The purpose of this article is to emphasize the critical role aging and senescence plays on mesenchymal stem cell (MSC) functionality and its influence on bone health. This review also highlights recent advancements in strategies to rejuvenate senescent MSCs to aid in delaying or preventing age-related illnesses associated with bone loss. Studies have expanded upon many established rejuvenation strategies including senolytic agents, drugs used to selectively eliminate senescent cells, and targeted inhibitors to the secretory profile of senescent cells. New routes for MSC rejuvenation including nanoplatform targets such as biomaterials, nanovesicles, and physical exercise are showing promise for future clinical applications. Ongoing clinical trials are progressing towards rejuvenation therapies that delay age-induced bone loss. This review provides an overview of the current research landscape into rejuvenation of senescent MSCs to combat bone loss due to age and highlights new platforms and strategies for rejuvenation that could have clinical relevance.
A decade has passed since we published a review entitled: “Cortical Bone Porosity: What Is It, Why Is It Important, and How Can We Detect It?” (Curr.Osteoporos.Rep. 2016;14(5):187 − 98), which addressed the growing shift from bone mass to microarchitecture in osteoporosis research. It culminated in a brief examination of animal models of cortical bone porosity and the potential of using imaging to dynamically track cortical remodeling. Here we reflect on a decade of progress in this research space - preclinical time-lapse imaging of cortical pores/remodeling. Our objectives are to: (1) review time-lapse micro-CT imaging of bone microarchitecture in murine models; (2) overview of the development of synchrotron propagation phase contrast micro-CT imaging to track cortical porosity/remodeling in rabbits; and (3) discuss challenges and future directions. Despite first being demonstrated over 20 years ago, time-lapse micro-CT of trabecular bone in preclinical models has been relatively limited. Synchrotron imaging of rabbits has recently enabled the first time-lapse views of individual cortical remodeling events and associated findings have included linear erosion rates (LER) of remodeling spaces consistent with values inferred in classic canine studies, diverse and complex remodeling space morphologies particularly in parathyroid hormone-dosed animals where LER is also reduced, and disruption of linear advance in glucocorticoid-dosed animals. Time-lapse imaging of animal models holds tremendous potential to shed new light on the dynamic process of cortical remodeling as well as related diseases and the efficacy of their treatments.
Through their extensive lacuno-canalicular network, osteocytes act as key regulators of bone remodelling and have more recently been recognized as contributors to bone repair. However, these processes occur in a highly vascularized tissue, and the relationship between osteocytes and bone vasculature remains poorly understood. This review summarizes current knowledge on osteocyte-vascular interactions, with a focus on communication mechanisms and their relevance to bone physiology, aging, and disease. Emerging evidence indicates that osteocyte-vascular communication occurs through several modalities. Indirect signalling involves paracrine factors secreted by osteocytes, including VEGF, sclerostin, neuropeptide Y, as well as extracellular vesicles, which modulate ECs’ behaviour. Direct communication has also been suggested through physical interactions between osteocytes and blood vessels, including mitochondrial transfer and potentially gap junctions. Recent studies have also identified lymphatic vessels within bone, raising the possibility of previously unrecognized interactions between osteocytes and the lymphatic vasculature. Together, these findings highlight diverse modes of communications and associated signalling pathways, through which osteocytes may regulate vascular function within bone. Despite emerging insights into osteocyte-bone vasculature crosstalk, the underlying mechanisms remain incompletely understood. Advances in experimental tools may improve our knowledge of this bidirectional dialogue, providing new perspectives on bone physiology, skeletal pathologies, and potential therapeutic strategies targeting this interaction.
