RESEARCH ARTICLE
Exercise and bone health across the lifespan
´
via Santos
.
Kirsty Jayne Elliott-Sale
.
Craig Sale
Received: 28 March 2017 / Accepted: 10 October 2017
Ó The Author(s) 2017. This article is an open access publication
Abstract With ageing, bone tissue undergoes sig-
nificant com positional, architectural and metabolic
alterations potential ly leading to osteoporosis. Osteo-
porosis is the most prevalent bone disorder, which is
characterised by progressive bone weakening and an
increased risk of fragility fractures. Although this
metabolic disease is conven tionally associated with
ageing and menopause, the predisposing factors are
thought to be established during childhood and
adolescence. In light of this, exercise interventions
implemented during maturation are likely to be highly
beneficial as part of a long-term strategy to maximise
peak bone mass and hence delay the onset of age- or
menopause-related osteoporosis. This notion is sup-
ported by data on exercise interventions implemented
during childhood and adolescence, which confirmed
that weight-bearing activity, particularly if undertaken
during peripubertal development, is capable of gener-
ating a significa nt osteogenic response leading to bone
anabolism. Recent work on human ageing and epige-
netics suggests that undertaking exercise after the
fourth decade of life is still important, given the anti-
ageing effect and health benefits provided, potentially
occurring via a delay in telomere shortening and
modification of DNA methyl ation patterns associated
with ageing. Exercise is among the primary modifiable
factors capable of influencing bone health by preserv-
ing bone mass and strength, preventing the death of
bone cells and anti-ageing action provided.
Keywords Exercise Lifespan Bone health Bone
adaptation Bone ageing Osteoporosis
Introduction
Ageing is accompanied by the loss of bone mass and
strength, predisposing the skeleton to the onset of
osteoporosis (Demontiero et al. 2012). Osteoporosis is
a metabolic disorder prevalent in post-menopausal
women, characterised by accentuated bone weaken-
ing, greater susceptibility to fragility fractures (Hern-
lund et al. 2013 ), but also higher mortality risks (Klop
et al. 2017; Panula et al. 2011). Hip fra ctures and
associated comorbidities in particular, are responsible
for the increase in 1-year mortality risks by more than
threefold when compared with those without a bone
fracture (Klop et al. 2017; Panula et al. 2011).
Osteoporosis is estimated to affect 22 million
women and 5.5 million men in the EU (Hernlund
et al. 2013). In 2010, there were 3.5 M osteoporotoic
fractures reported in the EU; 620,000 hip fractures,
520,000 vertebral fractures, 560,000 forearm fractures
L. Santos K. J. Elliott-Sale C. Sale (&)
Musculoskeletal Physiology Research Group, Sport,
Health and Performance Enhancement Research Centre,
School of Science and Technology, Nottingham Trent
University, Nottingham NG11 8NS, UK
e-mail: Craig.sale@ntu.ac.uk
123
Biogerontology
DOI 10.1007/s10522-017-9732-6
and 1,800,000 other fractures (Hernlund et al. 2013).
In the UK, 3.21 M people, aged over 50 years, are
living with osteoporosis, with more than 536,000 new
fragility fractures occur every year (Svedb om et al.
2013). The prevalence of osteoporosis is expected to
rise over the next decades by virtue of population
ageing. One-third of the UK population is 50 years old
or above, and current estimates suggest this age
segment will grow from 21.6 million in 2010 to 26.2
million in 2025, corresponding to an increase of 21%
(UK Office for National Statistics 2016).
Osteoporosis and other musculoskletal disorders,
particularly osteoarthritis and bone trauma, are
amongst the most common problems affecting the
elderly and are a leading cause of physical disability
(Gheno et al. 2012; Weinstein 2016). Limitations in
mobility and independance are psychologically dev-
astating and represent a huge economic challenge to
the sustainability of health care systems (Gheno et al.
2012; Weinstein 2016). Exercise, nutrition and phar-
macological interventions may help the management
of age-related bone loss and osteoporosis. Certain
types of exercise might result in improved bone
strength even after menopause, a time when bone mass
declines and the ability to rescue lost bone is impaired
(Polidoulis et al. 2011; Uusi-Rasi et al. 2003 ). With
regard to nutrition, vitamin D is essential in calcium
metabolism and oral intake may prevent fractures in
osteoporotic patients (Lips et al. 2006). Pharmacolog-
ical interventions are the gold standard with regards to
osteoporosis management and prevention of fragility
fractures, although their benefits are transient and
might induce rare but severe side effect s (Gozansky
et al. 2005; Woo et al. 2006). Some of the concerns
raised as a result of these side effects might well have
contributed to the declining prescription of these drugs
or the reduction in actual use of prescribed medica-
tions for low bone mass (Jha et al. 2015).
Exercise is one of the primary modifiable factors
associated with improved bone health outcomes, such
as high bone mineral density (BMD) and strength
(Weaver et al. 2016). Individuals who undertake
exercise on a regular basis are also more likely to
prevent age-relate bone loss and experience fewer falls
and fractures by virtue of developing stronger muscles
and bones, which improve balance (Liu-Ambrose
et al. 2004). In addition to this, exercise may provide a
‘rejuvenating effect’ and, as a result, the potential to
mitigate age-related bone loss and diseases (Loprinzi
et al. 2015). In this article, we review the benefits of
undertaking exercise throughout life as part of a
strategy to promote bone health across the lifespan,
and advance some cellular and molecular mechanisms
potentially activated upon exercise that underpin such
benefits. We will also highlight some areas where the
clinical benefits of exercise on bone health might have
been slightly exaggerated, given that increases in bone
mass as a result of exercise are typically in the range of
1–10% at the most and reductions in bone mass across
the lifespan are significantly greater (Riggs et al.
2004).
Bone and muscle are the two largest tissues of the
musculoskeletal system and they are coupled mechan-
ically, biochemically and molecularly (Brotto and
Bonewald 2015), with muscular contraction thought to
be the main source of mechanical strain leading to
bone adaptation (Bakker et al. 2001; Burr 1997). Bone
and muscle mass/strength are proportionally related,
as evidenced by a study showing that under disuse
conditions, muscle mass declines followed by a loss of
bone mass, while during recovery muscle mass gains
precede bone accretion (Sieva
¨
nen et al. 1996 ).
Although coupling between the two tissues and further
interactions with other elements of the musculoskele-
tal system, particularly tend ons, ligaments and carti-
lage is unquestionable, particularly in relation to the
prevention of falls (perhaps the major contributor to
bone fracture), this is beyond the scope of the present
review.
Ageing and bone loss
Ageing
Ageing is a physiolo gical process that results from the
accumulation of molecular and cellular damage over
time (WHO 2015). It is influenced by the human
genome and epigenetic changes triggered by environ-
mental and lifestyle factors (Govindaraju et al. 2015).
Human ageing is generally accompanied by a decline
of cognitive and motor functions (Moustafa 2014) and
is considered the main risk factor for developing
musculoskeletal, neurodegenerative and cardiovascu-
lar diseases (Niccoli and Partridge 2012). Genetic
studies on progeroid syndromes, clinical conditions of
premature ageing, have been useful to understand
physiological ageing and age-related diseases (Martin
Biogerontology
123
and Junko 2010). Research on Hutchison-Gilford and
Werner progeroid syndromes, in particular, have
allowed the identification of several hallmarks of
physiological ageing, such as telomere shortening,
mitochondrial dysfunction, oxidative stress and cell
senescence (Childs et al. 2015;Lo
´
pez-Otı
´
n et al.
2013). Briefly, telomeres are protective caps located at
the end of chromosomes with the purpose of prevent-
ing deterioration or fusion with other chromosomes.
Telomere shortening exacerbates human ageing, as
well as inducing metabolic alterations, such as insulin
resistance, b-cell failure and glucose intolerance
(Gardner et al. 2005; Shimizu et al. 2014). The
mitochondria are organelles that generate the majority
of the chemical energy utilised by cells, adenosine
triphosphate (ATP). Mitochondrial dysfunction is
caused by depletion of nicotinamide adenine dinu-
cleotide (NAD?) and downregulation of the tricar-
boxylic acid and oxidative phosphorylation
(OXPHOS) pathwa ys (Zhang et al. 2016), leading to
a decline in respiratory function and stem cell
senescence (Wiley et al. 2016; Zhang et al. 2016).
Senescent cells exhibit stress-induced permanent
proliferative arrest and are thought to drive ageing
and age-related pathologies (Baker et al. 2016; Childs
et al. 2015). While in proliferative arrest, senescent
cells secrete specific proteins, referred to as the se-
nescence-associated secretory phenotype (SASP),
which can exacerbate the proliferative arrest and also
induce senescence in a paracrine manner. Interest-
ingly, recen t evidence came to light showing that the
SASP can also exert a proregenerative effect through
cell plasticity and stemness (Ritschka et al. 2017).
