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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.
Aging exacerbates bone loss in both sexes and results in imbalanced bone resorption relative to formation.
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Hallmarks of skeletal aging include increased marrow adiposity, osteoblast/osteocyte apoptosis, and accumulation of senescent cells.
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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,
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
Secondary osteoporosis and metabolic bone disease in patients 50 years and older with osteoporosis or with a recent clinical fracture: a clinical perspective.
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.
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.
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.
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.
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.
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.
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,
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.
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.
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 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.
In addition to aging, increased fracture risk independent of BMD has also been established in specific populations, including patients treated with glucocorticoids
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.
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.
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.
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 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.)
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.
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.
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.
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.
Normal and pathological remodeling of human trabecular bone: three dimensional reconstruction of the remodeling sequence in normals and in metabolic bone disease.
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.
The aging-associated cortical bone loss may contribute to the greater prevalence of fractures, including a higher proportion of nonvertebral fractures, among the elderly.
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.
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.
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?.
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.
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,
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.
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
). 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,
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,
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Both are examples of the integrative hallmarks of aging, that is, altered intercellular communication and stem cell exhaustion, that are signatures of skeletal 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
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 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.)
Because of the mounting evidence from preclinical studies that several age-related diseases can be alleviated by therapeutically targeting fundamental mechanisms 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,
a logical strategy has been to use drugs that selectively kill senescent cells (ie, “senolytics”), which are in various stages of clinical development.
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
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.
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.
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.
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.
J Bone Miner Res.2018; 33 (Published correction appears in J Bone Miner Res. 2019;34(3):572): 211-220
For instance, low-intensity exercise, such as walking, sitting, and standing exercises, can be progressively increased as tolerated by patients (Table).
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.
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.
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.
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.
Association between calcium or vitamin D supplementation and fracture incidence in community-dwelling older adults: a systematic review and meta-analysis.
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.
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.
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.
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.
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.
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,
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.
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.
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.
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.
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.
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.
; 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.
In women, an increase in adjudicated serious cardiovascular events was observed with romosozumab compared with alendronate but not compared with placebo.
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.
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.
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.
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.
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.
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.
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.
Secondary osteoporosis and metabolic bone disease in patients 50 years and older with osteoporosis or with a recent clinical fracture: a clinical perspective.
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.
High-resolution peripheral quantitative computed tomographic imaging of cortical and trabecular bone microarchitecture in patients with type 2 diabetes mellitus.
Normal and pathological remodeling of human trabecular bone: three dimensional reconstruction of the remodeling sequence in normals and in metabolic bone disease.
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?.
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.
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.
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.
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.
J Bone Miner Res.2018; 33 (Published correction appears in J Bone Miner Res. 2019;34(3):572): 211-220
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.
Association between calcium or vitamin D supplementation and fracture incidence in community-dwelling older adults: a systematic review and meta-analysis.
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.
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.
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