Drugs For Treatment Of Osteoporosis Research Articles

Protocol for a mixed methods process evaluation for a randomised controlled trial to improve shared decision-making about, and uptake of, osteoporosis medicines: the iFraP study

Background High quality shared decision-making (SDM) conversations involve people with or at risk of osteoporosis and clinicians working together to decide, where appropriate, which evidence-based medicines best fit the person’s life, beliefs, and values. The improving uptake of Fracture Prevention drug treatments (iFraP) intervention comprises a computerised Decision Support Tool (DST), clinician training package and information resources, designed for use in UK Fracture Liaison Service (FLS) consultations. The iFraP intervention will be tested in a pragmatic, parallel-group, individual randomised controlled trial in patients referred to four FLSs in England. This mixed methods process evaluation aims to assess which components of iFraP were delivered and how (fidelity), whether iFraP results in a change in osteoporosis drug treatment initiation rates and how, and how context affects implementation of iFraP and outcomes. Methods We will collect quantitative data using (1) Case Report Forms completed by FLS clinicians; (2) self-reported questionnaires completed by patient participants; and (3) DST analytic data. We will collect qualitative data using (1) semi-structured interviews with patients who receive the iFraP intervention in their FLS appointment, FLS clinicians delivering iFraP appointments, and primary care clinicians that have consulted with a patient following their iFraP FLS appointment; and (2) FLS consultation recordings. A triangulation protocol will be used to integrate the quantitative and qualitative findings to generate novel insights about the intervention under evaluation. Discussion The process evaluation, alongside the trial, will help to understand what elements of the iFraP intervention were delivered and how, the mechanisms of impact and how context affected implementation and outcomes, and intervention acceptability. Mixed methods interpretation will lead to further insights about the implementation of SDM and DSTs in-practice. Trial registration ISRCTN: 10606407, 21/11/2022 https://doi.org/10.1186/ISRCTN10606407

Osteoporosis treatment: current drugs and future developments.

Osteoporosis is a common systemic metabolic disease characterized by a decrease in bone density and bone mass, destruction of bone tissue microstructure, and increased bone fragility leading to fracture susceptibility. Pharmacological treatment of osteoporosis is the focus of current research, and anti-osteoporosis drugs usually play a role in inhibiting bone resorption, promoting bone formation, and having a dual role. However, most of the drugs have the disadvantages of single target and high toxic and side effects. There are many types of traditional Chinese medicines (TCM), from a wide range of sources and mostly plants. Herbal plants have unique advantages in regulating the relationship between osteoporosis and the immune system, acupuncture therapy has significant therapeutic effects in combination with medicine for osteoporosis. The target cells and specific molecular mechanisms of TCM in preventing and treating osteoporosis have not been fully elucidated. At present, there is a lack of comprehensive understanding of the pathological mechanism of the disease. Therefore, a better understanding of the pathological signaling pathways and key molecules involved in the pathogenesis of osteoporosis is crucial for the design of therapeutic targets and drug development. In this paper, we review the development and current status of anti-osteoporosis drugs currently in clinical application and under development to provide relevant basis and reference for drug prevention and treatment of osteoporosis, with the aim of promoting pharmacological research and new drug development.

A pH and near-infrared light dual-responsive drug delivery system based on TiO2 nanotube arrays modified with polydopamine and Fe3+

This paper reports a novel drug delivery system based on TiO2 nanotube arrays (TNTs) modified with polydopamine (PDA) and Fe3+, which can load and release alendronate (NaAL), a drug for osteoporosis treatment, in a pH-responsive and near-infrared light-triggered manner. The samples were characterized by electron scanning microscopy(SEM/EDS), Fourier Transform infrared spectroscopy(FTIR), X-ray diffraction(XRD), X-ray Photoelectron Spectroscopy(XPS) and Thermogravimetry(TG). The drug release behavior of the samples was investigated under different pH and light conditions. The results showed that the TNTs-PDA-Fe3+ had improved drug loading capacity compared with the TNTs and TNTs-PDA. The drug release was pH-responsive and near-infrared light-triggered, the drug release from the sample with a pH of 4.6 was much greater than the pH of 11 and 7.4, and the photothermal conversion effificiency of TNTs-PDA-Fe3+-NaAL was 32.9 %. The drug release mechanism was attributed to the coordination bond between Fe3+ and NaAL, and the photothermal effect of the PDA. The cytotoxicity and biocompatibility of the samples were evaluated by MTT assay using mouse embryonic osteoblasts cells. The results indicated that the samples had no obvious cytotoxicity and could promote the cell proliferation and differentiation. The paper concludes that the TNTs-PDA-Fe3+-NaAL system is a potential implantable drug delivery platform for bone-related diseases.