We summarize and discuss evidence on management of chronic hypoparathyroidism (HypoPT) and primary hyperparathyroidism (PHPT) in pregnancy and lactation to provide guidance for clinical care. Women with HypoPT are at increased risk of certain pregnancy complications, though most pregnancies are uncomplicated. Conventional therapy with activated vitamin D and calcium is continued throughout pregnancy, but there are unpredictable changes in the required dosages warranting regular surveillance during pregnancy (e.g., all 3 to 4 weeks). Data on parathyroid hormone (PTH) replacement therapy in pregnancy are limited, but a few case reports suggest favourable outcomes with this treatment. During lactation, dosage requirements for conventional therapy of HypoPT are often reduced and usually normalize again after weaning. In women with PHPT, surgical treatment should be pursued before conception. PHPT is not associated with adverse pregnancy outcomes in women with mild hypercalcemia but maternal and fetal complications significantly increase with higher calcium concentrations. There is no clear threshold for this risk increase, but several studies and expert groups support a cut-off concentration of about 2.85 mmol/L in albumin-adjusted calcium and 1.45 mmol/L in ionized calcium. For pregnant women with PHPT and calcium above these cut-off concentrations, parathyroidectomy, preferentially in the second trimester, is recommended. Medical treatment for hypercalcaemic PHPT is limited and requires individual decision making. Immediately after delivery, hypercalcemia may worsen in women with PHPT. Clinical care of women with HypoPT and PHPT in pregnancy and lactation requires intensive surveillance and consideration of the specific changes in bone and mineral metabolism during these times.
This review compares three major North American osteoporosis guidelines: the American Association of Clinical Endocrinology (AACE), the Bone Health and Osteoporosis Foundation (BHOF), and the Osteoporosis Canada Clinical Practice Guideline (OCCPG). The paper evaluates differences in fracture risk assessment, diagnostic strategies, pharmacologic treatment recommendations, and follow-up approaches to determine how each guideline supports osteoporosis management and fracture prevention. Recent research supports anabolic therapies for patients at high fracture risk. Studies show these agents improve bone mineral density and reduce fracture rates, especially when followed by antiresorptive therapy. Emerging evidence also supports sequential treatment strategies and individualized risk assessment to optimize outcomes. All three guidelines emphasize fracture prevention and early diagnosis but differ in risk thresholds, use of FRAX, and recommendations for newer therapies. Current evidence suggests anabolic-first approaches may improve outcomes in high-risk patients. Future research should focus on long-term safety, comparative effectiveness, and personalized treatment strategies.
To investigate the role of short-chain fatty acids (SCFAs) in the pathogenesis of osteoporosis and their potential value as therapeutic targets. Recent studies have shown that SCFAs, metabolic products of gut microbiota, play a crucial regulatory role in bone remodeling. SCFAs achieve this by activating G protein-coupled receptors (GPCRs), inhibiting histone deacetylases (HDACs), and regulating signaling pathways involved in bone metabolism. This effectively suppresses osteoclast activity, reduces bone resorption, enhances osteoblast function, and alleviates oxidative stress, thereby promoting bone formation. These findings not only reveal the key mechanisms by which SCFAs maintain bone metabolic homeostasis but also highlight their potential for treating osteoporosis in the elderly and postmenopausal women. Related clinical trials and drug research are currently underway. This review explores the potential value and theoretical basis of targeting SCFAs for the prevention and treatment of osteoporosis, summarizes existing clinical trials and related drug research, and provides new directions for developing future treatment strategies.
Fracture risk calculators such as FRAX, the Garvan Fracture Risk Calculator, and QFracture are now embedded in clinical guidelines, yet they communicate only a single numerical probability. This review examines whether current tools adequately meet patients' informational needs and identifies critical gaps in fracture risk communication. Most patients want fracture risk information, but only approximately half actually receive it. Research consistently shows that patients globally prefer visual over numerical formats, yet existing tools do not communicate the consequences of fracture, including mortality, subsequent fracture risk, and loss of independence, nor do they contextualise risk within available treatment options. Three critical gaps are identified: the consequence gap (what fracture means for survival and function), the controllability gap (how treatment modifies risk), and the format gap (how risk is presented and understood). Moving fracture risk communication beyond a single number requires integrating consequence, context, and format. The digital platform BONEcheck addresses these gaps by incorporating mortality risk, refracture risk, skeletal age, treatment contextualisation, and multi-format presentation including icon arrays. Future research, clinical practice, and guideline development should prioritise a more complete, actionable, and patient-centred approach to fracture risk communication.
