Postmenopausal osteoporosis (PMOP), a prevalent skeletal disorder among women post-menopause, has emerged as a pressing global public health concern. Exosomes derived from serum have exhibited encouraging therapeutic potential in addressing PMOP, albeit with underlying mechanisms requiring deeper exploration. To elucidate these mechanisms, we devised a mouse model by surgically inducing ovariectomy and isolated exosomes from serum samples. Subsequently, we employed qRT-PCR, Western blotting, and immunofluorescence analysis to quantify relevant gene and protein expression patterns. To assess the biological effects on treated cells and tissues, we utilized ARS staining, oil red O staining, and micro-CT analysis. Additionally, we examined the METTL3/FOXO1 m6A site interaction and the FOXO1/YTHDF1 complex using dual-luciferase reporter assays and RIP assays. The m6A modification levels of FOXO1 were quantified via MeRIP-PCR. Furthermore, we engineered bone marrow mesenchymal stem cell exosomes by loading abundant METTL3 mRNA and decorating their surfaces with bone-targeting peptides. The successful synthesis and bone-targeting capabilities of these modified exosomes were validated through electron microscopy, in vivo imaging, and immunofluorescence staining. Our findings reveal that METTL3, in collaboration with YTHDF1 within serum-derived exosomes, enhances FOXO1 gene transcription by fostering m6A modification of FOXO1. This, in turn, promotes osteogenic differentiation of bone marrow mesenchymal stem cells while inhibiting lipogenic differentiation. Notably, our engineered exosomes, BT-oe-METTL3-EXO, not only harbor high levels of METTL3 but also demonstrate exceptional bone-targeting efficiency. In vitro studies demonstrated that BT-oe-METTL3-EXO significantly mitigated bone mass loss induced by ovariectomy in mice, bolstered osteogenic differentiation of mouse bone marrow mesenchymal stem cells, and inhibited lipogenic differentiation. Collectively, our research underscores the pivotal regulatory function of serum-derived exosomes in human bone marrow stem cells (hBMSCs) and underscores the promising therapeutic potential of BT-oe-METTL3-EXO for combating postmenopausal osteoporosis.

Medication-Related Osteonecrosis of the Jaw (MRONJ) is a condition marked by osteonecrosis of the jaw bone and other symptoms seen following invasive surgical procedures in patients administered bone-modifying agents. Once disease develops, a patient's ADL levels are significantly compromised. However, the pathogenesis of this disease is not clearly understood. Bisphosphonates (BPs) are bone resorption inhibitors commonly used to treat osteoporosis. Although not confirmed, it is generally believed that MRONJ risk is higher in the presence of injectable rather than oral formulations. Here, we assessed risk of developing ONJ in mice in the presence of 3 different BPs-zoledronate, ibandronate, or alendronate-that are administered clinically intravenously or via infusion.

Eight-week-old wild-type mice were administered zoledronate, alendronate, ibandronate or PBS vehicle subcutaneously once a week for 2 weeks. Then the right first molars in the mandible were extracted. Six-weeks later, osteonecrosis development was analyzed by histochemistry.

Among mice administered BPs, mice treated with zoledronate exhibited the highest frequency of osteocytes exhibiting osteonecrosis. Bone mineral density was higher in mice receiving zoledronate, alendronate, or ibandronate than in PBS control mice, but effects of the 3 drugs were comparable. Moreover, formation of multi-nuclear osteoclasts in vitro was most strongly inhibited by zoledronate, followed by alendronate and ibandronate.

Administration of BPs with high osteoclastogenesis inhibitory potential, such as zoledronate, increases risk of ONJ development after tooth extraction more than treatment with other agents tested, even at equivalent dosage.

The discontinuation of denosumab [antibody targeting receptor activator of nuclear factor kappa B ligand (RANKL)] therapy may increase the risk of multiple vertebral fractures; however, the underlying pathophysiology is largely unknown. In patients who underwent discontinuation after multiple injections of denosumab, the levels of tartrate-resistant acid phosphatase 5b increased compared to pretreatment levels, indicating a phenomenon known as "overshoot." The rate of decrease in bone mineral density during the withdrawal period was higher than the rate of decrease associated with aging, suggesting that the physiological bone metabolism had broken down. Overshoot and significant bone loss were also observed in mice receiving continuous administration of anti-RANKL antibody after treatment was interrupted, resembling the original pathology. In mice long out of overshoot, bone resorption recovered, but osteoblast numbers and bone formation remained markedly reduced. The bone marrow exhibited a significant reduction in stem cell (SC) antigen 1- and platelet-derived growth factor receptor alpha-expressing osteoblast progenitors (PαS cells) and alkaline phosphatase-positive early osteoblasts. Just before the overshoot phase, the osteoclast precursor cell population expands and RANKL-bearing extracellular vesicles (EVs) became abundant in the serum, leading to robust osteoclastogenesis after cessation of anti-RANKL treatment. Thus, accelerated bone resorption due to the accumulation of RANKL-bearing EVs and long-term suppression of bone formation uncoupled from bone resorption leads to the severe bone loss characteristic of denosumab discontinuation.

Denosumab (Dmab) discontinuation in osteoporosis leads to overshoot (rebound) of bone turnover, but its cause remains largely unclear. In a prospective trial, Dmab-treated Langerhans cell histiocytosis (LCH) patients showed no overshoot of bone turnover markers despite high short-term dosing. Findings suggest that total Dmab dose does not drive the overshoot of bone turnover markers.

In patients with osteoporosis, the length of treatment with denosumab (Dmab) is an important risk factor for the overshoot (rebound) of bone turnover markers following its discontinuation. Whether this is due to the higher total Dmab dose given and/or the severity of the disease is unknown. To address this question, long-term follow-up of changes in bone metabolism after stopping Dmab with doses higher than those used in osteoporosis is essential.

In a prospective, single-arm, open label, phase 2b clinical trial, ten adult patients with Langerhans cell histiocytosis (LCH), eight with bone lesions (four single, four multiple) and two without, were treated with Dmab sc injections 120 mg/2 months for 6 months (total 480 mg) and were followed for 24 months after the last injection.

Treatment reduced bone turnover markers to about 10% of pretreatment values, which increased after treatment arrest to a peak that did not exceed pretreatment levels; mean (± SD) peak serum CTX 0.522 ± 0.366 ng/mL and P1NP 72.2 ± 35.9 ng/mL were not significantly different from baseline (p = 0.11 and 0.65, respectively). Moreover, pretreatment and peak serum CTX values were significantly correlated (rs = 0.818, p = 0.007). No vertebral fractures, bone loss, or hypercalcemia were observed.

