Pathogenesis of osteoporosis pdf

Menstrual history as a determinant of current bone density in young athletes. Interac- Research directions in osteoporosis. Am J Med. Involutional osteoporosis. In: Oxford Textbook of Geriatric Medicine. Oxford University Press, Oxford, — Kanis JA, Passmore R. Calcium supplementation of the diet, II: not justified by present evidence. Br Med J. Muscle strength, physical fitness, and weight but not age predict femoral neck bone mass. J Bone Min Res. Krolner B, Toft B.

Vertebral bone loss: an unheeded side effect of therapeutic bed rest. Clin Sci. PubMed Google Scholar. Evidence of estrogen receptors in normal human osteoblast-like cells. Risk factors for spinal osteoporosis in men. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for personal use for details see Privacy Policy and Legal Notice.

Oxford Medicine Online. Publications Pages Publications Pages. Recently viewed 0 Save Search. Osteoporosis Oxford Rheumatology Library 2 ed. Richard W. Keen Richard W. Google Preview. Moreover, DXA cannot separate the more metabolically active, trabecular bone from the more structurally important cortical bone. To circumvent these problems, recent studies have used quantitative computed tomography QCT , along with newer image analysis tools, to assess age- and sex-specific changes in vBMD, bone size, geometry and structure at various skeletal sites.

Somewhat surprisingly, decreases in trabecular vBMD began before midlife and continued throughout life in both sexes Figure 3A , whereas cortical vBMD decreases began in midlife Figure 3B.

With aging, cortical area decreased slightly, and the cortex was displaced outwardly by periosteal and endocortical bone remodeling. These cross-sectional changes were subsequently confirmed by longitudinal data, which provided essentially identical results, including the documentation of substantial trabecular bone loss at multiple sites beginning in the third decade, well before the menopause in women or the onset of significant sex steroid deficiency in men Collectively, these findings indicate that age-related changes in bone are complex.

Some are beneficial to bone strength, such as periosteal apposition with outward cortical displacement. However, others are deleterious, such as increased endocortical resorption, increased cortical porosity, and large decreases in trabecular and cortical vBMD.

Individual values and smoother lines are given for premenopausal women in red, for postmenopausal women in blue, and for men in black. B Values for cortical vBMD at the distal radius in the same cohort. Color code is as in Panel A. Reproduced from Riggs et al. The recent application of high resolution peripheral QCT HRpQCT at the distal radius and tibia has also provided important new information on changes in trabecular and cortical microstructure with aging.

Over life, women undergo loss of trabeculae with an increase in TbSp, whereas men being young adult life with thicker trabeculae and primarily sustain trabecular thinning, with no net change in TbN or TbSp.

This has important biomechanical consequences, since decreases in TbN have been shown to have a much greater impact on bone strength as compared with decreases in TbTh These findings may help explain the lower life-long risk of fractures in men, and specifically their virtual immunity to age-related increases in distal forearm fractures.

To summarize, much of adult bone mass is achieved during childhood and particularly during adolescent growth. During this period, there is also a reproducible across multiple populations increase in fractures, predominantly of the distal radius, which appears to be due to transient decreases in cortical thickness and increase in cortical porosity 11 , at least at this site. By contrast, cortical bone remains stable in both sexes until the menopause in women and somewhat later in life in men, with subsequent decreases in cortical bone present in both sexes.

At a microstructural level, women lose bone primarily via decreases in trabecular numbers i. Albright and colleagues 21 initially postulated almost 70 years ago that osteoporosis in aging women was related to the postmenopausal state and estrogen deficiency and showed that estrogen treatment improved calcium balance in postmenopausal women. Using photon absorptiometry at the metacarpals, Lindsay et al. Subsequent work has now clearly demonstrated the importance of the menopause and estrogen deficiency as perhaps the major contributor to age-related bone loss in women, and this is illustrated well by the clinical example provided as Case 3 in Chapter 1.

Serum testosterone levels also decrease following the menopause, but this decrease is more modest, since testosterone continues to be produced by the adrenal cortex as well as the interstitial cells of the ovary The observed decrease in bone mass at multiple sites is associated with marked increases in biochemical markers of bone resorption, whereas markers of bone formation increase to a lessor extent Figure 4 , consistent with increased bone resorption as well as a relative deficit in bone formation in the setting of estrogen deficiency that leads to bone loss.

The rapid bone loss during the early postmenopausal years produces an increased flux of calcium from bone into the extracellular pool, but hypercalcemia does not develop due to compensatory increases in urinary calcium excretion 25 and decreases in intestinal calcium absorption 26 as well as decreases in parathyroid hormone PTH secretion Reproduced from Garnero et al.

