February 6, 2024

Synergistic Effect of 3 Joint Compounds on Osteoarthritis Pain

Evidence for a safe and effective joint pain treatment
A combination of krill oil, astaxanthin, and oral hyaluronic acid reduces pain from osteoarthritis.


Hill WS, Dohnalek MH, Ha Y, Kim SJ, Jung JC, Kang SB. A multicenter, randomized, double-blinded, placebo-controlled clinical trial to evaluate the efficacy and safety of a krill oil, astaxanthin, and oral hyaluronic acid complex on joint health in people with mild osteoarthritis. Nutrients. 2023;15(17):3769. 

Study Objective

To ascertain if a joint health supplement containing krill oil, astaxanthin, and lower–molecular weight hyaluronic acid (FlexPro MD®) is safe and clinically effective in reducing osteoarthritis pain when compared to a placebo

Key Takeaway                                 

This synergistic blend of functional joint compounds is safe and effective in alleviating joint pain associated with osteoarthritis, as well as improving quality of life.


A multicenter, double-blind, randomized, and placebo-controlled clinical trial at 2 clinic sites in Korea


Investigators recruited and screened 105 participants; they included 100 participants with a Korean Pain Visual Analog Scale (K-VAS) score of >30 mm. These participants all had Grade I or II knee or hip osteoarthritis on the Kellgren and Lawrence radiographic scale. Korean men and women included in this study were aged 30 to 75 years. They were randomly assigned (1:1) to either the intervention or placebo group. 

Of the 100 invited participants, 75 completed the clinical trial. The treatment group consisted of 37 participants, 16 male and 21 female. Of the 38 participants in the placebo group, 15 were male and 23 were female. Statistically, there were no significant differences between the 2 arms relative to exercise, smoking status, or alcohol consumption habits.

Exclusion criteria for the clinical trial were:

  • Nondegenerative etiology of arthritis
  • Atypical joint spacing
  • Periarticular osteophytes or irregular articular surface
  • Subchondral bone cyst of the joint complex
  • Cardiovascular, immune, or infectious pathology
  • Ongoing treatment for gastritis or gastric ulcer
  • Uncontrolled hypertension
  • Uncontrolled diabetes
  • Thyroid disease
  • Elevated liver enzymes
  • Creatinine level >2 times the upper limit of normal
  • Pregnancy or lactating women
  • Arthritis medications or supplements used within 2 weeks of screening 
  • Mental illness
  • Participating in other clinical trials within 2 months
  • Sensitivity or allergy to krill oil, astaxanthin, or hyaluronic acid


Patients in the intervention group were instructed to take a 600-mg capsule of FlexPro MD®, a commercially available dietary supplement, once daily, for 12 weeks. The supplement consisted of Antarctic krill oil, astaxanthin, and hyaluronic acid. The placebo group received an identical 600-mg capsule containing a reddish-brown liquid. This liquid consisted of palm oil, olive oil, soybean oil, and beeswax. It provided no joint health support. Patients took the placebo for 12 weeks, 1 capsule once daily. 

Neither arm of the study received instructions regarding taking the capsule with or without food. Investigators encouraged all participants to maintain their regular eating habits and levels of physical activity for the duration of the 12-week study. They also asked patients not to consume any additional dietary sources of the supplement ingredients.

Study Parameters Assessed

Investigators used outcome assessment tools, including pain and function scales, as well as laboratory and physical-exam studies, to gather data points at screening, week 6, and week 12 of the trial.

Primary Outcome

The primary assessment of efficacy in this study was the use of the Korean Visual Analog Scale (K-VAS) to validate any change in pain at 12 weeks. The K-VAS assesses joint pain by having the participants indicate their severity of pain on a 100-mm straight line, where 0 mm indicates no pain and 100 mm indicates unbearable pain.

Another primary outcome measure was that of supplement safety. Investigators assessed this by monitoring adverse events, conducting clinical pathology tests, assessing vital signs, performing physical measurements, and conducting electrocardiogram studies.

