Natural Treatments for Osteoarthritis

*Osteoarthritis Biomarkers and Treatments*

International. 2015. Article ID: 597652. https://doi.org/10.1155/2015/597652

[61] Goisis M, editor. Outpatient regenerative medicine. In: Fat Injection and PRP as Minor Officebased Procedures. 2019. DOI: 10.1007/978-3-319-44894-7

[62] Hattori H, Masuoka K, Sato M. Bone formation using human adipose tissue-derived stromal cells and a biodegradable scaffold. Journal of Biomedical Materials Research Part B: Applied Biomaterials. 2006;**76**:230-239

[63] Hattori H, Sato M, Masuoka K, et al. Osteogenic potential of human adipose tissue-derived stromal cells as an alternative stem cell source. Cells, Tissues, Organs. 2004;**178**:2-12

[64] Hattori H, Nogami Y, Tanaka T. Expansion and characterization of adipose tissue-derived stromal cells cultured with low serum medium. Journal of Biomedical Materials

2008;**87**:229-236

2006;**79**:25-34

Research. Part B, Applied Biomaterials.

[65] Masuoka K, Asazuma T, Hattori H. Tissue engineering of articular cartilage with autologous cultured adipose tissue-derived stromal cells using atelocollagen honeycomb-shaped scaffold with a membrane sealing in rabbits. Journal of Biomedical Materials Research. Part B, Applied Biomaterials.

**54**

Chapter 4

Abstract

Herbal Medicinal Products in the

Osteoarthritis (OA) is the most common form of arthritis, which represents a substantial economic burden for society and significantly affects patients' quality of life. Current conventional treatments of OA may be insufficiently effective and unsafe. In an attempt to overcome these limitations, many patients use herbal medicinal products (HMPs) and dietary supplements. A considerable number of herbal drugs and preparations (e.g., willow bark, Salicis cortex; devil's claw root, Harpagophyti radix; blackcurrant leaf, Ribis nigri folium; nettle leaf/herb, Urticae folium/herba; meadowsweet/meadowsweet flower, Filipendulae ulmariae herba/flos;

Keywords: osteoarthritis, herbal medicinal products, medicinal plants, mechanism

Osteoarthritis (OA) is the most common form of arthritis and the main cause of disability in elderly. Due to the aging population and obesity (major risk factors), its

approximately 12% of the older population (≥60 years). Symptomatic OA of hand (6.8%, ≥26 years) and hip (9.2%, ≥45 years) is also frequent. OA can influence patients' quality of life significantly, as it is usually accompanied with the pain and loss of physical function. OA often affects knees, hips, hands (distal and proximal interphalangeal joints and the base of thumb), cervical and lumbosacral spine, and feet (first metatarsal phalangeal joint). It is characterized by failure of all joint structures. Articular cartilage loss is the most prominent feature of the disease, but subchondral bone, synovial membrane, associated muscles, and ligaments are also affected. On cellular level, catabolic function of chondrocytes prevails over their

prevalence increases. It is estimated that symptomatic OA of knee affects

of action, active constituents, clinical efficacy

1. Introduction

57

rosemary leaf/oil, Rosmarini folium/aetheroleum; and juniper oil, Juniperi aetheroleum) are traditionally employed to relieve minor articular pain. Active constituents (e.g., sesquiterpene lactones, triterpenic acids, diarylheptanoids, iridoid glycosides, phenolic glycosides, procyanidins, and alkaloids) are not often fully known. Experimental studies suggest that herbal extracts/compounds are able to suppress inflammation, inhibit catabolic processes, and stimulate anabolic processes relevant to OA. Therapeutic benefit of most HMPs is expected solely from the experience of their long-standing traditional use. Efficacy and safety of several HMPs were assessed in clinical trials. The growing body of preclinical and clinical evidence provides rationale for the use of herbal products in the treatment of OA. However, at present, they cannot be recommended to patients with confidence.

Treatment of Osteoarthritis

Zoran Maksimović and Stevan Samardžić

#### Chapter 4

## Herbal Medicinal Products in the Treatment of Osteoarthritis

Zoran Maksimović and Stevan Samardžić

#### Abstract

Osteoarthritis (OA) is the most common form of arthritis, which represents a substantial economic burden for society and significantly affects patients' quality of life. Current conventional treatments of OA may be insufficiently effective and unsafe. In an attempt to overcome these limitations, many patients use herbal medicinal products (HMPs) and dietary supplements. A considerable number of herbal drugs and preparations (e.g., willow bark, Salicis cortex; devil's claw root, Harpagophyti radix; blackcurrant leaf, Ribis nigri folium; nettle leaf/herb, Urticae folium/herba; meadowsweet/meadowsweet flower, Filipendulae ulmariae herba/flos; rosemary leaf/oil, Rosmarini folium/aetheroleum; and juniper oil, Juniperi aetheroleum) are traditionally employed to relieve minor articular pain. Active constituents (e.g., sesquiterpene lactones, triterpenic acids, diarylheptanoids, iridoid glycosides, phenolic glycosides, procyanidins, and alkaloids) are not often fully known. Experimental studies suggest that herbal extracts/compounds are able to suppress inflammation, inhibit catabolic processes, and stimulate anabolic processes relevant to OA. Therapeutic benefit of most HMPs is expected solely from the experience of their long-standing traditional use. Efficacy and safety of several HMPs were assessed in clinical trials. The growing body of preclinical and clinical evidence provides rationale for the use of herbal products in the treatment of OA. However, at present, they cannot be recommended to patients with confidence.

Keywords: osteoarthritis, herbal medicinal products, medicinal plants, mechanism of action, active constituents, clinical efficacy

#### 1. Introduction

Osteoarthritis (OA) is the most common form of arthritis and the main cause of disability in elderly. Due to the aging population and obesity (major risk factors), its prevalence increases. It is estimated that symptomatic OA of knee affects approximately 12% of the older population (≥60 years). Symptomatic OA of hand (6.8%, ≥26 years) and hip (9.2%, ≥45 years) is also frequent. OA can influence patients' quality of life significantly, as it is usually accompanied with the pain and loss of physical function. OA often affects knees, hips, hands (distal and proximal interphalangeal joints and the base of thumb), cervical and lumbosacral spine, and feet (first metatarsal phalangeal joint). It is characterized by failure of all joint structures. Articular cartilage loss is the most prominent feature of the disease, but subchondral bone, synovial membrane, associated muscles, and ligaments are also affected. On cellular level, catabolic function of chondrocytes prevails over their

anabolic activity. This imbalance is promoted by pro-inflammatory cytokines, which stimulate chondrocytes to produce enzymes (collagenases and aggrecanases) able to degrade extracellular matrix composed of collagen type II and proteoglycans. Several mediators (e.g., TNF-α, IL-1β, NO, and PGE2) play an important role in the pathogenesis and progression of OA [1, 2].

cyclooxygenase inhibition and diminished production of prostaglandins [9]. Two randomized controlled clinical trials provided low-quality evidence that short-term treatment with standardized willow bark extracts (daily doses corresponded to 240 mg of salicin) was not efficient in reduction of pain and improvement of physical function in patients with OA of hip and knee [3, 10]. Additional welldesigned sufficiently powered studies are needed in order to estimate willow bark

Herbal Medicinal Products in the Treatment of Osteoarthritis

DOI: http://dx.doi.org/10.5772/intechopen.80593

Devil's claw root (Harpagophyti radix) consists of cut and dried, tuberous secondary roots of Harpagophytum procumbens DC. and/or Harpagophytum zeyheri Decne. [4]. Herbal tea and liquid or solid dosage forms containing different devil's claw root preparations (e.g., dry aqueous or hydroalcoholic extracts, liquid or soft hydroalcoholic extracts, tincture, powder) are used for the relief of minor articular pain, exclusively based upon long-standing traditional use. Patients with known hypersensitivity to devil's claw root or active gastric/duodenal ulcer must not use these products. Additionally, in cases of gallstones, a physician should be consulted

prior to use of devil's claw root preparations. Undesirable effects include hypersensitivity, as well as adverse reactions of the central nervous system and gastrointestinal tract [11]. Harpagophyti radix contains bitter iridoid glycosides (harpagide and harpagoside), triterpenoids, polyphenolic acids, phenylethyl glycosides, and flavonoids [7]. Devil's claw root preparations exhibited antiinflammatory activity in vitro by decreasing production of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and PGE2 in LPS-stimulated human monocytes [12] and by reducing levels of matrix metalloproteinases (MMP-1, MMP-3, MMP-9) in IL-1β-stimulated human chondrocytes [13]. Aqueous extract of H. procumbens downregulated expression of COX-2 and iNOS in the mouse fibroblasts and, as a result, decreased PGE2 and NO generation [14]. Harpagoside, similarly to devil's

claw root extracts, suppressed expression of IL-6 and MMP-13 in human

chondrocytes, probably via the inhibition of transcription factor activator protein-1 (AP-1) activity [15]. Antiosteoarthritic properties of three devil's claw root preparations were the subject of four randomized controlled clinical trials. In two studies investigating Flexiloges® (ethanolic (60%) extract, DER 4.5–5.5:1, daily dose 960 mg), there was no improvement in pain scores. However, the pain-relieving activity of Arthrotabs® (aqueous extract, DER 1.5–2.5:1, daily dose 2400 mg) was noticed in another study. Finally, one study indicated that Harpadol® (cryoground powder, daily dose 2610 mg) was comparable to diacerhein in reducing pain [10]. Blackcurrant leaf (Ribis nigri folium) is a dried leaf of Ribes nigrum L. [4]. Phytochemical analysis showed that it contains polyphenolic compounds (flavonoids, proanthocyanidins, hydroxycinnamic acid derivatives) and traces of essential oil [6]. Blackcurrant leaf is used in traditional medicine to reduce minor articular pain [16]. Hydroalcoholic extract of this herbal drug exerted beneficial effects in carrageenan-induced acute inflammation, cotton pellet granuloma, and Freund's adjuvant-induced arthritis in rats. It also acted as an antinociceptive agent in the acetic acid-induced writhing test in mice [17]. Prodelphinidins (Ribis nigri folium constituents) stimulated synthesis of type II collagen and proteoglycans, and decreased the generation of PGE2 in human chondrocytes [18]. Documented antiinflammatory, analgesic, and anabolic effects give credence to reported folkloric use. Meadowsweet herb (Filipendulae ulmariae herba—whole or cut, dried flowering tops) and meadowsweet flower (Filipendulae ulmariae flos, syn. Spiraeae flos—dried flowers) are herbal drugs obtained from Filipendula ulmaria (L.) Maxim. (syn. Spiraea ulmaria L.), which are traditionally used in treatment of minor articular pain [4, 19–21]. They are characterized by high content of polyphenols, particularly flavonoids and ellagitannins. Phenolic glycosides and salicylic acid are also present [6, 22]. In vitro anti-inflammatory action of

clinical effect.

59

Conventional treatment of OA encompasses non-pharmacotherapeutic approach (e.g., physiotherapy, correction of malalignment, weight control, and patient education), pharmacotherapy, and surgery. Nonsteroidal anti-inflammatory drugs (NSAIDs) are medicines used most often for the relief of osteoarthritic symptoms. Although NSAIDs are relatively efficient, their prolonged use or their use in susceptible individuals can cause serious side effects such as gastrointestinal toxicity, cardiovascular events, edema development, reversible renal insufficiency, and modest increase of blood pressure. Topical formulations of NSAIDs are slightly less efficient than the oral ones, but their advantage lies in better safety profile. However, irritation of the skin often occurs at the application area [1].

Some patients experiencing unsatisfactory efficacy and side effects of conventional therapy try to overcome current treatment deficiencies by using modalities of complementary and alternative medicine. In that regard, herbal medicinal products (HMPs) and dietary supplements have become considerably popular for alleviation of OA symptoms [3]. Besides expected direct effects, important indirect benefit of their use may be the decrease of required doses of concomitantly administered conventional drugs, as this may result in reduced side effects. At present, available scientific data are insufficient to support the use of these products in clinical management of OA. The aim of this review is therefore to present current knowledge on herbal treatment options in the therapy of OA, i.e., active constituents of plants and mechanisms of their action relevant to OA, advice for patients using herbal products, and results of clinical trials, if available.

#### 2. Herbal medicinal products for oral use in the treatment of osteoarthritis

Willow bark (Salicis cortex) is whole or fragmented dried bark of young branches or whole dried pieces of current-year twigs of various species of genus Salix including S. purpurea L., S. daphnoides Vill., and S. fragilis L. [4]. Herbal teas (infusion and decoction), powder, dry aqueous extracts, liquid hydroalcoholic extract, and tincture of willow bark are traditionally used for minor articular pain relief. Duration of the treatment is restricted to 4 weeks. In the case of hypersensitivity (to the willow bark, salicylates, or the other NSAIDs), asthma due to hypersensitivity to salicylates, active peptic ulcer disease, third trimester of pregnancy, glucose-6-phosphate dehydrogenase deficiency, children and adolescents younger than 18 (risk of Reye's syndrome), severe liver or renal dysfunction and coagulation disorders, the use of Salicis cortex-based HMPs is contraindicated. Concomitant application of salicylates and other NSAIDs is not recommended, unless advised by the physician. Willow bark preparations may interact with anticoagulants. Their use is not recommended in the first and second trimester of pregnancy, as well as during lactation. Side effects include allergic reactions and gastrointestinal symptoms [5]. The main constituents of willow bark with respect to the pharmacological action are phenolic glycosides (e.g., salicin, salicortin, 2′-O-acetylsalicortin, and/or tremulacin) [6, 7] although the other secondary metabolites (e.g., polyphenolic compounds) may also participate in the total anti-inflammatory activity [8]. Phenolic glycosides are considered as prodrug compounds that are metabolized to salicylic acid in gastrointestinal tract and liver. Beneficial effect is a result of

Herbal Medicinal Products in the Treatment of Osteoarthritis DOI: http://dx.doi.org/10.5772/intechopen.80593

anabolic activity. This imbalance is promoted by pro-inflammatory cytokines, which stimulate chondrocytes to produce enzymes (collagenases and aggrecanases)

proteoglycans. Several mediators (e.g., TNF-α, IL-1β, NO, and PGE2) play an

Conventional treatment of OA encompasses non-pharmacotherapeutic approach (e.g., physiotherapy, correction of malalignment, weight control, and patient education), pharmacotherapy, and surgery. Nonsteroidal anti-inflammatory drugs (NSAIDs) are medicines used most often for the relief of osteoarthritic symptoms. Although NSAIDs are relatively efficient, their prolonged use or their use in susceptible individuals can cause serious side effects such as gastrointestinal toxicity, cardiovascular events, edema development, reversible renal insufficiency, and modest increase of blood pressure. Topical formulations of NSAIDs are slightly less efficient than the oral ones, but their advantage lies in better safety profile.

able to degrade extracellular matrix composed of collagen type II and

However, irritation of the skin often occurs at the application area [1].

2. Herbal medicinal products for oral use in the treatment of

Willow bark (Salicis cortex) is whole or fragmented dried bark of young branches or whole dried pieces of current-year twigs of various species of genus Salix including S. purpurea L., S. daphnoides Vill., and S. fragilis L. [4]. Herbal teas (infusion and decoction), powder, dry aqueous extracts, liquid hydroalcoholic extract, and tincture of willow bark are traditionally used for minor articular pain relief. Duration of the treatment is restricted to 4 weeks. In the case of hypersensitivity (to the willow bark, salicylates, or the other NSAIDs), asthma due to hypersensitivity to salicylates, active peptic ulcer disease, third trimester of pregnancy, glucose-6-phosphate dehydrogenase deficiency, children and adolescents younger than 18 (risk of Reye's syndrome), severe liver or renal dysfunction and coagulation disorders, the use of Salicis cortex-based HMPs is contraindicated. Concomitant application of salicylates and other NSAIDs is not recommended, unless advised by the physician. Willow bark preparations may interact with anticoagulants. Their use is not recommended in the first and second trimester of pregnancy, as well as during lactation. Side effects include allergic reactions and gastrointestinal symptoms [5]. The main constituents of willow bark with respect to the pharmacological action are phenolic glycosides (e.g., salicin, salicortin, 2′-O-acetylsalicortin, and/or tremulacin) [6, 7] although the other secondary metabolites (e.g., polyphenolic compounds) may also participate in the total anti-inflammatory activity [8]. Phenolic glycosides are considered as prodrug compounds that are metabolized to salicylic acid in gastrointestinal tract and liver. Beneficial effect is a result of

osteoarthritis

58

Some patients experiencing unsatisfactory efficacy and side effects of conventional therapy try to overcome current treatment deficiencies by using modalities of complementary and alternative medicine. In that regard, herbal medicinal products (HMPs) and dietary supplements have become considerably popular for alleviation of OA symptoms [3]. Besides expected direct effects, important indirect benefit of their use may be the decrease of required doses of concomitantly administered conventional drugs, as this may result in reduced side effects. At present, available scientific data are insufficient to support the use of these products in clinical management of OA. The aim of this review is therefore to present current knowledge on herbal treatment options in the therapy of OA, i.e., active constituents of plants and mechanisms of their action relevant to OA, advice for patients using herbal products, and results of clinical trials, if available.

important role in the pathogenesis and progression of OA [1, 2].

