运动；机械负荷；CGRP；骨质疏松；骨代谢

Osteoporosis is a systemic metabolic bone disease characterized by decreased bone mass, destruction of bone microstructure, and increased risk of fractures. Traditional views mainly attribute it to an imbalance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption, but increasing evidence suggests that the pathogenesis and progression of osteoporosis are also regulated by complex interactions among the nervous system, immune system, and skeletal system. The neuro-immune-bone axis provides an important framework for integrating the bidirectional regulation between innervation, immune microenvironment, and bone remodeling process. This article systematically reviews the basis of interactions among sensory nerves, sympathetic nerves, immune cells, and bone cells in bone homeostasis, with a focus on the roles of sympathetic nerve activation, sensory neuropeptide imbalance, and immune inflammatory remodeling in the progression of osteoporosis. Furthermore, this article compares the differential imbalance patterns of this axis in postmenopausal osteoporosis, age-related osteoporosis, and secondary osteoporosis, and accordingly discusses its potential significance for disease classification and risk identification. At the therapeutic level, this article further distinguishes between clinically well-established management strategies and mechanistic interventions still in the exploratory stage. The former includes guideline-recommended anti-osteoporosis drugs, exercise, nutritional support, fall prevention, and control of primary diseases; the latter includes strategies such as sympathetic nerve regulation, CGRP-related interventions, Treg/Th17 balance regulation, and macrophage polarization, which are currently mainly based on animal experiments, mechanistic studies, observational evidence, or early translational research and cannot yet be considered routine clinical treatment. Therefore, the neuro-immune-bone axis is currently more suitable as a theoretical framework to explain the heterogeneity of osteoporosis and guide mechanistic research, and its practical value in precise classification, treatment selection, and clinical decision-making still requires further validation through prospective cohort and intervention trials. By integrating existing evidence, this article aims to offer a theoretical foundation for understanding the multi-system interaction mechanisms of osteoporosis, establishing an evidence stratification framework, and exploring future individualized interventions.

Multi-axis interactions among the skeletal system, immune system, and gut microbiota (GM) have become a prominent focus of interdisciplinary research. The brain–bone–gut axis, proposed in recent years, provides an integrative physiological framework describing a bidirectional regulatory network linking the central nervous system, bone metabolism, and the GM via neural, endocrine, and immune pathways, thereby offering a unified perspective on multi-organ comorbidities. This article systematically examines the interconnections and synergistic effects across three core pathways within this framework: the brain–bone axis, the gut–bone axis, and the gut–brain axis. It further emphasizes immune-inflammatory processes as a central hub that connects gut dysbiosis with bone metabolic disturbances and alterations in brain function. On this basis, we propose an integrated approach that combines microecological interventions with nutritional and exercise management to improve gut homeostasis, preserve skeletal health, and support brain function, with the overarching aim of generating coordinated benefits across organ systems.

Substance P (SP) is a neuropeptide that is released from sensory nerve endings and is widely present in nerve fibers. It acts on bones and related tissues by binding to receptors, thereby regulating bone metabolism, cartilage metabolism, and fracture healing. SP has attracted widespread attention as a signaling substance that can be recognized by both the immune system and the nervous system. Previous studies have shown that bone and chondrocytes can synthesize and secrete sensory neuropeptides and express their receptors, and can promote proliferation, differentiation, apoptosis, matrix synthesis, and the degradation of target cells through autocrine/paracrine modes. In this paper, we review the research progress made in this field in recent years in order to provide a reference for further understanding the regulatory mechanism of bone and cartilage physiology and pathological metabolism.

For the past two decades, the function of intrabony nerves on bone has been a subject of intense research, while the function of bone on intrabony nerves is still hidden in the corner. In the present review, the possible crosstalk between bone and intrabony peripheral nerves will be comprehensively analyzed. Peripheral nerves participate in bone development and repair via a host of signals generated through the secretion of neurotransmitters, neuropeptides, axon guidance factors and neurotrophins, with additional contribution from nerve‐resident cells. In return, bone contributes to this microenvironmental rendezvous by housing the nerves within its internal milieu to provide mechanical support and a protective shelf. A large ensemble of chemical, mechanical, and electrical cues works in harmony with bone marrow stromal cells in the regulation of intrabony nerves. The crosstalk between bone and nerves is not limited to the physiological state, but also involved in various bone diseases including osteoporosis, osteoarthritis, heterotopic ossification, psychological stress‐related bone abnormalities, and bone related tumors. This crosstalk may be harnessed in the design of tissue engineering scaffolds for repair of bone defects or be targeted for treatment of diseases related to bone and peripheral nerves.

Bone tissue is highly vascularized due to the various roles bone blood vessels play in bone and bone marrow function. For example, the vascular system is critical for bone development, maintenance and repair, and provides O2, nutrients, waste elimination, systemic hormones, and precursor cells for bone remodeling. Further, bone blood vessels serve as egress and ingress routes for blood and immune cells to and from the bone marrow. It is becoming increasingly clear that the vascular and skeletal systems are intimately linked in metabolic regulation and physiological and pathological processes. This review examines how agents such as mechanical loading, parathyroid hormone, estrogen, vitamin D and calcitonin, all considered anabolic for bone, have tremendous impacts on the bone vasculature. In fact, these agents influence bone blood vessels prior to impacting bone. Further, data reveal strong associations between vasodilator capacity of bone blood vessels and trabecular bone volume, and poor associations between estrogen status and uterine mass and trabecular bone volume. Additionally, this review highlights the importance of the bone microcirculation, particularly the vascular endothelium and NO-mediated signaling, in the regulation of bone blood flow, bone interstitial fluid flow and pressure, and the paracrine signaling of bone cells. Finally, the vascular endothelium as a mediator of bone health and disease is considered.

… expression of calcitonin gene related peptide (CGRP) and … the effects of LSPL infrasound on bone metabolism in vivo, and also … oscillation like physical exercise had valid osteogenesis …

Purpose: The aim of this study was to examine the inhibitory effect of teriparatide (TPTD) on pain and on bone loss in ovariectomized (OVX) mice. The mechanism of osteoporotic pain in OVX mice was evaluated through an examination of pain-related behavior as well as immunohistochemical examinations. Methods: Eight-week-old female ddY mice were OVX and assigned to one of three groups: (1) OVX mice treated with vehicle (OVX), (2) OVX mice treated with teriparatide (OVX-TPTD), or (3) SHAM-operated mice treated with vehicle (SHAM). Starting immediately after surgery, vehicle or TPTD was injected subcutaneously. After a 4-week treatment, mechanical sensitivity was tested using von Frey filaments. The proximal tibial metaphyses were analyzed three-dimensionally by microcomputed tomography (μCT). Calcitonin gene-related peptide (CGRP) and transient receptor potential channel vanilloid 1 (TRPV1) expressions in L3–5 dorsal root ganglion (DRG) neurons were examined using immunohistochemistry. Results: Ovariectomy induced bone loss and mechanical hyperalgesia in the hind limbs with upregulation of CGRP and TRPV1 expressions in DRG neurons innervating the hind limbs. Bone loss was prevented more effectively in the OVX-TPTD mice than in the OVX mice. Furthermore, mechanical hyperalgesia and upregulation of CGRP and TRPV1 expressions were significantly lower in the OVX-TPTD mice than in the OVX mice. Conclusion: TPTD treatment prevented ovariectomy-induced bone loss and ovariectomy-induced mechanical hyperalgesia in hind limbs, and it suppressed CGRP and TRPV1 expressions in DRG neurons. These results suggest that TPTD is useful for the treatment of osteoporotic pain in postmenopausal women.