Dmab withdrawal in patients with LCH was not followed by an overshoot of bone turnover markers or bone loss despite the administration in 6 months of a total dose equal to that given in osteoporosis for 4 years. Total Dmab dose is, thus, not an important determinant of the bone turnover overshoot after treatment withdrawal.

This study aimed to investigate the impacts of prior anti-osteoporosis treatments on bone mineral density (BMD) changes in Chinese postmenopausal women with osteoporosis following 1-year Denosumab (Dmab) therapy.

This retrospective cohort study enrolled 381 postmenopausal women, all receiving a 1-year Dmab treatment. Participants were stratified into five groups based on prior anti-osteoporosis treatments: no treatment (NT), alendronate (ALN), zoledronic acid (ZOL), teriparatide (TPT), and raloxifene (RAL). Potential factors influencing BMD changes were screened using least absolute shrinkage and selection operator (LASSO). The selected variables were then incorporated into a multivariate regression model to identify independent risk factors. Finally, after adjusting for confounders, the impacts of prior anti-osteoporosis treatment on sequential Dmab responses were evaluated.

1) Further BMD increases were observed after sequential 1-year Dmab with prior use of other anti-osteoporosis drugs; 2) Compared to the NT group, ZOL significantly reduced BMD changes at the lumbar spine (LS), femoral neck (FN), and total hip (TH) (LS: β = -0.01, P = 0.016; FN: β = -0.01, P = 0.010; TH: β = -0.01, P = 0.011); Significant negative associations with FN BMD changes were observed for the ALN group (β = -0.01, P< 0.001), and the RAL group (β = -0.01, P = 0.010) compared to the NT group; TPT showed no significant differences with the NT group at all sites; 3) Multiple analysis revealed baseline BMD were independently associated with changes in BMD (LS: β = -0.04, P = 0.009; FN: β = -0.19, P <0.001; TH: β = -0.14, P <0.001).

These findings indicated that prior anti-osteoporosis treatments differentially influenced BMD responses to 1-year Dmab therapy. While patients who had previously been treated with ZOL had limited subsequent BMD improvement, patients who had previously used TPT and had lower baseline BMD benefited more.

Introduction: Bone health optimization is a key component of the preoperative management of spine surgery patients, as poor bone quality increases the odds of mechanical complications. The present study aimed to achieve the following: (1) compare the relative efficacy of current osteoporosis medications in improving bone quality; (2) identify factors influencing treatment response in preoperative spine surgery patients. Methods: Patients treated at a single, multisite institution who received osteoporosis treatment were identified. Data were gathered on pre- and post-treatment lumbar spine Hounsfield Unit (HU) measurements, patient demographics, frailty scores (modified Frailty Index/mFI, risk analysis index/RAI), and pharmacologic treatment details. The primary outcome was a ≥7 point improvement in lumbar HU, and baseline and logistic regression models were utilized to identify factors associated with this improvement. Medications were grouped as anabolic (teriparatide, romosozumab) and antiresorptive (denosumab, alendronate) therapies. Results: A total of 267 patients were included (median age: 74 years; IQR [66-81]; 67.3% female), with 127 (47.6%) improving by ≥7 HU. The treatment agents used were alendronate (95), denosumab (113), romosozumab (31), and teriparatide (28). Univariable comparisons revealed significant differences across medication groups in age (p < 0.001), sex (p < 0.001), mFI (p < 0.001), RAI (p = 0.004), BMI (p < 0.001), pre-treatment HU (p = 0.022), and treatment duration (p < 0.001). The highest HU improvement rates (ΔHU ≥ 7) were observed in patients receiving the anabolic medications romosozumab (67.7%) and teriparatide (60.7%). Univariable logistic regression identified male sex (OR 0.54, p = 0.019), higher pre-treatment HU (OR 0.99, p = 0.006), and longer treatment duration (OR 0.97, p = 0.003) as factors associated with lower odds of HU improvement. Only romosozumab was associated with significantly higher odds of HU improvement relative to alendronate (OR 3.02, p = 0.012). In our multivariable analysis, male sex (OR 0.53, p = 0.028) and higher pre-treatment HU (OR 0.99, p = 0.002) remained significant predictors of HU improvement. However, medication type was not significant in the multivariable analysis. Conclusions: Our study highlights that male sex and higher pre-treatment HU were independently associated with lower odds of HU improvement, while medication type was not a significant predictor. Additionally, anabolic agents offered superior improvement relative to antiresorptive therapies.

Aging is associated with deterioration of muscle and bone health, resulting in increased fragility fracture risk. It is not known whether muscle mass and strength could impact the osteoporosis pharmacological response.

The aim of this study was to analyze the association between muscle mass and strength with the response to denosumab in osteoporosis.

Postmenopausal women at high fracture risk receiving denosumab (60 mg subcutaneously administered every 6 months) were considered. The likelihood of sarcopenia was estimated by administering the SARC-F questionnaire, muscle mass and performance were assessed by measuring calf circumference (CC) and hand grip strength, respectively. Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry.

130 women (age 70.2 ± 9.4 years) were recruited. Baseline BMD T-score values were - 2.6 ± 1.1 SD and - 2.3 ± 0.7 SD at lumbar spine and femoral neck, respectively; while CC and grip strength were 31.9 ± 2.9 cm and 22.7 ± 6.7 kg, respectively. The SARC-F score was associated with the 10-year probability of major osteoporotic fracture (r = 0.21, p < 0.05). The CC was positively associated with the T-score values of both lumbar spine (r = 0.262, p = 0.034) and femoral neck (r = 0.359, p = 0.004). Denosumab administration (treatment duration 43 months), lead to BMD improvement by + 9.6% at the lumbar spine and + 7.3% at the femoral neck (pall < 0.05). After adjustment for comorbidities, fracture risk and treatment duration, the CC (β = 1.76, SE = 0.82, p = 0.03) and the baseline femoral BMD (β = - 94.19, SE = 26.09, p = 0.0009) were independently associated with femoral BMD gain over time.

In postmenopausal osteoporotic women, the CC was positively and independently associated with denosumab treatment response.

Bone regeneration processes are associated with a systemic skeletal change in bone quality, increasing the risk of fragility fractures. This condition may be aggravated in osteoporotic patients due to their limited osteogenic capacity. This work evaluates the impairment of the bone quality in osteoporotic sheep during a bone regeneration process. It provides a deeper understanding about the complex multiscale dynamics of bone mineral density, microstructure and chemical composition across different bone tissues, locations and time points.

