Understanding the Mechanisms of Senile Osteoporosis: New Facts
for a Major Geriatric Syndrome
Gustavo Duque, MD, PhD, and Bruce R. Troen, MDwz
Knowledge of the underlying mechanisms of osteoporosis
in older adults has significantly advanced in recent years.
There is an acute loss of bone mineral density in the
peri-menopausal period, followed by a more gradual and
progressive decline, which is also seen in men. Markedly
increased bone resorption leads to the initial fall in bone
mineral density. With increasing age, there is also a signifi-
cant reduction in bone formation. This is mostly due to a
shift from osteoblastogenesis to predominant adipogenesis
in the bone marrow. This study reviews new evidence on
the pathophysiology of senile osteoporosis, with emphasis
upon the mechanism of action of current osteoporosis
treatments. New potential treatments are also considered,
including therapeutic approaches to osteoporosis in elderly
people that focus on the pathophysiology and potential re-
versal of the adipogenic shift in bone. J Am Geriatr Soc
56:935–941, 2008.
Key words: osteoporosis; osteoblast; osteoclast; bone
formation and resorption; adipogenesis
O steoporosis is defined as a deterioration in bone mass
and microarchitecture, with increasing fragility,
which predisposes the bone to fractures.1 Osteoporosis is
a major health problem that significantly affects the aging
population. Catastrophic effects on disability and mortality
accompany the increase in the incidence of osteoporotic
fractures in patients aged 65 and older.2 A combination of
factors, including genetics, nutrition, physical activity, and
bone turnover, determine bone mass and ultimately bone
From the Aging Bone Research Program, Nepean Clinical School, University
of Sydney, Penrith, New South Wales, Australia; wGeriatric Research Edu-
cation and Clinical Center, Research Service, Miami Veterans Affairs Medical
Center, Miami, Florida; and zDivision of Gerontology and Geriatric Med-
icine, Department of Medicine, Geriatrics Institute, Miller School of Med-
icine, University of Miami, Miami, Florida.
Address correspondence to Bruce R. Troen, MD, Professor of Medicine, 11
GRC/Miami VAMC, 1201 NW 16th Street, Miami, FL 33125. E-mail:
troen@miami.edu
DOI: 10.1111/j.1532-5415.2008.01764.x
JAGS 56:935–941, 2008
r 2008, Copyright the Authors
Journal compilation r 2008, The American Geriatrics Society
strength.3 After the acquisition of peak bone mass during
the third decade of life, there is a progressive decline of
approximately 0.5% a year, which is considered a ‘‘phys-
iological’’ age-related change.4 This steady age-related bone
loss alone does not necessarily predispose to osteoporotic
fractures, but in many patients, multiple factors, including
those mentioned above, in combination with the loss of
bone, increase the risk of fractures.5
The skeleton is organized into two compartments:
peripheral and axial. The peripheral (cortical) skeleton
constitutes 80% of skeletal mass and is composed primarily
of compact plates (lamellae) organized around central nu-
trient canals. The shafts of long bones consist almost en-
tirely of cortical bone that envelopes the central marrow
cavity.6
The axial, or central, skeleton is composed of approx-
imately 70% (by volume) and 35% (by weight) of
trabecular (cancellous) bone. Trabecular bone is a honey-
comb of vertical and horizontal struts (trabeculae), inside
which is found bone marrow. The metaphyseal ends of
long bones also contain trabecular bone, but they contain
no red marrow in adults. Because marrow elements are
the source of cells involved in bone turnover, the proximity
to the cellular elements that participate in its turnover
results in an earlier and more intense response by
trabecular bone to whole-body changes in the bone remod-
eling rate.7
There are two main pathophysiological processes that
can generate significant bone loss. The first is known as
postmenopausal osteoporosis, which results from estrogen
deprivation and affects mostly trabecular bone. This type of
osteoporosis is most frequently associated with vertebral
and wrist fractures and largely affects women.8 In contrast,
a second type of osteoporosis, known as senile osteoporosis,
most frequently affects cortical bone, predisposing older
women and men to hip fractures.9 Although the unitary
model for involutional osteoporosis holds that estrogen de-
ficiency plays an important role in the pathophysiology of
both types of osteoporosis, this review will focus on the
mechanisms underlying senile osteoporosis, which it is hy-
pothesized results from a combination of changes in bone
cellularity and responses to hormones and nutritional fac-
tors. Current and future therapeutic approaches based on
the cellular changes associated with estrogen deprivation
and aging will also be highlighted.
