Chapter 45
Osteoporosis in Adults
Robert Marcus
Stanford University, Stanford, CA, United States
I INTRODUCTION
Osteoporosis is a global skeletal disorder of decreased
bone strength in which the only important consequence is
an increased risk for fracture with minimal trauma. The
term porosis means “spongelike,” which aptly describes
the appearance of that portion of the skeleton, the trabecu-
lar skeleton, which is most afflicted with this disease
(Fig. 45.1). Bone strength is a complex function integrat-
ing bone mineral density (BMD) and bone quality. BMD
is the concept most familiar to the public, to patients, and
to physicians, but it is only one determinant of bone
strength, all other contributions that are not captured by
BMD measurement come under the rubric of “bone qual-
ity.” The term quality should more properly be considered
as the plural qualities because it encompasses a wide vari-
ety of characteristics that are enumerated later in this
chapter. Osteoporotic, or fragility, fractures traditionally
have been grouped according to their location, either in
the spine (vertebral) or nonspine, the latter including
those of the distal radius (Colles’ fractures) and the proxi-
mal femur (hip fracture). It is important to understand
that because of its global nature, osteoporosis imposes
an increased risk for virtually all fractures in affected
individuals.
Already more common than any other generalized
skeletal condition, osteoporosis continues to increase in
prevalence. Based on data from the National Health and
Nutrition Examination Survey III (NHANES) and from
the 2000 National Census, the National Osteoporosis
Foundation estimated that, in 2002, 20% of postmeno-
pausal white women in the United States had osteoporo-
sis, and an additional 52% had low bone density at the
hip [1]. In the whole population, approximately 8 million
have osteoporosis, of whom approximately 1.5 million
will fracture each year. One out of every two white
Nutrition in the Prevention and Treatment of Disease. DOI: http://dx.doi.org/10.1016/B978-0-12-802928-2.00045-X
© 2017 Elsevier Inc. All rights reserved.
women will experience an osteoporotic fracture at some
point in her lifetime [1 3].
Although men have a lower prevalence of osteoporosis
than women, perhaps 25% as great, fragility fractures cer-
tainly occur in men, and some of these, particularly at the
hip, carry a less favorable prognosis in men than for
women. The most common osteoporotic fractures occur
as compression deformities of the thoracic or lumbar
spine. Although two-thirds of these do not acutely pro-
duce symptoms, they must not be viewed in any sense as
benign events. Even mild compression fractures aggravate
by four- or fivefold the short-term risk for subsequent
fractures. Approximately one-third of vertebral fractures
produce symptoms when they occur and are referred to as
“clinical” vertebral fractures. These are more likely to be
of moderate or severe degree in deformity and are
the fractures most likely to result in long-term pain, defor-
mity, and disability. In the Study of Osteoporotic
Fractures (SOF), a long-term observational study of thou-
sands of older women, clinical vertebral fractures were
associated with an eightfold excess of mortality similar to
that observed with hip fracture [4]. The incidence of ver-
tebral fractures in women begins to rise early in the sixth
decade, corresponding in time to the menopausal loss of
endogenous estrogen. The incidence continues to increase
in succeeding decades (Fig. 45.2) [3].
At nonvertebral sites, forearm fractures, particularly at
the distal radius, also increase during the sixth decade but
stabilize thereafter, at which time the incidence of hip
fracture begins exponentially to increase [3]. Both fore-
arm and hip fractures result directly from a fall. Whether
an individual fractures the arm or the hip reflects the man-
ner of falling. Younger women with normal locomotion
generally fall while walking and break a fall by arm
extension. Older and more frail women often fall while
transferring from a seated to a standing position. If they
991
992 PART | H Bone Health and Disease

FIGURE 45.1 (A) Normal trabecular bone. Note the highly interconnected vertical and horizontal bars, fairly homogeneous size and shape of holes,
and platelike appearance of many of the trabecular units. (B) Osteoporotic bone. Note substantial reduction in the amount of bone substance per unit
volume compared to normal bone (A). Note the narrow rodlike appearance of vertical trabeculae compared to the normal platelike structures. Note the
wide variation in the size of holes throughout the trabecular structure. In many regions, trabecular struts are hanging in space without connection to
neighboring structures. Courtesy Dr. David Dempster. Copyright David Dempster.

4000 Men Women companion chapter in this volume on childhood bone

Incidence/100,000 person-years

development (Chapter 44: Osteoporosis: The Early Years)

3000 which the reader is strongly urged to consult.
Hip

2000 Hip Vertebrae

Vertebrae
1000
Colles'
35–39 ≥85
Age group, years
FIGURE 45.2 Age-specific incidence rates for hip, vertebral, and distal
forearm fractures in men and women. Data derived from the population of
Rochester, Minnesota. From C. Cooper, L.J. Melton, III, Epidemiology
of osteoporosis, Trends Endocrinol. Metab. 3 (1992) 224 229.
fail to elevate their centers of gravity sufficiently to sup-
port an upright posture, they fall backwards or to the side,
directly impacting the femoral greater trochanter and pos-
sibly leading to hip fracture [5,6].
This chapter focuses on the characteristics of a healthy
skeleton, the underlying pathophysiology of osteoporosis,
the characteristics of osteoporotic bone, approaches to
conserving bone throughout adult life, and therapeutic
approaches to treating skeletal fragility. A comprehensive
discussion of the various pharmacologic agents available
for patient management lies outside the scope of this
chapter, and the critical role of bone acquisition during
years of growth through adolescence appears in the
II THE SKELETON
Bone is a complex cellular tissue that contains, by weight,
approximately 30% organic constituents and 70% mineral.
Colles'
The most abundant protein in the organic compartment is
≥85 type I collagen, a fibrillar structure consisting of three
interweaving strands—normally two strands of alpha-1
collagen and one strand of alpha-2 collagen. Collagen
represents 98% of the organic phase of bone, and various
noncollagen proteins account for the remainder [7].
The mineral phase of bone is approximately 95%
hydroxyapatite, a highly organized crystal of calcium and
phosphorus. Other minerals normally found in bone min-
eral include sodium (indeed, approximately 30% of total
body sodium can be stored in bone crystal), magnesium,
and fluoride. Incorporation of fluoride and strontium into
bone crystal is of particular relevance because these com-
pounds have seen use as therapy for osteoporosis.
A Bone Cells
The processes of bone formation and breakdown (resorp-
tion) require cellular activity. Three major cell types
reside in bone and conduct these processes: osteoblasts,
osteocytes, and osteoclasts.
 Osteoporosis in Adults Chapter | 45 993

FIGURE 45.3 Low-power view of osteoblasts lining the bone surface.

