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Nutraceutical supplements in management of pain and disability in osteoarthritis: a systematic review and meta-analysis of randomized clinical trials

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• Published: 01 December 2020

Nutraceutical supplements in management of pain and disability in osteoarthritis: a systematic review and meta-analysis of randomized clinical trials

• Dawood Aghamohammadi, 
• Neda Dolatkhah, 
• Fahimeh Bakhtiari, 
• Fariba Eslamian & 
• Maryam Hashemian 

Scientific Reports volume 10, Article number: 20892 (2020) Cite this article

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Abstract

This study designed to eval‎uate the effect of nutraceutical supplementation on pain intensity and physical function in patients with knee/hip OA. The MEDLINE, Web of Science, Cochrane Library, Scopus, EMBASE, Google Scholar, Science direct, and ProQuest in addition to SID, Magiran, and Iranmedex were searched up to March 2020. Records (n = 465) were screened via the PICOS criteria: participants were patients with hip or knee OA; intervention was different nutritional supplements; comparator was any comparator; the outcome was pain intensity (Visual analogue scale [VAS]) and physical function (Western Ontario and McMaster Universities Arthritis [WOMAC] index); study type was randomized controlled trials. The random effects model was used to pool the calculated effect sizes. The standardized mean difference (SMD) of the outcome changes was considered as the effect size. The random effects model was used to combine the effect sizes. Heterogeneity between studies was assessed by Cochran's (Q) and I2 statistics. A total of 42 RCTs were involved in the meta-analysis. Nutritional supplementation were found to improve total WOMAC index (SMD = − 0.23, 95% CI − 0.37 to − 0.08), WOMAC pain (SMD = − 0.36, 95% CI − 0.62 to − 0.10) and WOMAC stiffness (SMD = − 0.47, 95% CI − 0.71 to − 0.23) subscales and VAS (SMD = − 0.79, 95% CI − 1.05 to − 0.05). Results of subgroup analysis according to the supplementation duration showed that the pooled effect size in studies with < 10 months, 10–20 months and > 20 months supplementation duration were 0.05, 0.27, and 0.36, respectively for WOMAC total score, 0.14, 0.55 and 0.05, respectively for WOAMC pain subscale, 0.59, 0.47 and 0.41, respectively for WOMAC stiffness subscale, 0.05, 0.57 and 0.53, respectively for WOMAC physical function subscale and 0.65, 0.99 and 0.12, respectively for VAS pain. The result suggested that nutraceutical supplementation of patients with knee/hip OA may lead to an improvement in pain intensity and physical function.

이 연구는 무릎/고관절 OA 환자의 통증 강도와 신체 기능에 대한 건강기능식품 보충제의 효과를 평가하기 위해 설계되었습니다. 2020년 3월까지 MEDLINE, Web of Science, Cochrane Library, Scopus, EMBASE, Google Scholar, Science direct 및 ProQuest와 SID, Magiran 및 Iranmedex를 검색했습니다. 참가자는 고관절 또는 무릎 관절염 환자, 중재는 다양한 영양 보충제, 비교군은 모든 비교군, 결과는 통증 강도(시각적 아날로그 척도[VAS]) 및 신체 기능(웨스턴 온타리오 및 맥마스터 대학 관절염[WOMAC] 지수), 연구 유형은 무작위 대조 시험이라는 PICOS 기준에 따라 기록(n = 465)을 선별했습니다. 무작위 효과 모델은 계산된 효과 크기를 풀링하는 데 사용되었습니다. 결과 변화의 표준화 평균 차이(SMD)를 효과 크기로 간주했습니다. 무작위 효과 모델은 효과 크기를 결합하는 데 사용되었습니다. 연구 간의 이질성은 코크란(Q) 및 I2 통계로 평가했습니다. 메타 분석에는 총 42개의 RCT가 참여했습니다. 영양 보충제는 총 WOMAC 지수(SMD = - 0.23, 95% CI - 0.37 ~ - 0.08), WOMAC 통증(SMD = - 0.36, 95% CI - 0.62 ~ - 0.10) 및 WOMAC 강직(SMD = - 0.47, 95% CI - 0.71 ~ - 0.23) 하위 척도 및 VAS(SMD = - 0.79, 95% CI - 1.05 ~ - 0.05) 개선하는 것으로 밝혀졌습니다. 보충 기간에 따른 하위 그룹 분석 결과, 보충 기간이 10개월 미만, 10~20개월, 20개월 이상인 연구의 풀링 효과 크기는 WOMAC 총점, 0. 14, 0.55, 0.05, WOAMC 통증 하위 척도는 각각 0.59, 0.47, 0.41, WOMAC 강직 하위 척도는 각각 0.05, 0.57, 0.53, WOMAC 신체 기능 하위 척도는 각각 0.65, 0.99, 0.12, VAS 통증은 각각 0.65, 0.99, 0.12로 나타났습니다. 

이 결과는 

무릎/고관절 OA 환자에게 

건강기능식품을 보충하면 

통증의 강도와 신체 기능이 개선될 수 있음을 시사합니다.

Introduction

Osteoarthritis (OA) as a degenerative chronic joint cartilage disorder is the most preval‎ent and principal reason for joint pain and functional impairment in the world1. OA is more preval‎ent in older adults and it will inflict incredible economic and societal charges and disturb life quality in different aspects subsequently in the future2. On the other hand, discomfort, pain and decreases in functional ability because of OA can consequence a greater risk of overweight/obesity, diabetes mellitus and falls and fractures3. Issues that chip into the development of OA consist of general factors (age, sex, overweight/obesity and nutrition) and local biomechanical factors (joint injury, physical activities and joint space)4.

Existing recommendations for the management of OA consist of three major classes: pharmacologic (i.e. opioids, non-steroidal anti-inflammatory drugs (NSAID), and COX-2 specific drugs), non-pharmacologic (i.e. rehabilitation to facilitate healthy body composition, lifestyle, and physical activity) and surgical treatment4,5,6,7. Present pharmacological treatments simply have a palliative effect on the relief of symptoms whereas not considering the essential problem of the cartilage disorder. Additionally, long-term consumption of these treatments has possible adverse events that might result drastic outcomes such as gastrointestinal problems, unwanted cardiovascular effects and adverse events on the cartilage8. Meanwhile, nutritional intervention demonstrates a continuing approach for management and inhibiting OA as an accompaniment to the traditional treatment of OA9,10,11,12. Nutraceutical supplements, such as chondroitin sulfate (CS), glucosamine sulfate (GS) and Methylsulfonylmethane (MSM), have been applied to manage OA and relieve symptoms in recent years13. Nutraceuticals are described as dietary supplements that comprise a condensed form of a considered bioactive ingredient, initially isolated from food, however existing in a nonfood matrix, and consumed to preserve or increase health situation in the amounts beyond those accessible from common foods13. Nevertheless, there is no agreement in regard to applying the term “nutraceutical” or “dietary supplement”. The “active aging” is a principle objective of dietary supplements, as indicated by the developing sales of vitamins and minerals14. Dietary bioactive combinations have been revealed to be impressive in the improvement of clinical symptoms and in decreasing inflammatory indices in subjects with OA15. Presently 69% of subjects with OA receive various forms of dietary supplements for their problem16.

