Bone最新文献

{"title":"Age-related differences in bone structural parameters using 3D-DXA and TBS in men and women: The Bunkyo Health Study","authors":"Hikaru Otsuka ,&nbsp;Hiroki Tabata ,&nbsp;Naoaki Ito ,&nbsp;Huicong Shi ,&nbsp;Takahito Iwashimizu ,&nbsp;Hideyoshi Kaga ,&nbsp;Yuki Someya ,&nbsp;Hitoshi Naito ,&nbsp;Abulaiti Abudurezake ,&nbsp;Saori Kakehi ,&nbsp;Yasuyo Yoshizawa ,&nbsp;Muneaki Ishijima ,&nbsp;Ryuzo Kawamori ,&nbsp;Hirotaka Watada ,&nbsp;Yoshifumi Tamura","doi":"10.1016/j.bone.2025.117549","DOIUrl":"10.1016/j.bone.2025.117549","url":null,"abstract":"<div><h3>Background</h3><div>Recent advancements in imaging technology, including trabecular bone score (TBS) and 3D-DXA, enable comprehensive bone structure assessment beyond traditional bone mineral density (BMD) measurements in osteoporosis. However, age-related differences in bone structure remain unclear.</div></div><div><h3>Method</h3><div>Using data from the Bunkyo Health Study, we analyzed bone structural parameters in 1372 participants (662 men, 710 women) for the proximal femur and 1053 participants (500 men, 553 women) for the lumbar spine, aged 65–84 years. Parameters included TBS of the lumbar spine and proximal femur measurements (3D-Shaper), including volumetric BMD of trabecular, cortical, and integral, cortical thickness, and surface BMD in each bone region. Age group comparisons (65–69, 70–74, 75–79, and 80–84 years) were performed using Kruskal–Wallis test with Bonferroni correction.</div></div><div><h3>Results</h3><div>In men, only cortical thickness significantly decreased in the proximal femur regions, particularly in the 80–84 age group compared to the 65–69 and 70–74 age groups (−2.3 %, <em>P</em> &lt; 0.05). In women, all parameters significantly decreased (<em>P</em> &lt; 0.001), especially in the 80–84 age group—cortical thickness (−3.9 %), cortical surface BMD (−9.6 %), cortical volumetric BMD (−4.0 %), and trabecular volumetric BMD (−8.4 %)—compared to the 65–69 age group. TBS was significantly lower in women aged 70–74 and 80–84 years compared to those aged 65–69 years (<em>P</em> &lt; 0.001); however, no significant changes were observed in men.</div></div><div><h3>Conclusions</h3><div>Women showed widespread changes across all parameters, whereas men exhibited primarily cortical thickness changes, suggesting the need for sex-specific approaches for osteoporosis assessment and fracture risk prediction.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"199 ","pages":"Article 117549"},"PeriodicalIF":3.5,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mild to moderate COPD, vitamin D deficiency, and longitudinal bone loss: the Multi-ethnic Study of Atherosclerosis","authors":"Elena Ghotbi ,&nbsp;Quincy A. Hathaway ,&nbsp;Roham Hadidchi ,&nbsp;Sara Momtazmanesh ,&nbsp;Michael P. Bancks ,&nbsp;David A. Bluemke ,&nbsp;R. Graham Barr ,&nbsp;Wendy S. Post ,&nbsp;Matthew Budoff ,&nbsp;Benjamin M. Smith ,&nbsp;João A.C. Lima ,&nbsp;Shadpour Demehri","doi":"10.1016/j.bone.2025.117550","DOIUrl":"10.1016/j.bone.2025.117550","url":null,"abstract":"<div><h3>Objective</h3><div>Despite the established association between chronic obstructive pulmonary disease (COPD) severity and risk of osteoporosis, even after accounting for the known shared confounding variables (e.g., age, smoking, history of exacerbations, steroid use), there is paucity of data on bone loss among mild to moderate COPD, which is more prevalent in the general population.</div></div><div><h3>Methods</h3><div>We conducted a longitudinal analysis using data from the Multi-Ethnic Study of Atherosclerosis. Participants with chest CT at Exam 5 (2010−2012) and Exam 6 (2016–2018) were included. Mild to moderate COPD was defined as forced expiratory volume in 1 s (FEV₁) to forced vital capacity ratio of &lt;0.70 and FEV₁ of 50 % or higher. Vitamin D deficiency was defined as serum vitamin D &lt; 20 ng/mL. We utilized a validated deep learning algorithm to perform automated multilevel segmentation of vertebral bodies (T1–T10) from chest CT and derive 3D volumetric thoracic vertebral BMD measurements at Exam 5 and 6.