Osteoarthritis Biomarkers and Treatments

cyclooxygenase inhibition and diminished production of prostaglandins [9]. Two randomized controlled clinical trials provided low-quality evidence that short-term treatment with standardized willow bark extracts (daily doses corresponded to 240 mg of salicin) was not efficient in reduction of pain and improvement of physical function in patients with OA of hip and knee [3, 10]. Additional welldesigned sufficiently powered studies are needed in order to estimate willow bark clinical effect.

Devil's claw root (Harpagophyti radix) consists of cut and dried, tuberous secondary roots of Harpagophytum procumbens DC. and/or Harpagophytum zeyheri Decne. [4]. Herbal tea and liquid or solid dosage forms containing different devil's claw root preparations (e.g., dry aqueous or hydroalcoholic extracts, liquid or soft hydroalcoholic extracts, tincture, powder) are used for the relief of minor articular pain, exclusively based upon long-standing traditional use. Patients with known hypersensitivity to devil's claw root or active gastric/duodenal ulcer must not use these products. Additionally, in cases of gallstones, a physician should be consulted prior to use of devil's claw root preparations. Undesirable effects include hypersensitivity, as well as adverse reactions of the central nervous system and gastrointestinal tract [11]. Harpagophyti radix contains bitter iridoid glycosides (harpagide and harpagoside), triterpenoids, polyphenolic acids, phenylethyl glycosides, and flavonoids [7]. Devil's claw root preparations exhibited antiinflammatory activity in vitro by decreasing production of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and PGE2 in LPS-stimulated human monocytes [12] and by reducing levels of matrix metalloproteinases (MMP-1, MMP-3, MMP-9) in IL-1β-stimulated human chondrocytes [13]. Aqueous extract of H. procumbens downregulated expression of COX-2 and iNOS in the mouse fibroblasts and, as a result, decreased PGE2 and NO generation [14]. Harpagoside, similarly to devil's claw root extracts, suppressed expression of IL-6 and MMP-13 in human chondrocytes, probably via the inhibition of transcription factor activator protein-1 (AP-1) activity [15]. Antiosteoarthritic properties of three devil's claw root preparations were the subject of four randomized controlled clinical trials. In two studies investigating Flexiloges® (ethanolic (60%) extract, DER 4.5–5.5:1, daily dose 960 mg), there was no improvement in pain scores. However, the pain-relieving activity of Arthrotabs® (aqueous extract, DER 1.5–2.5:1, daily dose 2400 mg) was noticed in another study. Finally, one study indicated that Harpadol® (cryoground powder, daily dose 2610 mg) was comparable to diacerhein in reducing pain [10].

Blackcurrant leaf (Ribis nigri folium) is a dried leaf of Ribes nigrum L. [4]. Phytochemical analysis showed that it contains polyphenolic compounds (flavonoids, proanthocyanidins, hydroxycinnamic acid derivatives) and traces of essential oil [6]. Blackcurrant leaf is used in traditional medicine to reduce minor articular pain [16]. Hydroalcoholic extract of this herbal drug exerted beneficial effects in carrageenan-induced acute inflammation, cotton pellet granuloma, and Freund's adjuvant-induced arthritis in rats. It also acted as an antinociceptive agent in the acetic acid-induced writhing test in mice [17]. Prodelphinidins (Ribis nigri folium constituents) stimulated synthesis of type II collagen and proteoglycans, and decreased the generation of PGE2 in human chondrocytes [18]. Documented antiinflammatory, analgesic, and anabolic effects give credence to reported folkloric use.

Meadowsweet herb (Filipendulae ulmariae herba—whole or cut, dried flowering tops) and meadowsweet flower (Filipendulae ulmariae flos, syn. Spiraeae flos—dried flowers) are herbal drugs obtained from Filipendula ulmaria (L.) Maxim. (syn. Spiraea ulmaria L.), which are traditionally used in treatment of minor articular pain [4, 19–21]. They are characterized by high content of polyphenols, particularly flavonoids and ellagitannins. Phenolic glycosides and salicylic acid are also present [6, 22]. In vitro anti-inflammatory action of

meadowsweet preparations was mediated by inhibition of complement activation, reduction of the production of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) and, to a certain degree, inhibition of cyclooxygenase and PGE2 generation [6, 23, 24]. In animal model of carrageenan-induced acute inflammation, lyophilized flower infusion of F. ulmaria exerted analgesic activity [25]. There is no literature data related to clinical effects of meadowsweet in OA.

that it significantly improved joint structure. There is limited evidence that it

which is used in the treatment of OA [35]. To assure optimal absorption, it is

It contains pentacyclic triterpenic acids, i.e., β-boswellic acid (BA), 11-ketoβ-boswellic acid (KBA), and acetyl-11-keto-β-boswellic acid (AKBA) [35]. These secondary metabolites could be responsible for the therapeutic activity, particularly BA that reaches relatively high concentration in the human plasma. BA, KBA, and AKBA acted as inhibitors of mPGES-1 and, hence, PGE2 synthesis. They reduced the activity of cathepsin G [36], a serine protease whose relevance in OA has been suggested in a recent study [37]. The suppressing effect of AKBA on production of TNF-α in monocytes was also reported [36]. Crude Boswellia serrata extract

mononuclear cells [38]. Results of investigations using animal models of inflammation and arthritis (e.g., adjuvant arthritis in Lewis rats, formaldehydeinduced arthritis in rats, dextran-induced edema in rats, and carrageenan-induced

edema in rats and mice) are in accordance with the in vitro observed antiinflammatory activity [36]. Two randomized placebo-controlled clinical trials conducted with Indian frankincense proprietary product 5-Loxin® (standardized to contain at least 30% AKBA) indicated that oral application of this enriched extract in a daily dose of 100 mg decreased pain and improved function in OA patients (n = 85) after 90 days treatment. The results of studies examining proprietary product Aflapin® (enriched with non-volatile oil and standardized to contain at least 20% AKBA) are consistent. New studies may change the estimations [10]. Concentration of MMP-3 in synovial fluid of patients using 5-Loxin® decreased, suggesting that therapeutic activity could be linked to the attenuation of cartilage destruction [39]. Pycnogenol® is standardized bark extract of French maritime pine (Pinus pinaster Aiton) rich in polyphenolic compounds (procyanidins, taxifolin, catechin, and phenolic acids) [40]. Pharmacokinetic studies demonstrated that certain antiinflammatory constituents of Pycnogenol® (ferulic acid and caffeic acid) and procyanidins gut microbiota metabolite δ-(3,4-dihydroxy-phenyl)-γ-valerolactone

were able to reach synovial fluid [40, 41]. δ-(3,4-Dihydroxy-phenyl)-γvalerolactone concentration-dependently reduced nitrite production and iNOS expression. Its affinity to accumulate in macrophages, monocytes, and endothelial cells were demonstrated [42]. Investigation conducted in patients with severe OA showed that expression of matrix metalloproteinases (MMP-3 and MMP-13) and IL-1β in chondrocytes was decreased after intake of Pycnogenol®, as well as level of ADAMTS-5 in serum [43]. Plasma obtained from volunteers taking Pycnogenol® orally for 5 days decreased activation of transcription factor NF-κB in macrophages and inhibited COX-1 and COX-2 [44, 45]. Additionally, gene expression of COX-2 and 5-LOX, leukotriene biosynthesis, and phospholipase A2 activity in polymorphonuclear leukocytes (isolated from the blood of volunteers) were reduced [46]. Moderate-quality evidence obtained from three randomized controlled clinical trials indicated that Pycnogenol® (daily doses 100 or 150 mg) decreased pain and improved physical function in patients with OA of knee and that it probably reduced consumption of NSAIDs. The effect size after three-month treatment was estimated to be large and clinically important. However, quality of evidence is insufficient to make any firm conclusion. It should be noted that the content of marker compound (procyanidins) differed in the investigated products [3, 10].

61

Indian frankincense (Olibanum indicum) is an air-dried gum-resin exudate, obtained by incision of the stem or branches of Boswellia serrata Roxb. ex Colebr. [4],

recommended to use Indian frankincense preparations with food. Cases of neutropenia were documented after long-term use of dry extract in a daily dose of up to 10 g.

downregulated inflammatory cytokines (TNF-α, IL-1β, and IL-6) in peripheral blood

prevented joint space narrowing [10].

DOI: http://dx.doi.org/10.5772/intechopen.80593

Herbal Medicinal Products in the Treatment of Osteoarthritis

Nettle leaf (Urticae folium) is whole or a cut dried leaf of Urtica dioica L., Urtica urens L., or their mixture [4], whereas nettle herb (Urticae herba) is dried cut or fragmented aerial part of Urtica dioica L., Urtica urens L., their hybrids or mixtures, collected or harvested during the flowering period [26]. Both herbal drugs are employed in folkloric medicine for alleviation of minor articular pain. Side effects include gastrointestinal and allergic reactions [26, 27]. Constituents of nettle leaf and/ or herb are caffeic acid esters, flavonoids, minerals, free amino acids, etc. [6]. Reputed benefit of nettle preparations in the treatment of OA complaints is supported by experimental findings that they suppressed activation of transcription factor NF-κB and inhibited IL-1β-stimulated production of MMP-1, MMP-3, and MMP-9 in human chondrocytes [28, 29]. Furthermore, oral intake of nettle leaf extract by healthy volunteers, during a three-week period, reduced production of pro-inflammatory cytokines (TNF-α, IL-1β) in whole blood ex vivo after LPS challenge [30].

Ash leaf (Fraxini folium) is by definition a dried leaf of Fraxinus excelsior L. or Fraxinus angustifolia Vahl (syn. Fraxinus oxyphylla M. Bieb), or of hybrids of these two species or of a mixture [4]. It is employed in ethnomedicine as herbal tea (infusion or decoction) to reduce minor articular pain [31]. Constituents occurring in ash leaf are coumarins, iridoids, secoiridoids, flavonoids, lignans, simple phenolic compounds, etc. [32]. Evidence from pharmacological studies that could explain recorded traditional use is scarce. Certain support was provided by experimental observation that esculin, a coumarin present in both species, decreased NO production in macrophages by inhibition of transcription factor NF-κB activation. Additionally, esculin was able to suppress inflammatory response (reduce levels of TNF-α and IL-6) induced by injecting LPS to mice [33].

Mixture of avocado and soybean unsaponifiables. Antiosteoarthritic properties of a mixture of avocado and soybean unsaponifiables (ASU) were extensively examined in the past. Phytochemical analysis of its composition revealed the presence of phytosterols (β-sitosterol, campesterol, and stigmasterol), fat-soluble vitamins, triterpene alcohols, and possibly furan fatty acids. Experimental studies provided significant evidence of ASU anabolic and anticatabolic action in cartilage. ASU stimulated the synthesis of extracellular matrix components (collagen and aggrecan) and inhibited production of pro-inflammatory molecules (TNF-α, IL-1β, IL-6, IL-8, MIP-1β, NO, and PGE2) probably by interfering with signaling of transcription factor NF-κB. Cartilage degradation may be decreased as a result of ASU ability to inhibit matrix metalloproteinases (MMP-2, MMP-3, and MMP-13) and stimulate expression of tissue inhibitor of metalloproteinases-1. Beneficial activity may also be related to the capacity of ASU to affect levels of transforming growth factor-β and vascular endothelial growth factor [34]. Four randomized controlled clinical studies recruiting 651 participants provided moderate-quality evidence that ASU proprietary product Piascledine® (mixture of unsaponifiable fractions of fatty oils of Persea gratissima (P) and Glycine max (G), 1/3 P + 2/3 G; daily dose 300 mg) generated small improvement in osteoarthritic symptoms with questionable clinical significance, after a treatment lasting 3–12 months. Adverse events of herbal intervention were not probably increased compared to the placebo group. Moderate-quality evidence showed that Piascledine® in higher daily dose (600 mg) also reduced OA symptoms. Available data did not support assumption

#### Herbal Medicinal Products in the Treatment of Osteoarthritis DOI: http://dx.doi.org/10.5772/intechopen.80593

meadowsweet preparations was mediated by inhibition of complement activation, reduction of the production of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) and, to a certain degree, inhibition of cyclooxygenase and PGE2 generation [6, 23, 24]. In animal model of carrageenan-induced acute inflammation, lyophilized flower infusion of F. ulmaria exerted analgesic activity [25]. There is no literature

Nettle leaf (Urticae folium) is whole or a cut dried leaf of Urtica dioica L., Urtica

Ash leaf (Fraxini folium) is by definition a dried leaf of Fraxinus excelsior L. or Fraxinus angustifolia Vahl (syn. Fraxinus oxyphylla M. Bieb), or of hybrids of these two species or of a mixture [4]. It is employed in ethnomedicine as herbal tea (infusion or decoction) to reduce minor articular pain [31]. Constituents occurring in ash leaf are coumarins, iridoids, secoiridoids, flavonoids, lignans, simple phenolic compounds, etc. [32]. Evidence from pharmacological studies that could explain recorded traditional use is scarce. Certain support was provided by experimental observation that esculin, a coumarin present in both species, decreased NO production in macrophages by inhibition of transcription factor NF-κB activation. Additionally, esculin was able to suppress inflammatory response (reduce levels of

Mixture of avocado and soybean unsaponifiables. Antiosteoarthritic properties of a mixture of avocado and soybean unsaponifiables (ASU) were extensively examined in the past. Phytochemical analysis of its composition revealed the presence of phytosterols (β-sitosterol, campesterol, and stigmasterol), fat-soluble vitamins, triterpene alcohols, and possibly furan fatty acids. Experimental studies provided significant evidence of ASU anabolic and anticatabolic action in cartilage. ASU stimulated the synthesis of extracellular matrix components (collagen and aggrecan) and inhibited production of pro-inflammatory molecules (TNF-α, IL-1β, IL-6, IL-8, MIP-1β, NO, and PGE2) probably by interfering with signaling of transcription factor NF-κB. Cartilage degradation may be decreased as a result of ASU ability to inhibit matrix metalloproteinases (MMP-2, MMP-3, and MMP-13) and stimulate expression of tissue inhibitor of metalloproteinases-1. Beneficial activity may also be related to the capacity of ASU to affect levels of transforming growth factor-β and vascular endothelial growth factor [34]. Four randomized controlled clinical studies recruiting 651 participants provided moderate-quality evidence that ASU proprietary product Piascledine® (mixture of unsaponifiable fractions of fatty oils of Persea gratissima (P) and Glycine max (G), 1/3 P + 2/3 G; daily dose 300 mg) generated small improvement in osteoarthritic symptoms with questionable clinical significance, after a treatment lasting 3–12 months. Adverse events of herbal intervention were not probably increased compared to the placebo group. Moderate-quality evidence showed that Piascledine® in higher daily dose (600 mg) also reduced OA symptoms. Available data did not support assumption

urens L., or their mixture [4], whereas nettle herb (Urticae herba) is dried cut or fragmented aerial part of Urtica dioica L., Urtica urens L., their hybrids or mixtures, collected or harvested during the flowering period [26]. Both herbal drugs are employed in folkloric medicine for alleviation of minor articular pain. Side effects include gastrointestinal and allergic reactions [26, 27]. Constituents of nettle leaf and/ or herb are caffeic acid esters, flavonoids, minerals, free amino acids, etc. [6]. Reputed benefit of nettle preparations in the treatment of OA complaints is supported by experimental findings that they suppressed activation of transcription factor NF-κB and inhibited IL-1β-stimulated production of MMP-1, MMP-3, and MMP-9 in human chondrocytes [28, 29]. Furthermore, oral intake of nettle leaf extract by healthy volunteers, during a three-week period, reduced production of pro-inflammatory

cytokines (TNF-α, IL-1β) in whole blood ex vivo after LPS challenge [30].

TNF-α and IL-6) induced by injecting LPS to mice [33].

60

data related to clinical effects of meadowsweet in OA.

Osteoarthritis Biomarkers and Treatments

that it significantly improved joint structure. There is limited evidence that it prevented joint space narrowing [10].

