Osteoporosis is a leading cause of disability in our aging population (38). It is estimated that $2.3 billion, or 1.3% of Canada’s total health care budget, is spent annually to treat osteoporosis (38). Postmenopausal women experience the highest rate of hip fracture, resulting in acute health care costs of $660 million annually (38). Hip fracture results in disability, loss of functionality, and premature death (25). Novel lifestyle interventions are needed for the prevention of osteoporosis in postmenopausal women. Exercise training has a beneficial effect on bone, but the effects are typically small, with bone mineral density (BMD) of the proximal femur or lumbar spine increasing by only 1%–2% per year (5,29).
Creatine is a nitrogen-containing compound naturally produced in the body and/or consumed in the diet from red meat and seafood (43). Creatine supplementation increases phosphorylcreatine stores in aging muscles (7), providing greater ability to resynthesize adenosine triphosphate, which may lead to increased resistance training capacity (15,19,20) and subsequent muscle accretion over time (7,15). Increased muscle mass from creatine may result in greater muscle pull on bone during training, which would increase the strain induced on bone and stimulate bone formation (13). We have previously shown that the increase in muscle mass from creatine supplementation and resistance training in older individuals correlates with increase in bone mineral content (11). In addition to this possible muscle–bone interaction, creatine may have a direct effect on bone because bone cells rely on the creatine kinase reaction for resynthesis of adenosine triphosphate from phosphorylcreatine and adenosine diphosphate (40). The addition of creatine to low-serum cell culture medium increased the metabolic activity and differentiation of osteoblasts, the cells involved in bone formation (18). Creatine supplementation may also affect osteoclasts, cells involved in bone resorption, because creatine supplementation reduces a marker of bone resorption (i.e., urinary cross-linked N-telopeptides of Type I collagen) in young men and women (16) and in older men during short-term (≤10 wk) resistance training (10). There have been only a couple of studies on the effects of creatine supplementation during exercise training on bone in postmenopausal women (22,37). These studies found no effects of creatine supplementation on BMD; however, they were of relatively short duration (i.e., 6 months). No long-term interventions (i.e., longer than 6 months) have been performed to investigate the effects of creatine supplementation on bone health in postmenopausal women.
The primary purpose of this study was to investigate the effects of creatine supplementation on properties of bone in postmenopausal women during a supervised 12-month resistance training program. Because this was the first study to investigate the longer-term (i.e., 12 months) effects of creatine on bone, we considered this a pilot study to investigate efficacy and safety. We hypothesized that creatine supplementation would result in greater increases in BMD and enhancement of bone geometric properties compared with placebo.
The study used a double-blind, parallel-group, randomized, controlled trial design to compare creatine monohydrate supplementation with placebo during a 12-month resistance training program. The settings were the cities of Saskatoon and Regina, Saskatchewan, Canada, and involved two centers (University of Saskatchewan and University of Regina). Participants were randomized on a 1:1 basis to either creatine monohydrate (0.1 g·kg−1·d−1) or placebo (corn starch maltodextrin) after exclusion criteria were applied. On training days, participants consumed the supplements in two equal doses immediately before (0.05 g·kg−1) and immediately after (0.05 g·kg−1) resistance training sessions (three times per week). On nontraining days, supplements (0.05 g·kg−1) were consumed with two meals. The creatine dosage of 0.1 g·kg−1·d−1 was chosen because we have previously shown that this dosage reduces bone resorption during resistance training in older men without resulting in adverse effects (10). Creatine or placebo was ingested before and after resistance training sessions because this supplementation strategy may be more effective for increasing muscle creatine uptake and concentration (24,34) and thus could lead to greater hypertrophy and strength. All participants performed resistance training because creatine supplementation has its maximal effect on muscle (and potentially bone) when combined with resistance training. Randomization was performed using a fixed block size of four (using a permuted block design with a computer random number generator) by a research assistant independent of the study. Creatine monohydrate and placebo were administered in a double-blind fashion in the form of powder mixed with water, juice, or milk. The allocation sequence was concealed from the research assistant enrolling and assessing participants. Participants were given their allocated study kits after completing all baseline assessments. All researchers and those involved in outcome assessment (i.e., the individuals performing exercise tests, bone densitometry, and data analysis) or supervision of training were blinded to group assignment. Another research assistant was in charge of all data entry, during which she remained blinded to group allocations (groups were coded). Statistical analyses were performed blinded (i.e., groups were coded). The study was approved by the biomedical research ethics boards at the University of Saskatchewan and University of Regina. Participants were informed of the risks and purposes of the study before a written consent was obtained. The study complied with the World Medical Association Declaration of Helsinki—Ethical Principles for Medical Research Involving Human Subjects. We adhered to the Consolidated Standards of Reporting Trials guidelines for reporting on randomized clinical trials (31,35). This trial was registered with clinicaltrials.gov (clinical trial number, NCT01057680).