Secondary outcomes included the measure of overall health status utilizing a KSF-36, which is a validated Korean variation of the SF-36 quality-of-life instrument. Investigators measured additional secondary outcomes at baseline, some at the 6-week interval and all of them at the 12-week timeframe. These included the Korean Western Ontario and McMaster Universities Osteoarthritis Index (K-WOMAC), serum C-reactive protein (CRP), urinary C-telopeptide of type II collagen (CTX-II), and a 5-point joint-improvement assessment performed by both the participant and investigator independently.

Key Findings

Overall, the treatment group had a significantly greater mean reduction in the outcome of the K-VAS score at week 12 when compared to the placebo group (20.8 mm vs 10.6 mm). Additionally, a statistically greater number of participants had adverse events in the placebo group when compared to the treatment group (16% vs 4%). These adverse events were mild to moderate and were predominantly categorized as gastric distress. These findings suggest that FlexPro MD is a safe and clinically effective natural supplement that may safely reduce pain due to osteoarthritis.

Investigators noted significant differences between the 2 groups in changes in the K-WOMAC index at 12 weeks. The treatment group demonstrated a mean change of –13 from baseline, whereas the placebo group showed a mean change of –5.5. This further suggests the efficacy of FlexPro MD. 

Serum CRP and urinary CTX-II levels showed no significant changes in either arm of the clinical trial at week 12. With CRP, in the treatment group, there was a mean decrease of 0.04 mg/dL, compared to 0.02 mg/dL in the placebo group. CTX-II levels at week 12 for the treatment group had a mean increase of 26.03 ng/mmol vs 66.03 ng/mmol for the placebo group. No statistically significant variation was noted between the groups.

The joint-improvement assessment scores demonstrated improvements at both week-6 and week-12 iterations of the evaluations. The scores for both the participant-directed and the investigator-directed assessments were significantly lower in the treatment arm of the study.


Research was supported by a grant from the Ministry of Trade, Industry and Energy (MOTIE) through the Middle Market Enterprises Global Research R&D Project and World Class Plus Program supervised by the Korea Institute for Advancement of Technology (KIAT). 

NOVAREX Co Ltd funded the study. Valensa International provided the FlexPro MD ingredients, and NOVAREX encapsulated the test products (eg, both FlexPro MD and placebo).

Practice Implications & Limitations

In the established landscape of osteoarthritis (OA) and its concomitant presentations, a significant portion of the clinical and scientific dialogue involves pain reduction and joint function as they relate to quality of life. Much of this discussion also revolves around the long-term side effects of nonsteroidal anti-inflammatory drug (NSAID) therapy in this chronic degenerative pathology. With the global prevalence of osteoarthritis having increased worldwide by 48% from 1990 to 2019 and the occurrence rate in North America being the highest,1 practitioners are seeking safer and more effective natural options for patient care.

This study contributes to the body of knowledge around natural functional-joint supplementation and its immediate safety. Specifically, it investigates a 3-compound complex made up of krill oil, astaxanthin, and hyaluronic acid (FlexPro MD). Each of these compounds, used independently, has various positive health impacts.2-,3,4 However, this study elucidates that, synergistically, they are effective and safe. This clinical trial used pain reduction and overall joint function and evaluated for adverse events to inform this position. Using validated assessment methods, the investigators reported that pain was reduced, function improved, and side effects were minimal.

Increasing mobility is both achievable and impactful.

It is logical to evolve the clinical dialogue translationally into other areas of clinical relevance. One such area is that of joint-pain reduction and joint-function improvement relative to better mobility and increased activity levels. It is well-established that lifestyle factors, including being sedentary, are often modifiable risk factors for obesity and cardiometabolic disease.5 As such, clinicians should feel confident incorporating natural approaches to improving pain and function into their treatment of patients with mobility and comorbid cardiometabolic concerns. Increasing mobility is both achievable and impactful.