Indian frankincense (Olibanum indicum) is an air-dried gum-resin exudate, obtained by incision of the stem or branches of Boswellia serrata Roxb. ex Colebr. [4], which is used in the treatment of OA [35]. To assure optimal absorption, it is recommended to use Indian frankincense preparations with food. Cases of neutropenia were documented after long-term use of dry extract in a daily dose of up to 10 g. It contains pentacyclic triterpenic acids, i.e., β-boswellic acid (BA), 11-ketoβ-boswellic acid (KBA), and acetyl-11-keto-β-boswellic acid (AKBA) [35]. These secondary metabolites could be responsible for the therapeutic activity, particularly BA that reaches relatively high concentration in the human plasma. BA, KBA, and AKBA acted as inhibitors of mPGES-1 and, hence, PGE2 synthesis. They reduced the activity of cathepsin G [36], a serine protease whose relevance in OA has been suggested in a recent study [37]. The suppressing effect of AKBA on production of TNF-α in monocytes was also reported [36]. Crude Boswellia serrata extract downregulated inflammatory cytokines (TNF-α, IL-1β, and IL-6) in peripheral blood mononuclear cells [38]. Results of investigations using animal models of inflammation and arthritis (e.g., adjuvant arthritis in Lewis rats, formaldehydeinduced arthritis in rats, dextran-induced edema in rats, and carrageenan-induced edema in rats and mice) are in accordance with the in vitro observed antiinflammatory activity [36]. Two randomized placebo-controlled clinical trials conducted with Indian frankincense proprietary product 5-Loxin® (standardized to contain at least 30% AKBA) indicated that oral application of this enriched extract in a daily dose of 100 mg decreased pain and improved function in OA patients (n = 85) after 90 days treatment. The results of studies examining proprietary product Aflapin® (enriched with non-volatile oil and standardized to contain at least 20% AKBA) are consistent. New studies may change the estimations [10]. Concentration of MMP-3 in synovial fluid of patients using 5-Loxin® decreased, suggesting that therapeutic activity could be linked to the attenuation of cartilage destruction [39].

Pycnogenol® is standardized bark extract of French maritime pine (Pinus pinaster Aiton) rich in polyphenolic compounds (procyanidins, taxifolin, catechin, and phenolic acids) [40]. Pharmacokinetic studies demonstrated that certain antiinflammatory constituents of Pycnogenol® (ferulic acid and caffeic acid) and procyanidins gut microbiota metabolite δ-(3,4-dihydroxy-phenyl)-γ-valerolactone were able to reach synovial fluid [40, 41]. δ-(3,4-Dihydroxy-phenyl)-γvalerolactone concentration-dependently reduced nitrite production and iNOS expression. Its affinity to accumulate in macrophages, monocytes, and endothelial cells were demonstrated [42]. Investigation conducted in patients with severe OA showed that expression of matrix metalloproteinases (MMP-3 and MMP-13) and IL-1β in chondrocytes was decreased after intake of Pycnogenol®, as well as level of ADAMTS-5 in serum [43]. Plasma obtained from volunteers taking Pycnogenol® orally for 5 days decreased activation of transcription factor NF-κB in macrophages and inhibited COX-1 and COX-2 [44, 45]. Additionally, gene expression of COX-2 and 5-LOX, leukotriene biosynthesis, and phospholipase A2 activity in polymorphonuclear leukocytes (isolated from the blood of volunteers) were reduced [46]. Moderate-quality evidence obtained from three randomized controlled clinical trials indicated that Pycnogenol® (daily doses 100 or 150 mg) decreased pain and improved physical function in patients with OA of knee and that it probably reduced consumption of NSAIDs. The effect size after three-month treatment was estimated to be large and clinically important. However, quality of evidence is insufficient to make any firm conclusion. It should be noted that the content of marker compound (procyanidins) differed in the investigated products [3, 10].

Rosehip (Rosae pseudofructus cum fructibus) is obtained from Rosa canina L. It represents pseudofruit, composed of achenes enclosed in a fleshy receptacle or hypanthium. Phytochemical investigations revealed that rosehip contains sugars, organic acids, pectins, procyanidins, catechins, flavonoids, carotenoids, triterpene acids, unsaturated fatty acids, and a galactolipid [7, 35]. R. canina hip preparations inhibited activation of transcription factor NF-κB, decreased expression of matrix metalloproteinases (MMP-1, MMP-3, MMP-9, and MMP-13) in chondrocytes, suppressed expression of COX-2 in human monocytes and chondrocytes, decreased generation of PGE2 and NO in murine macrophages, and reduced levels of proinflammatory cytokines (IL-1β, TNF-α, and IL-6) and chemokine CCL5 in various assays. Dried powder of R. canina hips given to animals during 3 weeks exerted activity in rat arthritis model (monoiodoacetate-induced) and suppressed production of MMP-3 and MMP-13. Rosehip preparations also displayed activity in animal models of acute inflammation [47]. Active constituents belong to different groups of compounds; e.g., galactolipid was able to modulate chemokines (CCL5 and IL-8), matrix metalloproteinases (MMP-1, MMP-3, and MMP-13) and aggrecanase ADAMTS-4 expression, whereas fatty acids (linoleic and linolenic) inhibited cyclooxygenases [47, 48]. It seems that reputed antirheumatic effect of rosehip is a sum of actions of several individual constituents. Data obtained from three clinical trials examining effects of rosehip powder provided modest and somewhat conflicting evidence that orally administered product (daily dose 5 g) is superior to placebo in the treatment of osteoarthritic pain [10].

tasting phenolic compounds (gingerols, gingerdiols, gingerdiones, dihydrogingerdiones, and shogaols) [7]. In a recent in vitro study, it has been shown that ginger extract was able to attenuate oxidative stress and reduce succeeding cell death of chondrocytes resulting from a mitochondrial apoptosis [56]. Ginger preparations also inhibited LPS-induced PGE2 formation in U937 cells and decreased levels of TNF-α and IL-1β in murine peritoneal macrophages [57]. In vivo, they suppressed carrageenan- and fresh egg albumin-induced edema in rats and exhibited analgesic action in models of chemically and thermally induced pain in mice [58, 59]. Ginger essential oil reduced acetic acid-induced writhing response in animals [57]. Intraperitoneally administered 6-gingerol exhibited analgesic and anti-inflammatory action, i.e., decreased formalin-induced licking time in late phase and suppressed carrageenan-induced edema and acetic acid-induced writing response [60]. In vitro assay showed considerable potential of 6-gingerol to inhibit prostaglandin biosynthesis [61]. Therapeutic effect of ginger in patients with OA was investigated in two randomized controlled cross-over clinical studies. In one trial, ibuprofen treatment was reported to be more effective than acetone extract of ginger root (DER 20:1, daily dose 510 mg) in terms of pain reduction and consumption of NSAIDs. Available data did not allow reanalysis. Another trial showed that CO2 extract of ginger root (daily dose: 1000 mg of extract, 40 mg of gingerol) significantly differed from placebo after a six-month study [10]. Although clinical trials investigating ginger were performed, its clinical benefit at this moment cannot be

Herbal Medicinal Products in the Treatment of Osteoarthritis

DOI: http://dx.doi.org/10.5772/intechopen.80593

Cat's claw (Uncaria tomentosa and U. guianensis), South American vines that share the same common name, are used traditionally to treat inflammatory conditions (e.g., arthritis) [62]. Active constituents of these medicinal plants are considered to be oxindole alkaloids (isorhynchophylline, rhynchophylline and their N-oxides, mitraphylline) and the quinovic acid glycosides [63]. According to the monograph of the World Health Organization, cat's claw bark (Uncariae cortex) consists of the dried stem bark of Uncaria tomentosa (Willd.) DC. (Rubiaceae) [64]. In vitro studies in murine macrophages showed that U. tomentosa and U. guianensis preparations suppressed TNF-α and PGE2 formation [62] and that aqueous bark extract of U. tomentosa inhibited activation of transcription factor NF-κB [65]. The observed anti-inflammatory activity was further supported by in vivo experiments. U. tomentosa bark extracts (spray-dried hydroalcoholic and aqueous freeze-dried) suppressed carrageenan-induced paw edema in mice [66]. Using in vivo model of acute inflammation, fractions of U. tomentosa bark extract yielded quinovic acid glycoside as one of pharmacologically active compounds [67]. Mitraphylline, pentacyclic oxindole alkaloid, decreased blood levels of pro-inflammatory cytokines

(IL-1β and TNF-α) in the LPS-challenged mice [68]. Double-blind placebo-

could exert immunostimulatory action; therefore, patients under risk of

controlled study in 45 patients within 4 weeks compared pain-relieving property of freeze-dried aqueous extract of U. guianensis bark (daily dose 100 mg) to placebo. A significant decrease in activity-related OA knee pain occurred in a group receiving U. guianensis preparation in the first week of trial. On the other hand, U. guianensis preparation did not reduce the pain at rest or at night. Serious side effects were not observed [62]. Clinical data were insufficiently reported for reanalysis [10]. Preclinical studies suggested that U. tomentosa (especially pentacyclic chemotype)

transplanted organ rejection should be advised not to use cat's claw products [63]. Bromelain is a mixture of proteolytic enzymes obtained from the fruit and stem

of pineapple (Ananas comosus L.) and other species of Bromeliaceae family [7]. Experimental evidence suggests that bromelain anti-inflammatory properties may be mediated by its ability to decrease levels of bradykinin and PGE2 and to modulate cell surface adhesion molecule implicated in arthritis. Investigations in animals

assessed with confidence.

63

Turmeric rhizome (Curcumae longae rhizoma) consists of whole, peeled, shortly boiled or steamed and dried rhizome of Curcuma longa L. (syn. C. domestica Valeton) [4]. Characteristic constituents are curcuminoids (phenolic diarylheptanoids), essential oil rich in turmerones (sesquiterpene ketones), and polysaccharides. It is popular in Ayurveda and Chinese medicine as an antiinflammatory agent [7]. Curcumin in vitro prevented the apoptosis of chondrocytes and decreased the production of matrix metalloproteinases and monocyte chemoattractant protein. It also suppressed expression of pro-inflammatory cytokines, cyclooxygenase, and PGE2 in chondrocytes. These effects were probably mediated by inhibition of IkB phosphorylation and thus transcription factor NF-κB activation. Regulation of AP-1 and protein kinase C was described as well. In vivo curcumin suppressed carrageenan-induced edema and formaldehyde-induced arthritis [49, 50]. Meta-analyses of randomized controlled trials indicated that curcumin was able to decrease circulating levels of pro-inflammatory cytokines TNF-α and IL-6 [51, 52]. Curcuminoids and Curcuma longa extract decreased oxidative stress in patients with OA, which suggested that antioxidant activity participated in turmeric beneficial action [53, 54]. A four-week multicenter randomized double-blind controlled clinical study showed that ethanol extract of turmeric rhizome (daily dose 1500 mg, 75–85% curcuminoids) was not inferior compared to ibuprofen (daily dose 1200 mg) in the management of knee OA. The number of side effects was similar in both groups, but incidence of gastrointestinal side effects was significantly higher in patients treated with ibuprofen [55]. Authors of a systematic review and meta-analysis concluded that a short-term treatment with curcumin and extract of Curcuma longa produced significant and clinically meaningful reduction of pain and improvement of physical function in patients with OA of knee. The quality of evidence was estimated to be very low to moderate. Characteristics of available studies limit possibility to make firm conclusion on the efficacy of turmeric rhizome preparations [3].

Ginger (Zingiberis rhizoma) is dried, whole or cut rhizome of Zingiber officinale Roscoe, with the cork removed, either completely or from wide, flat surfaces only [4]. It is characterized by the presence of essential oil and a mixture of pungent

#### Herbal Medicinal Products in the Treatment of Osteoarthritis DOI: http://dx.doi.org/10.5772/intechopen.80593

Rosehip (Rosae pseudofructus cum fructibus) is obtained from Rosa canina L. It

represents pseudofruit, composed of achenes enclosed in a fleshy receptacle or hypanthium. Phytochemical investigations revealed that rosehip contains sugars, organic acids, pectins, procyanidins, catechins, flavonoids, carotenoids, triterpene acids, unsaturated fatty acids, and a galactolipid [7, 35]. R. canina hip preparations inhibited activation of transcription factor NF-κB, decreased expression of matrix metalloproteinases (MMP-1, MMP-3, MMP-9, and MMP-13) in chondrocytes, suppressed expression of COX-2 in human monocytes and chondrocytes, decreased generation of PGE2 and NO in murine macrophages, and reduced levels of proinflammatory cytokines (IL-1β, TNF-α, and IL-6) and chemokine CCL5 in various assays. Dried powder of R. canina hips given to animals during 3 weeks exerted activity in rat arthritis model (monoiodoacetate-induced) and suppressed production of MMP-3 and MMP-13. Rosehip preparations also displayed activity in animal models of acute inflammation [47]. Active constituents belong to different groups of compounds; e.g., galactolipid was able to modulate chemokines (CCL5 and IL-8), matrix metalloproteinases (MMP-1, MMP-3, and MMP-13) and aggrecanase ADAMTS-4 expression, whereas fatty acids (linoleic and linolenic) inhibited cyclooxygenases [47, 48]. It seems that reputed antirheumatic effect of rosehip is a sum of actions of several individual constituents. Data obtained from three clinical trials examining effects of rosehip powder provided modest and somewhat conflicting evidence that orally administered product (daily dose 5 g) is superior

Turmeric rhizome (Curcumae longae rhizoma) consists of whole, peeled, shortly boiled or steamed and dried rhizome of Curcuma longa L. (syn. C. domestica

diarylheptanoids), essential oil rich in turmerones (sesquiterpene ketones), and polysaccharides. It is popular in Ayurveda and Chinese medicine as an anti-

and decreased the production of matrix metalloproteinases and monocyte

inflammatory agent [7]. Curcumin in vitro prevented the apoptosis of chondrocytes

chemoattractant protein. It also suppressed expression of pro-inflammatory cytokines, cyclooxygenase, and PGE2 in chondrocytes. These effects were probably mediated by inhibition of IkB phosphorylation and thus transcription factor NF-κB activation. Regulation of AP-1 and protein kinase C was described as well. In vivo curcumin suppressed carrageenan-induced edema and formaldehyde-induced arthritis [49, 50]. Meta-analyses of randomized controlled trials indicated that curcumin was able to decrease circulating levels of pro-inflammatory cytokines TNF-α and IL-6 [51, 52]. Curcuminoids and Curcuma longa extract decreased oxidative stress in patients with OA, which suggested that antioxidant activity participated in turmeric beneficial action [53, 54]. A four-week multicenter randomized double-blind controlled clinical study showed that ethanol extract of turmeric rhizome (daily dose 1500 mg, 75–85% curcuminoids) was not inferior compared to ibuprofen (daily dose 1200 mg) in the management of knee OA. The number of side effects was similar in both groups, but incidence of gastrointestinal side effects was significantly higher in patients treated with ibuprofen [55]. Authors of a systematic review and meta-analysis concluded that a short-term treatment with curcumin and extract of Curcuma longa produced significant and clinically meaningful reduction of pain and improvement of physical function in patients with OA of knee. The quality of evidence was estimated to be very low to moderate. Characteristics of available studies limit possibility to make firm conclusion on the efficacy of tur-

Ginger (Zingiberis rhizoma) is dried, whole or cut rhizome of Zingiber officinale Roscoe, with the cork removed, either completely or from wide, flat surfaces only [4]. It is characterized by the presence of essential oil and a mixture of pungent

Valeton) [4]. Characteristic constituents are curcuminoids (phenolic

to placebo in the treatment of osteoarthritic pain [10].

Osteoarthritis Biomarkers and Treatments

meric rhizome preparations [3].

62

tasting phenolic compounds (gingerols, gingerdiols, gingerdiones, dihydrogingerdiones, and shogaols) [7]. In a recent in vitro study, it has been shown that ginger extract was able to attenuate oxidative stress and reduce succeeding cell death of chondrocytes resulting from a mitochondrial apoptosis [56]. Ginger preparations also inhibited LPS-induced PGE2 formation in U937 cells and decreased levels of TNF-α and IL-1β in murine peritoneal macrophages [57]. In vivo, they suppressed carrageenan- and fresh egg albumin-induced edema in rats and exhibited analgesic action in models of chemically and thermally induced pain in mice [58, 59]. Ginger essential oil reduced acetic acid-induced writhing response in animals [57]. Intraperitoneally administered 6-gingerol exhibited analgesic and anti-inflammatory action, i.e., decreased formalin-induced licking time in late phase and suppressed carrageenan-induced edema and acetic acid-induced writing response [60]. In vitro assay showed considerable potential of 6-gingerol to inhibit prostaglandin biosynthesis [61]. Therapeutic effect of ginger in patients with OA was investigated in two randomized controlled cross-over clinical studies. In one trial, ibuprofen treatment was reported to be more effective than acetone extract of ginger root (DER 20:1, daily dose 510 mg) in terms of pain reduction and consumption of NSAIDs. Available data did not allow reanalysis. Another trial showed that CO2 extract of ginger root (daily dose: 1000 mg of extract, 40 mg of gingerol) significantly differed from placebo after a six-month study [10]. Although clinical trials investigating ginger were performed, its clinical benefit at this moment cannot be assessed with confidence.

