Postgraduate Medicine: Volume 121: No.4

An Overview of the Current Strategies

Frank Bonura, MD

Abstract: Osteoporosis is a major public health concern, resulting in increased fracture risk. Osteoporosis-related fractures impose a considerable economic burden on health care systems, and the disease has severe, debilitating consequences if left untreated. Measures for osteoporosis prevention should begin at childhood and include balanced nutrition, physical activity, and avoidance of risk factors such as smoking. In adulthood, early recognition of osteoporosis followed by timely and effective management can reduce fracture risk. However, the rates of screening and treatment for osteoporosis are low, even in patients who have sustained a fragility fracture. Comprehensive fracture risk assessment should be part of routine patient care. Nonpharmacologic strategies to improve or maintain bone health should always be implemented, but many patients also need pharmacologic intervention to achieve adequate fracture protection. Several pharmacologic therapies are currently available, and when choosing from the available options, clinicians should consider the efficacy and safety profiles of each therapy as well as the individual patient’s needs and overall health. Ideally, therapy should satisfy multiple criteria: fracture protection across multiple skeletal sites; rapid onset of action to maximize the timing of fracture protection; and minimal side effects with proven long-term safety.

Keywords: postmenopausal osteoporosis; fracture risk; screening; prevention; nonpharmacologic treatment; pharmacologic treatment

Osteoporosis is a skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, resulting in compromised bone strength and increased susceptibility to fracture.¹ Bone mass during adult life is a measure of the amount of bone accumulated from prenatal stages until maturity, along with that lost during aging.² Osteoporosis can, therefore, begin in childhood or even in prenatal stages, manifesting in later years. The disease typically progresses without symptoms, and bone loss is difficult to detect before a fragility fracture occurs. Although osteoporosis can be prevented and treated, it cannot be cured.³

The disease can be classified into 2 basic forms: primary and secondary. Primary osteoporosis results from cumulative bone loss as people age and undergo sex hormone changes. Secondary osteoporosis results from a variety of medical conditions, diseases, or the use of certain medications that adversely affect skeletal health.⁴ Although primary osteoporosis is the most common form of the disease, studies suggest that 20% to 30% of postmenopausal women and more than half of men with osteoporosis have a secondary cause.⁵ Glucocorticoid-induced osteoporosis is the most common cause of secondary osteoporosis and the association between glucocorticoid use and increased risk of fracture is well established.^6,7 These agents, even at low doses, can cause severe reductions in bone formation and can, to a lesser extent, increase bone resorption.^8,9

Osteoporosis affects approximately 10 million Americans, and an additional 34 million have low bone mass, which places them at risk of developing the disease.¹⁰ Because of demographic changes, the prevalence of osteoporosis is expected to increase to more than 14 million people by 2020.¹⁰ Approximately 1 in 2 women and 1 in 4 men aged > 50 years will have an osteoporosis-related fracture in their lifetime.³ Epidemiological studies have estimated that more than 2 million fractures occur every year in the United States as a result of osteoporosis,¹¹ and up to 90% of all hip and spine fractures in women aged 65 to 84 years can be attributed to this disease.¹² Osteoporosis is less prevalent in men than in women, but men account for 29% of fragility fractures in the United States.¹¹ Studies have also indicated that 30% to 50% of patients on glucocorticoid therapy sustain fragility fractures.¹³

Although the most common osteoporotic fractures are those of the spine, with an estimated 547 000 vertebral fractures occurring annually, nonvertebral fractures constitute 73% of all fractures. An estimated 297 000 hip fractures, 397 000 wrist fractures, 135 000 pelvic fractures, and 675 000 fractures at other nonvertebral sites occur each year in the United States.¹¹

Osteoporotic fractures are also responsible for almost 2.5 million medical visits, > 432 000 hospitalizations, and 180 000 nursing home admissions each year, creating a serious economic burden.⁴ The costs to the health care system associated with osteoporosis and related fractures were estimated at $17 billion in 2005, with each hip fracture costing on average over $40 000, whereas nonhip nonvertebral fractures and vertebral fractures comprised 22% and 6%, respectively, of the total costs.¹¹