The Current Status of Sequential Therapy with Commonly Used Anti-Osteoporosis Drugs

As the trend of population aging intensifies, the incidence of osteoporosis is rising correspondingly. Osteoporotic fractures are one of the primary causes of disability and death in elderly patients, placing a great burden on both families and society in terms of medical care resources. The monotherapy of osteoporosis drugs has certain limitations and sequential drug treatment should be considered under the following circumstances: (i) when bone resorption inhibitors fail to work, have been used for too long, or cause adverse reactions; (ii) when the recommended treatment course of bone formation promoters (such as parathyroid hormone analogues) has ended but the patient's fracture risk remains high and requires continued treatment; (iii) when short-acting drugs such as teriparatide or denosumab need to maintain treatment effects after discontinuation. The sequential therapy of osteoporosis drugs can be categorized according to the mechanism of action into the following schemes: (i) bone formation promoters followed by bone resorption inhibitors; (ii) bone resorption inhibitors followed by bone formation promoters; (iii) different types of bone resorption inhibitors used sequentially; (iv) other sequential drug treatments. Osteoporosis is a progressive disease, and the ageing of the human population cannot be reversed. Therefore, single-drug treatment is unlikely to achieve the goal of long-term disease prevention and control, making the exploration of long-term treatment plans for existing drugs a key aspect of osteoporosis drug treatment.

DeepmdQCT: A multitask network with domain invariant features and comprehensive attention mechanism for quantitative computer tomography diagnosis of osteoporosis

In the medical field, the application of machine learning technology in the automatic diagnosis and monitoring of osteoporosis often faces challenges related to domain adaptation in drug therapy research. The existing neural networks used for the diagnosis of osteoporosis may experience a decrease in model performance when applied to new data domains due to changes in radiation dose and equipment. To address this issue, in this study, we propose a new method for multi domain diagnostic and quantitative computed tomography (QCT) images, called DeepmdQCT. This method adopts a domain invariant feature strategy and integrates a comprehensive attention mechanism to guide the fusion of global and local features, effectively improving the diagnostic performance of multi domain CT images. We conducted experimental evaluations on a self-created OQCT dataset, and the results showed that for dose domain images, the average accuracy reached 91%, while for device domain images, the accuracy reached 90.5%. our method successfully estimated bone density values, with a fit of 0.95 to the gold standard. Our method not only achieved high accuracy in CT images in the dose and equipment fields, but also successfully estimated key bone density values, which is crucial for evaluating the effectiveness of osteoporosis drug treatment. In addition, we validated the effectiveness of our architecture in feature extraction using three publicly available datasets. We also encourage the application of the DeepmdQCT method to a wider range of medical image analysis fields to improve the performance of multi-domain images.

Melatonin induces RAW264.7 cell apoptosis via the BMAL1/ROS/MAPK-p38 pathway to improve postmenopausal osteoporosis.

