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Review Article
This review summarizes therapeutic strategies for postmenopausal osteoporotic fracture healing, covering pathophysiology involving estrogen deficiency, oxidative stress, and ferroptosis. It evaluates conventional pharmacological agents and advocates for multi-target alternative therapies, including natural bioactive compounds and traditional medicines, to optimize bone regeneration through integrative sequential management.
Postmenopausal osteoporosis (PMO) significantly increases the risk of fragility fractures. The profound estrogen deficiency, compounded by severe oxidative stress, ferroptosis, and an impaired osteoimmune microenvironment, disrupts the vital coupling of angiogenesis and osteogenesis. This disruption frequently leads to delayed fracture union and implant failure. This narrative review aims to consolidate the current literature regarding both conventional pharmacological interventions and specific alternative therapeutic strategies, providing a comprehensive conceptual framework for optimizing bone healing in PMO fractures. An extensive literature search of databases including the systematic-review and evidence-synthesis database, biomedical and pharmacological bibliographic database, multidisciplinary citation-indexing database, and public biomedical literature database was conducted for relevant studies published up to March 2026. While conventional antiresorptive and anabolic agents remain the gold standard for long-term secondary fracture prevention, their inherent limitations and "double-edged sword" effects during the acute fracture healing phase pose significant clinical challenges. Emerging evidence suggests that multi-target alternative therapies, particularly natural bioactive compounds and traditional Chinese medicine (TCM) formulas, offer a synergistic approach. By ameliorating systemic metabolic dysregulation and inhibiting lipid peroxidation-induced ferroptosis, these alternative therapies reshape localized immune-bone homeostasis. Addressing the delayed healing of postmenopausal fractures requires an evolution toward an integrative sequential management model. Although current supporting data predominantly derive from robust preclinical models, combining these alternative therapeutic strategies with conventional agents—and potentially utilizing advanced targeted biomaterial delivery systems—represents a highly promising frontier to optimize perioperative fracture management and enhance long-term skeletal integrity.
PMO is characterized by low bone mass and microarchitectural deterioration, significantly increasing the risk of fragility fractures1. The epidemiological and economic burdens are substantial; for instance, the extrapolated prevalence of clinically diagnosed vertebral fractures among U.S. postmenopausal women is approximately 9.3%2. Furthermore, the accumulation of fragility fractures exponentially amplifies clinical and societal costs. Postmenopausal women sustaining three or more fractures experience a 2.2-fold higher mortality rate and incur 1.4 times higher annual healthcare costs compared to those without fractures3.
The pathogenesis of fragility fractures in this demographic is primarily driven by the cessation of ovarian function and a precipitous decline in estrogen levels, which creates a baseline state of accelerated bone resorption4. This skeletal vulnerability is exacerbated by clinical risk factors such as lower body mass index, diabetes mellitus, and substance use5. Additionally, psychological factors play a critical role; depression severity is an independent predictor of osteoporosis and subsequent fractures1. Chronic stress and depressive states lead to sustained hypothalamic-pituitary-adrenal (HPA) axis activation and elevated cortisol, which directly inhibit osteoblast activity and promote osteoclastogenesis. This is accompanied by a chronic low-grade inflammatory state that further undermines skeletal integrity5.
Because fragility fractures indicate progressive skeletal deterioration, achieving rapid and optimal fracture union in postmenopausal patients remains a profound clinical challenge. The synergistic detrimental effects of prolonged estrogen deficiency, metabolic disturbances, and psychosocial stress severely impair the local bone microenvironment6. Therefore, there is an urgent need to explore effective therapeutic strategies to promote bone healing. This review aims to consolidate the current literature regarding pharmacological and alternative interventions for postmenopausal osteoporotic fractures, providing a comprehensive resource for orthopaedic clinicians to optimize fracture management and mitigate future care needs3.
To construct this narrative review, a comprehensive literature search was conducted for articles published up to March 2026 across major electronic databases, including public biomedical literature database, multidisciplinary citation-indexing database, biomedical and pharmacological bibliographic database, and the systematic-review and evidence-synthesis database. The primary search terms included combinations of "postmenopausal osteoporosis," "delayed fracture healing," "ferroptosis," "natural bioactive products," and "traditional Chinese medicine." It is important to note that as a narrative review designed to provide a broad theoretical and clinical perspective on integrative fracture management, strict systematic inclusion and exclusion criteria were not applied. Consequently, we acknowledge the inherent potential for selection bias in the literature presented.
