Bone Quality Is Just as Important as Density

by Etsuko Ueda

Bone Quality

Traditionally, the status of bone health has been measured by bone mineral density. However, the ineffectiveness of Fosamax in preventing bone fracture made it abundantly clear that there is more to bone strength than bone mineral density. It turned out that "bone quality" is just as important as BMD.

Hormones and bone quality

Here again hormones have significant role.
The figures below are taken from 3D imaging of bone structures for a 44 year old woman (A) and a 61 year old woman (B). The porosity is clearly seen in B compared to A. (Masako Ito, 2006)

The bone mineral density (BMD) commonly used to measure the strength of bone reflects the difference in porosity such as seen in the above examples. However, by volume, 50 % of bone is collagen (protein) which provides interlocked grid like structure (matrix) to hold the mineral contents together. If this collagen matrix is degraded and becomes brittle, the bone will become brittle like a chalk and easily snaps, and it will not be detected by BMD.
"Older people can have up to tenfold increased 10-year fracture risk in comparison with younger individuals with the same BMD... more than 50% of all fractures occur in women with osteopenia, as defined by a -2.5 < BMD T score ≤ -1; at-risk women in this group will not be detected by applying the World Health Organization BMD definition of osteoporosis." (Bone quality and osteoporosis therapy. Regina Matsunaga Martin, Pedro Henrique S Correa 2010).
The degradation of collagen and protein in general is a well known part of aging process that results in wrinkles, hardening of blood vessels, and hardening of all sorts of tissues including eyes, brain, kidney, liver, etc., and its mechanism is well known. The primary culprits are glucose (blood sugar) that causes sugar burn, and homocysteine, a potent source of free radicals that cause oxidative damages (Mitsuru Saito 2008 (Japanese)). They damage protein and produce hardened dysfunctional tissues. Bones and tendons become discolored and yellow-brownish. 
 Fractured Bone with degraded discolored collagen

Homocysteine (an intermediate metabolite of sulfur amino acid methionine, which is a building block and a metabolite of protein.) is well known for its toxicity owing to its byproducts such as superoxide and hydrogen peroxide (oxidative damage promoting free radicals) and association with the hardening of tissues. The reason diabetes causes so many health problems is because it greatly speeds up this process due to high blood sugar level, which in turn impairs kidney function that is critical for filtering and processing harmful homocysteine.
Furthermore, these damages start inflammation chain reactions, which in turn lead to all sorts of tissue damages and degradation and more oxidative damages. In case of collagen, this process allows glycation (sugar burn) to take over the part of the collagen tissue called cross-links and form advanced glycation end products as the tissue is newly generated. It prevents normal maturing and mineralization in case of bone tissues (Mitsuru Saito 2008 (Japanese)).
It should also be noted that any toxicity including low grade infections, inflammations, and some medications (including wrong hormone therapies) will increase free radicals and stress hormone cortisol. That alone is enough to cause some bone deterioration (and every part of your body for that matter).

Biochemical markers of bone quality degradation

How much your body, including bones, is subjected to this type of degradation can be monitored by analyzing the levels of homocysteine and pentosidine (one of collagen glycation end products) in blood and urine. Also, the accumulation of advanced glycation end-products (AGEs) in skin tissues can be used as an indicator of bone collagen degradation.
The good news is that both blood sugar level and homocysteine level can be controlled by diet, exercise, nutritional supplements, and hormones. Even the vicious cycle of impaired kidney function and high homocysteine level can be controlled to some extent. Homocysteine metabolic pathways are well known: including the critical enzymes and cofactor vitamins (B6, B12, choline, and Folic acid). Also the conditions that increase homocysteine levels are well known; impaired kidney function, cortisol, low estrogen/progesterone levels, genetic defects of critical enzymes. In other words, the remedies to slow down the degradation process is well know.
One reason Fosamax (or bisphosphonate in general) cannot protect your bone despite the increased BMD is that it degrades collagen cross-linking.
Another reason Fosamax (or bisphosphonate in general) cannot protect your bone despite the increased BMD is that it suppresses bone turnover too much. Bone mineralization occurs in two stages: Primary mineralization occurs when the new collagen matrix begins to mineralize quickly up to 50% to 60% of the maximum mineralization value. The secondary mineralization proceeds slowly for a number of years to fill the rest. If the removal rate is too fast, the bone tissues will be removed before they are fully mineralized and half-way mineralized bone tissues will increase. If the removal is too slow, on the other hand, over mineralized old and brittle bone tissues increase. Therefore it is important to strike the balance. This balance can be achieved better by estrogen than bisphosphonate (Microdamage accumulation in the monkey vertebra does not occur when bone turnover is suppressed by 50% or less with estrogen or raloxifene. Jiliang Li, Masahiko Sato, Chris Jerome, Charles H Turner, Zaifeng Fan, David B Burr 2005).
For more on bone quality and collagen cross-links, see

