3194 PART 12 Endocrinology and Metabolism

insight into the architecture of the skeleton (including the trabecular

bone score, a noninvasive addition to DXA).

■ 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 secondary hyperparathyroidism and an increase in the rate

of bone remodeling to assist in maintaining 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)2

D]

and enhanced gastrointestinal calcium absorption. PTH also reduces

renal calcium loss. Although these are appropriate compensatory

homeostatic responses for adjusting calcium economy, the longterm 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. 332). Such intakes should preferentially come from

dietary sources, with supplements used only when dietary intakes fall

short and cannot be modified easily. The supplement should be enough

to bring total intake to ~1200 mg/d. Recent studies have suggested

that there may be differences in safety based on calcium source; high

intakes primarily from supplement sources appear to result in a greater

risk of renal stones and perhaps cardiovascular calcifications (although

the literature is inconsistent and controversial). Increasing calcium

intake above this level does not improve calcium homeostasis or bone

formation. Increasing calcium intake by itself will not prevent bone loss

due to other factors (e.g., postmenopausal status)

■ VITAMIN D

(See also Chap. 409) Severe vitamin D deficiency causes rickets in

children and osteomalacia in adults. However, vitamin D insufficiency

(circulating levels of 25-hydroxyvitamin D [25(OH)D] that may be

inadequate but above the level that results in rickets) 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, obesity, malabsorption, or chronic

liver or renal disease. Dark-skinned individuals are also at high risk of

vitamin D in the insufficiency range or lower, but African Americans

have a low risk of osteoporosis, with better calcium homeostasis than

Caucasians.

Although there is considerable controversy about overall optimal

health targets for serum 25(OH)D, there is evidence that for optimal

skeletal health, serum 25(OH)D should be >75 nmol/L (30 ng/mL).

To achieve this level for most adults requires skin exposure to sunlight

(estimated to be exposure of face and arms for at least one-half hour

each day) or an intake of at least 800–1000 units/d, or even higher in

individuals with risk factors (as above).

Vitamin D insufficiency leads to compensatory secondary hyperparathyroidism and is an important risk factor for osteoporosis and

fractures. Some studies have shown that >50% of inpatients on a

general medical service exhibit biochemical features of vitamin D

deficiency, including increased levels of PTH and alkaline phosphatase

and lower levels of ionized calcium. Among those living in northern

latitudes, vitamin D levels decline during the winter months without

supplementation. This is associated with seasonal bone loss, reflecting

increased bone turnover. Even among healthy ambulatory individuals,

mild vitamin D deficiency is increasing in prevalence. In part, this is

due to decreased exposure to sunlight coupled with increased use of

potent sunscreens, although not all studies suggest that sunscreens

inhibit D synthesis in the skin. 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 falls

and fracture rates also have been documented among individuals in

CFU-GM

Activated T

lymphocytes

Activated

synovial

fibroblasts

Activated

dendritic

cells

RANKL

RANK

OPG

Preosteoclast

Multinucleated

osteoclast

Activated

osteoclast

Bone

T

Osteoblasts or bone

marrow stromal cells

Proresorptive and

calciotropic factors

1,25(OH)2 vitamin D3. PTH, PTHrP, PGE2, IL-1,

IL-6, TNF, prolactin, corticosteroids, oncostatin M, LIF

M-CSF

A

Apoptotic

osteoclast

T

Anabolic or antiresorptive factors

Estrogens, calcitonin, BMP 2/4, TGF-β, TPO, IL-17,

PDGF, calcium

M-CSF

B

FIGURE 411-5 Hormonal control of bone resorption. A. Proresorptive and calciotropic factors. B. Anabolic and antiosteoclastic factors. RANKL expression is induced

in osteoblasts, activated T cells, synovial fibroblasts, and bone marrow stromal cells. It binds to membrane-bound receptor RANK to promote osteoclast differentiation,

activation, and survival. Conversely, osteoprotegerin (OPG) expression is induced by factors that block bone catabolism and promote anabolic effects. OPG binds and

neutralizes RANKL, leading to a block in osteoclastogenesis and decreased survival of preexisting osteoclasts. CFU-GM, colony-forming units, granulocyte macrophage;

IL, interleukin; LIF, leukemia inhibitory factor; M-CSF, macrophage colony-stimulating factor; OPG-L, osteoprotegerin ligand; PDGF, platelet-derived growth factor; PGE2

,

prostaglandin E2

; PTH, parathyroid hormone; RANKL, receptor activator of nuclear factor-κB; TGF-β, transforming growth factor β; TNF, tumor necrosis factor; TPO,

thrombospondin. (Reproduced with permission from WJ Boyle et al: Osteoclast differentiation and activation. Nature 423:337, 2003.)

