Osteoarthritis (OA), the most common type of arthritis, is a chronic, painful, and inflammatory musculoskeletal disease causing functional impairment in approximately 27 million Americans; obesity and advancing age are important risk factors [1
]. While there is no cure, the current management of OA combines nonpharmacological and pharmacological interventions, and often involves costly joint replacement procedures [3
]. Non-steroidal anti-inflammatory drugs may lead to gastrointestinal side-effects, and effective, safer alternatives could benefit millions of patients. Nutraceuticals are good candidates for the management of OA, due to their safety profile and potential efficacy. However, the popularly used supplements, such as glucosamine, chondroitin sulfate, and avocado–soy unsaponifiables, have failed to show a convincing and significant mitigation of symptoms in a meta-analysis of randomized clinical trials, or lack long-term studies on the clinical symptoms and biomarkers of knee OA [4
Obesity is considered a significant risk factor for OA, and contributes to the chronic inflammation that underlies the pathogenesis and symptoms of the condition [7
]. Biomarkers of inflammation, especially serum C-reactive protein (CRP) and interleukin-6 (IL-6), and those of cartilage degradation, including matrix metalloproteinases (MMPs), have been positively correlated with pain and the progression of OA [9
]. Dietary bioactive compounds, such as curcumin [13
], ginger [15
], green tea polyphenols [16
], and herbal tea [17
] have been shown to be effective in the management of pain symptoms and in reducing inflammatory biomarkers of OA. However, such clinical studies are few in number and of short duration, mostly examine pain symptoms but not disease biomarkers, and involve non-obese and otherwise healthy participants. Among the nutritional supplements and foods containing bioactive compounds, polyphenol-rich dietary berries have been extensively studied for their protective associations with other chronic conditions, including hypertension [18
], type 2 diabetes [19
], and overall inflammation [20
], as reported in epidemiological studies. Berries, such as blueberries and red raspberries, have been shown to reduce the symptoms and progression of arthritis, such as pain and articular degeneration, in collagen-induced experimental models of arthritis [21
]. Our group has previously reported the safety and efficacy of berries, especially freeze-dried blueberries and strawberries, in improving features of the metabolic syndrome and decreasing surrogate biomarkers of atherosclerosis in clinical studies [23
]. To our knowledge, no previous clinical study has been reported on the effects of berries on OA of the knee in adults.
For this reason, we undertook the present study to examine the effects of freeze-dried strawberries on pain symptoms and on circulating biomarkers of inflammation and cartilage degradation in obese adults with symptomatic knee OA. Our primary aim was to determine the effects of freeze-dried strawberries on pain scores assessed by the Visual Analog Scale for Pain (VAS Pain) and those based on a Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP) survey, as well as on selected biomarkers of inflammation and cartilage degradation associated with knee OA in comparison to a control group.
Among the 35 participants who were screened, 17 qualified and completed the 26-week study (Figure 1
). The baseline characteristics of these participants are shown in Table 2
. There were no drop-outs in the study. Among the participants who completed the study, compliance was 100% for the strawberry group and 97% for the control group as assessed by mandatory thrice weekly visits, with the return of any unconsumed strawberry and control powder on the days the participants did not come to the clinic. No adverse events were reported in the study. As a measure of compliance, plasma ellagic acid was detectable in 17 participants in the strawberry phase (means ± SEMs (Standard error of means), 30.2 ± 3.6 ng/mL), whereas concentrations were not detectable at baseline, at the end of washout, and at the end of the control phase.
We examined associations of the selected biomarkers of inflammation and cartilage degradation with knee pain scores and HAQ-DI at baseline. As shown in Table 3
, in a multivariable model at baseline, IL-6 was significantly associated with constant pain, and MMP-8 with intermittent knee pain (both p
Among the selected inflammatory variables associated with knee OA measured in the study, serum IL-6 and IL-1β were significantly lower in the strawberry vs. control phase at week 12 (p
< 0.05, Table 4
), while no changes were noted in the serum hs-CRP and nitrite levels. Among the serum markers of cartilage degradation, MMP-3 was observed to be significantly lower in the strawberry vs. control phase at week 12 (p
< 0.05, Table 4
), while no significant changes were noted in MMP-8 between the two phases. As shown in Table 4
, anthropometrics, blood pressure, glucose, HbA1c, lipid profiles, and liver and kidney function tests did not differ between the strawberry and control phases of the crossover study.