From C.A. Lee, T.A. Einhorn, The bone organ system, form and function,
in: R. Marcus, D. Feldman, J. Kelsey, Osteoporosis, Academic Press, FIGURE 45.4 Osteocytes occupying individual lacunae with extensive
San Diego, CA, 2001, 3 20 [7], with permission. canalicular interconnections. From C.A. Lee, T.A. Einhorn, The bone
organ system, form and function, in: R. Marcus, D. Feldman, J. Kelsey,
Osteoporosis, Academic Press, San Diego, CA, 2001, 3 20 [7], with
Osteoblasts are the primary bone-forming cells. They permission.
derive from stem cells in the bone marrow stroma. These
stem cells are pluripotential, having the capacity to
develop along multiple lineages, including fibroblasts,
hematopoietic cells, myocytes, adipocytes, chondrocytes,
and osteoblasts. During linear growth, osteoblasts invade
a temporary cartilaginous template to form primary lamel-
lar bone. During remodeling (see later discussion), a wave
of osteoblast precursors migrates to the base of a resorp-
tion cavity, acquires the characteristics of mature osteo-
blasts, and lays down new bone (Fig. 45.3).
Osteocytes are osteoblasts that have become embedded
within their own secreted matrix. Each osteocyte sits in
its individual hole, or lacuna, connected to one another
throughout the bone matrix by a highly developed net-
work of channels, or canaliculi. Osteocytes appear to be
the monitors and responders to a bone’s mechanical envi- FIGURE 45.5 Low-power view of osteoclasts occupying resorption
lacunae. From C.A. Lee, T.A. Einhorn, The bone organ system, form and
ronment (Fig. 45.4). function, in: R. Marcus, D. Feldman, J. Kelsey, Osteoporosis, Academic
Osteoclasts are multinucleated giant cells of macro- Press, San Diego, CA, 2001, 3 20 [7], with permission.
phage lineage. They undertake the enzymatic destruction
of bone during the resorption phase of remodeling (see
later discussion). During this process, osteoclasts form a although dormant, retain the capacity in certain circum-
seal at the bone surface with the aid of anchoring proteins stances to convert into functional osteoblasts and lay
called integrins whose receptors exist in the bone matrix. down new bone. This appears to be one mechanism
This seal creates a sequestered region underneath the oste- through which administration of parathyroid hormone
oclast into which hydrogen ion is secreted using a car- (PTH) achieves a rapid increase in bone formation (see
bonic anhydrase-dependent pump and resulting in a section VB on Pharmacologic therapeutics).
highly acidic local environment. In addition, the osteo- Eighty percent of the adult skeleton consists of com-
clast secretes a variety of hydrolytic enzymes, such as pact bone. This is referred to as the cortical or appendicu-
cathepsins, which hydrolyze bone matrix (Fig. 45.5). lar skeleton and comprises mostly the long bones as well
A fourth cell is also observed in bone. So-called lin- as the outer shells of the central, or axial, skeleton, which
ing cells are seen as a syncytial layer of dormant cells includes the spine, sternum, pelvis, and the ends (meta-
that covers bone surfaces. This group of cells is thought physes) of long bones. The axial skeleton has a heavy
to serve a surveillance function that responds to micro- complement (perhaps 40% by weight or 80% by surface
scopic damage by locally stimulating new remodeling area) of a honeycomb-like series of vertical and horizontal
activity. Lining cells also originate from osteoblasts and, bars, or trabeculae, and is therefore frequently called
994 PART | H Bone Health and Disease
trabecular bone (in orthopedics this may also be called
cancellous bone). In adults, the trabecular bone of the
spine and pelvis constitutes the primary residence of red
bone marrow. Because the cells responsible for conduct-
ing the processes underlying adult bone loss originate in
the bone marrow, and because these processes occur on
the surfaces of bone, it should be no surprise that trabecu-
lar bone, with its rich complement of bone marrow and
extensive surface area, should be the bone compartment
that experiences the earliest and most rapid loss of bone
with aging.
At any time during adult life, the amount of bone con-
tained within the skeleton consists of that bone which was
present at the end of growth, the so-called “peak bone
mass,” minus that which has been lost. One frequently
encounters patients who report being told, following a
bone density test, that they have “lost 30% of their skele-
ton.” The problem with such conclusions is that one sim-
ply cannot determine from a single BMD measurement
whether a deficit in bone mineral reflects bone loss or
failure to achieve the peak bone mass that might have
been predicted for that individual. In fact, the majority of
young adults with low bone mass have not lost bone at all
but, rather, have age-related deficits related to poor acqui-
sition of peak bone mass. (See chapter 44 by Weaver on
childhood bone acquisition in this volume.)
B Physiologic Roles of the Skeleton
During vertebrate evolution, the skeleton acquired two
fundamental but not necessarily compatible functions. By
virtue of its dense mineralization, bone provides the struc-
tural rigidity necessary to withstand the effect of gravity
and support terrestrial locomotion. By adapting to region-
specific differences in its mechanical environment,
denser, stronger bone exists where it is needed without
requiring a universal increase in skeletal weight to the
point that mobility is jeopardized.
Bone also constitutes the primary repository in the
body for calcium. Indeed, 99.5% of body calcium is con-
tained within bone and can be mobilized to support the
extracellular calcium concentration at times of need. For
the great majority of vertebrates, the calcium environment
is extremely high, reflecting its very high concentration in
ocean water (B400 mg/L). Facing the threat of calcium
toxicity, ocean fish must be able to eliminate excess cal-
cium from their bodies, which they accomplish through
a calcium-dependent ATPase system in the gills.
Progression of vertebrates onto land, with freshwater far
more dilute in calcium, required mechanisms to promote
calcium extraction from the environment and to conserve
it within the body. PTH, the peptide secretory product of
the parathyroid glands (first appearing in amphibians),
serves this role. In response to minute-to-minute relatively
mild reductions in extracellular calcium concentration,
such as during the hours following a meal, PTH stimu-
lates the kidney to conserve calcium by regulating renal
tubular reabsorption efficiency. When calcium deficits
become sustained or severe, such as in the face of chroni-
cally inadequate dietary calcium, PTH stimulates the renal
production of 1,25(OH)2 vitamin D (calcitriol), the potent
hormonal form of the parent vitamin, which in turn
enhances intestinal calcium absorption. In this setting,
PTH also stimulates bone remodeling by initiating the for-
mation of new remodeling units and resulting in delivery
of calcium from the skeleton to the extracellular environ-
ment. Together, these actions restore plasma calcium con-
centrations to their normal level [8]. It must be
understood that PTH action on the skeleton does not
selectively remove calcium from the skeleton but is
accomplished by an increase in bone remodeling (see later
discussion) so that the release of mineral to the plasma
compartment is accompanied by a net loss of bone.
C Remodeling: The Key to Understanding
Age-Related Bone Loss
Many mammals, primates, and humans maintain skeletal
integrity through a continuous process of breakdown and
renewal known as remodeling. This process occurs life-
long, although during childhood and adolescence it is
overshadowed by the events of linear growth (modeling).
Once growth centers have fused and skeletal maturation
is complete, remodeling becomes the dominant—and
indeed, with rare exception, the only—mechanism
through which bone is added to or removed from the skel-
eton. Each remodeling event is carried out by discrete
bone multicellular units and consists of an initial phase of
bone resorption that is coupled to a longer phase of bone
formation (Fig. 45.6). These are initiated when cells of
macrophage lineage come from the bone marrow to points
on the bone surface and fuse into multinucleated osteo-
clasts that dig into and remove bone. The cavity thus cre-
ated reaches a depth of 60 μm within 6 8 weeks. In this
manner, both mineral and matrix constituents are returned
to the circulating extracellular fluid. Released from the
resorbed matrix is a rich assortment of cytokines and
growth factors that then attract into the base of the cavity
a wave of osteoblast precursor cells from the marrow
stroma. These transform into functional osteoblasts and
begin to lay down new bone matrix. Once the new bone
reaches a thickness of approximately 20 μm, it begins
to accumulate mineral. By the end of approximately
6 months, bone formation is complete and the bone is
restored almost to its basal state. However, like many bio-
logical processes, bone remodeling is not 100% efficient;
that is, the amount of new bone formed does not

