This review of currently available osteoporosis treatments highlights the unmet need for improved osteoporosis therapy; novel agents with improved benefit-risk profiles are discussed.
Published Online: July 28, 2011
E. Michael Lewiecki, MD, FACP, FACE
Osteoporosis is a major health problem with serious personal and economic consequences that affects more than 200 million individuals worldwide. A literature review was conducted to examine the benefits and challenges of current treatment options for postmenopausal osteoporosis and novel therapies evaluated for treatment and prevention of this disease. Despite availability of many effective pharmacologic treatments, long-term patient compliance and persistence with osteoporosis therapy are often suboptimal, resulting in reduced protection from fracture. Long-term compliance and persistence are essential for optimizing clinical outcomes and reducing the need for healthcare services. Tolerability and ease of drug administration are important factors infl uencing compliance. Based on overall assessment of the benefits and challenges of current treatment options, it is evident that there is an unmet need for new pharmacologic therapies for postmenopausal osteoporosis. Novel agents may offer improved benefi t-risk profi les and better patient compliance/persistence than conventional options.
(Am J Pharm Benefits. 2011;3(4):e77-e84)
A review of osteoporosis treatments, both commercially available and novel agents, was conducted to assess the benefits and challenges of each.
Multiple effective treatments are currently available for postmenopausal osteoporosis.
Adverse events, fear of side effects, and other factors contribute to suboptimal patient compliance/persistence that results in poor clinical outcomes and greater healthcare resource utilization.
Novel agents have unique benefit-risk profiles that may better suit the needs of individual patients.
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
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