0002-8614/08/$15.00
936 DUQUE AND TROEN
THE PROCESS OF BONE REMODELING
Bone turnover corresponds to the continuous cycle of
destruction and renewal of bone as a consequence of the
coupled action of bone-resorbing cells (osteoclasts) and
bone-forming cells (osteoblasts). The objectives of this
process are to replace microdamage and to adapt bone
shape and density to patterns of usage and the attendant
forces exerted. Both cell types are present in areas called
bone remodeling units (BMUs). Bone remodeling starts
with the destruction of old bone by osteoclasts, and is
followed by the deposition of osteoid (unmineralized bone)
by osteoblasts.10 Subsequently, the organic extracellular
matrix is mineralized.
Osteoclasts are derived from the monocytic hemato-
poietic lineage and share a common precursor with mac-
rophages.11 Bone resorption occurs within a tightly sealed
zone beneath the ruffled border of the osteoclast where it
has attached to the bone surface. Acidification of this ex-
tracellular compartment results in the demineralization of
bone, and cysteine proteases, most notably cathepsin K,
subsequently degrade the organic matrix.12 In contrast,
osteoblasts are fibroblastic-like cells that originate from the
stromal precursors in the bone marrow. These cells have the
capacity to form new osteoid and to stimulate its mineral-
ization.13 Multiple factors, including hormones (e.g.,
estrogens, parathyroid hormone (PTH), vitamin D), inter-
leukins (e.g., IL-1, IL-6, IL-11), other cytokines (tumor
necrosis factor alpha), and growth factors (bone morpho-
genetic proteins), regulate bone remodeling.11 This process
requires a coordinated communication between osteoblasts
and osteoclasts (Figure 1). Osteoblasts respond to external
Figure 1. Osteoblast–osteoclast coupling. Osteoblast produc-
tion of macrophage colony stimulating factor (M-CSF) and re-
ceptor activator of nuclear factor-kappa B ligand (RANKL) play
critical roles in the differentiation and activation of osteoclasts.
M-CSF acts to maintain monocytic stem cell survival, and
RANKL subsequently acts to commit the cell to osteoclast
differentiation, fusion, polarization, and activation. EphB4 and
ephrinB2 interact to limit osteoclast activity and stimulate
osteoblast differentiation. Transforming growth factor beta
(TGF-b) acts only upon release from the extracellular matrix
after osteoclastic resorption, which is mediated in large part by
the excretion of cathepsin K (CTSK).
MAY 2008–VOL. 56, NO. 5 JAGS
Figure 2. Cellular changes in senile osteoporosis. Changes in the
confluence of mesenchymal stem cells accompanied by a reduc-
tion in osteoblastogenesis result in the formation of fewer active
osteoblasts in the bone multicellular unit. In addition, increasing
levels of adipogenic differentiation lead to smaller numbers of
differentiated osteoblasts. Finally, increasing osteoblast apopto-
sis reduces the number of active osteoblasts in the bone multi-
cellular units.
