Bone fractures, a prevalent condition, are currently witnessing an upward trend in global incidence (1), predominantly linked to population ageing and increased life expectancy. According to United Nations research, the global population aged ≥65 years is projected to reach 1.5 billion by 2050 (2, 3). As the ageing process accelerates, the incidence of fractures continues to rise, imposing substantial socioeconomic burdens on individuals, families, and societies (4). Fracture patients often experience major symptoms such as restricted mobility and acute pain (5), which typically ease over a two-month period, with most individuals reaching optimal recovery within 3–6 months (6). Depending on the severity of the fracture, treatment may involve either conservative management or surgery. For non-displaced fractures, conservative treatment generally leads to good outcomes; according to the BMJ Clinical Practice Guidelines¹, recovery usually takes 3–4 weeks with relatively rapid pain relief. Displaced fractures, on the other hand, often require surgical intervention, which can support earlier functional recovery (around 10–14 weeks) (7), but may also carry about a 20% risk of non-union and persistent pain, potentially affecting quality of life (8–11). It is important to note that the duration of pain relief following surgery varies considerably among individuals (12).

Bone healing following a fracture is a complex physiological process that is typically divided into four stages: the fracture and inflammatory phase, the angio-mesenchymal phase, the bone formation phase, and the bone remodeling phase. Although each phase possesses distinct characteristics, they often occur alternately and exhibit a degree of overlap (13). The process of bone healing is influenced by a variety of factors, including the nature and extent of the injury, the damage to the surrounding soft tissues, blood supply, the differentiation capacity of osteoblasts, and the cellular microenvironment as internal factors. Additionally, external factors such as the stability of fracture fixation, the gap between fracture ends, the inflammatory response, and external physical stimuli also play a significant role in the healing process (14). In the final stage of bone healing, known as the bone remodeling phase, approximately 5–10% of long bone fractures may experience non-union (15). In cases of delayed healing or non-union during the fracture healing process, surgical intervention is often required. Autologous bone grafting, regarded as the gold standard for the treatment of fractures and bone defects, has been widely employed in clinical practice (16). In addition to surgical treatment, non-invasive physical agent modalities such as electrical stimulation, electromagnetic stimulation, low-intensity pulsed ultrasound, and low-level laser therapy have been shown to facilitate the acceleration of fracture healing and have gained widespread recognition in clinical practice. These adjunctive therapies provide effective supplementary strategies for optimizing the healing of fractures (17–20).

Most randomized controlled trials (RCTs) use standard care as a control, while few directly compare distinct physical agent modalities modalities. Traditional meta-analyses typically allow for the comparison of only two treatment methods at a time, failing to provide comprehensive evidence regarding the relative efficacy of various interventions for fracture healing. Network meta-analysis (NMA) addresses this limitation by facilitating simultaneous comparisons of multiple treatment options and enabling the ranking of each intervention based on various outcomes. This approach offers clinicians a clear, evidence-based framework for treatment decisions, thereby assisting in making informed and scientifically sound clinical choices when addressing complex cases of delayed healing or non-union (21).

Consequently, we conducted a NMA aimed at synthesizing the existing evidence to compare the efficacy of different physical agent modalities in promoting fracture healing and alleviating pain. The specific objective is to identify the most effective physical agent modalities approach, thereby providing robust support for clinical decision-making and assisting in the optimization of treatment strategies for fracture healing.

The protocol was registered with PROSPERO under registration number CRD420251030229.

