Bone Is an Endocrine Organ
PERSPECTIVE
Surprising Evidence
Janeah Saadeh
DC, ND, CMRP
As chiropractors, we apply physical forces to various parts of the body, especially targeting osseous structures, such as the spine, rib cage, pelvis, extremities, and in certain instances, the cranium. Discoveries over the past 60 years regarding the skeleton’s role in various physiological processes, including a surprisingly long list of endocrine functions, potentially implicate how various forms of manual therapy may influence the overall health and well-being of our patients. Introduction
The skeleton is one of our largest organs, comprising approximately 15% of our total body weight. Traditionally, it has been viewed as just a rigid scaffold to enable mobility. It allows for anchoring of muscles and ligaments and protection for the softer but highly important internal organs and the nervous system. Bone is known for its mineral-storing abilities, regulation of calcium/phosphorus homeostasis, and the marrow’s role in hematopoietic functions. However, “bones are a heck of a lot more than a place to store calcium,” says Patricia Buckendahl, a bone physiologist at Rutgers University (Underwood, 2019).
Research beginning in the 1970s demonstrates that bone produces at least five hormones:
1. Fibroblast growth factor 2 3 (FGF-23)
2. Dipeptidyl peptidase 4 (DPP-4)
3. Lipocalin 2 (LCN2)
4. Sclerostin
5. Osteocalcin (OCN)
OCN seems to have the most wide-ranging effects and has been the major topic for research. I will discuss it last. Continuing studies involving complex genetic manipulation of mice reveal more and more infonnation about bone’s role as an actual endocrine organ and how its honnones affect us. It is highly likely that more hormones will be discovered since it has become clear that our bones communicate by participating in a network of signals via their hormones (Cox, 2020).
Fibroblast growth factor 23, produced by osteocytes in bone, acts on the kidneys for hydroxylation of vitamin D and regulation of phosphate metabolism. If extra phosphate is circulating, this hormone tells the kidneys to shunt it. It also suppresses the production of 1,25 (OH) D3 and suppresses parathyroid hormone production (Han et al., 2020), suggesting that FGF-23 is intimately involved in the regulation of bone health.
Dipeptidyl peptidase-4, studied by Dr. Khosla at the Mayo Clinic, is made by the osteoclasts, and appears to play a role in a variety of functions from blood sugar management, immunoregulation, and tumorigenesis (Cox, 2020). Much is still unclear about its function, but pharmacology companies
are eagerly working on DPP-4 Inhibitors as a potential new class of osteoporosis drugs.
Lipocalin 2 was once thought to be produced mostly by fat cells. In 2017, physiologist Stavroula Kousteni of Columbia University Medical Center and colleagues reported that bones produced 10 times more LCN2 than fat cells. Studies also showed that the LCN2 released by bones has several interesting functions, including stopping the spread of bacterial invaders and playing a role in the brain for regulation of appetite (Martin, 2017).
Sclerostin, a protein product of the SOST gene, seems to keep bone growth in check by slowing down osteoblasts and is also released into circulation to help convert white fat to brown fat, thereby creating more efficient fuel (Martin, 2017). Osteocalcin: A Powerful Metabolic Regulator
Osteocalcin, also known as bone’s y-carboxyglutamic acid protein, is secreted solely by osteoblasts (Moser & van der Eerden, 2017). A marvel of the body is that osteocalcin circulates throughout the blood, collecting calcium and other minerals that bones need. When the hormone reaches the pancreas, it signals insulin-making cells to ramp up production of bone (Martin, 2017). As one of the richest non-collagenous proteins in bone matrix, OCN helps build strong bones with vitamin K (Shao et al., 2015). Following protein synthesis, the mature peptide first undergoes several splicing events and then gets y-carboxylated, resulting in a peptide with high affinity toward bone and the extracellular matrix. Due to the low pH inside the osteoclast resorption compartments, osteocalcin gets decarboxylated again, which reduces its affinity for bone and triggers the release of uncarboxylated osteocalcin into the circulation (Moser & van der Eerden, 2017). Thus, most OCN is found in the bone matrix, with a small amount circulating in the blood.
