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Pathogenesis of osteoporosis

Pathogenesis of osteoporosis
Literature review current through: Sep 2023.
This topic last updated: Jan 27, 2022.

INTRODUCTION — Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fractures. Throughout life, older bone is periodically resorbed by osteoclasts at discrete sites and replaced with new bone made by osteoblasts. This process is known as remodeling. Remodeling is orchestrated and targeted to a particular site that is in need for repair by osteocytes [1]. An oversupply of osteoclasts relative to the need for remodeling or an undersupply of osteoblasts relative to the need for cavity repair are the seminal pathophysiological changes in osteoporosis [2,3].

The amount of bone mass accrued by an individual reaches a peak by the third decade of life. Low peak bone mass probably contributes to the development of osteoporosis later in life. However, old age, sex steroid deficiency, lipid oxidation, decreased physical activity, use of glucocorticoids, and a propensity to fall are the most critical determinants of increased fracture risk.

This topic will address each of these pathogenetic factors and, when it is known, how they interact with each other. Bone remodeling and osteoporotic fracture risk assessment are reviewed separately. (See "Normal skeletal development and regulation of bone formation and resorption" and "Osteoporotic fracture risk assessment".)

DEFINITION — Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fractures. Although osteoporosis (a term used to define decreased bone mass per unit volume of anatomical bone) has become synonymous with decreased bone mineral density (BMD), this feature is not always present. Small bone size, unfavorable macroarchitecture (eg, increased length of the femoral neck), disrupted microarchitecture (image 1 and figure 1), cortical porosity, compromised quality of the material, and decreased viability of osteocytes (former osteoblasts buried within mineralized bone that sense and respond to changes in mechanical forces) are some other factors contributing to decreased strength.

The diagnosis of osteoporosis or estimates of the risk for developing it in the future rely almost exclusively on measures of bone mass by imaging studies such as dual-energy x-ray absorptiometry (DXA) (table 1) and quantitative computed tomography (QCT). These measures are fairly good clinical surrogates, but it is important to remember that the disease is bone fragility, and decreased BMD on DXA is just one of many risk factors. (See "Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women" and "Clinical manifestations, diagnosis, and evaluation of osteoporosis in men".)

PEAK BONE MASS ACQUISITION — Peak bone mass is the maximum bone mass achieved in life. The time of peak bone mass is not known with certainty, but probably occurs in the third decade of life in most individuals, with differences in timing due to genetic, hormonal, and environmental variables and to skeletal site (type of bone) and method of bone mineral density (BMD) measurement.

Genetics — A portion of the variation in BMD among humans has a genetic basis. Genome-wide association studies have so far identified approximately 518 genetic loci that influence BMD [4]. A remarkable number of these loci are involved in some aspect of Wnt/beta-catenin signaling, the receptor activator of nuclear factor kappa-B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) axis, or in mesenchymal cell differentiation. (See "Normal skeletal development and regulation of bone formation and resorption".)

A large-scale genome-wide association study meta-analysis has identified 15 genetic determinants of fracture, all of which also influenced BMD [5].

Ethnic variation — African Americans have higher and Asian Americans have lower BMD than White Americans, and African Americans have lower fracture rates at many skeletal sites, including hip, clinical vertebral, upper and lower appendages. Hispanic Americans and Asian Americans also have lower hip fracture rates than White Americans, and the difference for Hispanic Americans may depend on skeletal site. Importantly, BMD differences tend to be reduced in magnitude or removed if adjusted for body size differences [6].

Environmental factors — Acquisition of optimal bone mass is largely a reflection of increases in body size and skeletal loads mainly arising from muscle forces actuating bony levers such that limb muscle mass should be a reasonable measure of skeletal load. As children grow, they gain both body weight and muscle mass, with increasing muscle strength [7]. Optimizing bone strength during this time has an impact on future risk of fracture. Unfavorable body composition during sexual maturation may result in sub-optimal bone strength in both early adulthood and later life. Nevertheless, peak muscle growth occurs before peak in bone growth, and bone growth is not driven by muscle growth. Therefore, the importance of the muscle bone unit (MBU) for bone acquisition remains unclear.