Lastly, exces sive or persistent oxidative stress caused
by the action of free radicals, non-ionising radiation
and inflammatory agents, and from mitochondrial by-
products (e.g., peroxides), was proposed to contribute
to accumulated DNA damage and activation of
apoptotic signalling pathways, potentially accelerat-
ing ageing (Kryston et al. 2011; Lu et al. 2012).
Oxidative stress was identified as an important driver
of bone ageing. This marker will be further discussed
in the next section (Ambrogini et al. 2010; Manolagas
2010).
Age-related bone loss
Bone accretion occurs from birth and throughout
childhood and adolescence, with approximately 90%
of bone mass acquired by the age of 20 years (Henry
et al. 2004; Recker et al. 1992). Acquisition of bone
mass follows sex and age specific patterns, as
evidenced in Fig. 1. Men have greater BMD than
women and this difference becomes starker as sexual
maturation progresses (Hendrickx et al. 2015). When
women reach late 30s and men early 40s, BMD starts
to decline and this trend persists throughout life
(Fig. 1). Such decline is further accompanied by a
decrease in bone strength strength (Wall et al. 1979),
osteocyte death, deteoration of type I collagen (Bailey
and Knott 1999) and adipogenesis at the expense of
osteogenesis (Justesen et al. 2001
). Age-related bone
loss occurs due to greater bone resorption than bone
formation, a process that culminates in reduced
trabecular volume and diminished cortical bone width
(McCalden et al. 1993). For a comprehensive review
of these changes see (Boskey and Coleman 2010;
Manolagas and Parfitt 2010).
Oxidative stress has been identified as a critical
driver of bone ageing (Ambrogini et al. 2010;
Manolagas 2010). Production of mitochondrial super-
oxide anion (O
2
-
) in aged osteocytes led to increased
osteoclast-mediated bone resorption (Kobayashi et al.
2015). In addition to this, the presence of reactive
oxygen species (ROS) has been shown to attenuate b-
catenin signalling with concomitant activation of
PPARc favouring adipogenesis at the expense of
osteoblastogenesis and bone formation (Manolagas
2010). The loss of function of oxidative defense
Forkhead box O (FOXOs), a family of genes impli-
cated in ageing and longevity, triggers the apoptosis of
osteoblasts and osteocytes and the advance of an
osteoporotic phenotype (Ambrogini et al. 2010). In
this same study, the authors showed that an overex-
pression of FOXO3 in osteoblasts culminated in
increased bone mass. These findings demonstrate that
signalling pathways implicated in bone cell survival
and osteogenesis are negatively affected by oxidative
stress leading to age-related bone loss and potentially
osteoporosis.
The osteoporotic bone
Osteoporosis is the most prevalent disease in post-
menopausal women and is accompanied by an
increased risk of fragility fractures (Ji and Yu 2015).
Fragility fractures occur primarily in the spine, hip and
Biogerontology
123
wrist (NICE 2012). Hip fractures cause permanent
disability in 50% of the cases and death in 20%
(Sernbo and Johnell 1993). In the UK, 300,000
fragility fractures occur every year (British Orthopae-
dic Association 2007), with direct medical costs
estimated at £1.8 billion in 2000 and projected to
reach £2.2 billion by 2025 (Burge et al. 2001).
Osteoporosis arises from the imbalance between
bone reso rption (osteoclast-mediated) and bone for-
mation (osteoblas t-mediated), with bone resorption
exceeding bone formation. At histopathological level,
the osteoporotic bone is less compact as a result of
bone thining or loss, presents a strong reduction in the
trabecular connectivity and greater adiposity of the
bone marrow (Marcu et al. 2011).
Oxidative stress and oestrogen depletion are two
important mechanisms underpinning osteoporosis.
Oxidative stress was reported to direct commitment
of mesenchymal progenitors towards the adipogenic
lineage at the expense of osteoblastogenesis (Manola-
gas 2010), which can expl ain greater adipodicity of the
bone marrow in old and osteroporotic bone (Justesen
et al. 2001). Oestrogen has a protective role in bone
health e.g., by controlling bone resorption activity.
This was demonstrated by studies evidencing that
oestrogen inhibits osteoclast formation and activity
via increased production of osteoprotegerin (Hofbauer
et al. 1999) or transforming growth factor b (Hofbauer
et al. 1999; Hughes et al. 1996), and may also induce
apoptosis of osteoclast progenitor cells via blocking of
the cytokine receptor activator of NFjB ligand
(RANKL) (Lundberg et al. 2001). Oestrogen action
on bone resorption activity was further confirmed by a
study showing that selective deletion of the oestrogen
receptor-a (ERa) in osteoclast lineage cells increased
osteoclastogenesis activity and abrogated the oestro-
gen-mediated pro-apoptotic action in osteoclasts
(Almeida et al. 2013). These changes led to increased
bone resorption in women, but not in men, causing a
loss of cancellous, but not cortical, bone (Almeida
et al. 2013 ). When oestrogen is depleted in the
organism, e.g., post-menopause, this protective effect
on bone health is reduced or disappears and this
increases predisposition to the onset of bone diseases
like osteoporosis.
Osteoporosis is conventionally appraised by dual-
energy X-ray absorptiometry (DXA) and the resultant
BMD values are compared to the BMD of young
healthy individuals of the same gender, thus generat-
ing a T score. A T score of -1 and above is considered
normal, a score between -1 and -2.5 is indicative of
osteopenia, and a score of -2.5 or below signifies
osteoporosis. This categorisation was established by
the Word Health Organisation (WHO) to standardise
the diagnosis of oesteoporosis, particularly in Cau-
casian, postmenopausal women. BMD values can also
Fig. 1 Bone mass density
(BMD) across the lifespan.
Men exhibit higher BMDs
throughout life and are less
susceptible to age-related
bone loss than women.
Adapted from Hendrickx
et al. (2015)
Biogerontology
123
be compared to the BMD of age-matched individuals
with normal bone mass to generate a Z score. Z Scores
are mostly utilised in cases of severe osteoporosis.
BMD is, however, only one element of bone strength,
with areal BMD (aBMD) accounting for 65–75% of
the variance in bone strength. As such, there is a need
to also consider volumetric BMD, bone geometry and
bone architecture.
According to the severity of bone loss, the presence
of fragility fractures and other clinical factors, patients
may be prescribed with anti-osteoporotic drugs, pri-
marily the oral intake of bisphosphonates, such as
alendronate. Third generation (nitrogen-containing)
alendronate binds to bone mineral and is metabolised
by osteoclasts leading to the inhibition of bone
resorptive activities and an increase of bone strength
(Boivin et al. 2000). Another important anti-bone
resorption drug is strontium ranelate, although its
mechanism of action differs from bisphosphonates by
targeting bone formation and mineralisation directly,
rather than by suppressing osteoclast-mediated bone
resorption activity (Marie 2007). Denosumab is a
human monoclonal antibody that binds to RANKL,
inhibiting it. RANKL suppression impairs osteoclast
maturation and survival leading to the diminution of
bone resorption activity (Hanley et al. 2012). The
teriparatide human recombinant parathyroid hormone
(hrPTH), is clinically approved for the treatment of
osteoporosis due to its anabolic effect on bone and its
ability to rescue skeleton strength (Pazianas 2015).
The use of hrPTH is recommended for up to
24 months and has been shown to reduce fracture
risks (Lindsay et al. 2016; Neer et al. 2001).
The prescription of anti-osteoporotic drugs is vital
for the management of osteoporosis and its related co-
morbidities, although they are not always effective and
the benefits are transient (Gozansky et al. 2005).
Gozansky et al. (2005) investigated the efficacy of
oestrogen and raloxifene in conserving BMD during a
6-month exercise-based weight loss program (G ozan-
sky et al. 2005), where participants were allowed to
select the mode(s) of exercise e.g., treadmill, walking/
running, cycling, among others. The authors showed
that both pharmacological interventions failed to
maintain intact lumbar spine, total hip and trochanter
BMD in post-menopausal women enrolled in a lost
weight program, although BMD losses were more
pronounced in women belonging to the placebo group
(Gozansky et al. 2005). With regard to side effects,
long-term use of bisphosphonates can cause severe
collateral damage, such as jaw necrosis (Woo et al.
2006). In light of this, it has been advocated that
regular exercise might be one of the best non-
pharmacological approaches to support bone health
across the lifespan (Gomez-Cabello et al. 2012), either
by maximising peak bone mass during maturation,
delaying the onset of osteoporosis later in life (Tveit
et al. 2015; Warden et al. 2007) and/or by mitigating
the age and/or menopausal-related bone loss (Howe
et al. 2011; Polidoulis et al. 2011). Much of the
evidence in support of a positive effect of exercise on
bone is, howe ver, observational and many of the direct
exercise intervention studies have not shown such
large effects on bone. Over the next sections the
influence of exercise on age-related bone loss and
osteoporosis will be discussed.
