Osteoporosis management-current and future perspectives - A systemic review.

Introduction: Osteoporosis is a geriatric metabolic ailment distinguished by low bone mineral density (BMD) and strength with enhanced micro-architectural retrogression of the extracellular matrix, further increasing bone fragility risk. Osteoporotic fractures and associated complications become common in women and men after 55 and 65 years, respectively. The loss in BMD markedly enhances the risk of fracture, non-skeletal injury, and subsequent pain, adversely affecting the quality of life. Methods: Data summarised in this review were sourced and summarised, including contributions from 2008 to 2023, online from scientific search engines, based on scientific inclusion and exclusion criteria. Results: Biochemical serum markers such as BALP, collagen, osteocalcin, and cathepsin-K levels can reveal the osteoporotic status. DEXA scan techniques evaluate the whole body's BMD and bone mineral content (BMC), crucial in osteoporosis management. Anabolic and anti-osteoporotic agents are commonly used to enhance bone formation, minimize bone resorption, and regulate remodelling. The challenges and side effects of drug therapy can be overcome by combining the various drug moieties. Conclusion: The current review discusses the management protocol for osteoporosis, ranging from lifestyle modification, including physical exercise, pharmaceutical approaches, drug delivery applications, and advanced therapeutic possibilities of AI and machine learning techniques to reduce osteoporosis complications and fracture risk.

Australian clinicians' perceptions of patients with very high risk of fracture.

BACKGROUND: International osteoporosis guidelines have recommended treatment approaches based on fracture risk stratification, in particular, anabolic therapy for patients with very high risk (VHR) of fragility fracture. AIM: To summarise Australian clinicians' perceptions of patients at VHR of fracture. METHODS: Australian clinicians invited to educational webinars on anabolic treatments for osteoporosis were surveyed in March and April 2021 about a typical patient they had most recently seen and identified as at VHR of fracture. RESULTS: Of the 268 clinician attendees who were invited to complete the post-webinar surveys, 67 (25%) responded and permitted the publication of aggregated data. A typical patient perceived to have a VHR of fracture was a woman in her 80's, living at home, who had been diagnosed with osteoporosis between 5 and 10 years ago, and received treatment for 1-5 years' duration, most commonly denosumab. The patient frequently had a T-score below -3.0 SD (standard deviation), multiple fragility fractures and most commonly suffered a vertebral fracture in the past 12 months, whereas on an adequate regimen of osteoporosis medication. There was a mismatch between the patient being eligible for anabolic therapy (64.2%) and actually having been prescribed an anabolic treatment in the past (20.9%). CONCLUSIONS: Australian clinicians' perceptions of patients with a VHR of fracture and the use of anabolic agents appear to be heavily influenced by local reimbursement criteria. The mismatch between patients deemed eligible for reimbursed anabolic therapy and those prescribed an anabolic agent suggests treatment inertia.

Using sequential pharmacotherapy for the treatment of osteoporosis: an update of the literature.

INTRODUCTION: Osteoporosis, which is characterized by compromised bone density and heightened susceptibility to fractures, is a substantial public health concern, especially among the aging population. Underdiagnosis, undertreatment, and therapy non-adherence contribute to its impact. Anabolic and dual-action agents like teriparatide, abaloparatide, and romosozumab have emerged as effective treatments, allowing rapid gains in bone mineral density (BMD) and reducing fracture risk. However, administering treatments in the correct order is paramount, with an 'anabolic first' approach gaining traction for patients at high risk of fractures. This strategy involves starting anabolic therapies, followed by antiresorptive agents as maintenance therapy. It is important to note that the effectiveness of anabolic agents differs between treatment-naive and previously treated patients: tailored treatment approaches are therefore necessary. This comprehensive strategy adheres to clinical guidelines, emphasizing individualized care, early intervention, and patient-centered management to mitigate the burden of osteoporosis and enhance patients' quality of life. AREA COVERED: The aim of this review is to summarize recent evidence on the sequential treatment of osteoporosis and to provide recommendations on the best treatment strategies. EXPERT OPINION: Effective treatments, such as anabolic agents, are key in high-risk patients, who require an 'anabolic first' approach. Sequential therapy, specifically tailored to a patient's history, can help to optimize prevention and management of fractures.

