Estrogen appears to be the main steroid hormone modulating bone mass in both men and women, and cir
culating estrogen levels correlate with fracture risk [31].
At the cellular level two estrogen receptor subtypes ERα and ERβ are widely expressed in multiple bone cell types including osteocytes, osteoblasts, and osteoclasts [32].
Decreased estrogen levels induce osteocyte apoptosis and increased release of inflammatory cytokines such as TNF‐α and interleukins 1 and 7, which promote osteoclastogenesis [32].
Estrogen itself may have antioxidant properties and loss of estrogen may induce MSC damage through increased levels of ROS thus impairing osteoblast differ
entiation [24, 26, 27]. Thus the net effect of decreased estrogen levels at the cellular level is increased osteocyte and osteoblast apoptosis, decreased osteoclast apoptosis, and increased RANKL‐mediated differentiation [33].
Menopause‐related bone loss is a result of four distinct mechanisms [34–36]: (i) a decline in the net amount of bone deposited by each BMU; (ii) a transitory increase in the volume of bone resorbed by each BMU; (iii) an increase in the rate of bone remodeling—greater numbers of BMUs remodel the skeleton and each resorbs more bone and deposits less because sex hormone deficiency increases the life span of osteoclasts and reduces the life span of osteoblasts [33]; and (iv) a reduction in periosteal apposition associated with continued intracortical, endo
cortical, and trabecular bone loss.
As estrogen levels decrease in women between the ages of 40 and 50 there is an increase in the number of BMUs.
This increase in BMUs in their resorptive phase results in enlargement of the remodeling space deficit in matrix and mineral. The appearance of many BMUs in their resorptive phase excavating bone is matched by the fewer
BMUs initiated before menopause only now entering their formation phase. This perturbation of surface level remodeling is responsible for the accelerated decline in BMD associated with the menopause (Fig. 21.1).
As the postmenopausal state continues, those large numbers of BMUs initiated in early menopause move into their reversal then refilling phase but now refilling is incomplete because of the increased resorption depth and reduced osteoblastic refilling. The worsening negative BMU balance produces continued bone loss but more slowly than in early menopause because remodeling at the surface level has returned to steady state at a higher rate of remodeling. The loss of bone is now driven only by the rapidity of remodeling and the negative BMU balance, not the perturbation of remodeling at the surface level occurring in early menopause.
Because BMUs are present on bone surfaces and tra
becular bone has a larger surface area, initial bone loss occurs more rapidly—a greater proportion of the smaller trabecular than cortical bone volume is remodeled and lost after menopause. However, despite the slower remodeling of cortical bone, the slower remodeling of the larger cortical bone volume results in more cortical than trabecular bone loss as women transition from pre‐ to perimenopausal, peri‐ to postmenopausal, and then advance in the postmenopausal years. Cortical bone loss accounts for ~70% of all peri‐ and postmenopausal bone loss [14, 37].
Increased bone remodeling results in an increase in bone fragility in several ways. The resorption pits act as stress risers while loss of trabeculae and loss of connectivity Steady state remodeling
before menopause is slow and refilling of cavities is
complete
Complete refilling of fewer resorption sites
generated before menopause
Increased numbers of resorption sites
Incomplete refilling of many resorption sites generated in early
menopause
Accelerated bone loss Menopause
BMD
Slower bone loss
Fig. 21.1. Loss of bone after menopause. Before menopause, remodeling is slow with small numbers of remodeling sites in their formation phase and others in their resorption phase. At menopause the number of remodeling sites in their resorptive phase increases while the fewer numbers in their formation phase before menopause now enter their refilling phase so BMD rapidly declines. Later in menopause a new steady state is achieved at the higher remodelling rate so that now more similar numbers of remodelling sites are being excavated and incompletely refilled (see text).
158 Menopause and Age‐related Bone Loss
reduce bone strength [38] (Fig. 21.2). Cortical porosity reduces bone strength as a seventh power function of the porosity; the loss of strength by increasing the porosity of an already porous structure like trabecular bone reduces strength to the third power [39]. By contrast, in men, trabecular remodeling results in thinning rather than perforation, a process that compromises trabecular strength less [12].