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Pathophysiology of delayed healing in postmenopausal osteoporosis
The macro-impact of estrogen withdrawal on bone remodeling imbalance
Estrogen plays a pivotal role in maintaining skeletal homeostasis and regulating bone mechanical strength. The decline in ovarian function after menopause leads to a precipitous drop in estrogen levels, abruptly disrupting the delicate dynamic balance between osteoblasts (bone formation) and osteoclasts (bone resorption)7. Following a fracture, this baseline instability is further amplified, resulting in delayed callus formation, impaired endochondral ossification, and substandard callus mineralization, thereby significantly prolonging the overall fracture healing process and increasing the risk of non-union8,9.
Cellular cascade: osteoblast suppression and osteoclast hyperactivity
At the cellular and molecular levels, estrogen deficiency triggers a destructive cascade. On one hand, the absence of estrogen downregulates osteoprotegerin (OPG) expression and upregulates receptor activator of nuclear factor-κB ligand (RANKL) levels; this severe OPG/RANKL imbalance provides an optimal environment for osteoclast hyperproliferation and hyperactivity, causing the newly formed callus to be prematurely resorbed before adequate mineralization occurs10. On the other hand, the loss of estrogen's protective effects directly impairs the viability of the osteogenic lineage11. Studies indicate that estrogen withdrawal not only inhibits the osteogenic differentiation capacity of bone marrow mesenchymal stem cells (BMSCs) but also induces premature senescence and aberrant cell death—such as apoptosis and ferroptosis—in osteoblasts and osteocytes. This detrimental combination of “osteoblast exhaustion” and “osteoclast hyperactivity” constitutes the core cellular mechanism responsible for the poor quality of fracture healing in postmenopausal women9.
Microenvironmental deterioration: oxidative stress and impaired angiogenesis
Beyond direct cellular imbalances, the disruption of the local fracture microenvironment induced by estrogen withdrawal is equally critical to delayed healing. Estrogen inherently possesses potent antioxidant properties; its sudden decline leads to a massive accumulation of reactive oxygen species (ROS) within the local fracture microenvironment, triggering severe oxidative stress. This persistent oxidative environment not only further exacerbates lipid peroxidation and ferroptosis in osteoblasts, but more fatally, it severely impedes the reconstruction of the microvascular network (angiogenesis) at the fracture site12.
Skeletal regeneration is highly dependent on the “angiogenesis-osteogenesis coupling” mechanism, particularly the ingrowth of specific type H vessels (CD31+/Emcn+), which supply essential oxygen, nutrients, and osteoprogenitor cells to the newly forming callus13. The postmenopausal oxidative stress and inflammatory state significantly inhibit the migration and tube-formation capabilities of vascular endothelial cells, effectively cutting off the "lifeline" for callus remodeling. Thus, impaired angiogenesis intertwines with continuous cellular metabolic dysfunction, collectively forming the complex pathological network that renders postmenopausal osteoporotic fractures remarkably difficult to heal (Figure 1)14.
Conventional pharmacological interventions
The clinical management of PMO primarily relies on antiresorptive and anabolic agents, with the core objectives of enhancing bone mineral density (BMD) and reducing the severe morbidity and mortality associated with fragility fractures15. Given that the mortality rate can triple during the first year following a major osteoporotic fracture, timely and standardized pharmacological intervention is of paramount importance16.
Antiresorptive agents: the clinical cornerstone and their “double-edged sword” effect
Bisphosphonates (BPs) remain the first-line gold standard for treatment, with international guidelines typically recommending oral BP therapy for a duration of up to five years16,17. Although highly efficacious, prolonged or excessive suppression of bone turnover—including the administration of intravenous amino-bisphosphonates such as zoledronic acid—can yield counterproductive outcomes. This over-suppression may not only impede normal callus remodeling, thereby leading to delayed fracture healing, but is also intricately linked to the pathogenesis of atypical femoral fractures (AFFs)18.
Denosumab serves as another highly potent antiresorptive agent; however, its clinical efficacy is profoundly time-dependent. Upon discontinuation of the therapy, bone turnover markers exhibit a rapid “rebound" elevation”19. This post-cessation rebound effect is directly correlated with a sharply increased risk of spontaneous multiple vertebral fractures. Consequently, in clinical practice, the cessation of denosumab mandates strict sequential therapy with other antiresorptive agents to preserve bone mass and prevent rapid skeletal deterioration20,21.
Anabolic agents: accelerating the fracture healing process
In contrast to antiresorptive agents that primarily arrest bone loss, anabolic agents actively stimulate de novo bone formation. Teriparatide (recombinant human parathyroid hormone 1-34) effectively activates osteoblast function, promotes callus mineralization, and accelerates the transition from the fibrovascular phase to the bone remodeling phase during endochondral ossification, thereby significantly shortening the fracture healing timeline22,23. Furthermore, studies indicate that teriparatide demonstrates substantial potential in improving the microarchitectural characteristics of peri-implant bone tissue20.
