Osteoporosis

Osteoporosis, a condition characterized by decreased bone

strength, is prevalent among postmenopausal women but also
occurs in men and women with underlying conditions or major
risk factors associated with bone demineralization.

Its chief clinical manifestations are vertebral and hip fractures,

although fractures can occur at any skeletal site.

Osteoporosis affects >10 million individuals in the United States,

but only a small proportion are diagnosed and treated.
Definition
 Osteoporosis is defined as a reduction in the strength of bone that
leads to an increased risk of fractures.

 Loss of bone tissue is associated with deterioration in skeletal

microarchitecture.
The World Health Organization (WHO) operationally defines
osteoporosis as a bone density that falls 2.5 standard deviations
(SD) below the mean for young healthy adults of the same sex—
also referred to as a T-score of –2.5.

Postmenopausal women who fall at the lower end of the young

normal range (a T-score <–1.0) are defined as having low bone
density and are also at increased risk of osteoporosis.

More than 50% of fractures among postmenopausal women,

including hip fractures, occur in this group with low bone density.
Epidemiology
 The epidemiology of fractures follows the trend for loss of bone
density.

 Fractures of the distal radius increase in frequency before age 50

and plateau by age 60, with only a modest age-related increase
thereafter.

 In contrast, incidence rates for hip fractures double every 5 years

after age 70 (Fig. 354-1).
This distinct epidemiology may be related to the way people fall
as they age, with fewer falls on an outstretched hand and more
falls directly on the hip.

At least 1.5 million fractures occur each year in the United States
as a consequence of osteoporosis.

As the population continues to age, the total number of fractures

will continue to escalate.
Epidemiology of vertebral, hip, and Colles' fractures with age
Lateral spine x-ray showing severe osteopenia and a severe
wedge-type deformity (severe anterior compression).
Factors leading to osteoporotic fractures
Fractures are themselves risk factors for future fractures (Table 354-1).

Vertebral fractures increase the risk of other vertebral fractures as

well as fractures of the peripheral skeleton such as the hip and
wrist.
Wrist fractures also increase the risk of vertebral and hip
fractures.
Consequently, among individuals over age 50, any fracture
should be considered as potentially related to osteoporosis
regardless of the circumstances of the fracture.

Osteoporotic bone is more likely to fracture than is normal bone at

any level of trauma, and a fracture in a person over 50 should
trigger evaluation for osteoporosis.
Pathophysiology
Bone Remodeling
 Osteoporosis results from bone loss due to age-related changes in
bone remodeling as well as extrinsic and intrinsic factors that
exaggerate this process.
 These changes may be superimposed on a low peak bone mass.

 Consequently, understanding the bone remodeling process is

fundamental to understanding the pathophysiology of
osteoporosis.
During growth, the skeleton increases in size by linear growth and
by apposition of new bone tissue on the outer surfaces of the
cortex (Fig. 354-4).

The latter process is called modeling, a process that also allows

the long bones to adapt in shape to the stresses placed on them.

Increased sex hormone production at puberty is required for

skeletal maturation, which reaches maximum mass and density
in early adulthood.
It is around puberty that the sexual dimorphism in skeletal size
becomes obvious, although true bone density remains similar
between the sexes.

Nutrition and lifestyle also play an important role in growth,

though genetic factors primarily determine peak skeletal mass and
density.
 Mechanism of bone remodeling
The basic molecular unit (BMU) moves along the trabecular surface at a rate of about 10 μm/d.
The figure depicts remodeling over appx120 days.
A. Origination of BMU-lining cells contracts to expose collagen and attract preosteoclasts.
B. Osteoclasts fuse into multinucleated cells that resorb a cavity. Mononuclear cells continue
resorption, and preosteoblasts are stimulated to proliferate.
C. Osteoblasts align at bottom of cavity and start forming osteoid (black).
D. Osteoblasts continue formation and mineralization. Previous osteoid starts to mineralize
(horizontal lines).
E. Osteoblasts begin to flatten. F. Osteoblasts turn into lining cells; bone remodeling at initial
surface (left of drawing) is now complete, but BMU is still advancing (to the right).
Bone remodeling also is regulated by several circulating
hormones, including
estrogens, androgens, vitamin D, and parathyroid hormone
(PTH), as well as locally produced growth factors such as IGF-I
and immunoreactive growth hormone II (IGH-II), transforming
growth factor β (TGF-β), parathyroid hormone–related peptide
(PTHrP), interleukins (ILs), prostaglandins, and members of the
tumor necrosis factor (TNF) superfamily.
Calcium Nutrition
 Peak bone mass may be impaired by inadequate calcium intake
during growth among other nutritional factors (calories, protein,
and other minerals), leading to increased risk of osteoporosis later
in life.

