Growing Interest in BPC-157 Within Orthopaedic Sports Medicine: A Systematic Review

Abstract

Background: Body Protection Compound-157 (BPC-157) is a naturally occurring gastric peptide, which assists in the preservation of mucosal integrity and the overall tissue stability. Initial animal research indicates that it may be able to repair most musculoskeletal injuries, including muscle strains, ligament tears, tendon injuries, fractures, and muscle strains, faster. Even though it is not approved by the FDA, and a number of sporting agencies prohibit its use, it is still used by clinicians and athletes.

Purpose: The aim of the review was (1) to summarize all the existing literature on BPC-157 in the field of orthopedics and sports medicine, and (2) provide the description of what is known about the mechanisms of BPC-157, its effects on musculoskeletal tissues, its processing and elimination, and its safety profile.

Methods: We conducted a systematic search of PubMed, Cochrane and Embase since they began to exist up to June 3 2024 of English-language studies. PROSPERO has been searched on current or unpublished reviews on the subject. Included were studies that studied the mechanisms of BPC-157, musculoskeletal outcome, metabolism or safety. Two reviewers had reviewed records independently and in the cases of disagreement, a discussion was conducted or a third reviewer was involved where necessary.

Findings: There were 544 records (1993-2024) found in the search. Following the elimination of duplicates and screening, 35 studies that had been preclinical studies and 1 clinical study were included (36). The results suggest that BPC-157 can increase the functionality of growth-hormone-receptor, stimulate a number of growth-related and angiogenic pathways, and reduce the levels of inflammatory cytokines. In preclinical models it enhanced muscle, tendon, ligament and bone healing in various measures. A small retrospective human study of chronic knee pain demonstrated improvement in 7/ 12 subjects over a period of over six months. The metabolism seems to entail fast liver metabolism, short half-life (less than 30 minutes), and renal excretion. The preclinical safety trials revealed that it had no adverse effects on any organ system but no human safety data has been obtained.

Conclusion: Level IV and V of evidence indicates that BPC-157 is capable of being used to recover various musculoskeletal injuries. But unregulated production, contamination threat, and the unavailability of clinical safety data pose possible dangers. Clinicians would recommend that athletes adhere to the regulations of their sporting organizations concerning drugs and nutritional supplements.

Keywords: body protection compound-157, BPC-157, gastric pentadecapeptide, orthobiologics, peptide, sports, athlete.

Plain Language Summary

Analysis of the Existing Studies regarding a comparatively novel peptide, BPC-157.

BPC-157 is a natural substance that plays the role of maintaining the health of the tissues. People use it even though it has not been endorsed by the food and drug administration of the US and is prohibited in most of the competitive sports. This review took all the existing studies to elaborate on how it functions, its effects on the muscles, joints, the way the body processes it and whether it is safe. We reviewed 36 articles published since 1993.

The articles indicated that BPC-157 seems to stimulate healing by triggering growth-related pathways and decreasing inflammation. Animal experiments showed that there was an improvement in muscle, tendon, ligament and bone injuries. One small human trial showed that 7 out of 12 individuals who had chronic pain in the knee were relieved over six months after receiving one injection. Although animal researches did not show any toxic effects, the safety data has not yet been confirmed in humans. To conclude, BPC-157 is potentially useful in musculoskeletal healing, although unregulated formulations and a lack of clinical data are still problematic.

Introduction

The first compound to be reported was Body Protective Compound-157, which is found in gastric secretions. Its primary action is to sustain the tissue and the lining of the stomach. Interest has since increased due to the anti-inflammatory, angiogenic and wound-healing effects of the peptide in a large number of models. It has been found by preclinical studies that BPC-157 prevents the deterioration of multiple organs including liver, pancreas, heart, nerves, and gastrointestinal tract. It has potential uses in orthopedics and sports medicine, including muscle, bone, ligament and tendon injury recovery because of its capability to speed up the healing of tissue. In the preclinical research that has been conducted to date, there are very few or no severe adverse effects.

Although there is weak clinical support, BPC-157 is given injections into joint space or orally in some private medical practices to treat pain and the symptoms of arthritis. BPC-157 is also used to help general injuries, or in the case of musculoskeletal issues, such as muscle pains or tendon damage, among many other athletic uses. Most sports regulating bodies and regulatory authorities have recently formally prohibited the use of BPC-157 by name or indirectly by placing it under banned peptide hormones.

Table 1

Stances of regulatory agencies and major professional sports organizations regarding BPC-157.