Bone remodelling and adaptation to exercise
Bone is a heterogeneous tissue made up of two
components, an organic part comprised of collagenous
and non-collagenous proteins and cells and a mineral
component of hydroxyapatite (Boskey 2013). Bone
contains three major cell types: osteoblasts, which
derive from mesenchymal stem cells and are respon-
sible for bone formation; osteocytes, dendritic cells
terminally differentiated from osteoblasts embedded
in the bone matrix, accounting for more than 90% of
bone cells; and osteoclasts, large multinucleated cells
differentiated from hematopoietic progenitor cells that
mediate bone resorption (Schaffler et al. 2014;
Tatsumi et al. 2007). The coordinated action of
osteoblasts, osteoclasts and osteocytes orchestrate
bone modelling and remodelling. Bone modelling
occurs to accommodate the radial and longitudinal
growth of bone during the growing years and to adapt
the skeleton to mechanical strain, whereas remod-
elling happens mainly during adulthood to remove
microdamaged and old bone, adapt bone tissue to
mechanical loading and maintain the strength and
integrity of the skeleton (Sims and Martin 2014).
During modelling, osteoclastogenesis and osteogene-
sis work independently, whereas in remodelling, bone
resorption and formation are coupled, taking place in
bone remodelling units (Baron and Kneissel 2013).
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Bone adaptation to exercise
Exercise leads to bone adaptation and this process is
mediated by cellular mechanotransduction (Goodman
et al. 2015). Briefly, upon exercise, bone tissue
deforms, and the mechanosensors located throughout
the cells, such as stretch-activated ion channels
and integrins, change their original conformation
(Guilluy et al. 2014; Ross et al. 2013). Such confor-
mational changes trigger a signalling cascade to
provide an appropriate biochemical response (Good-
man et al. 2015), e.g., osteogenesis and bone accretion
at the site of deformation.
Osteocytes are mechanotransduction hot spots due
to their unique ability to detect and respond to
mechanical strains (Klein-Nulend and Bakker 2007).
Osteocytes control bone formation and resorption
through the differentiation of osteoblasts and osteo-
clasts and by stimulating the expression of the
osteoclastogenesis inhibitor, osteoprotegerin (Regard
et al. 2012). Osteoblasts also secrete osteoprotegerin
evidencing that this cell type also presents the
potential to regulate bone resorption activity (Uda-
gawa et al. 2000).
Of critical importance is the osteocyte’s ability to
mediate the anabolic actions of the Wnt/b-catenin
signalling pathway (Tu et al. 2015). This signalling
pathway is evolutionarily conserved and can be
categorised int o three forms: an inactive form, where
b-catenin is phosphorylated and degraded by ubiqui-
tination in the proteasome, and two active forms,
termed as canonical or non-canonical (Fig. 2). It is
activated upon mechanical loading e.g., generated
from exercise to initiate osteogenesis and bone
formation (Krishnan et al. 2006), either by direct
stimulation of the bone transcription factor RUNX2
(Gaur et al. 2005) or by crosstalking with PTH or
morphogenetic proteins (BMPs) signalling pathways
(Baron and Kneissel 2013; Gardinier et al. 2016). A
recent investigation showed that circulating PTH,
generated from physical activity, led to downregula-
tion of sclerostin (an anti-anabolic bone protein) in
osteocytes (Gardinier et al. 2016 ) was accompanied by
significant upregulation of fibroblast growth factor-23
(FGF-23) expression (Gardinier et al. 2016), a growth
factor governing phosphatase homoeostasis and vita-
min D metabo lism (Quarles 2012). Collectively, these
findings demostrate the vital role of osteocyte Wnt/b-
catenin signalling in the bone adaptation to exercise.
Exercise could be a means to maintain or enhance a
specific health outcome, such as maximising bone
accretion and/or improving bone strength. Bone adap-
tation to exercise is initiated by muscle contraction
and ground-reaction forces (Sharkey et al. 1995). Bone
traits, such as BMD, strength and architecture, change
and adapt to help the skeleton to cope with the loading
environment while preve nting injuries. To illustrate
the bone adaptation response, athletes undertaking
intermittent high impact exercise (Olympic fencers as
just one example) exhibit higher densities of cortical
and trabecular bone than matched controls (Chang
et al. 2009). Similarly, in athlete groups where a highly
active limb can be compared to a less active limb, such
as the racket arm versus non-racket arm of tennis
players (Haapasalo et al. 2000; Ireland et al. 2013)or
in the throwing arm vs non-throwing arm of baseball
players (Warden et al. 2014), there is a greater bone
mass observed in the more active limb. Conversely,
6-months of spaceflight results in a 10% loss in the
BMD of astronauts living under zero gravity condi-
tions, where gravitational mechanical loading and,
therefore, ground-reaction forces are missing (Si-
bonga 2013).
Upon beginning exercise, the skeleton is exposed
to different types of strains (deformation of tissue)
generated from compression, tensile and torsional
forces, and shear stress. Diferent types of strains can
occur at the same time and in the same bone (Judex
et al. 2009). In this study, a compression strain
occurred at 2500 ls on one side of the bone and a
tensile strain of 2000 ls on the other side. It is also
established that running generates tibial strains 2–3
times higher than walking (Burr et al. 1996) and
walking higher than cycling (Milgrom et al. 2000).
The optimal magnitude and frequency to initiate an
osteogenic response in humans is still uncertain as
most studies are undertaken in animals. On the other
side, the optimal exercise to induce osteogenesis and
bone anabolism is likely to change according to age,
sex, the individual (Weaver et al. 2016) and even
skeletal site, suggesting that only a personalised
approach would provide the precision information to
design the optimal osteogenic exercise regimen.
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123
Bone adaption to exercise across the lifespan
Exercise interventions during childhood
and adolescence
The promotion of physical exercise and healthy eating
habits during bone development maximises the
chances of accruing bone, potentially delaying the
onset of osteoporosis in later life. Such a perspective is
supported by longitudinal studies showing that indi-
viduals who were active during childhood had 8–10%
greater hip bone mineral content (BMC) in adulthood
(age 23–30 years) than their sedentary counterparts
(Baxter-Jones et al. 2008). A more recent longitudinal
trial showed that children engaged in school-based
exercise interventions for 9 months had higher whole-
body (6.2%), femoral neck (8.1%) and total hip (7.7%)
BMC compared with their non-exercising counter-
parts (Meyer et al. 2013). Three years after ceasing the
intervention, the benefits persisted, with a sustained
7–8% increment of BMC in the femoral neck and total
hip of conditioned individuals (Meyer et al. 2013). A
Fig. 2 Simplified diagram depicting canonical and non canon-
ical b-catenin signalling pathways in bone. Exercise enables
bone formation through the active canonical and non-canonical
b-catenin signalling pathways. Activation of the bone transcrip-
tion factor RUNX2 elicits osteogenesis and supresses PPAR-c-
mediated adipogenesis; Activation of WIF1: Wnt Inhibitory
Factor 1: SFRP: Secreted frizzled-related protein; LRP5/6:
Low-density lipoprotein receptor-related protein 5/6; APC:
adenomatous polyposis coli; GSK-3b: glycogen synthase kinase
3 beta; Ub: ubiquitination; P: phosphorylation; b-TrCP: beta-
transducin repeat containing E3 ubiquitin protein ligase; RSPO:
R-spondin 1; WNT3A: Wnt family member 3A; FRAT1:
FRAT1, WNT signalling pathway regulator; DVL: dishevelled
segment polarity protein 1; TCF/LEF: T cell factor/lymphoid
enhancer factor; DKK1: Dickkopf Wnt Signaling Pathway
Inhibitor 1; PTH: Parathyroid hormone; PTH1R: Parathyroid
hormone 1 receptor; SOST: Sclerostin; ROR2: receptor tyrosine
kinase like orphan receptor 2; RYK: receptor-like tyrosine
kinase; WNT5A: Wnt family member 5A; AKT1: AKT serine/
threonine kinase 1; IP3: Inositol trisphosphate; DAAM1:
Disheveled-associated activator of morphogenesis 1; JNK:
c-Jun N-terminal kinases; ROCK: Rho-associated protein
kinase; NFATc1: Nuclear factor of activated T-cells, cytoplas-
mic 1; PPAR-c: Peroxisome proliferator-activated receptor
gamma; RUNX2: Runt-related transcription factor 2. Adapted
from Baron and Kneissel (2013)
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123
cross-sectional study investigating the long-term ben-
efits of performing upper body exercise (ball throw-
ing) suggested that half of the benefit in bone size and
one-third of the benefit in bone strength was kept
throughout life (Warden et al. 2014). Tveit et al.