Normal bone remodeling cycle
a b
c away and replaced (albeit at the long-term price of grad-
d
e
g
f D Intercellular Communication
FIGURE 45.6 The bone remodeling cycle. This drawing represents a
region of trabecular bone. All remodeling events occur on the bone sur-
face. (a) 90% of bone surface is generally covered by thin layer of dor-
mant lining cells. (b) Coalescence of osteoclast precursors at a site on
the bone surface with creation of multinucleated osteoclasts. (c)
Osteoclasts remove a divot of bone, reaching 60 μm in depth by 6 8
weeks. (d) Soluble factors released by osteoclastic resorption recruit a
new wave of cell proliferation (preosteoblasts) into the base of the
resorption cavity. (e) Preosteoblasts acquire the osteoblast phenotype. (f)
Osteoblasts secrete new bone matrix, which begins to acquire mineral
after a thickness of approximately 20 μm is achieved. (g) New mineral-
ized bone almost fully replaces resorbed bone by approximately 6
months. Small deficits are left, reflecting remodeling inefficiency and
accounting for the process of age-related bone loss. Copyright Robert
Marcus.
completely make up for the older bone removed, so a
small bone deficit remains as a consequence of each
remodeling event, called the “remodeling imbalance.”
The cumulative effect of the hundreds of thousands of
remodeling units in play at any one time is the readily
observable phenomenon of age-related bone loss.
Consequently, anything that promotes an overall increase
in whole body bone remodeling aggravates the rate of
bone loss and, by contrast, interventions that slow remo-
deling constrain bone loss. This forms the basis for using
drugs that slow remodeling as a mainstay of osteoporosis
treatment, as discussed later in this chapter.
Another word should be said concerning matrix miner-
alization during the bone formation phase of remodeling.
Mineral is rapidly laid down for the initial several weeks
but thereafter changes to a slow, linear rate. Mineral is
never fully saturated in the bone, so it continues to accu-
mulate as long as that particular unit of bone survives.
The only thing to terminate this process would be the ini-
tiation of a new wave of osteoclastic resorption to clear
out this region of older bone. Thus, if overall remodeling
slows, bone survives longer and becomes more densely
mineralized. The consequences of this finding are also
discussed later.
Osteoporosis in Adults Chapter | 45 995
If, as described, bone remodeling leads to loss (and
presumably weakening) of bone, one may ask why it has
evolved and what its purpose may be. It appears that the
cardinal role of remodeling is to serve a scavenger func-
tion, through which fatigued or damaged bone is cleared
ual bone loss). In addition, remodeling is the means
by which PTH restores normocalcemia in response to
hypocalcemia.
Among Bone Cells: Triggers and Constraints
on Remodeling
Because initiation of each remodeling event begins with
delivery of osteoclasts or their precursors to the bone sur-
face, it is important to have passing familiarity with the
signals that control this initial event [9,10]. The key cell
for controlling osteoclast production is the osteoblast.
This bone-forming cell elaborates two distinct proteins, a
stimulator and a repressor, that regulate osteoclast produc-
tion. The osteoclast stimulator was initially called “osteo-
clast differentiation factor,” but now that its primary
target is known, it has been given the less transparent
name of RANK-ligand. RANK is an abbreviation for the
“receptor that activates NF-kappa β” (a gene present in
osteoclasts and other cells of macrophage origin). Under
stimulation by agents known to increase bone remodeling
(e.g., PTH and L-thyroxine), the osteoblast synthesizes
and extrudes RANK-ligand that binds to RANK located
on osteoclast precursors, leading to production of new
osteoclasts. The repressor molecule, also produced by
osteoblasts, is a protein called osteoprotegerin (OPG).
Production of this protein increases when the osteoblast
binds agents that inhibit remodeling, such as estrogen.
OPG exhibits high affinity for RANK-ligand and there-
fore acts as a false receptor, neutralizing the effect of any
RANK-ligand with which it comes into contact.
The RANK RANK-ligand OPG complex acts in a
push pull manner to regulate osteoclast production and
hence controls the rate of bone remodeling. When stimuli
favor greater remodeling, RANK-ligand production
increases, OPG decreases, and RANK is activated. When
remodeling is suppressed, RANK-ligand decreases, OPG
increases, and RANK is constrained. Interference with
RANK-ligand function is the basis of a recently devel-
oped therapy for osteoporosis (see Section V.B.1.f:
Denosumab).
III ADULT BONE MAINTENANCE
For many years, scientific inquiry into the basis of adult
bone loss and development of osteoporosis was highly
996 PART | H Bone Health and Disease
parochial. Nutrition scientists focused on the diet, exercise
physiologists and mechanical engineers focused on physi-
cal activity and the mechanical environment, and physi-
cians whose responsibility was to care for patients with
osteoporosis focused largely on menopausal estrogen loss.
It is now abundantly clear that acquisition and mainte-
nance of a healthy skeleton is far more complex than can
be explained by any of these individual spheres. One
needs to view the skeleton as subject to diverse influences
throughout life so that bone status at any particular time
is the result of a stochastic process by which each individ-
ual insult or event over a lifetime has made its indepen-
dent contribution.
A Major Influences on Age-Related
Bone Loss
Successful bone maintenance requires continued attention
to the same “hygienic” factors that influenced bone acqui-
sition: physical activity, diet, and reproductive status.
Bone maintenance requires sufficiency in all areas, and
the others do not compensate deficiency in one. For
example, amenorrheic athletes lose bone despite frequent
high-intensity physical activity and supplemental calcium
intake [11,12]. Successful bone maintenance is also jeop-
ardized by known toxic exposures such as smoking,
alcohol excess, immobility, systemic illnesses, and many
medications.
1 Habitual Physical Activity
The skeleton’s mechanical function was referred to previ-
ously. To accomplish this role in a manner that optimizes
bone strength while at the same time not unduly increas-
ing its weight, bones accommodate the loads imposed on
them by undergoing alterations in mass, in external geom-
etry, and in internal microarchitecture. The first enuncia-
tion of this principle is credited to the German scientist
Julius Wolff as “Wolff’s law” [13]. As a consequence of
such adaptation, steady-state bone mass reflects its
mechanical environment, a concept that applies when
comparing bone mass among individuals, different bones
within an individual, and even different regions within a
single bone. A substantial body of research has addressed
this concept. These studies are of two general types:
(1) comparisons of bone mass of athletes to that of seden-
tary controls and (2) descriptions of associations between
level of physical activity and bone mass within a general
population. The first type of study generally considers
only very active or sedentary individuals, and hence
extreme differences in activity are represented. In the latter
case, a broader range of physical activity is examined.
Considerable evidence indicates that elite athletes and
chronic exercisers have higher BMD than age-matched,
nonexercising subjects—a finding, not surprisingly, that
applies primarily to sites that undergo loading during the
exercise (reviewed in Ref. [14]). Activities associated
with high load magnitude at low number of repetitions
(cycles) are associated with substantial increases in bone
mass. For example, world-class and recreational weight
lifters have 10 35% greater lumbar spine BMD than sed-
entary age-matched controls. Comparing dominant to
nondominant limbs in athletes whose sport involves uni-
lateral loading represents a special case. For example,
increased BMD in the playing compared to the nonplay-
ing arm of tennis players has been repeatedly observed.
By contrast, swimming, a buoyant activity not associated
with counteracting the effect of gravity, does not appear
to increase BMD. In one study of elite university athletes,
swimmers actually had lower bone mass than gymnasts or
nonathletic controls, despite increased muscle bulk and
regular weight training [15]. Young athletes who spend
more than 20 hours each week in a buoyant environment
for many years may simply not experience sufficient
gravitational stress to promote fully the expected degree
of bone acquisition.
These comparisons of athletes and control subjects
must be interpreted with caution. Because no measure-
ments of bone mass are made prior to initiating the exer-
cise program, a causal relationship between exercise and
bone cannot be proven. It may be that individuals with
higher bone density are more apt to succeed in athletics,
and therefore they enter the “athlete” and chronic exercis-
ing groups. Conversely, elite swimmers may have
excelled in buoyant activity because of a lighter skeleton.
In many studies, important characteristics of the matched
controls have been overlooked. Factors such as menstrual
status, nutrient intake, and use of tobacco or alcohol may
have confounded the results. Finally, skeletal status is
most frequently expressed as the areal BMD (g/cm2), a
term that overestimates BMD in persons with large bones
and underestimates it in smaller people. Thus, if exerci-
sers and controls are not well matched for height, conclu-
sions based on BMD may be spurious.
With respect to the impact of habitual physical activity
within the general population, many studies now point to
a significant skeletal effect of physical activity on the
acquisition of bone during the second and third decades.
The situation is less clear for moderately active adults, in
whom no consistent relationship between current activity
level and bone mass has been established. In our own
work, strong relationships between estimates of daily
energy expenditure and BMD were completely negated
by normalizing the data for body weight or lean mass
[14]. Several reports document positive relationships
between lifelong physical activity and bone status.
Thus, cross-sectional studies generally support the
notion that elite athletes and chronic exercisers have

