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Skeletal Aging

      Abstract

      Aging represents the single greatest risk factor for chronic diseases, including osteoporosis, a skeletal fragility syndrome that increases fracture risk. Optimizing bone strength throughout life reduces fracture risk. Factors critical for bone strength include nutrition, physical activity, and vitamin D status, whereas unhealthy lifestyles, illnesses, and certain medications (eg, glucocorticoids) are detrimental. Hormonal status is another important determinant of skeletal health, with sex steroid concentrations, particularly estrogen, having major effects on bone remodeling. Aging exacerbates bone loss in both sexes and results in imbalanced bone resorption relative to formation; it is associated with increased marrow adiposity, osteoblast/osteocyte apoptosis, and accumulation of senescent cells. The mechanisms underlying skeletal aging are as diverse as the factors that determine the strength (and thus fragility) of bone. This review updates our current understanding of the epidemiology, pathophysiology, and treatment of osteoporosis and provides an overview of the underlying hallmark mechanisms that drive skeletal aging.

      Abbreviations and Acronyms:

      BMAT (bone marrow adipose tissue), BMD (bone mineral density), DXA (dual energy X-ray absorptiometry), FRAX (Fracture Risk Assessment Tool), MSC (mesenchymal stem cell), TUG (Timed Up and Go)
      Article Highlights
      • Aging exacerbates bone loss in both sexes and results in imbalanced bone resorption relative to formation.
      • Hallmarks of skeletal aging include increased marrow adiposity, osteoblast/osteocyte apoptosis, and accumulation of senescent cells.
      • Novel strategies to therapeutically target fundamental mechanisms of aging are gaining momentum as attractive options for preventing or delaying age-related diseases as group, including osteoporosis.
      In our recent evolutionary past, population growth and human life expectancy have increased dramatically in developed countries,
      • Oeppen J.
      • Vaupel J.W.
      Demography. Broken limits to life expectancy.
      and these trends are projected to continue.
      • Kontis V.
      • Bennett J.E.
      • Mathers C.D.
      • Li G.
      • Foreman K.
      • Ezzati M.
      Future life expectancy in 35 industrialised countries: projections with a Bayesian model ensemble.
      With longer life spans less shaped by natural selection, however, the period of disease-free life (ie, health span) has not kept pace, creating challenges that humans remain poorly equipped to handle, including an enormous burden of late-life morbidity due to age-related diseases and chronic morbidities that often coexist in the elderly. These include cancers, cardiovascular disease, renal and neurodegenerative diseases, metabolic dysfunction, frailty, pulmonary fibrosis, osteoarthritis, and osteoporosis, among numerous others.
      • Niccoli T.
      • Partridge L.
      Ageing as a risk factor for disease.
      One of the most common diseases associated with aging is osteoporosis (meaning “porous bone”), a skeletal fragility disorder characterized by reduced bone strength. Bone strength reflects both bone mineral density (BMD) and bone quality, with reductions in bone strength contributing to age-related morbidity through increasing susceptibility to fragility fractures. Despite a range of therapeutic options that are safe, effective, and approved for the prevention or treatment of osteoporosis, including oral or intravenous administration of bisphosphonates, estrogen, raloxifene, denosumab, teriparatide/abaloparatide, and romosozumab, most individuals with osteoporosis remain untreated. In fact, the proportion of persons receiving appropriate osteoporosis therapy after a hip fracture has actually decreased in recent years.
      • Kim B.T.
      • Mosekilde L.
      • Duan Y.
      • et al.
      The structural and hormonal basis of sex differences in peak appendicular bone strength in rats.
      This disconnect stems in part from concerns for rare adverse effects associated with osteoporosis-specific drugs, such as atypical femoral fractures and osteonecrosis of the jaw. Sadly, this reluctance to initiate or to adhere to osteoporosis therapies has contributed to a rising prevalence of osteoporosis and an increased fracture burden among the elderly.
      Bone is a unique tissue that serves paradoxical functions across the life span. For example, it must be light enough to permit movement yet strong to resist trauma. In the elderly, the most common form of major trauma results from the impact associated with falling. When an applied force exceeds a bone’s strength, structural failure in the form of a fracture will occur. Thus, optimizing bone strength reduces fracture risk. Although partly dependent on the amount of bone acquired during development and growth, skeletal strength is a function of its mass, material (both matrix and mineral), and both macroarchitecture and microarchitecture (eg, trabecular connectivity, cortical porosity). As reviewed in more detail later, numerous factors contribute to maximal bone strength across the life span, including genetics, sex steroid levels (particularly estrogen) in both women and men, nutrition, physical activity, and vitamin D status, whereas other factors, such as unhealthy lifestyles, illnesses, and certain medications (eg, glucocorticoids), can be detrimental to bone strength. As an example of the pivotal role for estrogen in maintenance of skeletal health, the rapid decline in estrogen levels that heralds menopausal onset is paralleled by accelerated and progressive bone loss. Coincident with such hormonal changes, aging itself further exacerbates bone loss in both sexes, and the underlying mechanisms mediating the pathogenesis of skeletal aging are as diverse as the factors that determine the strength (and thus fragility) of bone.
      Another issue of growing concern in the elderly is polypharmacy, which has been shown to be an independent risk factor for hip fractures.
      • Lai S.W.
      • Liao K.F.
      • Liao C.C.
      • Muo C.H.
      • Liu C.S.
      • Sung F.C.
      Polypharmacy correlates with increased risk for hip fracture in the elderly: a population-based study.
      Notably, most drug discovery efforts for osteoporosis and other aging-associated diseases have historically followed the mantra of treating each disease as a separate entity (ie, 1 disease, 1 drug), leading to a greater risk for adverse drug interactions in elderly populations. However, an approach focused on developing interventions to delay or to treat osteoporosis as well as other aging-associated diseases as a group has recently gained momentum.
      • Farr J.N.
      • Almeida M.
      The spectrum of fundamental basic science discoveries contributing to organismal aging.
      In addition to efforts to optimize physical activity and nutrition, an approach to therapeutically targeting basic mechanisms of aging may be feasible as recent preclinical models have shown health span extension in studies of aged animals.
      • Lopez-Otin C.
      • Blasco M.A.
      • Partridge L.
      • Serrano M.
      • Kroemer G.
      The hallmarks of aging.
      Fundamental to addressing these issues is additional understanding of the pathogenesis of skeletal aging. Herein, we provide an update on the current understanding of the epidemiology, optimal clinical assessment, pathophysiology, and treatment of osteoporosis as well as an overview of the underlying hallmark mechanisms that drive the aging process across tissues, including bone.

      Epidemiology of Osteoporosis and Fractures

      Among adults aged 50 years and older in the United States, BMD measurements obtained at the femoral neck and lumbar spine in the National Health and Nutrition Examination Survey 2005-2010 US Census population counts suggest that there are an estimated 10.2 million (10.3%) Americans with osteoporosis and that 54% (53.6 million) of US adults aged 50 years and older have osteopenia.
      • Wright N.C.
      • Looker A.C.
      • Saag K.G.
      • et al.
      The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine.
      Similar patterns have been observed across various racial and ethnic groups as well as in other developed countries.
      • Curtis E.M.
      • van der Velde R.
      • Moon R.J.
      • et al.
      Epidemiology of fractures in the United Kingdom 1988-2012: variation with age, sex, geography, ethnicity and socioeconomic status.
      Consistent with the incidence and prevalence of the disease, osteoporosis-related fractures are more common in women than in men, and it is generally estimated that 1 in 3 women and 1 in 5 men aged 50 years will suffer an osteoporotic fracture in their remaining lifetime.
      • Curtis E.M.
      • van der Velde R.
      • Moon R.J.
      • et al.
      Epidemiology of fractures in the United Kingdom 1988-2012: variation with age, sex, geography, ethnicity and socioeconomic status.
      • Kanis J.A.
      • Johnell O.
      • Oden A.
      • et al.
      Long-term risk of osteoporotic fracture in Malmo.
      • Melton L.J.
      • Chrischilles E.A.
      • Cooper C.
      • Lane A.W.
      • Riggs B.L.
      How many women have osteoporosis.
      • Melton III, L.J.
      • Atkinson E.J.
      • O'Connor M.K.
      • O'Fallon W.M.
      • Riggs B.L.
      Bone density and fracture risk in men.
      With life expectancy continuing to increase, these demographic trends are only expected to rise. Therefore, identifying at-risk persons through proper clinical assessments and treating those individuals at greatest risk for fragility fractures are increasingly important.

