Bone: Estrogen paradox

Estrogen has been widely used in perimenopause and menopause in order to slow down bone erosion and to increase bone mineral density (BMD) as well as to stop menopausal symptoms (Ultralow-dose micronized 17beta-estradiol and bone density and bone metabolism in older women: a randomized controlled trial. Karen M Prestwood, et. al. 2003) . Studies have indicated that estrogen can preserve bones by reducing the number of bone-resorbing (bone-eating) osteoclasts directly.

• More bone marrow mononuclear cells become osteoclasts when estrogen is lacking (Estrogen action on bone marrow osteoclast lineage cells of postmenopausal women in vivo. J Clowes, G Eghbali-Fatourechi, L McCready, M Oursler, S Khosla, B Riggs 2008 ).
• Estrogen protects bone by inducing Fas ligand in osteoblasts to regulate osteoclast survival. Susan A Krum, Gustavo A Miranda-Carboni, Peter V Hauschka, Jason S Carroll, Timothy F Lane, Leonard P Freedman, Myles Brown 2008;
• Estrogen Directly Attenuates Human Osteoclastogenesis, But Has No Effect on Resorption by Mature Osteoclasts. M G Sorensen, K Henriksen, M H Dziegiel, L B Tanko, M A Karsdal 2006
• Inhibition of bone resorption by 17beta-estradiol in human bone marrow cultures. U Sarma, M Edwards, K Motoyoshi, A M Flanagan 1998
• Estrogen directly acts on osteoclasts via inhibition of inward rectifier K+ channels. K Okabe, F Okamoto, H Kajiya, K Takada, H Soeda 2001
• Attenuation of the self-renewal of transit-amplifying osteoblast progenitors in the murine bone marrow by 17 beta-estradiol. G B Di Gregorio, M Yamamoto, A A Ali, E Abe, P Roberson, S C Manolagas, R L Jilka 2001
• Negative regulation of RANKL-induced osteoclastic differentiation in RAW264.7 Cells by estrogen and phytoestrogens. Veronica Garcia Palacios, Lisa J Robinson, Christopher W Borysenko, Thomas Lehmann, Sara E Kalla, Harry C Blair 2005
• Expression of the estrogen receptor during differentiation of human osteoclasts. Stefanie Denger, George Reid, Frank Gannon 2008.

Yet, the most puzzling is the fact that bone erosion starts during when estrogen level is still normal or higher than normal (the age estrogen dominance becomes prevalent, see Perimenopause: the complex endocrinology of the menopausal transition J C Prior 1998: excellent review), while the ovaries' ability to produce progesterone is declining. For most women, bone erosion starts in early 40's in honest. It picks up the pace in menopausal transition and it is most severe during the late perimenopause. (one year before and one your after the last menstruation) and bone erosion slows down once past perimenopause and early post menopause (see Fig. 1) as estrogen settles at a lower level.

The perimenopause is the time when ovarian function becomes irregular and weaker, but still a substantial amount of estrogen is secreted compared to post menopause, occasionally estrogen becomes even higher than normal. Interestingly, it is also the time menopausal symptoms are most severe (Revisiting the Duration of Vasomotor Symptoms of Menopause: A Meta-Analysis. Mary Politi, Mark Schleinitz, Nananda Col 2008).

Here, we need to remember that the occurrence and the severity of menopausal symptoms is not related to the absolute level of estrogen either. It has been shown that hormones other than estrogen such as FSH and Inhibin A and B have stronger correlation with menopausal symptoms and bone turnover markers than estrogen (It is another way of showing that you can have sever menopausal symptom and bone erosion with reasonable level of estrogen). Furthermore, the severity of menopausal symptoms is also affected by factors known to increase cardiovascular disease risk such as stress, smoking, and less physically active.