… articles evaluating bone metabolism and mechanisms for the ensuing putative bone loss in adult … that impact bone metabolism at baseline in obese subjects and post-RYGB procedure. …

OBJECTIVE This study aims to assess research trends on the association between osteoporosis and the Central Nervous System, investigate global research trends in this area, and systematically review their relationship. METHODS The Web of Science core collection database, PubMed database, and Scopus database were searched for relevant publications from 2015 to 2025, and countries, institutions, authors, keywords, and literature were analyzed and visualized using bibliometric software CiteSpace.6.4.1, Vosviewer 1.6.20, BICOMB, and gCLUTO to investigate scientific achievements, research collaboration networks, research hot spots, and research trends. RESULTS A total of 3062 articles published between 2015 and 2025 were retrieved from the Web of Science Core Collection, PubMed database, Scopus database, and analyzed using VOSviewer and CiteSpace. Results showed steady growth in publication volume, with the United States as the leading contributor. PLOS ONE is the journal with the highest citation count. Key authors and institutions included Liu, Yang, the South China University of Technology, and Harvard University. Major keywords included "cognitive impairment", "inflammatory response", "glutamic acid", "PTH", and "mesenchymal stem cells" represent current and forward-looking future research trends and target themes in the field. CONCLUSIONS This study employs bibliometrics to explore the interactions between osteoporosis and the central nervous system. The findings suggest that cognitive impairment, particularly Alzheimer's disease, exerts adverse effects on osteoporosis-related bone metabolism, with more pronounced impacts observed in women. Glutamate, inflammatory cytokines, and mesenchymal stem cells serve as key mediators in bone-brain communication. Concurrently, parathyroid hormone regulates bone metabolism by modulating the HPA axis, while excessive HPA axis activation promotes the development of osteoporosis. Notably, the "bone-brain axis" theory has deepened our understanding of how the central nervous system regulates skeletal metabolism. It reveals mechanisms whereby the brain transmits signals through regions like the hypothalamus, triggering a cascade of mediators that modulate osteoblast and osteoclast activity. This insight encourages researchers to adopt a holistic perspective, emphasizing not only the skeletal system itself but also the critical influence of brain state on the onset and progression of osteoporosis.

Osteoporosis, a metabolic disorder, remains challenging to treat due to limited understanding of its underlying mechanism. The annual cycle of “cyclic physiological osteoporosis (CPO)” and its full reversal in male deer represents a unique natural model for studying this condition. Deer antlers, weighing up to 25 kg/pair, derive over 60% of their mineral contents from deer skeleton during mineralization. Based on the literature, we propose to divide CPO and its reversal into two phases: Phase I (approximately 115 days): from hard antler casting to the end of antler linear growth, marked by simultaneous robust antler ossification and CPO development; and Phase II (up to 165 days): from end of Phase I to the onset of antler skin shedding, characterized by complete antler mineralization and CPO reversal. This review analyzes the paradoxical occurrence of robust antler ossification and skeleton CPO within the same endocrine microenvironment during phase I; total antler mineralization and full reversal of deer skeleton CPO in phase II. Furthermore, we will discuss potential insights for osteoporosis treatment using deer materials from the period of Phase II. Our goal is to identify novel substances and therapies that could be applied in clinical setting to effectively treat osteoporosis.

Osteoporosis is a systemic metabolic disease, mainly characterized by reduced bone mineral density and destruction of bone tissue microstructure. However, the molecular mechanisms of osteoporosis need further investigation and exploration. Increasing studies have reported that circular RNAs (circRNAs), a novel type of RNA molecule, play crucial roles in various physiological and pathological processes and bone-related diseases. Based on an in-depth understanding of their roles in bone development, we summarized the multiple regulatory roles and underlying mechanisms of circRNA–miRNA–mRNA networks in the treatment of osteoporosis, associated with bone marrow mesenchymal stem cells (BMSCs), osteoblasts, and osteoclasts. Deeper insights into the vital roles of circRNA–miRNA–mRNA networks can provide new directions and insights for developing novel diagnostic biomarkers and therapeutic targets in the treatment of osteoporosis.

Dear Editor, Migraine is a debilitating headache characterized by pulsating quality, and is often on one side of the head and aggravated by movement. Excessive bone resorption due to osteoclast activity can lead to diminished bone strength. Although it may appear ambiguous, a recent study by Wu et al.1 suggested a pathophysiological link between osteoporosis and migraine. Magnesium and vitamin D levels are known to be vital for proper bone function, while they may regulate the frequency of migraines2 by shaping nociceptive processes in unmyelinated calcitonin gene-related peptide (CGRP)-positive neurons, a process also influenced by ovarian hormones.3 Inflammatory mediators such as certain interleukins and tumor necrosis factor-α contribute to endothelial dysfunction and pain pathways in migraine,4 and exerts a significant influence on bone turnover that induces osteoporosis. Moreover, inflammatory mediators play roles in activating the trigeminovascular system, which in turn releases proinflammatory substances, particularly CGRP. Elevated CGRP levels have also been found in subjects with osteoporosis and may indirectly regulate osteoclast activity.5 Furthermore, both of these diseases include high prevalence rates of migraine and osteoporosis in patients with inflammatory bowel disease,6 possibly due to multiple factors such as gut microbiota profile, stress hormones, nutrients, and neuropeptides that affect different intestinal bacterial strains.7 Finally, migraine causes social withdrawal with a consequent reduction in motor activity, and less exposure to light due to a reaction from photophobia. We present 19 patients with migraine who presented pathological bone turnover. In our private clinic, we evaluated 19 Italian adult patients (15 fertile females and 4 males) aged between 20 and 40 years over the course of 1 year. These patients were suffering from migraine with aura or migraine without aura according to the third edition of the International Classification of Headache Disorders (ICHD-3), or one or more migraine attacks per month for at least 6 months. All subjects did not show associated comorbidities or present a history of fragility fracture. All patients were not sedentary, followed a Mediterranean diet, and had body mass indices of 18.42–25.12 kg/m2 (Table 1). However, we did not further detail exercise capacity, smoking, or alcohol consumption in detail. None of the patients had taken prophylactic or contraceptive therapies within the past 5 years, and they utilized nonsteroidal anti-inflammatory drugs or triptans for symptomatic therapy. The sex, age, and migraine frequency distributions are listed in Table 1. The findings of physical and neurological examinations were unremarkable for all patients. Considering the frequent vitamin D deficiency in patients with migraine, we also performed bone profile laboratory tests. Serological tests were performed under fasting conditions and without taking into account the menstrual cycle for females. Complete blood count, calcium, phosphate, creatinine, alkaline phosphatase, aminotransferases, thyroid-stimulating hormone, and parathyroid hormone levels were within their respective normal ranges. Vitamin D deficiency or insufficiency (defined as <20, and ≥20 and <30 ng/mL 25[OH]D, reAlberto Lerario

The skeletal system is an important support structure in the human body, and its homeostatic state is highly relevant to the development of a wide range of orthopaedic diseases. The search for key regulatory factors associated with skeletal development is essential for exploring potential therapeutic targets for bone diseases. Nerve Growth Factor (NGF), the first neurotrophic factor to be discovered, plays an important role in regulating immune cell function, influencing angiogenesis and participating in the physiological and pathological processes of bone homeostasis. Here, we mainly review the biological functions of NGF in the skeletal system and its molecular mechanisms, analyse the pathophysiological roles of the NGF signaling pathway in skeletal diseases such as osteoporosis, osteoarthritis, and fracture healing, and summarize the progress and challenges of the current clinical research on therapeutic strategies targeting NGF. In addition, we provide an overview of NGF and highlight the role of NGF in the regulation of bone formation and bone resorption. Therefore, by reviewing the literature related to NGF and bone diseases, this paper summarises the specific regulatory mechanisms of NGF in various bone diseases, which provides new perspectives and intervention targets for the treatment of skeletal diseases, especially in the field of diseases in which the effects of traditional treatments are limited. The therapeutic strategies targeting neurotrophic factors show broad prospects for clinical application.

… NPY have been detected after exercise and SP circulating levels … Recent studies suggest that CGRP may act on bone … only in nociception, but also in bone turnover, inflammation and …

Osteoporosis is a prevalent complication of diabetes, characterized by systemic metabolic impairment of bone mass and microarchitecture, particularly in the spine. Anemarrhenae Rhizoma/Phellodendri Chinensis Cortex (AR/PCC) herb pair has been extensively employed in Traditional Chinese Medicine to manage diabetes; however, its potential to ameliorate diabetic osteoporosis (DOP) has remained obscure. Herein, we explored the protective efficacy of AR/PCC herb pair against DOP using a streptozotocin (STZ)‐induced rat diabetic model. Our data showed that AR/PCC could effectively reduce the elevated fasting blood glucose and reverse the osteoporotic phenotype of diabetic rats, resulting in significant improvements in vertebral trabecular area percentage, trabecular thickness and trabecular number, while reducing trabecular separation. Specifically, AR/PCC herb pair improved impaired osteogenesis, nerve ingrowth and angiogenesis. More importantly, it could mitigate the aberrant activation of osteoblast pyroptosis in the vertebral bodies of diabetic rats by reducing increased expressions of Nlrp3, Asc, Caspase1, Gsdmd and IL‐1β. Mechanistically, AR/PCC activated antioxidant pathway through the upregulation of the antioxidant response protein Nrf2, while concurrently decreasing its negative feedback regulator Keap1. Collectively, our in vivo findings demonstrate that AR/PCC can inhibit osteoblast pyroptosis and alleviate STZ‐induced rat DOP, suggesting its potential as a therapeutic agent for mitigating DOP.