Currently, the effect of drug treatment for osteoporosis is relatively poor, and the side effects are numerous and serious. Melatonin is a potential drug to improve bone mass in postmenopausal women. Unfortunately, the mechanism by which melatonin improves bone metabolism remains unclear. The aim of this study was to further investigate the potential mechanism of melatonin in the treatment of osteoporosis. The effects of melatonin on mitochondrial apoptosis protein, bmal1 gene, and related pathway proteins of RAW264.7 (mouse mononuclear macrophage leukaemia cells) were analyzed by western blot. Cell Counting Kit-8 was used to evaluate the effect of melatonin on cell viability. Flow cytometry was used to evaluate the effect of melatonin on the apoptosis of RAW264.7 cells and mitochondrial membrane potential. A reactive oxygen species (ROS) detection kit was used to evaluate the level of ROS in osteoclast precursors. We used bmal1-small interfering RNAs (siRNAs) to downregulate the Bmal1 gene. We established a postmenopausal mouse model and verified the effect of melatonin on the bone mass of postmenopausal osteoporosis in mice via micro-CT. Bmal1 lentiviral activation particles were used to establish an in vitro model of overexpression of the bmal1 gene. Melatonin promoted apoptosis of RAW264.7 cells and increased the expression of BMAL1 to inhibit the activation of ROS and phosphorylation of mitogen-activated protein kinase (MAPK)-p38. Silencing the bmal1 gene weakened the above effects of melatonin. After that, we used dehydrocorydaline (DHC) to enhance the activation of MAPK-p38, and the effects of melatonin on reducing ROS levels and promoting apoptosis of RAW264.7 cells were also blocked. Then, we constructed a mouse model of postmenopausal osteoporosis and administered melatonin. The results showed that melatonin improves bone loss in ovariectomized mice. Finally, we established a model of overexpression of the bmal1 gene, and these results suggest that the bmal1 gene can regulate ROS activity and change the level of the MAPK-p38 signalling pathway. Our study confirmed that melatonin promotes the apoptosis of RAW264.7 cells through BMAL1/ROS/MAPK-p38, and revealed the therapeutic effect and mechanism of melatonin in postmenopausal osteoporosis. This finding enriches BMAL1 as a potential target for the treatment of osteoporosis and the pathogenesis of postmenopausal osteoporosis.

Pharmacological Interventions for Glucocorticoid-Induced Osteoporosis: An Umbrella Review.

There is still a lack of high-quality evidence-based studies on the efficacy of drug treatment for glucocorticoid-induced osteoporosis (GIOP). The purpose of this umbrella review is to comprehensively evaluate the existing evidence to determine the efficacy and safety of pharmacological interventions for GIOP. We searched PubMed, Embase, and the Cochrane Library for systematic reviews and/or meta-analyses (SRs) of randomized controlled trials (RCTs) aimed at evaluating drug therapy for GIOP. Both the methodological quality and the strength of recommendation of the endpoints included in the SRs were evaluated by using the AMSTAR-2 tool and GRADE system, respectively. Six SRs involving 7225 GIOP patients in 59 RCTs were included in this umbrella review. The results of the methodological quality evaluation showed that 2 high-quality, 2 low-quality and 2 critically low-quality SRs were included. The GRADE evaluation results showed that the quality of evidence and the strength of recommendation of 46 outcome indicators were evaluated in the umbrella review; there were 3 with high-level evidence, 20 with moderate-level evidence, 15 with low-level evidence, and 8 with very low-level evidence. Moderate- to high-level evidence suggests that teriparatide, bisphosphonates, and denosumab can improve the bone mineral density in patients with GIOP. The findings of this umbrella review can enable patients and clinical healthcare professionals to choose the best drug prescription.

Evaluation of bone density and hand grip strength in the course of drug treatment for osteoporosis : Areal-world study.

The aim of this clinical investigation was to assess the physical performance in osteoporotic patients undergoing drug treatment (DT) for years by measuring hand grip strength (HGS) and bone mineral density (BMD). Afurther aim was to detect the time until the occurrence of vertebral fractures (VF) and influencing factors. The investigation comprised 346 persons (276women, 70men) aged on average 66.9 ± 10.7years with confirmed osteoporosis (OP). Over amean period of 1384 ± 727days, OP was assessed every 2 years, including abone densitometry by dual X‑ray absorptiometry and HGS measurement. In subgroups OP patients were analyzed with and without abone density (BMD) increase, and with and without VFs. Under DT, calcium and vitaminD substitution, the median T‑score improved in the entire group from -3.2 to -3.1 standard deviations (SD; p = 0.002). HGS was reduced (median) from 26 kg to 24 kg (p < 0.001). The median interval until the occurrence of VF was 2652days (95% confidence interval [CI] 1825.2-3478.8days) and 1461days (95% CI 1246.5-1675.5, p < 0.001) in those with and without aBMD increase, respectively. Guideline-based DT improves bone density and causes alonger interval without VF. The HGS falls independent of BMD. The association between bone and muscle in patients with adeterioration of the musculoskeletal system is known as osteosarcopenia. Early muscle exercises would be meaningful in this setting.

