Unmet Needs in the Care of Postmenopausal Osteoporosis
Published Online: July 28, 2011
E. Michael Lewiecki, MD, FACP, FACE
Osteoporosis is an asymptomatic skeletal disorder characterized by compromised bone strength. It is a serious health concern, especially for aging postmenopausal women, due to an increased risk for fracture and associated complications.1 Approximately 200 million individuals are affected by osteoporosis worldwide, including one-third of women aged 60 to 70 years and two-thirds of women older than 80 years.2 Hip and vertebral fractures are associated with signifi cant morbidity and mortality.3,4 The economic burden of osteoporotic fractures is substantial,5 with hip fractures being the most costly type of fractures in terms of direct costs for healthcare services.6
The burden of osteoporosis on the healthcare system is expected to grow as the population ages; thus, it has become increasingly important to identify patients at high risk for fracture who are most likely to benefi t from treatment. The recently developed Fracture Risk Assessment Tool (FRAX) may be particularly useful for this purpose,7 especially in distinguishing those patients with osteopenia (bone mineral density [BMD] T-score between −1.0 and −2.5) who are at high fracture risk and could benefi t from pharmacologic treatment versus those who are not at high fracture risk and may not need pharmacologic treatment. FRAX is a computerbased algorithm that calculates the 10-year probability of a major osteoporotic fracture (clinical vertebral, hip, forearm, or humerus fracture) in untreated men and women between 40 and 90 years of age based on femoral neck BMD and clinical risk factors, such as prior fragility fracture and parental history of hip fracture. The selection of a drug for a patient needing treatment is complex; the prescribing physician must consider the benefi ts and limitations of each drug in the context of the patient’s comorbidities, prior drug experiences, affordability, and healthcare priorities and concerns. Further, long-term patient compliance and persistence with osteoporosis therapy have been shown to be poor, which may prevent patients from achieving optimal fracture protection8,9 and ultimately contribute to increased healthcare costs.10
This article is an update on the benefits and challenges of current treatment options for postmenopausal osteoporosis and includes a discussion of novel therapies that have been evaluated for this disease.
BENEFITS AND CHALLENGES OF CURRENTLY AVAILABLE OSTEOPOROSIS THERAPIES
Nonpharmacologic strategies to prevent bone loss and reduce fracture risk include lifestyle modification (eg, regular physical activity, smoking cessation, limiting alcohol), proper nutrition, and dietary supplementation (calcium, vitamin D, and possibly vitamin K), if needed.11 The National Osteoporosis Foundation recommends pharmacologic treatment for postmenopausal women with the following: a hip or vertebral fracture; a BMD T-score less than or equal to −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 hip fracture ≥3% or major osteoporotic fracture (hip, spine, proximal humerus, distal forearm) ≥20% based on the US adaptation of FRAX.12 The benefits and limitations of antiresorptive medications, such as bisphosphonates, hormone therapy (HT), selective estrogen receptor modulators (SERMs), salmon calcitonin, and strontium ranelate, along with the anabolic medication parathyroid hormone (teriparatide and the monoclonal antibody denosumab), are discussed in the following sections (Table 1).
Bisphosphonates reduce resorption of bone by inhibiting the bone resorption activity of osteoclasts.1 Bisphosphonates are typically considered as first-line therapy, as they have been shown to result in significant reductions in vertebral and nonvertebral fracture risk (approximately 20% to 50% relative to placebo) and improvements in BMD.13-15 While several oral and intravenous (IV) bisphosphonateformulations are available for the management of osteoporosis, there are no studies directly comparing their antifracture efficacy and it is unlikely that such studies will be performed.16
Oral bisphosphonates (alendronate, ibandronate, risedronate) may be associated with bothersome gastrointestinal (GI) adverse events, including dyspepsia, abdominal pain, gastritis, and esophagitis,14,17 which often lead to problems with patient compliance and/or persistence.18,19 These events are more common in clinical practice than in the clinical trial setting, where the frequency of reported GI adverse events is similar to that with placebo. A recent study compared the GI safety of weekly alendronate versus risedronate and found no important differences between these 2 agents.20 The strict dosing regimens associated with oral bisphosphonates (overnight fast, ingestion with plain water, postdose fasting for 30 to 60 minutes in the upright position) also pose a burden for patients and may contribute to decreased compliance and satisfaction with treatment.21,22
Intravenous bisphosphonates such as ibandronate and zoledronic acid are effective treatments for osteoporosis and are especially useful for patients who are unable to take oral bisphosphonates because of GI intolerance, GI contraindication, or malabsorption; however, they are generally more expensive than oral formulations for which generic options are available. Intravenous bisphosphonates may be associated with transient flu-like symptoms, particularly in bisphosphonate-naive patients.16,17 Primary care physicians are sometimes reluctant to recommend IV bisphosphonate treatment, probably in part
because of the challenge of managing the bureaucracy of prior authorizations and insurance coverage, as well as challenges related to administering IV infusions; if the physician does not have the capability of administering IV infusions in the office, the patient must be referred elsewhere for treatment.
