An Integrated Approach: Bisphosphonate Management for the Treatment of Osteoporosis

Supplements and Featured PublicationsAn Integrated Approach: Bisphosphonate Management for the Treatment of Osteoporosis
Volume 13
Issue 11 Suppl

Osteoporosis is underrecognized and undertreated despite the availability of effective therapies that reduce fracture risks. Bisphosphonates are currently the most widely prescribed pharmacologic treatment for osteoporosis. Oral bisphosphonates are typically managed under the pharmacy benefit of a health plan. With the recent availability of intravenous bisphosphonates, osteoporosis therapies now cross both the traditional pharmacy and medical benefit boundaries.

Determining the most appropriate and cost-effective treatment for specific populations requires best practices that integrate both pharmacy and medical benefit considerations. When developing policy as part of these best practices, medical directors and pharmacy directors must consider efficacy, safety, cost, convenience, and mode of administration for each of the bisphosphonate formulations.

This continuing education activity, based on a roundtable of managed care experts, explores new approaches for developing an effective bisphosphonate management policy for the treatment of osteoporosis.

(Am J Manag Care. 2007;13:S290-S308)


Gary Owens, MD

Incidence and PrevalenceOften referred to as a silent disease because bone loss can occur without symptoms, osteoporosis affects an estimated 10 million people in the United States and poses a major public health threat for an estimated 55% of people 50 years of age or older. Osteoporosis is a disease characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility and an increased susceptibility to fractures. Although osteoporosis affects both women and men, 80% of those affected are women.1

Burden and Cost of the Disease

Other cost considerations include that of treatment, and in particular, the cost of bisphosphonates, the most widely prescribed pharmacologic treatment for osteoporosis. When assessing the costs of bisphosphonate therapy, there are several important factors to consider:

• The actual product cost net of any rebate potential

• Drug administration (supplies)

However, for injectable bisphosphonates, there are several potential sites of care, including the primary care physician’s office, the specialist’s office, the infusion center (free-standing or hospital-based), or the home-care setting. Each site of care can represent a different cost to the health plan.

In addition to considering the prescriber and site of care when evaluating the cost of the current US Food and Drug Administration (FDA)-approved bisphosphonates, it is essential to examine the various dose strengths and dosing frequencies for each product. Currently, dosing options range from daily to yearly.

Exploring New Approaches

Osteoporosis is underrecognized and undertreated, not only in Caucasian women, but also in African American women.1 Many of the physical, emotional, and financial costs of bone disease and fractures can be prevented.2 Tremendous strides have been made in recent years to improve bone health and awareness, thanks to the National Osteoporosis Foundation, the Office of the Surgeon General (a division of the US Department of Health & Human Services), the World Health Organization (WHO), the American Society for Bone and Mineral Research, science, advocacy groups, professional societies, and other concerned parties. Improving bone health is an undertaking that must involve all stakeholders to be successful, and bone health itself must be viewed as a lifelong goal.

Healthcare professionals have been charged with a number of action steps toward improving bone health, based on the Surgeon General’s 2004 Report on Bone Health and Osteoporosis.2

Healthcare Professionals: Key Action Steps2

• During interactions with patients, emphasize the basics of good bone health (nutrition,physical activity)

• Help individuals practice behaviors that foster bone health

• Implement a comprehensive, systems-based approach to promoting bone health (provided the at-risk population is large enough to justify it). This approach might include reminder systems, systematic quality measurement and improvement, disease management programs on bone health, and appropriate financial incentives for providers and individuals

The roundtable participants shared formulary review challenges they encountered with a variety of treatment management programs, as well as approaches that were effective.

One approach involved initiating a specialty pharmacy program that coordinates both medical and pharmacy policy. For this integrated medical/ pharmacy benefit program to move forward without hurdles, it excludes oncology drugs because of the many unique issues surrounding cancer therapies. The same staff that develops the standard medical policies writes policies for all pharmacy and therapeutics (P&T) committee decisions. Along with the policy, a decision tree is developed to enable whoever is doing the review—whether it’s the medical director or the pharmacy director—to be consistent in their decision. A pharmacy benefit management company conducts the initial review of drugs that are outside the hospital. Appeals are handled by the pharmacists, and final appeals are handled by the medical director.