      Clinical Assessment of Skeletal Aging

      Assessing musculoskeletal health in older adults involves the careful evaluation of multiple layers of clinical, radiographic, and laboratory testing to elucidate the intricate interplay between bone, muscle, and fat. Indeed, the evaluation of age-related bone loss is generally best performed alongside evaluations of frailty and sarcopenia as well as the assessments of potential physical or cognitive dysfunction and additional social determinants of health.

      Assessment of Skeletal Fragility

      The ultimate indicator of skeletal fragility is the incidence of a fragility fracture. A fragility fracture is defined as any fracture that follows a fall from a standing height or less. Sites of injury that predict the incidence of subsequent fractures include fractures at the hip, spine, and distal forearm. Vertebral fractures that are clinically “silent” and therefore discovered incidentally on radiologic imaging are similarly considered to reflect underlying bone fragility.
      In addition to age, numerous factors can contribute to bone loss and increase the risk of fractures. These include race and ethnicity, lifestyle factors (smoking, alcohol), endocrine disorders (hyperparathyroidism, hypercortisolism), genetic disorders (cystic fibrosis), and medications (glucocorticoids, anticonvulsants).
      • Cosman F.
      • de Beur S.J.
      • LeBoff M.S.
      • et al.
      Clinician's guide to prevention and treatment of osteoporosis.
      Surrogate markers and clinical tools have been developed to identify patients at risk for fracture who would potentially benefit from intervention. Validated tools that identify common risk factors are available and can provide risk estimates for hip and major osteoporotic fractures. Commonly used tools include the Fracture Risk Assessment Tool (FRAX; https://www.sheffield.ac.uk/FRAX/) and the Garvan Institute bone fracture risk calculator (https://www.garvan.org.au/promotions/bone-fracture-risk/calculator/index.php). Whereas FRAX is currently most widely used in clinical practice, the Garvan tool may have additional value for evaluating fracture risk in patients with recurrent falls and factures.
      • van den Bergh J.P.
      • van Geel T.A.
      • Lems W.F.
      • Geusens P.P.
      Assessment of individual fracture risk: FRAX and beyond.
      Using low dose X-ray beams, dual energy X-ray absorptiometry (DXA) provides an estimate of bone mineral content and areal BMD. Low BMD has been associated with progressively increased risk of fragility fractures. In postmenopausal women and men 50 years or older, BMD is commonly expressed in terms of a T-score, which represents the standard deviation of an individual’s BMD from the young adult mean BMD. The World Health Organization defines a T-score of −1.0 or above as normal, a T-score between −1.0 and −2.5 as osteopenia, and a T-score of −2.5 or below as osteoporosis. DXA can also provide comprehensive vertebral morphometric measurements that indicate the presence of a vertebral compression deformity or fracture.
      The National Osteoporosis Foundation recommends measurement of BMD in women aged 65 years and older and men aged 70 years and older, in postmenopausal women and men older than 50 years with additional clinical risk factors, and in postmenopausal women and men aged 50 years and older who have fractured in adulthood.
      • Cosman F.
      • de Beur S.J.
      • LeBoff M.S.
      • et al.
      Clinician's guide to prevention and treatment of osteoporosis.
      Laboratory testing also aids in the assessment of skeletal fragility, given that as many as a third of postmenopausal women and 50% to 80% of men with osteoporosis may have a previously unrecognized metabolic bone disease.
      • Bours S.P.
      • van den Bergh J.P.
      • van Geel T.A.
      • Geusens P.P.
      Secondary osteoporosis and metabolic bone disease in patients 50 years and older with osteoporosis or with a recent clinical fracture: a clinical perspective.
      ,
      • Ebeling P.R.
      • Nguyen H.H.
      • Aleksova J.
      • Vincent A.J.
      • Wong P.
      • Milat F.
      Secondary osteoporosis.
      Testing should be individualized but may include serum electrolyte values (such as calcium and phosphorus), vitamin D levels, and kidney function. Serum and urine markers of bone turnover, such as procollagen type 1 N-terminal propeptide and C-telopeptide of type I collagen, may provide insight into the extent of a patient’s bone formation and resorption, respectively.

      Assessment of Falls, Frailty, and Sarcopenia

      Broadly defined, sarcopenia is the progressive loss of muscle mass and function. It is closely associated with frailty and an increased risk of falls and fractures as well as with other poor health outcomes including mortality. For diagnosis of sarcopenia, measurements of muscle mass, muscle strength, and physical performance are essential.
      A number of tools are available in the research setting but have limited clinical availability; cost incurred by some of these tools further limits their widespread use.
      • Cruz-Jentoft A.J.
      • Baeyens J.P.
      • Bauer J.M.
      • et al.
      Sarcopenia: European consensus on definition and diagnosis: report of the European Working Group on Sarcopenia in Older People.
      Body mass index and body circumference are not considered reliable to evaluate for sarcopenia. Total body DXA can provide estimates of lean muscle mass. Gait speed or Timed Up and Go (TUG) are easy tools to replicate in the clinical setting and can provide valuable physical performance assessment.
      • Studenski S.
      • Perera S.
      • Patel K.
      • et al.
      Gait speed and survival in older adults.
      ,
      • Bischoff H.A.
      • Stahelin H.B.
      • Monsch A.U.
      • et al.
      Identifying a cut-off point for normal mobility: a comparison of the timed ‘up and go' test in community-dwelling and institutionalised elderly women.
      In the TUG test, the patient is asked to stand up from a sitting position and to walk for 10 feet (3 meters) while being timed. Grip strength has also been shown to have significant clinical relevance but requires a calibrated dynamometer and consistent measurement environment.
      • Alley D.E.
      • Shardell M.D.
      • Peters K.W.
      • et al.
      Grip strength cutpoints for the identification of clinically relevant weakness.
      ,
      • Dodds R.M.
      • Syddall H.E.
      • Cooper R.
      • et al.
      Grip strength across the life course: normative data from twelve British studies.
      Commonly used fracture risk assessment tools (eg, the FRAX calculator) do not fully account for frailty or sarcopenia and may thus underestimate fracture risk in older adults.
      • Kanis J.A.
      • Johnell O.
      • Oden A.
      • Johansson H.
      • McCloskey E.
      FRAX and the assessment of fracture probability in men and women from the UK.
      The Fracture Risk Assessment in Long-term Care (FRAiL) calculator is a recently developed tool that relies on a host of clinical factors, including physical performance and muscle function, to predict the 2-year risk for hip fractures in adults residing in nursing homes.
      • Berry S.D.
      • Zullo A.R.
      • Lee Y.
      • et al.
      Fracture Risk Assessment in Long-term Care (FRAiL): development and validation of a prediction model.
      Fall risk is typically evaluated by inquiring about a history of falls, particularly within the past 12 months as recent falls are associated with an increased risk of subsequent falls.
      • Kiely D.K.
      • Kiel D.P.
      • Burrows A.B.
      • Lipsitz L.A.
      Identifying nursing home residents at risk for falling.
      Cognitive dysfunction, sensory deficits, and polypharmacy have all been associated with a higher risk of falls and hip fractures.
      • Muir S.W.
      • Gopaul K.
      • Montero Odasso M.M.
      The role of cognitive impairment in fall risk among older adults: a systematic review and meta-analysis.
      • Lawlor D.A.
      • Patel R.
      • Ebrahim S.
      Association between falls in elderly women and chronic diseases and drug use: cross sectional study.
      • Ensrud K.E.
      • Blackwell T.L.
      • Mangione C.M.
      • et al.
      Central nervous system–active medications and risk for falls in older women.
      • Wu Q.
      • Bencaz A.F.
      • Hentz J.G.
      • Crowell M.D.
      Selective serotonin reuptake inhibitor treatment and risk of fractures: a meta-analysis of cohort and case-control studies.
      • Rabenda V.
      • Nicolet D.
      • Beaudart C.
      • Bruyere O.
      • Reginster J.Y.
      Relationship between use of antidepressants and risk of fractures: a meta-analysis.