</div></div><div><h3>Results</h3><div>Of the 1226 participants, 173 had known mild to moderate COPD at baseline, while 1053 had no known COPD. After adjusting for age, race/ethnicity, sex, body mass index, bisphosphonate use, alcohol consumption, smoking, diabetes, physical activity, C-reactive protein and vitamin D deficiency, mild to moderate COPD was associated with faster decline in BMD (estimated difference, β = −0.38 mg/cm³/year; 95 % CI: −0.74, −0.02). A significant interaction between COPD and vitamin D deficiency (<em>p</em> = 0.001) prompted stratified analyses. Among participants with vitamin D deficiency (47 % of participants), COPD was associated with faster decline in BMD (−0.64 mg/cm³/year; 95 % CI: −1.17 to −0.12), whereas no significant association was observed among those with normal vitamin D in both crude and adjusted models.</div></div><div><h3>Conclusions</h3><div>Mild to moderate COPD is associated with longitudinal declines in vertebral BMD exclusively in participants with vitamin D deficiency over 6-year follow-up. Vitamin D deficiency may play a crucial role in bone loss among patients with mild to moderate COPD.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"199 ","pages":"Article 117550"},"PeriodicalIF":3.5,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bone turnover markers and mineral density in type 1 diabetes — A cross-sectional study: DIAFALL","authors":"Nicklas H. Rasmussen ,&nbsp;Annika Vestergaard Kvist ,&nbsp;Simon Lykkeboe ,&nbsp;Jakob Starup-Linde ,&nbsp;Aase Handberg ,&nbsp;Joop P. van den Bergh ,&nbsp;Peter Vestergaard","doi":"10.1016/j.bone.2025.117548","DOIUrl":"10.1016/j.bone.2025.117548","url":null,"abstract":"<div><h3>Introduction/aim</h3><div>This study investigated differences in bone turnover markers (BTMs) and their associations with areal bone mineral density (aBMD) in people with type 1 diabetes (T1D) to better understand the mechanisms underlying skeletal fragility, including sex- and hormone-related variations.</div></div><div><h3>Methods</h3><div>A cohort of 110 Caucasian participants with T1D were matched 1: 1 with age- and sex-matched controls. aBMD at the lumbar spine, femoral neck, legs, and arms was assessed using DXA. BTMs included P1NP, osteocalcin (OC), sclerostin, CTX-1, TRAcP, IGF-1, BASP, and osteopontin (OPN). Group comparisons were conducted using <em>t</em>-tests, and associations between BTMs and aBMD were examined using regression and Spearman correlations. Exploratory subgroup analyses stratified women by menopausal status.</div></div><div><h3>Results</h3><div>Bone formation markers (P1NP, OC) were significantly lower in T1D men compared to controls (P1NP: <em>p</em> = 0.046; OC: <em>p</em> = 0.002), reflecting suppressed bone formation. IGF-1 was reduced in both sexes (<em>p</em> &lt; 0.001) and correlated positively with aBMD in women (<em>p</em> &lt; 0.05), but not in men. Sclerostin levels were elevated in both sexes (<em>p</em> = 0.002–&lt;0.001) without correlating with aBMD. CTX-1 was reduced in T1D men (<em>p</em> = 0.004), while TRAcP was elevated in both sexes (<em>p</em> = 0.044), correlating negatively with aBMD in women. Men with T1D had significantly lower leg aBMD (<em>p</em> = 0.032) and reduced femoral neck bone mineral content (<em>p</em> = 0.041). No overall differences were observed among women; however, exploratory analyses revealed that postmenopausal women with T1D had higher TRAcP and sclerostin levels and lower femoral neck aBMD compared to premenopausal counterparts.</div></div><div><h3>Conclusion</h3><div>T1D was associated with significant alterations in certain BTMs and reduced aBMD in men, while skeletal effects in women appeared to be influenced by menopausal status. The weak and mostly non-significant correlations between BTMs and aBMD suggest that impaired bone quality, rather than bone mass alone, may be the primary driver of skeletal fragility in T1D. Hormonal status may further modify these effects in women.