Loss of musculoskeletal mass and function is a natural ageing trait, reinforced by an unhealthy life style. Loss of bone (osteoporosis) and muscle (sarcopaenia) are conditions whose prevalence are increasing because of the change in population distribution in the western world towards an older mean age. Improvements in lifestyle factors, such as diet, smoking and exercise, are the most powerful tools to combat this decline efficiently; however, public health interventions aimed at tackling these problems have shown abysmal success at the population level, mostly due to failure in compliance. With these issues in mind, we believe that the primary prevention modality in coming decades will be pharmacological. We review the basic biology of musculoskeletal ageing and what measures can be taken to prevent ageing-associated loss of musculoskeletal mass and function, with particular emphasis on pharmacological means.
Introduction
Loss of musculoskeletal function is a symptom secondary to organ failure, post-surgery immobilisation, and cancer, but is also an independent condition contributing to mortality and morbidity. Although the clinical impact of loss of musculoskeletal function is an appreciated concept in the field of geriatrics and gerontology, it continues to advance slowly in other clinical specialties.
Muscle mass and skeletal integrity are both lost as a natural consequence of ageing, starting in the late twenties and accelerating in the fifties . In the presence of inherited or environmental factors (e.g. smoking, unhealthy eating, overweight, and inactivity), this loss is accelerated . If the maximum levels of musculoskeletal mass were lower than normal during adolescence or early adulthood, or the rate of loss is increased, this loss can accumulate to a level where it becomes symptomatic in the form of fractures (for osteoporosis) and loss of operational independence (for muscle). Muscle loss can manifest as age-associated slow loss, termed sarcopenia, or aggressive, rapid muscle loss in association with critical illness, such as cancer, organ failure, or massive trauma, termed cachexia.
In most western countries, older individuals comprise a larger proportion of the population . As loss of muscle and bone tissue is inherent to the ageing process, this means that we should expect an increase in incidence and prevalence of musculoskeletal frailty. Historically, osteoporosis has been well characterised as a disease, as it is easily quantifiable and the clinical consequences are apparent (fracture compared with no fracture). The same cannot be said for loss of skeletal muscle mass and function, normally termed sarcopenia. Exactly how much skeletal muscle mass or function should be lost before it is considered pathological, and what biomarkers should be used to measure it? Furthermore, are these biomarkers readily available in clinics and hospitals? Muscle strength or function measurement often suffers from high intra-rater variability or reliance on equipment not normally found in healthcare settings . Similarly, normal techniques to measure muscle mass (e.g. Dual X-ray absorptiometry and bioimpedance) are sensitive to changes in hydration state and muscle fibrosis that are frequently present in elderly or multimorbid individuals, the groups most frequently subject to clinically relevant muscle loss . As of early 2013, a few different sets of diagnostic criteria have been proposed, but no single definition has been globally accepted . This absence of clear diagnostic criteria has been a major issue in spreading awareness of the fact that loss of muscle is not just a symptom secondary to other diseases, but a medical condition in itself.
So, loss of muscle and bone is a problem and a growing one at that, but how can we as clinicians and scientists deal with it in a strategic manner?
Public health interventions
It has been well proven that maintaining a healthy lifestyle, avoiding cigarette smoke and excessive alcohol consumption, ensuring adequate intake of essential nutrients, particularly proteins and vegetables, and engaging in physical activity that challenges cardiorespiratory and musculoskeletal fitness, are the best measures to prevent loss of musculoskeletal mass or function . For example, systematic resistance training can increase muscle strength enough to ensure that an individual will most likely never get below the functional capacity threshold ( Fig. 1 ), and bone strength enough to practically eliminate risk of developing osteoporosis, particularly if continued through adulthood .
Cardiovascular fitness is an even more trainable physiological trait, and most likely has an even greater effect on all-cause mortality and morbidity . It has been shown to have impressive positive effects on glucose control, lipid levels, blood pressure, and cancer incidence.
Together, positive lifestyle factors effectively slow ageing, whereas negative life style factors effectively accelerate ageing, thereby coining the terms unsuccessful ageing versus successful ageing ( Fig. 1 ). Obviously, these refer to the success of having the chronological age outrun the biological age.