or internal stimuli, producing macrophage colony stimu-
lating factor (M-CSF) and membrane-bound receptor acti-
vator of nuclear factor-kappa B ligand (RANKL), which are
critical factors necessary for osteoclastogenesis.12 RANKL
interacts with its cognate receptor (RANK) that osteoclasts
and their precursors express. The binding between RANK
and its ligand stimulates osteoclast differentiation and ac-
tivation and prevents osteoclast cell death.14 Concurrently,
a decoy receptor known as osteoprotegerin, which the
osteoblasts produce and inhibits RANK–RANKL signaling,
regulates this process.15 Many factors stimulate RANKL
expression, including PTH, vitamin D, cytokines, ILs, pro-
staglandins, and thiazolidinediones. Conversely, estrogen,
transforming growth factor beta (TGF-b), and mechanical
force inhibit RANKL expression. More recently, signaling
by ephrin has been thought to play an important role in
osteoclast–osteoblast coupling.16 This cellular communica-
tion is bidirectional and involves a transmembrane ligand
known as ephrinB2, which osteoclasts express, and its re-
ceptor, EphB4, which osteoblasts express. This signaling
seems to limit osteoclast activity while enhancing osteoblast
differentiation.16 Additional factors released from the bone
Figure 3. Changes in osteoblast–osteoclast interactions with
aging. Reduced physical activity and mechanical loading and
decreased levels of bioavailable estradiol and testosterone exert
diminished effects upon osteoblasts (depicted by the arrows with
the hatches) resulting in decreased osteoblast secretion of
osteoprotegerin (OPG) and increased expression and secretion
of receptor activator of nuclear factor-kappa B ligand (RANKL),
interleukin (IL)-1, IL-6, IL-11, and tumor necrosis factor alpha
(TNF-a). In turn, these compounds directly stimulate greater
osteoclast formation and activity. The reduced OPG also permits
greater binding of RANKL to RANK, which further facilitates
increased osteoclastogenesis and resorption. Adapted from
Troen.11
JAGS MAY 2008–VOL. 56, NO. 5
matrix by osteoclastic resorption and secreted by osteo-
clasts modulate osteoblast formation and activity; these
include TGF-b, bone morphogenetic proteins, platelet-
derived bone factor, and osteoclast inhibitory lectin.
If the remodeling cycle were completely efficient, bone
would never be lost or gained. Each BMU would completely
replace the packet of bone that was initially resorbed.
However, remodeling, like most biological processes, is not
entirely efficient; although this imbalance is minuscule for
any single normal bone-remodeling event, it leads to a sig-
nificant decline in bone mass of approximately 0.5% per
year, resulting in progressive age-related bone loss.9 After
completing their initial function, bone cells in BMUs un-
dergo different fates. Osteoclasts die by apoptosis, or pro-
grammed cell death, and are phagocytosed in situ.17 In
contrast, osteoblasts can undergo several possible fates.
They can become lining cells, migrate to a new BMU, be-
come embedded within the osteoid, become osteocytes, or
finally die by apoptosis (Figure 2).9 The predominance of
any of these fates will determine the amount of osteoblasts
available in the BMU and thus, ultimately, the differenti-
ation and activation of osteoclasts.
Age-Related Bone Loss
The changes in bone mass with aging are the consequence of
two processes: periosteal apposition, which takes place on
the outside of the bone, and endosteal bone resorption,
which takes place on the inside of the bone. Although men
and women have a similar decline in endosteal bone re-
sorption, periosteal apposition is less affected in men.18
This may explain why spine fractures occur less commonly
in men than in women.