As trabeculae are lost with continued remodeling, the cortical compartment becomes the main source of bone loss leading to increased cortical porosity and
“ trabecularization” of cortical bone as discussed previously [40]. Increased intracortical bone surface area facilitates continued high remodeling predisposing to appendicular fractures. High remodeling also reduces matrix mineral density as older more mineralized bone is replaced by newer less mineralized bone. This results in a more heterogeneously mineralized bone and decreased strength (Fig. 21.3).
Periosteal apposition is believed to increase as an adap
tive response to compensate for the loss of strength pro
duced by endocortical bone loss, so there will be no net loss of bone, no cortical thinning, and no loss of bone strength [41]. In a prospective study of over 600 women, Szulc et al. reported that endocortical bone loss occurred
in premenopausal women with concurrent periosteal apposition [42]. Because periosteal apposition was less than endocortical resorption, the cortices thinned but there was no net bone loss because the thinner cortex was now distributed around a larger perimeter, conserv
ing total bone mass. Moreover, resistance to bending increased despite bone loss and cortical thinning because this same amount of bone was now distributed further from the neutral axis (Fig. 21.4).
During the perimenopausal period endocortical resorp
tion increased yet periosteal apposition decreased.
The cortices thinned but bending strength remained unchanged despite bone loss and cortical thinning because periosteal apposition was still sufficient to shift the thin
ning cortex outwards. Bone fragility emerged only after menopause when accelerated endocortical bone resorp
tion and deceleration in periosteal apposition produced further cortical thinning. As periosteal apposition was now minimal, there was little outward displacement of the thinning cortex so cortical area now declined as did resistance to bending. During aging, both increasing endocortical bone resorption and reduced periosteal apposition cause net bone loss, alterations in the distribu
tion of the remaining bone, and the emergence of bone fragility [43].
Loss of strength
Number
% Density reduction Thickness
1.00
0.75
0.50
0.25
00 5 10 15
25%
60%
Fig. 21.2. Upper panels: trabecular platelike structure (left) and loss of trabecular connectivity (right). Perforation of trabeculae results in loss of connectivity which reduces strength more greatly than trabecular thinning (lower panel). Source: adapted from [12].
Reproduced with permission of John Wiley and Sons.
250 200 150 100 50
00 0.2 0.4 0.6 Porosity Ultimate stress
0.8 1.0 MPA
Fig. 21.3. Cortical porosity in specimens from 27‐year‐old, 70‐year‐old, and 80‐year‐old cadavers progressing from top, illustrating thinning of the cortex from within by intracortical remodeling. This is associated with a decline in ultimate stress. MPA = megapascal.
Source: adapted from [14]. Reproduced with permission of Elsevier.
*** *** ***
** **
** ***
*
*
*
***
Pre Peri Post
70 35 0 –356
0
–6 Change in
radius (mm/year)
Section modulus (mm3/year)
<0.05
Endocortical resorption
Periosteal apposition Net cortical width
Fig. 21.4. The amount of bone resorbed by endocortical resorption increases with age. The amount deposited by periosteal apposition decreases. The net effect is a decline in cortical thickness. In premenopausal women, the thinner cortex is displaced radially, increasing section modulus (Z). In perimenopausal women Z does not decrease despite cortical thinning because periosteal apposition still pro
duces radial displacement. In postmenopausal women, Z decreases because endocortical resorption continues, periosteal apposition declines, and little radial displacement occurs. Source: adapted from [42]. Reproduced with permission of John Wiley and Sons.
160 Menopause and Age‐related Bone Loss
SUMMARY
Bone loss resulting in bone fragility was thought to occur through two distinct mechanisms and lead to type I ( postmenopausal) or type II (age‐related or involutional) osteoporosis [44]. Increased understanding of the under
lying cellular mechanisms involved in bone loss reveals a common mechanism—the appearance of a negative BMU balance, the necessary and sufficient cause of bone loss, and microstructural deterioration producing bone fragility. After menopause, the negative BMU balance worsens, perhaps transiently but with rapid remodeling;
there is accelerated loss of trabecular and cortical bone.
The greater rapidity of remodeling compromises both compartments of bone: trabecular bone is lost more rap
idly, but in absolute terms the slower loss of the larger volume of cortical bone results in greater loss of cortical than trabecular bone and increased risk for fractures of the axial and appendicular skeleton.
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Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Ninth Edition. Edited by John P. Bilezikian.
© 2019 American Society for Bone and Mineral Research. Published 2019 by John Wiley & Sons, Inc.
Companion website: www.wiley.com/go/asbmrprimer