Apart from the socioeconomic burden, fragility fractures are responsible for significant morbidity and decreased quality of life because of pain, and loss of mobility, independence, and self-esteem.^4,14 Hip and vertebral fractures are also associated with increased mortality, with fracture-related mortality rates being higher in men than women.^4,15 Hip fractures are particularly devastating and painful. After a hip fracture, half of the patients experience some long-term loss of mobility that often will never return to pre-fracture levels, and up to 25% will require long-term care. Furthermore, in the 6 months after such a fracture, the mortality rate has been estimated to be 10% to 20%.^14,16 A hip fracture also carries a 2.5-fold and 2.3-fold increase in risk of subsequent vertebral and hip fracture, respectively.¹⁷

Vertebral fractures can be associated with substantial pain, height loss, and kyphosis, resulting in compression of internal organs. Thoracic fractures may restrict lung function, and fractures of the lower back can cause digestive problems.^16,18 In the long term, pain and deformity reduce the patient’s capacity to perform basic activities. This loss of independence may subsequently lead to low self-esteem and depression.^14,19 A population-based study showed that clinical vertebral fractures are associated with 20% mortality 5 years after diagnosis,²⁰ and approximately 20% of patients with an incident vertebral fracture will suffer a new vertebral fracture in the following year.²¹ Vertebral fractures are also associated with a 4.4-fold, 2.3-fold, and 1.4-fold increase in the risk of subsequent vertebral, hip, and wrist fracture, respectively.¹⁷

Fractures of the wrist are relatively common among middle-aged women, who tend to fall forward, as opposed to elderly patients, who tend to fall backwards or sideways, and fracture the hip.²² Although wrist fractures cause less morbidity than hip fractures, their consequences are often underestimated. Wrist fractures are painful, can require several procedures to reposition the bones, and are associated with at least 4 to 6 weeks of immobilization, resulting in loss of productivity and confidence.^4,14,19 Estimates indicate that a wrist fracture increases the risk of subsequent wrist, hip, and vertebral fracture by 3.3-fold, 1.9-fold, and 1.7-fold, respectively.¹⁷

Bone is under continuous remodeling, a process in which the old bone is removed and new bone is formed. From childhood throughout early adulthood, bone formation exceeds bone resorption, leading to an increase in bone mass, which reaches a maximum around the age of 30 years.^2,23 In the period between achieving peak bone mass and the start of menopause, bone resorption and bone formation are roughly balanced, and changes in bone mass tend to be minimal.²⁴ In the first few years after menopause bone resorption occurs at an accelerated rate, leading to loss of bone mass. Although the rate of bone resorption decreases thereafter, the loss of bone mass continues throughout the postmenopausal years.^23,24 On average, by the age of 80, women have lost approximately 30% of their peak bone mass.²⁵

Attaining an optimal peak bone mass is of primary importance for the prevention of osteoporosis and subsequent fractures.² Epidemiological studies indicate that a 10% increase in peak bone mass would decrease the risk of hip fracture by about 30%.¹ The greatest determinant of a woman’s peak bone mass is heredity. Studies in twins have suggested that up to 80% of the variability in peak bone mass might be a result of genetic factors.²⁶ It has also been shown that young daughters of women with osteoporosis have a lower bone mineral density (BMD) than what would be expected for their age.²⁷ Bone mass accumulation until maturity is also influenced by hormonal status, and estrogen appears to be necessary for the acquisition of peak bone mass in both men and women.^28,29 Factors such as nutrition, physical activity, health during growth, and smoking also affect bone mass accumulation and maintenance.^24,30 In addition, maternal smoking, nutrition, and physical activity appear to modulate bone mass acquisition during intrauterine life.³¹ Children, adolescents, and young adults should be encouraged to follow a balanced diet, exercise regularly, and avoid smoking.

The restrictive eating behavior of girls and women involved in sports that emphasize leanness as an attribute for success constitute a current medical concern.^32,33 The female athlete triad refers to the interrelationships among low-energy availability, menstrual dysfunction, and low BMD. Low-energy availability appears to be the factor that impairs reproductive and skeletal health.³⁴ Prevention, early diagnosis, and treatment are essential to avoid long-term and possibly irreversible health impairment.³⁴ The American College of Sports Medicine recommends that athletes be assessed for the triad at preparticipation physical and/or annual health screening examinations. Treatment should aim at increasing energy intake and/or reducing energy expenditure. If eating disorders are present, psychotherapy is also recommended.³⁴

In adult life, bone remodeling occurs in an orderly sequence of bone resorption, lasting about 2 weeks, followed by a phase of bone formation that takes 3 to 4 months.^4,35 This process is vital for bone health because it repairs microfractures, resulting from repeated stresses, by removing old bone and forming new bone.⁴ At a cellular level, the bone remodeling unit is composed of osteoblasts, which form bone, and osteoclasts, which break down bone. There are approximately 1 million bone remodeling units. Bone loss and decreased bone strength result from an imbalance between the activities of these 2 cell types.³⁵