Public health interventions, in the form of public recommendations or large-scale supervised lifestyle changes, have thus far demonstrated abysmal success in the cost–benefit analyses of clinical outcomes, primarily caused by long-term intervention adherence . Also, it has already been shown that health behaviour is strongly skewed across the various socioeconomic measures, with less educated people on lower income levels having much shorter expected life spans and, naturally, increased mortality and morbidity. This population also seems less amenable to behaviour modification, solidifying their position at the bottom of total and functional life expectancies .
Pharmacotherapy
Unless a miraculous scientific discovery enables us to motivate the demographic segments with the poorest health and the lowest propensity to advance their own health, this route (life style modification) is unlikely to succeed (on a public health scale). Although this may seem apathetic or even cynical to a health professional, the dominating method of primary prevention will most likely be pharmacological interventions, as this modality has historically shown greater succes in producing the desired compliance .
Historically, pharmacotherapy has only been acceptable in the direct treatment of diseases, but its use has already spilled over into prevention. This is a combined effect of the intent of improving public health (prevention is cheaper that treatment and ensures better quality of life) and expanding the business spheres of pharmaceutical companies. It seems that conditions that are progressing towards ‘real’ pathologies or biomarkers thereof, such as high blood pressure, the “wrong” high-density lipoprotein particle types, or hyperglycaemia, are treated to avoid progression. For example, beta-blockers are used to prevent progress of myocardial hypertrophy, and statins or fibrates are used to prevent progression of cardiovascular disease. This poses another dilemma, as no treatment is free of adverse effects: statins, for example, increase susceptibility to muscle damage and the risk of developing rhabdomyolysis, meaning that the treatment for metabolic dysfunction may negatively affect muscle health .
If or when this trend expands to musculoskeletal health, pharmacological interventions, such as hormone replacement therapy, could similarly be viewed as a means to slow or prevent the natural progression of loss of muscle mass and power as well as bone mineral content and integrity, rather than being used when the tissues are so atrophied that quite intense interventions are needed.
Pharmaceutical companies are alert to this development. The prospect of developing drugs to prevent the deterioration of musculoskeletal function between the ages of 45 and 50 years, and until people die, represents a potentially huge market.
Public health interventions
It has been well proven that maintaining a healthy lifestyle, avoiding cigarette smoke and excessive alcohol consumption, ensuring adequate intake of essential nutrients, particularly proteins and vegetables, and engaging in physical activity that challenges cardiorespiratory and musculoskeletal fitness, are the best measures to prevent loss of musculoskeletal mass or function . For example, systematic resistance training can increase muscle strength enough to ensure that an individual will most likely never get below the functional capacity threshold ( Fig. 1 ), and bone strength enough to practically eliminate risk of developing osteoporosis, particularly if continued through adulthood .
Cardiovascular fitness is an even more trainable physiological trait, and most likely has an even greater effect on all-cause mortality and morbidity . It has been shown to have impressive positive effects on glucose control, lipid levels, blood pressure, and cancer incidence.
Together, positive lifestyle factors effectively slow ageing, whereas negative life style factors effectively accelerate ageing, thereby coining the terms unsuccessful ageing versus successful ageing ( Fig. 1 ). Obviously, these refer to the success of having the chronological age outrun the biological age.
Public health interventions, in the form of public recommendations or large-scale supervised lifestyle changes, have thus far demonstrated abysmal success in the cost–benefit analyses of clinical outcomes, primarily caused by long-term intervention adherence . Also, it has already been shown that health behaviour is strongly skewed across the various socioeconomic measures, with less educated people on lower income levels having much shorter expected life spans and, naturally, increased mortality and morbidity. This population also seems less amenable to behaviour modification, solidifying their position at the bottom of total and functional life expectancies .
Pharmacotherapy
Unless a miraculous scientific discovery enables us to motivate the demographic segments with the poorest health and the lowest propensity to advance their own health, this route (life style modification) is unlikely to succeed (on a public health scale). Although this may seem apathetic or even cynical to a health professional, the dominating method of primary prevention will most likely be pharmacological interventions, as this modality has historically shown greater succes in producing the desired compliance .