3195Osteoporosis CHAPTER 411

northern latitudes who have greater vitamin D intake and have higher

25(OH)D levels (though one study suggested an increased fall risk with

25[OH]D levels >70 ng/mL). Although vitamin D levels are suspected

to affect risk and/or severity of other diseases, including cancers (colorectal, prostate, and breast), autoimmune diseases, multiple sclerosis,

cardiovascular disease, and diabetes, most controlled clinical trials

have not confirmed these effects. For most adults in the United States,

supplements of 1000–2000 IU/d are adequate and safe. Recent data

suggesting that those with low vitamin D levels have a more severe

clinical course than those with normal vitamin D levels have added

impetus to ensuring that vitamin D levels are normal in all adults, even

though a cause-and-effect relationship has not been demonstrated.

■ ESTROGEN STATUS

Estrogen deficiency causes bone loss by two distinct but interrelated

mechanisms: (1) activation of new bone remodeling sites and (2) initiation or exaggeration of an imbalance between bone formation and

resorption, in favor of the latter. The change in activation frequency

causes a transient bone loss until a new steady state between resorption

and formation is achieved. The remodeling imbalance, however, results

in a permanent decrement in mass. In addition, the very presence of

more remodeling sites in the skeleton increases the probability that

trabeculae will be penetrated, eliminating the template on which new

bone can be formed and accelerating the loss of bony tissue. The consequence is loss of skeletal architecture, particularly in trabecular bone,

and it is possible that at any given bone density the risk of a fracture

is likely to be greater in those who have experienced bone loss than

in those for whom that level of bone mass represents normal. Recent

addition of the trabecular bone score in DXA measurements is an

attempt to capture these architectural changes.

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. 395). Thus, with current life expectancy, an average woman

will spend ~30 years without an ovarian supply of estrogen. Breast

cancer treatment with aromatase inhibitors is an increasingly common

cause of even more severe estrogen deficiency. The mechanism by

which estrogen deficiency causes bone loss is summarized in Fig. 411-

5. Marrow cells (macrophages, monocytes, osteoclast precursors, mast

cells) as well as bone cells (osteoblasts, osteocytes, osteoclasts) express

both ERs (α and β). Loss of estrogen increases production of RANKL

and reduces production of osteoprotegerin, increasing osteoclast formation and recruitment. Estrogen also may play a role in determining

the life span of bone cells by controlling the rate of apoptosis. Thus,

in situations of estrogen deprivation, the life span of osteoblasts may

be decreased, whereas the longevity and activity of osteoclasts are

increased. The rate and duration of bone loss after menopause are

heterogeneous and unpredictable. Once surfaces are lost in cancellous

bone, the rate of bone loss declines. In cortical bone, loss is slower but

may continue for a longer time period.

Since remodeling is initiated at the surface of bone, it follows that

trabecular bone—which has a considerably larger surface area (80% of

the total) than cortical bone—will be affected preferentially by estrogen deficiency. Fractures occur earliest at sites where trabecular bone

contributes most to bone strength; consequently, vertebral fractures are

the most common early skeletal consequence of estrogen deficiency.

In males, estrogen may have an important role in regulation of bone

remodeling. In an experiment in which males were rendered estrogen

and androgen deficient, restoring estrogen supply reduced remodeling

rate more than restoring androgen.

■ PHYSICAL ACTIVITY

Inactivity, such as prolonged bed rest or paralysis, results in significant

bone loss. Concordantly, athletes have higher bone mass than nonathletes. 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. Continuing physical activity into the later years

appears to slow cognitive decline, another major reason for including

exercise programs for the aging population.

