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Hung Van Le* Biologics & Drug Targets, ProSci LLC, Rockaway, The United States ORCID https://orcid.org/0000-0002-6913-2373 (Hung Van Le)  Abstract This narrative review summarizes key recent clinical findings on the daily use of multivitamin-mineral (MVM) supplements, with emphasis on evidence most relevant to aging and personal health decisions. Recent randomized trials suggest that daily MVM use in older adults may provide modest but clinically meaningful benefits in selected domains, especially global cognition and episodic memory, with less consistent evidence for executive function. Additional findings support a reduction in cataract incidence, a potential benefit for some cancer outcomes, and a possible slowing of biological aging as measured by epigenetic clocks. By contrast, current evidence does not support clear benefits for cardiovascular disease prevention, adjudicated mild cognitive impairment, dementia incidence, or age-related macular degeneration. These findings both complement and contrast with current recommendations from major health agencies, which remain cautious and do not endorse routine MVM use for all adults. The practical implication is not that everyone should take a daily MVM, but that the newer evidence provides a stronger basis for individualized decision-making. Readers may find this information useful when considering their own diet, age, chronic conditions, medications, and family history, and when deciding whether discussion of MVM supplementation with a clinician is warranted as part of a broader strategy to support healthy aging. Introduction Although the topic may seem trivial and often appears in the news or in everyday conversation, the concerns are legitimate. Vitamin and mineral deficiencies are a worldwide problem, especially in lower-income countries where inadequate nutrition remains widespread. One recent estimate suggests that up to 5 billion of the world’s 8.3 billion people have micronutrient deficiencies, with different effects in males and females [1]. Even in higher-income settings, adequate intake is not guaranteed because diet, lifestyle, health status, cultural factors, and aging all influence nutritional needs. Fortunately, people in higher-income countries have access to abundant, generally clear guidance on meeting micronutrient needs through diet and, when appropriate, supplementation. In the United States, for example, the Centers for Disease Control and Prevention (CDC) provides guidance about micronutrients, the U.S. Preventive Services Task Force (USPSTF) offers its own recommendations, and the National Institutes of Health (NIH) Office of Dietary Supplements provides fact sheets for consumers and health professionals. Despite the guidance provided by health agencies, many people still rely primarily on advice from trusted clinicians when deciding whether to take multivitamin-mineral supplements (MVMs). Others, more skeptical of the medical establishment, related industries, or public health agencies, may follow medical news closely to better understand their health and the implications of new findings. Recent reports that daily MVM use may slow epigenetic clocks [2] are likely to renew interest in a familiar question: whether to take MVMs, and if so, at what stage of life. Do daily multivitamins slow epigenetic clocks and reduce biological age? The original study by Li et al. (2026) [3] was a prespecified ancillary analysis of the Cocoa Supplement and Multivitamin Outcomes Study (COSMOS), a large randomized, placebo-controlled trial involving 958 older adults with a mean age of 70 years. Participants received a daily multivitamin-multimineral supplement (Centrum Silver), cocoa extract, both interventions, or placebo. Researchers measured five DNA methylation-based “epigenetic clocks” at baseline and again after two years. The main finding for the multivitamin arm was a statistically significant slowing of biological aging on two of the five clocks studied, especially PCPhenoAge [4] and PCGrimAge [5]. The estimated effect corresponded to roughly 2.5 to 5 fewer months of biological aging over two years. Participants whose biological age exceeded their chronological age at baseline appeared to benefit most. Additional analyses suggested that participants whose clock measures improved also showed lower inflammation and better preservation of cognitive function. Methodologically, this is among the strongest supplement studies conducted to date because it was randomized, placebo-controlled, prospectively planned, and based on a relatively large, well-characterized cohort. The findings are thought-provoking, but by themselves they are unlikely to change clinical practice for prescribing multivitamin-mineral supplements to older adults. That caution is understandable because the study also has important limitations. Most importantly, epigenetic clocks are surrogate end points. They do not show that participants lived longer, avoided disability, prevented fractures, or reduced cardiovascular events. Instead, they reflect changes in biomarkers thought to track biological aging. Whether modest improvements in these clocks translate into meaningful clinical benefits remains uncertain. A biomarker can reach statistical significance without producing clear patient benefit. In addition, the effect size was modest, not all clocks changed, and the study was not designed to identify which components of the multivitamin-multimineral supplement produced the observed effect. Without a stronger mechanistic basis, targeted recommendations would be difficult. The most encouraging aspect of the study is its consistency with earlier COSMOS and Physicians’ Health Studies (PHS) examining the effects of daily multivitamin use on major health outcomes. The new findings on biological age, as measured by epigenetic clocks, should therefore be interpreted in the context of the broader clinical evidence from those large trials. Effects of daily MVM treatment on cancer incidence The effects of daily MVM use on cancer incidence were examined in both the PHS and COSMOS trials. In a randomized, double-blind, placebo-controlled trial, Gaziano et al. [6] evaluated daily MVM use in 14,641 U.S. male physicians aged 50 years or older in PHS II, including 1,312 men with a history of cancer at randomization. Median follow-up was 11.2 years (range, 10.7–13.3). Among men with and without a prior cancer history, daily MVM use was associated with a modest reduction in overall cancer incidence. Subgroup analyses further suggested that survivors of epithelial cancers may have benefited the most. A later COSMOS trial, reported by Sesso et al. [7], examined a larger and more heterogeneous cohort of 21,442 U.S. adults (12,666 women aged 65 years or older and 8,776 men aged 60 years or older) who were free of major cardiovascular disease and recently diagnosed cancer at baseline. This randomized, double-blind, placebo-controlled trial had a much shorter median follow-up of 3.6 years. In contrast to PHS II, COSMOS found no statistically significant difference in overall cancer incidence or all-cause mortality between the multivitamin and placebo groups. However, subgroup analyses by cancer site suggested a significant reduction in lung cancer incidence. These results are not necessarily contradictory. PHS II showed a small reduction in total cancer incidence after more than a decade of supplementation in male physicians, whereas COSMOS found no statistically significant reduction during a much shorter follow-up in an older, more heterogeneous population. Given the substantial differences in follow-up duration, demographic composition, and baseline risk, the two trials are best viewed as complementary rather than as directly comparable tests of the same hypothesis. Effects of daily MVM treatment on cognition, memory, and executive function Three COSMOS studies reported since 2023 have provided the clearest evidence to date on the cognitive effects of daily MVM supplementation in older adults. In COSMOS-Mind, a randomized, double-blind, placebo-controlled substudy of 2,262 participants (mean age 73 years; 60% women; 89% non-Hispanic White), Baker et al. [8] evaluated the effect of daily MVM use on global cognition after a mean follow-up of three years. Compared with placebo, daily MVM supplementation produced a statistically significant benefit in global cognition, with the largest effect among participants with a history of cardiovascular disease. Benefits were also observed for episodic memory and executive function. In the same year, Yeung et al. [9] analyzed a different COSMOS subgroup, COSMOS-Web, consisting of 3,562 older adults (mean age 71 years; 67% women; 93% non-Hispanic White) followed for up to three years. The primary end point was episodic memory at one year, with three secondary outcomes assessed over three years: episodic memory, performance on novel object recognition tasks, and executive function. Compared with placebo, participants assigned to daily MVM supplementation showed significantly better episodic memory at one year and across the full three-year follow-up. No significant differences were detected for the other two secondary outcomes. The most recent analysis, reported by Vyas et al. [10], drew on all three cognitive COSMOS subgroups: COSMOS-Clinic (573 participants, two years of follow-up), COSMOS-Web (2,472 participants, three years), and COSMOS-Mind (2,158 participants, three years). COSMOS-Clinic was used to assess global cognition as the primary end point, with episodic memory and executive function as secondary outcomes after two years. The study found modest benefits in global cognition and significantly more favorable change in episodic memory, but no benefit for executive function or attention. The authors then performed a meta-analysis across all three COSMOS cognitive subgroups, focusing on global cognition and episodic memory as primary outcomes. Compared with placebo, daily MVM supplementation was associated with significantly more favorable change over time in both domains. Taken together, these three studies suggest that daily MVM supplementation improves global cognition and episodic memory in older adults, whereas evidence for executive function is less consistent. Memory improvement appears to be the most robust and reproducible finding, and improvement in global cognition is reasonably well supported. A benefit for executive function remains plausible but is not yet firmly established. This may reflect greater biological heterogeneity in executive function or the use of measures that are noisier and less statistically powerful. Effects of daily MVM treatment on cognitive impairment and dementia Progressive decline in global cognition, memory, and executive function can lead to mild cognitive impairment (MCI) and, eventually, dementia—outcomes that can be formally adjudicated by expert panels. Sachs et al. [11] examined whether daily MVM supplementation, compared with placebo, affected the incidence of adjudicated MCI and all-cause dementia in the COSMOS-Mind cohort of 2,662 participants with a mean age of 73 years. After three years of follow-up, the incidence of neither outcome differed significantly between the MVM and placebo groups. However, among participants adjudicated as having MCI, those assigned to daily MVM performed better on tests of global cognition and executive function when scores at the time of adjudication were compared with scores obtained one year earlier. In the smaller subgroup adjudicated as having dementia, no clear differences were observed in global cognition, executive function, or memory. These latter results should be interpreted cautiously because the dementia subgroup was small and therefore statistically underpowered. Overall, COSMOS-Mind did not show that daily MVM supplementation reduces the incidence of cognitive impairment or dementia over three years, but the favorable cognitive findings within the MCI subgroup are consistent with the broader cognitive benefits reported elsewhere in COSMOS, including by Baker et al. (2023) [8]. Effects of daily MVM treatment on cataract and age-related macular degeneration (AMD) Cataracts are common in older adults, whereas AMD is less common but remains a major cause of vision loss. Christen et al. [12] evaluated whether long-term daily multivitamin supplementation affected the incidence of cataract and age-related macular degeneration in 14,641 male physicians aged 50 years or older in the Physicians’ Health Study. In this randomized, double-blind, placebo-controlled trial, participants were followed for a mean of 11.2 years. Daily multivitamin use was associated with a modest but statistically significant reduction in cataract risk, but it had no significant effect on visually significant AMD. The cataract finding is consistent with results from two smaller independent trials: Maraini et al. [13], which followed 1,020 participants aged 55 to 75 years for about nine years, and Sperduto et al. [14], which studied 2,141 participants aged 45 to 74 years in a rural Chinese community over five to six years. Effects of daily MVM treatment on cardiovascular disease Two large randomized trials—PHS II (Sesso, H. D. et al. [15]) and COSMOS (Sesso, H. D. et al. [7])—found that daily MVM supplementation did not reduce major cardiovascular events, myocardial infarction, stroke, or cardiovascular mortality. Mean treatment and follow-up durations were 11.2 years in PHS II and 3.6 years in COSMOS. The PHS II cohort included 14,641 U.S. male physicians aged 50 years or older, whereas COSMOS enrolled 21,442 U.S. adults, including 12,666 women aged 65 years or older and 8,776 men aged 60 years or older.  Discussion Taken together, the evidence reviewed here suggests that daily multivitamin-mineral (MVM) supplementation has produced several clinically relevant benefits in large randomized trials, although the strength of evidence varies by outcome. The most reproducible benefits have been observed in cognition among older adults, especially for global cognition and episodic memory in the COSMOS substudies, with less consistent evidence for executive function. Table 1 also indicates a modest reduction in overall cancer incidence in PHS II, a possible reduction in epithelial cancer incidence in that trial, a signal for lower lung cancer incidence in COSMOS, and a statistically significant reduction in cataract incidence in long-term follow-up studies. The newer COSMOS-Blood findings add a biologically interesting signal that daily MVM supplementation may modestly slow epigenetic aging, but this result should still be regarded as supportive rather than definitive because biological age is a surrogate marker rather than a hard clinical outcome. By contrast, the evidence does not currently support a reduction in cardiovascular events, mild cognitive impairment incidence, dementia incidence, or age-related macular degeneration. For personal health, these findings are potentially meaningful because they point to benefits in areas that strongly affect independence and quality of life with aging. Even modest preservation of memory or global cognition may matter to older adults who want to maintain functional autonomy, medication management, financial judgment, and social engagement. A small reduction in cancer incidence or cataract risk can also be clinically meaningful when applied over many years, especially because cataracts and cancer are common age-related conditions. At the same time, the significance of these benefits should not be overstated. The demonstrated effects are generally modest, they do not establish that MVMs are a substitute for a healthy diet, and they do not show broad protection across all major chronic diseases. The most reasonable interpretation is that daily MVM supplementation may serve as a low-risk supportive strategy for selected adults, particularly when micronutrient intake may be less reliable because of age, appetite changes, chronic illness, restricted diets, or medication use. These newer findings also create an important tension with current health agency recommendations. The U.S. Preventive Services Task Force (USPSTF) states that evidence remains insufficient to recommend for or against multivitamins for the prevention of cancer or cardiovascular disease in community-dwelling, nonpregnant adults, while specifically recommending against beta carotene and vitamin E for those purposes. That position is understandable because the USPSTF framework focuses on prevention of major clinical end points in generally healthy populations and gives substantial weight to consistency, magnitude of effect, and certainty across trials. Similarly, the NIH Office of Dietary Supplements emphasizes that MVMs do not replace healthy dietary patterns, that formulations vary substantially, and that supplements can help fill nutrient gaps but can also increase the risk of excessive intake of some nutrients. The CDC likewise frames micronutrient sufficiency as important for health but does not treat routine MVM use as a universal preventive intervention for all adults. In other words, the newer trial results do not necessarily overturn existing agency guidance; rather, they suggest that the evidence base for selected benefits of daily MVM supplementation in older adults is becoming stronger than many recommendations currently reflect. A practical way to leverage this information is to think about MVM supplementation through the lens of personal risk rather than as a universal rule. A person with a family history of cognitive decline, memory problems, cataracts, or certain cancers might view the current data as a reason to discuss a standard, age-appropriate MVM with a clinician, especially if dietary intake is inconsistent or if there are risk factors for micronutrient insufficiency such as gastrointestinal disease, vegetarian or highly restrictive eating patterns, low appetite, frailty, polypharmacy, or alcohol overuse. Someone with established cardiovascular disease should recognize that current evidence does not support MVM use as a strategy to prevent heart attack, stroke, or cardiovascular death, even though cognitive benefits may still be relevant in some subgroups. Likewise, a person with a strong family history of dementia should understand that the current evidence is more supportive for slowing cognitive decline than for preventing adjudicated dementia over the short term. This distinction matters because expectations should be realistic: MVMs may help preserve function in some domains, but they should not be presented as a proven way to prevent all age-related diseases. As for timing, the best time to think seriously about MVM supplementation is probably before nutritional vulnerability becomes obvious, but not necessarily in early adulthood for everyone. The clearest trial evidence in this review comes from adults in later life, generally from the early 60s onward, when risks of cognitive decline, cataract, cancer, and subclinical nutritional insufficiency become more relevant. For many people, midlife is therefore a reasonable time to begin considering whether their diet, health conditions, medications, and family history justify supplementation, while older adulthood is the period in which potential benefits may be most actionable. This does not mean that every healthy younger adult should take a daily MVM, nor does it imply that starting later guarantees benefit. Rather, it suggests that MVM use is best approached as part of anticipatory aging care: a decision revisited when diet quality declines, chronic disease accumulates, or family history raises concern about cognitive or age-related outcomes. In that sense, the new evidence is most useful not as a blanket recommendation, but as a prompt for individualized, age-aware decision-making grounded in both personal health context and the limits of the current evidence. Conclusion Our review summarizes the latest clinical findings on the daily use of multivitamin-mineral (MVM) supplements and shows that the evidence now supports selected benefits more clearly than many people may realize, particularly for global cognition, episodic memory, cataract risk, and possibly biological aging, with a potential benefit for some cancer outcomes, while benefits for cardiovascular disease, dementia, and some other outcomes remain unproven. In that sense, this review both supplements and contrasts current information and recommendations from health agencies, which appropriately remain cautious and do not endorse routine MVM use for all adults. The most useful implication is not a blanket recommendation, but a stronger basis for individualized reflection and action. At different stages of life, especially in midlife and older adulthood, individuals can use this information to consider their diet, health conditions, medications, and family history, discuss the possible role of MVM supplementation with their doctors, and decide whether a standard, age-appropriate product fits their overall preventive health strategy. Used thoughtfully, MVM supplementation may be one small but meaningful part of a broader plan to support healthy aging. References
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Hung Van Le* Biologics & Drug Targets, ProSci LLC, Rockaway, The United States ORCID https://orcid.org/0000-0002-6913-2373 (Hung Van Le) Abstract
