IF 3.6 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2025-10-30 DOI: 10.1016/j.bone.2025.117698

Martin Munteanu , Frank Rutsch , Yvonne Nitschke , Uwe Kornak , Cordula Kiewert , Julia Spiekermann , Jakob Höppner , Corinna Grasemann

Introduction

Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) is an ultra-rare disorder characterized by renal phosphate wasting and patients may exhibit an increased risk of vascular calcification. Phosphate supplementation, a standard treatment for hypophosphatemic rickets, may further increase this risk by elevating the calcium-phosphate product.

Aim

To expand the phenotypic spectrum of ARHR2 and heterozygous ENPP1 variant carriers and to review safety concerns related to phosphate supplementation in affected individuals.

Case report

We describe an 11-year follow-up of a pediatric patient with ARHR2, focusing on skeletal and extraskeletal manifestations, particularly the response to a brief period of phosphate supplementation. Additionally, we present a phenotypic analysis of four heterozygous family members, highlighting potential implications of carrier status.

Results

The patient was homozygous for the ENPP1 variant c.2677G > T, p.(Glu893*), exhibited progressive skeletal symptoms, and developed vascular calcifications following phosphate supplementation. Heterozygous family members showed mild alterations in bone and phosphate metabolism, suggesting a possible subclinical phenotype.

Conclusion

This case highlights the complexity of ARHR2 management, the importance of accurate genetic diagnosis, and concerns regarding the safety of phosphate supplementation. Close cardiovascular monitoring is essential, and future therapies should aim to correct phosphate imbalance without increasing calcification risk—potentially through combined treatment strategies or enzyme replacement therapy.

常染色体隐性低磷血症2型佝偻病（ARHR2）是一种以肾磷酸盐消耗为特征的超罕见疾病，患者可能表现出血管钙化的风险增加。磷酸盐补充，低磷血症佝偻病的标准治疗，可能进一步增加这种风险，通过提高钙-磷酸酯产品。目的：扩大ARHR2和杂合ENPP1变异携带者的表型谱，并回顾受影响个体补充磷酸盐的安全性问题。病例报告：我们对一名ARHR2儿童患者进行了11年的随访，重点关注骨骼和骨骼外表现，特别是对短暂补充磷酸盐的反应。此外，我们对四个杂合家族成员进行了表型分析，强调了携带者状态的潜在影响。结果：患者为ENPP1变异c.2677G > T, p.（Glu893*）纯合子，表现出进行性骨骼症状，并在补充磷酸盐后发生血管钙化。杂合子家族成员在骨和磷酸盐代谢方面表现出轻微的改变，提示可能的亚临床表型。结论：该病例强调了ARHR2治疗的复杂性，准确的遗传诊断的重要性，以及对磷酸盐补充安全性的关注。密切的心血管监测是必要的，未来的治疗应着眼于在不增加钙化风险的情况下纠正磷酸盐失衡——可能通过联合治疗策略或酶替代治疗。

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引用次数: 0

Loss of Tsc1 in Osterix-expressing cells leads to greater bone mass and strength in mice osterix表达细胞中Tsc1的缺失导致小鼠骨量和强度增加。

IF 3.6 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2025-10-30 DOI: 10.1016/j.bone.2025.117695

Han Kyoung Choi , Thomas Kim , Xiaoxi Wei , Karl J. Jepsen , Yuji Mishina , Nicholas Auyeung , Fei Liu

