Osteocalcin and Atherosclerosis

The Secret Cholesterol Theory

Completely accidentally I bumped into an article about osteocalcin, and it turned out to be something pretty important. My research about the fight-or-flight mechanism, which is associated with migraine, led me to this article. Those of you who follow me know that my research is in migraines and not with cholesterol. My understanding had been that when humans encounter danger or stress they respond with a “fight or flight” which is initiated by the central nervous system and stress hormones, such as adrenaline(1). According to this article this is not the case.

The initiation is performed by osteocalcin (defined and discusses below.) What’s osteocalcin’s connection to cholesterol? Actually, nothing directly but plenty indirectly, through calcium.  Atheroma is calcified (calcium filled) cholesterol forming atherosclerosis in all the wrong places, and a very negative condition. The sequence leading to it is as follows:

Stress => Osteocalcin = T2D, Atheroma, Calcium, CVD

Indeed! Who would have thought? As you know, there is a war going on about cholesterol and its role in cardiovascular disease, atherosclerosis, and death. The main, traditionalist camp is convinced that the cause of atherosclerosis is high LDL.

An opposing camp, rapidly gaining more and more adherents, suggests that atherosclerosis is caused by inflammatory processes, which may be the consequence of eating industrially produced PUFA oils–vegetable and seed oils; and/or consuming too much sugar—sugar is inflammatory and is associated with type 2 diabetes (T2D) and obesity. This camp also posits that there is no cardiovascular disease without T2D, the two are associated.

The predominant theory of the inflammatory concept suggests that the problem starts in the arteries where the artery walls are crossed by LDL particles—usually they mention small dense LDL particles. They are small and dense because they are oxidized and are not functional. These then lodge in the wall of the arteries, and after a host of immune attacks by macrophages, calcium also moves in from the blood and deposits, making the atheroma hard. This then may burst one day as the calcium gets loose (not much explanation on how and why that happens). According to this theory, the LDL particles magically cross like ghosts though the endothelium (a thin single-layer cell surface separating the lumen, which is where the blood flows from the smooth muscles of the artery) without any damage to the endothelium, and after they reached the outer wall, where the smooth muscle is, then settle…

This is a great theory up until this last part, and that is because examining such atheroma under microscope reveals that there are torn smooth muscle pieces in the atheroma. If so, the crossing of the LDL must have happened from the other side, the smooth muscle and not the lumen side through the endothelium.

Another inflammatory theory suggests that LDL crosses from the outside of the arteries—by Vladimir M. Subbotin in his awesome article here. His theory differs from the LDL particles crossing via the lumen, noting that the concentration of the atheroma is actually not close to the lumen but is deep inside on the bottom of the artery wall, closer to the tunica intima, the side of the artery facing the body. So, if the atheroma has torn smooth muscle cells in it, then clearly the entry is the region of the tear… right? Well that’s just me thinking too logically…

The fourth theory is the one that just came to my attention. Most of the articles on this theory are new. This discusses osteocalcin as the reason for calcification of the atheroma, independent of where the LDL managed to cross into the artery wall. This is the only theory it seems that ignores LDL’s presence and focuses instead on calcification.

Oddity

Before we continue, I must also mention that there is at least one tribe living today, Tsimane, that has high levels of atherosclerosis without CVD (2). Very few members had CAC scores over zero in this tribe, though many had high levels of inflammatory marker c-reactive protein, which was way over 3, the maximum normal cutoff in Western societies. This would indicate that the factor of importance really is the calcification of the atheroma and not the atheroma itself.

What is Osteocalcin?

Osteocalcin “is a non-collagenous protein hormone found in bone and dentin, first identified as a calcium-binding protein in chick bone. Because it has gla domains, its synthesis is vitamin K dependent.” (wikipedia)

The Role of Osteocalcin

Few argue that Cardiovascular Disease (CVD) is a metabolic disease and that it is somehow connected to glucose and insulin mismanagement of the body. The modern CVD theories agree and incorporate metabolic disease, many of them even define CVD as a metabolic disease. However, the development of the connection between metabolic disease and CVD is less understood and seldom discussed.