■ CHRONIC DISEASES

Various genetic and acquired diseases are associated with an increase in

the risk of osteoporosis (Table 411-2). 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. Both type 1 and type 2 diabetes mellitus are associated with an

increased fracture risk, with increased risk at higher bone density than

in the nondiabetic population. This may be due to differences in the

chemical composition of bone tissue that is more brittle than normal,

a predilection for conversion of precursors to adipose cells rather than

osteoblasts, and the sequelae of diabetes that increase the risk of falls

and injury.

Severe bone loss occurs in quadriplegic and paraplegic individuals

below the level of the injury. The combination of loss of muscle function and innervation of both muscle and bone contributes to failure to

recover mobility, which leads to a high fracture risk in those attempting

to pursue athletic activities despite their primary diagnosis (e.g., wheelchair athletes). Bone loss also follows a stroke and is again dependent

on the severity of the paralysis. The risk of fracture can be predicted by

the FRAX (Fracture Risk Assessment) score and seems highest in the

first year after stroke diagnosis. The increasing prevalence of transgender and gender nonconforming individuals has prompted a guideline

for evaluation of bone density in that population by the International

Society of Clinical Densitometry published in 2019.

TABLE 411-2 Diseases Associated with an Increased Risk of

Generalized Osteoporosis in Adults

Hypogonadal states

Turner’s syndrome

Klinefelter’s syndrome

Anorexia nervosa

Hypothalamic amenorrhea

Hyperprolactinemia

Other primary or secondary

hypogonadal states

Endocrine disorders

Cushing’s syndrome

Hyperparathyroidism

Thyrotoxicosis

Diabetes mellitus (both type 1 and 2)

Acromegaly

Adrenal insufficiency

Nutritional and gastrointestinal

disorders

Malnutrition

Parenteral nutrition

Malabsorption syndromes

Gastrectomy

Severe liver disease, especially biliary

cirrhosis

Pernicious anemia

Rheumatologic disorders

Rheumatoid arthritis

Ankylosing spondylitis

Hematologic disorders/malignancy

Multiple myeloma

Lymphoma and leukemia

Malignancy-associated parathyroid

hormone–related peptide (PTHrP)

production

Mastocytosis

Hemophilia

Thalassemia

Selected inherited disorders

Osteogenesis imperfecta

Marfan’s syndrome

Hemochromatosis

Hypophosphatasia

Glycogen storage diseases

Homocystinuria

Ehlers-Danlos syndrome

Porphyria

Menkes’ syndrome

Epidermolysis bullosa

Other disorders

Immobilization

Chronic obstructive pulmonary disease

Pregnancy and lactation

Scoliosis

Multiple sclerosis

Sarcoidosis

Amyloidosis

3196 PART 12 Endocrinology and Metabolism

■ MEDICATIONS

A large number of medications used in clinical practice have potentially detrimental effects on the skeleton (Table 411-3). 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 treatment or to other factors, as the effects

of medication are 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.

Other medications have less detrimental effects on the skeleton than

pharmacologic doses of glucocorticoids. Anticonvulsants are thought to

increase the risk of osteoporosis, although many affected individuals

have concomitant insufficiency of 1,25(OH)2

D, as some anticonvulsants induce the cytochrome P450 system and vitamin D metabolism.

Patients undergoing transplantation are at high risk for rapid bone loss

and fracture not only from glucocorticoids but also from treatment

with other immunosuppressants such as cyclosporine and tacrolimus

(FK506). In addition, these patients often have underlying metabolic

abnormalities such as hepatic or renal failure that predispose to bone

loss. Recently, long-term use of proton pump inhibitors has been

shown in observational studies to be associated with a higher risk

of fracture. Given their widespread and frequent long-term use, the

skeletal effect is important from a public health perspective and when

reviewing risk for fracture in individuals.

Aromatase inhibitors, which potently block the aromatase enzyme

that converts androgens and other adrenal precursors to estrogen, reduce circulating postmenopausal estrogen supply dramatically.

These agents, which are used in various stages for breast cancer treatment, also have been shown to have a detrimental effect on bone density and risk of fracture. Androgen deprivation therapies, used to treat

men with prostate cancer, also result in rapid loss of bone and increased

fracture risk. Various diabetes medications, including but not limited

to thiazolidinediones, and antidepressants, including the selective serotonin reuptake inhibitors, increase risk of osteoporosis and fracture. It

is difficult in some cases to separate the risk accrued by the underlying

disease from that attributable to the medication. Thus, both depression

and diabetes are risk factors for fracture by themselves.