Tuberous sclerosis complex 1 (Tsc1) negatively regulates mTORC1 signaling, but its role in postnatal skeletal development is not fully understood. Previous studies using various Cre drivers to target osteoblasts or mesenchymal lineage cells have generally shown higher bone mass accompanied by disorganized bone structure. However, our earlier study using Osx-Cre-mediated Tsc1 deletion demonstrated that conditional knockout mice (CKO) had lower femoral trabecular bone at one month of age, but early lethality prevented later-stage assessment. Furthermore, how postnatal mTOCRC1 hyperactivation affects bone accrual and mechanical properties remains unknown. In this report, we first evaluated the cortical bone phenotype of one-month-old CKO mice using nanoCT, immunostaining, and quantitative PCR (qPCR). CKO mice exhibited greater cortical bone mass, elevated osteoblast markers (Alpl, Bsp, Col1a1, Ocn) and transcription factors (Runx2, Osx), enhanced periosteal proliferation in vivo, and upregulated proliferation of primary femur cortical bone-derived osteoblasts in vitro. To overcome early lethality and assess the impact of postnatal mTORC1 hyperactivation, we utilized the built-in doxycycline (Dox) Turn-Off system in Osx-Cre mice to suppress Cre activity until 2 months of age. Postnatal Tsc1 deletion from 2 to 5 months led to robust cortical and trabecular bone gains in the femur, calvariae, and vertebrae. Picrosirius Red staining demonstrated that the femoral cortical bone in CKO mice exhibited organized collagen with lamellar features, indicating preserved tissue quality. Importantly, four-point bending tests demonstrated significantly improved femoral mechanical strength in CKO mice. In summary, our data reveal differential effects of Tsc1 deletion on trabecular and cortical bone at an early postnatal stage, and show that postnatal deletion results in robust bone gain with enhanced mechanical strength. These findings provide a more complete understanding of Tsc1-mTORC1 signaling as a key regulator of bone mass and challenge the assumption that mTORC1 hyperactivation yields mechanically inferior bone.

结节性硬化症复合体1 （Tsc1）负调控mTORC1信号，但其在出生后骨骼发育中的作用尚不完全清楚。先前使用各种Cre驱动因子靶向成骨细胞或间充质系细胞的研究通常显示出更高的骨量伴随着无序的骨结构。然而，我们早期使用osx - cre介导的Tsc1缺失的研究表明，条件敲除小鼠（CKO）在1月龄时具有较低的股小梁骨，但早期致命性阻碍了后期评估。此外，出生后mTOCRC1的过度激活如何影响骨的积累和力学性能仍然未知。在本报告中，我们首先使用纳米oct、免疫染色和定量PCR （qPCR）评估了1月龄CKO小鼠的皮质骨表型。CKO小鼠表现出更大的皮质骨量，升高的成骨细胞标志物（Alpl, Bsp, Col1a1, Ocn）和转录因子（Runx2, Osx），体内骨膜增殖增强，体外原发性股骨皮质骨源性成骨细胞增殖上调。为了克服早期致死率并评估出生后mTORC1过度激活的影响，我们在Osx-Cre小鼠中使用内置的多西环素（Dox）关闭系统抑制Cre活性直到2 个月大。出生后2至5 个月的Tsc1缺失可在股骨、颅骨和椎骨中产生强健的皮质骨和骨小梁骨。小天狼星红染色显示，CKO小鼠股骨皮质骨显示有组织的胶原，具有板层状特征，表明组织质量保存完好。重要的是，四点弯曲试验显示CKO小鼠股骨机械强度显著提高。总之，我们的数据揭示了Tsc1缺失对出生后早期骨小梁和皮质骨的不同影响，并表明出生后缺失导致骨生长强劲，机械强度增强。这些发现为Tsc1-mTORC1信号作为骨量的关键调节因子提供了更完整的理解，并挑战了mTORC1过度激活产生机械劣等骨的假设。

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引用次数: 0

Cathepsin K-lineage cells and mechanical loading independently modulate bone mass in the murine tibia 组织蛋白酶k系细胞和机械负荷独立调节小鼠胫骨骨量。

IF 3.6 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2025-10-29 DOI: 10.1016/j.bone.2025.117693

Tyler J. McNeill , Seoyeon Bok , Branden R. Sosa , Michelle Cung , Matthew B. Greenblatt , Marjolein C.H. van der Meulen