P083 How are beliefs about osteoporosis medicines elicited and addressed in clinical consultations: a video observational study

Abstract Background/Aims In shared decision-making conversations, patients with or at risk of osteoporosis and their clinicians collaborate to decide which drug treatments fit best for each person. The Perceptions and Practicalities Approach (PAPA) specifies three core considerations of drug uptake and commitment: 1) patient’s perceived personal need for treatment (necessity beliefs). 2) patient concerns about the potential adverse consequences of drugs (e.g. side effects). 3) practical difficulties (e.g. limitations in capacity and resources). This study aims to explore how discussions about perceptions and practicalities of osteoporosis drug treatment arise and evolve in the context of clinical consultations about osteoporosis. Methods Secondary analysis of 38 video-recorded primary care consultations from a Mayo Clinic trial evaluating the Osteoporosis Choice Decision Aid. Video-recorded consultations included ‘usual care’ (n = 24) and decision aid (n = 14). Patient participants were aged 50 and over with osteopenia or osteoporosis not already receiving drug treatment. A quantitative coding scheme, informed by the PAPA, was developed to extract: i) how clinicians framed the ‘problem’ of osteoporosis, including: bone density results, fracture risk, physical impact, social impact, or psychological impact of fracture. ii) whether clinicians asked about the patients’ views of osteoporosis, patients own bone health, and the necessity, concerns, or practical issues associated with osteoporosis drugs. iii) whether clinicians personalised discussions about osteoporosis drugs to patients perceived: importance or need, side effects or harms, or practical issues. Two independent study team members dual extracted data, with a third member resolving discrepancies. Extracted data was summarised using descriptive statistics. Results Commonly, clinicians framed osteoporosis using the patient’s bone density results (n = 38,100%) and fracture risk (n = 30,79%). In contrast, few clinicians acknowledged the potential physical impacts of fracture (n = 5,13%), with no clinicians discussing the possible psychological or social impacts. Clinicians asked 24 questions to elicit patient views in 16 of the 38 encounters (42%, range 0-4 questions per consult). The 24 questions concerned patient views about osteoporosis (n = 1,4%), their bone health (n = 5,21%), or the necessity (n = 1,4%), concerns (n = 2,8%), or practical issues associated with osteoporosis drugs (n = 2,8%). Importantly, 14 consultations (37%) contained no questions to elicit patient views. Across the 38 consultations, clinicians personalised information about the patient’s need for osteoporosis drugs in 15 consultations (39%), with less personalisation about the side effects/harms (n = 10,26%), or practical issues (n = 6,16%) associated with osteoporosis drugs. Conclusion Clinical consultations rarely considered key personal determinants of osteoporosis drug uptake and commitment. Even when clinicians used an osteoporosis decision aid, few discussions specifically elicited or addressed patients’ personal treatment necessity beliefs, concerns and practical difficulties. Additionally, clinicians seldom acknowledged the potential physical and psychosocial impacts of osteoporosis. The findings demonstrate the need for multicomponent interventions, incorporating the PAPA-based approach, to facilitate shared decision-making that takes account of patient perceptions and practicalities. Disclosure A.W. Hawarden: Grants/research support; AH is funded by a Versus Arthritis Clinical Doctoral Fellowship (grant reference 227260). L. Bullock: None. M. León-García: Grants/research support; ML-G had financial support from the Spanish Health Institute Carlos III (ISCIII) co-funded by the European Regional Development Fund (Grant number: F18/00014).. S.A. Hartasanchez: None. I. Hargraves: None. R. Horne: None. A. Maraboto: None. M. Kunneman: Grants/research support; MK had financial support from the Dutch Research Council (NWO) and The Netherlands Organisation for Health Research and Development (ZonMw) (#016.196.138). C. Jinks: Grants/research support; CJ is part funded by NIHR Applied Research Collaboration (ARC) West Midlands. Z. Paskins: Grants/research support; ZP is funded by the National Institute for Health Research (NIHR) [Clinician Scientist Award (CS-2018-18-ST2-010)/NIHR Academy].

Evaluation of the efficacy and safety of romosozumab (evenity) for the treatment of osteoporotic vertebral compression fracture in postmenopausal women: A systematic review and meta-analysis of randomized controlled trials (CDM-J).