As shown in Table 5
, the pain scores and HAQ-DI ratings were lower in the strawberry vs. control phase of the study. The knee pain scores measured as constant, intermittent, and total pain using ICOAP surveys were significantly lower following the strawberry vs. control phase at week 12 (p
< 0.05, Table 5
). No differences were noted in the VAS pain scores. Among the surveys related to general health and disability index, the HAQ-DI ratings were again significantly lower in the strawberry vs. control phase at week 12 (p
< 0.05, Table 5
). The VAS health scores were not affected by the strawberry treatment.
The dietary data did not reveal any significant differences in the mean intake of macro- and micro-nutrients throughout the study (Table 6
). No crossover effects were detected on any of the outcome variables.
To our knowledge, this is the first clinical study on the effects of dietary berries as a nutritional supplement on pain scores and key biomarkers of inflammation in obese adults with radiographic evidence of knee OA. Using a multi questionnaire approach, strawberry supplementation led to significant decreases in constant, intermittent, and total knee pain scores, and an improved disability index and overall health scores. Serum biomarkers of inflammation and cartilage degradation that have been associated with pain and dysfunction in knee OA, especially IL-6, IL-1β, and MMP-3, were also shown to be significantly lower in the strawberry-supplemented group. These findings support a role for foods high in bioactive compounds, such as strawberries, as an alternative or complementary treatment option in pain management that may also reduce surrogate markers of disease progression in knee OA.
Pain relief is one of the major targets of OA management. Symptoms of pain in OA are associated with inflammation and oxidative stress, cartilage degradation, and joint space narrowing [32
]. It is therefore logical to propose that antioxidant supplements may be of benefit. Strawberries are naturally rich in antioxidant polyphenols, and thus were selected for our study [35
]. Participants rated their pain in the range of mild to moderate intensity at baseline using the VAS as well as the ICOAP questionnaires. Other polyphenol containing supplements, such as curcumin [13
], green tea [16
], and herbal tea supplements [17
], have also shown significant decreases in knee pain scores in participants with similar intensity of knee pain as in our study. However, none of these studies reported effects on systemic markers of inflammation and disease progression underlying knee OA.
Together with previous reports, our findings support the analgesic effects of dietary polyphenols in adults with mild to moderate knee pain. Pain measurement in OA has been largely determined by questionnaires, such as those based on quality of life indicators. Meanwhile, physical examination and radiography have been used to stage the disease. We used the VAS, HAQ-DI, and ICOAP questionnaires: these have been widely employed to assess knee pain, quality of life, and disability in adults with OA [29
]. The ICOAP questionnaire is endorsed by the Osteoarthritis Research Society International (OARSI). It has been validated in large multi-country studies, and correlates well with other commonly used methods, such as the Western Ontario and McMaster Universities’ Osteoarthritis Index (WOMAC) scores [28
]. Based on our study findings, strawberries consistently improved pain scores as observed across all three sub-scales of ICOAP, evaluating constant, intermittent, and total pain; they also lowered HAQ-DI scores, reflecting functional improvement. We did not observe any difference in pain scores assessed by VAS survey in our participants. These differences could be explained by the visual expression of general pain intensity used in VAS scoring, when compared to the OA-specific magnitude of knee pain numerically rated by the ICOAP questionnaires. Based on the strengths and limitations of each assessment tool for pain, it is generally recommended to administer more than one questionnaire to capture the multi-dimensional aspects of adult pain. These findings merit follow up in larger trials to validate the findings.
