Endocrine DOI 10.1007/s12020-013-0070-4
REVIEW
Creatine supplementation and aging musculoskeletal health Darren G. Candow • Philip D. Chilibeck Scott C. Forbes
•
Received: 22 July 2013 / Accepted: 17 September 2013 Ó Springer Science+Business Media New York 2013
Abstract Sarcopenia refers to the progressive loss of muscle mass and muscle function and is a contributing factor for cachexia, bone loss, and frailty. Resistance training produces several physiological adaptations which improve aging musculoskeletal health, such as increased muscle and bone mass and strength. The combination of creatine supplementation and resistance training may further lead to greater physiological benefits. We performed meta-analyses which indicate creatine supplementation combined with resistance training has a positive effect on aging muscle mass and upper body strength compared to resistance training alone. Creatine also shows promise for improving bone mineral density and indices of bone biology. The combination of creatine supplementation and resistance training could be an effective intervention to improve aging musculoskeletal health. Keywords Sarcopenia Resistance training Bone health Meta-analysis Introduction Recently, the European Working Group on Sarcopenia in Older Adults (EWGSOP) and International Working Group
D. G. Candow (&) Faculty of Kinesiology and Health Studies, University of Regina, 3737 Wascana Parkway, Regina, SK S4S 0A2, Canada e-mail: [email protected] P. D. Chilibeck College of Kinesiology, University of Saskatchewan, Saskatoon, SK, Canada S. C. Forbes Faculty of Medicine, University of Calgary, Calgary, AB, Canada
on Sarcopenia have redefined sarcopenia to include both the progressive loss of muscle mass and muscle function [1, 2]. Due to the inherent variability among older adults, the severity of sarcopenia can be categorized by three distinct stages: (1) pre-sarcopenic: low muscle mass, (2) sarcopenic: low muscle mass and reduced muscle strength OR physical performance, and (3) severe sarcopenic: low muscle mass and reduced muscle strength AND physical performance [1]. Sarcopenia is a main contributing factor for cachexia [3], osteoporosis [4], and frailty [1]. Frailty is the most problematic consequence of aging and is defined as a state of physiological vulnerability leading to adverse outcomes such as falls and disability [5]. Consequently, annual healthcare costs associated with treating symptoms of sarcopenia are in the billions of dollars [6]. Therefore, improving aging muscle mass and muscle function is crucial for healthy and successful aging. The etiology of sarcopenia is multi-factorial and remains to be elucidated [7–9]; however, sarcopenia may be associated with changes in muscle fiber composition [10], chronic inflammation and oxidative stress [11], altered protein and hormonal kinetics [12], reduced satellite cell activity [13], insulin resistance [14], cell death [15], physical inactivity [16], and dietary modifications [17]. Resistance training produces several physiological adaptations which improve aging musculoskeletal health, such as increased muscle and bone mass and strength. The combination of creatine supplementation and resistance training may further augment these benefits. The purpose of this brief review is to highlight the potential effects of creatine supplementation and resistance training on aging musculoskeletal health. In the first part, we review the effects of creatine combined with resistance training on strength and lean tissue mass. In the second part, we describe the effects of creatine on measurements related to
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bone health. We performed meta-analyses to assess the effect of creatine supplementation during resistance training on general measures of upper body (i.e., chest press) and lower body (i.e., leg press) strength and on lean tissue mass. We did not perform meta-analyses on any of the bone health variables because of the paucity of studies that have evaluated similar bone health measurements.
Methods used to analyze the literature and perform the meta-analysis To synthesize results across studies we performed metaanalyses for strength and lean tissue mass. We chose strength measurements of chest press and leg press because they provide assessment of a large muscle mass in the upper- and lower body, respectively, and these strength measures were assessed in most studies. We searched the PubMed and SPORTDiscus databases using the key words ‘‘creatine supplementation’’ and a variety of synonyms for ‘‘resistance training’’ (e.g., ‘‘strength training’’) from January 1966 to June 2013. Our inclusion criteria for studies were participants over the age of 50 years, evaluation of creatine and placebo groups during a resistance training program and using a randomized design. Means and standard deviations for baseline and post-training measurements were extracted from each study for estimation of mean changes and the standard deviation of mean changes across the interventions. The homogeneity of the effect size among studies was assessed using a v2 test. Our tests indicated homogeneity across studies for all variables included in our meta-analyses. We therefore used fixed effects models to calculate the pooled mean net change of strength or lean tissue mass comparing creatine supplementation with placebo. Chest press and leg press strength were assessed using a variety of measurement techniques using different units of measurement across studies; therefore, the net change comparing creatine supplementation with placebo was expressed as a standardized mean difference by dividing the net change by the pooled standard deviation for the changes across the creatine and placebo groups. Mean changes and standard deviations for mean changes for individual studies and the pooled effects and their 95 % confidence intervals were calculated and Forest plots were generated using Review Manager 5.0 Software. Significance was set at p B 0.05.
Creatine and aging muscle Creatine is a naturally occurring nitrogen-containing compound found in the diet primarily in red meat and seafood [18]. The majority of creatine is stored in skeletal
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muscle as phosphocreatine (PCr), a high-energy phosphate involved in the rapid resynthesis of adenosine triphosphate (ATP) during intense muscle contraction [18]. Aging may have a negative impact on high-energy phosphate metabolism [19–21]. From a theoretical perspective, increasing intra-muscular creatine from exogenous creatine ingestion should enhance high-energy phosphate metabolism [22], which could result in greater resistance training capacity and subsequently muscle accretion and strength gains in older adults. Table 1 summarizes studies combining creatine and resistance training in older adults. For example, Chrusch et al. [23] showed that creatine monohydrate supplementation (0.3 g kg-1 9 5 days; 0.07 g kg-1 for 79 days) enabled older men (59–77 years of age) to train at a 31 % higher volume (load 9 sets 9 repetitions) over time which resulted in greater gains in muscle mass and strength compared to older men on placebo. Subsequent to these findings, Brose et al. [24] found a significant increase in intramuscular total creatine and muscle accretion (1.7 ± 1.2 kg) in healthy older adults who supplemented with creatine monohydrate (5 g day-1) during resistance training compared to placebo for 14 weeks. Further work from the same laboratory found greater increases in muscular endurance from creatine supplementation and resistance training compared to training alone in older adults [25]. We showed that creatine monohydrate supplementation (0.1 g kg-1) in close proximity to resistance training sessions for 10 weeks increased whole-body muscle size (sum of six limb muscle groups) compared to placebo in healthy older men (59–77 years of age) [26]. In a study focusing exclusively on older women (65 years of age) creatine monohydrate supplementation (5 gday-1 for 12 weeks) during resistance training enhanced training volume and induced greater increases in strength and muscle mass compared to placebo [27]. In addition to these findings, showing an anabolic effect on aging muscle, creatine may also exhibit anti-catabolic properties. Creatine decreases urinary excretion of 3-methylhistidine, an indicator of muscle protein catabolism, in older men during resistance training [26] and whole-body protein breakdown (e.g., plasma leucine rate of appearance) in younger men [28]. Furthermore, creatine supplementation may attenuate reactive and radical species ions [29, 30], which are contributing factors for sarcopenia [31]. In contrast to the positive studies described above, there are a number of studies that have found no evidence of an ergogenic effect from creatine monohydrate during resistance training in older men or women [32–35]. We have previously critically reviewed two of these studies [36], where we highlighted that the study by Bermon et al. [33] lacked statistical power and the study by Eijnde et al. [34] used a training program that involved muscular endurance training rather than strength training and therefore differed
Endocrine Table 1 Study characteristics and outcomes of research examining the influence of creatine in older adults with a resistance training program First author (year)
Study population
Intervention
Duration
Outcome measure
Aguiar et al. [27]
N = 18; healthy women; age = 64.9 ± 5 years
CR (5 g day-1 or PLA (maltodextrin) with a RT program (3 days week-1)
12 weeks
CR : bench press, knee extension, bicep curl, fat free mass, and muscle mass
Bemben et al. [32]
N = 42; healthy men; age = 48–72 years
14 weeks
$ upper or lower body strength
Bermon et al. [33]
N = 32 (16 men; 16 women); healthy adults; age = 67–80 years
RT PLA; RT CR (5 g day-1); RT Pro (35 g day-1); RT Pro (35 g day-1) ? CR (5 g day-1): RT = 3 days week-1 CR (20 g day-1 for 5 days followed by 3 g day-1); PLA (glucose); RT ? CR: RT = 3 days week-1
52 days
$ body composition, strength, endurance
Brose et al. [24]
N = 28 (15 men; 13 women); healthy adults; age = men = 68.7 ± 4.8; women = 70.8 ± 6.1
CR (5 g day-1) or PLA (7 g dextrose) with a RT program (3 days week-1)
14 weeks
CR : body mass, fat-free mass, lower body strength only in men.
Candow et al. [26]
N = 35; healthy men; age = 55–77 years
CR (0.1 g kg-1) or CR ? PRO (0.3 g kg-1) or PLA with a RT program (3 days week-1)
10 weeks
CR ? CR ? PRO conditions : body mass and muscle thickness.
Chilibeck et al. [44]
N = 29; healthy men; age = 71 years
CR (0.3 g kg-1 day-1 for 5 days followed by 0.07 g kg-1 day-1) or PLA; RT
12 weeks
CR : arms bone mineral content.