■ SMOKING

Smoking produces detrimental effects on bone mass 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).

■ OTHER POTENTIAL FACTORS

In the past few years, a large number of potential risk factors for fracture have been identified. These include excessive alcohol intake and

other drugs of abuse, pollution, use of triclosan, chronic obstructive

pulmonary disease, excess vitamin B, and hormonal therapies utilized

among the transgender population.

DIAGNOSIS

■ MEASUREMENT OF BONE MASS

Several noninvasive techniques are available for estimating skeletal

mass or BMD. They include single-energy x-ray absorptiometry

(SXA), DXA, quantitative computed tomography (CT), and ultrasound. DXA is a highly accurate x-ray technique that has become

the standard for measuring bone density. Though it can be used for

measurement in any skeletal site, clinical determinations usually are

made of the lumbar spine and hip. DXA also can be used to measure

the wrist total body bone mass and body composition. Two x-ray

energies are used to estimate mineralized tissue, allowing for correction for attenuation through soft tissue. The mineral content is divided

by bone area, which partially corrects for body and bone size. However, this correction is only partial since DXA is a two-dimensional

scanning technique and cannot estimate the depth or posteroanterior

length of the bone. Thus, small slim people tend to have lower than

average BMD, a feature that is important in interpreting BMD measurements. Bone spurs, which are common in osteoarthritis, tend to

falsely increase bone density mostly of the spine and are a particular

problem in measuring spine BMD in older individuals. Because DXA

measurement devices are provided by two different manufacturers, the

output varies in absolute terms. Consequently, it has become standard

practice to relate the results to “normal” values by using T-scores (a

T-score of 1 equals 1 SD), which compare individual results to those in

a young adult population that is matched for race and sex. The mean

value is given a score of zero and the range +2.5 to –2.5 (i.e., 2.5 SDs

above or below the mean). Z-scores (also SDs) compare individual

results to those of an age and gender-matched reference population.

Thus, a 60-year-old woman with a Z-score of –1 (1 SD below mean

for age) has a T-score of –2.5 (2.5 SD below mean for a young control

group) (Fig. 411-6). A T-score <–2.5 in the lumbar spine, femoral

neck, or total hip has been defined as osteoporosis. Although the

outputs from different instruments and, more importantly, different

manufacturers correlate well, different machines used over time may

show changes in BMD that may be attributed to biological changes or

simply the result of differences between machines. This is particularly

true with measurements of the hip. Consequently, it is recommended

that serial measurements be performed on the same machine and

preferably by the same technician.

As noted above, since >50% of fractures occur in individuals with

low bone mass (i.e., a T-score between –1.0 and –2.5), it is usual to

report fracture risk in addition to BMD. To that end the absolute fracture risk assessment tool FRAX often accompanies the report of bone

density. FRAX estimates include age, gender, height, weight, fracture

history, hip fracture in a parent, steroid use, rheumatoid arthritis, other

secondary causes, and bone density of the femoral neck. The program

then calculates the estimated risk over a 10-year time frame for major

osteoporosis-related fractures (clinical spine, hip, wrist, and proximal

humerus) as well as hip fracture.

CT can also be used to measure the spine and hip but is rarely used

clinically, in part because the radiation exposure and cost are both

TABLE 411-3 Drugs Associated with an Increased Risk of Generalized

Osteoporosis in Adults

Glucocorticoids Excessive thyroxine

Cyclosporine Aluminum

Cytotoxic drugs Gonadotropin-releasing hormone agonists

Anticonvulsants Heparin

Aromatase inhibitors

Selective serotonin reuptake

inhibitors

Lithium

Protein pump inhibitors

Thiazolidinediones

Androgen deprivation therapies

Z- and T-scores 3

BMD score

2

1

20 30 40 50

Age

+1 SD

–1 SD

0

60

T-Score = –2.5

Z-Score = –1

70 80 90

–1

–2

–3

0

FIGURE 411-6 Relationship between Z-scores and T-scores in a 60-year-old

woman. BMD, bone mineral density; SD, standard deviation.