Inflammation is believed to play a pivotal role in the pathophysiology of OA. Multiple cytokines and inflammatory molecules, especially CRP, IL-6, and IL-1β, and free radicals, such as nitric oxide, are implicated in the progression of OA [38
]. Inflamed chondrocytes then produce MMPs, leading to cartilage degradation and progression of OA [40
]. In experimental models of OA, green tea, curcumin, and some herbal supplements may reduce inflammatory molecules and MMPs [41
], while few of the reported clinical studies have determined the effects of the dietary bioactive compounds on inflammatory mediators. In a 16-week study assessing the effects of a high-polyphenol rosmarinic acid tea on pain in participants with knee OA, serum CRP was reported only at baseline but not after the intervention [17
]. Among the studies showing improvements in knee pain in OA following curcumin supplementation [13
], only one study reported data on inflammatory markers, including IL-6; however, these did not differ between the intervention and placebo groups after six weeks’ treatment [43
]. Thus, the study of inflammatory mediators is limited in previous reports of dietary supplements for OA.
In our study, 12 weeks of strawberry supplementation resulted in a significant decrease in IL-6, IL-1β, and MMP-3 in obese participants with knee OA, consistent with anti-inflammatory effects of dietary berries in OA management. These clinical observations are consistent with data showing that blueberry and raspberry extracts lower pain, inflammation, and edema, and articular destruction in experimental arthritis [21
]. Metalloproteinases zinc-dependent enzymes (MMPs) play a key role in extracellular matrix remodeling and cartilage metabolism in knee OA. Among the various isoforms of MMPs, MMP-3 plays an important role in cartilage degradation, and has been shown to be responsive to therapeutic agents in patients with various stages of OA [12
]. On the other hand, MMP-8 has been implicated in the degradation of already compromised cartilage matrix, and a few clinical studies have examined its response to therapeutic agents, and revealed conflicting results [45
]. Thus, future studies must address the role of dietary polyphenolic compounds on a comprehensive panel of serum MMPs to identify clinically responsive biomarkers in OA management.
Obesity has been strongly correlated with knee OA, and consequently weight loss studies, especially the Intensive Diet and Exercise for Arthritis (IDEA) trial, have demonstrated significant decreases in IL-6 and improvements in knee pain and function following diet and exercise interventions in obese older adults [31
]. Interestingly, the magnitude of the decrease in serum IL-6 in our study following the 12-week strawberry intervention was much larger than what was noted in the IDEA trial following an 18-month lifestyle intervention [31
]. IL-6 is a key inflammatory molecule that accelerates articular degradation and OA progression, and higher levels of systemic IL-6 are a significant predictor of OA [49
]. Furthermore, a reduction of IL-6 levels can significantly improve the metabolic syndrome, also considered a risk factor of OA [50
]. The IDEA trial also reported a concomitant decrease in CRP in obese older adults undergoing 5% total weight and fat mass loss following a dietary and exercise intervention [51
]. However, CRP was not significantly altered in the present study, and it may be that weight loss is essential to affect this marker of inflammation. Future studies must assess the combined effects of antioxidant bioactive compounds with weight loss in improving inflammatory profiles in knee OA.
Our study has limitations that affect the interpretation and generalizability of our findings. These include a small sample size, the absence of a dose–response design to assess effects at low vs. high dose of strawberries, and the absence of a non-OA control group. Participants had mild-to-moderate radiographic knee OA at baseline (Kellgren–Lawrence scores of 2.1) and mild-to-moderate knee pain. Whether patients with more severe knee OA (Kellgren–Lawrence score of 4) and higher levels of pain would benefit from strawberry intervention needs further investigation. We did not measure other biomarkers of OA pathology, such as those related to oxidative damage, or simultaneously measure these biomarkers in synovial fluid that would provide a more accurate determination of changes specific to the knee. Also, we did not assess the radiological outcomes at the end of the intervention. Also, being conducted in obese participants with mild-to-moderate symptoms of knee OA, our study findings may not be generalizable to the non-obese population or OA caused by sports injuries and other trauma, or to those needing pain relief after knee surgery.
The strengths of our study include a randomized, controlled cross-over study design, which accounts for most of the inter-individual variations in parallel arm studies. Also, based on the administration of a control powder that matched the freeze-dried strawberries in sensory qualities, we were able to keep the participants and study coordinators blinded to the identity of the test agents. In addition, we excluded participants who were taking supplements, such as fish oil and other herbal supplements for pain relief, as well as those participating in a weight loss program, and thus were able to exclude potential confounding by these factors.