Review Open Access
Copyright ©2014 Baishideng Publishing Group Inc. All rights reserved.
World J Rheumatol. Nov 12, 2014; 4(3): 22-34
Published online Nov 12, 2014. doi: 10.5499/wjr.v4.i3.22
Oral creatine supplementation: A potential adjunct therapy for rheumatoid arthritis patients
Thomas J Wilkinson, Thomas D O’Brien, Andrew B Lemmey
Thomas J Wilkinson, Thomas D O’Brien, Andrew B Lemmey, School of Sport, Health and Exercise Sciences, Bangor University, Wales LL57 2PZ, United Kingdom
Thomas D O’Brien, Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, England L3 3AF, United Kingdom
Author contributions: Wilkinson TJ gathered literature information and drafted manuscript; O’Brien TD and Lemmey AB advised on search methodology and critically revised the manuscript.
Correspondence to: Andrew B Lemmey, Professor, School of Sport, Health and Exercise Sciences, Bangor University, George Building, Normal Site, Holyhead Road, Wales LL57 2PZ, United Kingdom. a.b.lemmey@bangor.ac.uk
Telephone: +44-1248-383932
Received: June 28, 2014
Revised: September 19, 2014
Accepted: October 1, 2014
Published online: November 12, 2014

Abstract

Creatine is one of the most popular forms of protein supplements and is known to improve performance in healthy athletic populations via enhanced muscle mass and adenosine triphosphate energy regeneration. Clinical use of creatine may similarly benefit patients with rheumatoid arthritis (RA), an inflammatory condition characterised by generalised muscle loss termed “rheumatoid cachexia”. The adverse consequences of rheumatoid cachexia include reduced strength, physical function and, as a consequence, quality of life. Whilst regular high-intensity exercise training has been shown to increase muscle mass and restore function in RA patients, this form of therapy has very low uptake amongst RA patients. Thus, acceptable alternatives are required. The aim of this review is to consider the potential efficacy of creatine as an anabolic and ergonomic therapy for RA patients. To date, only one study has supplemented RA patients with creatine, and the findings from this investigation were inconclusive. However, trials in populations with similar losses of muscle mass and function as RA, including older adults and those with other muscle wasting conditions, indicate that creatine is an efficacious way of improving muscle mass, strength and physical function, and may offer an easy, safe and cheap means of treating rheumatoid cachexia and its consequences.

Key Words: Creatine supplementation, Nutritional supplement, Rheumatoid arthritis, Rheumatoid cachexia, Physical function

Core tip: Creatine supplementation primarily improves physical function by enhancing the re-synthesis of adenosine triphosphate via increased stores of phosphocreatine in the muscle. Through this pathway it provides greater levels of energy during physical activity and improves recovery. Creatine also augments muscle protein synthesis, thereby increasing muscle mass. These dual effects increase strength, reduce fatigue, and thereby improve function. In patients with conditions such as rheumatoid arthritis that are characterised by muscle loss and subsequent reductions in strength and physical function, creatine offers a potential therapeutic intervention for augmenting muscle mass and function that is safe, easy and inexpensive to administer.



INTRODUCTION

Patients with rheumatoid arthritis (RA) often experience a substantial loss of muscle mass (cachexia), which results in significant adverse consequences such as decreased strength, impaired physical function, and a reduction in quality of life. Unfortunately, current drug treatments for RA do not attenuate this muscle loss, nor fully restore physical function[1,2], and whilst exercise has been shown to be effective in restoring both muscle mass and function in RA patients (e.g.,[3]) the lack of uptake and adherence to sufficiently intense training means this form of therapy is unlikely to be widely adopted. Nutritional supplements offer a potential alternate therapeutic intervention that would be more easily adopted. One such nutritional supplement is oral administration of creatine (Cr). Creatine is a popular form of protein supplementation that has been widely demonstrated to improve physical function via enhanced energy regeneration and increased muscle mass[4]. Consequently, Cr supplementation potentially offers a low-cost and generally acceptable means for RA patients to restore muscle mass and functional capacity.

This article reviews the evidence regarding the potential of Cr as an adjunct treatment to improve muscle mass and function in RA patients. In the course of doing this, rheumatoid cachexia, its effect on patients, and the rationale for nutritional supplementation (such as Cr) to improve body composition and physical function will be discussed. Then the mechanisms and effectiveness of Cr in athletic populations will be described before we present a review of the existing evidence regarding the efficacy of Cr in RA-relevant clinical trials.

RHEUMATOID ARTHRITIS, CACHEXIA AND MUSCLE LOSS

Rheumatoid arthritis is an autoimmune disease predominantly affecting middle-aged and older females and is characterised by persistent synovitis, systemic inflammation, and the presence of specific autoantibodies[5]. This inflammation is associated with damage to the articular cartilage and bone[5], and a range of co-morbidities including cardiovascular disease[6], obesity[7], diabetes[8], osteoporosis[9], fatigue[10] and depression[11].

Additionally, RA is characterised by aberrant changes in body composition. The involuntary loss of muscle, often coupled with elevated adiposity, has been termed “rheumatoid cachexia”[12], and occurs in approximately 67% of patients[3,12-16] including those with controlled disease[12]. Much like sarcopenia (muscle loss due to ageing[17]), rheumatoid cachexia leads to a loss of strength[18] and reduced physical functioning[19,20] impairing performance of activities of daily living such as standing independently from a chair, walking, climbing stairs, and lifting and carrying[21]. Additionally, muscle wasting impairs immune function[22], and is a significant predictor of cardio-vascular disease and overall mortality[23-28].

The aetiology of rheumatoid cachexia is multifactorial and may involve increased production of excess inflammatory cytokines such as tumour necrosis factor-alpha (TNFα) and interleukins -1 and -6 (IL-1, IL-6) which are also implicated in the pathophysiology of RA itself[13,24-26]. On a cellular level, several key signalling pathways, such as nuclear factor-kappa B (NF-κB; catabolic) and insulin-growth factor-I (IGF-I; anabolic), regulate protein synthesis and degradation in the muscle[27]. Changes to these pathways “tip” the metabolic activity from anabolic to catabolic, thereby inducing muscle wasting[22].

TREATMENTS OF MUSCLE WASTING

Interventions that are effective in increasing muscle mass have been shown to improve physical function, reduce disability, and enhance quality of life in RA patients[29]. However, efficacious and safe anabolic interventions which are widely acceptable to rheumatoid patients have yet to be identified.

Medication and drug treatments

Rheumatoid cachexia and relatively poor physical function remain prevalent even in RA patients with well-controlled disease activity (i.e., approximately 20%-30% below the level seen in age- and sex-matched sedentary healthy controls[1,3]). Therefore, it is apparent that controlling disease activity alone is insufficient to restore body composition and function. Roubenoff et al[13] hypothesised that TNFα was central in causing rheumatoid cachexia, so it might be expected that anti-TNFα biologics would be the pharmaceutical anti-rheumatic treatment most likely to reverse rheumatoid cachexia. However, even these agents have proved ineffective in this regard[2,30,31]. In fact, in the trials conducted to date, anti-TNFα therapy have not only failed to increase lean mass in recent-onset[2,30] and established[31] RA patients, but appear to increase fat mass[2] and more disturbingly, trunk fat mass[31] relative to standard disease modifying anti-rheumatic drugs.

Similarly, yet to be published data from an on-going study by our group suggests that even in the current “Treat to Target” era, when disease activity is more tightly and successfully controlled, and clinical “remission” is regularly achieved, RA patients still experience significant loss of muscle (approximately 10%), increased adiposity (approximately 12%), and relatively poor physical function (approximately 20%-30% decreased), compared to age- and sex-matched healthy sedentary controls.

Progressive resistance training

High-intensity progressive resistance training (PRT) has been shown to substantially increase muscle mass, and as a consequence dramatically improve strength and restore normal levels of physical function in RA patients (e.g.,[3,16,32]). However, patient uptake of exercise is poor[33], and even patients who experience significant benefits of structured exercise cease training when supervision is withdrawn[34]. Thus, sustained exercise training is unlikely to be widely adopted as a therapy for reversing cachexia and restoring function.

Nutritional supplementation

Anabolic nutritional supplementation offers a potential treatment option that is easily administered, inexpensive, and makes limited demands of the patient. It has been reported that up to 75% of RA patients believe that food and nutrition may play an important role in their symptom severity, with up to 50% of RA patients reportedly trying some form of dietary manipulation in an attempt to attenuate symptomology[35]. Scientific evidence continues to suggest that diet should be part of routine care in those with wasting disorders (for review see Stamp[35]).

Our group previously investigated the effects of 12 wk of a mixture of β-hydroxy-β-methylbutyrate, glutamine and arginine (HMB/GLN/ARG) protein supplementation in 40 RA patients[15]. The results showed that both HMB/GLN/ARG and a control mixture of other, non-essential, amino acids (alanine, glutamic acid, glycine and serine) were effective in increasing muscle mass and improving physical function in RA patients. Thus it appears that protein per se is capable of significantly improving lean mass, total body protein and objective measures of physical function which reflect the ability to perform activities of daily living in RA patients.

Creatine, a combination of essential amino acids, has generally been shown to be more effective than other protein-based supplements in increasing lean mass. For example, Cribb et al[36] showed that Cr (1.5 g/kg per day for 11 wk) was able to significantly improve lean mass by +5.5%, compared to whey protein (+3.7%; P < 0.05) in 33 trained males. Further to this, in a meta-analysis[37] of 48 studies, both lean mass and strength gain were unaffected by whey protein and other supplementation such as androstenedione when compared to a placebo treatment, and only supplementation with either Cr or HMB resulted in a significant gains (Table 1). The superior gains in lean mass and strength from Cr relative to HMB, combined with the additional benefits of Cr to energy production and recovery identifies Cr as a potentially highly effective adjunct treatment for improving rheumatoid cachexia and physical function.

Table 1 Summary of the results from the meta-analysis by Nissen et al[37].
Supplement(n = studies)Average dosage (maintenance dose)Duration(wk)Net leanmass changeNet strength change
Cr (n = 18)19.4 g/d for 5.3 d (6.7 g/d)7.5+0.36%/wkb+1.09%/wkb
HMB (n = 9)3 g/d8+0.28%/wkb+1.40%/wkb
Chromium (n = 12)485 μg/d11.2+0.08%/wk+0.25%/wk
Androstenedione (n = 3)200 mg/d10.7+0.05%/wk-0.06%/wk
Protein (n = 4)1.15 g/kg per day6.3+0.12%/wk-0.18%/wk
DHEA (n = 2)125 mg/d10+0.12%/wk+0.06%/wk
WHAT IS CREATINE?

