Irisin and Secondary Osteoporosis in Humans

Irisin is a peptide secreted by skeletal muscle following exercise that plays an important role in bone metabolism. Numerous experiments in vitro and in mouse models have shown that the administration of recombinant irisin promotes osteogenesis, protects osteocytes from dexamethasone-induced apoptosis, prevents disuse-induced loss of bone and muscle mass, and accelerates fracture healing. Although some aspects still need to be elucidated, such as the dose- and frequency-dependent effects of irisin in cell cultures and mouse models, ample clinical evidence is emerging to support its physiological relevance on bone in humans. A reduction in serum irisin levels, associated with an increased risk of osteoporosis and bone fractures, was observed in postmenopausal women and in both men and women during aging, Recently, cohort studies of subjects with secondary osteoporosis showed that these patients have lower circulating levels of irisin, suggesting that this myokine could be a novel marker to monitor bone quality in this disease. Although there are still few studies, this review discusses the emerging data that are highlighting the involvement of irisin in some diseases that cause secondary osteoporosis.     

Therapeutic Treatments for Osteoporosis—Which Combination of Pills Is the Best among the Bad?

Osteoporosis is a chronical, systemic skeletal disorder characterized by an increase in bone resorption, which leads to reduced bone density. The reduction in bone mineral density and therefore low bone mass results in an increased risk of fractures. Osteoporosis is caused by an imbalance in the normally strictly regulated bone homeostasis. This imbalance is caused by overactive bone-resorbing osteoclasts, while bone-synthesizing osteoblasts do not compensate for this. In this review, the mechanism is presented, underlined by in vitro and animal models to investigate this imbalance as well as the current status of clinical trials. Furthermore, new therapeutic strategies for osteoporosis are presented, such as anabolic treatments and catabolic treatments and treatments using biomaterials and biomolecules. Another focus is on new combination therapies with multiple drugs which are currently considered more beneficial for the treatment of osteoporosis than monotherapies. Taken together, this review starts with an overview and ends with the newest approaches for osteoporosis therapies and a future perspective not presented so far.     

An Overview of the Molecular Mechanisms Contributing to Musculoskeletal Disorders in Chronic Liver Disease: Osteoporosis,Sarcopenia, and Osteoporotic Sarcopenia

The prevalence of osteoporosis and sarcopenia is significantly higher in patients with liver disease than in those without liver disease and osteoporosis and sarcopenia negatively influence morbidity and mortality in liver disease, yet these musculoskeletal disorders are frequently overlooked in clinical practice for patients with chronic liver disease. The objective of this review is to provide a comprehensive understanding of the molecular mechanisms of musculoskeletal disorders accompanying the pathogenesis of liver disease. The increased bone resorption through the receptor activator of nuclear factor kappa (RANK)-RANK ligand (RANKL)-osteoprotegerin (OPG) system and upregulation of inflammatory cytokines and decreased bone formation through increased bilirubin and sclerostin and lower insulin-like growth factor-1 are important mechanisms for osteoporosis in patients with liver disease. Sarcopenia is associated with insulin resistance and obesity in non-alcoholic fatty liver disease, whereas hyperammonemia, low amount of branched chain amino acids, and hypogonadism contributes to sarcopenia in liver cirrhosis. The bidirectional crosstalk between muscle and bone through myostatin, irisin, β-aminoisobutyric acid (BAIBA), osteocalcin, as well as the activation of the RANK and the Wnt/β-catenin pathways are associated with osteosarcopenia. The increased understandings for these musculoskeletal disorders would be contributes to the development of effective therapies targeting the pathophysiological mechanism involved.     

The Development of Molecular Biology of Osteoporosis

Osteoporosis is one of the major bone disorders that affects both women and men, and causes bone deterioration and bone strength. Bone remodeling maintains bone mass and mineral homeostasis through the balanced action of osteoblasts and osteoclasts, which are responsible for bone formation and bone resorption, respectively. The imbalance in bone remodeling is known to be the main cause of osteoporosis. The imbalance can be the result of the action of various molecules produced by one bone cell that acts on other bone cells and influence cell activity. The understanding of the effect of these molecules on bone can help identify new targets and therapeutics to prevent and treat bone disorders. In this article, we have focused on molecules that are produced by osteoblasts, osteocytes, and osteoclasts and their mechanism of action on these cells. We have also summarized the different pharmacological osteoporosis treatments that target different molecular aspects of these bone cells to minimize osteoporosis.     