Application of Escherichia coli-Derived Recombinant Human Bone Morphogenic Protein-2 to Unstable Spinal Fractures.

(1) Background: Recently, Escherichia coli-derived recombinant human bone morphogenetic protein-2 (E. coli-derived rhBMP-2) has been increasingly applied to different types of spinal surgeries and reported to achieve successful fusion. This pilot study aimed to evaluate the clinical efficacy and safety of rhBMP-2 in patients undergoing posterior instrumented fusions for unstable spinal fractures. (2) Methods: This study included ten consecutive patients undergoing spinal surgery using E. coli-derived rhBMP-2 with more than one year of follow-up. Radiologic outcomes were compared, including the average fracture healing period, local kyphosis correction, and clinical outcomes between preoperative and the last follow-up. (3) Results: The average time of radiographic union was 99.9 ± 45.4 (62-192) days, with an average use of 5.2 ± 3.9 months of anabolic agents. Radiologic parameters such as anterior vertebral height and vertebral wedge angle were significantly corrected postoperatively and at the last follow-up. Clinical outcomes other than leg pain were significantly improved after the surgery. In addition, four patients with preoperative neurologic deficits showed improved neurologic status. (4) Conclusions: Combined with the anabolic agents, applying E. coli-derived rhBMP-2 to the fractured vertebral body could be an effective surgical treatment for unstable spinal fractures. Further trials are needed to validate this result.

Osteoporosis: Spotlight on current approaches to pharmacological treatment.

Despite the availability of safe and effective anti-osteoporosis treatments, osteoporosis continues to be undertreated. The increase in fragility fractures, which is the main clinical consequence of osteoporosis, is a major problem for healthcare systems of countries. A broad range of drugs including antiresorptive and anabolic agents are used in the pharmacological treatment of osteoporosis. Fracture risk assessment in drug selection is of utmost importance in terms of guiding treatment. The recommended thresholds for osteoporosis treatment decision making are based on major osteoporotic and hip fracture probabilities from the Fracture Risk Assessment Tool (FRAX®). Currently, antiresorptive agents are usually the first choice to increase bone mineral density (BMD) and reduce the fracture risk. Bisphosphonates and antiresorptive drugs such as denosumab, a nuclear factor kappa-B ligand (RANKL) inhibitor, are the most widely used drugs in the treatment of osteoporosis. Bisphosphonates alone are unlikely to provide long-term protection against fracture and restore BMD in patients with severe osteoporosis and high fracture risk. In such patients, treatment with an anabolic agent such as teriparatide, abaloparatide, or romosozumab should be ideally initiated to achieve maximal gain in bone mass and preserve the microarchitecture. Ideally, an antiresorptive drug should be continued to maintain gain in bone mass.

[Osteoporosis: treatment of high-risk patients]. / Osteoporose: Behandlung von Hochrisikopatient*innen.

Nowadays, different drugs are available for specific treatment of osteoporosis. On the one hand, antiresorptives (raloxifene, bisphosphonates, denosumab) and, on the other hand, bone anabolic drugs (teriparatide and romosozumab) can be used. For both bone anabolic agents, superiority over oral bisphosphonates in high-risk patients was shown in randomized comparative studies. High-risk patients represent a subgroup of osteoporosis patients requiring treatment with a particularly high fracture risk. The very high risk can be recognized by the clinical manifestation (hip or vertebral fracture), the very low T­score and/or the clinical risk factors (exceeding the bone anabolic threshold of the DVO risk calculator). High-risk patients should be treated with bone anabolic drugs in the first line of treatment. Patients treated with antiresorptives, who develop a very high risk in the course of the disease should be escalated to bone anabolic compounds. Every bone anabolic treatment requires an antiresorptive follow-up treatment. Drug holidays are only possible in exceptional cases for high-risk patients.

Performance assessment of an equine metabolomics model for screening a range of anabolic agents.