Creatine, or methylguanidine-acetic acid, is a naturally occurring compound made from 3 amino acids; arginine, glycine, and methionine[4], and is synthesized within the body, primarily in the liver, kidney and pancreas[38].

Most (approximately 95%) of the total Cr pool is contained in skeletal muscle, with around 60% [75 mmol· kg dry weight (dw)-1] in the phosphorylated form, phosphocreatine (PCr)[39,40], and the remaining 40% (50 mmol· kg dw-1) existing as free Cr[41]. Muscle does not synthesize Cr itself but is dependent on Cr uptake through specific membrane sodium dependent transporters[42].

WHAT DOES CREATINE DO?
Changes in ATP energy synthesis

Creatine performs many roles in the body, the most important of which is in generating energy for the muscles. Muscle relaxation and contraction, and therefore the movement of the body, is fuelled by energy liberated from the dephosphorylation of adenosine triphosphate (ATP).

ATP ↔ adenosine diphosphate (ADP) + phosphate (P) + energy (catalysed by the enzyme ATPase)

The ATP stores in the body are limited (concentration in skeletal muscle approximately 24 mmol· kg/dw[40]), and without a means of resynthesizing ATP at an equally rapid rate, maximal exercise exhausts these stores within 1-2 s[43]. To overcome this storage limitation, the body is able to maintain a continuous ATP supply through different metabolic resynthesis pathways: either anaerobically in the cytosol, or aerobically in the mitochondrion.

As stated previously, Cr is primarily stored in the body in a phosphorylated form as PCr, with the muscle content of PCr 3-4 times higher than that of ATP[41]. In a process called dephosphorylation, some energy for ATP resynthesis comes directly from the hydrolysis (splitting) of phosphate from PCr[41].

PCr ↔ Cr + P + Energy [catalysed by the enzyme creatine kinase (CK)]

In this process, the liberated phosphate group can then combine with ADP in a reaction catalysed by CK to restore ATP levels[44] and maintain high cellular ATP/ADP ratios[45]:

ADP + P ↔ ATP + Cr (catalysed by CK)

As a consequence, it would be anticipated that increasing initial Cr stores and thereby delaying PCr depletion would enhance resynthesis of ATP and augment performance[46,47]. Ingestion of Cr supplements (20 g a day for 5 d) has been shown to increase the total Cr and PCr concentration of human skeletal (Table 2), and indeed, reduced blood lactate concentrations have been observed after high-intensity[48] and endurance exercise[49]; although these findings are not universal[50].

Table 2 Changes in creatine and phosphocreatine levels following Cr supplementation.
Mean baseline Cr levels1Increase after20 g/d for 5 d
CreatineApproximately 125 mmol· kg/dw[130] (90 to 160 mmol· kg/dw)[4]+ 25 mmol· kg/dw (approximately 20%)[144]
PhosphocreatineApproximately 50 mmol· kg/dw[41]+ 8 mmol· kg/dw (approximately 15%)[132]
Changes in muscle mass and protein synthesis

Creatine is an osmotically active substance. Thus, as skeletal muscle cell Cr and PCr concentrations rise, the cell will rapidly draw in extracellular water via osmosis in order to maintain equilibrium[51]. The uptake of Cr and water into the muscle accounts for the increases in body mass (approximately 1-2 kg) usually observed after a few days of supplementation (e.g.,[52]). Total body water has been reported to increase up to 3 litres (+9%)[45]; of which intra-cellular water has been shown to increase by between 0.77-3.0 litre (an increase of +3%-9% from baseline values) (e.g.,[53-56]) in the absence of changes in extra-cellular water[54].

The intramuscular uptake of Cr and the associated increase in intracellular water increases osmotic pressure, which in turn stimulates protein synthesis. Cellular hydration state is an important factor in controlling cellular protein turnover, i.e., an increase in cellular hydration inhibits proteolysis and stimulates protein synthesis[57], whereas cell shrinkage has opposite effects[51,58-61]. However, it is unclear whether acute Cr supplementation augments muscle protein by this mechanism[62,63].

Creatine has also been shown to stimulate muscle hypertrophy by inducing expression of muscle myogenic factors such as MRF4, MyoD and myogenin[64].

Deldicque et al[65,66] showed that the muscle gene expression of IGF-I was raised following Cr supplementation. This finding was corroborated by Burke et al[67] who found increased muscle content of IGF-I as a result of Cr supplementation combined with 8 wk of PRT. These findings are highly relevant to Cr’s anabolic potency as IGF-I produced locally in the muscle (mIGF-I) is thought to regulate adult skeletal muscle maintenance and hypertrophy[68]. Conversely, Cr supplementation in conjunction with PRT has been shown to lower serum levels of myostatin[69], a hormone that is highly expressed in RA synovial tissues and inhibits muscle growth by reducing myoblast (muscle) proliferation[70-72] and thus is associated with muscle atrophy[72] and joint destruction[73]. The anabolic response to Cr supplementation is particularly evident in type II muscle fibres[60,74], which is particularly interesting because RA patients present with preferential atrophy of type II fibres[75].

Reduction in inflammatory cytokines

Patients with RA exhibit high synovial levels and serum concentration of the cytokines TNFα and IL-1β[22]. These cytokines, in addition to causing synovial inflammation[76], also modulate the expression of enzymes controlling muscle protein degradation[27]. Bassit et al[77] investigated the effects of Cr supplementation (20 g/d for 5 d prior to competition) on plasma levels of the pro-inflammatory cytokines: TNFα, IL-1β, and prostaglandin E2 (PGE2) in triathletes after a half-ironman competition. These cytokines are typically raised following prolonged strenuous exercise[78], but Cr supplementation attenuated the increases in TNFα by 42% and 64%, IL-1β by 72% and 71%, and PGE2 by 85.5% and 91 %, 24 and 48 h post, respectively.

Creatine and bone degradation

RA patients are at 2-fold increased risk of having osteoporosis and approximately 28% of patients develop this condition[9,14]. In wheelchair-independent patients experiencing Duchenne dystrophy, Cr supplementation was able to enhance bone mineral density (+3%) and reduce urinary cross-linked N telopeptides of type I collagen (NTx) excretion, a marker for bone resorption[62]. In addition, Candow et al[79] also reported a reduction in NTx (-27%) vs placebo (+13%; P < 0.005), and similar findings were reported by Chilibeck et al[80] who showed that in elderly men, Cr was able to improve arm bone mineral density by +3.2% (P < 0.001) vs placebo (-1%) However, more research is needed in this area to understand the mechanisms behind this action.

Athletic performance

Creatine has repeatedly demonstrated efficacy in improving high-intensity short-term exercise performance and subsequent recovery. For example, in cycling, Cr supplementation has been shown to significantly enhance peak power output[48,81,82] and maximal work[39] during repetitive sprints. Similarly, runners who supplemented with Cr decreased their 100 m sprint time and total time for 6 m × 60 m sprint intervals[83], and highly trained football players improved their repeated sprint performance (6 m × 15 m sprints with 30 s recovery) and attenuated fatigue-induced decline in jumping ability following Cr supplementation[84]. Creatine supplementation has also been found to be effective in improving performance of a variety of sustained high-intensity activities (e.g., kayaking for 5 min[85]; 1000 m rowing[86]; and running 300 and 1000 m intervals (3-4 min rest)[87]). These functional benefits are attributed to increased ATP resynthesis, heightened availability of PCr in type II fibres, and increased total Cr stores[41]. These effects may be particularly beneficial to older adults or clinical populations who experience difficulty performing short-term, high intensity activities such as hurrying for a bus, crossing roads, climbing stairs, or digging in the garden.

Creatine has also been shown to improve strength related measures. In an analysis of 22 studies, athletes supplementing with Cr had an average +8% greater increase in muscle strength than placebo (for a review see Rawson et al[88]). Furthermore, Cr supplementation when combined with PRT has been shown to be more effective at increasing strength and weightlifting performance than PRT alone[89,90]. Improvements in strength translate into increased work capacity, and thus improved ability to perform activities of daily living such as walking, carrying shopping, doing housework, etc[16,19,21].

Although approximately 70%[91] of short-term studies on Cr supplementation report some ergogenic benefit, the responses are often variable amongst individuals[88], and supplementation generally does not result in improvements in endurance performance (e.g., repeated 6 km treadmill and terrain run performance[48,58,92,93]).

CRITICAL REVIEW OF RELEVANT CLINICAL LITERATURE
Aim

The aim of this review is to examine existing evidence assessing the efficacy of Cr supplementation in improving muscle mass and physical function, with particular reference to its potential use in treating rheumatoid cachexia and its consequences. To achieve this we searched for, and extracted relevant data from published research papers in RA and other conditions for which findings are likely transferable to the RA population, e.g., ageing population and other musculoskeletal and wasting diseases.

Search methods

Peer-reviewed research articles were included in this review provided they: (1) investigated the effects of Cr supplementation in RA patients or other populations deemed relevant to RA (i.e., elderly populations (> 60 years) or musculoskeletal disorders featuring loss of muscle and physical function); (2) included body composition (muscle and/or fat mass) and/or physical function as outcome measures; and (3) conducted an intervention of any design in RA patients; or undertook a blinded placebo-controlled trial for non-RA populations, to ensure only evidence of higher certainty of evidence was included. As the purpose of this review is to investigate alternative treatments to high-intensity exercise for restoring muscle mass and physical function, data on the additive effects of Cr supplementation and PRT were excluded. Publications were also excluded if they were a literature review, thesis, abstract, or a letter or comment, and the search was limited to English language citations.

PubMed and Google Scholar were searched from April to May 2014 using the search term “creatine supplementation” combined with “cachexia”; “clinical”; “patient”; “older adults”; “elderly”; “sarcopenia” and “rheumatoid arthritis”. In addition, the reference sections of the selected papers were hand-searched for relevant ancestral references. The title and abstract of each search result was first screened for relevance according to the inclusion criteria above, before full articles were obtained. Full-text articles were then screened before final inclusion in this review.

