Bench-to-bedside strategies for osteoporotic fracture: From osteoimmunology to mechanosensation

Osteoporosis is characterized by a decrease in bone mass and strength, rendering people prone to osteoporotic fractures caused by low-energy forces. The primary treatment strategy for osteoporotic fractures is surgery; however, the compromised and comminuted bones in osteoporotic fracture sites are not conducive to optimum reduction and rigid fixation. In addition, these patients always exhibit accompanying aging-related disorders, including high inflammatory status, decreased mechanical loading and abnormal skeletal metabolism, which are disadvantages for fracture healing around sites that have undergone orthopedic procedures. Since the incidence of osteoporosis is expected to increase worldwide, orthopedic surgeons should pay more attention to comprehensive strategies for improving the poor prognosis of osteoporotic fractures. Herein, we highlight the molecular basis of osteoimmunology and bone mechanosensation in different healing phases of elderly osteoporotic fractures, guiding perioperative management to alleviate the unfavorable effects of insufficient mechanical loading, high inflammatory levels and pathogen infection. The well-informed pharmacologic and surgical intervention, including treatment with anti-inflammatory drugs and sufficient application of antibiotics, as well as bench-to-bedside strategies for bone augmentation and hardware selection, should be made according to a comprehensive understanding of bone biomechanical properties in addition to the remodeling status of osteoporotic bones, which is necessary for creating proper biological and mechanical environments for bone union and remodeling. Multidisciplinary collaboration will facilitate the improvement of overall osteoporotic care and reduction of secondary fracture incidence.


INTRODUCTION
The major characteristic of osteoporosis is a decrease in bone mass and quality, 1 rendering people prone to osteoporotic fracture (fragility fracture) caused by low-energy trauma. 2 Osteoporosis is a prevailing skeletal disease of the elderly; nearly 200 million osteoporotic patients are diagnosed annually, and almost 9 million osteoporotic fractures occur worldwide. 3 Surgery is the primary treatment strategy for osteoporotic fracture; however, poor prognoses are presented due to the combination of biological and surgical factors. 4 The common sites of osteoporotic bones are usually compromised and comminuted, which makes it hard to achieve an optimum reduction and stable fixation. 3,5 Osteoporotic fractures occur mostly in elderly patients, who exhibit underlying, unfavorable systemic conditions that are prone to complications. 6 The abnormal remodeling status of bone with osteoporosis would deteriorate after bed braking, which poses a disadvantage with respect to fracture healing and bone callus strength; furthermore, the refracture risk following surgery increases significantly. 7 In terms of the complexity of treatment and poor prognosis, the annual facility-related hospital cost of osteoporotic fractures is the highest (up to $5.1 billion), followed by that of myocardial infarction and stroke. 8 Although the results of the clinical studies remain controversial, the majority have demonstrated that decreased callus area (20%-40%) and bone mineral density (BMD) occur in the fracture sites of elderly osteoporotic patients 4 . Studies have indicated that the delayed or nonunion of osteoporotic fractures is implicated in the scarce capacity of bone regeneration with aging. 9,10 Additionally, the bone properties of such patients are quite different from those of normal individuals and are manifested in the decrease of bone mechanics and mechanosensation, as well as the abnormal bone metabolism caused by immune disorders. 11 To improve the current unsatisfactory status of osteoporotic fracture treatment, we must first gain an in-depth understanding of the mechanism of fracture healing in elderly patients with osteoporosis. Herein, we highlight the pivotal roles of mechanical loading and osteoimmunology in aging-related osteoporotic fractures, guiding the intervention in osteoporotic fracture patients combined with an optimal treatment strategy for improving the overall standard of care and reducing the incidence of secondary fracture. mineralization. 13 Cortical bone consisting of dense and wellorganized lamellae has higher strength but a lower capacity to withstand a load that exceeds the elastic deformation range compared with that of trabecular bone, which is composed of unparallel lamellar units with variable porosity (50%-90%). 14 The mechanical competence of cancellous bone is based largely on the BMD, while the stiffness of cortical bone is highly dependent on its porosity. 3,15 In contrast to calcified matrix mineralization, the organic matrix (e.g., collagen and noncollagenous proteins) is thought to control bone ductility and its capacity to withstand an impact without cracking. 16 A large proportion (90%) of the organic matrix is composed of type I collagen, which undergoes numerous posttranslational modifications. 17 Among them, enzymatic modifications positively affect the biomechanical stability of bone, while nonenzymatic crosslinking is associated with a deterioration in these properties. 16 Noncollagenous proteins, including osteopontin (OPN) and osteocalcin (OCN), account for 10% of the organic matrix and limit crack energy through the control of hydroxyapatite size and orientation. 18 Whereas bone material properties provide only a static snapshot of bone quality, the abilities of self-regeneration and remodeling provide a dynamic profile of bone health. 