Jul 2026· Beni-Suef University Journal of Basic and Applied Sciences· Vol 15· 0 citations· 121 references
TL;DR
Combined and sequential therapies represent promising approaches for improving the management of PMO by maximizing therapeutic efficacy while minimizing adverse effects and the potential roles of genomics, bone metabolism biomarkers, and artificial intelligence in supporting personalized treatment strategies are discussed.
Abstract
Postmenopausal osteoporosis (PMO) is a systemic skeletal disorder caused primarily by estrogen deficiency, leading to impaired bone remodeling, progressive loss of trabecular bone, disruption of bone microarchitecture, increased bone marrow adiposity, and a substantially elevated risk of fragility fractures. As population aging accelerates worldwide, optimizing therapeutic strategies that effectively improve bone strength while ensuring long-term safety and cost-effectiveness has become an important clinical priority. This review summarizes recent advances in combination and sequential therapies for PMO, with a particular focus on their mechanisms of action, clinical efficacy, safety profiles, and practical applications. Current treatment strategies aim to restore the balance between bone formation and bone resorption through the complementary use of anabolic and antiresorptive agents. Emerging evidence indicates that combination therapies, such as receptor activator of nuclear factor-κB ligand inhibitors with platelet-derived growth factor-BB activators, and sequential regimens, including teriparatide followed by denosumab, can improve bone mineral density, reduce fracture risk, and modulate the osteogenic–adipogenic differentiation balance of mesenchymal stem cells. This review also compares the clinical outcomes, economic considerations, and safety concerns associated with different therapeutic approaches, including medication-related osteonecrosis of the jaw and vascular calcification. In addition, the potential roles of genomics, bone metabolism biomarkers, and artificial intelligence in supporting personalized treatment strategies are discussed. Overall, combination and sequential therapies represent promising approaches for improving the management of PMO by maximizing therapeutic efficacy while minimizing adverse effects. Continued clinical research and the integration of precision medicine are expected to further refine individualized treatment strategies and improve long-term patient outcomes.
Recent advances in molecular diagnostics, including bone turnover biomarkers, genomics, epigenomics, transcriptomics, proteomics, metabolomics, and liquid biopsy approaches, are transforming the laboratory follow-up of postmenopausal osteoporosis.
Erhan Oktay· Jana Nexus: Journal of Healt...· 0 citations
A practical clinical framework is proposed that integrates endocrine phenotype, vertebral imaging, trabecular bone score, and biochemical assessment into fracture-risk stratification and therapeutic decision-making, enabling improved identification of high- and very-high-risk patients and facilitating the appropriate use of anabolic and antiresorptive therapies.
I. Cincione, Robert A. Marcantonio, Marcellino Monda et al.· Frontiers in Endocrinology· 0 citations
Osteoporosis is a systemic skeletal disorder characterized by reduced bone mass, deterioration of bone microarchitecture, and increased susceptibility to fragility fractures. Although conventional antiresorptive and anabolic drugs effectively reduce fracture risk in many patients, their clinical utility is restricted by poor tissue specificity, systemic adverse effects, adherence problems, discontinuation-related risks, and their limited capacity to regenerate osteoporotic bone defects after trauma or surgery. Biomaterial-based strategies provide complementary opportunities by combining local structural support, controlled therapeutic delivery, and microenvironmental regulation. In this review, we discuss biomaterial design from an osteoporosis-specific perspective, emphasizing how disease-associated abnormalities—impaired osteoblast function, excessive osteoclast activity, reduced angiogenesis, inflammatory dysregulation, compromised extracellular matrix quality, and weakened mechanical integrity—can be addressed by scaffolds, targeted drug delivery systems, and biologically derived platforms. Ceramic, polymeric, and composite scaffolds are compared with respect to osteoconduction, ion-mediated signaling, mechanical support, and manufacturability. Bone-targeted nanoparticles, injectable hydrogels, and stimuli-responsive carriers are evaluated as strategies for the localized delivery of antiresorptive agents, anabolic molecules, nucleic acids, and osteogenic cues. We further summarize platelet-rich plasma/platelet-rich fibrin, growth factor-loaded matrices, mesenchymal stem cell–laden scaffolds, extracellular vesicle–functionalized systems, and gene-activated matrices as emerging biological or cell-free regenerative platforms. Finally, key translational barriers, including long-term safety, reproducible manufacturing, standardized osteoporotic models, and regulatory pathways for combination products, are discussed. Overall, biomaterials should not be viewed as replacements for established pharmacotherapy but as disease-tailored local interventions that may improve osteoporotic fracture repair and bone regeneration when integrated with rational clinical management.
