Glucocorticoid-induced Osteoporosis Research Articles

Eucommia, Cuscuta, and Drynaria Extracts Ameliorate Glucocorticoid-Induced Osteoporosis by Inhibiting Osteoclastogenesis Through PI3K/Akt Pathway.

Osteoporosis is one of the most common diseases in the world which resulted in heavy socioeconomic burden and a public health threat. Glucocorticoid-induced osteoporosis (GIO) is the most common secondary reason of osteoporosis. Therapeutic strategies using traditional Chinese medicine are under investigation for osteoporosis, with efforts to improve efficacy and clarify the mechanism. The combination of Eucommia, Cuscuta, and Drynaria is widely used in traditional Chinese decoction for osteoporosis treatment, but the experimental efficacy and mechanism are still unclear. Administration of E.C.D. extracts (Eucommia, Cuscuta, and Drynaria) in experimental GIO rats resulted in decreased urinal calcium, phosphorus loss, and decreased expression of RANKL, CTX in serum, increased serum calcium, phosphorus, and OPG level. E.C.D. extracts also improved bone density, structural integrity, and biomechanical function in experimental GIO rats. These finding were associated with E.C.D. extracts’ treatment efficacy to GIO in vivo. The balance between osteoclast and osteoblast activity is essential for bone remodeling and bone related disease. The E.C.D. extracts inhibited Raw 264.7 cell differentiation to osteoclast in vitro. On the other hand, it promoted OPG expression of bone marrow mesenchymal stromal cells (MSCs) which can suppress the osteoclast genesis. E.C.D. extracts also increased the Wnt1 and Runx2 expression which are related to osteoblast formation. It also regulated the paracrine effect of MSC to inhibit osteoclast differentiation. The analysis of HPLC and comprehensive pharmacology identified the constituents of E.C.D. extracts and the potential osteoporosis-related targets mediated by E.C.D. extracts. The KEGG enrichment analysis suggested that PI3K/Akt pathway may be involved in the regulation osteoclast genesis by E.C.D. extracts and the result of Western blot of vitro assays proved it. Collectively, these data demonstrate E.C.D. extracts can inhibit osteoclast differentiation to foster experimental osteoporosis both in vivo and in vitro and it may exert the function of inhibiting osteoclast differentiation through PI3K/Akt pathway.

TMT-based proteomics analysis to screen potential biomarkers of Achyranthis Bidentatae Radix for osteoporosis in rats.

This study aimed to explore the possible mechanism of Achyranthis Bidentatae Radix for the treatment of osteoporosis using tandem mass tag-based proteomics technique combined with mass spectrometry. Proteomics techniques combined with bioinformatics were used to analyze the biological functions of differentially expressed proteins. In addition, western blotting was performed to verify the expression of related proteins. A total of 3,752 proteins were identifiable by proteomic analysis. Furthermore, 93 differentially expressed proteins were identified, of which 61 were upregulated and 32 were downregulated. Differentially expressed proteins were primarily associated with oxidative phosphorylation (p=4.8×10-4 ) pathways and involved in transmembrane transport (p=3.5×10-3 ), exocytic process (p=1.2×10-2 ), cellular developmental process (p=1.3×10-2 ), adenosine triphosphate metabolic process (p=1.0×10-2 ) and other biological processes. Western blotting analysis showed that MT-CYB and NDUFA9 were differentially expressed in the bone microenvironment of rats with osteoporosis. We speculated that they were potential biomarkers linked to osteoporosis. This study employed proteomics to explore the potential therapeutic targets of Achyranthis Bidentatae Radix to treat osteoporosis. This revealed that mitochondria are a new target for the treatment of glucocorticoid-induced osteoporosis.