Historically, pharmacotherapy has only been acceptable in the direct treatment of diseases, but its use has already spilled over into prevention. This is a combined effect of the intent of improving public health (prevention is cheaper that treatment and ensures better quality of life) and expanding the business spheres of pharmaceutical companies. It seems that conditions that are progressing towards ‘real’ pathologies or biomarkers thereof, such as high blood pressure, the “wrong” high-density lipoprotein particle types, or hyperglycaemia, are treated to avoid progression. For example, beta-blockers are used to prevent progress of myocardial hypertrophy, and statins or fibrates are used to prevent progression of cardiovascular disease. This poses another dilemma, as no treatment is free of adverse effects: statins, for example, increase susceptibility to muscle damage and the risk of developing rhabdomyolysis, meaning that the treatment for metabolic dysfunction may negatively affect muscle health .
If or when this trend expands to musculoskeletal health, pharmacological interventions, such as hormone replacement therapy, could similarly be viewed as a means to slow or prevent the natural progression of loss of muscle mass and power as well as bone mineral content and integrity, rather than being used when the tissues are so atrophied that quite intense interventions are needed.
Pharmaceutical companies are alert to this development. The prospect of developing drugs to prevent the deterioration of musculoskeletal function between the ages of 45 and 50 years, and until people die, represents a potentially huge market.
Is the ageing defect intrinsic or extrinsic?
In ageing biology, especially with muscle ageing, the terminology of extrinsic or intrinsic age effects is frequently used. These refer to ‘extrinsic’ or ‘intrinsic’ effects to the muscle cells or satellite cells . Thus, extrinsic age effects are derived from the environment the muscle or muscle cells ‘sees’ (e.g. extra-cellular matrix, hormones, and cytokines), whereas intrinsic effects are manifested locally in the cells or tissues (e.g. telomere shortening or other DNA damage and epigenetic modifications). Although intrinsic ageing defects are inevitably influenced or caused by extrinsic factors, this terminology is of use when considering treatment options.
Extrinsic, circulating factors are the principal domain of pharmacotherapy; intrinsic effects may respond slower or not at all to regular pharmacotherapy. If drugs do not affect the intrinsic age defect, substitution of stem-cell populations of bone or muscle may be a viable route as accumulated defects in these cell types represents one of the sources of intrinsic aging defects.
Animal studies using the model of parabiosis between young and old animals have shown a significant extrinsic component to muscle ageing. In parabiosis, animals are sewn together so that their circulations form anastomoses, effectively sharing blood. When attaching young and old animals, so-called heterochronous parabiosis, this allows for transfer of soluble factors between the animals which effectively allows the blood of young animals to rescue a major part of the aging phenotype in the old animals . This model seems biologically sound; however, the effects are not necessarily reproduced in in-vitro models . Still, this does indicate that at least parts of the tissue ageing defects are mediated by humoral factors.
Muscle
How does muscle age?
Functionally, age causes significant loss of strength. Strength can be measured in a number of ways: maximum weight moved in a resistance exercise, maximum Torque produced eccentrically, isometrically or concentrically, maximum power produced or rate of force development (RFD). All of these parameters are affected adversely by age . Particularly, the ability to produce ‘fast strength’ (i.e. power or RFD) is impaired , whereas the ‘slow strength’ is less severely affected. Muscle endurance or the fatigue resistance of the muscle is not lost to the same extent as muscle strength . These functional changes can be accounted for by a number of biological changes in muscles.
With age, net atrophy of muscle tissue occurs. This loss is modest during adulthood, staying around 0.5% per year until around the age of 50 years, where the loss increases to 1.0 to 1.4% per year . This loss constitutes the real basis for sarcopaenia (literally, ‘poverty of flesh’). This loss of muscle tissue is accounted for by atrophy of individual muscle fibres and loss of muscle fibres.
First, general atrophy of muscle fibres occurs through loss of myofibrillar protein. This is particularly obvious for the fast (type II) fibres, showing 15–25% atrophy, with no significant loss in slow (type I) fibres. This atrophy is even more pronounced in the very fast type IIX fibres than in the type IIA .
Second, loss of muscle fibres occurs. It has been estimated from cadaver studies that 5% of muscle fibres are lost between the ages of 24 years and the ages of 50 years, whereas a dramatic loss of 35% occurs during the next 25 years . The loss of fibres does not seem to be specific to fibre types . With advanced age, however, hybrid muscle fibers increase in abundance, expressing proteins from slow as well as fast muscle fibres.
