Aging Clinical and Experimental Research

https://doi.org/10.1007/s40520-019-01191-w

REVIEW

Nutrition, osteoarthritis and cartilage metabolism

Osvaldo Daniel Messina1 · Maritza Vidal Wilman2   · Luis F. Vidal Neira2,3

Received: 19 February 2019 / Accepted: 2 April 2019

© Springer Nature Switzerland AG 2019

Abstract
Background  Osteoarthritis (OA) is a degenerative joint disease and a leading cause of adult disability. There is no cure for
OA and there is no effective treatment to stop its progression. Current pharmacologic treatments such as analgesics and
non-steroidal anti-inflammatory drugs may improve the pain and offer some relief but they do not affect the progression of
the disease. The chronic intake of these drugs may result in severe adverse events. The aim of this review is to revise the
effects of nutrition on cartilage metabolism and OA progression.
Methods  A systematic literature search was performed including those related to macro- and micro-nutrients’ actions on
cartilage and OA outcome. We selected peer-reviewed articles reporting the results of human clinical trials.
Results  Glucosamine and chondroitin sulfate have shown to delay OA knee progression in several clinical trials. The effec-
tiveness of some products considered nutraceuticals has been widely reviewed in the literature. This article presents a general
description of the effectiveness and mechanism of action of nutrients, vitamins, antioxidants and other natural components
considered as part of the normal diet. Many in vitro studies indicate the efficacy of specific nutrients in cartilage metabolism
and its involvement in OA. However, rigorous clinical studies needed to evaluate the efficacy of these compounds in humans
are still missing. The influence of nutrients and diet on the metabolism of cartilage and OA could represent a long-term
coadjuvant alternative in the management of patients with OA. Effects of diet modifications on lipid and cholesterol profiles,
adequate vitamin levels and weight reduction in obese patients could influence the course of the disease.
Conclusion  This review demonstrates that nutrition can improve the symptoms of OA. Glucosamine and chondroitin sulfate
have shown robustly to delay the progression of knee OA in several well-designed studies, however more controlled clinical
trials are needed to conclude that nutritional changes slow down the progression of the disease.

Keywords  Osteoarthritis · Cartilage · Nutrition · Cartilage metabolism

Introduction physical properties include resistance to stress and compres-

sion forces, as well as the ability to adapt to pressure [1].
Articular cartilage is a specialized type of hyaline tissue Chondrocytes are the only type of cell present in the car-
that covers the surface of the bones in the synovial joints, tilage and represent 1–5% of the cartilage and are embedded
favoring the sliding of the joint surfaces and improving fric- in an amorphic extracellular matrix composed mainly by
tion during movements. This avascular and aneural tissue is collagen which is responsible for force tension and proteo-
nourished by synovial fluid and subchondral bone, and its glycans that provide compression resistance to cartilage [2].
OA is the most prevalent form of joint disease and a
growing cause of disability worldwide. Globally, 18% of
* Maritza Vidal Wilman women and 9.6% of men aged over 60 years have sympto-
maritza.vidal55@hotmail.com matic OA with a quarter of these individuals unable to per-
1
Rheumatology IRO Medical Center and Hospital C
form routine daily activities. By 2050, a projected number
Argerich, Member of the Board of Governance, International of 130 million people will suffer from OA, constituting a
Osteoporosis Foundation (IOF), Buenos Aires, Argentina societal burden [3, 4].
2
Centro de Diagnóstico de Osteoporosis y Enfermedades The natural products used by patients to relieve symptoms
Reumáticas (CEDOR), Lima, Peru are now globally available and can be helpful in maintaining
3
Member of International Osteoporosis Foundation, Latin bone and joint health. Nutraceuticals, food or food products
America (IOF–LATAM), Lima, Peru

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 Aging Clinical and Experimental Research