Post-polio syndrome (PPS) is a progressive neuromuscular disorder that affects a substantial proportion of long-term survivors of poliomyelitis. Traditionally viewed as a consequence of motor unit exhaustion, PPS is increasingly recognized as a multifactorial condition involving neurodegeneration, chronic low-grade inflammation, and, more recently, persistent low-level poliovirus infection. These emerging insights point to a more complex disease model that integrates viral persistence, impaired humoral immunity, and metabolic stress in compensatory motor units. Vitamin D, a pleiotropic secosteroid hormone, has been implicated in several biological processes relevant to PPS, including immune regulation, mitochondrial function, and muscle physiology. Recent findings indicate that vitamin D deficiency is common in PPS patients and may contribute to impaired immune competence and disease progression. While vitamin D does not directly target the primary neurodegenerative process, it may enhance neuromuscular resilience through immunomodulatory and metabolic effects. This review examines the mechanistic intersections between vitamin D signaling and PPS pathophysiology, with particular emphasis on immune function, mitochondrial energetics, and neuromuscular junction stability. It further discusses the clinical role of vitamin D as a supportive intervention and evaluates the potential need for antiviral strategies considering evidence for persistent poliovirus infection. A multimodal therapeutic approach combining antiviral therapy, immune optimization, and metabolic support is proposed as a rational framework for future PPS management. Introduction Post-polio syndrome (PPS) is a late-onset neurological disorder that affects individuals decades after recovery from acute poliomyelitis caused by Poliovirus. Clinically, PPS is characterized by new or progressive muscle weakness, fatigue, pain, and functional decline following a prolonged period of neurological stability. The syndrome typically emerges 15 to 40 years after the initial infection and represents one of the most significant long-term complications of the global poliomyelitis epidemics of the 20th century. Although the incidence of acute poliomyelitis has declined dramatically due to widespread vaccination programs, the population of polio survivors remains substantial. Current estimates suggest that 15–20 million individuals worldwide are living with the sequelae of prior poliovirus infection [1], of whom approximately 20–85% may develop PPS depending on diagnostic criteria [2]. As this population ages, PPS represents an increasing clinical and public health challenge, particularly in regions with historically high poliomyelitis burden. Currently, there is no disease-modifying therapy for PPS. Management remains largely supportive and includes physical rehabilitation, with carefully tailored exercise programs to optimize motor unit function while avoiding overuse, symptomatic treatment for pain, fatigue, and sleep disturbances, and orthotic support and assistive devices to improve mobility. Among pharmacological approaches, intravenous immunoglobulin (IVIG) has shown modest benefits in selected patients, particularly in reducing pain and inflammatory markers, although its effects on muscle strength and long-term progression remain limited. In this context of limited therapeutic options, there is increasing interest in interventions that can enhance systemic resilience rather than directly reverse neuronal loss. Vitamin D has attracted attention due to its broad biological activity, including immunomodulatory, metabolic, and neuromuscular effects. Notably, recent studies have identified a high prevalence of vitamin D deficiency in PPS patients, raising the possibility that it may contribute to disease pathophysiology rather than merely reflect lifestyle factors. This review aims to integrate current knowledge on PPS with emerging insights into vitamin D biology and antiviral strategies. By examining the intersections between viral persistence, immune function, and neuromuscular degeneration, it seeks to propose a more comprehensive framework for understanding and managing PPS. Pathophysiology of Post-Polio Syndrome: from motor unit failure to persistent viral signaling Post-polio syndrome (PPS) is classically explained by progressive failure of enlarged motor units that compensated for the initial loss of anterior horn cells after acute poliomyelitis. Over decades, these metabolically stressed neurons undergo distal degeneration, leading to neuromuscular junction (NMJ) instability and denervation [3]. However, this “purely degenerative” view has been challenged by accumulating immunological data. Studies have demonstrated elevated cytokines in cerebrospinal fluid and blood, suggesting chronic low-grade inflammation [4-8]. This inflammatory component is substantially strengthened by recent work from Toniolo et al. [9] who reported evidence consistent with persistent low-level Poliovirus infection in long-term polio survivors with PPS. The evidence came from co-culturing PPS-derived samples, including peripheral blood leukocytes, cerebrospinal fluid, duodenal biopsy specimens, and skeletal muscle fragments, with poliovirus-susceptible cell lines. Poliovirus was then detected by RT-PCR in cell culture supernatants and by immunofluorescence in the cultured cell monolayers. This work was built on earlier studies by Leparc-Goffart et al. [10] and Julien et al. [11], which had identified poliovirus in the CSF of a smaller group of PPS patients using RT-PCR. The observed persistent infection supports a model in which ongoing viral persistence may drive chronic immune activation, rather than inflammation being purely secondary. The authors further described humoral immune deficiencies in PPS patients, altered neutralizing antibody profiles, and a high prevalence of vitamin D deficiency [12]. Together, these findings suggest that PPS may involve a triad of residual viral persistence, inadequate humoral immune control, and chronic low-grade inflammation. The available evidence reframes PPS as a hybrid condition, combining neurodegeneration, immune dysregulation, and possible viral persistence. Relevance of Vitamin D in PPS The prevalence of vitamin D deficiency raises questions about its ultimate role in the etiology of PPS. It could simply be a by-product of patients’ lifestyle (poor diet, inadequate mobility and physical activities, and limited sun exposure), or alternatively it could be a bona fide risk factor. A combination of both could be plausible as well. As an established pleiotropic modulator of multiple pathways [13] vitamin D could be uniquely positioned to affect the development of PPS. How vitamin D signaling intersects with PPS pathways is explored below. Immunomodulation and antiviral defense. Vitamin D signaling suppresses pro-inflammatory T helper 1 responses and reduces IFN-γ production [14]. Beyond dampening inflammation, vitamin D also enhances innate immune responses, supports antimicrobial peptide production, and modulates B cell function. In the context of the finding by Toniolo et al. [9,12], this is particularly relevant since vitamin D deficiency may exacerbate impaired humoral immunity, potentially allowing persistent poliovirus activity. Thus, vitamin D may not only reduce inflammation but also improve immune competence against residual viral antigenic stimulation. Muscle and mitochondrial energetics. Vitamin D influences skeletal muscle through improved mitochondrial oxidative function [15] and regulation of mitochondrial dynamics and respiration [16]. Given that PPS involves fatigable muscle and metabolically stressed motor units, vitamin D may enhance bioenergetic resilience, even if it does not halt neuronal loss. Neuromuscular junction stability and mitochondrial energetics. The progressive functional decline observed in Post-Polio Syndrome is closely linked to instability of the neuromuscular junction (NMJ), which represents the final common pathway of motor neuron degeneration. In PPS, surviving motor neurons form enlarged motor units that are metabolically overextended. Over time, this leads to distal axonal degeneration, impaired synaptic maintenance, and failure of reinnervation, with NMJ dysfunction preceding overt muscle fiber loss. A critical but often underemphasized aspect of NMJ stability is local energy supply. Maintenance of synaptic transmission, vesicle recycling, and ion homeostasis requires tightly regulated ATP production. This demand is met by mitochondria localized at both pre- and postsynaptic compartments, whose function is essential for sustaining neuromuscular signaling. In aging and neurodegenerative conditions, impairment of mitochondrial function—rather than sheer mitochondrial number—has been implicated as a limiting factor in synaptic resilience. Vitamin D has been shown to influence mitochondrial biology at multiple levels, including enhancement of oxidative phosphorylation, modulation of mitochondrial dynamics, and regulation of transcriptional programs involving PGC-1α [15,16]. Although there is no direct evidence that vitamin D regulates axonal mitochondrial transport or synapse-specific mitochondrial targeting, its effects on mitochondrial efficiency and cellular energetics provide a plausible mechanism for improving NMJ stability under conditions of metabolic stress. In this context, vitamin D may contribute to functional preservation of neuromuscular transmission by improving ATP availability in muscle and possibly nerve terminals, reducing oxidative stress that destabilizes synaptic structures, and supporting the metabolic demands of enlarged motor units. This interpretation aligns with the broader view of PPS as a disorder of metabolic exhaustion of compensatory motor units, where interventions that enhance bioenergetic capacity may delay functional decline. Collectively, these observations indicate that vitamin D may enhance the metabolic stability of existing synapses, thereby slowing functional deterioration. Clinical positioning: supplementation vs therapeutic dosing This leads to an important clinical consideration: in what context should vitamin D be used in PPS? As a nutritional supplement, maintaining adequate serum 25-hydroxyvitamin D levels (50-125 nmoles/L) is clearly warranted. PPS patients are at increased risk of deficiency due to reduced mobility and sun exposure, and correction of deficiency supports bone health, muscle function, and overall metabolic stability. The use of high-dose vitamin D as a therapeutic intervention remains uncertain. While high-dose regimens (100,000 IU cholecalciferol, every two weeks for 24 months) have shown benefits in Multiple in Sclerosis [17] and potentially in upper respiratory viral infections [18-20], there is currently no direct clinical evidence supporting such an approach in PPS. Moreover, vitamin D exhibits dose-dependent effects, and excessive supplementation may not yield proportional benefit. A more coherent approach is to incorporate vitamin D into a multimodal management strategy, alongside targeted physical therapy to optimize motor unit function, adequate protein and caloric intake, and interventions aimed at preserving mitochondrial and neuromuscular health. The goal here is to remove an exacerbating factor while hoping for disease modifications resulting from a beneficial effect on immune competence, muscle function, and bone health. The role of vitamin D supplementation in PPS is only supportive and there is clearly a need to look beyond seeking curative treatment. Therapeutic implications: beyond vitamin D Rationale for antiviral therapy. Evidence of persistent poliovirus infection and defective replication [10,11,9] supports consideration of antiviral therapy in PPS. Combined with physical rehabilitation and the immune and metabolic support potentially provided by vitamin D, an antiviral component could help form a more mechanistically comprehensive treatment strategy. However, no antiviral drugs are currently approved specifically for poliovirus, and historical drug-development efforts were limited in part by the success of global polio vaccination programs. Current development landscape. Momentum in the field has been sustained by the Polio Antivirals Initiative (PAI), which aims to develop therapies that reduce vaccine-derived poliovirus shedding in immunodeficient recipients of oral polio vaccines and mitigate the risk of prolonged excretion in a post-eradication setting. Current discovery efforts focus on four broad approaches: inhibitors of the viral capsid, viral protease, and RNA replication, as well as agents targeting host factors required for replication [21, 22]. Capsid inhibitors. Pleconaril and pocapavir are the most advanced candidates, having reached human studies in vaccine-derived poliovirus infection and oral poliovirus vaccine challenge models [23-27]. Pocapavir is also available for compassionate use through its developer, ViroDefense, or via the PAI. RNA-replication inhibitors. Ribavirin, a broad-spectrum inhibitor of viral RNA replication, has been used compassionately in a patient with vaccine-derived poliovirus infection but did not clear the virus [25]. In contrast, remdesivir was associated with viral clearance in that same patient [28]. Remdesivir (Veklury), a nucleoside analog widely used during the COVID-19 pandemic as an inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase, therefore represents an intriguing candidate for further study in persistent poliovirus infection. That signal should be interpreted cautiously: the remdesivir evidence is currently limited to a single case report and has not yet been independently replicated. Even so, its availability and established clinical safety profile make it a reasonable high-priority option for off-label compassionate use in carefully selected patients with documented persistent poliovirus infection and shedding. Other inhibitors and future directions. All known poliovirus protease inhibitors and agents targeting host factors remain at the preclinical stage [21,22]. Nevertheless, recent findings on persistent infection, together with renewed progress in antiviral development, provide a strong rationale for reinvigorating this field. From a compassionate-care perspective, such efforts are justified by the potentially large global burden. Conclusion Vitamin D is best understood as a pleiotropic adjunct in PPS, which may improve immune balance, mitochondrial function, and possibly NMJ resilience. Its deficiency, common in PPS, should be corrected as part of standard care. However, evidence for high-dose therapeutic use remains lacking and its effects are supportive rather than disease-modifying. In light of emerging evidence for persistent poliovirus infection and immune dysregulation, future therapeutic strategies should expand beyond supplementation alone. A combination approach including antiviral therapy, immune optimization, and metabolic support may offer the most rational path forward in PPS management. References
Acknowledgment: Dr. NhuCo Lethi provided the initial inspiration for this article on PPS.  Introduction The idea that aging itself might be modifiable is no longer confined to science fiction. A growing field known as geroscience has identified multiple biological pathways (Figure 1) that appear to drive aging and age-related disease [1,2]. Drugs that target these pathways are often referred to as gerotherapeutics. Once purely experimental, gerotherapeutics are now “coming of age.” Several existing medications originally developed for diabetes, osteoporosis, or transplantation, have been shown to either extend lifespan or improve healthspan in animal models and, in some cases, human observational studies [3,4]. While these therapies are not formally approved for “aging,” they are already being accessed by a small but growing group of individuals through specialized longevity clinics [5]. This raises an important question: Can the average patient access these therapies through their primary care physician—and should they? This article explores the science, the ethical and legal landscape, and the practical realities of lifespan-enhancing prescriptions.  Figure 1. Twelve hallmarks of the aging process proposed by López-Otín, C. et al. [1] Commonly Discussed Gerotherapeutics All were originally FDA-approved for specific metabolic or immune conditions but were not designed to extend lifespan. Their gerotherapeutic potential emerged through:
Legal and Ethical Considerations Patients and their primary care physician (PCP) will essentially have to walk the tightrope in this area since the path to a longevity prescription is paved with complex legal and ethical questions. Legally, once a drug is FDA-approved for one condition, a doctor can prescribe it for another. However, because "aging" is not currently recognized as a disease by the FDA, any prescription for the sole purpose of life extension is considered off-label. While legal, this often means insurance will not cover the cost, and the doctor assumes a higher degree of professional liability if side effects occur in a "healthy" patient. In addition, legality does not guarantee ethical appropriateness. Prescribing gerotherapeutics to otherwise healthy individuals raises at least four ethical concerns: 1. Evidence Gap While animal data are compelling, definitive human trials demonstrating lifespan extension are still lacking. The proposed TAME (Targeting Aging with Metformin) trial aims to address this gap [17]. 2. Risk vs. Benefit All medications carry risks:
3. Professional Guidelines Medical organizations emphasize:
4. Equity and Access Longevity therapies are currently more accessible to affluent individuals, raising concerns about widening health disparities. Considering the above, most physicians will not feel ethically compelled to prescribe gerotherapeutics to perfectly healthy individuals seeking life span extension. However, in this age of advanced molecular diagnostics and imaging, and affordable whole genome sequencing, how many could claim perfect health? Perhaps very few, while most might exhibit borderline conditions that could benefit from early interventions with gerotherapeutics within legal and ethical boundaries. The "Borderline" Path to Access The most ethically and clinically defensible pathway is not treating “aging,” but addressing early or borderline disease states. For the average person, the most viable way to access these drugs is through co-morbidity management. A primary care doctor is far more likely to prescribe a gerotherapeutic if the patient also has a "borderline" medical condition where the drug provides an immediate, approved clinical benefit. In other words, a prescription becomes more justifiable when:
The following are examples of strategic clinical entry points to gerotherapeutics. If you already know you have one or more of the following risk factors or borderline conditions, the table below may be directly relevant to a conversation with your doctor. If you're currently healthy with no known risk factors, a brief scan is sufficient — the closing summary table offers the clearest overview. 1. Prediabetes / Insulin Resistance Spectrum Relevant drug: Metformin, Acarbose This is probably the strongest and most widely accepted gray-zone indication. Clinical scenarios:
2. Early Cardiometabolic Syndrome (Even Without Diabetes) Relevant drug: SGLT2 inhibitors Clinical scenarios:
3. Stage 1 Chronic Kidney Disease (CKD) or Hyperfiltration Relevant drug: SGLT2 inhibitors Clinical scenarios:
4. Early Heart Failure Risk / Subclinical Cardiac Dysfunction Relevant drug: SGLT2 inhibitors Clinical scenarios:
5. Post-Transplant or Immune Dysregulation Contexts Relevant drug: Rapamycin Clinical scenarios:
6. Severe Postprandial Hyperglycemia with Normal Fasting Glucose Relevant drug: Acarbose Clinical scenarios:
7. Polycystic Ovary Syndrome (PCOS) with Mild Metabolic Dysfunction Relevant drug: Metformin Clinical scenarios:
8. Non-Alcoholic Fatty Liver Disease Relevant drugs:
9. Obesity with Early Metabolic Drift (But No Disease Yet) Relevant drugs:
10. Osteopenia (Not Yet Osteoporosis) Relevant drug: Bisphosphonates Clinical scenario:
11. “Normal Weight” but High Visceral Adiposity Relevant drug: GLP-1 receptor agonists Clinical scenario:
12. “Pre-Frailty” or Early Functional Decline Relevant drug: Bisphosphonates Clinical scenario:
13. Obesity (Now Explicitly a Disease) Relevant drugs:
14. Early Atherosclerotic Risk Without Overt Disease Relevant drugs:
15. Weight Regain After Lifestyle Intervention Relevant drug: GLP-1 receptor agonists Clinical scenario:
16. High Bone Turnover Without Low bone mineral density (BMD) Yet Relevant drug: Bisphosphonates Clinical scenario:
17. Metabolic Syndrome with Inflammatory Phenotype Relevant drugs:
18. High-Normal Uric Acid (Hyperuricemia) Relevant Drug:
19. Chronic "Inflammaging" (High-Sensitivity C-reactive protein (hs-CRP)) Relevant Drug:
In summary, the ease of getting a prescription for life span extension varies proportionally with the ethical barrier. The rank order is shown in the following Table for all six classes of gerotherapeutics:
Conclusion Gerotherapeutics represents a fascinating and rapidly evolving frontier in medicine. They represent a change in thinking about patient management, moving from a "reactive" model (fixing what is broken) to a "proactive" model (slowing the rate of decay). While science suggests that targeting aging biology is possible, clinical practice has not yet fully caught up. For now, these drugs are legally accessible through off-label prescribing although their use purely for longevity remains ethically debated. The most practical pathway towards gerotherapeutics is through existing or early-stage medical conditions. Patients interested in these therapies should engage in informed discussions with their physicians, focusing on individual risk factors rather than abstract longevity goals. As research advances and clinical trials mature, the boundary between prevention and enhancement may continue to blur. Until then, lifespan-enhancing prescriptions remain less about chasing immortality and more about thoughtfully managing the biology of aging as it begins to unfold. The most practical takeaway for an apparently healthy individual is this: don't settle for a cursory annual check-up. A more proactive approach — one that includes a detailed family history, targeted lab work, and relevant imaging — is far more likely to reveal the borderline conditions described above. If risk factors emerge, that becomes the opening for an informed conversation with your doctor about medications that address those risks while also supporting long-term healthspan. The goal isn't to ask for a longevity prescription. It's to ask the right questions about where your biology actually stands. References
Appendix
6 classes of gerotherapeutics, their original FDA-approved indications, relevance to geroscience, and evidence as gerotherapeutics. Metformin
Rapamycin (Sirolimus)
Acarbose
SGLT2 Inhibitors (e.g., Empagliflozin, Canagliflozin)
GLP-1 Receptor Agonists (e.g., Semaglutide, Tirzepatide)
Bisphosphonates (e.g. Alendronate, Zoledronate)
Most people do not ignore their health on purpose. They notice the fatigue that will not lift, the sleep that keeps breaking, the low-grade tension that never fully resolves, and they mean to do something about it. But between the noise of conflicting advice and the pressure of daily life, "doing something" stays perpetually on the list.
