3200 PART 12 Endocrinology and Metabolism

it is related to abnormal strain on muscles, ligaments, and tendons

and to secondary facet-joint arthritis associated with alterations in

thoracic and/or abdominal shape. Chronic pain may also be the

result of ribs sitting right on top of the iliac crest bones, particularly

in patients who have had multiple vertebral compression fractures.

Chronic pain is difficult to treat effectively and may require analgesics, sometimes including narcotic analgesics with the attendant

risk of addiction. Frequent intermittent rest in a supine or semireclining position is often required to allow the soft tissues, which are

under tension, to relax. Back and core-strengthening exercises may

be beneficial. Heat treatments help relax muscles and reduce the

muscular component of discomfort. Various physical modalities,

such as ultrasound and transcutaneous nerve stimulation, may be

beneficial in some patients. Pain also occurs in the neck region, not

as a result of compression fractures (which almost never occur in

the cervical spine as a result of osteoporosis) but because of chronic

strain associated with trying to elevate the head in a person with a

significant thoracic kyphosis.

Multiple vertebral fractures often are associated with psychological symptoms; this is not always appreciated. The changes in body

configuration and back pain can lead to marked loss of self-image

and a secondary depression. Altered balance, precipitated by the

kyphosis and the anterior movement of the body’s center of gravity,

leads to a fear of falling, a consequent tendency to remain indoors,

and the onset of social isolation. These symptoms sometimes can be

alleviated by family support and/or psychotherapy. Medication may

be necessary when depressive features are present.

Multiple studies show that patients presenting with fractures

after age 50 years (even fractures traditionally linked to osteoporosis) are largely not screened or treated for osteoporosis. Estimates

suggest that <25% of fracture patients receive follow-up care.

Recently, several studies have demonstrated the effectiveness of a

relatively simple and inexpensive program that reduces the risk of

subsequent fractures. In the Kaiser system, it is estimated that a 20%

decline in hip fracture occurrence was seen with the introduction

of a fracture liaison service. This approach has also been successful

in other non-U.S. health systems. This involves a health care professional (usually a nurse or physician’s assistant) whose job is to educate patients and coordinate evaluation and osteoporosis treatment

as patients move through the emergency room, inpatient care in an

acute care hospital, rehabilitation hospital care, and/or orthopedic

practice to outpatient management. If the Kaiser experience can be

repeated, there would not only be significant savings of health care

dollars but also a dramatic drop in hip fracture incidence and a

marked improvement in morbidity and mortality among the aging

population.

MANAGEMENT OF THE UNDERLYING DISEASE

Risk Factor Reduction After risk assessment, 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 and taken at the lowest

required dose. 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 iatrogenic thyrotoxicosis

can be associated with increased bone loss. In patients who smoke,

efforts should be made to facilitate smoking cessation. Reducing

risk factors for falling also includes alcohol abuse treatment and

a review of the medical regimen for any drugs that might be associated with orthostatic hypotension and/or sedation, including

hypnotics and anxiolytics. If nocturia occurs, the frequency should

be reduced, if possible (e.g., by decreasing or modifying diuretic

use), as arising in the middle of sleep is a common precipitant of a

fall. Patients should be instructed about environmental safety with

regard to eliminating exposed wires, curtain strings, slippery rugs,

and mobile tables. Avoiding stocking feet on wood floors, checking

carpet condition (particularly on stairs), and providing good light

in paths to bathrooms and outside the home are important preventive measures. Treatment for impaired vision is recommended,

particularly a problem with depth perception, which is specifically

associated with increased falling risk. Elderly patients with neurologic impairment (e.g., stroke, Parkinson’s disease, Alzheimer’s

disease) are particularly at risk of falling and require specialized

supervision and care. In patients with risk factors for falls, especially

those who live alone or spend significant time alone, medical alert

systems should be prescribed.

Nutritional Recommendations • Calcium A large body of

data indicates that less than optimal calcium intake results in bone

loss. Consequently, an adequate intake suppresses bone turnover.

Recommended intakes from an Institute of Medicine report are

shown in Table 411-7. The NHANES have consistently documented that average calcium intakes fall considerably short of these

recommendations. The preferred source of calcium is diet, but

many patients require calcium supplementation to bring intake

to ~1000 mg/d. Best sources of calcium include dairy products

(milk, yogurt, and cheese), nondaily milks (almond, rice, soy), and

fortified foods such as certain cereals, waffles, snacks, juices, and

crackers. Some of these fortified foods contain as much calcium per

serving as milk. Various vegetables and fruits, such as kale, broccoli,

and dried figs, contain reasonably high calcium content, although

some of it may not be fully bioavailable. Calcium intake calculators

are available at NOF.org or NYSOPEP.org and will give a rough idea

of total calcium intake.

If calcium supplements are required, they should be taken in doses

sufficient to bring total intake to the required level (~1000 mg/d).

Doses of supplements should be ≤600 mg per single dose, as the

calcium absorption fraction decreases at higher doses. Calcium

supplements should be calculated on the basis of the elemental

calcium content of the supplement, not the weight of the calcium

salt (Table 411-8). Calcium supplements containing carbonate

are best taken with food since they require acid for solubility.

Calcium citrate supplements can be taken at any time. To confirm

TABLE 411-7 Adequate Calcium Intake

LIFE STAGE GROUP

ESTIMATED ADEQUATE DAILY

CALCIUM INTAKE, mg/d

Young children (1–3 years) 500

Older children (4–8 years) 800

Adolescents and young adults

(9–18 years)

1300

Men and women (19–50 years) 1000

Men and women (51 years and older) 1200

Note: Pregnancy and lactation needs are the same as for nonpregnant women (e.g.,

1300 mg/d for adolescents/young adults and 1000 mg/d for those ≥19 years old).

Source: Data from Institute of Medicine. Dietary Reference Intakes for Calcium,

Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: The National

Academies Press; 1997.

TABLE 411-8 Elemental Calcium Content of Various Oral Calcium

Preparations

CALCIUM PREPARATION ELEMENTAL CALCIUM CONTENT

Calcium citrate 60 mg/300 mg

Calcium lactate 80 mg/600 mg

Calcium gluconate 40 mg/500 mg

Calcium carbonate 400 mg/g

Calcium carbonate + 5 μg vitamin D2

(OsCal 250)

250 mg/tablet

Calcium carbonate (Tums 500) 500 mg/tablet

Source: Adapted with permission from SM Krane, MF Holick, in Harrison’s

Principles of Internal Medicine, 14th ed. New York, NY: McGraw Hill; 1998.

3201Osteoporosis CHAPTER 411

bioavailability, calcium supplements can be placed in distilled vinegar. They should dissolve within 30 min.

