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Aging and Bone Metabolism

Robert J. Pignolo

10.1002/cphy.c220012

Source: Volume 13, Issue 1, January 2023

Published online: January 2023

Full Article on Wiley Online Library



Abstract

Changes in bone architecture and metabolism with aging increase the likelihood of osteoporosis and fracture. Age‐onset osteoporosis is multifactorial, with contributory extrinsic and intrinsic factors including certain medical problems, specific prescription drugs, estrogen loss, secondary hyperparathyroidism, microenvironmental and cellular alterations in bone tissue, and mechanical unloading or immobilization. At the histological level, there are changes in trabecular and cortical bone as well as marrow cellularity, lineage switching of mesenchymal stem cells to an adipogenic fate, inadequate transduction of signals during skeletal loading, and predisposition toward senescent cell accumulation with production of a senescence‐associated secretory phenotype. Cumulatively, these changes result in bone remodeling abnormalities that over time cause net bone loss typically seen in older adults. Age‐related osteoporosis is a geriatric syndrome due to the multiple etiologies that converge upon the skeleton to produce the ultimate phenotypic changes that manifest as bone fragility. Bone tissue is dynamic but with tendencies toward poor osteoblastic bone formation and relative osteoclastic bone resorption with aging. Interactions with other aging physiologic systems, such as muscle, may also confer detrimental effects on the aging skeleton. Conversely, individuals who maintain their BMD experience a lower risk of fractures, disability, and mortality, suggesting that this phenotype may be a marker of successful aging. © 2023 American Physiological Society. Compr Physiol 13:4355‐4386, 2023.