The homeostatic mechanisms limiting the early, rapid phase of bone loss following the menopause in women are still not well understood. One possibility is that once sufficient bone is lost, increased mechanical strain on cells specifically, osteocytes embedded within bone may trigger compensatory pathways to limit bone loss Nonetheless, ongoing estrogen deficiency in women is associated with progressive loss of trabecular and cortical bone.

The effects of estrogen deficiency are compounded later in life by the onset of secondary hyperparathyroidism, since aging in women and in men, see below is associated with a progressive increase in serum PTH levels Indeed, formal studies of parathyroid secretory dynamics by sequential infusions of calcium or EDTA have shown that, compared with young adult women, elderly women have greater basal, maximal, and non-suppressible levels of PTH secretion without alterations in the set-point for PTH secretion These functional properties are characteristic of parathyroid hyperplasia, and are consistent with a histological autopsy study showing a trend to parathyroid hyperplasia in elderly women and men The increase in PTH secretion with aging in women clearly contributes to the increase in bone turnover and bone loss, since McKane et al.

The increase in PTH with age in women and in men is likely due to multiple causes. As discussed in detail in Chapter 1, vitamin D deficiency is a significant problem among the elderly and certainly plays a major role It is also evident, however, that estrogen deficiency itself may contribute to age-related increases in PTH levels due to loss of the positive effects of estrogen on non-skeletal calcium homeostasis — specifically, on enhancing intestinal 26 and renal 34 calcium absorption.

Thus, the chronic loss of these extraskeletal actions of estrogen results in ongoing calcium wasting and ultimately, contributes to the development of secondary hyperparathyroidism. While estrogen deficiency is associated with increased bone resorption and a compensatory albeit insufficient increase in bone formation Figure 4 , recent studies in humans have directly demonstrated the importance of estrogen not only in suppressing bone resorption, but also in maintaining bone formation.

Thus, as shown in Figure 5 , acute estrogen deficiency is associated, as expected, with an increase in bone resorption markers; however, in contrast to chronically estrogen deficient women who have had time to mount a compensatory increase in bone formation 35 , following acute estrogen deprivation, bone formation markers decrease significantly Conversely, Hannon and colleagues 37 have shown that while chronic estrogen treatment is associated with reductions in bone resorption and formation markers, early after estrogen treatment, bone resorption markers fall, whereas bone formation markers actually increase.

Collectively, these data in women, which are further supported by studies in men see below provide convincing evidence that estrogen not only suppresses bone resorption, but is also critical for the maintenance of bone formation. Following estrogen deficiency, bone resorption increases, and due to the coupling of bone resorption and bone formation 38 , bone formation also increases over time; however, due to the absence of estrogen, there is a persistent gap between bone resorption and bone formation, leading to the observed bone loss.

A Short term increase in the bone resorption marker, serum C-telopeptide of type I collagen CTx and decrease in the bone formation marker, serum N-terminal propeptide of type I collagen PINP following the acute induction of estrogen deficiency in postmenopausal women adapted from While men do not have the equivalent of the menopause, total testosterone levels do decline with aging 39 , More importantly, a number of studies have now demonstrated that the biologically available fraction of testosterone and estrogen i.

The precise cause s for the age-related increase in SHBG levels remains unclear at present, but may be related, at least in part, to declining IGF-I levels.

Although both serum free or bioavailable testosterone and estradiol levels decline with age in men, it had generally been believed that because testosterone is the major sex steroid in men, it was the decrease in bioavailable testosterone levels that would be associated most closely with bone loss in men. Subsequent to this report, other similar cross-sectional studies have demonstrated significant positive associations between BMD by DXA and estrogen levels in men 39 , 42 — 47 , particularly circulating bioavailable estradiol levels.

These cross-sectional findings have subsequently been validated by longitudinal data. Thus, we 48 studied, in a longitudinal manner, elderly 60 to 90 years men in whom rates of change in BMD using DXA at various sites over 4 years were related to sex steroid levels. Forearm sites distal radius and ulna provided the clearest data, perhaps because of the greater precision of peripheral site measurements as compared with central sites, such as the spine or hip.

BMD at the forearm sites declined by 0. Above this level, there did not appear to be any relationship between the rate of bone loss and bioavailable estradiol levels. Similar findings were reported by Gennari and colleagues 49 where, in a cohort of elderly Italian men, those subjects with serum free estradiol levels below the median value lost bone over 4 years at the lumbar spine and femur neck, whereas the men with free estradiol levels above the median did not lose bone.

Moreover, at least in men, serum estradiol levels measured by either a sensitive radioimmunoassay or by tandem mass spectroscopy provided virtually identical correlations with BMD While these studies helped to establish that estrogen levels are associated with skeletal maintenance in males, they could not definitively establish causal relationships. In order to address this issue, Falahati-Nini et al. Endogenous estrogen and testosterone production were suppressed in 59 elderly men using a combination of a long acting GnRH agonist and an aromatase inhibitor.