INTRODUCTION: Despite their ban, Anabolic Androgenic Steroids (AAS) are considered as the most important threat for equine doping purposes. In the context of controlling such practices in horse racing, metabolomics has emerged as a promising alternative strategy to study the effect of a substance on metabolism and to discover new relevant biomarkers of effect. Based on the monitoring of 4 metabolomics derived candidate biomarkers in urine, a prediction model to screen for testosterone esters abuse was previously developed. The present work focuses on assessing the robustness of the associated method and define its scope of application. MATERIALS AND METHODS: Several hundred urine samples were selected from 14 different horses of ethically approved administration studies involving various doping agents' (AAS, SARMS, ß-agonists, SAID, NSAID) (328 urine samples). In addition, 553 urine samples from untreated horses of doping control population were included in the study. Samples were characterized with the previously described LC-HRMS/MS method, with the objective of assessing both its biological and analytical robustness. RESULTS: The study concluded that the measurement of the 4 biomarkers involved in the model was fit for purpose. Further, the classification model confirmed its effectiveness in screening for testosterone esters use; and it demonstrated its ability to screen for the misuse of other anabolic agents, allowing the development of a global screening tool dedicated to this class of substances. Finally, the results were compared to a direct screening method targeting anabolic agents demonstrating complementary performances of traditional and omics approaches in the screening of anabolic agents in horses.

Effects of new anti-doping measures on sports performance in elite female athletes.

Studies examining the effects of new anti-doping measures on sports performance in elite athletes are scarce. During the last decade, a number of new anti-doping methods for the detection of anabolic androgenic steroids were developed. We hypothesized that the implementation of these methods may cause a decrease of performance in athletic disciplines where given substances are widely used. For this purpose, the performance results for 10 athletic disciplines from country (Country A), which was widely accused of systematic doping use, were gathered and pooled into the 2012-2015 and 2016-2019 periods. These periods were seen as before and following the implementation periods, where the effects of new anti-doping methods could be manifested. Also, the performance results of their rival athletes from Country B were analyzed for comparison. The incidence of anti-doping rule violations for both countries was followed. The analysis revealed a decrease in performance results of Country A athletes in eight of 10 disciplines. The performance results of Country B's athletes in seven of 10 disciplines did not and in three disciplines did demonstrate statistically significant change. The decrease in performance of Country A athletes followed a high incidence of steroid detection cases by means of new anti-doping methods. It is highly likely that the consequent performance decrease is due to the implementation of new anti-doping methods. The results of the study bring new facts on the effects of new anti-doping methods implementation and demonstrate following decrease in performance results in population of athletes from the country widely accused of doping use.

Extensive expertise in endocrinology: advances in the management of glucocorticoid-induced osteoporosis.

Osteoporosis is a common consequence of long-term oral glucocorticoid therapy and the resulting fractures cause significant morbidity. Bone loss occurs rapidly after initiation of glucocorticoid therapy; the accompanying increase in risk of fracture is dose-dependent and occurs within a few months of starting therapy. The adverse effects of glucocorticoids on bone are mediated by inhibition of bone formation accompanied by an early but transient increase in bone resorption, due both to direct and indirect effects on bone remodelling. Fracture risk assessment should be performed as soon as possible after long-term glucocorticoid therapy (≥3 months) is initiated. FRAX can be adjusted for the dose of prednisolone but does not currently take fracture site, recency, or number into account and therefore may underestimate fracture risk, particularly in individuals with morphometric vertebral fractures. Vertebral fracture assessment should therefore be regarded as a routine part of fracture risk estimation in individuals receiving long-term glucocorticoid therapy. Bone protective therapy should be started promptly in individuals at high-risk, together with calcium and vitamin D supplements. Bisphosphonates are generally regarded as first-line options on the grounds of their low cost, but anabolic therapy should be considered as an alternative first-line option in very high-risk individuals.

Determination of oxprenolol, methandienone and testosterone in meat samples by UHPLC-Q-ToF.

The presence of some drugs in meat samples can cause threat to human health, therefore, its analysis is highly desirable for food safety purposes. In this work, a solid-phase extraction procedure for the determination of oxprenolol, a non-selective beta-blocker, and such anabolic agents as methandienone and testosterone in beef meat samples has been developed. Extraction conditions were optimized to achieve high sensitivity and accuracy of the results. The procedure was validated using meat samples free from target analytes. As a result, high selectivity and sensitivity were observed with the detection limits between 0.25 and 1.25 ng/g, and the results were not affected by matrix components. The proposed procedure was applied to the analysis of real beef samples purchased in the market, and the results have revealed the presence of contaminated samples. The concentration of oxprenolol in the contaminated sample was 7 ng/g, methandienone content in the sample was 30 ng/g, while testosterone level was 4 ng/g.

