Dr. Ron’s Research Review – December 2, 2015

©                                                                                                                 

This week’s research review focuses on estrogen deficiency and osteoporosis.

The unitary model for the pathogenesis of osteoporosis proposes that estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. In both genders, estrogen deficiency increases bone resorption and may also impair a compensatory increase in bone formation.  (Riggs et al., 1998) (Khosla et al., 2011)
The accelerated phase in women is most apparent during the first decade after menopause, involves disproportionate loss of cancellous bone (the spongy inner layer of bone that protects the bone marrow), and is mediated mainly by loss of the direct restraining effects of estrogen on bone cell function. The ensuing slow phase involves proportionate losses of cancellous and cortical bone, and is associated with progressive secondary hyperparathyroidism. This phase is mediated mainly by loss of estrogen action on extraskeletal calcium homeostasis which results in net calcium wasting and increases in the level of dietary calcium intake required to maintain bone balance.
Because elderly men have low circulating levels of both bioavailable estrogen and bioavailable testosterone and because recent data suggest that estrogen is at least as important as testosterone in determining bone mass in aging men, estrogen deficiency may also contribute substantially to the continuous bone loss of aging men.

Manolagas proposes a ‘‘revised’’ model of the pathogenesis of osteoporosis. This new model attempts a paradigm shift from the estrogen-centric account of the pathogenesis of involutional osteoporosis to one in which age-related mechanisms intrinsic to bone (specifically, oxidative stress) are the major driving force for bone loss throughout life, albeit aggravated by effects of sex steroid deficiency.

Dr. Ron


Articles

 

The unitary model for estrogen deficiency and the pathogenesis of osteoporosis: is a revision needed
            (Khosla et al., 2011) Download
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.

A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men.
            (Riggs et al., 1998) Download
We propose here a new unitary model for the pathophysiology of involutional osteoporosis that identifies estrogen (E) deficiency as the cause of both the early, accelerated and the late, slow phases of bone loss in postmenopausal women and as a contributing cause of the continuous phase of bone loss in aging men. The accelerated phase in women is most apparent during the first decade after menopause, involves disproportionate loss of cancellous bone, and is mediated mainly by loss of the direct restraining effects of E on bone cell function. The ensuing slow phase continues throughout life in women, involves proportionate losses of cancellous and cortical bone, and is associated with progressive secondary hyperparathyroidism. This phase is mediated mainly by loss of E action on extraskeletal calcium homeostasis which results in net calcium wasting and increases in the level of dietary calcium intake required to maintain bone balance. Because elderly men have low circulating levels of both bioavailable E and bioavailable testosterone (T) and because recent data suggest that E is at least as important as T in determining bone mass in aging men, E deficiency may also contribute substantially to the continuous bone loss of aging men. In both genders, E deficiency increases bone resorption and may also impair a compensatory increase in bone formation. For the most part, this unitary model is well supported by observational and experimental data and provides plausible explanations to traditional objections to a unitary hypothesis.

From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis.
            (Manolagas, 2010) Download
Estrogen deficiency has been considered the seminal mechanism of osteoporosis in both women and men, but epidemiological evidence in humans and recent mechanistic studies in rodents indicate that aging and the associated increase in reactive oxygen species (ROS) are the proximal culprits. ROS greatly influence the generation and survival of osteoclasts, osteoblasts, and osteocytes. Moreover, oxidative defense by the FoxO transcription factors is indispensable for skeletal homeostasis at any age. Loss of estrogens or androgens decreases defense against oxidative stress in bone, and this accounts for the increased bone resorption associated with the acute loss of these hormones. ROS-activated FoxOs in early mesenchymal progenitors also divert ss-catenin away from Wnt signaling, leading to decreased osteoblastogenesis. This latter mechanism may be implicated in the pathogenesis of type 1 and 2 diabetes and ROS-mediated adverse effects of diabetes on bone formation. Attenuation of Wnt signaling by the activation of peroxisome proliferator-activated receptor gamma by ligands generated from lipid oxidation also contributes to the age-dependent decrease in bone formation, suggesting a mechanistic explanation for the link between atherosclerosis and osteoporosis. Additionally, increased glucocorticoid production and sensitivity with advancing age decrease skeletal hydration and thereby increase skeletal fragility by attenuating the volume of the bone vasculature and interstitial fluid. This emerging evidence provides a paradigm shift from the "estrogen-centric" account of the pathogenesis of involutional osteoporosis to one in which age-related mechanisms intrinsic to bone and oxidative stress are protagonists and age-related changes in other organs and tissues, such as ovaries, accentuate them.


 

References

Khosla, S, LJ Melton, and BL Riggs (2011), ‘The unitary model for estrogen deficiency and the pathogenesis of osteoporosis: is a revision needed’, J Bone Miner Res, 26 (3), 441-51. PubMedID: 20928874
Manolagas, SC (2010), ‘From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis.’, Endocr Rev, 31 (3), 266-300. PubMedID: 20051526
Riggs, BL, S Khosla, and LJ Melton (1998), ‘A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men.’, J Bone Miner Res, 13 (5), 763-73. PubMedID: 9610739