Physical activity during childhood augments bone mass and density, but preservation of the increased BMD requires continued physical activity. Conversely, chronic diseases during childhood pose numerous threats to bone health, resulting in either immediate fragility fractures or subsequent fractures in adulthood caused by suboptimal peak bone mass [8]. Risk factors for impaired bone accrual in such children include:

Poor growth

Delayed maturation

Malnutrition

Muscle deficits

Decreased physical activity

Chronic inflammation

Medications such as glucocorticoids

AGE-RELATED BONE LOSS — Old age and estrogen deficiency are the two most critical factors for the development of osteoporosis in both women and men. However, it is unknown whether the cellular and molecular events responsible for the imbalance between resorption and formation in old age versus sex steroid deficiency are similar or distinct, or whether and how much sex steroid deficiency contributes to the age-dependent involution of the skeleton. Because of the abrupt decline of ovarian function at menopause in women and a slower decline of both androgen and estrogen levels in men with advancing age, the two conditions inexorably overlap, making it impossible to dissect their independent contribution to the cumulative anatomic deficit. Findings from the mouse model suggest that the adverse effects of old age on the skeleton are independent of estrogens and are due to molecular mechanisms that are distinct from those responsible for the effects of sex steroid deficiency [9-11]. Such bone-intrinsic molecular mechanisms likely include mitochondria dysfunction, oxidative stress, declining autophagy, DNA damage, osteoprogenitor and osteocyte senescence, senescence-associated secretory phenotype (SASP), and lipid peroxidation [12].

In both women and men, the balance between bone formation and resorption becomes progressively negative with advancing age (figure 2). Age-related bone loss begins immediately after peak bone mass for either sex, but most bone loss occurs after age 65 years. Men, however, are less likely to develop osteoporosis than women for two reasons. First, they gain more bone during puberty, and second, they lose less bone during aging because, unlike women, men do not experience an abrupt loss of estrogens. Older residents in long-term care have the greatest risk. Eighty-five percent of nursing home women over age 80 years have osteoporosis. Hip and nonvertebral fractures in older residents of nursing homes are 2.5 to 3.5 times more common than in the community [13].

Most fractures after age 65 years occur at predominantly cortical sites. High-resolution peripheral quantitative computed tomography (HRpQCT) of the radius and postmortem femurs of women between ages 50 and 80 years has revealed that most bone loss in old age is the result of increased intracortical porosity (figure 3) [14]. Importantly, the age-dependent increase in cortical porosity is not captured by dual-energy x-ray absorptiometry (DXA) bone mineral density (BMD) [15].

Besides its effects on bone mass, aging increases the risk of fractures, independently of bone mass, as highlighted by evidence that for the same BMD, a 20-year increase in age is accompanied by a fourfold increase in fracture risk (figure 2) [16]. Consistent with this, human cadaveric specimens demonstrate significant declines in whole bone strength with age, with younger specimens being 3- to 10-fold stronger than older specimens. Furthermore, population-based studies with 3D-QCT imaging have demonstrated significantly greater declines in vertebral compressive strength over life in women than men (-43 versus -31 percent). Declines in femoral strength in a sideways fall configuration are also significantly greater in women than men (-55 versus -39 percent) and exceed the declines in femoral BMD (-26 and -21 percent for women and men, respectively). In addition, cortical porosity increases by 176 percent and 259 percent from 20 to 90 years of age (figure 3).

Muscle strength and power decline 10 to 20 percent per decade after age 50 years. These declines obviously impact the risk of falls, and perhaps the severity of falls, but may also influence loads applied to vertebral bodies during daily activities. The influence of muscle strength on vertebral body compressive forces depends on the activity being performed. Vertebral compressive forces may remain unchanged, decrease, or greatly increase with reduced muscle strength. (See "Falls in older persons: Risk factors and patient evaluation" and "Falls: Prevention in community-dwelling older persons" and "Vitamin D and extraskeletal health", section on 'Falls'.)

