Lithium prevents glucocorticoid-induced osteonecrosis of the femoral head by regulating autophagy.

Autophagy may play an important role in the occurrence and development of glucocorticoid-induced osteonecrosis of the femoral head (GC-ONFH). Lithium is a classical autophagy regulator, and lithium can also activate osteogenic pathways, making it a highly promising therapeutic agent for GC-ONFH. We aimed to evaluate the potential therapeutic effect of lithium on GC-ONFH. For in vitro experiments, primary osteoblasts of rats were used for investigating the underlying mechanism of lithium's protective effect on GC-induced autophagy levels and osteogenic activity dysfunction. For in vivo experiments, a rat model of GC-ONFH was used for evaluating the therapeutic effect of oral lithium on GC-ONFH and underlying mechanism. Findings demonstrated that GC over-activated the autophagy of osteoblasts and reduced their osteogenic activity. Lithium reduced the over-activated autophagy of GC-treated osteoblasts through PI3K/AKT/mTOR signalling pathway and increased their osteogenic activity. Oral lithium reduced the osteonecrosis rates in a rat model of GC-ONFH, and restrained the increased expression of autophagy related proteins in bone tissues through PI3K/AKT/mTOR signalling pathway. In conclusion, lithium can restrain over-activated autophagy by activating PI3K/AKT/mTOR signalling pathway and up-regulate the expression of genes for bone formation both in GC induced osteoblasts and in a rat model of GC-ONFH. Lithium may be a promising therapeutic agent for GC-ONFH. However, the role of autophagy in the pathogenesis of GC-ONFH remains controversial. Studies are still needed to further explore the role of autophagy in the pathogenesis of GC-ONFH, and the efficacy of lithium in the treatment of GC-ONFH and its underlying mechanisms.

Canonical pathways for validating steroid-associated osteonecrosis in mice.

The present study aimed to establish and evaluate a preclinical model of steroid-associated osteonecrosis (SAON) in mice. Sixteen 24-week-old male C57BL/6 mice were used to establish SAON by two intraperitoneal injections of lipopolysaccharide (LPS), followed by three subcutaneous injections of methylprednisolone (MPS). Each injection was conducted on working day, with an interval of 24 h. Six cycles of injections were conducted. Additional twelve mice (age- and gender-matched) were used as normal controls. At 2 and 6 weeks after completing induction, bilateral femora and bilateral tibiae were collected for histological examination, micro-CT scanning, and bulk RNA sequencing. All mice were alive until sacrificed at the indicated time points. The typical SAON lesion was identified by histological evaluation at week 2 and week 6 with increased lacunae and TUNEL+ osteocytes. Micro-CT showed significant bone degeneration at week 6 in SAON model. Histology and histomorphometry showed significantly lower Runx2+ area, mineralizing surface (MS/BS), mineral apposition rate (MAR), bone formation rate (BFR/BS), type H vessels, Ki67+ (proliferating) cells, and higher marrow fat fraction, osteoclast number and TNFα+ areas in SAON group. Bulk RNA-seq revealed changed canonical signaling pathways regulating cell cycle, angiogenesis, osteogenesis, and osteoclastogenesis in the SAON group. The present study successfully established SAON in mice with a combination treatment of LPS and MPS, which could be considered a reliable and reproducible animal model to study the pathophysiology and molecular mechanism of early-stage SAON and to develop potential therapeutic approaches for the prevention and treatment of SAON.

Selenium nanoparticles/carboxymethyl chitosan/alginate antioxidant hydrogel for treating steroid-induced osteonecrosis of the femoral head.

Oxidative stress plays a crucial role in steroid-induced osteonecrosis of the femoral head (SONFH). Although several antioxidant strategies have been investigated for treating SONFH, their antioxidant efficiencies and therapeutic effects remain unsatisfactory. Here, we developed a selenium nanoparticles/carboxymethyl chitosan/alginate (SeNPs/CMC/Alg) antioxidant hydrogel and evaluated its ability to treat SONFH. In vitro assays indicated that the SeNPs/CMC/Alg hydrogel exhibited excellent properties, such as low cytotoxicity, sustained SeNPs release, and favorable antioxidant activity. Under oxidative stress, the SeNPs/CMC/Alg hydrogel promoted reactive oxygen species (ROS) elimination and enhanced the osteogenic and proangiogenic abilities of bone marrow mesenchymal stem cells (BMSCs). After establishing a rabbit model of SONFH, the SeNPs/CMC/Alg hydrogel was transplanted into the femoral head after core decompression (CD) surgery. Radiographic and histological analyses revealed that the hydrogel treatment alleviated SONFH by eliminating ROS and promoting osteogenesis and angiogenesis compared to those in the CD and CMC/Alg groups. In vitro and in vivo studies indicated that the Wnt/ß-catenin signaling pathway was activated by the SeNPs/CMC/Alg hydrogel in both hydrogen peroxide-conditioned BMSCs and necrotic femoral heads. These findings indicate that local transplantation of the SeNPs/CMC/Alg hydrogel is beneficial for treating SONFH, as it promotes ROS elimination and activation of the Wnt/ß-catenin signaling pathway.