Crucially, osteocalcin is associated with glucose management: “One of the functions regulated by bone through osteocalcin, an osteoblast specific hormone, is glucose homeostasis” (here). Studying up more about osteocalcin, we can learn that “bone is an endocrine organ regulating a growing number of physiological processes“(3)

As most of us who are students of heart disease, T2D, obesity, or other forms of metabolic diseases know, calcium is key marker of atherosclerosis. It is said that calcium appears at the site of the budding deposit that turns into atheroma, which provides support to the atheroma so it has less chance of bursting(4). While we may disagree about which side the LDL enters the artery to cause its trouble, we may most certainly agree that it is causing trouble most when it gets calcified.

When does osteocalcin enter the picture? Glad you asked. It comes with stress! And I think this is the real culprit and not T2D. That’s because stress initiates hormones that are responsible for generating glucose, initiating insulin resistance, and modifying glucose homeostasis. And what hormone may do all this? Osteocalcin.

Conclusion

I pride myself in finding holes in many arguments. I may not be always correct, but I strongly believe holes definitely exist in the current explanations of CVD. Could it be that the real cause of CVD is stress? See some article here or here(5) or here or here.

My suspicion is that we have been chasing the wrong suspect. Food certainly has much to do with CVD because eating the wrong food can cause stress—sugar is well understood to trigger stress and stress is well-understood to cause elevated blood sugar. And chronic elevated blood sugar leads to T2D which then leads to inflammatory processes. But stress on its own is also causing the release of osteocalcin, which then is just very happy to stick to wherever it can, causing calcification of atheroma. This is a new and intriguing theory, deserving your attention.

Comments are welcome, as always, and are moderated for appropriateness.

Angela

Sources:

1          Berger, J. M. et al. Mediation of the Acute Stress Response by the Skeleton. Cell Metabolism, doi:10.1016/j.cmet.2019.08.012.

2          Kaplan, H. et al. Coronary atherosclerosis in indigenous South American Tsimane: a cross-sectional cohort study. The Lancet 389, 1730-1739, doi:10.1016/S0140-6736(17)30752-3 (2017).

3          Wei, J. & Karsenty, G. An Overview of the Metabolic Functions of Osteocalcin. Current Osteoporosis Reports 13, 180-185, doi:10.1007/s11914-015-0267-y (2015).

4          Aimilios, K. et al. Basic Mechanisms in Atherosclerosis: The Role of Calcium. Medicinal Chemistry 12, 103-113, doi:http://dx.doi.org/10.2174/1573406411666150928111446 (2016).

5          Choi, B.-h. et al. Coronary artery calcification is associated with high serum concentration of undercarboxylated osteocalcin in asymptomatic Korean men. Clinical Endocrinology 83, 320-326, doi:10.1111/cen.12792 (2015).

About Angela A Stanton, Ph.D.

Angela A Stanton, PhD, is a Neuroeconomist focusing on chronic pain--migraine in particular--physiology, electrolyte homeostasis, nutrition, and genetics. She lives in Southern California. Her current research is focused on migraine cause, prevention, and treatment without the use of medicine. As a forever migraineur from childhood, her discovery was helped by experimenting on herself. She found the cause of migraine to be at the ionic level, associated with disruption of the electrolyte homeostasis, resulting from genetic variations of all voltage dependent channels, gates, and pumps (chanelopathy) that modulate electrolyte mineral density and voltage in the brain. In addition, insulin and glucose transporters, and several other variants, such as MTHFR variants of B vitamin methylation process and many others are different in the case of a migraineur from the general population. Migraineurs are glucose sensitive (carbohydrate intolerant) and should avoid eating carbs as much as possible. She is working on her hypothesis that migraine is a metabolic disease. As a result of the success of the first edition of her book and her helping over 5000 migraineurs successfully prevent their migraines world wide, all ages and both genders, and all types of migraines, she published the 2nd (extended) edition of her migraine book "Fighting The Migraine Epidemic: Complete Guide: How To Treat & Prevent Migraines Without Medications". The 2nd edition is the “holy grail” of migraine cause, development, and prevention, incorporating all there is to know. It includes a long section for medical and research professionals. The book is full of academic citations (over 800) to authenticate the statements she makes to make it easy to follow up by those interested and to spark further research interest. It is a "Complete Guide", published on September 29, 2017. Dr. Stanton received her BSc at UCLA in Mathematics, MBA at UCR, MS in Management Science and Engineering at Stanford University, PhD in Economics with dissertation in neuroscience (culminating in Neuroeconomics) at Claremont Graduate University, fMRI certification at Harvard University Medical School at the Martinos Center for Neuroimaging for experimenting with neurotransmitters on human volunteers, certification in LCHF/ketogenic diet from NN (Nutrition Network), certification in physiology (UPEN via Coursea), Nutrition (Harvard Shool of Public Health) and functional medicine studies. Dr. Stanton is an avid sports fan, currently power weight lifting and kickboxing. For relaxation (yeah.. about a half minute each day), she paints and photographs and loves to spend time with her family of husband of 45 years, 2 sons and their wives, and 2 granddaughters. Follow her on Twitter at: @MigraineBook, LinkedIn at https://www.linkedin.com/in/angelaastantonphd/ and facebook at https://www.facebook.com/DrAngelaAStanton/
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30 Responses to Osteocalcin and Atherosclerosis