Search results

The initial search returned 758 articles, excluding duplicates, of which 21 met the inclusion criteria and were selected for this review. One trail investigating Cr supplementation of RA patients was found[94]. This study was not controlled in any way so is considered to provide evidence of low certainty. The body composition and physical function data extracted from trials in older adults are presented in Table 3, and data extracted from trials in other relevant clinical populations appear in Table 4.

Table 3 Summary of studies investigating the effects of creatine supplementation on sarcopenia and function in older adults over 60 years.
Treatment arm(mean age ± SD)Supplementation periodStudy designBody composition changesPhysical function changesRef.
10 males (66.7 ± 1.9 yr)20 g/d for 10 d followed by 4 g/d for 20 dvs PL group (dextrose) (n = 10)2Body density, 2LM, 2%BF1Leg fatigue performance[99]
9 males (65.0 ± 2.1 yr)20 g/d for 5 dvs PL group (sucrose) (n = 8)1BM, 2LM2Strength[100]
10 females (67.0 ± 6.0 yr)0.3 g per kg/day for 7 dvs PL group (n = 6)No details1Objective function tests, 2Endurance capacity[97]
10 males (65.4 ± 1.5 yr)0.3 g per kg/day for 7 dvs PL group (powdered cellulose) (n = 8)1BM, 1LM1Strength, 1Power, 1Objective function tests[55]
15 females (63.3 ± 1.2 yr)0.3 g per kg/day for 7 dvs PL group (powdered cellulose) (n = 12)1BM, 1LM, 2%BF1Strength, 1Objective function tests[98]
7 males and 8 females (74.5 ± 6.4 yr)20 g/d for 7 d followed by 10 g/d for 7 dCross-over design2BM1Strength, 1Endurance (cycling capacity at fatigue threshold), 2Objective function tests[101]
7 males (72.5 ± 2.5 yr)20 g/d for 5 dvs PL group (maltodextrin) (n = 5)1BM, 2LM2MVC or contractile force[102]
4 males and 4 females (71.0 ± 1.9 yr)20 g/d for 5 d followed by 3 g/d for 8 wkvs PL (glucose) (n = 8)2Lower limb volume, 2BM, 2%BF2Strength 2Endurance[103]
15 females (66.1 ± 4.8 yr)20 g/d for 5 d followed by 5 g/d for 23 wkvs PL (dextrose) (n = 15)1LM, 2FM1Strength 1Objective function tests[104]
Table 4 Summary of clinical trials investigating the effects of creatine supplementation on body composition and physical function.
ConditionTreatment armSupplementation periodControl armBody composition changesPhysical function changesOther effectsRef.
Osteoarthritisn = 1810 g/d pre surgery; 5 g/d for 30 d post-surgeryvs PL (n = 19) (dextrose)2% BF, 2FM, 3LM (CSA), 3BW3Strength3PCr[106]
Fibromyalgian = 1620 g/d for 5 d followed by 5 g/d for 16 wkvs PL (n = 16) (dextrose)Not measured1Strength3QoL scores, 3Pain, 3Cognition, 1PCr[109]
Cancer (cachexia)n = 16 (colorectal cancer)20 g/d for 5 d followed by 5 g/d for 8 wkvs PL (n = 15) (cellulose)3LM1Strength3QoL scores[118]
n = 9 (adolescents with leukaemia (acute lymphoblastic)2 sets of 8 wk (with a 6 wk wash out in-between)vs control “natural history group” (n = 50)3LM, 2%BFNo details3Bone mineral content[119]
Duchenne muscular dystrophyn = 18 (adolescents)5 g/d for 8 wkvs PL (n = 15) (vitamin C)No details1Strength1PCr[113]
n = 15 (adolescents)5 g/d for 24 wkvs PL (n = 16) (cocoa powder)No details3Strength, 3Objective function tests[116]
n = 30 (adolescents)0.10 g per kg/d for 16 wkCross-over design (PL group dextrose)1LM1Strength2Bone breakdown markers[112]
n = 15 (adolescents) (12 with DMD and 3 with Becker dystrophy)3 g/d for 13 wkCross-over design (PL group maltodextrin)No details1Strength (MVC), 1Fatigue resistance[62]
Mytonic muscular dystrophy 1 (DM1)n = 345 g/d for 36 wkCross-over design (PL group dextrose)3LM3Strength, 3Objective function tests[115]
n = 3410.6 g/d for 10 d followed by 5.3 g/d for 45 dCross-over design (PL group cellulose)3LM3Strength3ADL, 3QoL scores[114]
Mytonic muscular dystrophy 2 (DM2)n = 1010 g/d for 13 wkvs PL (n = 10)No details3Strength3QoL scores[117]
Rheumatoid arthritis

Willer et al[94] was the only study identified that completed a trial of Cr in an RA population. Twelve RA patients were un-blinded to the Cr supplementation and no placebo group or control arm existed. Participants were given oral Cr supplementation for 21 d using recommended doses (day 1-5: 20 g/d; day 6-21: 2 g/d) and the effects on muscle strength, subjectively assessed function during activities of daily living (Health Assessment Questionnaire), and disease activity were examined. It was found that Cr supplementation increased muscle strength in 8 out of the 12 patients by an average of +14% (P = 0.02), as determined by the muscle strength index (the mean of 8 strength measurements during flexion and extension of the knee and elbow/max sample strength × 100[95]). This increase in muscle strength was not associated with changes in skeletal muscle Cr or PCr levels. Routine clinical measures of disease activity and subjectively evaluated physical function showed no changes.

The authors attributed the “limited effectiveness of Cr” to “alterations in the kinetics of Cr in patients with RA (e.g., reduced transport into the muscle, increased metabolism and/or excretion)”. However, this interpretation places emphasis on the subjectively assessed function, which was unchanged, rather than the objectively measured strength, which did improve significantly. It is known that the Health Assessment Questionnaire is weakly associated with objective measures of physical condition such as strength (r = -0.35) and joint mobility (r = 0.27)[96], and is often insensitive to changes in objective function (e.g.,[3,96]). Additionally, only 12 patients were used in the study, and with Cr supplementation reported to be ineffective in approximately 30% of individuals[46], it would be anticipated that only 8 of the RA patients in this investigation would see any benefit. Consistent with this prediction, strength increases were noted in 8 patients. Moreover, the study supplementation period only lasted 3 wk, much less than the 8-12 wk recommended by manufacturers and used by other studies. Thus, whilst the findings of Willer et al[94]’s trial are inconclusive, they do provide some indications that Cr may be effective in the RA population. Clearly more research is needed in this area.

Ageing and sarcopenia

Nine studies[55,97-104] were identified that investigated the effects of Cr supplementation in older adults and met the inclusion criteria. Four of these studies, reported that Cr increased body mass by 0.49-1.86 kg[55,98,100,102] and that this gain was predominantly lean mass (LM), with increases in muscle mass of up to +2.22 kg[55]. In contrast, no significant changes in body mass or LM were found in the remaining five studies[99-101,103,104], although a trend of increased LM (+0.3%) following Cr supplementation relative to placebo (P = 0.062) was found by one of these[104]. As expected, no significant changes in % body fat subsequent to Cr supplementation in older subjects were reported[55,99,100].

Three of the six studies that measured muscle strength changes reported improvements following Cr supplementation[55,98,101]. Gotshalk et al[55] reported strength increases of both maximal leg press (+7%-8%), knee extensor (+9%) and knee flexor muscles (+15%) in older males, whilst in females increases in leg press (+3.4% or 5.2 kg) and bench press (+4.4% or 1.7 kg) were found[98]. In a cross-over design, Stout et al[101] found that Cr significantly increased maximal isometric grip strength by +6.7%[101]. Conversely, Jakobi et al[102] found that 5 d of Cr supplementation was unable to increase elbow flexor maximal voluntary strength or any other muscle contractile properties (twitch and tetanic recordings from electrical stimulation of the muscles). Similar findings were reported by Rawson et al[100], who found no significant effect on isometric elbow flexor strength after 5 d supplementation, and Bermon et al[103] who found no increase in chest or strength compared to a placebo (P > 0.05).

All studies assessing short-term physical function reported significant improvements in lower-extremity functional tests such as the sit-to-stand in 30 s (SST-30) by up to 12%[55,97,98,105], and a tandem gait test by 6%[55] to 9%[98] following Cr supplementation. Lower body power (as assessed by a 10-s Wingate test) was shown to improve by +11%[55] and Rawson et al[99] reported that leg fatigue (as expressed as a % change in the total peak torque generate and assessed by 5 × 30 s knee extensions at 180° on an isokinetic dynamometer) was reduced by 9% (compared to a 5% increase in the placebo group, P < 0.05). Similar findings by Stout et al[101] showed lower body muscle endurance (cycling capacity at fatigue threshold) was improved by 15.6% compared to the placebo group. However, assessments of endurance capacity (i.e., 1-mile walk test; and gross mechanical efficiency, ventilatory threshold, and peak oxygen intake determined during cycle ergometry) were not significantly improved following Cr supplementation[97].

Trials in other clinical populations

One study[106] trialled Cr supplementation in osteoarthritis (OA). OA is the most common form of arthritis, and as with RA, is characterised by joint damage, muscle weakness, poor physical function[107], and predominantly affects females[108]. In this investigation, Roy et al[106] reported limited effects of Cr supplementation in OA patients recovering from total knee arthroplasty, despite a significant increase in serum Cr concentration, with no improvements in muscle strength (handgrip, dorsiflexion and quadriceps strength, 30-foot timed walk and 4-step climb) observed after 40 d (10 d pre surgery and 30 d post-surgery) of Cr supplementation relative to placebo.

One trial[109] reported the use of Cr supplementation in fibromyalgia, another chronic syndrome of unknown etiology, characterized by some similarities in symptomology to RA, including pain, muscle dysfunction, disability and fatigue[110]. Some of the fibromyalgia symptoms such as muscle dysfunction and fatigue could, in theory, be due to low muscle levels of ATP and PCr[109]. A randomised controlled trial of Cr supplementation in fibromyalgia patients[109] found that muscle PCr content increased and muscle strength improved relative to the placebo group (leg-press by 9.8%, P = 0.02; chest-press by 1.2%, P = 0.02; and isometric hand-grip strength by 6.4%, P = 0.07) in the Cr group.