Echinacoside alleviates glucocorticoid induce osteonecrosis of femoral head in rats through PI3K/AKT/FOXO1 pathway.

Steroid-induced osteonecrosis of the femoral head (SONFH), caused by glucocorticoid (GC) administration, is known to exhibit a high incidence worldwide. Although osteoblast apoptosis has been reported as an important cytological basis of SONFH, the precise mechanism remains elusive. Echinacoside (Ech), a natural phenylethanoid glycoside, exerts multiple beneficial effects, such as facilitation of cell proliferation and anti-inflammatory and anticancer activities. Herein, we aimed to explore the regulatory mechanism underlying glucocorticoid-induced osteoblast apoptosis and determine the protective efficacy of Ech against SONFH. We comprehensively surveyed multiple public databases to identify SONFH-related genes. Using bioinformatics analysis, we identified that the PI3K/AKT/FOXO1 signaling pathway was most strongly associated with SONFH. We examined the protective effect of Ech against SONFH using in vivo and in vitro experiments. Specifically, dexamethasone (Dex) decreased p-PI3K and p-AKT levels, which were reversed following Ech addition. Validation of the PI3K inhibitor (LY294002) and molecular docking of Ech and PI3K/AKT further indicated that Ech could directly enhance PI3K/AKT activity to alleviate Dex-induced inhibition. Interestingly, Dex upregulated the expression of FOXO1, Bax, cleaved-caspase-9, and cleaved-caspase-3 and enhanced MC3T3-E1 apoptosis; application of Ech and siRNA-FOXO1 reversed these effects. In vitro, Ech decreased the number of empty osteocytic lacunae, reduced TUNEL and FOXO1 positive cells, and improved bone microarchitecture. Our results provide robust evidence that PI3K/AKT/FOXO1 plays a crucial role in the development of SONFH. Moreover, Ech may be a promising candidate drug for the treatment of SONFH.

n-3 PUFAs Show Promise as Adjuvants in Chemotherapy, Enhancing their Efficacy while Safeguarding Hematopoiesis and Promoting Bone Generation.

Cancer ranks as the second leading cause of mortality in high-income countries, underscoring the critical need for effective therapeutic strategies. One prominent approach, chemotherapy, is widely employed for treating solid tumors. However, the significant adverse effects associated with chemotherapy, notably myeloablation and osteonecrosis, impart considerable challenges by compromising immune function and diminishing patients' quality of life. Furthermore, the emergence of chemotherapy resistance poses a formidable hurdle in achieving successful cancer treatment outcomes. In this context, the focus is on exploring alternative approaches to enhance the efficacy of cancer treatment and mitigate its adverse consequences. Among these approaches, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), two n-3 polyunsaturated fatty acids (PUFAs), have garnered substantial interest. These PUFAs exhibit the potential to influence membrane lipid composition and modulate critical gene expressions associated with cancer, such as Bcl-2, PI3K, NF-κB, and phosphorylated Akt, thereby potentially reducing cancer risk. Moreover, emerging evidence highlights their ability to augment chemotherapy efficacy, particularly in drug-resistant cancer cells. Importantly, both preclinical and clinical investigations have provided compelling evidence supporting the protective effects of n-3 PUFAs on healthy cells. Leveraging these findings, there has been growing attention on the exploration of n-3 PUFAs as adjuvants to chemotherapy. This strategic approach holds promise in mitigating the adverse effects linked to chemotherapy, notably myeloablation and osteonecrosis, while simultaneously enhancing its effectiveness in combating cancer. This comprehensive review delves into the multifaceted attributes of n-3 PUFAs, encompassing their cytotoxic properties, potential as chemopreventive agents, and their prospective role in ameliorating the adverse effects commonly associated with chemotherapy, with a particular emphasis on myeloablation and osteonecrosis. By elucidating the intricate interplay between n-3 PUFAs and cancer treatment paradigms, this review contributes to the expanding body of knowledge aimed at refining cancer therapeutic strategies and enhancing patient outcomes.