Effective health monitoring does not require a complicated system or a shelf full of devices. It requires knowing which signals matter, what they mean over time, and when to act. That clarity, not more data, is what turns good intentions into better health. Track Patterns, Not Moments The single most important principle in health monitoring is this: one reading rarely tells you anything useful. Your body fluctuates naturally from day to day based on sleep, stress, hydration, and dozens of other factors. What matters is what happens consistently over days and weeks. This applies to everything from blood pressure to energy levels. A blood pressure reading of 135/82 on a stressful Monday morning is different from readings that consistently hover above 130/80 over two weeks. The first might be noise. The second is a pattern worth discussing with your doctor. Start by choosing two or three signals to track, not 10. Sleep quality, energy level, and one physical metric relevant to your health history is a reasonable starting point for most adults. Add complexity only when a simpler system is already working. The Daily Check-In: Two Minutes, High Value A daily health check-in does not need to be elaborate. A simple note, like how you slept, your energy level, or any recurring symptom, takes about two minutes and builds the kind of longitudinal picture that even a thorough doctor's visit cannot fully capture. Over weeks, patterns emerge that would otherwise go unnoticed. Fatigue that worsens mid-week. Sleep deteriorates after certain foods or stressful periods. Energy improves after consistent morning movement. These are not dramatic revelations, but they are the kind of insights that lead to meaningful, sustainable changes. Keep your check-in in the same place every day: a notes app, a small journal, a simple spreadsheet. Consistency of format matters as much as consistency of habit. Vital Signs: What to Measure and What It Means For adults managing or monitoring specific health conditions, at-home vital sign tracking adds a valuable layer of awareness. The most commonly useful metrics are resting heart rate, blood pressure, and body weight, but each requires context to be meaningful.
Preventive Screenings Daily habits are only part of the picture. Preventive screenings, such as cholesterol checks, cancer screenings, blood glucose, vaccinations, and routine lab work, catch what home monitoring cannot. The U.S. Preventive Services Task Force (USPSTF) publishes evidence-based screening recommendations by age and risk factor, and they are a practical starting point for anyone unsure why they are due. If you have not reviewed your screening history recently, your annual physical is the right moment to do it. Bring a list of what you have done and when and ask your provider what is next. Surround Yourself with What Supports You Environment shapes behavior more than motivation does. If your surroundings quietly reinforce poor habits, even strong intentions tend to erode. One underrated strategy is making your wellness goals visible. One simple and often overlooked strategy is making your goals visible in your physical space. A quote that genuinely resonates with you when printed and placed where you start your morning does something a phone notification cannot. It is a quiet, consistent prompt that does not require willpower to notice. You can design and print posters tailored to whatever keeps you motivated, using an app that lets you customize templates and print something worth hanging on a wall. Bring Your Data to Your Doctor One of the most underused benefits of health tracking is what it makes possible in a clinical setting. A doctor seeing you for 15 minutes works from snapshots. You have weeks of context they do not. Before your next appointment, take five minutes to summarize what you have noticed, not raw numbers, but patterns and changes. "My resting heart rate has been trending up for the past three weeks" is more useful than a list of daily readings. "I've had consistent fatigue every afternoon for the past month, regardless of sleep" gives your provider something specific to work with. This kind of preparation helps your concerns be taken seriously, speeds up the diagnostic process, and puts you in a genuinely collaborative role in your own care. Start With One Habit for 30 Days The most effective health monitoring routine is the one you will maintain. Start with a single habit and keep it going for 30 days before adding anything else. Consistency, not comprehensiveness, is what turns monitoring into meaningful health insight. Over time, a simple, reliable system gives you something far more valuable than data: it gives you clarity about your own body, and the confidence to act on what you find.  Introduction Modern medicine has made remarkable progress in extending human lifespan, yet much of this extension has been driven by pharmaceuticals and technological interventions that often come with trade-offs. At the same time, there is growing scientific interest in whether behavioral practices—particularly meditation—can influence the rate of biological aging itself. Among these practices, Zen mindfulness meditation has gained attention not only for its neurological and psychological benefits, but also for its potential role in modulating biological clocks such as DNA methylation age and telomere dynamics. While early neuroimaging studies focused on structural and functional brain changes, more recent research has shifted toward deeper biological markers of aging. These include epigenetic clocks, which estimate biological age based on DNA methylation patterns, and telomeres, which shorten with cellular replication and stress. This blog examines the current evidence linking meditation—especially long-term mindfulness practices—to these aging markers, while also addressing the significant methodological challenges that complicate efforts to prove a causal relationship. Meditation and Epigenetic Aging: Slowing the Clock  One of the most compelling lines of research involves epigenetic clocks, particularly the Horvath DNA methylation clock. These clocks are considered among the most robust biomarkers of biological aging. A landmark study by Chaix et al. (2017) [1] in Psychoneuroendocrinology investigated long-term meditators and found that while their overall epigenetic age did not differ significantly from controls, age-related acceleration of the epigenetic clock was absent in experienced meditators. Moreover, years of meditation practice were inversely correlated with epigenetic age acceleration, suggesting a cumulative protective effect.  Similarly, Pavanello et al. (2019) [2] reported that a meditation-based intervention was associated with reductions in DNA methylation age over a relatively short period (~60 days). More recent work in 2023 by Dasanayaka et al.[3] further supports the idea that meditation may slow epigenetic aging trajectories, particularly in older adults. These findings align with the hypothesis that mindfulness practices may influence gene regulation pathways associated with inflammation, stress response, and metabolic function—key drivers of biological aging. Telomeres, Telomerase, and Cellular Longevity  Another major biological clock involves telomeres, the protective caps at the ends of chromosomes. Telomere shortening is widely regarded as a hallmark of cellular aging. Early theoretical work by Epel et al. (2009) [4] proposed that meditation could influence telomere maintenance indirectly through stress reduction and hormonal regulation, particularly by lowering cortisol and sympathetic nervous system activity. Empirical studies have provided partial support for this model. For example, Mendioroz et al. (2020) [5] in Scientific Reports found that experienced meditators exhibited longer telomeres and epigenetic differences in telomere-related regions. Other studies have reported increased telomerase activity—the enzyme responsible for maintaining telomere length—in individuals undergoing meditation or mindfulness-based interventions. However, the literature is not entirely consistent. Some longitudinal studies, including more recent controlled trials, have failed to detect significant changes in telomere length over shorter intervention periods. This inconsistency highlights the complexity of using telomeres as a reliable outcome measure in behavioral research. Beyond Clocks: Multi-Omic and Rapid Biological Effects In addition to long-term aging markers, meditation has been shown to induce short-term molecular changes that may influence aging indirectly. Studies such as Diez et al. (2023) [6] demonstrate that meditation can alter:
Why Is It So Difficult to Prove? Despite promising findings, establishing a definitive causal link between meditation and longevity remains a major challenge. Several key issues complicate clinical research in this area: 1. Duration Mismatch Biological aging unfolds over decades, yet most clinical trials last weeks to months. Detecting meaningful changes in epigenetic age or telomere length within such short timeframes is inherently difficult. 2. Heterogeneity of Meditation Practices “Zen mindfulness” encompasses a range of practices varying in intensity, frequency, and philosophical orientation. This lack of standardization makes it difficult to compare studies or replicate findings. 3. Selection Bias Long-term meditators often differ from the general population in important ways:
4. Small Sample Sizes Many studies involve relatively small cohorts, limiting statistical power and increasing the risk of false positives or inconsistent results. 5. Measurement Variability Different studies use different aging clocks (Horvath, Hannum, PhenoAge, GrimAge), which may not yield equivalent results. Similarly, telomere measurements can vary depending on methodology (qPCR vs. Southern blot). 6. Psychological and Placebo Effects Meditation interventions are difficult to blind, raising the possibility that expectation effects or general relaxation—not meditation per se—may drive observed benefits. Zen Mindfulness: A Unique Case? Zen meditation, with its emphasis on non-dual awareness, breath regulation, and sustained attentional control, may offer distinct biological advantages:
These factors are closely tied to pathways known to influence aging, including inflammation, oxidative stress, and metabolic health. However, few studies isolate Zen specifically, and most group it under broader “mindfulness” or “meditation” categories. Conclusion The scientific evidence to date suggests that meditation—particularly long-term mindfulness practices such as Zen—may slow aspects of biological aging, as reflected in epigenetic clocks and telomere biology. The most consistent finding is not that meditation reverses aging, but that it may attenuate the rate at which aging progresses, especially in individuals with sustained practice. However, the field remains in an early stage. The complexity of human aging, combined with methodological limitations in clinical trial design, makes it difficult to draw definitive conclusions. Larger, longer-term, and better-controlled studies will be necessary to determine whether meditation can meaningfully extend human lifespan—or whether its benefits are primarily confined to improving healthspan and resilience. In the meantime, meditation stands as a low-risk intervention with well-documented psychological and physiological benefits. Whether or not it ultimately proves to be a tool for extending life, it may already be one of the most accessible ways to improve the quality of the years we have. References
By Marjorie McMillian of comeongetwell.net Marjorie’s experience: With more years of mindfulness practice than I can count, I know firsthand how daunting those first steps can feel. I started small, bringing awareness to everyday moments like brushing my teeth, walking my dog, or drifting off to sleep. One mindful moment at a time was all it took to begin a practice that has since transformed my life. Contact me: https://www.comeongetwell.net/contact/ For health-conscious adults seeking wellness management, the hardest part often isn’t effort, it’s turning complex signals into steady, livable choices. Between wearables, assessments, and multiple personalized health strategies, the body can start to feel like a dashboard that never stops flashing, while stress quietly becomes the baseline. Mindfulness integration brings attention back to the mind-body connection, creating a clearer read on what helps, what harms, and what actually fits real life. Done consistently, it supports holistic well-being benefits that can be felt in everyday calm.
Quick Summary: Daily Mindfulness Practices
Understanding Mindfulness and Attention Training A useful way to define mindfulness is purposeful attention, placed on what is happening right now, without judging it. When you practice attention regulation, you notice distractions sooner and choose what you focus on. This shifts how your day feels, even when your schedule stays the same. This matters for personalized wellness because your focus shapes your choices in sleep, food, movement, and positive mindset habits. Two mindset moves strengthen the effect: gratitude, which nudges your body toward steadier stress responses, and self-talk awareness, which reduces the quiet mental friction that drains energy. Picture doing a weekly health checklist after a tough day. Mindfulness helps you spot the spiral of thoughts, name it, and return to one next step. You add one gratitude note, then rephrase harsh self-talk into a helpful instruction. With this foundation, daily habits become easier to choose and repeat. Mindfulness Habits You Can Repeat and Track These habits turn mindfulness into a simple routine you can log alongside sleep, meals, movement, and stress notes. Over time, they help you spot patterns, choose one next action, and keep your wellness checklist realistic even during busy weeks. Two-Minute Breath Anchor
Daily Mindfulness Integration Checklist This checklist turns mindfulness into trackable steps you can fold into your health log for clearer, personalized decisions. It also helps you stay realistic since only 14% of respondents practice meditation daily. ✔ Set one fixed cue for practice ✔ Track minutes practiced next to sleep and mood ✔ Record one gratitude note after dinner ✔ Eat one snack without screens, chewing slowly ✔ Schedule a 20-minute evening electronic detox ✔ Review your stress triggers weekly and choose one adjustment ✔ Confirm your plan fits your busiest day Check off one item today, then repeat it until it feels automatic. Commit to One Daily Mindfulness Habit for Measurable Calm Most wellness plans fail because life gets busy and tracking turns into pressure instead of support. A mindful approach keeps the focus on awareness over perfection, using integrated daily habits to steady attention and make choices easier to sustain. Over time, the mindfulness benefits summary is simple: less reactivity, clearer focus, better sleep, and behavioral health changes that show up in your mood, cravings, and recovery from stress, key signals for personalized wellness improvement. Mindfulness works when it becomes a small daily practice, not a someday goal. For the next seven days, you can choose one habit from the checklist and commit to doing it once daily, then note what changes. That commitment to mindful living builds the stability and resilience that make health progress last.