19 The cortical and trabecular bone both undergo lifelong remodeling coupled with bone resorption, which is mediated by osteoclasts following osteoblastic bone formation. 20 Osteoclasts are of hematopoietic stem cell (HSC) origin and share precursors with macrophages. 21 In the presence of macrophage colony-stimulating factor (M-CSF), osteoclast precursors differentiate to preosteoclasts by the binding of receptor activator of nuclear factor kappa-B ligand (RANKL) to its cognate receptor, receptor activator of nuclear factor kappa-B (RANK). These mononuclear preosteoclasts then fuse to form multinuclear bone-resorbing osteoclasts. 21 In contrast, osteoblasts are derived from mesenchymal stem cells (MSCs), 22 and osteoblastic bone formation is separated from resorption by a reversal phase for several weeks. 23 Mature osteoblasts then differentiate into osteocytes, which reside in small lacunae inside the calcified bone matrix. 24 The long dendritic extensions of osteocytes together with the cell bodies form the lacuno-canalicular network (LCN), which allows direct signal transduction. The speed of mineral accumulation in the bone remodeling cycle is also affected by numerous endocrine factors, such as parathyroid hormone (PTH) and estrogen, which are supplied by the bone vascular systems. 25,26 However, the normal regulation of bone remodeling could be interrupted as a consequence of skeletal senescence, 27,28 which impact the integrity and biomechanical properties of both cortical and cancellous bones. 29 The abnormal bone remodeling shifts toward bone resorption, which is either due to excessive activation of osteoclasts or to a low capacity of bone regeneration. 30 In addition, age-related loss of proteostasis and increased levels of oxidants result in the overaccumulation of inorganic pyrophosphate (PPi) or advanced glycation endproducts (AGEs). During the development of osteoporosis, osteocyte numbers per unit of bone area are gradually reduced, 31 resulting in decreased trabecular thickness and more intracortical porosity. 32 These considerable changes in the matrix composition and structure cause deterioration of bone quality and compromise its resistance to mechanical loading. 33 Thus, osteoporotic fractures are the macroscopic result of microstructural alterations that increase the susceptibility of bone to the applied load 34 (Fig. 1).

OSTEOIMMUNOLOGY IN HEMATOMA AND INFLAMMATORY PHASES
Secondary fracture healing occurs after a fracture without rigid fixation. Under the influence of active loading, an external callus is initiated to bridge the fracture gap 35 in a three-stage process consisting of inflammation, repair, and remodeling. 36 The first two of these partially overlapping phases restore bone structure and  Fig. 1 Static and dynamic changes in osteoporotic bone. An osteoporotic fracture is the macroscopic result of microstructural alterations that change the response of bone to the applied load. The aging process in osteoporotic bone would lead to overaccumulation of PPi, AGEs, and nonenzymatic crosslinking of collagen, which disturb the normal organization of bone material. With the increase of bone resorption and low rate osteogenesis, the osteocyte lacunae reduction leads to decreased trabecular thickness and more porous cortical bone. PTH parathyroid hormone, M-CSF macrophage colony-stimulating factor, RANKL receptor activator of nuclear factor kappa-B ligand, PPi inorganic pyrophosphate, AGEs advanced glycation end-products, MSCs mesenchymal stem cells. "Red" refers to upregulation; "Green" refers to downregulation continuity over a period of 3 months to allow full weight bearing. The last phase involves gradual remodeling of bone to withstand the usual strains of daily life. 37 In contrast, primary fracture healing without formation of a periosteal callus usually requires direct contact of compact bone or rigid surgical intervention that makes the fracture gap <200 μm. However, elderly osteoporotic bones, such as metaphyseal sites, which are highly susceptible to bone degradation, make it difficult to maintain anatomical reduction and rigid fixation using traditional screws due to inadequate insertional torque. 38 In this situation, the healing process will be more like indirect bony union with the response of loading and inflammation, forming a periosteal callus bridging the fracture gap. The specific osteoimmunology and mechanosensation status of patients with osteoporotic fractures affect these healing phases in different manners. 39 Bone fracture induces immediate inflammation and bleeding around bone extremities and within the medulla, where a template is formed for callus formation, called a hematoma. 40 Around the hematoma sites, inflammatory cells, such as macrophages/monocytes or B/T cells, are activated to release inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6) into the systemic circulation. 41 These cytokines are responsible for the initiation of immune and inflammatory responses, 42 including enhancement of blood flow and vessel permeability, as well as the recruitment of immune cells for pathogen clearance. 43 The limited inflammatory response is required to initiate the repair cascade and mobilize all the required factors involved in the early bridging of the fracture gap, especially in indirect bony unions without rigid fixation. 44 The interactions between the skeletal system and immune function, comprising osteoimmunology, in osteoporotic fractures are altered with age. 45 It has been reported that an ageassociated decline in the absolute numbers of human B cell precursors in bone marrow 46 leads to a significant decrease in the number of mature human B cells. 47,48 Compared with young adults, the B cell repertoire is less diverse in elderly individuals. 