Furthermore, age-related bone loss is also the conse-
quence of changes in hormones as well as cell number and
function. As previously described, increasing osteoclast for-
mation and activity, caused by higher levels of RANKL and
diminished osteoclast apoptosis, follow the declining estro-
gen levels in men and women (although more significantly
in women during perimenopausal years).19
A second hormone closely involved with age-related
changes in bone is vitamin D. There is widespread vitamin
D insufficiency in elderly people, irrespective of latitude.20
Reduction in sunlight exposure and decreased vitamin D–
rich food intake contribute to hypovitaminosis D.20 In ad-
dition, the capacity to metabolize vitamin D in the skin
diminishes with aging.21 Hypovitaminosis D often leads to
secondary hyperparathyroidism, which subsequently en-
hances osteoclastic bone resorption.22 In addition to the
hormonal changes, cellular changes in the bone microen-
vironment include changes in the mobility and differenti-
ation of mesenchymal stem cells, with subsequent
alterations in bone cellularity (Figure 3).23 These changes
in cellularity include higher levels of adipocytes with lower
number of osteoblasts.9 Osteoblasts and adipocytes share
the same precursors within the bone marrow, and therefore
adipogenesis increases at the expense of osteoblastogene-
sis.24 Additionally, greater apoptosis reduces the life span of
osteoblasts.9 In summary, cellular changes in aging bone
reduce the number of osteoblasts available for bone
remodeling and formation. Although the process of age-
related bone loss is the consequence of changes in hormonal
BIOLOGICAL MECHANISMS OF SENILE OSTEOPOROSIS 937
stimulation and bone cellularity, a proportion of subjects
lose their bone mass only at a ‘‘physiological basis,’’ where-
as a proportion of subjects will suffer ‘‘pathological bone
loss’’ leading to osteoporosis. Although diet, physical ac-
tivity, and genetics play a role in accelerated bone loss, it is
likely that there are additional hormonal and molecular
factors that remain to be elucidated.
Aging and Bone
Although much is known about the potential mechanisms
of age-related bone loss, the link between the normal aging
process and senile osteoporosis remains unclear. A mouse
model of deficiency in deoxyribonucleic acid repair and
transcription demonstrated that kyphosis and osteoporosis
accompany accelerated aging.25 Mice under excessive ox-
idative stress exhibit a similar bone phenotype.26 Further-
more, preservation of telomerase activity, which is usually
reduced in aging and in senescent cells, enhances osteoblast
survival and the generation of more lamellar bone.27 Prob-
ably the most interesting evidence of a link between aging
and senile osteoporosis is the recent description of lamin
A/C mutations in Hutchinson-Gilford progeria syndrome.28
Patients with this syndrome have severe osteoporosis and
changes compatible with aging bone,29 which are similar to
mouse models lacking lamin A/C that also have progeroid
features.30 Aging osteoblasts exhibit reduced expression of
lamin A/C,31 and alterations in lamin A/C expression in vivo
induce lower osteoblastic and osteocytic activity30 and alter-
ations in adipogenesis compatible with lipodistrophy and fat
redistribution.32 Although further research is required, the
regulation of lamin A/C expression may become an important
research field for the elucidation of some of the molecular
mechanisms underlying senile osteoporosis.33
Fat and Bone: An Odd Couple
The predominant feature of senile osteoporosis is the ac-
cumulation of bone marrow fat at the expense of osteo-
blastogenesis.34 This accumulation seems to be independent
of estrogen, because bone marrow fat appears in bone even
when estrogen levels are still normal, during the third and
fourth decade of life.35 Additionally, mice lacking estrogen
receptors do not display higher levels of adiposity within
their bone marrow than do wild-type mice.36 Therefore,
aging per se, independent of hormonal changes, appears to
contribute significantly to bone marrow adipogenesis, rais-
ing the possibility that senile osteoporosis is a type of lypo-
toxic disease. The role of bone marrow fat is still unclear.
Although it could just be occupying space that is vacated by
diminished hematopoiesis and reduced trabecular mass va-
cate, it could also play an important and maybe patholog-
ical role. Bone marrow adipocytes appear to exert a toxic
effect on osteoblasts.37 Cocultures of adipocytes and osteo-
blasts reveal that adipocytes inhibit osteoblast activity and
survival, possibly secondary to the release of adipokines
and fatty acids by the increased number of adipocytes
within the bone marrow.38 Recent data obtained in humans
treated with thiazolidiones (rosiglitazone) argue for a role
for bone marrow fat in senile osteoporosis. Rosiglitazone
induces the expression of peroxisome proliferator activated
receptor gamma 2 (PPARg2), which is a critical transcrip-
tion factor in the age-related increase in adipogenesis in the
938 DUQUE AND TROEN
bone marrow.39 Epidemiological studies reveal that sub-
jects treated with rosiglitazone suffer not only significant
bone loss,40 but also greater fracture risk.41 Recently, it has
been suggested that age-related bone loss represents the
‘‘obesity of bone.’’34 However, inhibition of PPARg activity
in diabetic mice, while reducing the accumulation of bone
marrow fat, did not prevent bone loss.42 In summary, bone
marrow fat induces changes in bone cellularity, especially in
the osteoblastic lineage that could explain some of the
changes seen in senile osteoporosis.