Osteoporotic vertebral compression fracture (OVCF) is a common fragile fracture resulting from osteoporosis. We compared the efficacy and safety of romosozumab and commonly used osteoporosis drug treatments for the treatment of OVCF in postmenopausal women. Through searching and screening five databases, we included randomized controlled trials (RCTs) published through June 18, 2021 comparing different treatments. Following the Preferred Reporting Items for Systematic Reviews statement, the main objective was to evaluate the mean difference and risk ratio of the treatment effect. The primary measures of romosozumab efficacy used in this study were vertebral, non-vertebral, and clinical fracture events, and secondary outcomes were bone mineral density (BMD) changes at the lumbar spine, total hip, and femoral neck and the incidence of adverse events (AEs), RESULTS: Nine RCTs including 12 796 participants were included in the analysis, and romosozumab was compared with placebo, alendronate, and teriparatide in the treatment of osteoporosis in postmenopausal women. The incidence of fractures, low BMD, and AEs was analyzed. Compared with the controls, three doses of romosozumab were linked to evident advantages in the treatment of low BMD and fractures but associated with increased hypersensitivity and injection site reaction risks. Furthermore, fewer AEs were observed in the romosozumab arms (210 mg: risk ratio=0.96, 95% confidence interval=0.93-0.99; 140 mg: risk ratio=0.28, 95% confidence interval=0.08-0.98) than in the alendronate and placebo arms. Our meta-analysis revealed the evident advantages of romosozumab in the treatment of osteoporosis and low BMD in postmenopausal women and increased risks of hypersensitivity and injection site reactions.

Input function and modeling for determining bone metabolic flux using [18 F] sodium fluoride PET imaging: A step-by-step guide.

Studies of skeletal metabolism using measurements of bone metabolic flux (Ki ) obtained with [18 F] sodium fluoride ([18 F]NaF) positron emission tomography (PET) scans have been used in clinical research for the last 30 years. The technique has proven useful as an imaging biomarker in trials of novel drug treatments for osteoporosis and investigating other metabolic bone diseases, including chronic kidney disease mineral and bone disorder. It has also been shown to be valuable in metastatic bone disease in breast cancer patients and may have potential in other cancer types, such as prostate cancer, to assess early bone fracture risk. However, these studies have usually required a 60-min dynamic PET scan and measurement of the arterial input function (AIF), making them difficult to translate into the clinic for diagnostic purposes. We have previously proposed a simplified method that estimates the Ki value at an imaging site from a short (4-min) static scan and venous blood samples. A key advantage of this method is that, by acquiring a series of static scans, values of Ki can be quickly measured at multiple sites using a single injection of the tracer. To date, the widespread use of [18 F]NaF PET has been limited by the need to measure the AIF required for the mathematical modeling of tracer kinetics to derive Ki and other kinetic parameters. In this report, we review different methods of measuring the AIF, including direct arterial sampling, the use of a semi-population input function (SP-AIF), and image-derived input function, the latter two requiring only two or three venous blood samples obtained between 30 and 60min after injection. We provide an SP-AIF model and a spreadsheet for calculating Ki values using the static scan method that others can use to study bone metabolism in metabolic and metastatic bone diseases without requiring invasive arterial blood sampling. The method shortens scan times, simplifies procedures, and reduces the cost of multicenter trials without losing accuracy or precision.

Using network pharmacology and molecular docking verification to explore the mechanism of ursolic acid in the treatment of osteoporosis.

Whether ursolic acid is an effective drug in treatment of osteoporosis (OP) and how it exhibit activity effect on OP is unclear. To investigated the potential molecular mechanism of ursolic acid in the treatment of OP and figured out its possible mechanism is necessary. The target genes of ursolic acid were screened by using the database of traditional chinese medicine systems pharmacology, PubMed database and UniProt database. OP-related target genes were searched by GeneCards database, and utilized online mapping tool to obtain common target genes of component-disease. String database was used to construct a protein-protein interaction (PPI) network of component-disease common target genes and perform topological analysis to screen core target genes. DAVID database was performed gene ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for component-disease shared target genes. Using the core target protein as the receptor and ursolic acid as the ligand, the molecular docking was performed using AutoDockVina 1.1.2 software. A total of 52 ursolic acid-related target genes and 4657 OP-related target genes were excavated, with a total of collective 43 target genes. The above-mentioned PPI network with shared target genes contains 43 nodes and 510 edges, with an average node degree value of 23.32. A total of 24 core target genes were obtained, mainly including tumor protein p53 (TP53), vascular endothelial growth factor A (VEGFA), interleukin-6 (IL6), tumor necrosis factor (TNF), caspase3 (CASP3), matrix metallo protein (MMP9), transcription factor AP-1 (JUN), activator of transcription 3 (STAT3), mitogen-activated protein kinase 8 (MAPK8), and prostaglandin endoperoxidase 2 (PTGS2), respectively. According to KEGG enrichment analysis, there are 126 treatment of OP signaling pathway were enriched. GO enrichment analysis revealed that 313 biological processes were identified. The molecular docking result showed that the binding energies were all lower than -5 kcal/mol, indicating strong binding activity to the protein by the 6 core target gene. The therapeutic effect of ursolic acid on OP may be achieved by regulating TP53, JUN, IL6, VEGFA, CASP3, and MAPK8 genes, respectively. It exhibits possible biological function in the treatment of OP mainly involve positive regulation of apoptotic process, response to drug, incytoplasm, cytosol, protein binding, identical protein binding. Its mechanism may related to multiple therapeutic targets and signaling pathways such as cancer pathway, hepatitis B, and TNF signaling pathway.