      Changes in BMD, Skeletal Microarchitecture, Material Properties, and Strength with Aging

      There has been considerable progress during the past few decades in our understanding of the patterns of changes in BMD and additional measurable components of bone strength. As noted before, bone health is most frequently assessed in clinical practice by DXA, which permits assessments of areal BMD. Changes in BMD throughout the life span from growth to aging are shown for women and men in Figure 1. Because of the widespread availability of DXA, the majority of emphasis has focused on bone mass and BMD, although given significant limitations of DXA,
      • Seeman E.
      An exercise in geometry.
      more recent research has relied on quantitative computed tomography, which has advantages for measuring volumetric BMD and bone structure as well as for separating trabecular (more metabolically active) and cortical (structurally relevant) compartments. Longitudinal studies using these tools have demonstrated lifetime losses of trabecular bone of about 45% in men and 55% in women, with cortical bone losses of about 18% in men and 25% in women.
      • Riggs B.L.
      • Melton III, L.J.
      • Robb R.A.
      • et al.
      Population-based study of age and sex differences in bone volumetric density, size, geometry, and structure at different skeletal sites.
      Bone loss is accelerated in women around the time of menopause, with losses of about 20% to 30% trabecular (spine) and 5% to 10% cortical (distal radius) bone during the 6- to 10-year perimenopausal transition.
      • Riggs B.L.
      • Melton III, L.J.
      • Robb R.A.
      • et al.
      Population-based study of age and sex differences in bone volumetric density, size, geometry, and structure at different skeletal sites.
      ,
      • Riggs B.L.
      • Melton L.J.I.
      • Robb R.A.
      • et al.
      A population-based assessment of rates of bone loss at multiple skeletal sites: evidence for substantial trabecular bone loss in young adult women and men.
      In both sexes, continuous bone loss occurs with aging unless pharmacologic intervention is undertaken.
      Figure thumbnail gr1
      Figure 1Skeletal changes in bone mineral density (BMD) throughout the female and male life span, including representative micrographs of cadaveric bone from 29-year-old and 90-year-old women showing the progressive loss of bone with aging. (Used with permission of Mayo Foundation for Medical Education and Research. All rights reserved.)
      Bone mass and BMD, however, are clearly not the only determinants of fracture risk. As an example, in the setting of equivalent femoral neck BMD T-scores as determined by DXA, older individuals are typically at significantly higher risk for fracture compared with younger persons.
      • Kanis J.A.
      • Johnell O.
      • Oden A.
      • Jonsson B.
      • De Laet C.
      • Dawson A.
      Risk of hip fracture according to the World Health Organization criteria for osteopenia and osteoporosis.
      In addition to aging, increased fracture risk independent of BMD has also been established in specific populations, including patients treated with glucocorticoids
      • Van Staa T.P.
      • Laan R.F.
      • Barton I.P.
      • Cohen S.
      • Reid D.M.
      • Cooper C.
      Bone density threshold and other predictors of vertebral fracture in patients receiving oral glucocorticoid therapy.
      and those with type 2 diabetes mellitus.
      • Schwartz A.V.
      • Vittinghoff E.
      • Bauer D.C.
      • et al.
      Association of BMD and FRAX score with risk of fracture in older adults with type 2 diabetes.
      These observations thus highlight the importance of assessing aspects of bone quality, including the material properties and microarchitecture of bone that have been shown to be altered in, for example, patients with type 2 diabetes mellitus.
      • Farr J.N.
      • Drake M.T.
      • Amin S.
      • Melton 3rd, L.J.
      • McCready L.K.
      • Khosla S.
      In vivo assessment of bone quality in postmenopausal women with type 2 diabetes.
      ,
      • Burghardt A.J.
      • Issever A.S.
      • Schwartz A.V.
      • et al.
      High-resolution peripheral quantitative computed tomographic imaging of cortical and trabecular bone microarchitecture in patients with type 2 diabetes mellitus.
      However, there is currently a paucity of data on longitudinal changes in these parameters that occur with aging. Nevertheless, with the recent availability of high-resolution peripheral quantitative computed tomography to measure bone microarchitecture in vivo, BMD-independent effects of aging have been shown. In one study of young vs older individuals with DXA-matched areal BMD, similar trabecular bone microarchitectural parameters were seen at the distal radius, but cortical porosity was significantly higher in the older individuals.
      • Nicks K.M.
      • Amin S.
      • Atkinson E.J.
      • Riggs B.L.
      • Melton 3rd, L.J.
      • Khosla S.
      Relationship of age to bone microstructure independent of areal bone mineral density.
      Thus, aspects of bone quality are likely at least partly to explain the BMD-independent higher fracture risk in elderly populations.

      Changes in Bone Remodeling with Aging

      Throughout life, the skeleton is a highly metabolically active organ that undergoes continuous bone remodeling with removal of old and damaged bone by osteoclasts followed by self-renewal and repair by osteoblasts, which lay down new bone matrix. The actions of osteoclasts and osteoblasts are both spatially and temporally coordinated, with this coordination at least in part overseen by osteocytes as well as by an array of both local and systemic factors released by various cell types to ultimately sculpt the unique composition and architecture of the skeleton. At the cellular level as shown in Figure 2, remodeling occurs by teams of short-lived cells composing basice multicellular units that constitute 3 consecutive phases: resorption, when osteoclasts digest old or damaged bone; reversal, when mononuclear cells invade the space; and formation, when osteoblasts are recruited to the site of resorption to fill in new bone until the excavated cavity is completely replaced.
      • Hattner R.
      • Epker B.N.
      • Frost H.M.
      Suggested sequential mode of control of changes in cell behaviour in adult bone remodelling.
      On a microscopic level, these remodeling cycles occur continuously throughout the skeleton, adjusting skeletal mass, size, and shape to meet mechanical demands, to respond to stress or injury, and to repair the continuous accumulation of microdamage that occurs with time. Collectively, these functions result from the complex interplay of cells in the bone microenvironment. However, around midlife in women and later in men, this normally balanced bone remodeling process becomes unbalanced, that is, increased resorption occurs along with insufficient formation, ultimately resulting in a net loss of bone.
      Figure thumbnail gr2
      Figure 2The bone remodeling cycle of resorption, reversal, and formation. Osteoclast and osteoblast precursors are recruited from the marrow to become active osteoclasts and osteoblasts on bone surfaces, where they arrange themselves into temporary structures termed basic multicellular units that execute bone remodeling in coordination with the actions of matrix-embedded osteocytes. (Used with permission of Mayo Foundation for Medical Education and Research. All rights reserved.)