In the 1990s, the discovery of the receptor activator of nuclear factor-kappa B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) signaling pathway led to a better understanding of how osteoblast–osteoclast interactions could regulate bone remodeling.³⁶ Receptor activator of nuclear factor-kappa B ligand is expressed on the surface of osteoblasts and their precursors, and stimulates osteoclastogenesis, causing bone resorption by binding to RANK, which is expressed by osteoclasts and their precursors.³⁷ Osteoblasts also produce and secrete OPG, which acts as a decoy receptor for RANKL.^38,39 The binding of OPG to RANKL inhibits the binding of RANK and RANKL, which in turn inhibits osteoclast formation, differentiation, function, and survival.³⁶ Thus, the balance of OPG/RANKL expression appears to control the bone remodeling process. Excess OPG decreases bone resorption and increases bone formation. In contrast, excess RANKL increases bone resorption and decreases bone formation, with a subsequent loss of bone mass.⁴⁰

The increased rate of bone resorption at menopause indicates a role for estrogen in bone loss, and data suggest that estrogen deficiency decreases OPG levels and upregulates RANKL expression. Receptor activator of nuclear factor-kappa B ligand was upregulated in bone marrow cell aspirates of estrogen-deficient postmenopausal women, and its expression was directly correlated with biochemical markers of bone resorption and inversely correlated with serum levels of 17β-estradiol.⁴¹ Studies have also shown that estrogen stimulates OPG synthesis by osteoblasts and bone marrow stromal cells.^42,43

In men, although total serum testosterone and estrogen levels remain relatively unchanged with age, their bioavailable fractions diminish progressively to 30% to 50% of the young adult average after the age of 80.⁴⁴ In a study alternating systemic blockade and replacement of estrogen and testosterone in men, estrogen was found to be the dominant sex steroid regulating bone resorption, whereas both estrogen and testosterone were important in regulating bone formation.⁴⁵

Despite the severe individual and health care burdens associated with fragility fractures, the rates of screening and treatment for osteoporosis remain low. A recent population-based study reported that in 2005, the proportion of women screened and treated for osteoporosis after a fragility fracture was 10.2% and 12.9%, respectively.⁴⁶ This paucity of care is reflected in the male population, and studies indicate that a very low proportion of men are evaluated for osteoporosis or receive antiresorptive therapy after a fragility fracture.^47,48 Also, among glucocorticoid users, bone density is not routinely assessed, and < 50% of patients receive medication for osteoporosis prevention or treatment.^49,50

Assessing fracture risk should be part of routine patient care. Several clinical risk factors for osteoporosis have been identified and should be evaluated at routine patient visits.^10,23,51,52 Nonmodifiable risk factors include advancing age, female sex, Asian or Caucasian ethnicity, history of fracture as an adult, family history of fracture in a first-degree relative (particularly maternal or paternal history of hip fracture), and rheumatoid arthritis. Modifiable risk factors comprise low body weight, hormone deficiency, long-term use of medications that affect bone homeostasis (eg, glucocorticoids), causes of secondary osteoporosis, smoking, excessive alcohol consumption, an inactive lifestyle, and a lifetime diet low in calcium and vitamin D. During a patient examination, height measurement may be useful to indicate occult vertebral compression fractures, which are indicative of osteoporosis.

Diagnosis of osteoporosis is established by BMD measurement. The decision to assess bone density should be based on the skeletal health and risk factor profile of the individual patient. Table 1 summarizes the indications for BMD testing according to the National Osteoporosis Foundation (NOF) guidelines.¹⁰ Of the many techniques developed to assess BMD, dual energy x-ray absorptiometry (DXA) is the gold standard. Dual energy x-ray absorptiometry BMD results are reported as grams of mineral per square centimeter scanned (g/cm²) and as a comparison to 2 norms: the expected BMD from a sex- and age-matched healthy population (Z-score); or the expected BMD from a sex-matched young adult healthy population (T-score). The difference between the patient’s score and the norm is expressed in standard deviations (SDs).^1,10