The Cellular Mechanisms of Osteoporosis Treatment:
Present and Future
Based on the cellular changes found with senile osteoporo-
sis, the main goals of treatment should include the regula-
tion of osteoclastic activity and thus bone turnover, a
recovery in the number of osteoblasts available to build new
bone, and finally the regulation of bone marrow adipogen-
esis.43 Although most of the treatments currently available
are antiresorptives that suppress osteoclastic activity, there
is new evidence that some of them may exert an anabolic
effect by stimulating osteoblastic activity and, in some
cases, inducing the transdifferentiation of adipocytes into
osteoblasts within the bone marrow (Table 1). Additionally,
some nonpharmacological approaches have also been
shown to alter bone cellularity.
Physical Activity
The mechanisms by which the skeleton responds to activity
remain incompletely understood, although overwhelming
evidence indicates that bone mass increases in response to
the cyclic administration of mechanical loads.44 Not only is
bone density higher in physically active people, but exercise
also reduces the rate of age-related bone loss.45 Osteocytes
and osteoblasts sense mechanical strain, and exercise stim-
ulates osteocyte activity and survival.46 Because the activity
of osteoblasts and osteoclasts is tightly coupled, it is likely
that a reduction in osteocyte and osteoblast apoptosis
would affect osteoclast activity and bone resorption.46 A
Table 1. Pharmacological Effect of Osteoporosis Medications on Bone Cellularity
Compound Osteoblast
Bisphosphonate differentiation66
activity66
apoptosis66
Calcitonin
Parathyroid hormone activity72
survival72
differentiation72
Selective estrogen receptor modulator
Strontium ranelate activity75
differentiation84
Vitamin D activity53
differentiation
apoptosis54
MAY 2008–VOL. 56, NO. 5 JAGS
yearlong multicomponent exercise regimen in women aged
70 to 78, which included jumping, maintained tibial shaft
structure better than controls, but did not alter proximal
femur bone mineral content.47 Another study in early post-
menopausal women using jumping exercise demonstrated
better bone strength but no change in markers of bone
turnover.48 In both studies, the exercise group exhibited
improvements in balance and leg power. Because falls are a
major risk factor for fractures, the benefits of exercise to
reduce fracture risk is likely to be multifactorial. Low-fre-
quency whole-body vibration can enhance hip bone mineral
density49 and bone mineral density and balance in post-
menopausal women,50 although studies have not been per-
formed on subjects aged 80 and older.
Calcium and Vitamin D
In elderly subjects, diminished absorption of calcium and
reduced serum levels of vitamin D typically result in high
PTH levels, leading to support of plasma calcium at the
expense of bone loss.22 A recent meta-analysis demonstrat-
ed that vitamin D supplementation of between 700 and
800 IU/d appears to reduce the risk of hip fractures 26%.51
The classical understanding of the mechanisms of action of
vitamin D on bone included the indirect effect on calcium
absorption in the bowel, with a subsequent normalization
of PTH.52 In contrast, recent evidence has demonstrated
that vitamin D has a more-sophisticated action in aging
bone. First, vitamin D has been shown to enhance new bone
formation in senescent animals by inducing osteoblasto-
genesis and osteoblastic activity.53 Second, vitamin D pre-
vents osteoblast apoptosis in vitro.54 Finally, vitamin D
inhibits bone marrow adipogenesis and PPARg2 expression
in aging mice, while concurrently stimulating osteogenic
genes.55 These studies, when correlated with the clinical
evidence, support the importance of vitamin D as a key
treatment for senile osteoporosis for the maintenance
of bone mass and bone quality and as a complement to
antiresorptive treatments.
