In this study, we found that after 8 weeks of treatment, hypertonic glucose injection demonstrated greater improvements in VAS, WOMAC, and SF-36 scores compared to PRP injection therapy. However, at 16 and 32 weeks post-treatment, the efficacy of PRP injection was superior to that of hypertonic glucose injection. From an economic perspective, the total cost of PRP injection therapy was significantly higher than that of hypertonic glucose injection therapy.
With the continuous maturation of PRP preparation techniques, its clinical applications have become increasingly widespread, including in chronic soft tissue injuries [22], reproductive medicine [23], and medical cosmetics [24]. PRP, derived from the centrifugation of the patient’s own venous blood, eliminates concerns about autoimmune reactions post-injection. Following centrifugation, the platelet concentration in PRP is typically 3–5 times higher than normal plasma levels [25], containing various growth factors such as platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), and vascular endothelial growth factor (VEGF) [26]. Among these factors, PDGF is released earliest [27] and has been shown to promote collagen and proteoglycan synthesis, facilitating cartilage tissue repair [28]. Sarban et al. observed significant cartilage regeneration in New Zealand rabbits after introducing PDGF-infused collagen sponges into knee cartilage defects, with new cartilage growth at the defect site after 12 weeks [29]. TGF-β plays a pivotal role in promoting mesenchymal stem cell differentiation into cartilage and regenerating chondrocytes [30]. It inhibits matrix metalloproteinase-13 (MMP13) activation, promotes MMP14 proteasome degradation, mitigates inflammatory responses in the knee joint, and slows the progression of knee osteoarthritis [31]. VEGF stimulates angiogenesis, enhances microcirculation within the knee joint, and improves the supply of nutrients and oxygen to damaged tissues [32]. The findings of this study suggest that intra-articular PRP injections significantly alleviated patient pain compared to pre-treatment levels. This improvement is likely due to the combined effects of various growth factors, which suppress inflammatory responses and may contribute to cartilage repair.
hypertonic glucose injection is a common non-surgical treatment method for various soft tissue injuries, including tendons and cartilage, in clinical practice. Following local injection of hypertonic glucose, the tissue undergoes self-repair through three stages: inflammatory response, cell proliferation, and tissue remodeling [33]. Studies have shown that intra-articular injection of hypertonic glucose increases the expression of inflammatory factors, such as RAGE, CA11, GDF-15, TREM-1, and IL-22, along with growth factors, including TGF-β and EGF, within the knee joint [34]. These inflammatory factors stimulate the activation of inflammatory cells and participate in the regulation of inflammation. Numerous studies have demonstrated that TGF-β and EGF promote the restoration of knee cartilage damage by enhancing the proliferation of mesenchymal stem cells [35, 36]. Hsieh et al. observed that, compared to injections of hyaluronic acid or saline, intra-articular injection of hyaluronic acid combined with hypertonic glucose significantly alleviated pain, improving patients’ fastest walking speed and stair-climbing time [37]. Similarly, Topol et al. reported that hypertonic glucose injection therapy not only alleviated pain and improved knee function in patients with KOA but also stimulated cartilage growth [38]. A 52-week study further demonstrated that hypertonic glucose injection significantly improved knee pain and function from 12 weeks to 52 weeks when compared to saline injection and home exercise therapy [39]. The results of this study align with previous findings, confirming that hypertonic glucose injection effectively reduces VAS and WOMAC scores, thereby improving pain and knee function.
Despite its effectiveness, the severe soreness, swelling, and pain experienced around the knee joint within 48 hours after hypertonic glucose injection are intolerable for many patients. Additionally, the long-term efficacy of hypertonic glucose therapy is inferior to that of PRP. Traditional knee injection methods also present challenges, as they often fail to ensure accurate delivery of the injection. Lam et al. found that conventional methods frequently result in liquid being injected into the infrapatellar fat pad rather than the knee joint cavity. To address this issue, they demonstrated that ultrasonography-guided injections via the infrapatellar approach significantly improve accuracy [40]. In this study, PRP and hypertonic glucose solutions were injected into the suprapatellar bursa under ultrasonographic guidance. The fluid was manually promoted to flow into the joint cavity, which not only reduced the complexity of the procedure but also improved injection accuracy. This study observed a safety outcome that warrants high attention: as many as 70.13% of patients reported experiencing severe pain following the injection of hypertonic glucose. This incidence rate is significantly higher than the common transient pain response rates reported in the literature for many other intra-articular injection therapies (such as hyaluronic acid, corticosteroids, or PRP injections) [cite relevant literature if available]. We believe this is primarily attributable to the strong physicochemical stimulatory effect of the hypertonic glucose solution. Its high osmotic pressure can cause acute inflammatory reactions and sensitization of nerve endings in the tissues at the injection site (synovium, ligament/tendon attachment points), thereby triggering significant pain sensations. This mechanism is similar to the ‘distension pain’ observed when hypertonic glucose is used in the treatment of soft tissue proliferative diseases. This high incidence of pain reactions carries significant clinical implications. It indicates that, although hypertonic glucose injection may show potential for improving certain mid-term KOA outcome measures, its clinical application must be based on a rigorous benefit-risk assessment. When making treatment decisions, this high probability of a significant adverse reaction must be a key consideration. Unfortunately, due to the retrospective design of this study, there were deficiencies in the systematic recording of the exact duration of pain in the medical records, which is a limitation. However, based on clinical experience and relevant literature, this post-injection pain is typically acute and transient, often reaching its peak within minutes to hours after the injection and significantly relieving or completely disappearing within 24 to 72 h. Future prospective studies must prospectively and standardize the assessment of pain intensity, onset time, peak time, duration, and relief patterns to more accurately depict its safety profile.
The data source for this study was medical records, which may contain incomplete or inaccurate information. Additionally, the lack of random allocation introduces the possibility of selection bias, as certain patients may have been chosen for a specific treatment method based on particular criteria. This study primarily evaluated short-term outcomes following treatment, including pain scores, functional status, and quality of life. However, as KOA is a chronic disease requiring long-term management and lifestyle interventions, the absence of extended follow-up data limits the comprehensive assessment of treatment effects. In the multivariate regression analysis, adjustments were made for potential confounding factors such as age, gender, and BMI. Nevertheless, other unconsidered confounding factors may remain, potentially influencing the interpretation and generalization of the results. Future research should address these limitations by conducting prospective, multicenter, double-blind clinical trials to minimize biases and confounding factors. Furthermore, incorporating imaging modalities such as MRI to evaluate cartilage growth and extending the follow-up period will provide more robust evidence to guide the clinical management of KOA. The primary follow-up endpoint set in this study was 32 weeks. We fully recognize that in the field of knee osteoarthritis (KOA) treatment research, especially when evaluating potential disease-modifying effects or delaying structural progression, “long-term” follow-up typically refers to ≥ 1 year or even longer periods. Therefore, a follow-up period of 32 weeks is insufficient to be defined as “long-term” in a strict sense, which limits our ability to explore the potential long-term impacts of hypertonic glucose injection on joint structure and also prevents us from determining whether its symptom-relieving effects can last beyond 32 weeks. This is an important limitation of this study. However, 32 weeks, as a “mid-term to longer-term” or “extended mid-term follow-up” time point, still has significant implications in assessing the clinical value of intra-articular injection therapies.
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