Osteoporosis In Clinical Practice Research Articles

Serum metabolomics analyses reveal biomarkers of osteoporosis and the mechanism of Quanduzhong capsules

With the aging of the population, the prevalence of osteoporosis (OP) is rising rapidly, making it an important public health concern. Early screening and effective treatment of OP are the primary challenges facing the management of OP today. Quanduzhong capsule (QDZ) is a single preparation composed of Eucommia ulmoides Oliv., which is included in the Pharmacopoeia of the People's Republic of China. It is used to treat OP in clinical practice, but its mechanisms are unclear. This study involved 30 patients with OP, 30 healthy controls (HC), and 28 OP patients treated with QDZ to identify potential biomarkers for the early diagnosis of OP and to investigate the potential mechanism of QDZ in treating OP. The serum samples were analyzed using targeted amino acid metabolomics. Significant differences in amino acid metabolism were identified between the OP cohort and the HC group, as well as between OP patients before and after QDZ treatment. Compared with HC, the serum levels of 14 amino acids in OP patients changed significantly. Kynurenine, arginine, citrulline, methionine, and their combinations are expected to be potential biomarkers for OP diagnosis. Notably, QDZ reversed the changes in levels of 10 amino acids in the serum of OP patients and significantly impacted numerous metabolic pathways during the treatment of OP. This study focuses on screening potential biomarkers for the early detection of OP, which offers a new insight into the mechanism study of QDZ in treating OP.

Development and validation of an eight-item calcium screener to assess daily calcium intake of patients with osteoporosis in clinical practice.

To validate a short food frequency questionnaire (screener) estimating daily average calcium intake from dietary sources to guide calcium supplementation of patients with osteoporosis in clinical practice. An eight-item calcium screener was developed based on existing literature, food consumption data and expert opinion. Convergent validity was determined by comparison with 3-day food records using mean difference, Spearman's correlation coefficients (SCC) and Bland-Altman analysis. Test-retest reliability was assessed by SCC and intraclass correlation coefficients (ICC). We calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) to identify patients requiring calcium supplementation (<1200 mg dietary calcium intake/day). Fifty-two patients filled out the eight-item calcium screener and the 3-day Food record (mean age of 66.8 ± 12.9 (SD)) and 38 patients filled out the screener twice for reliability analysis (mean age of 65.8 ± 12.8 (SD)). Dietary calcium intake between the calcium screener and food records showed a strong correlation (N = 52 patients, SCC = 0.53, p ≤ 0.001) and mean difference of 21 mg (p = 0.70). Bland-Altman analysis showed agreement within 95% confidence intervals for 49/52 comparisons (94%). Test-retest reliability of the calcium screener was excellent (SCC = 0.96, p ≤ 0.001; ICC = 0.99, p ≤ 0.001). The calcium screener shows good convergent validity, reliability and feasibility to estimate daily calcium intake of patients with osteoporosis in routine clinical practice.

Unraveling the potential mechanisms of the anti-osteoporotic effects of the Achyranthes bidentata-Dipsacus asper herb pair: a network pharmacology and experimental study.