Of the 145 participants who were recruited, 47 eligible postmenopausal women were randomized into two groups, as described previously (see Fig. 1 for flow of participants). Participants were recruited from March to October 2010, and all had completed the intervention by November 2011. Female participants were postmenopausal, as indicated by a questionnaire about their last menstrual period. If women reported that they were less than 2 yr postmenopause, menopausal status was verified by determining the levels of FSH and luteinizing hormone. Exclusion criteria were preexisting kidney abnormalities, creatinine clearance values below the normal reference range, previous fragility fractures (defined as fractures resulting from minimal trauma), having taken bisphosphonates, hormone replacement therapy, androgen therapy, selective estrogen receptor modulators, parathyroid hormone, or calcitonin within the past 12 months, having taken creatine supplementation in the previous 6 months, currently taking corticosteroids, or thiazide diuretics, Crohn disease, Cushing disease, severe osteoarthritis, or currently involved in resistance training (more than 20 min per session, more than twice per week). All exclusion criteria were determined by a questionnaire except creatinine clearance. Participants were recruited via newspaper advertisements and posters from the cities of Saskatoon and Regina, Saskatchewan, Canada.
Creatine monohydrate or placebo mixed in water, juice, or milk was consumed orally. Creatine (product name, creatine monohydrate 200 mesh; Rivalus Inc., Halifax, Nova Scotia, Canada) was administered at a dosage of 0.1 g·kg−1·d−1 (0.05 g·kg−1 before and after training sessions or with two meals on nontraining days). The placebo was isocaloric to the creatine monohydrate and contained maltodextrin. Contents of the creatine monohydrate powder were verified by testing in an independent laboratory (DNP International Co. Inc., Whittier, CA). The product was determined to be 99.92% pure and negative for contaminants. Exercise training involved fully supervised resistance training three times per week. Exercises during resistance training included the following: hack squat, hip abduction, adduction, flexion, and extension (on a multihip machine), hamstrings curl, quadriceps (knee) extension, back extension, bench press, lat pulldown, shoulder press, biceps curl, triceps extension (presses), wrist pronation and supination (with dumbbells), and ankle dorsiflexion and plantarflexion. Three sets of 10 repetitions to muscle fatigue for each exercise were performed at intensities corresponding to approximately 80% of one-repetition maximum (1RM) (i.e., the maximal amount of weight a participant could lift one time) for hack squat and bench press and at about 10RM (i.e., the maximal amount of weight that could be lifted 10 times) for the other exercises. Intensity of exercises was increased progressively on an individual basis. The duration of the intervention was 12 months.
Compliance with the creatine and placebo was assessed with logs. Compliance with the exercise program was assessed by attendance at the supervised exercise sessions. Participants were surveyed after the study to assess the effectiveness of our blinding by asking whether they thought they were on the creatine supplement or the placebo or they were not sure.
Measurements were made at baseline and 12 months, except for blood and urine outcomes, which were measured at baseline and 4, 8, and 12 months. We originally identified lumbar spine BMD as our primary outcome measurement (www.clinicaltrials.gov; clinical trial number, NCT01057680) because we expected this bone site to be most responsive to exercise training on the basis of a systematic review of exercise training in postmenopausal women (5). After posting this information at clinicaltrials.gov, we considered femoral neck BMD to be an important variable of interest because this bone site was identified as the primary assessment site in the Canadian fracture risk guidelines (33) and we subsequently determined, in a separate study, that the exercise program used in the current investigation was effective for increasing BMD at the femoral neck but not at the lumbar spine (14). Height and mass were measured by a standard stadiometer and a calibrated scale and were recorded to the nearest 0.1 cm and 0.1 kg, respectively.
