Medication-related osteonecrosis of the jaw (MRONJ), a severe side effect caused by antiresorptive antiangiogenic medication, particularly bisphosphonates (BPs), has become a challenging disease with serious and profound effects on the physical and mental health of patients. Although it occurs with high frequency and is harmful, the exact mechanism of MRONJ remains unknown, and systematic and targeted approaches are still lacking. Maxillofacial surgeons focus on the etiology of osteonecrosis in the mandible and maxilla as well as the appropriate oral interventions for high-risk patients. Adequate nursing care and pharmacotherapy management are also crucial. This review provides a current overview of the clinicopathologic feature and research of MRONJ caused by BPs, with an emphasis on the potential mechanisms and current therapy and prevention strategies of the disease. We are of the opinion that an in-depth comprehension of the mechanisms underlying MRONJ will facilitate the development of more precise and efficacious therapeutic approaches, resulting in enhanced clinical outcomes for patients.

Osteoporosis refers to excessive bone loss as reflected by the deterioration of bone mass and microarchitecture, which compromises bone strength. It is a complex multifactorial endocrine disease. Its pathogenesis relies on the presence of several endogenous and exogenous risk factors, which skew the physiological bone remodelling to a more catabolic process that results in net bone loss. This review aims to provide an overview of osteoporosis from its biology, epidemiology and clinical aspects (detection and pharmacological management). The review will serve as an updated reference for readers to understand the basics of osteoporosis and take action to prevent and manage this disease.

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.
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.
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.
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.
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.

BACKGROUND: Although emerging studies have provided evidence that osteocytes are actively involved in fracture healing, there is a general lack of a detailed understanding of the mechanistic pathway, cellular events and expression of markers at different phases of healing.
METHODS: This systematic review describes the role of osteocytes in fracture healing from early to late phase. Literature search was performed in PubMed and Embase. Original animal and clinical studies with available English full-text were included. Information was retrieved from the selected studies.
RESULTS: A total of 23 articles were selected in this systematic review. Most of the studies investigated changes of various genes and proteins expression patterns related to osteocytes. Several studies have described a constant expression of osteocyte-specific marker genes throughout the fracture healing cascade followed by decline phase with the progress of healing, denoting the important physiological role of the osteocyte and the osteocyte lacuno-canalicular network in fracture healing. The reports of various markers suggested that osteocytes could trigger coordinated bone healing responses from cell death and expression of proinflammatory markers cyclooxygenase-2 and interleukin 6 at early phase of fracture healing. This is followed by the expression of growth factors bone morphogenetic protein-2 and cysteine-rich angiogenic inducer 61 that matched with the neo-angiogenesis, chondrogenesis and callus formation during the intermediate phase. Tightly controlled regulation of osteocyte-specific markers E11/Podoplanin (E11), dentin matrix protein 1 and sclerostin modulate and promote osteogenesis, mineralisation and remodelling across different phases of fracture healing. Stabilised fixation was associated with the finding of higher number of osteocytes with little detectable bone morphogenetic proteins expressions in osteocytes. Sclerostin-antibody treatment was found to result in improvement in bone mass, bone strength and mineralisation.
CONCLUSIONS: To further illustrate the function of osteocytes, additional longitudinal studies with appropriate clinically relevant model to study osteoporotic fractures are crucial. Future investigations on the morphological changes of osteocyte lacuno-canalicular network during healing, osteocyte-mediated signalling molecules in the transforming growth factor-beta-Smad3 pathway, perilacunar remodelling, type of fixation and putative biomarkers to monitor fracture healing are highly desirable to bridge the current gaps of knowledge.The translational potential of this article: This systematic review provides an up-to-date chronological overview and highlights the osteocyte-regulated events at gene, protein, cellular and tissue levels throughout the fracture healing cascade, with the hope of informing and developing potential new therapeutic strategies that could improve the timing and quality of fracture healing in the future.