Taxifolin-mediated Nrf2 activation ameliorates oxidative stress and apoptosis for the treatment of glucocorticoid-induced osteonecrosis of the femoral head.

Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is the main complication secondary to long-term or excessive use of glucocorticoids (GCs). Taxifolin (TAX) is a natural antioxidant with various pharmacological effects, such as antioxidative stress and antiapoptotic properties. The purpose of this study was to explore whether TAX could regulate oxidative stress and apoptosis in GIONFH by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. We conducted qRT-PCR, Western blotting, TUNEL assays, flow cytometry, and other experiments in vitro. Microcomputed tomography analysis, hematoxylin-eosin staining, and immunohistochemical staining were performed to determine the therapeutic effect of TAX in vivo. TAX mitigated the overexpression of ROS and NOX gene expression induced by DEX, effectively reducing oxidative stress. Additionally, TAX could alleviate DEX-induced osteoblast apoptosis, as evidenced by qRT-PCR, Western blotting, and other experimental techniques. Our in vivo studies further demonstrated that TAX mitigates the progression of GIONFH in rats by combating oxidative stress and apoptosis. Mechanistic exploration revealed that TAX thwarts the progression of GIONFH through the activation of the Nrf2 pathway. Overall, our research herein reports that TAX-mediated Nrf2 activation ameliorates oxidative stress and apoptosis for the treatment of GIONFH.

Cyasterone has a protective effect on steroid-induced Osteonecrosis of the femoral head.

CONTEXT: Cyasterone alleviated the apoptosis of BMSCs induced by Dexamethasone via the PI3K/AKT signaling pathway. In addition, Cyasterone had a protective effect on SIONFH model rats by reducing the percentage of empty bone lacunae. OBJECTIVE: To study the effect of Cyasterone on apoptosis of rat BMSCs and its function on the SIONFH rat model. METHODS: Rat BMSCs were cultured and divided into Control, DXM and Cyasterone (DXM+Cyasterone) groups. The apoptosis of each group was detected by flow cytometry, the expressions of Caspase-3 and Caspase-9 were detected by immunofluorescence staining, and the mRNA and protein expressions of AKT, BAX, P53, P85, Bcl-2 and Cytochrome C were detected by qPCR and WB. In animal experiments, the femoral head of rats were subjected to HE staining and Micro-CT to observe the necrosis and repair conditions. RESULTS: The apoptosis rate of DXM and Cyasterone groups increased compared with Control group, and the apoptosis rate of Cyasterone group decreased compared with DXM group. Compared with DXM group, the mRNA expression of BAX, P53, P85 and Cytochrome C in Cyasterone group were increased, while the protein expression of AKT and Bcl-2 decreased. The histopathological and morphological analysis showed that Cyasterone promoted the trabecular bone structure in rat, which evenly benefit for the repair of SIONFH. CONCLUSION: Cyasterone can reduce the apoptosis of rat BMSCs induced by Dexamethasone, and help promoting the bone repair in SIONFH rats.

Osteonecrosis of the ear canal in a patient treated with bisphosphonate.

In this case report, a 68-year-old woman, with known insulin-dependent diabetes and myelomatosis, presented with ear pain in her right ear. Otomicroscopy showed exposed bone in the external auditory canal. The patient was examined with wound swab, biopsies, MRI and PET-CT scans to rule out necrotizing external otitis, cholesteatoma and malignancy. Later, the patient's bisphosphonate treatment for myelomatosis was suspected, because osteonecrosis of the external auditory canal is a rare side effect to this treatment. The bone lesion improved after local debridement and cessation of the bisphosphonate treatment.

Menaquinone-4 prevents medication-related osteonecrosis of the jaw through the SIRT1 signaling-mediated inhibition of cellular metabolic stresses-induced osteoblast apoptosis.