The BMD of the whole body, lumbar spine (L1 to L4 vertebrae), and proximal femur (including the femoral neck and total hip) were measured by dual-energy x-ray absorptiometry (DXA) in array mode (QDR Discovery Wi; Hologic, Inc., Bedford, MA) using QDR software for Windows XP (QDR Discovery). DXA technology was identical at both university centers. The reproducibility of these measures was as follows: whole body (coefficient of variation (CV), 0.9%; intraclass correlation coefficient (ICC), 0.98; SEM, 0.01 g·cm−2), lumbar spine (CV, 1.2%; ICC, 0.99; SEM, 0.012 g·cm−2), and proximal femur (CV, 0.9%; ICC, 0.99; SEM, 0.009 g·cm−2). Whole-body lean tissue mass (CV, 1.0%; ICC, 0.99; SEM, 0.44 kg) was assessed from the whole-body scans. Hip structural analysis, as described by Beck et al. (4), was used to assess the structural characteristics of the following three regions of the proximal femur from the DXA scans: the narrow neck region, which is located across the narrowest segment of the femoral neck, the intertrochanteric region along the bisector of the neck–shaft angle, and the femoral shaft, which is located 2 cm distal to the midpoint of the lesser trochanter. For each region, the distribution of the bone mass across the bone is extracted; then, subperiosteal width (SPW), bone cross-sectional area (CSA), which is equivalent to cortical area, cross-sectional moment of inertia (CSMI), and section modulus (Z) are determined. Like bone mineral content, CSA measures the amount of bone within the cross-section but expresses the quantity in terms of cortical equivalent surface area (important for axial bone strength) rather than mineral mass. The strength of bone in bending is associated with CSMI and Z. Reproducibility was as follows: narrow neck SPW (CV, 5.3%; ICC, 0.61; SEM, 0.16 cm), CSA (CV, 2.6%; ICC, 0.97; SEM, 0.076 cm2), CSMI (CV, 7.2%; ICC, 0.86; SEM, 0.16 cm4), and Z (CV, 3.5%; ICC, 0.96; SEM, 0.05 cm3); intertrochanteric SPW (CV, 1.8%; ICC, 0.94; SEM, 0.096 cm), CSA (CV, 2.2%; ICC, 0.99; SEM, 0.11 cm2), CSMI (CV, 4.3%; ICC, 0.97; SEM, 0.52 cm4), and Z (CV, 3.4%; ICC, 0.98; SEM, 0.13 cm3); as well as femoral shaft SPW (CV, 1.2%; ICC, 0.97; SEM, 0.034 cm), CSA (CV, 1.8%; ICC, 0.97; SEM, 0.073 cm2), CSMI (CV, 3.7%; ICC, 0.98; SEM, 0.12 cm4), and Z (CV, 2.1%; ICC, 0.99; SEM, 0.043 cm3). BMD and geometric measurements of multiple areas of the proximal femur were included as outcomes because each has been associated with fracture risk (26,42).
Ultrasound measurements were made over the distal radius and tibial shaft using a multisite bone sonometer (Sunlight, Omnisense 7000S; BeamMed Ltd., Petach Tikva, Israel). This gives a measurement of bone speed of sound, which reflects the architecture and density of the bone (39). Reproducibility was as follows: distal radius (CV, 1.5%; ICC, 0.86; SEM, 62 m·s−1) and tibial shaft (CV, 0.8%; ICC, 0.78; SEM, 33 m·s−1).
Elbow, knee, and ankle flexor and extensor muscle thickness was measured using B-mode ultrasound (Aloka SSD-500; Tokyo, Japan), as we have previously described (8). Reproducibility of muscle thickness measurements for each site was as follows: elbow flexors (CV, 2.6%; ICC, 0.96; SEM, 0.15 cm), elbow extensors (CV, 2.1%; ICC, 0.88; SEM, 0.18 cm), knee flexors (CV, 2.3%; ICC, 0.99; SEM, 0.14 cm), knee extensors (CV, 2.1%; ICC, 0.99; SEM, 0.15 cm), ankle plantarflexors (CV, 3.1%; ICC, 0.98; SEM, 0.21 cm), and ankle dorsiflexors (CV, 4.0%; ICC, 0.87; SEM, 0.18 cm).
Overnight fasting blood samples were drawn into Vacutainer serum separator tubes for the analysis of complete blood counts and markers of liver (bilirubin, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase) and kidney (urea and albumin) function. Blood was centrifuged at 3200 rpm for 10 min at 20°C. Urine was collected for 24 h and used with blood creatinine measurements for determination of creatinine clearance as an assessment of kidney function. Urine protein and microalbumin levels were also determined to assess kidney function. All blood and urine measurements were conducted on a fully automated random access analyzer for clinical chemistry (Cobas C 311; Roche Diagnostics, Mannheim, Germany) in our study hospital laboratory.
Strength in the lower body was assessed by determining the 1RM (the maximal amount of weight that a participant could lift one time) during the hack squat, whereas upper body strength was determined by the 1RM during the bench press, as previously described (15). Reproducibility of the strength measures was as follows: squat 1RM (CV, 31.3%; ICC, 0.77; SEM, 22.7 kg) and bench press 1RM (CV, 8.2%; ICC, 0.92; SEM, 5.7 kg).