Hung V. Le
Biologics & Drug Targets, ProSci LLC, Rockaway, The United States ORCID https://orcid.org/0000-0002-6913-2373 (Hung Van Le) 02/10/2026
Abstract
15-Hydroxyprostaglandin dehydrogenase (15-PGDH), encoded by HPGD, is the principal enzyme responsible for the metabolic inactivation of prostaglandin E₂ (PGE₂), a lipid mediator with central roles in inflammation, tissue repair, stem cell function, and cancer biology. By constraining PGE₂ signaling, 15-PGDH functions as a dominant endogenous brake on regeneration. Across multiple tissues, aging and injury are associated with increased 15-PGDH activity, leading to impaired repair capacity. Recent preclinical studies demonstrate that pharmacologic inhibition of 15-PGDH restores physiologic PGE₂ signaling and robustly enhances regeneration in skeletal muscle, neuromuscular junctions, cartilage, hematopoietic stem cell niches, and the neurovascular unit. In contrast, extensive cancer biology literature establishes 15-PGDH as a bona fide tumor suppressor that is frequently silenced in malignancy, where loss of enzymatic activity promotes tumor growth, angiogenesis, immune evasion, and metastasis. This duality presents both opportunity and challenge for drug development. This review synthesizes emerging biological and translational evidence supporting both inhibition and restoration of 15-PGDH, evaluates the current clinical and preclinical landscape, and examines safety considerations centered on oncogenic risk. We argue that successful therapeutic targeting of 15-PGDH will depend on context-specific strategies that optimize therapeutic index through temporal limitation, spatial restriction, biomarker-guided dosing, and careful patient selection.
1. Introduction
15-Hydroxyprostaglandin dehydrogenase (15-PGDH, encoded by HPGD) is the principal enzyme responsible for the metabolic inactivation of prostaglandin E₂ (PGE₂) and related lipid mediators. By catalyzing the NAD⁺-dependent oxidation of PGE₂ to inactive 15-keto-PGE₂, 15-PGDH functions as a critical “brake” on prostaglandin signaling. PGE₂, acting through EP receptors (EP1–EP4), exerts pleiotropic effects on inflammation, stem and progenitor cell function, tissue repair, vascular integrity, and cell survival. Across multiple tissues, aging and injury are associated with pathological upregulation of 15-PGDH, resulting in diminished local PGE₂ signaling and impaired regenerative responses. Pharmacologic or genetic inhibition of 15-PGDH therefore represents a strategy to restore endogenous repair programs (1-7), rather than introducing exogenous growth factors or cell therapies. This concept underlies the recent surge of interest in 15-PGDH inhibitors such as SW033291, SW209415, and MF-300 (8-10). However, PGE₂ is also a well-established pro-tumorigenic mediator, promoting proliferation, angiogenesis, immune evasion, and metastasis (11). In many cancers, HPGD expression is epigenetically silenced, and restoration of 15-PGDH suppresses tumor growth. Thus, 15-PGDH occupies a biologically paradoxical position: a regeneration brake in aging and injury, but a tumor suppressor in cancer. Any therapeutic strategy targeting this enzyme for inhibition must therefore hinge on achieving a favorable therapeutic index that maximizes benefit in degenerative or acute injury settings while minimizing long-term oncogenic risk. Conversely, strategy that aims to restore 15-PGDH expression and activity to achieve an anti-tumor effect must consider its degenerative side effects in normal tissues. 
Figure 1. Context-dependent roles of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in regeneration and tumor suppression. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH), encoded by HPGD, catalyzes the irreversible inactivation of prostaglandin E₂ (PGE₂) and functions as a metabolic gatekeeper of EP receptor signaling. Center, 15-PGDH determines local PGE₂ availability and signaling amplitude. Top, in aging and tissue injury, elevated 15-PGDH activity reduces PGE₂ below a functional threshold, impairing regeneration in skeletal muscle, neuromuscular junctions, cartilage, hematopoietic stem cell niches, and the neurovascular unit. Transient or spatially restricted inhibition of 15-PGDH restores physiologic PGE₂ signaling and re-engages endogenous repair programs. Bottom, in cancer, 15-PGDH acts as a tumor suppressor and is frequently silenced through epigenetic, oncogenic, and microRNA-mediated mechanisms, resulting in PGE₂ accumulation that promotes proliferation, angiogenesis, immune evasion, and metastasis. Restoration of 15-PGDH activity suppresses these tumor-promoting processes.
2. 15-PGDH across disease indications
2.1 Muscle and Neuromuscular Regeneration A convergent body of work identifies prostaglandin E₂ (PGE₂) as a central, physiologic regulator of skeletal muscle and neuromuscular regeneration, with the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) acting as a key negative checkpoint. In young, injured muscle, transient PGE₂ signaling is required for efficient repair, whereas in aging and denervation, aberrant accumulation of 15-PGDH lowers PGE₂ below a functional threshold, impairing regenerative capacity. Pharmacologic or genetic inhibition of 15-PGDH restores PGE₂ to youthful levels, re-engaging endogenous repair programs. At the level of skeletal muscle, PGE₂ directly targets muscle stem cells (MuSCs) through EP4 receptor signaling to drive rapid cell-cycle entry and clonal expansion during the early inflammatory phase of regeneration. Acute enhancement of PGE₂ signaling is sufficient to markedly augment muscle repair and recovery of strength, whereas suppression of prostaglandin synthesis (for example, by NSAIDs) compromises these processes (1). In aging, skeletal muscle exhibits a pronounced increase in 15-PGDH expression and activity, derived from both myofibers and tissue-resident macrophages, resulting in reduced PGE₂ availability. Short-term inhibition of 15-PGDH in aged mice reverses key features of sarcopenia, including reduced myofiber cross-sectional area, loss of muscle mass, and diminished contractile force. These effects are causally linked to PGE₂ restoration, as ectopic overexpression of 15-PGDH in young muscle is sufficient to induce rapid atrophy and weakness. Mechanistically, restoration of PGE₂ signaling through 15-PGDH inhibition orchestrates coordinated remodeling of aged muscle tissue. This includes suppression of transforming growth factor-β and ubiquitin–proteasome–mediated atrophy pathways, alongside enhanced autophagy flux and mitochondrial biogenesis with normalization of mitochondrial ultrastructure. The convergence of these pathways explains how modest, physiologic increases in PGE₂ can yield disproportionately large functional gains, distinguishing 15-PGDH inhibition from purely anabolic or anti-catabolic strategies (2). More recent work extends the relevance of 15-PGDH beyond muscle-intrinsic regeneration to neuromuscular connectivity. Denervation, whether acute after nerve injury or chronic during aging, induces robust expression of 15-PGDH in myofibers, particularly in fast-twitch fibers that are preferentially lost in sarcopenia and neuromuscular disease. Inhibition of 15-PGDH accelerates motor axon regeneration, restores neuromuscular junction (NMJ) structure, and improves force recovery after peripheral nerve injury. In aged animals with chronic denervation, 15-PGDH inhibition increases motor neuron viability and re-establishes functional NMJs. Importantly, restored PGE₂ signaling activates cAMP–CREB pathways not only in muscle but also in motor neurons, indicating coordinated pre- and postsynaptic regeneration (3). Taken together, these findings position 15-PGDH as a central, druggable regulator of muscle mass, strength, and neuromuscular integrity. Inhibition of this enzyme offers a unified therapeutic strategy for sarcopenia of aging, traumatic muscle and nerve injuries, and neuromuscular or muscular dystrophies characterized by denervation and impaired regeneration. By restoring endogenous PGE₂ signaling to physiologic levels, 15-PGDH inhibitors engage intrinsic repair mechanisms across the muscle–nerve unit, supporting their broader consideration as regenerative therapeutics across multiple indications. 2.2 Osteoarthritis and cartilage regeneration Singla et al. (4) demonstrate that 15-PGDH expression is increased in articular cartilage of aged and injured joints, particularly within hypertrophic-like chondrocyte populations. Both systemic and intra-articular inhibition of 15-PGDH with SW033291 led to robust regeneration of hyaline cartilage, reduced osteoarthritic pathology, and decreased pain behaviors in murine models. Single-cell RNA-seq and multiplexed imaging revealed a key mechanistic insight: cartilage regeneration did not arise from stem or progenitor cell expansion, but rather from phenotypic reprogramming of existing chondrocytes. SW033291 reduced hypertrophic, degenerative chondrocyte subsets and expanded extracellular-matrix-producing articular chondrocytes. This distinguishes 15-PGDH inhibition from many regenerative approaches that rely on proliferation, suggesting a potentially lower oncogenic burden within cartilage itself. Importantly, both local and short-term systemic inhibition were sufficient to achieve benefit, highlighting the feasibility of spatially restricted or temporally limited dosing, a key consideration for safety. 2.3 Hematopoietic aging and stem cell regeneration Chaudhary et al. (5) extend earlier work showing that 15-PGDH constrains hematopoietic stem cell (HSC) function by degrading PGE₂. In aged mice, 15-PGDH expression and enzymatic activity remain conserved in bone marrow and spleen, making it a viable target even late in life. Prolonged pharmacologic inhibition increased the number and functional capacity of HSCs and progenitors, improved engraftment after transplantation, accelerated multilineage reconstitution, and mitigated age-associated myeloid bias. A crucial observation is that 15-PGDH inhibition by SW033291 did not perturb steady-state hematopoiesis, but selectively enhanced regeneration under stress (e.g., transplantation). This context dependence suggests that 15-PGDH inhibition amplifies endogenous repair signals rather than inducing uncontrolled proliferation. Nonetheless, because hematopoietic tissues are intrinsically susceptible to malignant transformation, this indication sits close to the boundary where regenerative benefit and cancer risk intersect. Short peri-transplant courses (IV or parenteral) that boost HSC engraftment are an appealing clinical use because they are time-limited and target a high-value, high-risk clinical need (older transplant recipients). 2.4 Alzheimer’s disease and traumatic brain injury: Blood-Brain Barrier-centric neuroprotection Koh et al. (6) identify a novel role for 15-PGDH in the brain, localized predominantly to microglia and perivascular macrophages associated with the blood-brain barrier (BBB). In human and murine Alzheimer’s disease (AD), traumatic brain injury (TBI), and aging, 15-PGDH expression and activity are markedly elevated. This elevation correlates with oxidative stress, BBB breakdown, neuroinflammation, and cognitive decline. Pharmacologic inhibition or genetic reduction of 15-PGDH preserved BBB integrity, suppressed reactive oxygen species, reduced neurodegeneration, and most strikingly fully preserved cognitive function in mouse models of AD and TBI. Notably, these effects occurred without altering amyloid pathology, positioning 15-PGDH inhibition as a non-amyloid, vascular/immune mechanism of neuroprotection. The localization of 15-PGDH to BBB-associated myeloid cells suggests that targeted modulation of inflammatory lipid metabolism underlies the benefit. This cellular specificity again raises the possibility of achieving efficacy with limited systemic exposure. However, brain indications often require chronic or repeated dosing, which reopens the long-term cancer question unless dosing can be restricted or targeted (e.g., CNS-penetrant agents given episodically). 2.5 Ischemic stroke and ferroptosis suppression Xu et al. (7) provide a mechanistically detailed account of 15-PGDH in acute ischemic stroke. Overexpression of 15-PGDH exacerbated infarct size, edema, neurological deficits, and neuronal death, whereas inhibition with SW033291 was strongly neuroprotective in both in vivo rat middle cerebral artery occlusion (MCAO) models and in vitro oxygen glucose deprivation/reperfusion (OGD/R) neuronal cultures. The key mechanistic advance is the linkage of 15-PGDH to ferroptosis, an iron-dependent, lipid peroxidation-driven form of regulated cell death. 15-PGDH inhibition activated the PGE₂/EP4 axis, leading to c-AMP responsive element-binding protein (CREB)- and NF-κB-dependent transcriptional upregulation of glutathione peroxidase 4 (GPX4), the central suppressor of ferroptosis. Genetic ablation of GPX4 abolished the protective effect of PGDH inhibition, establishing a causal pathway. This work positions 15-PGDH inhibition as an acute neuroprotective strategy with a defined molecular endpoint (GPX4 restoration), well suited to short-duration intervention, arguably the safest therapeutic context for a target with oncogenic liabilities. 2.6 Cancer and tumor microenvironment: the countervailing evidence The comprehensive review by Tulimilli et al. (11) synthesizes decades of evidence identifying 15-PGDH as a bona fide tumor suppressor across colorectal, breast, gastric, lung, pancreatic, hepatic, and other cancers . In most malignancies, 15-PGDH expression is reduced via methylation of CpG islands in the promoter region, histone deacetylation in association with transcription repressors, microRNA regulation (e.g. miR-620 in breast and prostate cancer, miR-155 in esophageal cancer), inflammatory cytokines (e.g., IL-1β, TNF-α), and oncogenic signaling pathways (EGFR, β-catenin, Snail/Slug). Loss of 15-PGDH leads to PGE₂ accumulation, which drives proliferation, angiogenesis, immune evasion, and resistance to apoptosis. Conversely, restoring 15-PGDH expression suppresses tumor growth, induces apoptosis and cell-cycle arrest, and reduces metastasis in multiple in vitro and in vivo models. These data establish cancer predisposition as a credible, mechanism-based risk of chronic or systemic 15-PGDH inhibition. Table 1. Summary of 15-PGDH Inhibition Studies Across Disease Models
3. Clinical-translation landscape: MF-300, SW033291, (+)-SW209415
MF-300 (Epirium Bio): an oral 15-PGDH inhibitor (Phase-1 completed) MF-300 has completed first-in-human single and multiple ascending dose clinical trial. Publicly available report of this Phase-1 study indicate tolerability, dose-dependent pharmacokinetic (PK), and pharmacodynamic (PD) evidence of target engagement (changes in PGE₂ metabolites and other mechanistic biomarkers). Epirium is advancing MF-300 into Phase-2 development for sarcopenia (10). This is the first publicly reported human evidence that systemic 15-PGDH inhibition can deliver pharmacological effects in humans with acceptable acute tolerability, an important “feasibility” milestone. For chronic indications (sarcopenia), MF-300 shows promise mechanistically but demands a long-term safety and cancer-surveillance strategy in later trials. SW033291 (Case Western / academic program): a 15-PGDH inhibitor for pre-clinical studies SW033291 is the prototypical small-molecule 15-PGDH inhibitor used across multiple published preclinical studies: hematopoietic regeneration, colon/colitis models, bone/muscle repair, and more recently in AD/TBI/stroke neuroscience studies (8). Most studies rely heavily on SW033291 for in vivo pharmacology. SW033291 has a deep preclinical track record and has been used in investigator-led translational work (Case Western). If moved into humans, its profile supports both acute (IV/peri-transplant) and subchronic (oral/other) use cases, but clinical trial registration details have not been reported. (+)-SW209415: a water-soluble, IV-capable second-generation analogue Medicinal-chemistry work produced (+)-SW209415 (a racemate) with orders-of-magnitude improved aqueous solubility while retaining potency. This enables IV dosing for peri-operative or transplant use where short IV infusions could be given in a tightly controlled temporal window. Preclinical bone marrow transplantatio (BMT) models and other regeneration models show strong efficacy (9). SW209415 (IV) directly addresses the therapeutic-index problem for hematopoietic/transplant use by enabling short, high-impact dosing windows rather than chronic systemic exposure. 4. Safety, cancer risk, and the therapeutic-index problem In most cancers and preclinical tumor models, low 15-PGDH and high PGE₂ are associated with tumor initiation, progression, angiogenesis, and immune suppression. Restoring 15-PGDH is tumor-suppressive; conversely, sustained inhibition would raise PGE₂ and could accelerate latent premalignant clones or worsen tumor microenvironments. Successful development of a clinical candidate based on 15-PGDH inhibition depends on optimizing factors that could improve the therapeutic index for the indication of interest (Figure. 2). These factors could include limiting the duration of intervention. For example, short pulses as in peri-transplant or acute stroke/TBI, minimize cumulative PGE₂ exposure and therefore cancer-promotion risk. The SW209415 IV program is prototypical of this approach. Localized administration, as in intra-articular or topical administration for osteoarthritis, concentrates drug in the joint and lowers systemic exposure (1). Rigorous patient selection and monitoring could minimize baseline risk. Excluding or closely monitoring patients with high cancer risk or known premalignant lesions will reduce the near-term oncologic hazard. Dosing guided by biomarkers (urinary/tissue PGE₂ metabolite) could help determine minimal effective dose (7). MF-300 Phase-1 shows acute tolerability and favorable pharmacodynamic, lowering a key pharmacologic uncertainty in humans. However, it does not prove long-term safety (oncologic risk requires longer observation). Similarly, preclinical SW033291 / SW209415 data support efficacy and suggest short schedules are effective and therefore safer from an oncogenic perspective. Table 2. Countervailing Evidence and Safety Considerations for Targeting 15-PGDH
Figure 2. Optimizing therapeutic index. The opposing biological consequences of 15-PGDH modulation define a therapeutic-index problem. Successful clinical targeting of 15-PGDH—either by inhibition for regenerative indications or by restoration for cancer therapy—will require context-specific strategies that optimize benefit while minimizing risk through temporal limitation, spatial restriction, biomarker-guided dosing, and careful patient selection.