These biological changes at the muscle fibre level can be explained in part by death of motor neurones. Muscle fibres are arranged in motor units, with motor neurones activating groups of about 100–1000 fibres. Motor units are arranged in a continuum from slow to intermediate to fast motor units. Slow motor neurones innervate small groups of the small, slow but fatigue-resistant type I fibres, whereas fast motor units consist of fast motor neurones innervating large groups of the large, fast and more easily fatigueable fibres. With ageing, selective loss of fast motor neurons occurs, giving rise to orphan fast muscle fibres that are for the most part hi-jacked by slow motor units. These fibres convert partially to slow fibres, ending with a hybrid phenotype showing characteristics of both fast and slow fibres . As the ability to produce mechanical power (‘fast strength’) is fairly dependent on fibre type, this change affects the ability to produce power. It has been shown that the ability to produce power is a stronger predictor for mobility and operational independence than maximal strength .
Motor units are recruited in order of increasing size with increased force demands, commonly referred to as the Henneman size principle . This means that, with low force demands, small motor units, predominantly consisting of small, slow type I fibres, are recruited. As external force demands increases, the number of slow motor units recruited increases. Gradually, with increasing demands, recruitment also taps into intermediate motor units with mixed fast and slow fibre populations. Eventually, with high force is demanded from the muscle, fast motor units predominantly consist of fast muscle fibres, with the fastest and largest motor units containing the very fast type IIX fibres. Thus, when big, fast type II muscle fibres are incorporated into slow motor units (and eventually turned into a hybrid fiber), this causes irregularities in the size distribution of motor units. This in turn affects motor accuracy, especially with low force movements, as the recruitment order does not adjust well to the previously small motor units having grown bigger and stronger, owing to incorporation of previously fast muscle fibres. At the other end of the spectrum, force is lost as a result of death of fast motor units, limiting especially the ability to produce rapid movements, which is necessary in posture stabilisation, for example . Therefore, fast motor unit death is probably one of the reasons motor skills deteriorate with age .
In addition to these age effects, changes in tissue quality occur, especially with advanced age (over 80 years). At this point, loss of muscle architecture accelerates, and increasing amounts of intramuscular connective tissue and intramuscular fat deposits appear. This is probably caused by a shift towards increased fibrogenicity of resident interstitial mesenchymal stem cells and satellite cells in muscle.
Intrinsic ageing defects
Satellite cell defects
Skeletal muscle cells are multinucleated syncytia, formed by fusion of myoblasts. Postnatally, myoblasts are derived from the population of satellite cells, which are muscle-committed stem cells resting outside muscle fibres, until called upon, when muscle regeneration is ongoing. When activated, they undergo one or more divisions, form new fibres, or are integrated into existing ones and become myonuclei. It has been shown that, with age, the size of the satellite cell pool decreases , particularly around fast muscle fibres.
Satellite cells can be extracted from muscle tissues and cultured in vivo , forming myoblasts and even contracting myotubes. In these model systems, satellite cells derived from older individuals have been shown to replicate more slowly, differentiate less efficiently, and form smaller myotubes. As extrinsic factors are held constant in these in-vivo systems, this strongly indicates that an ageing defect is accumulated in the satellite cells.
It has also been shown that endurance and resistance exercise restore satellite cell count ; furthermore, testosterone treatment restores satellite cell number and activation in men as well as women . Thus, although an intrinsic ageing defect can be shown to exist in satellite cells, at least part of this appears to be downstream of extrinsic factors.
Mitochondrial DNA damage and oxidative stress
Oxidative stress is a natural consequence of oxidative metabolism, as this continuously generates high reactive oxygen species, which is the reason that all eukaryotic cells have a number of antioxidant defenses. With age, oxidative stress damages mitochondrial DNA . These DNA damages are propagated during mitochondrial biogenesis, leading to faulty metabolism with age. When the oxidative burden overcomes the antioxidant defenses, however, oxidative damage occurs. This is probably a fundamental part of the development of poor health, and one of the reasons that a poor lifestyle effectively accelerates ageing.