The ability of bone to adapt to external mechanical loads has been extensively studied, with mechanical stimuli increasing cortical and cancellous bone mass. However, the stem cell basis underlying this response is not well understood. To date, most studies focused on the role of differentiated cell populations in the skeletal response to loading. A recently discovered periosteal-specific skeletal stem cell marked by cathepsin K (CTSK) that drives intramembranous bone formation is a promising candidate to mediate load-induced bone formation. In this study, we sought to determine the influence of CTSK-lineage cells on the skeletal response to mechanical loading. We ablated cells expressing CTSK prior to initiating cyclic tibial compression for two weeks beginning at 16 weeks of age. We analyzed cortical and cancellous bone morphology at the tibial metaphysis and cortical bone morphology at the mid-diaphysis. Loading increased cortical, but not cancellous, bone mass. The amount of bone formed in response to loading did not differ when CTSK-expressing cells were ablated. CTSK-lineage cell ablation increased cortical bone mass primarily in regions subjected to tension and loading predominantly affected regions of bone under compression. To analyze the material composition of load-induced bone, we performed Raman spectroscopy along the periosteal surface of the diaphysis. CTSK-lineage cell ablation altered the influence of loading on B-type carbonate substation, a measure of tissue age. Overall, the amount of bone formed in response to loading did not differ in the absence of CTSK-lineage cells, but the material composition of load-induced cortical tissue was altered.

骨适应外部机械负荷的能力已被广泛研究，机械刺激增加皮质和松质骨量。然而，这种反应背后的干细胞基础尚不清楚。迄今为止，大多数研究集中在分化细胞群在骨骼对负荷反应中的作用。最近发现的由组织蛋白酶K （CTSK）标记的骨膜特异性骨干细胞驱动膜内骨形成，是介导负荷诱导骨形成的有希望的候选者。在这项研究中，我们试图确定ctsk谱系细胞对骨骼对机械负荷反应的影响。我们在16 周龄开始循环胫骨压迫前消融表达CTSK的细胞，持续两周。我们分析了胫骨干骺端皮质骨和松质骨的形态以及骨干中部皮质骨的形态。负荷增加了皮质骨量，但没有增加松质骨量。当ctsk表达细胞被消融时，响应负载形成的骨量没有差异。ctsk系细胞消融增加皮质骨量，主要是在受张力和负荷影响的区域，主要是受压迫的骨骼区域。为了分析载荷诱导骨的材料组成，我们沿着骨干骨膜表面进行了拉曼光谱分析。ctsk谱系细胞消融改变了负荷对b型碳酸盐变电所的影响，这是组织年龄的衡量标准。总体而言，在缺乏ctsk谱系细胞的情况下，响应负载形成的骨量没有差异，但负载诱导的皮质组织的物质组成发生了改变。

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引用次数: 0

Corrigendum to “Calorie restriction induces mandible bone loss by regulating mitochondrial function” [Bone 2025 Jan. 190:117326. doi: 10.1016/j.bone.2024.117326] “卡路里限制通过调节线粒体功能导致下颌骨骨质流失”的更正[骨2025年1月190日：117326]。doi: 10.1016 / j.bone.2024.117326]。

IF 3.6 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2025-10-29 DOI: 10.1016/j.bone.2025.117692

Linyi Liu , Phuong T. Le , Victoria E. DeMambro , Tiange Fengª , Hanghang Liu , Wangyang Ying , Roland Baron , Clifford J. Rosen

引用次数: 0

Reconsidering bone–muscle interactions in obese older adults with type 2 diabetes: Methodological limitations and future directions 重新考虑肥胖老年2型糖尿病患者骨肌相互作用：方法学局限性和未来方向。

IF 3.6 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2025-10-28 DOI: 10.1016/j.bone.2025.117699

Shangxuan Li

引用次数: 0

Revealing early subchondral bone structural changes in osteoarthritis progression in a collagenase-induced mouse model using microCT 在胶原酶诱导的小鼠模型中使用微ct揭示骨关节炎进展的早期软骨下骨结构变化。

IF 3.6 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2025-10-27 DOI: 10.1016/j.bone.2025.117687

Han Liu , Zihui Li , Catherine E. Davey , Kathryn S. Stok

Osteoarthritis (OA) is the most prevalent joint disorder affecting millions of people worldwide, and involves deterioration to subchondral bone. This study aims to reveal the early bone microstructural changes at high temporal resolution in a small animal model of OA with joint laxity and inflammation.