Long-term usage of bisphosphonates, especially zoledronic acid (ZA), induces osteogenesis disorders and medication-related osteonecrosis of the jaw (MRONJ) in patients, thereby contributing to the destruction of bone remodeling and the continuous progression of osteonecrosis. Menaquinone-4 (MK-4), a specific vitamin K2 isoform converted by the mevalonate (MVA) pathway in vivo, exerts the promotion of bone formation, whereas ZA administration suppresses this pathway and results in endogenous MK-4 deficiency. However, no study has evaluated whether exogenous MK-4 supplementation can prevent ZA-induced MRONJ. Here we showed that MK-4 pretreatment partially ameliorated mucosal nonunion and bone sequestration among ZA-treated MRONJ mouse models. Moreover, MK-4 promoted bone regeneration and inhibited osteoblast apoptosis in vivo. Consistently, MK-4 downregulated ZA-induced osteoblast apoptosis in MC3T3-E1 cells and suppressed the levels of cellular metabolic stresses, including oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and DNA damage, which were accompanied by elevated sirtuin 1 (SIRT1) expression. Notably, EX527, an inhibitor of the SIRT1 signaling pathway, abolished the inhibitory effects of MK-4 on ZA-induced cell metabolic stresses and osteoblast damage. Combined with experimental evidences from MRONJ mouse models and MC3T3-E1 cells, our findings suggested that MK-4 prevents ZA-induced MRONJ by inhibiting osteoblast apoptosis through suppression of cellular metabolic stresses in a SIRT1-dependent manner. The results provide a novel translational direction for the clinical application of MK-4 for preventing MRONJ.

Glucocorticoid Receptor Polymorphisms and Avascular Osteonecrosis After Kidney Transplantation.

INTRODUCTION: Glucocorticoids (GCs) are commonly prescribed as immunosuppressive agents after kidney transplantation and their most common non-traumatic adverse effect is Avascular Necrosis (AVN) of the femoral head. In this regard, this study aimed to evaluate the glucocorticoid receptor (GR) polymorphisms among kidney transplant recipients and their potential role as a risk factor for the incidence of AVN. METHODS: In this study, 99 renal transplant recipients were evaluated for the correlations of GR polymorphisms including N363S (rs6195), BclI (rs41423247), ER22/23EK (rs6189/rs6190), and A3669G (rs6198) with AVN after renal transplantation. RESULTS: Results showed that none of the renal-transplanted patients neither with GC hypersensitive polymorphisms (N363S and BclI) nor with GC-resistant polymorphisms (A3669G and ER22/23EK) developed AVN (P > .05). In addition, the medications of the renal recipients with AVN were significantly different from the nonAVN patients (P < .001). CONCLUSION: The study results indicate that the GR polymorphisms have no critical roles in the susceptibility to AVN after renal transplantation. However, further studies to confirm the results are recommended.  DOI: 10.52547/ijkd.7221.

Proanthocyanidins Inhibit Osteoblast Apoptosis via the PI3K/AKT/Bcl-xL Pathway in the Treatment of Steroid-Induced Osteonecrosis of the Femoral Head in Rats.

BACKGROUND: Steroid-induced osteonecrosis of the femoral head (SONFH) is a common clinical disease caused by massive or prolonged use of steroids. Its pathogenesis is unclear, but its incidence is increasing annually. It is characterized by an insidious and rapid onset, and high disability rate, causing a great burden on patients' daily life. Therefore, clarifying its pathogenesis and providing early and effective treatment for steroid osteonecrosis is important. METHODS: In vivo, we used methylprednisolone (MPS) to construct a SONFH rat model and employed Mirco-ct, Hematoxylin and eosin (H&E) staining, and TdT-mediated dUTP nick end labeling (TUNEL) staining analysis to evaluate the therapeutic effects of proanthocyanidins (PACs). Network pharmacology analysis was conducted to mine targets associated with femoral head necrosis, and PACs analyzed possible molecular mechanisms. In vitro, PACs were added at different doses after treatment of cells with dexamethasone (DEX), and human osteoblast-like sarcoma(MG-63) cell apoptosis was determined by Annexin V-FITC-PI. The mechanisms by which PACs regulate bone metabolism via the Phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)/Recombinant Human B-Cell Leukemia/Lymphoma 2 XL(Bcl-xL) axis were explored by Western blotting. RESULT: In vivo studies showed that PACs prevented SONFH in rat model. The PI3K/AKT/Bcl-xL signaling pathway was selected by network pharmacology approach; in vitro studies showed that proanthocyanidin-activated AKT and Bcl-xL inhibited osteoblast apoptosis. CONCLUSIONS: PACs can inhibit excessive osteoblast apoptosis in SONFH via the PI3K/AKT/Bcl-xL signaling axis and have potential therapeutic effects.