increased BMD, the magnitude of this difference likely
depending on the type and intensity of exercise, age, sex,
and hormonal status. However, data concerning moderate
physical activity remain uncertain.
One approach to eliminating the selection bias of
cross-sectional studies is a randomized controlled trial in
which exercise is the intervention. A number of properly
controlled studies of this sort have been reported.
Although most indicate a positive effect of imposed exer-
cise on BMD, the magnitude of response has been very
disappointing to those who anticipated the large differ-
ences observed in cross-sectional studies. Rarely do the
increases in BMD exceed 2% after 1 or 2 years of rigor-
ous training, regardless of the type of exercise used
(endurance vs resistance training) [16 19].
Understanding the meager response to exercise inter-
ventions is related to the fact that skeletal response to
mechanical loads is curvilinear in nature. Complete
immobilization, as seen with high-level spinal cord injury,
leads rapidly to devastating bone loss, with deficits
approaching 30 40% over several months. By contrast,
imposition of even substantial training regimens on nor-
mally ambulatory people or animals increases bone mass
by only a few percent over a similar period. This is illus-
trated in Fig. 45.7, in which the effect of walking on bone
mass is schematized. As an individual goes from immo-
bility to full ambulation, duration of time spent walking
becomes progressively less efficient for increasing bone
mass. A person who habitually walks 6 hours each day
might require another 4 6 hours just to add a few more
percent BMD. On the other hand, adding a more rigorous
stimulus, such as high-impact loading, for even a few
cycles would increase the response slope.
The worst thing that can happen to the skeleton is to
be immobilized. For maintaining bone mass during adult
30
20
+ High impact loading
10
Δ Bone density (%)
Sedentary
0
Moderately
–10 active
–20
–30
Complete
–40 immobility
0 4 8 12 16
Hours
FIGURE 45.7 The curvilinear nature of skeletal response to mechani-
cal loading. Copyright Robert Marcus.
Osteoporosis in Adults Chapter | 45 997
life, a certain degree of daily weight bearing is required,
and the vast majority of even sedentary individuals
achieve this. Small increments in BMD can be achieved
by increasing one’s daily exercise schedule, but, as a con-
sequence of Wolff’s law, these will remain only so long
as the added activity continues. For most individuals, par-
ticularly if they are elderly or frail, walking provides the
soundest and most prudent physical activity for skeletal
maintenance.
2 Nutrition
a Energy
Reflecting the major influence of weight-bearing activity
on bone, bone mass is strongly related to body weight, so
it should be no surprise that severe deficits in bone occur
in states of profound malnutrition. Although frank starva-
tion is extremely rare in developed societies, bone deficits
are frequently encountered in medical conditions associ-
ated with extremely low body mass, such as anorexia ner-
vosa, as well as various forms of intestinal malabsorption
and cachexia. It may be difficult to assign responsibility
for bone deficits in such patients to any specific nutrient
because patients generally show profound reductions in
the consumption of many nutrients. In teenagers with
anorexia nervosa, skeletal deficits appear very early, and
their magnitude is exacerbated because bone is lost at a
time when other girls of similar age are gaining bone at
an accelerated rate. Bachrach et al. [20] observed that
whole body bone mass correlates linearly with body mass
in normal teens, and that the bone mass of girls with
anorexia nervosa lies exactly on this curve. In other
words, skeletal deficits in young girls with anorexia ner-
vosa primarily reflect their body mass. When these girls
were observed over time, weight rehabilitation (a gain of
at least 5 kg) was associated with a gain in bone mass.
The next section deals specifically with a group of
skeletally important nutrients and nutrient groups. The
reader might find it helpful once having read this material
to consult the recently developed U.S. Government web-
site ChooseMyPlate (www.choosemyplate.gov) in which
Walking
alone food patterns were designed to meet the bone nutrient
requirements.
b Calcium
The concept that osteoporosis is a disease of calcium defi-
ciency was proposed more than a century ago, although a
central role for calcium intake did not emerge into the sci-
entific mainstream for many years. This largely reflected
the overpowering influence of Professor Fuller Albright,
20
who conceived of osteoporosis as a deficiency of bone
matrix due to osteoblast failure, usually as a consequence
of menopausal loss of estrogen [21]. Intensification of
interest in calcium occurred with the publication of three
998 PART | H Bone Health and Disease
independent reports. The first, by Matkovic et al. [22],
demonstrated a difference in hip fracture incidence in two
different regions of Croatia that were demographically
very similar except for a substantial difference in the cal-
cium content of local water supplies. Second was the pub-
lication of NHANES II, which showed that habitual
calcium intakes of American girls and women failed to
meet recommended dietary allowances (RDAs) as early
as age 11 years [23]. Third was a landmark paper by
Chapuy et al. [24] that clearly demonstrated the ability of
supplemental calcium and vitamin D to reduce the inci-
dence of hip fracture in a highly vulnerable population.
When one considers that the skeleton is the repository
for more than 99% of total body calcium, it is inconceiv-
able that individuals whose intakes are below the amount
necessary to maintain whole body calcium balance could
be in negative balance without losing bone. Calcium
may be considered a “threshold nutrient,” which means
that below a critical value some physiological function
(e.g., calcium balance) is dependent on intake, but at
intakes above that value no further impact accrues.
Because the mineral demands for growth, early adult, and
older adult maintenance differ substantially, the “threshold”
value and therefore the intake requirements also differ by
age [25,26]. Table 45.1 shows that recommendations
for calcium intake have increased substantially over
time from previous RDAs [27] and are closely allied to
those derived from the literature of formal calcium balance
studies [28].
In 2011, the Institute of Medicine (IOM) published
updated values for dietary reference intakes for calcium
and vitamin D following a comprehensive review of the
literature and scientific testimony. The full report is avail-
able online (see Tables 45.1 and 45.2). In general, the
IOM recommendations are reasonably close to earlier ela-
borations. One emphasis of the IOM statement was that
TABLE 45.1 Various Estimates of the Calcium Requirement (mg/day) in Women
Age (years) 1989 RDAa
1 5 800
6 10 800
11 24 1200
Pregnancy/lactation 1200
24 50/65 800
65 800
a
National Research Council [27].
b
Recommendations for women as proposed by the Consensus Development Conference on Optimal Calcium Intake [25].
c
The so-called adequate intakes of the new DRI values, multiplied by a factor of 1.2 to convert them into RDA format [26].
d
Estimates derived from published balance studies [28].
Source: Adapted from R.P. Heaney, Effects of protein on the calcium economy, in: B. Dawson-Hughes, R.P. Henry, Nutritional Aspects of Osteoporosis
2006, Elsevier, Amsterdam, 2007, 191 197 [48].
intakes above those shown as upper level increased the
risk of adverse experiences, such as kidney stones.
Although a consensus conference on optimal calcium
intake concluded that current habitual calcium intakes by
both men and women are inadequate for optimal bone
health [25], and several clinical trials demonstrated the
ability of calcium supplementation to constrain the rate of
bone loss and even reduce fractures [24,29 35], there
remains in the medical and research communities some
resistance to reaching consensus regarding the role of cal-
cium inadequacy in the pathogenesis of osteoporosis. In
part, this reflects considerable uncertainty in estimating
the amount of calcium that people habitually consume.
For example, dietary histories and food frequency ques-
tionnaires carry substantial imprecision. Also, it must be
remembered that calcium is not absorbed in a vacuum
but, rather, in the course of eating or drinking other foods,
and its availability from foods is highly influenced by
other nutrients. For example, although the calcium content
of spinach is quite good, it is rendered essentially nonab-
sorbable by the presence of oxalate and perhaps other
anions to which it binds [36]. Further consideration of the
roles of phosphorus, sodium, and protein appears later.
For adults, calcium intakes in the range of
1000 1500 mg/day are recommended. Note that indivi-
duals in early to middle adult life, such as 20 50 years of
age, have calcium intakes within reasonable proximity to
recommended values and, by virtue of being young
enough to undertake regular weight-bearing activity and
to maintain normal reproductive function, generally have
only modest stress on skeletal balance, as shown by very
low rates of bone loss. After menopause (average age, 51
years), and certainly at more advanced ages, declines in
endogenous reproductive hormones and in the insulin-like
growth factor I axis, coupled with overall trends toward
less physical activity, make it less likely that dietary
NIHb 1997 AIc Balanced
800 1100
800 1200 960 1100
1200 1500 1560 1600
1200 1500 1200 1560
1000 1200 800 1000
1500 1440 1500 1700
 Osteoporosis in Adults Chapter | 45 999