Hypocalcemia Is a Common Risk Factor for Osteoporosis in Taiwanese Patients with Cushing's Syndrome.

Background: Osteoporosis is a cardinal manifestation of Cushing’s syndrome. There is a lack of relevant research on risk factors for osteoporosis among patients with Cushing’s syndrome (CS) in Taiwan. Thus, this study was designed to explore the possible risk factors of osteoporosis. Methods: We gathered patients with a diagnosis of CS between 2001 and 2017 in the Chang Gung Research Database (CGRD). We extracted data including diagnoses and biochemistry from hospital records. The diagnosis of CS was based on ICD-9-CM codes (255.0). Osteoporosis was defined by a T value equal to or less than −2.5 in BMD examination and hypocalcemia was defined as serum calcium concentrations < 8.0 mg/dL. Results: A total of 356 patients with CS who made regular visits to the outpatient department were enrolled in this study. The mean age was 68.6 years, and 74.9% of the patients were female. Of them, 207 patients (58.1%) were diagnosed with osteoporosis. Multivariable logistic regression models indicated that serum calcium level was negatively associated with osteoporosis (OR 0.70, CI 0.54−0.91, p < 0.001) after adjustment for age, sex, and other confounding risk factors. In addition, hypocalcemia was associated with heart failure (HF) (OR 2.14, CI 1.02−4.47, p < 0.05), stroke (OR 2.58, CI 1.21−5.46, p < 0.05) and osteoporosis (OR 3.04, CI 1.24−7.41, p < 0.05) in multivariate analysis. Conclusions: Our study found that lower serum calcium levels were common among patients with CS and osteoporosis. Furthermore, CS patients with HF or stroke had high proportion of hypocalcemia. Therefore, these patients must pay more attention to adequate calcium supplementation and undergo the appropriate osteoporosis drug treatment to reduce the risk of subsequent fracture and disability.

Effects and mechanisms of natural alkaloids for prevention and treatment of osteoporosis.

Natural alkaloids are polycyclic, nitrogen-containing, and basic compounds obtained from plants. In this review, the advances in bioactive alkaloids with respect to their chemical structures, herbal sources, and effects for the prevention and treatment of osteoporosis are discussed. Anti-osteoporosis alkaloids are classified into six categories based on the chemical structure, namely, isoquinoline alkaloids, quinolizidine alkaloids, piperidine alkaloids, indole alkaloids, pyrrolizidine alkaloids and steroidal alkaloids. They promote mesenchymal stem cells differentiation, improve osteoblast proliferation, stimulate osteoblast autophagy and suppress osteoclast formation. These natural alkaloids can regulate multiple signaling pathways, including interrupting the tumor necrosis factor receptor associated factor 6- receptor activator of nuclear factor kappa B interaction, inhibiting the nuclear factor kappa B pathway in osteoclasts, activating the p38 mitogen-activated protein kinases pathway in osteoblasts, and triggering the wingless and int-1 pathway in mesenchymal stem cells. This review provides evidence and support for novel drug and clinical treatment of osteoporosis using natural alkaloids.

Characteristics Associated With 5-Year Fracture Risk Versus 5-Year Mortality Risk Among Late-Life Men.

