JBMR Plus最新文献

{"title":"Cardiovascular outcomes of romosozumab treatment-real-world data analysis.","authors":"Anat Tsur, Avivit Cahn, Ludmila Levy, Rena Pollack","doi":"10.1093/jbmrpl/ziae146","DOIUrl":"10.1093/jbmrpl/ziae146","url":null,"abstract":"<p><p>Romosozumab is a potent treatment for osteoporosis, with significant effects on bone density and fracture prevention. This study evaluated the cardiovascular safety of romosozumab in a real-world cohort of postmenopausal women at high fracture risk. We retrospectively evaluated postmenopausal women who initiated treatment with romosozumab between January 1, 2020, and June 30, 2023. We examined the occurrence of a major adverse cardiovascular event (MACE) across two distinct segments during the treatment period and after its conclusion. After applying inclusion and exclusion criteria, 847 women were followed for a median of 729 days (IQR: 445-1060). The incidence rate of MACE was 24.0 (95% CI 17.7-32.5) per 1000 person-years during the study period. The change in the rate of MACE from 0-90 days and 90-365 days post-treatment initiation was 0.04 and 0.06 events per 1000 days, respectively. The difference in the rate between these intervals was not statistically significant (<i>p</i> = .09). After 1 yr of treatment, the slope of MACE increased to 0.10, differing significantly from the preceding 12 mo on treatment (<i>p</i><.001). The incidence of MACE was higher in those with a background of previous cardiovascular disease or diabetes at all timepoints, as expected. The consistency in event rates during treatment suggests that romosozumab is not associated with an increase in MACE in postmenopausal women. This finding challenges reports suggesting an increase in cardiovascular events within the first year of romosozumab treatment.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"9 1","pages":"ziae146"},"PeriodicalIF":3.4,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647516/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836424","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":"Bending properties of human cartilaginous ribs and costal cartilage material vary with age, sex, and calcification.","authors":"Megan H Goh, Dennis E Anderson","doi":"10.1093/jbmrpl/ziae153","DOIUrl":"10.1093/jbmrpl/ziae153","url":null,"abstract":"<p><p>Costal cartilage plays an important functional role in the rib cage, but its mechanical properties have not been well characterized. The objective of this study is to characterize the properties of human costal cartilage and examine the effects of age, sex, rib level, and degree of calcification. We obtained cadaveric costal cartilage samples of ribs 3-6 with intact perichondrium from 24 donors (12 females and 12 males) evenly distributed by age (range 47-94 yr). Peripheral QCT scans were used to quantify geometric properties (area moments) and tissue calcification (as volume, length, and classified as central, peripheral, and mixed). Four-point bending tests were performed on each sample, and bending stiffness and modulus outcomes were evaluated by fitting data from mechanical testing with non-linear pseudo-elastic models (composed of linear and cubic components, separated into loading and unloading regimes). Effects of sex, age, rib level, and cartilage calcification on bending stiffness and modulus outcomes were assessed with mixed-effects regression models. Cartilage size (area moment) was larger in males than females and positively associated with age, while there was more calcification volume in cartilage of females than males. During loading, stiffness (linear and cubic) was larger in males, while modulus (linear and cubic) was larger in females. Linear stiffness and modulus were both negatively associated with age, positively associated with calcification, and varied between rib levels. Cubic (nonlinear) components of stiffness and modulus were positively associated with calcification and varied by rib, while modulus (but not stiffness) was negatively associated with age. During unloading, the linear stiffness and modulus values were much lower, though some similar associations were found. Overall, this study adds to our understanding of the behavior of costal cartilage as a nonlinear visco-elastic material, and the effects of sex, aging, and calcification on mechanical behavior.