  1. Jonathan Couchman says:

    Great work, Angela. I was really interested by your comments on the Tsimane and read Reference 2. I could not see that Ref 2 goes so far as you say: it indeed reports low CAC levels combined with high inflammation but it provides no evidence of CAC-free atherosclerosis.

    Your argument remains interesting but surely Ref 2 neither confirms nor contradicts it. Do you have a different view?

    Jonathan

    Liked by 1 person

    • Thanks Jonathan. You find some sentences on page 7 and 8 that, combined, can be used to interpret this paper as I did:

      “This low prevalence and extent of CAC exists in the presence of low HDL, a known coronary artery disease risk factor. In the Tsimane, the average HDL was 1·0 mmol/L. This finding might highlight a differential weight to LDL versus HDL cholesterol for CAC” formation… In this study, a high inflammatory burden was observed in the Tsimane with a low prevalence of CAC for all inflammatory markers… The current study used single measures of hs-CRP and other inflammatory biomarkers, previous work by the THLHP showed strong consistency in immune activation across multiple time points, suggesting much of the increased inflammation among Tsimane is chronic.30 Hs-CRP was marginally associated with CAC presence, but other inflammatory markers such as erythrocyte sedimentation rate, neutrophil count, interleukin 5, and interleukin 10 were noted to be inversely proportional to CAC. These findings run counter to previous industrialised population studies, for which the opposite has been found.” (first half page 7, rest page 8)

      And while these alone may not fully support my statement, with this sentence it does: “Our study is not without limitations. We employed CAC
      scoring as a direct measure of coronary atherosclerosis, but its non-contrast nature precludes assessment of noncalcified plaque constituents.” (page 8)

      Like

      • Jonathan Couchman says:

        Thank you for your detailed reply, Angela. It would be interesting to inspect the arteries of the Tsimane for confirmation, as I do think you could be onto something.

        I do congratulate you on your original thinking and fascinating website. You are doing a great public service that I hope brings you much satisfaction and pride. Well done indeed!

        It is extraordinary that the medical establishment steadfastly stands by falsehoods like the LDL theory or the benefits of carb-based diets, when the data don’t support the falsehoods. That said, high carb diets as such aren’t necessarily unhealthy: the Tsimane experience proves that. It’s complicated …

        Liked by 1 person

        • Thanks Jonathan. 🙂 I agree on both counts. It woudl be interesting to do a study like that but because the finding are then no longer hypotheses–deductive reasoning like I made and they hinted at in the paper–the findings will then stand up against the current dogma. There are two problems with that:

          1) when findings come in the face of 99.99999999999% of the published “research”, publishing in a journal that people read and journalists take to “new flash” that then spreads like wildfire are zero. Look at our current experience. One journal published that red meat is not harmful and had to do so in 5 articles in the same journal to be able to withstand the attacks for retraction. And the findings are not carried by newsflash like they would have been had they found the opposite! Sensationalism only pays off if someone gets paid! And here we connect to the 2nd point,

          2) when something shows (proves) that there is no need to treat most anyone with high cholesterol because high cholesterol and even plaques may not be the causes of heart disease (but perhaps the symptoms), and statins don’t save lives–and they don’t; none of us gets out of here alive and they only lengthen lifespan by 3-4 days after 10 years of statin use, so pointless–then there are not funds for such research.