Homocysteine and hormones

Effect of hormones on homocysteine level
Because of the well established associations among menopause, cardiovascular diseases, gender differences, and homocyteine level, the effects of hormones on homocysteine level have been explored long before homocysteine's effects on osteoporosis became apparent (Urinary pentosidine and plasma homocysteine levels at baseline predict future fractures in osteoporosis patients under bisphosphonate treatment. Masataka Shiraki, Tatsuhiko Kuroda, Yumiko Shiraki, Shiro Tanaka, Tsuyoshi Higuchi, Mitsuru Saito, 2011). It has been well demonstrated that estrogen or estrogen + progesterone can reduce homocyteine level (Hormone replacement therapy and plasma homocysteine levels. W M van Baal, R G Smolders, M J van der Mooren, T Teerlink, P Kenemans, 1999) and testosterone can increase it (Effects of sex steroids on plasma total homocysteine levels: a study in transsexual males and females. E J Giltay, E K Hoogeveen, J M Elbers, L J Gooren, H Asscheman, C D Stehouwer, 1998).
With experimental animals, surgical menopause (ovary removal) is routinely used to induce high homocysteine level. On the other hand, the homocysteine metabolic pathways are well known and hormones do not seem involved. Although, the underlying mechanism does not seem clearly understood, it is safe to assume that the link between the sex hormones and homocysteine level is not at the downstream of methyonin - homocysteine metabolism. Rather, the link seems to be at the upstream, the rate of muscle breakdown/rebuilding. In other words, testosterone increases the rate of muscle breakdown/rebuilding and estrogen slows it down. While surgical menopause (ovary removal) will increase the breakdown by the increased cortisol due to the distress of surgical menopause in addition to the lowered estrogen.
These effects of estrogen and testosterone were demonstrated with transsexual males and females also. A woman who starts to take a large dose of testosterone will see increased homocysteine level, while a man who starts to take estrogen will have a reduced homocysteine level (Effects of sex steroids on plasma total homocysteine levels: a study in transsexual males and females. E J Giltay, E K Hoogeveen, J M Elbers, L J Gooren, H Asscheman, C D Stehouwer, 1998).
Although the effect of sex hormones on homocysteine has been demonstrated, they explain only a small fraction of the total homocysteine level in general population, against the effects of base protein metabolism (Factors explaining the difference of total homocysteine between men and women in the European Investigation Into Cancer and Nutrition Potsdam study. J Dierkes, A Jeckel, A Ambrosch, S Westphal, C Luley, H Boeing, 2001), and among osteoporotic postmenopausal women, kidney function is the most dominant factor (Homocysteine levels and risk of hip fracture in postmenopausal women. Meryl S Leboff, Rupali Narweker, Andrea Lacroix, Lieling Wu, Rebecca Jackson, Jennifer Lee, Douglas C Bauer, Jane Cauley, Charles Kooperberg, Cora Lewis, Asha M Thomas, Steven Cummings, 2009).

Here again, progesterone mimicking drug, Provera (medroxyprogesterone acetate) has been proven to be very detrimental. HRT with medroxyprogesterone acetate (MPA) does not reduce homocysteine (due to increased cortisol activities; MPA acts like cortisol also.), while BMD studies demonstrated positive effects as reviewed earlier. 