BackgroundOsteoporosis and migraine are both important public health problems and may have overlapping pathophysiological mechanisms. The aim of this study was to use a Taiwanese population-based dataset to assess migraine risk in osteoporosis patients.MethodsThe Taiwan National Health Insurance Research Database was used to analyse data for 40,672 patients aged ≥20 years who had been diagnosed with osteoporosis during 1996–2010. An additional 40,672 age-matched patients without osteoporosis were randomly selected as the non-osteoporosis group. The relationship between osteoporosis and migraine risk was estimated using Cox proportional hazard regression models.ResultsDuring the follow-up period, 1110 patients with osteoporosis and 750 patients without osteoporosis developed migraine. After controlling for covariates, the overall incidence of migraine was 1.37-fold higher in the osteoporosis group than in the non-osteoporosis group (3.72 vs. 1.24 per 1000 person-years, respectively). Migraine risk factors included high Charlson Comorbidity Index score, female gender, hypertension, depression, asthma, allergic rhinitis, obesity, and tobacco use disorder.ConclusionsOur results indicate that patients with a history of osteoporosis had a higher risk of migraine.

… , allowing normal or physiological bone remodeling. By elevating … CGRP was found to be greater on the concave side with mechanical loading than the convex with much less loading, …

… mechanical stability during the early stages of bone healing. … (CGRP), thereby potently inducing angiogenesis and bone … and mechanical loading synergistically enhance bone quality…

Calcitonin gene-related peptide (CGRP) has 37 amino acids. Initially, CGRP had vasodilatory and nociceptive effects. As research progressed, evidence revealed that the peripheral nervous system is closely associated with bone metabolism, osteogenesis, and bone remodeling. Thus, CGRP is the bridge between the nervous system and the skeletal muscle system. CGRP can promote osteogenesis, inhibit bone resorption, promote vascular growth, and regulate the immune microenvironment. The G protein-coupled pathway is vital for its effects, while MAPK, Hippo, NF-κB, and other pathways have signal crosstalk, affecting cell proliferation and differentiation. The current review provides a detailed description of the bone repair effects of CGRP, subjected to several therapeutic studies, such as drug injection, gene editing, and novel bone repair materials.

Interoception is a core process through which the body perceives its internal state and regulates physiological homeostasis via bidirectional communication between the central and peripheral nervous system. Skeletal interoception is a specific circuitry for the brain control of the weight-bearing system, particularly responsible for sensing bone-derived internal signals to maintain skeletal homeostasis in response to mechanical loading. Recent studies uncovered that prostaglandin E2 (PGE2) plays a crucial role in skeletal interoception, and is therefore involved in major skeletal disorders and pain conditions such as low back pain, osteoarthritis and particularly ankle osteoarthritis (AOA). Ankle pain is clinically common, with a prevalence of 9%-15% among adults, severely impairing work productivity and quality of life. This article reviews the progress of skeletal interoception in skeletal pathogenesis and pain, with AOA as an example. Specifically, it discusses PGE2 and skeletal interoception in relation to pain and inflammation. We also attempted to interpret non-steroidal anti-inflammatory drugs (NSAIDs), surgical interventions and Traditional Chinese Medicine (TCM) therapies, especially acupuncture and electroacupuncture, in the therapy of pain and osteoarthritis from the viewpoint of skeletal interoception. Interoception is an emerging science in understanding how the brain regulates peripheral organs. Skeletal interoception mediated by PGE2 provides an opportunity to understand the potential of NSAIDs and acupuncture in regulating interoception for the treatment of skeletal disorders including ankle pain.

The regenerative repair after bone trauma is not merely an osteogenic process but a dynamic reconstruction involving the coordinated participation of multiple systems, including the nervous, immune, and vascular systems. In recent years, the regulatory role of the neuro-immune axis in bone regeneration has attracted increasing attention. Existing studies indicate that this axis may influence the quality of bone regeneration and functional recovery outcomes by modulating inflammation initiation, facilitating the transition from the inflammatory clearance phase to the reparative phase, and contributing to the remodeling of the local microenvironment. Specifically, neural signal-mediated regulation of early immune cell recruitment, macrophage polarization, and angiogenesis-osteogenesis coupling represents a critical upstream mechanism in post-traumatic bone regeneration. Conversely, an imbalance in the neuro-immune axis may be associated with adverse outcomes such as nonunion, chronic pain, and functional impairment. This article reviews the main mechanisms by which the post-traumatic neuro-immune axis regulates bone regeneration from four aspects: inflammation initiation, inflammation switching, microenvironment remodeling, and functional repair, and summarizes the research progress of related intervention strategies. Overall, targeting the neuro-immune axis may provide novel therapeutic strategies for promoting bone healing and improving functional recovery; however, most current evidence is derived from animal experiments, mechanistic studies, or early translational explorations, and its clinical value remains to be further validated.

Transient receptor potential vanilloid type 1 (TRPV1) is highly expressed on sensory neurons where it serves as a polymodal receptor for detecting physical and chemical stimuli. However, the role of TRPV1 in bone metabolism remains largely unclear. This study aimed to investigate the underlying mechanism of neuronal TRPV1 in regulating bone defect repair. In vivo experiment verified that TRPV1 activation could trigger dorsal root ganglion (DRG) producing the neuropeptide calcitonin gene-related peptide (CGRP) in mice. The accelerated bone healing of femoral defect in this process was observed compared to the control group (p < 0.05). Conversely, Trpv1 knockdown led to the reduced CGRP expression in DRG and nerves innervating femur bone tissue, following impaired bone formation and osteogenic capability in the defect region (p < 0.05), which could be rescued by local CGRP treatment. In vitro, results revealed that TRPV1 function in DRG neurons contributed essentially to the regulation of osteoblast physiology through affecting the production and secretion of CGRP. The capsaicin-activated neuronal TRPV1-CGRP axis could enhance the proliferation, migration and differentiation of osteoblasts (p < 0.05). Furthermore, we found that the promoting role of neuronal TRPV1 in osteogenesis were associated with Hippo signaling pathway, reflected by the phosphorylation protein level of large tumor suppressor 1 (LATS1), MOB kinase activator 1 (MOB1) and Yes-associated protein (YAP), as well as the subcellular location of YAP. Our study clarified the effects and intrinsic mechanisms of neuronal TRPV1 on bone defect repair, which might offer us a therapeutic implication for bone disorders.

Backgroud Bone defect repair is clinically challenging due to the limitations of traditional treatments. Tissue engineering holds great potential for constructing bone substitutes. This study evaluates the osteogenic capability of calcitonin gene-related peptide (CGRP)-induced rat adipose-derived stem cells (ADSCs) combined with calcium alginate (CaAlg) scaffolds both in vitro and in vivo. Methods ADSCs were isolated from rat inguinal fat pads, cultured, and characterized at passage 3. For in vitro experiments, cells were grouped and assessed over time using the CCK-8 assay for proliferation, alkaline phosphatase (ALP) activity assays, ALP staining, alizarin red staining (ARS), RT-PCR, and Western blotting for osteogenesis-related gene and protein expression. For in vivo experiments, constructs were evaluated after 12 weeks using X-ray, micro-CT, gross observation, and H&E staining. Results ADSCs had clear surface antigen characteristics and displayed an “S”-shaped proliferation curve post-osteogenic induction. In vitro, CGRP and CaAlg scaffolds synergistically enhanced ADSC osteogenic differentiation, with higher early ALP activity and late-stage mineralization in the CGRP-ADSCs-CaAlg group. Additionally, osteogenesis-related gene and protein expressions were upregulated in CGRP-induced and scaffold-combined groups. In vivo, bone formation was observed in both ADSCs-CaAlg and CGRP-ADSCs-CaAlg groups, but not in the control group. Conclusion These findings indicate that CGRP can induce ADSCs combined with CaAlg scaffolds to form tissue-engineered bone in vivo, with CGRP and CaAlg scaffolds showing a synergistic effect on promoting ADSC osteogenic differentiation.