          So, as you see, the study you recommend, as great as it is, could not be completed.

          In terms of carbs: I just heard a sentence in a lecture somewhere that grabbed my attention: “it’s not what we do that matters but what we don’t do”. To translate this to the Tsimane experience: int’s not that they eat a lot of carbs, some meat and fat. It’s what they don’t eat that makes the difference. They don’t eat any refined carbs, processed foods, industrialized processed seed and vegetable oils (this is the real killer by the way). I recommend you watch this video: https://www.youtube.com/watch?v=pHnPinYI2Yc

          Let’s see if I can embed:

          Like

  2. Fred Lander says:

    For the first time in over 70 years I had a run in with very severe migraines a few months ago and was able to trace it down to the tomatoes on the BLTs. I had not eaten any tomatoes for about 6 months as avoiding nightshades and then I bought some of the plum , which were easy to remove the skins and the seeds to get out the suspect lectins. No problems for about a week and then got sloppy about removing the seeds and skins and bought varieties which were much more difficult to do this. After about three weeks of this the migraines started and got really severe. About 2 or 3 days after suspending all tomatoes the migraines subsided and then disappeared. I can’t say it was the seeds, the α-tomatine in the tomatoes or what, for sure. I found a pretty decent discussion on the nightshades:

    “The largest series of solanine poisoning
    involved an English day school where 78 schoolboys developed
    diarrhea and vomiting after eating potatoes stored since the summer
    term.29 Symptoms began 7-19 hours after ingestion with vomiting,
    diarrhea, anorexia, and malaise. Of the 78 boys, 17 were admitted to the
    hospital. Other symptoms included fever (88%), altered mental status
    (drowsiness, confusion, delirium) (82%), restlessness (47%), headache
    (29%), and hallucinations (23%). Three boys were seriously ill with
    hypotension, tachycardia, and stupor out of proportion to fluid and
    electrolyte imbalance. These boys were discharged 6-11 days after
    admission, and they had nonspecific symptoms and visual blurring for
    several weeks after release from the hospital.
    Fatalities from solanine poisoning are not well documented in the”

    https://www.ncbi.nlm.nih.gov/pubmed/19446683

    Liked by 1 person

    • Thanks for your comment Fred. While solanine poisoning may cause severe distress and extreme headache. migraine is not a headache. Migraine may not even come with a pain in the head. Migraine is a very specific condition with a different brain from the norm, with channelopathy, hyper sensitive alert brains with sensory organs with much more neurons than normal and with several fold increase of connection. A migraine brain is physiologically different from a regular brain. So unless you have a migraine brain, you cannot experience migraines–you can experience headaches.

      A headache may be much stronger than a migraine headache. Migraine headaches are not the strongest headaches–though they come close. Cluster and thunderclap are two headaches that are much stronger.

      I suspect what you had were severe headaches but not migraines. 🙂

      Thanks,
      Angela

      Like

  3. James DownUnder says:

    Fascinating explanation of the ‘How & Why’. I’d love think you’ve got it.
    Thank you !

    There is a difference between how we react to happy stress…and horrible stress.
    The former is… like taking off on my First Solo Flight, and the thought was “This is going to be FUN”
    Horrible stress is standing up in front of an audience and realizing a zip is undone, and for the next 40 minutes…

    I’m also convinced that *mis-handled* stress – or ‘strain’ as Dr Kendrick calls it, is pivotal to CVD.
    In my case, CABG x5 very much so. Not only but also, my life history ticks too many boxes for Good cardiac health… eg, bullied at middle-High school, parents split when young, no siblings or extended family, too many shifts of residence to keep friends and inclination towards depressive episodes Plus my working life was rotating shifts, in a job I had no great passion for.

    Don’t forget the T2 Diabetes / obesity /fitness deficiency…
    Then, 12 months of constant stress, personal, financial and “legal”… resulting in loss of weight control / A1c regulation and self-image in a massive unending depression…. It’s no wonder – with hindsight – that my heart did it’s best to end it all for me !

    Proverbs Ch 17 verse 22 says it all – and notice the inclusion of…. bones !
    “A joyful heart is good medicine, But a broken spirit dries up the bones.”