Oxidative stress – Oxidative stress is a shared mechanism of the pathogenesis of several degenerative disorders associated with aging, including osteoporosis [17,18]. An increase in reactive oxygen species (ROS) has been implicated in the decreased bone formation associated with advancing age, as well as the increased resorption associated with estrogen deficiency [18]. In line with this evidence, increased ROS production in osteoblasts stimulates apoptosis and decreases bone formation. On the other hand, ROS, and in particular, H2O2, is a critical requirement for receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast generation, activation, and survival [19]. (See "Normal skeletal development and regulation of bone formation and resorption".)

Osteoblast and osteocyte senescence – Cellular senescence is a process in which cells stop dividing and undergo distinctive phenotypic alterations, including profound chromatin and secretome changes termed senescence-associated secretory phenotype (SASP) [20]. Nonproliferating, terminally differentiated cells also become senescent and exhibit the SASP. Cellular senescence is one of the hallmarks of aging in most, if not all, tissues [21]. Osteoblast progenitors as well as osteocytes from old mice exhibit typical features of cellular senescence [22-24]. Furthermore, cellular senescence of osteoprogenitors is associated with a decline in their number by more than 50 percent between 6 and 24 months of age in both female and male mice, as well as increased production of SASP-associated pro-osteoclastogenic cytokines, such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1-alpha, matrix metalloproteinase 13 (MMP13), CXCL12, and RANKL. Senescent osteocytes similarly exhibit SASP, including some of the same cytokines found in the osteoprogenitors. Notably, RANKL derived from senescent osteocytes is required for the age-associated cortical bone loss in mice [25]. Prevention of apoptosis by deleting Bak and Bax, two genes essential for apoptosis, in osteoblasts and osteocytes greatly potentiates the effects of old age on cortical porosity [26]. Notably, attenuation of apoptosis stimulates cellular senescence [27,28]. Increased production of SASP cytokines by senescent, apoptotic, or dysfunctional osteocytes and probably their affected neighbors (paracrine senescence), stimulate osteoclastogenesis, matrix degradation, focal bone resorption, and cortical porosity.

Autophagy – Autophagy is a major adaptive response to cellular starvation and an essential protein/organelle quality control. Declining autophagy with advancing age is a big component of the loss of proteostasis, another one of the hallmark mechanisms of aging. Attenuation of autophagy in osteocytes, by conditional deletion of the ATG7 gene, recapitulates most of the effects of old age in six-month-old mice, including cortical porosity. Along with several other lines of evidence [29-31], these findings support of the general idea that in line with the seminal role of osteocytes in the choreography of physiologic bone remodeling, in conditions of overwhelming stress, the physiological mechanisms of bone repair are exaggerated and become disease mechanisms [12].

SEX STEROID DEFICIENCY — Estrogen or androgen deficiency causes loss of bone associated with an increase in the bone remodeling rate, increased osteoclast and osteoblast numbers, and increased resorption and formation, albeit unbalanced. Conversely, estrogens or androgens decrease bone resorption, restrain the rate of bone remodeling, and help to maintain a focal balance between bone formation and resorption. These effects are the result of hormonal influences on the birth rate of osteoclast and osteoblast progenitors in the bone marrow, as well as pro-apoptotic effects on osteoclasts and anti-apoptotic effects on mature osteoblasts and osteocytes [2,3,18]. (See "Normal skeletal development and regulation of bone formation and resorption".)