Even though there are several publications in the medical literature in regard to the use of nutraceuticals as a complementary treatment of OA, there have been variable findings concerning whether or not these nutrients have any beneficial consequence. The purpose of this study is to perform a systematic review and meta-analysis of relevant randomized controlled trials (RCTs) to assess the efficiency of different dietary supplements in the management of the symptoms of hip/knee OA.

소개

퇴행성 만성 관절 연골 질환인 골관절염(OA)은

전 세계에서 관절 통증과 기능 장애의 가장 흔하고 주요한 원인입니다1.

OA는

노년층에서 더 많이 발생하며

향후 다양한 측면에서 엄청난 경제적, 사회적 비용을 초래하고 삶의 질을 저해할 것입니다2.

한편,

OA로 인한 불편함, 통증 및 기능 저하로 인해

과체중/비만, 당뇨병, 낙상 및 골절 위험이 높아질 수 있습니다3.

OA 발병에 영향을 미치는 문제는

일반적인 요인(연령, 성별, 과체중/비만, 영양)과 국소 생체역학적 요인(관절 부상, 신체 활동, 관절 공간)4 으로 구성됩니다.

OA 관리에 대한 기존 권장 사항은

크게 세 가지로 구성됩니다:

약리학(예: 아편 유사 제, 비스테로이드성 항염증제(NSAID), COX-2 특정 약물),

비약리학(예: 건강한 신체 구성, 생활 방식 및 신체 활동을 촉진하는 재활) 및

수술적 치료4,5,6,7.

현재의 약물 치료는

연골 질환의 본질적인 문제를 고려하지 않고

단순히 증상을 완화하는 완화 효과만 있습니다.

또한

이러한 치료제를 장기간 복용하면

위장 문제, 원치 않는 심혈관 영향 및 연골에 대한 부작용과 같은

급격한 결과를 초래할 수 있는 부작용이 발생할 수 있습니다8.

한편,

영양학적 개입은

전통적인 골관절염 치료와 함께 골관절염을

관리하고 억제하기 위한 지속적인 접근법을 보여줍니다9,10,11,12.

최근 몇 년 동안

콘드로이틴 설페이트(CS),

글루코사민 설페이트(GS),

메틸설포닐메탄(MSM)과 같은 건강기능식품이

OA 관리 및 증상 완화에 적용되었습니다13.

https://kr.iherb.com/pr/now-foods-glucosamine-chondroitin-120-veg-capsules/102343

건강기능식품은 처음에는 식품에서 분리되었지만 비식품 매트릭스에 존재하는 것으로 간주되는 생리 활성 성분의 응축된 형태로 구성된 식이 보충제로, 일반 식품에서 섭취할 수 있는 양 이상으로 건강 상태를 유지하거나 증진하기 위해 섭취하는 것으로 정의됩니다13. 그럼에도 불구하고 “건강기능식품” 또는 “식이 보충제”라는 용어 적용에 대한 합의는 이루어지지 않고 있습니다. 비타민과 미네랄 판매의 발전에서 알 수 있듯이 “활성 노화”는 식이 보충제의 주요 목표입니다14.

식이 생리 활성 조합은 임상 증상을 개선하고 OA 환자의 염증 지수를 감소시키는 데 인상적인 것으로 밝혀졌습니다15. 현재 골관절염 환자의 69%가 다양한 형태의 식이 보충제를 복용하고 있습니다16.

OA의 보완적 치료로 건강기능식품을 사용하는 것과 관련하여 의학 문헌에 여러 논문이 발표되었지만, 이러한 영양소가 유익한 결과를 가져오는지 여부에 관해서는 다양한 결과가 나왔습니다. 이 연구의 목적은 고관절/무릎 관절염 증상 관리에 있어 다양한 식이 보충제의 효율성을 평가하기 위해 관련 무작위 대조 시험(RCT)에 대한 체계적인 검토 및 메타 분석을 수행하는 것입니다.

Methods

The primary purpose of this systematic review and meta-analysis was to eval‎uate the efficacy and safety of dietary supplements in subjects with knee or hip OA. The current study has been planned based on the instructions in the Cochrane Collaboration handbook and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The study question was framed according to the PICOS (participants, interventions, comparators, outcomes, study design) criteria (Table 1), is as follows: Do nutraceutical supplements influence pain and functional status in patients with hip/knee osteoarthritis?

Table 1 PICOS criteria for inclusion and exclusion of studies.

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Literature search

Several search strategies were employed to recognize eligible studies. A medical librarian (FB) in an argument with the team (DA, ND and FB) performed a precise and comprehensive academic literature search of the titles, abstracts and keywords of all studies for competency independently through electronic databases (MEDLINE, Web of Science, Cochrane Library, Scopus, EMBASE, Google Scholar, Clininaltrial.gov, Science direct, and ProQuest in addition to SID, Magiran, Irandoc, and Iranmedex for Persian language literature) up to January 2020. Duplicate studies were excluded. At the same time, a hand search of the related references and cited articles of the included studies was conducted to recognize other appropriate studies that were lost by electronic search.

Search terms included a mix of Medical Subject Headings (MeSH) and a literature search was performed using the following MeSH terms for key concepts (with assistance from a librarian) targeting dietary supplements and hip or knee OA such as : (“supplement ”(All Fields) OR “nutraceuticals”(All Fields) OR “vitamin”(All Fields) OR “mineral”(All Fields) OR “plant”(All Fields)) AND (“OA” OR “osteoarthritis”(All Fields) OR “knee osteoarthritis”(All Fields) OR “hip osteoarthritis”(All Fields) OR “knee OA”(All Fields) OR “hip OA”(All Fields)). After the primary search, titles and abstracts were sent out from EndNote X7 into Microsoft Excel to be screened. Three reviewers separately reviewed all titles and abstracts and full texts (DA, ND, and MH). A fourth reviewer was conferred if discrepancies happened.