5. 15-PGDH reactivation as a cancer treatment modality?
Tulimilli, S.V. et al. (11) present a comprehensive picture of 15-hydroxyprostaglandin dehydrogenase (15-PGDH, encoded by HPGD) as a central node where inflammation, prostaglandin metabolism, and tumor biology intersect. In normal physiology, 15-PGDH serves as the principal catabolic enzyme for prostaglandin E₂ (PGE₂), converting it to inactive metabolites and thereby restraining the spectrum of PGE₂-driven signaling: proliferation, angiogenesis, immune modulation, and matrix remodeling. In many tumor types, however, this restraint is lost. The review synthesizes evidence from multiple cancers showing that HPGD expression is frequently suppressed and that this suppression is functionally important for tumor progression because it permits persistent, high local PGE₂ levels that favor malignant phenotypes. A key strength of the review is its emphasis on the multi-layered mechanisms by which cancers reduce 15-PGDH. Rather than a single on/off switch, repression occurs through convergent transcriptional, epigenetic, post-transcriptional and microenvironmental routes. Promoter CpG hypermethylation and recruitment of chromatin-repressive complexes (including HDACs) are repeatedly documented across tumor types and provide a durable block to transcription. On top of that, several oncogenic signaling programs, Wnt/β-catenin, EGFR/MAPK, and epithelial-to-mesenchymal transcription factors such as Snail and Slug, actively repress HPGD transcription. The tumor microenvironment amplifies repression: proinflammatory cytokines (IL-1β, TNF-α) and oxidative stress further suppress expression or activity. At the post-transcriptional level, a cohort of oncogenic microRNAs (e.g., miR-21, miR-155 and others cataloged in the review) target HPGD mRNA, reducing stability or translation and yielding multilayered, robust downregulation. The net effect is a tumor milieu that both makes and preserves high PGE₂. This mechanistic heterogeneity matters for pharmacology: it suggests multiple, rational levers to restore 15-PGDH activity, and the possibility for several translational approaches. Classic epigenetic drugs, DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors, can relieve promoter methylation and chromatin compaction and thereby re-enable transcription; these agents have the advantage of clinical availability but suffer from broad, nonselective genomic effects that can activate undesired genes and cause systemic toxicity. Targeting upstream signaling is another option: inhibitors of EGFR/MEK or modulators of Wnt signaling may indirectly derepress HPGD in tumors where those pathways dominate. MicroRNA antagonists (antagomirs) offer sequence specificity and could selectively restore HPGD post-transcriptionally, particularly if delivered locally or within tumor-targeted nanoparticles. Tulimilli, S.V. et al. (11) highlights gene-delivery approaches, viral or nanoparticle vectors expressing HPGD, which bypass endogenous repression and have shown tumor-suppressive effects in preclinical models. Finally, combination strategies that pair HPGD reactivation with other modalities, including blocking PGE₂ synthesis (COX-2/mPGES-1 inhibitors) and receptor binding (12), or anti-angiogenic agents are conceptually attractive because they both reduce PGE₂ production and accelerate its catabolism. The review makes several persuasive points for pursuing 15-PGDH as a cancer drug target. Restoring 15-PGDH consistently reduces tumor cell proliferation, invasiveness, and colony formation across multiple models; it curtails angiogenesis and can reprogram the tumor microenvironment away from an immunosuppressive, repair-favoring state. These effects are mechanistically coherent because PGE₂ acts on EP receptors to promote proliferation, survival and immune evasion; removing PGE₂ by enhanced catabolism should therefore reverse those signals. Moreover, HPGD status offers a potential biomarker: tumors with epigenetic silencing of HPGD and high COX-2/PGE₂ signatures may be most dependent on PGE₂ and thus most likely to respond to reactivation strategies. The availability of multiple modality options, epigenetic drugs, pathway inhibitors, miRNA tools, and gene therapy—makes HPGD a practical target for translational programs. Those upsides are tempered, properly, by the risks and caveats that Tulimilli, S.V. et al. (11) emphasizes. Because 15-PGDH is the main catabolic brake on PGE₂, systemic or chronic up-regulation of the enzyme will lower PGE₂ systemically and can blunt physiological PGE₂ roles in tissue repair and homeostasis. PGE₂ has established, context-dependent pro-regenerative effects in bone, muscle, hematopoietic stem cell niches, and in ischemic tissues; lowering PGE₂ in these contexts could delay wound healing, impair fracture repair, suppress stem/progenitor cell function, and reduce protective inflammatory resolution. The review therefore argues for therapeutic strategies that preserve the antitumor benefit while limiting deleterious systemic reductions in pro-regenerative prostaglandin signaling. From a translational standpoint synthesis of the available data points to several practical principles. First, localization matters: intratumoral or organ-targeted delivery of HPGD reactivation (gene delivery, local antagomirs, tumor-targeted nanoparticles) reduces systemic exposure and thus spares regenerative physiology elsewhere. Second, temporal control, short pulses timed around cytotoxic therapy or perioperative windows, may permit tumoral suppression without long-term impairment of repair. Third, combination approaches that both limit PGE₂ synthesis (COX-2/mPGES blockade) and restore catabolism may permit lower doses and mitigate compensatory feedback. Fourth, patient selection using HPGD/COX-2/PGE₂ signatures and exclusion of patients with high risk of wound-healing complications or ischemic vulnerability could focus benefit where the therapeutic index is favorable. Finally, the available information on 15-PGDH as tumor suppressor underscores the need for an evidence-driven research agenda. Preclinical models must include rigorous assessments of regeneration and repair endpoints (wound healing, bone/cartilage repair, hematopoietic recovery, and neurovascular resilience) alongside antitumor efficacy. Biomarkers that report both tumor PGE₂ activity and systemic prostaglandin levels will be essential to establish safe dosing regimens. And mechanistic work to identify tumor contexts where HPGD reactivation is most likely to yield durable responses (for example, tumors with epigenetic HPGD silencing and high PGE₂ dependence) will increase the chance of a favorable clinical outcome. In sum, Tulimilli, S.V. et al. (11) present 15-PGDH not as a simple oncoprotein or tumor suppressor but as a druggable metabolic node whose therapeutic value will depend on careful engineering of modality, timing, and patient selection to exploit tumor vulnerability while avoiding impairment of normal tissue regeneration.
6. Current translational landscape for 15-PGDH restoration in cancer
As discussed previously, multiple direct approaches ranging from gene therapy, targeting epigenetic silencing and microRNAs , and small molecules activators, could be undertaken to restore 15-PGDH activity in cancer cells. Unfortunately, most translational studies to date remain at the experimental pre-clinical level (13-16). Only indirect studies of 15-PGDH upregulation by Vitamin D have reached clinical trials stage for chemoprevention of cancer. Vitamin D upregulates 15-PGDH primarily through a genomic mechanism involving the Vitamin D Receptor (VDR). By acting as a ligand-activated transcription factor, the active form of Vitamin D (calcitriol) directly increases the production of the 15-PGDH enzyme at the mRNA level. Vitamin D supplemented with calcium is known to exert a "metabolic sandwich" effect to aggressively lower PGE2 levels. It not only upregulates 15-PGDH but also downregulates COX2 and EP2 receptor (17-21). To date the clinical studies showed no effect on cancer incidence in the general population although lower incidence could be demonstrated in some subgroups including individuals with normal body mass index (BMI), and potentially African Americans. These studies also showed a small reduction in cancer mortality in the treated group (22,23 ), providing the impetus for employing a more selective 15-PGDH reactivator to avoid the potential confounding effect of Vitamin D, which is highly pleiotropic affecting multiple metabolic pathways (24).
7. Conclusion
15-hydroxyprostaglandin dehydrogenase (15-PGDH) occupies a uniquely complex position at the intersection of regeneration, inflammation, aging, and cancer biology. Across diverse tissues, accumulated preclinical and emerging clinical evidence establishes 15-PGDH as a dominant endogenous brake on prostaglandin E₂ (PGE₂)–dependent repair programs. Inhibition of this enzyme restores physiologic PGE₂ signaling and reproducibly enhances regeneration in skeletal muscle, neuromuscular junctions, cartilage, hematopoietic stem cell niches, and neurovascular units. These effects are achieved not by supraphysiologic stimulation, but by reactivating latent, evolutionarily conserved repair pathways that decline with age or injury. At the same time, decades of cancer biology research demonstrate that loss of 15-PGDH is a hallmark of tumor progression in multiple malignancies, positioning the enzyme as a bona fide tumor suppressor. This duality defines both the promise and the challenge of therapeutically targeting 15-PGDH. Sustained or systemic inhibition carries a credible, mechanism-based oncogenic risk, while restoration or activation of 15-PGDH represents a rational anticancer strategy with its own potential liabilities related to impaired tissue repair. The translational path forward therefore hinges on therapeutic-index engineering rather than binary target validation. For 15-PGDH inhibition, the strongest near-term opportunities lie in indications that permit temporal or spatial restriction of drug exposure, including acute injury (stroke, TBI), peri-transplant hematopoietic regeneration, localized osteoarthritis, and possibly episodic treatment paradigms for sarcopenia. The development of agents such as MF-300, and IV-capable analogues like SW209415, demonstrates that pharmacologic modulation of 15-PGDH is feasible in humans and that short-duration or localized dosing strategies are realistic. Conversely, efforts to restore or augment 15-PGDH activity in cancer highlight a complementary therapeutic direction. Epigenetic reactivation, microRNA targeting, gene-delivery strategies, and combination approaches that simultaneously suppress PGE₂ synthesis and enhance catabolism all represent viable avenues for clinical exploration. In this context, careful patient selection based on tumor PGE₂ dependence and HPGD silencing status will be critical. Ultimately, 15-PGDH should be viewed not as a unidirectional drug target, but as a context-dependent metabolic node whose manipulation must be tailored to disease biology, treatment duration, and delivery strategy. Future clinical success will depend on rigorous biomarker-guided dosing, long-term safety surveillance, and parallel evaluation of regenerative and oncologic outcomes. If these challenges are met, targeting 15-PGDH—either by inhibition or restoration—has the potential to inaugurate a new class of therapeutics that modulate endogenous prostaglandin metabolism to restore tissue homeostasis across aging, injury, and cancer.
References
 Introduction In the previous two blogs, we discussed pulsed electromagnetic field therapy (December 17, 2025) and acupuncture (November 15, 2025) as potential treatments for osteoarthritis (OA), and we cited two comparative studies reporting that extracorporeal shock wave therapy (ESWT) was more effective than both modalities (1,2). However, the small sample sizes of these trials, together with conclusions based solely on meta-analyses, make such claims potentially tenuous. Nevertheless, it remains valuable to examine ESWT in greater detail—specifically, to review the clinical evidence supporting its effectiveness and to discuss its proposed mechanisms of action. We also review the range of ESWT devices currently available on the market for both medical professionals and consumers. Two types of shock waves In ESWT, a focused shock wave is a high-pressure, nonlinear acoustic pulse characterized by an extremely rapid rise time (<10 ns), a high positive peak pressure (10–100 MPa), short pulse duration (~1–10 µs), a subsequent tensile (negative-pressure) phase, and a broad frequency spectrum ranging from kilohertz to megahertz. In most focused ESWT devices used in medical practice, shock waves are generated using one of three physical principles: electrohydraulic (spark-gap), electromagnetic, or piezoelectric mechanisms (3). By contrast, some devices produce so-called radial shock waves, which are generated by the impact of a ballistic projectile and result in radially dispersing pressure waves with maximal pressure at the applicator surface rather than at depth. From a physical standpoint, these waves are closer to pressure pulses than to true shock waves, and radial devices are therefore not generally considered genuine shock wave generators. The practical implications of this distinction will be discussed further below when device characteristics are examined. ESWT device characteristics Five parameters are commonly used to characterize an ESWT device: 1. Energy Flux Density (EFD) is the most important parameter. It represents the amount of energy delivered per unit area per pulse, measured in mJ/mm2. Devices are typically classified as low-, medium-, or high-energy, as shown below. EFD (mJ/mm²) Classification < 0.08 Low energy 0.08–0.28 Medium energy > 0.28 High energy 2. Peak pressure includes both the positive (P⁺) and negative (P⁻) pressure components. P⁺ reflects the compressive force and is important for mechanotransduction, whereas P⁻ produces cavitation and plays a key role in biological signaling as well as in assessing potential tissue risk. Typical P⁺ values for focused ESWT devices range from 20 to 100 MPa, whereas radial devices operate at much lower pressures, typically 1–10 MPa. That said, peak pressure alone can be misleading because it does not account for pulse duration or focal size. 3. Pulse rise time and duration also influence biological effects. In most ESWT systems, rise times are less than 10 ns and pulse durations range from 1 to 10 μs. Shorter pulses tend to deliver high instantaneous mechanical stress, minimize thermal effects, and preferentially activate mechanical signaling pathways. 4. Pulse repetition frequency for most devices ranges from 1 to 8 Hz. In clinical practice, the total number of pulses per session vary from 500 to 3000, depending on the indication. While pulse repetition frequency does not alter the EFD, it directly affect overall treatment duration. 5. Focal volume and penetration depth represent a major distinction between focused and radial ESWT. In focused ESWT, energy is concentrated within an ellipsoid focal zone located at depths of approximately 10-60 mm. In contrast, radial ESWT delivers its highest energy at the skin surface, with rapid attenuation such that penetration rarely exceeds 1–2 cm. Focused ESWT is therefore often preferred for osteoarthritis—particularly knee osteoarthritis—where therapeutic targets may include deeper periarticular tissues, entheses, and subchondral bone. Comparing ESWT devices When comparing ESWT devices, the most important features to consider are the type of shock wave (focused vs. radial), the EFD at the focal point (mJ/mm²), and the focal depth and volume. Equally important are pulse reproducibility and whether device parameters are measured and reported in accordance with IEC standards. Clinical studies using ESWT, should at a minimum, specify the EFD and the total pulse count delivered during treatment. Numerous educational videos are available online explaining the differences and clinical roles of focused and radial ESWT. Two accessible examples that provide a useful overview of both techniques—and how they may complement one another—include: Clinical Proofs that ESWT is effective in the treatment of knee osteoarthritis Multiple randomized controlled trials and meta-analyses (4–8) consistently show that ESWT reduces pain and improves function in patients with knee osteoarthritis when compared with sham treatment or other conservative interventions. In many studies, these benefits persist for weeks to several months. Several trials also demonstrate a dose–response relationship, with medium-energy protocols producing superior clinical outcomes compared with low-energy treatments (9–11). In addition, focused ESWT—which is capable of reaching deeper structures such as subchondral bone—may provide better joint-related outcomes than radial devices (12). A simplified summary of reported EFD ranges and associated biological effects is shown below:
Importantly, the beneficial effects of ESWT may extend even to patients with advanced disease. A recent study by CP, K. et al. (13) reported clinical improvements in patients with Kellgren–Lawrence (K–L) grade 4 osteoarthritis. Similarly, a randomized clinical trial by Choi, I.J. et al. (14) demonstrated reductions in suprapatellar effusion and improvements in inflammatory symptoms following ESWT, providing in vivo support for its anti-inflammatory effects. Evidence for true disease-modifying effects—such as structural preservation of articular cartilage—remains mixed and incomplete. Preclinical studies and mechanistic human data suggest that ESWT can stimulate subchondral bone remodeling and activate anabolic signaling pathways in chondrocytes, which are biologically plausible disease-modifying mechanisms. However, robust long-term randomized controlled trials incorporating quantitative MRI endpoints or histological evidence of slowed cartilage loss are still scarce. Notably, at least one randomized controlled trial (15) reported potential adverse effects on cartilage under a specific low-dose protocol, highlighting that not all ESWT treatment regimens are necessarily structurally protective. In summary, the evidence supporting symptomatic relief from ESWT in knee osteoarthritis is strong, whereas convincing proof of durable cartilage preservation in humans will require more standardized, long-term imaging-based clinical trials. Comparing ESWT with other therapies for osteoarthritis A systematic review and meta-analysis by Chen, L. et al. (16) compared ESWT with a wide range of treatment modalities across different forms of osteoarthritis. The analysis focused specifically on pain reduction and functional improvement. The overall findings are summarized in the table below.