… that the neuropeptide calcitonin gene-related peptide (CGRP) can stimulate osteoblastic bone … play a role in bone metabolism is α-calcitonin gene-related peptide (CGRP), a 37-residue …

… The primary RNA transcript of the CT/CGRP gene encodes two distinct peptides, CT and calcitonin gene–related peptide-α (CGRPα) (20–22). Cell-specific alternative RNA processing …

As brain and bone disorders represent major health issues worldwide, substantial clinical investigations demonstrated a bidirectional crosstalk on several levels, mechanistically linking both apparently unrelated organs. While multiple stress, mood and neurodegenerative brain disorders are associated with osteoporosis, rare genetic skeletal diseases display impaired brain development and function. Along with brain and bone pathologies, particularly trauma events highlight the strong interaction of both organs. This review summarizes clinical and experimental observations reported for the crosstalk of brain and bone, followed by a detailed overview of their molecular bases. While brain-derived molecules affecting bone include central regulators, transmitters of the sympathetic, parasympathetic and sensory nervous system, bone-derived mediators altering brain function are released from bone cells and the bone marrow. Although the main pathways of the brain-bone crosstalk remain ‘efferent’, signaling from brain to bone, this review emphasizes the emergence of bone as a crucial ‘afferent’ regulator of cerebral development, function and pathophysiology. Therefore, unraveling the physiological and pathological bases of brain-bone interactions revealed promising pharmacologic targets and novel treatment strategies promoting concurrent brain and bone recovery.

… To investigate the possibility that decreased levels of calcitonin gene–related peptide and endothelial nitric oxide synthase are involved in the process, we studied bone samples from …

… α-Calcitonin gene-related peptide (αCGRP) together with CT are the products of the same … trabecular bone density and bone volume due to increased bone formation. Bone density loss …

… and is often co-stored with calcitonin gene-related peptide (CGRP), 35 a peptide found to be abundant in sensory nerves in bone tissues. 8'25 Antisera to neuropeptide Y, the C-flanking …

… observations that lower circulating calcitonin levels are associated with bone loss and that … calcitonin gene-related peptides being filled in with authentic calcitonin generelated peptide …

… Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide. Discovered 30 years ago, it is produced as a consequence of alternative RNA processing of the …

This review identifies the mechanosensitive ion channel Piezo1 as the central regulator of bone homeostasis. Piezo1 senses mechanical loads in osteocytes, osteoblasts, and bone marrow mesenchymal stem cells (BMSCs), converting them into Ca2+-dependent signals that activate key pathways, including CaMKII, YAP/TAZ, Wnt/β-catenin, and ERK. These cascades collectively promote osteoblast differentiation and suppress osteoclastogenesis via OPG/RANKL modulation. Age-related Piezo1 decline impairs bone mechanoresponsiveness, driving both senile and disuse osteoporosis. Piezo1 also integrates bone metabolism with vascular–immune interactions (e.g., promoting VEGFA release from bone marrow macrophages via the CaN/NFAT/HIF-1α pathway) and the gut–bone axis (e.g., intestinal Piezo1 deletion relieves osteoblast proliferation inhibition by reducing serotonin levels). Therapeutically, Piezo1 agonists restore bone mass in osteoporosis models by reactivating mechanotransduction, while physical interventions achieve similar effects. Outstanding challenges include optimizing mechanical parameters (e.g., vibration frequency, ultrasound intensity) for individualized therapy, disentangling pathway crosstalk under aging and inflammation, and developing bone-targeted delivery systems for Piezo1 modulators. Overall, Piezo1 emerges as a pivotal therapeutic target for osteoporosis.

… Thus, when osteocytes are ablated, aberrantly elevated bone resorption with impaired … of bone resorption and suppression of bone formation, resulting in marked bone loss and …

Background Osteocytes, composing over 90% of bone cells, are well known for their mechanosensing abilities. Aged osteocytes with impaired morphology and function are less efficient in mechanotransduction which will disrupt bone turnover leading to osteoporosis. The aim of this systematic review is to delineate the mechanotransduction mechanism at different stages in order to explore potential target for therapeutic drugs. Methods A systematic literature search was performed in PubMed and Web of Science. Original animal, cell and clinical studies with available English full-text were included. Information was extracted from the included studies for review. Results The 26 studies included in this review provided evidence that mechanical loading are sensed by osteocytes via various sensing proteins and transduced to different signaling molecules which later initiate various biochemical responses. Studies have shown that osteocyte plasma membrane and cytoskeletons are emerging key players in initiating mechanotransduction. Bone regulating genes expressions are altered in response to load sensed by osteocytes, but the genes involved different signaling pathways and the spatiotemporal expression pattern had made mechanotransduction mechanism complicated. Most of the included studies described the important role of osteocytes in pathways that regulate mechanosensing and bone remodeling. Conclusions This systematic review provides an up-to-date insight to different steps of mechanotransduction. A better understanding of the mechanotransduction mechanism is beneficial in search of new potential treatment for osteoporotic patients. By delineating the unique morphology of osteocytes and their interconnected signaling network new targets can be discovered for drug development. Translational potential of this article This systematic review provides an up-to-date sequential overview and highlights the different osteocyte-related pathways and signaling molecules during mechanotransduction. This allows a better understanding of mechanotransduction for future development of new therapeutic interventions to treat patients with impaired mechanosensitivity.

Bone is a highly mechanosensitive tissue, where mechanical signaling plays a central role in maintaining skeletal homeostasis. Mechanotransduction regulates the balance between bone formation and resorption through coordinated interactions among bone cells. Key mechanosensing structures—including the extracellular/pericellular matrix (ECM/PCM), integrins, ion channels, connexins, and primary cilia, translate mechanical cues into biochemical signals that drive bone adaptation. Disruptions in mechanotransduction are increasingly recognized as an important factor in osteoporosis. Under pathological conditions, impaired mechanical signaling reduces bone formation and accelerates bone resorption, leading to skeletal fragility. Defects in mechanotransduction disrupt key pathways involved in bone metabolism, further exacerbating bone loss. Therefore, targeting mechanotransduction presents a promising pharmacological strategy for osteoporosis treatment. Recent advances have focused on developing drugs that enhance bone mechanosensitivity by modulating key mechanotransduction pathways, including integrins, ion channels, connexins, and Wnt signaling. A deeper understanding of mechanosignaling mechanisms may pave the way for novel therapeutic approaches aimed at restoring bone mass, mechanical integrity, and mechanosensitive bone adaptation.

… bone metabolism and turnover rate. The aforementioned process, known as mechanotransduction… related pathways and mechanotransduction signaling on bone loss. More …

IntroductionBones are subjected to a variety of mechanical loads duringdaily activities. In the nineteenth century, Julius Wolffproposed that bones adapt their mass and 3D structure tothe loading conditions in order to optimize their load-bearing capacity, and that this process is driven bymechanical stress [1]. For the past centuries, an increasingnumber of theoretical and experimental results reveal thatosteocytes are the pivotal cells orchestrating this bio-mechanical regulation of bone mass and structure, whichis accomplished by the process of bone remodeling [2–5]Osteocytes are terminally differentiated cells of theosteogenic lineage that are derived from mesenchymalprecursor cells. A number of molecules have been iden-tified as important markers of osteocytes, such as matrixextracellular phosphoglycoprotein [6] sclerostin [7], dentinmatrix protein-1 [8], and phex protein [8]. The osteocytesare the most abundant cells in adult bone and are constantlyspaced throughout the mineralized matrix. Mature osteo-cytes have a characteristic dendritic cell shape, with pro-cesses radiating from the cell body through the canaliculi indifferent directions. These processes form an intercellularnetwork through gap and adherent junctions with surround-ing osteocytes, the cells lining the bone surface and bonemarrow. Through this unique 3D network, osteocytes areanatomically placed in a prime position not only to sensedeformations driven by stresses placed upon bone, butalso to respond with passage of signals to the neighboringcells [9].For more than a decade now, it is known that theosteocytes are very sensitive to stress applied to intact bonetissue [10–16]. Computer simulation models have shownthat mechanosensors lying at the surface of bone, asosteoblasts and bone lining cells do, would be less sensitiveto changes in the loading pattern than the osteocytes, lyingwithin the calcified matrix [3]. Interestingly, targetedablation of osteocytes in mice disturbs the adaptation ofbone to mechanical loading [16].Osteocytes as key players in the process of bonemechanotransductionIt is currently believed that when bones are loaded, theresulting deformation will drive the thin layer of interstitialfluid surrounding the network of osteocytes to flow fromregions under high pressure to regions under low pressure[17, 18]. This flow of fluid is sensed by the osteocyteswhich in turn produce signaling molecules that can regulatebone resorption through the osteoclasts, and bone formationthrough the osteoblasts, leading to adequate bone remodel-ing [17, 18]. This concept is known as the fluid flowhypothesis. Evidence has been increasing for the flow ofcanalicular interstitial fluid as the likely factor that informsthe osteocytes about the level of bone loading [2, 5, 17, 18].Nevertheless, Vatsa and colleagues [19, 20] proposed thatif osteocytes could sense matrix strains directly, the cellshape, cytoskeletal alignment and distribution of adhesionsites in osteocytes in situ would bear alignment to themechanical loading patterns. Indeed, it was shown that the