This specialty program covers drugs that are both provider-administered and self-administered. Some of the drugs require a prior authorization (PA). There is a 30-day supply maximum, after which time treatment is reassessed. The program has eliminated the need to differentiate between whether the treatment is given at the physician’s office or dispensed at the pharmacy.

Another approach involves putting into place a fully integrated system for osteoporosis management that fosters adequate use of the right drug at the right time, while controlling costs. Using a model focused primarily on prevention, the goal of this plan’s system is to identify patients early and treat them before the disease develops. The guidelines for this system are designed to provide a well-stratified population and a step-wise treatment for the affected population. They are also designed to assess primary and secondary prevention of osteoporosis fractures. All drugs that fall within the guidelines are covered under pharmacy benefits. The formulary is enforced by the pharmacy, and exceptions are granted via a process in which physicians merely initiate a formulary exception when they deem it necessary for a patient to be on a nonformulary regimen.

A third approach is from a nonprofit staff model health maintenance organization, which employs primary care physicians as part of its plan. Specialty care is contracted through a capitated arrangement with another organization. This approach allows for a large degree of control over primary care and very little control over specialty care. The P&T committee handles products that are provided through a written prescription and taken to a retail pharmacy. Conversely, all pharmaceuticals that are administered in a physician’s office or an infusion center are handled under the medical benefit. Integrating policy is subsequently challenging, and there are 3 separate committees handling different aspects of physical activity) pharmaceutical management. This approach calls for managing incentives and benefits, in addition to managing care.

Other formulary review challenges encountered, and corresponding policy approaches, are highlighted in Table 1.

Common situations that lead to developing guidelines and/or policy include: a divergence of coverage based on benefit category; contracts in place favoring other agents; guidelines in place recommending other agents; labeled indications favoring existing formulary agents; and a new dosage form being more expensive than an existing dosage form (ie, an injectable or intravenous therapy that costs more than an oral therapy, or vice versa).

Effective approaches in responses to these situations/ challenges include: developing a PA, which requires that certain conditions be met; and developing policies that require step therapy before use of a nonformulary agent, as well as those that require both medical and pharmacy checkpoints. Policies developed as a collaborative effort between the medical and pharmacy staff can be particularly effective.

Key Points

• Bisphosphonates are the most widely prescribed treatment for osteoporosis.

• Based on solutions responding to challenges encountered with other new drug products, health plans may find similar solutions to challenges with the new osteoporosis drugs. Integration of pharmacy and medical benefits is a key element.


Osteoporosis is a multifactorial disease that reflects the balance of environmental, genetic, and metabolic factors on bone remodeling, bone mass, and skeletal microarchitecture. The primary clinical consequence of these changes is the fragility fracture, which can lead to diminished physical functioning, reduction in quality of life, and increased mortality.2 To reduce the magnitude of this common disease, which disproportionately affects older women and men, the Healthy People 2010 objective establishes a national target to reduce the proportion of adults with osteoporosis in the next decade.11 This goal requires a better understanding of the mechanisms of action and the overall balance of risks and benefits of pharmacologic interventions such as the bisphosphonates, which are commonly prescribed to prevent bone loss and reduce fractures.

The foundation for reducing the magnitude of osteoporosis includes reducing the modifiable risk factors for fracture, enhancing a positive calcium balance and vitamin D sufficiency through dietary change and/or calcium plus vitamin D supplement use, stimulating bone formation through increased activity, and reducing the risk of falls. There is a body of evidence supporting that adequate calcium plus vitamin D intake is important for optimal bone health by ensuring acquisition of maximal peak bone mass in adolescence and slowing the rates of bone loss with age.12 Recent clinical trial data also suggest that calcium plus vitamin D reduces the risk of falls,13 and in women 60 years of age and older, may reduce the risk of hip fractures by 21%.14 The Institute of Medicine has recommended that adults have a total daily calcium intake of 1200 mg of elemental calcium, the amount of calcium usually present in 3 to 4 dairy servings daily.12 Unfortunately, recent studies suggest that many segments of the American population do not achieve the targeted intake of calcium, and that vitamin D insufficiency is reaching nearepidemic proportions.15 For individuals in whom adequate calcium plus vitamin D cannot be achieved through the diet and sun exposure, calcium plus vitamin D supplements may be utilized. To maximize absorption, supplements should be taken in divided doses, following a meal. However, calcium plus vitamin D adequacy is not sufficient intervention for the prevention of osteoporosis in individuals at increased risk for osteoporotic fracture because there appears to be minimal benefit of calcium plus vitamin D at reducing other types of fragility fracture.14