Currently, BPC-157 is not approved as a medical indication in America. As of 2023 the FDA has listed it as a Category 2 bulk drug substance meaning that there is not enough evidence to conclude on its safety and pharmaceutical manufacturers cannot compound it to use in clinical trials. In spite of this, products being sold as BPC-157 continued to be sold as dietary supplements or research chemicals, which does not fall under the normal FDA regulation. Since BPC-157 and like peptides are not considered controlled substances, they do not require possession to be unlawful, as is the case with anabolic steroids, and thus, they are not regulated since they are labeled, with none known about their quality or purity.

There has been a drastic increase in public interest. Search rates are at an all-time high, and online sources have millions of watchings and debates on the topic of BPC-157. Its use is similar to other gray-market drugs, including selective androgen receptor modulators, of which there is little safety data, but which are offered by private clinics and through online vendors. Despite the increasing use among athletes, no systematic review had ever considered the relevance of BPC -157 in orthopedic and sports medicine before. Therefore, this review compiled existing studies as a scientific review on its mechanism of action, musculoskeletal effects, metabolism, and safety profile.

Methods

A search of PROSPERO was done before the review process started to ensure no systematic reviews on this topic were ongoing or unpublished. The review was based on the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search terms were the Body Protective Compound -157 and BPC-157 with all the possible alternatives of the compound, gastric pentadecapeptide, BPC-15, PL-14736, bepecin, PLD-116, PCO-02, and their spacing and hyphenation variants were combined with the Boolean operator, OR.

The surveyed databases included the PubMed, the Embase, and Cochrane Library. All years available in each database were searched with no publication-date restrictions. Duplicate entries were eliminated with the help of Covidity (Veritas Health Innovation), and the non-English studies were excluded.

All articles were evaluated by two reviewers who did not know about each other on whether they were eligible or not. The process of review was divided into three stages. The initial step involved screening of titles and abstracts after duplicate removal. In case of agreement, full texts were screened by reviewers during the second phase, and the reasons to proceed to data extraction were once more reviewed. Conflicts were overcome by an unveiling of identities and deliberating; a third author was involved where there was a need.

All the articles included were stored in Covidence to be blinded in the screening. Preclinical and clinical trials that included any of the following were covered in the review: mechanisms of actions of BPC- 157 or its effects on the musculoskeletal system, its safety characteristics, or metabolism. They were reviews, abstracts of conferences, editorials, and meta-analyses.

After the selection of the articles, the appropriate data were obtained in each of the studies: the type or model used, the total sample, treatments used, any adverse reactions identified, and the most important outcomes. Each article was sorted by two reviewers into one or more of the following categories: mechanism of action, musculoskeletal outcomes, metabolic profile and safety profile. Subcategories were also included where necessary to provide clarity.

Results

The preliminary search presented 544 publications. Upon eliminating the duplicates and the multi-stage screening process 36 articles were included. The last group consisted of a preclinical study, as well as one clinical study.

Out of the 36 studies, 21 of them focused on the mechanism of action, 15 studies focused on musculoskeletal outcome, 3 studies focused on metabolic processing and clearance, and 4 studies focused on the possibility of a toxicity or safety issue. The summary of the article dissemination is given later in the review and figures are presented to show the involvement and flow of the selection.

The PRISMA flow diagram adopted by the researcher during the study selection process is described in Figure 1. It started with 544 entries in the database, and it reduced to 151 entries. Out of 393 they eliminated 336 in the first screening period. A further 21 full articles were filtered out following further evaluation to have 36 studies to review and group.

Mechanism of action

Among the 36 studies included, 21 were on the molecular and cellular mechanisms of BPC-157. The summary of these findings is presented in a figure (Fig. 2) which shows the main pathways affected by the peptide.

In many animal studies, BPC-157 was found to induce vascular endothelial growth factor (VEGF) both gene and protein. VEGF, which is associated with angiogenesis, was associated with improved blood vessels formation in several studies.

There were also other developmental pathways triggered. BPC-157 stimulated the phosphorylation of ERK1 and ERK2 which are important signaling proteins that mediate cell survival, growth, and tissue repair. Other downstream responses, including c -Fos, c -Jun and Egr -1, were also positive, suggesting possible contributions to cell migration, wound repair and structural rebuilding.

Other studies have observed AKT phosphorylation increased signifying its action in cell survival. High expression of KRAS gene was also noticed and could contribute to the propagation of cell propagation cues in some tissues.