    Blue Zones the world over, have close personal & social support as the Common Factor, with ‘wholesome’ diets coming in after. – They vary enough to put them in second place.

    Liked by 1 person

    • Glad you are coming around. Most everything broken can be repaired–though they may never look or behave like new, they will work just fine. 😉 Enjoy your new life and recovery!

      The “Blue Zone” is all fake… none of what they labeled as “Blue Zone” fits the mold today and some never fit the mold in the past (Like in Japan or even in Loma Linda, which is a stone throw away from where I live, and where I almost ended up doing some research. Including that even mustard is forbidden for its “excitatory effects”, it is a horrible vegan-special diet with more restrictions than a standard vegan. What keeps people live longer (or used to.. not anymore) is the strong social-community-like nature of Loma Linda.

      Like

  4. Roald Michel says:

    Yesterday night I asked you about a new drug for T2D called Rybelsus which was recently approved by the FDA. But my message isn’t visible anymore. So I sent this one.

    Liked by 1 person

    • Sorry, I have not yet been online since yesterday evening. Trying to finish writing a book, so I turned off all my online toys. 😉 I read both emails (I get an email when I get a message posted) just now.

      It is a GLP-1 drug, glucagon-like peptide 1, receptor agonist, meaning they increase glucagon-like peptide. There is a pretty bad safety record for these drugs when injected–this is the first one that is by a different mechanism; not sure what it is. Whatever it is, it is making T2D worse by forcefully reducing the symptoms, which is high blood glucose… it is like placing your broken arm on a rack and constantly hit it with a bat, while you are drugged to not feel the pain.

      These drugs are all misguided in that they only remove the symptom but to do so, they actually make the condition worse.

      Like

  5. Roald Michel says:

    Rybelsus for T2D is FDA approved now. Your take on this?

    Liked by 1 person

  6. Roald Michel says:

    Re: “But stress on its own is also causing the release of osteocalcin……..” Negative as well as positive stress?

    Talking about negative stress. I’m one of those who, for as long as I can remember, is living with it on a daily basis. Seems to me it’s based on my from childhood on developed and now ingrained anger with moron authorities hypocritically pushing their hidden agendas, as well as with their opportunistic lackeys, ignorant supporters, and indifferent followers. And yet………even after multiple visits to cardiologists triggered by a shitload of times I had all the classical symptoms of having a heart-disease/attack, I always came out clean. In my twenties a professor once told me: “Mister Michel, we can go on and on, but there’s nothing wrong with your heart.” Being now in my seventies, I’m told the same thing 😛

    Note: As a long time online friend I feel I also have to tell you, that since last month my stress level has increased exponentially. Why is that? Because Lucitta died. I know you’re extremely busy, but if you want to know more about the latter, then, because I know the 2 of you are friends there, go to her FB page. Or mine for that matter. On both you can find several entries regarding her death.

    Liked by 1 person

    • OMG Roald, I am so sorry! I have been too busy and didn’t visit her FB page. My deepest condolences to you and Vanessa! ❤ I have known that she was ill and all I can say is that at last she is in no pain. ❤ That won't heal your sorrow but at least her suffering is over. She was a wonderful person from the few times we exchanged words. She will be missed. ❤

      Like

      • Roald Michel says:

        Thx. It’s extremely hard to accept she’s gone. Trying now to find out what to do with the rest of my time. Currently I’m devouring a cocktail consisting grief, desperation, anger, hopelessness, aggression, and other foul ingredients.

        Still, what’s your take on my stress story?

        Liked by 1 person

        • I think what you are going through is totally normal and I would not call it an unnatural stress story. I would think that you need to mourn the best way you can, just be sure you do, because otherwise the pain won’t leave. I have not lost anyone that close to me in my life, so I cannot even imagine what you are going through now. I am not sure what I would do so I cannot even recommend anything other than change your lifestyle from what you had before. Change what you do and when you do it so that you are not reminded of little things you always did together. That’s what I would do. ❤

          Like

        • Roald Michel says:

          I see your point. It makes sense too. Given the way we lived together, also the real estate we own, all the stuff coming with all that, it will take a lot of time to organize/change same. And then there’s this too……. I don’t want to let her go 🎎

          The other thing I was asking your opinion about was related to that osteocalcin thingy, as stress didn’t do to me what was suggested by the article you shared.