Cat's claw (Uncaria tomentosa and U. guianensis), South American vines that share the same common name, are used traditionally to treat inflammatory conditions (e.g., arthritis) [62]. Active constituents of these medicinal plants are considered to be oxindole alkaloids (isorhynchophylline, rhynchophylline and their N-oxides, mitraphylline) and the quinovic acid glycosides [63]. According to the monograph of the World Health Organization, cat's claw bark (Uncariae cortex) consists of the dried stem bark of Uncaria tomentosa (Willd.) DC. (Rubiaceae) [64]. In vitro studies in murine macrophages showed that U. tomentosa and U. guianensis preparations suppressed TNF-α and PGE2 formation [62] and that aqueous bark extract of U. tomentosa inhibited activation of transcription factor NF-κB [65]. The observed anti-inflammatory activity was further supported by in vivo experiments. U. tomentosa bark extracts (spray-dried hydroalcoholic and aqueous freeze-dried) suppressed carrageenan-induced paw edema in mice [66]. Using in vivo model of acute inflammation, fractions of U. tomentosa bark extract yielded quinovic acid glycoside as one of pharmacologically active compounds [67]. Mitraphylline, pentacyclic oxindole alkaloid, decreased blood levels of pro-inflammatory cytokines (IL-1β and TNF-α) in the LPS-challenged mice [68]. Double-blind placebocontrolled study in 45 patients within 4 weeks compared pain-relieving property of freeze-dried aqueous extract of U. guianensis bark (daily dose 100 mg) to placebo. A significant decrease in activity-related OA knee pain occurred in a group receiving U. guianensis preparation in the first week of trial. On the other hand, U. guianensis preparation did not reduce the pain at rest or at night. Serious side effects were not observed [62]. Clinical data were insufficiently reported for reanalysis [10]. Preclinical studies suggested that U. tomentosa (especially pentacyclic chemotype) could exert immunostimulatory action; therefore, patients under risk of transplanted organ rejection should be advised not to use cat's claw products [63].

Bromelain is a mixture of proteolytic enzymes obtained from the fruit and stem of pineapple (Ananas comosus L.) and other species of Bromeliaceae family [7]. Experimental evidence suggests that bromelain anti-inflammatory properties may be mediated by its ability to decrease levels of bradykinin and PGE2 and to modulate cell surface adhesion molecule implicated in arthritis. Investigations in animals

confirmed that bromelain acted as an analgesic agent [69]. Anti-osteoarthritic property of orally administered bromelain (daily dose 500 mg) was compared with therapeutic activity of diclofenac (daily dose 100 mg) in a randomized single-blind active-controlled pilot study in 40 patients with mild-to-moderate knee OA. After a four-week treatment, there was no difference in symptoms relief between bromelain-treated and diclofenac-treated groups [70]. Bromelain (800 mg/day) was also compared with placebo in a randomized double-blind three-month long pilot study that included patients with moderate-to-severe OA of knee. The authors suggested that bromelain was not efficacious as an adjunctive treatment, but, due to the trial limitations, proposed that new studies should be performed [71]. Recent systematic review of clinical trials, examining dietary supplements used in the management of OA, has shown that the short-term treatment with bromelain was not effective in alleviation of pain and function improvement. Evidence quality was low [3].

Arnica flower (Arnicae flos) is, whole or partially broken, dried flower-head of

Arnica montana L. [4]. This herbal drug is employed traditionally for relief of bruises, sprains, and localized muscular pain. Semisolid and liquid dosage forms based on arnica preparations (tinctures or ethanolic liquid extract) are applied cutaneously. The use of arnica HMPs is contraindicated in patients with known hypersensitivity to arnica and other plants belonging to Asteraceae family. They should not be applied on broken skin. Reported side effects include allergic skin reactions [76]. Main constituents of arnica flower-heads are pseudoguianolide-type sesquiterpene lactones helenalin and 11α,13-dihydrohelenalin [7]. Contribution of these secondary metabolites to the anti-inflammatory effect is likely as it was shown that helenalin and 11α,13-dihydrohelenalin had the ability to interfere with the activation of transcription factor NF-κB [77]. In vitro experiments conducted on the pig skin indicated that sesquiterpene lactones can penetrate into it, and thus further support this assumption [78, 79]. Better permeation through stratum corneum (the outermost layer of the skin) was achieved when sesquiterpene lactones were applied in the form of arnica tinctures than as pure compounds [78]. Arnica flower preparations at low concentration/s were able to reduce levels of pro-inflammatory cytokines (IL-1 and TNF-α) in human mononuclear cells and of mRNA of matrix

Herbal Medicinal Products in the Treatment of Osteoarthritis

DOI: http://dx.doi.org/10.5772/intechopen.80593

metalloproteinases (MMP-1 and MMP-13) in human and bovine articular chondrocytes [80, 81]. Whole plant methanolic extract suppressed expression of iNOS and COX-2 in LPS-stimulated murine macrophages [82]. Presented literature data may help to rationalize the use of arnica in management of diseases with underlying inflammation. Moderate evidence from a single, double-blind randomized controlled clinical trial showed that topical application of arnica gel (A. Vogel Arnica Gel®, 50 g herbal tincture/100 g gel, extraction solvent 50% ethanol, and DER 1:20) three times per day probably decreased pain and improved function related to hand OA as ibuprofen gel (5%), with a similar number of

Rosemary leaf (Rosmarini folium) is whole, dried leaf of Rosmarinus officinalis

L. [4]. Its chemistry is characterized by the presence of essential oil, phenolic diterpenes (e.g., carnosol, carnosolic acid, and rosmanol), hydroxycinnamic derivatives, flavonoids, and triterpenoids [6]. Rosemary leaf bath additive is applied as an adjuvant to relieve minor muscular and articular pain, exclusively based upon long-standing traditional use [84]. Several rosemary compounds exhibited antiinflammatory action in vitro. Rosmarinic acid decreased levels of PGE2 and NO in rat chondrocytes [85]. Phenolic diterpene carnosol decreased concentrations of PGE2 and NO, and reduced gene expression of iNOS, IL-1α, IL-6, and CCL5 in LPSstimulated macrophages. In addition, it interfered with transcription factor NF-κB

activation and influenced expression of anabolic and catabolic genes in chondrosarcoma cell line SW1353 and in primary human chondrocytes [86]. Comfrey root (Symphyti radix) is obtained from Symphytum officinale L., a traditional medicinal plant that can be found throughout Europe, parts of Asia, and as a naturalized plant in North America. It contains allantoin, mucilage polysaccharides, phenolic acids (e.g., rosmarinic acid), glycopeptides, amino acids, triterpene saponins, and pyrrolizidine alkaloids with 1,2-unsaturated necine ring structures. Identity of active principles is not sufficiently known although it is assumed that allantoin and rosmarinic acid play an important role in biological activity [87]. Taking into account considerable hepatotoxic and carcinogenic potential of pyrrolizidine alkaloids, their content in comfrey products has to be specified, as daily exposure has to be below 0.35 μg [88]. Anti-inflammatory action of comfrey preparations was demonstrated in preclinical studies when they dose-dependently inhibited complement activation and suppressed carrageenan-induced rat paw edema [87]. Moderate evidence from a double-blind, randomized, bicenter,

adverse events [74, 83].

65

Purified purple passion fruit peel extract, obtained from South American climbing vine Passiflora edulis, contains considerable amounts of flavonoids and anthocyanins. Its therapeutic effects (daily dose 150 mg) in patients with OA of knee were examined in a randomized double-blind placebo-controlled short-term study. The observed reduction of pain and improvement of physical function were significant and clinically meaningful. The quality of provided evidence was moderate [3, 72].

#### 3. Herbal medicinal products for topical use in the treatment of osteoarthritis

Capsicum (Capsici fructus) is a dried ripe fruit of Capsicum annuum L. var. minimum (Miller) Heiser and small-fruited varieties of Capsicum frutescens L. [4]. With respect to its medicinal properties, the most important compounds are capsaicinoids (capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicins I and II, caprylic acid vanillylamide, etc.). Triglycerides, carotenoids, ascorbic acid, flavonoids, and a complex mixture of volatile compounds are also present [35]. Standardized products of capsicum (semisolid or liquid dosage forms, medicated plasters) are intended for the relief of muscle (e.g., low back pain) and osteoarthritic pain. They should be used continuously until relief of pain is achieved, but not longer than 3 weeks and with a subsequent, at least two-week break period. Its use is contraindicated in cases of broken skin, wounds, eczema, and hypersensitivity to herbal substance or capsaicinoids. The plasters and semisolid dosage forms are not intended for concomitant use with other products for external administration. Topical application of capsicum HMPs initially causes skin irritation that is manifested by erythema and warmth sensation. Next stage is characterized by prolonged (hours to weeks) desensitization to pain stimuli. Side effects include skin hypersensitivity and allergic reactions [35, 73]. Capsaicin acts as an agonist of vanilloid receptors on C-type nerve fibers and thus it leads to depletion of neuropeptide substance P and consequent antinociception [7]. Standardized product containing capsicum tincture (Capsica gel®, 0.0125% of capsaicin) was investigated in a cross-over, randomized, placebo-controlled trial recruiting 99 patients with the OA of knee, within 9 weeks. Gel (2 inches) was applied topically three times per day. The conducted study provided moderate-quality evidence that the product probably did not decrease pain and improve function. Adverse events were common and included skin irritation and burning sensation [74, 75]. Creams containing higher concentration of capsaicin (0.025–0.075%) are indicated in the treatment of OA symptoms [1].

confirmed that bromelain acted as an analgesic agent [69]. Anti-osteoarthritic property of orally administered bromelain (daily dose 500 mg) was compared with therapeutic activity of diclofenac (daily dose 100 mg) in a randomized single-blind active-controlled pilot study in 40 patients with mild-to-moderate knee OA. After a

four-week treatment, there was no difference in symptoms relief between bromelain-treated and diclofenac-treated groups [70]. Bromelain (800 mg/day) was also compared with placebo in a randomized double-blind three-month long pilot study that included patients with moderate-to-severe OA of knee. The authors suggested that bromelain was not efficacious as an adjunctive treatment, but, due to the trial limitations, proposed that new studies should be performed [71]. Recent systematic review of clinical trials, examining dietary supplements used in the management of OA, has shown that the short-term treatment with bromelain was not effective in alleviation of pain and function improvement. Evidence quality was

Purified purple passion fruit peel extract, obtained from South American climbing vine Passiflora edulis, contains considerable amounts of flavonoids and anthocyanins. Its therapeutic effects (daily dose 150 mg) in patients with OA of knee were examined in a randomized double-blind placebo-controlled short-term study. The observed reduction of pain and improvement of physical function were

significant and clinically meaningful. The quality of provided evidence was

3. Herbal medicinal products for topical use in the treatment of

Capsicum (Capsici fructus) is a dried ripe fruit of Capsicum annuum L. var. minimum (Miller) Heiser and small-fruited varieties of Capsicum frutescens L. [4]. With respect to its medicinal properties, the most important compounds are capsaicinoids (capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicins I and II, caprylic acid vanillylamide, etc.). Triglycerides, carotenoids, ascorbic acid, flavonoids, and a complex mixture of volatile compounds are also present [35]. Standardized products of capsicum (semisolid or liquid dosage forms, medicated plasters) are intended for the relief of muscle (e.g., low back pain) and osteoarthritic pain. They should be used continuously until relief of pain is achieved, but not longer than 3 weeks and with a subsequent, at least two-week break period. Its use is contraindicated in cases of broken skin, wounds, eczema, and hypersensitivity to herbal substance or capsaicinoids. The plasters and semisolid dosage forms are not intended for concomitant use with other products for external administration. Topical application of capsicum HMPs initially causes skin irritation that is manifested by erythema and warmth sensation. Next stage is characterized by prolonged (hours to weeks) desensitization to pain stimuli. Side effects include skin hypersensitivity and allergic reactions [35, 73]. Capsaicin acts as an agonist of vanilloid receptors on C-type nerve fibers and thus it leads to depletion of neuropeptide substance P and consequent antinociception [7]. Standardized product containing capsicum tincture (Capsica gel®, 0.0125% of capsaicin) was investigated in a cross-over, randomized, placebo-controlled trial recruiting 99 patients with the OA of knee, within 9 weeks. Gel (2 inches) was applied topically three times per day. The conducted study provided moderate-quality evidence that the product probably did not decrease pain and improve function. Adverse events were common and included skin irritation and burning sensation [74, 75]. Creams containing higher concentration of capsaicin (0.025–0.075%) are indicated in the

low [3].

moderate [3, 72].

Osteoarthritis Biomarkers and Treatments

osteoarthritis

treatment of OA symptoms [1].

64

Arnica flower (Arnicae flos) is, whole or partially broken, dried flower-head of Arnica montana L. [4]. This herbal drug is employed traditionally for relief of bruises, sprains, and localized muscular pain. Semisolid and liquid dosage forms based on arnica preparations (tinctures or ethanolic liquid extract) are applied cutaneously. The use of arnica HMPs is contraindicated in patients with known hypersensitivity to arnica and other plants belonging to Asteraceae family. They should not be applied on broken skin. Reported side effects include allergic skin reactions [76]. Main constituents of arnica flower-heads are pseudoguianolide-type sesquiterpene lactones helenalin and 11α,13-dihydrohelenalin [7]. Contribution of these secondary metabolites to the anti-inflammatory effect is likely as it was shown that helenalin and 11α,13-dihydrohelenalin had the ability to interfere with the activation of transcription factor NF-κB [77]. In vitro experiments conducted on the pig skin indicated that sesquiterpene lactones can penetrate into it, and thus further support this assumption [78, 79]. Better permeation through stratum corneum (the outermost layer of the skin) was achieved when sesquiterpene lactones were applied in the form of arnica tinctures than as pure compounds [78]. Arnica flower preparations at low concentration/s were able to reduce levels of pro-inflammatory cytokines (IL-1 and TNF-α) in human mononuclear cells and of mRNA of matrix metalloproteinases (MMP-1 and MMP-13) in human and bovine articular chondrocytes [80, 81]. Whole plant methanolic extract suppressed expression of iNOS and COX-2 in LPS-stimulated murine macrophages [82]. Presented literature data may help to rationalize the use of arnica in management of diseases with underlying inflammation. Moderate evidence from a single, double-blind randomized controlled clinical trial showed that topical application of arnica gel (A. Vogel Arnica Gel®, 50 g herbal tincture/100 g gel, extraction solvent 50% ethanol, and DER 1:20) three times per day probably decreased pain and improved function related to hand OA as ibuprofen gel (5%), with a similar number of adverse events [74, 83].

Rosemary leaf (Rosmarini folium) is whole, dried leaf of Rosmarinus officinalis L. [4]. Its chemistry is characterized by the presence of essential oil, phenolic diterpenes (e.g., carnosol, carnosolic acid, and rosmanol), hydroxycinnamic derivatives, flavonoids, and triterpenoids [6]. Rosemary leaf bath additive is applied as an adjuvant to relieve minor muscular and articular pain, exclusively based upon long-standing traditional use [84]. Several rosemary compounds exhibited antiinflammatory action in vitro. Rosmarinic acid decreased levels of PGE2 and NO in rat chondrocytes [85]. Phenolic diterpene carnosol decreased concentrations of PGE2 and NO, and reduced gene expression of iNOS, IL-1α, IL-6, and CCL5 in LPSstimulated macrophages. In addition, it interfered with transcription factor NF-κB activation and influenced expression of anabolic and catabolic genes in chondrosarcoma cell line SW1353 and in primary human chondrocytes [86].

Comfrey root (Symphyti radix) is obtained from Symphytum officinale L., a traditional medicinal plant that can be found throughout Europe, parts of Asia, and as a naturalized plant in North America. It contains allantoin, mucilage polysaccharides, phenolic acids (e.g., rosmarinic acid), glycopeptides, amino acids, triterpene saponins, and pyrrolizidine alkaloids with 1,2-unsaturated necine ring structures. Identity of active principles is not sufficiently known although it is assumed that allantoin and rosmarinic acid play an important role in biological activity [87]. Taking into account considerable hepatotoxic and carcinogenic potential of pyrrolizidine alkaloids, their content in comfrey products has to be specified, as daily exposure has to be below 0.35 μg [88]. Anti-inflammatory action of comfrey preparations was demonstrated in preclinical studies when they dose-dependently inhibited complement activation and suppressed carrageenan-induced rat paw edema [87]. Moderate evidence from a double-blind, randomized, bicenter,

placebo-controlled trial with 220 participants indicated that comfrey root gel Kytta-Salbe® f probably reduced pain related to knee OA after 3 weeks of external application (6 g daily, 3 2 g) [74, 89]. Investigated proprietary product contained 35% of liquid extract (DER 1:2, ethanol 60% V/V, allantoin 0.2–0.5%) and <0.35 ppm of pyrrolizidine alkaloids [89].

defined according to American College of Rheumatology (ACR) criteria and that participants are recruited without bias [10]. Furthermore, herbal preparations should be reported in detail, including dose, extraction method, and chemical characterization of active principle(s). Finally, study results should be recorded using reliable, valid outcome measures that combine pain and functional impairments in the identification of treatment response (as proposed by OMERACT-OARSI initiative) for

Herbal medicines that have been shown to be effective in the treatment of pain associated with OA could help lowering or ceasing the consumption of NSAIDs, reducing at the same time the incidence and severity of their adverse effects. This would also produce necessary long-term safety data, which are needed for most of

Currently available data are insufficient to acknowledge their use in OA treatment as clinically proven (i.e., with demonstrated efficacy and safety). However, it could be stated that the body of evidence is growing and that expectations on arrival of reliable, efficient, and safe herbal products, fulfilling the criteria of modern medicine

This work was supported by the Ministry of Education, Science and Technolog-

Department of Pharmacognosy, Faculty of Pharmacy, University of Belgrade,

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: zoran.maksimovic@pharmacy.bg.ac.rs

comparing the efficacy of different medicinal plant products [10].