Training volume was determined throughout the intervention by determining the product of total sets, repetitions, and weight lifted for all exercises in each training session.
Uncontrolled intervention factors
Dietary intake was determined by 3-d food logs and assessed by Nutribase Network Edition software (CyberSoft, Inc., Phoenix, AZ) at baseline and 12 months. Physical activity levels outside the training program were assessed by the Physical Activity Scale for the Elderly (PASE) questionnaire (41) at baseline and 12 months.
Adverse events were collected using adverse event forms throughout the trial. Adverse events were probed each time a research assistant had contact with the participants. This included a description of the adverse event, its relation to the intervention (not related, unlikely, possibly, probably, or definite), whether it was serious (i.e., resulted in death, life-threatening, required hospitalization, or resulted in persistent disability) or nonserious, and its intensity (mild, moderate, severe, or life threatening).
Baseline data were assessed with a one-way (between groups) ANOVA. All dependent variables were assessed with a 2 (groups, creatine vs placebo) × 2 (time, baseline vs 12 months) ANOVA, with repeated measures on the last factor, except for training volume, which was assessed by a 2 (groups) × 3 (time: baseline, 6 months, 12 months) ANOVA. Bonferroni post hoc tests were conducted when significant interactions were found. Relative (%) changes between groups were assessed with one-way ANOVA. Adverse events and compliance data across groups were compared by chi-square analysis. All analyses were performed using Statistica version 7 (Statsoft, Chicago, IL). Data were analyzed on an intent-to-treat basis, that is, an attempt was made to follow up participants who did not adhere to the exercise or supplementation. Participants who were lost to follow-up (i.e., those who either could not be contacted or dropped out and refused to attend the final testing session) were not included in the final analysis. For the women who attended all testing sessions, any missing data were assumed to be missing completely at random. Missing data included three participants in the creatine group and two in the placebo group for the hip structural analysis measurements (because of poor positioning for proper analysis) and one participant in the placebo group for bench press (the participant did not complete the test because of shoulder problems). Imputation of group means was used to account for these missing data. Baseline, nutritional, and physical activity data are presented as means (SD). All other data are presented as absolute change scores and their 95% confidence intervals. Significance was set at α = 0.05.
Baseline data are presented in Table 1. There were no differences between groups for any baseline measurements. At baseline, five participants from the creatine group were on medications (two participants were on statins and one each was on thyroid medication, nonsteroidal anti-inflammatory drugs, and aspirin) compared with nine participants from the placebo group (two participants were on statins, angiotensin-converting enzyme inhibitors, and nonsteroidal anti-inflammatory drugs, three were on thyroid medication, and one each was taking a proton pump inhibitor, beta-blocker, calcium channel blocker, and angiotensin receptor blocker). We did not consider any of our participants to be “fit” at baseline on the basis of the exclusion criteria that they could not be participating in strength training more than twice per week for 20 min each session, and none of our participants were consistently involved in aerobic training programs. Although we did not objectively measure indices of frailty, subjectively, we did not consider any of our participants to be frail on the basis of frailty criteria (6). Compliance with the resistance training sessions was 75% (mean of 117/156 sessions completed) for the creatine group and 77% (mean of 120/156 sessions completed) for the placebo group (P > 0.05). Compliance with the supplement was 79% and 78% for the creatine and placebo groups, respectively (P > 0.05). After the intervention, 53% of the creatine group participants and 44% of the placebo group participants (P > 0.05) correctly guessed which supplement they had received. The participant flow, along with losses and exclusions, is displayed in Figure 1. The final analysis included 33 women, with the remainder lost to follow-up. Loss to follow-up was similar between intervention groups (P > 0.05).
Changes in BMD are presented in Table 2. There was a group–time interaction for femoral neck BMD (P < 0.05). Post hoc analysis indicated a significant decrease from baseline to 12 months in the placebo group (P < 0.001), with no change in the creatine group. Relative changes (i.e., percent change from baseline) for femoral neck BMD are presented in Figure 2. There was a time main effect for hip BMD, with BMD decreasing across both groups (P < 0.05). There were no time main effects or group–time interactions for any other variable (Table 2).
Hip structural analysis and bone ultrasound
Changes in hip structural analyses and bone ultrasound measures are presented in Table 3. There was a group–time interaction for femoral shaft SPW, with greater increase in the creatine group compared with that in the placebo group (P < 0.05). There was a time main effect for femoral shaft CSA, with an increase over time across groups (P = 0.05). There were no time main effects or group–time interactions for any other variable (Table 3).