that provide medical health benefits, including prevention How does cartilage nourish?
and/or treatment of diseases, offer not only a safe alternative
to the current pharmacological therapies, but they can also Articular cartilage is avascular and is nourished by syno-
modify the symptoms in OA [5, 6]. vial fluid and subchondral vessels [1]. Experimental evi-
This review will focus mainly on the nutrients that usu- dence from animal models has shown that immature carti-
ally conform to a normal diet, but also nutraceuticals such lage can be nourished in both ways, but in mature animals,
as glucosamine, chondroitin and avocado/soybean unsaponi- the predominant source is synovial fluid due to the dense
fiables for the OA. calcified barrier of subchondral bone that could limit the
The efficacy of certain nutraceuticals such as glucosa- diffusion of fluid and soluble substances through the vas-
mine sulfate, chondroitin sulfate and avocado/soybean unsa- cular channels [1, 16].
ponifiables for the OA is widely reviewed in the literature Subchondral mechanism has been debated [17, 18];
and are considered as slow-acting drugs for osteoarthritis however, it has been reported that subchondral bone’s
(SYSADOAs) with robust evidence on OA symptoms and blood vessels may expand and penetrate the adjacent calci-
disease-modifying effects in the long term for some of these fied cartilage through channels and the nutrients may reach
products [7–10]. the cartilage through these perforations. This theory sup-
Multiple formulations for glucosamine and chondroi- ports the importance of this pathway for cartilage nourish-
tin are available, in some countries they are in a condition ment. It was postulated that 50% of glucose requirements,
of sale under medical prescription and in others as over- oxygen and water are given by perfusion from subchondral
the-counter products, but the latter may include different vessels [2, 19].
amounts of glucosamine and chondroitin, or in the case of Subchondral bone vascularization development corre-
glucosamine is composed of a different substance, mainly as lates with stress distribution and compressive forces acting
glucosamine hydrochloride, with a different efficacy profile on the cartilage and subchondral bone [19]. It has been
[11]. reported in animal models that calcified cartilage was per-
The efficacy of products for prescription-grade glucosa- meable to the diffusion of low-molecular weight solutes
mine and chondroitin have proven efficacy in controlled and and cyclic changes in the joint might favor the diffusion
properly designed clinical trials and have been subject to of large molecules to the cartilage [20]. Signal molecules
strict regulatory control. Over-the-counter products usually to maintain the communication and functional association
lack controlled clinical trials and may differ in the pharma- between calcified cartilage and subchondral bone (Osteo-
ceutical formulation or molecular form and purity [5, 11]. chondral Unit) may also reach cartilage and bone through
The recommendation to use only pharmaceutical-grade subchondral vessels and the osteocyte lacuna-canalicular
preparations for glucosamine sulfate (pCGS) and chondroi- network of bone [21].
tin sulfate is clearly supported by the recent guidelines [5].
Forty-seven percent of adults use alternative medica-
tions non-prescribed for the management of OA. Several
reports and reviews analyze the potential protective effects Proteins, amino acids and lipids in cartilage
of nutrients on cartilage metabolism and the development and osteoarthritis
of OA such as antioxidants (epicatechin, epigallocatechin
3-gallate EGCG, resveratrol), vitamin D, E and C, curcumin, Glucose is the main source of energy for chondrocytes, but
pomegranate extracts, omega 3 fatty acid, and Psidium gua- lipids in cartilage are also needed as an energy source for
java (guava) [12–14]. However, in some trials, the quality of these cells; additionally, they are incorporated as structural
these products is poorly regulated and their efficacy, toxicity components and signaling molecules and they represent
and mechanisms of action are largely unknown. about 1% of the dry weight of the cartilage. The cartilage
Interestingly, green-lipped mussel extract (GLM, Perna is also a tissue in which eicosanoids—derived from ara-
canaliculus) and glucosamine sulfate reduced OA symptoms chidonic acid—are actively produced [22, 23].
and induced changes in the microbiota profile, with a reduc- Amino acids (AA), in addition to being involved in the
tion in the Clostridia sp. in a clinical study being the most formation of proteins, are also precursors of a series of
notable. This finding suggests that nutritional supplements low-molecular weight molecules such as serotonin, dopa-
such as both used in this study may influence some of the mine, glucosamine, creatine, nitric oxide and others with
metabolic and immunological activities of the gastrointesti- important activities and functions [24, 25].
nal tract microbiota. This fact was consistent with a decrease Metabolomics analysis could quantitatively detect many
in inflammation and improved OA symptoms. Microbiota small-molecule metabolites in a sample (body fluids, cell,
may be important in the first-pass metabolism of these nutra- tissues), and it has been used to investigate the metabolic
ceuticals [15].