      Old Bone

      With aging, this fundamental remodeling imbalance drives bone loss and structural decay in both sexes. If this state of negative bone balance remains uncorrected (eg, by pharmacologic intervention), bone loss will continue from trabecular, endocortical, and intracortical surfaces, eventually resulting in an aged osteoporotic skeleton.
      • Seeman E.
      Age- and menopause-related bone loss compromise cortical and trabecular microstructure.
      Characteristics of osteoporotic bone include loss of trabecular connectivity, thinning or complete removal of trabeculae, endocortical bone loss resulting in cortical thinning, and increased remodeling within haversian canals resulting in increased cortical porosity.
      • Parfitt A.M.
      Skeletal heterogeneity and the purposes of bone remodeling: implications for the understanding of osteoporosis.
      Much of this bone loss reflects aging-associated deficits in osteoblast-mediated bone formation. For example, mean wall trabecular thickness, a surrogate measure of the work done by osteoblasts, decreases substantially with aging in both women and men.
      • Lips P.
      • Courpron P.
      • Meunier P.J.
      Mean wall thickness of trabecular bone packets in the human iliac crest: changes with age.
      However, although there is a fairly steady decline in circulating biochemical markers of bone formation in men with aging, higher circulating bone formation markers after menopausal onset are generally seen in women, reflecting higher bone turnover due to the coordinated coupling that occurs between osteoclasts, which remove bone, and osteoblasts, which work to replace bone within these excavated spaces.
      • Eriksen E.F.
      Normal and pathological remodeling of human trabecular bone: three dimensional reconstruction of the remodeling sequence in normals and in metabolic bone disease.
      ,
      • Khosla S.
      Pathogenesis of age-related bone loss in humans.
      Despite this increased bone turnover, however, because bone resorption in postmenopausal women remains higher relative to formation at a cellular level, a negative bone balance ensues. Thus, aging is associated with defective bone formation in both sexes.
      The adult skeleton comprises approximately 20% trabecular and 80% cortical bone. Given that loss of trabecular bone generally occurs both earlier and more rapidly than loss of cortical bone, the proportion of bone loss that is trabecular effectively decelerates with aging, leading to an inherent effective acceleration of cortical bone loss that ultimately dominates with advancing age.
      • Ensrud K.E.
      • Palermo L.
      • Black D.M.
      • et al.
      Hip and calcaneal bone loss increase with advancing age: longitudinal results from the study of osteoporotic fractures.
      ,
      • Zebaze R.M.
      • Ghasem-Zadeh A.
      • Bohte A.
      • et al.
      Intracortical remodelling and porosity in the distal radius and post-mortem femurs of women: a cross-sectional study.
      The aging-associated cortical bone loss may contribute to the greater prevalence of fractures, including a higher proportion of nonvertebral fractures, among the elderly.
      • Curtis E.M.
      • van der Velde R.
      • Moon R.J.
      • et al.
      Epidemiology of fractures in the United Kingdom 1988-2012: variation with age, sex, geography, ethnicity and socioeconomic status.
      • Kanis J.A.
      • Johnell O.
      • Oden A.
      • et al.
      Long-term risk of osteoporotic fracture in Malmo.
      • Melton L.J.
      • Chrischilles E.A.
      • Cooper C.
      • Lane A.W.
      • Riggs B.L.
      How many women have osteoporosis.
      • Melton III, L.J.
      • Atkinson E.J.
      • O'Connor M.K.
      • O'Fallon W.M.
      • Riggs B.L.
      Bone density and fracture risk in men.
      Furthermore, bone loss at specific skeletal locations (eg, at the femoral neck and distal forearm) probably increases the risk for fracture at those sites relative to others. Collectively, loss of both trabecular and cortical bone with aging contributes to both reduced bone quality and bone strength, ultimately placing older individuals at higher risk for fractures.

      Bone Marrow Adiposity

      The marrow cavity within bone is the only location in humans where bone and fat coexist adjacent to one another.
      • Devlin M.J.
      • Rosen C.J.
      The bone-fat interface: basic and clinical implications of marrow adiposity.
      Notably, whereas osteoblast numbers decline with advancing age and ultimately lead to reduced bone formation,
      • Lips P.
      • Courpron P.
      • Meunier P.J.
      Mean wall thickness of trabecular bone packets in the human iliac crest: changes with age.
      aging is also associated with bone marrow adipose tissue (BMAT) accumulation.
      • Schwartz A.V.
      • Sigurdsson S.
      • Hue T.F.
      • et al.
      Vertebral bone marrow fat associated with lower trabecular BMD and prevalent vertebral fracture in older adults.
      Within the marrow cavity, adipocytes accumulate along the endosteal surface and surrounding regions of the appendicular skeleton with both aging and osteoporosis but also in other settings, including anorexia nervosa, diabetes, calorie restriction, and skeletal unloading.
      • Bredella M.A.
      • Fazeli P.K.
      • Miller K.K.
      • et al.
      Increased bone marrow fat in anorexia nervosa.
      • Ecklund K.
      • Vajapeyam S.
      • Feldman H.A.
      • et al.
      Bone marrow changes in adolescent girls with anorexia nervosa.
      • Baum T.
      • Yap S.P.
      • Karampinos D.C.
      • et al.
      Does vertebral bone marrow fat content correlate with abdominal adipose tissue, lumbar spine bone mineral density, and blood biomarkers in women with type 2 diabetes mellitus?.
      • Trudel G.
      • Payne M.
      • Madler B.
      • et al.
      Bone marrow fat accumulation after 60 days of bed rest persisted 1 year after activities were resumed along with hemopoietic stimulation: the Women International Space Simulation for Exploration study.
      In addition, exposure to irradiation or chemotherapy can result in a profound, rapid accumulation of BMAT both locally and at skeletal sites distant to where the initial exposure occurred.
      • Wright L.E.
      • Buijs J.T.
      • Kim H.S.
      • et al.
      Single-limb irradiation induces local and systemic bone loss in a murine model.
      ,
      • Chandra A.
      • Lagnado A.B.
      • Farr J.N.
      • et al.
      Targeted reduction of senescent cell burden alleviates focal radiotherapy-related bone loss.
      Therefore, the physiologic and pathophysiologic roles of BMAT are diverse and context specific and remain incompletely understood.
      Despite such unknowns, it is now well recognized that BMAT accumulates within the marrow cavity at both appendicular and axial osteoporotic skeletal sites with advancing age and that this inverse relationship of decreased bone mass and increased marrow adiposity is a hallmark feature of skeletal aging. Studies in both animals and humans have begun to shed light on how and why this paradox may exist. For example, because both osteoblasts and adipocytes originate from the same pool of pluripotent mesenchymal stem cell (MSC) progenitors,
      • Bianco P.
      • Robey P.G.
      • Simmons P.J.
      Mesenchymal stem cells: revisiting history, concepts, and assays.
      their ultimate lineage fate may be altered by one or more fundamental mechanisms of aging (as reviewed later). Indeed, it is possible that the marked decrease in the number of osteoblasts found on bone surfaces in old age is due to an age-related change in lineage allocation toward one that favors the differentiation of MSCs into adipocytes.
      • Devlin M.J.
      • Rosen C.J.
      The bone-fat interface: basic and clinical implications of marrow adiposity.
      However, it remains unclear how and precisely from where bone marrow adipocytes arise. Thus, a simple dichotomous tradeoff between fat and bone is unlikely to be the only explanation for reduced bone formation with aging. An alternative potential mechanism is that dwindling MSC progenitor pools or insufficient activation or defective differentiation of these progenitors may underlie this observation. Despite numerous remaining questions, therapeutic interventions directed at modulating the bone marrow niche as well as specific cell populations within it may yet prove beneficial for slowing or perhaps even reversing the age-related defects in bone formation.

      Osteoblast and Osteocyte Apoptosis and Age-Related Changes in the Osteocyte Canicular Network