Skeletal loading is an important physiological regulator of bone mass. Theoretically, mechanical forces or administration of drugs that activate bone mechanosensors would be a novel treatment for osteoporotic disorders, particularly age-related osteoporosis and other bone loss caused by skeletal unloading. Uncertainty regarding the identity of the molecular targets that sense and transduce mechanical forces in bone, however, has limited the therapeutic exploitation of mechanosesning pathways to control bone mass. Recently, two evolutionally conserved mechanosensing pathways have been shown to function as “physical environment” sensors in cells of the osteoblasts lineage. Indeed, polycystin–1 (Pkd1, or PC1) and polycystin–2 (Pkd2, or PC2‚ or TRPP2), which form a flow sensing receptor channel complex, and TAZ (transcriptional coactivator with PDZ-binding motif, or WWTR1), which responds to the extracellular matrix microenvironment act in concert to reciprocally regulate osteoblastogenesis and adipogenesis through co-activating Runx2 and a co-repressing PPARγ activities. Interactions of polycystins and TAZ with other putative mechanosensing mechanism, such as primary cilia, integrins and hemichannels, may create multifaceted mechanosensing networks in bone. Moreover, modulation of polycystins and TAZ interactions identify novel molecular targets to develop small molecules that mimic the effects of mechanical loading on bone.

… Osteoporosis is a systemic skeletal disorder fundamentally characterized by an imbalance between bone formation and bone resorption, ultimately leading to reduced …

Bones are constantly exposed to mechanical forces from both muscles and Earth’s gravity to maintain bone homeostasis by stimulating bone formation. Mechanotransduction transforms external mechanical signals such as force, fluid flow shear, and gravity into intracellular responses to achieve force adaptation. However, the underlying molecular mechanisms on the conversion from mechanical signals into bone formation has not been completely defined yet. In the present review, we provide a comprehensive and systematic description of the mechanotransduction signaling pathways induced by mechanical stimuli during osteogenesis and address the different layers of interconnections between different signaling pathways. Further exploration of mechanotransduction would benefit patients with osteoporosis, including the aging population and postmenopausal women.

… its role in bone maintenance and mechanotransduction. Therapeutic … Bone turnover can be disrupted by menopause and … OBs-related bone synthesis and OCs-related bone resorption. …

… for osteocyte death to induce osteoclastic bone resorption, the molecular and cellular … bone loss, providing further evidence for the role of osteocytes in mechanotransduction. …

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor expressed in many cell types, including osteoblasts, osteocytes, and osteoclasts. Nrf2 has been considered a master regulator of cytoprotective genes against oxidative and chemical insults. The lack of Nrf2 can induce pathologies in multiple organs. Nrf2 deficiency promotes osteoclast differentiation and osteoclast activity, which leads to an increase in bone resorption. The role of Nrf2 in osteoblast differentiation and osteoblast activity is more complex. Nrf2 mediates anabolic effects within an ideal range. Nrf2 deletion suppresses load induced bone formation and delays fracture healing. Overall, Nrf2 plays an important role in the regulation of bone homeostasis in bone cells.

… mechanical cues, with mechanotransduction playing a key role in … osteoporosis and found that the alamandine/MrgprD receptor interaction reduces osteoclast activity and bone turnover…

Background Bone imbalance between anabolic and catabolic processes at the level of remodeling unit due to the prevalence of resorbing activity, represents a health problem of aging. The consequence is the negative balance of bone turnover that can lead to osteoporosis. Physical activity (PA) can play a central role in the comprehensive management of osteoporosis, since it induces the anabolism of bone tissue. Bone turnover biomarkers, reflecting the cellular activity linked to bone metabolism, can represent an evaluation tool to assess the efficacy of PA in the osteoporotic population. The aim of this systematic review, conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, was to investigate the effects of PA interventions on bone biomarkers in people with osteoporosis. Methods A comprehensive literature search of electronic databases was conducted through PubMed, Cochrane, Cinahl, Embase, Trip, to find randomized controlled trials (RCTs) investigating the topic of PA and bone turnover biomarkers in the osteoporosis population. In accordance with the Cochrane risk-of-bias tool, the quality of each study was assessed. Results Out of 992 identified articles, 136 full texts were screened. Only three RTCs matched the eligibility criteria. In one study, sub-maximal aerobic exercise improved Bone-specific alkaline phosphatase (bone formation biomarker) and Amino-terminal Crosslinked Telopeptide of type 1 collagen (bone resorption biomarker) in osteoporotic women. The other two studies showed a positive effect on total alkaline phosphatase (a non-specific bone formation biomarker) in women with osteoporosis. Conclusion The systematic review revealed possible exercise benefits in terms of improving bone formation and decreasing bone resorption biomarkers in the osteoporotic population. However, these results should be interpreted with caution, especially due to the limited number and poor quality of the studies included. Further research is needed to estimate the influence of PA on bone biomarkers in the osteoporosis management.

… may play a role in mechanotransduction within bone is also of clinical relevance, because it … interventions in bone loss pathologies. In particular, deleterious bone loss resulting from …

Bone density loss is a major concern for astronauts in space, largely due to altered mechanical stimuli in microgravity. These changes are thought to impact bone cells by directly affecting musculoskeletal cell physiology and disrupting mechanosensing and mechanotransduction pathways. This review focuses on the role of the primary cilium, a small, non-motile cellular structure, involved in these processes. Previously underestimated, the primary cilium is now known to act as a mechano- and chemo-sensor on the surface of most vertebrate cells, transmitting signals via multiple intracellular pathways. The primary cilium senses the extracellular fluid flow and its dynamic changes in physiological and pathological conditions, which may include exposure to microgravity, connecting its inactivation to bone density loss. This systematic review will compile and analyze current data on how weightlessness affects the mechanosensing functions of the primary cilium and its role in bone homeostasis disruption.

Mechanotransduction, the transfer of mechanical stimuli into various biological signals, is a vital biological process in multiple organ systems. The osteoclast (OC) plays a vital role in bone metabolism and repair. The role of mechanotransduction in osteoclasts and other bone cells is emerging. This commentary highlights a recent research report on a novel strategy for the precise regulation of OC formation via modulating matrix stiffness. Modulation of the mechanotransduction pathways in the skeletal system will pave the way for the development of a matrix stiffness-based strategy for bone tissue regeneration.

Physiological tooth movement during the process of orofacial rehabilitation, as well as the degree of skeletal responses to orthodontics procedures, depends on the bone remodeling processes that are controlled by the mechanosensitive receptors. Piezo1 has become one of the receptors of great attention over the last few years. Besides acting as a sensor of the mechanical microenvironment, Piezo1 is also important in alveolar bone remodeling because of its ability to regulate osteocyte activity. This is a review of how Piezo1 mediates orthodontic tooth movement (OTM) by detecting and transducing mechanical stimulating factors using various molecular pathways and by regulating the activities of osteoblasts and osteoclasts. Most recent research developments are summarized with the aim of determining the impact of Piezo1 channel inhibition on orthodontic tooth movement as well as elucidating the molecular pathways involved in the same. Additionally, the prospective clinical use of Piezo1 as a therapeutic target of orthodontic therapy is discussed. We also highlight the importance of Piezo1 in regulating bone formation and maintaining the balance between osteogenesis and osteoclastogenesis. In general, the results can be used to optimize the method of providing orthodontic treatment and develop new strategies in the field of orthodontics.