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"198 ","pages":"Article 117548"},"PeriodicalIF":3.5,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144169144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Calorie restriction induces mandible bone loss by regulating mitochondrial function” [Bone 190 (2024) 117326]","authors":"Linyi Liu ,&nbsp;Phuong T. Le ,&nbsp;Victoria E. DeMambro ,&nbsp;Tiange Feng ,&nbsp;Hanghang Liu ,&nbsp;Wangyang Ying ,&nbsp;Roland Baron ,&nbsp;Clifford J. Rosen","doi":"10.1016/j.bone.2025.117546","DOIUrl":"10.1016/j.bone.2025.117546","url":null,"abstract":"","PeriodicalId":9301,"journal":{"name":"Bone","volume":"198 ","pages":"Article 117546"},"PeriodicalIF":3.5,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144176112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bone histomorphometry for the diagnosis of renal osteodystrophy – a European consensus statement","authors":"Marie-Helene Lafage-Proust ,&nbsp;Hanne Skou Jørgensen ,&nbsp;Nathalie Bravenboer ,&nbsp;Anibal Ferreira ,&nbsp;Marie-Josée Bégin ,&nbsp;Jorge Cannata-Andia ,&nbsp;Daniel Cejka ,&nbsp;Pascale Chavassieux ,&nbsp;Martine Cohen-Solal ,&nbsp;Patrick D’Haese ,&nbsp;Astrid Fahrleitner-Pammer ,&nbsp;Ana Carina Ferreira ,&nbsp;Maria Fusaro ,&nbsp;Maude Gerbaix ,&nbsp;Neveen Hamdy ,&nbsp;Ditte Hansen ,&nbsp;Renate de Jongh ,&nbsp;Heikki Kröger ,&nbsp;Alexander D. Lalayiannis ,&nbsp;Syazrah Salam ,&nbsp;Pieter Evenepoel","doi":"10.1016/j.bone.2025.117544","DOIUrl":"10.1016/j.bone.2025.117544","url":null,"abstract":"<div><div>Histomorphometric analysis of an iliac bone biopsy remains the gold standard for the diagnosis of renal osteodystrophy (ROD), which comprises various histological lesions induced by chronic kidney disease (CKD). ROD belongs to the framework of CKD-associated osteoporosis. The use of bone biopsy in the routine management of CKD-associated osteoporosis has decreased over the past decades for various reasons, including diminishing expertise in performing the procedure, and major variability in processing bone samples and reporting of results. In this context, the European Renal Osteodystrophy group, a part of the CKD-mineral and bone disorder working group of the European Renal Association launched an initiative to evaluate various issues related to bone histomorphometry in the context of ROD. To this effect, 28 experts from 14 European countries engaged in rounds of discussions to reach a consensus related to the bone biopsy procedure, sample handling, and reading and reporting findings. Key conclusions include a recommendation that all practitioners in this field move towards reporting diagnostic findings by the turnover, mineralization, and volume (TMV) classification and that external quality control is prioritized to ensure validity and reproducibility of results. The consensus group recognises that the lack of an accepted normative reference for bone histomorphometry is a barrier towards uniform diagnostic definitions and recommends further collaborative efforts in this area. Until these issues are solved, transparent reporting on the choice of reference and diagnostic definitions applied should be adhered to, both in clinical reports and research settings.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"199 ","pages":"Article 117544"},"PeriodicalIF":3.5,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144188681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 celecoxib and muMab911 on strain adaptive bone remodeling and fracture repair in female mice: implications for rapidly progressive osteoarthritis","authors":"Nicholas Ruggiero ,&nbsp;Alexandra Ciuciu ,&nbsp;Ashkan Sedigh ,&nbsp;Ibtesam Rajpar ,&nbsp;David Shelton ,&nbsp;Patrice Belanger ,&nbsp;Kathryn Gropp ,&nbsp;John A. Collins ,&nbsp;Theresa A. Freeman ,&nbsp;Ryan E. Tomlinson","doi":"10.1016/j.bone.2025.117542","DOIUrl":"10.1016/j.bone.2025.117542","url":null,"abstract":"<div><div>Debilitating pain is the primary clinical feature of osteoarthritis (OA) that drives the enormous healthcare costs. Osteoarthritis-related pain is often treated with non-steroidal anti-inflammatory drugs (NSAIDs), which effectively relieve pain and inflammation by inhibition of prostaglandin synthesis. Antibodies directed against nerve growth factor (NGF) were tested some time ago as an alternative potential analgesic for musculoskeletal pain, including osteoarthritis-related pain. Unfortunately, clinical development of these drugs was put on hold due to adverse outcomes – primarily rapidly progressive osteoarthritis. Both prostaglandin synthesis and NGF have been implicated as critical mediators of strain adaptive bone remodeling, which may play a role in rapid osteoarthritis progression. Therefore, this study was designed to investigate the effects of