Osteoporosis was induced in fifteen Merino sheep. A critical-size defect was then created in the sheep's right hind metatarsus and subsequently regenerated using distraction osteogenesis. The animals were randomly sacrificed during bone regeneration, either on days 40 or 100 after surgery. Computed tomography, micro-computed tomography and chemical composition analyses were conducted on different bone tissues (cortical, trabecular and woven) at several skeletal locations (the operated metatarsus, the contralateral one and the iliac crest) to assess the individual bone quality changes relative to the non-osteoporotic time point.

After osteoporosis induction, the trabecular tissue experienced a 6.4% reduction in the bone mineral density, while no significant changes were reported in cortical tissue quality. During bone regeneration, the operated bone increased significantly the woven ossification whilst the cortical mineral density decreased by 18.7%. Simultaneously, an early deterioration in the microstructure and chemical composition of the trabecular bone was observed in the iliac crest, persisting over time in non-operated trabecular regions.

Osteoporosis causes uneven degradation to trabecular tissue quality across different bone locations. Furthermore, the bone regeneration process via bone transport in osteoporotic subjects leads to a systemic skeletal disorder that further impairs the bone quality, surpassing the damage caused by osteoporosis alone. This impairment appears to be intensified by the pre-existing osteoporotic condition.

Osteoporosis is a chronic metabolic bone disease characterized by progressive bone loss and structural deterioration, increasing fracture risk and morbidity. As the global population ages, its incidence is rising, underscoring the urgent need for more effective prevention and treatment strategies.

This review synthesizes the latest evidence and guidelines from leading international societies, establishing a contemporary framework for osteoporosis pharmacotherapy. It emphasizes best practices and explores future directions in treatment optimization and fracture prevention.

To optimize outcomes, enhancing early detection, refining treatment strategies, and prioritizing patient-centered care are essential. Improving diagnosis through increased use of bone mineral density (BMD) assessments and identifying secondary causes are critical steps to addressing underdiagnosis, particularly in men. Pharmacotherapies play a vital role in management; while bisphosphonates serve as a cost-effective first-line treatment, denosumab and anabolic agents like Teriparatide and romosozumab are essential alternatives for high-risk patients. Future directions in osteoporosis management emphasize advancing treatment strategies through novel drug targets and innovative delivery systems, alongside personalized medicine approaches considering individual genetic and comorbidity profiles. Enhanced adherence strategies and further research into combination therapies and monitoring tools are crucial for improving prevention and treatment outcomes, ultimately reducing the fragility fracture burden worldwide.

Osteoporosis awareness is important for nurses, their patients, families, and communities. Over 2 million osteoporosis fractures occur in the US every year, and up to one-third of patients die within a year of experiencing a hip fracture. Up to 80% of patients with hip fractures never fully regain pre-fracture independence. This article discusses osteoporosis risk factors, screening and treatment recommendations, self-help measures, and potential care gaps.

Fracture is an under-recognized but common complication of diabetes mellitus, with an incidence approaching twofold in type 2 diabetes mellitus (T2DM) and up to sevenfold in type 1 diabetes mellitus (T1DM) compared with that in the general population. Both T1DM and T2DM induce chronic hyperglycaemia, leading to the accumulation of advanced glycosylation end products that affect osteoblast function, increased collagen crosslinking and a senescence phenotype promoting inflammation. Together with an increased incidence of microvascular disease and an increased risk of vitamin D deficiency, these factors reduce bone quality, thereby increasing bone fragility. In T1DM, reduced anabolic stimuli as well as the presence of autoimmune conditions might also contribute to reduced bone mass and increased fragility. Diabetes mellitus is the most common cause of kidney failure, and fracture risk is exacerbated when chronic kidney disease (CKD)-related mineral and bone disorders are superimposed on diabetic changes. Microvascular pathology, cortical thinning and trabecular deterioration are particularly prominent in patients with T1DM and CKD, who suffer more fragility fractures than do other patients with CKD. This Review explores the pathophysiology of bone fragility in patients with diabetes mellitus and CKD and discusses techniques to predict fracture and pharmacotherapy that might reduce fracture risk.

Background and Objectives: Osteoporosis is a common chronic condition after menopause that increases the risk of fractures. In South Korea, the prevalence of osteoporosis among adults aged 50 and older is 22.4%, with 94.4% of treated patients being women, highlighting its significant impact on postmenopausal health. In this study, we examine the sales trends of osteoporosis medications in Korea from 2018 to 2023 to understand current usage patterns and market dynamics. Materials and Methods: This study is a retrospective analysis based on pre-recorded sales data from Intercontinental Marketing Services (IMS). Data covering a five-year period (2018-2023) were analyzed to examine the sales trends of osteoporosis medications, including bisphosphonates, selective estrogen receptor modulators (SERMs), parathyroid hormone analogs, denosumab, romosozumab, and others. Romosozumab, approved in November 2019, was included in the analysis. Given the nature of this study, no direct patient data or clinical interventions were involved. Results: The total market size for osteoporosis medications in South Korea reached USD 285.42 million in 2023, reflecting a 15.3% increase from 2022. Bisphosphonates, previously the dominant therapy, experienced an 11% decline in market share over five years. Meanwhile, denosumab, a receptor activator of the nuclear factor-κB ligand inhibitor, showed a remarkable growth rate of 957.6% from 2018 to 2023, surpassing bisphosphonates in their market share. Romosozumab, a newly introduced anabolic agent, accounted for 7.4% of the market, with sales increasing by 59% in 2023. Conclusions: This analysis revealed major shifts in treatment preferences, with newer drugs like denosumab and romosozumab gaining prominence over traditional bisphosphonates. These trends highlight the increasing clinical adoption of anabolic agents for high-risk patients and the impact of expanded reimbursement policies on osteoporosis management. Given the increasing use of advanced therapies, it is essential to monitor treatment access, patient adherence, and long-term clinical outcomes. Understanding these sales trends can aid healthcare professionals and policymakers in optimizing osteoporosis treatment strategies and ensuring better patient care.

Osteoporosis is a critical public health issue, particularly in the "older" (those aged over 75) and "oldest old" population (those aged 85 and above), who are at a heightened risk for fractures and related complications. This article reviews current osteoporosis treatments tailored for these age groups, emphasizing the balance between efficacy and safety, while considering cost/benefit aspects. We discuss pharmacological therapies available nowadays and their respective benefits and risks in the old population, based on the available literature on the subject. Special attention is given to specific features of this age category, like challenges of polypharmacy, physiological changes associated with age, comorbidities and patient adherence. This paper highlights the need for individualised treatment plans that consider the patient's overall health status, life expectancy and quality of life and the importance of continued innovation and personalized care in managing osteoporosis especially among the "older" population.