Lean tissue mass, muscle thickness, strength, and training volume
There were no differences between groups over time for lean tissue mass, muscle thickness measures, strength (Table 4), or training volume. Although there were no differences between groups for absolute changes, relative change (i.e., percent change from baseline) for bench press strength was greater in the creatine compared with that in the placebo group (64% vs 34%, P < 0.05). There was a time main effect for lean tissue mass (P < 0.01), which decreased. There were time main effects for all muscle thickness and strength measures, with each increasing (P < 0.01), except for quadriceps muscle thickness. There was a time main effect for training volume (P < 0.001). Training volumes (sets × repetitions × kilogram per session) were 9895 (SD, 6332), 18,899 (SD, 12,047), and 20,502 (SD, 11,956) kg for the creatine group and 10,749 (SD, 6350), 21,783 (SD, 12,089), and 23,871 (SD, 11,990) kg for the placebo group for the training sessions at the beginning, midpoint (6 months), and end (12 months) of the intervention, respectively.
Uncontrolled intervention factors: physical activity and dietary intake
Caloric (creatine group, 1904 (SD, 431) and 1741 (SD, 432) kcal·d−1; placebo group, 1854 (SD, 359) and 1816 (SD, 233) kcal·d−1 before and after the intervention, respectively), calcium (creatine group, 805 (SD, 152) and 956 (SD, 103) mg·d−1; placebo group, 844 (SD, 143) and 860 (SD, 121) mg·d−1 before and after the intervention, respectively), and vitamin D (creatine group, 20 (SD, 5) and 20 (SD, 7) μg·d−1; placebo group, 22 (SD, 7) and 21 (SD, 6) μg·d−1 before and after the intervention, respectively) intake did not differ between groups over the study. Likewise, physical activity scores (arbitrary units) from the PASE questionnaires did not differ between groups over the study (creatine: 171; SD, 81 to 198; SD, 69; placebo: 229; SD, 80 to 186; SD, 97 from before to after the intervention).
There were seven adverse events considered “possibly” or “probably” related to supplementation in the creatine group compared with four adverse events in the placebo group. There was no statistical difference between groups for total adverse events (P > 0.05). Five participants in the creatine group reported gastrointestinal adverse events including constipation, diarrhea, heartburn, irritable bowel, and nausea (all rated as “mild” in severity), and two reported muscle cramps (one was “mild” in severity, and another was “moderate”). One participant in the placebo group reported nausea (“mild” and “possibly” related), two had liver enzyme levels or bilirubin higher than the normal range (high alkaline phosphatase at 8 months rated as “mild” and “possibly” related) and high bilirubin at 4 and 12 months (“mild” and “possibly related”), and one had low creatinine clearance at 4 and 12 months (“mild” and “possibly related”). We grouped gastrointestinal adverse events and muscle cramping into a single category of adverse events on the basis of adverse events previously reported in studies of older individuals with creatine supplementation (15). When grouped into this category, the creatine group had a significantly higher number of these adverse events compared with that in placebo (P < 0.05). Additional adverse events reported during the study included musculoskeletal problems, such as joint pain, muscular soreness, strains, and sprains, all of which were mild to moderate in intensity, and with most rated as “possibly” related to the exercise. Categorized by supplement group, 20 creatine group participants had musculoskeletal adverse events compared with 17 placebo group participants (P > 0.05).
The most important finding from this study is that 12 months of creatine supplementation during a resistance training program in postmenopausal women preserved BMD at the femoral neck. For healthy aging, this result is important because osteoporotic fracture at the femoral neck is very deleterious (27,33,38). The creatine group lost 1.2% BMD at the femoral neck during the 1-yr intervention compared with a 3.9% loss in the placebo group. This difference approaches clinical significance because 5% decrease in BMD is associated with 25% greater risk of fracture (23). Creatine supplementation also increased SPW (i.e., outer diameter) at the femoral shaft (Table 3), which contributes to section modulus, therefore increasing the bending strength of bone (26). Furthermore, creatine increased upper body strength, which is consistent with other studies involving creatine supplementation and resistance training in postmenopausal women (1,22).