(2015) conducted a cross-sectional, cohort study
investigating the long-term, 30 years after retirement,
effects of soccer on BMD, bone structure and fracture
risk. They showed that exercise generated higher
BMD’s, larger bones and a lower fracture risk in
former athletes after retirement (Tveit et al. 2015).
Peak bone mass (PBM) is rega rded as a significant
predictor of future osteoporosis and fracture risk
(Specker et al. 2010). Bioinformatics’ and meta-
analyses calculations have estimated that a 10%
increase in PBM would delay the onset of osteoporosis
by 13 years (Hernandez et al. 2003) and reduce
fracture risk, resulting from osteoporosis, by up to
50% in post-menopausal women (Marshall et al.
1996). A 6.4% decrease in bone mass in childhood has
been associated with a twofold increase fracture risk
during adulthood (Boreham and McKay 2011). This
evidence suggests that exercise interventions, span-
ning childhood and adolescence, are effective, even
after the activity has ceased, although the timing of
initiation may be important. An interesting recent
study has also suggested that the age at which children
first start walking might influence their bone strength
in later life (Ireland et al. 2017). Ireland et al. (2017)
examined the associa tion betweent walking age (ob-
tained at 2 years old) and bone outcomes determined
by DXA and pQCT (between the ages of 60 and
64 year s old). Later independent walking age was
associated with lower height-adjusted hip, spine and
distal radius BMC in men, suggesting that the ability
to mechanically load the skeleton early during bone
development might be important in the development
of good bone health.
A systematic revi ew addressing bone mineral
changes in response to weight-bearing exercise (e.g.,
ball games dancing, jumping, and others) proposed
that bone adaptations peak during early puberty
(MacKelvie et al. 2002). More specifically, they
showed that weight-bearing exercise during childhoo d
had a positive effect on bone strength, while exercise
undertaken during prepubertal and peripubertal ages
caused an increment in bone mineral accrual (MacK-
elvie et al. 2002). These findings were reinforced by a
subsequent systematic review that analysed bone
mineral accrual in children and adolescents (Hind
and Burrows 2007). Despite osteogenesis and bone
anabolism being more pronounced during the peripu-
bertal stage, the ideal modality or training regimen to
optimise bone mass accrual remains to be elucidated.
Exercise interventions during adulthood
Adults might also also benefit from bone-loading
exercise, but systematic reviews and meta-analyses on
the topic (Bolam et al. 2015; Hamilton et al. 2010;
Martyn-St James and Carroll 2010) suggest that this
might occur to a lesser extent than in children and
adolescents (Hind and Burrows, 2007; Nogueira et al.
2014). Nonetheless, Heinone n et al. showed that pre-
menopausal women, aged 35–45 years, who per-
formed a high-impact exercise regimen, consisting
of jump and step training for 18-months, had progres-
sive increases in BMD at the femoral neck (a load
bearing site) when compared with inactive controls
(Heinonen et al. 1996). A meta-analysis, of ran-
domised controlled exercise trials lasting 24 weeks,
also showed improvements in femoral neck and
lumbar spine BMD (Kelley et al. 2013). Bassey
et al. (1998) examined bone accrual after a 12-month
exercise training intervention in both pre- and post-
menopausal women. Training consisted of vertical
jumping, 6 times per week, and resulted in a 2.8%
increase in femoral BMD in pre-menopausal women,
whereas no improvements were shown in post-
menopausal women after 12- or 18-months of training
and hormone replacement therapy (Bassey et al.
1998). The inability of post-menopausal women to
accrue bone mass after high impact training was later
confirmed by a 12-month randomised controlled trial
on the effect of weight-bearing jumping and oral
alendronate, alone or in combination, on bone mass
and structure (Uusi-Rasi et al. 2003). Exercise alone or
in combination with alendronate had no effect on bone
mass at the femoral neck or lumbar spine (Uusi-Rasi
et al. 2003). The ‘anabolic resistance’ to exercise
shown in post-menopausal women likely results, at
least in part, from depleted oestrogen levels (Ji and Yu
2015). Oestrogen is a pleiotropi c hormone, with a vital
role in skeletal growth and bone homoeostasis, as well
as in sexual dimorphism and reproduction (Weitz-
mann and Pacifici 2006). All bone cells have oestrogen
receptors and when circulating levels of oestrogen
drop, Wnt/b-catenin and the oestrogen ERb /GSK-3b-
Biogerontology
123
dependent signalling pathways are attenuated, leading
to reduced osteoblastic proliferation (Y in et al. 2015 ).
Attenuation of these signalling pathways, with con-
comitant diminished osteoblastic proliferation, is
thought to cause the lack of responsiveness of post-
menopausal women to bone-loading exercises (Yin
et al. 2015).
Although these studies have shown that osteogenic
and bone anabolic effects, resulting from exercise, are
less pronounced or are even negligible when coupled
with oestrogen depletion, post-menopausal women are
strongly advised to undertake exercise. Exercise, of
the right type, might well contribute to BMD preser-
vation, presumably by maintaining cortical and tra-
becular volumetric BMD (Polidoulis et al. 2011), and
by contributing to bone strength by means of cortical
bone thickening (Uusi-Rasi et al. 2003). Among the
exercise modalities tested in this population, walking
provided modest benefits, due to the minor mechanical
load exerted on the skeleton, while resistance and
multi-component exercise programmes, encompass-
ing strength, aerobic, and whole-body vibration exer-
cises, were more effective in mitigating the loss of
bone mass (Gomez-Cabello et al. 2012).
Exercise interventions during older age
Studies investigating exercise on bone health in older
people (50s and above) are scarce. A comparative
study, which enrolled men and women in their early
50s, demonstrated that after 24 weeks of moderate
strength or high intensity training, men that undertook
the high intensity program gained 1.9% BMD in
the spine, while women did not (Maddalozzo and
Snow 2000). Allison et al. (2015) conducted a
12-month rando mised controlled trial in male partic-
ipants, aged 65–80 years, who performed unilateral
hopping exercise, whilst the other leg remained as an
inactive control. In this trial, computer tomography
(CT) and DXA measurements demonstrated that
unilateral hopping caused an increase in BMC in both
legs, with the trained leg depicting localised changes
in the proximal femur. Cortical BMC at the trochanter
increased more in the exercising than in the control
leg, which is thought to be important for the structural
integrity of the bone (Allison et al. 2015). A similar
training programme, carried out over 12-months in
men aged 65–80 years, showed increased femoral
neck BMD, BMC and geometry (Allison et al. 2013).
Exercise might contribute to bone health by aug-
menting bone mass and bone strength during younger
age and by mitigating age-related bone loss. In practice,
however, this statement might be an oversimplification,
as there are undoubtedly several factors that mediate the
effects of exercise on the bone. Current or previous
habitual levels of exercise, exercise mode, type, inten-
sity and duration will all have a significant influence on
the magnitude of any effects on bone related outcomes.
Recently, Ireland and Rittweger (2017) also suggested
that participation motivation might also play a part in the
success or failure of exercise interventions targeted at
the bone (Ireland and Rittweger 2017), which is
certainly an area worthy of consideration.
Although the cellular and molecular mechani sms
underpinning bone outcomes are still under investiga-
tion, the role of the Wnt/b-catenin signalling pathway
both in bone health and as a target of anti-osteoporosis
interventions is becoming increasing clear (Karasik
et al. 2016; Korvala et al. 2012). It was reported that
mechanical loading exerted on mesenchymal stem
cells blocked adipogenic differentiation by rescuing b-
catenin-FOXO mediated transcription to b-catenin-
TCF/LEF mediated transcription (Fig. 3) (Case et al.
2013). This result was corroborated by an in vivo study
involving mice, which demonstrated that exercise
suppressed the accumulation of fat in the bone marrow
(Styner et al. 2014), except that in this case the authors
hypothesised that b-oxidation was the underpinning
mechanism. Another route by which exercise
might mitigate age-related bone loss is through the
prevention of osteocyte apoptosis (Fonseca et al. 2011;
Mann et al.
2006). This was evidenced by research
conducted with ovariectomized mice exposed to
exercise activity and human bone explants exposed
to mechanical tension, with both providing evidence
that mechanical stimulation prevented osteocyte death
(Fonseca et al. 2011; Mann et al. 2006), a fact that
contributes to pres ervation of bone strength.
