Keywords
FDA, Molecular hydrogen, Rheumatoid arthritis, Soft tissue injury
FDA, Molecular hydrogen, Rheumatoid arthritis, Soft tissue injury
As the oldest and the most abundant molecule in the universe, molecular hydrogen (H2) has been traditionally recognized as a biologically inert gas. However, several trials in the past 10 years reported beneficial effects of H2 in the clinical environment, revealing its possible role as a novel therapeutic agent in medicine1–5. Usually administered orally or via inhalation, H2 improves both patient- and clinician-reported outcomes, and biomarkers of different pathologies and disorders, from metabolic diseases to chronic systemic inflammatory disorders to cancer [for detailed review see Ref. 6]. Its clinical relevance seems to be particularly notable in the musculoskeletal medicine, with several small-scale short-term studies7–9 reporting that H2 was able to restore the health and functional abilities of patients after acute injuries or chronic illnesses affecting the muscles and bones. Since musculoskeletal conditions account for a large proportion of a general practitioner's workload10, one might consider H2 as a promising medication or adjuvant that could alleviate these prevalent conditions. In this opinion paper, the medicinal properties of H2 in musculoskeletal medicine are discussed to provide an updated and practical overview for health professionals working in this field.
Being prompted by the prominent effects of H2 on disuse muscle atrophy, cartilage trauma, and osteopenia in animal studies11–13, a number of clinical investigators from 2010 onwards evaluated the effectiveness of H2 in patients suffering from different muscle and bone ailments – from sprains and strains to chronic joint disorders to myopathies7–9. Typically, these studies were designed as single-blind pilot trials, with small sample sizes (< 40 participants) and of short duration (≤ 12 weeks). Although limited in size and scope, those studies can provide early support for specific therapeutic claims about H2 in musculoskeletal medicine. In a first trial, a combination of oral and topical H2 resulted in a faster return to normal joint flexibility in 36 young men who had suffered sports-related soft tissue injuries, when administered for 14 days as a complementary treatment to a traditional medical protocol for soft tissue injuries7. H2 intervention (hydrogen-rich packs 6 times per day for 20 min and 2 g of oral H2 daily) was found to augment plasma viscosity decrease after an injury, while other biomarkers of inflammation (C-reactive protein, interleukin-6) and clinical outcomes (pain scores at rest and at walking, degree of limb swelling) were not affected by the intervention7. Another study in Japan reported that drinking 530 ml of a liquid containing 4 to 5 ppm of H2 every day for 4 weeks significantly reduced disease activity in 20 patients with rheumatoid arthritis, as evaluated by changes in the degree of tenderness and swelling in 28 joints and C-reactive protein levels8. H2 was administered as an adjuvant to regular disease-modifying anti-rheumatic drugs and biological drugs, with the efficacy of H2 found to be not inferior comparing to abatacept, methotrexate or a combination of two. In total, 47.4% of patients went into remission, with anti-citrullinated protein antibody (ACPA)-positive patients (ACPA levels above 300 U/mL; patients with worse prognosis and higher rates of erosive damage) responding best to the treatment. Finally, the consumption of water containing a high concentration of H2 (31% saturation) for up to 12 weeks improved surrogate markers of muscle pain and fatigability in 22 patients with inherited and acquired myopathies treated with low-dose prednisone9. Taken together, the above studies seem to pave the way for a future use of H2 therapy in musculoskeletal medicine.
Compared with conventional treatment protocols in musculoskeletal medicine, based on drugs and methods that are well-described with respect to efficacy and safety14,15, H2 still has a long journey ahead before it can be recognized as a common remedy in this medical discipline. At the moment, H2 therapy is not adequately described in terms of approval, labeling, side effects, and pharmacovigilance information in musculoskeletal medicine. There are no dose escalation studies yet, and the optimal and safest dose range for H2 remains unknown; furthermore, no federal agency or industrial entity provides appropriate patient counseling information about H2. The US Food and Drug Administration (FDA) recently issued a notice (GRAS Notice No. 520)16 of a claim that the use of H2 solubilized in water (up to a concentration of 2.14%) is generally recognized as safe (GRAS) when it is added to beverages and beverage containers in order to prevent oxidation. Based on the information provided by the H2 gas-manufacturing company, as well as other information available to the FDA, the agency had no questions about the conclusion that hydrogen gas is GRAS under the intended conditions of use. However, the FDA has not made its own determination regarding the GRAS status of the subject use of H2 gas16. This seems to be the only formal information currently available concerning the use of H2 in food or medicine! Despite this lack of formal approval, there are many formulations and devices widely available in the market that claim to supply H2 for the use in musculoskeletal disorders, from gas-producing machines to dietary supplements and beverages, with H2 amount varying greatly across the different products. Consequently, consumers might be exposed to easy-to-acquire but questionable products containing H2.
Among other important medical issues that need to be addressed, including long-term safety or pharmacokinetics, the main question remains whether H2 should be considered as a dietary supplement or a medicine, since the FDA declares that a product intended for inhalation (such as H2) is not a dietary supplement17. Therefore, considering H2, or at least some H2 forms, for much stricter assessment and regulation by formally recognizing it as a drug in the future, might be more appropriate for this promising bioactive gas. So, it will take many more studies and tighter regulation before H2 therapy can be endorsed as a routine protocol (or adjuvant to standard treatment) in musculoskeletal medicine. In the meantime, H2 should be regarded as an experimental agent and not recommended to treat muscle or bone conditions in the general population.
This work was supported by the Science Foundation Serbia (Grant # 175037; Grant assigned to SM Ostojic).
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Competing Interests: No competing interests were disclosed.
Competing Interests: No competing interests were disclosed.
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