Last Friday’s post discussed osteoporosis, another post on the topic, and ways that we could avoid fractures while maintaining our abilities as we age. Our current approach to osteoporosis is outdated like our approach to most chronic illnesses. As with other chronic diseases, we identify risk factors for osteoporosis and then we intervene late with medication. Osteoporosis is a bone loss disease, and we give medication that rebuilds the bone. Wouldn’t it be better to never lose the bone while slowing the development of other chronic illnesses as well?
We all know that women lose most of their estrogen when they go through menopause. Estrogen doesn’t merely govern physical female characteristics. Estrogen is a hormone that is a survival switch in women of childbearing age. It protects women so that they can survive to have kids and raise them. That is a clear evolutionary benefit for our human species. Estrogen during that time protects women from artery disease and makes it more likely that they will survive injury or infection than men. It is a powerful antioxidant and anti-inflammatory molecule. Inflammation and increased oxidants are root causes of osteoporosis. Menopause and the loss of estrogen leads to increased inflammation and oxidant production.
The predominant human estrogen hormone is estradiol. Premarin is an estrogen pill that is made from pregnant mare urine and it does not contain estradiol. It contains “conjugated estrogens” It is a mixture of several types of estrogen molecules. That is one reason that estrogen treatment did not live up to its promise. According to this article from the Mayo Clinic, it is taking estrogen by mouth that increases the risk of dangerous blood clots and cancer. For maximum estrogen benefit, you should take the specific human estrogen estradiol in a patch that you put on your skin, and you should start it as you are becoming menopausal.
But here is the really shocking thing from the Mayo Clinic article. Estradiol produces critical anti-inflammatory, and antioxidant effects by regulating another hormone we have previously discussed. I have repeatedly written about angiotensin II in the context of heart disease, kidney disease, and high blood pressure. Losartan, a medicine that precisely blocks the effects of angiotensin II was developed years ago to treat high blood pressure. Since then, we have learned that losartan lowers the blood pressure, but it provides more protection for organs and cells than other medicines that lower the blood pressure to the same level. It slows the progression of heart failure and chronic kidney disease by reducing oxidant production and inflammation. Oxidant production and inflammation cause high blood pressure, chronic kidney disease, and heart failure. Losartan protects these organs by interfering precisely with the root causes of chronic disease.
Now we are learning that angiotensin II doesn’t just cause cardiovascular disease and related conditions like diabetes. It is also involved in cancer. More recently we are learning it is also involved in the origins of osteoporosis, a slowly developing bone disease. Angiotensin II causes osteoporosis in the same way that it leads to hypertension, heart failure, and cancer. It increases oxidant production and inflammation.
The story gets just a bit more complicated, but I know that you can handle it and it is very important. Angiotensin II works in a very specific way. It engages with a receptor on the surface of the cell and that leads to increased oxidant production and inflammation. Angiotensin II is like a ball and the receptor is like a catcher’s mitt. The fit between the ball and the mitt must be perfect to increase oxidant production and inflammation. Here is the most fascinating part of the tale. There are two angiotensin II receptors. One increases oxidant production and inflammation. That is the one many of us know about. The other produces antioxidant and anti-inflammatory effects. Losartan is like a misshapen ball. The mitt can catch it, but the fit is not perfect enough to increase oxidant production and inflammation. Losartan very precisely blocks the oxidant production and inflammation from angiotensin II.
Estradiol produces much of its antioxidant and anti-inflammatory effects by regulating angiotensin II. Before menopause, high levels of estradiol switch on the antioxidant anti-inflammatory pathway of angiotensin II that protects a young mother. After menopause, estradiol levels fall dramatically and that switches angiotensin II effects to oxidant production and inflammation that make us age and develop chronic illnesses more rapidly. The Mayo Clinic people think a combination of losartan and an estradiol patch begun at menopause could be very protective and slow the progression to chronic diseases like heart artery disease and osteoporosis. That makes perfect sense and there is some established evidence that drugs like losartan have a beneficial impact on osteoporosis, reducing the risk of hip fracture by 20%.
This is a great example of why I write about chronic diseases and aging. I am an internist who became more and more interested in artery disease and treating it more effectively with very specific diet, exercise, and medical protocols that can be replicated and scaled. I started by working to learn the best practices in treating artery disease, but the more I dug, the more I realized most (all?) chronic diseases and aging are related and they are caused by normal genes that are inappropriately switched on or regulated.
The osteoporosis story is a perfect example. Angiotensin II is essential for normal health. It is required to form a normal kidney in the fetus. Blocking angiotensin II in pregnant women produces birth defects in the kidney. Angiotensin II maintains your blood pressure when you are dehydrated, or salt depleted. It causes disease when we gain weight and there are persistently high levels produced by abdominal fat or it is no longer properly regulated by estradiol. The angiotensin II story is a great example of the new science of chronic illness. Chronic disease is most often not due to a DNA change or mutation. It is due to inappropriately activating genes that should be quiet or changes in gene regulation. When scientists were mapping our genes in the Human Genome Project, they thought there would be 80,000 genes to account for human complexity. They only found 20,000 and now you can understand why. The genes that make angiotensin II don’t merely impact the heart, kidneys, and blood vessels. They also are important in our bones. The same genes produce effects in many different settings.
It is also a great example of my journey. I am not a bone scientist or a female specialist. I saw patients with artery disease or a high risk of artery disease. The more I learned, the more interested I became in the common origins of chronic disease and aging. I read an article about improving the care of osteoporosis this week. Then I expanded on that article in Friday’s post. Afterwards, I thought, maybe the same genes are involved in osteoporosis as in vascular disease and diabetes. A brief search was truly eye opening. That has been the pattern of my study. Repeatedly I am finding that the same gene regulation and biochemical pathways are involved in most chronic diseases and cancer. This information should change our approach to chronic diseases.
Both estradiol and losartan are generic drugs. They are not going to make anyone a lot off money at this point, but we all have a huge stake in sorting this out because of the impact on women’s health—on our mothers, wives, daughters, sisters, friends, and neighbors. The NIH should sponsor a long-term controlled clinical study of the effect of an estradiol patch with losartan treatment on osteoporosis, vascular disease clotting and cancer. That is the only way we will know if this combination is worthwhile. That is the only way we will know if these interventions should be part of best practice medical treatments for women. This information also points to a need to shift from a system that is arranged around organ systems to one that is designed to address the gene regulation and molecular biology that impact all organs and cells. Help me push for that change in the way that we approach chronic disease and aging. It will take all of use to begin the change.
This article is very enlightening and encouraging. I will be 72 in just a few days. I have osteopenia but have read so much about all of the "side effects" of the current drugs used to treat it, that I only take Calcium and D-3 every day and get as much weight-bearing exercise as possible. Living on the 5th floor of a cement and granite building is a challenge, but the exercise is good for me. I would like to do more to prevent further bone loss, but with a method that would be more beneficial and less harmful overall. I wonder if what you have discussed above would be beneficial to those of us who already have bone loss?
I had my right knee replaced a year ago in March and my L hip replaced a year ago last September. I am pretty much bone-on bone in my L knee ( have had nerve ablation, which is still holding, a year later) and I have 3 compressed discs in my lower lumbar region. Aside from my joint issues, I am relatively healthy!
I would think funding such research might be of benefit to the insurance companies - for don't they pay if people break hips, etc?