celecoxib, an NSAID, and muMab911, an anti-NGF antibody, as well as the combination therapy on strain adaptive bone remodeling, bone mass and geometry, and bone healing in a murine model. Adult female C57BL/6 J mice received celecoxib through drinking water, up to 3 IP injections of muMab911, or both treatments over a period of two weeks. As expected, all treatments were effective for relieving injury-associated pain. Consistent with previous studies, we found that celecoxib alone and in combination with muMab911 impaired periosteal load-induced bone formation induced by axial forelimb compression. Furthermore, both treatments had minimal effects on osteoblast and osteocyte populations, bone structural and material properties, and cortical and trabecular bone mass. Moreover, treatment did not impair fracture healing or callus morphology, though both treatments suppressed NGF expression during healing. Together, these findings suggest that celecoxib and anti-NGF therapy diminish strain adaptive bone remodeling without broadly compromising bone mass or repair, potentially contributing to the accelerated OA progression observed clinically by weakening the subchondral bone's adaptive capacity.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"198 ","pages":"Article 117542"},"PeriodicalIF":3.5,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144131343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic insights into NETs-induced osteogenesis inhibition in BMSCs of rheumatoid arthritis","authors":"Fanzhang Yin ,&nbsp;Huiming Hong ,&nbsp;Yongqi Wang ,&nbsp;Yanan Wang ,&nbsp;Jingxue Zhang ,&nbsp;Xiaojun Tang ,&nbsp;Huayong Zhang ,&nbsp;Lingyun Sun","doi":"10.1016/j.bone.2025.117533","DOIUrl":"10.1016/j.bone.2025.117533","url":null,"abstract":"<div><div>In the field of chronic inflammatory rheumatism, while neutrophil extracellular traps (NETs) have been recognized as contributors to the pathogenesis of rheumatoid arthritis (RA), the underlying mechanism of the abnormal interaction between NETs and bone marrow mesenchymal stem cells (BMSCs) has remained unclear. Our study made several key findings. Firstly, we discovered that the osteogenic differentiation ability of BMSCs in RA patients was reduced. Additionally, we found that the increased production of NETs in RA patients impaired bone formation by weakening the osteogenic capacity of BMSCs. Specifically, NETs activated the NF-κB pathway in BMSCs, suppressing the expression of bone morphogenetic protein 2 (BMP2) and thus inhibiting osteogenesis, which could be counteracted by an NF - κB inhibitor. Moreover, NETs promoted BMSCs to secrete interleukin-8 (IL-8), attracting more neutrophils into the bone marrow. These findings highlight the role of NETs-induced activation of the p65/NF-κB pathway in inhibiting BMSC osteogenesis in RA and suggest that targeting p65 may be a potential therapeutic strategy for RA.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"198 ","pages":"Article 117533"},"PeriodicalIF":3.5,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144137871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to letter to editor ”sex-specific association between dietary carbohydrate intake and bone mineral density in adolescents”","authors":"Chunhong Guo ,&nbsp;Jianmin Qu ,&nbsp;Keyi Li","doi":"10.1016/j.bone.2025.117545","DOIUrl":"10.1016/j.bone.2025.117545","url":null,"abstract":"","PeriodicalId":9301,"journal":{"name":"Bone","volume":"198 ","pages":"Article 117545"},"PeriodicalIF":3.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144124867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the role of complement 5a in systemic bone loss after myocardial infarction","authors":"Priscilla M. Tjandra ,&nbsp;Sophie V. Orr ,&nbsp;Selena K. Lam ,&nbsp;Anika D. Kulkarni ,&nbsp;Yi-Je Chen ,&nbsp;Anna Adhikari ,&nbsp;Jill L. Silverman ,&nbsp;Crystal M. Ripplinger ,&nbsp;Blaine A. Christiansen","doi":"10.1016/j.bone.2025.117543","DOIUrl":"10.1016/j.bone.2025.117543","url":null,"abstract":"<div><div>Myocardial infarction (MI) and osteoporotic fracture are two of the leading causes of morbidity and mortality worldwide. We have previously established that MI in mice directly causes post-traumatic systemic bone loss and that the sympathetic nervous system plays a role in this