Chrusch et al. [23]
N = 30; healthy men; age = 60–84 years
CR (0.3 g kg-1 day-1 for 5 days followed by 0.07 g kg-1 day-1) or PLA with a RT (3 days week-1)
12 weeks
CR : lean tissue mass and lower body strength, lower body endurance, and average power. $ upper body strength, upper endurance, fat mass.
Deacon et al. [39]
N = 80 (50 men; 30 women); COPD; age = 68.2 ± 8.2 years
CR (22 g day-1 for 5 days followed by 3.76 g day-1); pulmonary rehabilitation
7 weeks
$ shuttle walk distance, knee extensor work.
Eijnde et al. [34]
N = 46; healthy men; age = 55–75 years
CR (5 g day-1) or PLA; Cardio-respiratory ? RT 2–3 days week-1
6 months
$ body weight, isometric strength
Eliot et al. [35]
N = 42; healthy men; age = 48–72 years
CR (5 g day-1) or CR ? PRO (35 g day-1) or PRO or PLA; RT 3 days week-1
14 weeks
$ body composition
Hass et al. [38]
N = 20 (17 men; 3 females); idiopathic parkinson disease; age = PLA: 62.8 ± 2.6 years: CR = 62.2 ± 2.6 years
CR (20 g day-1 for 5 days followed by 5 g day-1); PLA; RT = 2 days week-1
12 weeks
CR :upper body strength, chair rise performance. $ 1RM leg extension, muscular endurance.
Neves et al. [37]
N = 24; Post menopausal women with knee osteoarthritis; age = 55–65 years
CR (20 g day-1 for 1 week followed by 5 g day-1) or PLA; RT
12 weeks
CR : physical function, stiffness subscales, lower limb lean mass, quality of life. $ lower body strength.
Tarnopolsky et al. [25]
N = 39 (19 men; 20 women); healthy; age = 65–85 years
CR (5 g day-1) ? CLA (6 g day-1) or PLA; RT = 2 days week-1
6 months
CR ? CLA :muscular endurance, isokinetic knee extension strength, fat-free mass, and lower fat mass.
CR creatine, PLA placebo, RT resistance training, PRO protein, CLA conjugated linoleic acid, : significant increase compared to the placebo condition, $ no difference between the creatine and placebo conditions
substantially from other studies. The older men in the study by Eijnde et al. [34] had very high baseline levels of phosphocreatine, perhaps due to geographically-different intake of dietary creatine which may have made them less
sensitive to creatine supplementation. The studies of Eliot et al. [35] and Bemben et al. [32] were on the same research participants, but presented body composition results [35] and strength results [32] from one study in two
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different papers. Their results are limited by their statistical analyses: all participants were assigned the same resistance training program and were randomized to four groups in a factorial design: placebo, whey protein, creatine monhydrate, and creatine monohydrate ? whey protein supplementation. Despite using a factorial design, they analyzed their data as a ‘‘parallel group’’ design; therefore, not taking advantage of the increase in statistical power for comparing creatine versus non-creatine groups they would achieve by analyzing the data using a factorial ANOVA. Close inspection of their data reveal larger increases (especially for lean tissue mass; [35]) in many of their measures when comparing combined creatine groups to combined non-creatine groups, but failure to use the appropriate statistical testing on their data did not allow this statistical comparison. There have been a number of studies of creatine supplementation during resistance training in older adults with chronic conditions, including osteoarthritis, Parkinson disease, chronic obstructive pulmonary disease (COPD), and cardiovascular disease. As with healthy older adults, the effectiveness of creatine supplementation across these studies has varied. Postmenopausal women (mean age of 57 years) with knee osteoarthritis who supplemented with creatine monohydrate (20 g day-1 for 7 days, 5 g day-1 thereafter) for 12 weeks during a lower body resistance training program increased lower body lean tissue mass, but not leg press strength compared to a placebo group [37]. The creatine group also had significant improvements for stiffness and physical function, as evaluated by osteoarthritis subscales, and quality of life compared to placebo. Creatine monohydrate supplementation (20 g day-1 for 5 days, 5 g day-1 thereafter) during 12 weeks of resistance training improved upper body strength and chair-rise performance compared to placebo in patients with Parkinson disease (mean age of 62 years) [38]. In contrast, creatine monohydrate supplementation (20 g day-1 for 5 days, 3.76 g day-1 thereafter) during a 7-week resistance training program in patients with COPD (mean age of 68 years) was not effective for improving strength, lean tissue mass, and functional performance measurements compared to placebo [39]. Also, creatine monohydrate supplementation (15 g day-1 for 7 days, 5 g day-1 thereafter) during 3 months of resistance training in patients enrolled in a cardiac rehabilitation program (mean age 57.5 years) was not effective for improving knee extension strength or muscular endurance [40].
Meta-analyses results Mean changes and standard deviations for mean changes for individual studies and the pooled effects and their 95 %
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confidence intervals are presented along with Forest plots in Figs. 1, 2, 3. Chest press strength (p = 0.003) and lean tissue mass (p = 0.002) increased to a greater extent in creatine-supplemented groups compared to placebo pooled across studies; whereas there was no favorable effect of creatine for increasing leg press strength compared to placebo (p = 0.1). Results across studies, therefore, imply that creatine supplementation has a positive effect on aging muscle mass and some strength measures and could, therefore, be considered as an effective lifestyle intervention, along with resistance training, to improve aging muscle health.
Creatine and aging bone While the majority of research on creatine supplementation has focused on muscle biology, research over the past decade has also included indices of bone as a primary outcome measure [41]. In two studies involving young males with muscular dystrophy, a condition associated with rapid muscle and bone atrophy, creatine monohydrate supplementation increased lumbar spine bone mineral density by 3.9 % and decreased the urinary excretion of cross-linked N-telopeptides of Type I collagen, an indicator of bone resorption, by 19–33 % compared to young males who consumed a placebo [42, 43]. These preliminary studies provided the first lines of evidence that creatine may have a beneficial effect on bone health which could have application for the aging skeleton. Using a doubleblind, placebo-controlled, repeated measures design, Chilibeck et al. [44] showed that creatine monohydrate supplementation (0.3 g kg-1 9 5 days; 0.07 g kg-1 thereafter) during 12 weeks of supervised resistance training in healthy older males increased upper limb bone mineral content by 3.2 % compared to a non-significant decrease in men in the placebo group. The authors hypothesized that the greater increase in muscle mass from creatine supplementation [23] caused more pull on bone during training, which may have induced more strain on bone tissue resulting in bone formation [44]. Additional work from the same laboratory showed that older males who supplemented with creatine monohydrate (8 g day-1) during resistance training for 10 weeks experienced a significant reduction in bone resorption (-30 %), as measured by urinary cross-linked N-telopeptides of Type I collagen, compared to a non-significant increase (6 %) for older men on placebo during training [26]. More recently, creatine monohydrate supplementation (8 g day-1) during 52 weeks of resistance training decreased femoral neck bone loss and increased femoral shaft subperiosteal width, a predictor of bone bending strength [45], in postmenopausal women compared to placebo [46]. However, others
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Fig. 1 Forest plot for chest press strength. Note that the study by Bemben et al. [32] had groups that consumed creatine and protein versus protein, and groups that consumed creatine versus placebo. These are, therefore, entered separately in the meta-analysis.
Likewise, Brose et al. [24] and Tarnopolsky et al. [25] presented results separately for men and women; therefore, these are entered separately in the meta-analysis
Fig. 2 Forest plot for leg press strength. Note that the study by Bemben et al. [32] had groups that consumed creatine and protein versus protein, and groups that consumed creatine versus placebo. These are, therefore, entered separately in the meta-analysis.