To the best of our knowledge, this study represents the first NMA comparing the efficacy of different physical agent modalities for treating patients with fractures. This NMA meticulously reviewed the most recent data from 39 eligible randomized controlled trials, evaluating the effectiveness of physical agent modalities in fracture patients. This study confirms that physical agent modalities significantly promotes fracture healing and alleviates pain. To compare the effects of different physical agent modalities, we sought indirect evidence through pairwise comparisons. However, indirect treatment comparisons revealed no statistically significant differences in efficacy among the seven modalities. Subsequently, by calculating the SUCRA values for these therapies and conducting a ranking analysis, we found that both LLLT and ES significantly relieve pain, with the reduction in pain scores likely reaching or even exceeding the minimal clinically important difference. This indicates that their effects go beyond statistical significance and provide pain relief that is genuinely meaningful to patients. Such a degree of improvement can help enhance sleep quality and daily functioning, thereby improving overall quality of life and potentially reducing dependence on analgesic medications. Consequently, these two physical agent modalities demonstrate substantial clinical value as complementary approaches to pain management. UST markedly shortens fracture healing time, while CCEFS significantly increases the healing rate in patients with fractures, followed by PEMFS. These effects enable patients to regain physical function earlier, fundamentally reducing the risk of complications associated with prolonged immobilization or delayed healing, and ultimately leading to substantial savings in healthcare resources. In this context, these physical agent modalities serve not only as effective clinical tools for preventing fracture non-union but also as strategies that enhance the overall quality of treatment. They therefore provide strong evidence supporting the clinical prioritization of efficient physical therapy modalities. However, since only a few studies have examined the application of LLLT and CCEFS in patients with fractures, this result warrants cautious interpretation.

Patients with fractures often experience acute postoperative pain, which is typically managed with analgesic medications. However, such treatments frequently come with adverse side effects, including nausea, vomiting, delirium, constipation, and gastrointestinal dysfunction. The incidence of these side effects is particularly higher in the elderly population (75), and postoperative analgesic efficacy is often poorer compared to younger individuals (76). Consequently, the application of non-pharmacological and non-invasive analgesic methods in the management of acute postoperative pain has garnered increasing attention. Our research found that low-level laser therapy (LLLT) exhibits the best analgesic effects. However, due to the low certainty of evidence, further studies are required to validate this conclusion. LLLT is based on a specialized technical device capable of emitting light beams with precise characteristics for medical applications. It stimulates the mitochondria to produce ATP, enhances mitochondrial electron transport rates, regulates reactive oxygen species to reduce oxidative stress, and induces the activation of transcription factors such as AP-1, p53, NF-kB, and HIF, thereby promoting extracellular matrix deposition and activating anti-inflammatory and anti-apoptotic pathways. Clinically, these effects manifest as pain and inflammation relief, as well as facilitation of tissue repair (77–79). Literature indicates that in vitro, LLLT modulates the inflammatory response by activating the WNT pathway and inhibiting the NF-kB signaling pathway (80). In vivo, it regulates the levels of inflammatory precursor factors such as IL-1, IL-6, IL-8, and IL-18 to control the inflammatory response (81). Furthermore, LLLT positively influences bone tissue metabolism and fracture healing (82, 83) by stimulating microcirculation and increasing the activity of osteoblasts, thus enhancing the osteogenic effect (84). However, therapeutic benefits appear restricted to early healing phases (< 21 days post-fracture), with diminished efficacy in chronic non-union models.(85).

Beyond LLLT, electrical stimulation (ES) encompasses established analgesic approaches such as transcutaneous electrical nerve stimulation (TENS), non-invasive interactive neurostimulation (NIN), and interferential current (IFC). TENS delivers pulsed electrical currents transcutaneously, making it a prevalent non-pharmacological intervention for pain management (86, 87). It is capable of generating a sensation similar to acupuncture at frequencies of 2–4 Hz by stimulating Aδ and C fibers in the afferent nerves, thereby activating downstream pain inhibition pathways and producing a spatially diffuse analgesic effect (88). Studies by Gorodetskyi I et al. (49) and Lord SR et al. (89) have investigated the role of TENS in reducing acute postoperative pain in elderly patients following hip fractures, both reporting significant pain relief, which is consistent with our findings. Moreover, NIN has been shown to have a positive effect in the postoperative care of patients with femoral neck fractures (49), with its pain relief mechanism thought to involve segmental and descending neural inhibition (90). IFC operates on the principle of a low-frequency-modulated medium-frequency current created by the superposition of two medium-frequency currents with slight phase differences (91). IFC therapy is believed to alleviate pain through gate control mechanisms and the release of endogenous opioids (92). Although this therapy has been in use for decades, its physiological effects have not been fully substantiated, making it challenging to completely elucidate its analgesic action (93).