Our study is unique in that it is the first study in postmenopausal women to show that creatine, when consumed during a resistance training program, increases BMD at a clinically relevant site (i.e., the femoral neck). Two other studies have evaluated the effects of creatine supplementation during resistance training in postmenopausal women but did not find changes in BMD at the hip or lumbar spine (22,37). The interventions in the studies by Gualano et al. (22) and Tarnopolsky et al. (37) lasted only 6 months, whereas our intervention was for an entire year. The shorter duration of the intervention in the former studies could account for the lack of effect because the bone may take longer than 6 months to accrue in postmenopausal women. Two other studies have found increases in BMD or content with creatine supplementation (11,28). Louis et al. (28) found a 3% increase in lumbar spine BMD in five boys with Duchenne muscular dystrophy or Becker dystrophy who were independent of a wheelchair and given 3 g·d−1 of creatine over 3 months. Chilibeck et al. (11) found increases (3%) in bone mineral content of the arms in men (mean age, 71 yr) who supplemented with creatine (0.3 g·kg−1·d−1 for 5 d and 0.07 g·kg−1·d−1 thereafter) during 12 wk of resistance training. These human studies are supported by creatine supplementation studies in animal models (i.e., rats and mice). Most, but not all (2), have observed enhancement in BMD or other bone properties (3,30), including one study in ovariectomized rats (17), which was used as a model of postmenopausal osteoporosis.
We had previously shown that creatine supplementation during short-term resistance training programs (i.e., 5–10 wk) in older men (59–77 yr) and young men and women was effective for reducing bone resorption (i.e., reduced urinary excretion of cross-linked N-telopeptides of Type I collagen) (10,16). Creatine supplementation also reduced bone resorption in boys with muscular dystrophy (28,36). Creatine may therefore improve bone health through inhibition of osteoclasts (cells involved in bone resorption). Alternatively, cell culture studies indicate that creatine activates osteoblasts (cells involved in bone formation (18)). Stimulation of osteoblasts increases their production of osteoprotegerin, a cytokine that inhibits differentiation of the osteoclasts and, therefore, resorption of the bone (44). It has been proposed that creatine supplementation could increase the ability to train with greater volumes and therefore stimulate bone formation through increased muscle pull on bone (11). This is not supported by our results because training volumes did not differ over the study between the creatine and placebo groups.
The effect of creatine supplementation on muscle mass and strength was small in our study, with only a statistically significant relative (i.e., percent) change in bench press strength in the creatine compared with that in the placebo group (Table 4). With a relatively low participant number, we may have lacked statistical power for these measurements. In addition, the hack squat strength measure has poor reproducibility (i.e., CV, 31%) and this may have masked differences between groups. This was used for assessment of leg strength because we previously found that incorporation of this exercise in a training program was more effective for inducing changes in BMD in the hip region than using leg press exercise (12,14). This is most likely due to the upright posture during the hack squat and, therefore, greater loading on the hip region. The changes in strength and lean tissue mass were generally in favor of the creatine group and are similar in magnitude to statistically significant changes we detected in a meta-analysis of changes in strength and lean tissue mass with creatine supplementation in older individuals during resistance training programs (9). Studies specifically focusing on older women (1,7,22) support an effect of creatine during resistance training programs for increasing lean tissue mass, strength, and performance in functional tests. Two recent longer-term studies in older women found significant increases in lean tissue mass during 12–24 wk of resistance training when creatine was consumed compared with that when placebo was consumed (1,22). Both of these studies instructed participants to consume their supplements dissolved in sweetened beverages (i.e., fruit juice), whereas we instructed participants to consume supplements dissolved in water, juice, or milk. Creatine uptake into the muscle is stimulated by insulin that is released when sweetened beverages are consumed (21), and this could account for differences between studies regarding the effectiveness of creatine to increase lean tissue mass.
Our 12-month study of creatine supplementation resulted in minimal adverse events. There was no increase in liver or kidney abnormalities as measured by serum levels of liver enzymes, bilirubin, creatinine clearance, or other blood and urine markers. This is in agreement with shorter-term studies in older men and women (7,10,37), including a 12-wk study that found unchanged glomerular filtration rate with creatine supplementation in postmenopausal women (32). Our study resulted in a small increase in combined gastrointestinal adverse events and muscle cramping with creatine supplementation. This is similar to our previous shorter-term study of older men (15). It is unclear whether the increased muscle cramping is caused by changes in muscular properties with creatine supplementation. All adverse events in our study were rated as “mild” to “moderate” in severity, which means that they minimally affected ability to perform daily activities.
A limitation of our study is the relatively low participant number and, therefore, lack of statistical power for many of our measurements. For example, considering the lumbar spine BMD changes for the creatine and placebo groups (Table 2), an SD for the change of 0.043 g·cm−2, and power of 80%, we would require 200 participants per group to achieve significance at α = 0.05. We did not adjust our alpha level for some statistical tests, which raises the possibility of a Type I error for our changes that were statistically significant between creatine and placebo groups. We argue, however, that the differences for relative changes in BMD at an important bone site (i.e., −1.2% versus −3.9% at the femoral neck in creatine vs placebo groups, respectively) approach levels considered clinically significant (i.e., sufficient for prevention of fracture). The findings in the present study support future studies of longer-term creatine supplementation in a greater number of individuals. Participants only had a single familiarization session with the resistance training equipment before strength testing. This may have limited the reproducibility of our strength measures, as evidenced by the relatively high coefficients of variation for these measurements. A longer familiarization period is recommended for future studies. A final limitation of our study is the lack of intramuscular creatine or phosphorylcreatine measures.
