Current and Emerging Pharmacologic Therapies for the Management of Postmenopausal Osteoporosis

Abstract

Postmenopausal osteoporosis is an asymptomatic skeletal disease that is often underdiagnosed and undertreated. Osteoporotic fractures are associated with substantial morbidity and mortality and impaired quality of life—socially, emotionally, and financially. Considering the growing burden of osteoporotic fractures worldwide, there remains an ongoing need for progress in the diagnosis of osteoporosis, identification of individuals at high fracture risk, and treatment to prevent fractures. Adequate intake of calcium and vitamin D is recommended as baseline therapy for osteoporosis prevention and treatment. Available pharmacological agents for the management of postmenopausal osteoporosis may not be appropriate for all women. Oral bisphosphonates are generally considered first-line therapy for patients with osteoporosis, but their use may be limited by gastrointestinal side effects. Other agents include hormone therapy, the selective estrogen receptor modulator (SERM) raloxifene, salmon calcitonin, teriparatide (human recombinant parathyroid hormone), and strontium ranelate (in some countries). Factors that may contribute to poor compliance and persistence with current osteoporosis therapies include drug intolerance, complexity of dosing regimens, and poor understanding of the relative benefit and risk with treatment. Emerging therapies for postmenopausal osteoporosis include novel SERMs (bazedoxifene, lasofoxifene, ospemifene, arzoxifene) and denosumab. Because SERMs can display mixed functional estrogen receptor agonist or antagonist activity depending on the target tissue, they may confer beneficial effects on bone with limited stimulation of other tissues (e.g., breast, endometrium). Clinical investigation of these promising new agents is ongoing to evaluate efficacy and safety, with the goal of developing effective strategies to maximize long-term tolerance, compliance, and persistence with therapy.

Introduction

Postmenopausal osteoporosis is a silent (asymptomatic) disease characterized by decreased bone density and changes in bone microarchitecture that reduce bone strength and increase the risk of fractures. ¹ Although there are a number of approved agents for the prevention or treatment (or both) of postmenopausal osteoporosis, available options may not be appropriate for all women, primarily because of safety and tolerability concerns. Combined with the significant impact of osteoporotic fractures on a global scale, there remains an ongoing need for new therapies that are efficacious while minimizing adverse clinical outcomes. Because it is asymptomatic, osteoporosis is often underdiagnosed and undertreated, so that most patients who suffer fractures have not received previous antiresorptive therapy. ^2,3 Furthermore, treatment for osteoporosis is often associated with low long-term patient compliance and persistence, which can limit the effectiveness of therapy. ^4,5 The purpose of this article is to describe the prevalence and burden of postmenopausal osteoporosis, to examine challenges with current therapies, and to evaluate emerging treatment options.

Epidemiology

The prevalence of osteopenia and osteoporosis increases with age, with the majority of cases occurring in postmenopausal women. ¹ Approximately 200 million individuals around the world are affected, including one third of women between the ages of 60 and 70 years and two thirds of women ≥80 years. ⁶ Epidemiological data from the Third National Health and Nutrition Examination Survey (NHANES III) ⁷ showed that the incidence of osteopenia (bone mineral density [BMD] T-score between −1.0 and −2.5) was 37%–50% in American women ≥50 years, whereas the incidence of osteoporosis (T-score −2.5 or less) was 13%–18%.

A prospective analysis of data from 1142 patients ≥40 years with T-scores −2.0 or less in the Canadian Database for Osteoporosis and Osteopenia ⁸ showed that the risk of a first fracture increased by 3% for each advancing year of age (or by 18% for every 5 years). It has been estimated that the remaining lifetime risk of sustaining an osteoporotic fracture for an American woman 50 years of age is 40%, with the majority of fractures occurring after 75 years of age. ⁹

The association between BMD and fracture risk is well established. The proportion of hip and spine fractures that are attributable to low bone density at these skeletal sites has been estimated to be 80% in women between 45 and 64 years of age and 90% and 95% in those aged 65–84 years and ≥85 years, respectively. ¹⁰ Although the risk of fracture increases as BMD declines, there are numerically more fractures in those individuals with osteopenia than those with osteoporosis because so many more patients are in this category. The Study of Osteoporotic Fractures, ¹¹ which followed a cohort of postmenopausal women ≥65 years for 5 years, showed that 54% of hip fractures occurred in women who did not have osteoporosis according to the World Health Organization (WHO) criteria.

Despite the availability of diagnostic tools and evidence supporting the efficacy of preventive measures and treatments for osteopenia and osteoporosis, a significant proportion of those afflicted remains undiagnosed and untreated. ¹² The multinational IMPACT study ¹³ assessed the accuracy of radiographic diagnoses of vertebral fracture in women aged 65–80 years who were newly diagnosed with osteoporosis based on BMD measurements. Of 2451 women with evaluable lateral spine radiographs, 789 (32%) were found to have at least one vertebral fracture, and 266 (34%) of these women were not recognized as having a vertebral fracture in reports by local radiologists.