Likewise, Brose et al. [24] and Tarnopolsky et al. [25] presented results separately for men and women; therefore, these are entered separately in the meta-analysis
Fig. 3 Forest plot for lean tissue mass. Note that the study by Eliot et al. [35] had groups that consumed creatine and protein versus protein, and groups that consumed creatine versus placebo. These are, therefore, entered separately in the meta-analysis. Likewise, Brose
et al. [24] and Tarnopolsky et al. [25] presented results separately for men and women; therefore, these are entered separately in the metaanalysis
have found no beneficial effect from creatine supplementation on bone mineral density or measures of bone resorption and bone formation in healthy older adults following 14 weeks to 6 months of resistance training [24, 25]. In addition to these human studies, growing rats who consumed creatine monohydrate (2 % wet weight) for 8 weeks experienced a significant increase in lumbar spine
bone mineral density and femur bone strength compared to rats who consumed placebo [47]. In ovariectomized rats, an animal model of menopause, micronize creatine ingestion for 8 weeks led to a significant increase in the phosphate content of lumbar bone which may lead to greater bone quality over time [48]. Mechanistically, Gerber et al. [49] showed that 10 and 20 mM chemically pure creatine added
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to low serum cell culture medium increased the metabolic activity, differentiation, and mineralization of osteoblastlike cells which are involved in bone formation and reliant on the creatine kinase reaction for energy production [47]. Creatine supplementation increases phosphocreatine levels, a substrate for creatine kinase [50]. Along with increasing bone formation, stimulating osteoblast activity may increase the production of compounds (e.g., osteoprotegerin) which inhibit osteoclast activity and reduce bone resorption [51]; this is supported by the finding that Ntelopeptides, a measure of bone resorption, is reduced in some studies of creatine supplementation [26, 52]. In summary, there is evidence that creatine, with and without resistance training, has a positive effect on cells involved in the bone remodeling process which may help explain the increase in bone mineral and bone strength observed in humans and rodent models. Several organizations, such as the International Society of Sports Nutrition, as well as a joint position between the Dieticians of Canada, the American College of Sports Medicine, and the American Dietetic Association, have evaluated the safety and efficacy of creatine supplementation [53–56]. The most common side effects of creatine supplementation include weight gain, cramping, nausea, and diarrhea [54, 57]. These side effects are mostly based on anecdotal claims and creatine supplementation can be considered safe for healthy young and older adults [53–57]; however, the long term effects are still unknown and it is recommended that individuals with pre-existing renal disease or those with a potential risk for renal dysfunction not supplement with creatine [54]. There is evidence in younger individuals that a high dose ([20 g day-1) of creatine supplementation may lead to an increase in formaldehyde production [58]; therefore, a low-dose creatine supplementation protocol may be suggested for healthy older adults [26]. Burke et al. [59] found that a low dose (8 g day-1) of creatine monohydrate was effective for increasing muscle mass and strength in younger adults, while Candow et al. [26] found that a low-dose of creatine monohydrate (0.1 g kg-1 day-1) combined with protein was effective for increasing lean tissue mass and enhancing upper body strength in older men (59–77 years) without increasing formaldehyde production. In a recent review, Walliman et al. [57] recommended long-term low dose creatine for health benefits, particularly as one ages. As creatine is taken up by and forms phosphocreatine in brain tissue, others have recommended creatine monohydrate supplementation to combat conditions such as neurodegeneration and loss of cognitive function with aging [60, 61]. Future research, examining the long term effects of low-dose creatine supplementation in older adults is warranted.
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Conclusions Sarcopenia is a main contributing factor for bone and strength loss which can result in substantial economic, health, and societal burden. Resistance training is an effective intervention which increases aging muscle and bone mass and strength. In addition to resistance training, creatine supplementation has shown promise for augmenting the physiological adaptations from exercise in older adults. Therefore, the combination of resistance training and creatine supplementation should be considered when developing effective lifestyle interventions for improving aging musculoskeletal health. With this in mind, future research may also want to investigate the effects of resistance training and creatine supplementation in populations characterized by poor musculoskeletal health, such as the frail elderly. Conflict of interest of interest.
The authors declare that they have no conflict
References 1. A.J. Cruz-Jentoft, J.P. Baeyens, J.M. Bauer, Y. Boirie, T. Cederholm, F. Landi, F.C. Martin, J.P. Michel, Y. Rolland, S.M. Schneider, E. Topinkova´, M. Vandewoude, M. Zamboni, European Working Group on Sarcopenia in Older People.: sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing 39, 412–423 (2010) 2. R.A. Fielding, B. Vellas, W.J. Evans, S. Bhasin, J.E. Morley, A.B. Newman, G. Abellan van Kan, S. Andrieu, J. Bauer, D. Breuille, T. Cederholm, J. Chandler, C. De Meynard, L. Donini, T. Harris, A. Kannt, F. Keime Guibert, G. Onder, D. Papanicolaou, Y. Rolland, D. Rooks, C. Sieber, E. Souhami, S. Verlaan, M. Zamboni, Sarcopenia: an undiagnosed condition in older adults. Current consensus definition: prevalence, etiology, and consequences. International working group on sarcopenia. J. Am. Med. Dir. Assoc. 12, 249–256 (2011) 3. W.J. Evans, J.E. Morley, J. Argile´s, C. Bales, V. Baracos, D. Guttridge, A. Jatoi, K. Kalantar-Zadeh, H. Lochs, G. Mantovani, D. Marks, W.E. Mitch, M. Muscaritoli, A. Najand, P. Ponikowski, F. Rossi Fanelli, M. Schambelan, A. Schols, M. Schuster, D. Thomas, R. Wolfe, S.D. Anker, Cachexia: a new definition. Clin Nutr. 27, 793–799 (2008) 4. G. Crepaldi, S. Maggi, Sarcopenia and osteoporosis: a hazardous duet. J. Endocrinol. Invest. 28, 66–68 (2005) 5. A. Clegg, J. Young, S. Iliffe, M.O. Rikkert, K. Rockwood, Frailty in elderly people. Lancet 2, 752–762 (2013) 6. I. Janssen, D.S. Shepard, P.T. Katzmarzyk, R. Roubenhoff, The healthcare costs of sarcopenia in the United States. J. Am. Geriatr. Soc. 52, 80–85 (2004) 7. Kohara, K.: Sarcopenia obesity in aging population: current status and future directions for research. Endocrine. Epub ahead of print (2013) 8. S.C. Forbes, J.P. Little, D.G. Candow, Exercise and nutritional interventions for improving aging muscle health. Endocrine 42, 29–38 (2012)
Endocrine 9. J.P. Gumucio, C.L. Mendias, Atrogin-1, MuRF-1, and sarcopenia. Endocrine 43, 12–21 (2013) 10. R. Nilwik, T. Snijders, M. Leenders, B.B. Groen, J. van Kranenburg, L.B. Verdijk, L.J. van Loon, The decline in skeletal muscle mass with aging is mainly attributed to a reduction in type II muscle fiber size. Exp. Gerontol. 48, 492–498 (2013) 11. L.J. Greenlund, K.S. Nair, Sarcopenia—consequences, mechanisms, and potential therapies. Mech. Ageing Dev. 124, 287–299 (2003) 12. E. Ziv, D. Hu, Genetic variation in insulin/IGF-1 signaling pathways and longevity. Ageing Res Rev. 10, 201–204 (2011) 13. A.S. Brack, T.A. Rando, Intrinsic changes and extrinsic influences of myogenic stem cell function during aging. Stem Cell Rev. 3, 226–237 (2007) 14. A.M. Abbatecola, G. Paolisso, P. Fattoretti, W.J. Evans, V. Fiore, L. Dicioccio, F. Lattanzio, Discovering pathways of sarcopenia in older adults: a role for insulin resistance on mitochondria dysfunction. J. Nutr. Health Aging 15, 890–895 (2011) 15. E. Marzetti, R. Calvani, R. Bernabei, C. Leeuwenburgh, Apoptosis in skeletal myocytes: a potential target for interventions against sarcopenia and physical frailty—a mini-review. Gerontology 58, 99–106 (2012) 16. M.A. Tarnopolsky, A. Safdar, The potential benefits of creatine and conjugated linoleic acid as adjuncts to resistance training in older adults. Appl. Physiol. Nutr. Metab. 33, 213–227 (2008) 17. W.F. Nieuwenhuizen, H. Weenen, P. Rigby, M.M. Hetherington, Older adults and patients in need of nutritional support: review of current treatment options and factors influencing nutritional intake. Clin. Nutr. 29, 160–169 (2010) 18. M. Wyss, R. Kaddurah-Daouk, Creatine and creatinine metabolism. Physiol. Rev. 80, 1107–1213 (2000) 19. R.G. Larsen, D.M. Callahan, S.A. Foulis, J.A. Kent-Braun, Agerelated changes in oxidative capacity differ between locomotory muscles and are associated with physical activity behavior. Appl. Physiol. Nutr. Metab. 37, 88–99 (2012) 20. K.K. McCully, R.A. Fielding, W.J. Evans, J.S. Leigh Jr, J.D. Posner, Relationships between in vivo and in vitro measurements of metabolism in young and old human calf muscles. J. Appl. Physiol. 75, 813–819 (1993) 21. P. Mo¨ller, J. Bergstro¨m, P. Fu¨rst, K. Hellstro¨m, Effect of aging on energy-rich phosphagens in human skeletal muscles. Clin. Sci. (Lond) 58, 553–555 (1980) 22. S.A. Smith, S.J. Montain, R.P. Matott, G.P. Zientara, F.A. Jolesz, R.A. Fielding, Creatine supplementation and age influence muscle metabolism during exercise. J. Appl. Physiol. 85, 1349–1356 (1998) 23. M.J. Chrusch, P.D. Chilibeck, K.E. Chad, K.S. Davison, D.G. Burke, Creatine supplementation combined with resistance training in older men. Med. Sci. Sports Exerc. 33, 2111–2117 (2001) 24. A. Brose, G. Parise, M.A. Tarnopolsky, Creatine supplementation enhances isometric strength and body composition improvements following strength exercise training in older adults. J. Gerontol. A Biol. Sci. Med. Sci. 58, 11–19 (2003) 25. M. Tarnopolsky, A. Zimmer, J. Paikin, A. Safdar, A. Aboud, E. Pearce, B. Roy, T. Doherty, Creatine monohydrate and conjugated linoleic acid improves strength and body composition following resistance exercise in older adults. PLoS ONE 2, 991 (2007) 26. D.G. Candow, J.P. Little, P.D. Chilibeck, S. Abeysekara, G.A. Zello, S. Kazachkov, S.M. Cornish, P.H. Yu, Low-dose creatine combined with protein during resistance training in older men. Med. Sci. Sports Exerc. 40, 1645–1652 (2008) 27. A.F. Aguiar, R.S. Januario, R.P. Junior, A.M. Gerage, F.L. Pina, M.A. do Nascimento, C.R. Padovani, E.S. Cyrino, Long-term creatine supplementation improves muscular performance during