Background: Osteoporosis is a prevalent bone metabolism disease characterized by a reduction in bone density, leading to several complications that significantly affect patients' quality of life. The Achyranthes bidentata-Dipsacus asper (AB-DA) herb pair is commonly used in Traditional Chinese Medicine (TCM) to treat osteoporosis. This study aimed to investigate the therapeutic compounds and potential mechanisms of AB-DA using network pharmacology, molecular docking, molecular dynamics simulation, and experimental verification. Methods: Identified compounds of AB-DA were collected from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), Traditional Chinese Medicine Information Database (TCM-ID), TCM@Taiwan Database, BATMAN-TCM, and relevant literature. The main bioactive ingredients were screened based on the criteria of "OB (oral bioavailability) ≥ 30, DL (drug-likeness) ≥ 0.18." Potential targets were predicted using the PharmMapper and SwissTargetPrediction websites, while disease (osteoporosis)-related targets were obtained from the GeneCards, DisGeNET, and OMIM databases. The PPI network and KEGG/GO enrichment analysis were utilized for core targets and pathway screening in the STRING and Metascape databases, respectively. A drug-compound-target-pathway-disease network was constructed using Cytoscape software to display core regulatory mechanisms. Molecular docking and dynamics simulation techniques explored the binding reliability and stability between core compounds and targets. In vitro and in vivo validation experiments were utilized to explore the anti-osteoporosis efficiency and mechanism of sitogluside. Results: A total of 31 compounds with 83 potential targets for AB-DA against osteoporosis were obtained. The PPI analysis revealed several hub targets, including AKT1, CASP3, EGFR, IGF1, MAPK1, MAPK8, and MAPK14. GO/KEGG analysis indicated that the MAPK cascade (ERK/JNK/p38) is the main pathway involved in treating osteoporosis. The D-C-T-P-T network demonstrated therapeutic compounds that mainly consisted of iridoids, steroids, and flavonoids, such as sitogluside, loganic acid, and β-ecdysterone. Molecular docking and dynamics simulation analyses confirmed strong binding affinity and stability between core compounds and targets. Additionally, the validation experiments showed preliminary evidence of antiosteoporosis effects. Conclusion: This study identified iridoids, steroids, and flavonoids as the main therapeutic compounds of AB-DA in treating osteoporosis. The underlying mechanisms may involve targeting core MAPK cascade (ERK/JNK/p38) targets, such as MAPK1, MAPK8, and MAPK14. In vivo experiments preliminarily validated the anti-osteoporosis effect of sitogluside. Further in-depth experimental studies are required to validate the therapeutic value of AB-DA for treating osteoporosis in clinical practice.

Prevalence of Low Bone Mass and Osteoporosis in Ireland: the Dual-Energy X-Ray Absorptiometry (DXA) Health Informatics Prediction (HIP) Project.

Osteoporosis is a common disease that has a significant impact on patients, healthcare systems, and society. World Health Organization (WHO) diagnostic criteria for postmenopausal women were established in 1994 to diagnose low bone mass (osteopenia) and osteoporosis using dual-energy X-ray absorptiometry (DXA)-measured bone mineral density (BMD) to help understand the epidemiology of osteoporosis, and identify those at risk for fracture. These criteria may also apply to men ≥50 years, perimenopausal women, and people of different ethnicity. The DXA Health Informatics Prediction (HIP) project is an established convenience cohort of more than 36,000 patients who had a DXA scan to explore the epidemiology of osteoporosis and its management in the Republic of Ireland where the prevalence of osteoporosis remains unknown. In this article we compare the prevalence of a DXA classification low bone mass (T-score < -1.0) and of osteoporosis (T-score ≤ -2.5) among adults aged ≥40 years without major risk factors or fractures, with one or more major risk factors, and with one or more major osteoporotic fractures. A total of 33,344 subjects met our study inclusion criteria, including 28,933 (86.8%) women; 9362 had no fractures or major risk factors, 14,932 had one or more major clinical risk factors, and 9050 had one or more major osteoporotic fractures. The prevalence of low bone mass and osteoporosis increased significantly with age overall. The prevalence of low bone mass and osteoporosis was significantly greater among men and women with major osteoporotic fractures than healthy controls or those with clinical risk factors. Applying our results to the national population census figure of 5,123,536 in 2022 we estimate between 1,039,348 and 1,240,807 men and women aged ≥50 years have low bone mass, whereas between 308,474 and 498,104 have osteoporosis. These data are important for the diagnosis of osteoporosis in clinical practice, and national policy to reduce the illness burden of osteoporosis. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Jin-Tian-Ge ameliorates ovariectomy-induced bone loss in rats and modulates osteoblastogenesis and osteoclastogenesis in vitro