In a Danish study ³ that analyzed hospital records for patients diagnosed with osteoporosis or osteoporotic fractures, the annual incidence of osteoporosis in women ≥50 years old was estimated to be 58,568 per million inhabitants; however, only 4,823 cases were diagnosed, representing just 8.2% of the expected figure. In addition, only 28% of women who experienced a fracture had received previous antiresorptive drug therapy. Similar results were obtained in a Japanese study, ² in which 367 of 422 (87%) patients with osteoporosis-related fractures did not report any drug treatment before or after the incident fracture. Findings from an American study ¹⁴ of 95 patients ≥65 years undergoing surgery for hip fracture indicated that none of them received a bone density scan during hospitalization or were scheduled to have it as an outpatient procedure, and only 2% reported receiving pharmacological therapy for osteoporosis at discharge.

Impact of Osteoporotic Fractures on Health Outcomes

The consequences of osteoporotic fractures include increased morbidity and mortality, as well as adverse effects on quality of life—socially, emotionally, and financially. ^15,16 Hip fractures are regarded as the most devastating type of osteoporosis-related fractures; this may be due, in part, to loss of mobility and the resulting need for long-term care in many cases, as the average age at which hip fracture occurs is 82 years. ¹ However, other types of fractures can also have a substantial impact on health-related quality of life. For instance, multiple or severe vertebral fractures may be associated with significant pain, reduced pulmonary function, loss of height, and kyphosis, which can restrict movement and increase the risk of further falls and fractures. ^{1,17 –19} In addition, sustaining vertebral fractures has been shown to significantly impact emotional status. ²⁰

In a study ²¹ that evaluated the quality of life in postmenopausal women with osteoporosis using validated questionnaires (Qualeffo-41, Zung), 55% of osteoporotic women with fractures had a reduced quality of life compared with 32% of osteoporotic women without fractures and 11% of controls. For women with vertebral fractures, Qualeffo scores for pain, physical function, social function, and health perception parameters were significantly worse than in controls (p < 0.001). Moreover, a greater percentage of osteoporotic women with or without fractures (40%) experienced symptoms of depression compared with control patients (23%). ²¹ A recent cross-sectional study ²² showed that postmenopausal osteoporotic women with prevalent vertebral fractures had a significantly greater incidence of depressive symptoms than those without prevalent vertebral fractures as assessed by the Geriatric Depression Scale (p < 0.001).

Fractures are associated with significant mortality. Results of the Fracture Intervention Trial ²³ in postmenopausal women with low bone mass indicated that the risk of mortality after suffering a hip fracture was nearly 6 times greater and nearly 9 times greater following a spine fracture than those who did not experience a clinical fracture. Findings from another study ²⁴ demonstrated an excess mortality of approximately 20% over a 5-year period in women with hip and vertebral fractures.

Taken together, substantial evidence underscores the need for improved efforts in the management of postmenopausal osteoporosis. This includes a greater recognition of the disease, particularly in the identification of individuals at high risk for fracture. An algorithm for determination of fracture risk recently developed by the WHO, the Fracture Risk Assessment Tool (FRAX^®), is an important advance in this regard. ^25,26 It takes into account validated clinical risk factors for fracture in addition to BMD and may serve as a useful tool in facilitating treatment decisions.

Challenges with Current Strategies for Management of Osteoporosis

Prevention is an important part of dealing with any disease, and the National Osteoporosis Foundation (NOF) guidelines ²⁷ recommend BMD testing in all women aged ≥65 years and men aged ≥70 years. Younger postmenopausal women and men aged 50–69 years should be tested if their clinical risk factor profile reveals cause for concern. BMD assessment is also recommended for women in the menopausal transition with a specific risk factor (e.g., low body weight, prior low trauma fracture, or high-risk medication), adults >50 years of age who experience a fracture, adults with a condition or taking a medication associated with low bone mass or bone loss, and anyone taking or considering treatment for osteoporosis or showing evidence of bone loss. In addition, postmenopausal women discontinuing estrogen-based therapy should be tested. The guidelines recommend repeat BMD testing every 2 years for patients being treated for osteoporosis. More frequent testing may be warranted in certain clinical situations. ²⁷

Nonpharmacological strategies to reduce the risk of fracture include lifestyle modification (e.g., smoking cessation and limiting alcohol and caffeine use), nutritional guidance/dietary supplementation, and physical exercise. ²⁸ The NOF ²⁷ recommends pharmacological intervention for postmenopausal women and men aged ≥50 years with hip or vertebral (clinical or morphometric) fracture, a BMD T-score of ≤−2.5 at the femoral neck or spine, or a BMD T-score between −1.0 and −2.5 at the femoral neck or spine and a 10-year probability of a hip fracture ≥3% or a major osteoporosis-related fracture ≥20% based on the FRAX^®. Available therapies include bisphosphonates, hormone therapy, raloxifene, salmon calcitonin, and parathyroid hormone (Table 1). Most of these are antiresorptive agents that improve bone strength and reduce the risk of fracture primarily by decreasing bone turnover and maintaining or increasing BMD. Anabolic agents (i.e., parathyroid hormone) exert their effects by increasing bone formation.