Usefulness of quantitative bone SPECT/CT for evaluating medication-related osteonecrosis of the jaw treatment response.

OBJECTIVE: For assessment of therapeutic response in medication-related osteonecrosis of the jaw (MRONJ) cases, the clinical usefulness of quantitative bone single-photon computed tomography-computed tomography (SPECT/CT) results was investigated. MATERIALS AND METHODS: Sixteen patients (18 lesions) with a clinical diagnosis of MRONJ underwent bone SPECT/CT scanning before and during/after anti-inflammatory therapy given for 3 or more months. The GI-BONE software package was used to determine standard uptake values (SUVs), including maximum (SUVmax), peak (SUVpeak), and mean (SUVmean), and metabolic bone volume (MBV) and also total bone uptake (TBU). In both responders (downstage) and non-responders (upstage or no change), differences in quantitative values between the first and second SPECT/CT examinations were analyzed using a Wilcoxon test. RESULTS: Following therapy, significant reductions in SUVmax, SUVpeak, SUVmean, MBV and TBU values for 11 lesions were noted in the responders after therapy (p = 0.003, p = 0.006, p = 0.004, p = 0.003, and p = 0.002, respectively). On the other hand, those for the seven lesions in the non-responder group were not significantly different (p = 0.17, p = 0.16, p = 0.26, p = 0.96, and p = 0.12, respectively). Results for SUVmax change showed sensitivity and specificity values of 45.5% and 85.7%, respectively, for differentiating responders from non-responders, with - 37.3% the optimal cutoff value. Those for MBV change were 72.7 and 85.7%, respectively, with - 29.4% the optimal cutoff value. Those for TBU change were 81.8% and 85.7%, respectively, with - 36.3% the optimal cutoff value. CONCLUSION: The present findings showed that therapeutic response in MRONJ cases could be determined by use of quantitative SUV, MBV, and TBU values based on bone SPECT/CT findings.

Alpha-lipoic acid could be a promising treatment in steroid-induced osteonecrosis.

OBJECTIVE: Glucocorticoid-induced osteonecrosis is a serious debilitating health problem. In the present study, we investigated the effects of alpha-lipoic acid on glucocorticoid-induced osteonecrosis in rats. MATERIALS AND METHODS: A total of 40 male Wistar albino rats were equally assigned to 4 groups as control, methylprednisolone acetate (MPA), alpha-lipoic acid (ALA), and methylprednisolone acetate with alpha-lipoic acid (MPA+ALA). The animals in MPA group subcutaneously received 15 mg/kg/week for 2 weeks, whereas 100 mg/kg/day alpha-lipoic acid was intraperitoneal administered for 4 weeks to ALA group. The MPA+ALA group was subjected to both treatments in same doses. Osteonecrosis was confirmed and graded histologically. The serum concentrations of glucose, total cholesterol, low- and high-density lipoprotein, triglyceride, as well as the total oxidant and antioxidant status, oxidative stress index, prothrombin time and activated partial thromboplastin time were evaluated. Also, lipid peroxidation and DNA damage were immunohistochemically assessed in the bone. RESULTS: Osteonecrotic lesions were narrower in the MPA+ALA group than in the MPA group (p<0.05). As compared to the controls, the biochemical parameters in MPA and MPA+ALA groups were significantly increased (p<0.001). The oxidative stress index was significantly higher in the groups with MPA than the controls (p=0.002), but the animals treated with ALA alongside MPA displayed lesser scores than the ones injected with solely MPA (p=0.03). The administration of MPA elevated lipid peroxidation and DNA damage, which were successfully alleviated by ALA. CONCLUSIONS: Alpha-lipoic acid may be suggested to be a protective supplement in glucocorticoid-induced osteonecrosis in rats. The antioxidant capacity of alpha-lipoic acid may involve its beneficial effects.

Post-COVID-19 related osteonecrosis of the jaw (PC-RONJ): an alarming morbidity in COVID-19 surviving patients.