Myopathy is a muscle wasting disorder which primarily affects skeletal muscle. Much like rheumatoid cachexia seen in RA patients, this can cause a variety of complaints including progressive weakness and wasting of skeletal muscle, and fatigue (for a review see Kley et al[111]). Seven trials of Cr supplementation in populations with myopathies were found, with these investigations finding mixed results on the efficacy of oral Cr. In a cross-over design trial in 30 Duchenne muscular dystrophy (DMD) adolescents[112], the Cr supplementation phase increased lean mass by +0.7 kg and grip strength by approximately 20% compared to the placebo phase. In a similar design, Cr supplementation improved maximal strength and fatigue resistance in 15 other patients with DMD[62]. Further to these trials, improvements in muscle PCr/P ratio and preservation of calf muscle strength were also reported by Banerjee et al[113] in 18 DMD patients.

In contrast, in cross-over design trials of patients with Mytonic muscular dystrophy 1 (DM1), Cr failed to induce any changes in muscle strength, lean mass or disease symptoms[114,115], or improve function or strength in DMD patients[116] or patients with myotonic dystrophy type 2 (DM2)[117].

Two studies[118,119] were found that reported trials of Cr supplementation in cancer patients. Up to 80% of cancer patients have associated muscle wasting which is termed “cancer cachexia”[120]. Like other forms of cachexia, this is characterised by a preferential loss of skeletal muscle mass (with or without a loss of fat mass) which cannot be reversed through conventional methods of nutrition[121]. In patients with cancer, Cr supplementation improved handgrip strength by 5.5% (P = 0.019)[118] and reduced body fat accumulation (-3.5%; P < 0.05) relative to a placebo group[119].

Review conclusions

Around 70% of RA patients are middle-aged or elderly females[122], and the existing evidence indicates that Cr can be successful in countering the effects of sarcopenia in older populations independent of exercise training[123], specifically in older females[124,125]. Of nine included trials that have supplemented the elderly with Cr, only three[100,102,103] found no beneficial effect on lean mass, strength, or physical function. However, the magnitude of effect appears to be reduced relative to that observed in young healthy individuals[126], and the limited number of studies indicates that further work is needed to fully evaluate the role of Cr supplementation[127].

Creatine has been shown to be effective in a range of clinical conditions[128] including muscle wasting disorders[62,112,113], and cancer cachexia[118]. Despite the inconclusive findings of the solitary RA study[94], of the twelve clinical trials identified, six showed positive effects of Cr on muscle mass and/or strength and function measures.

FACTORS AFFECTING CREATINE EFFECTIVENESS IN CERTAIN INDIVIDUALS OR POPULATIONS

Apart from inadequate supplement duration or dose, various other factors influence Cr effectiveness. It has been reported that 20%-30% of individuals do not respond to Cr supplementation; when “non-responsiveness” is defined as an increase in resting total muscle Cr of < 10 mmol· kg/dw following 5 d loading at 20 g per day[46,88]. Syrotuik et al[129] found that based on pre-existing biological and physiological factors, “responders” (defined in that study as ≥ 20 mmol· kg/dw increase in intramuscular Cr) possessed a biological profile of (1) low initial levels of total Cr or PCr (approximately < 110 mmol· kg/dw); (2) higher percentage of type II fibres (> 63.1%); and (3) a higher preload muscle fibre cross-sectional area (CSA) (approximately > 1500 μm2). For individuals whose initial muscle Cr concentrations approach 150 mmol· kg/dw, Cr supplementation does not appear to augment muscle Cr uptake, increase PCr resynthesis, or improve performance[4,129,130]. Not surprisingly, optimal responses to Cr supplementation are generally observed in groups with reduced serum and muscle levels of Cr such as vegetarians and low meat eaters, which include many older individuals[58,125,130,131].

Although the majority of the studies reviewed found benefits of Cr supplementation in the elderly, it has been suggested that uptake of Cr into muscle is reduced in older adults (> 60 years) relative to younger subjects[99,132], and that subsequently older adults may require a longer Cr treatment period[56].

SAFETY OF CREATINE

Concerns about possible side effects of Cr supplementation have been raised in lay publications, mailing lists and online forums. However, none of the studies included in this review reported any adverse incidents during the trials ranging from 5 d to 36 wk. This is consistent with other studies of long term (10 mo to 5 years) (e.g.,[53,133,134]) or high dose Cr supplementation (10 g/d) (e.g.,[135,136]) that have reported no adverse side effects. According to Walliman[137], current evidence does “not hint towards any negative health effects of Cr”. Therefore, the anecdotal reports remain unsubstantiated and may be unrelated to Cr supplementation[44].

Concerns about the long-term safety of Cr have specifically been related to kidney function. Theoretically, the high nitrogen content (approximately 32%) of Cr could place additional strain on the kidney if taken in large excess for a long period of time[133]. Glomerular filtration rate (GFR) is widely accepted as the best overall measure of kidney function, with serum and urine creatinine levels the most commonly used markers for estimating GFR[136]. However, since Cr is converted to creatinine[47], it is normal for individuals who take Cr supplements to have elevated creatinine levels[138], thus falsely suggesting renal function impairment. Use of alternative GFR markers such as Cystatin C has shown that Cr supplementation does not promote renal dysfunction[136].

There is currently limited research on the effects of Cr supplementation in patients with exiting low GFR. A prospective report[139] suggests that short-term (35 d) Cr supplementation (5 d of 20 g/d followed by 5 g/d) does not affect kidney function in individuals with a single kidney and mildly decreased GFR. However, more research is needed in this area. Similarly, no evidence has emerged that Cr supplementation results in impaired liver function or liver damage[41,44,140,141].

PRESCRIPTION OF CREATINE TO PATIENTS
Type

Creatine supplements are usually taken as a tablet or powder (mixed with water), and exist in a variety of forms including Cr ethyl ester, Cr hydrochloride and the most commonly available Cr monohydrate (Cr complexed with a molecule of water). No differences in effectiveness have been found between these different Cr forms[142].

“Loading” dosage

Cr should be “loaded” into the muscle (using a high dose) for the first few days followed by a lower maintenance dose[41]. The most common “loading” dosage recommendation for Cr supplementation is 20 g/d (in four 5 g doses) for 5 d, as stores appear to be maximised within 5 to 6 d at this dose[130]. Alternate loading phases exist including daily doses based on body mass such as 0.25 g/kg[41] or 0.15 g/kg[143]. However, a constant dose of 3 g/d, without an intensive loading phase, achieved an increase in total Cr levels equal to a standard 5 d loading protocol and subsequent maintenance phase after 28 d[144].

“Maintenance”and frequency

Total muscle Cr can be maintained for at least 4-6 wk after the initial loading phase by the ingestion of small daily Cr doses of 2-5 g[41,144]. This period of low dosage is called the “maintenance phase”. Here, Cr is usually taken in 8 to 12 wk cycles, with a 4 to 5 wk “washout” period in between to allow serum Cr to return to baseline levels.

CONCLUSION

RA is characterised by a loss of muscle which causes reduced strength and physical functioning. Current anti-rheumatic pharmaceutical treatments are unable to reverse the effects of cachexia, and although high intensity exercise is highly effective in rectifying body composition and restoring physical function, uptake of, and adherence to, exercise training by RA patients is poor. Thus, other treatment options need investigation. Oral Cr supplementation offers a potentially efficacious, cheap and widely acceptable therapy for achieving these outcomes in RA patients. Creatine works primarily by enhancing the re-synthesis of ATP via increased stores of PCr in the muscle, and thus improving recovery during and after physical activity. Creatine also augments muscle protein synthesis thereby increasing muscle mass.

This review found only one study in which RA patients were supplemented with Cr[94] and its findings, whilst promising, were inconclusive. However, trials in populations with similar presentation to RA (i.e., reduced muscle mass and impaired physical function), including older females, indicate that Cr is an efficacious way to improve muscle mass, strength and physical function. Therefore, additional studies in RA populations are advocated, as confirmation of the efficacy of Cr supplementation would provide an easy, safe and effective means of reversing the effects of rheumatoid cachexia in the majority of the RA population.