49 As to T cells, studies exhibit reductions of proliferation and helper function in CD4+ T cells that recruit neutrophils and macrophages to infected sites of elderly individuals. 50 Consistent with this finding, the impaired neutrophil 51 /monocytes 52 -mediated phagocytosis also showed an age-dependent reduction. 53 In contrast, the expression of Toll-like receptors (TLRs), a group of pattern recognition receptors (PRRs) that trigger pro-inflammatory responses, 54 is increased in monocytes and dendritic cells in elderly people, accompanied by increased production of IL-1 and TNF-α. 55 In vitro and in vivo studies have shown that persistent tumor necrosis factor (TNF) expression impairs cell-mediated immune responses and Th2 differentiation from naïve T cells. [56][57][58] Moreover, constant stimulation by TNF-α elevates the threshold for T cell activation via the T-cell receptor (TCR), attenuating T cell responses to antigen 59 and negatively affecting angiogenesis during fracture healing. 60 Thus, the early immune responses and pathogen clearance of aged patients with osteoporotic fractures would be impaired or delayed due to the insufficient acquired immunity and dysfunction of the innate immune system. 61 Furthermore, pathogen infections induce host inflammation and contribute to local bone loss. The most frequent pathogen identified in bone infection is Staphylococcus. 62 Staphylococcus aureus protein A induces the production of inflammatory cytokines, such as TNF-α, 63 IL-6, interleukin-1 alpha (IL-1α), 64 interleukin-1 beta (IL-1β), 64 and neutrophil-attracting chemokines in local tissues. On the one hand, short-term (24 h) upregulated cytokines, such as TNF-α are essential for local recruitment of neutrophils, 41 macrophages, and T cells for pathogen clearance. 65,66 However, the long-term presence of these cytokines, especially TNF-α, IL-1, and IL-6, activates CD4+ T cells, promoting RANKL expression by osteoblasts 67 and synergizing directly with RANK to amplify osteoclastogenesis 68 and bone resorption. 69 In general, high levels of pro-inflammatory cytokines, either in the circulation or local tissues, are found in the aged population. 70 Serum IL-1, IL-6, and/or TNF-α levels have been shown to be upregulated in elderly patients with bone loss, 70 supporting the hypothesis of increased inflammation with aging. 71 In fact, TNF-α promotes bone resorption by both directly inducing osteoclast differentiation 72 and inhibiting osteoblast differentiation and function. 73,74 IL-1 drives osteoclast differentiation via a RANKL/RANK-independent mechanism. 75 IL-6 indirectly plays a positive role in osteoclast differentiation by binding IL-6 receptors expressed on osteoblastic cells to induce RANKL expression. 76 Neutrophils stimulate osteoclastogenesis by upregulating cell surface RANKL expression under TLR stimulation 77 or by inducing osteoblast retraction. 78 Interferon gamma (IFN-γ), secreted by anti-inflammatory macrophages (M2), inhibits osteoclast differentiation via rapid degradation of TRAF6. 79 However, macrophage polarization shows a shift toward macrophages (M1) that promote inflammatory cytokines as a consequence of aging. 80 In contrast, mature B cells are important regulators of a decoy receptor for RANKL, osteoprotegerin (OPG). In total, 40% of the OPG in bone marrow is produced by mature B cells alone. 81 The increased bone resorption and low levels of bone marrow OPG were demonstrated in B cell-deficient mice; this defect can be normalized by the transplantation of B cells. As a result of the decreased number of mature human B cells, the supply of OPG is low in patients with osteoporosis. Thus, current evidence supports that the high RANKL/OPG ratio caused by agingrelated inflammation and the lack of mature B cells is associated with the hyperactivation of osteoclastogenesis and aggravation of bone resorption in elderly patients with bone loss, which increases the incidence of further intraoperative or postoperative fractures (Fig. 2). Moreover, Nagae et al. concluded that overactivation of osteoclasts plays an important role in chronic pain after osteoporotic fracture by creating acidosis. 82 Hyper osteoclast activity may lead to pathological modifications of bone sensory nerve fibers, with an overexpression of acidsensitive pain receptors, which contributes to generating and maintaining pain in osteoporosis. 83

MOLECULAR BASIS OF BONE MECHANOSENSATION
Primary fracture healing occurs when the fracture site achieves rigid anatomical and mechanical fixation. Under these conditions, a soft callus enveloping the bone extremities subsequently calcifies to a peripheral solid callus by intramembranous ossification. 35 However, in elderly osteoporotic bones, the healing process will be more like indirect bony union by forming a periosteal callus bridging the fracture gap, since it is usually difficult for the compromised bones to maintain enough stress stimulation. 84 Among the bone multicellular units (BMUs), which consist of various cells involved in bone remodeling, the osteocytes embedded in the matrix function as major mechanosensitive cells. 85 Substantial evidence indicates that the mechanosensation of osteocytes is mediated by signaling molecules, such as Wnts, bone morphogenetic proteins (BMPs), nitric oxide (NO), and prostaglandin E2 (PGE2) in response to mechanical stimulation. 86 Furthermore, altered enzyme activity and RNA synthesis have been reported in osteoclasts after mechanical loading of intact bone, which further supports the mechanosensory role of osteocytes in bone. 87 Thus, adequate mechanical loading and mechanotransduction are pivotal factors in the repair and remodeling phase of fracture healing.