“+” indicates results favoring ESWT over the comparator; “–” indicates comparable or superior results for the comparator; “?” indicates insufficient or inconsistent evidence. HA: hyaluronic acid; PRP: Platelet Rich Plasma These findings can be contrasted with the results reported by Cao, S. et al. (2), who restricted their analysis to non-pharmacological interventions for knee osteoarthritis—a study discussed previously in the November 15, 2025 blog on acupuncture for knee OA. Selected results from that analysis are reproduced below for comparison. Efficacy rankings based on the Visual Analog Scale (VAS) pain scores: shock wave therapy > needle-knife (acupotomy) > laser therapy > acupuncture > ultrasound > exercise > transcutaneous electrical nerve stimulation Efficacy rankings based on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) subscales:
The two datasets overlap in their comparison of ESWT with ultrasound and acupotomy (needle-knife). For ultrasound, the findings are consistent: ESWT outperformed ultrasound in both analyses. In contrast, the results for acupotomy diverge. Cao, S. et al. reported that ESWT was superior for both pain reduction and functional improvement, whereas Chen, L. et al. found acupotomy to perform as well as—or better than—ESWT in these same outcomes. These discrepancies highlight the need for well-designed, head-to-head randomized controlled trials directly comparing treatment modalities. Meta-analyses based on small, heterogeneous trials with variable protocols and controls have inherent limitations and should be interpreted with appropriate caution. ESWT Mechanism of Action Clinical studies indicate that ESWT typically employs low- to medium-energy flux densities to elicit beneficial biological responses in osteoarthritis without causing tissue damage. How this mechanical energy interacts with cells and biomolecules—and which molecular pathways translate these interactions into therapeutic effects—is therefore of considerable interest. A clearer understanding of these mechanisms can inform more rational ESWT protocol design tailored to specific patient populations. ESWT delivers very high peak stresses with an extremely rapid rise time to cellular structures, particularly cell membranes. The resulting steep spatial pressure gradients, together with cavitation effects, activate mechanotransduction pathways, many of which have been identified over the past two decades. Most mechanistic studies to date have been conducted in animal models or in isolated cells and tissues derived from cartilage and subchondral bone. Dose effect, angiogenesis, cartilage/subchondral bone remodeling A clear dose-dependent effect of ESWT was demonstrated by Wang, C.-J. et al. (17) using a surgically induced knee osteoarthritis (KOA) rat model. In this study, an optimal dose of 800 pulses delivered at an energy flux density of 0.22 mJ/mm², administered once or twice weekly, was sufficient to inhibit deterioration of both articular cartilage and subchondral bone in periarticular regions. These effects were assessed using X-ray imaging, histomorphological analysis, and immunohistochemistry. Articular cartilage integrity was evaluated by immunostaining for collagen type II and matrix metalloproteinase-13 (MMP-13), whereas subchondral bone remodeling and angiogenesis were assessed through immunostaining of von Willebrand factor (vWF), vascular endothelial growth factor (VEGF), bone morphogenetic protein-2 (BMP-2), and osteocalcin. The main biological effects observed in response to ESWT can be summarized as follows:
Effect on bone homeostasis Direct effects of ESWT on bone homeostasis—specifically on osteoblast and osteoclast differentiation—have been reported by Li, B. et al. (18) and Chen, B. et al. (19). Using cultured rabbit bone marrow–derived stem cells, these authors demonstrated that ESWT promotes differentiation toward osteoblasts, as shown by classical histochemical staining and mRNA profiling of osteogenesis-related markers, including alkaline phosphatase (ALP), osteocalcin (OCN), osteoprotegerin (OPG), and runt-related transcription factor 2 (Runx2). In vivo, using a rabbit model of osteoporosis, ESWT increased trabecular bone volume, number, and thickness, while reducing trabecular separation in the femur when compared with untreated controls. To examine effects on osteoclastogenesis, immortalized mouse macrophage RAW264.7 cells induced with receptor activator of nuclear factor κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) were used as a model system. In this context, ESWT inhibited differentiation into osteoclasts, as determined by histochemical staining and reduced mRNA expression of two key osteoclast markers, cathepsin K and dendritic cell–specific transmembrane protein (DC-STAMP). ESWT also suppressed cell proliferation and reduced expression of NFATc1 as well as p65, a subunit of the NF-κB transcriptional complex, indicating that inhibition of NF-κB signaling underlies the anti-osteoclastogenic effect. Consistent with these findings, ESWT increased trabecular bone volume, number, and thickness and decreased trabecular separation in mouse femora. The principal cellular effects of ESWT on bone homeostasis can be summarized as follows:
Zhao, Z. et al. (20) identified an additional molecular pathway mediating the effects of ESWT in subchondral bone–derived stem cells. Using primary human stem cells isolated from patients with knee osteoarthritis, the authors showed that ESWT increased colony-forming capacity in a dose-dependent manner. This effect was driven by enhanced proliferation without measurable changes in apoptosis. Although no significant effect on osteogenic differentiation was observed, ESWT strongly suppressed adipogenic differentiation and modestly enhanced chondrogenic differentiation. Expression of cartilage-related markers, including collagen type II and proteoglycans, was consistently higher than in untreated controls. Notably, these phenotypic changes were associated with increased expression of the mechanosensitive co-transcriptional regulators YAP and TAZ and their translocation into the nucleus. YAP/TAZ signaling is well recognized for its role in mechanotransduction, organ size regulation, tissue regeneration, wound healing, and stem cell maintenance. These effects may be summarized schematically as:
Finally, it is worth noting the apparent discrepancy between the findings of Li, B. et al. (18), who observed ESWT-induced osteogenic differentiation in healthy rabbit bone marrow stem cells, and those of Zhao, Z. et al. (20), who did not detect osteogenic differentiation in subchondral bone stem cells derived from patients with knee osteoarthritis. Differences in species, tissue origin, and disease state may plausibly account for this divergence and underscore the complexity of translating mechanistic findings across experimental models. Apoptosis and autophagy The effects of ESWT on apoptosis and autophagy have been demonstrated in a cellular model of osteoarthritis using primary rat chondrocytes stimulated with interleukin-1β (IL-1β) (21). This model was validated by showing that IL-1β downregulated collagen type II expression, a hallmark of cartilage degeneration, and that ESWT was able to reverse this effect. The authors further demonstrated that ESWT inhibited IL-1β–induced apoptosis, as assessed by Annexin V–FITC/propidium iodide flow cytometry. In contrast, autophagy was enhanced, as evidenced by changes in both mRNA and protein expression of key autophagy markers, including Beclin-1, Atg5, LC3B, and p62. This dual effect—suppression of apoptosis alongside activation of autophagy—is consistent with the overall protective role of ESWT in cartilage degeneration. The anti-apoptotic effect of ESWT also aligns with earlier findings reported by Zhao, Z. et al. (22), who observed reduced nitric oxide (NO) levels in the knee joint and synovial fluid following ESWT in a rabbit model of knee osteoarthritis. Given the established pro-apoptotic role of NO in chondrocytes, this observation provides additional mechanistic support. The key molecular effects can be summarized as follows:
Reactive oxygen species (ROS) signaling Building on earlier reports of increased intracellular reactive oxygen species (ROS) following ESWT, Shen, P.-C. et al. (23) used primary porcine chondrocytes to characterize this response in greater detail. They demonstrated a dose-dependent but transient increase in ROS levels, peaking at approximately 10 minutes after treatment and returning to baseline within one hour. The authors identified xanthine oxidase as the primary source of ROS generation. Importantly, this transient ROS burst was followed by increased extracellular matrix (ECM) synthesis, without adverse effects on cell viability or proliferation. Enhanced ECM production was accompanied by increased phosphorylation of p38 mitogen-activated protein kinase (MAPK) and ERK1/2, as well as nuclear translocation of nuclear factor erythroid 2–related factor 2 (Nrf2), a key transcription factor regulating cellular antioxidant and detoxification pathways. These findings suggest that a brief, well-controlled ROS signal acts as a beneficial second messenger rather than a source of oxidative damage in the context of ESWT. The principal signaling events can be summarized as follows:
1a,25-Dihydroxy vitamin D3 rapid signaling pathway Using a surgically induced rat model of knee osteoarthritis combined with a proteomic approach, Hsu, S.-L. et al. (24) showed that ESWT treatment (800 impulses delivered at 0.18 mJ/mm² and 4 Hz) optimally induced expression of protein disulfide isomerase–associated 3 (Pdia-3) within two weeks of treatment. Pdia-3 has been implicated as a membrane-associated co-receptor for 1α,25-dihydroxyvitamin D₃ (1α,25(OH)₂D₃, calcitriol), which, together with the classical nuclear vitamin D receptor, mediates rapid, non-genomic signaling. This rapid signaling pathway is known to activate voltage-gated Ca²⁺ channels, increase intracellular Ca²⁺ flux, and trigger several downstream kinase cascades (25). Activation of the 1α,25-dihydroxyvitamin D₃ rapid signaling pathway in ESWT-treated articular cartilage and subchondral bone was supported by increased expression of four downstream effectors—ERK1, osteoprotegerin (OPG), alkaline phosphatase (ALP), and matrix metalloproteinase-13 (MMP-13)—all of which are associated with bone remodeling and formation. The proposed signaling cascade can be summarized as follows:
Vitamin D–related signaling is increasingly recognized as relevant in osteoarthritis because of its central role in regulating calcium homeostasis, bone turnover, and chondrocyte function. Articular cartilage and subchondral bone both express components of the vitamin D signaling machinery, and disturbances in this pathway have been associated with altered bone remodeling, cartilage degradation, and OA progression. Beyond its classical genomic actions, rapid, non-genomic vitamin D signaling influences mechanosensitive pathways, intracellular calcium flux, and kinase activation—processes that are highly responsive to mechanical stimuli. The ability of ESWT to engage this rapid signaling axis therefore provides a plausible mechanistic link between mechanical energy delivery and coordinated biological responses in cartilage and subchondral bone, particularly in the mechanically driven environment of osteoarthritis. Wnt5a/Ca2+ signaling pathway Evidence for activation of the Wnt5a/Ca²⁺ signaling pathway by ESWT was reported by Yu, L. et al. (26) using both an in vivo chemically induced rat model of knee osteoarthritis and in vitro experiments with bone marrow–derived mesenchymal stem cells (BMMSCs) isolated from rat femur and tibia. Immunostaining of subchondral bone plates from KOA rats treated with radial ESWT (1 bar, 6 Hz, 800 pulses) revealed higher Wnt5a expression compared with both sham-treated KOA rats and normal controls. This increased expression correlated with improved histological morphology, reflected by lower Mankin scores, relative to sham-treated animals. In vitro, BMMSCs exposed to ESWT exhibited a time-dependent increase in Wnt5a expression. Levels peaked approximately 30 minutes after treatment and gradually declined with longer exposure times of up to 3 hours. Quantitative RT-PCR indicated that optimal Wnt5a induction occurred at 0.6 bar with a 30-minute exposure. ESWT also induced expression of several downstream components of the Wnt5a/Ca²⁺ pathway, including calcium/calmodulin-dependent protein kinase II (CaMKII), phospholipase C (PLC), and protein kinase C (PKC), with variable temporal patterns over a 3-hour time course. The proposed signaling sequence may be summarized as:
The authors attributed the observed improvements in cartilage and subchondral bone morphology following ESWT to activation of the Wnt5a/Ca²⁺ signaling pathway. However, such a conclusion should be interpreted with caution. Wnt5a is a pleiotropic signaling molecule involved in a wide range of biological processes, including embryonic development, inflammation, and cancer. Notably, Wnt5a has also been implicated in osteoarthritis pathogenesis, where it may promote cartilage degradation and inflammation by activating catabolic pathways, increasing matrix-degrading enzymes such as MMPs, and disrupting joint homeostasis (27,28). Taken together, these findings suggest that while ESWT can modulate Wnt5a/Ca²⁺ signaling, the net biological outcome is likely to be highly context-dependent, influenced by dose, timing, tissue state, and disease severity. Mechanistic Summary Taken together, the available mechanistic evidence suggests that ESWT acts as a pleiotropic biomechanical stimulus that engages multiple, interconnected signaling pathways in cartilage and subchondral bone (Figure 1). At low to medium energy flux densities, ESWT delivers rapid, high-peak mechanical stress that activates mechanotransduction at the cell membrane, leading to downstream modulation of inflammation, apoptosis, autophagy, and tissue remodeling. ESWT promotes angiogenesis and subchondral bone remodeling, enhances osteoblast differentiation while suppressing osteoclastogenesis, and shifts stem cell fate away from adipogenesis toward chondrogenesis. Transient increases in reactive oxygen species function as second messengers that activate MAPK and Nrf2-dependent antioxidant pathways, supporting extracellular matrix synthesis without compromising cell viability. ESWT also engages rapid, non-genomic vitamin D signaling through Pdia-3, linking mechanical stimulation to calcium flux and bone-forming cascades. Finally, modulation of non-canonical Wnt5a/Ca²⁺ signaling highlights the context-dependent nature of ESWT responses, emphasizing the importance of dose, timing, and disease state. Collectively, these mechanisms provide a biologically plausible framework for the clinical benefits of ESWT in knee osteoarthritis while underscoring the need for carefully optimized treatment protocols. Common commercially available ESWT devices Commercially available ESWT systems can be broadly divided into two categories: clinical-grade devices intended for use by medical professionals and devices marketed directly to consumers for general wellness applications. Clinical ESWT Devices (Professional Use) Clinical ESWT devices are designed to deliver precisely controlled energy flux densities (EFDs) and pulse frequencies. These systems are capable of generating substantial mechanical forces that can modulate tissue physiology, including effects on subchondral bone remodeling, angiogenesis, and chondrocyte mechanotransduction. As such, their safe and effective use requires appropriate training in dosimetry, anatomical targeting, and patient selection. Improper self-application—particularly without imaging guidance or professional assessment—may result in subtherapeutic treatment or, in some cases, tissue injury. For this reason, focused ESWT devices operating at medium to high EFDs are typically restricted to clinical settings. It is also important to note that there are currently no FDA-approved focused ESWT devices intended for direct consumer or self-use, especially at the energy levels required to reach deep joint tissues such as the knee. Focused shockwave systems are generally regulated as prescription-only medical devices due to safety considerations and the need for clinical oversight. Many are used off-label for osteoarthritis based on clinician judgment and emerging evidence rather than explicit FDA indications. Examples of focused and radial ESWT devices commonly found in outpatient physical therapy, sports medicine, and rehabilitation clinics are listed below. Device parameters—such as pressure or EFD, pulse frequency, and applicator size—are adjustable and tailored to the clinical indication and patient tolerance. Focused type: OrthoGold 100 (MTS) Endopuls FSWT (Enraf-Nonius) PiezoWave2® (Richard Wolf) DolorClast® Focused Shock Waves (EMS Electro Medical System SA) Emfocus (GZ MTS Electronics Co., Ltd.): Electromagnetic focused ESWT Radial type: Endopuls 811 (Enraf-Nonius) DolorClast® Radial Shock Waves (EMS Electro Medical System SA) Softshock 2.0 (Medray Laser & Technology): Radial ESWT device. Z Wave® Q (Zimmer MedizinSystems): Radial ESWT device. Klinogicare Shockwave Storm Radial (Klinogicare) PHS Radial Shockwave, PHS6B (PHSDME) AWT Radial Shockwave Therapy (Hedone/clinics) INWAVE Radial Shockwave (INWAVE Medical) MTS SWT9 Radial ESWT System (GZ MTS Electronics Co., Ltd.) Modus ESWT® Radial Shockwave (Refizo) An example of a modular mixed-use type Duolith® SD1 Ultra (Storz Medical): A modular system for both focused and radial ESWT with optional Ultrasound diagnostics. Consumer-Targeted “Shockwave” Devices A separate category includes devices marketed directly to consumers for general wellness, pain relief, or soft-tissue massage. While some of these products advertise “shockwave” technology and adjustable energy output, they are not FDA-cleared for specific medical indications such as osteoarthritis or tendinopathy. Reported energy outputs are typically not standardized to clinical EFD measurements, are rarely independently verified, and lack validation in peer-reviewed clinical trials. These devices generally deliver lower, more variable energy levels rather than those of true therapeutic shock waves. Consequently, they should not be considered equivalent to clinical ESWT systems and should be used with caution. Examples of consumer-market devices include: Shape Tactics Radial Shockwave Therapy Device (Cavitation Machines) PSP20 Extracorporeal Shock Wave Therapy Machine (Pervita Medical) Q60A Extracorporeal Shock Wave Therapy (Sheyera) MODOY ESWT02 (MODOY) Finding a provider of shock wave therapy Primary care doctors, orthopedic surgeons, and physical therapists can offer reliable information or references. Additional resources and platforms include: Shockwave Provider Directories Several private or industry-associated directories list clinics or providers offering shockwave treatments:
These directories are not exclusively physical therapists, but they include PTs alongside other clinicians. Vendor-Specific “Find a Provider” Tools Some shockwave device manufacturers maintain provider locators through their own channels. For example, SoftWave Clinics site lets patients locate clinics (including physical therapy clinics) that use its technology. These are useful if you know the brand of devices being used in your area. Local Clinic Search and Therapy Networks You can also use generalized health provider search services (not specialty directories) to find ESWT-offering PT practices. For example, JustHealthy.com and similar “find a provider near me” services list nearby clinics offering shockwave therapy based on city or zip code.  References
 Introduction This is a continuation of our series on knee osteoarthritis. We discussed Pulsed Electromagnetic Field (PEMF) therapy and its applications in pain management in a blog post dated January 19, 2025. PEMF is known for its effectiveness in reducing pain and improving function in people with various musculoskeletal conditions, including knee osteoarthritis (knee OA). This position is supported by clinical data discussed in a health fact sheet produced by the National Center for Complementary and Integrative Health (NCCIH): “Magnets For Pain: What You Need To Know.” Here, we will update the information provided by the NCCIH on clinical effectiveness and mechanisms of action known to date, with a focus on knee osteoarthritis. Moreover, we will discuss commercial PEMF devices and associated protocols approved by the FDA specifically for the treatment of osteoarthritis, or approved only for the health and wellness consumer market but potentially applicable to osteoarthritis. Clinical trials supporting effectiveness in osteoarthritis including knee osteoarthritis. The cautious recommendation by the NCCIH that “Electromagnetic therapy may be a beneficial complementary therapy for treating osteoarthritis…” was based primarily on the meta-analysis of 12 clinical studies by Wu Z. et al. (2018) and the systematic review of 15 additional studies by Paolucci T. et al. (2020), encompassing a total of 1,370 patients with osteoarthritis affecting primarily the knees, ankles, hands, neck and lower back. Overall, these studies showed that electromagnetic therapy (mostly PEMF) reduced pain, improved physical function and reduced stiffness while being well tolerated. It could be a useful addition to the standard of care currently available to patients, although much remains to be done in optimizing protocols and validating them with larger trials. Since then a number of new randomized controlled clinical studies were reported through 2025. We will summarize some of the more relevant ones below: Hashemi, S. E. et al. (2024) conducted a small study with 70 female patients with primary knee OA. It investigated the effect of low-frequency PEMF (10-100 Hz; the device used was poorly identified but could be an Extremely Low Frequency (<100 Hz) and Low Intensity (< 10 mT) ASA Magnetotherapy device) in addition to a regular schedule of physical therapy. Exposure was 30 minutes at 40% intensity every week day for 3 weeks. Evaluations were conducted at baseline, after 3 weeks of treatment, and at 7 weeks follow-up. The results showed that the PEMF group experienced less pain (measured by the Visual Analog Scale, VAS), lower functional limitation, and reduced stiffness at 7 weeks compared to sham group. Physician Global Assessment (PGA) scores were also superior in the PEMF group versus sham. Similarly to the previous study, Wang, Q. W. et al. (2024) investigated the effect of PEMF in a group of 60 patients with confirmed end-stage osteoarthritis (Kellgren-Lawrence (KL) grade ≥ 3) in one or both knees. PEMF treatment was administered in addition to home-based stretching and strengthening exercises designed by physiotherapists. PEMF treatment consisted of two 10-minute sessions per week for 8 weeks delivered by a Quantum Tx machine generating a uniform 1 mT field intensity at 50 Hz pulse frequency. Both knees were treated in alternate sessions, so each knee was exposed to a total of 8 sessions. Evaluations were conducted at baseline and at 4 and 8 weeks of treatment. The results showed improved knee muscle strength and reduced pain as well as a promising tendency to improve performance-based physical function (as measured by 6-meter walk plus sit-to-stand time) in the PEMF group versus sham. Taken together, both studies supported supplementing exercise and physical therapy routines for knee OA patients with PEMF treatment. The magnetic pulse intensity and frequency required did not exceed 10 mT and 100 Hz, respectively. Session duration was 10 to 30 minutes at a frequency of 2 to 5 sessions per week for no more than 8 weeks. The duration of the beneficial effect beyond 8 weeks and the need for repetition remain to be determined. A recent review by Bhutada, G. et al. (2025) supports this conclusion. Maghroori, R. et al. (2025) further investigated the utility of PEMF as adjunct therapy in a more complex setting where the patient population was already subjected to two forms of therapy: an exercise regimen plus a nonsteroidal anti-inflammatory drug, meloxicam 15 mg daily. PEMF treatment consisted of a 30-minute session with pulse intensity and frequency of 50 Gauss (5 mT) and 75 Hz, respectively. Each patient in a group of 60 diagnosed with grade 2 or 3 knee OA, was treated with 8 sessions of PEMF or sham PEMF over 3 weeks. Evaluations at baseline, end of treatment, and follow-up at 6 weeks and 3 months after treatment showed that the addition of PEMF therapy substantially enhanced pain relief and physical function with no reported side effects. The findings support the use of PEMF as adjunct therapy for knee OA patients who are concomitantly treated with exercise and an NSAID agent. In a similar complex setting comprising a population of 120 patients suffering from knee OA, Kellgren-Lawrence (KL) grade ≥ 2, Wang, R. et al. (2026) investigated the effect of adding PEMF to two established therapies in China: exercise and external Chinese herbal therapy (Sanqi Shengyu External Application Cream). The PEMF protocol was distinct in using a much higher magnetic pulse intensity of 800 mT at a pulse frequency of 50 Hz for 30 minutes. Patients in the PEMF group were treated for a total of 20 sessions over 4 weeks. Evaluations were conducted at baseline, end of treatment, and at 4-week follow-up. The results of 4 treatment arms (exercise only as control, exercise + PEMF, exercise + external Chinese herbal therapy, and combination of exercise + PEMF + external Chinese herbal therapy) showed that the combined therapy group demonstrated superior outcomes, especially at the 4-week follow-up. The beneficial effect of external Chinese herbal therapy alone was durable, while that of PEMF diminished over time after intervention. The exercise-only control group also showed significant improvements but less pronounced than the active intervention groups. Direct comparison of the results by Maghroori, R. et al. (2025) and Wang, R. et al. (2026) would not be possible because of the differences in PEMF protocols and control design. Nevertheless, both sets of results support the application of PEMF as an adjunct to multimodal therapies that include exercise and anti-inflammatory agents. Studies to optimize PEMF dosing (i.e. carrier frequency, pulse intensity and frequency, treatment duration required to achieve specific goals: pain & stiffness reduction, function improvement, cartilage degradation) are crucial for advancing PEMF as a treatment option. To that effect, Yang, X. et al. (2025) reported that at fixed magnetic field intensity (3.8 mT), higher PEMF pulse frequency (75>50>8 Hz) resulted in better recovery in a rat model of knee osteoarthritis. Ye, L. I. (2025) reported some preliminary efforts in studies of varying field intensity in a mouse model, but detailed results have yet to be published. Two additional clinical trial results need to be discussed as a separate category considering the characteristics of the PEMF protocols and the commercial nature of the devices employed. In contrast to PEMF protocols using magnetic pulse intensity in the mT range and pulse frequency < 100 Hz, the following two trials employed PEMF with carrier frequency in the radiofrequency (27.12 MHz) range, i.e. magnetic pulse intensity probably in the μT range or less, and pulse frequency ranging from 2 to 1,000 Hz. At such low intensity and wide range of pulse frequencies these electromagnetic pulses (often referred to as Pulsed Radiofrequency/Shortwave Therapy, or PRF/PSWT) can still penetrate soft tissue to disrupt chronic pain signaling and induce analgesia, among other effects. Whether the two distinct sets of protocols operate similarly at the cellular or molecular level remains to be determined for particular biological applications Hackel, J. G. et al. (2025) reported a prospective study with 120 patients suffering from diverse soft tissue or joint pain (ankle, back, knee, wrist, elbow, shoulder, foot, hip, or neck) although knee pain predominated (43%) . Patients were randomized, but the study was not blinded and included two arms: PEMF and Standard of Care (SOC). Patients in the PEMF arm self-administered the treatment with a commercial device (Orthocor Active System) operating at 27.12 MHz carrier radiofrequency, pulse frequency of 2 Hz, pulse duration of 2 ms, and classified by the FDA as a short-wave diathermy device. The treatment consisted of daily 2-hour sessions for 14 days per manufacturer instructions. After 14 days, patients in the SOC arm were allowed to cross over. The two key endpoints for the study were efficacy measured by changes in pain score from baseline, and safety measured by the number of adverse events. The overall results showed that use of the Orthocor device was safe and led to significant reductions in pain and medication use compared to the standard of care for joint and soft tissue pain. Durtschi, M. S. et al., 2025, reported on a single-center, double-blind, randomized, controlled trial with 61 patients suffering from thumb carpometacarpal (CMC) osteoarthritis to test the effectiveness of another commercial PEMF device, the ActiPatch made by BioElectronics, classified by the FDA as Non-Thermal Shortwave Device. The device operates at 27.12-MHz carrier radiofrequency, pulse frequency of 1,000 Hz, pulse duration of 0.1 ms. The study consisted of two arms: patients in a treatment group wore the device overnight for 4 weeks whereas patients in the control group similarly wore a sham device not emitting the radiowave. Two endpoints were considered: pain reduction and function improvement. Evaluations were conducted at baseline, at 4 weeks end of treatment, and at 6 weeks follow-up. The results showed that both PEMF and sham groups achieved pain reduction and function improvement at the end of treatment (4 weeks), but no statistical difference could be discerned between the two groups. At 6 weeks follow-up, however, the pain reduction was sustained in the PEMF group only. The placebo effect was substantial but did not extend beyond the treatment period. Effectiveness ranking of PEMF versus Extracorporeal shock wave therapy (ESWT), Low-level laser (LLLT) and Microwave (MW) therapy. In a study of 120 patients aged 40-70 and diagnosed with knee OA, Kellgren-Lawrence (KL) grade 2-3, Pasin, T., & Dogruoz Karatekin, B. (2025) compared the efficacy of PEMF against two other non-pharmacological treatment modalities: extracorporeal shock wave therapy (ESWT) and low-level laser therapy (LLLT). The patients were divided into four groups of 30 participants each —three groups received their respective treatment interventions while one served as untreated control. The PEMF intervention consisted of 20-minute sessions twice weekly over 4 weeks, using a magnetic pulse intensity of 10 mT and and frequency of 30Hz. Overall, beneficial effects (pain reduction, decreased stiffness, and improved physical functions) were observed for all 3 interventions compared to the control group. However, PEMF was found to be less effective than ESWT and LLLT, which demonstrated roughly equal effectiveness. In summary: ESWT ≈ LLLT > PEMF. In another comparative study, Comino-Suárez, N. et al. (2025) investigated the effects of PEMF and microwave therapy (MW) combined with a standardized exercise regimen (EX). This three-arm randomized, blinded clinical trial included 60 patients with unilateral or bilateral knee osteoarthritis, Kellgren & Lawrence grade 2 or 3, divided into groups receiving EX+PEMF, E+sham PEMF, and EX+MW. All three interventions were delivered over 12 sessions (3 sessions per week for 4 weeks). The PEMF treatment consisted of 20-minute exposures at a pulse intensity of 10 mT and frequency of 50 Hz. Results showed that although all three groups exhibited improvement in most VAS and WOMAC scores after treatment and at 1- and 3-month follow-ups, the EX+PEMF group outperformed the other two, particularly during the 1- and 3-month follow-up periods. These finding complement and extend the report by Cao, S. et al. (2024) who compared the effectiveness of acupuncture for knee OA against 6 other non-pharmacological treatment modalities: needle-knife therapy (acupotomy), exercise, transcutaneous electrical nerve stimulation (TENS), ultrasound, shock wave therapy, and laser therapy (see our previous blog, 11/15/2025). Shock wave therapy was superior to all others based on VAS and WOMAC scale assessment following treatment. Mechanistic aspects Studies on the mechanism of pain modulation and articular cartilage stabilization by PEMF (Pilla, A. et al., 2011, Iwasaka, K. & Reddi, A., 2018, Bragin, D. E. et al., 2015) established the following basic understanding:
Since 2020, additional advances have been achieved in delineating the molecular features of osteoarthritic tissues and how they are affected by PEMF treatment . These advances are summarized below: Using a cellular model of human chondrocytes (C28/I2) stimulated with interleukin (IL)-1β and a mouse model of osteoarthritis, Zhou, S. et al. (2025) demonstrated that upregulation of Sirt1 (a transcription factor deacetylase) by PEMF blocks the activation of the pivotal pro-iinflammatory NF-κB signaling pathway, which is often overactive in osteoarthritic joints. This finding is important as it adds to our understanding of the molecular events induced by PEMF that lead to decreased inflammation at the joints and slowing of disease progression. Inhibiting the NF-κB signaling pathway induced by interleukin (IL)-1β is part of an overall strategy for developing therapeutic agents for the treatment of osteoarthritis. Working with primary human chondrocytes, Bao, C. et al. (2025) showed that the glycolysis rate increases in chondrocytes from arthritic cartilage, accompanied by upregulation of hexokinase II (HK2). Overexpression of HK2 promotes an inflammatory response and catabolism while inhibiting anabolic activities. Concommitant with the increased expression of HK2 was a decrease in expression of HMGA2, a DNA-binding protein capable of transcriptional regulation. The authors also showed that PEMF inhibits the expression of HEK2 and increases HMGA2, leading to a reversal of the iinflammatory and catabolic state in the chondrocytes. Lonidamine, an inhibitor of HK2, performed similarly. In a mouse model of osteoarthritis, lonidamine in combination with PEMF more effectively reversed cartilage degeneration. Finally, HK2 was proposed as a potential target for developing therapeutic agents for the treatment of osteoarthritis. Over past decades, exposure to PEMF has been shown to have beneficial effects not only in bone and cartilage but also in tendons and muscles. Tendinopathy and muscle atrophy tend to stress joint structures and contribute to the development of osteoarthritis. As a result, mechanistic studies in those tissues were also of interest. The information developed from either approach tends to enhance and complement each other. Using proteomic analysis of rat muscles subjected to experimentally induced tendinopathy, Torretta, E. et al. (2024) reported that glycolysis in these tissues is enhanced. When exposed to PEMF, changes in the pattern of cellular proteins support a switch towards oxidative phosphorylation, as evidenced by the increase in LDHB, which converts lactate to pyruvate, boosting NAD+ signaling, ATP production, and beta-oxidation of fatty acids. PEMF also increases the level of antioxidant proteins which control the damage caused by reactive oxygen species (ROS). Two key transcription co-activators, PGC1alpha and YAP, were upregulated by PMEF. The former is clearly linked to the increase in oxidative metabolism, anti-iinflammatory state, and antioxidant effects. The latter supports tissue repair and regeneration, and cell proliferation (Maiullari, S. et al., 2023). PEMF devices available to medical professionals and consumers In a previous blog post (01/19/2025) we discussed various venues for accessing electromagnetic therapy for pain management. Now we’ll dwell into the devices available on the market for both medical professionals (doctors, therapists) and the general consumers responding to medical guidance, or just interested in self-help for osteoarthritis. The market can be broadly categorized into devices cleared by regulatory bodies for specific medical uses and those marketed for general health, pain, and wellness (more common in the consumer market). I. Medical Device Market (Often FDA-Cleared/Approved) These devices are typically intended for use under the guidance of a healthcare professional, with specific indications for use that may include post-operative pain, edema, and osteoarthritis.