Herbal Medicinal Products in the Treatment of Osteoarthritis

DOI: http://dx.doi.org/10.5772/intechopen.80593

ical Development of the Republic of Serbia (grant no. 173021).

The authors declare no conflict of interest.

Zoran Maksimović\* and Stevan Samardžić

provided the original work is properly cited.

the herbal medicinal products.

in the near future, seem reasonable.

Acknowledgements

Conflict of interest

Author details

Belgrade, Serbia

67

Essential oils such as juniper oil, Juniperi aetheroleum; rosemary oil, Rosmarini aetheroleum; eucalyptus oil, Eucalypti aetheroleum; peppermint oil, Menthae piperitae aetheroleum; sweet birch oil, Betulae lentae aetheroleum; and wintergreen oil, Gaultheriae aetheroleum are employed for external treatment of articular pain and rheumatism. They are used in the form of bath additives and semisolid and liquid dosage forms. When applied to skin, essential oils act as irritants, which cause local increase of blood flow, reddening of the skin, and sensation of warmth thus antagonizing pain. Juniper oil must be avoided in the case of severe renal diseases [6, 7, 90, 91].

#### 4. Conclusion

Osteoarthritis (OA) is a slowly developing degeneration disease affecting joint cartilage and adjacent tissues. It is one of the most prevalent diseases and most common causes of disability in the elderly, associated with worsening symptoms of joint pain, stiffness, and limitation of articular movement. Therefore, it imposes a significant functional and economic burden not only on affected patients but also on health-care systems.

Contemporary therapy protocols involve an array of non-pharmacological, pharmacological, and surgical measures. Although non-pharmacological treatments represent a basis for OA treatment, pharmacotherapy is considered to be an important adjunct. Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently a cornerstone in OA pharmacotherapy. None of the therapeutic options are curative, but the aim of treatment is to relieve the pain, improve quality of life, and reduce the loss of physical functionality.

NSAIDs often have serious adverse effects, with gastrointestinal complications as the most frequently reported. Some patients do not respond well to conventional medical therapy. Facing unsatisfactory efficacy and adverse effects of conventional therapy, they try to overcome current treatment deficiencies by using herbal medicinal products.

Preclinical studies showed that a number of herbal extracts and respective constituents exhibited pharmacological properties that could be relevant for their beneficial effect in OA. They interfered with cytokine (IL-1β, TNF-α, and IL-6), PGE2, and NO production, modulated biosynthesis and activity of collagenases and aggrecanases, stimulated formation of extracellular matrix, and inhibited activation of transcription factor NF-κB. Active constituents are not often defined satisfactorily, but it could be said that they belong to various groups of secondary metabolites such as sesquiterpene lactones, triterpenic acids, galactolipids, diarylheptanoids, iridoid glycosides, phenolic glycosides, procyanidins, and alkaloids. Trials in humans support observations from in vitro and animal studies.

Unfortunately, this area is still far under-researched and needs further and better attention. Existing studies were frequently based on flawed research design, unclear and incomplete selection criteria, inadequate definition of the herbal interventions, or post hoc manipulation of data to support the authors' preferred conclusions [10]. The same authors urge on high quality and adequately powered clinical studies, advising future researchers that particular attention should be given to the detail of study design, which would ensure that participant samples are well

Herbal Medicinal Products in the Treatment of Osteoarthritis DOI: http://dx.doi.org/10.5772/intechopen.80593

defined according to American College of Rheumatology (ACR) criteria and that participants are recruited without bias [10]. Furthermore, herbal preparations should be reported in detail, including dose, extraction method, and chemical characterization of active principle(s). Finally, study results should be recorded using reliable, valid outcome measures that combine pain and functional impairments in the identification of treatment response (as proposed by OMERACT-OARSI initiative) for comparing the efficacy of different medicinal plant products [10].

Herbal medicines that have been shown to be effective in the treatment of pain associated with OA could help lowering or ceasing the consumption of NSAIDs, reducing at the same time the incidence and severity of their adverse effects. This would also produce necessary long-term safety data, which are needed for most of the herbal medicinal products.

Currently available data are insufficient to acknowledge their use in OA treatment as clinically proven (i.e., with demonstrated efficacy and safety). However, it could be stated that the body of evidence is growing and that expectations on arrival of reliable, efficient, and safe herbal products, fulfilling the criteria of modern medicine in the near future, seem reasonable.

#### Acknowledgements

placebo-controlled trial with 220 participants indicated that comfrey root gel Kytta-Salbe® f probably reduced pain related to knee OA after 3 weeks of external application (6 g daily, 3 2 g) [74, 89]. Investigated proprietary product contained 35% of liquid extract (DER 1:2, ethanol 60% V/V, allantoin 0.2–0.5%) and <0.35 ppm of

Essential oils such as juniper oil, Juniperi aetheroleum; rosemary oil, Rosmarini aetheroleum; eucalyptus oil, Eucalypti aetheroleum; peppermint oil, Menthae piperitae

Osteoarthritis (OA) is a slowly developing degeneration disease affecting joint cartilage and adjacent tissues. It is one of the most prevalent diseases and most common causes of disability in the elderly, associated with worsening symptoms of joint pain, stiffness, and limitation of articular movement. Therefore, it imposes a significant functional and economic burden not only on affected patients but also

Contemporary therapy protocols involve an array of non-pharmacological, pharmacological, and surgical measures. Although non-pharmacological treatments represent a basis for OA treatment, pharmacotherapy is considered to be an important adjunct. Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently a cornerstone in OA pharmacotherapy. None of the therapeutic options are curative, but the aim of treatment is to relieve the pain, improve quality of life, and reduce

NSAIDs often have serious adverse effects, with gastrointestinal complications as the most frequently reported. Some patients do not respond well to conventional medical therapy. Facing unsatisfactory efficacy and adverse effects of conventional therapy, they try to overcome current treatment deficiencies by using herbal

Preclinical studies showed that a number of herbal extracts and respective constituents exhibited pharmacological properties that could be relevant for their beneficial effect in OA. They interfered with cytokine (IL-1β, TNF-α, and IL-6), PGE2, and NO production, modulated biosynthesis and activity of collagenases and aggrecanases, stimulated formation of extracellular matrix, and inhibited activation of transcription factor NF-κB. Active constituents are not often defined satisfactorily, but it could be said that they belong to various groups of secondary metabolites such as sesquiterpene lactones, triterpenic acids, galactolipids, diarylheptanoids, iridoid glycosides, phenolic glycosides, procyanidins, and alkaloids. Trials in

Unfortunately, this area is still far under-researched and needs further and better attention. Existing studies were frequently based on flawed research design, unclear and incomplete selection criteria, inadequate definition of the herbal interventions, or post hoc manipulation of data to support the authors' preferred conclusions [10]. The same authors urge on high quality and adequately powered clinical studies, advising future researchers that particular attention should be given to the detail of study design, which would ensure that participant samples are well

humans support observations from in vitro and animal studies.

aetheroleum; sweet birch oil, Betulae lentae aetheroleum; and wintergreen oil, Gaultheriae aetheroleum are employed for external treatment of articular pain and rheumatism. They are used in the form of bath additives and semisolid and liquid dosage forms. When applied to skin, essential oils act as irritants, which cause local increase of blood flow, reddening of the skin, and sensation of warmth thus antagonizing pain. Juniper oil must be avoided in the case of severe renal diseases [6, 7,

pyrrolizidine alkaloids [89].

Osteoarthritis Biomarkers and Treatments

90, 91].

4. Conclusion

on health-care systems.

medicinal products.

66

the loss of physical functionality.

This work was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia (grant no. 173021).

#### Conflict of interest

The authors declare no conflict of interest.

#### Author details

Zoran Maksimović\* and Stevan Samardžić Department of Pharmacognosy, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia

\*Address all correspondence to: zoran.maksimovic@pharmacy.bg.ac.rs

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### References

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[2] Firestein GS, Budd RC, Gabriel SE, McInnes IB, O'Dell J, editors. Kelley and Firestein's Textbook of Rheumatology. 10th ed. Philadelphia: Elsevier; 2016

[3] Liu X, Machado GC, Eyles JP, Ravi V, Hunter DJ. Dietary supplements for treating osteoarthritis: A systematic review and meta-analysis. British Journal of Sports Medicine. 2018;52(3): 167-175. DOI: 10.1136/bjsports-2016-097333

[4] European Directorate for the Quality of Medicines (EDQM). European Pharmacopoeia. 8th ed. Strasbourg: Council of Europe; 2013

[5] Committee on Herbal Medicinal Products (HMPC). Final European Union Herbal Monograph on Salix [Various Species Including S. purpurea L., S. daphnoides Vill., S. fragilis L.], cortex. European Medicines Agency; 2017. Reference number: EMA/HMPC/ 80630/2016

[6] European Scientific Cooperative on Phytotherapy (ESCOP). ESCOP Monographs: The Scientific Foundation for Herbal Medicinal Products. 2nd ed. Exeter, Stuttgart, New York: The European Scientific Cooperative on Phytotherapy, Georg Thieme Verlag, Thieme New York; 2003

[7] Michael H, Joanne B, Simon G, Elizabeth MW. Fundamentals of Pharmacognosy and Phytotherapy. 2nd ed. Edinburgh: Churchill Livingstone; 2012

[8] Shara M, Stohs SJ. Efficacy and safety of white willow bark (Salix alba)

extracts. Phytotherapy Research. 2015; 29(8):1112-1116. DOI: 10.1002/ptr.5377 in primary human osteoarthritis chondrocytes. Journal of Orthopaedic Research. 2017;35(2):311-320. DOI:

DOI: http://dx.doi.org/10.5772/intechopen.80593

Herbal Medicinal Products in the Treatment of Osteoarthritis

phenolic compounds from the genus Filipendula. Chemistry of Natural Compounds. 2013;49(4):610-616. DOI:

[23] Drummond EM, Harbourne N, Marete E, Martyn D, Jacquier J, O'Riordan D, Gibney ER. Inhibition of proinflammatory biomarkers in THP1 macrophages by polyphenols derived from chamomile, meadowsweet and willow bark. Phytotherapy Research. 2013;27(4):588-594. DOI: 10.1002/

[24] Samardžić S, Arsenijević J, Božić D, Milenković M, Tešević V, Maksimović Z. Antioxidant, anti-inflammatory and gastroprotective activity of Filipendula ulmaria (L.) maxim. and Filipendula

Ethnopharmacology. 2018;213:132-137.

[25] Samardžić S, Tomić M, Pecikoza U, Stepanović-Petrović R, Maksimović Z. Antihyperalgesic activity of Filipendula ulmaria (L.) maxim. And Filipendula vulgaris Moench in a rat model of

Ethnopharmacology. 2016;193:652-656.

[26] Committee on Herbal Medicinal Products (HMPC). Final Community Herbal Monograph on Urtica dioica L. and Urtica urens L., herba. European Medicines Agency; 2008. Reference number: EMEA/HMPC/170261/2006

[27] Committee on Herbal Medicinal Products (HMPC). Final Community Herbal Monograph on Urtica dioica L.; Urtica urens L., folium. European Medicines Agency; 2010. Reference number: EMA/HMPC/508015/2007

[28] Riehemann K, Behnke B, Schulze-Osthoff K. Plant extracts from stinging nettle (Urtica dioica), an antirheumatic remedy, inhibit the proinflammatory transcription factor NF-κB. FEBS

vulgaris Moench. Journal of

inflammation. Journal of

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10.1007/s10600-013-0691-0

ptr.4753

[16] Committee on Herbal Medicinal Products (HMPC). Final European Union Herbal Monograph on Ribes nigrum L., folium. European Medicines Agency; 2017. Reference number: EMA/

[17] Mongold JJ, Susplugas P, Taillade C, Serrano JJ. Anti-inflammatory activity of Ribes nigrum leaf extract in rats. Plantes médicinales et phytothérapie.

[18] Garbacki N, Angenot L, Bassleer C, Damas J, TitsM. Effects of prodelphinidins isolated from Ribes nigrum on chondrocyte metabolism and COX activity. Naunyn-

Pharmacology. 2002;365(6):434-441. DOI: 10.1007/s00210-002-0553-y

[19] Committee on Herbal Medicinal Products (HMPC). Final Community Herbal Monograph on Filipendula ulmaria (L.) Maxim., flos - First Version. European Medicines Agency; 2011. Reference number: EMA/HMPC/

[20] Committee on Herbal Medicinal Products (HMPC). Final Community Herbal Monograph on Filipendula ulmaria (L.) Maxim., herba - First Version. European Medicines Agency; 2011. Reference number: EMA/HMPC/

[21] Committee on Herbal Medicinal Products (HMPC). Final Assessment Report on Filipendula ulmaria (L.) Maxim., herba and Filipendula ulmaria (L.) Maxim., flos - First Version. European Medicines Agency; 2011. Reference number: EMA/HMPC/

[22] Olennikov DN, Kruglova MY. A new quercetin glycoside and other

10.1002/jor.23262

HMPC/745353/2016

1993;26(2):109-116

434894/2010

434881/2010

434892/2010

69

Schmiedeberg's Archives of

[9] Awang DVC. Tyler's Herbs of Choice: The Therapeutic Use of Phytomedicinals. 3rd ed. Boca Raton, FL: CRC Press; 2009

[10] Cameron M, Chrubasik S. Oral herbal therapies for treating osteoarthritis. Cochrane Database of Systematic Reviews. 2014;5. DOI: 10.1002/14651858.CD002947.pub2

[11] Committee on Herbal Medicinal Products (HMPC). Final European Union Herbal Monograph on Harpagophytum procumbens DC. and/or Harpagophytum zeyheri Decne., radix. European Medicines Agency; 2016. Reference number: EMA/HMPC/627057/2015

[12] Fiebich BL, Muñoz E, Rose T, Weiss G, McGregor GP. Molecular targets of the anti-inflammatory Harpagophytum procumbens (Devil's claw): Inhibition of TNFα and COX-2 gene expression by preventing activation of AP-1. Phytotherapy Research. 2012;26(6): 806-811. DOI: 10.1002/ptr.3636

[13] Schulze-Tanzil G, Hansen C, Shakibaei M. Effect of a Harpagophytum procumbens DC extract on matrix metalloproteinases in human chondrocytes in vitro. Arzneimittel-Forschung. 2004;54(4):213-220. DOI: 10.1055/s-0031-1296962

[14] Jang M-H, Lim S, Han S-M, Park H-J, Shin I, Kim J-W, Kim N-Y, Lee J-S, Kim K-A, Kim C-J. Harpagophytum procumbens suppresses lipopolysaccharide-stimulated expressions of cyclooxygenase-2 and inducible nitric oxide synthase in fibroblast cell line L929. Journal of Pharmacological Sciences. 2003;93(3): 367-371. DOI: 10.1254/jphs.93.367

[15] Haseeb A, Ansari MY, Haqqi TM. Harpagoside suppresses IL-6 expression Herbal Medicinal Products in the Treatment of Osteoarthritis DOI: http://dx.doi.org/10.5772/intechopen.80593

in primary human osteoarthritis chondrocytes. Journal of Orthopaedic Research. 2017;35(2):311-320. DOI: 10.1002/jor.23262

References

2015. pp. 2226-2233

[1] Felson DT. Osteoarthritis. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson

Osteoarthritis Biomarkers and Treatments

extracts. Phytotherapy Research. 2015; 29(8):1112-1116. DOI: 10.1002/ptr.5377

[9] Awang DVC. Tyler's Herbs of Choice:

Phytomedicinals. 3rd ed. Boca Raton,

[10] Cameron M, Chrubasik S. Oral herbal therapies for treating

osteoarthritis. Cochrane Database of Systematic Reviews. 2014;5. DOI: 10.1002/14651858.CD002947.pub2

[11] Committee on Herbal Medicinal Products (HMPC). Final European Union Herbal Monograph on Harpagophytum procumbens DC. and/or Harpagophytum

[12] Fiebich BL, Muñoz E, Rose T, Weiss G, McGregor GP. Molecular targets of the anti-inflammatory Harpagophytum procumbens (Devil's claw): Inhibition of TNFα and COX-2 gene expression by preventing activation of AP-1. Phytotherapy Research. 2012;26(6): 806-811. DOI: 10.1002/ptr.3636

zeyheri Decne., radix. European Medicines Agency; 2016. Reference number: EMA/HMPC/627057/2015

[13] Schulze-Tanzil G, Hansen C, Shakibaei M. Effect of a Harpagophytum procumbens DC extract on matrix metalloproteinases in human chondrocytes in vitro. Arzneimittel-Forschung. 2004;54(4):213-220. DOI:

[14] Jang M-H, Lim S, Han S-M, Park H-J, Shin I, Kim J-W, Kim N-Y, Lee J-S, Kim K-A, Kim C-J. Harpagophytum