Inclusion and exclusion criteria

Inclusion criteria to choose studies for this systematic review and meta-analysis were: (1) RCT (either parallel or crossover designs); (2) a nutraceutical as an intervention either as an adjunctive to standard medicine or as a monotherapy and (3) adults who have been diagnosed with hip or knee OA; (4) sufficient data reported about mean changes for Western Ontario and McMaster Universities Arthritis (WOMAC) index (total score and subscales) and/or Visual analogue scale (VAS) at baseline and at the end of the trial in both intervention and placebo/control groups. Then selected possible clinical trials were excluded based on the exclusion criteria as follows: (1) duplications; (2) subjects have other critical diseases such cardiovascular disease, cancer, diabetes, etc.; (3) Studies with a short period of follow‐up (< 2 weeks); (4) review articles, semi-experimental studies without a control arm, animal studies, study protocols, letter to editors, case reports, case series, observational studies (cross-sectional, case–control and cohort) and unpublished trials.

No language limitations were applied to the search, but only studies published in English or Persian were incorporated because of translation constraints. Trials without full text and those that couldn’t attain the minimum quality appraisement score were not included in this systematic review.

Quality and risk-of-bias assessment

To estimate the risk of systematic errors in the all involved clinical trials, two authors (ND and FB) individually eval‎uated the risk of bias according to the Cochrane Collaboration consists of the subsequent domains: “randomization sequence generation, allocation concealment, blinding of subjects, personal, and outcome assessment, incomplete outcome data, and selective outcome reporting, as well as other sources of bias”. Incompatibilities between reviewers, were resolved by the fourth author (MH). All studies were judged for each series of bias separately, and the studies were decided to take a score of bias as “low risk”, “high risk”, or “unclear risk” if data was inadequate.

Data extraction

One reviewer extracted the data and abstracted it into an electronic form designed for this review, and a second reviewer confirmed it. Information extracted included: the first author’s name, publication details, location of the study, inclusion and exclusion criteria; the number of subjects for intervention and placebo groups, type of intervention, study design and duration, the mean and standard deviation (SD) for VAS and WOMAC index at baseline and at the end of the intervention in both intervention and control groups and safety.

The outcome measures

The studies that met inclusion criteria were reviewed and the outcomes of these RCTs that could be retained for meta-analysis were considered as the primary outcome in this review. Thereupon, the primary outcome measures included for this review were mean changes in WOMAC total, WOMAC pain, WOMAC stiffness, WOMAC physical function and pain (VAS).

Data synthesis and analysis

The number of subjects in each intervention group with mean and SD of study outcomes before and after the intervention was extracted from the articles included in the study. Then, the mean difference of study outcome was calculated and the mean difference of study outcomes was compared between the two groups. Because of the different scales used in the articles included in the study for the WOMAC index and VAS, the standardized mean difference (SMD) of the outcome changes between the two groups was considered as the effect size in this study. The random effects model was used to combine the effect sizes calculated in the articles. Heterogeneity between studies was assessed by Cochran's (Q) and I2 statistics, which expressed the percentage of variations between studies. In case of high heterogeneity between included studies, we performed subgroup analysis according to the treatment duration (< 10 months, 10–20 months and > 20 months) to eval‎uate the impression of these factors on the results. The Meta package in R software was used for data analysis. A p-value less than 0.05 was considered as significant level.

Publication bias

Egger's Regression Test and Funnel Plot were used to eval‎uate the presence or absence of publication bias. Publication bias was assessed for each study outcome. The Trim and Fill method was used to investigate the effect of publication bias on the results of the study.

Results

Study selection process

The systematic searching of the databases identified 1323 articles, of which 858 were excluded as duplicates, 372 were excluded by title and abstract and 52 were excluded after reviewing full texts (Fig. 1).

Figure 1

PRISMA diagram for the search and selection process of articles considered in this review.

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Study characteristics

This comprehensive systematic review and meta-analysis including 42 RCTs (4160 participants) and 33 supplements assessed the clinical effectiveness of different nutraceutical supplementation in the management of knee/hip OA symptoms, principally concentrating on pain and functional outcomes. The included articles in this systematic review were full articles published from January 2000 to March 2020. Papers were written in English or Persian. The details of the studies are summarized in Table 2.

Table 2 Summary table of included studies eval‎uating the effect of nutraceutical supplements in osteoarthritis.

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Risk of bias in included studies

The methodological quality according to the researchers’ decisions on each risk of bias point for each included study is shown in Figs. 2 and 3.

Figure 2

Diagram of bias in the included studies.

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Figure 3

Diagram of bias in the included studies.

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Efficacy of the interventionWOMAC (total)

The total score of the WOMAC was eval‎uated in the 28 articles reviewed. There were 1404 cases in the intervention group and 1360 in the control group. The mean follow-up duration of patients (lowest to maximum) was 17.4 (6–144) weeks. There was a significant heterogeneity between studies (Q-value = 110.58, df = 37, p-value < 0.001, I2 = 66.5%). Based on the meta-analysis results, it was observed that the Pooled Standardized Mean Difference between the intervention and control groups was 0.23 units (SMD = − 0.23, 95% CI − 0.37 to − 0.08, z-value = − 3.09, p-value = 0.002). Figure 4 shows the forest plot of the combination of results. Results of subgroup analysis according to the supplementation duration showed that the pooled effect size in studies with < 10 months as short term, 10–20 months as medium term and > 20 months as long term supplementation duration were 0.05, 0.27 and 0.36, respectively. Figure 5 shows the forest plot of the subgroups by the supplementation duration.

Figure 4

Forest plot presenting the standardized mean difference and 95% confidence interval for the impact of nutraceutical supplementation on WOMAC total score.

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Figure 5

Forest plot presenting the impact of nutraceutical supplementation on WOMAC total score (subgroup analysis based on duration of supplementation).

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WOMAC (pain)

In the included articles, 30 articles eval‎uated the

. There were 1715 subjects in the intervention group and 1665 subjects in the control group. The mean follow-up duration of patients (lowest to maximum) was 16.82 (3–144) weeks. There was a significant heterogeneity between studies (Q-value = 485.41, df = 40, p-value < 0.001, I2 = 92.2%). The Pooled Standardized Mean Difference between the intervention and control groups was 0.36 units (SMD = − 0.37, 95% CI − 0.63 to − 0.11, z-value = − 2.75, p-value = 0.006). The forest plot of the combination of results is presented in Fig. 6. The pooled effect size in studies with < 10 months as short term, 10–20 months as medium term and > 20 months as long term supplementation duration were 0.14, 0.55 and 0.05, respectively. The forest plot of the subgroups by the supplementation duration is presented in Fig. 7.

Figure 6

Forest plot presenting the standardized mean difference and 95% confidence interval for the impact of nutraceutical supplementation on WOMAC pain score.