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
resistance training in older women. Eur. J. Appl. Physiol. 113, 987–996 (2013) G. Parise, S. Mihic, D. MacLennan, K.E. Yarasheski, M.A. Tarnopolsky, Effects of acute creatine monohydrate supplementation on leucine kinetics and mixed-muscle protein synthesis. J. Appl. Physiol. 91, 1041–1047 (2001) R. Deminice, A.A. Jardao, Creatine supplementation reduces oxidative stress biomarkers after acute exercise in rats. Amino Acids 43, 709–715 (2011) P. Sestili, C. Martinelli, E. Colombo, E. Barbieri, L. Potenza, S. Sartini, C. Fimognari, Creatine as an antioxidant. Amino Acids 40, 1385–1396 (2011) A.P. Johnston, M. De Lisio, G. Parise, Resistance training, sarcopenia, and the mitochondrial theory of aging. Appl. Physiol. Nutr. Metab. 33, 191–199 (2008) M.G. Bemben, M.S. Witten, J.M. Carter, K.A. Eliot, A.W. Knehans, D.A. Bemben, The effects of supplementation with creatine and protein on muscle strength following a traditional resistance training program in middle-aged and older men. J. Nutr. Health Aging 14, 155–159 (2010) S. Bermon, P. Venembre, C. Sachet, S. Valour, C. Dolisi, Effects of creatine monohydrate ingestion in sedentary and weighttrained older adults. Acta Physiol. Scand. 164, 147–155 (1998) B.O. Eijnde, M. Van Leemputte, M. Goris, V. Labarque, Y. Taes, P. Verbessem, L. Vanhees, M. Ramaekers, B. Vanden Eynde, R. Van Schuylenbergh, R. Dom, E.A. Richter, P. Hespel, Effects of creatine supplementation and exercise training on fitness in men 55–75-year-old. J. Appl. Physiol. 95, 818–828 (2003) K.A. Eliot, A.W. Knehans, D.A. Bemben, M.S. Witten, J. Carter, M.G. Bemben, The effects of creatine and whey protein supplementation on body composition in men aged 48 to 72 years during resistance training. J. Nutr. Health Aging 12, 208–212 (2008) D.G. Candow, P.D. Chilibeck, Review: timing of creatine and protein supplementation during resistance training in the elderly. Appl. Physiol. Nutr. Metab. 33, 184–190 (2008) M. Neves Jr, B. Guolano, H. Roschel, R. Fuller, F.B. Benatii, A.L. Pinto, F.R. Lima, R.M. Pereira, A.H. Lancha Jr, E. Bonfa, Beneficial effect of creatine supplementation in knee osteoarthritis. Med. Sci. Sports Exerc. 43, 1538–1543 (2011) C.J. Hass, M.A. Collins, J.L. Juncos, Resistance training with creatine monohydrate improves upper-body strength in patients with Parkinson disease: a randomized trial. Neurorehabil. Neural Repair 21, 107–115 (2007) S.J. Deacon, E.E. Vincent, P.L. Greenhaff, J. Fox, M.C. Steiner, S.J. Singh, M.D. Morgan, Randomized controlled trial of dietary creatine as an adjunct therapy to physical training in chronic obstructive pulmonary disease. Am. J. Respir. Care Med. 178, 233–239 (2008) V.A. Cornelissen, J.G.M. Defoor, A. Stevens, D. Schepers, P. Hespel, M. Decramer, L. Mortelmans, F. Dobbels, J. Vanhaecke, R.H. Fagard, L. Vanhees, Effect of creatine supplementation as a potential adjuvant therapy to exercise training in cardiac patients: a randomized controlled trial. Clin. Rehabil. 24, 988–999 (2010) D.G. Candow, P.D. Chilibeck, Potential of creatine supplementation for improving aging bone health. J. Nutr. Health Aging 14, 149–153 (2010) M. Louis, J.R. Poortmans, M. Francaux, J. Berre, N. Boisseau, E. Brassine, D.J. Cuthbertson, K. Smith, J.A. Babraj, T. Waddell, M.J. Rennie, No effect of creatine supplementation on human myofibrillar and sarcoplasmic protein synthesis after resistance exercise. Am. J. Physiol. Endocrinol. Metab. 285, 1089–1094 (2003) M.A. Tarnopolsky, D.J. Mahoney, J. Vajsar, C. Rodriguez, T.J. Doherty, B.D. Roy, D. Biggar, Creatine monohydrate enhances strength and body composition in Duchenne muscular dystrophy. Neurology 62, 1771–1777 (2004)
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Endocrine 44. P.D. Chilibeck, M.J. Chrusch, K.E. Chad, S.K. Davison, D.G. Burke, Creatine monohydrate and resistance training increase bone mineral content and density in older men. J. Nutr. Health Aging 9, 352–353 (2005) 45. T.J. Beck, L.A. Kohlmeier, M.A. Petit, G. Wu, M.S. Leboff, J.A. Cauley, S. Nicholas, Z. Chen, Confounders in the association between exercise and femur bone in postmenopausal women. Med. Sci. Sports Exerc. 43, 80–89 (2011) 46. P.D. Chilibeck, J. Rooke, L. Paus-Jenssen, D. Candow, The effect of creatine monohydrate supplementation combined with resistance training on bone mineral density in older men and women. Appl. Physiol. Nutr. Metab. 37(S1), S6 (2012) 47. A. Antolic, B.D. Roy, M.A. Tarnopolsky, R.F. Zernicke, G.R. Wohl, S.G. Shaughnessy, J.M. Bourgeois, Creatine monohyderate increases bone mineral density in young Sprague–Dawley rats. Med. Sci. Sports Exerc. 39, 816–820 (2007) 48. R.A. de Souza, M. Xavier, F.F. da Silva, M.T. de Souza, M.G. Tosato, A.A. Martin, J.C. Castilho, W. Ribeiro, L. Silveira Jr, Influence of creatine supplementation on bone quality in the ovariectomized rat model: an FT-Raman spectroscopy study. Lasers Med. Sci. 27, 487–495 (2012) 49. I. Gerber, I. ap Gwynn, M. Alini, T. Wallimann, Stimulatory effects of creatine on metabolic activity, differentiation and mineralization of primary osteoblast-like cells in monolayer and micromass cell cultures. Eur. Cell Mater. 10, 8–22 (2005) 50. D.G. Burke, P.D. Chilibeck, G. Parise, D.G. Candow, D. Mahoney, M. Tarnopolsky, Effect of creatine and weight training on muscle creatine and performance in vegetarians. Med. Sci. Sports Exerc. 35, 1946–1955 (2003) 51. H. Yasuda, N. Shima, N. Nakagawa, S.I. Mochizuki, K. Yano, N. Fujise, Y. Sato, M. Goto, K. Yamaguchi, M. Kuriyama, T. Kanno, A. Murakami, E. Tsuda, T. Morinaga, K. Higashio, Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro. Endocrinology 139, 1329–1337 (1998)
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52. S.M. Cornish, D.G. Candow, N.T. Jantz, P.D. Chilibeck, J.P. Little, S. Forbes, S. Abeysekara, G.A. Zello, Conjugated linoleic acid combined with creatine monohydrate and whey protein supplementation during strength training. Int J Sport Nutr Exerc. Metab. 19, 79–96 (2009) 53. T.W. Buford, R.B. Kreider, J.R. Stout, M. Greenwood, B. Campbell, M. Spano, T. Ziegenfuss, H. Lopez, J. Landis, J. Antonio, International society of sport nutrition position stand: creatine supplementation and exercise. J. Int. Soc. Sports Nutr. 4, 6 (2007) 54. H.J. Kim, C.K. Kim, A. Carpentier, J.R. Poortmans, Studies on the safety of creatine supplementation. Amino Acids 40, 1409–1418 (2011) 55. R. Jager, M. Purpura, A. Shao, T. Inoue, R.B. Kreider, Analysis of the efficacy, safety, and regulatory status of novel forms of creatine. Amino Acids 40, 1369–1383 (2011) 56. Dietitians of Canada, American College of Sports Medicine, N.R. Rodriguez, N.M. Di Marco, S. Langley, American College of Sports Medicine position stand. Nutrition and athletic performance. Med. Sci. Sports Exerc. 41, 709–731 (2009) 57. T. Wallimann, M. Tokarska-Schlattner, U. Schlattner, The creatine kinase system and pleiotropic effects of creatine. Amino Acids 40, 1271–1296 (2011) 58. J.R. Poortmans, A. Kumps, P. Duez, A. Fofonka, A. Carpentier, M. Francaux, Effect of oral creatine supplementation on urinary methylamine, formaldehyde, and formate. Med. Sci. Sports Exerc. 37, 1717–1720 (2005) 59. D.G. Burke, S. Silver, L.E. Holt, T. Smith Palmer, C.J. Culligan, P.D. Chilibeck, The effect of continuous low dose creatine supplementation on force, power, and total work. Int J Sport Nutr Exerc. Metab. 10, 235–244 (2000) 60. T. Klopstock, M. Elstner, A. Bender, Creatine in mouse models of neurodegeneration and aging. Amino Acids 40, 1297–1303 (2011) 61. E.S. Rawson, A.C. Venezia, Use of creatine in the elderly and evidence for effects on cognition function in young and old. Amino Acids 40, 1349–1362 (2011)
REVIEW
Creatine supplementation and aging musculoskeletal health Darren G. Candow • Philip D. Chilibeck Scott C. Forbes
•
Received: 22 July 2013 / Accepted: 17 September 2013 Ó Springer Science+Business Media New York 2013
Abstract Sarcopenia refers to the progressive loss of muscle mass and muscle function and is a contributing factor for cachexia, bone loss, and frailty. Resistance training produces several physiological adaptations which improve aging musculoskeletal health, such as increased muscle and bone mass and strength. The combination of creatine supplementation and resistance training may further lead to greater physiological benefits. We performed meta-analyses which indicate creatine supplementation combined with resistance training has a positive effect on aging muscle mass and upper body strength compared to resistance training alone. Creatine also shows promise for improving bone mineral density and indices of bone biology. The combination of creatine supplementation and resistance training could be an effective intervention to improve aging musculoskeletal health. Keywords Sarcopenia Resistance training Bone health Meta-analysis Introduction Recently, the European Working Group on Sarcopenia in Older Adults (EWGSOP) and International Working Group