Phytohormones have garnered considerable interest as potential modulators of the gut-bone axis. Denosumab (Deno), a widely utilized therapeutic agent for postmenopausal osteoporosis, has not been previously investigated for its effects on gut health. The objective of this study was to assess the efficacy of isoflavones (SI), naringin (Nar), and Deno in the management of postmenopausal osteoporosis by targeting the gut-bone axis.

The postmenopausal osteoporosis model in mice was established via bilateral oophorectomy. Subsequently, mice in the Deno group received subcutaneous injections of Deno at a dosage of 10 mg/kg, administered twice weekly. In contrast, mice in the SI and Nar groups were subjected to oral gavage with 200 mg/kg/day of SI and Nar, respectively. The treatment period for all groups lasted for 8 weeks. Upon the conclusion of the experiment, a thorough evaluation of the effects of SI, Nar, and Deno on bone and gut health in mice was conducted through immunological, pathological, imaging, and multi-omics methodologies.

Deno, SI, and Nar significantly alleviated the physical symptoms in postmenopausal mice. However, only SI and Nar significantly modulated the gut microbiota. Akkermansia was significantly enriched after the gavage of SI and Nar. Akkermansia has the capacity to not only augment bone mass and alleviate strength deterioration via extracellular vesicles, but it also influences bone metabolism by diminishing inflammation and modulating lipid metabolism. Notably, no significant changes in the gut microbiota were observed in the Deno group, which may be attributed to the differences in the method of administration, as Deno was administered via subcutaneous injection rather than gavage.

SI and Nar may influence the gut-bone axis through Akkermansia and have the potential of alternative treatment options for postmenopausal osteoporosis. Although the gut microbiota is not significantly affected by the subcutaneous administration of Deno, the long-term management of postmenopausal osteoporosis and the exploration of various management models warrant additional scrutiny. Furthermore, this study has yet to establish a dose-response relationship, indicating that further research is essential to clarify the regulatory effects of varying doses of SI and Nar on postmenopausal osteoporosis especially the modulation of gut microbiota.

Osteoporosis is a national health priority, and over six million Australians over the age of 50 years have poor bone health. Fragility fractures due to osteoporosis are associated with an increased morbidity and mortality risk and a high economic cost to the community. It is a chronic condition requiring long-term management. Despite notable advances in pharmacotherapy, large treatment gaps remain. Antiresorptive drugs have been the foundation of treatment; however, their efficacy wanes and rare adverse effects accumulate with prolonged use. Osteoanabolic drugs form new bone and can also restore deteriorated bone microarchitecture, in addition to increasing bone mineral density. Currently, antiresorptive drugs are used as first-line drugs for osteoporosis. However, recent studies have highlighted the superiority of anabolic drugs for fracture reduction over antiresorptives. Furthermore, for patients at very high risk or imminent risk of fracture, the use of sequential therapy with an osteoanabolic medication followed by an antiresorptive is superior to achieving optimal long-term bone health outcomes. This article will discuss the evidence supporting the anti-fracture benefits of osteoanabolic drugs, emphasising their benefits as first-line agents for osteoporosis. Challenges surrounding transitions between osteoanabolic and antiresorptive medications are also discussed, highlighting considerations for the optimal treatment sequence with a focus on recent updates to Australian prescribing recommendations and PBS requirements.

Medication-related osteonecrosis of the jaw (MRONJ) is a rare and challenging complication of anti-resorptive therapy. This review addresses the critical issue of risk management in patients with osteoporosis who require dentoalveolar surgery while undergoing anti-resorptive therapy. Dental practitioners should be aware of these risks; however, they should not refuse treatment based solely on them. This review discusses the risks through five major factors: invasive dentoalveolar surgeries, concomitant oral infection, type of medication, duration of medication, and preoperative drug discontinuation. Additionally, we discussed the local factors associated with dental practices. Our review underscored the importance of personalized risk assessment, considering each patient's unique drug history and oral condition. Based on a comprehensive literature review and clinical evidence, we proposed specific guidelines for preoperative drug interruption tailored to different anti-resorptive agents. These recommendations aimed to balance osteoporosis management by minimizing the risk of MRONJ during oral surgical interventions and bridging the knowledge gap in managing patients with osteoporosis requiring dental care. This review will allow clinicians to improve their practice and optimize patient outcomes by providing evidence-based strategies.

Receptor activator of nuclear factor kappa-B ligand (RANKL) plays a critical role in bone metabolism and the pathogenesis of osteoporotic fractures. This study aims to conduct a bibliometric analysis of global research pertaining to RANKL and osteoporotic fractures to identify key trends, influential studies, and collaborative networks.

A literature search was conducted to identify articles found in the Web of Science Core Collection database regarding RANKL and osteoporotic fractures from 2001 to 2024. A bibliometric analysis was performed using VOSviewer, CiteSpace, and R 4.3.3 for the publication volume, country and institution contributions, journal impact, author influence, and research hotspots.

A total of 214 articles were analyzed. Publication rates have steadily increased, with a peak of 21 papers in 2020. The U.S., China, and South Korea were the top contributing countries, and leading institutions included Harvard University and Dankook University. The Journal of Bone and Mineral Research, Osteoporosis International, and Bone were the journals of highest impact. At the level of authors, Heiss-Christian published the highest number and Christiansen-Claus had the strongest citation impact (1,368 citations). Research evolved from basic biological mechanisms (2001-2010) through clinical applications (2011-2017) to recent renewed interest in fundamental RANKL biology (2018-2024). Key research hotspots included postmenopausal osteoporosis, bone mineral density, and osteoclast differentiation, with emerging focus on RANKL's role beyond skeletal metabolism.

This bibliometric analysis provides a comprehensive overview of RANKL research in osteoporotic fractures, highlighting key priorities for future investigation. Future studies should prioritize understanding RANKL's broader physiological roles, developing better predictive markers, and optimizing personalized treatment strategies.

Osteoporosis requires life-long management. This involves the use of different drugs in various sequences followed by long-term maintenance therapy. This review highlights the important transitions among osteoporosis therapies and outlines a strategy of intermittent bisphosphonate therapy for long-term maintenance.

Over the past few years, the effects and limitations of long-term treatment with bisphosphonates and denosumab have become apparent as have several key factors in the sequential use of anti-remodeling drugs and osteoanabolic agents. Strategies for transitions from estrogen, bisphosphonates, denosumab and the bone-forming drugs will be discussed, based on extant evidence, clinical experience and expert opinion. By appropriate selection of both the initial and subsequent drugs for the prevention and treatment of osteoporosis, therapeutic benefits can be optimized and safety issues minimized. Developing a strategy for long-term maintenance of the benefits of the initial therapies can provide a life plan for managing patients with osteoporosis.