Resumen ejecutivo de las guías de práctica clínica en la osteoporosis posmenopáusica, glucocorticoidea y del varón (actualización 2022). Sociedad Española de Investigación Ósea y del Metabolismo Mineral (SEIOMM) / Executive summary clinical practice guideline of postmenopausal, glucocortcioid-induced and male osteoporosis (2022 update). Spanish Society for Bone and Mineral Metabolism Investigation (SEIOMM)

Esta versión actualizada de las guías de osteoporosis de la Sociedad Española de Investigación en Osteoporosis y Metabolismo Mineral (SEIOMM) incorpora la información más relevante publicada en los últimos 7años, desde las guías de 2015, con estudios de imagen, como la valoración de la fractura vertebral y el análisis del índice trabecular óseo. Además, los avances terapéuticos incluyen los nuevos fármacos anabólicos, los estudios comparativos de la eficacia de los fármacos y la terapia secuencial y combinada. Por ello se actualizan también las recomendaciones de los tratamientos (AU)

This updated version of the Spanish Society for Research in Osteoporosis and Mineral Metabolism (SEIOMM) osteoporosis guides incorporate the most relevant information published in the last 7years, since the 2015 guides, with imaging studies, such as vertebral fracture assessment and bone trabecular score analysis. In addition, therapeutic advances include new anabolic agents, comparative studies of drug efficacy, and sequential and combined therapy. Therefore, therapeutic algorithms are also updated (AU)

Executive summary clinical practice guideline of postmenopausal, glucocortcioid-induced and male osteoporosis (2022 update). Spanish Society for Bone and Mineral Metabolism Investigation (SEIOMM).

This updated version of the Spanish Society for Research in Osteoporosis and Mineral Metabolism (SEIOMM) osteoporosis guides incorporate the most relevant information published in the last 7 years, since the 2015 guides, with imaging studies, such as vertebral fracture assessment and bone trabecular score analysis. In addition, therapeutic advances include new anabolic agents, comparative studies of drug efficacy, and sequential and combined therapy. Therefore, therapeutic algorithms are also updated.

Prevalence of Prohibited Substance Use and Methods by Female Athletes: Evidence of Gender-Related Differences.

To achieve optimal sports performances, women and men may show specific doping practices because of the physiological and psychological gender differences, but there are few data on this topic. Here, we report the apparent use of prohibited substances and methods by female athletes based on analyses of the doping tests collected by the French Anti-Doping Agency from 2013 to 2019. We compared the frequency of use and the ergogenic and side effects to those of their male counterparts. The results revealed lower use of prohibited substances in female vs. male athletes, with significantly fewer anabolic agents, hormone and metabolic modulators, and cannabinoids. Gender specificity in utilization of substance classes was also shown. Relatively lower use of hormone modulators and cannabinoids and higher use of beta-2 agonists, diuretics and glucocorticoids were found in the woman cohort compared with men cohort, combined with the different choice of substances, possibly because of the altered ergogenic and/or side effects. However, no impact due to gender regarding the sports disciplines was observed, with both women and men showing similar use of anabolic agents, mainly in the anaerobic sports, and EPO and corticoids, mainly in endurance or mixed sports. Further studies are needed to put these French data into a global perspective, comparing uses across countries and exploring possible new developments in the fight against doping in women.

Medical treatment of osteoporosis.

Osteoporosis is a common chronic condition that markedly increases the risk of fractures. Osteoporotic-related fractures increase morbidity and mortality and impair quality of life. Therefore, a correct approach for fracture prevention seems mandatory. Lifestyle changes should be recommended to all patients, including weight reduction if patients are obese/overweight, increasing physical activity and avoiding alcohol consumption and smoking. Additionally, calcium and vitamin D3 should be prescribed until the vitamin D deficit is resolved. Osteoporosis treatment options mainly include antiresorptives (i.e. estrogens, selective estrogen receptor modulators, bisphosphonates, denosumab) and anabolic agents (i.e. teriparatide, abaloparatide, romosozumab). Although presenting differences in efficacy and side effects, they have all been shown to increase bone mineral density (BMD) and to reduce osteoporotic-related fractures. Monotherapy with antiresorptive agents, particularly oral bisphosphonates, should be considered routinely as the first option for treatment of postmenopausal women. However, in the case of side effects, therapeutic failure or the need for long-term use, anabolic agents may be considered. In high-risk patients, anabolic agents may be considered as an initial therapeutic option. The combination of antiresorptive and anabolic agents may be useful to increase BMD compared with monotherapy, but more information is warranted to determine the effects on fracture risk.