      Throughout life, all normal nucleated cells experience various internal and external stressful stimuli (eg, DNA damage, oxidative stress, oncogenic insults), and in response, their default fate is apoptosis, although a cell can undergo alternative fates, such as cellular senescence (as reviewed later and in more detail elsewhere
      • Khosla S.
      • Farr J.N.
      • Tchkonia T.
      • Kirkland J.L.
      The role of cellular senescence in ageing and endocrine disease.
      ). However, when the signals to die overpower the various mechanisms of survival, programed cell death (ie, apoptosis) ensues. Because bone is a tissue that must constantly self-renew, apoptosis is necessary for the regeneration of new cells and to initiate bone remodeling. For example, the number of osteoblasts on bone surfaces and their life span, which is only about 12 days in mice and 150 days in humans,
      • Weinstein R.S.
      • Jilka R.L.
      • Parfitt A.M.
      • Manolagas S.C.
      Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids.
      ,
      • Parfitt A.M.
      • Han Z.H.
      • Palnitkar S.
      • Rao D.S.
      • Shih M.S.
      • Nelson D.
      Effects of ethnicity and age or menopause on osteoblast function, bone mineralization, and osteoid accumulation in iliac bone.
      are regulated by a multitude of factors in the bone microenvironment that fine-tune both their birth from MSCs and their death by apoptosis.
      • Manolagas S.C.
      Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis.
      Indeed, whereas a subset of osteoblasts will differentiate into either lining cells or osteocytes, the majority (∼60% to 90%) undergo apoptosis.
      • Jilka R.L.
      • Weinstein R.S.
      • Bellido T.
      • Parfitt A.M.
      • Manolagas S.C.
      Osteoblast programmed cell death (apoptosis): modulation by growth factors and cytokines.
      ,
      • Jilka R.L.
      • Weinstein R.S.
      • Parfitt A.M.
      • Manolagas S.C.
      Quantifying osteoblast and osteocyte apoptosis: challenges and rewards.
      Although aging contributes to increased osteoblast apoptosis and reduced osteoblast numbers,
      • Weinstein R.S.
      • Jilka R.L.
      • Parfitt A.M.
      • Manolagas S.C.
      Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids.
      ,
      • Parfitt A.M.
      • Han Z.H.
      • Palnitkar S.
      • Rao D.S.
      • Shih M.S.
      • Nelson D.
      Effects of ethnicity and age or menopause on osteoblast function, bone mineralization, and osteoid accumulation in iliac bone.
      osteocytes by contrast are long-lived cells that survive under normal circumstances essentially until their local environment is remodeled; however, when they eventually do undergo apoptosis, their empty lacunae hold the remnants of their degraded DNA. Osteocyte apoptosis results in the recruitment of osteoclasts to the vicinity to thereby initiate remodeling and is exacerbated with, for example, glucocorticoid excess,
      • O'Brien C.A.
      • Jia D.
      • Plotkin L.I.
      • et al.
      Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength.
      unloading,
      • Aguirre J.I.
      • Plotkin L.I.
      • Stewart S.A.
      • et al.
      Osteocyte apoptosis is induced by weightlessness in mice and precedes osteoclast recruitment and bone loss.
      and aging.
      • Tiede-Lewis L.M.
      • Xie Y.
      • Hulbert M.A.
      • et al.
      Degeneration of the osteocyte network in the C57BL/6 mouse model of aging.
      ,
      • Schurman C.A.
      • Verbruggen S.W.
      • Alliston T.
      Disrupted osteocyte connectivity and pericellular fluid flow in bone with aging and defective TGF-β signaling.
      Under these conditions, osteocyte apoptosis contributes to the disruption of the osteocyte lacunar-canalicular system, including loss of osteocyte connectivity as well as deficient pericellular fluid flow, and results in deficient bone quality.
      • Tiede-Lewis L.M.
      • Xie Y.
      • Hulbert M.A.
      • et al.
      Degeneration of the osteocyte network in the C57BL/6 mouse model of aging.
      ,
      • Schurman C.A.
      • Verbruggen S.W.
      • Alliston T.
      Disrupted osteocyte connectivity and pericellular fluid flow in bone with aging and defective TGF-β signaling.
      By contrast, normal physiologic strains imparted from mechanical loading are important to the generation of survival signals (eg, nitric oxide, prostaglandins [prostaglandin E2], and WNTs) that prevent osteocyte apoptosis.
      • Klein-Nulend J.
      • Semeins C.M.
      • Ajubi N.E.
      • Nijweide P.J.
      • Burger E.H.
      Pulsating fluid flow increases nitric oxide (NO) synthesis by osteocytes but not periosteal fibroblasts—correlation with prostaglandin upregulation.
      • Ajubi N.E.
      • Klein-Nulend J.
      • Nijweide P.J.
      • et al.
      Pulsating fluid flow increases prostaglandin production by cultured chicken osteocytes—a cytoskeleton-dependent process.
      • Joeng K.S.
      • Lee Y.C.
      • Lim J.
      • et al.
      Osteocyte-specific WNT1 regulates osteoblast function during bone homeostasis.
      • Noble B.S.
      • Peet N.
      • Stevens H.Y.
      • et al.
      Mechanical loading: biphasic osteocyte survival and targeting of osteoclasts for bone destruction in rat cortical bone.
      In addition, autophagy is an essential intracellular recycling pathway whereby, for example, during periods of calorie restriction (ie, fasting), misfolded proteins and damaged organelles are escorted for lysosomal degradation to thereby maintain cell survival, which suggests that impaired osteocyte autophagy that occurs with glucocorticoid excess, skeletal aging, or obesity-associated inflammation may exacerbate osteocyte apoptosis.
      • Yao W.
      • Dai W.
      • Jiang J.X.
      • Lane N.E.
      Glucocorticoids and osteocyte autophagy.
      • Onal M.
      • Piemontese M.
      • Xiong J.
      • et al.
      Suppression of autophagy in osteocytes mimics skeletal aging.
      • Ju L.
      • Han J.
      • Zhang X.
      • et al.
      Obesity-associated inflammation triggers an autophagy-lysosomal response in adipocytes and causes degradation of perilipin 1.
      Therefore, adequate exercise and healthy dietary habits represent important lifestyle choices to maintain the integrity of the mechanosensory osteocyte canicular network and thus bone health in the elderly.

      Fundamental Aging Mechanisms that Contribute to the Pathogenesis of Skeletal Aging