Protective Effect of Ciclopirox against Ovariectomy-Induced Bone Loss in Mice by Suppressing Osteoclast Formation and Function

Postmenopausal osteoporosis is closely associated with excessive osteoclast formation and function, resulting in the loss of bone mass. Osteoclast-targeting agents have been developed to manage this disease. We examined the effects of ciclopirox on osteoclast differentiation and bone resorption in vitro and in vivo. Ciclopirox significantly inhibited osteoclast formation from primary murine bone marrow macrophages (BMMs) in response to receptor activator of nuclear factor kappa B ligand (RANKL), and the expression of genes associated with osteoclastogenesis and function was decreased. The formation of actin rings and resorption pits was suppressed by ciclopirox. Analysis of RANKL-mediated early signaling events in BMMs revealed that ciclopirox attenuates IκBα phosphorylation without affecting mitogen-activated protein kinase activation. Furthermore, the administration of ciclopirox suppressed osteoclast formation and bone loss in ovariectomy-induced osteoporosis in mice and reduced serum levels of osteocalcin and C-terminal telopeptide fragment of type I collagen C-terminus. These results indicate that ciclopirox exhibits antiosteoclastogenic activity both in vitro and in vivo and represents a new candidate compound for protection against osteoporosis and other osteoclast-related bone diseases.     

Reciprocal Roles of Angiotensin II and Angiotensin II Receptors Blockade (ARB) in Regulating Cbfa1/RANKL via cAMP Signaling Pathway: Possible Mechanism for Hypertension-Related Osteoporosis and Antagonistic Effect of ARB on Hypertension-Related Osteoporosis

Hypertension is a risk factor for osteoporosis. Animal and epidemiological studies demonstrate that high blood pressure is associated with increased calcium loss, elevated parathyroid hormone, and increased calcium movement from bone. However, the mechanism responsible for hypertension-related osteoporosis remains elusive. Recent epidemiological studies indicate the benefits of Angiotensin II Receptors Blockade (ARB) on decreasing fracture risks. Since receptors for angiotensin II, the targets of ARB, are expressed in both osteoblasts and osteoclasts, we postulated that angiotensin II plays an important role in hypertension-related osteoporosis. Cbfa1 and RANKL, the important factors for maintaining bone homeostasis and key mediators in controlling osteoblast and osteoclast differentiation, are both regulated by cAMP-dependent signaling. Angiotensin II along with factors such as LDL, HDL, NO and homocysteine that are commonly altered both in hypertension and osteoporosis, can down-regulate the expression of Cbfa1 but up-regulate RANKL expression via the cAMP signaling pathway. We thus hypothesized that, by altering the ratio of Cbfa1/RANKL expression via the cAMP-dependent pathway, angiotensin II differently regulates osteoblast and osteoclast differentiation leading to enhanced bone resorption and reduced bone formation. Since ARB can antagonize the adverse effect of angiotensin II on bone by lowering cAMP levels and modifying other downstream targets, including LDL, HDL, NO and Cbfa1/RANKL, we propose the hypothesis that the antagonistic effects of ARB may also be exerted via cAMP signaling pathway.     

Alliin Attenuated RANKL-Induced Osteoclastogenesis by Scavenging Reactive Oxygen Species through Inhibiting Nox1