Differences in Nervous Autonomic Control in Response to a Single Session of Exercise in Bodybuilders Using Anabolic Androgenic Steroids.

Considering the role of autonomic nerve activity in blood pressure control, this study aimed to investigate the cardiac autonomic nerve responses after an aerobic exercise session in Anabolic Androgenic Steroids (AAS) users. Twenty men (AAS, n = 9; control group, n = 11) performed an aerobic exercise session (60 min, 70 to 80% of HRmax). Heart rate variability (HRV) was assessed before and during a 60-min post-exercise recovery period. RMSSD (root mean square successive difference of the RR intervals) and the LF/HF ratio (low frequency/high frequency spectra) were also evaluated. The Student's t-test for independent samples was used to compare differences between initial group characteristics. Repeated measures ANOVA was used to compare pre- and post-exercise HRV recovery (p < 0.05). AAS had a lower SDNN (standard deviation of the intervals) (40.8 ± 16.8 vs. 71.6 ± 24.7 ms; p = 0.04, d = 1.4) and a higher LF/HF (3.4 ± 2.1 vs. 1.8 ± 0.9%; p = 0.03, d = 0.9) before exercise. AAS and controls had similar RMSSD (14.0 ± 15.8 vs. 18.9 ± 12.1 ms; p = 0.20) and a LF/HF (2.8 ± 1.6 vs. 2.4 ± 1.2 ms; p = 0.41) immediately post-exercise. The between-groups comparison revealed a higher HF/LF at 30 min (4.3 ± 1.4 vs. 2.5 ± 1.3%; p = 0.008, d = 1.3) and 60 min (5.0 ± 2.2 vs. 2.3 ± 0.8%; p = 0.001, d = 1.6) for the AAS group in the recovery time. This study demonstrated impaired parasympathetic activity at rest and immediately after the exercise session as an adverse effect of AAS usage, but similar behavior regarding the restoration of sympathetic activity.

Discovery of 3-amino-4-{(3S)-3-[(2-ethoxyethoxy)methyl]piperidin-1-yl}thieno[2,3-b]pyridine-2-carboxamide (DS96432529): A potent and orally active bone anabolic agent.

The continuing investigation of SAR of 3-aminothieno[2,3-b]pyridine-2-carboxamide derivatives has been described. In this study, C4-piperidine derivatives with polar functional groups were synthesized to develop orally available bone anabolic agents. The optimized compound 9o (DS96432529), which exhibited the best PK profile and high in vitro activity, showed the highest in vivo efficacy in this series. Moreover, significant synergistic effects were observed following co-administration of DS96432529 and alendronate or parathyroid hormone. The mechanism of action is most likely mediated through CDK8 inhibition.

Bilateral Nipple Enlargement as a Secondary Effect of Anabolic Drugs: A Histopathological Mimicker of Smooth Muscle Hamartoma.

Smooth muscle hamartoma are usually solitary and congenital, may affect the genital area and nipples. Histopathologically, they are characterized by the presence of mature smooth muscle bundles. We present a 40 year-old male with bilateral nipple enlargement excised with clinical suspicion of bilateral leiomyoma. Skin biopsy shows mature, irregularly arranged smooth muscle bundles and lactiferous ducts between them. Immunohistochemistry is positive for smooth muscle actin, desmin and fumarase, but negative for estrogen and progestogen receptors. The presence of lactiferous ducts excludes bilateral leiomyomas. Even when, histopathologically, this can be interpreted as the nipple-type of muscular hamartoma of the breast, clinical history favors an anabolic drug-induced lesion. Bodybuilders present gynecomastia and nipple enlargement as frequent problems, but we have not found any histopathological description of these nipple lesions. We consider that dermatologists should be aware of the presence of them and dermatopathologists should know their histopathological features to avoid misdiagnosis as neoplasms.

New Avenues for Treatment and Prevention of Drug-Induced Steatosis and Steatohepatitis: Much More Than Antioxidants.