3197Osteoporosis CHAPTER 411

much higher than with DXA. High-resolution peripheral quantitative

computed tomography (HR-pQCT) can be used to measure bone in

the forearm or tibia and is a research tool that provides information

on skeletal architecture noninvasively. Magnetic resonance imaging

(MRI) can also be used to obtain some architectural information on

the forearm and perhaps the hip but, again, is primarily a research tool

at present.

Ultrasound can be used to measure bone mass by calculating the

attenuation of the signal as it passes through bone or the speed with

which it traverses the bone. Although the ultrasound technique was

purported to assess properties of bone other than mass (e.g., quality),

this has not been confirmed. Because of its relatively low cost and

mobility, ultrasound bone density measurement is amenable for use as

a screening procedure in stores or health fairs.

All these techniques for measuring BMD have been approved by

the U.S. Food and Drug Administration (FDA) on the basis of their

capacity to predict fracture risk. The hip is the preferred site of measurement in most individuals, since it allows prediction of hip fracture

risk, the most important consequence of osteoporosis, better than any

other bone density measurement site. When hip measurements are

performed by DXA, the spine is usually measured at the same time. In

younger individuals such as perimenopausal or early postmenopausal

women, spine measurements may be a more sensitive indicator of bone

loss. When the spine or hip is not measurable due to severe degenerative spine disease or scoliosis or prior spine or hip surgery, BMD of the

wrist is often measured.

■ INDICATIONS FOR BONE MASS MEASUREMENT

Several clinical guidelines have been developed for the use of

bone densitometry in clinical practice (Table 411-4). The National

Osteoporosis Foundation (NOF) guidelines recommend bone mass

measurements in postmenopausal women who have one or more

risk factors for osteoporosis in addition to age, sex, and estrogen

deficiency. The guidelines further recommend that bone mass measurement be considered in all women by age 65, a position ratified by

the U.S. Preventive Health Services Task Force. In males, the use of

bone density determination is not recommended until the age of 70

years in the absence of multiple risk factors or the occurrence of an

osteoporosis-related fracture.

The FRAX score incorporates risk factors (age, prior fracture,

family history of hip fracture, low body weight, cigarette consumption, excessive alcohol use, steroid use, and rheumatoid arthritis)

with BMD to assess the 10-year fracture probabilities. Fracture risk

probability calculators are available as part of the report from all

DXA machines and also available online (https://www.sheffield.ac.uk/

FRAX/) (Fig. 411-7). In the United States, it has been determined to

be cost effective to treat if the 10-year major osteoporotic fracture risk

from FRAX is ≥20% and/or the 10-year risk of hip fracture is ≥3%.

FRAX is an imperfect tool, as it does not include any assessment of

fall risk, and secondary causes are excluded when BMD is entered.

More importantly, it does not distinguish the contribution toward

future fracture probability from an acute recent fracture versus the

lesser importance of the more remote fracture. Moreover, there is no

mandate for vertebral fracture diagnosis and no additional fracture

probability estimated for patients who have had multiple fractures.

Nonetheless, it is useful as an educational tool for patients, particularly for those who are excessively worried about BMD levels despite

relative youth and health.

■ VERTEBRAL IMAGING

DXA equipment can also be used to obtain lateral images of the thoracic and lumbar spine, a technique called vertebral fracture assessment (VFA). While not as definitive as a radiograph, it is an excellent

screening tool for vertebral abnormality in both women and men based

on age and BMD even in the absence of any specific symptoms since

the majority of vertebral fractures are asymptomatic for a long time.

Furthermore, the VFA can be used to evaluate vertebral abnormality

as a cause of height loss or back pain that suggests the possibility of an

undiagnosed vertebral fracture.