Mechanical forces, including fluid flow as well as compressive/ tensile forces in the LCN, 13 induce cell-level physical signals of shear stress, electric/streaming potentials, and substrate strain by acting on cell surface sensors and within the signaling pathways. 88 To date, evidence strongly suggests that integrins on the surface of bone cells are ubiquitous sensors of mechanical forces capable of detecting alterations in the mechanical environment in the extracellular milieu. 89 Shear strain is detected by primary cilia via polycystin 1 (PC1) and transient receptor potential cation channel subfamily V member 4 (TRPV4), which activate signal transducer and activator of transcription (STAT) signals to induce ion flux. 90 Wnt signaling is also activated by cilia via the noncanonical pathway, resulting in β-catenin degradation. 91,92 The role of canonical Wnt in the suppression of the SOST gene (sclerostin) has also been demonstrated. 93 Furthermore, fluid shear stress can activate voltage-sensitive calcium channels on the plasma membrane, leading to influx of Ca 2+ , which induces PGE2 synthesis via ATP and inhibits NO generation as a second messenger. 94,95 PGE2 and ATP are released via connexin hemichanels formed following extracellular signal-regulated kinase1/2 (ERK1/2)-induced transcription of connexin-43 (Cx43). 96,97 Compressive/tensile forces impose hydraulic pressure in the lacunarcanalicular system, 89 which increases cellular deformation of osteocytes 98 . The substrate strain at the membrane can be sensed by integrins that transmit force to the cell cytoskeleton via ERK, proto-oncogene tyrosine-protein kinase Src (SRC) and replication origin activator (ROA) to induce stress fiber polymerization. 98 The cell nucleus plays crucial roles in response to cellular mechanotransduction. Transcriptional regulation in the cell nucleus converts incoming mechanoresponsive signals into biological signaling and even directly responds to cellular deformation. 99 These intracellular signaling pathways converge to modulate osteogenic transcription factors in addition to regulators of growth factors and matrix proteins required for osteogenesis. Evidence suggests that mechanical signals induce OPG and suppress RANKL to inhibit osteoclast differentiation. 100 The morphological changes of osteocytes with aging have been reported to influence their mechanosensitivity and the response to loads. 101 Changes in LCN volume due to the increased rate of osteocytic osteolysis with aging or trauma have been shown to affect local bone mechanosensation. 102 Additionally, age-related changes in periosteal modeling arise from cell function/signaling deficits combined with increased marrow adiposity leading to a reduced pool of osteoblast progenitors. 103,104 Furthermore, periosteal lining cell numbers and osteoblast life-span are reduced by an increased rate of apoptosis. 105 There is an age-related switch in macrophage differentiation from the anti-inflammatory (M2) phenotype that mediates tissue repair to the inflammatory (M1) phenotype. 53 As a consequence of the decline in the secretion of anti-inflammatory and osteogenic cytokines, the bone regeneration capability could be impaired in the process of remodeling osteoporotic fractures. 7 In osteoporotic fractures, the inevitable immobilization and stress shielding achieved by orthopedic surgery reduce the mechanical loading compared with that at normal sites. 106 The deficiency of stress loading on surface sensors of bone cells is accompanied by NF-κB activation of osteoblasts and neighboring immune cells that promotes RANKL production to trigger osteoclastogenesis and bone resorption. 107,108 This process results in the excess removal of bone mass, 93 which therefore leads to a coarse trabecular pattern and thinning of cortical bone. Estrogen controls the adaptation of osteoblasts and osteocytes to mechanical loads via binding to the estrogen receptor (ER) or activation of TGF1 receptors. 