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Figure 7

Forest plot presenting the impact of nutraceutical supplementation on WOMAC pain score (subgroup analysis based on duration of supplementation).

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WOMAC (stiffness)

In the included articles, 29 articles assessed the WOMAC Stiffness subscale. There were 1539 subjects in the intervention group and 1513 subjects in the control group. The mean follow-up duration of patients (lowest to maximum) was 17.76 (3–144) weeks. There was a significant heterogeneity between studies (Q-value = 353.55, df = 38, p-value < 0.001, I2 = 88.8%). The Pooled Standardized Mean Difference between the intervention and control groups was 0.48 units (SMD = − 0.48, 95% CI − 0.72 to − 0.24, z-value = − 2.88, p-value < 0.001). The forest plot of the combination of results is presented in Fig. 8. The pooled effect size in studies with < 10 months as short term, 10–20 months as medium term and > 20 months as long term supplementation duration were 0.59, 0.47 and 0.41, respectively. The forest plot of the subgroups by the supplementation duration is presented in Fig. 9.

Figure 8

Forest plot presenting the standardized mean difference and 95% confidence interval for the impact of nutraceutical supplementation on WOMAC stiffness score.

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Figure 9

Forest plot presenting the impact of nutraceutical supplementation on WOMAC stiffness score (subgroup analysis based on duration of supplementation).

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WOMAC (physical function)

In the included articles, 29 articles assessed the WOMAC Physical Function subscale. There were 1496 subjects in the intervention group and 1494 subjects in the control group. The mean follow-up duration of patients (lowest to maximum) was 7.21 (3–144) weeks. There was a significant heterogeneity between studies (Q-value = 583.74, df = 37, p-value < 0.001, I2 = 94.0%) The Pooled Standardized Mean Difference between the intervention and control groups was 0.25 units (SMD = − 0.25, 95% CI − 0.57 to − 0.07, z-value = − 1.55, p-value = 0.12). The forest plot of the combination of results is presented in Fig. 10. The pooled effect size in studies with < 10 months as short term, 10–20 months as medium term and > 20 months as long term supplementation duration were 0.05, 0.57 and 0.53, respectively. The forest plot of the subgroups by the supplementation duration is presented in Fig. 11.

Figure 10

Forest plot presenting the standardized mean difference and 95% confidence interval for the impact of nutraceutical supplementation on WOMAC physical function score.

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Figure 11

Forest plot presenting the impact of nutraceutical supplementation on WOMAC physical function score (subgroup analysis based on duration of supplementation).

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Pain (VAS)

In the included articles, 23 articles assessed the VAS. There were 1081 subjects in the intervention group and 1072 subjects in the control group. The mean follow-up duration of patients (lowest to maximum) was 15.35 (2–96) weeks. There was a significant heterogeneity between studies (Q-value = 246.05, df = 30, p-value < 0.001, I2 = 86.5%). The Pooled Standardized Mean Difference between the intervention and control groups was 0.79 units (SMD = − 0.79, 95% CI − 1.06 to − 0.52, z-value = − 5.77, p-value < 0.001). The forest plot of the combination of results is presented in Fig. 12. The pooled effect size in studies with < 10 months as short term, 10–20 months as medium term and > 20 months as long term supplementation duration were 0.65, 0.99 and 0.12, respectively. The forest plot of the subgroups by the supplementation duration is presented in Fig. 13.

Figure 12

Forest plot presenting the standardized mean difference and 95% confidence interval for the impact of nutraceutical supplementation on VAS.

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Figure 13

Forest plot presenting the impact of nutraceutical supplementation on VAS (subgroup analysis based on duration of supplementation).

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Publication bias for WOMAC index total score

Figure 14 illustrates a Funnel Plot to investigate the publication bias for the WOMAC index total score. According to Eggers Regression Test, the publication bias was not significant (t-value = 1.51, df = 36, p-value = 0.13).

Figure 14

Funnel plot of the publication bias for the WOMAC total score.

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Publication bias for WOMAC index pain subscale

Figure 15 illustrates a Funnel Plot to investigate the publication bias for the WOMAC index pain subscale. According to Eggers Regression Test, the publication bias was not significant (t-value = − 0.42, df = 39, p-value = 0.67).

Figure 15

Funnel plot of the publication bias for the WOMAC pain subscale.

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Publication bias for WOMAC index stiffness subscale

Figure 16 illustrates a Funnel Plot to investigate the publication bias for the WOMAC index stiffness subscale. According to Eggers Regression Test, the publication bias was significant (t-value = − 2.13, df = 37, p-value = 0.03). Trim and Fill test was performed to modify the publication bias and 11 studies added to adjust for the missed study through this method. The results of the Trim and Fill test demonstrate that the pooled effect size was 0.08 (Adjusted SMD = 0.08, 95% CI − 0.33 to − 0.16).

Figure 16

Funnel plot of the publication bias for the WOMAC stiffness subscale.

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Publication bias for WOMAC index physical function subscale

Figure 17 illustrates a Funnel Plot to investigate the publication bias for the WOMAC index physical function subscale. According to Eggers Regression Test, the publication bias was not significant (t-value = − 0.41, df = 39, p-value = 0.68).

Figure 17

Funnel plot of the publication bias for the WOMAC physical function subscale.

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Publication bias for VAS

Figure 18 illustrates a Funnel Plot to investigate the publication bias for the VAS. According to Eggers Regression Test, the publication bias was significant (t-value = − 3.03, df = 29, p-value = 0.004). Trim and Fill test was performed to modify the publication bias and 9 studies added to adjust for the missed study through this method. The results of the Trim and Fill test demonstrate that the pooled effect size was 0.35 (Adjusted SMD = − 0.35, 95% CI − 0.64 to − 0.07).

Figure 18

Funnel plot of the publication bias for the VAS.

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Adverse events

The adverse events and dropout rates are summarized in Table 3. The dropout rate ranged from 0 to 41%.

Table 3 Adverse events and dropout rate reported by 41 studies.

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Discussion

This meta-analysis demonstrated that nutraceutical supplementation may lead to an improvement in total and also pain and stiffness subscales of WOMAC and VAS but did not affect WOMAC physical function subscale. The existing modalities for managing OA are basically symptomatic and have not been confirmed to slow, arrest or inverse the joint subversion and cartilage degradation progression8. For this reason, over the past few years, attention has been focused on the impact of nutritional supplements in managing and preventing OA, considering its risk–benefit ratio and low cost and great acceptance by patients. Nutraceuticals provide a great variety of products with a broad range of properties such as anti-inflammatory and antioxidant13,58,59. Nevertheless, their efficacy in OA is uncertain, yet.