In muscle, these oxidative stress damages are particularly abundant in mitochondrial DNA. It has been shown that, with training, the concentration of mtDNA damage can be reduced or ‘watered’ out by new mitochondrial biogenesis, most likely from new mitochondria from satellite cells . It has been suggested that the death of motor neurones described above can be attributed to unchecked oxidative stress (i.e. overproduction of reactive oxygen or underproduction of endogenous antioxidants), both of which are connected to dysfunctional mitochondria . This is supported by the fact that chronic endurance exercise seems to reduce motor unit loss with age . Endurance exercise maintains mitochondrial function and endogenous antioxidant mechanisms, reducing the risk of unchecked oxidative stress.
Therefore, although oxidative stress and mtDNA damage are intrinsic ageing traits, they are readily affected by external factors, most notably exercise. Less convincing evidence shows that bioactive compounds can reduce the amount of damaged mtDNA, in the same way exercise does, or reduces oxidative stress in muscle fibres.
Muscle protein is continually turned over at a rate of 1–2% per day, but the myonuclei are also turned over. Every now and then, a myonuclei breaks down and its place is taken by the nucleus from an activated satellite cell, and this rate seems to increase with exercise. Even the aged mitochondria, characterised by damages to the mitochondrial DNA, can be watered out by mitochondrial biogenesis derived from un-used and un-aged satellite cell mitochondria or a hitherto unknown pool of intact muscle fibre mitochondria . Thus, almost all the ‘age-able’ components of muscle seem to have the capability to undergo remodelling, thereby clearing out accumulated age defects.
When muscle does manifest increased irreversible age defects, such as increased fibrogenicity, it seems to be an accumulated effect of a number of external factors. When enough of these ageing defects have accumulated, some of the ageing effect becomes permanent or quasi-permanent.
Extrinsic ageing defect
Extracellular matrix niche defects
The extracellular matrix (ECM) has historically been understood to be a somewhat passive structure, but recent evidence supports the idea that the ECM is more biologically active than we previously thought. Extracellular matrix components may act as signalling molecules, in so-called juxtacrine signalling, and growth factors are bound to ECM components, causing release upon ECM turnover or muscle damage . This is a relatively new field within muscle research, but several signalling pathways have been hypothesised to be involved in cell–cell or cell–ECM interactions, with particular focus on signalling through the Notch receptor, activated by the Delta and Jagged family of ligands. Upon injury, myofibres and satellite cells express surface protein ligands belonging to the Delta family. These directly interact with Notch receptors on nearby satellite cells, activating them and stimulating their proliferation. With advanced age, this upregulation of Delta fails, in part, which explains the waning ability to deal with muscle injury with age .
Another pathway associated with juxtacrine signalling affecting satellite cells, is the Wnt/Frizzled pathway. Wnt glycoproteins are secreted from myofibres and satellite cells to activate the Frizzled receptor, giving rise to increased levels of beta catenin, This, in turn, is thought to stimulate satellite cell proliferation . In addition, Wnt plays a complex role in satellite cell-related transdifferentiation. In young animals, it maintains the myogenic commitment and lineage but, in old animals, the reverse seems to be the case, as it stimulates convergence towards a fibrogenic phenotype in satellite cells . One of the Wnt ligands, Wnt10b, is also involved in maintaining a balance between adipogenic and myogenic commitment of myoblasts, underscoring the complex role of the Wnt signalling pathway. Wnt signalling has been reviewed thoroughly by Yin et al. recently .
Sex hormones and age-related hypogonadism
Age-related hypogonadism has been shown to adversely affect the entire musculoskeletal system. With women, this is particularly evident during menopause, where oestrogen levels drop rapidly over the course of the perimenopause. In men, this decline is spread out from the age of about 30 years, and declining throughout the course of life. At the age of 50 years, 50% of men are below the lowest percentile of testosterone levels in young men . Because of this gradual drop in sex hormones in men, it has historically been hard to separate male hypogonadism-related symptoms from ‘normal’ ageing symptoms. Hence, the presence of a male ‘andropause’ is still a contested topic.
Both sex hormones, especially testosterone, have been shown to control muscle mass directly; however, it has been shown that adequate levels of sex hormones are required for adaptations to exercise . It is tempting to hypothesise that the age-associated decreases in sex hormones impairs the ability of the body to respond to everyday physical activity, thereby contributing indirectly to loss of muscle mass, although this is hard to prove.