109 Delayed ER expression was shown to be correlated with impaired callus formation capacity in the healing process. 110 A study in humans suggested that mechanical interventions enhance periosteal modeling and bone strength in the young skeleton, 111 while the effects are markedly diminished in the elderly skeleton. 111,112 In vitro studies indicate that the age-related increase in osteocyte degradation and reduction in the basal level of mechanosensation significantly affect second messenger signaling to modulate bone regeneration 111 (Fig. 3). An optimal strategy for improving the treatment of osteoporotic fractures must address both biological and mechanical issues based on the molecular mechanisms of mechanical loading in fracture healing. 93

ANTI-INFLAMMATORY EFFECTS OF MECHANICAL LOADING
After the fracture gap has been bridged by a callus, the woven bone is slowly replaced with lamellar bone structures. Balanced resorption and formation of new bone require a normal  environment without excessive inflammation. 37 In these longterm phases, mechanics play a pivotal role, not only as the forces driving remodeling but also as the regulators that function to inhibit inflammation and abrogate the associated repression of growth factors and matrix synthesis. 113 The traumatic signals caused by fracture and surgery initiate pro-inflammatory signaling cascades via activation of NF-κB transcription factors. 114,115 NF-κB activation leads to the production of high levels of NO and superoxide that mediate both bone damage and matrix degradation. 116 Mediators such as TNF-α, IL-1β, and matrix metalloproteinases (MMPs) play key roles in the pathogenesis of inflammatory bone diseases and injuries. 117 In IL-1β-treated osteoblast-like cells, mechanical signals have been shown to rapidly (within 10 min) and dramatically inhibit NF-κB nuclear translocation. 118 The mechanism involves the inhibition of TNF receptor-associated factor 6 (TRAF6) phosphorylation and subsequent activation of the inhibitor of NF-κB kinase (IKK) complex. 119 This process prevents the proteosomal degradation of NF-κB inhibitor alpha (IκBα) and NF-κB inhibitor beta (IκBβ) phosphorylation, which in turn inhibits nuclear translocation of NF-κB and subsequent pro-inflammatory gene transcription. 120 In fact, mechanotransduction at low magnitudes is a potent anti-inflammatory signal 121 that counters the NF-κB signaling cascade. 122 In vitro studies in osteoblasts have shown that the pro-inflammatory mediators suppressed by mechanical signals (tensile, compressive, and shear) include IL-1β-induced NO, COX-2, PGE2, cytokines (IL-1β and TNF-α), and MMPs. 123 Simultaneously, mechanical signals upregulate the expression of growth factors, such as BMPs, OCN, and alkaline phosphatase (ALKP), which are inhibited during inflammation. 124 Several anti-inflammatory cytokines (IL-10) and tissue inhibitors of metalloproteinases (TIMPs) that are inhibited during inflammation are upregulated by mechanical signals. For instance, IL-10 and TIMP-II synthesized by low magnitudes of mechanical signals can suppress inflammation and matrix breakdown in osteoblast and osteoblast-like cells. 125 In contrast, exogenous PGE2 was demonstrated to function as an intercellular messenger for enhancement of the mechanosensitivity of bone to loading forces both in vitro and in vivo. 126 Furthermore, in the presence of PGE2 signaling, osteocytes release NO in response to mechanical stimulation via cytoskeletal adaptation and mitogen-activated protein kinase (MAPK) pathways. 127 Additionally, mechanical loading increases ER-α expression at the fracture callus, which is beneficial for mechanical signal transduction and fracture repair. 128,129 These data indicate that rigid fixation and adequate mechanical loading are a means of improving the immune environment that benefits bone healing 130 (Fig. 4).