Several controlled clinical trials of calcium, mostly with accompanying vitamin D, have confirmed reductions in clinical fractures,

including fractures of the hip (~20–30% risk reduction), particularly in elderly individuals who are more likely to be dietarily

deficient. All recent studies of pharmacologic agents have been

conducted in the context of calcium replacement (± vitamin D).

Thus, it is standard practice to ensure an adequate calcium and

vitamin D intake in patients with osteoporosis whether they are

receiving additional pharmacologic therapy or not. A systematic

review confirmed a greater BMD response to antiresorptive therapy

when calcium intake was adequate.

Although side effects from supplemental calcium are minimal

(eructation and constipation mostly with carbonate salts), individuals with a history of kidney stones should have a 24-h urine

calcium determination before starting increased calcium to avoid

exacerbating hypercalciuria. A recent analysis of published data

has suggested that high intakes of calcium from supplements are

associated with an increase in the risk of renal stones, calcification

in arteries, and potentially an increased risk of heart disease and

stroke. This is an evolving story with data both confirming and

refuting the finding. Since high calcium intakes also increase the

risk of renal stones and confer no extra benefit to the skeleton, the

recommendation that total intakes should be between 1000 and

1500 mg/d seems reasonable.

Vitamin D Diet alone rarely contains sufficient vitamin D to

maintain target circulating levels (serum 25[OH]D consistently

>75 μmol/L [30 ng/mL]). Vitamin D is synthesized from a precursor in the skin under the influence of heat and ultraviolet light

(Chap. 409). Production is blocked by sunscreen and sun avoidance.

However, large segments of the population do not obtain sufficient

vitamin D from either skin production or dietary sources. Since

vitamin D supplementation at doses that would achieve these serum

levels is safe and inexpensive, the National Academy of Medicine

(formerly, Institute of Medicine [IOM]) 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 (based on obtaining a serum level

of 20 ng/mL, lower than the level recommended by most other

guidelines). 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. The IOM report suggests that it is safe to take up to

4000 IU/d. For those with osteoporosis or those at risk of osteoporosis, 1000–2000 IU/d can usually maintain serum 25(OH)D above

30 ng/mL. Vitamin D supplementation by itself does not appear

to reduce fracture risk, but the combination of adequate calcium

intake and vitamin D does decrease fracture risk. Low vitamin D

levels appear associated with more serious outcomes in response

to COVID-19. Whether this is a cause-and-effect relationship or a

chance occurrence is not known, but it certainly argues for ensuring

normal circulation levels of vitamin D.

Other Nutrients Other nutrients such as salt, high animal

protein intakes, and caffeine may have modest effects on calcium

excretion or absorption. Adequate vitamin K status is required for

optimal carboxylation of osteocalcin. States in which vitamin K

nutrition or metabolism is impaired, such as with long-term warfarin therapy, have been associated with reduced bone mass. Research

concerning cola-based soda beverage intake is controversial but

suggests a possible link to reduced bone mass through factors that

appear independent of caffeine.

Magnesium is abundant in foods, and magnesium deficiency is

quite rare in the absence of a serious chronic disease. Magnesium

supplementation may be warranted in patients with inflammatory

bowel disease, celiac disease, chemotherapy, severe diarrhea, malnutrition, or alcoholism. Dietary phytoestrogens, which are derived

primarily from soy products and legumes (e.g., garbanzo beans

[chickpeas] and lentils), exert some estrogenic activity but are insufficiently potent to justify their use in place of a pharmacologic agent

in the treatment of osteoporosis.

Patients with hip fractures are often frail and relatively malnourished. Some data suggest an improved outcome in such patients

when they are provided calorie and protein supplementation.

Excessive protein intake can increase renal calcium excretion, but

this can be corrected by an adequate calcium intake. Strontium as

a dietary mineral has also been implicated with strontium ranelate approved in some countries for treatment of osteoporosis. No

evidence suggests that strontium in doses used in supplements can

reduce fracture risk, but by virtue of replacing calcium in bone with

the larger strontium atom, this supplement can produce an increase

in bone density of questionable significance.

Exercise Exercise in young individuals increases the likelihood

that they will attain the maximal genetically determined peak

bone mass. Meta-analyses of studies performed in postmenopausal

women indicate that weight-bearing exercise helps prevent bone

loss but does not appear to result in substantial gain of bone mass.

This beneficial effect wanes if exercise is discontinued. Most of the

studies are short term, and a more substantial effect on bone mass

is likely if exercise is continued over a long period. Exercise also has

beneficial effects on neuromuscular function, and it improves coordination, balance, and strength, thereby reducing the risk of falling.

A walking program is a practical way to start. Other activities such

as dancing, racquet sports, cross-country skiing, and use of gym

equipment, are also recommended, depending on the patient’s personal preference and general condition. Even women who cannot

walk benefit from swimming or water exercises, not so much for the

effects on bone, which are quite minimal, but because of effects on

muscle. Exercise habits should be consistent, optimally at least three

times a week. For most patients, we suggest participation in exercise

regimens that the patient enjoys in order to improve adherence. We

also emphasize the importance of making exercise a social activity,

again to improve adherence. Many individuals experience a fear of

falling that can lead to social isolation and depression. Group exercises can help to alleviate this problem by providing sense of social

connectivity among participants.

Tai chi is a traditional Chinese martial art that utilizes a series

of gentle, flowing movements to promote and maintain flexibility, balance, endurance, proprioception, and strength. It involves

constant movement through all three spatial dimensions. As a

three-dimensional exercise, tai chi may be incorporated as part of

balance training program for individuals with osteoporosis. Tai chi

is generally considered a safe activity. The evidence for fall prevention in tai chi has been evaluated in randomized controlled trials.

Results have been controversial; however, recent systematic reviews

have provided a growing body of evidence to indicate that participating in tai chi can significantly reduce the risk of falls in older

adults. The benefit appears to be greater when tai chi is practiced

with increased frequency.

It is recommended that individuals with osteoporosis or osteoporotic vertebral fractures participate in exercise programs that

involve both resistance and balance training. Slow, controlled

movements are recommended in order to avoid injuries. Exercise

modifications and avoidance of certain postures (such as spinal

flexion) may be advised for those with prior injuries and back

or joint pain. Caution should be taken to avoid activities that

can lead to potential fractures, such as performing activities on

slippery surfaces or twisting or bending the spine quickly while

transitioning between different positions. Precautions should be

taken to avoid injury when exercising with loads and performing

exercises that challenge balance. For individuals with osteoporosis

who have a high risk for fracture, vertebral fractures, sedentary

lifestyle, or comorbid conditions that impact exercise tolerance,

consultation with physical therapists to learn safe exercise practices is recommended.