Bisphosphonates have been associated with rare but highly publicized adverse events.23 Oral alendronate and risedronate and IV ibandronate and zoledronic acid have been associated with osteonecrosis of the jaw in patients treated for osteoporosis, with most cases occurring in cancer patients treated with high cumulative doses of IV bisphosphonates.24,25 Long-term use of oral alendronate and risedronate may be associated with persistent bone, joint, or muscle pain.25 Low-trauma femoral shaft fractures have been reported in patients treated with an oral bisphosphonate, although a causal relationship has not been established.26
Hormone therapy, either estrogen monotherapy or combined estrogen/progestin therapy, is primarily indicated for the treatment of menopausal symptoms such as hot flushes, night sweats, and vaginal dryness, but is also approved for the prevention of osteoporosis.27-30 Hormone therapy has been shown to improve BMD and reduce the risk of hip, vertebral, and other fractures by approximately 30% to 40% relative to placebo.31-33 However, because of potential safety concerns associated with long-term HT, including stroke and thromboembolic events31,34,35 as well as breast cancer with combined estrogen/progestin therapy,34 current guidelines recommend that HT be used at the lowest effective dose for the minimum length of time after a careful consideration of the risks and benefits for an individual woman.1,36
Selective Estrogen Receptor Modulators
Selective estrogen receptor modulators, also referred to as estrogen agonists/antagonists, are a class of compounds that can exhibit estrogen receptor agonist or antagonist activity depending on the target tissue. 1,37 Raloxifene is currently the only SERM approved in the United States for the prevention and treatment of postmenopausal osteoporosis; it is also indicated for reduction in the risk of invasive breast cancer in postmenopausal women with osteoporosis and/or postmenopausal women at high risk of invasive breast cancer.38
Large, multicenter, double-blind, randomized trials in postmenopausal women have shown that raloxifene significantly increases femoral neck, spine, hip, and total body BMD compared with placebo.39,40 These and other studies have shown that treatment with raloxifene reduces vertebral fracture risk by approximately 30% to 50% relative to placebo,40-42 but does not have significant effects on nonvertebral fracture risk (including hip).40,41 Raloxifene has also been shown to be as effective as tamoxifen in decreasing the risk of invasive breast cancer (incidence,4.41 per 1000 vs 4.30 per 1000, respectively; risk ratio 1.02; 95% confidence interval, 0.82-1.28).43 However, raloxifene has been associated with a significant increase in the risk of venous thromboembolic events and fatal stroke,44 as well as an increased incidence of hot flushes and leg cramps.40,41 Because of these safety concerns and the lack of efficacy in nonvertebral fracture risk reduction, raloxifene is generally considered as second-line therapy for women who do not tolerate first-line bisphosphonate therapy.45 Raloxifene is most suitable for women in their early postmenopausal years who are not at high risk for hip fracture, do not require treatment for vasomotor symptoms, and are not at high risk for venous thromboembolic events, stroke, or coronary artery disease, particularly those at high risk for breast cancer.38
Salmon calcitonin, an inhibitor of bone resorption, is approved for the treatment but not prevention of osteoporosis.1 Intranasal salmon calcitonin has been shown to reduce the risk of new vertebral fracture by 33% relative to placebo and to significantly increase lumbar spine BMD, but has shown no significant effect on hip BMD or on nonvertebral fracture risk.46 It may also have an analgesic effect in osteoporosis patients with acute pain due to vertebral fractures.47 Although intranasal salmon calcitonin is generally well tolerated and has no known drug interactions, 48 there have been reports of a significant increase in rhinitis (eg, nasal congestion, nasal discharge, or sneezing). 46 Because the antifracture effect of salmon calcitonin is considered lower than that of other available antiresorptive therapies,1,20,49 it is generally reserved for osteoporosis patients who are unwilling or unable to take other agents.1
Strontium ranelate, a therapeutic agent that may have both antiresorptive and anabolic effects in bone,50 is used outside the United States as a first-line treatment option for osteoporosis.51 Randomized clinical trials demonstrated that strontium ranelate produces significant and sustained reductions in vertebral and nonvertebral fracture risk compared with placebo in postmenopausal women with osteoporosis.52-55 Common adverse events associated with strontium ranelate include nausea, diarrhea, and headache.56
Teriparatide (human recombinant parathyroid hormone 1-34) is the only anabolic agent approved for the treatment of osteoporosis in the United States.57 When administered as a daily subcutaneous injection at a 20-μg dose, teriparatide has been shown to improve BMD and reduce vertebral fracture risk by 65% and nonvertebral fracture risk by 35% relative to placebo.58,59 Adverse events associated with teriparatide treatment include nausea, headache, dizziness, and leg cramps.58 In preclinical rat studies, 20 to 24 months of teriparatide treatment was associated with the development of osteosarcoma.60 Although this does not appear to be a risk in humans, there is ongoing surveillance of postmarketing reported cases; treatment time in humans is limited to 2 years.57 Teriparatide is considerably more expensive than other osteoporosis agents61 and is indicated for use in patients at high risk for fracture.62