Osteoporosis remains a pressing worldwide health concern. Understanding disease progression and evaluating treatment responses requires comprehensive skeletal assessment. This review presents a novel skeletal assessment – time-lapse high-resolution peripheral quantitative computed tomography (time-lapse HR-pQCT) – and highlights its capability in assessing bone formation and resorption. Time-lapse analysis was validated for in vivo bone remodeling assessment in micro-CT-based preclinical studies two decades ago. Recently, clinical time-lapse HR-pQCT research has demonstrated its feasibility in assessing bone turnover in patients with chronic kidney disease, and in characterizing the spatial distribution of long-term bone gain and loss in response to medications, mechanical loading, disease, and injury. Moving forward, time-lapse HR-pQCT requires validation against the gold standard bone biopsy with quantitative histomorphometry. Time-lapse HR-pQCT is a skeletal assessment capable of evaluating and longitudinally monitoring changes in bone density, microarchitecture, and remodeling dynamics. Rigorous validation and application to clinical imaging modalities will enable its broader implementation.
This study aimed to investigate the potential of Cone Beam Computed Tomography (CBCT) parameters to identify primary osteoporosis in jawbones. Early diagnosis of osteoporosis is crucial but challenging. Dual X-ray Absorptiometry (DXA) is the gold standard to measure bone density, nevertheless it has limitations including cost, radiation dose, and 2D imaging. CBCT is a volumetric imaging technique commonly used in dentistry that showed promise as an alternative tool due to its high spatial resolution and excellent analysis of bone structures. Mandibular and maxillary CBCT indices showed a strong correlation with Bone Mineral Density (BMD) assessed by DXA. Regional indices (Anterior, Molar, and Posterior), quantitative indices (Computed Tomography Mandibular Index, Computed Tomography Index Superior and Inferior), Radiographic Density, Fractal Dimension, and the qualitative index named Computed Tomography Cortical Index seemed appropriate for the detection of primary osteoporosis. Morphometric parameters for trabecular bone did not show differences between osteoporotic and non-osteoporotic patients. Future studies should assess diagnostic accuracy of such CBCT indices and formulate standardized measurement protocols.
To elucidate the association between testosterone and skeletal health in men. In this review, i) we discuss the influence of testosterone on bone metabolism, ii) review population studies demonstrating the relationship between sex steroid concentrations and bone mineral density (BMD) and bone quality, and iii) summarize data from seminal trials of testosterone therapy and its effects on bone density and fracture risk. In population studies, low testosterone (and estradiol) levels in men are associated with reduced bone mass and a higher risk of fracture. Clinical studies of testosterone replacement in men with organic hypogonadism show robust improvement in BMD. To the contrary, clinical trials of testosterone therapy in middle aged and older men with age-related low testosterone have shown modest increases in BMD (mainly vertebral BMD). Results of the TRAVERSE trial unexpectedly showed higher fracture rates in men randomized to testosterone therapy. Testosterone plays an important role in the maintenance of male skeleton. Most studies of testosterone therapy have demonstrated some degree of improvement in BMD, However, considering that testosterone treatment has not demonstrated reduction in fracture rates, we recommend that hypogonadal men who are at high risk for fracture receive treatment with agents that have proven anti-fracture efficacy.
This review summarizes the potential impact of stimulant medications on bone health, to raise awareness and optimize their safe use. Stimulant medications can impair bone health through inadequate nutrient/calorie intake and stimulation of the sympathetic nervous system, which regulates bone metabolism. However, their use decreases fracture risk in younger populations ( ≤ 25 years old) with attention deficit/hyperactivity disorder (ADHD), likely through reductions in impulsivity and injury. Special care may be needed when fractures occur while using these medications, as recent data suggest psychostimulants are associated with impaired fracture healing. Prescription and non-prescription use of psychostimulants have increased. Their ultimate effect on bone health may be a balance between effective behavioral modification and adverse effects on bone metabolism related to nutrition and sympathetic activation. Future research should investigate how psychostimulants affect acquisition of peak bone mass, stability of bone mineral density (BMD) when used through mid/late-life, and fracture healing.