Fracture patients frequently endure acute postoperative pain, conventionally managed with analgesics. However, these pharmacological interventions often induce adverse effects such as nausea, constipation, delirium, and gastrointestinal dysfunction. According to our study, physical agent modalities significantly shortens the time to fracture healing and improves the complete healing rate in fracture patients. SUCRA ranking in this study indicates that ultrasound therapy (UST) can markedly reduce the time to complete fracture healing (days) compared to other physical agent modalities, which aligns with the findings of Kristiansen et al. (54) who reported that treatment with low-intensity pulsed ultrasound (LIPUS) shortened radiological healing times by 38%. When ultrasound propagates through biological tissues, it generates micro-mechanical strain, which stimulates biochemical responses at the cellular level and promotes bone formation (94). Fracture patients often experience prolonged immobilization, leading to a deficiency of mechanical load at the injury site. However, ultrasound can produce mechanical forces that improve the mechanical environment of the affected area, potentially facilitating endochondral ossification, a key mechanism in fracture healing (95, 96). Additionally, the mechanical stress generated by ultrasound further promotes osteogenesis, protein synthesis, calcium uptake, and DNA synthesis in various cell types (97). As ultrasound transmits through the tissue to the bone, cells adjacent to the fracture site convert biomechanical stimuli into biochemical responses via integrins, which serve as crucial molecular mediators of mechanotransduction (98). Furthermore, ultrasound stimulation increases the expression of integrins, enhancing the adhesion of osteoblasts at the fracture site, thereby aiding in fracture healing (99, 100).

Early clinical studies suggest that high-intensity ultrasound stimulation in the range of 5000 to 25000 mW/cm² may induce adverse effects including necrosis, cessation of bone healing, and fibrous tissue formation (101, 102). Consequently, low-intensity pulsed ultrasound (LIPUS) has consequently become the clinical standard (103). LIPUS has been shown to positively influence fracture healing regardless of the patient’s age, smoking status, the presence of a fracture gap, fibular fractures, or the location of distal fractures (104). Animal studies indicate that LIPUS not only accelerates the formation of bone callus but also enhances the mechanical strength at the fracture site (105, 106). During the fracture healing process, The periosteum serves as a primary reservoir for osteoprogenitor cells during bone regeneration, playing a central role in callus formation. Tam et al. (107) demonstrated that LIPUS interventions positively stimulate osteogenesis and the activation of cell differentiation in human periosteal cells. Additionally, cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) are key biological processes involved in the mineralization and remodeling phases of bone healing (108), COX-2 promotes fracture healing by upregulating genes associated with endochondral ossification and angiogenesis (98, 109), whereas PGE2 enhances collagen synthesis in cultured bone and further stimulates osteoblast proliferation (110). Tang et al. (99) and Kokubu T et al. (111) found that expression of COX-2 and PGE2 in osteoblasts was significantly increased when cells were subjected to ultrasound stimulation.

Pulsed Electromagnetic Fields Stimulation (PEMFS) has emerged as a clinical mainstay (2), demonstrating particular efficacy during the angiogenic-osteogenic coupling phase of bone repair and remodeling (112). Multiple studies have demonstrated that PEMFS actively promotes bone healing by regulating voltage-gated ion channels, increasing cytosolic calcium ion concentrations, enhancing early angiogenesis, and facilitating the differentiation and maturation of osteoblasts (113). Research indicates that PEMFS upregulates TGF-β expression and promotes the proliferation and osteogenic differentiation of stem cells via coordinated signaling through BMP, ERK/MAPK, and Notch pathways (114–117). The effectiveness of PEMFS is closely related to exposure duration, to significantly enhance fracture healing, PEMFS should be applied for at least 8 h per day over a period of 45–60 days (118). Furthermore, studies have found that PEMFS can upregulate the expression of placental growth factor (PIGF) and brain-derived neurotrophic factor (BDNF). PIGF, a member of the vascular endothelial growth factor (VEGF) subfamily, is a key regulator of angiogenesis and vasculogenesis (119). BDNF promotes angiogenesis through two mechanisms: Firstly, by locally activating subsets of endothelial cells, and secondly, by recruiting bone marrow-derived cells. These both mechanisms contribute to the formation of new blood vessels, thereby facilitating bone formation (120). Additionally, Parhampour et al. (121) discovered that PEMFS can improve bone metabolic disorders and restore joint function.