Denosumab is a fully human monoclonal antibody that inhibits bone resorption by binding to the receptor activator of nuclear factor κB ligand, a cytokine that stimulates the formation, activity, and survival of osteoclasts.63,64 Denosumab is administered as a 60-mg subcutaneous injection every 6 months. Results from phase II and III studies63,65 showed that denosumab significantly increased BMD compared with placebo, with similar or greater effects than those seen with alendronate. Denosumab also decreased bone turnover marker levels compared with placebo.65 In postmenopausal women with osteoporosis, denosumab reduced the risk of vertebral fractures, nonvertebral fractures, and hip fractures compared with placebo.66 Denosumab has been shown to be generally well tolerated, 63,65 and most reported adverse events were mild to moderate in severity.63 There was an increased incidence of infections classified as serious adverse events in some trials,65,67 but not in the large phase III pivotal fracture trial.66 A higher incidence of cellulitis classified as a serious adverse event was observed with denosumab versus placebo in the phase III trial.66
EFFECTS OF POOR COMPLIANCE/ PERSISTENCE ON CLINICAL AND ECONOMIC OUTCOMES
Although there are many effective pharmacologic options for the prevention and/or treatment of postmenopausal osteoporosis, compliance and persistence with therapy are poor.19 A study by McCombs and colleagues using paid claims data from a large health insurer investigated compliance with bisphosphonates, HT (both estrogen only and combined estrogen/progestin), and raloxifene in 58,109 patients undergoing drug therapy for osteoporosis.10 The 1-year compliance rates were below 25% for all osteoporosis therapies investigated. The mean unadjusted duration of continuous therapy was 245 days for bisphosphonates, 262 days for estrogen-only HT, 292 days for estrogen plus progestin HT, and 221 days for raloxifene.10 Noncompliance with bisphosphonate use is a continuing challenge,68 and in clinical practice, it has been reported that 50% to 75% of patients discontinue the use of bisphosphonates in their first year of therapy.10,68 Results from a systematic review suggest that compliance and persistence with bisphosphonate therapy may improve with weekly versus daily dosing schedules; however, overall compliance and persistence rates remained suboptimal.19
Poor compliance/persistence with therapy hinders osteoporosis patients from obtaining the maximum benefit associated with their treatment, which can lead to decreased protection from fracture8,9 and potentially translate into increased healthcare costs and decreased patient quality of life.69,70 On the other hand, good compliance with osteoporosis therapy has been shown to be associated with a significant reduction in the risk of hip and vertebral fracture and a significant reduction in physician services, hospital outpatient services, and hospital care.10 The reasons for poor compliance/persistence are numerous, but include the cost of treatment, lack of interest in taking medication, non–treatment-related health issues, and complex dosing regimens.71,72 Although increased compliance/persistence is a goal in osteoporosis therapy, it should never compromise the ultimate goal of antifracture efficacy.73 Taken together, there remains an ongoing need for the development of safe and effective therapeutic options to meet the individual needs of women.
COST-EFFECTIVENESS OF OSTEOPOROSIS THERAPY
Evidence suggests that osteoporosis treatment can be cost-effective if appropriately targeted to at-risk populations, as savings from fracture prevention compensate for treatment costs.74 A recent economic analysis specific to the United States was conducted, incorporating cost and health consequences of clinical fractures, to identify a treatment intervention threshold whereby osteoporosis therapy would be cost-effective based on quality-adjusted life-years gained.75 Utilizing the FRAX algorithm to predict fracture risk, a 10-year hip fracture probability of 3% was identified as this threshold, as stated by the National Osteoporosis Foundation in its updated treatment guidelines.12
THERAPIES THAT HAVE BEEN EVALUATED IN PHASE III TRIALS FOR POSTMENOPAUSAL OSTEOPOROSIS
There are a few pharmacologic agents that have completed phase III clinical trials for the prevention and/or treatment of postmenopausal osteoporosis. Bazedoxifene and lasofoxifene have recently been approved for use in the European Union.
Selective Estrogen Receptor Modulators
The SERMs are attractive agents for postmenopausal osteoporosis because of their ability to have estrogen receptor agonist or antagonist activity depending on the target tissue.37 The ideal SERM would have estrogen receptor agonist activity in tissues where the effects of estrogens are favorable (eg, skeleton, central nervous system) and have neutral or estrogen receptor antagonist activity in tissues where the stimulatory effects of estrogens are not desired (eg, breast, endometrium).37 Because each SERM shows a unique tissue-selectivity profile, it is important to consider the potential place in therapy of new agents in
development on an individual basis.