Exercise, besides supporting bone health outcomes
such as BMD and bone strength, provides an anti-
ageing effect by virtue of preventing telomere erosion
(Fig. 3) (Loprinzi et al. 2015). A longitudinal study, of
6503 participants aged 20–84 years, showed that
exercise interv entions prevented or delayed telomere
shortening, therefore exhibiting an ‘age-defying’ or
rejuvenating action (Loprinzi et al. 2015). This study
suggested that (i) a dose–response relationship exists
between exercise and reduced telomere erosion and
Biogerontology
123
(ii) this relationship was significant in participants
aged 40–64 years. According to this, undertaking
exercise after the fourth decade of life appears to
improve systemic health on account of the counter-
ageing effect provided. This systemic effect may
mitigate ageing and accordingly age-related bone loss
and age-related osteoporosis. Notably, individuals
with osteoporosis exhibit shorter telomeres than
healthy ones (Valdes et al. 2007), a fact that supports
the notion that preventing or delaying systemic ageing
is beneficial to bone health. Due to the progress of
molecular biology, it is possible that bone health may
also now be appraised by the assessment of telom ere
length given that leucocyte telomere shortening cor-
relates with lower BMD at the lumbar spine, femoral
neck and total hip (Nielsen et al. 2015).
Beside the mechanisms illustrated here, we
acknowledge that exercise might contribute to bone
health through other routes as, for example, changes in
hormone levels or by targeting signalling pathways
other than Wnt/b-catenin signalling, such as the BMP
or RANK/RANKL.
Exercise is also linked with epigenetic modifica-
tions, in particular, changes in DNA methylation
patterns and gene expression (Brunet and Berger 2014;
Jung and Pfeifer 2015;Ro
¨
nn et al. 2013). DNA
methylation is an epigenetic modification typically
leading to long-term gene repression, achieved by the
addition of a methyl group to the five position of a
cytosine ring (Cedar and Bergman 2009). The rela-
tionship betwee n exercise and DNA methylation was
demonstrated in an epidemiological study comprising
two groups; healthy volunteers and type II diabetics
(Ro
¨
nn et al. 2013). In this study, participants per-
formed spinning and aerobic exercise over a 6-month
period, with an average attendance of 1.8 times per
week. DNA methylation changed in participants from
both groups; more specifically in 7663 genes, one-
Fig. 3 Activation of FOXO transcription signalling upon
oxidative stress (left) in the context of the aged bone; Rescue
of TCF/LEF transcription (a), prevention of osteocyte apoptosis
(b) and prevention of telomere erosion (c) induced by exercise
potentially contribute to bone health
Biogerontology
123
third of which showed altered mRNA expression
levels (Ro
¨
nn et al. 2013). In another study, young
sedentary participants of both sexes were exposed to
acute bouts of exercise to ascertain whether acute
exercise could change DNA methyl ation patterns.
DNA was hypomethylated in skeletal muscle, in a
dose-responsive fashion, with similar findings in
mouse muscles 45 min after ex vivo contraction, both
suggesting a putative role of exercise in epigenetic
modification through DNA methylation (Barre
`
s et al.
2012). The causal relationship between exercise and
changes in DNA methylation was further corroborated
by an investigation enrolling young male and female
individuals in a 3-month fully supervised one-legged
exercise training programme. Here, DNA methylation
patterns changed in 4919 sites across the genome of
the trained leg group (Lindholm et al. 2014). These
epigenetic studies allowed identification of changes in
DNA methylation patterns resulting from exercise on
healthy, type II diabetic and young sedentary popula-
tions. To undertake similar studies in the older
individual might reveal an age reversin g epigenetic
signature induced by exercise that might be utilised as
a technique to asses not only bone health but also the
effect of exercise in older individuals with chronic
bone diseases.
Conclusions
Osteoporosis is a bone metabolic disease that prevails
in post-menopausal women. The first line of treatment
relies on anti-osteoporotic drugs, particularly bispho-
sphonates, although this type of therapy can only be
provided for a limited period of time and the benefits
are transient. Exercise has the potential to provide a
means of non-pharmacological intervention, with
long-lasting effects that can delay the onset of
osteoporosis, particularly if performed during the
peripubertal stage, a time during which exercise-
induced osteogenesis and bone anaboli sm is more
accentuated. There are no current data, however, to
directly compare appropriate exercise with pharma-
cological interventions designed to prevent bone loss
or increase bone mass. These studies are urgently
required to determine the extent to which exercise may
or may not be able to provide a sole (highly unlikely)
or adjunct therapeutic intervention against
osteoporosis.
Exercise might be recommended following the
menopause to mitigate the age- and menopausal-
related loss of bone and to strengthen cortical bone.
During growth and development PBM should be
maximised, with exercise potentially provi ding a
means to help achieve this. During middle- and
older-age, weight-bearing exercises should be per-
formed to maintain bone mass and increase bone
strength. It remains largely unknown, however, what
the best type of exercise is in terms of mode, type,
intensity and duration to maximise bone responses. It
is likely that any exer cise would need to be high-
intensity, high-impact, multidirectional and possibly
unaccustomed in order to optimise osteogenic
responses, but this approach might not be suitable for
all.
Glossary
Acronym Definition
Dual-energy
X-ray
absorptiometry
DXA Standard methods to measure
BMD. Two X-ray beams with
different energy levels are
conveyed to the patient’s
bone. After subtracting the
signal from soft tissue, the
obtained absorption values
allow to estimate bone BMD
Computed
tomography
CT Imagining technique that
allows obtaining detailed
scans of areas inside the body
Bone mineral
density
BMD Refers to the amount of mineral
matter per square centimetre
of bone. BMD is utilised as
predictor of osteoporosis and
fracture risk. Parameter
utilised to estimate bone
strength
Aerial bone
mineral density
aBMD It is a reasonable estimate of
BMC and bone strength, not
an accurate measurement of
true bone mineral density,
which is mass divided by
volume. Parameter utilised to
estimate bone strength
Bone mineral
content
BMC Estimated by DXA, these
measurements reflect BMD at
specific body parts, spine, hip,
wrist, femur or other selected
part of the skeleton. The
values obtained are divided
by the surface area of the bone
being measure to create BMD
Biogerontology
123
Acronym Definition
Peak bone mass PBM Amount of bone gained by the
time a stable skeletal state has
been attained. At a population
level, peak bone mass reflects
the maximum bone mass
attained across the lifespan. It
is a predictor of osteoporosis
Volumetric peak
bone mass
vPBM Refers the amount of peak bone
mineral content per cubic
centimetre of bone
Open Access This article is distributed under the
terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/
licenses/by/4.0/), which permits unrestricted use, dis-
tribution, and reproduction in any medium, provided
you give appropriate credit to the original author(s)
and the source, provide a link to the Creative Com-
mons license, and indicate if changes were made.
References
Allison SJ, Folland JP, Rennie WJ, Summers GD, Brooke-
Wavell K (2013) High impact exercise increased femoral
neck bone mineral density in older men: a randomised
unilateral intervention. Bone 53(2):321–328. doi:10.1016/
j.bone.2012.12.045
Allison SJ, Poole KES, Treece GM, Gee AH, Tonkin C,
Rennie WJ, Brooke-Wavell K (2015) The influence of
high-impact exercise on cortical and trabecular bone
mineral content and 3D distribution across the proximal
femur in older men: a randomized controlled unilateral
intervention. J Bone Miner Res 30(9):1709–1716. doi:10.
1002/jbmr.2499
Almeida M, Iyer S, Martin-Millan M, Bartell SM, Han L,
Ambrogini E, Manolagas SC (2013) Estrogen receptor-
alpha signaling in osteoblast progenitors stimulates cor-
tical bone accrual. J Clin Investig 123(1):394–404. doi:10.
1172/JCI65910
Ambrogini E, Almeida M, Martin-Millan M, Paik J, DePinho
RA, Han L, Manolagas SC (2010) FoxO-mediated
defense against oxidative stress in osteoblasts is indis-
pensable for skeletal homeostasis in mice. Cell Metab
11(2):136–146. doi:10.1016/j.cmet.2009.12.009
Bailey AJ, Knott L (1999) Molecular changes in bone collagen
in osteoporosis and osteoarthritis in the elderly. Exp
Gerontol. doi:10.1016/S0531-5565(99)00016-9
Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong
J, Pezeshki A (2016) Naturally occurring p16Ink4a-posi-
tive cells shorten healthy lifespan. Nature
530(7589):184–189
Bakker AD, Soejima K, Klein-Nulend J, Burger EH (2001) The
production of nitric oxide and prostaglandin E2 by pri-
mary bone cells is shear stress dependent. J Biomech.
doi:10.1016/S0021-9290(00)00231-1
Baron R, Kneissel M (2013) WNT signaling in bone home-
ostasis and disease: from human mutations to treatments.
Nat Med 19:179–192
Barre
`
s R, Yan J, Egan B, Treebak J, Rasmussen M, Fritz T,
Zierath J (2012) Acute exercise remodels promoter
methylation in human skeletal muscle. Cell Metab
15(3):405–411. doi:10.1016/j.cmet.2012.01.001
Bassey E, Rothwell M, Littlewood J, Pye D (1998) Pre-and
postmenopausal women have different bone mineral
density responses to the same high-impact exercise.