Estrogen — The onset of cortical bone loss in women is closely tied to estrogen deficiency, attesting to the adverse effect of estrogen deficiency on skeletal homeostasis and its contribution to the age-associated bone loss [32]. However, a significant proportion of trabecular bone loss throughout life is age related and estrogen independent [18,32]. The age-dependent loss of trabecular bone in the spine accelerates after the menopause, as does the rate of fractures at the wrist, spine, and hip. Between menopause and the age of 75 years, women lose approximately 22 percent of their total body bone mineral. It has been estimated that of this, 13.3 percent is due to aging and 7.75 percent is due to estrogen deprivation. In the femoral neck, 14 percent of the loss is "age related" and only 5.3 percent because of estrogen deprivation [33].

The accelerated phase of cancellous (trabecular) bone loss caused by menopause results predominantly from trabecular perforation and loss of connectivity (image 1 and figure 1). This phase is followed a few years later by a phase of slower bone loss that primarily affects cortical sites. The slower phase occurs in both women and men and is associated with a decrease in osteoblast number and bone formation rate and reduced number of trabeculae. In line with this, decreased wall width, the hallmark of decreased osteoblast work output, is the most consistent histological finding in older women and men with osteoporosis [34-36].

Estrogen deficiency also contributes to the development of osteoporosis in men [37,38]. Estrogens derived from androgen aromatization and acting via the estrogen receptor (ER) are important for skeletal homeostasis in men, as evidenced by bone abnormalities in men with ER or aromatase mutations, as well as results of short-term clinical experimentation with administration of aromatase inhibitors [39]. In addition, several clinical studies show correlation between a decrease in bioavailable estradiol, but not testosterone, and bone mass in older men [32]. Studies of mouse models with targeted deletion of the ER and the androgen receptor (AR) in specific cell types have elucidated that the antiresorptive effects of estrogens or androgens in the cancellous versus the cortical bone compartment are mediated by different cell types [40-42]. The protective effect of estrogens on the cancellous bone compartment are mediated via signaling through the ER-alpha expressed in cells of the osteoclast lineage [43,44]. On the other hand, ER-alpha signaling in cells of the osteoblast lineage is responsible for the protective effect of estrogens against endocortical resorption in females, but it plays no role in their effects on cancellous bone resorption. Whether ER-alpha also plays a role on cancellous or cortical bone formation remains controversial [41,45-48].

Importantly, whereas the accelerated cancellous (trabecular) bone loss caused by estrogen deficiency at menopause results predominantly from trabecular perforation and loss of connectivity, the later phase of slower bone loss that occurs in both older women and men primarily affects cortical sites and is associated with a decrease in osteoblast number and bone formation rate [49]. Additionally, bone loss in older men is associated with trabecular thinning rather than perforation [50].

Androgens — Androgens are critical for the homeostasis of the male skeleton in humans as evidenced by the low bone mass of men with idiopathic hypogonadotropic hypogonadism or complete androgen insensitivity syndrome. (See "Etiology of osteoporosis in men".)

As in the case of estrogens, the effects of androgens on the cancellous and cortical bone compartment in the male mouse are also mediated via different cell types. Whereas the antiresorptive effects of estrogens on cancellous bone result from direct actions on osteoclasts, the antiresorptive effects of androgens on cancellous bone are exerted indirectly via osteoblasts and osteocytes, but not on osteoclasts or via aromatization to estrogens [42,51-54]. Consistent with this evidence, trabecular number is preserved in men with homozygous loss of function mutation of ER-alpha, indicating that the AR can preserve trabecular number in the absence of the ER-alpha [55]. Nevertheless, in cortical bone, estrogens protect against resorption in both females and males, at least in part, via ER-alpha-mediated actions (upon aromatization of androgens to estrogens in males) on uncommitted mesenchymal progenitors [42]. These latest insights from the mouse model are remarkably consistent with evidence in men that estrogens account for approximately 70 percent and testosterone for at most approximately 30 percent of the protective effect of sex steroids on bone resorption, and the fact that the skeleton is approximately 80 percent cortical and approximately 20 percent cancellous [56].