D. G. Candow (&) Faculty of Kinesiology and Health Studies, University of Regina, 3737 Wascana Parkway, Regina, SK S4S 0A2, Canada e-mail: [email protected] P. D. Chilibeck College of Kinesiology, University of Saskatchewan, Saskatoon, SK, Canada S. C. Forbes Faculty of Medicine, University of Calgary, Calgary, AB, Canada
on Sarcopenia have redefined sarcopenia to include both the progressive loss of muscle mass and muscle function [1, 2]. Due to the inherent variability among older adults, the severity of sarcopenia can be categorized by three distinct stages: (1) pre-sarcopenic: low muscle mass, (2) sarcopenic: low muscle mass and reduced muscle strength OR physical performance, and (3) severe sarcopenic: low muscle mass and reduced muscle strength AND physical performance [1]. Sarcopenia is a main contributing factor for cachexia [3], osteoporosis [4], and frailty [1]. Frailty is the most problematic consequence of aging and is defined as a state of physiological vulnerability leading to adverse outcomes such as falls and disability [5]. Consequently, annual healthcare costs associated with treating symptoms of sarcopenia are in the billions of dollars [6]. Therefore, improving aging muscle mass and muscle function is crucial for healthy and successful aging. The etiology of sarcopenia is multi-factorial and remains to be elucidated [7–9]; however, sarcopenia may be associated with changes in muscle fiber composition [10], chronic inflammation and oxidative stress [11], altered protein and hormonal kinetics [12], reduced satellite cell activity [13], insulin resistance [14], cell death [15], physical inactivity [16], and dietary modifications [17]. Resistance training produces several physiological adaptations which improve aging musculoskeletal health, such as increased muscle and bone mass and strength. The combination of creatine supplementation and resistance training may further augment these benefits. The purpose of this brief review is to highlight the potential effects of creatine supplementation and resistance training on aging musculoskeletal health. In the first part, we review the effects of creatine combined with resistance training on strength and lean tissue mass. In the second part, we describe the effects of creatine on measurements related to
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bone health. We performed meta-analyses to assess the effect of creatine supplementation during resistance training on general measures of upper body (i.e., chest press) and lower body (i.e., leg press) strength and on lean tissue mass. We did not perform meta-analyses on any of the bone health variables because of the paucity of studies that have evaluated similar bone health measurements.
Methods used to analyze the literature and perform the meta-analysis To synthesize results across studies we performed metaanalyses for strength and lean tissue mass. We chose strength measurements of chest press and leg press because they provide assessment of a large muscle mass in the upper- and lower body, respectively, and these strength measures were assessed in most studies. We searched the PubMed and SPORTDiscus databases using the key words ‘‘creatine supplementation’’ and a variety of synonyms for ‘‘resistance training’’ (e.g., ‘‘strength training’’) from January 1966 to June 2013. Our inclusion criteria for studies were participants over the age of 50 years, evaluation of creatine and placebo groups during a resistance training program and using a randomized design. Means and standard deviations for baseline and post-training measurements were extracted from each study for estimation of mean changes and the standard deviation of mean changes across the interventions. The homogeneity of the effect size among studies was assessed using a v2 test. Our tests indicated homogeneity across studies for all variables included in our meta-analyses. We therefore used fixed effects models to calculate the pooled mean net change of strength or lean tissue mass comparing creatine supplementation with placebo. Chest press and leg press strength were assessed using a variety of measurement techniques using different units of measurement across studies; therefore, the net change comparing creatine supplementation with placebo was expressed as a standardized mean difference by dividing the net change by the pooled standard deviation for the changes across the creatine and placebo groups. Mean changes and standard deviations for mean changes for individual studies and the pooled effects and their 95 % confidence intervals were calculated and Forest plots were generated using Review Manager 5.0 Software. Significance was set at p B 0.05.
Creatine and aging muscle Creatine is a naturally occurring nitrogen-containing compound found in the diet primarily in red meat and seafood [18]. The majority of creatine is stored in skeletal
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muscle as phosphocreatine (PCr), a high-energy phosphate involved in the rapid resynthesis of adenosine triphosphate (ATP) during intense muscle contraction [18]. Aging may have a negative impact on high-energy phosphate metabolism [19–21]. From a theoretical perspective, increasing intra-muscular creatine from exogenous creatine ingestion should enhance high-energy phosphate metabolism [22], which could result in greater resistance training capacity and subsequently muscle accretion and strength gains in older adults. Table 1 summarizes studies combining creatine and resistance training in older adults. For example, Chrusch et al. [23] showed that creatine monohydrate supplementation (0.3 g kg-1 9 5 days; 0.07 g kg-1 for 79 days) enabled older men (59–77 years of age) to train at a 31 % higher volume (load 9 sets 9 repetitions) over time which resulted in greater gains in muscle mass and strength compared to older men on placebo. Subsequent to these findings, Brose et al. [24] found a significant increase in intramuscular total creatine and muscle accretion (1.7 ± 1.2 kg) in healthy older adults who supplemented with creatine monohydrate (5 g day-1) during resistance training compared to placebo for 14 weeks. Further work from the same laboratory found greater increases in muscular endurance from creatine supplementation and resistance training compared to training alone in older adults [25]. We showed that creatine monohydrate supplementation (0.1 g kg-1) in close proximity to resistance training sessions for 10 weeks increased whole-body muscle size (sum of six limb muscle groups) compared to placebo in healthy older men (59–77 years of age) [26]. In a study focusing exclusively on older women (65 years of age) creatine monohydrate supplementation (5 gday-1 for 12 weeks) during resistance training enhanced training volume and induced greater increases in strength and muscle mass compared to placebo [27]. In addition to these findings, showing an anabolic effect on aging muscle, creatine may also exhibit anti-catabolic properties. Creatine decreases urinary excretion of 3-methylhistidine, an indicator of muscle protein catabolism, in older men during resistance training [26] and whole-body protein breakdown (e.g., plasma leucine rate of appearance) in younger men [28]. Furthermore, creatine supplementation may attenuate reactive and radical species ions [29, 30], which are contributing factors for sarcopenia [31]. In contrast to the positive studies described above, there are a number of studies that have found no evidence of an ergogenic effect from creatine monohydrate during resistance training in older men or women [32–35]. We have previously critically reviewed two of these studies [36], where we highlighted that the study by Bermon et al. [33] lacked statistical power and the study by Eijnde et al. [34] used a training program that involved muscular endurance training rather than strength training and therefore differed
Endocrine Table 1 Study characteristics and outcomes of research examining the influence of creatine in older adults with a resistance training program First author (year)
Study population
Intervention
Duration
Outcome measure
Aguiar et al. [27]
N = 18; healthy women; age = 64.9 ± 5 years
CR (5 g day-1 or PLA (maltodextrin) with a RT program (3 days week-1)
12 weeks
CR : bench press, knee extension, bicep curl, fat free mass, and muscle mass
Bemben et al. [32]
N = 42; healthy men; age = 48–72 years
14 weeks
$ upper or lower body strength
Bermon et al. [33]
N = 32 (16 men; 16 women); healthy adults; age = 67–80 years
RT PLA; RT CR (5 g day-1); RT Pro (35 g day-1); RT Pro (35 g day-1) ? CR (5 g day-1): RT = 3 days week-1 CR (20 g day-1 for 5 days followed by 3 g day-1); PLA (glucose); RT ? CR: RT = 3 days week-1
52 days
$ body composition, strength, endurance
Brose et al. [24]
N = 28 (15 men; 13 women); healthy adults; age = men = 68.7 ± 4.8; women = 70.8 ± 6.1
CR (5 g day-1) or PLA (7 g dextrose) with a RT program (3 days week-1)
14 weeks
CR : body mass, fat-free mass, lower body strength only in men.
Candow et al. [26]
N = 35; healthy men; age = 55–77 years
CR (0.1 g kg-1) or CR ? PRO (0.3 g kg-1) or PLA with a RT program (3 days week-1)
10 weeks
CR ? CR ? PRO conditions : body mass and muscle thickness.
Chilibeck et al. [44]
N = 29; healthy men; age = 71 years
CR (0.3 g kg-1 day-1 for 5 days followed by 0.07 g kg-1 day-1) or PLA; RT
12 weeks
CR : arms bone mineral content.