Romosozumab, a novel agent with a dual mechanism of promoting bone formation and inhibiting bone resorption, has shown immense clinical value for patients with severe PMO, particularly those at an imminent risk due to a recent fracture. Real-world evidence further underscores its indispensable role in high-risk populations that are either unresponsive or intolerant to conventional therapies24,25.
Although conventional pharmacological interventions demonstrate definitive efficacy in the secondary prevention of fractures, their "double-edged sword" effects during the acute fracture healing phase (e.g., BP-induced delayed union) and the prohibitive costs associated with anabolic agents present significant clinical hurdles. These limitations underscore the urgent clinical imperative to explore specific alternative therapies, such as traditional medicine interventions, which offer multi-target synergistic effects to optimize the bone healing microenvironment.
Specific alternative and traditional therapies
Given the potential limitations of conventional pharmacological interventions in promoting acute fracture healing (e.g., suppressed callus remodeling) and the adverse events associated with their long-term administration, exploring specific alternative therapies with multi-target synergistic effects has emerged as a research hotspot in orthopedics26. Natural bioactive products and traditional medicines exhibit unique clinical advantages in ameliorating the complex bone metabolic microenvironment and accelerating bone regeneration26,27.
Natural bioactive products: the osteogenic value of phytomedicine
Natural bioactive compounds, encompassing flavonoids, polyphenols, and terpenoids, have been identified as core material bases for regulating bone metabolism and promoting bone regeneration28. Among these, icariin, a representative plant-derived flavonoid, has garnered considerable attention for its multi-pathway regulatory potential in bone and joint diseases29. Preclinical in vitro and in vivo evidence suggests that icariin significantly enhances osteoblast activity and suppresses excessive osteoclast differentiation by activating the Wnt/β-catenin signaling pathway and modulating the RANKL/RANK/OPG balance29,30. Furthermore, in osteoporotic animal models, flavonoids such as quercetin leverage exceptional antioxidant properties to effectively scavenge reactive oxygen species (ROS) at the fracture site; this mitigates oxidative stress, thereby fostering a more favorable local microenvironment for fracture repair in the context of estrogen deficiency31,32.
Beyond direct ROS scavenging, recent in vitro mechanistic studies reveal that quercetin also protects bone marrow mesenchymal stem cells (BMSCs) from oxidative stress-induced ferroptosis, thereby preserving their osteogenic lineage commitment in hostile microenvironments32. Expanding to other bioactive classes, cell-based assays demonstrate that curcumin, a natural polyphenolic compound, effectively attenuates intracellular ROS accumulation and protects osteoblasts from oxidative damage via Nrf2 pathway activation, preserving osteogenic capacity under severe oxidative stress33. Additionally, in ovariectomized rodent models, resveratrol, a stilbenoid polyphenol, mitigates estrogen-deficiency-induced bone loss by stimulating SIRT1 expression and the downstream Wnt/β-catenin signaling pathway, thereby optimizing the local bone remodeling microenvironment34. Collectively, these findings underscore that diverse natural monomers provide rich, multi-targeted molecular strategies—particularly through suppressing oxidative stress and ferroptosis—to restore the local osteogenic microenvironment.
Clinical evidence and sequential management models
Traditional medicine formulas demonstrate clinical benefits in the long-term management of PMO. For instance, the traditional qi-tonifying multi-herbal formulation is widely employed in clinical practice to attenuate bone loss and alleviate associated clinical symptoms, with its efficacy and safety in postmenopausal cohorts currently undergoing systematic evidence-based evaluation. However, human clinical evidence explicitly evaluating these formulas for direct fracture union, callus formation, or acute perioperative outcomes remains largely unavailable. Current supporting data are predominantly derived from preclinical models and retrospective descriptive prescribing data35. Concurrently, within modern orthopedic clinical decision-making, integrating these multi-target alternative therapies with conventional sequential treatment strategies (e.g., initiating therapy with an anabolic agent followed by an antiresorptive agent) is considered a pivotal direction for optimizing long-term outcomes in elderly osteoporotic patients36,37 (Table 1).
