There is an extremely high burden currently placed on health care systems due to low bone mineral density, which leads to osteoporosis. This can lead to falls in the elderly, especially women.
The consequences are quite severe and have causes hip fractures and in some cases, death.
Although there is a benefit in exercise programs like resistance training and walking in enhancing bone mineral density, the short-term effects are small and may not have clinical significance.
Creatine is a well-known compound which has been shown to have a range of benefits from enhancing muscle strength and growth to enhancing cognitive abilities.
When creatine combines with phosphate (as phosphocreatine), it provides a source of cellular energy for many cells, including bone cells(1).
In vitro (i.e., outside the body) research shows that adding creatine to low serum cell culture medium enhances metabolic activity and differentiation of osteoblasts, the cells involved in bone formation(1).
Creatine supplementation has also been demonstrated to reduce bone resorption (i.e., bone catabolism) in muscular dystrophy patients(2) and in older men during a supervised resistance training program(3) (see figure below).
The figure above shows that the creatine group showed a decrease in cross-linked N-telopeptides of type I collagen (NTx) (−27% for creatine group vs +13% for placebo group). NTx is an indicator of bone resorption(3) so this decrease in the NTx in the creatine group demonstrated that supplementing with creatine while resistance training mitigated bone resorption.
Preliminary research in this areas indicated that creatine supplementation combined with supervised resistance training increased bone mineral density of the femoral neck in postmenopausal women, with the enhanced bone mineral density reaching levels that come near those thought to clinically reduce the risk of fracture(4) (see figure below).
A 5% increase in bone mineral density is predicted to reduce the risk of fracture by 25%(5).
Figure: Relative changes in femoral neck BMD. Closed diamonds represent changes for individual creatine group participants, and open circles represent placebo group participants. The horizontal bars represent the group means, and the vertical bars represent the SD. *Creatine participants lost significantly less BMD at the femoral neck compared with placebo participants (P < 0.05)(4)
In addition to bone mineral density, geometric properties of bone also affect bone strength. Geometric properties around the proximal femur, assessed using hip structural analysis, are good predictors for fracture(6).
Recent work in this area has shown that femoral neck section modulus (a predictor of bone bending strength, tended to increase in older men who supplemented with creatine during 1 year of supervised resistance training(7).
Research also showed that geometric properties around other bone sites (e.g., cross-sectional area of the tibia) were enhanced with creatine supplementation and supervised resistance training programs in older men and postmenopausal women(8).
Considering some of the positive short-term research on creatine supplementation, exercise and bone properties, a recent study investigated whether creatine supplementation during a longer-term (i.e., 2 years) supervised resistance training and walking program could improve bone mineral density at the femoral neck in postmenopausal women.
In addition, they also determined the effects of creatine on bone mineral density of the lumbar spine and on geometric properties at the proximal femur(9).
Two hundred and thirty-seven postmenopausal women (mean age, 59 years) were randomized to receive creatine (0.14 g/kg bodyweight or placebo during a resistance training (3 days per week) and walking (6 days per week) program for 2 years.
Although there was no effect on bone mineral density, creatine supplementation preserved several geometric properties at the proximal femur compared with placebo (i.e., sectional modulus and buckling ratio at the narrow part of the femoral neck, and cortical thickness, subperiosteal width, section modulus, and buckling ratio at the femoral shaft).
The preservation of section modulus and cortical thickness (in comparison with the decrease in the placebo group) would preserve strength in bending and compression, respectively, whereas the increased buckling ratio in the placebo group indicates an increased susceptibility of cortical bending under compressive loads(6).
A decrease in subperiosteal width in the creatine group relative to the placebo group at the femoral shaft is also associated with reduced risk of fracture. Essentially, the group that supplemented with creatine showed evidence of stronger bones.
At the cellular level, creatine stimulates differentiation of osteoblasts (i.e., cells involved in bone formation), but osteoclasts (cells involved in bone resorption) are also dependent on creatine kinase, the enzyme involved in breakdown of phosphocreatine(10), and therefore might also be responsive to creatine supplementation.