3202 PART 12 Endocrinology and Metabolism

PHARMACOLOGIC TREATMENT OF OSTEOPOROSIS

Several guidelines for the treatment of osteoporosis have been published over the past few years. Patients presenting with fractures

of the hip and spine should be evaluated for treatment. Patients

presenting with low-trauma fractures in the setting of a BMD in

the low bone mass or osteoporosis range should be treated with

pharmacologic agents. Most guidelines also suggest that patients

be considered for treatment when BMD T-score is ≤–2.5, a level

consistent with the diagnosis of osteoporosis. Treatment should also

be considered in postmenopausal women with fracture or multiple

risk factors even if BMD is not in the osteoporosis range. Treatment

thresholds depend on cost-effectiveness analyses but, in the United

States, are a >20% 10-year major fracture probability and >3%

10-year hip fracture probability. It must be emphasized, however,

that as with other diseases, risk assessment is an inexact science

when applied to individual patients. Fractures are chance occurrences that can happen to anyone and do! Patients often accept risks

that are higher than the physician might like out of concern for the

(usually considerably lower) risks of adverse events of drugs.

Pharmacologic therapies for osteoporosis are either antiresorptive or anabolic. The antiresorptive agents include medications that

have broad effects such as hormone/estrogen therapy and selective

estrogen receptor modulators (SERMS) as well as those agents that

are specific for the treatment of osteoporosis (bisphosphonates,

denosumab, and calcitonin). The anabolic agents are teriparatide,

abaloparatide, and romosozumab. Denosumab, considered as an

antiresorptive, allows bone formation to continue, and thus, there is

an increase in bone density beyond that occurring with agents that

inhibit resorption directly leading to a reduction in bone formation.

Antiresorptive Agents • 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, transdermally, or by subcutaneous implant.

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.

For oral estrogens, the standard recommended doses have been

0.3 mg/d for esterified estrogens, 0.625 mg/d for conjugated equine

estrogens, and 5 μg/d for ethinyl estradiol. For transdermal estrogen, the commonly used dose supplies 50 μg of estradiol per day,

but a lower dose may be appropriate for some individuals. Doseresponse data for conjugated equine estrogens indicate that lower

doses (0.3 and 0.45 mg/d) are effective. Doses even lower have also

been shown to slow bone loss.

Fracture Data Epidemiologic databases indicate that women

who take estrogen replacement have a 50% reduction, on average,

of osteoporosis-related fractures, including hip fractures. The beneficial effect of estrogen is greatest among those who start replacement early and continue the treatment; the benefit declines after

discontinuation to the extent that there is no residual protective

effect against fracture by 10 years after discontinuation. The first

clinical trial evaluating fractures as secondary outcomes, the Heart

and Estrogen-Progestin Replacement Study (HERS) trial, showed

no effect of hormone therapy on hip or other clinical fractures in

women with established coronary artery disease. These data made

the results of the Women’s Health Initiative (WHI) exceedingly

important (Chap. 395). The estrogen-progestin arm of the WHI in

>16,000 postmenopausal healthy women indicated that hormone

therapy reduces the risk of hip and clinical spine fracture by 34%

and that of all clinical fractures by 24%.

A few smaller clinical trials have evaluated spine fracture occurrence as an outcome with estrogen therapy. They have consistently

shown that estrogen treatment reduces the incidence of vertebral

compression fracture.

The WHI has provided a vast amount of data on the multisystemic effects of hormone therapy. Although earlier observational

studies suggested that estrogen replacement might reduce heart disease, the WHI showed that combined estrogen-progestin treatment

increased risk of fatal and nonfatal myocardial infarction by ~29%,

confirming data from the HERS study. Other important relative

risks included a 40% increase in stroke, a 100% increase in venous

thromboembolic disease, and a 26% increase in risk of breast cancer. Subsequent analyses have confirmed the increased risk of stroke

and, in a substudy, showed a twofold increase in dementia. Benefits

other than the fracture reductions noted above included a 37%

reduction in the risk of colon cancer. These relative risks have to be

interpreted in light of absolute risk (Fig. 411-8). For example, out of

10,000 women treated with estrogen-progestin for 1 year, there will

be 8 excess heart attacks, 8 excess breast cancers, 18 excess venous

thromboembolic events, 5 fewer hip fractures, 44 fewer clinical

fractures, and 6 fewer colorectal cancers. These numbers must be

multiplied by the number of years of hormone treatment. There

was no effect of combined hormone treatment on the risk of uterine

cancer or total mortality.

It is important to note that these WHI findings apply specifically

to hormone treatment in the form of conjugated equine estrogen

plus medroxyprogesterone acetate. The relative benefits and risks

of unopposed estrogen in women who had hysterectomies vary

somewhat. They still show benefits against fracture occurrence

and increased risk of venous thrombosis and stroke, similar in

magnitude to the risks for combined hormone therapy. In contrast,

though, the estrogen-only arm of WHI indicated no increased

risk of heart attack or breast cancer. The data suggest that at least

some of the detrimental effects of combined therapy are related to

the progestin component. In addition, there is the possibility, suggested by primate data, that the risk accrues mainly to women who

have some years of estrogen deficiency before initiating treatment.

Nonetheless, there is marked reluctance among women for estrogen

therapy/hormone therapy, and the U.S. Preventive Services Task

Force has specifically suggested that estrogen therapy/hormone

therapy not be used for disease prevention.

Mode of Action Two subtypes of ERs, α and β, have been

identified in bone and other tissues. Cells of monocyte lineage

express both ERα and ERβ, as do osteoblasts. Estrogen-mediated

effects vary with the receptor type. Using ER knockout mouse

models, elimination of ERα produces a modest reduction in bone

mass, whereas mutation of ERβ has less of an effect on bone. A

male patient with a homozygous mutation of ERα had markedly

decreased bone density as well as abnormalities in epiphyseal

closure, confirming the important role of ERα in bone biology.

60

50

40

30

20

10

0

Number of cases

in 10,000 women/year

Risks

7 8 8

6 5

18

CHD Stroke Breast Deaths

cancer

VTE Hip

fracture

Endometrial

cancer

Colorectal

cancer

Benefits

Reduced

events

Additional events

Neutral

FIGURE 411-8 Effects of hormone therapy on event rates: green, placebo;

purple, estrogen and progestin. CHD, coronary heart disease; VTE, venous

thromboembolic events. (Adapted with permission from Women’s Health Initiative.

WHI HRT Update.)