The World Health Organization (WHO) has defined low bone mass (osteopenia) as a BMD between −1.0 and −2.5 SD below the norm for young healthy adults of the same sex (T-score < −1.0 and > −2.5), whereas osteoporosis is indicated by a BMD of −2.5 SD or below (T-score ≤ −2.5).¹ Dual energy x-ray absorptiometry measurements can be done both centrally (spine, hip, forearm) and peripherally (wrist, heel, finger). Peripheral BMD measurements are useful for screening purposes, but only central BMD assessment can be used for diagnosis of osteoporosis according to the WHO criteria and for monitoring treatment efficacy.^10,53 Central DXA BMD measurements should be done at both the spine and the hip. If this is not possible, the forearm may be used as an alternative site.⁵³ Precision BMD assessment is essential for accurate results and should be standard clinical practice. Each DXA facility should determine its precision error and calculate the least significant change to determine if BMD change over time is real or due to chance.⁵³

Assessment of fracture risk should encompass all aspects of risk. The risk of fracture ultimately depends on bone strength. Bone mineral density is a strong predictor of fracture risk, accounting for 75% to 85% of bone strength. The risk of fracture increases approximately 1.5-fold for each SD decrease from age-adjusted BMD.⁵⁴ However, BMD measurements do not evaluate bone quality, which is another determinant of bone strength.^52,55 The risk of fracture is high when osteoporosis is diagnosed, but patients with BMD scores outside the osteoporotic range may still be at high risk of sustaining an osteoporotic fracture. Indeed, a recent study has shown that 80% of women aged 50 to 59 years sustaining fragility fractures did not have a diagnosis of osteoporosis according to the WHO definition.⁵⁶

The International Society for Clinical Densitometry (ISCD) recommends vertebral fracture assessment in:⁵³ (I) postmenopausal women with low bone mass (osteopenia) by BMD criteria, and (a) any 1 of the following: age ≥ 70 years, historical height loss > 4 cm (1.6 in), prospective height loss > 2 cm (0.8 in), self-reported vertebral fracture (not previously documented) or (b) ≥ 2 of the following: age 60 to 69 years, self-reported prior nonvertebral fracture, historical height loss of 2 to 4 cm, chronic systemic diseases associated with increased risk of vertebral fractures; (II) men with low bone mass (osteopenia) by BMD criteria and (a) any 1 of the following: age ≥ 80 years, historical height loss > 6 cm (2.4 in), prospective height loss > 3 cm (1.2 in), self-reported vertebral fracture (not previously documented) or (b) ≥ 2 of the following: age 70 to 79 years, self-reported prior nonvertebral fracture, historical height loss of 3 to 6 cm, on pharmacologic androgen-deprivation therapy or following orchiectomy, chronic systemic diseases associated with increased risk of vertebral fractures; (III) women or men on chronic glucocorticoid therapy (equivalent to ≥ 5 mg of prednisone daily for ≥ 3 months); and (IV) postmenopausal women or men with osteoporosis by BMD criteria, if documentation of one or more vertebral fractures will alter clinical management.

Irrespective of BMD, any type of fragility fracture signals underlying problems with the patient’s bone health and should always warrant further BMD testing.^4,57 Nevertheless, women sustaining a wrist fracture are often overlooked. A 5-year population-based study has shown that only 5% of women suffering a distal forearm fracture had bone density testing within 12 months of sustaining the fracture.⁵⁸ Wrist fractures are not routinely recognized by clinicians or patients as a manifestation of osteoporosis; hence, an important opportunity for secondary prevention is lost.⁵⁸

To aid clinicians in recognizing patients at risk of fracture, the WHO has recently developed a fracture risk assessment tool (FRAX^⊙), which is particularly useful in identifying among the group of patients with osteopenia those at higher risk of fracture.^52,59 This tool integrates clinical risk factors with femoral neck BMD, and the output is the 10-year probability of hip fracture or any major osteoporotic fracture (hip, spine, shoulder, or wrist). The risk factors included in the WHO fracture risk assessment tool are age, sex, personal history of fracture, low body mass index, use of oral glucocorticoid therapy for 3 months or longer, rheumatoid arthritis or other secondary causes of osteoporosis, parental history of hip fracture, and current smoking and alcohol intake of 3 or more drinks per day.^10,52,59 After comprehensive fracture risk assessment, guidelines can assist the clinician in selecting patients who should be considered candidates for pharmacologic therapy. Table 2 lists the NOF recommendations for treatment.^10,52,59