status, this is so because these beverages have been

TABLE 45.2 Dietary Reference Intakes for Calcium substituted for milk, thus exchanging a calcium-rich drink
(mg/day) for one that contains essentially no calcium [39].
Age Estimated RDA Upper
Average Level d Protein
Requirement Intake
For many years, a concept has circulated as a subtext in
Infants osteoporosis research that consumption of excess protein,
0 6 months 1000 particularly from animal sources, is an important contrib-
6 12 months 1500 utor to the development of osteoporosis. This is consid-
ered the consequence of the fact that protein catabolism
1 3 years 500 700 2500
generates ammonium ion from ammonia and sulfate from
4 8 years 800 1000 2500 sulfur-containing amino acids. When protein intake
9 18 years 1300 1300 3000 increases, citrate and carbonate ions are released from
bone to neutralize these acids, and, because urinary cal-
19 30 years 1000 1000 2500
cium is closely linked to renal acid excretion, urinary cal-
31 50 years 1000 1000 2500 cium rises. However, plant proteins contain amounts of
51 70 men 1000 1000 2000 sulfur similar to those in eggs, milk, and meats, and there-
51 70 1200 1200 2000
fore increased intake of protein from either animal or
women plant sources similarly increases urinary calcium.
Furthermore, the impact of protein on calcium balance
. 70 years 1200 1200 2000
depends to a major degree on other nutrients contained in
Pregnant/Lactating the consumed food. For example, milk calcium compen-
14 18 years 1100 1300 3000 sates for urinary calcium losses generated by milk protein,
19 50 years 800 1000 2500
potassium in such plants as legumes and grains decreases
calcium excretion, and the high phosphorus content of
Source: Institute of Medicine, The 2011 Report on dietary requirements meat offsets the calciuric effect of the protein [40].
for calcium and vitamin D, J. Clin. Endocrinol. Metab. 96 (2011) 53 58.
Nutritional status assessments of patients with osteo-
porosis do not support a view that these patients have
enjoyed a life of luxurious protein consumption. Barger-
deficiency will be buffered and more likely that age-
Lux et al. [41] reported that women with low calcium
related bone loss will be aggravated.
intakes generally consumed insufficient amounts of multi-
ple nutrients, including protein. Sellmeyer et al. [42]
c Phosphorus reported higher protein intakes to be associated with
Various domestic animals respond to excessive dietary greater age-related bone loss in the SOF cohort. However,
phosphorus by increasing the endogenous concentration a substantial body of evidence does not sustain this view.
of PTH, resulting in negative calcium balance and bone Protein consumption was reported to be an important pos-
loss. In such animals, optimal dietary ratios of calcium to itive predictor of bone mass in elderly women [43]. In the
phosphorus approach 1.0. This has led to a popular theory Framingham cohort, Hannan et al. [44] reported bone loss
that because calcium:phosphorus ratios in human diets over time to be inversely related to protein intake, with
typically are well below 1.0, phosphorus overconsumption rates of loss in the highest quartile of protein consumption
initiates a similar process in humans. less than one-third of those in the lowest quartile.
Firm evidence to support a role for phosphorus excess Kerstetter et al. [45] conducted a series of controlled bal-
in human osteoporosis has not been forthcoming. In con- ance studies that showed that although calciuria increased
trast, some evidence indicates that intestinal calcium with increased protein intake, this did not come from
absorption and balance are fairly impervious to very wide bone but was rather a reflection of improved intestinal
variations in daily phosphorus consumption [37,38]. calcium absorption. In a randomized controlled trial,
Separate mention should be made concerning the role of Dawson-Hughes and Harris [46] showed that the improve-
phosphorus-containing soft drinks. Cola drinks contain ment in BMD in subjects supplemented with calcium and
phosphoric acid as their source of effervescence, and one vitamin D was confined mainly to individuals whose pro-
reads frequently in the lay press that the high content of tein intake was in the highest tertile. Delmi et al. [47]
phosphorus in colas is an important contributor to devel- found that supplemental protein improved recovery from
oping osteoporosis. However, although excessive soft hip fracture, accelerated hospital discharge, and also slo-
drink consumption may well contribute to poor bone wed bone loss in the contralateral hip. Heaney [48]
1000 PART | H Bone Health and Disease
concluded that the weight of evidence shows high protein
intake to be osteoprotective, but only if calcium intake is
adequate, whereas the protective effect of calcium occurs
only when protein intake is relatively high.
e Sodium
Urinary excretion of calcium and that of sodium are highly
linked, and increased sodium intake is known to promote
calcium excretion. A similar effect occurs with most diuretic
agents (with the single exception of thiazides, which uncou-
ple the handling of these two cations). Thus, it is not unrea-
sonable to expect that increased dietary sodium might be
conducive to negative calcium balance and aggravate bone
loss. In a 2-year prospective trial, Devine et al. [49] exam-
ined the influence of urinary sodium excretion and dietary
calcium intake on bone density of postmenopausal women.
Urinary sodium excretion (a robust indication of intake) cor-
related negatively with changes in BMD, and the data sug-
gested that halving sodium intake had the same effect on
BMD as increasing daily calcium intake by 891 mg [49].
f Vitamin D
The importance of vitamin D to skeletal maintenance is thor-
oughly discussed elsewhere in this volume. When severe,
vitamin D deficiency is associated with significant undermi-
neralization of bone matrix, a condition known as osteomala-
cia [50]. At milder levels of vitamin D inadequacy, impaired
calcium absorption promotes compensatory secretion of
PTH, which increases bone remodeling and aggravates bone
loss. Maintaining vitamin D adequacy is an important and
widespread issue for the general population and for the vast
majority of patients with osteoporosis. It appears that optimal
vitamin D status is achieved at 25-hydroxyvitamin D con-
centrations of approximately 30 ng/mL (80 nmol/L). To
achieve this goal, previously recommended vitamin D con-
sumption of 400 800 units/day is not adequate, and doses
of 1000 2000 units/day are preferable.
3 Reproductive Hormonal Status
Decades of studies in animals and humans support the
concept that achieving and maintaining normal gonadal
function is a critical determinant of bone health during
pubertal bone acquisition and throughout adult life in
both women and men. Indeed, the impact of menopausal
loss of endogenous estrogen on skeletal balance can be so
profound that many investigators have focused solely on
the contribution of estrogen withdrawal to osteoporosis
without regard for the other contributions described previ-
ously. We now understand that permanent loss of estrogen
at menopause is not the only circumstance in which
gonadal status has a skeletal impact. During earlier adult
life, transient episodes of oligo- or amenorrhea may also
be associated with at least transient bone loss [51].
The mechanisms by which estrogen withdrawal affects
the skeleton involve multiple organs. The direct skeletal
effect of the most potent circulating estrogen, 17-β estra-
diol, is to suppress the rate of bone remodeling. This is
achieved by downregulating the formation of osteoclasts.
In some rodents, this effect has been related to the sup-
pression of an osteoclast-stimulating cytokine, interleukin-
6 [52,53]. In other animal models and in humans, strong
evidence has been presented for the participation of other
cytokines, including interleukins and transforming growth
factor-β [54]. In addition, estrogen withdrawal reduces
osteoblast production of OPG, the decoy receptor for
RANK-ligand discussed previously [55]. These cytokine
effects are reversed when estrogen is replaced. The use of
estrogen as pharmacologic therapy for the prevention and
treatment of osteoporosis is described later.
IV DIAGNOSIS OF OSTEOPOROSIS
Because traditional radiographic techniques cannot distin-
guish osteoporosis until it is severe, diagnosis was, until
recently, clinical, requiring a history of one or more low-
trauma fractures. Although highly specific, such a grossly
insensitive diagnostic criterion offered no assistance to
physicians who hope to identify and treat affected indivi-
duals who have been fortunate not yet to have sustained a
fracture. The focus in this section is the measurement of
BMD. However, one must be cognizant of a wide variety
of risk factors other than bone density that may pro-
foundly influence an individual’s risk for fracture. A par-
tial list of these factors is presented in Table 45.3.
The introduction of accurate noninvasive bone mass
measurements afforded the opportunity to estimate a per-
son’s fracture risk and to make an early diagnosis of oste-
oporosis. Large prospective studies have shown that a
reduction in BMD of 1 standard deviation (SD) from the
mean value for an age-specific population confers a two-
or threefold increase in long-term fracture risk [56 59].
In a manner similar to that by which serum cholesterol
concentration predicts risk for heart attack or blood pres-
sure predicts risk for stroke, BMD measurements can suc-
cessfully identify subjects at risk of fracture and can help
physicians select those individuals who will derive great-
est benefit for initiation of therapy. Indeed, the gradient
of risk associated with a 1 SD difference in BMD is even
greater than those for cholesterol and heart attack.
Several factors limit the ability of BMD measurements
to predict an individual’s fracture risk with great accu-
racy. The normative data against which BMD compari-
sons are most often made have been determined for
Caucasian men and women and do not necessarily apply
to other ethnic groups. This problem is gradually being
overcome as ethnic-specific BMD data have begun to
penetrate the literature. BMD is clearly related to body