3203Osteoporosis CHAPTER 411

The mechanism of estrogen action in bone is an area of active

investigation (Fig. 411-5). Although data are conflicting, estrogens

may inhibit osteoclasts directly. However, the majority of estrogen

(and androgen) effects on bone resorption are mediated indirectly

through paracrine factors produced by osteoblasts. These actions

include (1) increasing osteoprotegerin production by osteoblasts,

(2) increasing IGF-I and TGF-β, and (3) suppressing IL-1 (α and

β), IL-6, TNF-α, and osteocalcin synthesis. The indirect estrogen

actions primarily decrease bone resorption.

Progestins In women with a uterus, daily progestin or cyclical

progestins at least 12 days per month are prescribed in combination

with estrogens to reduce the risk of uterine cancer. Medroxyprogesterone acetate and norethindrone acetate blunt the high-density

lipoprotein response to estrogen, but micronized progesterone does

not. Neither medroxyprogesterone acetate nor micronized progesterone appears to have an independent effect on bone; at lower

doses of estrogen, norethindrone acetate may have an additive benefit. In breast tissue, progestins may account for the increased risk

of breast cancer with combination treatment.

SERMs Two SERMs are used currently in postmenopausal

women: raloxifene, which is approved by the FDA for the prevention and treatment of osteoporosis as well as the prevention of

breast cancer, and tamoxifen, which is approved for the prevention

and treatment of breast cancer. A third SERM, bazedoxifene, is

marketed in combination with conjugated estrogen for treatment of

menopausal symptoms and prevention of bone loss. Bazedoxifene

protects the uterus and breast from effects of estrogen and makes

the use of progestin unnecessary.

Tamoxifen reduces bone turnover and bone loss in postmenopausal women compared with placebo groups. These findings

support the concept that tamoxifen acts as an estrogenic agent in

bone. There are limited data on the effect of tamoxifen on fracture

risk, but the Breast Cancer Prevention study indicated a possible

reduction in clinical vertebral, hip, and Colles’ fractures. Tamoxifen

is not FDA approved for prevention or treatment of osteoporosis.

The major benefit of tamoxifen is on breast cancer occurrence and

recurrence in women with ER-positive tumors. The breast cancer prevention trial indicated that tamoxifen administration over

4–5 years reduced the incidence of new invasive and noninvasive

breast cancer by ~45% in women at increased risk of breast cancer.

The incidence of ER-positive breast cancers was reduced by 65%.

Tamoxifen increases the risk of uterine cancer in postmenopausal

women, limiting its use for breast cancer prevention in women at

low or moderate risk.

Raloxifene (60 mg/d) has effects on bone turnover and bone mass

that are very similar to those of tamoxifen, indicating that this agent

is also estrogenic on the skeleton. The effect of raloxifene on bone

density (+1.4–2.8% vs placebo in the spine, hip, and total body)

is somewhat less than that seen with standard doses of estrogens.

Raloxifene reduces the occurrence of vertebral fracture by 30–50%,

depending on the population; however, there are no data confirming that raloxifene can reduce the risk of nonvertebral fractures

after 8 years of observation.

Raloxifene, like tamoxifen and estrogen, has effects in other

organ systems. The most beneficial effect appears to be a reduction

in invasive breast cancer (mainly decreased ER-positive) occurrence of ~65% in women who take raloxifene compared to placebo.

In a head-to-head study, raloxifene was as effective as tamoxifen

in preventing breast cancer in high-risk women, and raloxifene is

FDA approved for this indication. In a further study, raloxifene had

no effect on heart disease in women with increased risk for this

outcome. In contrast to tamoxifen, raloxifene is not associated with

an increase in the risk of uterine cancer or benign uterine disease.

Raloxifene increases the occurrence of hot flashes but reduces

serum total and low-density lipoprotein cholesterol, lipoprotein(a),

and fibrinogen. Raloxifene, with its positive effects on breast cancer

and vertebral fractures, has become a useful agent for the treatment

of the younger asymptomatic postmenopausal woman. In some

women, a recurrence of menopausal symptoms may occur. Usually

this is evanescent but occasionally is sufficiently impactful on daily

life and sleep that the drug must be withdrawn. Raloxifene increases

the risk of deep-vein thrombosis and may increase the risk of death

from stroke among older women. Consequently, it is not usually

recommended for women over age 70 years.

MODE OF ACTION OF SERMS

All SERMs bind to the ER, but each agent produces a unique

receptor-drug conformation. As a result, specific coactivator or corepressor proteins are bound to the receptor (Chap. 377), resulting

in differential effects on gene transcription that vary depending

on other transcription factors present in the cell. Another aspect

of selectivity is the affinity of each SERM for the different ERα

and ERβ subtypes, which are expressed differentially in various

tissues. These tissue-selective effects of SERMs offer the possibility

of tailoring estrogen therapy to best meet the needs and risk factor

profile of an individual patient.

Bisphosphonates Bisphosphonates have become the mainstay

of osteoporosis treatment, in part related to cost as they become

generic. Alendronate, risedronate, ibandronate, and zoledronic acid

are approved for the prevention and treatment of postmenopausal

osteoporosis. Alendronate, risedronate, and zoledronic acid are

also approved for the treatment of steroid-induced osteoporosis,

and risedronate and zoledronic acid are approved for prevention of

steroid-induced osteoporosis. Alendronate, risedronate, and zoledronic acid are also approved for treatment of osteoporosis in men.

Alendronate decreases bone turnover and increases bone mass in

the spine by up to 8% versus placebo and by 6% versus placebo in

the hip. Multiple trials have evaluated its effect on fracture occurrence. The Fracture Intervention Trial provided evidence in >2000

women with prevalent vertebral fractures that daily alendronate

treatment (5 mg/d for 2 years and 10 mg/d for 9 months afterward)

reduces vertebral fracture risk by ~50%, multiple vertebral fractures

by up to 90%, and hip fractures by up to 50%. Several subsequent

trials have confirmed these findings (Fig. 411-9). For example, in a

study of >1900 women with low bone mass treated with alendronate

(10 mg/d) versus placebo, the incidence of all nonvertebral fractures

was reduced by ~47% after only 1 year. In the United States, the

70-mg weekly dose is approved for treatment of osteoporosis and

the dose of 35 mg per week is approved for prevention, with those

doses showing equivalence to daily dosing based on bone turnover

and bone mass response.

Consequently, once-weekly therapy generally is preferred

because of lower incidence of gastrointestinal side effects and ease

of administration. Alendronate should be taken with a full glass of

water before breakfast after an overnight fast, as bisphosphonates

are poorly absorbed. Because of the potential for esophageal irritation, alendronate is contraindicated in patients who have stricture

or inadequate emptying of the esophagus. It is recommended that

patients remain upright (standing or sitting) for at least 30 minutes

after taking the medication to avoid esophageal irritation and that

food and fluids (other than water) be avoided for the same duration.