Because vertebral fractures are often asymptomatic when they first

occur, the diagnosis of vertebral fracture is rarely made at the time of

the fracture occurrence. Since vertebral fractures, whether symptomatic or asymptomatic, are associated with the same clinical sequelae,

it is critical that patients with these fractures are identified. Vertebral

fracture prevalence in the United States based on the National Health

and Nutrition Evaluation Studies (NHANES) population appears to

be ~10% in the 1970s and 20% in the 1980s, when the strictest criteria for diagnosis are utilized. The NOF and other organizations have

recommended that women by the age of 65 and men by the age of

70 undergo vertebral imaging if a T-score is ≤–1.5 at the spine, hip,

or femoral neck. Vertebral imaging is also recommended for women

by the age of 70 and men by the age of 80 if a T-score is <–1.0. For

younger individuals, vertebral imaging is recommended for those with

an osteoporosis related fracture, height loss, or glucocorticoid use.

(See Table 411-5.)

APPROACH TO THE PATIENT

Osteoporosis

The development of underlying skeletal changes is a gradual process occurring under a variety of influences throughout adult

life. Recognition of these influences allows intervention at several

points, although the need for aggressive management is clearly

dependent on a careful evaluation of each individual patient.

The menopausal transition affects all women by their late 50s

and represents an opportunity to initiate a discussion about bone

loss, the role of estrogen loss, and other risk factors that might

exacerbate it. Assessment of fracture risk using a tool such as

FRAX (with or without bone density) provides a 10-year estimate

of hip and major osteoporosis-related fracture risk and opens the

discussion about preventive steps including, if required, the use of

medication. If risk is low, then nutrition and lifestyle are the focus.

If menopausal symptoms are prominent and estrogen intervention

is needed, then the added protection against bone loss should be

emphasized.

Among older women, the occurrence of a fracture should precipitate an evaluation of skeletal status including bone density testing.

In this case, any fracture, whether traumatic or not, should trigger

the assessment. Although osteoporosis is associated with a risk

of fracture on minimal trauma, individuals with osteoporosis are

consequently more likely to fracture at greater levels of trauma, and

such individuals should not be excluded from osteoporosis evaluation simply because of the level of trauma. This concept, while

obvious, still needs emphasis with individual patients, physicians,

and payors.

Patients who present with hip or spine fractures by definition

have osteoporosis and will require treatment for both the fracture

itself and the underlying skeletal disorder. Other long bone fractures (e.g., distal radius) are triggers for evaluation of the skeleton

upon which treatment decisions can be based.

In all individuals presenting with a fracture as a result of a fall,

fall prevention strategies are an important adjunct to other lifestyle

and nutritional interventions that must be reviewed with all patients.

ROUTINE LABORATORY EVALUATION

There is no established algorithm for the evaluation of women

who present with osteoporosis. A general evaluation that includes

TABLE 411-4 Indications for Bone Mineral Density Testing

• Women aged ≥65 and men aged ≥70; regardless of clinical risk factors

• Younger postmenopausal women, women in the menopausal transition, and

men aged from 50 to 69 with clinical risk factors for fracture

• Adults who have a fracture at or after age 50

• Adults with a condition (e.g., rheumatoid arthritis) or taking a medication (e.g.,

glucocorticoids at a daily dose >5 mg prednisone or equivalent for >3 months

associated with low bone mass or bone loss

3198 PART 12 Endocrinology and Metabolism

FIGURE 411-7 FRAX calculation tool. When the answers to the indicated questions are filled in, the calculator can be used to assess the 10-year probability of fracture. The

calculator (available online at http://www.shef.ac.uk/FRAX/tool.jsp?locationValue=9) also can risk adjust for various ethnic groups.

TABLE 411-5 Indications for Vertebral Testing

Consider vertebral imaging tests for the following individualsa

• All women aged ≥70 and all men aged ≥80 if bone mineral density (BMD)

T-score at the spine, total hip, or femoral neck is <1.0

• Women aged from 65 to 69 and men aged from 70 to 79 if BMD T-score at the

spine, total hip, or femoral neck is <1.5

• Postmenopausal women and men aged ≥50 with specific risk factors:

• Low-trauma fracture during adulthood (aged ≥50)

• Historical height loss of ≥1.5 in. (4 cm)b

• Prospective height loss of ≥0.8 in. (2 cm)c

• Recent or ongoing long-term glucocorticoid treatment

a

If bone density testing is not available, vertebral imaging may be considered

based on age alone. b

Current height compared to peak height during childhood. c

Cumulative height loss measured during interval medical assessment.

complete blood count, serum and 24-h urine calcium, and renal

and hepatic function tests is useful for identifying selected secondary causes of low bone mass, particularly for women with fractures

or unexpectedly low Z-scores. An elevated serum calcium level suggests hyperparathyroidism or malignancy, whereas a reduced serum

calcium level may reflect malnutrition or a malabsorption disease,

such as celiac disease. In the presence of hypercalcemia, a serum

PTH level differentiates between hyperparathyroidism (PTH↑) and

malignancy (PTH↓), and a high PTHrP level can help document

the presence of humoral hypercalcemia of malignancy (Chap. 410).