Pulsed electromagnetic fields attenuate glucocorticoid-induced bone loss by targeting senescent LepR+ bone marrow mesenchymal stromal cells

Glucocorticoids induce cellular senescence, including of stem/progenitor cells in the bone marrow of growing long bone, which leads to bone loss in glucocorticoid–induced osteoporosis. There is no specific drug available to treat this disease. Clearance of senescent cells has been reported to be an effective therapy for osteoporosis. LepR+ cells in the bone marrow are the key kind of stem/progenitor cells conducive to bone remodeling in adulthood. Here, we show that glucocorticoids induce cellular senescence, demonstrated by increased activity of senescence-associated β-galactosidase (SA-βGal+) cells and simultaneous upregulation of coimmunofluorescence staining of p16INK4a with LepR in longitudinal femoral sections. We applied pulsed electromagnetic fields (PEMFs), which alleviated bone loss in glucocorticoid-induced osteoporosis mice. We found the increased accumulation of senescent LepR+ cells in the bone marrow of adult mice after glucocorticoid treatment, and this could be counteracted by PEMFs. Moreover, PEMFs maintained type H vessel formation and osteogenesis. This process was modulated by the polycomb histone methyltransferase enhancer of zeste homolog 2 (EZH2) and its trimethylation of histone H3 on lysine 27 (H3K27me3). These results provide evidence that PEMFs alleviate bone loss induced by glucocorticoids by eliminating senescent cells, maintaining angiogenesis-osteogenesis coupling, and shedding light on the mechanisms, providing a potential method to treat glucocorticoid-induced osteoporosis.

Benzofuran pyran hybrid prevents glucocorticoid induced osteoporosis in mice via modulation of canonical Wnt/β-catenin signaling.

Glucocorticoid induced osteoporosis (GIOP) is the second most leading cause of osteoporosis. We have identified a compound, a benzofuran pyran hybrid compound 4e that has osteogenic potential and we wanted to assess its efficacy in GIOP in male mice. We assessed the effect of dexamethasone and compound 4e on primary osteoblasts using various cell based and immunofluorescence assays. For in vivo studies we administered methylprednisolone and compound 4e as a prophylactic measure in male Balb/c mice for 28 days and then evaluated the effect on bone microarchitecture by microCT, bone formation by histology along with clinically relevant bone markers. Compound 4e preserved osteoblast differentiation as evident by higher ALP positive cells and mineralization in compound treated groups. Compound 4e also increased the expression of osteogenic genes. This compound guarded β-catenin expression both in vitro and in vivo as confirmed by western blot and immunofluorescence assays. This led to the preservation of bone microarchitecture and cortical thickness at 2.5 mg kg−1 and 5 mg kg−1 doses. Further compound 4e enhanced bone formation rate and regulated osteocyte death. The osteogenic potential of compound 4e was reflected by an increased level of serum marker osteocalcin and decreased levels of SOST and CTX-I. Overall, Compound 4e is able to overcome the catabolic effect of dexamethasone on bone by targeting the canonical WNT/β-catenin signaling as evidenced by both in vitro and in vivo studies.

The role of systemic diseases and local conditions as risk factors.

The role of systemic diseases and local conditions as risk factors.

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.

A randomized trial of alendronate as prophylaxis against loss in bone mineral density following lymphoma treatment

AbstractLymphoma patients often receive high glucocorticoid doses as part of standard therapy. Observational studies have shown a substantial risk of glucocorticoid-induced osteoporosis (GIO) with associated fractures. The aim of the SIESTA trial was to determine if oral alendronate (ALN) is a safe and effective prophylaxis against GIO in lymphoma. SIESTA was a single-center, randomized, double-blinded, phase 2 study of lymphoma patients planned for glucocorticoid-containing chemotherapy. After randomization, patients received weekly ALN 70 mg or placebo for a total of 52 weeks. Bone mineral density (BMD) was assessed at baseline, after completion of chemotherapy (end of treatment [EOT]) (4 to 6 months), and at the end of the study (EOS) (12 months). Vertebral fracture and biomarkers were assessed at baseline and EOS. Patients with baseline BMD assessment and at least 1 follow-up BMD assessment were analyzed for efficacy. The primary endpoint was a change in lumbar spine T-score from baseline to EOS. Of the 59 patients enrolled, 23 of 30 in the ALN arm and 24 of 29 in the placebo arm were analyzed for efficacy. The mean change in T-score from baseline to 12 months at the lumbar spine was +0.15 for ALN and -0.12 for placebo (P = .023). The difference in ΔTEOS between the ALN and placebo groups was larger among females (ALN 0.28; placebo -0.28; P = .01). Biomarker analyses confirmed reduced bone resorption in ALN-treated patients. In conclusion, ALN is a safe and effective primary prophylaxis against loss in BMD following glucocorticoid-containing chemotherapy. Despite reduced BMD loss in the ALN arm, the treatment did not influence fracture risk in this small cohort of patients.