Footnotes

P- Reviewer: Kemal NAS, Turiel M S- Editor: Ji FF L- Editor: A E- Editor: Wu HL

References
1.  Lunt M, Watson KD, Dixon WG, Symmons DP, Hyrich KL. No evidence of association between anti-tumor necrosis factor treatment and mortality in patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum. 2010;62:3145-3153.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 60]  [Cited by in F6Publishing: 44]  [Article Influence: 5.5]  [Reference Citation Analysis (0)]
2.  Engvall IL, Tengstrand B, Brismar K, Hafström I. Infliximab therapy increases body fat mass in early rheumatoid arthritis independently of changes in disease activity and levels of leptin and adiponectin: a randomised study over 21 months. Arthritis Res Ther. 2010;12:R197.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 69]  [Cited by in F6Publishing: 56]  [Article Influence: 6.3]  [Reference Citation Analysis (0)]
3.  Lemmey AB, Marcora SM, Chester K, Wilson S, Casanova F, Maddison PJ. Effects of high-intensity resistance training in patients with rheumatoid arthritis: a randomized controlled trial. Arthritis Rheum. 2009;61:1726-1734.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 137]  [Cited by in F6Publishing: 101]  [Article Influence: 12.5]  [Reference Citation Analysis (0)]
4.  Casey A, Greenhaff PL. Does dietary creatine supplementation play a role in skeletal muscle metabolism and performance? Am J Clin Nutr. 2000;72:607S-617S.  [PubMed]  [DOI]  [Cited in This Article: ]
5.  Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet. 2010;376:1094-1108.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1795]  [Cited by in F6Publishing: 707]  [Article Influence: 163.2]  [Reference Citation Analysis (0)]
6.  Gremese E, Ferraccioli G. The metabolic syndrome: the crossroads between rheumatoid arthritis and cardiovascular risk. Autoimmun Rev. 2011;10:582-589.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 62]  [Cited by in F6Publishing: 54]  [Article Influence: 6.2]  [Reference Citation Analysis (0)]
7.  García-Poma A, Segami MI, Mora CS, Ugarte MF, Terrazas HN, Rhor EA, García E, Ramos MP, Alva M, Castañeda I. Obesity is independently associated with impaired quality of life in patients with rheumatoid arthritis. Clin Rheumatol. 2007;26:1831-1835.  [PubMed]  [DOI]  [Cited in This Article: ]
8.  Lee TJ, Park BH, Son HK, Song R, Shin KC, Lee EB, Song YW. Cost of illness and quality of life of patients with rheumatoid arthritis in South Korea. Value Health. 2012;15:S43-S49.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 16]  [Cited by in F6Publishing: 8]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
9.  Haugeberg G, Uhlig T, Falch JA, Halse JI, Kvien TK. Bone mineral density and frequency of osteoporosis in female patients with rheumatoid arthritis: results from 394 patients in the Oslo County Rheumatoid Arthritis register. Arthritis Rheum. 2000;43:522-530.  [PubMed]  [DOI]  [Cited in This Article: ]
10.  Helal AMH, Shahine EM, Hassan MM, Hashad DI, Moneim RA. Fatigue in rheumatoid arthritis and its relation to interleukin-6 serum level. Egypt Rheum. 2012;34:153-157.  [PubMed]  [DOI]  [Cited in This Article: ]
11.  Sheehy C, Murphy E, Barry M. Depression in rheumatoid arthritis--underscoring the problem. Rheumatology (Oxford). 2006;45:1325-1327.  [PubMed]  [DOI]  [Cited in This Article: ]
12.  Roubenoff R, Roubenoff RA, Ward LM, Holland SM, Hellmann DB. Rheumatoid cachexia: depletion of lean body mass in rheumatoid arthritis. Possible association with tumor necrosis factor. J Rheumatol. 1992;19:1505-1510.  [PubMed]  [DOI]  [Cited in This Article: ]
13.  Roubenoff R, Roubenoff RA, Cannon JG, Kehayias JJ, Zhuang H, Dawson-Hughes B, Dinarello CA, Rosenberg IH. Rheumatoid cachexia: cytokine-driven hypermetabolism accompanying reduced body cell mass in chronic inflammation. J Clin Invest. 1994;93:2379-2386.  [PubMed]  [DOI]  [Cited in This Article: ]
14.  Engvall IL, Svensson B, Tengstrand B, Brismar K, Hafström I. Impact of low-dose prednisolone on bone synthesis and resorption in early rheumatoid arthritis: experiences from a two-year randomized study. Arthritis Res Ther. 2008;10:R128.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 31]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
15.  Marcora S, Lemmey A, Maddison P. Dietary treatment of rheumatoid cachexia with beta-hydroxy-beta-methylbutyrate, glutamine and arginine: a randomised controlled trial. Clin Nutr. 2005;24:442-454.  [PubMed]  [DOI]  [Cited in This Article: ]
16.  Marcora SM, Lemmey AB, Maddison PJ. Can progressive resistance training reverse cachexia in patients with rheumatoid arthritis? Results of a pilot study. J Rheumatol. 2005;32:1031-1039.  [PubMed]  [DOI]  [Cited in This Article: ]
17.  Morley JE, Abbatecola AM, Argiles JM, Baracos V, Bauer J, Bhasin S, Cederholm T, Coats AJ, Cummings SR, Evans WJ. Sarcopenia with limited mobility: an international consensus. J Am Med Dir Assoc. 2011;12:403-409.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 617]  [Cited by in F6Publishing: 473]  [Article Influence: 61.7]  [Reference Citation Analysis (0)]
18.  van Bokhorst-de van der Schueren MA, Konijn NP, Bultink IE, Lems WF, Earthman CP, van Tuyl LH. Relevance of the new pre-cachexia and cachexia definitions for patients with rheumatoid arthritis. Clin Nutr. 2012;31:1008-1010.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 20]  [Cited by in F6Publishing: 15]  [Article Influence: 2.2]  [Reference Citation Analysis (0)]
19.  Giles JT, Ling SM, Ferrucci L, Bartlett SJ, Andersen RE, Towns M, Muller D, Fontaine KR, Bathon JM. Abnormal body composition phenotypes in older rheumatoid arthritis patients: association with disease characteristics and pharmacotherapies. Arthritis Rheum. 2008;59:807-815.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 140]  [Cited by in F6Publishing: 106]  [Article Influence: 10.8]  [Reference Citation Analysis (0)]
20.  Summers GD, Deighton CM, Rennie MJ, Booth AH. Rheumatoid cachexia: a clinical perspective. Rheumatology (Oxford). 2008;47:1124-1131.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 86]  [Cited by in F6Publishing: 76]  [Article Influence: 6.6]  [Reference Citation Analysis (0)]
21.  Baumgartner RN, Wayne SJ, Waters DL, Janssen I, Gallagher D, Morley JE. Sarcopenic obesity predicts instrumental activities of daily living disability in the elderly. Obes Res. 2004;12:1995-2004.  [PubMed]  [DOI]  [Cited in This Article: ]
22.  Walsmith J, Roubenoff R. Cachexia in rheumatoid arthritis. Int J Cardiol. 2002;85:89-99.  [PubMed]  [DOI]  [Cited in This Article: ]
23.  Malmstrom TK, Miller DK, Herning MM, Morley JE. Low appendicular skeletal muscle mass (ASM) with limited mobility and poor health outcomes in middle-aged African Americans. J Cachexia Sarcopenia Muscle. 2013;4:179-186.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 55]  [Cited by in F6Publishing: 49]  [Article Influence: 6.9]  [Reference Citation Analysis (0)]
24.  Rall LC, Rosen CJ, Dolnikowski G, Hartman WJ, Lundgren N, Abad LW, Dinarello CA, Roubenoff R. Protein metabolism in rheumatoid arthritis and aging. Effects of muscle strength training and tumor necrosis factor alpha. Arthritis Rheum. 1996;39:1115-1124.  [PubMed]  [DOI]  [Cited in This Article: ]
25.  Roubenoff R, Walsmith J, Lundgren N, Snydman L, Dolnikowski GJ, Roberts S. Low physical activity reduces total energy expenditure in women with rheumatoid arthritis: implications for dietary intake recommendations. Am J Clin Nutr. 2002;76:774-779.  [PubMed]  [DOI]  [Cited in This Article: ]
26.  Rall LC, Roubenoff R. Rheumatoid cachexia: metabolic abnormalities, mechanisms and interventions. Rheumatology (Oxford). 2004;43:1219-1223.  [PubMed]  [DOI]  [Cited in This Article: ]
27.  Fanzani A, Conraads VM, Penna F, Martinet W. Molecular and cellular mechanisms of skeletal muscle atrophy: an update. J Cachexia Sarcopenia Muscle. 2012;3:163-179.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 164]  [Cited by in F6Publishing: 130]  [Article Influence: 18.2]  [Reference Citation Analysis (0)]
28.  Giles JT, Allison M, Blumenthal RS, Post W, Gelber AC, Petri M, Tracy R, Szklo M, Bathon JM. Abdominal adiposity in rheumatoid arthritis: association with cardiometabolic risk factors and disease characteristics. Arthritis Rheum. 2010;62:3173-3182.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 107]  [Cited by in F6Publishing: 86]  [Article Influence: 9.7]  [Reference Citation Analysis (0)]
29.  Lemmey AB. Efficacy of progressive resistance training for patients with rheumatoid arthritis and recommendation regarding its prescription. Int J Clin Rheum. 2011;6:189-205.  [PubMed]  [DOI]  [Cited in This Article: ]
30.  Marcora SM, Chester KR, Mittal G, Lemmey AB, Maddison PJ. Randomized phase 2 trial of anti-tumor necrosis factor therapy for cachexia in patients with early rheumatoid arthritis. Am J Clin Nutr. 2006;84:1463-1472.  [PubMed]  [DOI]  [Cited in This Article: ]
31.  Metsios GS, Stavropoulos-Kalinoglou A, Douglas KM, Koutedakis Y, Nevill AM, Panoulas VF, Kita M, Kitas GD. Blockade of tumour necrosis factor-alpha in rheumatoid arthritis: effects on components of rheumatoid cachexia. Rheumatology (Oxford). 2007;46:1824-1827.  [PubMed]  [DOI]  [Cited in This Article: ]
32.  Sharif S, Thomas JM, Donley DA, Gilleland DL, Bonner DE, McCrory JL, Hornsby WG, Zhao H, Lively MW, Hornsby JA. Resistance exercise reduces skeletal muscle cachexia and improves muscle function in rheumatoid arthritis. Case Rep Med. 2011;2011:205691.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 11]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
