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The unitary model for estrogen deficiency and the pathogenesis of osteoporosis: Is a revision needed?

Khosla, Sundeep, Melton, L Joseph, Riggs, B Lawrence·2011·Journal of Bone and Mineral Research
DOI 10.1002/jbmr.262PMC PMC3179298
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Abstract

Over a decade ago, we proposed a “unitary” model for the pathogenesis of osteoporosis that identified estrogen deficiency as the predominant cause of both the early, accelerated, and late slow phases of bone loss in postmenopausal women and as a contributing cause of the continuous phase of bone loss in aging men. While this was a plausible model then, new data over the intervening years suggest a need to modify these concepts. Indeed, based largely on rodent studies, a “revisionist” view of the pathogenesis of osteoporosis has been proposed recently that attempts a paradigm shift from the estrogen-centric model to one in which bone loss is largely independent of estrogen deficiency and is driven instead by cell-autonomous age-related factors. However, detailed clinical investigative studies using quantitative computed tomography demonstrate that the onset of cortical bone loss in humans is closely tied to estrogen deficiency; thus the estrogen-centric view is likely correct for cortical bone, which comprises over 80% of the skeleton and is the major structural determinant of fracture risk at most skeletal sites. By contrast, these same studies also demonstrate that trabecular bone loss begins in sex hormone–replete young adults of both sexes. This suggests that a significant proportion of trabecular bone loss is either estrogen-independent or, as suggested by some studies, requires higher levels for its regulation. In this perspective, we critically review these and other findings, leading us to conclude that our original model requires modification but not revision. © 2011 American Society for Bone and Mineral Research.

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Fig. 1 (A) Values for cortical vBMD at the distal radius in a population sample of Rochester, MN, women and men between the ages of 20 and 97 years. Individual values and smoother lines are given for premenopausal women in red, for postemenopausal women in blue, and for men in black. (B) Values for vertebral trabecular vBMD in the same cohort. Color code is as in panel A. All changes with age were significant (p < .05). (Reproduced from Riggs et al.(4))
Fig. 1 (A) Values for cortical vBMD at the distal radius in a population sample of Rochester, MN, women and men between the ages of 20 and 97 years. Individual values and smoother lines are given for premenopausal women in red, for postemenopausal women in blue, and for men in black. (B) Values for vertebral trabecular vBMD in the same cohort. Color code is as in panel A. All changes with age were significant (p < .05). (Reproduced from Riggs et al.(4))CC BY · PubMed Central
Fig. 2 (A) Age-specific changes in cortical vBMD at the distal radius and tibia in women. Data are shown with a smooting spline and the 95% CI. Premenopausal women (solid lines) are plotted against age in years, whereas postmenopausal women (broken lines) are plotted against years since menopause. (B) Corresponding changes in trabecular vBMD at the distal radius and distal tibia. (Adapted from Riggs et al.(5))
Fig. 2 (A) Age-specific changes in cortical vBMD at the distal radius and tibia in women. Data are shown with a smooting spline and the 95% CI. Premenopausal women (solid lines) are plotted against age in years, whereas postmenopausal women (broken lines) are plotted against years since menopause. (B) Corresponding changes in trabecular vBMD at the distal radius and distal tibia. (Adapted from Riggs et al.(5))CC BY · PubMed Central
Fig. 3 (A) Trabecular bone volume/total volume (BV/TV) and (B) cortical vBMD (Ct vBMD) in 6-month-old (control) mice, aged/sham-operated mice, aged/ovariectomized (ovx) mice, and aged/ovariectomized mice replaced throughout life with physiologic doses of estradiol using continuous-release pellets (aged/ovx/E). *p < .05; **p < .01; and ***p < .001 versus young controls. (Adapted from Syed et al.(13))
Fig. 3 (A) Trabecular bone volume/total volume (BV/TV) and (B) cortical vBMD (Ct vBMD) in 6-month-old (control) mice, aged/sham-operated mice, aged/ovariectomized (ovx) mice, and aged/ovariectomized mice replaced throughout life with physiologic doses of estradiol using continuous-release pellets (aged/ovx/E). *p < .05; **p < .01; and ***p < .001 versus young controls. (Adapted from Syed et al.(13))CC BY · PubMed Central
Fig. 4 Schematic illustration, based on the data of Khosla and colleagues,(36) of the relationship between (A) cortical vBMD and (B) trabecular vBMD and serum estradiol levels. Note that while cortical vBMD is correlated with estradiol levels at low estradiol levels, no relationship is evident at high estradiol levels, consistent with a threshold below which cortical bone becomes estrogen-deficient. By contrast, trabecular vBMD remains correlated with estradiol levels at low and high serum estradiol levels, suggesting either the absence of a threshold or a threshold considerably higher than that present for cortical bone. Shown also are the relative changes in cortical (▵cort) and trabecular (▵trab) bone as estrogen levels fall from estrogen sufficiency (point A) to estrogen deficiency (point B).
Fig. 4 Schematic illustration, based on the data of Khosla and colleagues,(36) of the relationship between (A) cortical vBMD and (B) trabecular vBMD and serum estradiol levels. Note that while cortical vBMD is correlated with estradiol levels at low estradiol levels, no relationship is evident at high estradiol levels, consistent with a threshold below which cortical bone becomes estrogen-deficient. By contrast, trabecular vBMD remains correlated with estradiol levels at low and high serum estradiol levels, suggesting either the absence of a threshold or a threshold considerably higher than that present for cortical bone. Shown also are the relative changes in cortical (▵cort) and trabecular (▵trab) bone as estrogen levels fall from estrogen sufficiency (point A) to estrogen deficiency (point B).CC BY · PubMed Central

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Cited by

Metadata

Authors
Khosla, S., Melton, L. J., & Riggs, B. L.
Affiliations
Endocrine Research Unit, College of Medicine, Mayo Clinic, Rochester, MN, USA
Venue
Journal of Bone and Mineral Research
Publisher
Oxford University Press (OUP)
Published
2010-10-06
Volume
26
Issue
3
Pages
441-451
ISSN
  • 0884-0431
  • 1523-4681
DOI
10.1002/jbmr.262
PMC
PMC3179298
Cited by
305
References
16
Language
en
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)

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