BackgroundTiger bone, which had been one of the most famous traditional Chinese medicine for 2000 years, was originate from the skeleton of Panthera tigris L., and had the actions of anti-inflammatory, analgesic, immune-regulatory and promoting healing of bone fracture, and was used for the treatment of osteoporosis and rheumatoid arthritis. Jin-Tian-Ge (JTG), the artificial tiger bone powder, were prepared from skeletons of several farmed animals to substitute the natural tiger bone, and has been used for the treatment of osteoporosis in clinical practice. However, the characteristic and mechanism of action of JTG for the therapy of osteoporosis need to be further evidenced by using modern pharmacological methods. The aim of this work is to investigate the bone-protective effects of JTG, and explore the possible underlying mechanism.MethodsOvariectomy (OVX) rats were orally administrated JTG or estradiol valerate (EV) for 12 weeks. We investigated the pharmacodynamic effects of JTG on anti-bone loss in OVX rats, and also investigated the role of JTG in promoting osteogenesis and inhibiting osteoclast differentiation.ResultsJTG increased the bone mineral density (BMD), improved the bone microarchitecture and biomechanical properties in ovariectomized rast, whereas reversed the bone high turnover in OVX rats as evidenced by serum biochemical markers in OVX rats. JTG increased osteogenic differentiation of BMSCs in vitro, and up-regulated the expression of the key proteins of BMP and Wnt/β-catenin pathways. JTG also inhibited the osteoclastogenesis of BMM as evidenced by the alteration of the TRAP activity, F-actin construction and the expression of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), c-Fos, Cathepsin K (Ctsk) and matrix metallopeptidase 9 (MMP9) of OCs induced with RANKL and LPS, reduced the expression and phosphorylation of NF-κB in OCs.ConclusionsJTG prevented bone loss in OVX rats and increased osteogenic differentiation of BMSCs through regulation of the BMP and Wnt/β-catenin pathway, inhibited osteoclastogenesis by suppressing the NF-κB pathway, suggesting that JTG had the potentials for prevention and treatment of osteoporosis by modulating formation and differentiation of osteoblast and osteoclast.

Inhibiting uptake of extracellular vesicles derived from senescent bone marrow mesenchymal stem cells by muscle satellite cells attenuates sarcopenia.

ObjectiveOsteoporosis is associated with senescence of bone marrow mesenchymal stem cells (BMSCs). Extracellular vesicles derived from senescent BMSCs (BMSC-EVs) could be uptaken by muscle satellite cells (SCs). We hypothesized that inhibiting the uptake of harmful BMSC-EVs by SCs could prevent patients with osteoporosis complicated with sarcopenia.MethodsBioinformatics analysis was used to analyze senescent SCs. Myogenic potential of SCs was measured using myogenesis assay and immunofluorescence while muscle atrophy was measured using histological evaluation. And the interaction of cluster of differentiation (CD) 81 and the membrane proteins of SCs was verified using biotin pulldown assay.. CD81-specific siRNA (si-CD81) was used to knockdown CD81 and anti-CD81 antibody (anti-CD81 Ab) was used to block CD81.ResultsDifferentially expressed genes in senescent SCs were enriched in muscle cell differentiation. The myogenic potential of senescent SCs was significantly decreased. Senescent BMSC-EVs impaired myogenesis of SCs. CD81 on the surface of BMSC-EVs could bind to membrane proteins of SCs. Both knockdown of CD81 and blocking CD81 prevented the uptake of senescent BMSC-EVs by SCs, thus relieving harmful effects of senescent BMSC-EVs on muscle atrophy.ConclusionBlocking CD81 on the surface of senescent BMSC-EVs attenuates sarcopenia in aged mice, which could be useful for prevention of sarcopenia in patients with osteoporosis in clinical practice.Translational potential of this articleInhibiting uptake of extracellular vesicles derived from senescent bone marrow mesenchymal stem cells by muscle satellite cells can prevent muscle atrophy in aged mice and has potential for application in treating sarcopenia.