Table 1.

FDA ^a -Approved Therapies for Postmenopausal Osteoporosis

	Prevention	Treatment
Bisphosphonates
Alendronate	x	x
Risedronate	x	x
Ibandronate b	x	x
Zoledronic acid		x
Raloxifene	x	x
Systemic estrogen products	x
Teriparatide		x
Salmon calcitonin		x

a

FDA, Food and Drug Administration.

b

Intravenous injection (4 times per year) approved for treatment only. Oral formulation approved for prevention and treatment.

Vitamin D and calcium supplementation

Adequate intake of vitamin D/calcium is recommended as an inexpensive baseline therapy for the prevention and treatment of osteoporosis for all patients and is included in most clinical trials evaluating newer therapeutic osteoporosis agents. ^29,30 Evidence suggests that vitamin D/calcium supplementation may have favorable effects on BMD and even reduce the risk of fracture, ^{31 –34} although some recent randomized controlled clinical trials have shown no evidence of a reduced fracture risk with vitamin D/calcium supplementation. ^{34 –36} Calcium supplementation has shown little effect in the first 5 years of the menopausal transition, when the majority of bone loss can be attributed to decreased estrogen production. ³¹ A meta-analysis ³⁷ showed that the treatment effect is greatest with calcium doses of ≥1200 mg.

Vitamin D deficiency is common in adults and can be caused by lack of sun exposure, intestinal fat malabsorption problems, and sequestration of vitamin D in the body fat in obese individuals. ²⁹ Measurement of 25(OH)D (the major circulating form of vitamin D) is recommended for patients with low BMD, as vitamin D deficiency contributes to osteopenia and osteoporosis. ²⁹ Exposure to sunlight, often combined with adequate supplementation, has been suggested to be the first-line treatment for patients with vitamin D deficiency. ²⁹ Of the two forms of vitamin D, ergocalciferol (vitamin D₂) and cholecalciferol (vitamin D₃), cholecalciferol appears to be more potent in increasing the level of circulating vitamin D and is the preferred form of supplementation. ²⁸ The greatest treatment effect is observed with doses of vitamin D of ≥800 IU.

Additional benefits of vitamin D/calcium supplementation in elderly people are a notable reduction in the incidence of falls, which may be attributed to effects on muscle strength and balance, ^{38 –40} and a possible reduction in cancer risk. ⁴¹

Bisphosphonates

Bisphosphonates are generally considered first-line therapy for patients with osteoporosis. Numerous studies ^{42 –49} have shown that bisphosphonates lead to significant improvements in BMD and reductions in vertebral and nonvertebral fracture risk (approximately 20%–50% relative to placebo) in postmenopausal women with osteoporosis. However, evidence suggests that oral bisphosphonates are associated with gastrointestinal toxicity, including dyspepsia, abdominal pain, gastritis, and esophagitis. ^{48,50 –52} A systematic review ⁵³ of 14 studies assessing the use of oral bisphosphonates for the treatment of osteoporosis found that concern over adverse side effects contributed to suboptimal patient compliance and/or persistence with therapy.

Because oral bisphosphonates have low bioavailability and maximal dosing is limited by the risk of gastrointestinal adverse effects, compliance with complicated dosing regimens is a critical requirement to ensure bioavailability and achieve efficacy. ⁴⁶ These drugs must be taken with plain water, on an empty stomach after an overnight fast, up to an hour before eating or ingesting other liquids or medications; patients must remain upright for 30–60 minutes after dosing. ^45,46 More recent formulations allow for weekly or monthly oral dosing ^47,54,55 ; however, regardless of the frequency of dosing, the strict dosing regimen remains a burden to patients. Evidence indicates that inconvenient dosing is a primary reason for lack of compliance and patient dissatisfaction with oral bisphosphonates. ^56,57

Intravenous bisphosphonates, including ibandronate and zoledronic acid, have been approved more recently as a treatment alternative for postmenopausal osteoporosis. Although their increased potency allows for more prolonged suppression of bone turnover and longer dosing intervals, intravenous bisphosphonates are generally more expensive than the oral formulations and are sometimes associated with transient flu-like symptoms (acute-phase reactions) and self-limited myalgia. ^43,46,58,59