MANAGEMENT OF HEMATOMA AND PERIOPERATIVE INFECTION
The most satisfactory bone healing depends on a good biological environment and appropriate mechanical loading for bone repair  and remodeling. Orthopedic surgeons are encouraged to familiarize themselves with the molecular basis of skeletal senescence, mechanical loading and osteoimmunology in osteoporotic fractures, which is critical for determining an appropriate surgical technique or nonsurgical intervention 3 . In terms of the decrease in early immune responses and pathogen clearance in aged patients with osteoporotic fractures, special preoperative management is required to achieve a better local healing environment. Previous studies have revealed the osteoimmunological role of hematoma in fracture healing, especially in the inflammatory phase. 42,131 However, there is still no consensus on hematoma management among surgeons. Grundnes and Reikeras reported that early removal of the hematoma (2-7 days) after fracture greatly prohibited bone healing in an animal fracture model. 132 Other researchers, however, found that hematoma without normal fibrinolysis was an obstacle to cellular trafficking, which subsequently inhibited fracture healing by impeding macrophage accumulation. 133 Thus, in clinical practice, early hematoma in the fracture site should be preserved and induced to "mature". Indeed, the use of fibrin biomaterials, including platelet-rich plasma (PRPs), platelet-rich fibrin (PRFs) and other treatments, 134 mimicking the structure of the natural hematoma, has demonstrated promising effects on the improvement of fracture healing. In addition, earlystage treatment with recombinant human platelet-derived growth factor-BB (rhPDGF-BB) could be beneficial for vascularization and angiogenesis in local sites, 135 which would promote the recruitment of progenitors and accelerate bone remodeling in fracture healing of the elderly. 136 In short, hematoma is a natural factor that enhances fracture healing and should be preserved in fracture sites, although thorough mechanisms are needed to be well investigated. Due to the decline of immune responses and pathogen clearance dysfunction in elderly patients with osteoporotic fractures, the prevention of perioperative infection through the use of adequate doses of antibiotics is important for maintaining a normal environment for initiating fracture healing (Fig. 5). Consequently, in orthopedic surgery, antibiotics, such as antibiotic-augmented acrylic cements/beads are increasingly used in topical form. 137 However, the enhanced antibiotic treatment doses are thousands of times higher than those required to inhibit bacterial growth. 137 Current evidence suggests that this concentration is detrimental to abnormal bone remodeling as a result of negative effects on mitochondrial physiology. 137 Thus, local antibiotic vehicles must be designed to deliver sufficiently high concentrations to inhibit bacterial growth without affecting bone cell metabolism. 138

ANTI-INFLAMMATION AND REGULATION OF BONE REMODELING
Increased RANKL/OPG ratios caused by aging-related inflammation are associated with hyperactivation of osteoclastogenesis and exacerbation of bone resorption in elderly patients, leading to subsequent impairment of bone healing and inflammatory pain. Anti-inflammation therapy is a potential strategy that may benefit aging-related osteoporotic fracture by reducing inflammation and providing protection against bone loss. Studies have shown that healthy transgenic mice injected with anti-TNF-α repeatedly promote T cell responses to cognate peptide antigen. 139 In the clinical setting, anti-TNF-α (infliximab, Remicade) rapidly and remarkably restores the responses of T cells from rheumatoid arthritis (RA) patients. 56 Treatment with infliximab protects against bone loss and improves the formation/resorption marker ratio in this population, suggesting beneficial systemic and local bone effects. 140,141 Although anti-inflammatory therapies have not been used clinically to treat osteoporosis, they have shown good promise in mouse models. Indeed, pharmacological or genetic ablation of TNF 142 and IL-1 143 by somatic gene therapy 144 has been used effectively to prevent ovariectomy-induced bone loss in mice. Thus, anti-inflammation therapy is a potential strategy that may benefit osteoporosis patients because of reduced  Fig. 4 Anti-inflammatory effects of mechanical loading. The mechanotransduction at low magnitudes is a potent signal to counter inflammation activated by the NF-κB signaling cascade. IL-1 interleukin-1, LPS lipopolysaccharide, TRAF2 TNF receptor-associated factor 2, TRAF6 TNF receptor-associated factor 6, PGE2 prostaglandin E2, NO nitric oxide, COX-2 cyclooxygenase-2, TNF-α tumor necrosis factor alpha, IKK inhibitor of NF-κB kinase, IκBα NF-κB inhibitor alpha, IκBβ NF-κB inhibitor beta, BMPs bone morphogenetic proteins; OCN osteocalcin; ALKP alkaline phosphatase; RANKL receptor activator of nuclear factor kappa-B ligand, MAPK mitogen-activated protein kinase, MMPs matrix metalloproteinases. "Red" refers to upregulation; "Green" refers to downregulation inflammation in addition to protection against bone loss. However, the risk of infection is increased in patients undergoing anti-inflammation treatment, suggesting that anti-inflammatory drugs should be discontinued for a period of time before surgery. 145 Because chronic inflammation affects bone healing, the anti-inflammatory drug should be reused in osteoporotic fracture after an acute immune response to alleviate inflammation-induced bone loss. The recent development of antiresorptive agents (e.g., bisphosphonates, RANKL inhibitor) represents a significant advance in therapeutic options for improving bone quality and metabolism. 146 Bisphosphonates are commonly used in osteoporosis to prevent and reduce pain by modifying osteoclast activity. 147 Following an osteoporotic fracture, early intervention with antiresorptive drugs after surgery would not affect fracture union. 148 However, bisphosphonate-dependent repair processes become progressively dominant in the late phases, suggesting that continuous administration of alendronate causes delayed healing in mechanically compromised situations. 149 Denosumab, a RANKL inhibitor, can significantly reduce the high RANKL/OPG ratio in the inflammatory and repair phases of fracture healing with agingrelated osteoporosis 150 and has been identified as an efficacious osteoporosis treatment option with low rates of adverse events. 151 Calcitonin effectively relieves bone pain and can reduce bone loss in osteoporotic fractures, although short-term (3 months) use is recommended. 152,153 In summary, reducing the frequency of postoperative syndromes in patients with osteoporosis requires not only regulation of the immune response but also balanced bone resorption and osteogenesis (Fig. 5). Studies have demonstrated that anti-inflammation therapy combined with a bone resorption blocking drug 154 reverses systemic bone loss, 155 while the timing and extent of immune intervention require further clinical exploration.