Figure 1. Figure 1. Factors that contribute to age‐related bone loss and their cellular and tissue manifestations. Age‐related osteoporosis is multifactorial and manifests as characteristic cellular and histological changes to bone.
Figure 2. Figure 2. The association of BMD with risk of fracture as a function of age. Fracture risk approximately doubles with every 1 standard deviation drop in T‐score. Intrinsic and extrinsic factors confer additional risk independent of BMD, such that individuals with T‐scores in the osteopenic range but with risk factors are at higher likelihood of fracture than with consideration of BMD alone (e.g., brown shaded area).
Figure 3. Figure 3. Osteoporosis is a geriatric syndrome due to multisystem involvement, and contributions made by older age, multifactorial risk factors, functional impairment, and multimorbidity.
Figure 4. Figure 4. Racial differences contribute to the risk of hip and vertebral fractures. Non‐Hispanic whites and Hispanic Americans have the greatest risk for hip fractures. Asian Americans and non‐Hispanic whites have the greatest risk for vertebral fractures.
Figure 5. Figure 5. Changes in cortical bone structure with aging. Due to periosteal apposition in the setting of endocortical resorption, there is outward cortical displacement with aging resulting in a decrease in cortical thickness and area. Concomitant alterations include increases in cortical porosity, trabecularization, and heterogeneity of mineralized bone as well as a decrease in ultimate stress. These changes tend to occur more prominently in women compared to men.
Figure 6. Figure 6. Changes in trabecular bone structure with aging. In women, there is a loss of trabecular bone with increased trabecular spacing. In men, there is a thinning of trabecular bone rather than trabecular bone loss.
Figure 7. Figure 7. Bone MSC (bMSC) lineage switching with aging and osteoporosis. There is a substantial increase in bone marrow adiposity with aging, largely due to the Wnt pathway inhibitor SOST (sclerostin) in the context of transcription and other factors that promote adipocyte over osteoblast differentiation of bMSCs. Normal (→), and enhanced (–→) pathways are indicated; inhibited pathways are noted (‖). Upwardly curved arrow indicates renewal and expansion (↻).
Figure 8. Figure 8. Aging‐related changes in bone mechanical responsiveness. Osteocytes are the primary mechanosensors in bone, and with aging, there is a drop in osteocyte density, loss of osteocyte dendritic processes, and disruption of the connectivity of canalicular network. The loss of connexin‐43 is associated with osteocyte cell death, empty lacunae, and deteriorative changes in the canalicular network. Wnt signaling pathway‐mediated mechanical transduction is also limited by sclerostin inhibition. Dashed arrows (⤏) indicate reduced pathways and solid lines (—) indicate enhanced pathways; inhibited pathways are noted (⊢).
Figure 9. Figure 9. Bone remodeling imbalance with aging and menopausal status. (A) Bone remodeling is normally a constant dynamic process that couples bone resorption to bone formation. (B) With aging, bone remodeling becomes uncoupled due to cellular senescence, lineage switching that favors adipogenesis over osteogenesis, and a relative increase in sclerostin. With postmenopausal status in women (and decreased estrogen level in men), there is an increase in osteoclast differentiation and activation frequency as well as an enhanced stimulation of sclerostin. In both aging and menopause increased levels of RANKL and IL‐6 favor osteoclast differentiation. Reduced (⤏), normal (→), and enhanced (—, →) pathways are indicated; inhibited pathways are noted (‖); bMSC, bone mesenchymal stem cell.
Figure 10. Figure 10. Renal osteodystrophy contributes to age‐related bone loss. Its two most common forms are based on the effects of elevated or depressed parathyroid hormone (PTH), manifested as osteitis fibrosa (high bone turnover), or adynamic bone disease (low bone turnover). Defects in bone mineralization are common in all forms of renal osteodystrophy but elevated levels of FGF23 are a major inducer of osteomalacia.
Figure 11. Figure 11. Cellular senescence in bone aging. Aging disrupts homeostatic processes in bone, causing increased osteoclast resorption and reduced bone formation and mineralization by osteoblasts. Bone MSCs (bMSC) produce a reduced number of osteoblasts and preferentially undergo adipogenic differentiation. Loss of osteocyte connectivity and disruption of the canalicular network accompanies osteocyte death and the accumulation of empty lacunae. Activation of osteoclasts promotes resorption, leading to bone loss. Senescent osteocytes are prominent in the aging bone microenvironment. Important drivers of cellular senescence, in general, include telomere dysfunction and a DDR that induces cell cycle arrest mediated by p16Ink4a or p21, with subsequent suppression of Cyclin D, CDK4/6, Cyclin E, and CDK2. Activation of NF‐κB promotes the transcription of pro‐inflammatory SASP factors. Mitochondrial dysfunction, disruption of protein homeostasis (i.e., proteostasis), chromatin modifications, miRNA‐regulation of senescence‐related genes, and alterations of the nuclear lamina are among the typical features of cellular senescence. Senolytic compounds and senomorphic agents target senescent cells and the SASP, respectively. Figure is courtesy of Abhishek Chandra, PhD, Mayo Clinic College of Medicine.
Figure 12. Figure 12. Possible age‐related changes in muscle‐bone interactions. Factors with beneficial effects are secreted in response to muscle contraction and skeletal loading. RANKL and TGFβ, released during the resorptive phase of bone remodeling, have negative effects on muscle, while detrimental effects on both muscle and bone are mediated by myostatin. IL‐7, IL6, and myostatin contribute to osteoclast differentiation, recruitment, and activation, which in turn increases bone resorption. Dashed lines (‐ ‐ ‐) indicate putative age‐related changes.
Figure 13. Figure 13. Resilience to age‐related bone loss confers health and life span advantages. Maintenance of BMD through exercise, genetic predisposition, and/or zoledronate is associated with decreased mortality, disability, and fractures. Zoledronate, independent of its effects on fracture reduction confers a mortality advantage.


Figure 1. Factors that contribute to age‐related bone loss and their cellular and tissue manifestations. Age‐related osteoporosis is multifactorial and manifests as characteristic cellular and histological changes to bone.


Figure 2. The association of BMD with risk of fracture as a function of age. Fracture risk approximately doubles with every 1 standard deviation drop in T‐score. Intrinsic and extrinsic factors confer additional risk independent of BMD, such that individuals with T‐scores in the osteopenic range but with risk factors are at higher likelihood of fracture than with consideration of BMD alone (e.g., brown shaded area).


Figure 3. Osteoporosis is a geriatric syndrome due to multisystem involvement, and contributions made by older age, multifactorial risk factors, functional impairment, and multimorbidity.


Figure 4. Racial differences contribute to the risk of hip and vertebral fractures. Non‐Hispanic whites and Hispanic Americans have the greatest risk for hip fractures. Asian Americans and non‐Hispanic whites have the greatest risk for vertebral fractures.


Figure 5. Changes in cortical bone structure with aging. Due to periosteal apposition in the setting of endocortical resorption, there is outward cortical displacement with aging resulting in a decrease in cortical thickness and area. Concomitant alterations include increases in cortical porosity, trabecularization, and heterogeneity of mineralized bone as well as a decrease in ultimate stress. These changes tend to occur more prominently in women compared to men.


Figure 6. Changes in trabecular bone structure with aging. In women, there is a loss of trabecular bone with increased trabecular spacing. In men, there is a thinning of trabecular bone rather than trabecular bone loss.


