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  • R. Keith McCormick, DC

Osteocalcin - Part II

(This is Part II about the importance of looking at osteocalcin levels when assessing bone loss. If you missed the last blog on osteocalcin you might want to read it first.)

Not only is osteocalcin production by the osteoblasts important for healthy bones but this protein/hormone is also involved in memory retention, blood glucose control as a "coordinated endocrine regulation between bone mass and energy metabolism" (1), and even sex, through testosterone production. This makes the skeleton not just a highly complex composite framework designed for structural support, but also a bona fide (pun intended) endocrine organ. And now, new research by Karsenty (2) (Cell Metabolism) broadens our understanding of the extensive biological role that osteocalcin plays in human physiology.


Karsenty’s new research shows that osteocalcin, a hormone produced by the skeleton, is the prime stimulus to the acute stress response, better known as the “fight-or-flight” response. When the brain senses a dangerous or threatening situation (real or perceived), the amygdala signals the hypothalamus to stimulate both the sympathetic and parasympathetic nervous systems in a balanced autonomic nervous system response. Thousands of years ago when lions and tigers and bears threatened our survival, this autonomic response:

(1) raised heart and breathing rates

(2) heightened senses

(3) shunted blood away from the skin and gut

(4) redirected blood towards muscle and brain cells, and finally

(5) dumped huge amounts of energy laden sugar into our blood.

The result was, and still is, that we humans (and animals) can perform remarkable feats of strength and endurance in certain times of acute stress. The problem arises when this life saving response hangs around too long.


In an atmosphere of chronic stress, there is a stimulation of the hypothalamus-pituitary-adrenal (HPA) axis. This means that huge amounts of the stress hormone, cortisol, are dumped into the body by the adrenal glands...what many people refer to as the adrenal stress response. When there is chronic stress, this response can lead to lots of bad things--such as high blood pressure, heart disease, anxiety, depression and so many more stress response-related disorders including osteoporosis. Cortisol is beneficial in the short term, but when it remains elevated in the blood day-in and day-out for months at a time, it causes disease. Osteoclasts in the skeleton are hyper-stimulated by cortisol. In fact, next to the medication prednisone, cortisol has the greatest stimulating effect on osteoclasts when compared to any other other substance.


In his study, Karsenty found that osteocalcin dampens parasympathetic activity thus essentially allowing the sympathetic adrenal release of cortisol to flow unchecked in a “fight-or-flight” response. When assessing the causes of bone loss and monitoring the effectiveness of therapy, it can be extremely helpful to look at various laboratory biomarkers including osteocalcin and cortisol. In fact, the blood levels of these two hormones are often directly correlated. You would think that the higher the osteocalcin (an indicator of osteoblastic bone-building activity) the better. But it isn't always so. In a person's youth, osteocalcin levels are high (indicating that they are building lots of new bone) but then level out in a person's 30s and 40s. When a woman goes through menopause, or a man andropause, or when a person is chronically stressed, osteocalcin levels return to an elevated level. But THIS rise in osteocalcin may simply reflect a rise in the whole level of bone remodeling activity (both higher levels of osteoclastic and osteoblastic activity). The end result is a higher level of bone loss and osteoporosis. A combination of stress AND menopause/andropause can cause great damage to skeletal integrity.


The bottom line is that these biomarkers, and others, are helpful in determining the cause(s) of bone loss and monitoring therapy. In future blogs I will be talking about other lab tests that are helpful when assessing various aspects of osteoporosis.


1) Wei, J and Karsenty, 2015. G. Rev Endocr Metab Disord. 16(2):93-98.


2) Berger, J.M., et al. 2019. Mediation of the Acute Stress Response by the Skeleton. Cell Metab doi:10.1016/j.cmet.2019.08.012.

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