Sigma-1 receptor attenuates osteoclastogenesis by promoting ER-associated degradation of SERCA2.

Sigma‐1 receptor (Sigmar1) is a specific chaperone located in the mitochondria‐associated endoplasmic reticulum membrane (MAM) and plays a role in several physiological processes. However, the role of Sigmar1 in bone homeostasis remains unknown. Here, we show that mice lacking Sigmar1 exhibited severe osteoporosis in an ovariectomized model. In contrast, overexpression of Sigmar1 locally alleviated the osteoporosis phenotype. Treatment with Sigmar1 agonists impaired both human and mice osteoclast formation in vitro. Mechanistically, SERCA2 was identified to interact with Sigmar1 based on the immunoprecipitation‐mass spectrum (IP‐MS) and co‐immunoprecipitation (co‐IP) assays, and Q615 of SERCA2 was confirmed to be the critical residue for their binding. Furthermore, Sigmar1 promoted SERCA2 degradation through Hrd1/Sel1L‐dependent ER‐associated degradation (ERAD). Ubiquitination of SERCA2 at K460 and K541 was responsible for its proteasomal degradation. Consequently, inhibition of SERCA2 impeded Sigmar1 deficiency enhanced osteoclastogenesis. Moreover, we found that dimemorfan, an FDA‐approved Sigmar1 agonist, effectively rescued bone mass in various established bone‐loss models. In conclusion, Sigmar1 is a negative regulator of osteoclastogenesis, and activation of Sigmar1 by dimemorfan may be a potential treatment for osteoporosis in clinical practice.

Treatment of osteoporosis in clinical practice: first experience with the Russian generic drug of zoledronic acid

Objective: to evaluate the effect of the generic drug of zoledronic acid on bone mineral density (BMD) and markers of bone metabolism in patients with osteoporosis (OP), as well as possible long-term adverse reactions (AR) 12 months after drug administration.Patients and methods. The study included 30 postmenopausal women with OP (mean age 64±8 years) who signed an informed consent of participance in clinical observation. Patients received a single dose of generic zoledronic acid (5 mg) as a 15-minute infusion. All patients additionally took calcium and vitamin D. The dynamics of BMD and bone metabolism markers, as well as the safety and tolerability of the drug, were evaluated. Fractures that might have occurred during follow-up should have been reported as ARs.Results and discussion. During treatment with generic zoledronic acid, the increase in BMD in the lumbar region was 4.9% (p&lt;0.0001), in the femoral neck –2.7% (p&lt;0.01), and in the femur as a whole – 3.0% (p&lt;0.0001). Positive dynamics (increase in BMD&gt;2%) in the spine was detected in 26 (86.7%) patients, in the proximal femur – in 20 (66.7%) patients. There was a decrease in the intensity of pain in both the thoracic (by 62%; p=0.038) and lumbar (by 29%; p=0.022) spine. Three months after the administration of the drug, a decrease in the level of bone metabolism markers was revealed: CTX – by an average of 29.7%, and P1NP – by an average of 25.5%. ARs were post-dose reactions that occurred within the first 48 hours after drug infusion. Remote ARs, fractures of peripheral bones and vertebrae were not recorded.Conclusion. The use of the generic drug of zoledronic acid has demonstrated its positive effect on BMD and markers of bone metabolism, as well as safety.

Diagnosis and therapy of postmenopausal osteoporosis in clinical practice

Diagnosis and therapy of postmenopausal osteoporosis in clinical practice

A personalized approach to therapy for comorbid osteoporosis in clinical practice

A personalized approach to therapy for comorbid osteoporosis in clinical practice

Detecting pathological features and predicting fracture risk from dual-energy X-ray absorptiometry images using deep learning