Drug-induced lipid accumulation in the liver may induce two clinically relevant conditions, drug-induced steatosis (DIS) and drug-induced steatohepatitis (DISH). The list of drugs that may cause DIS or DISH is long and heterogeneous and includes therapeutically relevant molecules that cannot be easily replaced by less hepatotoxic medicines, therefore making specific strategies necessary for DIS/DISH prevention or treatment. For years, the only available tools to achieve these goals have been antioxidant drugs and free radical scavengers, which counteract drug-induced mitochondrial dysfunction but, unfortunately, have only limited efficacy. In the present review we illustrate how in vitro preclinical research unraveled new key players in the pathogenesis of specific forms of DISH, and how, in a few cases, proof of concept of the beneficial effects of their pharmacological modulation has been obtained in vivo in animal models of this condition. The key issue emerging from these studies is that, in selected cases, liver toxicity depends on mechanisms unrelated to those responsible for the desired, primary pharmacological effects of the toxic drug and, therefore, specific strategies can be designed to overcome steatogenicity without making the drug ineffective. In particular, the hepatotoxic drug could be given in combination with a second molecule intended to selectively antagonize its liver toxicity whilst, ideally, potentiating its desired pharmacological activity. Although most of the evidence that we discuss is from in vitro or animal models and will need to be further explored and validated in humans, it highlights new avenues to be pursued in order to improve the safety of steatogenic drugs.

Colestasis inducida por anabólicos: reporte de caso y revisión de la literatura / Anabolic-induced cholestasis: case report and literature review

La función metabólica y de excreción está determinada principalmente por la actividad hepática, esto predispone al hígado a lesión inducida por toxicidad, en donde la disfunción es mediada directa o indirectamente por xenobióticos y/o sus metabolitos. La enfermedad hepática inducida por fármacos (DILI) es una condición poco frecuente, que se relaciona hasta con el 50% de las insuficiencias hepáticas agudas, y de ahí su importancia. La lesión directa puede estar dirigida a hepatocitos, conductos biliares y estructuras vasculares; no obstante, diferentes xenobióticos pueden interferir con el flujo de bilis mediante el bloqueo directo de proteínas de trasporte en los canalículos. Actualmente no existen marcadores absolutos para el diagnóstico de esta entidad y las manifestaciones clínicas pueden ser variables, desde el espectro de alteraciones bioquímicas en ausencia de síntomas, hasta insuficiencia hepática aguda y daño hepático crónico, por lo cual es principalmente un diagnóstico de exclusión basado en evidencia circunstancial. A partir de esta inferencia, se han desarrollado escalas y algoritmos para evaluar la probabilidad de lesión hepática inducida por medicamentos, tóxicos, herbales o suplementos. En la mayoría de los casos, es característico que la condición del paciente mejore cuando se elimina el fármaco responsable del daño. Aunque el patrón colestásico generalmente tiene mejores tasas de supervivencia en comparación con otros patrones, también se asocia con un alto riesgo de desarrollar enfermedad hepática crónica o ser el desencadenante de manifestaciones inmunológicas en el hígado. Se presenta el caso clínico de un paciente con patrón colestásico de DILI por uso de esteroides anabólicos.

Metabolic and excretory function is determined mainly by liver activity which can make this organ susceptible to toxic injury, where dysfunction is directly or indirectly mediated by xenobiotics and/ or their metabolites. Drug-induced liver disease (DILI) is a rare condition, which is associated with up to 50% of acute liver failure, and hence its importance. Direct injury can be directed to hepatocytes, bile ducts, and vascular structures, however, different xenobiotics can interfere with bile flow by directly blocking transport proteins in the canaliculi. Currently there are no definite markers for the diagnosis of this condition, and clinical manifestations can be variable, including biochemical changes in the absence of symptoms to acute liver failure and chronic liver damage, which makes it mainly an exclusion diagnosis based on clinical evidence. Scales and algorithms have been developed to assess the probability of drug, toxic, herbal, or supplement-induced liver injury. In most cases, the patient's condition typically improves when the drug responsible for the injury is removed. Although the cholestatic pattern generally has better survival rates compared to other patterns, it is also associated with a high risk of developing chronic liver disease or acting as a trigger for immune disorders in the liver. The clinical case of a patient with a cholestatic pattern of DILI due to the use of anabolic steroids is presented.