Chrusch et al. [23]
N = 30; healthy men; age = 60–84 years
CR (0.3 g kg-1 day-1 for 5 days followed by 0.07 g kg-1 day-1) or PLA with a RT (3 days week-1)
12 weeks
CR : lean tissue mass and lower body strength, lower body endurance, and average power. $ upper body strength, upper endurance, fat mass.
Deacon et al. [39]
N = 80 (50 men; 30 women); COPD; age = 68.2 ± 8.2 years
CR (22 g day-1 for 5 days followed by 3.76 g day-1); pulmonary rehabilitation
7 weeks
$ shuttle walk distance, knee extensor work.
Eijnde et al. [34]
N = 46; healthy men; age = 55–75 years
CR (5 g day-1) or PLA; Cardio-respiratory ? RT 2–3 days week-1
6 months
$ body weight, isometric strength
Eliot et al. [35]
N = 42; healthy men; age = 48–72 years
CR (5 g day-1) or CR ? PRO (35 g day-1) or PRO or PLA; RT 3 days week-1
14 weeks
$ body composition
Hass et al. [38]
N = 20 (17 men; 3 females); idiopathic parkinson disease; age = PLA: 62.8 ± 2.6 years: CR = 62.2 ± 2.6 years
CR (20 g day-1 for 5 days followed by 5 g day-1); PLA; RT = 2 days week-1
12 weeks
CR :upper body strength, chair rise performance. $ 1RM leg extension, muscular endurance.
Neves et al. [37]
N = 24; Post menopausal women with knee osteoarthritis; age = 55–65 years
CR (20 g day-1 for 1 week followed by 5 g day-1) or PLA; RT
12 weeks
CR : physical function, stiffness subscales, lower limb lean mass, quality of life. $ lower body strength.
Tarnopolsky et al. [25]
N = 39 (19 men; 20 women); healthy; age = 65–85 years
CR (5 g day-1) ? CLA (6 g day-1) or PLA; RT = 2 days week-1
6 months
CR ? CLA :muscular endurance, isokinetic knee extension strength, fat-free mass, and lower fat mass.
CR creatine, PLA placebo, RT resistance training, PRO protein, CLA conjugated linoleic acid, : significant increase compared to the placebo condition, $ no difference between the creatine and placebo conditions
substantially from other studies. The older men in the study by Eijnde et al. [34] had very high baseline levels of phosphocreatine, perhaps due to geographically-different intake of dietary creatine which may have made them less
sensitive to creatine supplementation. The studies of Eliot et al. [35] and Bemben et al. [32] were on the same research participants, but presented body composition results [35] and strength results [32] from one study in two
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different papers. Their results are limited by their statistical analyses: all participants were assigned the same resistance training program and were randomized to four groups in a factorial design: placebo, whey protein, creatine monhydrate, and creatine monohydrate ? whey protein supplementation. Despite using a factorial design, they analyzed their data as a ‘‘parallel group’’ design; therefore, not taking advantage of the increase in statistical power for comparing creatine versus non-creatine groups they would achieve by analyzing the data using a factorial ANOVA. Close inspection of their data reveal larger increases (especially for lean tissue mass; [35]) in many of their measures when comparing combined creatine groups to combined non-creatine groups, but failure to use the appropriate statistical testing on their data did not allow this statistical comparison. There have been a number of studies of creatine supplementation during resistance training in older adults with chronic conditions, including osteoarthritis, Parkinson disease, chronic obstructive pulmonary disease (COPD), and cardiovascular disease. As with healthy older adults, the effectiveness of creatine supplementation across these studies has varied. Postmenopausal women (mean age of 57 years) with knee osteoarthritis who supplemented with creatine monohydrate (20 g day-1 for 7 days, 5 g day-1 thereafter) for 12 weeks during a lower body resistance training program increased lower body lean tissue mass, but not leg press strength compared to a placebo group [37]. The creatine group also had significant improvements for stiffness and physical function, as evaluated by osteoarthritis subscales, and quality of life compared to placebo. Creatine monohydrate supplementation (20 g day-1 for 5 days, 5 g day-1 thereafter) during 12 weeks of resistance training improved upper body strength and chair-rise performance compared to placebo in patients with Parkinson disease (mean age of 62 years) [38]. In contrast, creatine monohydrate supplementation (20 g day-1 for 5 days, 3.76 g day-1 thereafter) during a 7-week resistance training program in patients with COPD (mean age of 68 years) was not effective for improving strength, lean tissue mass, and functional performance measurements compared to placebo [39]. Also, creatine monohydrate supplementation (15 g day-1 for 7 days, 5 g day-1 thereafter) during 3 months of resistance training in patients enrolled in a cardiac rehabilitation program (mean age 57.5 years) was not effective for improving knee extension strength or muscular endurance [40].
Meta-analyses results Mean changes and standard deviations for mean changes for individual studies and the pooled effects and their 95 %
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confidence intervals are presented along with Forest plots in Figs. 1, 2, 3. Chest press strength (p = 0.003) and lean tissue mass (p = 0.002) increased to a greater extent in creatine-supplemented groups compared to placebo pooled across studies; whereas there was no favorable effect of creatine for increasing leg press strength compared to placebo (p = 0.1). Results across studies, therefore, imply that creatine supplementation has a positive effect on aging muscle mass and some strength measures and could, therefore, be considered as an effective lifestyle intervention, along with resistance training, to improve aging muscle health.
Creatine and aging bone While the majority of research on creatine supplementation has focused on muscle biology, research over the past decade has also included indices of bone as a primary outcome measure [41]. In two studies involving young males with muscular dystrophy, a condition associated with rapid muscle and bone atrophy, creatine monohydrate supplementation increased lumbar spine bone mineral density by 3.9 % and decreased the urinary excretion of cross-linked N-telopeptides of Type I collagen, an indicator of bone resorption, by 19–33 % compared to young males who consumed a placebo [42, 43]. These preliminary studies provided the first lines of evidence that creatine may have a beneficial effect on bone health which could have application for the aging skeleton. Using a doubleblind, placebo-controlled, repeated measures design, Chilibeck et al. [44] showed that creatine monohydrate supplementation (0.3 g kg-1 9 5 days; 0.07 g kg-1 thereafter) during 12 weeks of supervised resistance training in healthy older males increased upper limb bone mineral content by 3.2 % compared to a non-significant decrease in men in the placebo group. The authors hypothesized that the greater increase in muscle mass from creatine supplementation [23] caused more pull on bone during training, which may have induced more strain on bone tissue resulting in bone formation [44]. Additional work from the same laboratory showed that older males who supplemented with creatine monohydrate (8 g day-1) during resistance training for 10 weeks experienced a significant reduction in bone resorption (-30 %), as measured by urinary cross-linked N-telopeptides of Type I collagen, compared to a non-significant increase (6 %) for older men on placebo during training [26]. More recently, creatine monohydrate supplementation (8 g day-1) during 52 weeks of resistance training decreased femoral neck bone loss and increased femoral shaft subperiosteal width, a predictor of bone bending strength [45], in postmenopausal women compared to placebo [46]. However, others
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Fig. 1 Forest plot for chest press strength. Note that the study by Bemben et al. [32] had groups that consumed creatine and protein versus protein, and groups that consumed creatine versus placebo. These are, therefore, entered separately in the meta-analysis.
Likewise, Brose et al. [24] and Tarnopolsky et al. [25] presented results separately for men and women; therefore, these are entered separately in the meta-analysis
Fig. 2 Forest plot for leg press strength. Note that the study by Bemben et al. [32] had groups that consumed creatine and protein versus protein, and groups that consumed creatine versus placebo. These are, therefore, entered separately in the meta-analysis.