response. However, the systemic injury response is mediated by multiple systems. In this study, we investigated the role of complement 5a (C5a), one of the main mediators driving multiple organ dysfunction after trauma. MI was surgically induced in 12-week-old male C57BL/6 J mice (B6/J), C5a receptor 1 knockout mice (<em>C5aR1</em>^{<em>−/−</em>}) and B10·D2-Hc0 H2d H2-T18c/oSnJ (B10·D2), (JAX Strain # 000461) mice that are deficient in serum C5. Systemic and localized bone changes were analyzed at 7-, 14- and 28-days post-MI using micro-computed tomography and three-point bending mechanical testing. Osteoclast number and activity was quantified using tartrate-resistant acid phosphatase (TRAP) staining, and voluntary activity levels were measured using open field. We found that MI induced peak trabecular bone loss 7 days after injury in the L5 vertebral body and caused reductions in femoral cortical bone 28 days post-MI. However, MI did not impact femoral trabecular bone in this timeframe. B10·D2 mice had reduced trabecular and cortical bone morphology compared to B6 and <em>C5aR1</em>^−/− mice, but did not exhibit an altered response to MI. Osteoclast activity 7-days post-MI was increased in <em>C5aR1</em>^−/− mice compared to B6 and B10·D2 mice, but MI did not impact osteoclast activity at this time point. Altogether, these findings suggest that C5a may influence overall response to MI and bone morphology instead of post-traumatic systemic bone loss response following MI, though likely not as a primary mechanism.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"198 ","pages":"Article 117543"},"PeriodicalIF":3.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144144798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Markedly discordant hypophosphatasia in a young girl","authors":"Vikram Prakash ,&nbsp;Samer Elbabaa ,&nbsp;Richard Banks ,&nbsp;Gabriel de Carlos ,&nbsp;William H. McAlister ,&nbsp;Steven Mumm ,&nbsp;Michael P. Whyte","doi":"10.1016/j.bone.2025.117541","DOIUrl":"10.1016/j.bone.2025.117541","url":null,"abstract":"<div><div><em>Hypophosphatasia</em> (HPP) is the inborn-error-of-metabolism from deactivating mutation(s) of <em>ALPL</em>, the gene that encodes the cell surface “tissue-nonspecific” isoenzyme of alkaline phosphatase (TNSALP). HPP's “biochemical signature” comprises low serum alkaline phosphatase activity together with elevated plasma levels of the TNSALP natural substrates phosphoethanolamine (PEA), pyridoxal 5′-phosphate (PLP), and inorganic pyrophosphate (PPi). Excess extracellular PPi (ePPi) inhibits mineralization and affected children prematurely shed deciduous teeth and often suffer weakness and rickets. Yet, HPP severity is greatest among all dento-osseous disorders and not fully explained by autosomal dominant versus autosomal recessive inheritance involving &gt;470 <em>ALPL</em> mutations. Discordance of HPP phenotype sometimes manifests even among full siblings sharing an identical <em>ALPL</em> genotype.</div><div>Herein, a girl's markedly discordant HPP featured at presentation life-threatening hypercalcemia, failure-to-thrive, and renal compromise. Subsequent pseudotumor cerebri syndrome caused blindness, and then craniosynostosis required cranial vault reconstruction. However, she was not deformed, had moderate hypophosphatasemia, normal plasma PLP level, and mild radiographic features of HPP rickets. Elevated plasma N-terminal parathyroid hormone-related protein (PTHrP) suggested malignancy, but corrected after kidney transplantation. HPP was diagnosed when whole exome sequencing revealed heterozygous <em>ALPL</em> c.1034C&gt;T, p.A345V found in mild pediatric HPP and transmitted by her mother who considered herself well. Genes conditioning ePPi formation and underlying other skeletal diseases were intact. Hypercalcemia, unresponsive to bone antiresorptive drugs, corrected promptly with asfotase alfa TNSALP supplementation therapy. Her markedly discordant findings highlight genotype/phenotype plasticity for pediatric HPP, and her clinical course importance for early diagnosis.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"199 ","pages":"Article 117541"},"PeriodicalIF":3.5,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144133148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}