Seventy-five male C57BI/10 mice aged nine weeks were recruited and assigned to three cross-sectional cohorts, baseline, control, and OA. Of these, forty-seven ten-week-old mice assigned to the OA cohort received intra-articular injection of collagenase on the right knee to destabilize the right tibiofemoral joint. Micro-computed tomography (microCT) scan was performed after humanely killing the mice at nine time points (eight weeks in total). Quantitative morphometric analysis (QMA) was performed to measure structure of subchondral cortical and epiphyseal femoral and tibial bone, and osteophyte activity.

Early pathological changes caused by collagenase-injection were characterized by bone morphometry measures and osteophyte detection. Compared to control joints, bone loss, lower bone volume fraction, thinner trabeculae, larger trabecular spacing, smaller trabecular number, thinner cortical bone, and osteophyte formation were observed in osteoarthritic joints at multiple time points, with changes detectable as early as one week post disease induction. Additionally, a non-linear pattern of structural changes was observed throughout the experiment, with a critical transition occurring within three weeks after disease induction. These findings underscore the necessity of early and frequent quantification to capture rapidly changing bone microstructure alterations in early stage of OA, potentially enabling earlier diagnosis, intervention, and treatment of OA.

骨关节炎（OA）是影响全世界数百万人的最常见的关节疾病，涉及软骨下骨的恶化。本研究旨在以高时间分辨率揭示骨性关节炎伴关节松弛和炎症的小动物模型的早期骨微结构变化。招募了75只9周龄雄性C57BI/10小鼠，并将其分配到三个横断面队列：基线组、对照组和OA组。其中，47只10周大的小鼠被分配到OA组，在右膝关节内注射胶原酶来破坏右胫股关节的稳定。在9个时间点（共8周）人道杀死小鼠后进行微计算机断层扫描（microCT）。采用定量形态学分析（QMA）测定软骨下皮质骨、骨骺、股骨和胫骨的结构及骨赘活性。采用骨形态测定和骨赘检测对胶原酶注射后的早期病理改变进行表征。与对照关节相比，骨关节炎关节在多个时间点观察到骨丢失、骨体积分数降低、小梁变薄、小梁间距变大、小梁数目变小、皮质骨变薄和骨赘形成，这些变化早在疾病诱发后一周就可以检测到。此外，在整个实验过程中观察到非线性结构变化模式，在疾病诱发后三周内发生关键转变。这些发现强调了早期和频繁量化的必要性，以捕获OA早期快速变化的骨微观结构改变，从而有可能实现OA的早期诊断、干预和治疗。

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引用次数: 0

Response to the letter to the editor: “Comparative effectiveness of romosozumab versus teriparatide for fracture prevention: A new-user, active comparator design” 对致编辑的信的回应：“在骨质疏松研究中使用日本索赔数据库作为真实证据的结构性挑战”。

IF 3.6 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2025-10-27 DOI: 10.1016/j.bone.2025.117696

Ryoji Tominaga , Tatsuyoshi Ikenoue , Ryosuke Ishii , Noriaki Kurita , Masataka Taguri

引用次数: 0

In C57BL/6J mice, weight loss in previously obese mice reduced bone mass and shifted the cortical bone metabolome 在C57BL/6J小鼠中，先前肥胖小鼠的体重减轻减少了骨量并改变了皮质骨代谢组。

IF 3.6 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2025-10-27 DOI: 10.1016/j.bone.2025.117690

Carolyn Chlebek , Casey McAndrews , Benjamin Aaronson , Hope D. Welhaven , Kanglun Yu , Samantha N. Costa , Joseph Shaver , Sophia Silvia , Victoria E. DeMambro , Ronald K. June , Meghan E. McGee-Lawrence , Clifford J. Rosen