In clinical trials, overall gastrointestinal symptomatology was no

different with alendronate than with placebo, but in practice, all oral

bisphosphonates have been associated with esophageal irritation

and inflammation.

Risedronate also reduces bone turnover and increases bone mass.

Controlled clinical trials have demonstrated 40–50% reduction in

vertebral fracture risk over 3 years, accompanied by a 40% reduction in clinical nonspine fractures. The only clinical trial specifically

designed to evaluate hip fracture outcome (HIP) indicated that

risedronate reduced hip fracture risk in women in their seventies

with confirmed osteoporosis by 40%. In contrast, risedronate was

not effective at reducing hip fracture occurrence in older women

(80+ years) without proven osteoporosis. Studies have shown that

35 mg of risedronate administered once weekly is therapeutically

equivalent to 5 mg/d. The instructions for oral administration

3204 PART 12 Endocrinology and Metabolism

FIGURE 411-9 Effects of various bisphosphonates on fracturs. A. Clinical vertebral fractures. B. Nonvertebral fractures. C. Hip fractures. Plb, placebo; RRR, relative risk

reduction. (Data from DM Black et al: J Clin Endocrinol Metab 85:4118, 2000; C Roux et al: Curr Med Res Opin 4:433, 2004; CH Chesnut et al: J Bone Miner Res 19: 1241, 2004;

DM Black et al: N Engl J Med 356:1809, 2007; JT Harrington et al: Calcif Tissue Int 74:129, 2003.)

Vertebral fractures

* *

PLB

RIS

Risedronate

pooled, post hoc

* *

* *

0

1

2

3

4

0

1

2

3

4

Percent of patients

PLB

ALN

Alendronate

pooled, post hoc

0

2

4

6

0

1

2

3

PLB

IBAN

49↓*

Ibandronate

preplanned

PLB

ZOL

Zoledronate

preplanned

?

0 0 12 24 36 6 12 0 12 24 36 0 12 24 36

Months Months Months Months

69%↓*

77%↓*

45%↓*

A

*

*

Alendronate pooled, post hoc

0 12 24 36

0

5

10

15

Percent of patients

PLB

ALN

27%↓*

Months

Nonvertebral fractures

Risedronate pooled, post hoc

* * * *

* * * * * *

PLB

RIS

0

0 12 24 36

5

10

15

59%↓*

Months

Zoledronate preplanned

0

0 12 24 36

5

10

15

PLB

ZOL

25%↓*

?

B Months

1

2

3

0

Placebo (n = 3861)

Zolendronate (n = 3875)

0 3 6 9 12 15 18 21 24 27 30 33 36

Hip fractures

RRR

41%

Cumulative incidence of hip fractures over 3 years

Cumulative incidence (%)

C Time to first hip fracture (months)

3205Osteoporosis CHAPTER 411

noted for alendronate apply to all three oral bisphosphonates. There

is also a preparation of risedronate (35 mg) that can be taken after

breakfast. Risedronate is the only bisphosphonate that has this

dosing flexibility.

Ibandronate is the third amino-bisphosphonate approved in the

United States. Ibandronate (2.5 mg/d) has been shown in clinical

trials to reduce vertebral fracture risk by ~40% but with no overall

effect on nonvertebral fractures. In a post hoc analysis of subjects

with a femoral neck T-score of ≤–3, ibandronate reduced the risk of

nonvertebral fractures by ~60%. In clinical trials, ibandronate doses

of 150 mg/month PO or 3 mg every 3 months IV had greater effects

on turnover and bone mass than did 2.5 mg/d. Patients should take

oral ibandronate in the same way as other bisphosphonates, but with

1 h elapsing before other food or drink (other than plain water).

Zoledronic acid is a potent bisphosphonate with a unique administration regimen (5 mg by 30-min IV infusion at most annually).

Zoledronic acid data confirm that it is highly effective in fracture

risk reduction. In a study of >7000 women followed for 3 years,

zoledronic acid 5 mg IV annually) reduced the risk of vertebral

fractures by 70%, nonvertebral fractures by 25%, and hip fractures by 40%. These results were associated with less height loss

and disability. In the treated population, there was an increased

risk of almost 25% of an acute phase reaction in patients with no

prior bisphosphonate exposure (fever, myalgias, headache, malaise), but effects were short-lived (2–3 days). Detailed evaluation

of all bisphosphonates failed to confirm a risk of atrial fibrillation.

Zoledronic acid has also been studied in a placebo-controlled trial

of women and men within 3 months of an acute hip fracture. The

risk of recurrent fracture was reduced by 35%, and there was a 28%

reduction in mortality that was greater than might be expected by

the reduction in hip fracture alone.

Common Bisphosphonate Adverse Events All bisphosphonates have been associated with some musculoskeletal and joint

pains of unclear etiology, which are occasionally severe. There is

potential for renal toxicity, and bisphosphonates are contraindicated in those with an estimated glomerular filtration rate <30–35

mL/min. Hypocalcemia can occur.

There has been concern about two potential side effects associated with bisphosphonate use. The first is osteonecrosis of the jaw

(ONJ). ONJ usually follows a dental procedure in which bone is

exposed (dental extractions and implants). It is presumed that the

exposed bone becomes infected and dies. ONJ is more common

among cancer patients receiving high doses of bisphosphonates

for skeletal metastases. It is rare among persons with osteoporosis

on usual doses of bisphosphonates. Oral antibiotic rinses and oral

systemic antibiotics may be useful to prevent this rare adverse event

if risk is perceived to be particularly high. The second is called

atypical femoral fracture. These are unusual fractures that occur

in the subtrochanteric femoral region or across the femoral shaft

distal to the lesser trochanter. They are often preceded by pain in

the lateral thigh or groin that can be present for weeks, months,

or even years before the fracture. The fractures occur on trivial

trauma, are horizontal with a medial beak, and are noncomminuted. A committee put together by the American Society for Bone

and Mineral Research described the major and minor criteria for

these fractures, which appear to be related to duration of bisphosphonate therapy. The overall risk appears quite low, especially when

compared to the number of hip fractures saved by these therapies,

but they often require surgical fixation and are difficult to heal.

Some evidence suggests that if the fractures are found early, when

there is evidence of periosteal stress reaction or stress fracture,

prior to the occurrence of overt fracture, that teriparatide can help

heal the fracture and preclude the need for surgical repair. We

routinely inform patients initiating bisphosphonates that if they

develop thigh or groin pain they should inform us. Routine x-rays

will sometimes detect cortical thickening or even a stress fracture,

but more commonly, MRI or technetium bone scan is required.