33.  Sokka T, Kautiainen H, Pincus T, Verstappen SM, Aggarwal A, Alten R, Andersone D, Badsha H, Baecklund E, Belmonte M. Work disability remains a major problem in rheumatoid arthritis in the 2000s: data from 32 countries in the QUEST-RA study. Arthritis Res Ther. 2010;12:R42.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 143]  [Cited by in F6Publishing: 101]  [Article Influence: 13.0]  [Reference Citation Analysis (0)]
34.  Lemmey AB, Williams SL, Marcora SM, Jones J, Maddison PJ. Are the benefits of a high-intensity progressive resistance training program sustained in rheumatoid arthritis patients? A 3-year followup study. Arthritis Care Res (Hoboken). 2012;64:71-75.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 35]  [Cited by in F6Publishing: 25]  [Article Influence: 3.9]  [Reference Citation Analysis (0)]
35.  Stamp LK, J MJ, Cleland LG. Diet and rheumatoid arthritis: a review of the literature. Semin Arthritis Rheum. 2005;35:77-94.  [PubMed]  [DOI]  [Cited in This Article: ]
36.  Cribb PJ, Williams AD, Stathis CG, Carey MF, Hayes A. Effects of whey isolate, creatine, and resistance training on muscle hypertrophy. Med Sci Sports Exerc. 2007;39:298-307.  [PubMed]  [DOI]  [Cited in This Article: ]
37.  Nissen SL, Sharp RL. Effect of dietary supplements on lean mass and strength gains with resistance exercise: a meta-analysis. J Appl Physiol (1985). 2003;94:651-659.  [PubMed]  [DOI]  [Cited in This Article: ]
38.  American College of Sports Medicine. The physiological and health effects of oral creatine supplementation. Med Sci Sports Exerc. 2010;32:706-717.  [PubMed]  [DOI]  [Cited in This Article: ]
39.  Casey A, Constantin-Teodosiu D, Howell S, Hultman E, Greenhaff PL. Creatine ingestion favorably affects performance and muscle metabolism during maximal exercise in humans. Am J Physiol. 1996;271:E31-E37.  [PubMed]  [DOI]  [Cited in This Article: ]
40.  Harris RC, Hultman E, Nordesjö LO. Glycogen, glycolytic intermediates and high-energy phosphates determined in biopsy samples of musculus quadriceps femoris of man at rest. Methods and variance of values. Scand J Clin Lab Invest. 1974;33:109-120.  [PubMed]  [DOI]  [Cited in This Article: ]
41.  Bogdanis GC, Papaspyrou A, Maridaki M. Muscle Metabolism and Fatigue During Sprint Exercise: Effects Of Creatine Supplementation. Serb J Sport Sci. 2007;1:37-57.  [PubMed]  [DOI]  [Cited in This Article: ]
42.  Longo N, Ardon O, Vanzo R, Schwartz E, Pasquali M. Disorders of creatine transport and metabolism. Am J Med Genet C Semin Med Genet. 2011;157C:72-78.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 60]  [Cited by in F6Publishing: 43]  [Article Influence: 6.0]  [Reference Citation Analysis (0)]
43.  Burton DA, Stokes K, Hall GM. Physiological effects of exercise. Contin Educ Anaesth Crit Care Pain. 2004;4:185-188.  [PubMed]  [DOI]  [Cited in This Article: ]
44.  Kreider RB, Ferreira M, Wilson M, Grindstaff P, Plisk S, Reinardy J, Cantler E, Almada AL. Effects of creatine supplementation on body composition, strength, and sprint performance. Med Sci Sports Exerc. 1998;30:73-82.  [PubMed]  [DOI]  [Cited in This Article: ]
45.  Bemben MG, Bemben DA, Loftiss DD, Knehans AW. Creatine supplementation during resistance training in college football athletes. Med Sci Sports Exerc. 2001;33:1667-1673.  [PubMed]  [DOI]  [Cited in This Article: ]
46.  Greenhaff PL. Creatine and its application as an ergogenic aid. Int J Sport Nutr. 1995;5 Suppl:S100-S110.  [PubMed]  [DOI]  [Cited in This Article: ]
47.  Wyss M, Kaddurah-Daouk R. Creatine and creatinine metabolism. Physiol Rev. 2000;80:1107-1213.  [PubMed]  [DOI]  [Cited in This Article: ]
48.  Balsom PD, Söderlund K, Sjödin B, Ekblom B. Skeletal muscle metabolism during short duration high-intensity exercise: influence of creatine supplementation. Acta Physiol Scand. 1995;154:303-310.  [PubMed]  [DOI]  [Cited in This Article: ]
49.  Tang FC, Chan CC, Kuo PL. Contribution of creatine to protein homeostasis in athletes after endurance and sprint running. Eur J Nutr. 2014;53:61-71.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 14]  [Cited by in F6Publishing: 8]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
50.  Engelhardt M, Neumann G, Berbalk A, Reuter I. Creatine supplementation in endurance sports. Med Sci Sports Exerc. 1998;30:1123-1129.  [PubMed]  [DOI]  [Cited in This Article: ]
51.  Lang F, Busch GL, Ritter M, Völkl H, Waldegger S, Gulbins E, Häussinger D. Functional significance of cell volume regulatory mechanisms. Physiol Rev. 1998;78:247-306.  [PubMed]  [DOI]  [Cited in This Article: ]
52.  Powers ME, Arnold BL, Weltman AL, Perrin DH, Mistry D, Kahler DM, Kraemer W, Volek J. Creatine Supplementation Increases Total Body Water Without Altering Fluid Distribution. J Athl Train. 2003;38:44-50.  [PubMed]  [DOI]  [Cited in This Article: ]
53.  Poortmans JR, Francaux M. Long-term oral creatine supplementation does not impair renal function in healthy athletes. Med Sci Sports Exerc. 1999;31:1108-1110.  [PubMed]  [DOI]  [Cited in This Article: ]
54.  Ziegenfuss TN, Lowery LM, Lemon PW. Acute fluid volume changes in men during three days of creatine supplementation. J Ex Physiol. 1998;1:1-9.  [PubMed]  [DOI]  [Cited in This Article: ]
55.  Gotshalk LA, Volek JS, Staron RS, Denegar CR, Hagerman FC, Kraemer WJ. Creatine supplementation improves muscular performance in older men. Med Sci Sports Exerc. 2002;34:537-543.  [PubMed]  [DOI]  [Cited in This Article: ]
56.  Chrusch MJ, Chilibeck PD, Chad KE, Davison KS, Burke DG. Creatine supplementation combined with resistance training in older men. Med Sci Sports Exerc. 2001;33:2111-2117.  [PubMed]  [DOI]  [Cited in This Article: ]
57.  Ingwall JS, Weiner CD, Morales MF, Davis E, Stockdale FE. Specificity of creatine in the control of muscle protein synthesis. J Cell Biol. 1974;62:145-151.  [PubMed]  [DOI]  [Cited in This Article: ]
58.  Balsom PD, Harridge SD, Söderlund K, Sjödin B, Ekblom B. Creatine supplementation per se does not enhance endurance exercise performance. Acta Physiol Scand. 1993;149:521-523.  [PubMed]  [DOI]  [Cited in This Article: ]
59.  Bessman SP, Savabi F.  The role of the phosphocreatine energy shuttle in exercise and muscle hypertrophy. Creatine and Creatine phosphate: Scientific and Clinical Perspectives. 1st ed. New York: Academic Press 1988; 185-198.  [PubMed]  [DOI]  [Cited in This Article: ]
60.  Sipilä I, Rapola J, Simell O, Vannas A. Supplementary creatine as a treatment for gyrate atrophy of the choroid and retina. N Engl J Med. 1981;304:867-870.  [PubMed]  [DOI]  [Cited in This Article: ]
61.  Häussinger D, Roth E, Lang F, Gerok W. Cellular hydration state: an important determinant of protein catabolism in health and disease. Lancet. 1993;341:1330-1332.  [PubMed]  [DOI]  [Cited in This Article: ]
62.  Louis M, Lebacq J, Poortmans JR, Belpaire-Dethiou MC, Devogelaer JP, Van Hecke P, Goubel F, Francaux M. Beneficial effects of creatine supplementation in dystrophic patients. Muscle Nerve. 2003;27:604-610.  [PubMed]  [DOI]  [Cited in This Article: ]
63.  Parise G, Mihic S, MacLennan D, Yarasheski KE, Tarnopolsky MA. Effects of acute creatine monohydrate supplementation on leucine kinetics and mixed-muscle protein synthesis. J Appl Physiol (1985). 2001;91:1041-1047.  [PubMed]  [DOI]  [Cited in This Article: ]
64.  Hespel P, Op’t Eijnde B, Van Leemputte M, Ursø B, Greenhaff PL, Labarque V, Dymarkowski S, Van Hecke P, Richter EA. Oral creatine supplementation facilitates the rehabilitation of disuse atrophy and alters the expression of muscle myogenic factors in humans. J Physiol. 2001;536:625-633.  [PubMed]  [DOI]  [Cited in This Article: ]
65.  Deldicque L, Louis M, Theisen D, Nielens H, Dehoux M, Thissen JP, Rennie MJ, Francaux M. Increased IGF mRNA in human skeletal muscle after creatine supplementation. Med Sci Sports Exerc. 2005;37:731-736.  [PubMed]  [DOI]  [Cited in This Article: ]
66.  Deldicque L, Atherton P, Patel R, Theisen D, Nielens H, Rennie MJ, Francaux M. Effects of resistance exercise with and without creatine supplementation on gene expression and cell signaling in human skeletal muscle. J Appl Physiol (1985). 2008;104:371-378.  [PubMed]  [DOI]  [Cited in This Article: ]
67.  Burke DG, Candow DG, Chilibeck PD, MacNeil LG, Roy BD, Tarnopolsky MA, Ziegenfuss T. Effect of creatine supplementation and resistance-exercise training on muscle insulin-like growth factor in young adults. Int J Sport Nutr Exerc Metab. 2008;18:389-398.  [PubMed]  [DOI]  [Cited in This Article: ]
68.  Adams GR. Invited Review: Autocrine/paracrine IGF-I and skeletal muscle adaptation. J Appl Physiol (1985). 2002;93:1159-1167.  [PubMed]  [DOI]  [Cited in This Article: ]
69.  Saremi A, Gharakhanloo R, Sharghi S, Gharaati MR, Larijani B, Omidfar K. Effects of oral creatine and resistance training on serum myostatin and GASP-1. Mol Cell Endocrinol. 2010;317:25-30.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 40]  [Cited by in F6Publishing: 32]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
70.  Schiaffino S, Dyar KA, Ciciliot S, Blaauw B, Sandri M. The role of myostatin in muscle wasting: an overview. J Cachexia Sarcopenia Muscle. 2011;2:143-151.  [PubMed]  [DOI]  [Cited in This Article: ]
71.  Schiaffino S, Dyar KA, Ciciliot S, Blaauw B, Sandri M. Mechanisms regulating skeletal muscle growth and atrophy. FEBS J. 2013;280:4294-4314.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 688]  [Cited by in F6Publishing: 533]  [Article Influence: 86.0]  [Reference Citation Analysis (0)]