The healthy skeleton requires a perfect coordination of the formation and degradation of bone. Metabolic bone disease like osteoporosis is resulted from the imbalance of bone formation and/or bone resorption. Osteoporosis also reflects lower level of bone matrix, which is contributed by up-regulated osteoclast-mediated bone resorption. It is reported that monocytes/macrophage progenitor cells or either hematopoietic stem cells (HSCs) gave rise to multinucleated osteoclasts. Thus, inhibition of osteoclastic bone resorption generally seems to be a predominant therapy for treating osteoporosis. Recently, more and more natural compounds have been discovered, which have the ability of inhibiting osteoclast differentiation and fusion. Alliin (S-allyl-l-cysteine sulfoxides, SACSO) is the major component of aged garlic extract (AGE), bearing broad-spectrum natural antioxidant properties. However, its effects on bone health have not yet been explored. Hence, we designed the current study to explore its effects and role in receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast fusion and differentiation. It was revealed that alliin had an inhibitory effect in osteoclasteogenesis with a dose-dependent manner via blocking the c-Fos-NFATc1 signaling pathway. In addition, alliin decreased the generation of reactive oxygen species (ROS) and down-regulated the expression of NADPH oxidase 1 (Nox1). The overall results revealed that alliin could be a potential therapeutic agent in the treatment of osteoporosis.     

The Impact of the “Osteo” Component of Osteosarcopenia on Fragility Fractures in Post-Menopausal Women

Osteosarcopenia, the coexistence of bone and muscle loss, is common in older adults, but its definition lacks international consensus. This cross-sectional study (n = 1199 post-menopausal women) aimed to determine the association between osteosarcopenia and fragility fractures and to investigate the impact of the definition of the “osteo” component. Bone mineral density and bone microarchitecture were measured by dual-energy X-ray absorptiometry and the trabecular bone score (TBS), respectively. The “osteo” component of osteosarcopenia was classified as osteoporosis (T-score ≤ −2.5 SD), osteopenia/osteoporosis (T-score < −1 SD), and high-fracture-risk osteopenia (−2.5 SD < T-score < −1 SD)/osteoporosis (T-score ≤ −2.5 SD). The Fracture Risk Assessment Tool was used to identify high-fracture-risk osteopenia. Altogether, 30.3%, 32.2%, 14.4%, and 23.1% of participants had osteosarcopenia, osteoporosis alone, sarcopenia alone, and neither condition, respectively. The odds ratios between osteosarcopenia and fragility fractures were 3.70 (95% CI: 1.94–7.04) for osteosarcopenia, 2.48 (95% CI: 1.30–4.71) for osteoporosis alone, and 1.87 (95% CI: 0.84–4.14) for sarcopenia alone. Women with osteosarcopenia also had lower TBS, indicating worse bone microarchitecture. In conclusion, women with osteosarcopenia were more likely to have previously sustained a fracture compared to those without osteosarcopenia, with sarcopenia alone, and with osteoporosis alone. The relationship between osteosarcopenia and fracture risk may be best identified when considering high-fracture-risk osteopenia and osteoporosis.     

Osteoporosis: From Molecular Mechanisms to Therapies 3.0

Osteoporosis is a common skeletal disorder that occurs as a result of an imbalance between bone resorption and bone formation, with bone breakdown exceeding bone building. Bone resorption inhibitors, e.g., bisphosphonates, have been designed to treat osteoporosis. Teriparatide, an anabolic agent, stimulates bone formation and corrects the characteristic changes in the trabecular microarchitecture. However, these drugs are associated with significant side effects. It is therefore crucial that we continue to research the pathogenesis of osteoporosis and seek novel modes of therapy. This editorial summarizes and discusses the themes of the six articles published in our Special Issue “Osteoporosis: From Molecular Mechanisms to Therapies 3.0”, a continuation of our 2020 Special Issue "Osteoporosis: From Molecular Mechanisms to Therapies". These Special Issues detail important global scientific findings that contribute to our current understanding of osteoporosis.     

The Effects of Exercise and Activity-Based Physical Therapy on Bone after Spinal Cord Injury