      Rather than living in a disease-free state or suffering from only a single age-related disease, the elderly typically experience multimorbidity. It is increasingly recognized that this is at least in part due to myriad fundamental biologic aging mechanisms that drive many if not all chronic diseases of aging.
      • Lopez-Otin C.
      • Blasco M.A.
      • Partridge L.
      • Serrano M.
      • Kroemer G.
      The hallmarks of aging.
      Importantly, when these biologic underpinnings are triggered in an age-dependent manner, chronic diseases tend to accumulate in a groupwise fashion. Therefore, an improved knowledge of the underlying aging processes shared across tissues and systems is fundamental for any future efforts to therapeutically target these mechanisms to delay the appearance or progression of age-related diseases in unison. Accordingly, a major current goal within the field of geroscience is to develop interventions that slow aging to improve quality of life by extension of years of health while simultaneously compressing years spent with multimorbidity.
      In a seminal review,
      • Lopez-Otin C.
      • Blasco M.A.
      • Partridge L.
      • Serrano M.
      • Kroemer G.
      The hallmarks of aging.
      9 fundamental mechanisms of aging that cause functional decline were identified. Importantly, all are both shared across various tissues and common to mammalian organisms. These hallmarks of aging include genomic instability, epigenetic alterations, telomere attrition, loss of proteostasis, cellular senescence, mitochondrial dysfunction, dysregulated nutrient sensing, stem cell exhaustion, and altered intercellular communication.
      • Lopez-Otin C.
      • Blasco M.A.
      • Partridge L.
      • Serrano M.
      • Kroemer G.
      The hallmarks of aging.
      Each of these aging hallmarks meets the following criteria: it is manifested during aging; experimental aggravation accelerates aging; and experimental amelioration slows aging and extends health span.
      • Lopez-Otin C.
      • Blasco M.A.
      • Partridge L.
      • Serrano M.
      • Kroemer G.
      The hallmarks of aging.
      These hallmark mechanisms of aging are linked in that either aggravation or amelioration of one hallmark could in theory accelerate or alleviate other hallmarks. Importantly, there is now substantial evidence, for example, in old mice, demonstrating that therapeutically targeting fundamental aging mechanisms can collectively delay the onset of or alleviate the progression of numerous age-related diseases.
      With regard to bone, research on the fundamental biology of the aging skeleton has accelerated rapidly during the past few decades. An interesting outcome of this surge is the now ample evidence that each of the identified hallmarks of aging is present within bone, that each can drive skeletal aging, and that each fundamental mechanism is manifested in old bone to varying degrees.
      • Farr J.N.
      • Almeida M.
      The spectrum of fundamental basic science discoveries contributing to organismal aging.
      As is the case with aging in other tissues, primary hallmarks of bone aging include genomic instability, telomere attrition, epigenetic alterations, and loss of proteostasis (eg, autophagy), each of which universally acts as a stressor to induce damage to a variety of cell types within the bone microenvironment.
      • Farr J.N.
      • Almeida M.
      The spectrum of fundamental basic science discoveries contributing to organismal aging.
      In particular, long-lived cells, such as osteocytes in bone, appear to be uniquely susceptible to these age-associated insults.
      • Farr J.N.
      • Khosla S.
      Cellular senescence in bone.
      ,
      • Farr J.N.
      • Kaur J.
      • Doolittle M.L.
      • Khosla S.
      Osteocyte cellular senescence.
      In contrast, the antagonistic hallmarks of aging (ie, dysregulated nutrient sensing, mitochondria dysfunction, and cellular senescence) evolved to limit cellular damage. Whereas they are effective in doing so initially, with advancing age they become exacerbated and in turn deleterious.
      • Lopez-Otin C.
      • Blasco M.A.
      • Partridge L.
      • Serrano M.
      • Kroemer G.
      The hallmarks of aging.
      As an example, cells in the bone microenvironment that incur damage in the form of primary aging hallmarks may become senescent as a compensatory mechanism to prevent malignant transformation.
      • Collado M.
      • Blasco M.A.
      • Serrano M.
      Cellular senescence in cancer and aging.
      However, as senescent cells accumulate in the aged bone microenvironment, which has been demonstrated in old mice and humans,
      • Farr J.N.
      • Fraser D.G.
      • Wang H.
      • et al.
      Identification of senescent cells in the bone microenvironment.
      these damaged cells themselves may further contribute to skeletal aging through their release of senescence-associated factors (eg, inflammatory cytokines, chemokines) that act as proresorptive factors or potentially contribute to alter the lineage allocation of MSC progenitors into BMAT.
      • Farr J.N.
      • Khosla S.
      Cellular senescence in bone.
      Both are examples of the integrative hallmarks of aging, that is, altered intercellular communication and stem cell exhaustion, that are signatures of skeletal aging.
      • Farr J.N.
      • Almeida M.
      The spectrum of fundamental basic science discoveries contributing to organismal aging.
      Therefore, safely interfering with fundamental mechanisms of aging may represent new therapeutic strategies for age-related chronic diseases, including, for example, targeting cellular senescence in old age to prevent osteoporosis
      • Farr J.N.
      • Xu M.
      • Weivoda M.M.
      • et al.
      Targeting cellular senescence prevents age-related bone loss in mice.
      and extending the health span.
      • Kaur J.
      • Farr J.N.
      Cellular senescence in age-related disorders.
      In summary, aging exacerbates bone loss in both sexes and results in imbalanced bone resorption relative to formation. It is associated with increased marrow adiposity, osteoblast/osteocyte apoptosis, and accumulation of senescent cells (Figure 3).
      Figure thumbnail gr3
      Figure 3Hallmarks of skeletal aging in old bone. BMSC, bone marrow stem cell. (Used with permission of Mayo Foundation for Medical Education and Research. All rights reserved.)

      Targeting Fundamental Aging Mechanisms in Humans

      Because of the mounting evidence from preclinical studies that several age-related diseases can be alleviated by therapeutically targeting fundamental mechanisms of aging,
      • Lopez-Otin C.
      • Blasco M.A.
      • Partridge L.
      • Serrano M.
      • Kroemer G.
      The hallmarks of aging.
      potential interventions to test this approach in humans are gaining momentum. For example, because senescent cells accumulate with age in various tissues and at anatomic sites of disease,
      • Khosla S.
      • Farr J.N.
      • Tchkonia T.
      • Kirkland J.L.
      The role of cellular senescence in ageing and endocrine disease.
      a logical strategy has been to use drugs that selectively kill senescent cells (ie, “senolytics”), which are in various stages of clinical development.
      • Robbins P.D.
      • Jurk D.
      • Khosla S.
      • et al.
      Senolytic drugs: reducing senescent cell viability to extend health span.
      Indeed, given that pharmacologic elimination of senescent cells using first-generation senolytics prevents aspects of skeletal aging with apparent advantages over antiresorptive therapy in old mice
      • Farr J.N.
      • Khosla S.
      Cellular senescence in bone.
      ,
      • Farr J.N.
      • Xu M.
      • Weivoda M.M.
      • et al.
      Targeting cellular senescence prevents age-related bone loss in mice.
      ,
      • Kaur J.
      • Farr J.N.
      Cellular senescence in age-related disorders.
      and also improves physical function and resilience,
      • Xu M.
      • Pirtskhalava T.
      • Farr J.N.
      • et al.
      Senolytics improve physical function and increase lifespan in old age.
      the aim of an ongoing randomized controlled trial (ClinicalTrials.gov identifier NCT04313634) in older women with a high cellular senescence burden is to translate these novel findings in mice to humans. Thus, depending on the success of similar ongoing and future trials, drugs that target fundamental aging mechanisms may one day complement currently approved osteoporosis-specific therapies to simultaneously prevent or to delay multiple age-related diseases.

      Management of Skeletal Fragility

      Efforts to prevent the age-related increase in fractures are aimed at bone loss as well as at addressing underlying chronic illnesses that may contribute to skeletal fragility and sarcopenia. Importantly, the “osteoporosis prescription” should be individualized to each patient’s goals and take into account comorbidities and psychosocial factors. In addition, identifying access to community resources, such as geriatric-friendly fitness centers, transportation, and affordable home modification strategies, is likely to contribute significantly to the success of the management plan.
      • Coll P.P.
      • Phu S.
      • Hajjar S.H.
      • et al.
      The prevention of osteoporosis and sarcopenia in older adults.

      Physical Activity

      Exercise programs designed to strengthen core muscles and to improve balance have consistently been shown to reduce the risk of falls.
      • Guirguis-Blake J.M.
      • Michael Y.L.
      • Perdue L.A.
      • Coppola E.L.
      • Beil T.L.
      Interventions to prevent falls in older adults: updated evidence report and systematic review for the US Preventive Services Task Force.
      ,
      • Sherrington C.
      • Fairhall N.J.
      • Wallbank G.K.
      • et al.
      Exercise for preventing falls in older people living in the community.
      In addition, resistance training, including weight-bearing and medium- to high-impact exercise, for 12 to 18 months can modestly improve BMD.
      • Sherrington C.
      • Fairhall N.J.
      • Wallbank G.K.
      • et al.
      Exercise for preventing falls in older people living in the community.
      • Troy K.L.
      • Mancuso M.E.
      • Butler T.A.
      • Johnson J.E.
      Exercise early and often: effects of physical activity and exercise on women's bone health.
      • Howe T.E.
      • Rochester L.
      • Neil F.
      • Skelton D.A.
      • Ballinger C.
      Exercise for improving balance in older people.
      • Howe T.E.
      • Shea B.
      • Dawson L.J.
      • et al.
      Exercise for preventing and treating osteoporosis in postmenopausal women.
      High-intensity progressive training, including in a supervised multimodal program, can similarly lead to improvements in BMD and physical performance.
      • Daly R.M.
      • Gianoudis J.
      • Kersh M.E.
      • et al.
      Effects of a 12-month supervised, community-based, multimodal exercise program followed by a 6-month research-to-practice transition on bone mineral density, trabecular microarchitecture, and physical function in older adults: a randomized controlled trial.
      • Gianoudis J.
      • Bailey C.A.
      • Ebeling P.R.
      • et al.
      Effects of a targeted multimodal exercise program incorporating high-speed power training on falls and fracture risk factors in older adults: a community-based randomized controlled trial.
      • Watson S.L.
      • Weeks B.K.
      • Weis L.J.
      • Harding A.T.
      • Horan S.A.
      • Beck B.R.
      High-intensity resistance and impact training improves bone mineral density and physical function in postmenopausal women with osteopenia and osteoporosis: the LIFTMOR randomized controlled trial.
      In older adults, exercise programs should be personalized to be safe, sustainable, and reproducible.
      • Dent E.
      • Morley J.E.
      • Cruz-Jentoft A.J.
      • et al.
      International Clinical Practice Guidelines for Sarcopenia (ICFSR): screening, diagnosis and management.
      ,
      WHO guidelines approved by the Guidelines Review Committee.
      For instance, low-intensity exercise, such as walking, sitting, and standing exercises, can be progressively increased as tolerated by patients (Table).
      TableMayo Clinic Osteoporosis Exercise Chart
      Type, intensity, and frequency of the exercises are individualized by the treating physician or physical therapist.
      Low-intensity exercises
      Walking and standing posture
      • Walking purpose: to strengthen legs and heart and improve balance
      • Standing posture purpose: to learn to stand properly, which will improve posture Wall arch: to stretch shoulders and calves and tone the back and abdomen Chin tuck: to help straighten head and shoulders Chest stretch: to stretch chest and improve back posture Upper back extension: to stretch chest, strengthen upper back muscles, and improve back posture Pelvic tilt: to strengthen lower back and abdominal muscles Back and shoulder stretch: to stretch upper back and shoulders
      Moderate-intensity exercises
      Back posture exercise: to flatten upper back, stretch chest, and improve posture