Bazedoxifene. Bazedoxifene is in late-stage clinical development for the prevention and treatment of postmenopausal osteoporosis.76 Findings from a large, 3-year prospective phase III trial of 7492 postmenopausal women with osteoporosis showed that bazedoxifene 20 and 40 mg/day and raloxifene 60 mg/day significantly reduced new vertebral fracture rates by 42%, 37%, and 42%, respectively, relative to placebo.77 The overall incidence of nonvertebral fractures was not different among
groups. In a subgroup analysis of 1772 patients at higher risk for fracture, bazedoxifene 20 mg/day significantly decreased nonvertebral fracture risk by 50% relative to placebo and by 44% relative to raloxifene 60 mg/day77; independent analyses of fracture data from the overall study population confirmed that the treatment effects of bazedoxifene on morphometric vertebral and all clinical fractures increased with increasing fracture probability as estimated by FRAX.78
In a 2-year phase III trial of 1583 postmenopausal women at risk for osteoporosis, bazedoxifene 10, 20, and 40 mg/day and raloxifene 60 mg/day were shown to effectively prevent bone loss and reduce serum levels of bone turnover markers (osteocalcin and C-telopeptide) relative to placebo, with favorable effects on the lipid profile.79 Bazedoxifene was generally safe and well tolerated in both phase III trials, with no evidence of endometrial or breast stimulation.80-82 Reports of hot flushes, leg cramps, and deep vein thrombosis have been shown to be higher with bazedoxifene compared with placebo.77 Bazedoxifene is also currently under clinical investigation in combination with conjugated estrogens (tissue selective estrogen complex) for the treatment of menopausal symptoms (hot flushes and vulvar vaginal atrophy) and osteoporosis prevention in postmenopausal women with an intact uterus.83
Lasofoxifene. Lasofoxifene has been evaluated for the treatment of postmenopausal osteoporosis.84 A 2-year phase II study of lasofoxifene 0.25 and 1.0 mg/day versus raloxifene 60 mg/day in 410 postmenopausal women showed that treatment with lasofoxifene significantly increased lumbar spine BMD compared with raloxifene or placebo.85 Lasofoxifene and raloxifene were equally effective in decreasing levels of bone turnover markers and increasing total hip BMD versus placebo.85 The incidence of hot flushes and leg cramps was comparable in patients receiving lasofoxifene and raloxifene, but higher than the incidence with placebo.85
Results from a 3-year phase III trial of women with postmenopausal osteoporosis showed that treatment with lasofoxifene 0.25 and 0.5 mg/day significantly reduced vertebral fracture risk by 31% and 42%, respectively, relative to placebo.86 Lasofoxifene 0.5 mg/day reduced the risk of nonvertebral fracture by 22% compared with placebo.86 Both doses of lasofoxifene increased BMD at the spine and femoral neck and reduced levels of bone marker turnover versus placebo.87 Lasofoxifene also significantly decreased the risk of breast cancer.86 Although no increase in endometrial hyperplasia or carcinoma was noted, treatment with lasofoxifene has been shown to be associated with significant increases in endometrial thickness, rates of endometrial polyps, vaginal bleeding, and the number of diagnostic uterine procedures compared with placebo.88 Treatment with lasofoxifene has also been associated with an increase in venous thromboembolic events.88 Preliminary clinical data indicate that treatment with lasofoxifene may improve the signs and symptoms of vaginal atrophy, such as dyspareunia.89-91 Lasofoxifene is also currently being evaluated for the prevention of breast cancer.
Arzoxifene. Arzoxifene, another SERM recently studied for the prevention and treatment of postmenopausal osteoporosis, was not found sufficiently different from or superior to raloxifene to merit submission for regulatory approval.92
Despite the availability of therapeutic agents proved to reduce fracture risk in women with postmenopausal osteoporosis, many patients do not take medication correctly or for a long enough period of time to benefit from fracture risk reduction. Poor compliance and persistence are associated with negative clinical outcomes, subsequently leading to increased healthcare costs. Novel pharmacologic agents for the prevention and/or treatment of postmenopausal osteoporosis may offer improved risk-benefit profiles compared with conventional options. Denosumab provides a robust antiresorptive effect with the convenience of infrequent dosing and subcutaneous administration. Newer SERMs for postmenopausal osteoporosis have distinctive tissueselective activity profiles that may offer unique benefits for individual women. Other agents in development for osteoporosis include odanacatib,93 orally administered cathepsin K inhibitor, and AMG 785,94 a monoclonal antibody against sclerostin.
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