation with Ga-68-DOTATATE PET/CT between 2017 and 2023 were conducted at a tertiary medical center. True positive (TP) lesions were defined by histological confirmation of PMT. There were 22 TP lesions identified among 18 patients, with a mean SUV_max of 16.8 (±10.9). Sensitivity, specificity, and accuracy of Ga-68-DOTATATE PET/CT were 85.7%, 77.8%, and 83.3% on patient-based analysis, and 84.6%, 56.3%, and 73.8% on lesion-based analysis. Lesions such as subacute fractures, parathyroid adenomas, thymus uptake, vertebral hemangiomas, bone enchondromas, liver hemangiomas, and avascular necrosis were some of the pitfalls in interpretation. Ga-68-DOTATATE PET/CT led to a significant impact on clinical management in 24 (80%) of patients. The presence of DOTATATE-avid fractures was significantly associated with a localizing scan on univariable (OR 15.0, 95% CI 2.80-110, <i>p</i> = .001) and multivariable analysis (OR 9.45, 95% CI 1.33-98.4, <i>p</i> = .003). Ga-68-DOTATATE PET/CT has good accuracy for the localization of TIO, with superior sensitivity compared to F-18-FDG PET/CT. This significantly impacted clinical treatment decisions. Although DOTATATE-avid fractures may be a source of false positives, they may also indicate a higher probability of a localizing study.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"9 5","pages":"ziaf040"},"PeriodicalIF":3.4,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11995880/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144010225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alpha-smooth muscle actin-expressing dermal sheath cells are a major cellular contributor to heterotopic subcutaneous ossifications in a mouse model of Albright hereditary osteodystrophy.","authors":"Patrick McMullan, Peter Maye, Sierra H Root, Qingfen Yang, Sarah Edie, David Rowe, Ivo Kalajzic, Emily L Germain-Lee","doi":"10.1093/jbmrpl/ziaf038","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziaf038","url":null,"abstract":"<p><p>Heterotopic ossifications (HOs) are the pathologic process by which bone inappropriately forms outside of the skeletal system. Despite HOs being a persistent clinical problem in the general population, there are no definitive strategies for their prevention and treatment due to a limited understanding of the cellular and molecular mechanisms contributing to lesion development. One disease in which the development of heterotopic subcutaneous ossifications (SCOs) leads to morbidity is Albright hereditary osteodystrophy (AHO). Albright hereditary osteodystrophy is caused by heterozygous inactivation of <i>GNAS</i>, the gene that encodes the α-stimulatory subunit (Gα_s) of G proteins. Previously, we had shown using our laboratory's AHO mouse model that SCOs develop around hair follicles. Here we show that SCO formation occurs due to inappropriate expansion and osteogenic differentiation of cells that express alpha-smooth muscle actin and that are located within the dermal sheath. We also show in AHO patients and mice that <i>secreted frizzled related protein 2</i> (<i>SFRP2)</i> expression is upregulated in regions of SCO formation and that elimination of <i>Sfrp2</i> in male AHO mice leads to earlier development, greater severity, and acceleration of formation of SCOs. These studies provide key insights into the cellular and molecular mechanisms contributing to SCO development and have implications for potential therapeutic modalities not only for AHO patients but also for patients suffering from HOs with other etiologies.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"9 5","pages":"ziaf038"},"PeriodicalIF":3.4,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12009542/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Family mapping of previously identified patients with pathogenic or likely pathogenic <i>ALPL</i> variants using predictive genotyping and detailed phenotyping approach: the FAME case-control study.","authors":"Tatiane Vilaca, Fatma Gossiel, Sophie Delaney, Duncan Baker, Sylvia Keigwin, Richard Eastell, Meena Balasubramanian","doi":"10.1093/jbmrpl/ziaf034","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziaf034","url":null,"abstract":"<p><p>Hypophosphatasia (HPP) is an inborn error of metabolism caused by loss-of-function variants in the <i>ALPL</i> gene, which encodes the tissue nonspecific isozyme of alkaline phosphatase (ALP). There is no typical phenotype in adults. We used a genotyping first approach to determine whether <i>ALPL</i> pathogenic variants were associated with musculoskeletal symptoms, mineral metabolism abnormalities, and an impact on quality of life. We recruited individuals with a pathogenic (or likely pathogenic) variant in <i>ALPL</i> gene (<i>n</i> = 26) and their relatives (<i>n</i> = 44). We performed genetic tests and compared the relatives with positive (<i>n</i> = 