In summary, creatine supplementation was effective for preserving BMD at the femoral neck for over 12 months in postmenopausal women participating in a resistance training program. Creatine also increased SPW (i.e., outer diameter) of the femoral shaft, which may lead to greater bone bending strength. The changes in femoral neck BMD with creatine approached levels considered clinically significant. This justifies future larger clinical trials for evaluation of the effects of creatine on bone health.
This study was funded by the Saskatchewan Health Research Foundation and the Canada Foundation for Innovation. Supplements were kindly provided by Rivalus, Inc.
The authors declare no conflicts of interest.
The results of the present study do not constitute endorsement by the American College of Sports Medicine.
1. Aguiar AF, Januário RS, Junior RP, et al. Long-term creatine supplementation improves muscular performance during resistance training in older women. Eur J Appl Physiol
. 2013; 113(4): 987–96.
2. Alves CR, Murai IH, Ramona P, et al. Influence of creatine supplementation on bone mass of spontaneously hypertensive rats [in English, Portuguese]. Rev Bras Reumatol
. 2012; 52(3): 453–61.
3. Antolic A, Roy BD, Tarnopolsky MA, et al. Creatine monohydrate increases bone mineral density in young Sprague–Dawley rats. Med Sci Sports Exerc
. 2007; 39(5): 816–20.
4. Beck TJ, Kohlmeier LA, Petit MA, et al. Confounders in the association between exercise and femur bone in postmenopausal women. Med Sci Sports Exerc
. 2011; 43(1): 80–9.
5. Bonaiuti D, Shea B, Iovine R, et al. Exercise for preventing and treating osteoporosis in postmenopausal women. Cochrane Database Syst Rev
. 2002; 3: CD000333.
6. Bouillon K, Kivimaki M, Hamer M, et al. Measures of frailty in population-based studies: an overview. BMC Geriatr
. 2013; 13: 64.
7. 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(1): 11–9.
8. Candow DG, Chilibeck PD. Differences in size, strength, and power of upper and lower body muscle groups in young and older men. J Gerontol A Biol Sci Med Sci
. 2005; 60(2): 148–56.
9. Candow DG, Chilibeck PD, Forbes SC. Creatine supplementation and aging musculoskeletal health. Endocrine
. 2014; 45(3): 354–61.
10. Candow DG, Little JP, Chilibeck PD, et al. Low-dose creatine combined with protein during resistance training in older men. Med Sci Sports Exerc
. 2008; 40(9): 1645–52.
11. 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(5): 352–5.
12. Chilibeck PD, Davison KS, Whiting SJ, Suzuki Y, Janzen CL, Peloso P. The effect of strength training combined with bisphosphonate (etidronate) therapy on bone mineral, lean tissue, and fat mass in postmenopausal women. Can J Physiol Pharmacol
. 2002; 80(10): 941–50.
13. Chilibeck PD, Sale DG, Webber CE. Exercise and bone mineral density. Sports Med
. 1995; 19(2): 103–22.
14. Chilibeck PD, Vatanparast H, Pierson R, et al. Effect of exercise training combined with isoflavone supplementation on bone and lipids in postmenopausal women: A randomized clinical trial. J Bone Miner Res
. 2013; 28(4): 780–93.
15. 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(12): 2111–7.
16. Cornish SM, Candow DG, Jantz NT, et al. Conjugated linoleic acid combined with creatine monohydrate and whey protein supplementation during strength training. Int J Sport Nutr Exerc Metab
. 2009; 19(1): 79–96.
17. de Souza RA, Xavier M, da Silva FF, et al. Influence of creatine supplementation on bone quality in the ovariectomized rat model: an FT-Raman spectroscopy study. Lasers Med Sci
. 2012; 27(2): 487–95.
18. Gerber I, ap Gwynn I, Alini M, Wallimann T. Stimulatory effects of creatine on metabolic activity, differentiation and mineralization of primary osteoblast-like cells in monolayer and micromass cell cultures. Eur Cell Mater
. 2005; 15: 108–22.
19. Gotshalk LA, Kraemer WJ, Mendonca MA, et al. Creatine supplementation improves muscular performance in older women. Eur J Appl Physiol
. 2008; 102(2): 223–31.