      Sitting stretch: to stretch calf and thigh muscles and improve muscle tone of legs

      Calf stretch: to stretch back of thighs and calf muscles, improve posture, and stretch heel cords

      Upper back lift: to strengthen back muscles

      Abdomen strengthening: to strengthen abdomen

      Shoulders strengthening: to help strengthen shoulder and back muscles

      Spine and hip exercise: to strengthen arms, spine, and hips and improve muscle tone
      Modified from Mayo Clinic Osteoporosis Exercise Chart, Mehrsheed Sinaki, Stephen Hodgson, patient education booklet MIC200054. Used with permission of Mayo Foundation for Medical Education and Research. All rights reserved.
      a Type, intensity, and frequency of the exercises are individualized by the treating physician or physical therapist.
      Yoga has gained significant enthusiasm in the past number of years, particularly in older adults. Moderate-duration yoga exercises may in fact improve balance and prevent falls.
      • Schmid A.A.
      • Van Puymbroeck M.
      • Koceja D.M.
      Effect of a 12-week yoga intervention on fear of falling and balance in older adults: a pilot study.
      ,
      • Youkhana S.
      • Dean C.M.
      • Wolff M.
      • Sherrington C.
      • Tiedemann A.
      Yoga-based exercise improves balance and mobility in people aged 60 and over: a systematic review and meta-analysis.
      Sudden rotational movements or excessive flexion of the spine, however, can predispose to vertebral compression fractures and should be avoided.
      • Sfeir J.G.
      • Drake M.T.
      • Sonawane V.J.
      • Sinaki M.
      Vertebral compression fractures associated with yoga: a case series.
      There is also moderate-quality evidence that Tai chi improves balance, reduces falls, and benefits overall bone health, particularly in older adults and women with osteoarthritis.
      • Zou L.
      • Wang C.
      • Chen K.
      • et al.
      The effect of Taichi practice on attenuating bone mineral density loss: a systematic review and meta-analysis of randomized controlled trials.

      Calcium and Vitamin D

      Both calcium and vitamin D play central roles in maintenance of the musculoskeletal system. Hypovitaminosis D in older men and women is associated with decreased muscle strength and an increased risk of hip fractures.
      • Visser M.
      • Deeg D.J.
      • Lips P.
      Longitudinal Aging Study Amsterdam. Low vitamin D and high parathyroid hormone levels as determinants of loss of muscle strength and muscle mass (sarcopenia): the Longitudinal Aging Study Amsterdam.
      ,
      • Cauley J.A.
      • Lacroix A.Z.
      • Wu L.
      • et al.
      Serum 25-hydroxyvitamin D concentrations and risk for hip fractures.
      Vitamin D replacement improves both BMD and muscle function
      • Zhao J.G.
      • Zeng X.T.
      • Wang J.
      • Liu L.
      Association between calcium or vitamin D supplementation and fracture incidence in community-dwelling older adults: a systematic review and meta-analysis.
      and, in institutionalized older adults, may also reduce the risk for falls.
      • Bischoff-Ferrari H.A.
      • Dawson-Hughes B.
      • Willett W.C.
      • et al.
      Effect of vitamin D on falls: a meta-analysis.
      • Uusi-Rasi K.
      • Patil R.
      • Karinkanta S.
      • et al.
      Exercise and vitamin D in fall prevention among older women: a randomized clinical trial.
      • Reid I.R.
      Osteoporosis: evidence for vitamin D and calcium in older people.
      In ambulatory healthy older women residing in nursing homes, treatment with 800 IU of vitamin D and 1200 mg of elemental calcium was associated with a significant reduction in hip and nonvertebral fractures compared with placebo.
      • Chapuy M.C.
      • Arlot M.E.
      • Duboeuf F.
      • et al.
      Vitamin D3 and calcium to prevent hip fractures in elderly women.
      A pooled analysis of trials looking at vitamin D supplementation and osteoporotic fractures showed similar results in older men and women independent of the type of dwelling.
      • Bischoff-Ferrari H.A.
      • Willett W.C.
      • Orav E.J.
      • et al.
      A pooled analysis of vitamin D dose requirements for fracture prevention.
      On the other hand, in a randomized controlled trial of older men and women with history of falls, various doses of vitamin D failed to reduce fall risk, although all groups had improvement in overall physical performance.
      • Bischoff-Ferrari H.A.
      • Dawson-Hughes B.
      • Orav E.J.
      • et al.
      Monthly high-dose vitamin D treatment for the prevention of functional decline: a randomized clinical trial.
      ,
      • Waterhouse M.
      • Sanguineti E.
      • Baxter C.
      • et al.
      Vitamin D supplementation and risk of falling: outcomes from the randomized, placebo-controlled D-Health Trial.
      In the absence of malabsorptive conditions, daily vitamin D supplementation is preferred to larger intermittent doses (such as monthly or annually), which were associated with an increased risk of falls in older adults.
      • Bischoff-Ferrari H.A.
      • Dawson-Hughes B.
      • Orav E.J.
      • et al.
      Monthly high-dose vitamin D treatment for the prevention of functional decline: a randomized clinical trial.
      • Waterhouse M.
      • Sanguineti E.
      • Baxter C.
      • et al.
      Vitamin D supplementation and risk of falling: outcomes from the randomized, placebo-controlled D-Health Trial.
      • Ginde A.A.
      • Blatchford P.
      • Breese K.
      • et al.
      High-dose monthly vitamin D for prevention of acute respiratory infection in older long-term care residents: a randomized clinical trial.
      • Pekkarinen T.
      • Valimaki V.V.
      • Aarum S.
      • et al.
      The same annual dose of 292000 IU of vitamin D (cholecalciferol) on either daily or four monthly basis for elderly women: 1-year comparative study of the effects on serum 25(OH)D concentrations and renal function.
      It is recommended that all adults aged 70 years and older receive 1200 mg of calcium per day and 800 IU of vitamin D per day from all sources, including diet. Dietary sources of calcium are varied and include dairy products and nuts, whereas vitamin D is limited to oily fish and fortified juices. Excessive doses of either calcium or vitamin D can be associated with adverse events, but daily calcium intake of up to 2000 to 2500 mg and daily vitamin D intake of up to 4000 IU are considered safe.
      • Reid I.R.
      Osteoporosis: evidence for vitamin D and calcium in older people.
      ,
      • Ross A.C.
      • Manson J.E.
      • Abrams S.A.
      • et al.
      The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know.