PURPOSE: The recent coronavirus disease (COVID-19) pandemic mainly affects the respiratory system; however, several oral and maxillofacial post-COVID-19 complications have also been observed. This series reports the growing number of osteonecrosis cases associated with post-COVID-19 patients. MATERIALS AND METHODS: This is a retrospective, multi-center case series that reports cases with maxillary osteonecrosis after various periods of SARS-CoV-2 infection in the period between January and August 2021 based on the PROCESS guidelines. RESULTS: Twelve cases were reported with post-COVID-19 manifestation of spontaneous osteonecrosis of the maxillary jaw. Five patients were hospitalized during COVID-19 management and all of the twelve cases had at least one systematic Co-morbidity, and undertake corticosteroids prescription based on the COVID-19 disease treatment protocol. The mean onset of osteonecrosis symptoms appearance was 5.5 ± 2.43 weeks calculated from the day of the negative PCR test. The management was successfully done through surgical debridement and pre and post-operative antibiotics. No anti-fungal medications were prescribed as the fungal culture and the histopathological report were negative. CONCLUSION: Post-COVID-related osteonecrosis of the jaw (PC-RONJ) could be now considered as one of the potential post-COVID-19 oral and maxillofacial complications that occurs unprovokedly and mainly in the maxilla.

Inhibition of HMGB1/RAGE Signaling Reduces the Incidence of Medication-Related Osteonecrosis of the Jaw (MRONJ) in Mice.

Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication of antiresorptive or antiangiogenic medications, used in the treatment of bone malignancy or osteoporosis. Bone necrosis, mainly represented by osteocytic death, is always present in MRONJ sites; however, the role of osteocyte death in MRONJ pathogenesis is unknown. High mobility group box 1 (HMGB1) is a non-histone nucleoprotein that in its acetylated form accumulates in the cytoplasm, whereas non-acetylated HMGB1 localizes in the nucleus. SIRT1 deacetylase regulates cellular localization of HMGB1. Interestingly, HMGB1 is released during cell necrosis and promotes inflammation through signaling cascades, including activation of the RAGE receptor. Here, we utilized a well-established mouse MRONJ model that utilizes ligature-induced experimental periodontitis (EP) and treatment with either vehicle or zolendronic acid (ZA). Initially, we evaluated HMGB1-SIRT1 expression in osteocytes at 1, 2, and 4 weeks of treatment. Significantly increased cytoplasmic and perilacunar HMGB1 expression was observed at EP sites of ZA versus vehicle (Veh) animals at all time points. SIRT1 colocalized with cytoplasmic HMGB1 and presented a statistically significant increased expression at the EP sites of ZA animals for all time points. RAGE expression was significantly higher in the submucosal tissues EP sites of ZA animals compared with those in vehicle group. To explore the significance of increased cytoplasmic and extracellular HMGB1 and increased RAGE expression in MRONJ pathogenesis, we used pharmacologic inhibitors of these molecules. Combined HMGB1/RAGE inhibition resulted in lower MRONJ incidence with statistically significant decrease in osteonecrotic areas and bone exposure versus non-inhibitor treated ZA animals. Together, our data point to the role of HMGB1 as a central alarmin, overexpressed at early phase of MRONJ pathogenesis during osteocytic death. Moreover, HMGB1-RAGE pathway may represent a new promising therapeutic target in patients at high risk of MRONJ. © 2022 American Society for Bone and Mineral Research (ASBMR).

Bone Targeting Agents in Patients with Prostate Cancer: General Toxicities and Osteonecrosis of the Jaw.

INTRODUCTION: Bone metastases are the most frequent site of secondary localization of prostate cancer (PCa) and are present in about 90% of cases of advanced disease. Consequently, an adequate management of bone involvement is of pivotal importance in the therapeutic approach and skeletal-related events (SREs) need to be closely monitored and promptly assessed and treated. Bone targeting agents (BTAs), consisting in bisphosphonates and denosumab, are an essential part of the treatment of metastatic prostate cancer that accompanies systemic treatments throughout the most part of the history of the disease. Activity and safety of bone targeting agents: These treatments are correlated to better outcomes in terms of reduction of SREs and, in metastatic castration resistant setting, of increased overall survival (OS), but several important adverse events have to be managed and prevented. Of these, osteonecrosis of the jaw (ONJ) is extremely invalidating and should be managed with a special attention. DISCUSSION: The role of BTAs in prostate cancer is pivotal throughout many stages of the disease, but several toxicities should be quickly recognized and treated. We aim at recollecting evidence on clinical benefit of BTAs, common and specific toxicities, and explore the pathophysiology and clinical aspects of osteonecrosis of the jaw. We present a review of the literature to report the role of the different types of bone targeting agents in the management of prostate cancer with bone metastases with a particular focus on common toxicities and ONJ to recollect current evidences on the activity of these compounds and the correct management of their adverse events.