Spinal cord injury (SCI) produces paralysis and a unique form of neurogenic disuse osteoporosis that dramatically increases fracture risk at the distal femur and proximal tibia. This bone loss is driven by heightened bone resorption and near-absent bone formation during the acute post-SCI recovery phase and by a more traditional high-turnover osteopenia that emerges more chronically, which is likely influenced by the continual neural impairment and musculoskeletal unloading. These observations have stimulated interest in specialized exercise or activity-based physical therapy (ABPT) modalities (e.g., neuromuscular or functional electrical stimulation cycling, rowing, or resistance training, as well as other standing, walking, or partial weight-bearing interventions) that reload the paralyzed limbs and promote muscle recovery and use-dependent neuroplasticity. However, only sparse and relatively inconsistent evidence supports the ability of these physical rehabilitation regimens to influence bone metabolism or to increase bone mineral density (BMD) at the most fracture-prone sites in persons with severe SCI. This review discusses the pathophysiology and cellular/molecular mechanisms that influence bone loss after SCI, describes studies evaluating bone turnover and BMD responses to ABPTs during acute versus chronic SCI, identifies factors that may impact the bone responses to ABPT, and provides recommendations to optimize ABPTs for bone recovery.     

Osteoporosis Due to Hormone Imbalance: An Overview of the Effects of Estrogen Deficiency and Glucocorticoid Overuse on Bone Turnover

Osteoporosis is a serious health issue among aging postmenopausal women. The majority of postmenopausal women with osteoporosis have bone loss related to estrogen deficiency. The rapid bone loss results from an increase in bone turnover with an imbalance between bone resorption and bone formation. Osteoporosis can also result from excessive glucocorticoid usage, which induces bone demineralization with significant changes of spatial heterogeneities of bone at microscale, indicating potential risk of fracture. This review is a summary of current literature about the molecular mechanisms of actions, the risk factors, and treatment of estrogen deficiency related osteoporosis (EDOP) and glucocorticoid induced osteoporosis (GIOP). Estrogen binds with estrogen receptor to promote the expression of osteoprotegerin (OPG), and to suppress the action of nuclear factor-κβ ligand (RANKL), thus inhibiting osteoclast formation and bone resorptive activity. It can also activate Wnt/β-catenin signaling to increase osteogenesis, and upregulate BMP signaling to promote mesenchymal stem cell differentiation from pre-osteoblasts to osteoblasts, rather than adipocytes. The lack of estrogen will alter the expression of estrogen target genes, increasing the secretion of IL-1, IL-6, and tumor necrosis factor (TNF). On the other hand, excessive glucocorticoids interfere the canonical BMP pathway and inhibit Wnt protein production, causing mesenchymal progenitor cells to differentiate toward adipocytes rather than osteoblasts. It can also increase RANKL/OPG ratio to promote bone resorption by enhancing the maturation and activation of osteoclast. Moreover, excess glucocorticoids are associated with osteoblast and osteocyte apoptosis, resulting in declined bone formation. The main focuses of treatment for EDOP and GIOP are somewhat different. Avoiding excessive glucocorticoid use is mandatory in patients with GIOP. In contrast, appropriate estrogen supplement is deemed the primary treatment for females with EDOP of various causes. Other pharmacological treatments include bisphosphonate, teriparatide, and RANKL inhibitors. Nevertheless, more detailed actions of EDOP and GIOP along with the safety and effectiveness of medications for treating osteoporosis warrant further investigation.     

The Pathophysiology of Osteoporosis after Spinal Cord Injury

Spinal cord injury (SCI) affects approximately 300,000 people in the United States. Most individuals who sustain severe SCI also develop subsequent osteoporosis. However, beyond immobilization-related lack of long bone loading, multiple mechanisms of SCI-related bone density loss are incompletely understood. Recent findings suggest neuronal impairment and disability may lead to an upregulation of receptor activator of nuclear factor-κB ligand (RANKL), which promotes bone resorption. Disruption of Wnt signaling and dysregulation of RANKL may also contribute to the pathogenesis of SCI-related osteoporosis. Estrogenic effects may protect bones from resorption by decreasing the upregulation of RANKL. This review will discuss the current proposed physiological and cellular mechanisms explaining osteoporosis associated with SCI. In addition, we will discuss emerging pharmacological and physiological treatment strategies, including the promising effects of estrogen on cellular protection.     