20) and negative (<i>n</i> = 24) genetic test. We applied standard questionnaires and physical tests (Brief Pain Inventory [BPI]; Western Ontario and McMaster Universities Arthritis [WOMAC]; Modified Hypophosphatasia Impact Patient Survey; Short Form of 36 Survey [SF-36]; and the Short Physical Performance Battery). In fasting blood samples, we measured creatinine, calcium, phosphate (P), parathyroid hormone (PTH), ALP, bone ALP, 25OHD-, 1,25(OH)2D, CTX, type 1 procollagen N-terminal peptide (PINP), osteocalcin, and tartrate-resistant acid phosphatase5b (TRACP5b). Relatives with positive genetic test had lower ALP (IU/L) [32.5(12.8) vs 87.8(32.6) <i>p</i> < .001], bone ALP (ng/mL) [6.3(4.3, 9.8) vs 17.5 (13.12-25.7) <i>p</i> < .001], PTH (pg/L) [28.6(20.6, 38.1) vs 40.05(25.7, 52.3) <i>p</i> = .03], and higher PLP(nmol/L) [162.0 (91.75, 337.5) vs 37.5 (18.25, 60.5) <i>p</i> < .001] and P(mmol/L) [1.36 (0.18) vs 1.05 (0.2) <i>p</i> < .001]. We did not find significant differences in fractures or musculoskeletal features between the groups. Greater pain scores were observed on BPI in relatives with positive genetic tests, and bone and muscle pain were more often reported by this group, but statistical tests were not significant. No differences were found in physical performance or quality of life. In conclusion, we assessed relatives of individuals with pathogenic or likely pathogenic variants in the <i>ALPL</i> gene regardless of the presence of signs and symptoms. Biochemical abnormalities were more common in gene-positive relatives, but the prevalence of musculoskeletal symptoms was comparable in relatives with positive and negative genetic tests.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"9 5","pages":"ziaf034"},"PeriodicalIF":3.4,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11993272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144006241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevention of glucocorticoid-induced impairment of bone metabolism-a randomized, placebo-controlled, single centre proof-of-concept clinical trial.","authors":"Giulia Gregori, Lisa Johansson, Lena Silberberg, Henrik Imberg, Per Magnusson, Marcus Lind, Mattias Lorentzon","doi":"10.1093/jbmrpl/ziaf031","DOIUrl":"10.1093/jbmrpl/ziaf031","url":null,"abstract":"<p><p>Oral glucocorticoid (GC) therapy rapidly and deleteriously affects bone metabolism and blood glucose regulation. The gut microbiota regulates bone metabolism and a prior study found that <i>Limosilactobacillus reuteri</i> ATCC PTA6475 (<i>L. reuteri</i>) reduced bone loss over 12 mo in older women<i>.</i> Mice treated either with broad-spectrum antibiotics or with <i>L. reuteri</i> did not experience GC-induced trabecular bone loss. This proof-of-concept, randomized, double-blind, placebo-controlled trial aimed to investigate if daily supplementation with <i>L. reuteri</i>, compared with placebo, could mitigate or prevent the negative effects of oral GC on bone turnover and blood glucose regulation in healthy young adults. Twenty-one men and 29 women, aged 18-45, were randomized to either placebo or <i>L. reuteri</i> (1 × 10¹⁰ CFU/d) treatment for 2 wk, followed by open-label oral prednisolone 25 mg daily for 7 d. Primary outcomes were changes in blood bone status indices (osteocalcin, C-terminal telopeptide cross-links of collagen type-I (CTX), and type-I procollagen intact N-terminal propeptide [PINP]) from baseline to 7 d after starting oral GC. Secondary endpoints included changes in blood glucose levels using continuous glucose monitoring during the same period (ClinicalTrials.gov NCT04767711). Blood samples were collected from participants in the morning after overnight fasting. Forty-six participants completed the 30-d study. The <i>L. reuteri</i> and placebo groups were well balanced in terms of baseline characteristics (age, BMI, sex, dietary intake, and physical activity). No significant differences were found between <i>L. reuteri</i> vs placebo for percent changes in CTX (-0.3 [95%CI -19.2-18.7], <i>p</i> = .98) or PINP (4.2 [-6.3-14.8], <i>p</i> = .43), or in osteocalcin levels (14.2 [-7.8-36.3], <i>p</i> = .21), although the group-to-group difference in osteocalcin was larger. There was no effect of treatment on mean blood glucose (-0.1 [-0.3-0.1] mmol/L, <i>p</i> = .28). In conclusion, we failed to detect a significant effect of <i>L. reuteri</i> supplementation on GC-related adverse effects on bone status indices in this proof-of-concept RCT. Larger studies are needed to identify any potential smaller effects.