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changes and biomarkers in OA [25, 26]. Amino acids’ cartilage degeneration, lowering the risk of pain worsening
profile alterations have been identified in serum, synovial and symptoms in patients with knee OA [34, 35].
fluid and urine samples from OA patients [25]. The find- The Western-type diet rich in red meat, high-fat dairy
ing that most serum AA levels were altered, suggest that products and refined grains has been associated with higher
metabolism and profiles of AA are also involved in the levels of CRP and IL-6 (proinflammatory diet), in contrast
pathogenesis of OA [24]. with Mediterranean diet, which is rich in fish and high in
Among the lipids, cholesterol and fatty acids are the most whole grains, green vegetables and fruits, and is thus asso-
involved in the pathophysiology of articular cartilage. Lipids ciated with lower levels of inflammation [35, 36]. Veronese
may be available for chondrocytes directly from synovial in a longitudinal cohort study with a follow-up period of
fluid or by “de novo” synthesis, because these cells contain 4 years demonstrated that higher adherence to Mediterra-
the proteins necessary for the metabolism of fatty acids and nean diet is associated with a lower risk of pain worsening
the synthesis of cholesterol [23]. and symptomatic forms of knee OA [37].
The cellular membrane of the chondrocytes has a high
cholesterol content which emphasizes its structural impor-
tance; in addition the mature cartilage contains a high Role of vitamins and micronutrients
amount of saturated fatty acids, linoleic acid, oleic acid and in cartilage and osteoarthritis
palmitic acid [23, 27]. The total composition of the fatty
acids in the cartilage can be modulated by the intake of fatty Vitamins with antioxidant properties retard or inhibit the
acids with the diet. In animal models, it has been shown that oxidation of substrates susceptible to attack by reactive oxy-
diets containing high levels of omega 3 (ω-3), and fatty acids gen species (ROS); its protective role has been evaluated in
may decrease the content of arachidonic and linoleic acid, different chronic diseases.
and decreasing proteoglycan synthesis may damage articular There are important methodological issues when analyz-
cartilage [27, 28]. ing the association between vitamins and micronutrients
It is considered that the most important role of fatty acids with the onset, progression or control of symptoms of osteo-
in cartilage is its conversion to eicosanoids; and ω-3 and ω-6 arthritis that make it difficult to draw definite conclusions.
fatty acids are substrates for the cyclooxygenase and lipoxy- Among the problems are the enough number of participants
genase enzymes that synthesize prostaglandins and leukot- in the clinical trials, the lack of adequate control groups and
rienes, the former with anti-inflammatory properties and the the chemical, source and nature of the evaluated vitamin or
latter with proinflammatory and prothrombotic actions [29]. micronutrient [38].
The osteoarthritic cartilage has high amounts of fatty Ethnicity can probably influence some dietary prefer-
acids and an increased expression of metalloproteinases ences, pain disparities, and the poor absorption of certain
(MMPs), and cyclooxygenase and lipoxygenase-derived vitamins such as vitamin D for the skin in people with dark
eicosanoids, which can contribute to the pathogenesis of skin, but also in the prevalence and the requirement of
OA [22, 28]. major procedures as total knee arthroplasty in osteoarthritis
The effect of lipids on OA is still a matter of debate; fatty [39–41].
acids could alter the cartilage destruction process, but the Some vitamins with antioxidant properties such as
individual effects of each fatty acid appear to be different. tocopherol (vitamin E), precursors of vitamin A, carot-
Linoleic acid has a proinflammatory effect, while oleic acid enoids and ascorbate (vitamin C) may provide some protec-
and palmitic acid seem to inhibit cartilage destruction and tion against cellular injury when intracellular antioxidant
inflammation [30]. enzymes have been overwhelmed; since these micronutri-
Wang found a correlation between the intake of ω-6 ents are obtained from the diet, it is postulated that a high
fatty acids and the development of bone marrow lesions but intake could have a protective effect against diseases related
without volume loss in the cartilage [31]. In asymptomatic to aging [13]. MacAllindon did not find a significant associa-
women without clinical evidence of knee OA, elevated lev- tion between the intake of antioxidant micronutrients includ-
els of cholesterol and triglycerides were associated with the ing vitamin C, E and carotene with the incidence of OA of
development of incidental bone marrow lesions during a the knees, but subjects in the higher tertile intake of vitamin
2-year follow-up period [32]. However, Dorée found that C had a reduced risk of developing knee pain [12]. After
HDL cholesterol was associated with a decrease in the size controlling the confounding variables, Peregoy found that
and resolution of bone marrow lesions and rather seemed vitamin C supplementation may be beneficial in preventing
to have a protective effect against incidental bone marrow incident OA of the knees in the Clearwater Osteoarthritis
lesions [33]. Study [42].
Some authors also pointed the benefits of olive oil and Some clinical studies have shown contradictory results,
the Mediterranean diet in ameliorating the progression of one study found that patients with knee OA who consumed