          Liked by 1 person

        • You have no choice but to let her go because you have a future to think of. How you feel now is transient–regardless how long it lasts. ❤

          In terms of stress and how it affected you. Not sure I understand what you mean: do you mean the fight-or-flight?? I think that there are several types of stresses and it is not clear that fight-or-flight and/or osteocalcin is part of each type. I don't suppose that the stress released by skydiving for the first time is the same experience as getting a first job, or having a loved one die, or getting your first new car. Each of these is a stress but each is very different in what they activate, plus they differ among people.

          For example, when I was teaching in the university, I often had classes of several hundred in huge lecture halls and sometimes those lecture halls were filled with faculty to whom I lectured. The stress I felt totally fit me–I got a "high" from that stress. Yet pull a few typical people off the street and place them into that situation and watch some faint from stress. Feeling happy and looking forward to public speaking would have a very different stress response than feeling scared of public speaking. Same activity, different stress response.

          So I think there is a lot more to this that none of the articles I discussed covered. Plus, in some situations, fight-or-flight exists without us actually being conscious of it. Migraine is very typical for that. I discuss this in my book. The first step in migraine is a fight-or-flight but few of us actually feel the fight-or-flight.

          However, we may have its symptoms only we call these something else, even though they are all part of fight-or-flight: a sudden urge of a bowel movement out of regular timing and much bigger, a sudden urge to frequent urination, a bit faster heart rate than usual, being a bit out of breath perhaps, maybe a slight dizziness, a bit of nausea and maybe even vomiting, and many more. These are all symptoms of fight-or-flight without feeling anxiety. So you may have had the fight-or-flight without discovering it.

          Like

        • Roald Michel says:

          Yes, I too can flourish under positive stress. That’s why I asked: “Negative as well as positive stress?”

          Re: “Could it be that the real cause of CVD is stress?” & “…..osteocalcin, which then is just very happy to stick to wherever it can, causing calcification of atheroma.” Seems (well….um…..up till now) not to have happened in my case 😛

          Re: “fight-or-flight”. There’s also “freeze” ⛄️

          Liked by 1 person

        • I suppose CVD takes some time to develop and probably there are genetic factors mixed in there based on our reactions.

          Yes, I am sure it is extremely hard to accept that she is gone. I don’t know what to recommend since I have not had the experience–I don’t have the right to recommend. Your body and mind will tell you how to advance. ❤

          Like

    • chris c says:

      Oh I’m so sorry! i wondered where you’d gone.

      Liked by 1 person

  7. BRILLIANT piece, thank you!!

    Liked by 1 person

  8. alcura says:

    I’ve heard the same line where stress is the key trigger of CVD from Dr. Malcolm Kendrick. Thanks for another great post!

    Liked by 1 person

    • chris c says:

      Yes and in a recent post one of the replies was from someone looking at calcium metabolism.

      I spent most of my life suffering from reactive hypoglycemia. A lack of Phase 1 insulin means my glucose spikes on eating carbs, then the Phase 2 turns up and knocks it back down again but fails to shut off and the rapid drop in glucose releases counterregulatory hormones including cortisol, epinephrine and norepinephrine which explains my mood symptoms and reacting as if |I was under stress when I wasn’t. All gone thanks to a low carb/keto diet. Maybe one more mechanism where diabetes is a cardiovascular risk.

      I came across osteocalcin before in the context of diabetes also. \now to read these papers . . .

      Liked by 1 person

      • Many of the migraineurs I work with have reactive hypoglycemia. To recover from that, I place them on the carnivore diet. It seems to work very well for most–not all so far.

        Like

      • chris c says:

        It’s amazing what you can see in retrospect! I used to get migraines, but they were comparatively mild and uncommon, so I lived with them, On the other hand I never had “normal” headaches, ie. without visual and sometimes aural disturbances.

        Now I realise they occurred in the afternoon or evening a few hours after eating too many carbs. Yet another symptom that went away once I nailed my blood glucose.

        Ok I’ve read your references, fascinating stuff! I only read one of them before. This one

        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213520/

        looks to have some good links too.

        Liked by 1 person

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