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"9 1","pages":"ziae153"},"PeriodicalIF":3.4,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11653008/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854202","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":"Administration and cancer-control outcomes of bone-modifying agents in real-world patients with metastatic castration-resistant prostate cancer.","authors":"Mike Wenzel, Benedikt Hoeh, Clara Humke, Maria Welte, Cristina Cano Garcia, Carolin Siech, Fred Saad, Pierre I Karakiewcz, Derya Tilki, Thomas Steuber, Markus Graefen, Miriam Traumann, Felix K H Chun, Philipp Mandel","doi":"10.1093/jbmrpl/ziae157","DOIUrl":"10.1093/jbmrpl/ziae157","url":null,"abstract":"<p><p>Hormonal agents administered for metastatic castration-resistant prostate cancer (mCRPC) may lead to osteoporosis, skeletal events, reduced quality of life, and even reduced overall survival (OS). Bone-modifying agents may prevent those events but their effect on cancer-control outcomes remains uncertain. Relying on our institutional tertiary-care database, we explored the effect of bone-modifying agents (bisphosphonates such as zoledronic acid and denosumab) on OS and progression-free survival in patients with mCRPC with at least 1 bone metastasis using Kaplan-Meyer estimates and Cox regression models. Of 420 patients with mCRPC, 60% received bone-modifying agents who were younger (68 vs 69 years), with more systemic treatment lines for mCRPC (3 vs 2), and a higher proportion of initial de novo metastatic disease (72% vs 62%, all <i>p</i> ≤ .04) than patients without bone-modifying agents. In progression-free survival analyses, no significant differences were observed between both groups. In OS analyses, significant median OS differences were observed in favor of patients with bone-modifying agents (58 vs 45 months; hazard ratio [HR]: 0.66), even after multivariable adjustment (HR: 0.37; both <i>p</i> ≤ .01). In bone-modifying agent-stratified analyses, 57% received denosumab vs 43% bisphosphonates, with a significantly higher rate of Eastern Cooperative Oncology Group status of ≥2 in the bisphosphonates group. In progression-free and OS analyses, no significant differences were observed between bisphosphonates and denosumab patients, with numerically better results in progression-free survival analysis for denosumab after adjusting for covariates. The cumulative rate of osteonecrosis of the jaw at any treatment time was 12% in both groups and significantly decreased over time. Real-world data suggest a relatively low administration rate of bone-modifying agents in patients with osseous mCRPC. However, real-world data also suggest an OS benefit when bone-modifying agents are used, even after controlling for possible confounding patient and tumor characteristics.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"9 1","pages":"ziae157"},"PeriodicalIF":3.4,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11646308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828563","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":"Course and treatment of severe osteoporosis complicated by calciphylaxis: a case report.","authors":"Ayako Tominaga, Keiji Wada, Yoshiharu Kato, Ken Okazaki","doi":"10.1093/jbmrpl/ziae154","DOIUrl":"10.1093/jbmrpl/ziae154","url":null,"abstract":"<p><p>Calciphylaxis, also known as calcific uremic arteriolopathy (CUA), is a rare disorder with many unknown treatment and diagnostic aspects. It is characterized by calcification and thrombosis of small blood vessels. This disease leads to progressive skin calcification, necrotizing ulcers, and infections and is associated with a high mortality rate. Although primarily affected sites tend to be on skin, those affecting bones are also significant. We report a case of CUA complicated with rapidly progressing multiple vertebral fractures and severe osteoporosis. The patient experienced a series of five vertebral fractures within 5 months after hospitalization, and blood tests revealed abnormally high levels of bone resorption marker bone-type tartrate-resistant acid phosphatase (TRACP-5b). Consequently, intravenous sodium thiosulfate and hyperbaric oxygen therapy were administered for the treatment of skin lesions caused by calciphylaxis, and brace therapy and denosumab treatment were initiated for vertebral fractures. This approach rapidly decreased TRACP-5b levels and arrested the chain of vertebral fractures. We concluded that to maintain the quality of life of patients with CUA, early treatment of primary skin lesions as well as comorbid conditions is essential.