Dual-energy X-ray absorptiometry (DXA) is the gold standard imaging method for diagnosing osteoporosis in clinical practice. The DXA images are commonly used to estimate a numerical value for bone mineral density (BMD), which decreases in osteoporosis. Low BMD is a known risk factor for osteoporotic fractures. In this study, we used deep learning to identify lumbar scoliosis and structural abnormalities that potentially affect BMD but are often neglected in lumbar spine DXA analysis. In addition, we tested the approach's ability to predict fractures using only DXA images. A dataset of 2949 images gathered by Kuopio Osteoporosis Risk Factor and Prevention Study was used to train a convolutional neural network (CNN) for classification. The model was able to classify scoliosis with an AUC of 0.96 and structural abnormalities causing unreliable BMD measurement with an AUC of 0.91. It predicted fractures occurring within 5 years from the lumbar spine DXA scan with an AUC of 0.63, meeting the predictive performance of combined BMD measurements from the lumbar spine and hip. In an independent test set of 574 clinical patients, AUC for lumbar scoliosis was 0.93 and AUC for unreliable BMD measurements was 0.94. In each classification task, neural network visualizations indicated the model's predictive strategy. We conclude that deep learning could complement the well established DXA method for osteoporosis diagnostics by analyzing incidental findings and image reliability, and improve its predictive ability in the future.

Operationalizing Treat-to-Target for Osteoporosis.

Treat-to-target (TTT) for osteoporosis is a concept for individualizing patient treatment decisions that focuses on achieving an acceptable level of fracture risk rather than response to treatment alone. While a response to treatment is essential in order to achieve an acceptable level of risk, it is not necessarily sufficient. Some patients have a good response to treatment yet remain at high level of fracture risk. Since there is no way to directly measure bone strength in patients treated for osteoporosis, a surrogate measurement must be used. Bone mineral density (BMD) is commonly used to select patients for treatment and has emerged as the most useful surrogate for assessing reduction of fracture risk after treatment is started. Recent large meta-regression studies have shown a robust correlation between larger increases in BMD with treatment and greater reductions in fracture risk. Application of TTT for osteoporosis involves assessing fracture risk before starting treatment and initiating treatment with an agent that is most likely to reduce fracture risk to an acceptable level, represented by a target BMD T-score, over a reasonable period of time. This review offers suggestions for implementing TTT for osteoporosis in clinical practice and managing patients who fail or succeed in reaching the target. More study is needed to fully validate the use of TTT for osteoporosis for initiating and modifying treatments to reduce fracture risk.

The management of patient with osteoporosis in clinical practice

Osteoporosis is a systemic skeletal disorder characterized by increased bone fragility, which is associated with an enhanced fracture risk. The first fracture often represents indeed the clinical manifestation of this condition. In the present document we provided an overview of the economic and clinical impact of a not-adequate therapeutic appropriateness and suboptimal adherence to osteoporosis therapy, that are both widely reported in literature despite osteoporotic treatments have proved their efficacy in reducing fracture risk. Adequate treatment and adherence were reported to be associated with a lower risk of re-fracture and all-cause mortality. Moreover, healthcare costs in osteoporotic patients with previous fractures were significantly lower in those receiving osteoporosis treatment rather than among untreated patients. Nevertheless, these two key-factors are not improving over time. The measurement of indicators of adherence and therapeutic appropriateness allows to analyse the utilization profile of the drugs indicated for the treatment of osteoporosis and to evaluate the presence of possible deviation between the prescriptive behaviours observed in clinical practice and the recommendations reported in the guidelines. The periodic monitoring of such indicators together with prescribing audit activity could represent a useful tool for the optimization of osteoporosis management and to achieve a correct resource allocation. (Rheumatology)

Panax Notoginseng Saponins Prevent Bone Loss by Promoting Angiogenesis in an Osteoporotic Mouse Model.