Ferroptosis: A New Regulatory Mechanism in Osteoporosis.

Osteoporosis can be caused by a multitude of factors and is defined by a decrease in bone density and mass caused by the destruction of bone microstructure, resulting in increased bone brittleness. Thus, it is a systemic bone disease in which patients are prone to fracture. The role of ferroptosis in the pathogenesis of osteoporosis has become a topic of growing interest. In this review, we discuss the cell morphology, basic mechanisms of ferroptosis, the relationship between ferroptosis and osteoclasts and osteoblasts, as well as the relationship between ferroptosis and diabetic osteoporosis, steroid-induced osteoporosis, and postmenopausal osteoporosis. Emerging biomedical research has provided new insights into the roles of ferroptosis and osteoporosis, such as in cellular function, signaling pathways, drug inhibition, and gene silencing. The pathophysiology and mechanism of ferroptosis and osteoporosis need to be further studied and elucidated to broaden our understanding of iron metabolism and immune regulation. Studies using animal models of osteoporosis in vivo and cell models in vitro will help clarify the relationship between ferroptosis and osteoporosis and provide research ideas for the elucidation of new mechanisms and development of new technologies and new drugs for the treatment of osteoporosis in the future.

Guideline adherence by physicians for management of glucocorticoid-induced osteoporosis in Japan: a nationwide health insurance claims database study.

Adherence of physicians to guidelines for glucocorticoid (GC)-induced osteoporosis (GIO) management is currently unclear. This study aimed to clarify the state of guideline adherence by physicians in Japan and identify factors associated with guideline adherence using a nationwide health insurance claims database (NDBJ). Patients aged ≥ 50years who were prescribed GC for ≥ 90days after 180days without a GC prescription and who were followed up for osteoporosis (OP) management for the subsequent 360days during the period spanning 2012-2018 were selected from the NDBJ. Guideline adherence was evaluated with the proportion of patients who received OP management as recommended by the Japanese guidelines. Information on previous vertebral and hip fractures, dementia, and polypharmacy was obtained. Factors associated with OP management were evaluated by logistic regression analysis. A total of 512,296 patients were considered to be at high risk of fracture according to the guidelines. Proportions of patients receiving OP management (BMD testing or anti-OP medications) have increased in recent years. In 2017, 33.7% of men and 55.3% of women received OP management in the initial 90days of GC therapy. Female sex, previous anti-OP medications, polypharmacy, and higher GC dose were significantly associated with receiving OP management, while dementia showed an inverse association. A prior history of hip fracture, a strong risk factor for future fracture, was not significantly associated with receiving OP management. Although guideline adherence by physicians has increased in recent years, it remains suboptimal. Further efforts to improve guideline adherence are necessary. The present study is not registered.

Elaborate the Mechanism of Ancient Classic Prescriptions (Erzhi Formula) in Reversing GIOP by Network Pharmacology Coupled with Zebrafish Verification.

Osteoporosis is a degenerative disease that endangers human health. At present, chemical drugs used for osteoporosis have serious side effects. Therefore, it is valuable to search herbs with high safety and good curative effect in antiosteoporosis. Erzhi formula (EZF), an ancient classic compound, has been reported to have a beneficial effect in antiosteoporosis, but its mechanism is unclear. In this paper, the active compounds of EZF were found in Systems Pharmacology Database, and gene targets related to osteoporosis were obtained in GeneCards. The GO functional and KEGG pathway enrichment analysis were performed by Metascape. The network of “components-targets-signal pathway” was constructed by Cytoscape. Next, molecular docking between the active components and hub genes related to the PI3K-Akt signaling pathway was conducted by Autodock. In the verification experiment, the zebrafish induced by prednisolone (PNSL) was used to reproduce glucocorticoid-induced osteoporosis (GIOP) model, and then the reversal effects of EZF were systematically evaluated according to the behavior, skull staining area, bone mineralization area (BMA), average optical density (AOD), and cumulative optical density (COD). Finally, it was shown that 24 components in EZF could regulate 39 common gene targets to exert antiosteoporosis effect. Besides, the main regulatory mechanisms of EZF were 4 signaling pathways: PI3K-Akt, JAK-STAT, AGE-RAGE, and cancer pathway. In PI3K-Akt signaling pathway, wedelolactone, dimethyl wedelolactone, specnuezhenide, ursolic acid, acacetin, beta-sitosterol, apigenin, and kaempferol can bind tightly with EGF, IL-2, and IL-4 genes. Compared with the model group, the moving distance, swimming speed, and cumulative swimming time of zebrafish in EZF group were significantly increased (P < 0.05). Meanwhile, the BMA and COD of zebrafish were significantly improved after the intervention of EZF (P < 0.05). In summary, the 24 components of EZF exert their antiosteoporosis effects by regulating 39 related gene targets, among which the PI3K signaling pathway is crucial. EZF can promote bone formation and reversed GIOP through “multicomponent/multitarget/multipathway” and the medium dose of EZF may be the most suitable concentration for the treatment of GIOP in zebrafish model.