Obesity is linked to increased fracture risk. Despite the negative effects of weight loss on the skeleton, patients with obesity are advised to lose weight via calorie restriction. Obesity and weight loss individually alter both whole-body and local metabolism. Little is known about changes to bone mass and metabolome following calorie restriction in obese preclinical models. We hypothesized that caloric restriction would reduce bone mass in obese mice and would alter the cortical bone metabolome. To induce obesity, 8-week-old male and female C57BL/6J mice received 60 % kCal high-fat diet for 12 weeks. From 20 to 30 weeks of age, mice either remained obese or lost weight through 30 % caloric restriction. Controls consumed 10 % kCal low-fat diet. Compared to obesity, calorie restriction elicited cortical bone loss and trabecular thinning. Weight loss also reduced bone formation. Both obesity and subsequent calorie restriction altered the cortical bone metabolome in a sex-dependent manner. Metabolic pathways altered with diet generally mapped to amino acid or fatty acid metabolism. In males, weight loss was associated with a downregulation of pathways related to tryptophan, tyrosine, ubiquinone, and fatty acids. In females, calorie restriction downregulated taurine and hypotaurine metabolism but upregulated pyrimidine metabolism, nicotinate and nicotinamide metabolism, and pantothenate and CoA biosynthesis. In summary, despite improvements in components of systemic metabolism, caloric restriction in obese preclinical models reduced bone mass and did not restore the cortical metabolome to control conditions.

肥胖与骨折风险增加有关。尽管减肥对骨骼有负面影响，但建议肥胖患者通过限制卡路里来减肥。肥胖和减肥分别改变了全身和局部的新陈代谢。在肥胖临床前模型中，对卡路里限制后骨量和代谢组的变化知之甚少。我们假设热量限制会减少肥胖小鼠的骨量，并改变皮质骨代谢组。为了诱导肥胖，8周龄的雄性和雌性C57BL/6 J小鼠给予60 % kCal高脂肪饮食12 周。从20到30 周龄，小鼠要么保持肥胖，要么通过30% %的热量限制减肥。对照组食用10 %千卡的低脂饮食。与肥胖相比，热量限制引起皮质骨丢失和小梁变薄。减肥也会减少骨骼的形成。肥胖和随后的卡路里限制都以性别依赖的方式改变了皮质骨代谢组。随饮食改变的代谢途径通常与氨基酸或脂肪酸代谢有关。在男性中，体重减轻与色氨酸、酪氨酸、泛醌和脂肪酸相关通路的下调有关。在女性中，热量限制下调了牛磺酸和次牛磺酸的代谢，但上调了嘧啶代谢、烟酸和烟酰胺代谢以及泛酸和辅酶a的生物合成。总之，尽管改善了全身代谢成分，但在肥胖临床前模型中，热量限制减少了骨量，并没有使皮质代谢组恢复到控制状态。

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引用次数: 0

The C-type lectin receptor mincle is functionally expressed by murine bone cells and can mediate inflammatory osteoblast responses to Staphylococcus aureus c型凝集素受体微环在小鼠骨细胞中功能性表达，可介导炎性成骨细胞对金黄色葡萄球菌的反应

IF 3.6 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2025-10-25 DOI: 10.1016/j.bone.2025.117689

Erin L. Mills , Quinton A. Krueger , Aiza Noyal , M. Brittany Johnson , Ian Marriott

It is now apparent that osteoblasts and osteoclasts have immune functions that play a critical role in shaping host responses and the abnormal bone remodeling associated with staphylococcal infections. Both cell types express various pattern recognition receptors (PRRs) that enable them to perceive pathogens and initiate the production of mediators that can exacerbate infection-induced inflammatory bone loss. Macrophage-inducible C-type lectin (Mincle) is a tyrosine activation motif–coupled PRR that can recognize glycolipids from diverse pathogens to initiate inflammatory mediator production. In the lung, an important role for Mincle has been suggested in host defense against Gram positive bacteria. In the present study, we report that RNA Tag-Seq analysis of S. aureus infected murine osteoclasts and osteoblasts revealed enrichment of genes associated with C-type lectin receptor-mediated responses and elevated expression of mRNA encoding Mincle and its key downstream signaling components. We have found robust levels of Mincle protein in murine osteoclasts and osteoblasts, and demonstrated the inducible expression of this molecule in primary human osteoblasts. The functional nature of Mincle expression by osteoclasts and osteoblasts was confirmed by the ability of Mincle-specific agonists to elicit inflammatory cytokine production by these cells. Importantly, we have shown that the cytokine responses of S. aureus challenged murine and human osteoblasts are attenuated following Mincle blockade. Together, these studies support the assertion that bone cells functionally express Mincle and that this C-type lectin can mediate, at least in part, the inflammatory immune responses of osteoblasts to S. aureus challenge.