TABLE 45.3 Partial List of Risk Factors for Osteoporosis
and Related Fractures
Major Factors
G Personal history of fracture as an adult
G History of fragility fracture in a first-degree relative
G Low body weight (less than approximately 127 lb)
G Current smoking
G Use of oral corticosteroid therapy for more than 3 months
Additional Risk Factors
G Impaired vision
G Estrogen deficiency at an early age (,45 years)
G Thyroid hormone excess
G Intestinal malabsorption
G Some varieties of hypercalciuria
Selected Medications (cyclosporin and related agents,
thiazolidinediones, possibly selective serotonin inhibitors)
G Dementia
G Poor health/frailty
G Recent falls
G Low calcium intake (lifelong)
G Immobilization or low physical activity
G Alcohol in amounts .2 drinks per day
Source: Adapted from National Osteoporosis Foundation, Physician’s
Guide to Prevention and Treatment of Osteoporosis, Excerpta Medica,
Belle Mead, NJ, 1998 [1].
weight, but routine clinical bone mass assessments are not
weight-adjusted. Various features of bone geometry that
affect bone strength and fracture risk are not considered
in the clinical interpretation of bone mass measurements.
These include bone size, the distribution of bone mass
around its bending axis (moments of inertia), and some
derivative functions such as the hip axis length [59].
Moreover, bone mass measurements cannot distinguish
individuals with low mass and intact microarchitecture
from those with equal mass who have trabecular disrup-
tion and cortical porosity. They also cannot distinguish
other aspects of bone quality.
In 1994, a group of senior investigators in this field
offered a working definition of osteoporosis based exclu-
sively on bone mass [60]. The reasoning behind this pro-
posal, made on behalf of the World Health Organization,
was that the clinical significance of osteoporosis lies
exclusively in the occurrence of fracture, that bone mass
predicts long-term fracture risk, and that selection of rig-
orous diagnostic criteria would minimize the number of
Osteoporosis in Adults Chapter | 45 1001
patients who are incorrectly diagnosed. The authors sug-
gested a cutoff BMD value of 2.5 SD below the average
for healthy young adult women. Using this value, approx-
imately 30% of postmenopausal women would be desig-
nated as osteoporotic, which gives a realistic projection of
lifetime fracture rates. In addition, Kanis et al. [60] pro-
posed that BMD values of 1 or 2 SD below the young
adult mean be designated as “osteopenic.” Such values
identify individuals at modestly increased risk for fracture
but for whom a diagnosis of osteoporosis would not be
justified because it would mislabel far more individuals
than would actually be expected ever to fracture.
This approach has proven useful for clinical manage-
ment, but it has limitations. Its application to young people
prior to their acquisition of peak bone mass would, of
course, be inappropriate. The BMD measurement is sub-
ject to several confounding factors, including bone size
and geometry. Because BMD correlations among skeletal
sites are not strong, designating a person “normal” based
on a single site, such as the lumbar spine, necessarily over-
looks individuals with low bone density elsewhere, such
as the hip. It seems reasonable to suppose that adjustment
of bone density readings for such factors as body size,
bone geometry, and ethnic background might improve the
accuracy of this technique. Finally, studies indicate that
although individuals with low BMD are at greater relative
risk to fracture, many fractures in the population are expe-
rienced by individuals with normal bone mass [61 63].
Knowledge of a low bone density at a particular point in
time offers no information regarding the adequacy of peak
bone mass attained, the amount of bone that may have
been lost, or the quality of bone that remains.
The World Health Organization completed an initia-
tive to give individuals an estimate of their absolute
10-year fracture risk. It is based on the concept that BMD
plus clinical risk factors predict fracture risk better than
BMD or clinical risk factors alone. When BMD is not
available, fracture risk can be calculated with only the
clinical risk factors. This published initiative, called
FRAX, is readily available for routine use via an online
calculator (www.shef.ac.uk/FRAX). It is also included in
current Dual-Energy X-ray Absorptiometry software and
available as a smartphone application. Separate calcula-
tion tools are provided at this website for individuals
living in many other countries worldwide. In many coun-
tries, osteoporosis treatment guides include intervention
thresholds based on FRAX fracture risk calculations.
A Beyond BMD: The Question of Bone
Quality
As stated in the introduction to this chapter, osteoporosis
is a condition of decreased bone strength, where strength
is a composite function of BMD and bone quality.
1002 PART | H Bone Health and Disease
Several diverse qualitative characteristics have been
described that directly influence bone strength. The more
important factors—bone geometry, microarchitectural
integrity, mineralization state, and remodeling rate—are
briefly considered here. For more detailed information,
the reader may consult Seeman and Delmas [64]. The first
factor is overall bone geometry. A bone of greater diame-
ter is better able than a smaller bone to withstand either a
compressive or a bending force. One reason that men are
relatively less susceptible to forearm fractures than are
women is the fact that long bones of men are wider.
A second feature, particularly in trabecular bone, is
microarchitectural integrity. Normal trabecular bone is a
honeycomb of highly connected vertical and horizontal
trabeculae (Fig. 45.1A), and the holes, or spaces between
the trabeculae, are fairly uniform. By contrast, osteopo-
rotic trabecular bone gives the appearance of Swiss
cheese (Fig. 45.1B). The holes are not uniform because
excessive bone resorption has perforated the trabeculae,
leaving confluent, sometimes extremely large holes that
represent the permanent loss of entire trabecular units.
A third important qualitative factor is the state of bone
remodeling. It will be remembered that each remodeling
event begins with the removal by osteoclasts of a divot of
bone from trabecular surface. At any one time, then, there
are hundreds of thousands of resorption holes, or lacunae,
on bone surfaces. These holes are an inherent point of
weakness to the bone, permitting very modest mechanical
loads to overload the structure and fracture it. In mechani-
cal engineering parlance, such points of weakness are
called “stress concentrators.” Mechanical stresses that are
generated across an area of bone divert from their normal
path of stress transmission to focus on the area of weak-
ening, thereby overloading it. Thus, individuals with high-
er levels of bone remodeling activity will have more
stress-concentrating lacunae on their bone surfaces, giving
them a greater chance for fracture than somebody in a
low remodeling state. Finally, the degree of bone mineral-
ization is also an important feature of bone quality.
Roughly speaking, except in extreme cases, the more min-
eralized the bone matrix, the greater its mechanical
strength. Because a portion of bone continues to accumu-
late mineral as long as it exists, individuals with lower
remodeling rates will have bone that is older, and there-
fore more mineralized and stronger, than individuals
whose bone is remodeled more rapidly.
One message from this inquiry into bone quality
is that a BMD measurement simply does not describe a
sufficient amount of information about the nature of the
skeleton ever to be a gold standard for the presence
of osteoporosis. Unfortunately, currently, no
suitable noninvasive measurements are available for rou-
tine assessment of bone quality in patients outside a
research environment. Therefore, one is forced to rely on
BMD measures to some degree. That being said, one also
should not depend on changes in BMD over time as a
true index of whether patients have improved or deterio-
rated in response to therapeutic interventions. One impor-
tant indication of overall bone quality is whether a given
person has already sustained a low-trauma fracture.
Evidence has been published that individuals with such
fractures have more serious disruption of qualitative mea-
sures seen on bone biopsies than individuals who have
not fractured [65]. Therefore, the presence of a vertebral
compression fracture on a radiograph of the spine may
reasonably permit the physician to conclude that the
patient has poor bone quality.
V OSTEOPOROSIS PREVENTION
AND TREATMENT
A Hygienic Management
The term hygienic is used here in the sense of being non-
pharmacologic. It refers to the appropriate attention to
lifestyle factors that either protect or damage bone. These
principles have universal application regardless of
whether one wishes to forestall bone loss and develop-
ment of osteoporosis or treat established disease.
1 Physical Activity
As described previously, the skeleton adapts to its
mechanical environment so that the steady-state amount
of bone reflects daily exposure to mechanical forces.
Although the skeletal response to vigorous exercise, such
as weight lifting (resistance activity) or running (endur-
ance activity), may be greater than that observed with
walking, the majority of middle-aged and older indivi-
duals are more likely to persist long term with a program
of walking. A progressive schedule of walking 30 minutes
or more several days each week provides a mechanical
load to the legs and axial skeleton and should form the
basis of skeletal maintenance for ambulatory persons in
their middle and advanced years. Younger individuals
should certainly be encouraged to pursue more vigorous
activities, but it must be remembered that the effects of
high-load environments persist only so long as the high
loading schedule continues. If a person stops training, the
bone perceives a reduction in mechanical environment
and adaptive responses will lead to loss of bone until a
new steady state is reached.
2 Dietary Factors
With respect to overall dietary intakes, substantial weight
loss during adult life is a risk factor for fractures. Weight-
loss programs are associated with measurable decreases
in BMD, and the impact of so-called yo-yo weight