Rebound bone loss following denosumab discontinuation is an important barrier in the effective long-term treatment of skeletal disorders. This is driven by increased osteoclastic bone resorption following the offset of RANKL inhibition, and sequential osteoclast-directed therapy has been utilized to mitigate this. However, current sequential treatment strategies intervene following the offset of RANKL inhibition and this approach fails to consistently prevent bone loss. Our previous work, using a mouse model of denosumab discontinuation, has shown that the processes that drive the rebound phenomenon occur earlier than when bone loss is detected, namely a rise and overshoot in serum tartrate-resistant acid phosphatase (TRAP). We identified that these changes in serum TRAP may provide an earlier window of opportunity to intervene with sequential therapy following RANKL inhibition withdrawal. Here, we show that early treatment with zoledronate (10 mg/kg, 3 wk following the last dose of OPG:Fc), preceding the rise and overshoot in serum TRAP, effectively mitigates rebound bone density loss through preventing the overshoot in serum TRAP. Further, we show that multiple doses of zoledronate (early treatment and during anticipated BMD loss) is superior in consolidating bone density gains made with RANKL inhibition and preventing rebound BMD loss as measured by DXA. Importantly, we demonstrate the efficacy of early and multi-dose zoledronate strategy in preventing bone loss in both growing and skeletally mature mice. MicroCT analysis showed improved trabecular bone structure in both the femur and lumbar vertebrae with zoledronate treatment compared with control. These increases in bone mass translated to increased fracture resistance in skeletally mature mice. This work provides a novel approach of early and multi-dose sequential treatment strategy following withdrawal of RANKL inhibition, contributing valuable insight into the clinical management of patients who discontinue denosumab therapy.

Upon denosumab discontinuation, an observed overshoot phenomenon in bone turnover may occur, potentially leading to a reduction in bone mineral density and the occurrence of vertebral fractures. Several theories have been proposed to explain this phenomenon, one of which is that osteoclast precursors might be accumulating during treatment. Our aim was to study the effects of denosumab on osteoclast precursors in postmenopausal women. This cross-sectional observational study included 30 postmenopausal women with osteopenia or osteoporosis, divided into 2 groups: 15 treated with denosumab (mean duration 4 years, range 6 months-9 years) and 15 treatment-naïve controls. Peripheral blood mononuclear cells were isolated from whole blood and were stained for CD14, MCSFR, CD11b, and TNFRII. Osteoclast precursors (CD14+/MCSFR+, CD14+/CD11b + OR CD14+/TNFRII+) were identified with fluorescent activated cell sorting. The proportion of osteoclasts was determined by calculating their percentage of the total cell population in each whole blood sample. To confirm the expected suppression of bone turnover in the subjects treated with denosumab, we measured serum PINP, CTX, and TRACP5b. Denosumab-treated patients exhibited a significantly higher count of CD14+/CD11b + osteoclast precursors compared with controls (median 4% vs 0.75%, p=.011). There was no correlation with the duration of treatment. Bone turnover markers were significantly lower in the group treated with denosumab than controls. Our findings indicate an increase in osteoclast precursors, which could explain the overshoot phenomenon observed after discontinuing denosumab.

Denosumab produces a continuous increase in bone mineral density over ten years, associated with a low risk of vertebral and non-vertebral fractures. Denosumab is well tolerated and easy to manage in daily clinical practice. For all these reasons, this treatment has a huge success. On the other hand, discontinuation of treatment is associated with a severe rebound effect including a sharp increase in bone turnover markers, loss of the bone density gained and a risk of nearly 20% of multiple vertebral fractures in postmenopausal women. High doses of potent bisphosphonates are needed to maintain bone turnover markers in the low range of premenopausal women, to mitigate this rebound effect. Prolonged treatment with denosumab is associated with a greater rebound effect and increases the risk of an early rebound effect. The occurrence of rare side effects such as osteonecrosis of the jaw or atypical femoral fracture, as well as the onset of severe renal failure, leave clinicians at a therapeutic impasse. Continuing denosumab or switching to bisphosphonates remains suboptimal and, currently, no evidence clarifies the optimal treatment approach for these patients. The aim of this review is to give a very practical clinical approach to the use of denosumab (duration of treatment), and to the management of rebound effect and possible adverse effects.

The purpose of this review is to describe the approach to osteoporosis management in men in the setting of limited evidence.

Although men have less fractures than women, men have greater mortality after fractures as well as increased complications, including infection and major cardiovascular events. Unfortunately, men are not routinely screened for osteoporosis, partially due to limited insurance coverage in the United States. Due to screening barriers and lack of robust evidence of fracture reduction with therapeutic agents in men, treatment rates have also been low. A 2022 network meta-analysis of osteoporosis treatment in men found that with all the randomized controlled trials performed in men, there was only sufficient power to show vertebral fracture reduction. A large case-control observational study from 2024 did find that osteoporosis treatment reduced odds of hip fracture similarly in men and women. Men have fractures, with greater morbidity and mortality than women. Although osteoporosis research is lacking in men, providers should assess fracture risk in men and allow them the opportunity to reduce their fracture risk.

Rebound vertebral fractures (VFs) after denosumab (Dmab) withdrawal have been documented, highlighting the need for further research into this phenomenon and the importance of a well-planned strategy for discontinuing Dmab.

From the TriNetX US network, we enrolled osteoporosis patients aged 50 years or older who had withdrawn from at least 2 doses of Dmab and compared them with a matched cohort who had received at least 1 dose of zoledronate (ZOL) before discontinuation. We analyzed hazard ratios (HRs) with 95% confidence intervals (CIs) and conducted Kaplan-Meier analyses, along with subgroup analyses, drug discontinuation modification, and sensitivity analyses.

After matching propensity scores (n = 10 422) between the 2 cohorts (Dmab: 11 104 and ZOL: 15 976), we found that the risks of VFs (HR = 1.479, 95% CI = 1.222-1.789) and its subcategories-thoracic (1.309, 1.023-1.674), lumbar (1.865, 1.425-2.440), and collapsed fractures (1.928, 1.462-2.542)-as well as all-cause mortality (1.588, 1.475-1.710), were significantly higher in the Dmab group compared with the ZOL group. Stratified analyses showed increased VF risks in Dmab patients who were female, aged 50-64, 65 years or older, and white, regardless of fracture history compared with those using ZOL.