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"9 1","pages":"ziae154"},"PeriodicalIF":3.4,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11653006/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854203","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":"Exploring the role of peripheral nerves in trauma-induced heterotopic ossification.","authors":"Clifford T Pereira, Sean H Adams, K C Kent Lloyd, Trina A Knotts, Aaron W James, Theodore J Price, Benjamin Levi","doi":"10.1093/jbmrpl/ziae155","DOIUrl":"10.1093/jbmrpl/ziae155","url":null,"abstract":"<p><p>Recent studies have linked pain and the resultant nociception-induced neural inflammation (NINI) to trauma-induced heterotopic ossification (THO). It is postulated that nociception at the injury site stimulates the transient receptor potential vanilloid-1 (the transient receptor potential cation channel subfamily V member 1) receptors on sensory nerves within the injured tissues resulting in the expression of neuroinflammatory peptides, substance P (SP), and calcitonin gene-related peptide (CGRP). Additionally, BMP-2 released from fractured bones and soft tissue injury also selectively activates TRVP1 receptors, resulting in the release of SP and CGRP and causing neuroinflammation and degranulation of mast cells causing the breakdown the blood-nerve barrier (BNB), leading to release of neural crest derived progenitor cells (NCDPCs) into the injured tissue. Parallel to this process BMP-2 initiates the NCDPCs toward osteogenic differentiation. CGRP has direct osteogenic effects on osteoprogenitor cells/mesenchymal stem cells, by activating BMP-2 via canonical Wnt/β-catenin signaling and cAMP-cAMP-response element binding protein signaling. BMP-2 binds to TGF-βRI and activates TGF-β-activated kinase 1 (TAK1) leading to phosphorylation of SMAD1/5/8, which binds to the co-activator SMAD4 and translocates to the nucleus to serve as transcription factor for BMP responsive genes critical in osteogenesis such as <i>Runx2</i> and others. Thus, NINI phenotypes, and specifically CGRP induction, play a crucial role in THO initiation and progression through the activation of the BMP pathway, breakdown of the BNB, leading to the escape of NCDPCs, and the osteogenic differentiation of the latter.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"9 1","pages":"ziae155"},"PeriodicalIF":3.4,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11646309/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828565","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":"Palovarotene (Sohonos), a synthetic retinoid for reducing new heterotopic ossification in fibrodysplasia ossificans progressiva: history, present, and future.","authors":"Edward C Hsiao, Maurizio Pacifici","doi":"10.1093/jbmrpl/ziae147","DOIUrl":"10.1093/jbmrpl/ziae147","url":null,"abstract":"<p><p>Retinoids are metabolic derivatives of vitamin A and play crucial roles in the regulation of various tissues and organs during prenatal and postnatal development. Active retinoids, like all-trans-retinoic acid, are synthesized in the cytoplasm and subsequently interact with nuclear retinoic acid receptors (RARα, RARβ, and RARγ) to enhance transcription of specific genes. In the absence of retinoids, RARs can still bind to response elements of target genes but repress their transcription. Chondrogenic cell differentiation and cartilage maturation in the growth plate require the absence of retinoid signaling and transcriptional repression by unliganded RARs. This led to the hypothesis that synthetic retinoid agonists may be pharmacological agents to inhibit those cellular processes and counter the excessive formation of cartilage and bone in conditions like heterotopic ossification (HO). HO can be instigated by diverse culprits including trauma, invasive surgeries, inflammatory disorders, or genetic conditions. One such genetic disease is fibrodysplasia ossificans progressiva (FOP), a rare disorder driven by activating mutations in the <i>ACVR1</i> gene. Patients with FOP have severe and progressive HO formation in soft tissues, leading to extensive permanent loss of mobility and increased mortality. Synthetic retinoid agonists selective for RARα or RARγ showed efficacy against injury-induced and genetic HO in mouse models. The RARγ agonists showed the highest effectiveness, with palovarotene being selected for clinical trials in patients with FOP. Post hoc analyses of phase II and phase III clinical trials showed that palovarotene has significant disease-modifying effects for FOP, but with significant risks such as premature growth plate closure in some younger subjects. This review provides an overview of retinoid and RAR roles in skeletal development and discusses the identification of palovarotene as a potential FOP therapy, the clinical data supporting its regulatory approval in some countries, and the potential applications of this drug for other relevant disorders besides FOP.