Bone series articles:

  1. Menopause and What Really Happens to your Bones
  2. False Promise of Fosamax
  3. Estrogen Paradox
  4. Role of Progesterone in Bone Health
  5. Stress Hormones Destroy Bones
  6. Menopause and How estrogen helps bone health?
  7. Sad State of Progesterone Research
  8. Bone Quality Is Just as Important as Density  <<You are here
  9. How to Maintain Bone Health


Stress Hormones Destroy Bones

by Etsuko Ueda

It isn't just estrogen and progesterone that go through changes. FSH and LH rise and so does the stress hormone cortisol, while most hormones, including human growth hormone, DHEA, insulin-like growth factors, inhibins, thyroid, etc. start to decline as early as mid 30's.
Amongst, the hormone well known for its destructive power on bone is a stress hormone cortisol, and it is well established that cortisol increases with age. 

Catabolic effect of Cortisol

Cortisol, also known as glucocorticoid, is well known for it's catabolic (breakdown) effects on bones, muscles, and protein in general. This is one of catabolic hormones along with epinephrine and glucagon. 
Cortisol increases especially during the late perimenopause and early post menopause years when menstrual irregularities are greatest, and menopausal symptoms are most severe.

Cortisol is an important stress hormone that allows us to be alert and energetic to face life's challenges with less pain. But it comes with a price, and our body is not built to stay in that state days and weeks on end, much less months and years. Except for a lucky few (less than 10%), women go through a stressful menopausal symptoms during the late perimenopause and early post menopause years (Bresilda Sierra, et.al. 2005), which is accompanied by elevated cortisol, epinephrine, and norepinephrine levels (Pituitary hormones during the menopausal hot flash. D R Meldrum, J D Defazio, Y Erlik, J K Lu, A F Wolfsen, H E Carlson, J M Hershman, H L Judd, 1984. Biophysical and endocrine-metabolic changes during menopausal hot flashes: increase in plasma free fatty acid and norepinephrine levels. M Cignarelli, E Cicinelli, M Corso, M R Cospite, G Garruti, E Tafaro, R Giorgino, S Schonauer. 1989). That is, unless something is done about it (Here lies a dilemma of research on menopause. You have to find women who agree to do nothing about it, which may not be easy or ethical, and potential for biased sampling).
"Glucocorticoids (GCs) are used frequently in a variety of diseases because of their strong anti-inflammatory and immunosuppressive effects. However, corticosteroids have many metabolic side effects, such as insulin resistance, hypertension, glaucoma, and osteoporosis. GC-induced osteoporosis (GIOP) is one of the most devastating side effects because bone loss during long-term GC treatment is generally irreversible and because of its clinical manifestations (eg, vertebral and nonvertebral fractures)." (Advances in glucocorticoid-induced osteoporosis. Debby den Uyl, Irene E M Bultink, Willem F Lems, 2011).
The mechanism has been identified at molecular level: Glucocorticoid preserves osteoclasts (cells involved in bone resorption) while reducing and impairing osteoblasts and osteocytes (cells involed in bone formation and mineralization). In addition, it impairs bone metabolism via inhibition of calcium resorption in the gastrointestinal tract and inhibition of the kidney's ability to reabsorb calcium (Glucocorticoid-induced osteoporosis: pathophysiology and therapy. E. Canalis & G. Mazziotti & A. Giustina & J. P. Bilezikian, 2010).