Hormone therapy

Hormone therapy (estrogen monotherapy or combined estrogen/progestin therapy) is approved in the United States for prevention of postmenopausal osteoporosis, although the primary indication is for treatment of moderate to severe menopausal symptoms (i.e., vasomotor symptoms, vaginal atrophy). ¹ Hormone therapy has been shown to effectively reduce the risk of hip, vertebral, and other fractures (approximately 30%–40% relative to placebo). ^{60 –62} Discontinuation of estrogen therapy has been associated with accelerated bone loss, suggesting that long-term, continuous use is necessary to achieve efficacy. ⁶³

Results from two large, prospective clinical studies suggest that long-term estrogen-based therapy may be associated with an increased risk of adverse health outcomes, such as stroke and venous thromboembolic events. ^{60,64 –66} A small but significant increase in breast cancer risk was seen in women receiving combined estrogen/progestin therapy in the Women's Health Initiative (WHI) study ⁶⁴ ; in contrast, the use of estrogen therapy alone in hysterectomized women was associated with a 23% lower incidence of invasive breast cancer compared with placebo (p = 0.06), a finding that did not reach statistical significance. ⁶⁰ Based on these findings, many international and national organizations have issued a recommendation that women use hormone therapy only at the lowest effective dose for the minimum length of time based on treatment goals and after careful consideration of the associated risks and benefits. ^1,67

Raloxifene

Raloxifene is a selective estrogen receptor modulator (SERM) approved for the prevention and treatment of postmenopausal osteoporosis. Raloxifene has been shown to reduce vertebral fracture risk by approximately 30%–50% relative to placebo in postmenopausal women with osteoporosis. ^{68 –70} Treatment with raloxifene has not demonstrated significant reductions in the incidence of fractures at the hip or other nonvertebral sites.

Clinical studies ^{69,71 –73} have shown that treatment with raloxifene decreases the risk of invasive breast cancer by 50%–80% relative to placebo, which is similar to the risk reduction observed with tamoxifen. Raloxifene has been shown to significantly increase the risk of venous thromboembolic events, ^{68,69,71,72,74} and results of the Raloxifene Use for The Heart (RUTH) study ⁷² demonstrated a 49% increase in the incidence of fatal stroke with raloxifene treatment compared with placebo. Raloxifene use is not recommended in women with a previous history of or at high risk for thromboembolic disease or those who are pregnant, ⁷⁵ and in women at risk for stroke, the risk–benefit balance should be carefully considered. Raloxifene is also associated with an increased incidence of vasomotor symptoms (ie, hot flashes) and leg cramps. ^68,69

Because clinical data on reductions in fracture risk with raloxifene therapy are not as extensive as those for bisphosphonates, and considering the potential for vasomotor symptoms, venous thromboembolic events, and increased risk for fatal stroke in high-risk populations, raloxifene for postmenopausal osteoporosis is generally considered as a second-line therapy following poor tolerability with first-line agents. ⁷⁵

Salmon calcitonin

Salmon calcitonin is approved for the treatment of postmenopausal osteoporosis. In a study of postmenopausal women with osteoporosis, intranasal salmon calcitonin 200 IU/day was shown to reduce the risk of new vertebral fractures by 33% relative to placebo; however, significant reductions in fracture risk were not seen at doses of 100 or 400 IU/day. ⁷⁶ A significant increase in BMD was observed with the 400 IU/day dose, but no significant effect on hip BMD or nonvertebral fracture risk was noted at any dose. Intranasal salmon calcitonin is associated with an increased incidence of mild to moderate rhinitis (defined as nasal congestion, nasal discharge, or sneezing). ^76,77 Because of its relatively low potency compared with other available treatment options, it is generally reserved for osteoporotic women who are unwilling or unable to take other osteoporosis agents. ^1,78

Parathyroid hormone

Teriparatide (human recombinant parathyroid hormone 1–34) administered by daily subcutaneous injection has been shown to stimulate bone formation and resorption, increase BMD, and reduce the risk of vertebral fractures by 65%–69% and nonvertebral fractures by 35%–40% relative to placebo. ⁷⁹ In a comparative study ⁸⁰ with alendronate, teriparatide was associated with significantly greater increases in lumbar spine BMD (p < 0.001) and a significantly lower incidence of nonvertebral fractures (p < 0.05). Teriparatide is associated with an increased incidence of nausea, dizziness, and leg cramps. ^79,80 A maximum treatment duration of 2 years is recommended because of limited evidence of efficacy beyond 2 years and preclinical studies showing the development of osteosarcoma in rats. ⁸¹ Teriparatide is considerably more expensive than other available osteoporosis agents and is indicated for postmenopausal women and men with osteoporosis who are at high risk for fractures, including those with a history of osteoporotic fracture, very low BMD (i.e., T-score <−3.0), or multiple risk factors for fracture or those who have failed or shown intolerance to previous osteoporosis therapy. ^81,82