STRATEGIES FOR MECHANICAL LOADING ENHANCEMENT AND RIGID FIXATION
The biochemical responses of osteocytes to mechanical loads are mediated by signals induced via a variety of mechanosensitive proteins, such as primary cilia, integrins, and activated ion channels. 156 However, it is as yet unclear how osteocytes perceive and differentiate responses to two drastically opposite magnitudes of mechanical signals, that is, those of physiological magnitudes that initiate regenerative responses and of traumatic signals that initiate bone damage and resorption. 87 Appropriate use of bone formation promoters (e.g., calcium/vitamin D), mainly for osteoblasts and osteocytes, helps to further enhance the mechanical induction and repair of bone structure. Patients over 65 years old with BMD less than −2.5SD or postmenopausal women with multiple osteoporotic vertebral fractures or hip fractures who have not responded to bisphosphonate therapy should be switched to the available anabolic agents, 7,131 including recombinant human parathyroid hormone (rhPTH,   ) and parathyroid hormone-related protein (PTHrP). 30 Strontium ranelate is now considered effective in enhancing the biomechanical properties of bone for resistance fragility fractures. Strontium ranelate increases bone formation and decreases bone resorption, thereby rebalancing bone remodeling, which is conducive to new bone formation. 157 Numerous studies have shown that strontium ranelates functions in improvement in all parameters related to bone quality and strength. 158 The sclerostin monoclonal antibody, such as romosozumab, has been shown to lead to gains in hip BMD. 159 In addition, BMPs, which belong to transforming growth factor-beta (TGF-β) family members, 160 lead to synergistic induction of downstream TGFβ signaling for osteogenesis combined with physical microenvironment. 161 Tricalcium phosphate and polymethylmethacrylate (PMMA) are usually employed to augment bone cement and increase the stability of implant fixation in  osteoporotic bone. 162,163 These cements undergo interdigitation in porous bone 38 to increase the surface area of contact and provide additional resistance against the screw threads. PMMA has also been used for the delivery of drugs, such as antibiotics, via bone cements. 164 However, PMMA undergoes an exothermic reaction during the drying process, with the potential to initiate thermal bone necrosis. 165 In addition, PMMA is difficult to remove in cases of revision or infection without integrating into the bony architecture. 166 In contrast, the integration of tricalcium phosphate into the bone provides a potential scaffold for biological activity and cell growth in a demineralized bone matrix. 167 Allograft fibulas are used in bone with low BMD as tools for reduction as well as the provision of medial calcar support. 168 As mechanical stimulation is a potent anti-inflammatory signal, sufficient postsurgery mechanical loading interventions, including physical therapy and rehabilitation, are helpful for building a supportive mechanical and biological environment around the local fracture sites for bone healing. Low intensity vibration (LIV) improves bone quality by activating cells responsible for bone remodeling and biasing the differentiation of mesenchymal and HSC progenitors toward osteoblastogenesis. 169,170 However, current evidence is insufficient to support the benefit of ultrasound and extracorporeal shockwave therapies (ECSW) for fracture healing in clinical practice 171 (Fig. 5). Mechanical bone strength is vital for the stable anchorage of hardware required for fracture repair. Due to the impaired bone strength and complicated immunology environment in elderly individuals with osteoporosis, more suitable implants with better mechanical characteristics are required to improve aging-related osteoporotic fracture healing. Measurement of the thickness and porosity of cortical bone prior to surgery is important in guiding hardware selection for the repair of osteoporotic fractures. Thus, it is of great importance to identify parameters for evaluating bone quality (Fig. 5). Only 60% of the variation in bone densitometry was measured by dual-energy X-ray absorptiometry (DXA) because it is hard to recognize differences in both trabecular and cortical bone geometrical macrostructure. 172 Both trabecular connectivity and cortical porosity significantly influence bone strength parameters, including stiffness to resist deformation and elasticity to absorb energy. 173 To determine a better intervention, state-of-the-art clinical imaging techniques will help in measuring bone structural parameters, instead of focusing on BMD alone. 174 Evaluation of the grayscale intensity map of DXA imaging can provide more precise information for bone structural parameters Reduction of thread-bone interface that produces torque 183,184,196,197 Bicortical lag screw Potential improvement of thread purchase BMD, TBS SMI BV/TV DXA HR-pQCT Medial malleolus fractures 185,198,199 Traditional compared with BMD measurement. 175 The trabecular bone score (TBS) correlates positively with trabecular connectivity based on evaluation of the DXA image. 