Lumican Inhibits Osteoclastogenesis and Bone Resorption by Suppressing Akt Activity

Lumican, a ubiquitously expressed small leucine-rich proteoglycan, has been utilized in diverse biological functions. Recent experiments demonstrated that lumican stimulates preosteoblast viability and differentiation, leading to bone formation. To further understand the role of lumican in bone metabolism, we investigated its effects on osteoclast biology. Lumican inhibited both osteoclast differentiation and in vitro bone resorption in a dose-dependent manner. Consistent with this, lumican markedly decreased the expression of osteoclastogenesis markers. Moreover, the migration and fusion of preosteoclasts and the resorptive activity per osteoclast were significantly reduced in the presence of lumican, indicating that this protein affects most stages of osteoclastogenesis. Among RANKL-dependent pathways, lumican inhibited Akt but not MAP kinases such as JNK, p38, and ERK. Importantly, co-treatment with an Akt activator almost completely reversed the effect of lumican on osteoclast differentiation. Taken together, our findings revealed that lumican inhibits osteoclastogenesis by suppressing Akt activity. Thus, lumican plays an osteoprotective role by simultaneously increasing bone formation and decreasing bone resorption, suggesting that it represents a dual-action therapeutic target for osteoporosis.     

Amniotic Fluid Stem Cell-Derived Extracellular Vesicles Counteract Steroid-Induced Osteoporosis In Vitro

Background—Osteoporosis is characterized by defects in both quality and quantity of bone tissue, which imply high susceptibility to fractures with limitations of autonomy. Current therapies for osteoporosis are mostly concentrated on how to inhibit bone resorption but give serious adverse effects. Therefore, more effective and safer therapies are needed that even encourage bone formation. Here we examined the effect of extracellular vesicles secreted by human amniotic fluid stem cells (AFSC) (AFSC-EV) on a model of osteoporosis in vitro. Methods—human AFSC-EV were added to the culture medium of a human pre-osteoblast cell line (HOB) induced to differentiate, and then treated with dexamethasone as osteoporosis inducer. Aspects of differentiation and viability were assessed by immunofluorescence, Western blot, mass spectrometry, and histological assays. Since steroids induce oxidative stress, the levels of reactive oxygen species and of redox related proteins were evaluated. Results—AFSC-EV were able to ameliorate the differentiation ability of HOB both in the case of pre-osteoblasts and when the differentiation process was affected by dexamethasone. Moreover, the viability was increased and parallelly apoptotic markers were reduced. The presence of EV positively modulated the redox unbalance due to dexamethasone. Conclusion—these findings demonstrated that EV from hAFSC have the ability to recover precursor cell potential and delay local bone loss in steroid-related osteoporosis.     

Oxytocin and Bone: Review and Perspectives

Recent data demonstrate the anabolic effect of oxytocin on bone. Bone cells express oxytocin receptors. Oxytocin promotes osteoblasts differentiation and function, leading to an increased bone formation with no effect on bone resorption and an improvement of bone microarchitecture. Oxytocin is synthetized by osteoblasts, and this synthesis is stimulated by estrogen. Animal studies demonstrate a direct action of oxytocin on bone, as the systemic administration of oxytocin prevents and reverses the bone loss induced by estrogen deficiency. Although oxytocin is involved in bone formation in both sexes during development, oxytocin treatment has no effect on male osteoporosis, underlining the importance of estrogen that amplifies its local autocrine and paracrine secretion. There are few human data showing a decrease in the oxytocin serum level in anorexia nervosa independently of estrogen and in amenorrheic women associated with impaired bone microarchitecture; in post-menopausal women a higher oxytocin serum level is associated with higher bone density, but not in osteoporotic men. Oxytocin displays many effects that may be beneficial in the management of osteoporosis, cardiovascular diseases, cognitive disorders, breast cancer, diabetes and body fat gain, all age-related diseases affecting elderly women, opening exciting therapeutic perspectives, although the issue is to find a single route, dosage and schedule able to reach all these targets.     