Drug-induced osteopathy in rheumatology

Osteopathy in rheumatology can either be primary a condition as aconsequence of inflammatory rheumatic diseases but can also be drug induced. The most severe clinical manifestations are insufficiency fractures and osteonecrosis. The risk of fractures is highest for patients treated with glucocorticoids depending on the daily intake, the cumulative glucocorticoid dosage and the duration of administration. An incidence rate of nearly 13% was reported after administration of glucocorticoids lasting > 1year. Cases of osteonecrosis under glucocorticoids are, in contrast, less frequent and not associated with glucocorticoid-induced osteoporosis. The antiresorptive substances bisphosphonates and denosumab, as well as romosumab are effective and important in treating osteoporosis; however, they can also cause atypical fractures, particularly of the femur as well as osteonecrosis of the jawbone. According to the most recent guidelines the benefits of bisphosphonate treatment have only been verified for 3-5 years and for denosumab for 3years. There are clear preventive recommendations to avoid osteonecrosis of the jaw. Ultimately, the disease-modifying antirheumatic drugs (DMARD) methotrexate and leflunomide also affect the metabolism of bones. There is arare but very characteristic form of osteopathy associated with methotrexate, mainly occurring in cases of long-term treatment. The typical manifestations are insufficiency fractures, particularly of the distal tibia, which persist for many years under continuous methotrexate administration. The treatment is the discontinuation of methotrexate and in most cases the fractures will heal within 3-4months. Leflunomide has been associated with cases of persisting pseudarthrosis that only disappeared after awash-out of the active metabolite.

Distinct Glucocorticoid Receptor Actions in Bone Homeostasis and Bone Diseases.

Glucocorticoids (GCs) are steroid hormones that respond to stress and the circadian rhythm. Pharmacological GCs are widely used to treat autoimmune and chronic inflammatory diseases despite their adverse effects on bone after long-term therapy. GCs regulate bone homeostasis in a cell-type specific manner, affecting osteoblasts, osteoclasts, and osteocytes. Endogenous physiological and exogenous/excessive GCs act via nuclear receptors, mainly via the GC receptor (GR). Endogenous GCs have anabolic effects on bone mass regulation, while excessive or exogenous GCs can cause detrimental effects on bone. GC-induced osteoporosis (GIO) is a common adverse effect after GC therapy, which increases the risk of fractures. Exogenous GC treatment impairs osteoblastogenesis, survival of the osteoblasts/osteocytes and prolongs the longevity of osteoclasts. Under normal physiological conditions, endogenous GCs are regulated by the circadian rhythm and circadian genes display oscillatory rhythmicity in bone cells. However, exogenous GCs treatment disturbs the circadian rhythm. Recent evidence suggests that the disturbed circadian rhythm by continuous exogenous GCs treatment can in itself hamper bone integrity. GC signaling is also important for fracture healing and rheumatoid arthritis, where crosstalk among several cell types including macrophages and stromal cells is indispensable. This review summarizes the complexity of GC actions via GR in bone cells at cellular and molecular levels, including the effect on circadian rhythmicity, and outlines new therapeutic possibilities for the treatment of their adverse effects.