Orthodontic tooth movement is characterized by periodontal tissue responses to mechanical loading, leading to clinically relevant functional adaptation of jaw bone. Since osteocytes are significant in mechanotransduction and orchestrate osteoclast and osteoblast activity, they likely play a central role in orthodontic tooth movement. In this review, we attempt to shed light on the impact and role of osteocyte mechanotransduction during orthodontic tooth movement. Mechanically loaded osteocytes produce signaling molecules, e.g., bone morphogenetic proteins, Wnts, prostaglandins, osteopontin, nitric oxide, sclerostin, and RANKL, which modulate the recruitment, differentiation, and activity of osteoblasts and osteoclasts. The major signaling pathways activated by mechanical loading in osteocytes are the wingless-related integration site (Wnt)/β-catenin and RANKL pathways, which are key regulators of bone metabolism. Moreover, osteocytes are capable of orchestrating bone adaptation during orthodontic tooth movement. A better understanding of the role of osteocyte mechanotransduction is crucial to advance orthodontic treatment. The optimal force level on the periodontal tissues for orthodontic tooth movement producing an adequate biological response, is debated. This review emphasizes that both mechanoresponses and inflammation are essential for achieving tooth movement clinically. To fully comprehend the role of osteocyte mechanotransduction in orthodontic tooth movement, more knowledge is needed of the biological pathways involved. This will contribute to optimization of orthodontic treatment and enhance patient outcomes.

Previously we observed that capsaicin treatment in rats inhibited sensory neuropeptide signaling, with a concurrent reduction in trabecular bone formation and bone volume, and an increase in osteoclast numbers and bone resorption. Calcitonin gene-related peptide (CGRP) is a neuropeptide richly distributed in sensory neurons innervating the skeleton and we postulated that CGRP signaling regulates bone integrity. In this study we examined CGRP effects on stromal and bone cell differentiation and activity in vitro. CGRP receptors were detected by immunocytochemical staining and real time PCR assays in mouse bone marrow stromal cells (BMSCs) and bone marrow macrophages (BMMs). CGRP effects on BMSC proliferation and osteoblastic differentiation were studied using BrdU incorporation, PCR products, alkaline phosphatase (ALP) activity, and mineralization assays. CGRP effects on BMM osteoclastic differentiation and activity were determined by quantifying tartrate-resistant acid phosphatase positive (TRAP+) multinucleated cells, pit erosion area, mRNA levels of TRAP and cathepsin K, and nuclear factor-κB (NF-κB) nuclear localization. BMSCs, osteoblasts, BMMs, and osteoclasts all expressed CGRP receptors. CGRP (10-10-10-8M) stimulated BMSC proliferation, up-regulated the expression of osteoblastic genes, and increased ALP activity and mineralization in the BMSCs. In BMM cultures CGRP (10-8M) inhibited receptor activator of NF-κB ligand (RANKL) activation of NF-κB. CGRP also down-regulated osteoclastic genes like TRAP and cathepsin K, decreased the numbers of TRAP+ cells, and inhibited bone resorption activity in RANKL stimulated BMMs. These results suggest that CGRP signaling maintains bone mass both by directly stimulating stromal cell osteoblastic differentiation and by inhibiting RANKL induced NF-κB activation, osteoclastogenesis, and bone resorption.

… that CGRP administration not only stimulated osteoblast differentiation, as demonstrated by upregulated expression levels of ATF4 and OC in the hCGRP‑treated osteoblasts, … signaling …

Background Impaired fracture healing represents an ongoing clinical challenge, as treatment options remain limited. Calcitonin gene-related peptide (CGRP), a neuropeptide targeted by emerging anti-migraine drugs, is also expressed in sensory nerve fibres innervating bone tissue. Method Bone healing following a femoral osteotomy stabilized with an external fixator was analysed over 21 days in αCGRP-deficient and WT mice. Bone regeneration was evaluated by serum analysis, µCT analysis, histomorphometry and genome-wide expression analysis. Bone-marrow-derived osteoblasts and osteoclasts, as well as the CGRP antagonist olcegepant were employed for mechanistic studies. Findings WT mice with a femoral fracture display increased CGRP serum levels. αCGRP mRNA expression after skeletal injury is exclusively induced in callus tissue, but not in other organs. On protein level, CGRP and its receptor, calcitonin receptor-like receptor (CRLR) complexing with RAMP1, are differentially expressed in the callus during bone regeneration. On the other hand, αCGRP-deficient mice display profoundly impaired bone regeneration characterised by a striking reduction in the number of bone-forming osteoblasts and a high rate of incomplete callus bridging and non-union. As assessed by genome-wide expression analysis, CGRP induces the expression of specific genes linked to ossification, bone remodeling and adipogenesis. This suggests that CGRP receptor-dependent PPARγ signaling plays a central role in fracture healing. Interpretation This study demonstrates an essential role of αCGRP in orchestrating callus formation and identifies CGRP receptor agonism as a potential approach to stimulate bone regeneration. Moreover, as novel agents blocking CGRP or its receptor CRLR are currently introduced clinically for the treatment of migraine disorders, their potential negative impact on bone regeneration warrants clinical investigation. Funding This work was funded by grants from the Else-Kröner-Fresenius-Stiftung (EKFS), the Deutsche Forschungsgemeinschaft (DFG), and the Berlin Institute of Health (BIH).

… , osteoblastic bone formation follows osteoclastic bone resorption along a hierarchical sequence of events. Osteoblast function is intimately tied to osteoclast … /RANK signaling leads to …

… signals whose targets can be osteoclasts and osteoblasts at … These actions of CGRP on osteoblasts could be relevant to … a rapid proliferation of CGRP immunoreactive nerves [48, 49]. …

Objective The present study aimed to investigate the underlying mechanism of mechanical stimulation in regulating osteogenic differentiation. Materials and methods Osteoblasts were exposed to compressive force (0–4 g/cm^2) for 1–3 days or CGRP for 1 or 3 days. Expression of receptor activity modifying protein 1 (RAMP1), the transcription factor RUNX2, osteocalcin, p38 and p-p38 were analyzed by western blotting. Calcium mineralization was analyzed by alizarin red straining. Results Using compressive force treatments, low magnitudes (1 and 2 g/cm^2) of compressive force for 24 h promoted osteoblast differentiation and mineral deposition whereas higher magnitudes (3 and 4 g/cm^2) did not produce osteogenic effect. Through western blot assay, we observed that the receptor activity-modifying protein 1 (RAMP1) expression was upregulated, and p38 mitogen-activated protein kinase (MAPK) was phosphorylated during low magnitudes compressive force-promoted osteoblast differentiation. Further investigation of a calcitonin gene-related peptide (CGRP) peptide incubation, a ligand for RAMP1, showed that CGRP at concentration of 25 and 50 ng/ml could increase expression levels of RUNX2 and osteocalcin, and percentage of mineralization, suggesting its osteogenic potential. In addition, with the same conditions, CGRP also significantly upregulated RAMP1 and phosphorylated p38 expression levels. Also, the combination of compressive forces (1 and 2 g/cm^2) with 50 ng/ml CGRP trended to increase RAMP1 expression, p38 activity, and osteogenic marker RUNX2 levels, as well as percentage of mineralization compared to compressive force alone. This suggest that RAMP1 possibly acts as an upstream regulator of p38 signaling during osteogenic differentiation. Conclusion These findings suggest that CGRP-RAMP1/p38MAPK signaling implicates in osteoblast differentiation in response to optimal magnitude of compressive force. This study helps to define the underlying mechanism of compressive stimulation and may also enhance the application of compressive stimulation or CGRP peptide as an alternative approach for accelerating tooth movement in orthodontic treatment.

… Cultures of normal human osteoblasts were treated with SP, CGRP, VIP, NPY or TH at three … role in transmitting signals between bone cells such as osteoblasts and osteoclasts, cells …

… relationship between CGRP, the canonical Wnt signaling and apoptosis in human osteoblasts (… Effects of CGRP on human osteoclast-like cells formation: A possible connection with the …

… does not seem to be rapidly degraded to an inactive form in our experimental system, and we conclude that CGRP has stimulated (a) particular signaling pathway(s) to down-regulate …

Simple Summary Postmenopausal women face a high risk of osteoporosis, and the resulting chronic pain, fractures, and limited mobility impose a heavy burden on patients and society. While resistance exercise benefits bone health, it remains unclear whether long-term regular exercise can promote the healing of bone injuries caused by osteoporosis and how it works. This study tested the effects of 10-week weight-bearing ladder climbing in rat models simulating postmenopausal osteoporosis. The results showed that the exercise enhanced muscle strength, balanced hormones related to bone health, and reduced body weight in the osteoporotic rats. It also increased bone density and improved bone structure and strength—importantly, these benefits still existed 21 days after stopping exercise. Furthermore, in bone injury tests conducted after exercise cessation, rats that had undergone prior exercise showed significantly accelerated bone healing. This exercise exerts its effects by lowering a protein that inhibits muscle growth and regulating biological mechanisms that protect bones and muscles, with these effects remaining evident 21 days post-exercise. This study confirms that weight-bearing ladder climbing is a safe, drug-free way to alleviate postmenopausal bone loss, strengthen bones, and aid bone injury healing, providing important support for using exercise as a clinical intervention.