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 Aging Clinical and Experimental Research

vitamin C and E in the highest tertile had an increased risk association between decreased levels of vitamin D and the
of knee OA compared with those in the lower tertile [43]. In risk of increased loss of joint cartilage in OA [58]; however,
other studies, the association is contradictory or even nega- Zhang reported that vitamin D deficiency was associated
tive [44, 45]. In rural Japanese inhabitants, the mean tertile with an increased risk of radiological progression of knee
of alpha-tocopherol intake had a lower risk of OA, but did OA [59].
not find this association in the superior tertile [46]. Finally, different studies have analyzed the effect of vita-
Chin suggests that high levels of antioxidants such as min D supplements on the symptoms and progression of
vitamin E may act as pro-oxidants and cause articular car- OA. McAlindon found that vitamin D supplementation at the
tilage damage, so there could be a U-shaped relationship right dose raised the plasma levels of vitamin D to 36 ng/mL
between vitamin E and joint health, which would be ben- or more but it did not reduce pain or loss of joint volume in
eficial at low concentrations and harmful at high concentra- patients with symptomatic knee OA [60]. Jin reported that
tions. Finally, the different isoforms of vitamin E may have vitamin D supplementation for 2 years did not prevent the
different biological effects, but most studies have focused loss of articular cartilage and did not improve the pain in
on alpha-tocopherol [47]. However, the available informa- subjects with symptomatic knee OA [61]. On the contrary,
tion is not conclusive about a beneficial effect of antioxidant Sanghi reported a small benefit of vitamin D supplementa-
vitamin supplements to recommend their intake beyond a tion in reducing pain and improving function in patients with
healthy diet that includes adequate amounts of these nutri- OA [62]. Zheng, in a post hoc analysis of the VIDEO study,
ents [48]. found small benefit in slowing the loss of joint cartilage,
Vitamin K is involved in the mineralization of bone and reducing joint inflammation and improving physical function
cartilage, and the association with OA has been evaluated in in subjects with OA [63].
different studies, particularly focused on vitamin K1 (phyl- Despite the available evidence, it would be premature to
loquinone). Some cross-sectional studies have shown that make any conclusion or recommendation about the efficacy
decreased serum vitamin K1 levels are associated with a of vitamins in reducing the development or progression of
higher prevalence of OA of the knees and hands [49, 50]. In OA, and it is clear that more research is needed to clarify
longitudinal studies, subclinical vitamin K deficiency was this topic.
associated with an increased risk of developing radiologi- Among minerals, magnesium is the second most abun-
cal changes of knee OA and cartilage lesions on MRI [51], dant intracellular cation and one of the most important
and in subjects with very low levels of vitamin K, a greater micronutrients for human health and is strongly associated
progression of articular cartilage and meniscus damage was with immune responses. Some evidence shows a probable
observed [52]. relationship between magnesium and OA. Decreased lev-
However; a randomized clinical trial in which the effect els of magnesium and calcium have been found in endemic
of vitamin K1 was compared with placebo, found no effect areas of OA, and in a study of twin women with OA, reduced
on radiographic OA of the hands. Only subjects who were levels of serum magnesium were found [64, 65].
deficient in this vitamin at baseline and who reached enough It is postulated that magnesium deficiency might cause an
concentrations during follow-up had a benefit in joint space uncontrolled growth of crystals with high calcium content
narrowing at the end of the study [53]. in the cartilage causing damage to this tissue. In addition,
In another clinical study in older adults, the elevated sta- magnesium seems to promote the differentiation and viabil-
tus of vitamin K1 was associated with better scores of physi- ity of chondrocytes [66]. Animal models have shown that
cal performances at baseline, although the longitudinal data magnesium may also play a role in pain by altering cytosine
was less consistent, the authors suggest that this vitamin and neurotransmitter levels [67]. Additionally, magnesium
is important in maintaining function but does not alter the has been linked to the immune response, and reduced levels
functional decline rate [54]. of magnesium in the diet have been associated with elevated
The role of vitamin D in the risk of developing OA is C-reactive protein and other inflammatory markers, suggest-
controversial and Heidari found significantly decreased lev- ing a role in low-grade inflammation that could participate
els of vitamin D in subjects under 60 years old with OA of in the initiation and progression of OA [68, 69].
the knees in relation to controls, consistent with the onset A cross-sectional study found a modest but significant
of early OA [55], and Chaganti reported that men deficient inverse relationship between magnesium intake and the
in vitamin D were twice as likely to develop radiological radiographic incidence of knee OA in white participants,
hip OA [56]. but not in black subjects [70], and a prospective cohort
Other clinical trials and meta-analysis have tried to assess study in patients with radiological OA of the knees found
vitamin D status and the risk of progression of OA; Ber- that low magnesium intake was associated with greater pain
gink found that low vitamin D intake increased the progres- and poorer outcomes in functional tests in patients with OA
sion of radiological OA of the knees [57]. Felson found no with low dietary fiber intake [71].

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Aging Clinical and Experimental Research

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