 During the adult phase of life, insufficient calcium intake

contributes to relative secondary hyperparathyroidism and an
increase in the rate of bone remodeling to maintain normal serum
calcium levels.
PTH stimulates the hydroxylation of vitamin D in the kidney,
leading to increased levels of 1,25-dihydroxyvitamin D
[1,25(OH)2D] and enhanced gastrointestinal calcium absorption.
PTH also reduces renal calcium loss.

Although these are all appropriate compensatory homeostatic

responses for adjusting calcium economy, the long-term effects are
detrimental to the skeleton because the increased remodeling rates
and the ongoing imbalance between resorption and formation at
remodeling sites combine to accelerate loss of bone tissue.
Total daily calcium intakes <400 mg are detrimental to the
skeleton, and intakes in the range of 600–800 mg, which is about
the average intake among adults in the United States, are also
probably suboptimal.

The recommended daily required intake of 1000–1200 mg for

adults accommodates population heterogeneity in controlling
calcium balance (Chap. 73).
Vitamin D
 Severe vitamin D deficiency causes rickets in children and
osteomalacia in adults.
 However, there is accumulating evidence that vitamin D
insufficiency may be more prevalent than previously thought,
particularly among individuals at increased risk such as the
elderly; those living in northern latitudes; and individuals with
poor nutrition, malabsorption, or chronic liver or renal disease.

 Dark-skinned individuals are also at high risk of vitamin D

deficiency.
An expert consensus panel has suggested that the accepted levels
for serum 25-hydroxyvitamin D [25(OH)D] have been set too low
and that optimal targets for serum 25(OH)D are >75 nmol/L (30
ng/mL).

To achieve this level for most adults requires an intake of 800–

1000 units/d, particularly in individuals who avoid sunlight or
routinely use ultraviolet-blocking lotions.

Vitamin D insufficiency leads to compensatory secondary

hyperparathyroidism and is an important risk factor for
osteoporosis and fractures.
Treatment with vitamin D can return levels to normal [>75 μmol/L
(30 ng/mL)] and prevent the associated increase in bone
remodeling, bone loss, and fractures.

Reduced fracture rates also have been documented among

individuals in northern latitudes who have greater vitamin D
intake and have higher 25(OH)D levels (see below).

Vitamin D adequacy also may affect risk and/or severity of other

diseases, including cancers (colorectal, prostate, and breast),
autoimmune diseases, and diabetes.
Estrogen Status
 Estrogen deficiency probably causes bone loss by two distinct but
interrelated mechanisms:

 (1) activation of new bone remodeling sites and

 (2) exaggeration of the imbalance between bone formation and

resorption.
The most common estrogen-deficient state is the cessation of
ovarian function at the time of menopause, which occurs on
average at age 51 (Chap. 348).

Thus, with current life expectancy, an average woman will spend

about 30 years without an ovarian supply of estrogen.
Physical Activity
 Inactivity such as prolonged bed rest or paralysis, results in
significant bone loss.
 Concordantly, athletes have higher bone mass than does the
general population.

 These changes in skeletal mass are most marked when the

stimulus begins during growth and before the age of puberty.
 Adults are less capable than children of increasing bone mass after
restoration of physical activity.
Epidemiologic data support the beneficial effects on the skeleton
of chronic high levels of physical activity.
Fracture risk is lower in rural communities and in countries where
physical activity is maintained into old age.

However, when exercise is initiated during adult life, the effects of

moderate exercise on the skeleton are modest, with a bone mass
increase of 1–2% in short-term studies of <2 years' duration.