토론

이 메타 분석에 따르면 건강기능식품 보충제는 WOMAC 및 VAS의 전체 및 통증과 뻣뻣함 하위 척도를 개선할 수 있지만 WOMAC 신체 기능 하위 척도에는 영향을 미치지 않는 것으로 나타났습니다. 기존의 퇴행성 관절염 관리 방식은 기본적으로 증상에 대한 치료이며 관절 전복 및 연골 퇴화 진행을 늦추거나 중단 또는 역전시키는 것으로 확인되지 않았습니다8. 이러한 이유로 지난 몇 년 동안 영양 보충제의 위험 대비 편익 비율과 저렴한 비용, 환자들의 높은 수용성을 고려하여 OA 관리 및 예방에 대한 영양 보충제의 영향에 관심이 집중되어 왔습니다. 건강기능식품은 항염증 및 항산화13,58,59 와 같은 광범위한 특성을 가진 매우 다양한 제품을 제공합니다. 그럼에도 불구하고 OA에 대한 효능은 아직 불확실합니다.

Short term nutraceutical supplementation in OA patients

In studies with short term duration of supplementation, significant effects of nutraceutical supplement only were seen on VAS and WOMAC stiffness scores. Among these, three supplements [Low dose Sierrasil (2 g/day) in addition to cat's claw extract in patients with mild to moderate knee OA according to Kellgren and Lawrence scoring system for classification of knee OA60 and fortified milk-based bioactive micronutrient beverage and SKI 306X in knee OA patients with unspecified disease severity] had significant effects on VAS pain intensity. Low dose Sierrasil in addition to cat's claw extract and l-carnitine had a considerable effect also on WOMAC all subscales in patients with mild to moderate knee OA. Additionally, milk protein concentrate (MPC) showed significant effects on WOMAC stiffness score in knee OA patients with unspecified disease severity and Chicken comb extract with a high content of hyaluronic acid had a considerable effect on WOMAC total score, in patients with mild to severe knee OA according to Kellgren and Lawrence scoring system for classification of knee OA60.

Sierrasil is an indigenous mineral product isolated from the Sierra Mountains in the USA with a cultural history of usage in the treatment of joint pain and established cartilage degradation reducing properties61. SKI306X is a herbal mixture (Clematis mandshurica, Trichosanthes kirilowii and Prunella vulgaris) applied for the management of inflammatory diseases and is clinically accepted for the treatment of OA in Far East Asia62. In the systematic review of RCTs by Ameye and Chee2 moderate evidence was established for SKI306X in improving the symptoms in OA patients. Hyaluronic acid or hyaluronan (sodium hyaluronate) is accountable for the viscoelasticity and lubricating impacts of synovial fluid of the joint and has been shown to have the biophysical and biochemical roles in synovial tissues63. However, in a recent systematic review and meta-analysis by Liu et al.64, collagen hydrolysate, extract of the skin of the passion fruit (PFP), Curcuma longa extract, Boswellia serrata extract, pycnogenol and L-carnitine exhibited clinically important effects for pain alleviation in short term and only two supplements (green-lipped mussel extract and undenatured type II collagen (UC-II) showed clinically important effects on pain reduction at medium term. However, we founded that long term UC- II supplementation had considerable effects on WOMAC total and also WOMAC pain and physical function scale scores in patients with mild Knee OA. UC-II is a natural component which comprises a glycosylated, undenatured type-II collagen. Studies have revealed that UC-II restrain joint health in both OA and rheumatoid arthritis (RA) diseases48.

OA 환자의 단기 건강기능식품 보충제 섭취

단기간의 보충제를 섭취한 연구에서 건강기능식품 보충제만 섭취했을 때 VAS 및 WOMAC 강직 점수에 유의미한 효과가 나타났습니다. 이 중 세 가지 보충제[켈그렌과 로렌스의 무릎 OA 분류 체계에 따른 경증에서 중등도 무릎 OA 환자에게 저용량 시에라실(2g/일)과 캣츠클로 추출물 추가 투여60 및 강화 우유 기반 생리 활성 미량 영양소 음료와 질병 중증도가 불특정한 무릎 OA 환자의 SKI 306X]가 VAS 통증 강도에 유의미한 영향을 미쳤습니다.

저용량 시에라실과 고양이 발톱 추출물 및 l-카르니틴은 경증에서 중등도 무릎 관절염 환자의 WOMAC 모든 하위 척도에도 상당한 영향을 미쳤습니다. 또한, 우유 단백질 농축액(MPC)은 질환 중증도가 불특정인 무릎 OA 환자에서, 히알루론산 함량이 높은 닭발 추출물은 무릎 OA 분류를 위한 켈그렌과 로렌스 점수 체계에 따라 경증에서 중증 무릎 OA 환자에서 WOMAC 총점60 에 유의미한 영향을 미치는 것으로 나타났습니다.

시에라실은 미국 시에라 산맥에서 분리된 토착 미네랄 제품으로, 관절 통증 치료에 사용되어 온 문화적 역사와 연골 분해 감소 효과가 입증된 제품입니다61. SKI306X는 염증성 질환 관리에 적용되는 허브 혼합물(클레마티스 만수리카, 트리코산테스 키릴로위, 프루넬라 벌가리스)로 극동 아시아에서 OA 치료에 임상적으로 인정받고 있습니다62. Ameye와 Chee의 체계적 문헌고찰2에서 SKI306X가 OA 환자의 증상을 개선하는 데 있어 중간 정도의 근거가 확립되었습니다. 히알루론산 또는 히알루로난(히알루론산나트륨)은 관절 활액의 점탄성 및 윤활 작용을 담당하며 활액 조직에서 생물물리학적 및 생화학적 역할을 하는 것으로 나타났습니다63. 그러나 최근 Liu 등의 체계적 문헌고찰 및메타분석64에 따르면 콜라겐 가수분해물, 패션프루트 껍질 추출물(PFP), 커큐마 롱가 추출물, 보스웰리아 세라타 추출물, 피크노제놀 및 L-카르니틴은 단기간에 통증 완화에 임상적으로 중요한 효과를 보였으며, 초록입홍합 추출물 및 변성되지 않은 제2형 콜라겐(UC-II)만 중기에 통증 감소에 임상적으로 중요한 효과를 나타냈다고 보고했습니다. 그러나 장기적으로 UC-II 보충제를 섭취하면 경증 무릎 관절염 환자의 WOMAC 총점 및 WOMAC 통증과 신체 기능 척도 점수에 상당한 영향을 미친다는 사실을 발견했습니다. UC-II는 변성되지 않은 글리코실화된 타입 II 콜라겐으로 구성된 천연 성분입니다. 연구에 따르면 UC-II는 OA와 류마티스 관절염(RA) 질환 모두에서 관절 건강을 억제하는 것으로 밝혀졌습니다48.