72.  Zimmers TA, Davies MV, Koniaris LG, Haynes P, Esquela AF, Tomkinson KN, McPherron AC, Wolfman NM, Lee SJ. Induction of cachexia in mice by systemically administered myostatin. Science. 2002;296:1486-1488.  [PubMed]  [DOI]  [Cited in This Article: ]
73.  Dankbar B, Wunrau C, Wehmeyer C, Pap T. Myostatin–a new player in inflammatory bone loss. Ann Rheum Diseases. 2011;70:A75-A76.  [PubMed]  [DOI]  [Cited in This Article: ]
74.  Söderlund K, Greenhaff PL, Hultman E. Energy metabolism in type I and type II human muscle fibres during short term electrical stimulation at different frequencies. Acta Physiol Scand. 1992;144:15-22.  [PubMed]  [DOI]  [Cited in This Article: ]
75.  Wortmann RL Inflammatory diseases of muscle. Textbook of Rheumatology. 4th ed. Philadelphia: WB Saunders Company 1993; 1159–1188.  [PubMed]  [DOI]  [Cited in This Article: ]
76.  Choy E. Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis. Rheumatology (Oxford). 2012;51 Suppl 5:v3-v11.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 447]  [Cited by in F6Publishing: 352]  [Article Influence: 49.7]  [Reference Citation Analysis (0)]
77.  Bassit RA, Curi R, Costa Rosa LF. Creatine supplementation reduces plasma levels of pro-inflammatory cytokines and PGE2 after a half-ironman competition. Amino Acids. 2008;35:425-431.  [PubMed]  [DOI]  [Cited in This Article: ]
78.  Morley JE, Baumgartner RN, Roubenoff R, Mayer J, Nair KS. Sarcopenia. J Lab Clin Med. 2001;137:231-243.  [PubMed]  [DOI]  [Cited in This Article: ]
79.  Candow DG, Little JP, Chilibeck PD, Abeysekara S, Zello GA, Kazachkov M, Cornish SM, Yu PH. Low-dose creatine combined with protein during resistance training in older men. Med Sci Sports Exerc. 2008;40:1645-1652.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 89]  [Cited by in F6Publishing: 35]  [Article Influence: 7.4]  [Reference Citation Analysis (0)]
80.  Chilibeck PD, Chrusch MJ, Chad KE, Shawn Davison K, Burke DG. Creatine monohydrate and resistance training increase bone mineral content and density in older men. J Nutr Health Aging. 2005;9:352-353.  [PubMed]  [DOI]  [Cited in This Article: ]
81.  Tarnopolsky MA. Potential benefits of creatine monohydrate supplementation in the elderly. Curr Opin Clin Nutr Metab Care. 2000;3:497-502.  [PubMed]  [DOI]  [Cited in This Article: ]
82.  Wiroth JB, Bermon S, Andreï S, Dalloz E, Hébuterne X, Dolisi C. Effects of oral creatine supplementation on maximal pedalling performance in older adults. Eur J Appl Physiol. 2001;84:533-539.  [PubMed]  [DOI]  [Cited in This Article: ]
83.  Skare OC, Skadberg AR. Creatine supplementation improves sprint performance in male sprinters. Scand J Med Sci Sports. 2001;11:96-102.  [PubMed]  [DOI]  [Cited in This Article: ]
84.  Mujika I, Padilla S, Ibañez J, Izquierdo M, Gorostiaga E. Creatine supplementation and sprint performance in soccer players. Med Sci Sports Exerc. 2000;32:518-525.  [PubMed]  [DOI]  [Cited in This Article: ]
85.  McNaughton LR, Dalton B, Tarr J. The effects of creatine supplementation on high-intensity exercise performance in elite performers. Eur J Appl Physiol Occup Physiol. 1998;78:236-240.  [PubMed]  [DOI]  [Cited in This Article: ]
86.  Rossiter HB, Cannell ER, Jakeman PM. The effect of oral creatine supplementation on the 1000-m performance of competitive rowers. J Sports Sci. 1996;14:175-179.  [PubMed]  [DOI]  [Cited in This Article: ]
87.  Harris RC, Viru M, Greenhaff PL, Hultman E. The effect of oral creatine supplementation on running performance during maximal short-term exercise in man. J Physiol. 1993;467:74-74.  [PubMed]  [DOI]  [Cited in This Article: ]
88.  Rawson ES, Volek JS. Effects of creatine supplementation and resistance training on muscle strength and weightlifting performance. J Strength Cond Res. 2003;17:822-831.  [PubMed]  [DOI]  [Cited in This Article: ]
89.  Volek JS, Kraemer WJ, Bush JA, Boetes M, Incledon T, Clark KL, Lynch JM. Creatine supplementation enhances muscular performance during high-intensity resistance exercise. J Am Diet Assoc. 1997;97:765-770.  [PubMed]  [DOI]  [Cited in This Article: ]
90.  Larson-Meyer DE, Hunter GR, Trowbridge CA, Turk JC, Ernest JM, Torman SL, Harbin PA. The effect of creatine supplementation on muscle strength and body composition during off-season training in female soccer players. J Strength Con Res. 2000;14:434-442.  [PubMed]  [DOI]  [Cited in This Article: ]
91.  Kreider RB. Effects of creatine supplementation on performance and training adaptations. Mol Cell Biochem. 2003;244:89-94.  [PubMed]  [DOI]  [Cited in This Article: ]
92.  Stroud MA, Holliman D, Bell D, Green AL, Macdonald IA, Greenhaff PL. Effect of oral creatine supplementation on respiratory gas exchange and blood lactate accumulation during steady-state incremental treadmill exercise and recovery in man. Clin Sci (Lond). 1994;87:707-710.  [PubMed]  [DOI]  [Cited in This Article: ]
93.  Chilibeck PD, Magnus C, Anderson M. Effect of in-season creatine supplementation on body composition and performance in rugby union football players. Appl Physiol Nutr Metab. 2007;32:1052-1057.  [PubMed]  [DOI]  [Cited in This Article: ]
94.  Willer B, Stucki G, Hoppeler H, Brühlmann P, Krähenbühl S. Effects of creatine supplementation on muscle weakness in patients with rheumatoid arthritis. Rheumatology (Oxford). 2000;39:293-298.  [PubMed]  [DOI]  [Cited in This Article: ]
95.  Stucki G, Schönbächler J, Brühlmann P, Mariacher S, Stoll T, Michel BA. Does a muscle strength index provide complementary information to traditional disease activity variables in patients with rheumatoid arthritis? J Rheumatol. 1994;21:2200-2205.  [PubMed]  [DOI]  [Cited in This Article: ]
96.  van den Ende CH, Breedveld FC, Dijkmans BA, Hazes JM. The limited value of the Health Assessment Questionnaire as an outcome measure in short term exercise trials. J Rheumatol. 1997;24:1972-1977.  [PubMed]  [DOI]  [Cited in This Article: ]
97.  Cañete S, San Juan AF, Pérez M, Gómez-Gallego F, López-Mojares LM, Earnest CP, Fleck SJ, Lucia A. Does creatine supplementation improve functional capacity in elderly women? J Strength Cond Res. 2006;20:22-28.  [PubMed]  [DOI]  [Cited in This Article: ]
98.  Gotshalk LA, Kraemer WJ, Mendonca MA, Vingren JL, Kenny AM, Spiering BA, Hatfield DL, Fragala MS, Volek JS. Creatine supplementation improves muscular performance in older women. Eur J Appl Physiol. 2008;102:223-231.  [PubMed]  [DOI]  [Cited in This Article: ]
99.  Rawson ES, Wehnert ML, Clarkson PM. Effects of 30 days of creatine ingestion in older men. Eur J Appl Physiol Occup Physiol. 1999;80:139-144.  [PubMed]  [DOI]  [Cited in This Article: ]
100.  Rawson ES, Clarkson PM. Acute creatine supplementation in older men. Int J Sports Med. 2000;21:71-75.  [PubMed]  [DOI]  [Cited in This Article: ]
101.  Stout JR, Sue Graves B, Cramer JT, Goldstein ER, Costa PB, Smith AE, Walter AA. Effects of creatine supplementation on the onset of neuromuscular fatigue threshold and muscle strength in elderly men and women (64 - 86 years). J Nutr Health Aging. 2007;11:459-464.  [PubMed]  [DOI]  [Cited in This Article: ]
102.  Jakobi JM, Rice CL, Curtin SV, Marsh GD. Neuromuscular properties and fatigue in older men following acute creatine supplementation. Eur J Appl Physiol. 2001;84:321-328.  [PubMed]  [DOI]  [Cited in This Article: ]
103.  Bermon S, Venembre P, Sachet C, Valour S, Dolisi C. Effects of creatine monohydrate ingestion in sedentary and weight-trained older adults. Acta Physiol Scand. 1998;164:147-155.  [PubMed]  [DOI]  [Cited in This Article: ]
104.  Gualano B, Macedo AR, Alves CR, Roschel H, Benatti FB, Takayama L, de Sá Pinto AL, Lima FR, Pereira RM. Creatine supplementation and resistance training in vulnerable older women: A randomized double-blind placebo-controlled clinical trial. Exp Gerontol. 2014;53:7-15.  [PubMed]  [DOI]  [Cited in This Article: ]
105.  Neves M, Gualano B, Roschel H, Lima FR, Lúcia de Sá-Pinto A, Seguro AC, Shimizu MH, Sapienza MT, Fuller R, Lancha AH. Effect of creatine supplementation on measured glomerular filtration rate in postmenopausal women. Appl Physiol Nutr Metab. 2011;36:419-422.  [PubMed]  [DOI]  [Cited in This Article: ]
106.  Roy BD, de Beer J, Harvey D, Tarnopolsky MA. Creatine monohydrate supplementation does not improve functional recovery after total knee arthroplasty. Arch Phys Med Rehabil. 2005;86:1293-1298.  [PubMed]  [DOI]  [Cited in This Article: ]
107.  Slemenda C, Brandt KD, Heilman DK, Mazzuca S, Braunstein EM, Katz BP, Wolinsky FD. Quadriceps weakness and osteoarthritis of the knee. Ann Intern Med. 1997;127:97-104.  [PubMed]  [DOI]  [Cited in This Article: ]
108.  Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, Deyo RA, Gabriel S, Hirsch R, Hochberg MC, Hunder GG. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 2008;58:26-35.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2610]  [Cited by in F6Publishing: 1933]  [Article Influence: 200.8]  [Reference Citation Analysis (0)]
109.  Alves CR, Santiago BM, Lima FR, Otaduy MC, Calich AL, Tritto AC, de Sá Pinto AL, Roschel H, Leite CC, Benatti FB. Creatine supplementation in fibromyalgia: a randomized, double-blind, placebo-controlled trial. Arthritis Care Res (Hoboken). 2013;65:1449-1459.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 34]  [Cited by in F6Publishing: 23]  [Article Influence: 4.3]  [Reference Citation Analysis (0)]