Exercise is commonly recommended in the prevention and management of osteoporosis. The most common method to monitor bone mass and its response to interventions is bone densitometry. While closely associated with risk of fracture, densitometry-derived areal bone mineral density (aBMD) does not provide a reliable indication of bone geometry or morphological adaptation to stimuli. In fact, the effects of exercise interventions on aBMD are frequently modest, and may not fully represent the benefit of exercise to bone. Animal models suggest that mechanical loading indeed influences bone geometry and thus strength. Such an effect in humans has the potential to reduce osteoporotic fracture. The aim of the current narrative review is to provide an overview of what is known about the effects of exercise on bone geometry, with a focus on relevance to osteoporosis.

… In particular, the questionnaire did not distinguish between weight bearing exercise (jogging) and non-weight bearing exercise (swimming), and consequently might underestimate the …

This study examined the effects of high-impact weight-bearing exercise on bone mineral density (BMD) and bone metabolic markers in middle-aged premenopausal women. Forty middle-aged premenopausal women were initially enrolled, but thirty-one participants (40.34 ± 3.69 years) completed in the study. The subjects were randomly divided into two groups including the high-impact weight-bearing exercise group (HWE, n = 14) and control group (CON, n = 17). The HWE group participated in the exercise for 50 min a day, three days per week for four months, while the CON group maintained their regular lifestyle. The HWE program included 10 different high-impact weight-bearing exercises such as jumping and running. BMD was measured using DXA (Hologic, QDR 4500W, Marlborough, MA, USA). The bone metabolic markers including serum 25-(OH) D, intact parathyroid hormone (PTH), osteoprotegerin (OPG), osteopontin (OPN), receptor activator of nuclear factor κB ligand (RANKL), osteocalcin (OC), C-terminal telopeptide of type 1 collagen (CTX), and calcium were analyzed. The results showed that the BMDs of femur, lumbar, and forearm did not significantly change during the intervention period in both the HWE and CON groups. A significant decrease in bone formation markers such as OC (F = 10.514, p = 0.003, ηp2 = 0.266) and an increase in bone resorption marker including CTX (F = 8.768, p = 0.006, ηp2 = 0.232) were found only in the CON group, while these values did not change in the HWE group. There was a significant increase in serum 25-(OH) D (F = 4.451, p = 0.044, ηp2 = 0.133) in the HWE group. Our findings suggest that four months of HWE is not sufficient to improve BMD and bone metabolic markers, but this impact exercise program may prevent the age-associated changes in bone turnover markers in middle-aged premenopausal women.

… bone mineral density (BMD). The aim of this study was to investigate the preventive effect of weight-bearing training on bone … osteoporosis is urgent. Our preliminary results show that …

The present study was designed to assess the effect of different types of exercises on the BMD values in female professional atheletes. The case control study was conducted on 59 healthy female atheletes aged between 20 and 30 years who were a member of the country’s national teams in the past three years. They were involved in weight-bearing (soccer and golf) and non-weight bearing (swimming and rowing) exercises. The BMD values of the L1–L4 anteroposterior lumbar spine and femoral subregions were recorded using a DXA bone densitometer and compared to that of a group of age and sex-matched non-athletes. Mean BMD values at all the studied sites were highest among the footballers and lowest among the golf players. Except for the spine, a significant difference between the BMD values at all the studied sites. As for spine, a significant difference was only seen in the BMD values of the footballers and that of golf players. There was no significant difference between the BMD values of the controls and those involved in either weight bearing or non-weight bearing exercises. The considerable difference noted in BMD values at different sites in footballers and golf players’ points out the great influence of weight-bearing exercises on the bone structure. The bones’ response to exercises is site-specific. High-impact weight bearing exercises stressing bones in a variety of directions are more effective in improving BMD values. Athletes involved in non-weight bearing exercises should do certain weight-bearing exercises to strengthen their bones.

Bone is richly innervated by nerve growth factor-responsive (NGF-responsive) tropomyosin receptor kinase A-expressing (TrKa-expressing) sensory nerve fibers, which are required for osteochondral progenitor expansion during mammalian skeletal development. Aside from pain sensation, little is known regarding the role of sensory innervation in bone repair. Here, we characterized the reinnervation of tissue following experimental ulnar stress fracture and assessed the impact of loss of TrkA signaling in this process. Sequential histological data obtained in reporter mice subjected to fracture demonstrated a marked upregulation of NGF expression in periosteal stromal progenitors and fracture-associated macrophages. Sprouting and arborization of CGRP+TrkA+ sensory nerve fibers within the reactive periosteum in NGF-enriched cellular domains were evident at time points preceding periosteal vascularization, ossification, and mineralization. Temporal inhibition of TrkA catalytic activity by administration of 1NMPP1 to TrkAF592A mice significantly reduced the numbers of sensory fibers, blunted revascularization, and delayed ossification of the fracture callus. We observed similar deficiencies in nerve regrowth and fracture healing in a mouse model of peripheral neuropathy induced by paclitaxel treatment. Together, our studies demonstrate an essential role of TrkA signaling for stress fracture repair and implicate skeletal sensory nerves as an important upstream mediator of this repair process.

The aim of the study was to examine the acute response of biochemical bone turnover markers (BTM) to high-impact jumping exercise, and to quantify the ground reaction forces (GRF) achieved during each jumping exercise, in postmenopausal women. In a randomized controlled cross-over study over three days, 29 postmenopausal women (age (mean±SD): 60.0±5.6 years) were randomly assigned to 6 x 10 repetitions of three different jumps: countermovement jump (CMJ), drop jump (DJ), diagonal drop jump (DDJ). A fourth day without jumping served as a control (CON). Blood samples were collected before (PRE), after (POST), and 2 hours after (2Hr) exercise. Bone turnover was evaluated by bone formation markers (procollagen type-1 amino-terminal propeptide (P1NP) and osteocalcin (OC)) and the bone resorption marker C-terminal telopeptide of type-1 collagen (CTX). Peak anteroposterior (Fx), mediolateral (Fy), and vertical (Fz) GRF were measured using a force platform. From PRE to POST, P1NP increased (p<0.01) by 7.7±1.8%, 9.4±1.3%, and 10.6±1.6% for CMJ, DJ, and DDJ, which were higher (p<0.01) than CON. OC increased (p<0.05) by 5.5±1.8% for DJ, which was higher (p<0.05) than CON. CTX was not significantly changed at POST. There were no significant differences in BTM Δ-values between the jumps at any time point. For the CMJ, the combined three-axis peak GRF was positively associated with the PRE to POST Δ-change in P1NP (r=0.71, p<0.05). The acute, jumping-induced increase in P1NP and OC without any rise in CTX may indicate increased bone formation. Moreover, the study shows a dose-response relationship between GRF and the acute P1NP response after countermovement jumps.

In order to validate whether bones' functional adaptation to mechanical loading is a local phenomenon, we randomly assigned 21 female C57BL/6 mice at 19 weeks of age to one of three equal numbered groups. All groups were treated with isoflurane anesthesia three times a week for 2 weeks (approximately 7 min/day). During each anaesthetic period, the right tibiae/fibulae in the DYNAMIC + STATIC group were subjected to a peak dynamic load of 11.5 N (40 cycles with 10-s intervals between cycles) superimposed upon a static “pre-load” of 2.0 N. This total load of 13.5 N engendered peak longitudinal strains of approximately 1400 microstrain on the medial surface of the tibia at a middle/proximal site. The right tibiae/fibulae in the STATIC group received the static “pre-load” alone while the NOLOAD group received no artificial loading. After 2 weeks, the animals were sacrificed and both tibiae, fibulae, femora, ulnae and radii analyzed by three-dimensional high-resolution (5 μm) micro-computed tomography (μCT). In the DYNAMIC + STATIC group, the proximal trabecular percent bone volume and cortical bone volume at the proximal and middle levels of the right tibiae as well as the cortical bone volume at the middle level of the right fibulae were markedly greater than the left. In contrast, the left bones in the DYNAMIC + STATIC group showed no differences compared to the left or right bones in the NOLOAD or STATIC group. These μCT data were confirmed by two-dimensional examination of fluorochrome labels in bone sections which showed the predominantly woven nature of the new bone formed in the loaded bones. We conclude that the adaptive response in both cortical and trabecular regions of bones subjected to short periods of dynamic loading, even when this response is sufficiently vigorous to stimulate woven bone formation, is confined to the loaded bones and does not involve changes in other bones that are adjacent, contra-lateral or remote to them.