20. 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(3): 537–43.
21. Green A, Hultman E, Macdonald I, Sewell D, Greenhaff P. Carbohydrate ingestion augments skeletal muscle creatine accumulation during creatine supplementation in humans. Am J Physiol
. 1996; 271: E821–6.
22. Gualano B, Macedo AR, Alves CR, et al. Creatine supplementation and resistance training in vulnerable older women: a randomized double-blind placebo-controlled clinical trial. Exp Gerontol
. 2014; 53: 7–15.
23. Guyatt GH, Cranney A, Griffith L, et al. Summary of meta-analyses of therapies for postmenopausal osteoporosis and the relationship between bone density and fractures. Endocrinol Metab Clin North Am
. 2002; 31: 659–79.
24. 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(3): 367–74.
25. Johnell O, Kanis J. Epidemiology of osteoporotic fractures. Osteoporos Int
. 2005; 16(2 suppl): S3–7.
26. LaCroix AZ, Beck TJ, Cauley JA, et al. Hip structural geometry and incidence of hip fracture in postmenopausal women: what does it add to conventional bone mineral density? Osteoporosis Int
. 2010; 21: 919–29.
27. Lorrain J, Paiement G, Chevrier N, et al. Population demographics and socioeconomic impact of osteoporotic fractures in Canada. Menopause
. 2003; 10(3): 228–34.
28. Louis M, Lebacq J, Poortmans JR, et al. Beneficial effects of creatine supplementation in dystrophic patients. Muscle Nerve
. 2003; 27(5): 604–10.
29. Martyn-St James M, Carroll S. A meta-analysis of impact exercise on postmenopausal bone loss: the case for mixed loading exercise programmes. Br J Sports Med
. 2009; 43: 898–908.
30. Miranda H, de Souza RA, Tosato MG, et al. Effect of different doses of creatine on the bone in thirty days of supplementation in mice: FT-Raman study. Spectroscopy
. 2011; 25: 225–33.
31. Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trial. BMJ
. 2010; 340: c869.
32. Neves M Jr, Gualano B, Roschel H, et al. Effect of creatine supplementation on measured glomerular filtration rate in postmenopausal women. Appl Physiol Nutr Metab
. 2011; 36(3): 419–22.
33. Papaioannou A, Morin S, Cheung AM, et al., Scientific Advisory Council of Osteoporosis Canada. 2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary. CMAJ
. 2010; 182(17): 1864–73.
34. Robinson TM, Sewell DA, Hultman E, Greenhaff PL. Role of submaximal exercise in promoting creatine and glycogen accumulation in human skeletal muscle. J Appl Physiol (1985)
. 1999; 87(2): 598–604.
35. Schulz KF, Altman DG, Moher D, CONSORT Group. CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. Ann Int Med
. 2010; 152: 726–32.
36. Tarnopolsky MA, Mahoney DJ, Vajsar J, et al. Creatine monohydrate enhances strength and body composition in Duchenne muscular dystrophy. Neurology
. 2004; 62(10): 1771–7.
37. Tarnopolsky M, Zimmer A, Paikin J, et al. Creatine monohydrate and conjugated linoleic acid improve strength and body composition following resistance exercise in older adults. PLoS ONE
. 2007; 2(10): e991.
38. Tarride JE, Hopkins RB, Leslie WD, et al. The burden of illness of osteoporosis in Canada. Osteoporos Int
. 2012; 23(11): 2591–600.
39. van den Bergh JP, van Lenthe GH, Hermus AR, Corstens FH, Smals AG, Huiskes R. Speed of sound reflects Young’s modulus as assessed by microstructural finite element analysis. Bone
. 2000; 26: 519–24.
40. Wallimann T, Hemmer W. Creatine kinase in non-muscle tissues and cells. Mol Cell Biochem
. 1994; 133–134: 193–220.
41. Washburn RA, Smith KW, Jette AM, Janney CA. The Physical Activity Scale for the Elderly (PASE): development and evaluation. J Clin Epidemiol
. 1993; 46(2): 153–62.
42. Wu CC, Wang CJ, Shyu YI. Variations in bone mineral density of proximal femora of elderly people with hip fractures: a case–control analysis. J Trauma
. 2011; 71: 1720–5.
43. Wyss M, Kaddurah-Daouk R. Creatine and creatinine metabolism. Physiol Rev
. 2000; 80(3): 1107–213.
44. Yasuda H, Shima N, Nakagawa N, et al. Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro. Endocrinology
. 1998; 139(3): 1329–37.