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"9 1","pages":"ziae147"},"PeriodicalIF":3.4,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11646086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828607","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":"Unusual <i>PHEX</i> variants implicate uncommon genetic mechanisms for X-linked hypophosphatemic rickets.","authors":"Lama Alzoebie, Dong Li, Xiang Wang, David R Weber, Michael A Levine","doi":"10.1093/jbmrpl/ziae152","DOIUrl":"10.1093/jbmrpl/ziae152","url":null,"abstract":"<p><p>X-linked hypophosphatemic rickets (XLH), the most common form of hereditary rickets, is characterized by renal phosphate wasting and abnormal vitamin D metabolism due to elevated circulating levels of the phosphatonin fibroblast growth factor 23 (FGF23). Dominant inactivating variants of the phosphate regulating endopeptidase homolog, X-linked (<i>PHEX</i>), gene are present in patients with XLH, and more than half of affected patients carry de novo variants. We report on 3 families in whom affected members had highly unusual <i>PHEX</i> pathogenic variants. In 1 family we identified a previously described deep intronic <i>PHEX</i> variant (c.1768 + 173A>G) in the proband and her affected son. This variant is also near a previously reported PHEX variant (c.1768 + 177_1768 + 180dupGTAA) and is predicted to affect splicing by SpliceAI (delta score: 0.95) through creation of a new donor splice site. In a second proband we identified 2 pathogenic de novo and novel <i>PHEX</i> variants, c.2083delT (p.Ser695Profs*45) and c.2085delC (p.Tyr696Thrfs*44), that were present on different alleles, consistent with mosaicism for 3 <i>PHEX</i> alleles. The third proband also carried 2 <i>PHEX</i> variants (c.755 T>C [p.Phe252Ser] and c.759G>A [p.Met253Ile]), but in this case both variants were present on the same <i>PHEX</i> allele. These studies expand the molecular catalog of pathogenic <i>PHEX</i> variants in XLH and emphasize the importance of deep intronic sequencing and comprehensive family studies. Conventional approaches to genetic diagnosis may not be adequate to identify or characterize the disease-causing variants in the <i>PHEX</i> gene in some patients with likely XLH.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"9 1","pages":"ziae152"},"PeriodicalIF":3.4,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11646311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828701","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":"<i>CDC73</i> c.1155-3A>G is a pathogenic variant that causes aberrant splicing, disrupted parafibromin expression, and hyperparathyroidism-jaw tumor syndrome.","authors":"Leor Needleman, Nicolette Chun, Sathvika Sitaraman, Marilyn Tan, Deborah E Sellmeyer, Electron Kebebew, Justin P Annes","doi":"10.1093/jbmrpl/ziae149","DOIUrl":"10.1093/jbmrpl/ziae149","url":null,"abstract":"<p><p>Germline and somatic pathogenic variants in the <i>CDC73</i> gene, encoding the nuclear protein parafibromin, increase the risk for parathyroid carcinoma and cause hereditary primary hyperparathyroidism (PHPT) syndromes known as familial isolated hyperparathyroidism (FIHP) and hyperparathyroidism-jaw tumor syndrome (HPT-JT). The identification of pathogenic germline variants in PHPT-susceptibility genes can influence surgical planning for parathyroidectomy, guide screening for potential syndromic manifestations, and identify/exonerate at-risk family members. Numerous types of pathogenic germline variants have been described for <i>CDC73</i>-related conditions, including deletion, truncating, missense, and splice site mutations. Here, we report identification of a non-coding germline <i>CDC73</i> variant (<i>CDC73</i> c.1155-3A > G), previously categorized as a variant of uncertain significance (VUS), in a family with HPT-JT. This variant, found in two family members with PHPT, altered <i>CDC73</i> splicing in peripheral blood cells and disrupted parafibromin immunostaining in associated parathyroid adenomas, strongly evidencing its pathogenicity. Sestamibi scintigraphy yielded nondiagnostic localization results for both patients' parathyroid adenomas, consistent with prior studies suggesting lower sensitivity for small or cystic lesions. Our findings demonstrate key aspects of <i>CDC73</i>-related disorders, highlight the diagnostic value of RNA testing, and exemplify the importance of obtaining a thorough, three-generational family history.