LYMPHOCYTES AND CYTOKINES — An increase of reactive oxygen species (ROS) in the bone marrow in both aging and estrogen deficiency has been associated with expansion of T and B lymphocytes, nuclear factor kappa-B (NF-kB) activation, and increased production of osteoclastogenic cytokines, including interleukin (IL)-1, IL-6, IL-7, tumor necrosis factor (TNF), prostaglandin E2, macrophage colony-stimulating factor (M-CSF), and receptor activator of NF-kB ligand (RANKL). Conversely, estrogens or nonaromatizable androgens decrease NF-kB activation and cytokine production [57,58]. The extent to which the effects of estrogens (or androgens) on T and B lymphocytes and cytokines (as opposed to direct effects on bone cells) contribute to the overall antiresorptive effects of sex steroids and the role of these changes to the development of osteoporosis remain unclear [59,60].

DECREASED OSTEOCYTE VIABILITY

Role of osteocytes — Osteocytes are former osteoblasts entombed in the mineralized matrix. In contrast to osteoclasts and osteoblasts, which are relatively short lived and transiently present only on a small fraction of the bone surface, osteocytes are deployed throughout the skeleton, are far more abundant than either osteoclasts (1000 times) or osteoblasts (10 times), are long lived, and their death is dependent on the age of the bone [61].

Osteocytes choreograph the remodeling process on the bone surface by virtue of their ability to sense effete bone and direct the homing of osteoclasts to the site that is in need of remodeling. Indeed, osteocytes are the essential sources of the receptor activator of nuclear factor kappa-B ligand (RANKL) that controls bone remodeling, indicating that the cells best able to detect the need for matrix removal directly control the process [1,62]. Moreover, osteocyte RANKL is responsible for the bone loss associated with mechanical unloading. In addition to RANKL, osteocytes are the source of the Wnt antagonist sclerostin, a limiting factor for osteoblast generation and bone mass accrual that mediates the homeostatic adaptation of bone to mechanical loading [63]. Furthermore, osteocytes control and modify the mineralization of the matrix produced by osteoblasts by secreting factors such as matrix extracellular phosphoglycoprotein (MEPE) and the phosphaturic hormone fibroblast growth factor 23 (FGF23) [64,65]. (See "Normal skeletal development and regulation of bone formation and resorption".)

Osteocyte death increases in prevalence with age and is dependent on the age of the bone, not on the age of the subject. Osteocyte death is followed by hypermineralization of perilacunar bone and later by filling of canaliculi with mineralized connective tissue [66]. These changes, collectively referred to as micropetrosis, probably lead to increased brittleness of bone [67]. In deep bone, total lacunar density is lower than in superficial bone and falls substantially with age, so that micropetrosis, the only process that could lead to obliteration of lacunae, occurs in cancellous as well as in cortical bone [68]. There is a close spatial relationship between empty lacunae and microscopic fatigue damage [69], but it is unclear which occurs first, although both are the expected consequences of excessive bone age.

Age-related decline in osteocytes — The age-related decline in osteocyte number is accompanied by reduced bone strength [57,70]; several mechanisms likely contribute to this relationship. First, reduced osteocyte density in central cancellous bone is associated with increased surface remodeling [71], which is an independent contributor to bone fragility [72]. Second, there is disruption of signals necessary for microdamage repair [73]; these signals may be released during or shortly after osteocyte apoptosis, but if the osteocyte is already dead, such signals cannot be generated. Third, and probably most important, osteocyte death leads to a decline in bone vascularity and hydration, which reduces bone strength by mechanisms not yet fully understood, but which probably include changes in crystallinity and promotion of micropetrosis [67,74]. Conversely, protection of osteocytes from the adverse effect of aging on their apoptosis maintains bone crystallinity, vasculature volume, circulation of interstitial fluid, and strength.