[15] Haseeb A, Ansari MY, Haqqi TM. Harpagoside suppresses IL-6 expression

10.1055/s-0031-1296962

procumbens suppresses

lipopolysaccharide-stimulated expressions of cyclooxygenase-2 and inducible nitric oxide synthase in fibroblast cell line L929. Journal of Pharmacological Sciences. 2003;93(3): 367-371. DOI: 10.1254/jphs.93.367

The Therapeutic Use of

FL: CRC Press; 2009

Principles of Internal Medicine. 19th ed. New York: McGraw-Hill Education;

[2] Firestein GS, Budd RC, Gabriel SE, McInnes IB, O'Dell J, editors. Kelley and Firestein's Textbook of Rheumatology. 10th ed. Philadelphia: Elsevier; 2016

[3] Liu X, Machado GC, Eyles JP, Ravi V, Hunter DJ. Dietary supplements for treating osteoarthritis: A systematic review and meta-analysis. British Journal of Sports Medicine. 2018;52(3):

[4] European Directorate for the Quality of Medicines (EDQM). European Pharmacopoeia. 8th ed. Strasbourg:

[5] Committee on Herbal Medicinal Products (HMPC). Final European Union Herbal Monograph on Salix [Various Species Including S. purpurea L., S. daphnoides Vill., S. fragilis L.], cortex. European Medicines Agency; 2017. Reference number: EMA/HMPC/

[6] European Scientific Cooperative on Phytotherapy (ESCOP). ESCOP

Monographs: The Scientific Foundation for Herbal Medicinal Products. 2nd ed. Exeter, Stuttgart, New York: The European Scientific Cooperative on Phytotherapy, Georg Thieme Verlag,

167-175. DOI: 10.1136/bjsports-

Council of Europe; 2013

Thieme New York; 2003

[7] Michael H, Joanne B, Simon G, Elizabeth MW. Fundamentals of Pharmacognosy and Phytotherapy. 2nd ed. Edinburgh: Churchill Livingstone;

[8] Shara M, Stohs SJ. Efficacy and safety of white willow bark (Salix alba)

2016-097333

80630/2016

2012

68

JL, Loscalzo J, editors. Harrison's

[16] Committee on Herbal Medicinal Products (HMPC). Final European Union Herbal Monograph on Ribes nigrum L., folium. European Medicines Agency; 2017. Reference number: EMA/ HMPC/745353/2016

[17] Mongold JJ, Susplugas P, Taillade C, Serrano JJ. Anti-inflammatory activity of Ribes nigrum leaf extract in rats. Plantes médicinales et phytothérapie. 1993;26(2):109-116

[18] Garbacki N, Angenot L, Bassleer C, Damas J, TitsM. Effects of prodelphinidins isolated from Ribes nigrum on chondrocyte metabolism and COX activity. Naunyn-Schmiedeberg's Archives of Pharmacology. 2002;365(6):434-441. DOI: 10.1007/s00210-002-0553-y

[19] Committee on Herbal Medicinal Products (HMPC). Final Community Herbal Monograph on Filipendula ulmaria (L.) Maxim., flos - First Version. European Medicines Agency; 2011. Reference number: EMA/HMPC/ 434894/2010

[20] Committee on Herbal Medicinal Products (HMPC). Final Community Herbal Monograph on Filipendula ulmaria (L.) Maxim., herba - First Version. European Medicines Agency; 2011. Reference number: EMA/HMPC/ 434881/2010

[21] Committee on Herbal Medicinal Products (HMPC). Final Assessment Report on Filipendula ulmaria (L.) Maxim., herba and Filipendula ulmaria (L.) Maxim., flos - First Version. European Medicines Agency; 2011. Reference number: EMA/HMPC/ 434892/2010

[22] Olennikov DN, Kruglova MY. A new quercetin glycoside and other

phenolic compounds from the genus Filipendula. Chemistry of Natural Compounds. 2013;49(4):610-616. DOI: 10.1007/s10600-013-0691-0

[23] Drummond EM, Harbourne N, Marete E, Martyn D, Jacquier J, O'Riordan D, Gibney ER. Inhibition of proinflammatory biomarkers in THP1 macrophages by polyphenols derived from chamomile, meadowsweet and willow bark. Phytotherapy Research. 2013;27(4):588-594. DOI: 10.1002/ ptr.4753

[24] Samardžić S, Arsenijević J, Božić D, Milenković M, Tešević V, Maksimović Z. Antioxidant, anti-inflammatory and gastroprotective activity of Filipendula ulmaria (L.) maxim. and Filipendula vulgaris Moench. Journal of Ethnopharmacology. 2018;213:132-137. DOI: 10.1016/j.jep.2017.11.013

[25] Samardžić S, Tomić M, Pecikoza U, Stepanović-Petrović R, Maksimović Z. Antihyperalgesic activity of Filipendula ulmaria (L.) maxim. And Filipendula vulgaris Moench in a rat model of inflammation. Journal of Ethnopharmacology. 2016;193:652-656. DOI: 10.1016/j.jep.2016.10.024

[26] Committee on Herbal Medicinal Products (HMPC). Final Community Herbal Monograph on Urtica dioica L. and Urtica urens L., herba. European Medicines Agency; 2008. Reference number: EMEA/HMPC/170261/2006

[27] Committee on Herbal Medicinal Products (HMPC). Final Community Herbal Monograph on Urtica dioica L.; Urtica urens L., folium. European Medicines Agency; 2010. Reference number: EMA/HMPC/508015/2007

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Letters. 1999;442(1):89-94. DOI: 10.1016/S0014-5793(98)01622-6

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MJ, Kamarul T, Bagheri A, Tekiyehmaroof N, Sharifi AM. Protective effect of ginger (Zingiber officinale roscoe) extract against oxidative stress and mitochondrial apoptosis induced by interleukin-1β in cultured chondrocytes. Cells, Tissues, Organs. 2017;204(5–6):241-250. DOI:

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function in adult patients with knee osteoarthritis. Nutrition Research. 2010; 30(9):601-606. DOI: 10.1016/j. nutres.2010.08.010

[73] Committee on Herbal Medicinal Products (HMPC). Final European Union herbal Monograph on Capsicum annuum L. var. minimum (Miller) Heiser and small fruited varieties of Capsicum frutescens L., fructus. European Medicines Agency; 2015. Reference number: EMA/HMPC/ 674139/2013

[74] Cameron M, Chrubasik S. Topical herbal therapies for treating osteoarthritis. Cochrane Database of Systematic Reviews. 2013;5. DOI: 10.1002/14651858.CD010538

[75] Kosuwon W, Sirichatiwapee W, Wisanuyotin T, Jeeravipoolvarn P, Laupattarakasem W. Efficacy of symptomatic control of knee osteoarthritis with 0.0125% of capsaicin versus placebo. Journal of the Medical Association of Thailand. 2010;93(10): 1188-1195

[76] Committee on Herbal Medicinal Products (HMPC). Final Community Herbal Monograph on Arnica montana L., flos. European Medicines Agency; 2014. Reference number: EMA/HMPC/ 198793/2012

[77] Lyss G, Schmidt TJ, Merfort I, Pahl HL. Helenalin, an anti-inflammatory sesquiterpene lactone from Arnica, selectively inhibits transcription factor NF-kappaB. Biological Chemistry. 1997; 378(9):951-961. DOI: 10.1515/ bchm.1997.378.9.951

[78] Wagner S, Suter A, Merfort I. Skin penetration studies of Arnica preparations and of their sesquiterpene lactones. Planta Medica. 2004;70(10): 897-903. DOI: 10.1055/s-2004-832613

[79] Wagner S, Merfort I. Skin penetration behaviour of sesquiterpene lactones from different Arnica preparations using a validated GC-MSD method. Journal of Pharmaceutical and Biomedical Analysis. 2007;43(1):32-38. DOI: 10.1016/j.jpba.2006.06.008

[80] Jäger C, Hrenn A, Zwingmann J, Suter A, Merfort I. Phytomedicines prepared from Arnica flowers inhibit the transcription factors AP-1 and NFkappaB and modulate the activity of MMP1 and MMP13 in human and bovine chondrocytes. Planta Medica. 2009;75(12):1319-1325. DOI: 10.1055/s-0029-1185668

[81] Klaas CA, Wagner G, Laufer S, Sosa S, Della Loggia R, Bomme U, Pahl HL, Merfort I. Studies on the antiinflammatory activity of phytopharmaceuticals prepared from Arnica flowers. Planta Medica. 2002; 68(5):385-391. DOI: 10.1055/s-2002-32067

[82] Verma N, Tripathi SK, Sahu D, Das HR, Das RH. Evaluation of inhibitory activities of plant extracts on production of LPS-stimulated pro-inflammatory mediators in J774 murine macrophages. Molecular and Cellular Biochemistry. 2010;336(1–2):127-135. DOI: 10.1007/ s11010-009-0263-6

[83] Widrig R, Suter A, Saller R, Melzer J. Choosing between NSAID and arnica for topical treatment of hand osteoarthritis in a randomised, doubleblind study. Rheumatology International. 2007;27(6):585. DOI: 10.1007/s00296-007-0304-y

[84] Committee on Herbal Medicinal Products (HMPC). Final Community Herbal Monograph on Rosmarinus officinalis L., folium. European Medicines Agency; 2010. Reference number: EMA/HMPC/13633/2009

[85] Chen W-P, Jin G-J, Xiong Y, Hu P-F, Bao J-P, Wu L-D. Rosmarinic acid down-regulates NO and PGE2 expression via MAPK pathway in rat

chondrocytes. Journal of Cellular and Molecular Medicine. 2018;22(1): 346-353. DOI: 10.1111/jcmm.13322

[86] Schwager J, Richard N, Fowler A, Seifert N, Raederstorff D. Carnosol and related substances modulate chemokine and cytokine production in macrophages and chondrocytes. Molecules. 2016;21(4):465. DOI: 10.3390/molecules21040465

[87] Staiger C. Comfrey: A clinical overview. Phytotherapy Research. 2012; 26(10):1441-1448. DOI: 10.1002/ ptr.4612

[88] Committee on Herbal Medicinal Products (HMPC). Final European Union Herbal Monograph on Symphytum officinale L., radix. European Medicines Agency; 2015. Reference number: EMA/HMPC/572846/2009

[89] Grube B, Grünwald J, Krug L, Staiger C. Efficacy of a comfrey root (Symphyti offic. radix) extract ointment in the treatment of patients with painful osteoarthritis of the knee: Results of a double-blind, randomised, bicenter, placebo-controlled trial. Phytomedicine. 2007;14(1):2-10. DOI: 10.1016/j.phymed.2006.11.006

[90] Committee on Herbal Medicinal Products (HMPC). Final Community Herbal Monograph on Juniperus communis L., aetheroleum. European Medicines Agency; 2010. Reference number: EMA/HMPC/12402/2010

[91] Committee on Herbal Medicinal Products (HMPC). Final Community Herbal Monograph on Rosmarinus officinalis L., aetheroleum; 2010. Reference number: EMA/HMPC/ 235453/2009

**75**

**Chapter 5**

**Abstract**

functıonal capacity

**1. Introduction**

increasing [6].

Osteoarthritis

*Zuhal Kunduracilar and Kartal Selici*

major driver of healthcare costs due to arthritis.

**Keywords:** osteoarthritis, cardiovascular disease, aerobic capacity,

Hypertension, diabetes mellitus, cardiovascular diseases, and osteoarthritis (OA) are the leading diseases of the most common disease clusters [1, 2]. Knee OA is a common health problem in the general population [3]. It is characterized by the abrasion of joint cartilage, changes in the extracellular matrix, subchondral bone ossification, and osteophyte formation [4]. The socioeconomic load of OA, which has a serious morbidity and disability rate, is very heavy. In the United States, 30.8 million patients with OA caused a medical expenditure of over 340 billion dollars between 2008 and 2011 [5]. The worldwide prevalence of symptomatic knee OA is

The most common localization of OA is the knee joint, and symptomatic knee OA affects 24% of the general population [7]. The fact that hypertension, diabetes, and cardiovascular diseases are found together with OA has led to the speculation of a metabolic "OA phenotype" [2]. It was hypothesized that obesity, dyslipidemia, impaired fasting blood sugar, and hypertension contribute to the incidence and progression of OA, which, in turn, led to another hypothesis that OA is an independent metabolic risk factor for cardiovascular diseases [8, 9]. A series of cross-sectional

Cardiovascular and Functional

Capacity of Patients with Knee

Patients suffer from pain and disability and have associated reductions in muscle

and cardiopulmonary function. Patients with knee and hip OA have a 15–20% decrease in aerobic capacity. The reduced aerobic capacity of patients with lower limb osteoarthritis affects their independence in performing everyday activities. More research is needed to determine the optimal types and dosing of aerobic conditioning with osteoarthritis. Persons at risk for osteoarthritis have one or more of the following risk factors: age over 50, female gender, a first-order family member with OA, previous history of a major knee or hip injury or surgery, obesity, history of joint trauma, or a job requiring bending and carrying. Hip osteoarthritis can also be secondary to developmental defects. Disability not only reduces the quality of life for individuals but also jeopardizes their ability to live independently; it increases the risk of hospitalization, institutionalization, and mortality and is a

#### **Chapter 5**

lactones from different Arnica

preparations using a validated GC-MSD method. Journal of Pharmaceutical and Biomedical Analysis. 2007;43(1):32-38. DOI: 10.1016/j.jpba.2006.06.008

Osteoarthritis Biomarkers and Treatments

chondrocytes. Journal of Cellular and Molecular Medicine. 2018;22(1): 346-353. DOI: 10.1111/jcmm.13322

[86] Schwager J, Richard N, Fowler A, Seifert N, Raederstorff D. Carnosol and related substances modulate chemokine

and cytokine production in macrophages and chondrocytes. Molecules. 2016;21(4):465. DOI: 10.3390/molecules21040465

ptr.4612

[87] Staiger C. Comfrey: A clinical overview. Phytotherapy Research. 2012; 26(10):1441-1448. DOI: 10.1002/

[88] Committee on Herbal Medicinal Products (HMPC). Final European Union Herbal Monograph on

[89] Grube B, Grünwald J, Krug L, Staiger C. Efficacy of a comfrey root (Symphyti offic. radix) extract ointment in the treatment of patients with painful osteoarthritis of the knee: Results of a double-blind, randomised, bicenter, placebo-controlled trial. Phytomedicine. 2007;14(1):2-10. DOI: 10.1016/j.phymed.2006.11.006

[90] Committee on Herbal Medicinal Products (HMPC). Final Community Herbal Monograph on Juniperus communis L., aetheroleum. European Medicines Agency; 2010. Reference number: EMA/HMPC/12402/2010

[91] Committee on Herbal Medicinal Products (HMPC). Final Community Herbal Monograph on Rosmarinus officinalis L., aetheroleum; 2010. Reference number: EMA/HMPC/

235453/2009

Symphytum officinale L., radix. European Medicines Agency; 2015. Reference number: EMA/HMPC/572846/2009

[80] Jäger C, Hrenn A, Zwingmann J, Suter A, Merfort I. Phytomedicines prepared from Arnica flowers inhibit the transcription factors AP-1 and NFkappaB and modulate the activity of MMP1 and MMP13 in human and bovine chondrocytes. Planta Medica. 2009;75(12):1319-1325. DOI: 10.1055/s-

[81] Klaas CA, Wagner G, Laufer S, Sosa S, Della Loggia R, Bomme U, Pahl HL,

phytopharmaceuticals prepared from Arnica flowers. Planta Medica. 2002; 68(5):385-391. DOI: 10.1055/s-

[82] Verma N, Tripathi SK, Sahu D, Das HR, Das RH. Evaluation of inhibitory activities of plant extracts on production of LPS-stimulated pro-inflammatory mediators in J774 murine macrophages. Molecular and Cellular Biochemistry. 2010;336(1–2):127-135. DOI: 10.1007/

[83] Widrig R, Suter A, Saller R, Melzer J. Choosing between NSAID and arnica

osteoarthritis in a randomised, double-

International. 2007;27(6):585. DOI: 10.1007/s00296-007-0304-y

[84] Committee on Herbal Medicinal Products (HMPC). Final Community Herbal Monograph on Rosmarinus officinalis L., folium. European Medicines Agency; 2010. Reference number: EMA/HMPC/13633/2009

[85] Chen W-P, Jin G-J, Xiong Y, Hu P-F, Bao J-P, Wu L-D. Rosmarinic acid down-regulates NO and PGE2 expression via MAPK pathway in rat

for topical treatment of hand

blind study. Rheumatology

Merfort I. Studies on the antiinflammatory activity of

0029-1185668

2002-32067

s11010-009-0263-6

74

## Cardiovascular and Functional Capacity of Patients with Knee Osteoarthritis

*Zuhal Kunduracilar and Kartal Selici*

#### **Abstract**

Patients suffer from pain and disability and have associated reductions in muscle and cardiopulmonary function. Patients with knee and hip OA have a 15–20% decrease in aerobic capacity. The reduced aerobic capacity of patients with lower limb osteoarthritis affects their independence in performing everyday activities. More research is needed to determine the optimal types and dosing of aerobic conditioning with osteoarthritis. Persons at risk for osteoarthritis have one or more of the following risk factors: age over 50, female gender, a first-order family member with OA, previous history of a major knee or hip injury or surgery, obesity, history of joint trauma, or a job requiring bending and carrying. Hip osteoarthritis can also be secondary to developmental defects. Disability not only reduces the quality of life for individuals but also jeopardizes their ability to live independently; it increases the risk of hospitalization, institutionalization, and mortality and is a major driver of healthcare costs due to arthritis.