With the well-documented depth and breadth of side effects of long-term NSAID use,6 natural practitioners are seeking safer and more accessible options for pain relief. The positive pain-reduction outcomes of this study show promise that joint-pain reduction is possible and sustainable. This, in turn, contributes to easing the morbidity associated with long-term NSAID use.

Two of the 3 compounds in FlexPro MD are associated with positive cardiovascular effects. Krill oil is a source of phospholipid-bound omega-3 polyunsaturated fatty acids. These healthy fats contribute to the reduction of serum triglycerides, as well as the increase of high-density lipoprotein.2,7 Astaxanthin is a carotenoid pigment that has notable antioxidant and cardioprotective effects. It has also been shown to lower cholesterol and markers of cardiovascular risk.3 With this multifaceted efficacy, natural practitioners have the ability to manage multiple patient presentations at once.

Areas of further discovery in both the realm of clinical practice and study design bring 2 striking issues to the forefront. Are all natural functional-joint supplements created equal in quality and does this impact our outcomes? Secondly, does the natural classification of a compound make it inherently safe to use and to increase in dosage? Clinical practitioners will suggest that their positive patient outcomes are proof of the concept that reputable sources of therapeutic compounds need to be given primary consideration. While this is widely adopted by practitioners, ongoing studies are needed to better support this position. Dovetailing into this perspective, this study introduces the singularity or plurality of compounds, along with their synergistic efficacy, into the discussion. There is also a common trend in natural supplementation to synergize compounds for improved outcomes; however, more studies are welcome in elucidating the mechanisms of action. This is especially the case as cross-reactions of compounds and medications is a legitimate concern. 

Lastly, the clinical discussion of higher doses correlating with improved outcomes is worthy of mention. Despite a perception of natural compounds being inherently safer, clear cautions and contraindications do exist, and the “more is better” and the “natural is safer” approaches have their risks and limitations. Again, practitioners in all healing disciplines welcome studies to support the safety and efficacy of the natural compounds that produce such positive clinical outcomes.

In closing, clinicians managing degenerative arthritis have several emerging bodies of scholarly evidence and clinical outcomes to inform their decisions. As they incorporate the use of multifaceted natural joint-health supplements, trends in natural medicine are showing that they are safe and tolerated as they provide benefits inclusive of, but not limited to, decreased pain, improved joint function, and improved quality of life.8

Categorized Under


  1. Safiri S, Kolahi AA, Smith E, et al. Global, regional and national burden of osteoarthritis 1990-2017: a systematic analysis of the Global Burden of Disease Study 2017. Ann Rheum Dis. 2020;79(6):819-828.  
  2. Mozaffarian D, Maki KC, Bays HE, et al. Effectiveness of a novel ω-3 krill oil agent in patients with severe hypertriglyceridemia: a randomized clinical trial. JAMA Netw Open. 2022;5(1):e2141898.  
  3. Ciaraldi TP, Boeder SC, Mudaliar SR, Giovannetti ER, Henry RR, Pettus JH. Astaxanthin, a natural antioxidant, lowers cholesterol and markers of cardiovascular risk in individuals with prediabetes and dyslipidaemia. Diabetes Obes Metab. 2023;25(7):1985-1994.  
  4. Papalia R, Albo E, Russo F, et al. The use of hyaluronic acid in the treatment of ankle osteoarthritis: a review of the evidence. J Biol Regul Homeost Agents. 2017;31(4 Suppl 2):91-102.  
  5. Lavie CJ, Ozemek C, Carbone S, Katzmarzyk PT, Blair SN. Sedentary behavior, exercise, and cardiovascular health. Circ Res. 2019;124(5):799-815.  
  6. Coxib and traditional NSAID Trialists' (CNT) Collaboration, Bhala N, Emberson J, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013;382(9894):769-779.  
  7. Abdelhamid AS, Brown TJ, Brainard JS, et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2020;3(3):CD003177. 
  8. Obara K, Cardoso JR, Reis BM, Matos MA, Kawano MM. Quality of life in individuals with knee osteoarthritis versus asymptomatic individuals. Musculoskeletal Care. 2023;21(4):1364-1370.