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"9 4","pages":"ziaf031"},"PeriodicalIF":3.4,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950668/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143752743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial histomorphometry reveals that local peripheral nerves modulate but are not required for skeletal adaptation to applied load in mice.","authors":"Alec T Beeve, Mohamed G Hassan, Anna Li, Nicole Migotsky, Matthew J Silva, Erica L Scheller","doi":"10.1093/jbmrpl/ziaf006","DOIUrl":"10.1093/jbmrpl/ziaf006","url":null,"abstract":"<p><p>Mechanical loading is required for bone health and results in skeletal adaptation to optimize strength. Local nerve axons, particularly within the periosteum, may respond to load-induced biomechanical and biochemical cues. However, their role in the bone anabolic response remains controversial. We hypothesized that spatial alignment of periosteal nerves with sites of load-induced bone formation would clarify this relationship. To achieve this, we developed RadialQuant, a custom tool for spatial histomorphometry. Tibiae of control and neurectomized (sciatic/femoral nerve cut) pan-neuronal Baf53b-tdTomato reporter mice were loaded for 5 days. Bone formation and periosteal nerve axon density were then quantified simultaneously in non-decalcified sections of the mid-diaphysis using RadialQuant. In control animals, anabolic loading induced maximal periosteal bone formation at the site of peak compression, as has been reported previously. By contrast, loading did not significantly change overall periosteal nerve density. Neurectomy depleted ~90% of all periosteal axons, with near-total depletion on load-responsive surfaces. Neurectomy alone also caused de novo bone formation on the lateral aspect of the mid-diaphysis. However, neurectomy did not inhibit load-induced increases in periosteal bone area, mineralizing surface, or bone formation rate. Rather, neurectomy spatially redistributed load-induced bone formation toward the lateral tibial surface with a reduction in periosteal bone formation at the posterolateral apex (-63%) and enhancement at the lateral surface (+1360%). Altogether, this contributed to comparable load-induced changes in cortical bone area fraction. Our results show that local skeletal innervation modulates but is not required for skeletal adaptation to applied load in our model. This supports the continued use of loading and weight-bearing exercise as an effective strategy to increase bone mass, even in settings of peripheral nerve damage or dysfunction.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"9 3","pages":"ziaf006"},"PeriodicalIF":3.4,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11878550/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dental manifestations of hypophosphatasia: translational and clinical advances.","authors":"Elis J Lira Dos Santos, Fatma F Mohamed, Kaitrin Kramer, Brian L Foster","doi":"10.1093/jbmrpl/ziae180","DOIUrl":"10.1093/jbmrpl/ziae180","url":null,"abstract":"<p><p>Hypophosphatasia (HPP) is an inherited error in metabolism resulting from loss-of-function variants in the <i>ALPL</i> gene, which encodes tissue-nonspecific alkaline phosphatase (TNAP). TNAP plays a crucial role in biomineralization of bones and teeth, in part by reducing levels of inorganic pyrophosphate (PP_i), an inhibitor of biomineralization. HPP onset in childhood contributes to rickets, including growth plate defects and impaired growth. In adulthood, osteomalacia from HPP contributes to increased fracture risk. HPP also affects oral health. The dentoalveolar complex, that is, the tooth and supporting connective tissues of the surrounding periodontia, include 4 unique hard tissues: enamel, dentin, cementum, and alveolar bone, and all can be affected by HPP. Premature tooth loss of fully rooted teeth is pathognomonic for HPP. Patients with HPP often have complex oral health issues that require multidisciplinary dental care, potentially involving general or pediatric dentists, periodontists, prosthodontists, and orthodontists. The scientific literature to date has relatively few reports on dental care of individuals with HPP. Animal models to study HPP included global <i>Alpl</i> knockout mice, <i>Alpl</i> mutation knock-in mice, and mice with tissue-specific conditional <i>Alpl</i> ablation, allowing for new studies on pathological mechanisms and treatment effects in dental and skeletal tissues. Enzyme replacement therapy (ERT) in the form of injected, recombinant mineralized tissue-targeted TNAP has been available for nearly a decade and changed the prognosis for those with HPP. However, effects of ERT on dental tissues remain poorly defined and limitations of the current ERT have prompted exploration of gene therapy approaches to treat HPP. Preclinical gene therapy studies are promising and may contribute to improved oral health in HPP.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"9 2","pages":"ziae180"},"PeriodicalIF":3.4,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11770227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}