In our study, CCEFS demonstrated significant effects on fracture healing and was ranked first in the third outcome measure based on the SUCRA rankings. As a non-invasive bone growth stimulation method, CCEFS has the potential to enhance osteoblast function and increase new bone formation (122). An in vitro study revealed the mechanism of action of CCEFS, which involves the activation of voltage-gated calcium channels in the plasma membrane, leading to increased cytosolic calcium concentration and phospholipase A2 (PLA2) activity (123). The rise in cytosolic calcium activates the calmodulin pathway, further upregulating the expression of osteogenic-related genes, including fibroblast growth factor (FGF) 2, osteocalcin (OCN), TGF-β, BMP, and alkaline phosphatase (ALP) (124, 125). PLA2 promotes the synthesis of PGE2, thereby further facilitating the osteogenic process (126). Additionally, a study (127) have reported that CCEFS has a positive impact on alleviating chronic pain. However, our NMA did not demonstrate a significant effect of CCEFS on post-fracture pain relief. This may be attributed to the inclusion of only one relevant study (62), which, although indicating that CCEFS could more rapidly relieve pain, found no significant difference in the overall level of pain relief compared to the control group.

In the included studies, the number of investigations on LLLT, MS, ESWT, and CCEFS was relatively limited, largely reflecting the characteristics of each technique and their current clinical use. ESWT carries a potential risk of secondary injury due to possible adverse effects such as hematoma formation and increased pain (128). Research on MS has focused mainly on neurological rehabilitation (129), with comparatively less application in fracture treatment. CCEFS already has a well-established therapeutic protocol for fracture healing (122), and its technical stability has resulted in fewer novel research directions. For LLLT, progress in fracture pain management has been slow, partly due to the lack of standardization in pain assessment tools (such as VAS, NRS, and the McGill Pain Questionnaire) and partly because current clinical practice still relies heavily on pharmacological analgesia (130). These factors may together contribute to the current relative scarcity of research on these therapies in the field of fracture rehabilitation.

First, restricted study availability and underpowered sample sizes compromised generalizability while reducing statistical precision. Second, there was an imbalance in the number of comparisons and sample sizes among the physical agent modalities. Among the three different outcome measures, studies on UST constituted the largest proportion, while those on CCEFS and MS comprised the smallest, which may have impacted the research findings. Third, we acknowledge the substantial heterogeneity observed in this study, which may largely stem from clinical differences among the included trials, such as variations in fracture type, duration of intervention, and device parameters. Because the original studies provided insufficient data, we were unable to perform subgroup analyses to further explore the specific influence of these factors. Therefore, the findings of this network meta-analysis should be interpreted as representing an overall effect across diverse clinical contexts. Future studies should adopt more standardized designs and provide more detailed reporting to better account for these key variables. Fourth, the lack of direct comparisons between physical agent modalities, relying instead on indirect evidence, may limit the reliability and comprehensiveness of the conclusions. Finally, the use of SUCRA scores does not account for differences in study quality and relies solely on relative ranking to evaluate treatment efficacy. Including low-quality studies may introduce bias and lead to systematic errors in effect size estimation. When such biased estimates are incorporated into a network meta-analysis model, they can distort the true comparative effectiveness between treatments, causing the SUCRA rankings to deviate from reality and reducing their overall reliability. Given that the design of the SUCRA scoring system focuses on relative efficacy while neglecting effect size, it may inadvertently undermine the clinical significance of the treatment effects.

Physical agent modalities demonstrate therapeutic potential in fracture management, effectively reducing pain and enhancing osseous regeneration. In indirect head-to-head comparisons, although different physical agent modalities did not show clear advantages or disadvantages in pain relief and fracture healing, this study provides valuable insights for clinical decision-making. Notably, LLLT and ES displayed potential advantages in pain alleviation, while UST and CCEFS exhibited superior effectiveness in promoting fracture healing. However, these preliminary conclusions require validation through high-quality, large-sample randomized controlled trials, and further clinical research is necessary to confirm the efficacy of these interventions.