Prior to developing a management plan, the clinician should exclude possible secondary causes of osteoporosis or bone loss. About 20% of postmenopausal women with osteoporosis have a secondary cause that can be identified and treated separately.⁵ Secondary osteoporosis can result from a variety of medical conditions, including endocrine, hematopoietic or nutritional disorders, and vitamin D deficiency. Diseases, such as malabsorption or celiac, liver, or chronic kidney diseases, as well as the use of glucocorticoids, aromatase inhibitors, and gonadotropin-releasing hormone antagonists, can also cause or contribute to osteoporosis.⁴ Table 3 lists routine tests to be considered for all women with osteoporosis, and specialized tests that can be carried out if the medical evaluation suggests secondary causes of bone loss.^22,60

Ideally, osteoporosis should be prevented before bone mass is lost and fracture occurs. It is the responsibility of clinicians to communicate clearly to their patients the risks associated with postmenopausal bone loss and how to minimize risks in a timely manner. Gynecologists in particular are in a unique position because they serve as primary caregivers for many women at risk or approaching risk of fracture. Early recognition of osteoporosis with rapid and effective management can prevent first or subsequent fractures. Prevention and treatment measures should be tailored to the individual patient, taking into consideration the patient’s age, risk-factor profile, lifestyle, and medical condition.

A healthy lifestyle is essential to help prevent osteoporosis and reduce fracture risk. Measures that have a positive impact on bone health include a balanced diet rich in calcium and vitamin D, regular weight-bearing and muscle-strengthening exercise, smoking cessation, avoidance of excessive alcohol consumption, and prevention of falls.¹⁰

Bone mass contains a high proportion of calcium, and vitamin D regulates calcium absorption. A diet rich in calcium and vitamin D is vital to achieve optimal peak bone mass.⁶¹ After menopause, intestinal calcium absorption is decreased, and renal secretion of calcium is greater than before menopause. This leads to an increase in calcium requirements. Pre-vitamin D is produced in the skin after sun exposure, and then converted in the liver to 25-hydroxycholecalciferol [25(OH)D], which is further hydroxylated in the kidneys to the active form of vitamin D; 1,25-dihydroxycholecalciferol [1,25(OH)2D].²² In older women, inadequate sunlight exposure can often lead to vitamin D deficiency.²³ Vitamin D deficiency can cause secondary hyperparathyroidism, increased bone turnover, bone loss, and muscle weakness, with a consequent increase in the risk of falls.⁶² A meta-analysis of clinical trials demonstrated that a vitamin D dosage of 700 to 800 IU/day was associated with a significant decrease in the risk of nonvertebral fractures, including those of the hip.⁶³ A more recent study also suggested that combined vitamin D and calcium supplementation prevents hip and other nonvertebral fractures.⁶⁴ Furthermore, researchers have reported that patients can obtain maximum benefit from osteoporosis medications only if they have an adequate intake of calcium and vitamin D.⁶⁵

For adults younger than 50 years, the NOF recommends calcium and vitamin D intakes of 1000 mg/day and 400 to 800 IU/day, respectively.¹⁰ A calcium intake of at least 1200 mg/day and a vitamin D intake of 800 to 1000 IU/day are recommended for all individuals aged > 50 years.¹⁰ In the United States, the average postmenopausal diet provides only 600 to 700 mg of calcium per day,¹⁰ and > 70% of women aged 51 to 70 years do not take the recommended levels of vitamin D.⁶⁶ Dairy products are the best source of calcium because of their high content of elemental calcium, high absorption rate, and low cost.²³ Dietary sources of vitamin D include vitamin D-fortified products and fatty fish.²³ For those unable to consume enough dietary calcium and vitamin D, supplements are available. Because of absorption limitations, calcium supplements should be taken in divided dosages of 500 to 600 mg or less. The most common forms of calcium supplements are calcium carbonate and calcium citrate. Calcium carbonate is best absorbed when taken with food, whereas calcium citrate is absorbed well when taken on an empty stomach or with food.²³ Two types of vitamin D supplements are vitamin D₂ (ergocalciferol) and vitamin D₃ (cholecalciferol). Previous research has suggested that vitamin D₃ is a better choice than vitamin D₂. However, more recent studies show that vitamin D₂ and vitamin D₃ are equally good for bone health.⁶⁷

Optimal serum levels of 25(OH)D are estimated to be 75 nmol/L (30 ng/mL) or higher.^10,68 To achieve these levels in patients with vitamin D deficiency, supplemental intake has to be increased considerably. For example, a daily supplemental intake of 400 IU of vitamin D has a modest effect on the serum concentration of 25(OH)D, increasing levels by 7 to 12 nmol/L.⁶⁹ It has been reported that to raise 25(OH)D concentrations from 50 to 80 nmol/L, an additional intake of approximately 1700 IU per day is required.⁷⁰ A recent risk assessment for vitamin D focusing on the risk of hypercalcemia indicated an upper safe limit of vitamin D consumption by adults of 10 000 IU daily.⁷¹