The presence of an abnormality requires, at minimum, a period of

modified weight bearing and may need prophylactic rodding of the

femur. It is important to realize that these may be bilateral (~50%

of the time), and when an abnormality is found, the other femur

should be checked. It is unknown whether patients who have these

atypical femur fractures can ever receive antiresorptive therapies

again in the future, but it seems prudent to avoid their use for the

majority of these individuals.

Mode of Action 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 in

the thyroid gland (Chap. 410). 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.

Injectable calcitonin produces small increments in bone mass

of the lumbar spine. However, difficulty of administration and

frequent reactions, including nausea and facial flushing, make

general use limited. A nasal spray containing calcitonin (200

IU/d) is available for treatment of osteoporosis in postmenopausal

women. One study suggests that nasal calcitonin produces small

increments in bone mass and a small reduction in new vertebral

fractures in calcitonin-treated patients (at one dose) versus those

on calcium alone. There has been no proven effectiveness against

nonvertebral fractures. Calcitonin is not indicated for prevention

of osteoporosis and is not sufficiently potent to prevent bone loss

in early postmenopausal women. Calcitonin might have an analgesic effect on bone pain, both in the subcutaneous and possibly

in the nasal form. Concerns have been raised about an increase

in the incidence of cancer associated with calcitonin use. Initially,

the cancer noted was of the prostate, but an analysis of all data

suggested a more general increase in cancer risk. In Europe, the

European Medicines Agency has removed the osteoporosis indication, and an FDA Advisory Committee has voted for a similar

change in the United States.

Mode of Action 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.

Denosumab Denosumab is a novel agent that, given twice

yearly by subcutaneous administration in a randomized controlled

trial in postmenopausal women with osteoporosis, has been

shown to increase BMD in the spine, hip, and forearm and reduce

vertebral, hip, and nonvertebral fractures over a 3-year period by

70, 40, and 20%, respectively (Fig. 411-10). Other clinical trials

indicate ability to increase bone mass in postmenopausal women

with low bone mass (above osteoporosis range) and in postmenopausal women with breast cancer treated with aromatase inhibitor

therapies. In the oncology literature, denosumab reduces the risk

of fractures in women on aromatase inhibitors. In a study of men

with prostate cancer treated with androgen deprivation therapy,

denosumab increased bone mass and reduced vertebral fracture

occurrence. An analysis of five placebo-controlled studies has

suggested reduced risk of falls in patients with osteoporosis treated

with denosumab.

Denosumab was approved by the FDA in 2010 for the treatment

of postmenopausal women who have a high risk for osteoporotic

fractures, including those with a history of fracture or multiple risk

3206 PART 12 Endocrinology and Metabolism

0–36 0–12 >12–24 >12–36

8

7

6

5

4

3

2

1

0

Crude incidence (%)

RR, 0.32

p <0.001

RR, 0.39

p <0.001

RR, 0.22

p <0.001

RR, 0.35

p <0.001

Placebo

Placebo

Placebo

Denosumab

Denosumab

Denosumab

A New vertebral fracture

B Time to first nonvertebral fracture

C Time to first hip fracture

Month

9

8

7

6

5

4

3

2

1

0

Cumulative incidence (%)

Cumulative incidence (%)

0 6 12 18

Month

24 30 36

0 6 12 18

Month

24 30 36

No. at risk

Placebo

Denosumab

3906

3902

3750

3759

3578

3594

3410

3453

3264

3337

3121

3228

3009

3130

No. at risk

Placebo

Denosumab

3906

3902

3799

3796

3672

3676

3538

3566

3430

3477

3311

3397

3221

3311

1.4

1.2

1.0

0.8

0.6

0.4

0.2

0.0

FIGURE 411-10 Effects of denosumab on the following: A. new vertebral fractures;

and B. and C. times to nonvertebral and hip fracture. RR, relative risk. (Reproduced

with permission from SR Cummings et al: Denosumab for prevention of fractures in

postmenopausal women with osteoporosis. N Engl J Med 361:756, 2009.)

factors for fracture, and those who have failed or are intolerant to

other osteoporosis therapy. Denosumab is also approved for the

treatment of osteoporosis in men at high risk for fracture, women

with breast cancer on aromatase inhibitors, and men with prostate

cancer on androgen deprivation treatment. A long-term observational extension of the pivotal trial in postmenopausal women has

provided evidence that BMD continues to increase in both the spine

and hip with 3–10 years of denosumab treatment, with fracture

rates that are at least as low as those seen with denosumab during

the active placebo-controlled portion of the trial.

Denosumab may increase the risk of ONJ and atypical femur

fractures similarly to bisphosphonates. Estimated incidence is

5/10,000 patient-years for ONJ and 1/10,000 patient-years for

atypical femur fractures. Denosumab can cause hypersensitivity

reactions, hypocalcemia, and skin reactions including dermatitis,

rash, and eczema. Early concerns about an imbalance in infections

with denosumab have largely been allayed.

When denosumab is discontinued, there is a rebound increase

in bone turnover and an apparent acceleration of bone loss. This

likely reflects the maturation of osteoclast precursors that have

accumulated in marrow when the drug was administered and

can become mature bone resorbing cells once the drug is withdrawn. The consequences of this rebound increase in remodelingassociated bone loss are a rapid increase in the risk of fracture, particularly vertebral fracture, and a specific increase in the occurrence

of multiple vertebral fractures. In patients who need to stop denosumab or in patients in whom BMD and fracture risk reduction

goals have been met, temporary use of bisphosphonate treatment

may prevent the rebound increase in remodeling and rapid bone

loss. In clinical practice, a single infusion of zoledronic acid seems

to maintain BMD for 1–2 years but may need to be repeated. Oral

bisphosphonates can also be prescribed. In both cases, the required

duration of bisphosphonate use to eliminate the rebound effect is

not clear and may vary considerably among patients.

Mode of Action Denosumab is a fully human monoclonal antibody to RANKL, the final common effector of osteoclast formation,

activity, and survival. Denosumab binds to RANKL, inhibiting its

ability to initiate formation of mature osteoclasts from osteoclast

precursors and to bring mature osteoclasts to the bone surface and

initiate bone resorption. Denosumab also plays a role in reducing

the survival of the osteoclast. Through these actions on the osteoclast, denosumab induces potent antiresorptive action, as assessed

biochemically and histomorphometrically.

Anabolic Agents • Parathyroid Hormone Endogenous

PTH is an 84-amino-acid peptide that is largely responsible for

calcium homeostasis (Chap. 410). 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 endogenous hyperparathyroidism is associated

with maintenance of trabecular bone mass but loss of cortical bone.

On the basis of these findings, early small-scale observational studies showed that PTH analogues could augment trabecular BMD.

