Estradiol falls at menopause and when it drops below a threshold a series of events take place that result in increased bone remodeling. With each remodeling cycle more bone is removed than replaced and the faster the rate of these cycles the more true this becomes. This series of events is typical of all human women.
Men never produce estrogen directly but several well controlled studies were published in the early 1990s showing that bone density in men is determined by their estrogen levels not testosterone levels. This was a surprise to me because it made no sense at the time. I knew men did not make estrogen and that their risk for osteoporosis was much lower than that seen in women. I had always assumed it was because of testosterone. This mistaken view was reinforced by the knowledge that hypogonadal men, those with low testosterone levels were at similar high risk for developing osteoporosis as menopausal women. However, the data does not lie. The explanation is testosterone is converted inside the cell through the process of intracrinology by an enzyme called aromatase to estrogen in both men and women. This is a normal and natural metabolic pathway for testosterone to follow and in men; the estrogen created in this way protects their bone from loss. In fact, most normal 60-year-old men have much higher estradiol levels than their healthy 58-year-old wives not on hormone replacement.
There are two primary regulatory sex steroids, estradiol, and testosterone. These two hormones control DNA activity in every cell in the body and literally reign supreme over our human existence. I call these two the Queen and King of nuclear regulatory steroid hormones because of the fundamental roll they play in shaping our human experience on every level including the biological, behavioral, and cultural. You may think I am exaggerating about this but I assure you I am not.
Testosterone is necessary for bone formation because the mesenchymal stem cell cannot differentiate into an osteoblast unless testosterone occupies its nuclear receptor. Loss of estrogen in ether gender triggers more rapid bone remodeling, a protective highly conserved genetic human characteristic that provides the older members of our species with more ready access to their rich skeletal stores of calcium, magnesium, protein, and electrolytes when external access to these precious elements may not be as readily available due to being older and not as able as we were when young. Nature knows you can’t take it with you and that you either use it or loose it.
All members of the human race who lived and currently live in central content of the old world where mankind evolved the place we today know as Africa, possess age-related slow mineral withdrawal phenotype that provides humans with ready withdrawals from minerals stored in their skeletal bank. Those who migrated out of Africa 50,000 years ago and ended up probably chasing herds of deer and moose into the Northern European forests had to adapt to the low UV light conditions. They did so by loosing their skin pigment and conserving specific polymorphisms that occurred in the way their bodies managed bone and mineral metabolism. The result was a more exuberant reaction to low serum calcium with higher rates of bone remolding and levels of parathyroid hormone. As a result, the skeleton of the postmenopausal women descended from these hunters remodel slightly more aggressively than other human women or their eugonadal brothers and fathers. Dark skinned people who migrated to the US from African in the last 500 years maintain the original phenotype the evolved on the central continent in our ancestors hundreds of thousands of years ago. This explains why they do not suffer from osteoporosis in the same way white women do. In fact, no other humans have the osteoporosis genetic complex, only whites. This explains why the fracture rates are so different between groups of humans that evolved apart for as little as 50,000 years but are genetically identical and clearly of one single race, the human race.
It is the loss of the Queens influence, estradiol at menopause that triggers the osteoporosis genetic complex in white women of Northern European ancestry. The same loss in women of other ancestries also leads to slightly higher rates of bone loss and eventually higher fracture rates but at 40% less than that seen in these white women and 50% less than seen in all men. The fractures that occur in the affected white women occur on average about a decade before they occur in the other humans of either gender.
The osteoporosis seen in all people that occurs later in life than in the white women described above is age related osteoporosis or what was called in the politically incorrect past senile osteoporosis. In my opinion, age related osteoporosis is a human condition that affects all humans the same regardless of bone density and is driven primarily by age. I think it is due to frailty and that the cause of frailty is loss of testosterone, which as you recall began at age 30. As the level of testosterone falls, the ability of the mesenchymal stem cell to differentiate into a bone forming osteoblast is impaired.
Natural aging in both men and women result in lower levels of sex steroid levels that peak at age 30 and decline predictably at a rate of 1.5% per annum for the remainder of life. In women though, menopause causes a dramatic collapse of the levels of a both estrogen, testosterone and progesterone. The progesterone is gone never to return. Testosterone is made from adrenal produced DHEA. Via aromatase, some of the testosterone is converted into estradiol in both women and men but the levels of androgen are so low to begin with in women the amount of estradiol produced is minor compared to their male counter-parts. The reason for this is men make so much more testicular testosterone that circulates freely in the bloodstream. The testosterone is picked up by receptors on cells armed with aromatase is rapidly converted to estradiol and then explored back into system where it provides some benefits.
Normative bone densitometry data from white women not on hormones or other drug therapy known to affect bone or mineral metabolism between age 50 and 60 years of age revealed a bone loss rate of 12% or 1.2% per annum in the lateral spine.
Some of the key actors in the events that cause bone loss at menopause have now been identified and their roles and scripts recorded.
Menopause unfolds the same for all women leading to an increase in bone remodeling for the same reasons. Interestingly though the outcomes in terms of osteoporosis and fracture rates are very different for some women compared to others.
The osteocytes direct the play by production of a number of proteins one of which is called RANK-L. This protein controls the fate of the bone absorbing osteoclast cells and stimulates them to begin a bone remodeling cycle. An increase in RANK-L causes the formation of many new osteoclasts from the pool of hematologic stem cells. Osteoclasts are charged with removing old and damaged bone from the skeleton. RANK-L also stimulates the activity of osteoclasts meaning how actively they approach their task. When estrogen is absent and remodeling becomes unmodulated by estradiol, the result is excessive and rapid bone absorption.
Bone formation by osteoblasts is coupled to absorption of bone by osteoclasts, which must precede it. The two activities are tightly coupled. The bone that is absorbed by osteoclasts contains growth factors and chemotactic agents (chemical messages) placed there 7 years ago by the osteoblasts that made the bone.
The growth factors act like messages in a time capsule for the yet to be born great grand daughters of the osteoblasts that buried them in bone substance during the process of the bone formation long ago. The messages released from the bone time capsule tell the mesenchymal stem cells that are destined to become osteoblast cells to change into this cell type and then where to go to replace the bone absorbed by the osteoclasts.
Testosterone plays an important role at this point. The pre-osteoblast stem cell requires testosterone to be present within their nucleolus occupying the nuclear receptor in order to become osteocytes. If testosterone is absent, then the cell differentiates into a fat cell. Once they arrive in the bay absorbed by the osteoclasts the message also contains exactly the right combination of fertilizing growth factors to stimulate the stem cells to differentiation into osteoblasts and to proliferate into enough cells to do the job of filling up the hole left in the bone.
Normally bone remodeling is characterized by bone absorption being only a little greater in quantity to the following bone formation. Remodeling unmodulated by estradiol and testosterone results more rapid and prolonged absorption followed by a shorted period of formation. This is observed to some extent in all human females at menopause but not to the same extent as observed in those white women of Northern European ancestry that carry the genetic osteoporosis phenotype. What transpires in them is significantly more bone is removed than is put back and the cycle is speeded up. The osteoclasts are speeded up and the osteoblasts cannot keep up. After each remodeling cycle, less bone is in the skeleton than was present before hand. If this goes on long enough, the disease osteoporosis is the outcome.
Each basic structural unit that does the remodeling is made up of a few thousand cells and can easily fit on a pinpoint with room to spare. The BSU is tiny and there are millions of BSU active all at once all over the skeleton. There are enough active to completely breakdown and replace 1% of the bone in the skeleton each month or 14% annually. This is a continuous process all day long, every day of the year all the days of our life. It is resource and energy intensive. That provides some context.