Yuhong Zeng

Osteoporosis is a chronic, progressive bone condition that impacts over 200 million people globally, with fragility fractures significantly burdening healthcare systems and diminishing patient quality of life. Exercise is universally recommended as a foundational non-pharmacological intervention for osteoporosis management; however, a persistent translational gap separates the efficacy demonstrated in controlled trials from the outcomes observed in real-world clinical practice. This narrative review identifies and critically examines the multifaceted challenges confronting the evidence-based application of exercise therapy in contemporary osteoporosis care. Seven principal interrelated dilemmas are elucidated: the surrogate endpoint dependency on bone mineral density (BMD) rather than fracture incidence, profound heterogeneity of osteogenic effects across exercise modalities, the tension between effective osteogenic thresholds (≥70% 1RM) and safety concerns in high-risk subgroups, the absence of validated patient stratification tools, poor real-world adherence amid scarce supervised infrastructure and fragmented care pathways, pervasive nutritional inadequacies that undermine the skeletal response to mechanical loading, and methodologically heterogeneous evidence for traditional mind-body exercises that limits their equivalence to progressive resistance training. The reversibility of bone gains upon detraining further underscores that exercise must be conceptualized as a lifelong behavior rather than a time-limited intervention. Future priorities include fracture-powered pragmatic trials, validated osteoporosis-specific pre-exercise risk stratification instruments, implementation science addressing behavioral and systemic barriers, and integrated multidisciplinary care models that unite exercise professionals with bone specialists and dietitians. Until such evidence matures, clinicians must navigate a landscape of conditional recommendations, individualized risk-benefit assessments, and honest communication of uncertainty to patients.

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.

Background: Eldecalcitol (ELD) and denosumab are some of the most common therapeutic options for osteoporosis management. ELD effectively increases bone mineral density (BMD) in osteoporotic patients, independent of baseline vitamin D status or calcium intake. However, the efficacy of denosumab combined with either ELD or native vitamin D plus calcium in postmenopausal Chinese women with osteoporosis has not been established. Methods: In this single-center, randomized, open-label, active-controlled clinical trial, postmenopausal women with osteoporosis (defined as a BMD T-score ≤ −2.5 at the lumbar spine [LS], total hip [TH], or femoral neck [FN], or low bone mass with fragility fracture history) were enrolled from Xi’an Honghui Hospital in China and randomized 1:1 to two 12-month treatment regimens: the ELD group received ELD (0.75 μg orally daily) combined with denosumab (60 mg subcutaneously every 6 months), while the control group received the same denosumab regimen plus native vitamin D (800 IU orally daily) and calcium (600 mg orally daily). The primary endpoint was the 12-month percent change in LS BMD from baseline. Secondary endpoints included changes in FN- and TH-BMD from baseline, bone turnover markers, serum parathyroid hormone, quality of life, and the incidence of new fractures. Results: Of the 100 randomized participants, 45 in the ELD group and 46 in the control group were included in the efficacy analysis. After 12 months of treatment, LS-BMD increased significantly in both groups (both p < 0.05), with a greater increase in the ELD group than in the control group (6.75% vs. 4.99%), yielding a statistically significant between-group least-squares mean difference of 1.75% (95% CI, 0.10 to 3.41; p = 0.038). The reduction in serum β-CTX was significantly smaller in the ELD group than in the control group at 3 months (91.00% vs. 93.62%, p = 0.002), with no significant between-group differences thereafter. Seven fractures were reported (one non-vertebral in the ELD group; one vertebral and five non-vertebral in the control group). No significant between-group differences in FN- or TH-BMD, quality of life, or overall adverse event rates were observed. Both regimens were generally well-tolerated, without clinically meaningful calcium-related safety signals. Conclusions: Combination therapy with denosumab and eldecalcitol improved LS-BMD more effectively than denosumab with native vitamin D and calcium in postmenopausal Chinese women with osteoporosis. Clinical trial number: ClinicalTrials.gov identifier NCT05884372, registered on 1 June 2023.