Glucocorticoid-induced osteoporosis-Focus treatment (part2)

The following substances are approved for the treatment of glucocorticoid-induced osteoporosis: the oral bisphosphonates alendronate and risedronate, the intravenous bisphosphonate zoledronate, the RANKL antibody denosumab as antiresorptive substances and teriparatide as osteoanabolic substance. In comparison to placebo areduction of vertebral fractures is proven for all mentioned substances. Thereby, teriparatide is more effective than alendronate and risedronate with respect to the reduction of vertebral fractures. The severity of osteoporosis, especially the presence of osteoporotic fractures, the approach of treatment (preventive or curative) and contraindications are factors that are important for the differentiated application of the mentioned substances. Furthermore, it must be noted that the effect of osteoanabolic treatment must be stabilized by asubsequent antiresorptive treatment and that after termination of antiresorptive treatment with denosumab atemporary bisphosphonate treatment is required to prevent arebound phenomenon.

Zebrafish models for glucocorticoid-induced osteoporosis.

Glucocorticoid-induced osteoporosis (GIOP) is the most common form of secondary osteoporosis due to excessive or long-term glucocorticoid administration, disturbing the homeostasis between bone formation and bone resorption. The bone biology of zebrafish shares a high degree of similarities with mammals. In terms of molecular level, genes and signaling pathways related to skeletogenesis are also highly correlated between zebrafish and humans. Therefore, zebrafish have been utilized to develop multiple GIOP models. Taking advantage of the transparency of zebrafish larvae, their skeletal development and bone mineralization can be readily visualized through in vivo staining without invasive experimental handlings. Moreover, the feasibility of using scales or fin rays to study bone remodeling makes adult zebrafish an ideal model for GIOP research. Here, we reviewed current zebrafish models for GIOP research, focused on the tools and methods established for examining bone homeostasis. As an in vivo, convenient, and robust model, zebrafish have an advantage in performing high-throughput drug screening and could be used to investigate the action mechanisms of therapeutic drugs.

Stimulation of osteoclast formation and bone resorption by glucocorticoids: Synergistic interactions with the calcium regulating hormones parathyroid hormone and 1,25(OH)2-vitamin D3.

Osteoporosis is a significant health problem, with skeletal fractures increasing morbidity and mortality. Excess glucocorticoids (GC) represents the leading cause of secondary osteoporosis. The first phase of glucocorticoid-induced osteoporosis is increased bone resorption. In this Chapter, in vitro studies of the direct glucocorticoid receptor (GR) mediated cellular effects of GC on osteoclasts to affect bone resorption and indirect effects on osteoblast lineage cells to increase the RANKL/OPG ratio and stimulate osteoclastogenesis and bone resorption are reviewed in detail, together with detailed descriptions of in vivo effects of GC in different portions of the skeleton in research animals and humans. Brief sections are devoted to contrasting functions of GC in osteonecrosis, vitamin D formation, in vitro and in vivo bone resorptive actions dependent on vitamin D receptor and vitamin D toxicity, as well as the molecular basis of GR action. Included are also more detailed assessments of the interactions of GC with the major calcium regulating hormones, 1,25(OH)2-vitamin D3 and parathyroid hormone, describing the in vitro increases in RANKL/OPG ratios, osteoclastogenesis and synergistic bone resorption that occurs when GC is combined with either 1,25(OH)2-vitamin D3 or parathyroid hormone. Additionally, a molecular basic for the synergistic interaction of GC with 1,25(OH)2-vitamin D3 is provided along with a suggested molecular basic for the interaction between GC and parathyroid hormone.

Animal Model for Glucocorticoid Induced Osteoporosis: A Systematic Review from 2011 to 2021.

Clinical and experimental data have shown that prolonged exposure to GCs leads to bone loss and increases fracture risk. Special attention has been given to existing emerging drugs that can prevent and treat glucocorticoid-induced osteoporosis GIOP. However, there is no consensus about the most relevant animal model treatments on GIOP. In this systematic review, we aimed to examine animal models of GIOP centering on study design, drug dose, timing and size of the experimental groups, allocation concealment, and outcome measures. The present review was written according to the PRISMA 2020 statement. Literature searches were performed in the PubMed electronic database via Mesh with the publication date set between April, 2011, and February 2021. A total of 284 full-text articles were screened and 53 were analyzed. The most common animal species used to model GIOP were rats (66%) and mice (32%). In mice studies, males (58%) were preferred and genetically modified animals accounted for 28%. Our work calls for a standardization of the establishment of the GIOP animal model with better precision for model selection. A described reporting design, conduction, and selection of outcome measures are recommended.

Dexamethasone Administration in Mice Leads to Less Body Weight Gain over Time, Lower Serum Glucose, and Higher Insulin Levels Independently of NRF2.