Among its many health benefits, regular weight-bearing and muscle-strengthening exercises are known to have a positive effect on bone mass⁷² and can also improve agility, strength, and balance, which may reduce the risk of falls.¹⁰

Research has shown that postmenopausal women who smoke have a higher fracture rate than nonsmokers.⁷³ Furthermore, women smokers have lower BMD and tend to lose bone more rapidly when compared with nonsmokers.^74,75 Adolescent smoking is also associated with low bone density.²⁴ Although the mechanisms associated with these effects are not completely known, evidence suggests that smoking decreases calcium absorption⁷⁵ and lowers 17β-estradiol levels.⁷⁶ Patients should be counseled on the detrimental effects of smoking and encouraged to follow smoking cessation programs.

High alcohol consumption has been linked to low bone density in adults.²³ Consumption of 3 or more alcoholic drinks per day is detrimental to bone health, increases the risk of falling, and requires intervention when identified.¹⁰

More than one-third of adults aged ≥ 65 years fall each year in the United States, and 20% to 30% of people who fall suffer moderate to severe injuries.⁷⁷ A fall is the precipitating factor in nearly 90% of all fractures, and as a result fall prevention should be routine care for all postmenopausal women.⁷⁸ Many falls can be prevented if factors that may affect balance such as poor vision or hearing are reviewed and corrected.¹⁰ Postmenopausal women should be evaluated on a yearly basis for their risk of falls, and their number of falls per year should be noted.

In addition to nonpharmacologic interventions, some patients may need pharmacologic therapy to achieve adequate protection against fracture. Two main classes of medications are available for postmenopausal osteoporosis; antiresorptive agents, which decrease bone resorption; and anabolic agents, which promote bone formation.

The US Food and Drug Administration (FDA)-approved antiresorptive agents for the treatment and/or prevention of osteoporosis are bisphosphonates (alendronate, risedronate, ibandronate, and zoledronic acid), estrogen/hormone therapy, the estrogen agonist-antagonist raloxifene, and calcitonin. The antiresorptive action of bisphosphonates results from their affinity to bone mineral and their impairment of osteoclast cell function through the inhibition of farnesyl diphosphate synthase, a key enzyme for osteoclast activity.⁷⁹ Estrogen and raloxifene inhibit osteoclast formation by stimulating OPG synthesis and inhibiting RANKL expression in osteoblasts.^41,42 Calcitonin acts directly on osteoclasts, inhibiting their activity.⁴

Alendronate is indicated for the prevention and treatment of postmenopausal osteoporosis, treatment of osteoporosis in men, and treatment of glucocorticoid-induced osteoporosis.^10,80 Risedronate^10,81 and zoledronic acid^10,82 are approved for the prevention and treatment of postmenopausal osteoporosis, treatment of osteoporosis in men, and prevention and treatment of glucocorticoid-induced osteoporosis. Ibandronate^10,83 and raloxifene^10,84 are approved for both preventing and treating postmenopausal osteoporosis, whereas clacitonin^10,85 is approved only for treating postmenopausal osteoporosis. Estrogen/hormone therapy is approved for the prevention of osteoporosis, and relief of vasomotor symptoms and vulvovaginal atrophy associated with menopause.¹⁰

Teriparatide, a recombinant form of parathyroid hormone, is the only anabolic agent approved for the treatment of postmenopausal osteoporosis. The anabolic action of teriparatide results from its direct stimulation of osteoblastic bone formation, leading to an increase in trabecular bone density and connectivity.⁸⁶ Teriparatide is indicated for the treatment of postmenopausal osteoporosis in women at high risk of fracture and to increase bone mass in men with primary or hypogonal osteoporosis who are at high risk of fracture.^10,87

When selecting a treatment plan, clinicians should consider the clinical outcomes of each therapy in terms of efficacy, onset of efficacy, tolerability, and safety. As multiple skeletal sites are frequently involved in fragility fractures,¹¹ choosing a treatment plan that provides fracture protection at both vertebral and nonvertebral sites is important. Evidence from prospective studies regarding site-specific antifracture efficacy of each therapy is summarized in Table 4.^88-99 An early onset of treatment efficacy maximizes protection and is particularly important for patients who have already sustained a fragility fracture, as most subsequent fractures tend to occur 1 to 2 years after the initial fracture.^21,100 Table 5 provides an overview of the data from prospective and retrospective analyses regarding the onset of fracture risk reduction of each therapy at key skeletal sites.^{90,92,94-96,98,99,101-105} Because osteoporosis is a chronic disease, choosing a treatment plan with an established long-term safety profile is also important.