In the heterochronic parabiosis models mentioned previously, it has been shown that testosterone is at least one of the circulating factors that is able to rejuvenate muscle. Sinha et al. showed that, in young and old parabiotic castrated mice, surgically joined muscle (from young and old animals) is not rejuvenated; however in parabiotic, mice treated with testosterone, muscles seemed fully rejuvenated. So far, this has only been shown for male animals, but the evidence points to sex hormones carrying a similar effect in female animals .
Inflammatory environment
It is known that the adaptational response to exercise or habitual physical activity is, to some extent, dependent on inflammatory cytokines, particularly prostaglandin E . Other prostaglandins, particularly prostaglandin F, have been shown to exhibit catabolic effects clearly on muscle. Thus, part of the inflammatory cascade is used by muscle for signalling in anabolic or catabolic responses. It has been shown that the use of non-steroidal anti-inflammatory drugs (NSAIDs) inhibits the normal response to resistance training in young people, as it prevents increases in protein synthesis and hypertrophy ; on the contrary, it has been shown to actually improve the training response in elderly people , indicating that the inflammatory environment somehow shifts towards a state that does not favour retention of muscle mass. Non-steroidal anti-inflammatory drugs have been shown to restore the anabolic response to feeding in old animals, which is otherwise impaired with ageing .
Thus, when inflammatory cytokines are upregulated, they form chronic low-grade inflammation that is detrimental to muscle health. Evidence suggests that inhibition of this inflammation may be beneficial to muscle health. Moreover, potent inflammatory cytokines, such as IL-6 and TNFα, are known to increase with age, and it has been suggested that they mediate impaired myogenicity of muscle; indeed, both have been shown to be catabolic mediators in themselves . Both of these also increase with age, and the age-associated increase in these and others inflammatory cytokine have also been implicated in the accumulation of muscle frailty with age.
Myostatin signalling
Myostatin is a member of the growth and differentiation factor superfamily. It is a hormone and cytokine, whose function it is to limit muscle growth. In the embryonic stage, it stimulates the terminal differentiation of myoblasts, therefore limiting the numbers of muscle cells formed. In the post-embryonic developmental stages, however, it limits muscle size . Myostatin defects have been identified in dogs, cattle, sheep and mice, unanimously resulting in hyperplasia-driven hypertrophy. Myostatin inhibition in the postnatal state have been shown to cause muscle hypertrophy driven by muscle fibre growth in mice as well as in humans, although this type of intervention seems to work better in rodents, possibly owing to their higher resting levels of myostatin.
Also, during muscle loss from cachexia, glucocorticoids or immobilisation, myostatin has been shown to increase whereas, during anabolisation, it has been shown to decrease . It is still unclear to what extent these changes in myostatin signalling are mediators of the changes in muscle mass or symptoms thereof.
Bone
How does bone age?
Bone ageing is a complicated process. It includes imbalances primarily at the systemic level, but also to some extent locally in the bone tissue. It is well known that bone loss is associated with age, and this is a key component of age-associated fragility . Site-dependent differences exist with age-related bone loss, although the reason for these differences are unclear. Primary causes of age-related bone loss, independent of secondary causes such as loss of gonadal steroids, are still poorly understood .
Locally, bone remodelling is a process ensuring that bone is continuously exchanged . This process is a tight balance between the activity of the bone-resorbing osteoclasts and bone-forming osteoblasts . As a function of time, the bones are exposed to continuous mechanical stress, and this leads to accumulation of microcracks and microfractures . The presence of microcracks leads to activation of targeted bone remodelling, in which osteoclasts remove the damaged bone area, and then subsequently stimulate the recruitment and activation of osteoblasts leading to formation of bone. In normal healthy adults, this process is balanced, meaning that all removed bone is replaced by new bone . Hence, the overall age of the bone tissue is fairly constant during healthy adulthood . Bone remodelling rates are, however, vastly different depending on the individual bone type, with trabecular bone in the vertebrae being highly remodelled and thus ‘young’ in terms of tissue age, whereas cortical bone is remodelled much less and therefore ‘old’ in terms of tissue age .