There was evidence that BPC-157 may affect the FAK-paxillin pathway which is important in the regulation of cell attachment, motility, proliferation, and survival. Exposing rats in a rat tendon fibroblast model to BPC 157 enhanced the expression of focal adhesion kinase and paxillin genes. There was also greater expression of growth hormone receptor in similar tendon fibroblast cultures which are indicative of increased sensitivity of cells to growth-hormone-induced repair and regeneration signals by BPC-157.

In addition to the growth and repair pathways, BPC-157 influenced the activity of nitric oxide. Several studies had higher levels of nitric oxide production and higher levels of nitric oxide synthase. Nitric oxide as a vasodilator could be beneficial in the recovery of local blood flow following an injury.

Also interaction with inflammatory pathways was observed. Multiple studies demonstrated lowered COX -2 gene expression, lessening of myeloperoxidase action, and a drop in the amount of inflammatory cytokines, including IL-6 and TNF-a of which the amount is raised during inflammation, indicating that BPC-157 is capable of alleviating the inflammatory reaction in some settings.

Lastly, the peptide may have been shown to have an effect on dopamine and serotonin systems. Serotonin production in various regions of the brain was increased and decreased in animal models and there was also the effect on stimulant induced behavior. The results are not yet comprehensive in explaining the overall effect on the nervous system, but indicate that BPC-157 has an interaction with neurochemical functions and may have an effect on mood or stress-related reactions.

Musculoskeletal Outcomes

Fourteen studies were studied in which musculoskeletal outcomes were related to BPC-157. These researches were on muscular injury, tendon rupture, ligament rupture, and problems of the bones.

In three models of rats injured by muscle transection or crush injuries, BPC-157 led to better structural and functional indicators. Findings comprised an increase in load-to-failure limits, healthier muscle fibers, reduced gapping at injured locations, and the enhanced motor activity. The evidence indicated a greater, better, organized tissue was formed through healing.

In a number of preclinical studies, tendon recovery was also benefited. In the study carried out on Achilles and quadriceps tendon transection, improvement in biomechanical performance was observed following BPC-157 intervention. Microscopic analysis of the tissue showed improved tissue structure and the limb use in functional tests showed improvement in the animals. Multiple studies showed a reduction in inflammation.

These results were supported by laboratory experiments. The BPC-157 showed an increase of tendon fibroblast cultures in survival rates, migration and proliferation. The growth hormone receptors of these cells were also higher meaning that the peptide could have an effect on tendon regeneration.

Another field was in bone healing. A nonunion model in rabbits has reported that BPC-157 fixed the defect just like the conventional techniques like injection of bone marrow or grafts. The bones that were treated were more completely mineralized, stronger and formed lamellar bone rather than disorganized scar tissue.

There was a repeat interest in inflammation throughout musculoskeletal injuries. BPC-157 decreased swelling, stiffness and local nodules in animal models of induced arthritis. A microscopic evaluation of injured muscle and tendon always demonstrated a reduction in inflammatory cells in the case of the use of BPC-157.

Repeatedly, vascular effects were observed as well. Several studies have found greater local blood vessel growth and an elevation in VEGF expression in muscle, tendon and ligament injury models treated with BPC -157. Such modifications are likely to improve nutrient delivery and the general recovery of the tissue.

In one study of medial collateral ligament injury, BPC-157 decreased instability, restored biomechanics, enhanced motor activity and decreased gross look and microscopic architecture.

It identified only a single human study. It is a retrospective study that looked at injections that were administered on people with chronic knee pains. Among twelve respondents, seven respondents reported a lasting duration of more than six months and that the symptoms improved when given a single injection. These were however self-reported, and not standardized clinical measures.

Metabolism and Excretion

Three studies were investigating the process of BPC-157 digestion and excretion. In animals highest levels were typically found in the kidneys, then livers, bile and in the case of human liver in microsomes, massive breakdown by liver enzymes; presumably, the cytochrome P450 system. The rest of the metabolites were primarily excreted via urine but extra studies are required to eliminate the option of further renal metabolism.

Single and repeated intramuscular or intravenous doses had a rather short half-life, under 30 mins. In one study, metabolites were detected in the urine up to approximately four days with a 0.1 ng/mL limit with high-resolution mass spectrometry. A similar study reported the same finding with a few metabolites detected up to five days following the dosage ranging between 0.03 and 0.11ng/mL. These are way below the anti-doping detection limits, meaning that urine testing of such studies may be used in screening of the athletes in terms of drug abuse.