It is not known if any of these agents used to reduce fracture risk in women with postmenopausal osteoporosis is more or less effective than any of the others because no randomized head-to-head clinical trial comparing agents—with fractures as the primary end point—has been completed. ⁸³

Strontium ranelate

Strontium, at low doses, reduces bone resorption and increases bone formation in healthy animals receiving a normal calcium diet. Administration of strontium to ovariectomized rats has been shown to prevent bone loss associated with estrogen deficiency, presumably by decreasing bone resorption. Findings in other models of osteopenia indicate an increase in bone formation with strontium. ⁸⁴ The results of in vitro studies suggest that this may be the result of strontium's role in influencing bone cell recruitment and function.

In a phase II study ⁸⁵ of postmenopausal women with osteoporosis (N = 353), strontium ranelate 2 g/day demonstrated significantly greater increases in lumbar spine BMD at 12 and 24 months compared with placebo. The proportion of subjects experiencing a new vertebral fracture during the second year of treatment was reduced by 44% for strontium ranelate 2 g/day vs. placebo. In a separate study, ⁸⁶ strontium ranelate 1 g/day demonstrated significant increases in lumbar spine and femoral neck BMD at 2 years compared with placebo.

In the Treatment of Peripheral Osteoporosis study, ⁸⁷ more than 5000 women with postmenopausal osteoporosis received treatment with strontium ranelate 2 g/day or placebo for 3 years. Compared with placebo, strontium ranelate reduced the incidence of vertebral fractures by 45% at 1 year and 39% at 3 years (p < 0.001 for both). Also, the risk of nonvertebral fractures was reduced by 16% with strontium ranelate vs. placebo (p = 0.04). Although the risk of hip fracture was reduced by 15%, this was not significantly different from placebo. After the first 3 months of treatment, nausea and diarrhea were more frequent with strontium ranelate treatment than with placebo, but this difference was not apparent thereafter. Findings from a separate study ⁸⁸ in a comparable (but smaller) population demonstrated similar outcomes. Strontium ranelate is marketed in Europe, Australia, and some other countries but is not yet available in the United States. It is provided as granules that must be suspended in plain water and consumed immediately at least 2 hours after eating (ideally at bedtime). ^{85 –88}

Poor Compliance with Therapy and Impact on Clinical Outcomes

Despite the availability of numerous treatment options for osteoporosis, persistence with therapy remains suboptimal. ⁸⁹ A systematic review ⁵³ of the literature found that the average duration of therapy (i.e., persistence) with osteoporosis treatments, primarily bisphosphonates, was generally <1 year. Although persistence with bisphosphonate therapy has been shown to be greater with less frequent dosing (i.e., weekly vs. daily regimen), the overall proportion of patients continuing therapy remains low. ^53,90 Results of a survey ⁹⁰ of women receiving bisphosphonate therapy in the United States, France, and the United Kingdom demonstrated that the 44% of women on the weekly regimen (in the United States) persisted with treatment for 12 months compared with 32% of women on the daily regimen (p < 0.001).

Evidence indicates that raloxifene may be associated with lower rates of treatment discontinuation compared with bisphosphonates. ^57,91 In a study ⁵⁷ of postmenopausal Asian women, the 12-month completion rate for daily treatment with either alendronate or risedronate was significantly lower than that with raloxifene (37.5% vs. 50.2%, p < 0.001). Results of a Spanish study ⁹¹ that evaluated daily therapy with raloxifene or alendronate over a 1-year period also showed significantly higher compliance rates in patients receiving raloxifene vs. alendronate (68.7% vs. 54.0%, p < 0.001). In both studies, women taking raloxifene reported greater satisfaction with treatment compared with those taking bisphosphonates (p < 0.01). ^57,91 Discontinuation rates for women taking hormone therapy appear to be generally similar to or greater than that for women taking bisphosphonates or raloxifene. ⁸⁹