Likewise, Brose et al. [24] and Tarnopolsky et al. [25] presented results separately for men and women; therefore, these are entered separately in the meta-analysis
Fig. 3 Forest plot for lean tissue mass. Note that the study by Eliot et al. [35] had groups that consumed creatine and protein versus protein, and groups that consumed creatine versus placebo. These are, therefore, entered separately in the meta-analysis. Likewise, Brose
et al. [24] and Tarnopolsky et al. [25] presented results separately for men and women; therefore, these are entered separately in the metaanalysis
have found no beneficial effect from creatine supplementation on bone mineral density or measures of bone resorption and bone formation in healthy older adults following 14 weeks to 6 months of resistance training [24, 25]. In addition to these human studies, growing rats who consumed creatine monohydrate (2 % wet weight) for 8 weeks experienced a significant increase in lumbar spine
bone mineral density and femur bone strength compared to rats who consumed placebo [47]. In ovariectomized rats, an animal model of menopause, micronize creatine ingestion for 8 weeks led to a significant increase in the phosphate content of lumbar bone which may lead to greater bone quality over time [48]. Mechanistically, Gerber et al. [49] showed that 10 and 20 mM chemically pure creatine added
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to low serum cell culture medium increased the metabolic activity, differentiation, and mineralization of osteoblastlike cells which are involved in bone formation and reliant on the creatine kinase reaction for energy production [47]. Creatine supplementation increases phosphocreatine levels, a substrate for creatine kinase [50]. Along with increasing bone formation, stimulating osteoblast activity may increase the production of compounds (e.g., osteoprotegerin) which inhibit osteoclast activity and reduce bone resorption [51]; this is supported by the finding that Ntelopeptides, a measure of bone resorption, is reduced in some studies of creatine supplementation [26, 52]. In summary, there is evidence that creatine, with and without resistance training, has a positive effect on cells involved in the bone remodeling process which may help explain the increase in bone mineral and bone strength observed in humans and rodent models. Several organizations, such as the International Society of Sports Nutrition, as well as a joint position between the Dieticians of Canada, the American College of Sports Medicine, and the American Dietetic Association, have evaluated the safety and efficacy of creatine supplementation [53–56]. The most common side effects of creatine supplementation include weight gain, cramping, nausea, and diarrhea [54, 57]. These side effects are mostly based on anecdotal claims and creatine supplementation can be considered safe for healthy young and older adults [53–57]; however, the long term effects are still unknown and it is recommended that individuals with pre-existing renal disease or those with a potential risk for renal dysfunction not supplement with creatine [54]. There is evidence in younger individuals that a high dose ([20 g day-1) of creatine supplementation may lead to an increase in formaldehyde production [58]; therefore, a low-dose creatine supplementation protocol may be suggested for healthy older adults [26]. Burke et al. [59] found that a low dose (8 g day-1) of creatine monohydrate was effective for increasing muscle mass and strength in younger adults, while Candow et al. [26] found that a low-dose of creatine monohydrate (0.1 g kg-1 day-1) combined with protein was effective for increasing lean tissue mass and enhancing upper body strength in older men (59–77 years) without increasing formaldehyde production. In a recent review, Walliman et al. [57] recommended long-term low dose creatine for health benefits, particularly as one ages. As creatine is taken up by and forms phosphocreatine in brain tissue, others have recommended creatine monohydrate supplementation to combat conditions such as neurodegeneration and loss of cognitive function with aging [60, 61]. Future research, examining the long term effects of low-dose creatine supplementation in older adults is warranted.
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Conclusions Sarcopenia is a main contributing factor for bone and strength loss which can result in substantial economic, health, and societal burden. Resistance training is an effective intervention which increases aging muscle and bone mass and strength. In addition to resistance training, creatine supplementation has shown promise for augmenting the physiological adaptations from exercise in older adults. Therefore, the combination of resistance training and creatine supplementation should be considered when developing effective lifestyle interventions for improving aging musculoskeletal health. With this in mind, future research may also want to investigate the effects of resistance training and creatine supplementation in populations characterized by poor musculoskeletal health, such as the frail elderly. Conflict of interest of interest.
The authors declare that they have no conflict
References 1. A.J. Cruz-Jentoft, J.P. Baeyens, J.M. Bauer, Y. Boirie, T. Cederholm, F. Landi, F.C. Martin, J.P. Michel, Y. Rolland, S.M. Schneider, E. Topinkova´, M. Vandewoude, M. Zamboni, European Working Group on Sarcopenia in Older People.: sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing 39, 412–423 (2010) 2. R.A. Fielding, B. Vellas, W.J. Evans, S. Bhasin, J.E. Morley, A.B. Newman, G. Abellan van Kan, S. Andrieu, J. Bauer, D. Breuille, T. Cederholm, J. Chandler, C. De Meynard, L. Donini, T. Harris, A. Kannt, F. Keime Guibert, G. Onder, D. Papanicolaou, Y. Rolland, D. Rooks, C. Sieber, E. Souhami, S. Verlaan, M. Zamboni, Sarcopenia: an undiagnosed condition in older adults. Current consensus definition: prevalence, etiology, and consequences. International working group on sarcopenia. J. Am. Med. Dir. Assoc. 12, 249–256 (2011) 3. W.J. Evans, J.E. Morley, J. Argile´s, C. Bales, V. Baracos, D. Guttridge, A. Jatoi, K. Kalantar-Zadeh, H. Lochs, G. Mantovani, D. Marks, W.E. Mitch, M. Muscaritoli, A. Najand, P. Ponikowski, F. Rossi Fanelli, M. Schambelan, A. Schols, M. Schuster, D. Thomas, R. Wolfe, S.D. Anker, Cachexia: a new definition. Clin Nutr. 27, 793–799 (2008) 4. G. Crepaldi, S. Maggi, Sarcopenia and osteoporosis: a hazardous duet. J. Endocrinol. Invest. 28, 66–68 (2005) 5. A. Clegg, J. Young, S. Iliffe, M.O. Rikkert, K. Rockwood, Frailty in elderly people. Lancet 2, 752–762 (2013) 6. I. Janssen, D.S. Shepard, P.T. Katzmarzyk, R. Roubenhoff, The healthcare costs of sarcopenia in the United States. J. Am. Geriatr. Soc. 52, 80–85 (2004) 7. Kohara, K.: Sarcopenia obesity in aging population: current status and future directions for research. Endocrine. Epub ahead of print (2013) 8. S.C. Forbes, J.P. Little, D.G. Candow, Exercise and nutritional interventions for improving aging muscle health. Endocrine 42, 29–38 (2012)
Endocrine 9. J.P. Gumucio, C.L. Mendias, Atrogin-1, MuRF-1, and sarcopenia. Endocrine 43, 12–21 (2013) 10. R. Nilwik, T. Snijders, M. Leenders, B.B. Groen, J. van Kranenburg, L.B. Verdijk, L.J. van Loon, The decline in skeletal muscle mass with aging is mainly attributed to a reduction in type II muscle fiber size. Exp. Gerontol. 48, 492–498 (2013) 11. L.J. Greenlund, K.S. Nair, Sarcopenia—consequences, mechanisms, and potential therapies. Mech. Ageing Dev. 124, 287–299 (2003) 12. E. Ziv, D. Hu, Genetic variation in insulin/IGF-1 signaling pathways and longevity. Ageing Res Rev. 10, 201–204 (2011) 13. A.S. Brack, T.A. Rando, Intrinsic changes and extrinsic influences of myogenic stem cell function during aging. Stem Cell Rev. 3, 226–237 (2007) 14. A.M. Abbatecola, G. Paolisso, P. Fattoretti, W.J. Evans, V. Fiore, L. Dicioccio, F. Lattanzio, Discovering pathways of sarcopenia in older adults: a role for insulin resistance on mitochondria dysfunction. J. Nutr. Health Aging 15, 890–895 (2011) 15. E. Marzetti, R. Calvani, R. Bernabei, C. Leeuwenburgh, Apoptosis in skeletal myocytes: a potential target for interventions against sarcopenia and physical frailty—a mini-review. Gerontology 58, 99–106 (2012) 16. M.A. Tarnopolsky, A. Safdar, The potential benefits of creatine and conjugated linoleic acid as adjuncts to resistance training in older adults. Appl. Physiol. Nutr. Metab. 33, 213–227 (2008) 17. W.F. Nieuwenhuizen, H. Weenen, P. Rigby, M.M. Hetherington, Older adults and patients in need of nutritional support: review of current treatment options and factors influencing nutritional intake. Clin. Nutr. 29, 160–169 (2010) 18. M. Wyss, R. Kaddurah-Daouk, Creatine and creatinine metabolism. Physiol. Rev. 80, 1107–1213 (2000) 19. R.G. Larsen, D.M. Callahan, S.A. Foulis, J.A. Kent-Braun, Agerelated changes in oxidative capacity differ between locomotory muscles and are associated with physical activity behavior. Appl. Physiol. Nutr. Metab. 37, 88–99 (2012) 20. K.K. McCully, R.A. Fielding, W.J. Evans, J.S. Leigh Jr, J.D. Posner, Relationships between in vivo and in vitro measurements of metabolism in young and old human calf muscles. J. Appl. Physiol. 