The osteoblast lineage has traditionally been viewed through a structural and metabolic lens, yet growing evidence indicates that these cells possess diverse functions, including roles in innate and adaptive immune responses. To establish a coherent mechanistic framework, we performed a systematic review of the literature concerning immune signalling, antigen presentation, and pathogen responses across the osteoblast lineage. We identified 463 unique studies, with 43 meeting the inclusion criteria. Our synthesis reveals a stage-specialised immune continuum. Osteoprogenitors appear to initiate early inflammatory signalling while mature osteoblasts operate as microbial sensors and conditional antigen-presenting cells via inducible expression of cell membrane and cytosolic pattern recognition receptors, and a functional major histocompatibility complex class II apparatus. Osteocytes, the most abundant and long-lived bone cell type, are also capable of detecting microbial danger and activate extensive interferon, chemokine and cytokine programmes within the lacunocanalicular network. Together, these properties define a stromal immune system that coordinates both innate and adaptive immunity across bone surfaces and the mineralised matrix. This osteoblast lineage-integrated immune architecture provides a conceptual basis for understanding osteomyelitis incidence and persistence, biomaterial–immune interactions, as well as inflammatory bone remodelling, reframing this lineage as a previously underappreciated regulator of skeletal and systemic immunity.
Traumatic brain injury (TBI) is increasingly recognized as a systemic disorder with significant effects on skeletal biology. This review summarizes current evidence describing how TBI impacts fracture healing, heterotopic ossification, and long-term bone remodeling. Clinical observations and experimental models demonstrate that TBI can accelerate early fracture callus formation and increase the risk of heterotopic ossification, suggesting a transient pro-osteogenic state following injury. Proposed mechanisms include neuroinflammatory cytokine release, sympathetic nervous system activation, neuroendocrine dysregulation, and mobilization of osteoprogenitor cells. Conversely, persistent neuroinflammation, hypothalamic–pituitary axis dysfunction, oxidative stress, and altered autonomic signaling are associated with impaired fracture remodeling, increased bone resorption, and progressive bone loss. Emerging data implicate extracellular vesicle-mediated signaling as a key pathway linking brain injury to skeletal outcomes. TBI induces a contextual, biphasic skeletal response with both osteogenic and degenerative consequences. Understanding this duality is essential for optimizing fracture care and preserving bone health after neurotrauma.
Osteopetrosis is a heterogeneous group of bone diseases with increased bone density as a result of defective osteoclast function or differentiation. The clinical presentations range from the early, often lethal, infantile malignant forms to the mild autosomal dominant forms. This review provides recent updates in preclinical findings regarding molecular genetics, diagnosis, and novel therapeutic approaches in osteopetrosis. The diagnosis is radiologic, supported by biochemical and genetic examination to identify mutations in the key genes involved in osteoclasts, TCIRG1, CLCN7, OSTM1, SNX10, RANK, and RANKL. Treatment is at present largely the management of complications and includes vitamin D and calcium supplements, IFN-γ therapy, and hematopoietic stem cell transplantation (HSCT), the latter being the treatment of choice for most forms of osteopetrosis. Two gene therapy- and iPSCs-derived strategies, based on reconstituting the function of osteoclasts, have been recently developed for the management of this hereditary bone disease. Furthermore, emerging findings suggest the possible involvement of epigenetic mechanisms, such as non-coding RNAs (ncRNAs), in osteopetrosis pathophysiology, paving the way for potential novel diagnostic biomarkers and tailored molecular treatments. The aim of this review is to provide an overview of recent progress in molecular genetics, diagnosis, and novel therapeutic strategies in osteopetrosis and to illustrate conceivable scenarios in regenerative and gene-based therapy.
Osteoporosis affects more than 53 million Americans and contributes to nearly 2 million fragility fractures each year, yet most patients who sustain fractures never receive guideline-recommended pharmacotherapy. Traditional step-therapy typically begins with bisphosphonates and reserves anabolic agents for later-line use, whereas sequential therapy prioritizes anabolic treatment followed by antiresorptive consolidation. This review synthesizes the evidence comparing these treatment paradigms and examines their relevance to orthopedic populations, in whom bone quality directly influences fracture healing, fixation, fusion, and implant-related outcomes. Among 37 studies meeting PRISMA-ScR inclusion criteria, anabolic-first sequential therapy generally produced greater gains in bone mineral density and greater fracture risk reduction than step-therapy or antiresorptive monotherapy. In one representative trial, romosozumab followed by denosumab achieved a 16.8
Osteoporotic fractures remain a major cause of morbidity and mortality worldwide. Current clinical assessment metrics (e.g., bone mineral density) are limited in their ability to identify fracture risk and bone strength. Statistical Shape and Appearance Modelling (SSAM) offers a method to quantify anatomical geometry and density patterns. This review examines advancements in SSAM for osteoporosis research. Recent literature demonstrates that SSAM can capture detailed bone geometry and internal density distribution. Increasingly, these models are combined with computational analytics, including finite element analysis and machine learning, to assess the mechanical and structural behavior of bone. SSAM provides a robust quantitative framework for bone research. Notably, SSAM is used to reconstruct 3D subjects from clinical 2D images for biomechanical evaluation. Although clinical adoption remains limited by generalizability, the advancement of deep learning and complex SSAM pipelines supports its potential for osteoporosis screening and fracture risk prediction.