Recent investigations have furnished mechanistic evidence supporting the integration of specific TCM formulations into PMO management, primarily in animal models. The kidney-tonifying multi-herbal formulation, a kidney-tonifying multi-herbal formula, significantly increased bone mineral density (BMD) and improved trabecular microarchitecture (Bone volume/total volume (bone volume fraction) BV/TV, Trabecular number Tb.N, Trabecular separation (or trabecular spacing) Tb.Sp) in preclinical ovariectomized rat models, with high-dose efficacy comparable to alendronate. Untargeted metabolomics identified isoliquiritigenin (ISL) as a key bioactive constituent that modulates the IL-17/NF-κB/MAPK axis. Molecular docking confirmed high-affinity ISL binding to PTGS2, MAPK14, GSK3B, and c-Fos (binding energies < −6.0 kcal/mol), while experimental validation demonstrated dose-dependent suppression of NF-κB p65, TNF-α, IL-17A, and downstream osteoclastogenic effectors (CTSK, MMP9)38. These findings underscore YSQGM's dual capacity to restore bone metabolic balance and reshape the osteoimmune microenvironment.
Clinically, the traditional bone-strengthening and analgesic multi-herbal formulation has demonstrated comparable skeletal benefits to standard pharmacotherapy with superior holistic symptomatic control. In a randomized clinical trial of 100 postmenopausal women, 24-week ZGZT treatment significantly increased femoral BMD (P < 0.001) and produced greater reductions in TCM syndrome scores and low back pain numeric rating scale (NRS) scores than alendronate sodium (P < 0.05). Biochemically, ZGZT significantly lowered serum AMPK, IL-17, and IL-1 while elevating estradiol (E2) and iron (P < 0.001); positive correlations between AMPK and both BMD (r = 0.296) and E2 (r = 0.280) suggest AMPK/mTOR-mediated autophagy modulation as a contributory mechanism. Importantly, while these outcomes are statistically significant, the source study did not report absolute changes in relevant outcomes, between-group differences, effect sizes, or confidence intervals, nor did it assess acute fracture healing parameters39.
Real-world retrospective prescribing data further contextualize the therapeutic positioning of TCM in contemporary practice. A retrospective cohort of 363,529 osteoporosis patients in Eastern China (2019–2024) revealed that TCM constituted 15.3% of anti-osteoporosis prescriptions, ranking third after active vitamin D analogs (71.9%) and bisphosphonates (22.0%). Although TCM utilization declined over the study period (15.3% to 11.6%, P < 0.001) concomitant with rising denosumab adoption (2.9% to 21.8%), TCM featured in 36.6% of triple/quadruple combination regimens, predominantly co-prescribed with vitamin D analogs and bisphosphonates40. These prescribing patterns highlight an existing clinical infrastructure for integrative protocols that remains under-optimized.
Inhibiting ferroptosis: a novel regulatory target for alternative therapies
The highly oxidative microenvironment post-menopause frequently precipitates ferroptosis in osteoblasts, a critical pathological nexus leading to delayed fracture healing. Emerging preclinical mechanistic studies reveal that specific natural bioactive products can effectively inhibit osteoblast ferroptosis by activating antioxidant signaling pathways, such as the Nrf2/ARE axis, thereby fortifying cellular defenses against lipid peroxidation41. This precise intervention targeting a novel modality of regulated cell death provides a profound molecular biological rationale for the application of alternative therapies during the perioperative period of osteoporotic fractures.
Clinical implications
Clinical translation of integrative interventions
The management of PMO and its associated complications, such as delayed union or non-union, remains a formidable challenge in orthopedic surgery42. While conventional monotherapies—primarily antiresorptives or anabolics—demonstrate clear efficacy in modulating bone turnover, they are often constrained by long-term adverse profiles or complex "double-edged sword" effects on acute fracture healing. The evidence synthesized in this review suggests that multi-target alternative therapies, particularly kidney-tonifying and blood-activating traditional Chinese medicines (TCMs), offer significant translational value in both perioperative management and long-term skeletal maintenance.
Recent high-quality evidence from a network meta-analysis supports the clinical synergy of these interventions: the combination of kidney-tonifying TCMs (KTCMs) with bisphosphonates (BPs) not only achieves a superior increase in bone mineral density (BMD) at the lumbar spine and femoral neck compared to BP monotherapy but also significantly attenuates pain as measured by Visual Analog Scale (VAS) scores, without increasing the incidence of adverse events43. More crucially, in catastrophic clinical scenarios such as non-union following internal fixation of femoral neck fractures, integrated protocols—combining traditional pharmacological modulation with modern surgical stabilization—have been shown to effectively re-activate the "dormant" fracture site, promoting robust callus bridging and achieving clinical union44. This suggests a viable salvage strategy for elderly, fragile patients to avoid the morbidity of revision arthroplasty (Figure 2).