With the aging of the population and the extension of life expectancy, osteoporosis is becoming a global epidemic. Although there are several drugs used to treat osteoporosis in clinical practice, such as parathyroid hormone or bisphosphonates, they all have some serious side effects. Therefore, a safer drug is called for osteoporosis, especially for the prevention in the early stage of the disease, not only the treatment in the later stage. Panax notoginseng saponin (PNS), a traditional Chinese herb, has been used as anti-ischemic drug due to its function on improving vascular circulation. In order to verify whether Panax notoginseng saponins (PNS) could be used to prevent osteoporosis, ovariectomy (OVX) was induced in female C57BL/C6J mice, followed by orally administration with 40 mg/kg/d, 80 mg/kg/d, and 160 mg/kg/d of three different dosages of PNS for 9 weeks. Serum biochemical analysis, micro-CT, histological evaluation, and immunostaining of markers of osteogenesis and angiogenesis were performed in the sham, osteoporotic (OVX), and treatment (OVX+PNS) groups. Micro-CT and histological evaluation showed that compared to sham group, the bone mass of OVX group reduced significantly, while it was significantly restored in the moderate-dose PNS (40 mg/kg and 80 mg/kg) treatment groups. The expression of CD31 and osteocalcin (OCN) in the bone tissue of treatment group also increased, suggesting that PNS activated osteogenesis and angiogenesis, which subsequently increased the bone mass. These results confirmed the potential function of PNS on the prevention of osteoporosis. However, in the high dose of PNS (160 mg/kg) group, the antiosteoportic effect had been eliminated, which also suggested the importance of proper dose of PNS for the prevention and treatment of osteoporosis in postmenopausal women.

Back pain and spinal osteoporosis in clinical practice

Back pain is a common clinical and socioeconomic problem. Back pain is a symptom, not a nosological form. Osteoporosis is a skeletal disease in which, despite normal bone mineralization, bone loss and bone (structure) integrity is observed. The article considers the main causes of primary and secondary osteoporosis. The main modifiable and unmodifiable risk factors for osteoporosis and fractures are presented. The main pathological conditions and diseases associated with the risk of osteoporosis are described. The problem of osteoporosis of the spine as one of the causes of mechanical painful episodes in the back of elderly patients is considered in depth. Clinical features of compression vertebral fractures in osteoporosis in women after menopause are presented. The methods of conservative treatment of osteoporosis are considered. The greatest attention is paid to such effective antiosteoporotic drugs as bisphosphonates. The data on the efficacy and tolerability of alendronic acid preparations as the most studied preparation from the group of bisphosphonates are analyzed. The information on the new medicinal form of alendronic acid – sparkling soluble tablets (Binosto) is presented.

The 2018 Guidelines for the diagnosis and treatment of osteoporosis in Greece.

The purpose of this report was to update the Guidelines for the Management of Osteoporosis in Greece that was published in 2011. In line with the GRADE system, the working group initially defined the main clinical questions that should be addressed when dealing with the diagnosis and management of osteoporosis in clinical practice in Greece. Following a literature review and discussion on the experience gained from the implementation of the 2011 Guidelines transmitted through the national electronic prescription network, the Hellenic Society for the Study of Bone Metabolism (HSSBM) uploaded an initial draft for an open dialogue with the relevant registered medical societies and associations on the electronic platform of the Greek Ministry of Health. After revisions, the Central Health Council approved the final document. The 2018 Guidelines provide comprehensive recommendations on the issues of the timing of fracture risk evaluation and dual-energy X-ray absorptiometry (DXA) measurement, interpretation of the DXA results, the diagnostic work-up for osteoporosis, the timing as well as the suggested medications for osteoporosis treatment, and the follow-up methodology employed during osteoporosis treatment. These updated guidelines were designed to offer valid guidance on fracture risk assessment, diagnosis-pharmacological treatment-follow-up of osteoporosis based on updated information and national evidence from clinical practice and the healthcare setting. Clinical judgment is essential in the management of every individual patient for the purpose of achieving the optimal outcome in the safest possible way.

Mining and Functional Verification of Calcitonin Genes from the Genome Database.