• Perimenopause: the complex endocrinology of the menopausal transition  J C Prior 1998: excellent review.
• The relationship of longitudinal change in reproductive hormones and vasomotor symptoms during the menopausal transition. John F Randolph Jr, MaryFran Sowers, Irina Bondarenko, Ellen B Gold, Gail A Greendale, Joyce T Bromberger, Sarah E Brockwell, Karen A Matthews, 2005. 
• Relation of demographic and lifestyle factors to symptoms in a multi-racial/ethnic population of women 40-55 years of age., E B Gold, B Sternfeld, J L Kelsey, C Brown, C Mouton, N Reame, L Salamone, R Stellato, 2000
• Bone Turnover Across the Menopause Transition: Correlations with Inhibins and FSH.
  Daniel S Perrien, Sara J Achenbach, Samuel E Bledsoe, Brandon Walser, Larry J Suva, Sundeep Khosla, Dana Gaddy. 2006 
   
  

It should also be noted that estrogen cannot stop bone erosion of Anorexic girls. (Mechanisms and treatment options for bone loss in anorexia nervosa., S Grinspoon, D Herzog, A Klibanski, 1997; The effects of estrogen administration on bone mineral density in adolescents with anorexia nervosa., M T Munoz, G Morande, J A Garcia-Centenera, F Hervas, J Pozo, J Argente, 2002; Bone mineralization, hypothalamic amenorrhea, and sex steroid therapy in female adolescents and young adults., A C Hergenroeder, 1995; Severity of osteopenia in estrogen-deficient women with anorexia nervosa and hypothalamic amenorrhea., S Grinspoon, K Miller, C Coyle, J Krempin, C Armstrong, S Pitts, D Herzog, A Klibanski, 1999).

The accelerated bone loss during menopause transition years is a well establish phenomenon as can be seen in Figure 1. below.

Figure 1. Source: Change in bone mineral density as a function of age in women and men and association with the use of antiresorptive agents, Claudie Berger et. al. 2008

 

It is well established that the accelerated bone loss does not continue all through menopause years, and paradoxically, it slows down once passed the transition period and estrogen level has settled at a level lower than the transition period.

• V Seifert-Klauss, et. al. 2005, 2006 reported as much as 10.6% BMD drop in 2 years or 6% drop per year in late perimenopause. The highest levels of bone turnover markers were also seen during this period.
• A Japanese study (Age, menopause, bone turnover markers and lumbar bone loss in healthy Japanese women., M Iki, E Kajita, Y Dohi, H Nishino, Y Kusaka, C Tsuchida, K Yamamoto, Y Ishii, 1996) reported an average BMD drop of 2.4% per year in perimenopausal women compared to 0.01% drop in premenopausal and 0.85% for over-all postmenopausal women.
• A study in the US (Bone Mineral Density Changes during the Menopause Transition in a Multiethnic Cohort of Women. Joel S. Finkelstein, et. al. 2008) observed BMD decline continue into early menopause years at a rapid pace of 1.8~2.3% in the spine and 1.0~1.4% in the hip. The total BMD decline during the 5 years of late perimenopause to early postmenopause would be, on average, 7~10% in the spine and 5~7% in the hip, amounts that are associated with approximately 50~100% higher fracture rates.
• Bone turnover marker studies also show increased bone turnover markers with clear association with BMD loss in perimenopause, but not in post menopausal years.

• Changes of biochemical bone markers during the menopausal transition. Hilkea Rosenbrock, Vanadin Seifert-Klauss, Susanne Kaspar, Raymonde Busch, Peter B Luppa 2002 (Significant inverse correlations with the two years changes of the bone mineral density were found for bone ALP, CTX, OC and DPD in the perimenopausal group. The measurement of a comprehensive panel of biochemical bone markers clearly shows that metabolic changes in bone metabolism appear pronounced in the perimenopause, a period still presenting satisfactory estrogen supply.)
• Biochemical markers of bone turnover predict bone loss in perimenopausal women but not in postmenopausal women-the Japanese Population-based Osteoporosis (JPOS) Cohort Study., M Iki, A Morita, Y Ikeda, Y Sato, T Akiba, T Matsumoto, H Nishino, S Kagamimori, Y Kagawa, H Yoneshima 2006
• Bone turnover markers and bone density across the menopausal transition., P R Ebeling, L M Atley, J R Guthrie, H G Burger, L Dennerstein, J L Hopper, J D Wark 1996

• The transition does not have to be natural. A rapid drop rather than the absolute estrogen level seems to be the key. Withdrawal of hormone replacement therapy is associated with significant vertebral bone loss in postmenopausal women. F A Tremollieres, J M Pouilles, C Ribot 2001

Clearly, there is something more than estrogen that is affecting the bone health during the transition period.

1. Menopause and What Really Happens to your Bones
2. False Promise of Fosamax
3. Estrogen Paradox  <<You are here
   
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
9. How to Maintain Bone Health