Poor persistence with treatment may be associated with smaller decreases in bone turnover, smaller increases in BMD, and a higher risk of fracture and disability. ⁹² Poor long-term compliance may lead to increased healthcare costs and substantially reduced quality of life, as the likelihood of fractures is increased. ^{92 –94} A recent study ⁹⁵ showed that noncompliant users of bisphosphonate therapy were 50% more likely to sustain an osteoporotic fracture than were compliant users. The results of a claims database study ⁹⁶ assessing alendronate and risedronate therapy in women ≥45 years demonstrated that those who were compliant with therapy over a 24-month period had a 21% reduction in the incidence of fractures compared with those who were not adherent to treatment (p < 0.001). The largest reduction in risk was noted for hip fractures (30% relative to nonadherent patients). Persistence with therapy (defined as a prescription refill gap of ≤30 days) was associated with a significant reduction in the incidence of all, vertebral, hip, and wrist fractures. ⁹⁷ An analysis ⁹⁸ of data from another health insurance database demonstrated that compliance with bisphosphonate or raloxifene therapy for 1 year significantly reduced the risk of hip and vertebral fractures by 60% and 40%, respectively. This effect of compliance on the effectiveness of osteoporosis therapies mirrors that observed with other chronic diseases. For instance, in a meta-analysis ⁹⁹ of 21 studies evaluating a range of chronic diseases (including cardiovascular diseases, HIV, and diabetes), good compliance with treatment was associated with a 44% decrease in mortality risk.

The reasons for noncompliance with therapy are variable and dependent on the patient and clinical setting. Medication tolerability may play a key role in persistence with therapy. ⁴ In a study ¹⁰⁰ that analyzed dispensed prescriptions for osteoporosis medications in women ≥55 years, there was a significant association between frequency of gastrointestinal adverse events (measured by the concomitant use of selected medications) and decreased persistence with bisphosphonate therapy. In another study, ⁹¹ a significantly greater percentage of women treated with alendronate (9.9%) vs. raloxifene (3.4%) experienced gastrointestinal adverse events that led to study withdrawal (p < 0.001). Poor compliance with oral bisphosphonates has also been associated with the inconvenience and complexity of the dosing regimen. ^53,57 Intravenous administration of bisphosphonates may improve compliance in patients who have trouble with the frequent dosing or gastrointestinal intolerance associated with oral bisphosphonates. ¹⁰¹ Safety concerns are the most commonly cited reason for noncompliance with hormone therapy. ⁸⁹

Patients may also fail to continue an osteoporosis medication because they cannot “feel” a benefit or observe evidence of a response to therapy, do not believe their diagnosis, or have a limited understanding of fracture risk. ^4,53,89 An analysis ¹⁰² of pharmacy claims data showed that patients were more likely to remain on treatment if they had received BMD testing before and after initiation of therapy or had experienced a fracture before and after starting therapy. Patients residing in nursing homes were also more likely to continue treatment, perhaps because of the staff's involvement in drug administration and monitoring. Sometimes, distrust of the pharmaceutical industry or misconceptions regarding the risk of very rare events, such as osteonecrosis of the jaw with bisphosphonates, ¹⁰³ are factors in patients failing to begin or continue therapy.

The lack of an observed change in BMD with antiresorptive therapy does not necessarily indicate treatment failure, as a key determinant of BMD change is the baseline remodeling rate. ¹⁰⁴ Individuals with high baseline remodeling rates generally have greater increases in BMD with therapy than those with low baseline remodeling rates. ¹⁰⁴ Although fracture risk may be reduced in both cases, ¹⁰⁴ a small increase in BMD may be discouraging and cause a patient to discontinue therapy. Technical errors in the use of dual energy x-ray absorptiometry (DXA) technology (e.g., failure to maintain proper calibration of DXA system, improper patient positioning, mislabeling of scans) can also lead to uninformed patient care decisions. ¹⁰⁵ Educating physicians on the proper use of DXA and educating physicians and patients alike on the limitations of BMD testing may help to improve patient compliance. ¹⁰⁵

Suppression of biochemical markers of bone turnover (e.g., C-telopeptide and N-telopeptide) can be detected with antiresorptive therapy after 3–6 months and with anabolic therapies after 1–3 months. ²⁷ Short-term determinations of bone turnover markers have been shown to accurately identify individuals responding to therapy and are reliable predictors of the magnitude of change in BMD and fracture risk. ^{106 –108} Thus, measuring bone markers before and after initiation of therapy may help to identify and encourage treatment responders, thereby improving compliance. One study ⁵ showed that consultation with a nurse 3 months after initiation of treatment enhanced compliance regardless of whether or not the patient received information about changes in bone turnover markers. This suggests that the opportunity to discuss treatment issues alone may contribute to improved compliance.

New Therapies

Novel SERMs

A number of novel SERMs are currently undergoing clinical development for the prevention and treatment of postmenopausal osteoporosis. SERMs are known to exhibit estrogen receptor agonist and antagonist activity depending on the target tissue. An ideal SERM for postmenopausal osteoporosis would preserve bone mass and reduce the risk of fractures while minimizing adverse effects, particularly endometrial and breast stimulation. Clinical development of several other SERMs previously evaluated for postmenopausal osteoporosis (e.g., idoxifene, levormeloxifene) was discontinued because of adverse uterine effects, particularly increased endometrial thickness. ^{109 –113}