Oxidative stress, hypoxia, glucocorticoid excess, estrogen loss, changes in the perilacunar matrix, and cytokines are among the factors implicated for the increased osteocyte death with age. Under stress conditions, osteocytes deploy a self-preservation mechanism called autophagy. Autophagy promotes resistance of osteocytic cells to oxidative stress-induced apoptosis, while expression of autophagy-related genes in bone declines with age.

Mechanical strain is a requirement of osteocyte viability and physiological levels of mechanical strain prevent apoptosis of cultured osteocytic cells [75]. Conversely, reduced mechanical forces with unloading increase the prevalence of osteocyte apoptosis, followed by bone resorption and loss of bone mineral and strength [76]. In addition, reduced physical activity in old age, bed rest, or space flight invariably leads to bone loss [77].

Osteocytes are cellular targets of estrogen and androgen action. Estrogens or androgens inhibit osteoblast and osteocyte apoptosis [78,79]. Conversely, estrogen or androgen deficiency increases the prevalence of osteocyte apoptosis in humans [31], rats [80], and mice [79]. It has been postulated that mechanical stain, perceived by a hypothetical skeletal mechanostat, leads to changes in bone remodeling in order to adjust bone mass to a level that is appropriate for the current ambient mechanical forces [81]. It is also hypothesized that estrogen decreases the minimum effective strain necessary to initiate bone formation [82]. In support of this hypothesis, estrogens and exercise may exert additive effect on bone mass in humans [77]. In addition, the increased bone formation that normally occurs in response to mechanical loading is diminished in the estrogen-deficient state in mice [83]. Evidence for a role of the estrogen receptor (ER) in the pro-survival effect of mechanical strain on osteocytes is consistent with the poor osteogenic response to loading exhibited by mice lacking the ERs alpha or beta [84]. Increased osteocyte apoptosis following sex steroid deficiency could also affect bone mass [1,63,85].

GLUCOCORTICOID EXCESS — Endogenous or pharmacologic glucocorticoid excess is a common cause of osteoporosis. Unlike the postmenopausal form of the disease, but similar to the osteoporosis of old age, the rate of remodeling is low and the predominant abnormality is decreased bone formation. In addition, glucocorticoid excess, similar to aging, decreases bone strength disproportionately to its adverse effect on bone mass [86]. Glucocorticoid-induced osteoporosis frequently presents with fractures of the spine, ribs, and hip as early as three months following the initiation of long-term therapy and before any detectable decline on bone mass. This clearly suggests that pathologic changes other than decreased bone mineral density (BMD) are the cause of the increased fragility in this condition. (See "Clinical features and evaluation of glucocorticoid-induced osteoporosis".)

The deleterious effects of glucocorticoid excess on bone result from direct effects on osteoblasts, osteocytes, and osteoclasts [87-90]. This is a departure from earlier ideas that the adverse effects of glucocorticoids on bone are secondary to effects on calcium handling and the production of parathyroid hormone (PTH) or gonadal steroids. Indeed, glucocorticoid excess directly suppresses osteoblastogenesis, strongly and rapidly stimulates osteoblast and osteocyte apoptosis, and prolongs the lifespan of osteoclasts. Changes in the production of local growth factors, including insulin-like growth factors (IGF) and their binding proteins, and Wnt-beta catenin signaling may contribute.

Glucocorticoid-induced loss of bone strength results in part from increased death of osteocytes and decreased skeletal hydration. Endogenous glucocorticoid production and sensitivity to the effects of glucocorticoids increase with age, inexorably contributing to the effects of old age in the development of osteoporosis. Increased sensitivity to glucocorticoids is the result of increased bone expression of 11-beta-hydroxysteroid dehydrogenase (11-beta-HSD) type 1, the enzyme that activates glucocorticoids. In both aging and pharmacologic hyperglucocorticoidism, increased apoptosis of osteocytes can account for the loss of bone strength that occurs before the loss of BMD and the mismatch between BMD and the risk of fracture in patients with glucocorticoid-induced osteoporosis [74,91,92].