After adjusting for drug discontinuation, Dmab showed an increased risk of VFs within the first 2 years, contributing to an elevated overall mortality risk. Sensitivity analyses revealed consistent results across different regions.

In patients receiving long-term treatment with denosumab, denosumab discontinuation via sequential treatment with zoledronate, resulted in a minor decrease in bone mass density (BMD) of 0-2.5% within the first year and stabile BMD in the second year, thus showing that repeated treatments with zoledronate limit the loss of BMD, when discontinuing denosumab.

Discontinuing denosumab (DMAb) rapidly decreases bone mineral density (BMD) and increases the risk of multiple vertebral fractures. We wanted to examine if the recommendation stated in the ECTS position paper on DMAb discontinuation can prevent the bone loss in a clinical setting.

We conducted a retrospective cohort study based on medical records of patients referred for DMAb discontinuation. We administered zoledronate (ZOL) 6 months after the last DMAb injection and 3, 6, 12, and 24 months thereafter if p-C-terminal collagen crosslinks (CTX) increased above 0.5 μg/l or BMD decreased (≥ 5% at the hip, ≥ 3% at the spine) at months 12 and 24.

We included 66 women and men discontinuing DMAb after a mean treatment duration of 6.7 ± 2.7 (mean ± SD) years. BMD decreased 12 months after the initial ZOL treatment by 2.5 ± 4.2% and 1.9 ± 2.5% at the LS and TH, respectively (n = 44) (p ≤ 0.001 for all). There was no significant change in FNBMD (0.0 ± 5.1) (p > 0.05). No significant change in BMD was seen from month 12 to month 24 at any site (p > 0.05 for all). Thirty percent and twenty-two percent of patients experienced flu-like symptoms after the first and second ZOL infusion. No fractures occurred during the study period.

Adhering to the recommendation in the ECTS position statement, a mean of 3 infusions of ZOL limited the bone loss 12 and 24 months after DMAb discontinuation, thereby preserving most of the BMD gained during DMAb treatment. The frequent occurrence of flu-like symptoms after ZOL proves to be a challenge, showing that routine prophylaxis against acute phase responses should be considered in patients treated with ZOL after discontinuing DMAb.

Pathological fractures under anti-osteoporotic and antirheumatic treatment are very rare events. Nevertheless, atypical femoral fractures occur during antiresorptive treatment with bisphosphonates or denosumab, the latter especially in patients previously treated with bisphosphonates. Treatment with teriparatide can be helpful. While glucocorticoids have a well-known influence on the development of osteoporosis and thus also fractures, the probably unproblematic use in the low-dose range has so far found little acceptance. Methotrexate-induced osteopathy is also a rare phenomenon but is now well accepted and known. There are several approved medications for the treatment of glucocorticoid-induced osteoporosis and for methotrexate-induced osteopathy, discontinuation of methotrexate is particularly essential.

Osteoporosis and osteoarthritis are key diseases of musculoskeletal ageing and are increasing in prevalence and burden with the progressively ageing population worldwide. These conditions are thus particularly common in 'the oldest old', and there are complexities of managing them within the context of extensive multimorbidity, physical and mental disability, and polypharmacy, the rates for all of which are high in this population. In this narrative review, we explore the epidemiology of osteoporosis and osteoarthritis in the oldest old before examining trials and real-world data relating to the pharmacological treatment of these diseases in older adults, including anti-resorptives and bone-forming agents in osteoporosis and symptomatic slow-acting drugs for osteoarthritis, paracetamol, and non-steroidal anti-inflammatory drugs in osteoarthritis, recognising that the oldest old are usually excluded from clinical trials. We then review the potential benefits of nutritional interventions and exercise therapy before highlighting the health economic benefits of interventions for osteoporosis and osteoarthritis. The high prevalence of risk factors for both disease and adverse events associated with treatment in the oldest old mean that careful attention must be paid to the potential benefits of intervention (including fracture risk reduction and improvements in osteoarthritis pain and function) versus the potential harms and adverse effects. Further direct evidence relating to such interventions is urgently needed from future research.

Romosozumab, a monoclonal antibody against sclerostin, is a newly licensed dual-acting osteoporosis treatment for patients at very high risk of fracture. Sclerostin inhibition leads to stimulation of bone formation and simultaneous inhibition of bone resorption. Only three cases of atypical femur fractures were reported out of 5,621 patients who received romosozumab in the pivotal randomised controlled trials FRAME and ARCH; however, most enrolled clinical trial patients were osteoporosis treatment-naïve or had a prolonged washout period. We report a case of an atypical femur fracture that occurred after the completion of romosozumab treatment which was followed by one dose of 5 mg intravenous zoledronic acid. The patient had previously received a 2-year course of subcutaneous teriparatide and subsequent three consecutive yearly intravenous zoledronic acid infusions, followed by a 2-year treatment break. This case highlights the risks of prolonged suppression of bone resorption, which includes romosozumab due to its dual action and the need for further research on how to minimise such deleterious medication effects. Patients who are switched from prolonged antiresorptive treatment to romosozumab, should be risk-assessed and counselled for the risk of atypical femur fracture.

Objective Although patients with neuroimmunological disorders often need to be treated with glucocorticoids and are at risk of developing glucocorticoid-induced osteoporosis, no research has focused on the treatment of glucocorticoid-induced osteoporosis in such patients. Methods We compared the efficacy of denosumab and bisphosphonates in glucocorticoid-induced osteoporosis in neuroimmunological diseases. In 57 patients with neuroimmunological disorders treated with corticosteroids (34 with neuromyelitis optica spectrum disorders, 16 with myasthenia gravis, and 7 with others), we retrospectively studied the long-term effects of denosumab (n=23) and bisphosphonates (n=34) on spine and total hip bone mineral density (BMD) measured by dual energy X-ray absorptiometry. Results There were no significant differences in the age, lumbar spine BMD, or mean dose or duration of prednisolone administration at baseline between the denosumab and bisphosphonate groups. During the follow-up period of up to 6 years, the increase in the lumbar spine and total hip BMD was greater in the denosumab group than in the bisphosphonate group (p<0.01). Insufficient bone fractures were observed in 2 (9%) of the 23 patients in the denosumab group and in 2 (6%) of the 34 patients in the bisphosphonate group (not significant). Conclusion Denosumab is more effective than bisphosphonates in increasing the BMD of patients with neuroimmunological disorders receiving glucocorticoids.