Bazedoxifene

Bazedoxifene is currently in late-stage clinical development for the prevention and treatment of postmenopausal osteoporosis. ¹¹⁴ In preclinical studies, ^{115 –118} bazedoxifene demonstrated bone-sparing effects and had a favorable impact on the lipid profile without evidence of endometrial or breast stimulation. In rodent models, treatment with bazedoxifene had positive effects on BMD and bone histology and strength and reduced total cholesterol levels. In addition, bazedoxifene was found to inhibit 17β-estradiol–induced and raloxifene-induced increases in uterine wet weight. Bazedoxifene treatment also antagonized 17β-estradiol–induced proliferation of MCF-7 human breast cancer cells in a dose-dependent manner. In a 6-month phase II study ¹¹⁹ of healthy postmenopausal women (N = 497), bazedoxifene 2.5–40 mg/day showed no significant change in endometrial thickness as measured by transvaginal ultrasound compared with placebo. There was no case of endometrial hyperplasia with any dose of bazedoxifene.

Among the new SERMs in clinical development, bazedoxifene is the first to have reported results from phase III trials. In a 3-year phase III trial (N = 7492) ¹²⁰ that evaluated bazedoxifene in treating postmenopausal women with osteoporosis, the incidence of new vertebral fractures was reduced by 42%, 37%, and 42% with bazedoxifene 20 mg/day, bazedoxifene 40 mg/day, and raloxifene 60 mg/day, respectively, relative to placebo (p < 0.05). In a subgroup of women (n = 1772) at higher risk for fracture based on known skeletal risk factors (low femoral neck BMD or prevalent vertebral fracture), bazedoxifene 20 mg significantly reduced the risk of nonvertebral fracture relative to placebo by 50% (p = 0.02) and raloxifene 60 mg by 44% (p = 0.05). Bazedoxifene was generally well tolerated, with no evidence of endometrial or breast stimulation. ^{120 –122}

In a 2-year phase III study ¹²³ of postmenopausal women with normal or low bone mass (N = 1583), treatment with bazedoxifene 10, 20, and 40 mg/day and raloxifene 60 mg/day was shown to prevent bone loss, whereas placebo was associated with a significant loss of BMD at all skeletal sites. Of note, this loss of BMD in placebo-treated women occurred despite daily supplementation with elemental calcium (600 mg). Significant reductions in serum osteocalcin and C-telopeptide levels from baseline and relative to placebo with bazedoxifene and raloxifene treatment were observed as early as 3 months and sustained through study end (p < 0.001). No adverse effects on the endometrium or breast were noted with bazedoxifene treatment. ^123,124 There were no diagnoses of endometrial hyperplasia or endometrial carcinoma in bazedoxifene-treated subjects. Bazedoxifene did not increase the incidence of breast cancer or breast pain compared with placebo.

Lasofoxifene

Lasofoxifene is undergoing clinical investigation for the prevention and treatment of postmenopausal osteoporosis and for the treatment of vaginal atrophy. In preclinical studies of rodent models, lasofoxifene was shown to prevent bone loss, preserve bone strength, and reduce total cholesterol levels. ^125,126 Lasofoxifene also demonstrated a low potential for vaginal or uterine tissue proliferation in immature rats. ¹²⁷ In a study ¹²⁸ of surgically postmenopausal cynomolgus monkeys, lasofoxifene was shown to preserve BMD and reduce bone turnover.

In a phase II study ¹⁰⁷ (N = 394) of healthy postmenopausal women, treatment with lasofoxifene 0.017, 0.05, 0.15, and 0.5 mg/day was shown to significantly increase lumbar spine BMD compared with placebo after 1 year (p < 0.001). There were no reports of endometrial cancer, hyperplasia, or other abnormal pathology in the study; however, small but statistically significant increases in mean endometrial thickness were observed with all doses of lasofoxifene relative to placebo. In a 2-year phase II trial ¹²⁹ (N = 410), lasofoxifene 0.25 and 1.0 mg/day were associated with significant increases in lumbar spine BMD compared with placebo or raloxifene 60 mg (p ≤ 0.05) in postmenopausal women. Effects on hip BMD were similar between the lasofoxifene and raloxifene groups. The incidence of hot flashes and leg cramps was comparable in subjects receiving lasofoxifene or raloxifene and higher than that in subjects receiving placebo. Significant increases in mean endometrial thickness were observed with lasofoxifene treatment compared with placebo (p < 0.001).