… failure with a minimum use of material, bone mass and its architecture are continuously being adapted to the prevailing mechanical loads. It is currently believed that mechanical …

… axial load-controlled fatigue loading of cortical bone specimens. … are greatly increased at loading levels above critical damage … Changes in mechanical loading are refiected in skeletal …

… those in bone as an organ, particularly with regard to the anisotropic structure of bone tissue… and dynamics to mechanical loading parameters, including loading magnitude, frequency, …

… shows that bones tend to primarily adjust their apparent strength, not necessarily BMC nor … current bone measurements for evaluation of the skeletal response to mechanical loading …

Exercise promotes gain in bone mass through adaptive responses of the vertebrate skeleton. This mechanism counteracts age- and disease-related skeletal degradation, but remains to be fully understood. In life sciences, zebrafish emerged as a vertebrate model that can provide new insights into the complex mechanisms governing bone quality. To test the hypothesis that musculoskeletal exercise induces bone adaptation in adult zebrafish and to characterize bone reorganization, animals were subjected to increased physical exercise for four weeks in a swim tunnel experiment. Cellular, structural and compositional changes of loaded vertebrae were quantified using integrated high-resolution analyses. Exercise triggered rapid bone adaptation with substantial increases in bone-forming osteoblasts, bone volume and mineralization. Clearly, modeling processes in zebrafish bone resemble processes in human bone. This study highlights how exercise experiments in adult zebrafish foster in-depth insight into aging-related bone diseases and can thus catalyze the search for appropriate prevention and new treatment options.

Bone adaptation optimizes mass and structure, but the mechano-response is already reduced at maturation. Downregulation of sclerostin was believed to be a mandatory step in mechano-adaptation, but in young mice it was shown that load-induced formation can occur independent of sclerostin, a product of the Sost gene. We hypothesized that the bone formation and resorption response to loading is not affected by Sost deficiency, but is age-specific. Our findings indicate that the anabolic response to in vivo tibial loading was reduced at maturation in Sost Knockout (KO) and littermate control (LC) mice. Age affected all anabolic and catabolic parameters and altered Sost and Wnt target gene expression. While load-induced cortical resorption was similar between genotypes, loading-induced gains in mineralizing surface was enhanced in Sost KO compared to LC mice. Loading led to a downregulation in expression of the Wnt inhibitor Dkk1. Expression of Dkk1 was greater in both control and loaded limbs of Sost KO compared to LC mice suggesting a compensatory role in the absence of Sost. These data suggest physical activity could enhance bone mass concurrently with sclerostin-neutralizing antibodies, but treatment strategies should consider the influence of age on ultimate load-induced bone mass gains.

Advancing age and reduced loading are associated with a reduction in bone formation. Conversely, loading increases periosteal apposition and may reduce remodeling imbalance and slow age‐related bone loss, an important outcome for the proximal femur, which is a common site of fracture. The ability to take advantage of bone's adaptive response to increase bone strength has been hampered by a lack of knowledge of which exercises and specific leg muscles load the superior femoral neck: a common region of microcrack initiation and progression following a sideways fall. We used an in vivo method of quantifying focal strains within the femoral neck in postmenopausal women during walking, stair ambulation, and jumping. Relative to walking, stair ambulation and jumping induced significantly higher strains in the anterior and superior aspects of the femoral neck, common regions of microcrack initiation and progression following a fall. The gluteus maximus, a hip extensor muscle, induced strains in the femoral neck during stair ambulation and jumping, in contrast to walking which induced strains via the iliopsoas, a hip flexor. The ground reaction force was closely associated with the level of strain during each task, providing a surrogate indicator of the potential for a given exercise to load the femoral neck. The gluteal muscles combined with an increased ground reaction force relative to walking induce high focal strains within the anterosuperior region of the femoral neck and therefore provide a target for exercise regimens designed to slow bone loss and maintain or improve microstructural strength. Model files used for calculating femoral neck strains are available at uitbl.mechse.illinois.edu/downloads © 2018 American Society for Bone and Mineral Research.

Structural gender differences in bone mass – characterized by wider but not thicker bones – are generally attributed to opposing sex steroid actions in men and women. Recent findings have redefined the traditional concept of sex hormones as the main regulators of skeletal sexual dimorphism. GH–IGF1 action is likely to be the most important determinant of sex differences in bone mass. Estrogens limit periosteal bone expansion but stimulate endosteal bone apposition in females, whereas androgens stimulate radial bone expansion in males. Androgens not only act directly on bone through the androgen receptor (AR) but also activate estrogen receptor-α or -β (ERα or ERβ) following aromatization into estrogens. Both the AR and ERα pathways are needed to optimize radial cortical bone expansion, whereas AR signaling alone is the dominant pathway for normal male trabecular bone development. Estrogen/ERα-mediated effects in males may – at least partly – depend on interaction with IGF1. In addition, sex hormones and their receptors have an impact on the mechanical sensitivity of the growing skeleton. AR and ERβ signaling may limit the osteogenic response to loading in males and females respectively, while ERα may stimulate the response of bone to mechanical stimulation in the female skeleton. Overall, current evidence suggests that skeletal sexual dimorphism is not just the end result of differences in sex steroid secretion between the sexes, but depends on gender differences in GH–IGF1 and mechanical sensitivity to loading as well.

Neuropeptides such as vasoactive intestinal peptide (VIP) and calcitonin gene-related peptide (CGRP) are present in nerve fibers of bone tissues and have been suggested to potentially regulate bone remodeling. Oscillatory fluid flow (OFF)-induced shear stress is a potent signal in mechanotransduction that is capable of regulating both anabolic and catabolic bone remodeling. However, the interaction between neuropeptides and mechanical induction in bone remodeling is poorly understood. In this study, we attempted to quantify the effects of combined neuropeptides and mechanical stimuli on mRNA and protein expression related to bone resorption. Neuropeptides (VIP or CGRP) and/or OFF-induced shear stress were applied to MC3T3-E1 pre-osteoblastic cells and changes in receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL) and osteoprotegerin (OPG) mRNA and protein levels were quantified. Neuropeptides and OFF-induced shear stress similarly decreased RANKL and increased OPG levels compared to control. Changes were not further enhanced with combined neuropeptides and OFF-induced shear stress. These results suggest that neuropeptides CGRP and VIP have an important role in suppressing bone resorptive activities through RANKL/OPG pathway, similar to mechanical loading.

… response to alterations in mechanical loading patterns. Thus, … mechanical loading parameters and the magnitude and distribution of loadinduced fluid displacements within cortical bone …

… the effect of mechanical load applied to a whole bone, to the bone fluid flow around the cells buried in the bone. The model predicts that the maximum cellular stimulatory signal for bone …

A highly accurate (+/-3%) mechanical loading and measurement system combined with a trabecular bone diffusion culture-loading chamber has been developed, which provides the ability to study trabecular bone (and possibly) cartilage under controlled culture and loading conditions over long periods of time. The loading device has been designed to work in two main modes, either to apply a specific compressive strain to a trabecular bone cylinder or to apply a specific force and measure the resulting deformation. Presently, precisely machined bone cylinders can be loaded at frequencies between 0.1 Hz to 50 Hz and amplitudes over 7,000 microepsilon. The system allows accurate measurement of many mechanical properties of the tissue in real time, including visco-elastic properties. This paper describes the technical components, reproducibility, precision, and the calibration procedures of the loading system. Data on long term culture and mechanical responses to different loading patterns will be published separately.

… bone mass after 18 weeks of loading from the same histomorphometric changes in the current study, which are that loading inhibited bone resorption and stimulated bone … in the bone …

… The strength and elastic modulus of cancellous bone depend on the direction of the load employed, as normally measured at SI (superior-interior), AP (anterior-posterior), or ML (medial-…