It is argued that more active individuals are less likely to fall and
are more capable of protecting themselves upon falling, thereby
reducing fracture risk.
Chronic Disease
 Various genetic and acquired diseases are associated with an
increase in the risk of osteoporosis (Table 354-2).
 Mechanisms that contribute to bone loss are unique for each
disease and typically result from multiple factors, including
nutrition, reduced physical activity levels, and factors that affect
rates of bone remodeling.

 In most, but not all, circumstances the primary diagnosis is made

before osteoporosis presents clinically.
Diseases Associated with an Increased Risk of Generalized Osteoporosis in Adults
Medications
 A large number of medications used in clinical practice have
potentially detrimental effects on the skeleton (Table 354-3).
 Glucocorticoids are the most common cause of medication-
induced osteoporosis.
 It is often not possible to determine the extent to which osteoporosis is
related to glucocorticoid or to other factors, as treatment is superimposed
on the effects of the primary disease, which in itself may be associated with
bone loss (e.g., rheumatoid arthritis).
 Excessive doses of thyroid hormone can accelerate bone
remodeling and result in bone loss.
Cigarette Consumption
 The use of cigarettes over a long period has detrimental effects on
bone mass.
 These effects may be mediated directly by toxic effects on
osteoblasts or indirectly by modifying estrogen metabolism.
 On average, cigarette smokers reach menopause 1–2 years earlier
than the general population.
 Cigarette smoking also produces secondary effects that can modulate
skeletal status, including intercurrent respiratory and other illnesses, frailty,
decreased exercise, poor nutrition, and the need for additional medications
(e.g., glucocorticoids for lung disease).
Measurement of Bone Mass
Several noninvasive techniques are available for estimating
skeletal mass or density.

They include
1. Dual-energy X-ray Absorptiometry (DXA),
2. Single-energy X-ray Absorptiometry (SXA),
3. Quantitative CT, and
4. Ultrasound (US).

DXA is a highly accurate x-ray technique that has become the

standard for measuring bone density in most centers.
Treatment Osteoporosis
The perimenopausal transition is a good opportunity to initiate a
discussion about risk factors for osteoporosis and consideration of
indications for a BMD test.

A careful history and physical examination should be performed to

identify risk factors for osteoporosis.

A low Z-score increases the suspicion of a secondary disease.

Height loss >2.5–3.8 cm (>1–1.5 in.) is an indication for
radiography or vertebral fracture assessment by DXA to rule out
asymptomatic vertebral fractures, as is the presence of significant
kyphosis or back pain, particularly if it began after menopause.

For patients who present with fractures, it is important to ensure

that the fractures are not caused by an underlying malignancy.

Usually this is clear on routine radiography, but on occasion, CT,

MRI, or radionuclide scans may be necessary.
Management of Osteoporotic Fractures
 Treatment of a patient with osteoporosis frequently involves
management of acute fractures as well as treatment of the
underlying disease.
 Hip fractures almost always require surgical repair if the patient is
to become ambulatory again.
 Depending on the location and severity of the fracture, condition
of the neighboring joint, and general status of the patient,
procedures may include open reduction and internal fixation with
pins and plates, hemiarthroplasties, and total arthroplasties.
Management of the Underlying
Disease
Risk Factor Reduction
 Patients should be thoroughly educated to reduce the impact of
modifiable risk factors associated with bone loss and falling.
 Medications should be reviewed to ensure that all are necessary.
 Glucocorticoid medication, if present, should be evaluated to
determine that it is truly indicated and is being given in doses that
are as low as possible.
 For those on thyroid hormone replacement, TSH testing should be
performed to determine that an excessive dose is not being used,
as thyrotoxicosis can be associated with increased bone loss.
Nutritional Recommendations
1. Calcium
 A large body of data indicates that optimal calcium intake reduces
bone loss and suppresses bone turnover.

 Recommended intakes from an Institute of Medicine report are

shown in Table 354-6.
2. Vitamin D

Vitamin D is synthesized in skin under the influence of heat and

ultraviolet light (Chap. 352).