Myricetin Prevents Alveolar Bone Loss in an Experimental Ovariectomized Mouse Model of Periodontitis

Periodontitis is a common chronic inflammatory disease, which leads to alveolar bone resorption. Healthy and functional alveolar bone, which can support the teeth and enable their movement, is very important for orthodontic treatment. Myricetin inhibited osteoclastogenesis by suppressing the expression of some genes, signaling pathways, and cytokines. This study aimed to investigate the effects of myricetin on alveolar bone loss in an ovariectomized (OVX) mouse model of periodontitis as well as in vitro osteoclast formation and bone resorption. Twenty-four healthy eight-week-old C57BL/J6 female mice were assigned randomly to four groups: phosphate-buffered saline (PBS) control (sham) OVX + ligature + PBS (vehicle), and OVX + ligature + low or high (2 or 5 mg∙kg⁻¹∙day⁻¹, respectively) doses of myricetin. Myricetin or PBS was injected intraperitoneally (i.p.) every other day for 30 days. The maxillae were collected and subjected to further examination, including micro-computed tomography (micro-CT), hematoxylin and eosin (H&E) staining, and tartrate-resistant acid phosphatase (TRAP) staining; a resorption pit assay was also performed in vitro to evaluate the effects of myricetin on receptor activator of nuclear factor κ-B ligand (RANKL)-induced osteoclastogenesis. Myricetin, at both high and low doses, prevented alveolar bone resorption and increased alveolar crest height in the mouse model and inhibited osteoclast formation and bone resorption in vitro. However, myricetin was more effective at high dose than at low dose. Our study demonstrated that myricetin had a positive effect on alveolar bone resorption in an OVX mouse model of periodontitis and, therefore, may be a potential agent for the treatment of periodontitis and osteoporosis.     

Molecular Targeted Therapy for the Bone Loss Secondary to Pyogenic Spondylodiscitis Using Medications for Osteoporosis: A Literature Review

Pyogenic spondylodiscitis can cause severe osteolytic and destructive lesions in the spine. Elderly or immunocompromised individuals are particularly susceptible to infectious diseases; specifically, infections in the spine can impair the ability of the spine to support the trunk, causing patients to be bedridden, which can also severely affect the physical condition of patients. Although treatments for osteoporosis have been well studied, treatments for bone loss secondary to infection remain to be elucidated because they have pathological manifestations that are similar to but distinct from those of osteoporosis. Recently, we encountered a patient with severely osteolytic pyogenic spondylodiscitis who was treated with romosozumab and exhibited enhanced bone formation. Romosozumab stimulated canonical Wnt/β-catenin signaling, causing robust bone formation and the inhibition of bone resorption, which exceeded the bone loss secondary to infection. Bone loss due to infections involves the suppression of osteoblastogenesis by osteoblast apoptosis, which is induced by the nuclear factor-κB and mitogen-activated protein kinase pathways, and osteoclastogenesis with the receptor activator of the nuclear factor-κB ligand-receptor combination and subsequent activation of the nuclear factor of activated T cells cytoplasmic 1 and c-Fos. In this study, we review and discuss the molecular mechanisms of bone loss secondary to infection and analyze the efficacy of the medications for osteoporosis, focusing on romosozumab, teriparatide, denosumab, and bisphosphonates, in treating this pathological condition.     

Bisphosphonates Reduce Smoking-Induced Osteoporotic-Like Alterations by Regulating RANKL/OPG in an Osteoblast and Osteoclast Co-Culture Model

Co-culture models have become mandatory for obtaining better insights into bone homeostasis, which relies on the balance between osteoblasts and osteoclasts. Cigarette smoking (CS) has been proven to increase the risk of osteoporosis; however, there is currently no proven treatment for osteoporosis in smokers excluding cessation. Bisphosphonates (BPs) are classical anti-osteoclastic drugs that are commonly used in examining the suitability of bone co-culture systems in vitro as well as to verify the response to osteoporotic stimuli. In the present study, we tested the effects of BPs on cigarette smoke extract (CSE)-affected cells in the co-culture of osteoblasts and osteoclasts. Our results showed that BPs were able to reduce CSE-induced osteoporotic alterations in the co-culture of osteoblasts and osteoclasts such as decreased matrix remodeling, enhanced osteoclast activation, and an up-regulated receptor activator of nuclear factor (NF)-kB-ligand (RANKL)/osteoprotegerin (OPG) ratio. In summary, BPs may be an effective alternative therapy for reversing osteoporotic alterations in smokers, and the potential mechanism is through modulation of the RANKL/OPG ratio.