With increasing age, bone remodelling becomes eschewed towards a condition of continuous, albeit slow, bone loss, a phenomenon that seems to be primarily mediated by a loss of bone formation by the osteoblasts ; however, exactly how this affects bone age is not completely clear. Increased bone tissue age seems to have a direct effect on the osteoclasts, as aged bone matrix has been shown to stimulate bone resorption to a markedly higher level than young bone matrix .
Indications of bone tissue age are provided by measuring the ratio of alpha to beta isomerised collagen type I, as alpha to beta is a spontaneous process occurring with time, and the ratio between these two forms is related to bone tissue age . This ratio can be measured using the alpha and beta-forms of the bone resorption marker CTX-I. Studies using this parameter have shown that, in cases of accelerated bone loss, the alpha to beta ratio is increased, indicating an overall decrease in bone tissue age owing to the pathology . An intriguing finding is that potent antiresorptives, such as the bisphosphonates, cause increased bone age, both measured using the alpha to beta ratio, and when measuring the mineralisation density; oestrogen or selective oestrogen receptor modulators (SERMs), however, do not cause increased bone age . The consequences of these findings are not yet clear, it has been indicated that the massive suppression of bone remodelling induced by bisphosphonates may have deleterious effects on bone integrity .
Extrinsic and intrinsic factors in bone ageing
Factors contributing to skeletal ageing
Skeletal ageing is characterized by a systemic loss of bone, leading to increased fragility. The extent to which the age-related bone loss is occurs primarily in the tissue or is systemic in nature is somewhat unclear; however, several extrinsic factors that play a role in age-related bone loss have been identified; the most important is the loss of sex steroid production .
Sex hormones and age-related hypogonadism
A primary contributor is the gonadal steroids, and it is well-established that loss of production of gonadal steroids leads to bone loss owing to accelerated bone turnover . This phenomenon is especially prominent in women, where a clear link exists between menopause and subsequent acceleration of bone turnover, leading to loss . In addition, the continuous loss of testosterone contributes to accelerated bone loss in men . Finally, oestrogen levels in men have been shown to be related to bone density at both cortical and trabecular sites. The lower the oestrogen levels, the lower the bone density and the higher the bone loss, indicating a bone protective role of oestrogen is also present in men .
Loss of gonadal steroid production causes upregulation of osteoclast generation and bone resorption. The coupling between osteoclasts and osteoblasts ensures that bone formation also is upregulated; however, this does not completely compensate for the upregulation of resorption and bone loss ensues . In women, it is well known that restoration of oestrogen levels is protective against bone loss, whereas long-term efficacy is somewhat blunted owing to the coupling of resorption and formation . In men, oestrogen treatment also attenuates bone loss, as does testosterone treatment, thereby again underlining the protective effects of gonadal steroids on bone in both genders . The extent to which the protective effects of testosterone in men are mediated by aromatase-mediated conversion of testosterone to oestrogen are still being studied, but studies in men deficient in aromatase have highlighted the relevance of this process . The molecular mechanisms of oestrogen and testosterone in bone tissues are outside the scope of this chapter, and for these we refer to the review by Marie and Kassem M .
Intrinsic effects of ageing on bone
Impaired osteoblast viability
Intrinsic mechanisms are also involved in the ageing of the skeleton. Several studies have compared the effects of ageing on bone cell functions, and these studies have shown that proliferation is reduced, whereas apoptosis is increased in aged osteoblast precursors, resulting in overall reduced bone formation potential . Furthermore, transplantation of osteoblast precursor mesenchymal stem cells from young to old animals improve bone density , suggesting that part of the bone ageing phenotype is caused by the marrow mesenchymal stem cells. So far, it is unclear what genetic or epigenetic mechanisms are behind these ageing defects.
Reinforced osteoclast activity
In a similar manner, it has been shown that the osteoclast precursor pool in the blood is expanded, and that osteoclast viability is increased ex vivo in old animals compared with young , documenting that some degree of age imprinting occurs. Intrinsic processes have also been shown to be being involved in age-related bone loss; however, elucidating to what extent these methods are specifically related to bone cell function and bone ageing is highly complex, there is a way to go before it can be solidly concluded whether an effect is intrinsic or extrinsic.
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