Glucocorticoids are used widely on a long-term basis in autoimmune and inflammatory diseases. Their adverse effects include the development of hyperglycemia and osteoporosis, whose molecular mechanisms have been only partially studied in preclinical models. Both these glucocorticoid-induced pathologies have been shown to be mediated at least in part by oxidative stress. The transcription factor nuclear erythroid factor 2-like 2 (NRF2) is a central regulator of antioxidant and cytoprotective responses. Thus, we hypothesized that NRF2 may play a role in glucocorticoid-induced metabolic disease and osteoporosis. To this end, WT and Nrf2 knockout (Nrf2KO) mice of both genders were treated with 2 mg/kg dexamethasone or vehicle 3 times per week for 13 weeks. Dexamethasone treatment led to less weight gain during the treatment period without affecting food consumption, as well as to lower glucose levels and high insulin levels compared to vehicle-treated mice. Dexamethasone also reduced cortical bone volume and density. All these effects of dexamethasone were similar between male and female mice, as well as between WT and Nrf2KO mice. Hepatic NRF2 signaling and gluconeogenic gene expression were not affected by dexamethasone. A 2-day dexamethasone treatment was also sufficient to increase insulin levels without affecting body weight and glucose levels. Hence, dexamethasone induces hyperinsulinemia, which potentially leads to decreased glucose levels, as well as osteoporosis, both independently of NRF2.

When to Start and Stop Bone-Protecting Medication for Preventing Glucocorticoid-Induced Osteoporosis

Glucocorticoid-induced osteoporosis (GIOP) leads to fractures in up to 40% of patients with chronic glucocorticoid (GC) therapy when left untreated. GCs rapidly increase fracture risk, and thus many patients with anticipated chronic GC exposures should start anti-osteoporosis pharmacotherapy to prevent fractures. In addition to low awareness of the need for anti-osteoporosis therapy among clinicians treating patients with GCs, a major barrier to prevention of fractures from GIOP is a lack of clear guideline recommendations on when to start and stop anti-osteoporosis treatment in patients with GC use. The aim of this narrative review is to summarize current evidence and provide considerations for the duration of anti-osteoporosis treatment in patients taking GCs based on pre-clinical, clinical, epidemiologic, and pharmacologic evidence. We review the pathophysiology of GIOP, outline current guideline recommendations on initiating and stopping anti-osteoporosis therapy for GIOP, and present considerations for the duration of anti-osteoporosis treatment based on existing evidence. In each section, we illustrate major points through a patient case example. Finally, we conclude with proposed areas for future research and emerging areas of interest related to GIOP clinical management.

Herbal Preparation (Bromelain, Papain, Curcuma, Black Pepper) Enhances Mineralization and Reduces Glucocorticoid-Induced Osteoporosis in Zebrafish.

Natural foods with antioxidant properties, such as curcuma, papain, bromelain and black pepper, have been indicated as a potential natural therapeutic approach against osteoporosis. Zebrafish are an excellent animal model to study the effects of herbal preparations on osteogenesis and bone metabolism, both in physiological and in pathological conditions. Our study was aimed at evaluating whether curcuma-bromelain-papain-pepper herbal preparation (CHP) administered in embryos and adult fish is capable of promoting bone wellness in physiological and osteoporotic conditions. The effect of CHP has been studied in embryonic osteogenesis and glucocorticoid-induced osteoporosis (GIOP) in an adult fish model in which drug treatment induces a bone-loss phenotype in adult scales very similar to that which characterizes the bones of human patients. CHP prevented the onset of the osteoporotic phenotype in the scales of GIOP in adult zebrafish, with the osteoblastic and osteoclastic metabolic activity maintaining unaltered. CHP is also able to attenuate an already established GIOP phenotype, even if the alteration is in an advanced phase, partially restoring the normal balance of the bone markers alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) and stimulating anabolic reparative processes. The results obtained indicated CHP as a potential integrative antioxidant therapy in human bone-loss diseases.

Herbal Preparation (Bromelain, Papain, Curcuma, Black Pepper) Enhances Mineralization and Reduces Glucocorticoid-Induced Osteoporosis in Zebrafish

Herbal Preparation (Bromelain, Papain, Curcuma, Black Pepper) Enhances Mineralization and Reduces Glucocorticoid-Induced Osteoporosis in Zebrafish