现在很明显，成骨细胞和破骨细胞具有免疫功能，在形成宿主反应和与葡萄球菌感染相关的异常骨重塑中起关键作用。这两种细胞类型都表达各种模式识别受体（PRRs），使它们能够感知病原体并启动可加剧感染诱导的炎症性骨质流失的介质的产生。巨噬细胞诱导的c型凝集素（Mincle）是一种酪氨酸激活基元偶联的PRR，可以识别来自不同病原体的糖脂，从而启动炎症介质的产生。在肺部，Mincle已被认为在宿主防御革兰氏阳性细菌中起重要作用。在本研究中，我们报告了对金黄色葡萄球菌感染的小鼠破骨细胞和成骨细胞的RNA Tag-Seq分析显示，与c型凝集素受体介导的应答相关的基因富集，编码Mincle及其关键下游信号成分的mRNA表达升高。我们在小鼠破骨细胞和成骨细胞中发现了强大的Mincle蛋白水平，并证明了该分子在原代人成骨细胞中的诱导表达。Mincle特异性激动剂能够诱导这些细胞产生炎性细胞因子，证实了破骨细胞和成骨细胞表达Mincle的功能性质。重要的是，我们已经表明，金黄色葡萄球菌挑战小鼠和人类成骨细胞的细胞因子反应在Mincle阻断后减弱。总之，这些研究支持骨细胞功能表达Mincle的断言，并且这种c型凝集素可以至少部分地介导成骨细胞对金黄色葡萄球菌攻击的炎症免疫反应。

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引用次数: 0

A review of bone fracture healing modelling: from mechanobiological theory to personalized rehabilitation protocols 骨折愈合模型的综述：从机械生物学理论到个性化康复方案。

IF 3.6 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2025-10-21 DOI: 10.1016/j.bone.2025.117688

Lunjian Li , Minoo Patel , Lihai Zhang

Despite standard rehabilitation protocols, many patients still suffer from limited mobility, delayed union, or even non-union. This underscores the need for personalized rehabilitation protocols. Fracture healing is a dynamic process governed by the interplay of mechanical stimuli and biochemical signalling pathways. This review first summarizes current understanding of the biological and mechanobiological mechanisms that regulate bone repair. It also discusses different simulation models, including the finite element method (FEM), agent-based models (ABM), reaction–diffusion models (RDM), and machine learning (ML), and evaluates their respective strengths. Recent advances in patient-specific models are also reviewed, particularly those integrating CT-derived geometry, bone properties, and musculoskeletal (MSK) loading. These approaches enable individualized predictions of healing and can inform clinical rehabilitation strategies. Finally, the key challenges and future priorities for implementing these technologies in clinical practice are discussed, providing insights to support the development of more precise and patient-specific fracture care.

尽管有标准的康复方案，许多患者仍然受到活动受限，延迟愈合，甚至不愈合的困扰。这强调了个性化康复方案的必要性。骨折愈合是一个机械刺激和生化信号通路相互作用的动态过程。这篇综述首先总结了目前对调节骨修复的生物学和机械生物学机制的理解。它还讨论了不同的仿真模型，包括有限元法（FEM）、基于代理的模型（ABM）、反应扩散模型（RDM）和机器学习（ML），并评估了它们各自的优势。本文还回顾了患者特异性模型的最新进展，特别是那些整合了ct衍生几何、骨特性和肌肉骨骼（MSK）载荷的模型。这些方法可以实现个性化的康复预测，并可以为临床康复策略提供信息。最后，讨论了在临床实践中实施这些技术的关键挑战和未来的优先事项，为支持更精确和患者特异性骨折护理的发展提供了见解。

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引用次数: 0

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