Osteoporosis is a chronic condition primarily affecting postmenopausal women, significantly impacting their well-being and quality of life. Traditional treatment approaches include medications, vitamins, and exercise, but there is a growing interest in alternative therapies that enhance bone health. This review was conducted by searching multiple databases, including PubMed, Medline, and Google Scholar, for studies related to osteoporosis treatment. Articles focusing on both traditional therapies such as bisphosphonates, calcium, and vitamin D supplementation, and newer advancements like vibration therapy and bone-building devices such as Osteoboost were included. Traditional treatments, such as vitamin supplementation, exercise, and bisphosphonates, remain foundational in osteoporosis management, helping to maintain bone density and reduce fracture risks. Recent developments, including vibration therapy and Osteoboost, show promising results in bone regeneration without the use of medication. While traditional therapies continue to play an essential role, advancements like vibration therapy present novel alternatives for managing osteoporosis. Further research is necessary to optimize these approaches, ensuring they maximize benefits while minimizing risks, ultimately improving patient outcomes and quality of life.

Romosozumab following anti-resorptive can be an effective sequential treatment strategy to improve bone strength. However, whether the transition to romosozumab after denosumab is associated with greater improvement in bone mineral density (BMD) and trabecular bone score (TBS) compared with denosumab continuation remains unclear. In this propensity score-matched cohort study, we analyzed data from postmenopausal women who initiated denosumab between 2017 and 2020. Individuals who were transited to 12 mo of romosozumab after denosumab were 1:1 matched to those who continued an additional 12 mo of denosumab (n = 86 for each group; denosumab-romosozumab [DR] and denosumab-denosumab [DD]). Mean BMD gain by denosumab treatment in matched DR and DD groups from denosumab initiation to transition (median 4 times [range 2-8]) was +4.8% and +2.0% in the lumbar spine (LS) and total hip, respectively. DR group showed greater LS BMD gain compared with the DD group (+6.8 vs +3.3% point, p<.001) for 12 mo post-transition independent of the duration of prior denosumab treatment, yielding greater overall LS BMD gain in DR compared with DD (+11.6% vs +8.0%, p<.001). DD group showed continued improvement of hip BMD, whereas hip BMD was maintained but not improved in the DR group. DR group was associated with greater TBS improvement than the DD group (2.9% vs 1.0%, p = .042). One month after the transition to romosozumab from denosumab, P1NP immediately increased above the level of denosumab initiation with relatively suppressed CTx, creating a transient anabolic window. For 12 mo follow-up, 1 incident morphometric vertebral fracture and 1 patella fracture were observed in DD, whereas 1 ankle fracture was observed in the DR group. Romosozumab following denosumab improved LS BMD and TBS greater than denosumab continuation in postmenopausal women.

Denosumab significantly increased lumbar spine and total hip bone mineral density in patients with hip fractures, with comparable efficacy to that in other than hip fracture patients. Its effect was more pronounced in medication-naïve patients, suggesting its efficacy regardless of hip fracture status.

Denosumab, a potent antiresorptive agent, has been recognised to increase bone mineral density (BMD) and reduce fracture risk in vertebrae and hips. Despite its widespread use, no sequential follow-up studies have investigated its effects on BMD in patients with hip fractures. This study aimed to analyse the effect of denosumab on BMD gain in patients with hip fractures and investigate the incidence of subsequent hip fractures.

This retrospective study analysed 371 patients treated with denosumab for at least 3 years, including 122 patients with hip fractures. 1:1 propensity score matching was used to compare BMD changes in the lumbar spine, total hip, and femoral neck, as well as additional hip fracture incidence between the hip fracture and the other than hip fracture group. Ultimately, 122 patients in each group were compared. Subgroup analysis compared osteoporosis medication-naïve patients with those with prior medication use.

The hip fracture and other than hip fracture group exhibited significant annual increases in lumbar spine and total hip BMD, with no significant differences between them after matching. The femoral neck BMD increased significantly only in the first year. The incidence of additional hip fractures did not differ significantly between the groups. Moreover, the effect of denosumab on BMD increase was more pronounced in patients without a previous medication history for anti-osteoporosis treatment than in those with such a history.

Denosumab significantly increased lumbar spine and total hip BMD in patients with hip fractures, with comparable efficacy to that in other than hip fracture patients. Its effect was more pronounced in medication-naïve patients, suggesting its efficacy regardless of hip fracture status.

Osteoporosis is a metabolic skeletal disease characterized by low bone mass and strength, and increased risk for fragility fractures. It is a major health issue in aging populations, due to fracture-associated increased disability and mortality. Antiresorptive treatments are first line choices in most of the cases.

Bone homeostasis is complicated, and multiple factors can compromise skeletal health. Bone turnover is a continuous process regulated by the coupled activities of bone cells that preserves skeletal strength and integrity. Imbalance between bone resorption and formation leads to bone loss and increased susceptibility to fractures. Antiresorptives prevent bone loss and reduce fracture risk, by targeting osteoclastogenesis and osteoclast function and survival. Their major drawback is the coupling of osteoclast and osteoblast activity, due to which any reduction in bone resorption is followed by suppression of bone formation.

During the last couple of decades significant progress has been made in understanding of the genetic and molecular basis of osteoporosis. Critical pathways and key molecules that mediate regulation of bone resorption have been identified. These factors may underpin novel therapeutic avenues for osteoporosis, but their potential for translation into clinical applications is yet to be tested.

This study compared denosumab and zoledronic acid for treating osteoporosis in drug-naïve postmenopausal Korean women. Over 3 years, both drugs significantly increased bone mineral density. However, denosumab also improved fat-free mass, suggesting it may be a better initial treatment for osteoporosis with low muscle mass, assuming all other conditions remain constant.

Denosumab (DMAB) and zoledronic acid (ZOL), which are strong antiresorptive agents, are used to treat osteoporosis in postmenopause. Nonetheless, the data on their comparative efficacy in drug-naïve patients remain limited. Our research compared the therapeutic efficacy of DMAB and ZOL in drug-naïve postmenopausal Korean women with osteoporosis.

In total, 120 women were enrolled and equally divided to the DMAB and ZOL groups. The bone density and biochemical parameters of the patients were monitored over 3 years. Furthermore, the changes in fat-free mass (FFM), which comprises muscle mass, were assessed by bioelectric impedance analysis. Baseline characteristics, including age, BMI, and the prevalence of fractures, were similar between the groups at the onset of the study. Serum 25(OH), calcium and, phosphorus levels and baseline bone mineral density (BMD) were also comparable between the groups.

Following 3 years of treatment, both groups exhibited a significant increase in BMD versus the baseline value. In particular, BMD increased by 9.7% and 5.1% at the lumber spine and total hip, respectively, in the DMAB group, versus increases of 7.1% and 4.4%, respectively, in the ZOL group. The increase in FFM was greater in the DMAB group. BMI-adjusted FFM decreased by 1.3% in the ZOL group, versus an increase of 3.6% in the DMAB group.