110.  Leader A, Amital D, Rubinow A, Amital H. An open-label study adding creatine monohydrate to ongoing medical regimens in patients with the fibromyalgia syndrome. Ann N Y Acad Sci. 2009;1173:829-836.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 9]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
111.  Kley RA, Tarnopolsky MA, Vorgerd M. Creatine for treating muscle disorders. Cochrane Database Syst Rev. 2011;CD004760.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 24]  [Cited by in F6Publishing: 13]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
112.  Tarnopolsky MA, Mahoney DJ, Vajsar J, Rodriguez C, Doherty TJ, Roy BD, Biggar D. Creatine monohydrate enhances strength and body composition in Duchenne muscular dystrophy. Neurology. 2004;62:1771-1777.  [PubMed]  [DOI]  [Cited in This Article: ]
113.  Banerjee B, Sharma U, Balasubramanian K, Kalaivani M, Kalra V, Jagannathan NR. Effect of creatine monohydrate in improving cellular energetics and muscle strength in ambulatory Duchenne muscular dystrophy patients: a randomized, placebo-controlled 31P MRS study. Magn Reson Imaging. 2010;28:698-707.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 52]  [Cited by in F6Publishing: 43]  [Article Influence: 4.7]  [Reference Citation Analysis (0)]
114.  Walter MC, Reilich P, Lochmüller H, Kohnen R, Schlotter B, Hautmann H, Dunkl E, Pongratz D, Müller-Felber W. Creatine monohydrate in myotonic dystrophy: a double-blind, placebo-controlled clinical study. J Neurol. 2002;249:1717-1722.  [PubMed]  [DOI]  [Cited in This Article: ]
115.  Tarnopolsky M, Mahoney D, Thompson T, Naylor H, Doherty TJ. Creatine monohydrate supplementation does not increase muscle strength, lean body mass, or muscle phosphocreatine in patients with myotonic dystrophy type 1. Muscle Nerve. 2004;29:51-58.  [PubMed]  [DOI]  [Cited in This Article: ]
116.  Escolar DM, Buyse G, Henricson E, Leshner R, Florence J, Mayhew J, Tesi-Rocha C, Gorni K, Pasquali L, Patel KM. CINRG randomized controlled trial of creatine and glutamine in Duchenne muscular dystrophy. Ann Neurol. 2005;58:151-155.  [PubMed]  [DOI]  [Cited in This Article: ]
117.  Schneider-Gold C, Beck M, Wessig C, George A, Kele H, Reiners K, Toyka KV. Creatine monohydrate in DM2/PROMM: a double-blind placebo-controlled clinical study. Proximal myotonic myopathy. Neurology. 2003;60:500-502.  [PubMed]  [DOI]  [Cited in This Article: ]
118.  Norman K, Stübler D, Baier P, Schütz T, Ocran K, Holm E, Lochs H, Pirlich M. Effects of creatine supplementation on nutritional status, muscle function and quality of life in patients with colorectal cancer--a double blind randomised controlled trial. Clin Nutr. 2006;25:596-605.  [PubMed]  [DOI]  [Cited in This Article: ]
119.  Bourgeois JM, Nagel K, Pearce E, Wright M, Barr RD, Tarnopolsky MA. Creatine monohydrate attenuates body fat accumulation in children with acute lymphoblastic leukemia during maintenance chemotherapy. Pediatr Blood Cancer. 2008;51:183-187.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 18]  [Cited by in F6Publishing: 15]  [Article Influence: 1.4]  [Reference Citation Analysis (0)]
120.  Tan BH, Fearon KC. Cachexia: prevalence and impact in medicine. Curr Opin Clin Nutr Metab Care. 2008;11:400-407.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 177]  [Cited by in F6Publishing: 73]  [Article Influence: 13.6]  [Reference Citation Analysis (0)]
121.  Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, Jatoi A, Loprinzi C, MacDonald N, Mantovani G. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011;12:489-495.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2341]  [Cited by in F6Publishing: 946]  [Article Influence: 234.1]  [Reference Citation Analysis (0)]
122.  Symmons D, Turner G, Webb R, Asten P, Barrett E, Lunt M, Scott D, Silman A. The prevalence of rheumatoid arthritis in the United Kingdom: new estimates for a new century. Rheumatology (Oxford). 2002;41:793-800.  [PubMed]  [DOI]  [Cited in This Article: ]
123.  Rawson ES, Venezia AC. Use of creatine in the elderly and evidence for effects on cognitive function in young and old. Amino Acids. 2011;40:1349-1362.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 59]  [Cited by in F6Publishing: 52]  [Article Influence: 5.9]  [Reference Citation Analysis (0)]
124.  Aguiar AF, Januário RS, Junior RP, Gerage AM, Pina FL, do Nascimento MA, Padovani CR, Cyrino ES. Long-term creatine supplementation improves muscular performance during resistance training in older women. Eur J Appl Physiol. 2013;113:987-996.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]
125.  Brose A, Parise G, Tarnopolsky MA. Creatine supplementation enhances isometric strength and body composition improvements following strength exercise training in older adults. J Gerontol A Biol Sci Med Sci. 2003;58:11-19.  [PubMed]  [DOI]  [Cited in This Article: ]
126.  Moon A, Heywood L, Rutherford S, Cobbold C. Creatine supplementation: can it improve quality of life in the elderly without associated resistance training? Curr Aging Sci. 2013;6:251-257.  [PubMed]  [DOI]  [Cited in This Article: ]
127.  Devries MC, Phillips SM. Creatine supplementation during resistance training in older adults-a meta-analysis. Med Sci Sports Exerc. 2014;46:1194-1203.  [PubMed]  [DOI]  [Cited in This Article: ]
128.  Chung YL, Alexanderson H, Pipitone N, Morrison C, Dastmalchi M, Ståhl-Hallengren C, Richards S, Thomas EL, Hamilton G, Bell JD. Creatine supplements in patients with idiopathic inflammatory myopathies who are clinically weak after conventional pharmacologic treatment: Six-month, double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 2007;57:694-702.  [PubMed]  [DOI]  [Cited in This Article: ]
129.  Syrotuik DG, Bell GJ, Burnham R, Sim IL, Calvert RA, Maclean IM. Absolute and relative strength performance following creatine monohydrate supplementation combined with periodized resistance training. J Strength Con Res. 2000;14:182-190.  [PubMed]  [DOI]  [Cited in This Article: ]
130.  Harris RC, Söderlund K, Hultman E. Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin Sci (Lond). 1992;83:367-374.  [PubMed]  [DOI]  [Cited in This Article: ]
131.  Delanghe J, De Slypere JP, De Buyzere M, Robbrecht J, Wieme R, Vermeulen A. Normal reference values for creatine, creatinine, and carnitine are lower in vegetarians. Clin Chem. 1989;35:1802-1803.  [PubMed]  [DOI]  [Cited in This Article: ]
132.  Stec ES, Rawson MJ. Benefits of creatine supplementation for older adults. Braz J Biomotric. 2010;4:215-226.  [PubMed]  [DOI]  [Cited in This Article: ]
133.  Poortmans JR, Auquier H, Renaut V, Durussel A, Saugy M, Brisson GR. Effect of short-term creatine supplementation on renal responses in men. Eur J Appl Physiol Occup Physiol. 1997;76:566-567.  [PubMed]  [DOI]  [Cited in This Article: ]
134.  Poortmans JR, Francaux M. Renal dysfunction accompanying oral creatine supplements. Lancet. 1998;352:234.  [PubMed]  [DOI]  [Cited in This Article: ]
135.  Earnest CP, Almada AL, Mitchell TL. High-performance capillary electrophoresis-pure creatine monohydrate reduces blood lipids in men and women. Clin Sci (Lond). 1996;91:113-118.  [PubMed]  [DOI]  [Cited in This Article: ]
136.  Lemon PW. Dietary creatine supplementation and exercise performance: why inconsistent results? Can J Appl Physiol. 2002;27:663-681.  [PubMed]  [DOI]  [Cited in This Article: ]
137.  Walliman T. Comment on “Creatine is an approved, effective and safe dietary supplement that is NOT causing toxic hepatitis!”. Food Chem Toxicol. 2013;51:453–454.  [PubMed]  [DOI]  [Cited in This Article: ]
138.  Shao A, Hathcock JN. Risk assessment for creatine monohydrate. Regul Toxicol Pharmacol. 2006;45:242-251.  [PubMed]  [DOI]  [Cited in This Article: ]
139.  Gualano B, Ugrinowitsch C, Novaes RB, Artioli GG, Shimizu MH, Seguro AC, Harris RC, Lancha AH. Effects of creatine supplementation on renal function: a randomized, double-blind, placebo-controlled clinical trial. Eur J Appl Physiol. 2008;103:33-40.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 45]  [Cited by in F6Publishing: 28]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
140.  Mayhew DL, Mayhew JL, Ware JS. Effects of long-term creatine supplementation on liver and kidney functions in American college football players. Int J Sport Nutr Exerc Metab. 2002;12:453-460.  [PubMed]  [DOI]  [Cited in This Article: ]
141.  Schröder H, Terrados N, Tramullas A. Risk assessment of the potential side effects of long-term creatine supplementation in team sport athletes. Eur J Nutr. 2005;44:255-261.  [PubMed]  [DOI]  [Cited in This Article: ]
142.  Spillane M, Schoch R, Cooke M, Harvey T, Greenwood M, Kreider R, Willoughby DS. The effects of creatine ethyl ester supplementation combined with heavy resistance training on body composition, muscle performance, and serum and muscle creatine levels. J Int Soc Sports Nutr. 2009;6:6.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 47]  [Cited by in F6Publishing: 30]  [Article Influence: 3.9]  [Reference Citation Analysis (0)]
143.  Vorgerd M, Grehl T, Jager M, Muller K, Freitag G, Patzold T, Bruns N, Fabian K, Tegenthoff M, Mortier W. Creatine therapy in myophosphorylase deficiency (McArdle disease): a placebo-controlled crossover trial. Arch Neurol. 2000;57:956-963.  [PubMed]  [DOI]  [Cited in This Article: ]
144.  Hultman E, Söderlund K, Timmons JA, Cederblad G, Greenhaff PL. Muscle creatine loading in men. J Appl Physiol (1985). 1996;81:232-237.  [PubMed]  [DOI]  [Cited in This Article: ]