A low urine calcium (<50 mg/24 h) suggests malnutrition, or

malabsorption; a high urine calcium (>300 mg/24 h) during normal calcium intake (excluding calcium supplements for at least a

week before the urine collection) is indicative of hypercalciuria.

Hypercalciuria occurs primarily in three situations: (1) a renal

calcium leak, which is more common in males with osteoporosis;

(2) absorptive hypercalciuria, which can be idiopathic or associated

with increased 1,25(OH)2

D in granulomatous disease; or (3) hematologic malignancies or conditions associated with excessive bone

turnover such as Paget’s disease, hyperparathyroidism, and hyperthyroidism. Renal hypercalciuria is treated with thiazide diuretics,

which lower urine calcium and help improve calcium economy. In

this setting, thiazides alone can improve bone mass and possibly

reduce risk of fracture. They might also reduce renal stone risk.

Individuals who have osteoporosis-related fractures or bone density in the osteoporotic range should have a measurement of serum

25(OH)D level since the intake of vitamin D required to achieve a

target level >30 ng/mL is highly variable. Hyperthyroidism should

be evaluated by measuring thyroid-stimulating hormone (TSH).

When there is clinical suspicion of Cushing’s syndrome, urinary

free cortisol levels or a fasting serum cortisol should be measured

after overnight dexamethasone. When bowel disease, malabsorption, or malnutrition is suspected, serum albumin, cholesterol, and

a complete blood count should be checked. Asymptomatic malabsorption may be heralded by anemia (macrocytic—vitamin B12 or

folate deficiency; microcytic—iron deficiency) or low serum cholesterol or urinary calcium levels. If these or other features suggest

malabsorption, further evaluation is required. Asymptomatic celiac

3199Osteoporosis CHAPTER 411

TABLE 411-6 Biochemical Markers of Bone Metabolism in Clinical Use

Bone formation

Serum bone-specific alkaline phosphatase

Serum osteocalcin

Serum propeptide of type I procollagen

Bone resorption

Urine and serum cross-linked N-telopeptide

Urine and serum cross-linked C-telopeptide

disease with selective malabsorption is being found with increasing

frequency; the diagnosis can be made by testing for transglutaminase

IgA antibodies but may require confirmation by endoscopic biopsy.

A trial of a gluten-free diet can also be confirmatory (Chap. 325).

When osteoporosis is found associated with symptoms of rash,

multiple allergies, diarrhea, or flushing, mastocytosis should be

considered and excluded by using 24-h urine histamine collection

or serum tryptase.

Myeloma can masquerade as generalized osteoporosis, although

it more commonly presents with bone pain and characteristic

“punched-out” lesions on radiography. Serum and urine electrophoresis and/or evaluation for serum free light chains in urine are

required to exclude this diagnosis. More commonly, a monoclonal gammopathy of undetermined significance (MGUS) is found,

and the patient is subsequently monitored to ensure that this is

not an incipient myeloma. MGUS itself may be associated with

an increased risk of osteoporosis. A bone marrow biopsy may be

required to rule out myeloma (in patients with equivocal electrophoretic results) and also can be used to exclude mastocytosis,

leukemia, and other marrow infiltrative disorders such as Gaucher’s

disease.

An important cause of fracture among the aging population is

diabetes, both type 1 and type 2. Patients with diabetes appear, at

any given bone density, to be at higher risk of fracture than nondiabetics. The reasons include the effects on muscle and nerve that

increase the risk of falls, but also the possibility that there is an

underlying skeletal fragility as part of the metabolic consequences

of diabetes itself.