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"9 1","pages":"ziae149"},"PeriodicalIF":3.4,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11646312/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828561","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":"Low-calorie and high-protein diet has diverse impacts on the muscle, bone, and bone marrow adipose tissues.","authors":"Beatriz Coimbra Romano, Iana Mizumukai de Araújo, Mariana S P Ribeiro, Luciana T Parreiras E Silva, Ingid Dick-de-Paula, Sandra Y Fukada, Felipe Manoel Porto, Vanda Jorgetti, Francisco de Assis Pereira, Lucila Leico Kagohara Elias, Francisco José Albuquerque de Paula","doi":"10.1093/jbmrpl/ziae150","DOIUrl":"10.1093/jbmrpl/ziae150","url":null,"abstract":"<p><p>The present study was designed to evaluate the influence of a high-protein diet under conditions of calorie restriction (CR) in the muscle, adipose tissue, bone, and marrow adipose tissue (MAT). It included three groups of 20 female Wistar Hannover rats, fed with the following diets for 8 wk: control group (C) fed with an AIN93M diet, CR group (R) fed with an AIN-93M diet modified to 30% CR, and CR + high-protein group (H) fed with an AIN-93M diet modified to 30% CR with 40% protein. Body composition was determined by DXA. The femur was used for histomorphometry and the estimation of adipocytes. Microcomputed tomography (μCT) was employed to analyze the bone structure. Hematopoietic stem cells from the bone marrow were harvested for osteoclastogenesis. Body composition revealed that the gain in lean mass surpassed the increase in fat mass only in the H group. Bone histomorphometry and μCT showed that a high-protein diet did not mitigate CR-induced bone deterioration. In addition, the number of bone marrow adipocytes and the differentiation of hematopoietic stem cells into osteoclasts were higher in H than in the other groups. These results indicated that under CR, a high-protein diet was beneficial for muscle mass. However, as the μCT scanning detected significant bone deterioration, this combined diet might accentuate the detrimental effect on the skeleton caused by CR. Remarkably, the H group rats exhibited greater MAT expansion and elevated hematopoietic stem cell differentiation into osteoclasts than the CR and control counterparts. These data suggest that a high protein may not be an appropriate strategy to preserve bone health under CR conditions.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"9 1","pages":"ziae150"},"PeriodicalIF":3.4,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11646085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828571","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":"Sex hormone deficiency in male and female mice expressing the Alzheimer's disease-associated risk-factor TREM2 R47H variant impacts the musculoskeletal system in a sex- and genotype-dependent manner.","authors":"Roquelina Pianeta, Padmini Deosthale, Natasha Sanz, Rachel Kohler, Chiebuka Okpara, Matthew Arnett, Iqra Asad, Amber Rogers, Madison Gerbig, Alyson Essex, Ziyue Liu, Joseph M Wallace, Lilian I Plotkin","doi":"10.1093/jbmrpl/ziae144","DOIUrl":"10.1093/jbmrpl/ziae144","url":null,"abstract":"<p><p>The R47H variant of the triggering receptor expressed on myeloid cells 2 (TREM2) is a risk factor for Alzheimer's disease in humans and leads to lower bone mass accrual in female but not male 12-mo-old mice. To determine whether, as with aging, gonadectomy results in sex-specific musculoskeletal effects, gonad removal or SHAM surgery was performed in 4-mo-old TREM2^R47H/+ mice and WT male and female littermates (<i>n</i> = 10-12/group), with sexes analyzed separately. Body weight was lower in males, but higher in females after gonadectomy, independently of their genotype. Gonadectomy also leads to decreased BMD in males at all sites and in the whole body (total) and spine in female mice for both genotypes. Total and femur BMD was lower in gonadectomized male mice 6-wk post-surgery, independently of the genotype. On the other hand, BMD was only lower in ovariectomized WT but not TREM2^R47H/+ mice in all sites measured at this time point. Bone formation and resorption marker levels were not affected by orchiectomy, whereas CTX was higher 3 wk after surgery and P1NP showed a tendency toward lower values at the 6-wk time point only in ovariectomized WT mice. Micro-CT analyses showed no differences resulting from gonadectomy in structural parameters in femoral cortical bone for either sex, but lower tissue mineral density in males of either genotype 6-wk post-surgery. Nevertheless, biomechanical properties were overall lower in gonadectomized males of either genotype, and only for WT ovariectomized mice. Distal femur cancellous bone structure was also affected by gonadectomy in a genotype- and sex-dependent manner, with genotype-independent changes in males, and only in WT female mice. Thus, expression of the TREM2 R47H variant minimally alters the impact of gonadectomy in the musculoskeletal system in males, whereas it partially ameliorates the consequences of ovariectomy in female mice.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":"9 1","pages":"ziae144"},"PeriodicalIF":3.4,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11646090/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828663","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}