Medium term nutraceutical supplementation in OA patients

In the subgroup analysis, the greatest efficacy of nutraceutical supplements on WOMAC index total score and its subscales and also VAS was related to medium term supplementation (10 to 20 months). Most of these studies involved patients with mild to moderate knee OA according to Kellgren and Lawrence scoring system for classification of knee OA60 or American College of Rheumatology Classification Criteria for Knee Osteoarthritis65 which supplements were administered as an adjunctive to symptomatic treatments (NSAIDs and/or analgesics) except nine of them (three33,47,54 involved patients with knee and/or hip OA, four24,32,44,52 involved patients with severe knee OA and two53,55 involved patients for which supplements were administered as a monotherapy and no concomitant treatment were allowed).

Among studies with medium term of supplementation, WOMAC total score was considerably improved through supplementation with CS in patients with mild to moderate knee OA, Deer bone extract (DBE) in patients with moderate to severe knee OA and PFP and collagen peptides isolated from pork skin (PCP) in patients with mild to severe knee OA.

OA is described by damage of type II collagen and GAGs, which are present in the joint. The lessening of GAGs is an essential factor leading to enhanced cartilage deprivation in the OA. CS, a central structural part of cartilage, is a sulfated GAG. Investigations in animal models have suggested that dietary supplements of CS prevent articular cartilage depreciation66. This protecting consequence is related to the anti-inflammatory activities of CS by increasing the synthesis of hyaluronic acid and proteoglycans, and decreasing the production of proteolytic enzymes and nitric oxide57. Deer horn extract has been considered as a noteworthy health restorative in traditional medicine amongst several Asian countries67. Oily DBE and CPC were recently revealed to have anti-inflammatory properties and reduce the morphological deviations related with osteoarthritic cartilage damage in animal models of OA68,69.

The WOMAC all subscale scores were improved through medium term supplementation with A. paniculata purified extract (ParActin) (in patients with mild knee OA), DBE (in patients with moderate to severe knee OA) and MSM (in knee OA patients with unknown severity). PFP improved only WOMAC pain and physical function subscales in patients with mild to severe knee OA, Boswellia serrata extract improved only WOMAC pain and stiffness subscales score and VAS in patients with mild to moderate knee OA and Artemisia annua extract (ART) improved considerably only WOMAC stiffness subscale in knee OA with unknown severity.

골관절염 환자의 중기 건강기능식품 보충제 섭취

하위 그룹 분석에서 건강기능식품 보충제가 WOMAC 지수 총점 및 하위 척도와 VAS에 미치는 가장 큰 효과는 중기 보충제(10~20개월)와 관련이 있는 것으로 나타났습니다. 이러한 연구의 대부분은 무릎 골관절염의 분류를 위한 켈그렌과 로렌스 점수 체계60 또는 미국 류마티스 학회의 무릎 골관절염 분류 기준65 에 따라 경증에서 중등도의 무릎 골관절염 환자를 대상으로 하였으며, 이 중 9 건(333.)을 제외하고는 증상 치료(NSAID 및/또는 진통제)에 보조적으로 보충제를 투여하였습니다, 47,54는 무릎 및/또는 고관절 골관절염 환자, 424,32,44,52는 중증 무릎 골관절염 환자, 253,55는 보충제를 단독 요법으로 투여하고 병용 치료가 허용되지 않은 환자를 대상으로 했습니다).

보충제 투여 기간이 중간 정도인 연구 중 경증에서 중등도 무릎 OA 환자에게는 CS를, 중등도에서 중증 무릎 OA 환자에게는 사슴 뼈 추출물(DBE)을, 경증에서 중증 무릎 OA 환자에게는 돼지 피부에서 분리한 콜라겐 펩타이드(PCP)를 보충했을 때 WOMAC 총점이 상당히 개선된 것으로 나타났습니다.

OA는 관절에 존재하는 II형 콜라겐과 GAG의 손상으로 설명됩니다. GAG의 감소는 OA의 연골 박탈을 강화하는 필수 요소입니다. 연골의 중심 구조 부분인 CS는 황화된 GAG입니다. 동물 모델에 대한 연구에 따르면 CS의 식이 보충제가 관절 연골 감가상각을 예방하는 것으로 나타났습니다66. 이러한 보호 효과는 히알루론산과 프로테오글리칸의 합성을 증가시키고 단백질 분해 효소와 산화질소 생성을 감소시킴으로써 CS의 항염증 작용과 관련이 있습니다57. 사슴뿔 추출물은 여러 아시아 국가에서 전통 의학에서 주목할 만한 건강 회복제로 여겨져 왔습니다67. 최근 OA68,69의 동물 모델에서 유성 DBE와 CPC가 항염증 작용을 하고 골관절염 연골 손상과 관련된 형태학적 편차를 감소시키는 것으로 밝혀졌습니다.

경증 무릎 관절염 환자에서 A. 파니쿨라타 정제 추출물(ParActin), 중등도~중증 무릎 관절염 환자에서 DBE, 중증도 불명의 무릎 관절염 환자에서 MSM을 중기적으로 보충하면 WOMAC의 모든 하위 척도 점수가 개선되는 것으로 나타났습니다. PFP는 경증에서 중등도 무릎 OA 환자에서 WOMAC 통증 및 신체 기능 하위 척도만 개선했으며, 보스웰리아 세라타 추출물은 경증에서 중등도 무릎 OA 환자에서 WOMAC 통증 및 강직 하위 척도 점수 및 VAS만 개선했으며, 아르테미시아 안누아 추출물(ART)은 중증도 불명의 무릎 OA에서 WOMAC 강직 하위 척도만 유의하게 개선한 것으로 나타났습니다.

Long term nutraceutical supplementation in OA patients

Regarding long term supplementation, skimmed milk containing probiotic Lactobacillus casei Shirota (LcS) had considerably effects on WOMAC total and also WOMAC stiffness scale score and UC- II had considerably effects on WOMAC total and also WOMAC pain and physical function scale scores in patients with mild Knee OA according to Kellgren and Lawrence scoring system for classification of knee OA60. Boswellia serrata extract improved WOMAC stiffness scale score in knee OA patients with unspecified disease severity. No supplements were recognized with significant effects on VAS reduction in the long term. However Liu et al.64, identified that no supplement had important effects on pain alleviation and physical function improvement in long term in patients with hand, hip or knee OA. These different conclusions are somehow because of different eligibility criteria for included studies and also different scales used for measuring pain and physical function.