J Bone Miner Res 13(12):1805–1813
Baxter-Jones ADG, Kontulainen SA, Faulkner RA, Bailey DA
(2008) A longitudinal study of the relationship of physical
activity to bone mineral accrual from adolescence to
young adulthood. Bone 43(6):1101–1107. doi:10.1016/j.
bone.2008.07.245
Boivin GY, Chavassieux PM, Santora AC, Yates J, Meunier PJ
(2000) Alendronate increases bone strength by increasing
the mean degree of mineralization of bone tissue in
osteoporotic women. Bone. doi:10.1016/S8756-
3282(00)00376-8
Bolam KA, Skinner TL, Jenkins DG, Galva
˜
o DA, Taaffe DR
(2015) The osteogenic effect of impact-loading and
resistance exercise on bone mineral density in middle-
aged and older men: a pilot study. Gerontology 62:22–32
Boreham CAG, McKay HA (2011) Physical activity in child-
hood and bone health. Br J Sports Med 45(11):877–879.
doi:10.1136/bjsports-2011-090188
Boskey AL (2013) Bone composition: relationship to bone
fragility and antiosteoporotic drug effects. BoneKEy Rep
2:447
Boskey AL, Coleman R (2010) Aging and bone. J Dent Res
89(12):1333–1348. doi:10.1177/0022034510377791
British Orthopaedic Association (2007) The care of patients
with fragility fractures Blue Book. British Orthopaedic
Association, London
Brotto M, Bonewald L (2015) Bone and muscle: interactions
beyond mechanical. Bone. doi:10.1016/j.bone.2015.02.
010
Brunet A, Berger SL (2014) Epigenetics of aging and aging-
related disease. J Gerontol A 69(Suppl 1):S17–S20.
doi:10.1093/gerona/glu042
Burge RT, Worley D, Johansen A, Bhattacharyya S, Bose U
(2001) The cost of osteoporotic fractures in the UK:
projections for 2000–2020. J Med Econ 4(1–4):51–62
Burr DB (1997) Muscle strength, bone mass, and Age-Related
bone loss. J Bone Miner Res 12(10):1547–1551
Burr DB, Milgrom C, Fyhrie D, Forwood M, Nyska M, Finestone
A, Simkin A (1996) In vivo measurement of human tibial
strains during vigorous activity. Bone 18(5):405–410
Case N, Thomas J, Xie Z, Sen B, Styner M, Rowe D, Rubin J
(2013) Mechanical input restrains PPARc2 expression
and action to preserve mesenchymal stem cell multipo-
tentiality. Bone. doi:10.1016/j.bone.2012.08.122
Cedar H, Bergman Y (2009) Linking DNA methylation and
histone modification: patterns and paradigms. Nat Rev
Genet 10(5):295–304
Biogerontology
123
Chang G, Regatte R, Schweitzer M (2009) Olympic fencers:
adaptations in cortical and trabecular bone determined by
quantitative computed tomography. Osteoporos Int
20(5):779–785
Childs BG, Durik M, Baker DJ, Van Deursen JM (2015)
Cellular senescence in aging and age-related disease: from
mechanisms to therapy. Nat Med 21(12):1424–1435
Demontiero O, Vidal C, Duque G (2012) Aging and bone loss:
new insights for the clinician. Ther Adv Musculoskelet
Dis 4(2):61–76
Fonseca H, Moreira-Gonc¸alves D, Esteves JLS, Viriato N, Vaz
M, Mota MP, Duarte JA (2011) Voluntary exercise has
long-term in vivo protective effects on osteocyte viability
and bone strength following ovariectomy. Calcif Tissue
Int 88(6):443
Gardinier JD, Al-Omaishi S, Morris MD, Kohn DH (2016)
PTH signaling mediates perilacunar remodeling during
exercise. Matrix Biol 52–54:162–175. doi:10.1016/j.
matbio.2016.02.010
Gardner JP, Li S, Srinivasan SR (2005) Rise in insulin resis-
tance is associated with escalated telomere attrition. Cir-
culation 111:2171–2177
Gaur T, Lengner CJ, Hovhannisyan H, Bhat RA, Bodine PVN,
Komm BS, Lian JB (2005) Canonical WNT signaling
promotes osteogenesis by directly stimulating Runx2 gene
expression. J Biol Chem 280(39):33132–33140. doi:10.
1074/jbc.M500608200
Gheno R, Cepparo JM, Rosca CE, Cotten A (2012) Muscu-
loskeletal disorders in the elderly. J Clin Imaging Sci.
doi:10.4103/2156-7514.99151
Gomez-Cabello A, Ara I, Gonza
´
lez-Agu
¨
ero A, Casajus J,
Vicente-Rodriguez G (2012) Effects of training on bone
mass in older adults. Sports Med 42(4):301–325
Goodman CA, Hornberger TA, Robling AG (2015) Bone and
skeletal muscle: key players in mechanotransduction and
potential overlapping mechanisms. Bone 80:24–36
Govindaraju D, Atzmon G, Barzilai N (2015) Genetics, life-
style and longevity: lessons from centenarians. Appl
Transl Genomics 4:23–32. doi:10.1016/j.atg.2015.01.001
Gozansky W, Van Pelt R, Jankowski C, Schwartz R, Kohrt W
(2005) Protection of bone mass by estrogens and ralox-
ifene during exercise-induced weight loss. J Clin Endo-
crinol Metab 90(1):52–59
Guilluy C, Osborne LD, Landeghem LV et al (2014) Isolated
nuclei adapt to force and reveal a mechanotransduction
pathway in the nucleus. Nat Cell Biol 16:376–381
Haapasalo H, Kontulainen S, Sievanen H, Kannus P, Jarvinen
M, Vuori I (2000) Exercise-induced bone gain is due to
enlargement in bone size without a change in volumetric
bone density: a peripheral quantitative computed tomog-
raphy study of the upper arms of male tennis players.
Bone 27(3):351–357. doi:10.1016/S8756-3282(00)00331-
8
Hamilton CJ, Swan VJD, Jamal SA (2010) The effects of
exercise and physical activity participation on bone mass
and geometry in postmenopausal women: a systematic
review of pQCT studies. Osteoporos Int 21:11–23
Hanley D, Adachi J, Bell A, Brown V (2012) Denosumab:
mechanism of action and clinical outcomes. Int J Clin
Pract 66(12):1139–1146
Heinonen A, Kannus P, Sieva
¨
nen H, Oja P, Pasanen M, Rinne
M, Vuori I (1996) Randomised controlled trial of effect of
high-impact exercise on selected risk factors for osteo-
porotic fractures. Lancet 348(9038):1343–1347. doi:10.
1016/S0140-6736(96)04214-6
Hendrickx G, Boudin E, Van Hul W (2015) A look behind the
scenes: the risk and pathogenesis of primary osteoporosis.
Nat Rev Rheumatol 11(8):462–474
Henry YM, Fatayerji D, Eastell R (2004) Attainment of peak
bone mass at the lumbar spine, femoral neck and radius in
men and women: relative contributions of bone size and
volumetric bone mineral density. Osteoporos Int
15:263–273
Hernandez CJ, Beaupre
´
GS, Carter DR (2003) A theoretical
analysis of the relative influences of peak BMD, age-re-
lated bone loss and menopause on the development of
osteoporosis. Osteoporos Int 14:843–847
Hernlund E, Svedbom A, Iverga
˚
rd M et al (2013) Osteoporosis
in the european union: medical management, epidemiol-
ogy and economic burden. Arch Osteoporos 8:1–136
Hind K, Burrows M (2007) Weight-bearing exercise and bone
mineral accrual in children and adolescents: a review of
controlled trials. Bone 40(1):14–27. doi:10.1016/j.bone.
2006.07.006
Hofbauer LC, Khosla S, Dunstan CR, Lacey DL, Spelsberg
TC, Riggs BL (1999) Estrogen stimulates gene expression
and protein production of osteoprotegerin in human
osteoblastic cells. Endocrinology 140(9):4367–4370.
doi:10.1210/endo.140.9.7131
Howe TE, Shea B, Dawson LJ, Downie F, Murray A, Ross C,
Creed G (2011) Exercise for preventing and treating
osteoporosis in postmenopausal women. Cochrane Data-
base Syst Rev. doi:10.1002/14651858.CD000333.pub2
Hughes DE, Dai A, Tiffee JC, Li HH, Mundy GR, Boyce BF
(1996) Estrogen promotes apoptosis of murine osteoclasts
mediated by TGF-beta. Nat Med 2(10):1132–1136
Ireland A, Rittweger J (2017) Exercise for osteoporosis: how to
navigate between overeagerness and defeatism. J Muscu-
loskelet Neuronal Interact 17(3):155–161
Ireland A, Maden-Wilkinson T, McPhee J, Cooke K, Narici M,
Degens H, Rittweger J (2013) Upper limb muscle-bone
asymmetries and bone adaptation in elite youth tennis
players. Med Sci Sports Exerc 45(9):1749–1758. doi:10.