Alendronate and risedronate have been evaluated for up to 10 and 7 years of treatment, respectively, and their long-term safety profile is well established.^106,107 Long-term safety data for ibandronate and zoledronic acid have not been reported. Side effects of oral bisphosphonates (alendronate, risedronate, and ibandronate) include gastrointestinal tract intolerance (such as abdominal pain, irritation of the esophagus, and nausea) and musculoskeletal pain.^80,81,83 Bisphosphonates are poorly absorbed and must be taken on an empty stomach. To counteract the gastrointestinal side effects, patients should take the tablet with a full glass of water first thing in the morning, and remain in an upright position without eating or drinking for at least 30 minutes (60 minutes for ibandronate). Intravenous formulations of bisphosphonates (ibandronate and zoledronic acid) are associated with a short-term acute reaction characterized by flu-like symptoms.^82,108 Bisphosphonates are cleared by the kidneys, and are contraindicated for patients with renal impairment. Bisphosphonates are also contraindicated in patients with low blood calcium because they can cause hypocalcemia.^{80,81,83,84,108}

The possible association between bisphosphonate use and the rare occurrence of osteonecrosis of the jaw (ONJ) has been the subject of recent studies. However, a causal relationship has not been demonstrated.¹⁰⁹ Osteonecrosis of the jaw is defined as an area of exposed bone in the maxillofacial region that does not heal within 8 weeks after identification by a health care provider.¹⁰⁹ Osteonecrosis of the jaw has been reported mainly in patients with multiple myeloma or metastatic cancer, who are receiving high doses of intravenous bisphosphonates and undergoing dental procedures.¹⁰⁹ The task force of the American Society for Bone and Mineral Research reported, in a systematic review of published and unpublished data, that the risk of ONJ associated with oral bisphosphonate treatment for osteoporosis seems to be low, estimated to be between 1 in 10 000 and < 1 in 100 000 patient-treatment years.¹⁰⁹ As such, the risk-to-benefit ratio should be considered for each individual patient.¹¹⁰

Patients should also be informed about the risk of developing ONJ, and health care providers should encourage their patients to practice good oral hygiene and have regular dental visits. In patients taking oral bisphosphonates for longer than 3 years, nonsurgical approaches are advised for periodontal disease. However, if an invasive dental procedure is required, no data suggest that terminating bisphosphonate therapy may improve dental outcomes.¹⁰⁹ Estrogen plus progestin therapy has been shown to increase the risks of breast cancer,¹¹¹ coronary heart disease,¹¹² and thromboembolic events¹¹³ within a 5-year period. In postmenopausal women with prior hysterectomy, estrogen alone did not increase the risk of breast cancer but was associated with an increased risk of stroke and deep vein thrombosis over an average period of 6.8 years.¹¹⁴ Due to these safety concerns, if estrogen/hormone therapy is considered solely for preventing postmenopausal osteoporosis, the FDA recommends that approved non-estrogen treatments should be considered first.¹⁰

Side effects associated with raloxifene treatment include hot flashes and leg cramps.⁸⁴ In addition, raloxifene increases the risks of deep vein thrombosis and pulmonary embolism in postmenopausal women, but reduces the risk of invasive breast cancer.^115,116

Calcitonin nasal spray is well tolerated, and its safety has been studied for up to 5 years,⁹⁸ but it can cause nasal stuffiness, dry mouth, and nausea.⁸⁵

Because of concern about the possible development of osteosarcoma, teriparatide therapy should be limited to a maximum of 2 years. Side effects of teriparatide include leg cramps, dizziness, and nausea.⁸⁷ Patients with an increased risk of osteosarcoma and those who have had prior radiation therapy of the skeleton, skeletal malignancy, or hypercalcemia should not receive teriparatide therapy.¹⁰

In summary, for postmenopausal women with osteoporosis, bisphosphonates are usually the first line of treatment. For early postmenopausal women with low bone mass who have moderate or severe vasomotor symptoms without any contra-indications, estrogen/hormone therapy could be considered for a period of < 5 years. For women with low bone mass or osteoporosis of the spine who are at risk of breast cancer, raloxifene therapy is an option, but the risk-to-benefit ratio should be considered for each patient. Teriparatide therapy should be considered for women undergoing treatment with bisphosphonates who continue to sustain fractures, or women with severe osteoporosis, but only for < 2 years.