There is a growing field of interest and research indicating the protective benefits of dietary polyphenols in decreasing risk for chronic diseases59 through accepting electrons from free radicals, distracting chain oxidation reactions, and improving cellular antioxidative capability16. The results of several studies suggested that supplementation with polyphenols and botanical extracts (e.g., Boswellia serrata extract, PFP, ParActin, ART and cat's claw extract) decrease the serum levels of TNF-α and MMP-3 in synovial fluid in patients with knee OA compared with the control groups53,70,71. Cellular and animal models have suggested also the benefits of such compounds and food ingredients (e.g., probiotics) in inhibiting inflammatory paths and reducing the production of iNOS, COX-2 and MMP enzymes to decrease the catabolic destruction of the cartilage16,72,73,74,75,76.

A very important point in our findings which must be considered is that GS and vitamin D with the greatest interest in administration and consumption among OA patients, do not exhibit a clinically significant effect on knee or hip OA. GS is a water-soluble amino monosaccharide, considered as a desired substrate for the biosynthesis of GG chains and is in great amounts in cartilage matrix and synovial fluid. Glucosamine was thought to afford building substrates for the cartilage extracellular matrix biosynthesis. Later studies have established additional clarifications for its anti-inflammatory and anti-catabolic properties. A Cochrane review of RCTs of all GS formulations in OA patients, restricted to studies with satisfactory concealment, failed to display any advantage of GS for pain77. Hereafter, GS was firstly suggested by European League Against Rheumatism (EULAR) and Osteoarthritis Research Society International (OARSI) for pain management and structure enhancement in OA patients, but not in the most recent National Institute for Health and Care Excellence (NICE) guidelines.

It has been theorized that vitamin D supplementation in patients with knee OA might be a practicable and cost-effective approach for managing clinical symptoms and making a structural advance. However most clinical trials showed that vitamin D supplementation does not improve cartilage volume or knee pain41,46,78. In line with our findings, the results of a systematic review of RCTs covering 1189 patients by Hussein79 did not recommend vitamin D supplementation in patients with knee OA.

Our study opens new horizons for the managing of degenerative joint diseases. We collected clinical trials of nutraceuticals and dietary supplements and the findings were really hopeful and encouraging. However, there is a need for more well-designed randomized clinical trials which can confirm‎ the safety and efficacy of such products. This could help clinicians in endorsing them for OA patients.

OA 환자의 장기적인 건강기능식품 보충제 섭취

프로바이오틱스 락토바실러스 카제이 시로타(LcS)가 함유된 탈지분유를 장기적으로 보충한 결과, 무릎 OA 분류를 위한 켈그렌 및 로렌스 점수 체계에 따라 경증 무릎 OA 환자의 WOMAC 총점 및 WOMAC 강직도 점수, UC-II에 상당한 영향을 미쳤으며 WOMAC 통증 및 신체 기능 점수에도 상당한 영향을 미쳤습니다60. 보스웰리아 세라타 추출물은 질병 중증도가 불특정인 무릎 OA 환자의 WOMAC 강직도 척도 점수를 개선했습니다. 장기적으로 VAS 감소에 유의미한 효과가 있는 보충제는 확인되지 않았습니다. 그러나 Liu등64 은 손, 고관절 또는 무릎 관절염 환자에서 장기적으로 통증 완화 및 신체 기능 개선에 중요한 영향을 미치는 보충제는 없다는 것을 확인했습니다. 이러한 상이한 결론은 연구에 포함된 자격 기준과 통증 및 신체 기능 측정에 사용된 척도가 다르기 때문일 수 있습니다.

식이 폴리페놀이 활성산소로부터 전자를 흡수하고 연쇄 산화 반응을 방해하며 세포 항산화 능력을 향상시킴으로써 만성 질환의 위험을 감소시키는 보호 효과59 를 나타내는 연구와 관심이 증가하고 있습니다16 . 여러 연구 결과에 따르면 폴리페놀과 식물 추출물(예: 보스웰리아 세라타 추출물, PFP, 파락틴, ART 및 캣츠클로 추출물)을 보충하면 대조군에 비해 무릎 OA 환자의 활액 내 TNF-α와 MMP-3의 혈청 수치가 감소한다고 합니다53,70,71. 세포 및 동물 모델에서도 이러한 화합물과 식품 성분(예: 프로바이오틱스)이 염증 경로를 억제하고 연골의 이화 작용 파괴를 줄이기 위해 iNOS, COX-2 및 MMP 효소의 생성을 감소시키는 이점을 제시했습니다16,72,73,74,75,76.

이번 연구 결과에서 고려해야 할 매우 중요한 점은 OA 환자들 사이에서 투여 및 섭취에 가장 관심이 높은 GS와 비타민 D가 무릎 또는 고관절 OA에 임상적으로 유의미한 영향을 미치지 않는다는 점입니다. GS는 수용성 아미노 단당류로, GG 사슬의 생합성을 위한 바람직한 기질로 간주되며 연골 기질과 활액에 다량으로 존재합니다. 글루코사민은 연골 세포 외 기질 생합성을 위한 기질을 구축할 수 있는 것으로 여겨졌습니다. 이후 연구를 통해 글루코사민의 항염증 및 항 이화 작용에 대한 추가적인 설명이 밝혀졌습니다. 만족스러운 은폐가 이루어진 연구로 제한하여 OA 환자를 대상으로 한 모든 GS 제형에 대한 RCT에 대한 코크란 리뷰에서는 통증에 대한 GS의 이점을 보여주지 못했습니다77. 이후 유럽 류머티즘 연맹(EULAR)과 국제 골관절염 연구회(OARSI)에서 OA 환자의 통증 관리 및 구조 개선을 위해 GS를 처음 제안했지만, 가장 최근의 국립보건의료연구원(NICE) 가이드라인에는 포함되지 않았습니다.

무릎 관절염 환자에게 비타민 D를 보충하는 것이 임상 증상을 관리하고 구조적 개선을 위한 실용적이고 비용 효율적인 접근법이라는 이론이 있습니다. 그러나 대부분의 임상시험에서 비타민D 보충제는 연골의 양이나 무릎 통증을 개선하지 못하는 것으로 나타났습니다41,46,78. 우리의 연구 결과와 일치하게, 1189명의 환자를 대상으로 한 후세인79의 체계적 문헌고찰 결과에서도 무릎 OA 환자에게 비타민 D 보충제를 권장하지 않았습니다.