1249/MSS.0b013e31828f882f
Ireland A, Muthuri S, Rittweger J, Adams JE, Ward KA, Kuh
D, Cooper R (2017) Later age at onset of independent
walking is associated with lower bone strength at fracture-
prone sites in older men. J Bone Miner Res
32(6):1209–1217. doi:10.1002/jbmr.3099
Jha S, Wang Z, Laucis N, Bhattacharyya T (2015) Trends in
media reports, oral bisphosphonate prescriptions, and hip
fractures 1996–2012: an ecological analysis. J Bone
Miner Res 30(12):2179–2187. doi:10.1002/jbmr.2565
Ji M, Yu Q (2015) Primary osteoporosis in postmenopausal
women. Chronic Dis Transl Med 1(1):9–13. doi:10.1016/
j.cdtm.2015.02.006
Judex S, Gupta S, Rubin C (2009) Regulation of mechanical
signals in bone. Orthod Craniofac Res 12(2):94–104.
doi:10.1111/j.1601-6343.2009.01442.x
Jung M, Pfeifer G (2015) Aging and DNA methylation. BMC
Biol 13:1–8
Biogerontology
123
Justesen J, Stenderup K, Ebbesen E, Mosekilde L, Steiniche T,
Kassem M (2001) Adipocyte tissue volume in bone
marrow is increased with aging and in patients with
osteoporosis. Biogerontology 2(3):165–171
Karasik D, Rivadeneira F, Johnson ML (2016) The genetics of
bone mass and susceptibility to bone diseases. Nat Rev
Rheumatol 12:323–334
Kelley GA, Kelley KS, Kohrt WM (2013) Exercise and bone
mineral density in premenopausal women: a meta-analysis
of randomized controlled trials. Int J Endocrinol
2013:741639. doi:10.1155/2013/741639
Klein-Nulend J, Bakker AD (2007) Osteocytes: mechanosen-
sors of bone and orchestrators of mechanical adaptation.
Clin Rev Bone Miner Metab 5(4):195–209
Klop C, van Staa TP, Cooper C, Harvey NC, de Vries F (2017)
The epidemiology of mortality after fracture in england:
variation by age, sex, time, geographic location, and
ethnicity. Osteoporos Int 28:161–167
Kobayashi K, Nojiri H, Saita Y et al (2015) Mitochondrial
superoxide in osteocytes perturbs canalicular networks in
the setting of age-related osteoporosis. Sci Rep
5(9148):1–11
Korvala J, Ju
¨
ppner H, Ma
¨
kitie O, Sochett E, Schnabel D, Mora
S, Cole WG (2012) Mutations in LRP5 cause primary
osteoporosis without features of OI by reducing wnt sig-
naling activity. BMC Med Genet 13(1):26
Krishnan V, Bryant HU, Macdougald OA (2006) Regulation of
bone mass by wnt signaling. J Clin Investig
116(5):1202–1209. doi:10.1172/JCI28551
Kryston TB, Georgiev AB, Pissis P, Georgakilas AG (2011)
Role of oxidative stress and DNA damage in human
carcinogenesis. Mutat Res 711(1–2):193–201. doi:10.
1016/j.mrfmmm.2010.12.016
Lindholm ME, Marabita F, Gomez-Cabrero D, Rundqvist H,
Ekstro
¨
m T, Tegne
´
r J, Sundberg CJ (2014) An integrative
analysis reveals coordinated reprogramming of the epi-
genome and the transcriptome in human skeletal muscle
after training. Epigenetics 9(12):1557–1569. doi:10.4161/
15592294.2014.982445
Lindsay R, Krege J, Jin L, Stepan J (2016) Teriparatide for
osteoporosis: importance of the full course. Osteoporos Int
27:2395–2410
Lips P, Hosking D, Lippuner K, Norquist JM, Wehren L,
Maalouf G, Chandler J (2006) The prevalence of vitamin
D inadequacy amongst women with osteoporosis: an
international epidemiological investigation. J Intern Med
260(3):245–254. doi:10.1111/j.1365-2796.2006.01685.x
Liu-Ambrose TY, Khan KM, Eng JJ, Heinonen A, McKay HA
(2004) Both resistance and agility training increase cor-
tical bone density in 75-to 85-year-old women with low
bone mass: a 6-month randomized controlled trial. J Clin
Densitom 7(4):390–398
Lo
´
pez-Otı
´
n C, Blasco MA, Partridge L, Serrano M, Kroemer G
(2013) The hallmarks of aging. Cell 153(6):1194–1217.
doi:10.1016/j.cell.2013.05.039
Loprinzi PD et al (2015) Movement-based behaviors and
leukocyte telomere length among US adults. Med Sci
Sports Exerc 47:2347–2352
Lu B, Chen H, Lu H (2012) The relationship between apoptosis
and aging. Adv Biosci Biotechnol 3:705–711
Lundberg P, Lundgren I, Mukohyama H, Lehenkari PP, Horton
MA, Lerner UH (2001) Vasoactive intestinal peptide
(VIP)/pituitary adenylate cyclase-activating peptide
receptor subtypes in mouse calvarial osteoblasts: presence
of VIP-2 receptors and differentiation-induced expression
of VIP-1 receptors. Endocrinology 142(1):339–347.
doi:10.1210/endo.142.1.7912
MacKelvie KJ, Khan KM, McKay HA (2002) Is there a critical
period for bone response to weight-bearing exercise in
children and adolescents? A systematic review. Br J
Sports Med 36(4):250–257 ; discussion 257
Maddalozzo G, Snow C (2000) High intensity resistance
training: effects on bone in older men and women. Calcif
Tissue Int 66:399–404
Mann V, Huber C, Kogianni G, Jones D, Noble B (2006) The
influence of mechanical stimulation on osteocyte apop-
tosis and bone viability in human trabecular bone.
J Musculoskelet Neuronal Interact 6(4):408–417
Manolagas SC (2010) From estrogen-centric to aging and
oxidative stress: a revised perspective of the pathogenesis
of osteoporosis. Endocr Rev 31:266–300
Manolagas SC, Parfitt AM (2010) What old means to bone.
Trends Endocrinol Metab 21(6):369–374
Marcu F, Bogdan F, Mutiu G, Lazar L (2011) The
histopathological study of osteoporosis. Rom J Morphol
Embryol 52(1):321–325
Marie PJ (2007) Strontium ranelate: new insights into its dual
mode of action. Bone 40(5, Supplement 1):S5–S8. doi:10.
1016/j.bone.2007.02.003
Marshall D, Johnell O, Wedel H (1996) Meta-analysis of how
well measures of bone mineral density predict occurrence
of osteoporotic fractures. BMJ (Clin Res Ed)
312(7041):1254–1259
Martin George M, Junko Oshima (2010) Lessons from human
progeroid syndromes. Nature 408:263–266
Martyn-St JM, Carroll S (2010) Effects of different impact
exercise modalities on bone mineral density in pre-
menopausal women: a meta-analysis. J Bone Miner Metab
28(3):251–267
McCalden RW, McGeough JA, Barker MB, Court-Brown CM
(1993) Age-related changes in the tensile properties of
cortical bone. The relative importance of changes in
porosity, mineralization, and microstructure. J Bone Joint
Surg 75(8):1193–1205
Meyer U, Ernst D, Zahner L, Schindler C, Puder JJ, Kraenzlin
M, Kriemler S (2013) 3-year follow-up results of bone
mineral content and density after a school-based physical
activity randomized intervention trial. Bone 55(1):16–22.
doi:10.1016/j.bone.2013.03.005
Milgrom C, Finestone A, Simkin A, Ekenman I, Mendelson S,
Millgram M et al (2000) In-vivo strain measurements to
evaluate the strengthening potential of exercises on the
tibial bone. J Bone Joint Surg 82(4):591–594
Moustafa AA (2014) Motor and cognitive changes in normal
aging. Front Aging Neurosci 6(331):1–3
Nogueira RC, Weeks BK, Beck BR (2014) Exercise to improve
pediatric bone and fat: a systematic review and meta-
analysis. Med Sci Sports Exerc 46:610–621
Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA,
Reginster J, Mitlak BH (2001) Effect of parathyroid
hormone (1-34) on fractures and bone mineral density in
Biogerontology
123
postmenopausal women with osteoporosis. N Engl J Med
344(19):1434–1441. doi:10.1056/
NEJM200105103441904
Niccoli T, Partridge L (2012) Ageing as a risk factor for dis-
ease. Curr Biol 22(17):R741–R752. doi:10.1016/j.cub.