Subsequent controlled clinical trials have confirmed that PTH

can increase bone mass and reduce fracture occurrence. The first

randomized controlled trial in postmenopausal women showed

that PTH (1–34) (teriparatide), when superimposed on ongoing

estrogen therapy, produced substantial increments in bone mass

(13% over a 3-year period compared with estrogen alone) and

reduced the risk of vertebral compression deformity. In the pivotal

study (median, 19 months’ duration), 20 μg PTH (1–34) daily

by subcutaneous injection (with no additional therapy) reduced

vertebral fractures by 65% and nonvertebral fractures by 40–50%

(Fig. 411-11). Teriparatide produces rapid and robust increases

in bone formation and then bone remodeling overall, resulting in

substantial increases in bone mass and improvements in microarchitecture, including cancellous connectivity and cortical width.

The BMD effects, particularly in the hip, are lower when patients

switch from bisphosphonates to teriparatide, possibly in proportion

to the potency of the antiresorptive agent. The hip BMD effect is

particularly impaired when patients switch from denosumab to

teriparatide. In patients on denosumab who need teriparatide treatment, there may be a role for combination therapy. In previously

untreated women, teriparatide is administered as monotherapy

and followed by a potent antiresorptive agent such as denosumab

or a bisphosphonate. Combination therapy is generally avoided

3207Osteoporosis CHAPTER 411

FIGURE 411-12 Effect of parathyroid hormone (PTH) treatment on bone

microarchitecture. Paired biopsy specimens from a 64-year-old woman before (A)

and after (B) treatment with PTH. (Reproduced with permission from DW Dempster

et al: Effects of daily treatment with parathyroid hormone on bone microarchitecture

and turnover in patients with osteoporosis: A paired biopsy study. J Bone Miner Res

16:1846, 2001.)

FIGURE 411-11 Effects of teriparatide (TPT) on the following: A. new vertebral

fractures; and B. and C. nonvertebral fragility fractures. (A and B are data from

RM Neer et al: Effect of parathyroid hormone (1–34) on fractures and bone mineral

density in postmenopausal women with osteoporosis. N Engl J Med May 344:1434,

2001. C reproduced with permission from RM Neer et al: Effect of parathyroid

hormone (1–34) on fractures and bone mineral density in postmenopausal women

with osteoporosis. N Engl J Med May 344:1434, 2001.)

Relative:

65%

Absolute:

9.3%

Effect of teriparatide on the risk of new

vertebral fractures

Relative:

69%

Absolute:

9.9%

Risk reduction

Number of women with 1 or

more new vertebral fractures 50

70

60

10

12

14

15

Placebo

(n = 448)

TPTD20

(n = 444)

TPTD40

(n = 434)

64

40

8

0

2

4

6 30

20

10

0

% of women

22 19

A

Effect of teriparatide on the risk of nonvertebral

fragility fractures

Relative:

53%

Absolute:

2.9%

Relative:

54%

Absolute:

3.0%

Risk reduction

Number of women with

nonvertebral fragility fractures 25

35

30

4

5

6

Placebo

(n = 544)

TPTD20

(n = 541)

TPTD40

(n = 552)

20

2

0

1

3

15

0

10

5

30 14 14

% of women

B

*p <0.05 vs. placebo

4

5

6

7

8

Placebo

Effect of teriparatide on the risk of nonvertebral

fragility fractures (time to first fracture)

Months since randomization

0

0246 8 10 12 14 16 18 20

1

2

3 TPTD20

TPTD40

*

% of women**

*

C

because of cost and potential inhibition of the anabolic activity of

teriparatide.

In women with painful acute osteoporotic vertebral fractures,

teriparatide reduced subsequent vertebral fractures by ~50% compared with risedronate. There was no difference in nonvertebral

fracture outcome between the two medications. A study comparing

teriparatide with risedronate in patients with prevalent vertebral

fractures showed significant benefit for teriparatide against vertebral fractures and nearly significant benefit for teriparatide against

nonvertebral fractures.

Side effects of teriparatide are generally mild and can include

muscle pain, weakness, dizziness, headache, and nausea. Rodents

given prolonged treatment with PTH in high doses (3–60 times

the human dose) developed osteogenic sarcomas after ~18 months

of treatment. Rare cases of osteosarcoma have been described in

patients treated with teriparatide consistent with the background

incidence of osteosarcoma in adults. Long-term surveillance studies

of a high proportion of patients diagnosed with osteosarcoma as

adults in both the United States and Scandinavia reveal no prior

exposure to teriparatide in any of the cases.

Teriparatide use may be limited by cost and its mode of administration (daily subcutaneous injection). Alternative modes of delivery

have been investigated, but none have proven successful. Because of

the rodent osteosarcoma data and the maximum duration of teriparatide in the pivotal trial of 2 years, the FDA has limited teriparatide treatment to 2 years, with that becoming the lifetime maximal

use. As a result, consideration is often given to restricting initial

use to 1 year (using bone density response at 1 year as a guide) and

saving the second year for future use if necessary.

Mode of Action Exogenously administered PTH appears to

have direct actions on osteoblast activity, with biochemical and

histomorphometric evidence of de novo bone formation within

a week or two in response to teriparatide. There is subsequently

resorption. Subsequently, teriparatide activates bone remodeling

but still appears to favor bone formation over bone resorption.

Teriparatide given by daily injection stimulates osteoblast recruitment and activity through activation of Wnt signaling. Teriparatide

produces a true increase in bone tissue and an apparent restoration

of bone microarchitecture (Fig. 411-12).

Abaloparatide Abaloparatide is a synthetic analogue of human

PTHrP, which has significant homology to PTH and also binds the

PTH type 1 receptor. Abaloparatide and teriparatide exert different

binding affinities to the two different receptor conformations, R0

and RG. Compared to teriparatide, abaloparatide binds with similar

high affinity to the RG conformation but with much lesser affinity

to the R0

 conformation. These differences appear to result in a similar bone formation stimulus but lesser bone resorption stimulus,

and abaloparatide was specifically chosen for development among

a large number of PTH and PTHrP analogues for what appeared to

be an optimized anabolic profile.

In the phase 3 Abaloparatide Comparator Trial in Vertebral

Endpoints (ACTIVE) study, 2463 postmenopausal women with

osteoporosis were randomized to blinded daily subcutaneous abaloparatide versus placebo or open-label teriparatide. At 18 months,

spine BMD increase was similar with abaloparatide and teriparatide

(11.2% abaloparatide and 10.5% teriparatide); in the total hip, BMD

3208 PART 12 Endocrinology and Metabolism

increments were slightly larger with abaloparatide (4.2 vs 3.3%).