**Keywords:** osteoarthritis, cardiovascular disease, aerobic capacity, functıonal capacity

#### **1. Introduction**

Hypertension, diabetes mellitus, cardiovascular diseases, and osteoarthritis (OA) are the leading diseases of the most common disease clusters [1, 2]. Knee OA is a common health problem in the general population [3]. It is characterized by the abrasion of joint cartilage, changes in the extracellular matrix, subchondral bone ossification, and osteophyte formation [4]. The socioeconomic load of OA, which has a serious morbidity and disability rate, is very heavy. In the United States, 30.8 million patients with OA caused a medical expenditure of over 340 billion dollars between 2008 and 2011 [5]. The worldwide prevalence of symptomatic knee OA is increasing [6].

The most common localization of OA is the knee joint, and symptomatic knee OA affects 24% of the general population [7]. The fact that hypertension, diabetes, and cardiovascular diseases are found together with OA has led to the speculation of a metabolic "OA phenotype" [2]. It was hypothesized that obesity, dyslipidemia, impaired fasting blood sugar, and hypertension contribute to the incidence and progression of OA, which, in turn, led to another hypothesis that OA is an independent metabolic risk factor for cardiovascular diseases [8, 9]. A series of cross-sectional

studies showed a positive relationship between OA and cardiovascular diseases and metabolic syndrome [2, 10, 11].

In 2017, Kendzerska et al. in a study comprising 18,490 patients with 10.0% hip OA, 15.3% knee OA, and 16.3% hand OA found that 31.9% cardiovascular events occurred in approximately 13.4 years in these patients, especially in the knee OA group. They also mentioned that the walking difficulty in knee OA severely increased the risk of a cardiovascular event.

Many cardiovascular events could be prevented by managing OA, with an increase in the cardiovascular capacity and mobility [12]. A low socioeconomic level has been reported to be directly related to the incidence of age and obesity [13, 14]. A low income level, educational status, prolongation of life, and obesity were the important factors in the increase of OA in Brazil [15]. De Rezende et al. in their study comprising 198 patients with OA imparted a training to 150 of them. The physical activity level before the training was mild in 11 participants, moderate in 12 participants, and high in 2 participants, and after the training, it was mild in 74 participants, moderate in 40 participants, and high in 9 participants [15].

#### **2. Motivators and obstacles of physical activity in patients with knee OA**

Physical activity is especially accepted as a treatment method for patients with cardiovascular, vascular, and metabolic diseases. The World Health Organization recommends daily recreational or leisure activities, transportation, profession, household chores, games, sports, and planned exercises in the context of family and community activities [16]. Patients with OA typically have lower levels of physical activity compared with the general population [17].

In 2017, Kanavaki et al. conducted a systematic review of qualitative evidence on the inhibitors and facilitators of physical activity in knee and hip OA. A total of 5449 studies were identified; of these, 2657 abstracts were screened and 51 full texts were evaluated. Seven authors were contacted for more information. Ten studies with qualitative metadata that included 173 middle-aged patients were reviewed. The selected studies were found to be of moderate and high quality. The results suggested that half of the studies did not have a clear data analysis or were not well defined and only a few provided the desired characteristics. In the present study, the inhibitors and facilitators were examined under three conceptual headlines: physical health, interpersonal and psychological factors, and socioenvironmental factors. Facilitators in physical health included mobility, getting rid of symptoms, and health. Facilitators in interpersonal and psychological factors included beneficial exercise, information about exercise, maintaining motivation despite OA, organizations, prioritization, personal effort, responsibility, and the will to be physically more active. Facilitators in social environment included support from health professionals and social support to make the physical activity easier. Inhibitors in physical health included pain and other symptoms and perceived functional limitations. Inhibitors in interpersonal and psychological factors included non-effective physical activity, harmful or suspicious activity, loss of motivation, and loss of behavioral regulation. Inhibitors in social environment included lack of advice and encouragement from health workers, social comparison as demotivation, and lack of social support [18].

In 2017, Gay et al. conducted a qualitative study on the motivation and inhibitors for physical activity in patients with knee OA. A total of 27 patients with a mean age of 67 years were included in the study, of which 17 were women. The physical motivators for physical activity included well-being, reduced pain, and self-perception;

**77**

*Cardiovascular and Functional Capacity of Patients with Knee Osteoarthritis*

personal activity included life style and psychological well-being; social activity included relationships and opinions of friend circles; and for environmental activity included living conditions. The motivators were found to differ according to gender. Inhibitors for physical activity were as follows: psychological—fear of pain and lack of motivation and physical—knee pain and asthenia. Moreover, life events such as potential depression and hospitalization were also identified as inhibitors

Nociceptive and neuropathic pain accompanying the disease leads to disorders in mood and sleep, which, in turn, lead to a decrease in the quality of life [20]. In 2017, Aşkın et al. conducted a study comprising 60 patients with knee OA with neuropathic pain and found that 66.7% had significantly reduced functional capacities and quality of life as a result of the clinical evaluation carried out with the chair stand test. Although inhibitors and facilitators increase the effectiveness of treatment in the development of cardiovascular and functional capacity within OA management, they also help decrease the symptoms in a shorter period of time, contribute to the quality of life, and thus facilitate the decrease of morbidity-

In a recent meta-analytic study by Hall et al., 40% of patients with OA were found to have cardiovascular diseases and 10–14% of those who had diabetes mellitus together with OA also suffered from obesity and metabolic syndrome [22, 23]. Calders et al. performed a systematic review and meta-analysis in which 17 studies were examined. In this study, worsening OA-related pain was associated with comorbid disease. Studies also found that heart disease, hypertension, and diabetes mellitus associated with OA led to a further deterioration in physical

Chronic inflammation is a global major health problem that affects tens of millions of people in North America and Europe [25, 26]. The long-term use of nonsteroidal anti-inflammatory drugs in OA increased the blood pressure and even leads to heart attack, stroke, heart failure, arrhythmias, and sudden cardiac death. The presence of these diseases accompanied by OA increased the danger even more [27]. Among joint-related diseases, patients with osteoarthritis (OA) are the most prone to develop hypertension. This situation constitutes a risk factor for cardiovascular and cerebrovascular diseases [28]. Patients with OA have an increased risk of experiencing a stroke because of a decrease in the mobility [29]. With increasing elderly population, obesity and decreased physical activity have increased the incidence and prevalence of OA, which, on the other hand, have accelerated vascular comorbidity [30]. Along with vascular diseases, the overlap of OA prevalence has also raised the question of possible common mechanisms and the development of

The chronic or intermittent increase in systemic inflammation suggests a connection between OA and vascular diseases. OA is a noninflammatory systemic chronic disease. Systemic inflammatory mechanisms in OA are still being discussed [8, 31, 32]. For example, chronic and low-grade inflammation occurs with age, and OA is a disease that more often occurs with an advanced age. However, changes also occur in the blood immune system in these patients who were suggested to have a systemic change in the inflammatory process that is associated with OA independent of age [31, 33–35]. Among OA and cardiovascular diseases, there are inflammatory cytokines (e.g., interleukin-6) [36, 37], oxidative pathways [38, 39], and C-reactive protein containing [31, 40, 41] common inflammatory mediators.

preventive and therapeutic strategies for this situation [31].

*DOI: http://dx.doi.org/10.5772/intechopen.81680*

for physical activity [19].

induced deaths [21].

functioning [24].

**3. Comorbid diseases in OA**

*Cardiovascular and Functional Capacity of Patients with Knee Osteoarthritis DOI: http://dx.doi.org/10.5772/intechopen.81680*

personal activity included life style and psychological well-being; social activity included relationships and opinions of friend circles; and for environmental activity included living conditions. The motivators were found to differ according to gender. Inhibitors for physical activity were as follows: psychological—fear of pain and lack of motivation and physical—knee pain and asthenia. Moreover, life events such as potential depression and hospitalization were also identified as inhibitors for physical activity [19].

Nociceptive and neuropathic pain accompanying the disease leads to disorders in mood and sleep, which, in turn, lead to a decrease in the quality of life [20]. In 2017, Aşkın et al. conducted a study comprising 60 patients with knee OA with neuropathic pain and found that 66.7% had significantly reduced functional capacities and quality of life as a result of the clinical evaluation carried out with the chair stand test. Although inhibitors and facilitators increase the effectiveness of treatment in the development of cardiovascular and functional capacity within OA management, they also help decrease the symptoms in a shorter period of time, contribute to the quality of life, and thus facilitate the decrease of morbidityinduced deaths [21].

#### **3. Comorbid diseases in OA**

*Osteoarthritis Biomarkers and Treatments*

metabolic syndrome [2, 10, 11].

**knee OA**

increased the risk of a cardiovascular event.

activity compared with the general population [17].

studies showed a positive relationship between OA and cardiovascular diseases and

In 2017, Kendzerska et al. in a study comprising 18,490 patients with 10.0% hip OA, 15.3% knee OA, and 16.3% hand OA found that 31.9% cardiovascular events occurred in approximately 13.4 years in these patients, especially in the knee OA group. They also mentioned that the walking difficulty in knee OA severely

Many cardiovascular events could be prevented by managing OA, with an increase in the cardiovascular capacity and mobility [12]. A low socioeconomic level

has been reported to be directly related to the incidence of age and obesity [13, 14]. A low income level, educational status, prolongation of life, and obesity were the important factors in the increase of OA in Brazil [15]. De Rezende et al. in their study comprising 198 patients with OA imparted a training to 150 of them. The physical activity level before the training was mild in 11 participants, moderate in 12 participants, and high in 2 participants, and after the training, it was mild in 74

participants, moderate in 40 participants, and high in 9 participants [15].

**2. Motivators and obstacles of physical activity in patients with** 

Physical activity is especially accepted as a treatment method for patients with cardiovascular, vascular, and metabolic diseases. The World Health Organization recommends daily recreational or leisure activities, transportation, profession, household chores, games, sports, and planned exercises in the context of family and community activities [16]. Patients with OA typically have lower levels of physical

In 2017, Kanavaki et al. conducted a systematic review of qualitative evidence on the inhibitors and facilitators of physical activity in knee and hip OA. A total of 5449 studies were identified; of these, 2657 abstracts were screened and 51 full texts were evaluated. Seven authors were contacted for more information. Ten studies with qualitative metadata that included 173 middle-aged patients were reviewed. The selected studies were found to be of moderate and high quality. The results suggested that half of the studies did not have a clear data analysis or were not well defined and only a few provided the desired characteristics. In the present study, the inhibitors and facilitators were examined under three conceptual headlines: physical health, interpersonal and psychological factors, and socioenvironmental factors. Facilitators in physical health included mobility, getting rid of symptoms, and health. Facilitators in interpersonal and psychological factors included beneficial exercise, information about exercise, maintaining motivation despite OA, organizations, prioritization, personal effort, responsibility, and the will to be physically

more active. Facilitators in social environment included support from health professionals and social support to make the physical activity easier. Inhibitors in physical health included pain and other symptoms and perceived functional limitations. Inhibitors in interpersonal and psychological factors included non-effective physical activity, harmful or suspicious activity, loss of motivation, and loss of behavioral regulation. Inhibitors in social environment included lack of advice and encouragement from health workers, social comparison as demotivation, and lack

In 2017, Gay et al. conducted a qualitative study on the motivation and inhibitors for physical activity in patients with knee OA. A total of 27 patients with a mean age of 67 years were included in the study, of which 17 were women. The physical motivators for physical activity included well-being, reduced pain, and self-perception;

**76**

of social support [18].

In a recent meta-analytic study by Hall et al., 40% of patients with OA were found to have cardiovascular diseases and 10–14% of those who had diabetes mellitus together with OA also suffered from obesity and metabolic syndrome [22, 23]. Calders et al. performed a systematic review and meta-analysis in which 17 studies were examined. In this study, worsening OA-related pain was associated with comorbid disease. Studies also found that heart disease, hypertension, and diabetes mellitus associated with OA led to a further deterioration in physical functioning [24].

Chronic inflammation is a global major health problem that affects tens of millions of people in North America and Europe [25, 26]. The long-term use of nonsteroidal anti-inflammatory drugs in OA increased the blood pressure and even leads to heart attack, stroke, heart failure, arrhythmias, and sudden cardiac death. The presence of these diseases accompanied by OA increased the danger even more [27]. Among joint-related diseases, patients with osteoarthritis (OA) are the most prone to develop hypertension. This situation constitutes a risk factor for cardiovascular and cerebrovascular diseases [28]. Patients with OA have an increased risk of experiencing a stroke because of a decrease in the mobility [29]. With increasing elderly population, obesity and decreased physical activity have increased the incidence and prevalence of OA, which, on the other hand, have accelerated vascular comorbidity [30]. Along with vascular diseases, the overlap of OA prevalence has also raised the question of possible common mechanisms and the development of preventive and therapeutic strategies for this situation [31].

The chronic or intermittent increase in systemic inflammation suggests a connection between OA and vascular diseases. OA is a noninflammatory systemic chronic disease. Systemic inflammatory mechanisms in OA are still being discussed [8, 31, 32]. For example, chronic and low-grade inflammation occurs with age, and OA is a disease that more often occurs with an advanced age. However, changes also occur in the blood immune system in these patients who were suggested to have a systemic change in the inflammatory process that is associated with OA independent of age [31, 33–35]. Among OA and cardiovascular diseases, there are inflammatory cytokines (e.g., interleukin-6) [36, 37], oxidative pathways [38, 39], and C-reactive protein containing [31, 40, 41] common inflammatory mediators.

Inflammation leads to vascular endothelial dysfunction in places with previous cardiovascular events. Impaired flow-mediated dilation responses in patients with OA in this group showed a weak vascular endothelial function. This situation might be a marker for peripheral vascular dysfunction [31, 42].

Osteoprotegerin (OPG), which is a systemic vascular mechanism, a key in the bone resorption modifier, and associated with vascular endothelia, is one of the precursors of early atherosclerosis. OPG plays a role in both bone remodeling and atherosclerosis. OPG serum levels were found to be high in patients with advanced OA. A high OPG level may lead to the progression of OA and dysfunctional vascular remodeling [31, 43]. Khazraji et al. emphasized in a compilation study, examining the relationship between OA and cerebrovascular disease, that the common relationship between cerebrovascular hemodynamics and cognitive functions in people with and without OA risk needs to be explored [31].

The decrease in aerobic capacity in the lower extremity OA negatively affects independence in daily life activities. Studies have shown that various aerobic exercises, such as walking, running, cycling, aquatic exercises, and aerobic dance, have a positive effect on pain, joint stiffness, functional capacity, and aerobic capacity in patients with hip and knee OA [44]. Studies have stated that walking in patients with OA can improve aerobic capacity and physical activity without increasing the stress in the joints and can be used safely [45]. In 2011, Escalante et al. conducted a systematic review of the effect of exercises on functional aerobic capacity in patients with lower extremity OA. The study found that although aerobic exercise programs were recommended for patients with knee and hip OA, only a few randomized control studies were performed. They have stated that there was no consensus in terms of the content, duration, and frequency of the exercise programs, and the exercise programs including tai chi, aerobic, and mixed exercises had better results compared with hydrotherapy [45].

Although swimming is the ideal exercise for patients with OA, only a few studies have investigated the effect of regular swimming on vascular dysfunction and inflammation. Similar studies have shown that ground-based exercises have similar benefits. Alkatan et al. conducted a randomized controlled study with middle-aged patients with OA in 2016. One group was given supervised swimming and the other group cycling training for 12 weeks. After the training, central arterial stiffness determined by carotid femoral pulsation wave velocity decreased in both groups. Also, according to simultaneous ultrasonography and applanation tonometry, the carotid artery stiffness decreased. In the swimming group, the evaluation of the brachial flow-mediated dilation showed a development in vascular endothelial functions, but no change was observed in the cycling group [42].

#### **4. Factors affecting cardiovascular function and functional capacity**

Garza et al. conducted a study in the year 2017 with 33 patients aged more than 40. All the patients were diagnosed with OA. They have founded that decreased ischiotibial muscle flexibility reduced the functional capacity, also flexibility and functional capacity increased and pain decreased through exercise [46]. Obesity is considered to be one of the most important and potentially preventable risk factors for OA. Besides the mechanical load of obesity on OA, leptin, visfatin, adiponectin, and resistin were found to have metabolic effects on the pathogenesis and progression of adipokines and others. Obesity has an important role in the reduction of functional capacity in OA, as a result of the disability [47].