However, large segments of the population do not obtain sufficient

vitamin D to maintain what is now considered an adequate supply
[serum 25(OH)D consistently >75 μmol/L (30 ng/mL)].
Since vitamin D supplementation at doses that would achieve
these serum levels is safe and inexpensive, the Institute of
Medicine recommends daily intakes of 200 IU for adults <50
years of age, 400 IU for those 50–70 years, and 600 IU for those
>70 years.

Multivitamin tablets usually contain 400 IU, and many calcium

supplements also contain vitamin D.

Some data suggest that higher doses (≥1000 IU) may be required
in the elderly and chronically ill.
Pharmacologic Therapies
Until fairly recently, estrogen treatment, either by itself or in
concert with a progestin, was the primary therapeutic agent for
prevention or treatment of osteoporosis. However, a number of
new drugs have appeared, and more are expected in the near
future. Some are agents that specifically treat osteoporosis
(bisphosphonates, calcitonin, PTH); others such as selective
estrogen response modulators (SERMs), have broader effects. The
availability of these drugs allows therapy to be tailored to the
needs of an individual patient.
Estrogens
 A large body of clinical trial data indicates that various types of
estrogens (conjugated equine estrogens, estradiol, estrone,
esterified estrogens, ethinyl estradiol, and mestranol) reduce bone
turnover, prevent bone loss, and induce small increases in bone
mass of the spine, hip, and total body.
The effects of estrogen are seen in women with natural or surgical
menopause and in late postmenopausal women with or without
established osteoporosis. Estrogens are efficacious when
administered orally or transdermally. For both oral and
transdermal routes of administration, combined estrogen/progestin
preparations are now available in many countries, obviating the
problem of taking two tablets or using a patch and oral progestin.
One large study, referred to as PEPI (Postmenopausal
Estrogen/Progestin Intervention Trial), indicated that C-21
progestins alone do not augment the effect of standard estrogen
doses on bone mass.
Bisphosphonates
 Alendronate, risedronate, and ibandronate are approved for the
prevention and treatment of postmenopausal osteoporosis.
Risedronate and alendronate are approved for the treatment of
steroid-induced osteoporosis, and risedronate also is approved for
prevention of steroid-induced osteoporosis. Both alendronate and
risedronate are approved for treatment of osteoporosis in men.
Bisphosphonates are structurally related to pyrophosphates,
compounds that are incorporated into bone matrix.
Bisphosphonates specifically impair osteoclast function and
reduce osteoclast number, in part by inducing apoptosis. Recent
evidence suggests that the nitrogen-containing bisphosphonates
also inhibit protein prenylation, one of the end products in the
mevalonic acid pathway, by inhibiting the enzyme farnesyl
pyrophosphate synthase. This effect disrupts intracellular protein
trafficking and ultimately may lead to apoptosis. Some
bisphosphonates have very long retention in the skeleton and may
exert long-term effects. The consequences of this, if any, are
unknown.
Calcitonin
 Calcitonin is a polypeptide hormone produced by the thyroid
gland (Chap. 353). Its physiologic role is unclear as no skeletal
disease has been described in association with calcitonin
deficiency or excess. Calcitonin preparations are approved by the
FDA for Paget's disease, hypercalcemia, and osteoporosis in
women >5 years past menopause.
Calcitonin suppresses osteoclast activity by direct action on the
osteoclast calcitonin receptor. Osteoclasts exposed to calcitonin
cannot maintain their active ruffled border, which normally
maintains close contact with underlying bone.
Parathyroid Hormone
 Endogenous PTH is an 84-amino-acid peptide that is largely
responsible for calcium homeostasis (Chap. 353). Although
chronic elevation of PTH, as occurs in hyperparathyroidism, is
associated with bone loss (particularly cortical bone), PTH also
can exert anabolic effects on bone. Consistent with this, some
observational studies have indicated that mild elevations in PTH
are associated with maintenance of trabecular bone mass.
Exogenously administered PTH appears to have direct actions on
osteoblast activity, with biochemical and histomorphometric
evidence of de novo bone formation early in response to PTH,
before activation of bone resorption. Subsequently, PTH activates
bone remodeling but still appears to favor bone formation over
bone resorption. PTH stimulates IGF-I and collagen production
and appears to increase osteoblast number by stimulating