Adipocyte Osteoclast
differentiation79
activity66
apoptosis66
activity80
apoptosis81
differentiation82 activity72
differentiation83
activity83
activity84
survival84
differentiation55 activity85
transdifferentiation
to osteoblasts55
JAGS MAY 2008–VOL. 56, NO. 5
Steroid Hormones
It is known that, in women, loss of estrogen has multiple
effects. First, there is decreased efficiency of intestinal ab-
sorption of calcium.56 Second, estrogen deficiency directly
permits the recruitment of greater numbers of osteoclasts,
which individually also seem to resorb bone with greater
efficiency.19 Furthermore, estrogen deficiency leads to en-
hanced production and secretion of cytokines that stimulate
osteoclastogenesis, osteoclast activation, and bone resorp-
tion.19 Subsequent perforation of trabeculae reduces the
available scaffold for initiation of new bone formation.
Therefore, entire trabecular elements may be permanently
eliminated. Finally, because estrogen inhibits osteocyte ap-
optosis, estrogen deficiency results in fewer of the cells that
typically respond to mechanical forces to maintain the
skeleton.57 Low-dose estradiol can significantly reduce
bone turnover in healthy community-dwelling women aged
65 and older, without significant side effects.58 Although
replacement of estrogen at perimenopause and at later ages
protects bone mass and significantly protects against frac-
ture, concerns about adverse health consequences have sig-
nificantly curtailed their use.59
The skeletal role of androgens upon cancellous bone is
largely mediated by local aromatization into estrogens.60
Androgen deficiency in men induces cancellous bone loss
similar to estrogen deficiency in postmenopausal women.60
In elderly men with hypogonadism, the resultant testoster-
one deficiency contributes to osteoporosis. Although treatment
of frank androgen deficiency with androgen replacement
therapy is beneficial for bone,61–63 the effect of androgen
replacement on fracture incidence remains unknown. Al-
though there has been one comprehensive review of re-
placement in hypogonadal men,64 evidence addressing
potential benefits of replacement therapy in partially an-
drogen-deficient elderly men is lacking, and the overall
effects on all target tissues and quality of life and survival
need to be further explored.
Bisphosphonates
Bisphosphonates, such as alendronate, risedronate, ibad-
ronate, and more recently zoledronate, regulate bone re-
sorption by reducing the number of osteoclasts in the BMU
and inducing their apoptosis.65 The mechanism of action of
bisphosphonates includes suppressing the capacity of
osteoclasts to resorb bone due to the modification of their
shape, loss of their enzymatic capacity, and shortened sur-
vival.66 This results in a marked reduction in bone turnover
that enhances secondary mineralization of preformed ost-
eons.66 Despite the reduction in bone turnover, bone mass
increases during treatment with bisphosphonates. A poten-
tial anabolic effect of bisphosphonates might explain this
effect. Recently, it has been reported that alendronate stim-
ulates osteoblastic differentiation while inhibiting adipo-
genesis in vitro.67 This could explain why, despite the fact
that bisphosphonates decrease the levels of bone turnover, a
gain in bone mass is seen when used in osteoporotic pa-
tients. Although this gain in bone mass is associated with
fracture reduction in patients with menopausal osteoporo-
sis,66 evidence of the effect of bisphosphonates on fracture
prevention in older populations is limited.68 However, re-
cent studies have shown that yearly intravenous zoledronic
acid significantly reduces vertebral and nonvertebral frac-
BIOLOGICAL MECHANISMS OF SENILE OSTEOPOROSIS 939
tures (including hip fractures) in postmenopausal women69
and significantly reduces nonvertebral fractures (but not
necessarily hip fracture) in elderly women who have already
suffered a hip fractures.70
Anabolic Treatment of Senile Osteoporosis
Anabolic treatments increase the amount of bone laid down
in each remodeling unit by enhancing osteoblastogenesis,
decreasing adipogenesis, or protecting osteoblasts against
apoptosis. Subsequently, more osteoblasts in the BMU will
form more new bone and induce an increase in the remod-
eling rate (through the activation of osteoclasts), both of
which will increase the amount of bone tissue and
trabecular thickness.71 Currently, PTH and its analog teri-
paratide (recombinant PTH (1–34)) are the only approved
anabolic treatments for osteoporosis.72 Intermittent daily
dosing of PTH induces osteoblast differentiation, inhibits
adipogenesis, and suppresses osteoblast apoptosis.72 This is
in marked contrast to the bone resorption that the persistent
elevation of PTH in disease states such as primary hyper-
parathyroidism and some malignancies causes. Teriparatide
is indicated in postmenopausal women and in men with
severe osteoporosis (T-score
 3.5, or o  2.5 in the set-
ting of recurrent fracture) or in patients with established
glucocorticoid-induced osteoporosis who require long-term
steroid treatment.73,74 Teriparatide is effective in commu-
nity-dwelling ambulatory women aged 75 and older; treat-
ment enhances bone mineral density, reduces vertebral and
nonvertebral fractures, and is as safe as in younger wom-
en.74 Limitations to the administration of PTH in older
adults include cost, mode of administration (subcutaneous),
and the requirement of a motivated and cognitively intact
patient or caregiver.