Once treatment has been initiated, an integral part of osteoporosis management is the monitoring of treatment efficacy. Monitoring will help identify patients who do not respond to therapy and those who are noncompliant. When using serial BMD measurements to monitor patient response to therapy, measurement should be done on the same machine, and if a machine is changed, a cross-calibration assessment must be performed.⁵³ According to the International Society for Clinical Densitometry, measurements should be performed before and 1 year after therapy initiation, with longer intervals once efficacy has been established.⁵³ Nevertheless, it should be noted that post-treatment increase in spinal BMD only accounts for a relatively small proportion of the fracture-risk reduction, and greater increases in BMD do not necessarily translate into greater fracture risk reduction.^117-119 Additionally, reductions in fracture risk may occur before changes in BMD become significant.¹²⁰

A high bone turnover indicates rapid bone loss and increased fracture risk. Antiresorptive agents reduce the levels of biochemical markers of bone turnover 3 to 6 months after treatment initiation, and these markers can be useful in determining patient response to therapy.¹²⁰ Bone resorption markers (N-telopeptide of type 1 collagen, C-telopeptide of type 1 collagen, pyridinoline, and deoxypyridinoline) should be measured at baseline and at 3 months and 6 months after therapy initiation, whereas bone formation markers (bone alkaline phosphatase, osteocalcin, and propeptides of type 1 collagen) should be assessed at baseline and at 6 months after starting therapy.^4,121 The pre-analytical variability of bone turnover markers is affected by many factors (circadian, menstrual, and seasonal variation, diseases, and medications)¹²² and, therefore, imprecision associated with bone turnover marker measurements is greater than that of DXA BMD measurements. To decrease variability, biological samples should be obtained in a standardized manner, and cut-off values for the use of these markers to monitor therapy should be standardized.^10,120,122

Pain from vertebral fractures is usually self-limiting and can be treated with analgesics and rest. Vertebroplasty and kyphoplasty are surgical interventions indicated for the management of vertebral compression fractures in patients who are unresponsive to conventional pain relief.^22,123 Vertebroplasty is an image-guided procedure, during which a cement is injected into weak or collapsed vertebrae to stabilize the fracture.^22,123,124 During kyphoplasty, a small vertebral balloon is used to elevate the collapsed vertebra. The balloon is then deflated and removed, and the cavity is filled with cement, forming an internal cast that stabilizes the fracture.¹²⁵ To date, studies do not indicate a difference in efficacy between vertebroplasty and kyphoplasty.¹²⁶

A recent systematic review of the available evidence indicated that vertebroplasty has provided substantial pain relief in 60% to 100% of patients and is associated with decreased analgesic use, improved mobility, and better quality of life.¹²⁴ Contraindications to vertebroplasty include asymptomatic compression fractures, active infection, uncorrectable coagulopathy, preexisting radiculopathy, allergy to the bone cement or opacification agent, severe cardiopulmonary disease, or pregnancy. Risks include pain, cement leakage, hemorrhage, nausea, fever, nerve-root irritation, and rib or vertebral posterior element fractures. Rare but serious complications may be severe hematomas, neurologic complications, cerebral arterial embolization, pulmonary infarct, and clinical symptoms due to cement embolization.^22,124

Although osteoporosis is usually associated with the elderly population, the disease can begin in childhood. Prevention strategies such as a balanced nutrition, regular exercise, and the avoidance of risk factors should be implemented from an early age. In adult years, these prevention strategies, and early identification and management of at-risk patients will reduce the individual and socioeconomic burden associated with the disease. All fragility fractures are important indicators of diminished bone health and warrant further fracture risk assessment. Should osteoporosis be diagnosed, a management plan should be developed. Therapies with long-term safety data, sustained efficacy at all relevant sites, and rapid action should be considered for pharmacologic management, if needed. Regardless of diagnosis, all patients should be encouraged to adopt a bone-healthy diet and lifestyle, as it is never too early to improve bone strength and decrease the risk of future fracture.

The author received editorial/writing support in the preparation of this manuscript, which was funded by The Alliance for Better Bone Health (Procter & Gamble Pharmaceuticals and sanofi-aventis US, Inc.). The author was fully responsible for all content and editorial decisions and received no financial support or other form of compensation related to the development of the manuscript.



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