Bone series articles:

  1. Menopause and What Really Happens to your Bones
  2. False Promise of Fosamax
  3. Estrogen Paradox
  4. Role of Progesterone in Bone Health
  5. Stress Hormones Destroy Bones <<You are here
  6. Menopause and How estrogen helps bone health?
  7. Sad State of Progesterone Research
  8. Menopause and Bone Quality
  9. How to Maintain Bone Health


Sad state of progesterone research on bone

Role of progesterone on bone health in post menopause years

During premenopause years when estrogen is regularly secreted (menstruation cannot occur without estrogen), the level of progesterone hold the key to maintaining bone health, as reviewed earlier. Therefore, it is reasonable to assume that to be the case in post menopause hormone supplementation as well. However, when you read through the so far accumulated hormone supplementation research, you might come away with an impression that the effects of progesterone, real or fake, on bone are negligible or secondary at best to the bone spearing effects of estrogen (Long-term effects of progestins on bone quality and fractures. Jos H H Thijssen 2007 for a review). Although, many animal studies suggest otherwise as shown below 
Due to the unfortunate history of HRT dominated by progesterone mimicking drugs and high dose oral progesterone, studies that illustrate proper use of progesterone are rare. One pioneering study by John R. Lee ("Osteoporosis Reversal: The Role of Progesterone," by John R. Lee, (International Clinical Nutrition Review 1990, see also What Your Doctor May Not Tell You About Menopause, by John R. Lee, M.D. with Virginia Hopkins, 1996, Warner Books.) used transdermal progesterone 20~40mg/day for 21 days/month. Only 40% of his patients used estrogen (oral estradiol 0.3mg or premarin 0.65mg, or vaginal estrogen) corresponding to the need to control menopausal symptoms. The age of patients ranged from 38 to 83 and BMD at lumbar spine ranged 0.5~1.3 g/cm2 at the start. The most interesting aspect of this study is the increase of BMD (roughly 2~23% or 0.03~0.16g/cm2 gain) proportional to the severity of the bone erosion regardless of age for both estrogen and non-estrogen users. This is a highly desirable outcome since you do not want BMD build-up in people who already have healthy BMD. That would be an indication of old bone accumulation rather than new bone formation.

When you compare Lee's data with BMD gain typically seen with antiresorptive agents (estrogen or bisphosphonates such as Fosamx) compiled by Claudie Berger et. al. 2008 (Change in bone mineral density as a function of age in women and men and association with the use of antiresorptive agents) there is a large (10 fold) difference in the magnitude of gain. With antiresorptive agents the gain ranges -0.04 ~ 0.01g/cm2 , while the gains were 0.03~0.16g/cm2 in Lee's.

Another attempt to demonstrate the efficacy of real estrogen + real progesterone supplementation on bones of early postmenopausal women with osteopenia (average BMD around 0.9g/cm2), used transdermal estradiol (increasing and decreasing doses of 25~75 microg/day) and oral progesterone (cyclic 50 mg/daily for 6 days and, subsequently, 100 mg daily for the next 6 days) imitating rise and fall of estrogen and progesterone throughout the therapeutic cycle. When compared to an oral estrogen + fake progesterone (1 mg estradiol valerate [358.39 g/mol] + 2 mg estriol [288.39 g/mol] + 0.25 mg levonorgestrel [312.466 g/ mol]), a slight advantage of combined bio-identical hormone therapy was observed in BMD gains. However, the bone building osteoblasts activity marker used (osteocalcin) did not show any increase, while bone collagen synthesis marker (carboxyterminal propeptide of type I procollagen) showed clear decrease over the 1 year trial period, indicating collagen that keeps bone from getting brittle was decreasing although BMD was increasing (see Bone Quality Is Just as Important as Density).
Compared to 17~18% BDM gain in 3 years (about 6% per year) seen in Lee's patients starting with BMD comparable to Stanosz's study, Stanosz's patients gained 3.8% in one year. There is no way to tell if this reflects a significant difference in the efficacy of the HRT protocols used, and if it does, if it is due to the effects of additional nutrition and exercise used by Lee's patients. However, one thing for sure is the detrimental effects of progesterone mimicking drugs and progesterone overdose that have been used by most HRT studies including the above Stanosz, et. al. study (see Hormone overdose: How can you tell?).