Figure 7. Bone MSC (bMSC) lineage switching with aging and osteoporosis. There is a substantial increase in bone marrow adiposity with aging, largely due to the Wnt pathway inhibitor SOST (sclerostin) in the context of transcription and other factors that promote adipocyte over osteoblast differentiation of bMSCs. Normal (→), and enhanced (–→) pathways are indicated; inhibited pathways are noted (‖). Upwardly curved arrow indicates renewal and expansion (↻).


Figure 8. Aging‐related changes in bone mechanical responsiveness. Osteocytes are the primary mechanosensors in bone, and with aging, there is a drop in osteocyte density, loss of osteocyte dendritic processes, and disruption of the connectivity of canalicular network. The loss of connexin‐43 is associated with osteocyte cell death, empty lacunae, and deteriorative changes in the canalicular network. Wnt signaling pathway‐mediated mechanical transduction is also limited by sclerostin inhibition. Dashed arrows (⤏) indicate reduced pathways and solid lines (—) indicate enhanced pathways; inhibited pathways are noted (⊢).


Figure 9. Bone remodeling imbalance with aging and menopausal status. (A) Bone remodeling is normally a constant dynamic process that couples bone resorption to bone formation. (B) With aging, bone remodeling becomes uncoupled due to cellular senescence, lineage switching that favors adipogenesis over osteogenesis, and a relative increase in sclerostin. With postmenopausal status in women (and decreased estrogen level in men), there is an increase in osteoclast differentiation and activation frequency as well as an enhanced stimulation of sclerostin. In both aging and menopause increased levels of RANKL and IL‐6 favor osteoclast differentiation. Reduced (⤏), normal (→), and enhanced (—, →) pathways are indicated; inhibited pathways are noted (‖); bMSC, bone mesenchymal stem cell.


Figure 10. Renal osteodystrophy contributes to age‐related bone loss. Its two most common forms are based on the effects of elevated or depressed parathyroid hormone (PTH), manifested as osteitis fibrosa (high bone turnover), or adynamic bone disease (low bone turnover). Defects in bone mineralization are common in all forms of renal osteodystrophy but elevated levels of FGF23 are a major inducer of osteomalacia.


Figure 11. Cellular senescence in bone aging. Aging disrupts homeostatic processes in bone, causing increased osteoclast resorption and reduced bone formation and mineralization by osteoblasts. Bone MSCs (bMSC) produce a reduced number of osteoblasts and preferentially undergo adipogenic differentiation. Loss of osteocyte connectivity and disruption of the canalicular network accompanies osteocyte death and the accumulation of empty lacunae. Activation of osteoclasts promotes resorption, leading to bone loss. Senescent osteocytes are prominent in the aging bone microenvironment. Important drivers of cellular senescence, in general, include telomere dysfunction and a DDR that induces cell cycle arrest mediated by p16Ink4a or p21, with subsequent suppression of Cyclin D, CDK4/6, Cyclin E, and CDK2. Activation of NF‐κB promotes the transcription of pro‐inflammatory SASP factors. Mitochondrial dysfunction, disruption of protein homeostasis (i.e., proteostasis), chromatin modifications, miRNA‐regulation of senescence‐related genes, and alterations of the nuclear lamina are among the typical features of cellular senescence. Senolytic compounds and senomorphic agents target senescent cells and the SASP, respectively. Figure is courtesy of Abhishek Chandra, PhD, Mayo Clinic College of Medicine.


Figure 12. Possible age‐related changes in muscle‐bone interactions. Factors with beneficial effects are secreted in response to muscle contraction and skeletal loading. RANKL and TGFβ, released during the resorptive phase of bone remodeling, have negative effects on muscle, while detrimental effects on both muscle and bone are mediated by myostatin. IL‐7, IL6, and myostatin contribute to osteoclast differentiation, recruitment, and activation, which in turn increases bone resorption. Dashed lines (‐ ‐ ‐) indicate putative age‐related changes.


Figure 13. Resilience to age‐related bone loss confers health and life span advantages. Maintenance of BMD through exercise, genetic predisposition, and/or zoledronate is associated with decreased mortality, disability, and fractures. Zoledronate, independent of its effects on fracture reduction confers a mortality advantage.
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Article Title: Aging and Bone Metabolism
 

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Robert J. Pignolo. Aging and Bone Metabolism. Compr Physiol 2023, 13: 4355-4386. doi: 10.1002/cphy.c220012