While we have known that OCN has bone-building functions, in 2007, geneticist Gerard Karsenty of Columbia University and his colleagues discovered that OCN also acts on multiple organs, including adipose tissue, liver, muscle, pancreas, testes, and the brain.
Primarily, the uncarboxylated version of this hormone targets the beta cells in the pancreas and insulin-targeting tissue in muscle, liver, and fat cells. There is also evidence that OCN plays a strong role in glucose metabolism, insulin secretion, and insulin resistance (Shao et al., 2015). The effect is to enhance insulin production in the pancreas, increase the number of beta cells in the pancreas, increase glucose utilization in peripheral tissues, and reduce visceral fat. In addition, OCN increases production of adiponectin in fat cells, which leads to increased glucose uptake into fat and muscle cells (Novkovic, 2021). It is well known that type 1 and type 2 diabetics have increased risk of bone fractures, and it is believed that OCN plays a large role in that.
Jamah Saadeh, DC, ND, CMRP, has practiced in the Atlanta area for over 35 years. She has a BS in Medical Technology from the University of North Carolina at Chapel Hill, a DC from Life Chiropractic College in Marietta, Georgia, and an ND from Trinity College. She also recently finished the Matrix Repatterning certification program. Learn more about Matrix Repatterning at matrixinstitute.net or info@matrixrepatterning. com
We have known for many years that bone, via osteoclasts and osteoblasts, has a very unique ability to destroy and remodel itself. It is as if bone continually reinvents itself. We also know that “the energy requirements for bone modeling and remodeling are quite high. Bone resoiption followed by bone formation is a cellular process that relies on daily synthesis of proteins” (Oldknow, MacRae, & Farquharson, 2015) and thus requires a significant amount of energy. It should not be surprising then, given these energy requirements, that bone is directly involved in energy management via glucose homeostasis and insulin secretion. It has been described as a bone-endocrine-energy loop that involves leptin, fat cells, gut-derived hormones, and OCN (Wei & Karsenty, 2015). (Figure 1).
Additionally, OCN is innately involved in muscle function and strengthening. It acts in muscle to increase ATP (Cox, 2020). Another finding shows that OCN supports muscle function during exercise via IL-6 release. As IL-6 is released into the blood, the uptake of glucose and fatty acids is increased, which promotes production of more OCN. Thus, it appears that these two mediate crosstalk between bone and muscle during exercise (Han et al., 2020). There may also be a role in muscle growth.
The anti-aging/osteocalcin connection has been discussed in more than one paper. It is generally accepted that peak bone mass occurs in our twenties. Karsenty describes OCN as an anti-aging hormone. He sums it up with “osteocalcin acts in the muscle to increase the ability to produce ATP, the fuel that allows us to exercise. In the brain, it regulates the secretion of
most neurotransmitters that are needed for memory. The circulating levels of osteocalcin decline in humans around mid-life, which is roughly the time when the physiological functions, such as memory and the ability to exercise, begin to decline” (Cox, 2020). He found that if he increased OCN levels in older mice, many age-related signs improved. One of the ways to increase your OCN is via exercise, which most of us intuitively know can help slow the aging process.
OCN also has a role in male reproduction via testicular function and sperm counts. It had previously been known that estrogen can affect bone formation, but now we know that bone, via its hormone OCN, can regulate fertility via testicle secretion and testosterone (Shao et al., 2015). Karsenty’s lab has evidence that suggests this hormone might even help shape fetal brain development (Martin, 2017). And yet another exciting finding that Karsenty’s team revealed involves the decarboxylated OCN and the brain itself. Not only was it demonstrated that this hormone could cross the blood-brain banier, but it was also found to have unexpected central roles in brain development and cognitive functions (Shan, 2019).