Fake progesterone with glucocorticoid activity

If anyone says progesterone is bad for your bone, they are talking about fake progesterone that has glucocorticoid activity. Real progesterone can bind to glucocorticoid receptors, but does not act like cortisol (Synthetic progestins used in HRT have different glucocorticoid agonist properties. Dominique Koubovec, Katharina Ronacher, Elisabeth Stubsrud, Ann Louw, Janet Patricia Hapgood 2005). Instead, it blocks excessive cortisol action (Steroid hormone receptor expression and action in bone. R Bland 2000 for a review). 
Progesterone, cortisol, and vascular constriction
Real progesterone can block cortisol receptors to block excessive cortisol activity. Furthermore, vascular constriction is dependent on Ca+ (Vascular responses of ophthalmic arteries to exogenous and endogenous norepinephrine. H Ohkubo, S Chiba 1989), and progesterone, as a fast acting Ca+ blocker, can reduce excessive blood vessel constriction.
Even Medroxyprogesterone acetate (provera), a progesterone mimicking drug with significant cortisol activity, was demonstrated to reduce Glucocorticoid-induced osteoporosis in men. Effective therapy of glucocorticoid-induced osteoporosis with medroxyprogesterone acetate. E O Grecu, A Weinshelbaum, R Simmons, 1990.

Problematic Progesterone studies

Most studies (including the now infamous Women's Health Initiative clinical trials) have used progesterone mimicking drugs (some with high cortisol activity) instead of real progesterone. Those that used real progesterone are flawed with overdose (see the overdose section below), in addition to design limitations and the lack of critical information or analysis such as correlation among menopausal symptom, cortisol, initial BMD levels, and BMD gains, making it difficult to interpret. 

Problem of hormone overdose

More is not better when it comes to hormones, supplemented or your own. (see also Hormone overdose: How can you tell?)
Progesterone overdose   

Estrogen overdose and cortisol

Also, let's not forget that when you add progesterone to estrogen, the effects of estrogen increases many fold because progesterone increases estrogen receptors, and extremely high level of estrogen can intensify stress reaction and cortisol.  (see also Hormone overdose: How can you tell?)
In terms of clinical experiment, therefore, you cannot just compare estrogen supplementation against estrogen + progesterone supplementation without reducing estrogen dosage in estrogen + progesterone group, especially when estrogen dosage is far more than necessary to control menopausal symptoms to begin with (e.g. 2mg is 40 times more than what's needed, which is 0.05mg). 
The notion that estrogen dominance, the consequence of Ovulatory Disturbances, is detrimental to bone health is an old news. Actually, it can do a lot more harm than weakening bone. It was pointed out by Ray Peat and John R. Lee decades ago. The logical approach to this problem is progesterone supplementation using low dose transdermal form, and its effectiveness has also been known (see Estrogen dominance: it's not just a theory and Safe Use of Hormones: the Hard Evidence). If you are wondering why there aren't very many researchers following up Ray Peat and John R. Lee's work, I suggest you read Natural Hormones: Why doctors are clueless? and The Hormone War is Heating Up.


Role of Progesterone on Bone Health

Progesterone's bone building effects have long been known in laboratory experiments (Stimulatory effects of estrogen and progesterone on proliferation and differentiation of normal human osteoblast-like cells in vitro. B A Scheven, C A Damen, N J Hamilton, H J Verhaar, S A Duursma, 1992; also see Steroid hormone receptor expression and action in bone. R Bland, 2000 for a review). Furthermore, progesterone declines long before estrogen (right around the time bone starts to decline) as corpus luteum's progesterone secretion function gets weaker and ovulation starts to fail long before menstruation finally stops. 
Fig. 2 is a graph showing typical perimenopause cycle pattern variations including cycles with estrogen rising without corresponding progesterone and/or bleeding.  
Figure 2. PDG = progesterone metabolite in urine, E1G = estrogen metabolite in urine. The dark bands on the day axis indicate menstruation bleeding days. Source: Progesterone and ovulation across stages of the transition to menopause. Kathleen O'Connor, Rebecca Ferrell, Eleanor Brindle, Benjamin Trumble, Jane Shofer, Darryl Holman, Maxine Weinstein 2009

What does the reduced progesterone do to your bone?