fluctuations, although unclear, carries some skeletal risk.
As discussed previously, the nutrients of most relevance
to skeletal maintenance are calcium and vitamin D. A
daily calcium intake of 1200 1500 mg should be the goal
for most healthy adults. Consuming a quart of nonfat milk
each day could approach this, but it is very unlikely that
most adults, even dairy enthusiasts, will consistently
accomplish that. Each quart of milk contains approxi-
mately 1100 mg calcium, although this may vary some-
what depending on its fat content. Because calcium is
contained within the aqueous phase of milk, an equal vol-
ume of low-fat or skim milk has more water, and hence
more calcium, than whole milk. In addition, some brands
of reduced-fat milk are enriched by the addition of milk
solids, which further increases calcium content.
Many segments of the population experience loss of
lactase, the enzyme necessary for the hydrolysis of the
major milk sugar lactose. Many afflicted individuals
experience bloating, cramps, or other symptoms of intesti-
nal distress if they consume lactose-containing dairy pro-
ducts. Several strategies can be recommended for such
individuals. Lactose-free milk is readily available in mar-
kets. Lactose in this product has been prehydrolyzed to its
constituent sugars, glucose and galactose, by incubation
with commercial lactase. This milk has a slightly sweet
taste due to the taste of its hexose sugars. For those who
do not care for this taste, lactase tablets can be taken
immediately prior to drinking milk. Yogurt and other pro-
ducts in which lactose is hydrolyzed provide an excellent
substitute for milk. Many cheeses are rich in calcium (not
cottage cheese, however) but have the complicating fea-
ture of high sodium content. The calcium:sodium ratio of
most liquid dairy products is approximately 1.0, but the
ratio is well below 1 for hard cheeses. Given the relation-
ship between sodium intake and calciuria [49], depending
on cheese calcium consumption may not be effective.
Other reasonably good food sources of calcium
include small fish (anchovies, herrings, and sardines),
nuts, and some green vegetables (broccoli). However, it is
quite difficult to attain calcium adequacy with these foods
alone without also consuming dairy products. For exam-
ple, it may require 6 cups of broccoli to provide as much
calcium as would be consumed in a single 8-ounce glass
of milk.
For many individuals, a calcium supplement offers the
most convenient approach to reaching target levels of cal-
cium intake. Many calcium salts are available on an over-
the-counter basis. Calcium carbonate has the advantage of
having the highest percentage by weight in calcium (40%
of calcium carbonate is calcium) so that the fewest num-
ber of pills need to be taken. Calcium citrate is a reliable
calcium supplement. It has been alleged that individuals
who have achlorhydria or are taking medications that
reduce gastric acid secretion better absorb the citrate salt
Osteoporosis in Adults Chapter | 45 1003
than the carbonate. However, it has been shown that when
calcium carbonate is taken with food, there is sufficient
acidity in the food to permit normal calcium absorption
[66]. Therefore, my general recommendation for indivi-
duals who will likely not consume more than 1000 mg
calcium per day through food alone is to take a 500 mg
calcium supplement as calcium carbonate each morning
with breakfast. For individuals with osteoporosis who are
receiving pharmacological treatment, I increase that rec-
ommendation to 1000 mg calcium/day.
In 2008, Bolland et al. [67] reported on a calcium
intervention trial in older women, in which consumption
of calcium as supplement, but not as food, was associated
with an increased risk for cardiovascular complications,
including myocardial infarction. Subsequently, the same
group published a meta-analysis from which they con-
cluded that “calcium supplements without vitamin D are
associated with an increased risk of myocardial infarc-
tion” [68]. This publication created a storm of contro-
versy. Although the meta-analysis was constructed from
multiple clinical trials, the most cases came from the
single trial reported by Bolland and colleagues [67].
Myocardial infarction was not an end point of that trial,
and cases were not adjudicated. The 2-year pill compli-
ance rate was only 55% and was lower yet in the group
receiving calcium. Although the conclusions were based
on an intervention in older women, a number of the stud-
ies included in the meta-analysis included both men and
women, and none independently showed even a trend
toward a cardiovascular adverse effect. All these factors
could introduce bias into group comparisons. Moreover,
some independent studies failing to support the views of
Bolland et al. were not represented in the meta-analysis
[68]. In particular, a well-designed and executed clinical
trial in which cardiovascular end points were prespecified
showed no impact of calcium supplementation on either
atherosclerotic vascular mortality or first hospitalization,
either during the 5-year clinical trial or during a 4.5-year
follow-up period [69]. Given the importance of this topic,
a committee from the American Society for Bone
and Mineral Research evaluated the available data and
concluded that “the weight of evidence is insufficient to
conclude that calcium supplements cause adverse cardio-
vascular events; however, the debate continues.”
B Pharmacologic Therapy
The variety of approved drugs for the prevention and
treatment of osteoporosis has expanded enormously dur-
ing approximately the past decade (Table 45.4). These are
grouped into two general categories—antiresorptive
(sometimes called anticatabolic) and bone-forming (or
anabolic). The first category contains the great majority
of registered products. Although the fundamentals of their
1004 PART | H Bone Health and Disease
TABLE 45.4 Approved Medications for the Prevention
and Treatment of Osteoporosis
Antiresorptive
G Calcium/vitamin D
G Estrogens
G Bisphosphonates
G Alendronate
G Risedronate
G Ibandronate
G Zoledronatic acid
G Calcitonin
G Strontium ranelate (not approved in United States)
Bone-forming
G Teriparatide
G PTH (1 84) (not approved in United States)
mechanism of action differ from one product to the next,
they all act ultimately to inhibit either the development of
osteoclasts from their precursors or the activity of mature
osteoclasts. Such actions confer skeletal protection in two
ways, both of which are predictable consequences of
slowing the remodeling rate by 30 70%, as per the previ-
ous discussion of bone quality. First, and perhaps most
important, at least during the first year or so of therapy,
reducing the creation of new resorption lacunae results in
a major reduction in the prevalence of stress concentrators
on bone surfaces. Second, because any given point on the
bone surface will survive longer when the remodeling
rate is low, the bone continues to gain mineral for a
longer period of time and ultimately becomes relatively
hypermineralized.
By contrast, only one bone-forming agent—the 1 34
fragment of human PTH (teriparatide; see later discus-
sion)—is approved, as of this writing, in the United States
for the treatment of osteoporosis. Its actions involve the
direct stimulation of bone-forming osteoblasts.
Selection of appropriate therapies for individual
patients is beyond the scope of this chapter. The following
material briefly describes each of these approved products.
1 Antiresorptive Agents
a Calcium and Vitamin D
Strictly speaking, calcium and vitamin D have an antire-
sorptive activity on bone. By slightly elevating blood cal-
cium concentrations, endogenous PTH secretion is
reduced and overall bone remodeling decreases. The role
of calcium and vitamin D in skeletal maintenance was
described previously. Calcium administration to osteopo-
rotic women with previous vertebral fractures has been
shown to decrease the risk for subsequent fracture [33]
and, when combined with a modest amount of vitamin D,
has been shown to reduce the incidence of hip fracture in
elderly women [24]. Suffice it to say that calcium and
vitamin D adequacy are essential components of all suc-
cessful therapies, and the general approach described pre-
viously must be pursued if any pharmacologic regimen is
to succeed. Indeed, therapeutic failures are frequently
attributable to inadequate vitamin D status. Note that all
major osteoporosis trials were designed to show an effect
of drug on bone turnover, BMD, and fracture incidence
superior to that of the control regimens, which invariably
consisted of calcium and vitamin D.
b Estrogen
The use of estrogen to treat postmenopausal osteoporosis
has been popular for at least 50 years. The era of the
1970s and 1980s saw the publication of many small clini-
cal trials demonstrating the effects of various estrogen
and estrogen/progestin combinations in early and post-
menopausal women to improve calcium balance, to sup-
press markers of bone turnover, to increase BMD, and in
small series to protect against vertebral compression frac-
tures [70]. Because the available studies did not demon-
strate a compelling case that estrogen administration to
women with established osteoporosis led to a significant
reduction in fracture incidence, U.S. Food and Drug
Administration (FDA) approval of estrogen was specified
for prevention of osteoporosis, not for treatment. With
publication of results from the Women’s Health Initiative,
we now have conclusive evidence for the nonvertebral
fracture efficacy of estrogen, even in women who were
not osteoporotic or at high risk for fracture [71].
Unfortunately, the Women’s Health Initiative also estab-
lished that estrogen, particularly when given in combina-
tion with progestin, increased the development of breast
cancer, myocardial infarction, and other cardiovascular
events and potentially contributed to cognitive decline.
Thus, although estrogens remain highly effective when
treating women with hot flashes, current opinion holds
that they should be used at the lowest possible dose and
for the shortest possible duration and are not recom-
mended as long-term therapy for prevention or treatment
of osteoporosis.
c Selective Estradiol Receptor Modulators
These compounds are neither hormones nor estrogens but,
rather, molecules that interact with the estradiol receptor
in multiple tissues of the body. For a comprehensive
description of selective estradiol receptor modulator