Conclusively, both DMAB and ZOL are effective antiresorptive agents that improved BMD over 3 years in drug-naïve individuals. Moreover, DMAB might represent a more reliable initial option for patients with osteoporosis accompanied by low muscle mass.

Rheumatoid arthritis (RA) and prolonged high-dose glucocorticoid (GC) treatment are established risk factors for osteoporosis.

In this study, we aimed to evaluate the therapeutic efficacy of denosumab according to the GC dose considered to increase the risk of glucocorticoid-induced osteoporosis (GIOP) in patients with RA.

A retrospective analysis of collected data on RA patients with osteoporosis starting denosumab.

We included 418 patients with RA who were started on denosumab therapy and categorized them into those with and without GC intake ⩾2.5 mg/day for >3 months. The T-score and areal bone mineral density (aBMD) at the lumbar spine, total hip, and femur neck, as well as serum bone turnover markers, were measured at baseline and 12 months. We performed between-group and within-group comparisons of the BMD values at baseline and at 12 months.

Denosumab significantly increased the T-scores and aBMD at the lumbar spine, total hip, and femur neck after 12 months, regardless of GC intake. However, apart from the T-score at the lumbar spine, the other parameters did not show significant between-group differences. Similarly, in patients with anti-cyclic citrullinated peptide (CCP) antibody positivity or those treated with biologic or targeted synthetic disease-modifying antirheumatic drugs (DMARDs), although there were significant increases in the T-score and areal BMD at all sites in both groups, there were no significant between-group differences.

Our findings suggest that the GC dose considered to increase the risk of GIOP did not significantly attenuate the therapeutic efficacy of denosumab in RA patients, including those positive for anti-CCP antibodies and users of biologic or targeted synthetic DMARDs.

Osteoporosis is a common comorbidity in patients with SLE, and bone loss in patients with SLE has a multifactorial aetiology. This study aimed to evaluate the therapeutic efficacy of denosumab in patients with SLE with osteoporosis and to analyse the factors influencing therapeutic efficacy.

A total of 166 patients with SLE with osteoporosis who initiated denosumab between January 2016 and December 2023 were included. Changes in the T-score and areal bone mineral density (BMD) at the lumbar spine, total hip and femur neck from denosumab initiation to 12 months were measured. Correlation analysis was performed between the degree of BMD improvement and covariates including SLE-specific factors such as SLE duration, SLE Disease Activity Index 2000 (SLEDAI-2K) score, glucocorticoid dose and hydroxychloroquine use. Multiple linear regression analysis was conducted to identify predictors of the therapeutic efficacy of denosumab.

Denosumab significantly increased BMD and decreased bone turnover markers at 12 months compared with baseline. The degree of BMD improvement revealed a significant negative correlation with SLEDAI-2K score, hydroxychloroquine use, prior osteoporosis treatment and baseline BMD values. In contrast, body mass index and c-telopeptide of collagen type 1 levels were positively correlated with the degree of BMD improvement. Higher baseline BMD values, SLEDAI-2K scores and hydroxychloroquine use were significant predictors of attenuated BMD improvement.

Our study suggests that denosumab is an effective treatment option for osteoporosis in patients with SLE. The therapeutic efficacy of denosumab can be predicted by baseline BMD values, SLEDAI-2K scores and hydroxychloroquine use.

Life quality of osteoporosis patients is affected significantly due to the severely complications of fracture and pain. RANKL, indicated as the key mediator of osteoporosis, plays a pathogenic role of osteoclasts induction. To target this program, two medications, bisphosphonate and Denosumab, were developed and achieved remarkable advantages in clinics. Unfortunately, fracture-related side-effects always emerge unavoidably, after either long-term administration of bisphosphonates or Denosumab withdrawing. To address these challenges, vaccine-based approach has been adopted to achieve sustainable protection through induction and maintenance of effective antibodies in mild level over decades.

A Denosumab binding peptide was firstly identified as the basic component of vaccine. This peptide was then fused with diphtheria toxin T domain, a widely used adjuvant protein. Its capabilities to penetrate the autologous tolerance and induce the immune responses was then demonstrated with in-silicon evaluation. Finally, the efficacy of the DR3 vaccine was assessed through immunization on the human RANKL transgenic mice model of osteoporosis.

The DTT-RANKL(220-245)3 vaccine, termed as DR3, were predicted as highly antigenic and non-allergenicity. This molecule was comprised of 46.5 % of helix, 8.5 % strand and 45.1 % coil, the optimized Z-value of the tertiary structure was 6.39, and the favored area in the Ramachandran plot was 96.1 % after refinement. Molecular docking showed a tight binding of DR3 vaccine to TLR2 (-9.2 kcal/mol) and TLR4 (-9.5 kcal/mol). In addition, the immune stimulation indicated robust responses post administration of DR3 vaccine, including high level production of of antibodies and cytokines, activated T and B lymphocytes, and the long-last immune memory. In agree with the simulation, vaccinated mice generated high titers anti-hRANKL antibodies and elevated levels of IL-4 and IL-10 at 7th week post immunization.

DR3 vaccine was aroused to benefit the prevention and treatment of osteoporosis, and other bone-resorptive diseases potentially.

Osteoporosis has been usually considered a female disease, generally causing more fracture risk and complications in adult and older women compared to older men. While vertebral fractures occur in a small proportion of men during middle age, men generally fracture about 10 years later than women, with significant increases in fracture risk after about age 75. Independent of age, men experiencing fragility fractures have a higher risk of life-threatening events compared to women, but the risk of secondary fragility fracture overlaps between men and women. Often, male osteoporosis recognizes the overlap between secondary causes and primary osteoporosis risk factors. Assessment through physical examination, history, and laboratory tests is recommended, with dual-energy X-ray absorptiometry of bone density being the preferred diagnostic test for osteoporosis in men. A treatment program should include awareness of diet and vitamin D status, fall risk reduction, and pharmaceutical therapy. Medications that are fracture-reducing in older women should also achieve fewer fractures in older men; however, there is a paucity of studies in men with the primary outcome of fracture risk reduction. Most older men with osteoporosis should be treated with oral or intravenous bisphosphonates, denosumab especially when on androgen deprivation therapy, and initial anabolic treatment should be considered for men at very high risk of fracture. This review summarizes the main features of osteoporosis and fragility fractures in men and reports findings from the available pharmacological and non-pharmacological studies conducted in men.