75, 813–819 (1993) 21. P. Mo¨ller, J. Bergstro¨m, P. Fu¨rst, K. Hellstro¨m, Effect of aging on energy-rich phosphagens in human skeletal muscles. Clin. Sci. (Lond) 58, 553–555 (1980) 22. S.A. Smith, S.J. Montain, R.P. Matott, G.P. Zientara, F.A. Jolesz, R.A. Fielding, Creatine supplementation and age influence muscle metabolism during exercise. J. Appl. Physiol. 85, 1349–1356 (1998) 23. M.J. Chrusch, P.D. Chilibeck, K.E. Chad, K.S. Davison, D.G. Burke, Creatine supplementation combined with resistance training in older men. Med. Sci. Sports Exerc. 33, 2111–2117 (2001) 24. A. Brose, G. Parise, M.A. Tarnopolsky, Creatine supplementation enhances isometric strength and body composition improvements following strength exercise training in older adults. J. Gerontol. A Biol. Sci. Med. Sci. 58, 11–19 (2003) 25. M. Tarnopolsky, A. Zimmer, J. Paikin, A. Safdar, A. Aboud, E. Pearce, B. Roy, T. Doherty, Creatine monohydrate and conjugated linoleic acid improves strength and body composition following resistance exercise in older adults. PLoS ONE 2, 991 (2007) 26. D.G. Candow, J.P. Little, P.D. Chilibeck, S. Abeysekara, G.A. Zello, S. Kazachkov, S.M. Cornish, P.H. Yu, Low-dose creatine combined with protein during resistance training in older men. Med. Sci. Sports Exerc. 40, 1645–1652 (2008) 27. A.F. Aguiar, R.S. Januario, R.P. Junior, A.M. Gerage, F.L. Pina, M.A. do Nascimento, C.R. Padovani, E.S. Cyrino, Long-term creatine supplementation improves muscular performance during
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
resistance training in older women. Eur. J. Appl. Physiol. 113, 987–996 (2013) G. Parise, S. Mihic, D. MacLennan, K.E. Yarasheski, M.A. Tarnopolsky, Effects of acute creatine monohydrate supplementation on leucine kinetics and mixed-muscle protein synthesis. J. Appl. Physiol. 91, 1041–1047 (2001) R. Deminice, A.A. Jardao, Creatine supplementation reduces oxidative stress biomarkers after acute exercise in rats. Amino Acids 43, 709–715 (2011) P. Sestili, C. Martinelli, E. Colombo, E. Barbieri, L. Potenza, S. Sartini, C. Fimognari, Creatine as an antioxidant. Amino Acids 40, 1385–1396 (2011) A.P. Johnston, M. De Lisio, G. Parise, Resistance training, sarcopenia, and the mitochondrial theory of aging. Appl. Physiol. Nutr. Metab. 33, 191–199 (2008) M.G. Bemben, M.S. Witten, J.M. Carter, K.A. Eliot, A.W. Knehans, D.A. Bemben, The effects of supplementation with creatine and protein on muscle strength following a traditional resistance training program in middle-aged and older men. J. Nutr. Health Aging 14, 155–159 (2010) S. Bermon, P. Venembre, C. Sachet, S. Valour, C. Dolisi, Effects of creatine monohydrate ingestion in sedentary and weighttrained older adults. Acta Physiol. Scand. 164, 147–155 (1998) B.O. Eijnde, M. Van Leemputte, M. Goris, V. Labarque, Y. Taes, P. Verbessem, L. Vanhees, M. Ramaekers, B. Vanden Eynde, R. Van Schuylenbergh, R. Dom, E.A. Richter, P. Hespel, Effects of creatine supplementation and exercise training on fitness in men 55–75-year-old. J. Appl. Physiol. 95, 818–828 (2003) K.A. Eliot, A.W. Knehans, D.A. Bemben, M.S. Witten, J. Carter, M.G. Bemben, The effects of creatine and whey protein supplementation on body composition in men aged 48 to 72 years during resistance training. J. Nutr. Health Aging 12, 208–212 (2008) D.G. Candow, P.D. Chilibeck, Review: timing of creatine and protein supplementation during resistance training in the elderly. Appl. Physiol. Nutr. Metab. 33, 184–190 (2008) M. Neves Jr, B. Guolano, H. Roschel, R. Fuller, F.B. Benatii, A.L. Pinto, F.R. Lima, R.M. Pereira, A.H. Lancha Jr, E. Bonfa, Beneficial effect of creatine supplementation in knee osteoarthritis. Med. Sci. Sports Exerc. 43, 1538–1543 (2011) C.J. Hass, M.A. Collins, J.L. Juncos, Resistance training with creatine monohydrate improves upper-body strength in patients with Parkinson disease: a randomized trial. Neurorehabil. Neural Repair 21, 107–115 (2007) S.J. Deacon, E.E. Vincent, P.L. Greenhaff, J. Fox, M.C. Steiner, S.J. Singh, M.D. Morgan, Randomized controlled trial of dietary creatine as an adjunct therapy to physical training in chronic obstructive pulmonary disease. Am. J. Respir. Care Med. 178, 233–239 (2008) V.A. Cornelissen, J.G.M. Defoor, A. Stevens, D. Schepers, P. Hespel, M. Decramer, L. Mortelmans, F. Dobbels, J. Vanhaecke, R.H. Fagard, L. Vanhees, Effect of creatine supplementation as a potential adjuvant therapy to exercise training in cardiac patients: a randomized controlled trial. Clin. Rehabil. 24, 988–999 (2010) D.G. Candow, P.D. Chilibeck, Potential of creatine supplementation for improving aging bone health. J. Nutr. Health Aging 14, 149–153 (2010) M. Louis, J.R. Poortmans, M. Francaux, J. Berre, N. Boisseau, E. Brassine, D.J. Cuthbertson, K. Smith, J.A. Babraj, T. Waddell, M.J. Rennie, No effect of creatine supplementation on human myofibrillar and sarcoplasmic protein synthesis after resistance exercise. Am. J. Physiol. Endocrinol. Metab. 285, 1089–1094 (2003) M.A. Tarnopolsky, D.J. Mahoney, J. Vajsar, C. Rodriguez, T.J. Doherty, B.D. Roy, D. Biggar, Creatine monohydrate enhances strength and body composition in Duchenne muscular dystrophy. Neurology 62, 1771–1777 (2004)
123
Endocrine 44. P.D. Chilibeck, M.J. Chrusch, K.E. Chad, S.K. Davison, D.G. Burke, Creatine monohydrate and resistance training increase bone mineral content and density in older men. J. Nutr. Health Aging 9, 352–353 (2005) 45. T.J. Beck, L.A. Kohlmeier, M.A. Petit, G. Wu, M.S. Leboff, J.A. Cauley, S. Nicholas, Z. Chen, Confounders in the association between exercise and femur bone in postmenopausal women. Med. Sci. Sports Exerc. 43, 80–89 (2011) 46. P.D. Chilibeck, J. Rooke, L. Paus-Jenssen, D. Candow, The effect of creatine monohydrate supplementation combined with resistance training on bone mineral density in older men and women. Appl. Physiol. Nutr. Metab. 37(S1), S6 (2012) 47. A. Antolic, B.D. Roy, M.A. Tarnopolsky, R.F. Zernicke, G.R. Wohl, S.G. Shaughnessy, J.M. Bourgeois, Creatine monohyderate increases bone mineral density in young Sprague–Dawley rats. Med. Sci. Sports Exerc. 39, 816–820 (2007) 48. R.A. de Souza, M. Xavier, F.F. da Silva, M.T. de Souza, M.G. Tosato, A.A. Martin, J.C. Castilho, W. Ribeiro, L. Silveira Jr, Influence of creatine supplementation on bone quality in the ovariectomized rat model: an FT-Raman spectroscopy study. Lasers Med. Sci. 27, 487–495 (2012) 49. I. Gerber, I. ap Gwynn, M. Alini, T. Wallimann, Stimulatory effects of creatine on metabolic activity, differentiation and mineralization of primary osteoblast-like cells in monolayer and micromass cell cultures. Eur. Cell Mater. 10, 8–22 (2005) 50. D.G. Burke, P.D. Chilibeck, G. Parise, D.G. Candow, D. Mahoney, M. Tarnopolsky, Effect of creatine and weight training on muscle creatine and performance in vegetarians. Med. Sci. Sports Exerc. 35, 1946–1955 (2003) 51. H. Yasuda, N. Shima, N. Nakagawa, S.I. Mochizuki, K. Yano, N. Fujise, Y. Sato, M. Goto, K. Yamaguchi, M. Kuriyama, T. Kanno, A. Murakami, E. Tsuda, T. Morinaga, K. Higashio, Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro. Endocrinology 139, 1329–1337 (1998)
123
52. S.M. Cornish, D.G. Candow, N.T. Jantz, P.D. Chilibeck, J.P. Little, S. Forbes, S. Abeysekara, G.A. Zello, Conjugated linoleic acid combined with creatine monohydrate and whey protein supplementation during strength training. Int J Sport Nutr Exerc. Metab. 19, 79–96 (2009) 53. T.W. Buford, R.B. Kreider, J.R. Stout, M. Greenwood, B. Campbell, M. Spano, T. Ziegenfuss, H. Lopez, J. Landis, J. Antonio, International society of sport nutrition position stand: creatine supplementation and exercise. J. Int. Soc. Sports Nutr. 4, 6 (2007) 54. H.J. Kim, C.K. Kim, A. Carpentier, J.R. Poortmans, Studies on the safety of creatine supplementation. Amino Acids 40, 1409–1418 (2011) 55. R. Jager, M. Purpura, A. Shao, T. Inoue, R.B. Kreider, Analysis of the efficacy, safety, and regulatory status of novel forms of creatine. Amino Acids 40, 1369–1383 (2011) 56. Dietitians of Canada, American College of Sports Medicine, N.R. Rodriguez, N.M. Di Marco, S. Langley, American College of Sports Medicine position stand. Nutrition and athletic performance. Med. Sci. Sports Exerc. 41, 709–731 (2009) 57. T. Wallimann, M. Tokarska-Schlattner, U. Schlattner, The creatine kinase system and pleiotropic effects of creatine. Amino Acids 40, 1271–1296 (2011) 58. J.R. Poortmans, A. Kumps, P. Duez, A. Fofonka, A. Carpentier, M. Francaux, Effect of oral creatine supplementation on urinary methylamine, formaldehyde, and formate. Med. Sci. Sports Exerc. 37, 1717–1720 (2005) 59. D.G. Burke, S. Silver, L.E. Holt, T. Smith Palmer, C.J. Culligan, P.D. Chilibeck, The effect of continuous low dose creatine supplementation on force, power, and total work. Int J Sport Nutr Exerc. Metab. 10, 235–244 (2000) 60. T. Klopstock, M. Elstner, A. Bender, Creatine in mouse models of neurodegeneration and aging. Amino Acids 40, 1297–1303 (2011) 61. E.S. Rawson, A.C. Venezia, Use of creatine in the elderly and evidence for effects on cognition function in young and old. Amino Acids 40, 1349–1362 (2011)