(SERM) physiology, the reader is referred to the review
of Siris and Muchmore [72]. Briefly summarized, unlike
estrogens, SERMs interact with the estradiol receptor and
activate estrogen-regulated genes in a manner that is tis-
sue specific. For example, like estrogen, tamoxifen stimu-
lates uterine hyperplasia and suppresses bone remodeling,
but unlike estrogen, it inhibits estrogen actions at the
breast. On the other hand, raloxifene has no effect on the
endometrium, acts like estrogen on bone, and antagonizes
estrogen action at the breast. Although several such mole-
cules were introduced into clinical medicine before their
mechanisms of action were clarified (e.g., tamoxifen),
recent years have seen the development of numerous
molecules in this class for the intended purpose of treating
osteoporosis. As of this writing, only two SERMs, raloxi-
fene (Evista, Eli Lilly & Co.) and bazedoxifine, in combi-
nation with a low dose of conjugated estrogens (Duavee,
Pfizer Inc.) are FDA approved for preventing osteoporo-
sis. Raloxifene has been shown to prevent the develop-
ment of frank osteoporosis in women with low bone mass
and also to offer substantial long-term protection against
vertebral fracture in women with established osteoporosis
[73], thus it is approved also for treatment of established
osteoporosis. At the approved dose of 60 mg daily, raloxi-
fene offers significant protection against the development
of estrogen receptor-positive breast cancer, for which it
also has received FDA approval.
d Bisphosphonates
Bisphosphonates are analogs of the naturally occurring
phosphate ester pyrophosphate, in which a carbon atom
has replaced the central oxygen bridge. This substitution
renders the compounds nonsusceptible to hydrolysis by
alkaline phosphatase, a ubiquitous enzyme that hydro-
lyzes pyrophosphate. Bisphosphonates are poorly
absorbed from the gut, but once absorbed they are taken
up by bone. The presence of two phosphate groups per-
mits the molecule to bind avidly to hydroxyapatite so that
the half-life of bisphosphonates in the skeleton may be a
matter of many years. In theory, osteoclasts imbibe the
bisphosphonate during the course of bone resorption,
resulting in osteoclast death and a decrease in resorption.
Differences in one of the two side chains underlie differ-
ences in action among agents of this class. The first gen-
eration of bisphosphonates acted to inhibit intermediary
metabolism. More recent compounds that have amino
groups on the side chain act in a manner similar to the
statin class of antilipid drugs—that is, inhibiting the
mevalonate synthesis pathway, but at a level (farnesyl
diphosphate synthetase) that is further downstream, lead-
ing to interference with prenylation of plasma membrane
lipids [74]. First developed and introduced for the treat-
ment of Paget’s disease of bone in the 1960s, several
Osteoporosis in Adults Chapter | 45 1005
bisphosphonates have shown significant improvement in
BMD and reductions in fracture. Three oral bisphospho-
nates are currently approved for prevention and treatment
of osteoporosis: alendronate (Fosamax) [75], risedronate
(Actonel) [76,77], and ibandronate (Boniva) [78]. The last
may also be administered by intravenous infusion.
Another very potent bisphosphonate, zoledronic acid, has
received FDA approval for treatment of osteoporosis.
This agent is administered only once each year by intrave-
nous infusion.
In recent years, it has become apparent that some
patients receiving long-term potent bisphosphonates may
experience potentially serious complications of treatment,
including osteonecrosis of the jaw (ONJ) and nonclassical
or “atypical” hip fractures [79]. Although the precise
mechanisms by which such complications may be induced
remain unsettled, it appears likely that they reflect in
some manner the degree to which bone remodeling has
been suppressed. For example, because of its role in
chewing, the mandible receives some of the heaviest
mechanical loads of any bone in the body. To maintain
mandibular health and prevent fatigue damage, it is neces-
sary to have a robust and responsive remodeling system.
In the presence of potent antiresorptive therapy, remodel-
ing might not be adequate to prevent tissue breakdown
and subsequent necrosis. Similarly, a number of case
reports and patient series have described the occurrence
of fractures in the subtrochanteric region of the femur in
patients exposed to long-term bisphosphonates. These
transverse fractures show a characteristic radiographic
appearance, with thickening of the bony cortex and
“beaking” of the fracture fragment. In a very large
population-based study, it was determined that although
there is a small added risk for such atypical fractures, the
overall benefit:risk ratio for bisphosphonates remained
substantially positive in that the overall fracture incidence
in bisphosphonate-treated patients was considerably lower
than that of nontreated patients [80]. Nonetheless, a trend
in treatment strategy has attended the emergence of ONJ
and atypical fractures, in that many experts now recom-
mend bisphosphonate therapy be stopped following 5 con-
secutive years of treatment, with subsequent monitoring
of BMD so that treatment can be restarted if and when
bone loss recurs. The degree to which undertaking such a
“drug holiday” may promote further bone loss and frac-
tures remains under study.
e Calcitonin
This 32-amino acid peptide is a natural hormone through-
out the vertebrate phylum. Its primary physiological role
appears to be to reduce the rate of bone remodeling by
inhibiting the action of mature osteoclasts. Calcitonin
obtained from salmon is considerably more potent than
1006 PART | H Bone Health and Disease
the human hormone and has been approved for treatment
of osteoporosis [81]. Although calcitonin can be given by
subcutaneous injection, most patients take the drug as a
nasal spray (Miacalcin). In approved doses, calcitonin is a
relatively weak antiresorptive drug with efficacy charac-
teristics that are far less pronounced than those of the
other approved antiresorptive agents.
f Denosumab
In Section II.D, Intercellular Communication Among
Bone Cells: Triggers and Constraints on Remodeling, I
described the role of the RANK RANK-ligand
(RANKL) system for regulating bone turnover. In 2010,
the FDA approved denosumab, a human monoclonal anti-
body that specifically binds to RANKL, prevents the acti-
vation of RANK on the surface of osteoclasts and their
precursors, and thereby inhibits osteoclast formation and
function, substantially decreasing the rate of bone remo-
deling [82]. In its pivotal clinical trial, denosumab
reduced the occurrence of all categories of fragility frac-
ture: vertebral, hip, and nonvertebral. Based on its mecha-
nism of action, denosumab is considered a potent
antiresorptive drug. Marketed under the trade name Prolia
(Amgen), it is approved for treatment of men and post-
menopausal women with osteoporosis at high risk of frac-
ture. The drug is administered by vein every 6 months
and is generally well tolerated. Some concern has been
expressed regarding the tendency for patients to experi-
ence lower blood calcium concentrations when treated
with denosumab, and hypocalcemia is considered a con-
traindication for its use. In addition, in clinical trials, seri-
ous infections leading to hospitalization were more
frequent in the denosumab group than with placebo.
These include bacterial endocarditis, skin infections, and
infections in the abdomen and urinary tract. ONJ has been
reported in a few patients receiving denosumab.
g Strontium Ranelate
Strontium has received approval in Europe and Asia for
treatment of osteoporosis. It becomes incorporated
directly into the bone mineral, which creates an artifactual
increase in BMD. However, strontium does appear to be
an effective antiresorptive compound and has been shown
to reduce fracture risk. Because no studies of this com-
pound have been conducted in the United States, it does
not appear that strontium can ever receive FDA approval
and so it is unlikely to be introduced into the U.S. market.
2 Bone Formation Therapy
a Teriparatide (Forteo and Forsteo in Europe)
Teriparatide is the generic term for the 1 34 fragment
of human PTH. It is approved as a single daily subcuta-
neous injection for up to 2 years at a dose of 20 μg/day.
Teriparatide is the first bone anabolic agent approved for
treatment of osteoporosis. (The full-length PTH (1 84)
molecule has not received approval in the United States
but is marketed in Europe. Its actions are qualitatively
similar to those of teriparatide.) Teriparatide directly sti-
mulates osteoblasts to form new bone and results in con-
siderably greater increases in BMD than are observed
with antiresorptive drugs. In addition, teriparatide
uniquely repairs the disrupted microarchitecture of tra-
becular bone to a normal pattern and also increases the
thickness of cortical bone. These effects result in sub-
stantial reduction in both vertebral and nonvertebral
fracture [83]. Teriparatide given very long term at high
dose to Fischer 344 rats led to a high rate of osteosar-
coma. Other animal models have shown no such effect,
and although a relationship to human carcinogenesis
seems very unlikely, one cannot be certain that no rela-
tionship exists. Because duration of therapy was a criti-
cal element for carcinogenesis in rats, teriparatide use is
currently restricted to 2 years. Teriparatide is marketed
by Eli Lilly & Co. as Forteo (and as Forsteo in Europe)
for the treatment of men and postmenopausal women
with osteoporosis whose physicians consider them at
high risk for fracture. As of this writing, teriparatide has
been generally available for more than 13 years, and no
carcinogenesis signal has yet appeared. As opposed to
several of the antiresorptive agents, it is not a drug for
prevention of osteoporosis.
VI CONCLUSION
Efforts are underway to bring forth additional compounds
of both the antiresorptive and bone-formation classes.
Other developmental targets currently focus on bone-
forming agents, and new PTH analogs and modes of
delivery for teriparatide are in human trials, as is suppres-
sion of a bone formation-inhibiting molecule, sclerostin.
Still largely in animal studies, strategies to activate a
newly discovered anabolic pathway in bone, the Wnt
pathway, have begun.
Thus, the future of pharmacologic therapy for osteo-
porosis seems reasonably bright. However, the overall
outlook for this disease remains clouded. With aging of
the population, trends toward increasingly sedentary life,
and substandard intakes of critical nutrients, the world-
wide burden of osteoporotic fractures is likely to
increase dramatically. Even now, it is difficult in the
United States to get appropriate diagnosis and treatment
for afflicted patients, even those with multiple fractures.
With growing competition from other aspects of health
care and with continued threats of onerous governmental
and health insurance constraints on reimbursement for
osteoporosis diagnosis and treatment, it is not at all cer-
tain that an explosive increase in fragility fractures and
their consequences will be avoided.

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