Specifically, in both aging and glucocorticoid excess, the volume of the bone vasculature and solute transport from the peripheral circulation to the lacunar-canalicular system is decreased, leading to decreased skeletal hydration. The molecular underpinning of these effects is decreased angiogenesis resulting from decreased vascular endothelial growth factor (VEGF) production by osteoblasts/osteocytes, as well as decreased VEGF action. These changes represent a chain of interconnected pathogenetic mechanisms as indicated by anatomical evidence that the cellular processes of osteocytes are in direct contact with the bone vasculature (figure 4). Together with evidence that dehydration of bone decreases strength, these new insights reveal that endogenous glucocorticoids increase skeletal fragility in old age as a result of cell autonomous effects on osteocytes leading to interconnected decrements in bone angiogenesis, vasculature volume, and osteocyte-lacunar-canalicular fluid.

OXIDIZED LIPIDS — Clinical and epidemiologic studies, as well as studies in animals, indicate a link between osteoporosis, atherosclerosis, and cardiovascular disease [93,94]. Bone loss and vascular calcification progress in parallel with advancing age and aortic calcification is inversely related to bone density and directly related to fractures in postmenopausal women [95]. Women in the highest quartile for increased atherosclerosis exhibit four times greater yearly bone loss than women in the lowest quartile. Lipid oxidation plays a critical role in the development of atherogenesis [96].

Hyperlipidemia leads to atherogenesis by promoting the formation of oxidized forms of low-density lipoprotein (LDL) cholesterol and phospholipids. These oxidation-modified moieties, in turn, induce potent inflammatory responses in the subendothelial matrix of the arteries, thereby triggering the pathogenetic changes that are ultimately responsible for the generation of the atherosclerotic lesion [97]. The same oxidized moieties cause skeletal inflammation and attenuation of Wnt signaling, Wnt ligand expression, and bone formation, providing a mechanistic explanation for the link between atherosclerosis and osteoporosis [98-100].

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SUMMARY

Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fractures. Although osteoporosis has become synonymous with decreased bone mineral density (BMD), this feature is not always present. Small bone size, unfavorable macroarchitecture (eg, increased length of the femoral neck), disrupted microarchitecture (image 1 and figure 1), cortical porosity (figure 3), compromised quality of the material, and decreased viability of osteocytes (former osteoblasts buried within mineralized bone that sense and respond to changes in mechanical forces) are some of the other factors contributing to decreased strength. (See 'Definition' above.)

Multiple mechanisms are responsible for the syndrome of increased bone fragility with advancing age that we inexactly term osteoporosis. Low peak bone mass probably contributes to the development of osteoporosis later in life. However, old age, sex steroid deficiency, lipid oxidation, decreased physical activity, use of glucocorticoids, and a propensity to fall are the most critical determinants of increased fracture risk. (See 'Peak bone mass acquisition' above and 'Age-related bone loss' above and 'Sex steroid deficiency' above.)

The overarching cause of osteoporosis is aging. Bone-intrinsic mechanisms, including mitochondria dysfunction, oxidative stress, declining autophagy, DNA damage, osteoprogenitor and osteocyte senescence, senescence-associated secretory phenotype (SASP), and lipid peroxidation, may be primary culprits. Bone-extrinsic mechanisms, ie, age-related changes in other organs and tissues, such as the ovaries and the innate immune system, are contributory. The effects of aging are independent of estrogen deficiency and mechanistically distinct. The extent to which these two mechanisms contribute to bone fragility in humans remains to be determined. (See 'Age-related bone loss' above and 'Sex steroid deficiency' above.)

With continuing advances in our understanding of this complex disease and technical innovations in genetics and proteomics, as well improved imaging approaches, it is reasonable to expect that in the near future, new classes of drugs targeting age-related mechanisms have the potential to treat more than one age-related disease, including osteoporosis, simultaneously.

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Topic 2044 Version 20.0

References

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