2012.07.024
NICE (2012) Osteoporosis: assessing the risk of fragility
fracture. NICE, London
Nielsen BR, Linneberg A, Bendix L, Harboe M, Christensen K,
Schwarz P (2015) Association between leukocyte telom-
ere length and bone mineral density in women
25–93 years of age. Exp Gerontol 66:25–31. doi:10.1016/
j.exger.2015.04.004
Panula J, Pihlajama
¨
ki H, Mattila VM, Jaatinen P, Vahlberg T,
Aarnio P, Kivela
¨
S (2011) Mortality and cause of death in
hip fracture patients aged 65 or older-a population-based
study. BMC Musculoskelet Disord 12(1):1
Pazianas M (2015) Anabolic effects of PTH and the ‘anabolic
window’. Trends Endocrinol Metab 26(3):111–113.
doi:10.1016/j.tem.2015.01.004
Polidoulis I, Beyene J, Cheung AM (2011) The effect of
exercise on pQCT parameters of bone structure and
strength in postmenopausal women—a systematic review
and meta-analysis of randomized controlled trials.
Osteoporos Int 23:39–51
Quarles LD (2012) Role of FGF23 in vitamin D and phosphate
metabolism: implications in chronic kidney disease. Exp
Cell Res 318(9):1040–1048. doi:10.1016/j.yexcr.2012.02.
027
Recker RR, Davies KM, Hinders SM et al (1992) Bone gain in
young adult women. JAMA 268:2403–2408
Regard JB, Zhong Z, Williams BO, Yang Y (2012) Wnt sig-
naling in bone development and disease: making stronger
bone with wnts. Cold Spring Harbor Perspect Biol. doi:10.
1101/cshperspect.a007997
Riggs BL, Melton LJ, Robb RA, Camp JJ, Atkinson EJ,
Peterson JM, Khosla S (2004) Population-based study of
age and sex differences in bone volumetric density, size,
geometry, and structure at different skeletal sites. J Bone
Miner Res 19(12):1945–1954. doi:10.1359/jbmr.040916
Ritschka B, Storer M, Mas A, Heinzmann F, Ortells MC,
Morton JP, Keyes WM (2017) The senescence-associated
secretory phenotype induces cellular plasticity and tissue
regeneration. Genes Dev 31(2):172–183. doi:10.1101/gad.
290635.116
Ro
¨
nn T, Volkov P, Davega
˚
rdh C et al (2013) A six months
exercise intervention influences the genome-wide DNA
methylation pattern in human adipose tissue. PLoS Genet
9(6):e1003572
Ross TD, Coon BG, Yun S, Baeyens N, Tanaka K, Ouyang M,
Schwartz MA (2013) Integrins in mechanotransduction.
Curr Opin Cell Biol 25(5):613–618. doi:10.1016/j.ceb.
2013.05.006
Schaffler MB, Cheung W, Majeska R, Kennedy O (2014)
Osteocytes: master orchestrators of bone. Calcif Tissue Int
94(1):5–24
Sernbo I, Johnell O (1993) Consequences of a hip fracture: a
prospective study over 1 year. Osteoporos Int
3(3):148–153
Sharkey NA, Ferris L, Smith TS, Matthews DK (1995) Strain
and loading of the second metatarsal during heel-lift.
J Bone Joint Surg 77(7):1050–1057
Shimizu I, Yoshida Y, Suda M, Minamino T (2014) DNA
damage response and metabolic disease. Cell Metab
20:967–977
Sibonga JD (2013) Spaceflight-induced bone loss: is there an
osteoporosis risk? Curr Osteoporos Rep 11(2):92–98
Sieva
¨
nen H, Heinonen A, Kannus P (1996) Adaptation of bone
to altered loading environment: a biomechanical approach
using X-ray absorptiometric data from the patella of a
young woman. Bone. doi:10.1016/8756-3282(96)00111-1
Sims NA, Martin TJ (2014) Coupling the activities of bone
formation and resorption: a multitude of signals within the
basic multicellular unit. BoneKEy Rep 3:481
Specker BL, Wey HE, Smith EP (2010) Rates of bone loss in
young adult males. Int J Clin Rheumtol 5:215–228
Styner M, Thompson WR, Galior K, Uzer G, Wu X, Kadari S,
Rubin J (2014) Bone marrow fat accumulation accelerated
by high fat diet is suppressed by exercise. Bone. doi:10.
1016/j.bone.2014.03.044
Svedbom A, Hernlund E, Ivergard M et al (2013) Osteoporosis
in the european union: a compendium of country-specific
reports. Arch Osteoporos 8:137
Tatsumi S, Ishii K, Amizuka N, Li M, Kobayashi T, Kohno K,
Ikeda K (2007) Targeted ablation of osteocytes induces
osteoporosis with defective mechanotransduction. J En-
docrinol. doi:10.1016/j.cmet.2007.05.001
Tu X, Delgado-Calle J, Condon KW et al (2015) Osteocytes
mediate the anabolic actions of canonical wnt/b-catenin
signaling in bone. PNAS 20:E478–E486
Tveit M, Rosengren B, Nilsson J, Karlsson M (2015) Exercise
in youth: high bone mass, large bone size, and low frac-
ture risk in old age. Scand J Med Sci Sports
25(4):453–461
Udagawa N, Takahashi N, Yasuda H, Mizuno A, Itoh K, Ueno
Y, Suda T (2000) Osteoprotegerin produced by osteo-
blasts is an important regulator in osteoclast development
and function. Endocrinology 141(9):3478–3484. doi:10.
1210/endo.141.9.7634
UK Office for National Statistics (2016) Mid-2015 population
estimates. UK Office for National Statistics, London
Uusi-Rasi K, Kannus P, Cheng S, Sieva
¨
nen H, Pasanen M,
Heinonen A, Vuori I (2003) Effect of alendronate and
exercise on bone and physical performance of post-
menopausal women: a randomized controlled trial. Bone
33(1):132–143. doi:10.1016/S8756-3282(03)00082-6
Valdes A, Richards J, Gardner J, Swaminathan R, Kimura M,
Xiaobin L, Spector T (2007) Telomere length in leuko-
cytes correlates with bone mineral density and is shorter
in women with osteoporosis. Osteoporos Int
18(9):1203–1210
Wall J, Chatterji S, Jeffery J (1979) Age-related changes in the
density and tensile strength of human femoral cortical
bone. Calcif Tissue Int 27(1):105–108
Warden SJ, Fuchs RK, Castillo AB et al (2007) Exercise when
young provides lifelong benefits to bone structure
andStrength. J Bone Miner Res 22:251–259
Warden SJ, Mantila Roosa SM, Kersh ME, Hurd AL, Fleisig
GS, Pandy MG, Fuchs RK (2014) Physical activity when
young provides lifelong benefits to cortical bone size and
Biogerontology
123
strength in men. Proc Natl Acad Sci USA
111(14):5337–5342. doi:10.1073/pnas.1321605111
Weaver CM, Gordon CM, Janz KF, Kalkwarf HJ, Lappe JM,
Lewis R, Zemel BS (2016) The national osteoporosis
foundation’s position statement on peak bone mass
development and lifestyle factors: a systematic review and
implementation recommendations. Osteoporos Int
27:1281–1386. doi:10.1007/s00198-015-3440-3
Weinstein SL (2016) The burden of musculoskeletal condi-
tions. J Bone Joint Surg 98:1331. doi:10.2106/JBJS.16.
00595
Weitzmann MN, Pacifici R (2006) Estrogen deficiency and
bone loss: an inflammatory tale. J Clin Invest
116(5):1186–1194. doi:10.1172/JCI28550
WHO (2015) Ageing and health. Fact Sheet 404. http://www.
who.int/mediacentre/factsheets/fs404/en/
Wiley CD, Velarde M, Lecot P et al (2016) Mitochondrial
dysfunction induces senescence with a distinct secretory
phenotype. Cell Metab 23:303–314
Woo S, Hellstein JW, Kalmar JR (2006) Systematic review:
bisphosphonates and osteonecrosis of the jaws. Ann Intern
Med 144(10):753–761
Yin X, Wang X, Hu X, Chen Y, Zeng K, Zhang H (2015) ERb
induces the differentiation of cultured osteoblasts by both
wnt/b-catenin signaling pathway and estrogen signaling
pathways. Exp Cell Res 335(1):107–114. doi:10.1016/j.
yexcr.2015.04.020
Zhang H, Ryu D, Wu Y (2016) NAD
?
repletion improves
mitochondrial and stem cell function and enhances life
span in mice. Science 352:1436–1443
Biogerontology
123