With more countries in the world entering elderly society, osteoporosis is a common disease among the elderly, especially middle-aged and elderly women. Although calcitonin is an effective drug used to treat osteoporosis in clinical practice, it also exists such problems as high cost, short half-life, and high immunogenicity. Therefore, to explore more efficient calcitonin has important clinical significance. Given the emergence of new-generation gene sequencing, numerous genome sequences of marine species have been revealed. This study aimed to identify new, highly active Calcitonins (CTs) from the gene database. Candidate CT sequences were obtained by BLAST and analyzed. The evolutionary tree of these sequences was constructed using the Neighbor-Joining method of MEGA 7 software. Secondary structures were analyzed by Circular Dichroism (CD). The biological activities of CTs were estimated using the standard of the rat hypocalcemic activity assay in vivo. The half-life and immunogenicity of CT sequences were determined by ELISA. The physicochemical properties of peptides were analyzed with ProtParam and HeliQuest. A total of 64 candidate CT gene and amino acid sequences from different species were obtained by BLAST using the salmon CT (sCT) sequence as the query sequence. These sequences were clustered to 27 different CT polypeptide sequences, and then the evolutionary tree was constructed. A total of 13 sequences were selected for chemical synthesis and activity assay. Results showed that although their secondary structures were similar, four types of candidate CTs had 30% higher activities than sCT, three other types had similar activities to sCT, and the remaining four types had much lower activities than sCT. Among the three designed CTs, the activities of CT-01 and CT-02 were at least 50% higher than those of sCT. Furthermore, all three CT sequences had a similar half-life to sCT and lower immunogenicity. CTs from Monodelphis domestica, Gallus gallus, Ornithorhynchus anatinus, and Carassius auratus had high activities. The exploration and mining of the marine-life genome database can be extremely valuable considering broad application prospect.

Effects of Teriparatide in Patients with Osteoporosis in Clinical Practice: 42-Month Results During and After Discontinuation of Treatment from the European Extended Forsteo\xae Observational Study (ExFOS)

This study aimed to describe clinical outcomes in patients prescribed teriparatide and followed up for 18 months after stopping the drug in real-life conditions. The Extended Forsteo® Observational Study analysed incident clinical fractures in 6-month intervals using logistic regression with repeated measures. Changes in back pain (visual analogue scale) and health-related quality of life (HRQoL; EQ-5D questionnaire) were analysed using mixed models for repeated measures. Patients were analysed if they had a post-baseline visit, regardless of whether and for how long they took teriparatide. Of 1531 patients analysed (90.7% female, mean age: 70.3 years), 76 (5.0%) never took teriparatide. Median treatment duration was 23.6 months. The adjusted odds of clinical fracture decreased by 47% in the > 12- to 18-month treatment period (p = 0.013) compared with the first 6-month period, with no statistically significant reduction in the > 18- to 24-month interval. The clinical fracture rate remained stable during the 18 months’ post-teriparatide, when approximately 98% of patients took osteoporosis medication (51% bisphosphonates). Clinical vertebral fractures were reduced at every time period compared with the first 6 months. Adjusted mean back pain scores decreased and EQ-5D scores increased significantly at each post-baseline observation. In a real-life clinical setting, the risk of clinical fractures declined during 24 months of teriparatide treatment. This reduction was maintained 18 months after stopping teriparatide. In parallel, patients reported significant improvements in back pain and HRQoL. The results should be interpreted in the context of the non-controlled design of this observational study.

Experience in using Prolia in patients with postmenopausal osteoporosis in clinical practice