Background: The therapeutic efficacies of pulsed electromagnetic fields (PEMFs) for postmenopausal osteoporosis are well established; however, their effects on male osteoporosis remain uncertain. Osteoporosis development is often associated with dysregulation of systemic iron metabolism. This study aimed to investigate the therapeutic effects of PEMFs on orchiectomy (ORX)-induced osteoporosis in mice and determine whether the mechanism involves regulation of systemic iron metabolism. Methods: Twenty-four 10-week-old male C57BL/6J mice were divided into the sham, ORX, and ORX + PEMF groups (n = 8 each). The ORX + PEMF group received PEMF treatment (15 Hz, peak of 3.82 mT, 40 min/d for 2 months) starting 2 weeks post-surgery. The bone loss was assessed via micro-computed tomography, biomechanical testing, dynamic histomorphometry, and TRAP staining. The systemic iron metabolism was evaluated via Prussian blue staining, atomic absorption spectrometry, and serum ELISA (hepcidin, ferritin). Results: PEMF treatment partially prevented ORX-induced bone loss in the lumbar spine, as evidenced by significant improvements in the microstructure and mechanical properties of the bone, along with partially restored bone formation and suppressed bone resorption compared to the untreated ORX mice. However, PEMF application showed no significant protective effects on the femoral bone microstructure or cortical parameters. Crucially, PEMF treatment did not alter the markers of systemic iron metabolism, meaning that no changes were observed in the tissue iron deposition, iron content, serum ferritin level, serum hepcidin level, or liver hepcidin expression. Conclusion: PEMF therapy exerts site-specific protective effects against ORX-induced osteoporosis in the lumbar spine of male mice to partially restore bone formation and reduce resorption. This therapeutic efficacy is independent of any alterations in the systemic iron metabolism. The findings of this study support PEMF application as a potential physical therapy for male osteoporosis while highlighting the need for site-optimized strategies.

Background/Objectives: Fragility fractures, particularly in the vertebra and hip, are a significant health concern in the elderly, often associated with osteoporosis. Emerging evidence suggests a link between lipid profiles and bone health, but the characteristics of lipid biomarkers in patients with fragility fractures remain underexplored. Methods: This study analyzed serum lipid biomarkers, including total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in 10,540 patients aged 50 and older with either vertebral or hip fragility fractures. We compared lipid levels between the two fracture groups and examined the relationship between lipid profiles and baseline characteristics of patients. Results: Patients with vertebral fractures exhibited significantly higher serum levels of TC, TG, HDL-C, and LDL-C compared to those with hip fractures. These differences remained statistically significant after adjusting for confounding variables. Multivariable regression analysis revealed that age was inversely associated with TC, TG, and LDL-C, but positively associated with HDL-C. All lipid levels were significantly higher in women than in men. Time from fracture to admission and BMI were positively associated with TG levels and inversely associated with HDL-C. Vertebral fracture patients had a higher prevalence of abnormally high TC (3.03% vs. 0.78%), TG (9.15% vs. 3.54%), and LDL-C (2.80% vs. 1.04%), but lower prevalence of abnormally low HDL-C (20.53% vs. 26.66%; p < 0.001 for all). Conclusions: Our findings highlight distinct lipid profile characteristics in patients with vertebral and hip fragility fractures, suggesting that physiological or metabolic changes following different fracture types may differentially influence lipid metabolism. These insights may inform targeted prevention and management strategies for fragility fractures.

The accumulation of intracellular reactive oxygen species (ROS) is widely recognized to stimulate the development of osteoclasts, a crucial factor in the onset of osteoporosis. The ROS scavenging capability of Prussian blue nanoparticles (PBNPs) is exceptional, and they possess excellent biocompatibility. However, the effects of PBNPs on osteoporosis remain unknown. Present study aimed to investigate whether PBNPs could inhibit osteoclast differentiation and prevent ovariectomy (OVX)‐induced bone loss by suppressing ROS. In vitro experiments demonstrated that PBNPs attenuated osteoclastogenesis and downregulated the expression of osteoclast‐related genes. Mechanistically, PBNPs reduce cellular ROS by blocking RANKL‐induced ROS generation and increasing the expression of ROS scavenging enzymes, which in turn block the NF‐κB, ERK, JNK, and p38 pathways, thereby reducing NFATc1 signaling. According to in vivo experimental results, OVX caused a significant rise in ROS in the bone marrow, an increase in osteoclastic number on the bone surface, and substantial bone loss; however, PBNPs significantly reduced ROS and successfully protected OVX‐induced bone damages. In conclusion, this study showed for the first time that PBNPs prevented OVX‐induced bone loss and attenuate osteoclastogenesis, indicating that PBNPs may be a viable alternative therapy for the management of osteoclast‐associated bone disorders.