이번 연구는 퇴행성 관절 질환 관리에 새로운 지평을 열었습니다. 우리는 건강기능식품과 식이 보조제에 대한 임상시험을 수집했고 그 결과는 정말 희망적이고 고무적이었습니다. 하지만 이러한 제품의 안전성과 효능을 확인할 수 있는 보다 잘 설계된 무작위 임상시험이 필요합니다. 이는 임상의가 OA 환자에게 이러한 제품을 추천하는 데 도움이 될 수 있습니다.

본 연구는 이 체계적 문헌고찰 및 메타분석의 결과를 설명할 때 고려해야 할 몇 가지 한계점이 있습니다. 첫째, OA 환자를 대상으로 한 건강기능식품 연구가 증가하고 있음에도 불구하고 기존 과학 문헌을 체계적으로 검토한 결과 이 특정 리뷰에 포함된 연구 수가 예상보다 적었습니다. 많은 연구에서 측정되지 않는 변수(예: VAS 및 WOMAC)를 고려했기 때문에 포함 기준이 중요한 역할을 했다고 생각합니다. 둘째, 출판 편향 가능성이 있습니다. 일부 미발표 초록과 논문은 입수할 수 없어 포함되지 않았습니다. 셋째, 제한된 리소스로 인해 영어와 페르시아어만 선택했기 때문에 언어 편향이 발생할 수 있습니다. 이로 인해 표본 크기가 상당히 줄어들 수 있으며, 이에 따라 통계적으로 유의미한 결과를 설명할 수 있는 능력이 저하될 수 있습니다. 넷째, 결과 간의 이질성도 고려해야 할 문제입니다. 하위 그룹 분석을 수행했지만 이러한 이질성을 완전히 최소화하는 데는 성공하지 못했습니다. 마지막으로, OA의 중증도, 지역, 인종 등 본 체계적 문헌고찰 및 메타분석에서 고려하지 못한 측면이 있을 수 있습니다.

이러한 한계에도 불구하고 이 체계적 문헌고찰 및 메타분석은 무릎/고관절 OA 환자의 통증 및 신체 장애와 관련하여 건강기능식품 보충제에 대한 임상시험을 고려한 최초의 체계적인 연구를 제공합니다. 또한 건강기능식품 유형에 따라 하위 그룹 분석을 실시하여 보다 적합한 결과 지표를 적용하여 메타분석을 진행했습니다.

결론적으로, 대증 치료(NSAID/ COX-2 억제제 및 진통제)와 함께 건강기능식품을 보충하면 무릎/고관절 OA 환자의 통증과 신체 기능을 효과적으로 개선할 수 있는 것으로 나타났습니다. 하위 그룹 분석에서는 특히 경증에서 중증 무릎 관절염 환자에게 10~20개월(중기) 보충제를 섭취했을 때 가장 큰 효과가 있는 것으로 나타났습니다. 글루코사민 및 비타민 D와 같이 본 연구에서 유의미한 효능이 입증된 보충제는 아니지만, 잘 알려지지 않은 일부 보충제(보스웰리아 세라타 추출물, DBE, PFP, PCP, 파액틴, ART 및 피크노제놀)는 통증 감소와 신체 기능 개선에 가장 큰 효과가 있으며 부작용은 미미한 것으로 나타났습니다. 특히 저용량 시에라실을 제외한 경증에서 중등도 무릎 관절염 환자에게는 최소 10주 동안 기존의 증상 치료 및 물리 치료와 함께 이러한 보충제를 안전한 용량으로 시도해 볼 것을 권장하며, 이 외에도 캣츠클로 추출물, 강화 생리 활성 미량 영양소 음료, SKI 306X를 함께 복용하는 것이 좋습니다, L-카르니틴, MPC, 히알루론산은 10주 미만의 보충으로 통증 및/또는 장애 감소에 유익한 효과가 있을 것으로 예상되며, 프로바이오틱스 LcS와 UC-II는 경증 무릎 OA 환자에게도 20주 미만의 보충으로 유익한 효과가 있을 것으로 예상됩니다. 염증 바이오마커나 영상 연구와 같은 보다 정확한 결과 측정 도구가 향후 연구에 도입되어 보다 설득력 있는 근거가 될 수 있을 것입니다.

The present study has some limitations that need to be considered in explicating the results of this systematic review and meta-analysis. Firstly, in spite of an increasing body of nutraceutical researches in subjects with OA, the number of studies included in this specific review after a systematic review of the existing scientific literature was lower than what would have been predicted. We believe that our inclusion criteria had a significant role, because we considered variables (i.e. VAS and WOMAC) that are not measured in many studies. Secondly, there is probable publication bias. Some unpublished abstracts and articles were not included because of unavailability. Thirdly, the language may lead to bias as we selected only the English and Persian language due to limited resources. These may considerably reduce our sample size and accordingly our ability to delineate statistically significant findings. Fourthly, the heterogeneity between the results is an issue need to be considered. Although we did a subgroup analysis, we were not successful to completely minimize these heterogeneities. Finally, there may be some possible aspects not considered in the present systematic review and meta-analysis, such as the severity of OA, region, and race.

In spite of the stated limitations, this systematic review and meta-analysis provides the first systematic work to consider clinical trials on nutraceutical supplementation in relation to pain and physical disability in patients with knee/hip OA. In addition, subgroup analysis was implemented according to the nutraceutical type and we applied more suitable consequence indicators to direct this meta-analysis.

In conclusion, nutraceutical supplementation mostly along with symptomatic treatments (NSAIDs/ COX-2 inhibitors and analgesics) may effectively improve pain and physical function in patients with knee/hip OA. In the subgroup analysis, the greatest efficacy of nutraceutical supplements was related to 10–20 month (medium term) supplementation especially in patients with mild to severe knee OA. Despite recognized supplements with no established significant efficacy in our study (such as glucosamine and vitamin D), some not well-known supplements (Boswellia serrata extract, DBE, PFP, PCP, ParActin, ART and Pycnogenol) seem to have largest benefits in decreasing pain and improving physical function with negligible adverse events. It is recommended to trying these supplements in a safe doses along with conventional symptomatic treatments and physical therapy for at least 10 weeks especially for those with mild to moderate knee OA except low dose Sierrasil in addition to cat's claw extract, fortified bioactive micronutrient beverage, SKI 306X, L-carnitine, MPC and hyaluronic acid which are expected to have beneficial effects in decreasing pain and/or disability in less than 10 weeks of supplementation and also probiotic LcS and UC-II which are not anticipated to have favorable effects in less than 20 weeks of supplementation even in patients with mild knee OA. Other more precise outcome measurement tools, such as inflammatory biomarkers or image study, should probably be introduced into future studies to make them more convincing evidence.