For the large segment of the older adult population defined to be at high risk for osteoporotic fracture, pharmacologic interventions for osteoporosis should be considered. The treatments for osteoporosis can be divided into 2 major categories: antiresorptive (medications that reduce bone turnover) and anabolic (medications that stimulate bone formation). FDA-approved antiresorptive medications include estrogen with or without progestin, the selective estrogen receptor modulator raloxifene, the bisphosphonates (Table 2),16-20 and calcitonin. Teriparatide is the only anabolic agent currently approved. All medications that have received an FDA indication for treatment of osteoporosis have demonstrated efficacy in preventing bone loss and reducing fractures (usually vertebral). Thus, to choose between the available agents and optimize management decisions, it is necessary to carefully examine the pharmacology and mechanism of action of the medications, the time to onset of action, effectiveness at nonvertebral skeletal sites, and the side-effect profile.

The nitrogen-containing bisphosphonates have become a major choice for therapy for postmenopausal osteoporosis, osteoporosis in men, and glucocorticoid-induced osteoporosis. The current FDA-approved bisphosphonates (Table 2) include:

• Alendronate (Fosamax®; Merck & Co, Inc, Whitehouse Station, NJ)

• Risedronate (Actonel®; Procter & Gamble Pharmaceuticals, Cincinnati, OH)

Bisphosphonates are stable analogues of pyrophosphatase. When taken orally, approximately 1% of the dosage is absorbed. Up to 50% of the absorbed oral dose or the intravenously administered dose is adsorbed to the skeletal system.21 The remainder of the dose is excreted renally. The circulating half-life of bisphosphonates is short; this is in contrast to the long skeletal half-life, which is estimated to exceed a decade. However, the biologic implication of this prolonged skeletal retention appears to be somewhat limited, because of sequestration of the retained drug at sites often distant from active osteoclastic action.

The FDA-approved, nitrogen-containing bisphosphonates differ on the basis of 2 side chains: one that confers effects on binding affinity to the bone mineral and another that affects antiresorptive potency. All bisphosphonates avidly bind to the hydroxyapatite crystal,14 but the individual medications within the class have differing profiles of mineral binding, targeting, and release. Zoledronic acid exhibits the greatest adsorption affinity for bone mineral with the longest retention, thereby leading to its ability to be dosed at annual intervals. The order of binding affinity from most avid to least for the other agents is alendronate, ibandronate, and risedronate.22-25 In addition to the dosing interval, binding affinity may affect persistence of effect after medication discontinuation.

Bisphosphonates exhibit an antiresorptive effect through reduction in osteoclast activity, diminished recruitment and differentiation of osteoclast precursors, and increased apoptosis of mature osteoclasts.26 The mechanism underlying these effects is related to suppression of farnesyl pyrophosphate synthase (FPPS),27 an enzyme in the cholesterol-synthesis pathway. Inhibition of FPPS reduces the prenylation of small guanine triphosphatases that are necessary for aspects of osteoclast action.28 Because of the differences in the side chain between drugs in the bisphosphonate class, the bisphosphonates also differ with respect to the inhibitory potency at the target enzyme (FPPS), with zoledronic acid being the most potent, followed in order of potency by risedronate, ibandronate, and alendronate.22-25

The combined effect of these 2 actions, mineral adsorption and potency, results in the reduction of bone remodeling, which is clinically reflected by a suppression of bone turnover markers. With oral bisphosphonates, the bone resorption markers decline to approximately half of baseline values at 1 month and reach a nadir by 3 months.29-31 This decline in bone resorption is subsequently followed by a fall in bone formation rates. Although there are small differences in the time to nadir and ultimate reduction in the turnover between the individual bisphosphonates, whether these differences translate into significantly different clinical responses is still unknown and remains an area of intense scientific inquiry.