Bridging systemic metabolism and the osteoimmune microenvironment
The core advantage of these alternative therapies lies in the integration of “macro-metabolic regulation” with “micro-local targeting”. Modern research indicates that PMO-related healing impairment is not merely a localized failure of osteoblastic function but a manifestation of systemic metabolic dysregulation and chronic low-grade inflammation, often termed “inflammaging”.
Clinical data demonstrate that active components from traditional herbs, such as Drynaria fortunei, improve lipid metabolic disorders in elderly postmenopausal patients by regulating the Notch1-NLRP3 inflammasome pathway45. By suppressing systemic inflammatory responses, these interventions indirectly eliminate systemic inhibitors of osteoblast activity. Furthermore, emerging basic research is shifting focus toward the “osteoimmune microenvironment,” where lysosomes serve as critical hubs integrating nutrient sensing, ion signaling, and immune-bone coupling46. The multi-target nature of natural bioactive products likely reshapes local immune homeostasis at the fracture site—potentially by modulating lysosomal function and autophagic flux in macrophages and osteoclasts—thereby providing an idealized microenvironment for callus remodeling27,46.
Drug-herb interactions and safety considerations
While the integration of multi-target alternative therapies offers distinct advantages, the potential for drug-herb interactions remains a critical clinical consideration, particularly in the elderly population. Accumulating evidence indicates that many natural bioactive products and traditional Chinese medicines (TCM) contain phytochemicals capable of modulating the activity of the human cytochrome P450 (CYP) enzyme system, which serves as the primary metabolic pathway for most conventional pharmacological agents. For instance, certain medicinal plants and their bioactive compounds have been shown to act as inducers or inhibitors across major CYP isoforms (such as CYP1A2, CYP2C9, CYP2D6, and CYP3A4)47. Co-administering these herbal formulations with conventional bone-modifying drugs could inadvertently alter substrate pharmacokinetics, thereby increasing the risk of systemic toxicity or sub-therapeutic efficacy. This risk is further exacerbated in postmenopausal and elderly cohorts, who typically exhibit age-related physiological declines, including up to a 30% reduction in hepatic drug clearance and a 50% decrease in renal excretion function48. Therefore, when orthopedic clinicians prescribe sequential or concurrent regimens integrating conventional agents (e.g., bisphosphonates) with multi-target TCM formulas, rigorous medication reconciliation is paramount. Strict dose monitoring and regular assessments of liver and kidney function are essential to mitigate adverse pharmacokinetic interactions and ensure the safe optimization of the osteoimmune microenvironment.
Despite the promising conceptual framework of specific alternative therapies, several critical limitations warrant objective consideration. Foremost, most mechanistic insights regarding natural bioactive compounds (e.g., ferroptosis inhibition by flavonoids) and targeted hydrogel delivery systems are exclusively derived from preclinical in vitro studies and in vivo ovariectomized (OVX) rodent models. Human randomized controlled trial (RCT) data specifically evaluating these alternative interventions during the acute perioperative phase of fracture healing remain exceedingly sparse and heterogeneous. Furthermore, existing clinical trials for TCM formulas often exhibit limitations in sample size, lack standardized blinding protocols, and predominantly focus on subjective symptomatic relief (e.g., pain scores) rather than objective radiographic parameters of fracture union.
Future translational research must bridge this translational gap by prioritizing: 1) Evidence Quality Enhancement: Large-scale, multi-center, rigorously blinded RCTs are urgently required to validate preclinical findings in human cohorts, specifically aiming to establish standard intervention windows and definitive radiographic outcomes for alternative therapies. 2) Targeted Delivery Systems: As demonstrated in recent preclinical innovations leveraging advances in material science, future efforts should focus on encapsulating validated bioactive monomers (e.g., flavonoids that inhibit ferroptosis or modulate lysosomal function) into “smart”. 3) hydrogels or nano-carriers. Such localized, controlled-release systems could overcome the low oral bioavailability of plant-derived compounds and achieve precise spatial intervention within the osteoimmune microenvironment of non-unions (Figure 3)46.
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The management of postmenopausal osteoporotic fractures represents a complex clinical challenge that extends far beyond mechanical fixation. The profound cessation of estrogen orchestrates a cascade of detrimental cellular events—characterized by osteoblast exhaustion, osteoclast hyperactivity, severe oxidative stress, and the induction of ferroptosis—which collectively paralyze the local osteoimmune microenvironment and impede callus remodeling. While conventional pharmacological agents remain indispensable for long-ter...
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The authors have no conflicts of interest to declare.
This research was not funded.
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