Safety Profile

Three articles were dedicated to safety and possible toxicity. They checked several organs of both animals and laboratory models and did not observe any indications of acute toxicity. Rats and dogs fed either single or repeated doses of very low to high dose over six weeks did not have any visible damage in liver, spleen, thymus or stomach and microscopic examination disclosed no significant changes in lungs, kidneys, ovaries, brain or prostate.

Reactions at the local injection sites were also examined. In one of the studies, no irritation, tissue breakdown, discoloration, swelling, or ulceration were reported in rabbit quadriceps muscle after a single dose was administered to the muscle in a period of two days.

Even though the excretion of BPC 157 occurs through the kidney and its metabolism occurs in the liver, the organ did not cause harm to either in a short period of time. Protective effects were even demonstrated in the liver by one study. Induced liver damage through the use of ligation, bile duct obstruction or chemicals showed that the animals pre-treated using BPC-157 experienced reduced cell damage and less liver enzyme levels which was not generated in the untreated animals.

One study evaluated genetic damage, birth defects or abnormal cell reproduction. Ames tests, micronucleus assays and chromosomal analyses revealed no evidence of mutations and genetic damages. The repeated injections in pregnant animal models had no effects on fetal growth, organ development, or pregnancy in the case of injections.

In all the studies, and through a large number of different dosing strategies and routes, oral, intraperitoneal, intravenous, intramuscular, no lethal or toxic dose was observed. But these were only able to observe within a six-week period. There were no long-term safety studies performed and there are no human safety data available and hence the risk profile in the context of longer than short-term preclinical settings are not known.

Discussion

The systematic review reveals that BPC-157 has a promising biological effects particularly on musculoskeletal injuries. In animal experiments the peptide was useful in repairing damaged structures, reinforcing tissues and restoring functional activity to torn muscles, fractured bones, injured ligaments and damaged tendons. These advantages are probably connected with the improved growth of blood vessels, decreased inflammation, and the stimulation of growth-related pathways that are mentioned above.  

The liver quickly metabolizes it, it is excreted through the urine and only a few days after use it is detectable by modern mass spectrometry. These properties compare with other peptide substances which are in use or abused by athletes.

The use of short-term animal safety studies showed that there were no organ toxicity, no acute side effects, and no genetic or reproductive residual. But we have no human clinical data, and we are involved in the risks, long-term effects, and possible complications unknown.

It is due to this evidence gap that the review recommends caution particularly among athletes. When there is increased interest in the use of the peptide as injury recovery, clinicians are advised to enquire of patients regarding the supplements they take, as well as whether they are aware of the rules of their sport. Such peptides have an additional risk of being uncontrolled productions, with some being of varying purity, composition, and even contaminated.

The review observes that the research environment is changing rapidly, and new research is being introduced. Therefore, the findings are not the final answer, but they provide an indication of what is known currently. It will require the future research, particularly the clinical trials in humans, before they can be able to make a confident recommendation.

The discussion provides the frailties of anti-doping against peptides such as BPC-157. It has a low detection limit and is quickly metabolized, which is unfavorable to monitoring, like growth hormone and erythropoietin. Such substances are also used by many athletes when not competing and reduce the possibility of detection by the existing testing in the sport. This highlights the necessity of proper education, complement counseling, and constant update of policies in sports.

There is still scant evidence of tissue repair benefits but speculative without subjecting human beings to strict trials. There are online reports of such negative effects as anxiety, joint pains, and heart palpitations, but they cannot be scientifically verified and it may be contamination, underlying health problems or drug interactions. Clinicians are advised to observe such reporting particularly in athletes or patients who use alternative forms of treatment.

Conclusion

Through preliminary evidence, BPC -157 aids in various domains of tissue healing in animal models, including the healing of torn tendons, damaged ligaments, muscle injury, and bone fractures. The peptide is known to regulate various biological processes that involve cell survival, angiogenesis and control of inflammation. The liver metabolizes it and is excreted in the urine and has short half-life like other peptide hormones.

Despite the lack of short-term toxicity in animals, the safety of human beings remains unknown. It should be used cautiously by athletes and clinicians since there is a lack of high-quality clinical evidence. The market is unregulated, which is also a source of safety concerns, as it can cause contamination, or the wrong dosing.

To provide improved athlete care and proper guidance, the clinicians are advised to inquire directly about the use of supplements, clarify on the risks at hand and assist the patients to comprehend the applicable testing and compliance policies of their sport or organization.

The initial positive preclinical evidence should be verified or dismissed by further studies, in particular, by the well-designed human clinical trials. BPC-157 is still of interest, to date, and has encouraging laboratory findings although without full real-world knowledge.