OCN accumulates in the brainstem, thalamus, and hypothalamus and can bind specifically with neurons in these areas. It is involved in the synthesis of several neurotransmitters (serotonin, GABA, and dopamine) and their signaling (Shan, 2019). These neurotransmitters play significant roles in motivation, learning, mood, and memory. The hippocampus, mainly responsible for memory storage and conversion, is highly affected in glucose neurotoxicity, as seen in diabetics. We know the brain is a very insulin-sensitive organ, and now we see that OCN plays a role there. Osteocalcin-deficient mice were also found to be more passive, have increased anxiety, and decreased memory Furthermore, OCN was demonstrated to affect spatial learning (Moser & van der Eerden, 2017).
In several human studies, low OCN was linked to decreased cognitive function (Shan, 2019). This and the previously mentioned findings by Karsenty led him to hypothesize “that animals evolved bony skeletons to escape danger” (Novkovic, 2021). Karsenty said, “I think evolution has invented osteocalcin as a survival hormone because to escape predators, you need your bones to be able to signal to your muscles to mn.. .you also need to remember where to find food or where the predator was an hour ago... more and more we think it evolved as a hormone to help animals escape” (Cox, 2020).
I think one of the most fascinating newer OCN studies discusses osteocalcin’s role in our body’s stress response. These studies that Karsenty and colleagues perfonned using mice seem to suggest “that osteocalcin—not adrenaline—is the gatekeeper that determines when bodies shift into fight-or-flight mode” (Underwood, 2019). The researchers also discovered how this occurs in the brain. When the amygdala senses a threat, it instructs the osteoclasts of the bone to release OCN into the bloodstream. OCN then inhibits the parasympathetic nervous system, which allows the sympathetic system to go into flight-fight-fright mode. These studies shed light on why patients with damaged adrenal glands and poor adrenaline output can still have an intense stress response when threatened. And to note, Karsenty repeated this type of study in humans. He had subjects engage in public speaking and other anxiety-producing events. Not only were heart rate and blood pressure elevated, but OCN levels also rose. Patricia Buckendahl presented the first evidence that osteocalcin acts as a stress honnone in rats 20 years ago, but back then, no one took her idea seriously. Now the additional evidence does indeed “support the hypothesis that bones evolved to help animals escape predators” (Underwood, 2019).
While these studies reveal much new infonnation about bone’s role, there is still a lot we do not understand. Many researchers commented that it is highly likely that more honnones will be discovered and/or more biochemical pathways revealed. Treatments for slowing aging, hnproving memory and cognition, and hope for treating Parkinson’s disease patients are being discussed (Shan, 2019).
How Do Our Treatments Influence Bone?
As a chiropractor who practices a fonn of treatment called Matrix Repatterning, which specifically targets bone size and shape, I wondered what evidence there was for any possible influence on osteocalcin and the other hormones produced by bone. Does treatment of bone using this technique, or any other chiropractic modality, have the potential to regulate these hormones and thus improve blood sugar management, muscle function, neurotransmitter levels, memory, spatial awareness, and even our patients’ stress responses?
During my training in Matrix Repatteming, Dr. George Roth shared evidence from the University of California, where researchers discovered that injury to bone causes certain glue-like collagen strands between the trabeculae to uncoil, resulting in a permanent enlargement of the structure (Figure 2) (Fantner et al., 2005). In addition, we now know that collagen fibers within bone are piezoelectrically active (MacGuintie). By incorporating these features of bone, this fonn of treatment has been able to demonstrate measurable changes in bone size, based on preand post-treatment imaging (Roth, 2022). This may explain how the application of this gentle form of treatment, and likely many other forms of chiropractic care, appear to provide so many clinical benefits.
Eureka!
The following quote from the NIH’s National Library of Medicine’s Bone Health and Osteoporosis: A Report of the Surgeon General may just have validated how performing manual treatments, such as Matrix Repatterning, most likely does affect the osteocytes and their hormonal activity. “Very small changes in the shape of the bone can act on the cells inside bone (the osteocytes), which produce chemical signals that allow the skeleton to respond to changes in mechanical loading” (National Institute of Health, 2004).
