11/15/2013

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