Alpha-Ketoglutarate Preserves Bone Integrity and May Prevent Osteoporosis Onset

Bones have an incredible ability to adapt to different loads and activities. To do this, bone tissue must be in a constant state of remodeling. The honeycomb-network of calcium and other minerals inside bones is constantly reabsorbed to enable rebuilding. 

As we age, this process becomes less efficient, and as a result, too much bone may be lost and too little may be rebuilt. These weakened bones become brittle and are prone to fractures. This condition is known as osteoporosis, which translates to “porous bone”.

In some cases, bones become so frail that fractures occur spontaneously or with minor bumps. Osteoporosis affects both men and women, but it is more common in women after menopause. This condition impairs mobility and decreases the quality of life. Because many people are affected by osteoporosis, it is a public health issue due to the strain it places on healthcare resources (2). As a result, researchers continue to search for therapies that may treat, or prevent, osteoporosis. 

Alpha-ketoglutarate, or AKG, has long been known for its essential role in energy production within cells. AKG is also an important stimulator of protein synthesis and inhibitor of muscle loss. 

In recent years, AKG has been studied for its bone-preserving properties. Researchers have noted AKG’s ability to diminish the breaking-down of the internal framework in bones and its ability to promote the rebuilding of bone tissue.

Alpha-Ketoglutarate Supports Healthy Bones

Strategies for osteoporosis prevention vary, with some being as basic as implementing healthier diets or promoting exercise. Medication-based therapies using bisphosphonates or parathyroid hormone can sometimes be effective, but they come at the cost of potentially dangerous side-effects, such as osteosarcoma (3,4).

In recent years, AKG has been researched extensively because of the critical role it plays in the production of cellular energy, amino acids, and collagen. Animal studies have shown that supplementing with AKG supports bone development and protects against bone loss (5, 6).

For this reason, researchers have proposed AKG supplementation for patients with osteoporosis. In one recent study published in Nature Communications, researchers set out to examine the effect of AKG supplementation on osteoporosis prevention in a rodent animal model (7).

AKG Increases Bone Mass

For the study, the researcher’s first step was to establish a baseline for the levels of AKG in rodents at different ages. Their results showed that AKG levels declined with age.

To achieve similar AKG levels to their younger counterparts, the researchers supplemented the older animals with a small dose of AKG in their drinking water. After some time, the researchers examined the bones of these animals and found a considerable increase in their bone volume.  

Longer bones were consistently found to be thicker after supplementation with AKG. Upon further examination, these animals had an increase in the mineral density of their bones. Together, these results show that the natural process of bone remodeling and remineralization had been jump-started once again. In fact, the bone formation rates in the AKG supplemented older animals were comparable to those from the younger group.

AKG and Age-Related Bone Loss

After confirming the AKG’s effect on bone mass and density, the researchers set out to examine the effects on age-related bone loss. To do so, they followed the AKG supplemented group and examined them against a control group that had not received AKG. The results showed that the supplemented group lost bone at a much slower rate than the control group. These results are promising for the treatment of osteoporosis because this result was seen in female mice, who lose bone at a higher rate than their male counterparts like what has been observed in humans. 

These results were further examined to understand how AKG exerts its beneficial effect on bone preservation. The researchers determined that AKG has a protective effect on the mesenchymal stem cells present in bone. These cells are responsible for the upkeep of the inner structure and density of bone. The natural aging process disrupts mesenchymal stem cells, impairing the mineralization process and the capacity to heal. 

Conclusion

This experimental model shows that supplementation with AKG may have therapeutic potential for osteoporosis. However, more research is needed to evaluate long-term effects of AKG supplementation in humans.

References:

1. Wu N, Yang M, Gaur U, Xu H, Yao Y, Li D. Alpha-Ketoglutarate: Physiological Functions and Applications. Biomol Ther (Seoul). 2016;24(1):1-8. doi:10.4062/biomolther.2015.078
2. Lane NE. Epidemiology, etiology, and diagnosis of osteoporosis. Am J Obstet Gynecol. 2006;194(2 Suppl):S3-S11. doi:10.1016/j.ajog.2005.08.047
3. Barrett-Connor E, Stuenkel CA. Hormone replacement therapy (HRT)--risks and benefits. Int J Epidemiol. 2001;30(3):423-426. doi:10.1093/ije/30.3.423
4. Whitaker M, Guo J, Kehoe T, Benson G. Bisphosphonates for osteoporosis--where do we go from here?. N Engl J Med. 2012;366(22):2048-2051. doi:10.1056/NEJMp1202619
5. Dobrowolski P, Tomaszewska E, Bienko M, Radzki RP, Pierzynowski SG. The effect of dietary administration of 2-oxoglutaric acid on the cartilage and bone of growing rats. Br J Nutr. 2013;110(4):651-658. doi:10.1017/S0007114512005570
6. Dobrowolski P, Tomaszewska E, Radzki RP, et al. Can 2-oxoglutarate prevent changes in bone evoked by omeprazole?. Nutrition. 2013;29(3):556-561. doi:10.1016/j.nut.2012.07.014
7. Wang Y, Deng P, Liu Y, et al. Alpha-ketoglutarate ameliorates age-related osteoporosis via regulating histone methylations. Nat Commun. 2020;11(1):5596. Published 2020 Nov 5. doi:10.1038/s41467-020-19360-1