BONE BIOPSY

Tetracycline labeling of the skeleton allows determination of the

rate of remodeling as well as evaluation for other metabolic bone

diseases. The current use of BMD tests, in combination with hormonal evaluation and biochemical markers of bone remodeling, has

largely replaced the clinical use of bone biopsy, although it remains

an important tool in the diagnosis of chronic kidney disease–

mineral bone disease (CKD-MBD), in evaluating the mechanism

of action of osteoporosis pharmacologies, and in clinical research.

BIOCHEMICAL MARKERS

Several biochemical tests are available that provide an index of

the overall rate of bone remodeling (Table 411-6). Biochemical

markers usually are characterized as those related primarily to bone

formation or bone resorption. These tests measure the overall state

of bone remodeling at a single point in time. Clinical use of these

tests has been hampered by biologic variability (in part related to

circadian rhythm) as well as analytic variability, although the latter

is improving.

For the most part, remodeling markers do not predict rates of

bone loss well enough in individuals to make accurate assessment

of potential future changes in bone density. However, they do

provide adjunct information that assists in both evaluation of the

patient and in assessment of treatment response. Markers of bone

resorption may help in the prediction of fracture risk, independently of bone density, particularly in older individuals. In women

≥65 years, when bone density results are greater than the usual

treatment thresholds noted above, a high level of bone resorption

should prompt consideration of treatment. The primary use of

biochemical markers is for monitoring the response to treatment.

With the introduction of antiresorptive therapeutic agents, bone

remodeling declines rapidly, with the fall in resorption occurring

earlier than the fall in formation. Inhibition of bone resorption

is maximal within 3 months or so. Thus, measurement of bone

resorption (serum C-terminal telopeptide measured in a fasting

specimen is the preferred marker) before initiating therapy and

2–6 months after starting therapy provides an earlier estimate

of patient response than does bone densitometry. A decline in

resorptive markers can be ascertained after treatment with bisphosphonates, denosumab, or estrogen; this effect is less marked

after treatment with weaker agents such as raloxifene or calcitonin.

Bone turnover markers are also useful in monitoring the effects of

1–34hPTH, or teriparatide, which rapidly increases bone formation

(P1NP is the most sensitive, but osteocalcin is also a very good

formation marker) and later bone resorption. The recent suggestion

of “drug holidays” (see below) has opened another use for biochemical markers, allowing evaluation of the off-effect of drugs such as

bisphosphonates.

TREATMENT

Osteoporosis

MANAGEMENT OF PATIENTS WITH 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. These surgical procedures are followed by

intense rehabilitation in an attempt to return patients to their prefracture functional level. Long bone fractures often require either

external or internal fixation. Other fractures (e.g., vertebral, rib,

and pelvic fractures) can often be managed with supportive care,

requiring no specific orthopedic treatment.

Only ~25–30% of vertebral compression fractures present with

sudden-onset back pain. For acutely symptomatic fractures, treatment with analgesics is required, including nonsteroidal antiinflammatory agents and/or acetaminophen, sometimes with the

addition of a narcotic agent. (A few small, randomized clinical

trials suggest that calcitonin may reduce pain related to acute

vertebral compression fracture). A technique that involves percutaneous injection of artificial cement (polymethylmethacrylate)

into the vertebral body (vertebroplasty or kyphoplasty) may offer

significant pain relief in some patients; however, controlled trials

of these procedures have provided some doubt of their efficacy in

the longer term. Furthermore, risks include acute extravasation of

cement outside of the vertebral body with neurologic impairment

and possibly an increased risk of vertebral fracture in adjacent

vertebrae due to increased rigidity of the treated vertebral body.

Short periods of bed rest may be helpful for pain management, but

in general, early mobilization is recommended as it helps prevent

further bone loss associated with immobilization. Occasionally,

use of a soft elastic-style brace may facilitate earlier mobilization.

Muscle spasms often occur with acute compression fractures and

can be treated with muscle relaxants and heat treatments. Severe

pain usually resolves within 6–10 weeks. More chronic severe pain

might suggest the possibility of multiple myeloma or other underlying conditions.

Vertebral fractures cause height loss because of the loss of

vertebral body height during compression of the vertebral body.

These fractures can produce kyphotic posture, particularly when

wedge shaped, or just loss of thoracic height. Chronic pain following vertebral fracture is probably not bony in origin; instead,