Note: While the primary FDA indications for many Orthofix and DJO devices are bone healing (non-union fractures or spinal fusion), PEMF technology, in general, is cleared for conditions like post-operative osteoarthritis and pain/edema. The ActiPatch is specifically cleared for knee osteoarthritis for non-prescription use. Except for the two Orthofix devices (Physio-Stim and Spinal-Stim) all others in the list are in fact Pulsed Radiofrequency/ Shortwave Therapy types operating at 27.12 MHz carrier frequency. II. Health & Wellness Consumer Market These are typically sold directly to consumers for home use, often marketed for general wellness, pain relief, improved circulation, and reduced inflammation, which are beneficial for osteoarthritis symptoms. They may not have specific FDA clearance for treating osteoarthritis but are marketed under general wellness claims.
Concluding remarks The available evidence supports the effectiveness of PEMF as an adjunctive treatment for different forms of osteoarthritis, particularly for relief from pain and inflammation. Proof of a beneficial effect on cartilage degradation remains at the experimental level in animal models. It has yet to be validated quantitatively in a randomized clinical setting with adequate control. Conservatively, patients could opt for any of the FDA-approved device and protocol under guidance from medical professionals, and as adjunct to exercises and physical therapy in addition to judicious application of pharmacological interventions. Devices approved for marketing for home use and general wellness are likely safe enough for those willing to explore therapeutic approaches still under development. References
Wu, Ziying, Xiang Ding, Guanghua Lei, Chao Zeng, Jie Wei, Jiatian Li, Hui Li et al. "Efficacy and safety of the pulsed electromagnetic field in osteoarthritis: a meta-analysis." BMJ open 8, no. 12 (2018): e022879. doi: 10.1136/bmjopen-2018-022879 https://doi.org/10.1136/bmjopen-2018-022879 Paolucci, T., Pezzi, L., Centra, A. M., Giannandrea, N., Bellomo, R. G., & Saggini, R. (2020). Electromagnetic field therapy: a rehabilitative perspective in the management of musculoskeletal pain–a systematic review. Journal of pain research, 1385-1400. DOI https://doi.org/10.2147/JPR.S231778 https://doi.org/10.2147/JPR.S231778 Hashemi, S. E., Gök, H., Güneş, S., Ateş, C., & Kutlay, Ş. (2024). Efficacy of pulsed electromagnetic field therapy in the treatment of knee osteoarthritis: A double-blind, randomized-controlled trial. Turkish Journal of Physical Medicine and Rehabilitation, 71(1), 66. doi: 10.5606/tftrd.2024.14486 Wang, Q. W., Ong, M. T. Y., Man, G. C. W., Franco-Obregón, A., Choi, B. C. Y., Lui, P. P. Y., ... & Yung, P. S. H. (2024). The effects of pulsed electromagnetic field therapy on muscle strength and pain in patients with end-stage knee osteoarthritis: A randomized controlled trial. Frontiers in Medicine, 11, 1435277. https://doi.org/10.3389/fmed.2024.1435277 Bhutada, G., Telang, A. A., & Yadav, V. (2025). Impact of Pulsed Electromagnetic Field Therapy Combined With Traditional Exercises on Knee Osteoarthritis Pain, Range of Motion, and Functional Activities-A Review Article. Research Journal of Science and Technology, 17(3), 220-224. https://rjstonline.com/HTML_Papers/Research%20Journal%20of%20Science%20and%20Technology__PID__2025-17-3-4.html Maghroori, R., Safinataj, S., & Vahdatpour, B. (2025). Efficacy of Pulsed Electromagnetic Field Therapy as an Adjunct to Meloxicam and Exercise in Grade II and III Knee Osteoarthritis: A Randomized, Single-Blind Clinical Trial. Middle East Journal of Rehabilitation and Health Studies, 13(13), e164013. https://doi.org/10.5812/mejrh-164013 Wang, R., Li, F., Xia, M., Bu, Q., Li, L., Li, X., ... & Yang, L. (2026). Effects of Sanqi Shengyu External Application Cream and Pulsed Electromagnetic Field on Knee Osteoarthritis in Older Adults: A Randomized Controlled Trial. Physiotherapy Research International, 31(1), e70121. https://doi.org/10.1002/pri.70121 Yang, X., Li, X., Song, H., Wu, T., Li, J., & He, C. (2025). Effects of Whole‐Body Exposure to Pulsed Electromagnetic Field at Different Frequencies on Knee Osteoarthritis. Bioelectromagnetics, 46(6), e70016. https://doi.org/10.1002/bem.70016 Ye, L. I. (2025). The Mechanism of Pulsed Electromagnetic Field (PEMF) Therapy for Cartilage Degradation-Driven Knee Osteoarthritis (KOA): Do Magnetosensitive Protein Complexes Exist?. Osteoarthritis and Cartilage, 33(6), 821. DOI: 10.1016/j.joca.2025.03.088 Hackel, J. G., Paci, J. M., Gupta, S., Maravelas, D. A., North, T. J., & Paunescu, A. (2025). Evaluating Noninvasive Pulsed Electromagnetic Field Therapy for Joint and Soft Tissue Pain Management: A Prospective, Multi-center, Randomized Clinical Trial. Pain and Therapy, 14(2), 723-735. https://doi.org/10.1007/s40122-025-00711-z Durtschi, M. S., Rajakumar, V., Kenney, D. E., Pham, N. S., Ladd, A. L., & Chou, R. C. (2025). Clinical Efficacy of Pulsed Electromagnetic Field Therapy on Thumb Carpometacarpal Joint Pain: A Double-Blind, Randomized, Controlled Trial. HAND, 15589447251371088. https://doi.org/10.1177/15589447251371088 Pasin, T., & Dogruoz Karatekin, B. (2025). Comparison of Short-Term effects of extracorporeal shock wave therapy, Low-Level laser therapy and pulsed electromagnetic field therapy in knee osteoarthritis: A randomized controlled study. Journal of Clinical Medicine, 14(2), 594. https://doi.org/10.3390/jcm14020594 Comino-Suárez, N., Jiménez-Tamurejo, P., Gutiérrez-Herrera, M. A., Aceituno-Gómez, J., Serrano-Muñoz, D., & Avendaño-Coy, J. (2025). Effect of pulsed electromagnetic field and microwave therapy on pain and physical function in older adults with knee osteoarthritis: A randomized clinical trial. Journal of Geriatric Physical Therapy, 10-1519. DOI: 10.1519/JPT.0000000000000444 Cao, S., Zan, Q., Wang, B., Fan, X., Chen, Z., & Yan, F. (2024). Efficacy of non-pharmacological treatments for knee osteoarthritis: A systematic review and network meta-analysis. Heliyon, 10(17). DOI: 10.1016/j.heliyon.2024.e36682 Pilla, A., Fitzsimmons, R., Muehsam, D., Wu, J., Rohde, C., & Casper, D. (2011). Electromagnetic fields as first messenger in biological signaling: application to calmodulin-dependent signaling in tissue repair. Biochimica et Biophysica Acta (BBA)-General Subjects, 1810(12), 1236-1245. https://doi.org/10.1016/j.bbagen.2011.10.001 Iwasa, K., & Reddi, A. H. (2018). Pulsed electromagnetic fields and tissue engineering of the joints. Tissue Engineering Part B: Reviews, 24(2), 144-154. https://doi.org/10.1089/ten.teb.2017.0294 Bragin, D. E., Statom, G. L., Hagberg, S., & Nemoto, E. M. (2015). Increases in microvascular perfusion and tissue oxygenation via pulsed electromagnetic fields in the healthy rat brain. Journal of neurosurgery, 122(5), 1239-1247. DOI link: https://doi.org/10.3171/2014.8.JNS132083 Zhou, S., Wen, H., He, X., Han, X., & Li, H. (2025). Pulsed electromagnetic field ameliorates the progression of osteoarthritis via the Sirt1/NF-κB pathway. Arthritis research & therapy, 27(1), 33. https://doi.org/10.1186/s13075-025-03492-0 Bao, C., Zhu, S., Pang, D., Yang, M., Huang, J., Wang, F., ... & He, C. (2025). Hexokinase 2 Suppression Alleviates the Catabolic Properties in Osteoarthritis via HMGA2 and Contributes to Pulsed Electromagnetic Field-mediated Cartilage Protection. International Journal of Biological Sciences, 21(4), 1459. https://doi.org/10.7150/ijbs.101597 Torretta, E., Moriggi, M., Capitanio, D., Orfei, C. P., Raffo, V., Setti, S., ... & Gelfi, C. (2024). Effects of pulsed electromagnetic field treatment on skeletal muscle tissue recovery in a rat model of collagenase-induced tendinopathy: results from a proteome analysis. International Journal of Molecular Sciences, 25(16), 8852. https://doi.org/10.3390/ijms25168852 Maiullari, S., Cicirelli, A., Picerno, A., Giannuzzi, F., Gesualdo, L., Notarnicola, A., ... & Moretti, B. (2023). Pulsed electromagnetic fields induce skeletal muscle cell repair by sustaining the expression of proteins involved in the response to cellular damage and oxidative stress. International Journal of Molecular Sciences, 24(23), 16631. https://doi.org/10.3390/ijms242316631  Introduction In a previous blog, we discussed two non-pharmacological treatment options for osteoarthritis: exercise and low-dose radiation therapy. Today, we turn to the realm of alternative medicine and examine the role of acupuncture. Practitioners of Traditional East Asian Medicine (TEMA) would likely laugh and brush off the question of whether acupuncture works for osteoarthritis. Specific acupuncture points for treating knee, hip, and shoulder pain were described in classical texts centuries ago—although, of course, not in modern Western medical terms. TEMA practitioners do not question acupuncture’s efficacy; they rely on the accumulated experience of generations before them. In the Western medical tradition, however, anecdotal experience alone is not accepted as proof of effectiveness. We expect evidence from rigorous clinical trials, ideally double-blinded and randomized. In this review, we will focus on the clinical evidence available to date regarding acupuncture’s efficacy in knee osteoarthritis, along with research into its potential mechanisms for pain reduction and functional improvement. We will also situate acupuncture within the context of current standards of care for knee osteoarthritis and compare these findings with recommendations from professional medical societies and governmental health agencies. We will not address how to locate the “best” acupuncture practitioners for osteoarthritis, as recommendations from physicians, relatives, and friends are often the most reliable—though, of course, you may also consult your favorite AI chatbot. The Effect of Acupuncture on Knee Osteoarthritis Pain As discussed in the 02/24/2024 blog post, President Richard Nixon’s 1972 visit to China and the cultural exchanges that followed greatly increased Western interest in acupuncture. Scientific research and clinical trials expanded rapidly. To date, these trials support acupuncture as an effective, safe, and recommended therapy for the symptomatic management of pain, including osteoarthritis pain. However, most studies have been relatively small and heterogeneous in terms of patient selection, acupuncture techniques, treatment duration, and control group design (single-blind, double-blind, placebo, no treatment, etc.). High-quality randomized controlled trials and meta-analyses provide the most meaningful insights, summarized below. Comparisons between acupuncture and various control conditions (1) were as follows:
Overall, current clinical evidence indicates that acupuncture can reduce pain and improve function in knee osteoarthritis patients for 3 to 6 months after treatment. Reported adverse events were mild and transient—mainly brief needling pain and small hematomas. Only a small percentage of participants experienced side effects, reinforcing that acupuncture is a generally safe treatment option. The studies included all three commonly used forms of acupuncture: manual, electroacupuncture, and dry needling. Acupuncture points used across studies were standard points traditionally selected for knee osteoarthritis. Acupressure effectiveness Acupressure is a less invasive variant of acupuncture in which pressure is applied to the same acupoints used in traditional needling. Recently, Yeung, W.-F. et al. (2) reported the results of a randomized, controlled clinical trial involving 314 middle-aged and older adults with probable knee osteoarthritis. Participants in the treatment group were trained to perform self-administered acupressure, while the control group received only knee health education. The study found that acupressure produced meaningful pain reduction lasting up to 3 months. However, improvements in physical function did not reach statistical significance. Only 13% of participants reported mild, self-resolving adverse events. Overall, acupressure appears to be a safe and effective method for managing knee osteoarthritis pain, and it is also highly cost-effective due to its self-care nature. Following are three Youtube videos for self-help. Comparison with other non-pharmacological therapies A natural next question is how acupuncture compares with other non-pharmacological therapies for knee osteoarthritis. Numerous clinical studies have evaluated one non-pharmacological treatment against another. More recently, Cao, S. et al. (3) conducted a network meta-analysis comparing the clinical efficacy of seven distinct non-pharmacological therapies for knee osteoarthritis, including acupuncture. The other therapies evaluated were needle-knife therapy (acupotomy), exercise, transcutaneous electrical nerve stimulation (TENS), ultrasound, shock wave therapy, and laser therapy. Pain and symptom assessments were based on two standard tools: the Visual Analog Scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC).
The results of the network meta-analysis were as follows: Efficacy rankings based on VAS pain scores: shock wave therapy > needle-knife > laser therapy > acupuncture > ultrasound > exercise > transcutaneous electrical nerve stimulation Efficacy rankings based on total WOMAC score: shock wave therapy > needle-knife > laser therapy > acupuncture > ultrasound > transcutaneous electrical nerve stimulation > exercise Efficacy rankings based on WOMAC subscales:
In nearly all ranking systems—except for the WOMAC stiffness subscale—shock wave therapy emerged as the most effective treatment. Acupuncture consistently ranked in the middle tier. TENS, exercise, and ultrasound generally ranked the lowest, depending on the specific measure. What these rankings mean for patient care and clinical practice remains uncertain. Importantly, the authors of the study explicitly caution that additional rigorous, well-designed randomized controlled trials are still needed to validate and refine these conclusions. Mechanistic aspects Multiple animal and human studies have shown that acupuncture exerts anti-inflammatory effects in the synovium, influences cartilage homeostasis, and modulates neural pathways involved in pain perception (4–6).
Much progress has been made in elucidating the mechanisms underlying acupuncture’s clinical benefits. Future human studies, particularly those focusing on optimal dosing and the key pathways involved in synovial stabilization, will improve our understanding of knee osteoarthritis and help solidify acupuncture’s role as an evidence-based treatment option. Guidelines by professional societies and government health agencies The American College of Rheumatology (ACR) and Arthritis Foundation, the American Academy of Orthopaedic Surgeons (AAOS), and the Osteoarthritis Research Society International (OARSI) all limit their recommendations for acupuncture to conditional, limited, or uncertain (7–9). The National Center for Complementary and Integrative Health (NCCIH) aligns its guidance with the ACR/Arthritis Foundation recommendations. Core non-pharmacological treatments for knee osteoarthritis continue to emphasize self-management programs, aerobic and/or strength-training exercise, and weight loss for individuals who are overweight. Notably, Tai Chi is strongly recommended as a form of therapeutic exercise. The National Institute for Health and Care Excellence (NICE) in the UK stands out with its more definitive position, issuing a “not recommended” guideline for acupuncture in knee osteoarthritis (10). However, NICE acknowledges in its commentary that electroacupuncture may have potential benefits, while also noting that the specific patient population likely to respond is unclear. NICE additionally concluded that acupuncture is not cost-effective based on its economic assessments. It is important to recognize that these guidelines may not reflect the most recent evidence. The ACR/Arthritis Foundation, AAOS, and OARSI recommendations were published in 2019, 2021 and 2019, respectively, while NICE’s guidance dates to 2022. The cautious and conservative positions of these organizations are understandable given the shortcomings of the acupuncture trials and the lack of large, industry-funded studies of the type commonly performed for pharmaceuticals. Implications for the patients Navigating the increasing amount of information on acupuncture for osteoarthritis depends greatly on the preferences and inclinations of both patients and their physicians. Incorporating this information into patient education programs can certainly help patients make more informed decisions. From this author’s perspective, acupuncture is a reasonable and viable option when core recommendations and standard drug therapies fail to meet a patient’s needs. It is also an option worth considering before turning to more aggressive interventions such as radiation therapy or surgery. References
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