It is plausible that perhaps creatine supplementation stimulates remodeling of bone (i.e., both formation and resorption) to alter geometric properties and whether formation or resorption predominates may depend on the location of bone in the proximal femur.
The use of peripheral quantitative computed tomography (a high-resolution type of quantitative computed tomography (QCT), used for making measurements of the bone mineral density in a peripheral part of the body is considered a gold standard method. This measurement demonstrates a beneficial effect of creatine supplementation on bone geometry indicated by increased total area of bone at the distal and shaft sections of the tibia during a resistance training program in postmenopausal women and older men(8).
Mechanistically, creatine may activate cells involved in bone formation (i.e., osteoblasts) or may reduce cells involved in bone resorption (i.e., osteoclasts).
Exercise stimulates creatine uptake into muscle, hence why it may be especially effective when combined with exercise.
This leads to increased phosphocreatine stores inside the cell, which stimulates adenosine triphosphate (ATP) resynthesis during short-term, high intensity exercise. Creatine supplementation is therefore more effective for increasing lean tissue mass when combined with resistance training than creatine supplementation alone without training(11).
The increase in lean tissue may potentiate increased mechanical stress on bone, which stimulates a net bone formation and enhances geometric properties in bone(12).
Figure: Role of physical activity in bone–muscle crosstalk. Physical activity plays a central role in bone–muscle crosstalk and the health of these tissues by regulating osteokine and myokine production and optimizing mechanical stress(13).
Although 2 years of creatine supplementation during a resistance training and walking program in postmenopausal women had no beneficial effects on bone mineral density, there were several improvements in bone geometry at the proximal femur (i.e., increased cortical thickness and section modulus, and reduced subperiosteal width and buckling ratio).
These changes may be protective against hip fracture.
Future research should focus on longer-term follow-up with larger sample sizes to confirm protection against hip fracture with creatine supplementation.
References
1. Gerber I, ap Gwynn I, Alini M, et al: 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
2. Tarnopolsky MA, Mahoney DJ, Vajsar J, et al: Creatine monohydrate enhances strength and body composition in Duchenne muscular dystrophy. Neurology 62:1771-7, 2004
3. Candow DG, Little JP, Chilibeck PD, et al: Low-dose creatine combined with protein during resistance training in older men. Med Sci Sports Exerc 40:1645-52, 2008
4. Chilibeck PD, Candow DG, Landeryou T, et al: Effects of Creatine and Resistance Training on Bone Health in Postmenopausal Women. Med Sci Sports Exerc 47:1587-95, 2015
5. 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 31:659-79, xii, 2002
6. 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? Osteoporos Int 21:919-29, 2010
7. Candow DG, Chilibeck PD, Gordon J, et al: Effect of 12 months of creatine supplementation and whole-body resistance training on measures of bone, muscle and strength in older males. Nutr Health 27:151-159, 2021
8. Candow DG, Chilibeck PD, Gordon JJ, et al: Efficacy of Creatine Supplementation and Resistance Training on Area and Density of Bone and Muscle in Older Adults. Med Sci Sports Exerc 53:2388-2395, 2021
9. Chilibeck PD, Candow DG, Gordon JJ, et al: A 2-yr Randomized Controlled Trial on Creatine Supplementation during Exercise for Postmenopausal Bone Health. Med Sci Sports Exerc 55:1750-1760, 2023
10. Chang EJ, Ha J, Oerlemans F, et al: Brain-type creatine kinase has a crucial role in osteoclast-mediated bone resorption. Nat Med 14:966-72, 2008
11. 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 53:7-15, 2014
12. Kirk B, Feehan J, Lombardi G, et al: Muscle, Bone, and Fat Crosstalk: the Biological Role of Myokines, Osteokines, and Adipokines. Curr Osteoporos Rep 18:388-400, 2020
13. Cariati I, Bonanni R, Onorato F, et al: Role of Physical Activity in Bone-Muscle Crosstalk: Biological Aspects and Clinical Implications. J Funct Morphol Kinesiol 6, 2021