A 3-year, randomized, double-blind, placebo-controlled phase III trial ¹³⁰ of postmenopausal women with osteoporosis showed that lasofoxifene 0.25 and 0.5 mg/day significantly reduced the risk of vertebral fracture by 31% and 42%, respectively, relative to placebo (p < 0.002). Further, the risk of nonvertebral fracture was reduced by 22% with lasofoxifene 0.5 mg/day relative to placebo (p = 0.02). ¹³⁰ Both doses of las-ofoxifene were also shown to significantly increase BMD at the spine and femoral neck compared with placebo (p < 0.001) and to reduce levels of bone turnover markers. ¹³¹ Compared with placebo, however, lasofoxifene was associated with a significant increase in endometrial thickness and rates of endometrial polyps and vaginal bleeding. Further, lasofoxifene treatment increased the number of diagnostic uterine procedures compared with placebo. ¹³² Also completed is a 2-year phase III study comparing the effects of lasofoxifene, raloxifene, and placebo on BMD response, low-density lipoprotein cholesterol (LDL-C), and vaginal pH and Maturation Index. ¹³³

Ospemifene

Ospemifene is currently undergoing clinical evaluation for the treatment of vulvar vaginal atrophy and for the prevention and treatment of osteoporosis in postmenopausal women. Ospemifene has been shown to prevent bone loss, preserve bone strength, and reduce total cholesterol levels in ovariectomized rats; in immature rats, ospemifene demonstrated a dose-dependent increase in uterine wet weight. ¹³⁴ In phase II studies ^{135 –137} of healthy postmenopausal women, treatment with ospemifene 30, 60, and 90 mg/day was shown to reduce bone turnover; ospemifene had a similar effect on markers of bone resorption and bone formation as raloxifene. Ospemifene was associated with a significant estrogenic effect on the vaginal epithelium, as demonstrated by decreased parabasal cells and increased intermediate and superficial cells on a Papanicolaou test. ¹³⁶

Arzoxifene

Arzoxifene was originally developed for the prevention and treatment of breast cancer; however, phase III studies evaluating arzoxifene for estrogen–positive or hormone receptor–positive breast cancer were discontinued early because of evidence from an interim analysis indicating inferiority of arzoxifene relative to tamoxifen for progression-free survival and time to treatment failure. ¹³⁸ Arzoxifene is also under investigation for the prevention and treatment of postmenopausal osteoporosis. In rodent models, ^139,140 treatment with arzoxifene was shown to prevent bone loss, preserve bone strength, and reduce total cholesterol levels without evidence of endometrial stimulation. Arzoxifene is currently under clinical evaluation in ongoing phase III studies ^{141 –143} of osteoporosis prevention and treatment, based on findings from phase I and II studies demonstrating a reduction in bone turnover with arzoxifene. ^{144 –147}

Denosumab

Denosumab (formerly known as AMG 162) is a fully human monoclonal antibody that inhibits the receptor activator of nuclear factor kappa B ligand, a molecule that enhances the differentiation, function, and survival of osteoclasts. Denosumab is administered by subcutaneous injection every 3 or 6 months and has been studied for the treatment of skeletal diseases, such as bone metastases and multiple myeloma, ¹⁴⁸ as well as for osteoporosis. In a 2-year phase II study ^149,150 of postmenopausal women with osteopenia or osteoporosis (N = 412), denosumab treatment was associated with significant increases in BMD at the lumbar spine, hip, and distal radius compared with placebo. These changes were similar to or greater than those seen with once-weekly alendronate, with the most efficacious doses being denosumab 30 mg every 3 months or 60 mg every 6 months. Discontinuation of denosumab for 2 years was associated with almost complete reversal of BMD gains observed during treatment. ¹⁵¹ In contrast, discontinuation of alendronate led to modest decreases in BMD at the lumbar spine; BMD loss at the total hip was more substantial, but the values remained greater relative to baseline. ¹⁵¹ Findings from a 1-year phase III study ¹⁵² of postmenopausal women with low bone mass were consistent with those seen in the 2-year phase II study, as denosumab was associated with significantly greater increases in BMD at the lumbar spine, femoral neck, trochanter, and distal radius compared with alendronate. Findings from phase II and III studies have shown that denosumab is generally well tolerated with a reduction in the risk of vertebral, nonvertebral, and hip fractures. ^{149,150,152,153}

Summary

Osteoporosis is a skeletal disease that increases the risk of fractures, causing increased morbidity, mortality, and impaired quality of life. It represents a significant social and economic burden, particularly in postmenopausal women. Although our understanding of the pathophysiological origins of osteoporosis has improved greatly over the past two decades and effective diagnostic tools and therapeutic agents have been developed, osteoporosis remains an underdiagnosed and undertreated disease. Evidence indicates that even when treatment is initiated, compliance and persistence are poor. Factors that may contribute to poor compliance with therapy include inadequate patient understanding of fracture risk, complexity of dosing for some agents, adverse events with treatment, fear of adverse events, misleading DXA results, and difficulties in assessing the relative benefit and risk of treatment. Promising new agents, now under investigation in clinical trials, have been developed with the goal of simplifying the dosing regimen and enhancing the benefit–risk profile, thereby improving long-term clinical outcomes.