Difficulty in walking in people with hip and knee OA constitutes a great risk for all-cause mortality and cardiovascular events [48, 49]. In 2016, Hawker et al.

**79**

*Cardiovascular and Functional Capacity of Patients with Knee Osteoarthritis*

conducted a study using 1996 patients (with a mean age of 71.4 years) with hip and knee OA and found that 77.7% had hypertension, 54% had cardiovascular diseases, 42.9% had obesity, and 15.3% were smokers. The HAQ walking difficulty score in these patients was found to be two-third. This interval showed that these patients had medium-to-serious disabilities. Of these patients, 54.9% used a walking aid. An average of 6.1 years later, 184 people (51.3%) experienced one or more complications specific to diabetes; 5.7 years later, 191 patients experienced cardiovascular

**5. Approaches to increase cardiovascular function and functional** 

quality of life also led to a decrease in functional capacity [57].

Besides facilitating weight loss in the management of knee OA [51, 52], exercise is strongly recommended because of its positive changes in symptoms and functional capacity [53, 54]. The aquatic environment allows an individual to exercise because it reduces the load on the joints. Recent studies compared ground-based exercises with aquatic exercises in terms of lower extremities of patients with OA and found that aquatic exercises statistically significantly reduced the pain [55]. Kunduracılar et al. investigated the effect of two different aquatic exercises on pain, functional and exercise capacity, and balance with a program that lasted for 4 weeks, 5 days a week, implemented on 89 patients diagnosed with OA. They applied ground-based exercises together with lower extremity aquatic exercises to one group and ground-based exercises together with upper and lower extremity exercises and body exercises to the other group. The control group was only given ground-based exercises. All three groups were positively affected in terms of pain, balance, and functional capacity. However, the second group, where both exercises were given, was found to have the best outcome in terms of increased functional and exercise capacity [56]. Bernad-Pineda et al. conducted a study comprising 1849 patients with knee (61.5%) and hip (19%) OA in 2014 and found that a decrease in

The studies showed that exercise played an important role in the management of OA-related symptoms and also contributed to the functional capacity in the everyday life activities of the patients. In 2017, Peeler et al. went on with the hypothesis that unsafe and ineffective exercise practices might exacerbate the symptoms in the joint. They used a new treadmill, without the risk of exacerbation during exercises, in patients with pathology in the lower extremities, within a low-load exercise training that allows lower body positive pressure (LBPP). The treadmill uses a waist-high air chamber filled with positive air pressure (i.e., LBPP) to accurately and reliably diminish body weight during exercise. The 12-week LBPP-supported treadmill program in this study comprising 31 patients increased the functional capacity of the patients and allowed them to freely carry out their daily activities. The study concluded that the 12-week LBPP-supported treadmill program was a safe exercise for patients with mild and medium OA without exacerbating the symptoms [58]. Another way to strengthen the muscles via exercise is the whole-body vibration (WBV). In recent years, WBV has been used frequently to improve muscle performance [59]. Many studies have documented that WBV is very effective in increasing the functional capacity and metabolism in age-related muscle atrophies [60, 61]. In this training, contrary to the other exercise programs, less pressure was put on the joint. Recent studies have shown that this technique was statistically more successful in reducing symptoms and regaining functions in patients with OA [62]. Bokaeian et al. in a study in 2016 applied strengthening training for the quadriceps and hamstring muscles to a group with knee OA (n = 139) and the

*DOI: http://dx.doi.org/10.5772/intechopen.81680*

events [50].

**capacity**

*Cardiovascular and Functional Capacity of Patients with Knee Osteoarthritis DOI: http://dx.doi.org/10.5772/intechopen.81680*

conducted a study using 1996 patients (with a mean age of 71.4 years) with hip and knee OA and found that 77.7% had hypertension, 54% had cardiovascular diseases, 42.9% had obesity, and 15.3% were smokers. The HAQ walking difficulty score in these patients was found to be two-third. This interval showed that these patients had medium-to-serious disabilities. Of these patients, 54.9% used a walking aid. An average of 6.1 years later, 184 people (51.3%) experienced one or more complications specific to diabetes; 5.7 years later, 191 patients experienced cardiovascular events [50].

#### **5. Approaches to increase cardiovascular function and functional capacity**

Besides facilitating weight loss in the management of knee OA [51, 52], exercise is strongly recommended because of its positive changes in symptoms and functional capacity [53, 54]. The aquatic environment allows an individual to exercise because it reduces the load on the joints. Recent studies compared ground-based exercises with aquatic exercises in terms of lower extremities of patients with OA and found that aquatic exercises statistically significantly reduced the pain [55]. Kunduracılar et al. investigated the effect of two different aquatic exercises on pain, functional and exercise capacity, and balance with a program that lasted for 4 weeks, 5 days a week, implemented on 89 patients diagnosed with OA. They applied ground-based exercises together with lower extremity aquatic exercises to one group and ground-based exercises together with upper and lower extremity exercises and body exercises to the other group. The control group was only given ground-based exercises. All three groups were positively affected in terms of pain, balance, and functional capacity. However, the second group, where both exercises were given, was found to have the best outcome in terms of increased functional and exercise capacity [56]. Bernad-Pineda et al. conducted a study comprising 1849 patients with knee (61.5%) and hip (19%) OA in 2014 and found that a decrease in quality of life also led to a decrease in functional capacity [57].

The studies showed that exercise played an important role in the management of OA-related symptoms and also contributed to the functional capacity in the everyday life activities of the patients. In 2017, Peeler et al. went on with the hypothesis that unsafe and ineffective exercise practices might exacerbate the symptoms in the joint. They used a new treadmill, without the risk of exacerbation during exercises, in patients with pathology in the lower extremities, within a low-load exercise training that allows lower body positive pressure (LBPP). The treadmill uses a waist-high air chamber filled with positive air pressure (i.e., LBPP) to accurately and reliably diminish body weight during exercise. The 12-week LBPP-supported treadmill program in this study comprising 31 patients increased the functional capacity of the patients and allowed them to freely carry out their daily activities. The study concluded that the 12-week LBPP-supported treadmill program was a safe exercise for patients with mild and medium OA without exacerbating the symptoms [58].

Another way to strengthen the muscles via exercise is the whole-body vibration (WBV). In recent years, WBV has been used frequently to improve muscle performance [59]. Many studies have documented that WBV is very effective in increasing the functional capacity and metabolism in age-related muscle atrophies [60, 61]. In this training, contrary to the other exercise programs, less pressure was put on the joint. Recent studies have shown that this technique was statistically more successful in reducing symptoms and regaining functions in patients with OA [62]. Bokaeian et al. in a study in 2016 applied strengthening training for the quadriceps and hamstring muscles to a group with knee OA (n = 139) and the

*Osteoarthritis Biomarkers and Treatments*

Inflammation leads to vascular endothelial dysfunction in places with previous cardiovascular events. Impaired flow-mediated dilation responses in patients with OA in this group showed a weak vascular endothelial function. This situation might

Osteoprotegerin (OPG), which is a systemic vascular mechanism, a key in the bone resorption modifier, and associated with vascular endothelia, is one of the precursors of early atherosclerosis. OPG plays a role in both bone remodeling and atherosclerosis. OPG serum levels were found to be high in patients with advanced OA. A high OPG level may lead to the progression of OA and dysfunctional vascular remodeling [31, 43]. Khazraji et al. emphasized in a compilation study, examining the relationship between OA and cerebrovascular disease, that the common relationship between cerebrovascular hemodynamics and cognitive functions in people

The decrease in aerobic capacity in the lower extremity OA negatively affects independence in daily life activities. Studies have shown that various aerobic exercises, such as walking, running, cycling, aquatic exercises, and aerobic dance, have a positive effect on pain, joint stiffness, functional capacity, and aerobic capacity in patients with hip and knee OA [44]. Studies have stated that walking in patients with OA can improve aerobic capacity and physical activity without increasing the stress in the joints and can be used safely [45]. In 2011, Escalante et al. conducted a systematic review of the effect of exercises on functional aerobic capacity in patients with lower extremity OA. The study found that although aerobic exercise programs were recommended for patients with knee and hip OA, only a few randomized control studies were performed. They have stated that there was no consensus in terms of the content, duration, and frequency of the exercise programs, and the exercise programs including tai chi, aerobic, and mixed exercises

Although swimming is the ideal exercise for patients with OA, only a few studies

have investigated the effect of regular swimming on vascular dysfunction and inflammation. Similar studies have shown that ground-based exercises have similar benefits. Alkatan et al. conducted a randomized controlled study with middle-aged patients with OA in 2016. One group was given supervised swimming and the other group cycling training for 12 weeks. After the training, central arterial stiffness determined by carotid femoral pulsation wave velocity decreased in both groups. Also, according to simultaneous ultrasonography and applanation tonometry, the carotid artery stiffness decreased. In the swimming group, the evaluation of the brachial flow-mediated dilation showed a development in vascular endothelial

**4. Factors affecting cardiovascular function and functional capacity**

Garza et al. conducted a study in the year 2017 with 33 patients aged more than 40. All the patients were diagnosed with OA. They have founded that decreased ischiotibial muscle flexibility reduced the functional capacity, also flexibility and functional capacity increased and pain decreased through exercise [46]. Obesity is considered to be one of the most important and potentially preventable risk factors for OA. Besides the mechanical load of obesity on OA, leptin, visfatin, adiponectin, and resistin were found to have metabolic effects on the pathogenesis and progression of adipokines and others. Obesity has an important role in the reduction of

Difficulty in walking in people with hip and knee OA constitutes a great risk for all-cause mortality and cardiovascular events [48, 49]. In 2016, Hawker et al.

functions, but no change was observed in the cycling group [42].

functional capacity in OA, as a result of the disability [47].

be a marker for peripheral vascular dysfunction [31, 42].

with and without OA risk needs to be explored [31].

had better results compared with hydrotherapy [45].

**78**

WBV technique along with the strengthening exercises to another group (n = 15) in three sessions per week for a total of 8 weeks. The results showed an increase in quadriceps muscle strength and functional activity [63]. In 2017, Waller et al. conducted a 4-month program of postmenopausal high-intensity aquatic resistance training, which included 87 postmenopausal patients with mild OA, to examine its effect on body composition and walking speed of the patients. After the study, the patients were followed up for 12 months. The findings revealed that the walking speed increased and the cardiovascular system developed; however, while the gains in the increased walking speed were maintained, the cardiovascular gains were lost in the 12-month follow-up [64].

### **6. Conclusion**

In conclusion, the assessment of cardiovascular and functional capacity and the inclusion of training programs in the treatment of OA reduced the load of the disease. Besides, these programs could reduce the frequency of comorbid illnesses, hospital admissions, and deaths associated with OA. It could increase the quality of life of the patients and is believed to make positive changes on survival. However, further studies in this regard might be more beneficial, and OA grievances should be prioritized in health policies.

### **Conflict of interest**

The authors declare no conflict of interest.

### **Author details**

Zuhal Kunduracilar1 \* and Kartal Selici<sup>2</sup>

1 Department of Physiotherapy and Rehabilitation, Afyon School of Health, Afyonkarahisar Health Sciences University, Afyonkarahisar, Turkey

2 Department of Physiotherapy and Rehabilitation, Health Sciences Faculty, Zonguldak Bülent Ecevit University, Zonguldak, Turkey

\*Address all correspondence to: zuhalkun@gmail.com

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**81**

*Cardiovascular and Functional Capacity of Patients with Knee Osteoarthritis*

effect of osteoarthritis definition on prevalence and incidence estimates: A systematic review. Osteoarthritis and Cartilage. 2011;**19**(11):1270- 1285. Available from: http://www. sciencedirect.com/science/article/pii/

[8] Berenbaum F. Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!). Osteoarthritis and Cartilage. 2013;**21**(1):16-21. Available from: http://www.sciencedirect.com/ science/article/pii/S1063458412010254

[9] Zhuo Q , Yang W, Chen J, Wang Y. Metabolic syndrome meets osteoarthritis. Nature Reviews Rheumatology. 2012;**8**:729. DOI: 10.1038/nrrheum.2012.135

[10] Liu S-H, Waring ME, Eaton CB, Lapane KL. Association of objectively measured physical activity and

metabolic syndrome among U.S. adults with osteoarthritis. Arthritis Care & Research. 2015;**67**(10):1371-1378. Available from: http://www.ncbi.nlm. nih.gov/pmc/articles/PMC4573382/

[11] Yoshimura N, Muraki S, Oka H, Tanaka S, Kawaguchi H, Nakamura K, et al. Accumulation of metabolic risk factors such as overweight, hypertension, dyslipidaemia, and impaired glucose tolerance raises the risk of occurrence and progression of knee osteoarthritis: A 3-year follow-up of the ROAD study. Osteoarthritis and Cartilage. 2012;**20**(11):1217- 1226. Available from: http://www. sciencedirect.com/science/article/pii/

[12] Kendzerska T, Jüni P, King LK, Croxford R, Stanaitis I, Hawker GA. The longitudinal relationship between hand, hip and knee osteoarthritis and cardiovascular events: A populationbased cohort study. Osteoarthritis and Cartilage. 2017;**25**(11):1771-1780.

S1063458412008618

S1063458411002457

*DOI: http://dx.doi.org/10.5772/intechopen.81680*

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[2] Puenpatom RA, Victor TW. Increased prevalence of metabolic syndrome in individuals with osteoarthritis: An analysis of NHANES III data. Postgraduate Medicine. 2009;**121**(6): 9-20. DOI: 10.3810/pgm.2009.11.2073

pmc/articles/PMC4262985/

[3] Jiang L, Rong J, Zhang Q , Hu F, Zhang S, Li X, et al. Prevalence and associated factors of knee osteoarthritis in a community-based population in Heilongjiang, Northeast China. Rheumatology International. 2012;**32**(5):1189-1195. DOI: 10.1007/

[4] Kluzek S, Newton JL, Arden NK. Is osteoarthritis a metabolic disorder? British Medical Bulletin. 2015;**115**(1):111-121. DOI: 10.1093/bmb/

[5] Yelin E, Weinstein S, King T. The burden of musculoskeletal diseases in the United States. Seminars in Arthritis and Rheumatism. 2016;**46**(3):259-260.

sciencedirect.com/science/article/pii/

[6] Silverwood V, Blagojevic-Bucknall M, Jinks C, Jordan JL, Protheroe J, Jordan KP. Current evidence on risk factors for knee osteoarthritis in older adults: A systematic review and metaanalysis. Osteoarthritis and Cartilage. 2015;**23**(4):507-515. Available from: http://www.sciencedirect.com/science/

article/pii/S1063458414013429

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s00296-010-1773-y

ldv028

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*Osteoarthritis Biomarkers and Treatments*

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be prioritized in health policies.

**Conflict of interest**

**80**

**Author details**

**6. Conclusion**

Zuhal Kunduracilar1

provided the original work is properly cited.

\* and Kartal Selici<sup>2</sup>

The authors declare no conflict of interest.

Zonguldak Bülent Ecevit University, Zonguldak, Turkey

\*Address all correspondence to: zuhalkun@gmail.com

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

1 Department of Physiotherapy and Rehabilitation, Afyon School of Health,

WBV technique along with the strengthening exercises to another group (n = 15) in three sessions per week for a total of 8 weeks. The results showed an increase in quadriceps muscle strength and functional activity [63]. In 2017, Waller et al. conducted a 4-month program of postmenopausal high-intensity aquatic resistance training, which included 87 postmenopausal patients with mild OA, to examine its effect on body composition and walking speed of the patients. After the study, the patients were followed up for 12 months. The findings revealed that the walking speed increased and the cardiovascular system developed; however, while the gains in the increased walking speed were maintained, the cardiovascular gains

In conclusion, the assessment of cardiovascular and functional capacity and the inclusion of training programs in the treatment of OA reduced the load of the disease. Besides, these programs could reduce the frequency of comorbid illnesses, hospital admissions, and deaths associated with OA. It could increase the quality of life of the patients and is believed to make positive changes on survival. However, further studies in this regard might be more beneficial, and OA grievances should

2 Department of Physiotherapy and Rehabilitation, Health Sciences Faculty,

Afyonkarahisar Health Sciences University, Afyonkarahisar, Turkey

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and pain in patients with knee

article/pii/S166557961730042X

S1043466618302692

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cardiovascular disease: A review of initiators and protective factors. Inflammopharmacology. 2016;**24**(1):1- 10. DOI: 10.1007/s10787-015-0255-y

of mitogen-activated protein kinases and nuclear factor-κB in human osteoarthritis chondrocytes. Rheumatology (Oxford, England). 2011;**50**(5):838-851. Available from: http://www.ncbi.nlm.nih.gov/pmc/

articles/PMC3077911/

2017;**30**(02):128-133

articles/PMC2713363/

NEJM199901143400207

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**84**

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[53] C Hochberg M, D Altman R, April K, Benkhalti M, Guyatt G, Mcgowan J, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in

osteoarthritis of the hand, hip, and knee. Arthritis Care & Research. 2012;**64**:465-474

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**87**

Section 4

Bone Changes in OA

Section 4