Until recently, it was assumed that the only interaction between muscle and bone is mechanical, that the muscle acts as a pulley and the bone as a lever to move the organism. A relatively new concept is that muscle, especially contracted muscle, acts as a secretory organ, regulating metabolism. An even newer concept is that bone, especially the osteocytes in bone, act as endocrine cells targeting other organs such as kidney and more recently, muscle. These two new concepts logically led to the third concept: that muscle and bone communicate via soluble factors. Crosstalk occurs through muscle factors such as myostatin, irisin, and a muscle metabolite, β-aminoisobutyric acid, BAIBA, and through bone factors such as osteocalcin, transforming growth factor beta, TGFβ, Prostaglandin E2, PGE2 and Wnts. Some of these factors have positive and some negative effects on the opposing tissue. One feature both bone and muscle have in common is that their tissues are mechanically loaded and many of their secreted factors are regulated by load. This mechanical loading, also known as exercise, has beneficial effects on many systems leading to the hypothesis that muscle and bone factors can be responsible for the beneficial effects of exercise. Many of the characteristics of aging and diseases associated with aging such as sarcopenia and osteoporosis and neurological conditions such as Alzheimer\'s disease and dementia, are delayed by exercise. This beneficial effect has been ascribed to increased blood flow increasing oxygen and nutrients, but could also be due to the secretome of the musculoskeletal system as outlined in this review.

OBJECTIVE: To explore the types of orthodontic force-induced mechanical stimuli that regulate osteocyte function.
METHODS: In orthodontics, a tooth can be moved through the alveolar bone when an appropriate orthodontic force is applied. These mechanical loads stimulate cells within the bone tissue around the tooth. These cellular responses lead to bone resorption on the side of the tooth where the pressure has been applied and bone deposition on the side of the tooth experiencing tension. Recently, osteocytes were identified to function as mechano-sensory cells in bone tissue that direct bone resorption and bone formation. Based on recent literature, the proposed function of osteocytes during orthodontic tooth movement is explored with better understanding.
RESULTS: Several stimuli regulating osteocyte function have been highlighted, and their potential roles in events initiating osteocyte sensing of orthodontic force have been explored in detail. The most popular hypotheses for osteocyte response include stress-induced bone matrix deformation/microcrack formation and fluid-flow shear stress.
CONCLUSIONS: Understanding osteocyte function under mechanical stress may have profound implications in future orthodontic treatments.

Bone is a remarkable tissue that can respond to external stimuli. The importance of mechanical forces on the mass and structural development of bone has long been accepted. This adaptation behaviour is very complex and involves multidisciplinary concepts, and significant progress has recently been made in understanding this process. In this review, we describe the state of the art studies in this area and highlight current insights while simultaneously clarifying some basic yet essential topics related to the origin of mechanical stimulus in bone, the biomechanisms associated with mechanotransduction, the nature of physiological bone stimuli and the test systems most commonly used to study the mechanical stimulation of bone.

The rising prevalence of overweight and obesity among pediatric populations has become a major global concern. The objective of this review is to demonstrate potential interactions between the products released by fat tissue and the hormonal production of bone tissue in obese children and adolescents. Advancing the understanding of the complex interactions between adipocyte and osteocyte activities may contribute to the mechanistic understanding of the body\'s responses to weight loss during adolescence. This knowledge could also reveal any side effects encountered with these interventions. Currently, the concept of bone-adiposity crosstalk has not been fully elucidated, and the mechanisms remain controversial. Understanding the local interactions between the released products by fat tissue and hormones produced in bone tissue requires further investigations.

Bisphosphonates (BPs) are drugs commonly used in the treatment of various disease arising or affecting bone tissue. There is a standard use in bone neoplasia and metastasis, hormonal and developmental disorders as well as for compensation of adverse effects in several medical therapies. Many in-vivo and in-vitro studies have assessed the efficacy of this drug and its function in cellular scale. In this concern, BPs are described to inhibit the resorptive function of osteoclasts and to prevent apoptosis of osteoblasts and osteocytes. They can preserve the osteocytic network, reduce fracture rate, and increase the bone mineral content, which is therapeutically used. Connexin 43 (Cx43) is a crucial molecule for basal regulation of bone homeostasis, development, and differentiation. It is described for signal transduction in many physiological and pathological stimuli and recently to be involved in BP action.

Thiazolidinediones represent a class of molecules used in the treatment of type 2 diabetes mellitus. Despite interesting effects in lowering blood glucose and HbA1c levels durably, an augmentation of the fracture risk in women has emerged in the past years. This review is providing the readers with information about the cellular and molecular mechanisms involved in bone and bone cells in response to these drugs.