References
1. Underwood, E. (2019) Hormones secreted by bones may help us escape danger. Science, https://www.science.org/conten... hormone-secreted-bones-may-help-us-escape-danger# :~:text=When%20a%20brain%20region%20called.slow%20heart%20 rate%20and%20breathing..
2. Cox, D. (2020) Does the key to anti-aging lie in our bones?. The Guardian, https://www.theguardian.coin/science/2020/iul/04/doesthe-kev-to-anti-ageing-lie-in-our-bones.
3. Han, Y., You, X., Xing, W., Zhang, Z., & Zou, W. (2018). Paracrine and endocrine actions of bone-the functions of secretory proteins from osteoblasts, osteocytes, and osteoclasts. Bone Research, 6, 16. https://doi.org/10.1038/s41413...
4. Martin, C. (2017) Bones make honnones that communicate with the brain and other organs. Science News, https://www.sciencenews.org/ article/bones-make-honnones-communicate-brain-and-other-organs
5. Moser, S. C., & van der Eerden, B. C. J. (2019). Osteocalcin: A versatile bone-derived honnone. Frontiers in Endocrinology, 9, 794. https://doi.org/10.3389/fendo....
6. Shao, J., Wang, Z., Yang, T., Ying, H., Zhang, Y., & Liu, S. (2015). Bone regulates glucose metabolism as an endocrine organ through osteocalcin. International Journal of Endocrinology, 2015, 967673. https://doi.org/10.1155/2015/9...
7. Novkovic, B. (2021) What is osteocalcin? Definition, function, and health effects. SelfDeCode Labs Blog post, January 19, 2021. https://iabs.scirdccodc.com/bl...
I am excited to share my expanded understanding of the interconnected nature of all of the structures of the body via the biotensegrity matrix, which Dr. Roth has shared with us. As I apply these principles to release the deeper layers of restriction (primarily within bone), I am constantly amazed at its powerful effects on the health and well-being of my patients, including improved neurology, balanced myofascial tone, increased range of motion, restored joint stability, and reduced pain.
My deeper awareness of the wide-ranging effect that bone has on the production of these hormones and their physiological effects on the entire body adds a new dimension to my work. I sincerely hope that more studies are done on this topic in the future.
8. Oldknow, K. J., MacRae, V. E., & Farquharson, C. (2015). Endocrine role of bone: recent and emerging perspectives beyond osteocalcin. The Journal of Endocrinology, 225(1), R1-R19. https://doi.org/10.1530/JQE-14...
9. Wei, J., & Karsenty, G. (2015). An overview of the metabolic functions of osteocalcin. Reviews in Endocrine & Metabolic Disorders, 75(2), 93-98. https://doi.org/10.1007/slll54...
10. Shan, C„ Ghosh, A., Guo, X. Z„ Wang, S. M„ Hou, Y. F., Li, S. T„ & Liu, J. M. (2019). Roles for osteocalcin in brain signalling: implications in cognitionand motor-related disorders. Molecular Brain, 72(1), 23. https://doi.org/10.1186/sl3041...
11. Fantner, G. E., Hassenkam, T., Kindt, J. H., Weaver, J. C., Birkedal, H., Pechenik, L., Cutroni, J. A., Cidade, G. A., Stucky, G. D., Morse, D. E., & Hansma, P. K. (2005). Sacrificial bonds and hidden length dissipate energy as mineralized fibrils separate during bone fracture. Nature Materials, 4(8), 612-616. https://doi.org/10.1038/nmatl4...
12. Streaming and piezoelectric potentials in connective tissues. MacGuintie, L.A. In: Blank M (ed) Electromagnetic fields: biological interactions and mechanisms. Advances in Chemistry Series 250. American Chemical Society, Washington DC, eh. 8, pp 125-142, 1995.
13. Roth, G.B. (2022). Matrix Repatteming, Practitioner Manual, Matrix Institute: Toronto.
14. National Institutes of Health, National Library of Medicine. Bone Health and Osteoporosis: A Report of the Surgeon General. Office of the Surgeon General 2004. https://www.ncbi. nlm.nih.gov/books/ NBK45504/