To evaluate the efficiency and safety of long-term Prolia therapy in patients with postmenopausal osteoporosis (OP). The open prospective study enrolled 98 women (mean age, 68±9 years; mean menopause duration, 17±4 years) with postmenopausal OP, who were followed up in an outpatient setting at the National Medical Research Center for Preventive Medicine and who had been treated with denosumab 60 mg subcutaneously every 6 months for 12 months or more. The maximum follow-up period was 4 years: 48, 29, 11, and 10 patients were treated for 12, 24, 36, and 48 months, respectively. The patients were allocated into 2 groups: those who received and those who had not previously received antiosteoporotic therapy. Bone mineral density (BMD) was measured using dual-energy X-ray densitometry of the lumbar spine (LI-LIV) and proximal femur (PF). The ten-year probability of major osteoporotic fractures was estimated once in 72 patients not previously receiving antiosteoporotic therapy before the prescription of denosumab. In the patients not previously receiving therapy, the median 10-year probability of major fractures using the FRAX algorithm was 14.9%; that of femoral neck (FN) fractures was 3.7%. During denosumab treatment, the BMD increase in the lumbar spine was 4.2% at 12 months, 7.5% at 24 months, was 8.8% at 36 months; that in FN was 3.1, 3.9, and 5.3%, that in PF was 2.8, 4.1, and 5%; and that in the 1/3 forearm was 0.9, 1.4, and 2.6%, respectively (p < 0.001). In the persons receiving and not previously receiving the therapy, the BMD increase was similar, i.e. there was an additional positive effect when switching to denosumab. The decrease in the serum concentration of C-terminal telopeptide of type I collagen (CTX-I) was 54% at 6 months after initiation of denosumab therapy (p < 0.001) and 72% at 12 months (p<0.001); and the achieved marker level remained unchanged at 48 months. Transition from the OP zone to osteopenia one was noted in 23 patients with low BMD (T-score -2.5 SD) in LI-LII and in 12 patients with that in FN at 12 months of denosumab therapy and this was in 25 patients at 24 months. Nine-eight patients receiving the first Prolia injection refused to continue treatment on their own; adverse events were not the reason for drug discontinuation. Therapy with denosumab was effective in increasing BMD in routine outpatient practice and in allowing 25% of patients to achieve target values of this indicator. The marked decrease in the level of the bone resorption marker STX suggested that the drug had antiresorptive potency. The frequency of adverse reactions was low, confirming the good tolerability and safety profile of the drug. The convenience of the scheme and route of drug administration contributed to strict compliance with the doctor's recommendations. Denosumab was effective in increasing BMD not only in untreated patients, but also in those who had previously received antiosteoporotic therapy. The pharmacokinetic characteristics of denosumab, which contribute to its uniform distribution in trabecular and cortical bone tissue, regardless of active bone remodeling, and the fact that the clearance of the drug is independent of kidney function offer an advantage of administering the drug to patients with significant loss of FN and radius BMD and of reducing kidney function.

Glucocorticoid receptor and Histone deacetylase 6 mediate the differential effect of dexamethasone during osteogenesis of mesenchymal stromal cells (MSCs).

Lineage commitment and differentiation of mesenchymal stromal cells (MSCs) into osteoblasts in vitro is enhanced by a potent synthetic form of glucocorticoid (GC), dexamethasone (Dex). Paradoxically, when used chronically in patients, GCs exert negative effects on bone, a phenomenon known as glucocorticoid-induced osteoporosis in clinical practice. The mechanism on how GC differentially affects bone precursor cells to become mature osteoblasts during osteogenesis remains elusive. In this study, the dose and temporal regulation of Dex on MSC differentiation into osteoblasts were investigated. We found that continuous Dex treatment led to a net reduction of the maturation potential of differentiating osteoblasts. This phenomenon correlated with a decrease in glucocorticoid receptor (GR) expression, hastened degradation, and impaired sub cellular localization. Similarly, Histone Deacetylase 6 (HDAC6) expression was found to be regulated by Dex, co-localized with GR and this GR-HDAC6 complex occupied the promoter region of the osteoblast late marker osteocalcin (OCN). Combinatorial inhibition of HDAC6 and GR enhanced OCN expression. Together, the cross-talk between the Dex effector molecule GR and the inhibitory molecule HDAC6 provided mechanistic explanation of the bimodal effect of Dex during osteogenic differentiation of MSCs. These findings may provide new directions of research to combat glucocorticoid-induced osteoporosis.