Identifying late-life men who might benefit from treatment to prevent fracture is challenging given high mortality. Our objective was to evaluate risks of clinical fracture, hip fracture, and mortality prior to fracture among men aged at least 80 years. Study participants included 3 145 community-dwelling men (mean [standard deviation] age 83 [2.8] years) from the Osteoporotic Fractures in Men (MrOS) Study. We used separate multivariable Fine-Gray competing risk models with prespecified risk factors (age, hip bone mineral density [BMD], recent fracture [<5 years], fall history [previous year], and multimorbidity [# conditions]) to estimate subdistribution hazard ratios and absolute 5-year risks of any clinical fracture and mortality prior to clinical fracture. Secondary analysis considered a hip fracture. There were 414 incident clinical fractures and 595 deaths without prior fracture within 5 years. BMD, fall history, and recent fracture were strong predictors of clinical fracture. Age and multimorbidity were strong predictors of mortality before fracture. After accounting for competing risks, age, BMD, and fall history were each associated with both risks of hip fracture and mortality before hip fracture. Model discrimination varied from 0.65 (mortality before fracture) to 0.79 (hip fracture). Estimated mortality differed substantially among men with similar clinical fracture risk due to a modest correlation between fracture risk and competing mortality risk = 0.37. In late-life men, strong risk factors for clinical fracture and hip fracture include fall history, BMD, and recent fracture. Osteoporosis drug treatment decisions may be further enhanced by consideration of fracture risk versus overall life expectancy.

Trends in osteoporosis diagnosis and management in Australia

SummaryTrends in bone mineral density monitoring, and drug treatment for osteoporosis, in Australia were examined. Rates of DEXA scanning have increased in response to changes to government policy affecting reimbursement. The drug denosumab is being utilised at an increasing rate, while bisphosphonate use has declined. Osteoporosis prevalence remained stable over the same timeframe, while rate of hip fractures declined, suggesting that introduction of osteoporosis screening was associated with a reduction in adverse osteoporosis outcomes, but may also have been associated with overutilisation.IntroductionRadiology interventions to diagnose and medications to manage osteoporosis in Australia are reimbursed under the Medicare benefits schedule (MBS) and Pharmaceutical Benefits Scheme (PBS). Monitoring of these databases enables changes in utilisation of these practices to be monitored over time. MethodsThis study examined rates of utilisation for bone mineral density (BMD) measurement and osteoporosis pharmacotherapy subsidised under the MBS. Rates of osteoporosis and hip fracture were estimated using data reported by the Australian Bureau of Statistics (ABS) and Australian Institute for Health and Welfare (AIHW). ResultsRates of BMD measurement increased since the technology was first reimbursed, with changes to policy regarding reimbursement for screening for individuals over 70 leading to an increase in BMD measurement after 2007. Prescribing rates also increased over time, initially with the introduction of oral bisphosphonates and subsequently for denosumab, which has subsequently become the most commonly prescribed agent for osteoporosis management in Australia, while bisphosphonate use has declined. Osteoporosis prevalence in Australia has remained relatively static at 3–4% of the population since 2001 to 2017, while rates of minimal trauma hip fracture hospitalisations have declined from 195 per 100,000 to 174 per 100,000 in the same timeframe. ConclusionAvailable data indicates that osteoporosis screening rates changed over time from 2001 to 2018 and that changes to government policy had a significant effect on the rates at which screening was performed. Over the same timeframe, there was a sustained reduction in hip fracture hospitalisation rates, with no change to reported osteoporosis prevalence. This suggests that policy changes permitting unlimited access to BMD measurement were associated with a reduction in osteoporotic fractures, but may also have been associated with overutilisation. Prospective studies to assess the efficacy of specific policies to ensure screening is performed in accordance with best-practice guidelines may be desirable.