New vertebral fracture incidence was reduced by 86% with abaloparatide and 80% with teriparatide compared with placebo (both

p <.001). The hazard ratio for abaloparatide versus teriparatide was

not quoted. Nonvertebral fractures were reduced by 43% with abaloparatide (p = .05) and by 28% with teriparatide (not significant;

p = .22). The ACTIVE study was extended, with 92% of eligible

participants from the abaloparatide and placebo arms transitioned

to open-label alendronate for a total treatment period of 24 months

of alendronate. Both vertebral and nonvertebral fractures were less

common in the group who transitioned from abaloparatide to alendronate, suggesting that the fracture benefit of abaloparatide can be

maintained with antiresorptive treatment.

Romosozumab Romosozumab is a humanized antibody that

blocks the osteocyte production of sclerostin, resulting in an

increase in bone formation and decline in bone resorption. In

the pivotal trial (FRAME), 7180 postmenopausal women with

osteoporosis were randomized to receive blinded monthly subcutaneous romosozumab (210 mg) or placebo for 1 year followed by

transition to open-label subcutaneous denosumab (60 mg) every

6 months for an additional year. BMD increased over 13% in the

spine and almost 7% in the hip in 1 year with romosozumab. At

1 year, the incidence of new vertebral fractures in the romosozumab

group was significantly reduced by 73% compared with placebo.

Clinical fracture risk (nonvertebral fractures and clinical vertebral

fractures combined) was significantly reduced by 36%. Nonvertebral fractures were also reduced, but the difference just missed

statistical significance perhaps due to geographical differences; in

the high-enrolling Latin American region, there was no significant reduction in nonvertebral fractures, probably due to a very

low background incidence in that region. In the rest of the world,

nonvertebral fractures were significantly reduced by >40%. During

the second year of the FRAME study, both groups transitioned to

denosumab. Over 24 months, women who had received romosozumab during the first 12 months and then denosumab had 75%

fewer new vertebral fractures than those who had received placebo

for a year followed by denosumab. There were also nearly significant trends toward reduced clinical and nonvertebral fractures in

the romosozumab/denosumab group. Compared with baseline,

BMD increased by 17.6% in the spine and 8.8% in the total hip in

the romosozumab/denosumab group. Safety and tolerability of the

two drugs were similar, with a slightly higher incidence of injection

site reactions in the denosumab group. The FRAME study is in

an ongoing extension where all participants received continued

denosumab for an additional year. A parallel trial of very-high-risk

patients, all of whom have prevalent vertebral fractures, is also

ongoing and is comparing romosozumab to alendronate for 1 year,

followed by transition to or continuation of alendronate for 2 additional years. In one study, there was an increase in cardiovascular

side effects prompting a warning on the label.

OTHER PHARMACOLOGIC AGENTS NOT APPROVED IN THE

UNITED STATES

Odanacatib, a cathepsin K inhibitor, inhibits the osteoclast collagenase enzyme, preventing bone resorption but not affecting

osteoclast viability. This agent was in late-stage drug development.

In a very large controlled clinical trial (~17,000 postmenopausal

women with osteoporosis), bone mass increased substantially in

the spine and hip, and vertebral, hip, and all nonvertebral fractures

were reduced. Unfortunately, odanacatib was associated with a

significantly increased risk of stroke, and the development of this

agent was aborted in September 2016.

Testosterone has been used to treat osteoporosis associated with

low testosterone levels in men. There are data that indicate that testosterone can increase bone density, but there are no data indicating

improvement in any fracture endpoints. Since there are many other

effects of testosterone, especially in older men (including prostate

hypertrophy), decisions to use it for treatment of osteoporosis have

to take the multisystemic effects into account.

Sodium fluoride was tested in two large parallel clinical trials in

the late 1980s. Although BMD increased substantially, the increase

was in part due to fluoride incorporation in the hydroxyapatite

crystal. Fracture risk was not reduced and, in fact, was increased

in nonvertebral sites. Therefore, fluoride is no longer considered a

viable option for osteoporosis treatment.

Strontium ranelate has never been approved for osteoporosis in

the United States but is approved in Europe and some other countries outside of the United States. It increases bone mass throughout

the skeleton, but much of the increase is related to strontium incorporation into hydroxyapatite. In clinical trials, the drug reduced the

risk of vertebral fractures by 37% and that of nonvertebral fractures

by 14%. It appears to be modestly antiresorptive while at the same

time not causing as much of a decrease in bone formation (measured biochemically). In 2014, the use of strontium was restricted

because of an increased risk of cardiovascular disease and severe

skin reactions. Small increased risks of venous thrombosis also

occur.

Several small studies of growth hormone, alone or in combination with other agents, have not shown consistent or substantial

positive effects on skeletal mass.

NONPHARMACOLOGIC APPROACHES

Protective pads worn around the outer thigh, which cover the

trochanteric region of the hip, can prevent hip fractures in elderly

residents in nursing homes. The use of hip protectors is limited

largely by issues of compliance and comfort, but new devices are

being developed that may circumvent these problems and provide

adjunctive treatments.

Kyphoplasty and vertebroplasty are also useful nonpharmacologic

approaches for the treatment of painful vertebral fractures. The data

do not support routine surgical intervention for vertebral fractures

since, while this can reduce pain, there is concern about long-term

vertebral fracture risk.

TREATMENT MONITORING

There are currently no well-accepted guidelines for monitoring

treatment of osteoporosis. Because most osteoporosis treatments

produce small or moderate bone mass increments on average, it is

reasonable to consider BMD as a monitoring tool. Changes must

exceed ~4% in the spine and 6% in the hip to be considered significant in any individual. The hip is the preferred site due to larger

surface area and greater reproducibility. Medication-induced increments may require several years to produce changes of this magnitude (if they do at all). Consequently, it can be argued that BMD

should be repeated at intervals of every 2 years. Only significant

BMD reductions should prompt a change in medical regimen, as it

is expected that many individuals will not show responses greater

than the detection limits of the current measurement techniques.

Biochemical markers of bone turnover can help in treatment

monitoring, with significant changes seen within 3 months of initiating treatment with approved medications and the possible benefit

of improving adherence. It remains unclear which endpoint is most

useful. If bone turnover markers are used, a determination should

be made before therapy is started and repeated ≥3–4 months after

therapy is initiated. In general, a change in bone turnover markers

must be 30–40% lower than the baseline to be significant because of

the biologic and technical variability in these tests. Because markers

change more rapidly than bone density, they are often early signs

of treatment effect. Currently collagen C-telopeptide measured on

a fasting serum sample in the morning is the preferred marker of

bone resorption, and osteocalcin or the propeptide of type 1 collagen (P1NP) is the preferred marker for formation.

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