176 Combining TBS and BMD measurements provides an improved prediction of bone strength compared with BMD alone. 177,178 Evaluations of structural, material, and mechanical properties based on bone biopsy specimens provide a reliable assessment of local bone characteristics, which are vital independent determinants of bone strength. 179 The DensiProbe can be a helpful tool for intraoperative assessment of mechanical peak torque in mechanical testing setups, 180 providing information that can be valuable in choosing implants. Furthermore, this approach does not increase the risk to the patient or increase the surgeon's workload since the central peg hole can be used for the next procedure. 180 Cortical and cancellous screws are traditional designs, with the former having relatively narrower outer diameters and decreased thread pitch. 181 In both cases, the fixation strength depends on the torque generated between the bone and thread that resists shear. 182 During insertion of a cancellous bone screw into the osteoporotic bone, the torque reaches the plateau prior to the contact of all the screw threads. 183 The changes in screw geometry that confer an advantage on cancellous screws are lost below a threshold BMD of 0.4 g·cm -1 . 184 The plateau torque (T Plateau), which is an efficient predictor of insertion failure at the femoral head, is significantly dependent on aspects of the bone microarchitecture, such as the structure model index (SMI) and bone volume fraction (BV/TV). 185 Previous studies suggest that a more plate-like bone structure, a higher BV/TV, and a higher surface-to-volume ratio provide a structural environment that favors cutting of the screw threads into the bone, resulting in an increased T Plateau. 186 Unstable and comminuted fracture patterns as well as early implant-bone fatigue in osteoporotic bones lead to implant loosening and fixation failure. 3 Locking-plate technology provides a more advantageous biomechanical environment that facilitates the formation of a fixed angle between the plate and screw. 187 Despite the greater overall stability, locking plates may create an excessively rigid construct, which is predisposed to peri-implant fracture. 188 In proximal humeral fractures with low BMD, 189 computed tomography (CT) assessments suggest that locking plates do not reduce the rate of mechanical failure. In elderly patients with low BMD, tibial plateau fracture is associated with increased comminution and compromised fixation, suggesting that external fixation might be a more effective option than dual plating. 190 An intramedullary nail (IMN) is a load-sharing device with the advantage of promoting secondary bone healing while preserving the surrounding soft tissues and minimizing fractureinduced hematomas. 191 The loss of interlocking screw fixation can be mitigated through a number of strategies, including the application of washers and interlocking screws in multiple planes. However, cortical thinning of osteoporotic bone increases the intramedullary canal diameter, and a larger-diameter nail is required to achieve a diaphyseal fit and stability. Therefore, an early quantitative computed tomography (QCT) assessment of the cortical thickness is critical in using IMN in osteoporotic fractures. Intra-articular and complex fractures in patients with osteoporosis pose unique challenges for surgeons. These patients have inadequate subchondral bone quality to allow for anatomic reductions, and the stability of the implant is difficult to maintain after the reintroduction of weight-bearing and increased range of motion. 192 Primary arthroplasty (total hip/knee/elbow arthroplasty) has been adopted to obtain adequate weight-bearing and early mobilization, which has a superior prognosis compared to internal fixation in acute acetabular fractures, displaced intraarticular tibial plateau fractures and complex distal humeral fractures. 193 Despite the advent of locked anatomic plates, a majority of experts recommend arthroplasty in the context of poor bone quality and small fracture fragments (Table 1).

CONCLUSION AND PERSPECTIVE
Low bone mass and compromised bone structure in osteoporotic fractures are undesirable for the reduction and rigid fixation, and the decreased regeneration and mechanosensation ability of osteoporotic bone also affect the healing. The initiation of supportive management, including anti-inflammatory drugs and sufficient application of antibiotics, is key for creating the proper environment for bone repair and homeostasis in patients with osteoporotic fractures. The adverse effects of insufficient mechanical loading in bone healing are critical factors that should be considered around the orthopedic procedure. Bench-to-bedside strategies for bone augmentation and hardware selection should be made according to further elucidation of the biomechanics and molecular mechanisms involved in bone repair. Multidisciplinary collaboration will facilitate the improvement of overall osteoporotic care and the reduction of secondary fracture incidence.