      Pharmacotherapy

      Pharmacologic interventions to prevent age-related bone loss and to reduce the risk of fractures include estrogen, raloxifene, 4 bisphosphonates (alendronate, ibandronate, risedronate, and zoledronate), denosumab (RANKL-neutralizing monoclonal antibodies), teriparatide (parathyroid hormone 1-34), abaloparatide (parathyroid hormone–related peptide analogue), and romosozumab (sclerostin-neutralizing monoclonal antibodies). The skeletal benefits and overall risks associated with these drugs in patients with osteoporosis have been reviewed,
      • Khosla S.
      • Hofbauer L.C.
      Osteoporosis treatment: recent developments and ongoing challenges.
      particularly in older adults.
      • Sfeir J.G.
      • Pignolo R.J.
      Pharmacologic interventions for fracture risk reduction in the oldest old: what is the evidence?.
      Estrogen has been shown to improve BMD and to reduce overall fracture risk, although its use is limited to the early postmenopausal years, given the associated risk of cardiovascular events and breast cancer in older women.
      • Cauley J.A.
      • Robbins J.
      • Chen Z.
      • et al.
      Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial.
      Bisphosphonates, whether in oral or intravenous form, are the most commonly prescribed osteoporosis pharmacotherapy; they provide 40% to 70% reduction in risk of both vertebral and hip fractures. Although generally well tolerated, their prolonged use may be associated with extremely rare yet serious adverse effects including atypical femoral fractures and osteonecrosis of the jaw.
      • Shane E.
      • Burr D.
      • Abrahamsen B.
      • et al.
      Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research.
      ,
      • Khosla S.
      • Burr D.
      • Cauley J.
      • et al.
      Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research.
      Denosumab is a more potent antiresorptive agent that provides a similar fracture risk reduction to bisphosphonates but a more robust increase in BMD.
      • Bone H.G.
      • Wagman R.B.
      • Brandi M.L.
      • et al.
      10 Years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension.
      Denosumab may be associated with hypocalcemia, particularly in patients with advanced kidney disease, as well as with an increased risk of mild upper respiratory or superficial skin infections.
      • McClung M.R.
      • Lewiecki E.M.
      • Cohen S.B.
      • et al.
      Denosumab in postmenopausal women with low bone mineral density.
      Delayed dosing or discontinuation of denosumab, particularly after long-term use, is associated with a rapid rebound bone loss and an increased risk of vertebral fractures.
      • Zanchetta M.B.
      • Boailchuk J.
      • Massari F.
      • et al.
      Significant bone loss after stopping long-term denosumab treatment: a post FREEDOM study.
      Osteoanabolic agents (ie, teriparatide and abaloparatide) stimulate bone formation and provide a greater increase in BMD than antiresorptive agents, which translates into a reduction of 30% to 50% in nonvertebral fractures and 60% to 80% in vertebral fractures.
      • Neer R.M.
      • Arnaud C.D.
      • Zanchetta J.R.
      • et al.
      Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis.
      ,
      • Miller P.D.
      • Hattersley G.
      • Riis B.J.
      • et al.
      Effect of abaloparatide vs placebo on new vertebral fractures in postmenopausal women with osteoporosis: a randomized clinical trial.
      Although abaloparatide is stable at room temperature for up to 30 days, teriparatide requires refrigeration at temperatures between 36 and 46 °F (2 to 8 °C). These are both self-administered as daily injections, and their use is largely limited to patients with a high fracture risk because of greater costs and possible higher rates of discontinuation among older adults.
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      ,
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      Postmarketing surveillance data showed that teriparatide did not increase the risk of adult osteosarcoma
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      Teriparatide did not increase adult osteosarcoma incidence in a 15-year US postmarketing surveillance study.
      ; therefore, in November 2020, the US Food and Drug Administration no longer requires a black box warning to that effect.
      Romosozumab, a dual antiresorptive and osteoanabolic agent, provides approximately 70% reduction in vertebral fractures during 1 year but a nonsignificant reduction in nonvertebral fractures.
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      Romosozumab treatment in postmenopausal women with osteoporosis.
      In women, an increase in adjudicated serious cardiovascular events was observed with romosozumab compared with alendronate but not compared with placebo.
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      Romosozumab or alendronate for fracture prevention in women with osteoporosis.
      A similar increase was seen in men receiving romosozumab compared with placebo.
      • Lewiecki E.M.
      • Blicharski T.
      • Goemaere S.
      • et al.
      A phase III randomized placebo-controlled trial to evaluate efficacy and safety of romosozumab in men with osteoporosis.
      Aggregate data from 6 romosozumab trials showed a slight increase (relative risk, 1.39; 95% CI, 1.01 to 1.90) in composite 4-point major adverse cardiovascular events (myocardial infarction, stroke, heart failure, and atrial fibrillation), although the risk was not significant when each event was considered separately.
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      Denosumab or romosozumab therapy and risk of cardiovascular events in patients with primary osteoporosis: systematic review and meta-analysis.
      It is thus recommended to avoid romosozumab in patients with a high cardiovascular risk, specifically those with a history of a cardiovascular event in the preceding year.

      Nonskeletal Benefits of Osteoporosis Therapy

      Preclinical and clinical studies have also examined additional nonskeletal effects of a number of these drugs. This may influence the choice of therapy, particularly in frail older adults. In addition, consideration should be given to patients’ neurobehavioral and social environments in choosing the most appropriate drug.
      Zoledronate infusion every 18 months has been shown to reduce the overall incidence of cancers, particularly breast cancer in women with osteopenia.
      • Reid I.R.
      • Horne A.M.
      • Mihov B.
      • et al.
      Effects of zoledronate on cancer, cardiac events, and mortality in osteopenic older women.
      A 3.3% absolute risk reduction in mortality was also seen in the HORIZON Recurrent Fracture Trial, with similar mortality benefits being observed in other trials of zoledronate.
      • Boonen S.
      • Black D.M.
      • Colon-Emeric C.S.
      • et al.
      Efficacy and safety of a once-yearly intravenous zoledronic acid 5 mg for fracture prevention in elderly postmenopausal women with osteoporosis aged 75 and older.
      ,
      • Lyles K.W.
      • Colon-Emeric C.S.
      • Magaziner J.S.
      • et al.
      Zoledronic acid and clinical fractures and mortality after hip fracture.
      However, a single zoledronate infusion did not improve secondary functional outcomes in institutionalized frail women 65 years or older.
      • Greenspan S.L.
      • Perera S.
      • Ferchak M.A.
      • Nace D.A.
      • Resnick N.M.
      Efficacy and safety of single-dose zoledronic acid for osteoporosis in frail elderly women: a randomized clinical trial.
      Nonskeletal effects of denosumab have similarly been investigated, particularly in patients with osteosarcopenia. In postmenopausal women, denosumab was associated with a significant increase in lean mass and grip strength after 3 years.
      • Bonnet N.
      • Bourgoin L.
      • Biver E.
      • Douni E.
      • Ferrari S.
      RANKL inhibition improves muscle strength and insulin sensitivity and restores bone mass.
      In community-dwelling older adults, denosumab significantly improved balance measures and decreased the fear of falls compared with zoledronate; measures of physical function (ie, gait speed and TUG test) improved significantly to comparable degrees with both agents.
      • Phu S.
      • Bani Hassan E.
      • Vogrin S.
      • Kirk B.
      • Duque G.
      Effect of denosumab on falls, muscle strength, and function in community-dwelling older adults.
      Denosumab also reduced fall incidence in a pooled analysis of 5 trials, with a greater reduction observed in those younger than 75 years.
      • Chotiyarnwong P.
      • McCloskey E.
      • Eastell R.
      • et al.
      A pooled analysis of fall incidence from placebo-controlled trials of denosumab.

      Conclusion

      As the population ages to longer life spans less shaped by natural selection, healthspan will not keep pace, creating challenges that humans remain poorly equipped to handle, including an enormous burden of late-life morbidity due to age-related diseases and chronic morbidities that often coexist in the elderly. The skeleton is not exempt as aging exacerbates bone loss in both sexes and results in imbalanced bone resorption relative to formation and is associated with increased marrow adiposity, osteoblast/osteocyte apoptosis, and accumulation of senescent cells. Whereas available pharmacologic interventions are safe, effective, and important in preventing skeletal aging, new approaches focused on developing interventions to delay or to treat osteoporosis as well as other aging-associated diseases as a group have gained momentum.

      Potential Competing Interests

      The authors report no competing interests.

      Supplemental Online Material

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