replication, enhancing osteoblast recruitment, and inhibiting
apoptosis. Unlike all other treatments, PTH produces a true
increase in bone tissue and an apparent restoration of bone
microarchitecture (Fig. 354-13).
Glucocorticoid-Induced
Osteoporosis
Osteoporotic fractures are a well-characterized consequence of the
hypercortisolism associated with Cushing's syndrome. However,
the therapeutic use of glucocorticoids is by far the most common
form of glucocorticoid-induced osteoporosis.
Glucocorticoids are used widely in the treatment of a variety of
disorders, including chronic lung disorders, rheumatoid arthritis,
and other connective tissue diseases, inflammatory bowel disease,
and after transplantation.
Osteoporosis and related fractures are serious side effects of
chronic glucocorticoid therapy. Because the effects of
glucocorticoids on the skeleton are often superimposed on the
consequences of aging and menopause, it is not surprising that
women and the elderly are most frequently affected. The skeletal
response to steroids is remarkably heterogeneous, however, and
even young, growing individuals treated with glucocorticoids can
present with fractures.
The risk of fractures depends on the dose and duration of
glucocorticoid therapy, although recent data suggest that there
may be no completely safe dose. Bone loss is more rapid during
the early months of treatment, and trabecular bone is affected
more severely than cortical bone. As a result, fractures have been
shown to increase within 3 months of steroid treatment. There is
an increase in fracture risk in both the axial skeleton and the
appendicular skeleton, including risk of hip fracture. Bone loss
can occur with any route of steroid administration, including high-
dose inhaled glucocorticoids and intraarticular injections.
Alternate-day delivery does not appear to ameliorate the skeletal
effects of glucocorticoids.
Pathophysiology
 Glucocorticoids increase bone loss by multiple mechanisms,
including (1) inhibition of osteoblast function and an increase in
osteoblast apoptosis, resulting in impaired synthesis of new bone;
(2) stimulation of bone resorption, probably as a secondary effect;
(3) impairment of the absorption of calcium across the intestine,
probably by a vitamin D–independent effect;
(4) increase of urinary calcium loss and perhaps induction of some
degree of secondary hyperparathyroidism; (5) reduction of adrenal
androgens and suppression of ovarian and testicular secretion of
estrogens and androgens; and (6) induction of glucocorticoid
myopathy, which may exacerbate effects on skeletal and calcium
homeostasis as well as increase the risk of falls.
Evaluation of the Patient
 Because of the prevalence of glucocorticoid-induced bone loss, it
is important to evaluate the status of the skeleton in all patients
starting or already receiving long-term glucocorticoid therapy.
Modifiable risk factors should be identified, including those for
falls.
Examination should include testing of height and muscle strength.
Laboratory evaluation should include an assessment of 24-h
urinary calcium. All patients on long-term (>3 months)
glucocorticoids should have measurement of bone mass at both
the spine and the hip using DXA. If only one skeletal site can be
measured, it is best to assess the spine in individuals <60 years
and the hip in those >60 years.
Prevention
 Bone loss caused by glucocorticoids can be prevented, and the risk
of fractures significantly reduced. Strategies must include using
the lowest dose of glucocorticoid for disease management. Topical
and inhaled routes of administration are preferred, where
appropriate. Risk factor reduction is important, including smoking
cessation, limitation of alcohol consumption, and participation in
weight-bearing exercise, when appropriate. All patients should
receive an adequate calcium and vitamin D intake from the diet or
from supplements.
Treatment Glucocorticoid-Induced Osteoporosis

 Only bisphosphonates have been demonstrated in large clinical

trials to reduce the risk of fractures in patients being treated with
glucocorticoids. Risedronate prevents bone loss and reduces
vertebral fracture risk by 70%. Similar beneficial effects are
observed in studies of alendronate.
Controlled trials of hormone therapy have shown bone-sparing
effects, and calcitonin also has some protective effect in the spine.
Thiazides reduce urine calcium loss, but their role in prevention of
fractures is unclear. PTH has been studied in a small group of
women with glucocorticoid-induced osteoporosis, among whom
bone mass increased substantially, and teriparatide is being
investigated in a larger multicenter trial.