Xiaoqing Qiu, Ya Ren· Frontiers in Bioengineering...· 0 citations
Denosumab is a first-line therapy for osteoporosis, yet the rebound increase in bone turnover markers, rapid bone loss, and elevated fracture risk following its discontinuation have become major challenges in clinical management. This review systematically summarizes the potential mechanisms underlying exacerbated bone loss after denosumab withdrawal and the corresponding sequential treatment strategies. Current mechanistic studies have focused on several hypotheses, including the accumulation of osteomorphs and osteoclast precursors, imbalance in the RANKL/OPG ratio, uncoupling of bone remodeling, and osteocyte-mediated aberrant microdamage repair, which collectively contribute to the burst activation of bone resorption upon treatment cessation. To address this risk, international consensus recommends proactive sequential antiresorptive therapy for patients discontinuing denosumab. For short-term users (≤2.5 years), sequential administration of a single dose of zoledronic acid or alendronate can effectively preserve bone mineral density. For long-term users (>2.5 years), zoledronic acid should be initiated 6 months after the last dose, accompanied by intensive monitoring based on bone turnover markers and repeated dosing as needed. Additionally, emerging strategies such as early transition to romosozumab or alternating use with bisphosphonates have shown potential. Future studies are required to validate the underlying mechanisms in humans and to optimize sequential treatment regimens through prospective trials, thereby enabling individualized therapy and safe discontinuation.
Jiancheng Yang, Ming Yang, Yuhong Zeng· Frontiers in Aging· 0 citations
Bone metabolism-related disorders represent a significant global health burden, due to their high prevalence and substantial socioeconomic costs, particularly osteoporosis. Conventional antiresorptive and anabolic agents have well-established clinical utility, such as bisphosphonates, denosumab, teriparatide, and romosozumab. Nevertheless, their long-term clinical use remains limited by safety concerns and inadequate efficacy in a subset of patients. In this review, we highlight recent chemical innovations designed to mechanistically reprogram the skeletal microenvironment and overcome those longstanding barriers. We also analyze how the metabolic coupling signals govern bone bioenergetics, particularly within the Wnt and RANKL axes. We place specific focus on three emerging and transformative strategies: proteolysis-targeting chimeras (PROTACs), bone-targeted senolytics, and direct metabolic modulators. Ultimately, we provide a multidisciplinary roadmap for the development of next-generation therapeutics to achieve durable skeletal restoration in patients with bone metabolic disorders.
Yeqiong Song, Rui-Xin Zhang, Xin-Yu Zhang et al.· Frontiers in Chemistry· 0 citations
Osteoporosis is the most prevalent chronic metabolic bone disease, affecting approximately 200 million individuals worldwide. With the rapid acceleration of global aging, osteoporosis has emerged as a major global health challenge, significantly increasing the occurrence rate of fractures and the associated medical burden. In recent years, considerable progress has been made in understanding the molecular mechanisms underlying osteoporosis, including bone remodeling, osteoblast-osteoclast communication, and signaling pathways such as RANKL/RANK/OPG and Wnt/β-catenin. These mechanistic studies have been translated into clinical applications. Emerging therapies, including targeted biologics and precision medicine approaches, offer novel strategies and methods for future prevention and treatment. This review summarizes recent advances in research, with a particular focus on therapeutic agents and mechanistic studies of osteoporosis. Following the mainline of “mechanism–target–translation,” this review proposes new research perspectives and approaches, and provides an outlook on future research directions for the disease, aiming to promote the development of more effective diagnostic and therapeutic strategies.
Ping Xie, Jie Cai, Zheng-Jie Yu et al.· Frontiers in Endocrinology· 0 citations
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