Osteocytes form an extensive cellular network and communicate both with neighboring bone cells and with distant organs. Here, we review evidence on which tissues osteocytes communicate with, and the molecular “language” they use. Recent work has expanded osteocyte communication beyond the classical triad of receptor activator of nuclear factor κB ligand, sclerostin, and fibroblast growth factor 23. Within bone, osteocytes coordinate remodeling through direct cell-cell contacts and rapidly released mediators, acting on timescales relevant to mechanotransduction. Beyond bone, osteocytes signal to adipose tissue, muscle, kidney, cartilage, and vasculature. Extracellular vesicles are increasingly implicated as messengers, as their cargo (RNAs and proteins) can influence stem cell lineage allocation and bone–cartilage interactions. Osteocytes may also support vascular function via mitochondria transfer. Osteocytes integrate mechanical and metabolic cues and transmit information through a broader repertoire of signaling molecules than traditionally appreciated. Recognizing the diversity of target cells and mediators will refine concepts of osteocyte-bone and osteocyte-organ crosstalk and highlight mechanisms that could be targeted to reduce skeletal fragility.
While GWAS has identified many loci associated with bone mineral density (BMD), translating these findings into functional insights and treatments remains challenging. Post-GWAS methods such as Transcriptome-Wide Association Study (TWAS), Phenome-Wide Association Study (PheWAS), and Mendelian Randomization (MR) provide complementary strategies to prioritize genes and causal risk factors. This review summarizes findings from these studies. TWASs have identified many potential causal genes for BMD, but only a few, such as PPP6R3, have been confirmed through functional validation. Several MR studies have provided increasing evidence of causal relationships between inflammatory bowel disease, NAFLD, COPD, and lower BMD, along with a higher risk of osteoporosis. PheWAS and MR also identify bone marrow fat as a risk factor for decreased BMD. It is essential to bridge the critical gap between statistical discovery and biological validation. Moreover, the lack of bone-specific transcriptomic data remains a significant limitation, underscoring the need to generate such datasets. At the same time, all MR evidence should be corroborated with other sources to strengthen causal conclusions.
Health-related quality of life (HRQOL) in patients with osteoporotic vertebral compression fractures (OVCFs) varies significantly. This review summarizes the mechanisms of HRQOL impairment and evaluates the clinical evidence for vertebral augmentation (VA) procedures, specifically percutaneous vertebroplasty (PV), balloon kyphoplasty (BKP), and third-generation percutaneous vertebral augmentation systems (TVA). Additionally, we identify key factors influencing postoperative HRQOL recovery. OVCFs severely impair physical function and psychosocial well-being, increasing mortality risk by approximately 22
Emerging evidence indicates that interferons (IFNs) are crucial links between immune activation and skeletal remodeling, highlighting their roles in immune–skeletal interactions. This review highlights the IFN–JAK-STAT (the Janus kinase–signal transducer and activator of transcription) axis as a central signaling hub mediating osteoimmunology and provides an updated overview of its molecular mechanisms and its therapeutic relevance. Interferons play a crucial role in health and disease and consist of three major classes: Type I, II, and III IFNs. All IFNs transduce their signaling through the JAK–STAT pathway. Dysregulated JAK–STAT signaling is a key clinical feature of various pathological conditions, including autoimmune diseases and cancers. Several IFN-targeted and IFN-based therapies have been approved by the FDA for these indications. However, the assessment of skeletal events associated with IFN-related therapeutic strategies remains incomplete, which represents a gap in our knowledge. The role of IFNs in bone metabolism depends on the context and stage, and IFNs can yield opposing effects on skeletal health. A better understanding of the complex regulatory mechanisms downstream of IFN signaling under physiological and pathological conditions is critical for developing targeted interventions to restore the balance between immune response and skeletal health.