Future Perspectives for the Treatment of Senile
Osteoporosis
The goals of treatment of osteoporosis in older adults
should include the formation of high-quality new bone (i.e.,
higher trabecular thickness and lower cortical porosity that
will reduce the risk of fracture). This effect is obtained only
if osteoblasts are able to function normally and therefore
regulate the number of active osteoclasts in the BMU. The
toxic effect of bone marrow adipogenesis should also be
managed (or prevented) so that osteoblast formation and
activity can be maintained and possibly even enhanced.
Strontium ranelate, which has been approved for use in
Europe and Canada, is a new molecule that inhibits bone
resorption and stimulates bone formation, with proven
efficacy to reduce fracture incidence.75 In addition, stron-
tium ranelate reduces the risk of vertebral and nonvertebral
fractures in women aged 80 and older.76 Perhaps strontium
in concert with vitamin D will optimize osteoblastogenesis
and concurrently minimize adipogenesis. Resveratrol,
which is derived from grape skins and may underlie the
‘‘red wine’’ paradox, inhibits adipocyte formation while
stimulating markers of osteoblast formation in an in vitro
mouse model, apparently by antagonizing PPARg action.77
In addition, in a rat model, mechanical loading has been
shown to enhance osteoblastogenesis and diminish adipo-
genesis by reducing PPARg2,78 raising the possibility that
exercise will also play an important role in future studies
and interventions.
940 DUQUE AND TROEN
CONCLUSION
Bone is an active tissue that not only supports the body, but
is also an active metabolic organ with multiple cell–hor-
mone interactions. It is likely that the regulation of cellular
differentiation, activation, and coupling affects fracture risk
in older adults. Selection of optimal treatment should in-
clude each patient’s particular characteristics and a com-
plete understanding of the cellular mechanisms involved to
provide the most effective treatment. Although most of the
treatments available are directed toward the regulation of
bone resorption, future studies are likely to lay the foun-
dation for the development of anabolic treatments to more
directly maintain bone mass and quality in older adults.
ACKNOWLEDGMENTS
Conflict of Interest: Dr. Duque serves as consultant and on
the speakers bureau for Procter and Gamble pharmaceuti-
cals and Merck-Frosst Canada. Dr. Duque holds a career
award from the Fonds de la Recherche en Santé du Québec
and an operating grant from the Canadian Institutes of
Health Research. Dr. Troen is supported in part by grants
from the Department of Veterans Affairs (Merit Review)
and the Indian Trail Foundation and by the Miami Geriatric
Research, Education, and Clinical Center and the Division
of Gerontology and Geriatric Medicine at the University of
Miami Miller School of Medicine.
Author Contributions: Dr. Duque and Dr. Troen co-
wrote the manuscript.
Sponsors’ Role: The sponsors and supporters of Dr.
Duque and Dr. Troen exerted no influence in the prepara-
tion of this manuscript.
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