Medication-related osteonecrosis of the jaw after tooth extraction in patients receiving pharmaceutical treatment for osteoporosis: A retrospective cohort study

Background/purposeBone resorption inhibitors, such as bisphosphonates (BPs) and anti-receptor activator of nuclear factor kappa B ligand antibodies (denosumab; Dmab), are used to treat osteoporosis and effectively reduce the risk of fracture. However, medication-related osteonecrosis of the jaw (MRONJ) has been reported as a rare adverse effect. Invasive tooth extraction procedures are reportedly a factor in the development of MRONJ. In this study, we aimed to retrospectively observe and clinically examine the effect of medication status on MRONJ development after tooth extraction in patients receiving drug treatment for osteoporosis. Materials and methodsThis study was conducted among patients who visited our hospital between December 2015 and December 2021. We collected and analyzed the medical information of patients who underwent dental extractions while using osteoporosis medications, including oral and injectable BPs and Dmab. ResultsAmong antiresorptive medication users, 40 patients (70 teeth) underwent extraction. The mean duration of BP/Dmab use was 40.4 months, and the mean duration of drug holiday was 6.9 months. MRONJ after tooth extraction was not seen in BP users, but we observed two cases in Dmab users. A significant difference in MRONJ development was confirmed with the use of injectable compared with oral medication administration (odds ratio＝5.01). ConclusionThe use of injectable bone resorption inhibitors was associated with a higher risk of developing MRONJ. The route of administration, duration of medication, and withdrawal period should be carefully considered to prevent MRONJ after tooth extraction.

Metformin Promotes Differentiation and Attenuates H2O2-Induced Oxidative Damage of Osteoblasts via the PI3K/AKT/Nrf2/HO-1 Pathway.

At present, the drug treatment of osteoporosis is mostly focused on inhibiting osteoclastogenesis, which has relatively poor effects. Metformin is a drug that can potentially promote osteogenic differentiation and improve bone mass in postmenopausal women. We aimed to detect the molecular mechanism underlying the osteogenic effect of metformin. Our study indicated that metformin obviously increased the Alkaline phosphatase activity and expression of osteogenic marker genes at the mRNA and protein levels. The PI3K/AKT signaling pathway was revealed to play an essential role in the metformin-induced osteogenic process, as shown by RNA sequencing. We added LY294002 to inhibit the PI3K/AKT pathway, and the results indicated that the osteogenic effect of metformin was also blocked. Additionally, the sequencing data also indicated oxidation-reduction reaction was involved in the osteogenic process of osteoblasts. We used H2O2 to mimic the oxidative damage of osteoblasts, but metformin could attenuate it. Antioxidative Nrf2/HO-1 pathway, regarded as the downstream of PI3K/AKT pathway, was modulated by metformin in the protective process. We also revealed that metformin could improve bone mass and oxidative level of OVX mice. In conclusion, our study revealed that metformin promoted osteogenic differentiation and H2O2-induced oxidative damage of osteoblasts via the PI3K/AKT/Nrf2/HO-1 pathway.

Qualitative focus group interview study of communication between patients, dentists and physicians for efficient osteonecrosis of the jaw practices

ObjectivesTo investigate problems and the current status of existing methods of communication between patients, dentists and physicians for the prevention and treatment of medication-related osteonecrosis of the jaw (MRONJ).DesignA focus...

A-769662 stimulates the differentiation of bone marrow-derived mesenchymal stem cells into osteoblasts via AMP-activated protein kinase-dependent mechanism.

AMP-activated protein kinase (AMPK) signaling shows an important role in energy metabolism and has recently been involved in osteogenic and adipogenic differentiation. In this study we aimed to investigate the role of AMPK activator, A-769662, in regulating the differentiation of mesenchymal stem cells derived from bone marrow (BMSCs) into osteoblastic and adipocytic cell lineage. The effect of A-769662 on osteogenesis was assessed by quantitative alkaline phosphatase (ALP) activity, matrix mineralization stained with Alizarin red, and gene expression analysis by quantitative polymerase chain reaction (qPCR). Adipogenesis was determined by Oil Red O staining for fat droplets and qPCR analysis of adipogenic markers. A-769662 activated the phosphorylation of AMPKα1 during the osteogenesis of mBMSCs as revealed by western blot analysis. A-769662 promoted the early stage of the commitment of mouse (m) BMSCs differentiation into osteoblasts, while inhibiting their differentiation into adipocytes in a dose-dependent manner. The effects of A-769662 on stimulating osteogenesis and inhibiting adipogenesis of mBMSCs were significantly eliminated in the presence of either AMPKα1 siRNA or Compound C, an inhibitor of AMPK pathway. In conclusion, we identified A-769662 as a new compound that promotes the commitment of BMSCs into osteoblasts versus adipocytes via AMPK-dependent mechanism. Thus our data show A-769662 as a potential osteo-anabolic drug for treatment of osteoporosis.