If you look at studies that recorded monthly hormonal status along with bone metabolism status, you can see a clear bone building role of progesterone (Progesterone and bone: a closer link than previously realized. V Seifert-Klauss, M Schmidmayr, E Hobmaier, T Wimmer 2012).
A monthly cycle can be divided into 2 parts: before ovulation (follicular phase) and after ovulation (luteal phase). Progesterone is secreted only after ovulation while estrogen is secreted in both before and after. In terms of presence or absence of the two hormones during the luteal phase (after ovulation) of a monthly cycle, there are 4 possible combinations. The conditions in #2 in the table below are the conditions that cause estrogen dominance and the comparison between #1 and #2 will reveal the role of progesterone in the presence of normal or higher than normal estrogen level.
luteal phase
Progesterone present
Progesterone absent or low
Estrogen present
1. Normal cycle
2. Ovulatory Disturbances (no ovulation or short/weak luteal phases)
Estrogen very low
3. does not happen in naturally occurring condition.
4. skipped cycle or surgical/natural menopause
The researchers have found that in perimenopause women (42% of the cycles did not have ovulation) the bone formation marker BAP increased during the luteal phase of ovulatory cycles with high progesterone levels, but not during anovulatory (no progesterone) cycles. The bone resorption marker pyridinoline decreased during the luteal phase of ovulatory cycles with high progesterone levels and decreased to a lesser extent in anovulatory cycles. In other words, progesterone promotes bone building AND suppresses bone resorption. Naturally, those who maintained normal BMD had more normal ovulatory cycles. For those who lost BMD over the 2 year study period, 42% of the BMD change was correlated with skipped cycles, bone resorption, and cortisol.
Studies on younger women (n = 458, mean age 31 years) demonstrated that BMD increased 0.5% per year in association with normal ovulation, and decreased by 0.7% per year in women with ovulatory disturbances (Progesterone and Bone: Actions Promoting Bone Health in Women. by Vanadin Seifert-Klauss, Jerilynn C Prior 2010: meta-analysis and review).
These pre- and peri menopause conditions that results in lower progesterone is a phenomenon well known as estrogen dominance, and lower BMD is only one of many health risks it causes. The logical thing to do in these conditions is to boost progesterone by low dose transdermal progesterone made of real progesterone (That's what has been recommended by Ray Peat and John R. Lee as a preventative treatment for estrogen dominance) as opposed to progesterone mimicking drugs used in birth control drugs and hormone therapy drugs.
Also, let's not forget that stress (high cortisol) reduces progesterone secretion for a prolonged period (Stress and female reproductive function: a study of daily variations in cortisol, gonadotrophins, and gonadal steroids in a rural Mayan population. Pablo A Nepomnaschy, Kathy Welch, Dan McConnell, Beverly I Strassmann, Barry G England 2004; Stress and the menstrual cycle: relevance of cycle quality in the short- and long-term response to a 5-day endotoxin challenge during the follicular phase in the rhesus monkey. E Xiao, L Xia-Zhang, A Barth, J Zhu, M Ferin 1998; Inadequate luteal function is the initial clinical cyclic defect in a 12-day stress model that includes a psychogenic component in the Rhesus monkey. Ennian Xiao, Linna Xia-Zhang, Michel Ferin. 2002), thus amplify the harmful effects of cortisol in pre- and peri-menopause years (So imagine how disadvantaged your body is in post menopause years without real progesterone supplementation).
As I said, the logical thing to do in these situations is to boost progesterone, however, I have yet to come across a study that is designed to examine the effects of progesterone supplementation during pre- and peri-menopause years. If you are a researcher in this field, here is a chance to make a name for yourself. Just make sure that progesterone is transdermal, real, potent, and does not exceed 40mg/day.


Bone series articles:

  1. Menopause and What Really Happens to your Bones
  2. False Promise of Fosamax
  3. Estrogen Paradox
  4. Role of Progesterone in Bone Health  <<You are here
  5. Stress Hormones Destroy Bones
  6. Menopause and How estrogen helps bone health?
  7. Sad State of Progesterone Research
  8. Bone Quality Is Just as Important as Density
  9. How to Maintain Bone Health