Physiologic estrogen and testosterone levels were maintained by simultaneously placing the men on estrogen and testosterone patches delivering doses of sex steroids that mimicked circulating estradiol and testosterone levels in this age group.

Since gonadal and aromatase blockade was continued throughout the 3 week period, separate effects of estrogen versus testosterone in the absence of aromatisation to estrogen on bone metabolism could be delineated. Estrogen alone Group B was almost completely able to prevent the increase in bone resorption, whereas testosterone alone Group C was much less effective. Using a somewhat different design, Leder et al.

Percent changes in A bone resorption markers urinary deoxypyridinoline [Dpd] and N-telopeptide of type I collagen [NTx] and B bone formation markers serum osteocalcin and N-terminal extension peptide of type I collagen [PINP] in a group of elderly men mean age 68 yrs made acutely hypogonadal and treated with an aromatase inhibitor Group A , treated with estrogen alone Group B , testosterone alone Group C , or both Group D.

See text for details. Adapted from Falahati-Nini et al. The reductions in both osteocalcin and PINP levels with the induction of sex steroid deficiency Group A were prevented with continued estrogen and testosterone replacement Group D.

Interestingly, serum osteocalcin, which is a marker of function of the mature osteoblast and osteocyte 54 , was maintained by either estrogen or testosterone ANOVA P values of 0. Collectively, these findings provided conclusive proof of an important and indeed, dominant role for estrogen in bone metabolism in the mature skeleton of adult men.

Moreover, several recent studies have now extended these findings and evaluated the relative role of estrogens and androgens on fracture risk in men. Thus, Amin and colleagues 56 related sex steroid levels in aging men from the Framingham Study to the risk for hip fractures.

In this study, men mean age, 71 years evaluated between and were followed until the end of The men were stratified into 3 groups, according to serum estradiol and testosterone levels.

Based on 39 men who sustained a hip fracture during follow up, incidence rates for hip fracture per person-years were Following adjustment for age, body mass index, height, and smoking status, the adjusted hazard ratios HRs for men in the low and middle estradiol groups, relative to the high estradiol group, were 3. By contrast, in similar adjusted analyses evaluating men by their testosterone levels, the investigators found no significant increased risk for hip fracture associated with low testosterone levels.

Somewhat contrasting findings were reported from men in the Dubbo cohort by Meier and colleagues 57 who found that while serum testosterone was not related to lumbar spine or femoral neck BMD in men over the age of 60 years, lower testosterone levels were stronger predictors of low trauma fractures than were estradiol levels, despite the fact that estradiol was significantly associated with spine and hip BMD in these men.

The most definitive data addressing this issue have come from the MrOS cohort. In multivariable proportional hazards regression models, free estradiol and sex hormone binding globulin SHBG , but not free testosterone, were independently associated with fracture risk. In further subanalyses, free estradiol was inversely associated with clinical vertebral fractures HR per SD decrease, 1.

Furthermore, consistent again with a threshold effect, the inverse relation between serum estradiol and fracture risk was non-linear. LeBlanc et al. Taken together, these studies using fracture as outcomes have provided further support for a key role for estradiol in determining fracture risk in aging men, as well as the presence of a threshold estradiol level which may vary, depending on the particular assay used below which fracture risk increases in men. Testosterone may also contribute to fracture risk, particularly in the setting of high SHBG levels.

Moreover, it is probable that a significant component of the testosterone effect on risk of fracture is mediated by non-skeletal effects, such as on muscle mass, balance, or risk of falls, although further studies directly addressing this issue are needed. In addition to sex steroids, a number of other endocrine pathways have recently been linked with bone loss in both experimental and clinical studies.

Thus, Sun et al. In contrast to these findings, studies by a different group with the identical FSH-receptor null mice used by Sun et al.

Moreover, recent findings demonstrate that at least in men, sex steroid deficiency alone is sufficient to increase bone resorption markers, even in the setting of suppressed FSH levels Thus, the precise role of increases in FSH with aging in women and in men in mediating age-related bone loss remains unclear at this time.

Recent studies also indicate that inhibins A and B, which decline following the menopause in women and with aging in men, may also regulate bone metabolism.

Thus, declining inhibin levels correlate with bone turnover markers in perimenopausal women 64 , and in vitro studies have found that inhibins suppress osteoblast and osteoclast development Considerable attention has also recently been focused on the possible role of serotonin in bone metabolism.

In a cross-sectional analysis of MrOS data, Haney et al. By contrast, other antidepressants trazodone hydrochloride, tricyclic antidepressants were not associated with decreased BMD. These clinical findings are of particular interest given recent provocative data by Yadav and colleagues 67 showing that duodenum-derived serotonin inhibits bone formation, unveiling perhaps an entirely novel entero-skeletal regulatory system.

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