Efficacy of Bisphosphonates for Preventing Bone Loss and Reducing FracturesBMD: Bisphosphonate therapy results in modest gains in bone density.29-34 The gains in BMD at the spine continue over several years; gains at the hip plateau somewhat earlier. The effect of intermittent versus daily dosing regimens on BMD is equivalent, suggesting that the total effective dose rather than dosing interval is the most important regulator of BMD response. There are small differences in the magnitude of BMD response between individual bisphosphonates noted in head-to-head comparison studies, but the observed gains in bone mass cannot be predicted to translate to better efficacy in fracture reduction because analyses suggest that less than 20% of the vertebral fracture reduction is explained by apparent BMD changes.35,36

Fractures: Bisphosphonate therapy has also been shown to result in clinically significant reductions in fractures. Attempts to compare relative efficacy and time to onset of action between drugs are constrained by the lack of direct head-to-head randomized controlled trials (RCTs) with fracture outcomes between the individual bisphosphonates. Differences in the study populations, clinical trial design, and the definitions used for morphometric fractures may account for some of the apparent differences in magnitude of effect. However, a review of the separate pivotal placebo-controlled clinical trials does provide some background to explore the unique characteristics of the individual drugs in response to fracture efficacy.

Radiographic vertebral fractures: Bisphosphonate therapy significantly reduces morphometric vertebral fractures. Treatment with daily doses of alendronate, risedronate, or ibandronate reduces the risk of vertebral fractures by 40% to 50% after 3 years.30,34,36,37 A somewhat greater risk reduction in radiographic vertebral fractures was noted for intravenous (IV) zoledronic acid.32

Clinical vertebral fractures: Clinical vertebral fractures (CVFs), defined as symptomatic fractures associated with pain and diminished physical function, account for up to 20% to 30% of morphometric fractures. Bisphosphonate therapy also significantly reduces these clinically apparent fractures, which are an important patient-centered outcome. Alendronate (5 mg daily for 2 years and then 10 mg daily for the remaining year) reduces CVFs by 52% at 3 years, with a statistically significant decrease in CVFs seen as early as 12 months after initiating treatment.37 Risedronate (5 mg daily) reduces CVFs by 69% at 12 months with data supporting an early onset of effect within 6 months.38 Daily ibandronate (2.5 mg) reduces CVF by 62%, with a 50% reduction in CVF with the intermittent dose (20 mg every other day for 12 doses every 3 months) after 3 years of therapy.39 Finally, zoledronic acid (5 mg infusion annually) reduced CVFs by 77% after 3 years of therapy.32

Hip and nonvertebral fracture: The response of hip and nonvertebral fracture (NVF) risk reduction with bisphosphonate therapy has been more varied.40 Alendronate demonstrated a 50% significant reduction in hip fractures in patients at high risk for fracture (those with low bone mass and a prevalent vertebral fracture). The data supporting NVF reduction in individual alendronate trials are modest; however, a meta-analysis of all clinical trial data suggests a reduction in NVFs with alendronate therapy.41 Risedronate is FDA-approved for NVFs reduction and has demonstrated a 33% to 39% reduction in NVFs over 36 months. This risk reduction is again seen early in the course of treatment with a 59% risk reduction noted at 6 months.42 In a clinical trial designed to specifically examine the efficacy of risedronate on hip fracture risk in elderly women, treatment with risedronate for 36 months in 70 to 79-year-old women with osteoporosis resulted in a 40% decrease in hip fractures.43 In contrast, there was no statistically significant benefit noted for women older than age 80 whose risk for hip fracture was primarily determined by characteristics that contribute to an increased risk for falls. The incidence of NVF in ibandronate-treated patients was similar to placebotreated patients after 3 years of therapy.34 There are no published data on the effect of ibandronate on hip fracture risk. Finally, there is a 25% reduction in NVF and a 41% reduction in hip fractures at 36 months with zoledronic acid.32

Comparing bisphosphonate effects: Taken as a group, these results support that all bisphosphonates are effective agents for treatment of osteoporosis; however, the individual bisphosphonates potentially differ on NVF response and time to onset of action. Individual differences in clinical trial design, including selection criteria for the study population, might affect the observed effects from the RCTs because the efficacy of bisphosphonates appears to be greater in patients at the highest risk for fracture. Because of this limitation and the lack of direct clinical trial comparisons on fracture outcomes, relative efficacy should not be concluded from these studies. However, an opportunity to extend our insight into potential differences in treatment response between the drugs may be gleaned from observational studies. Observational studies using data derived from healthcare utilization help to expand the RCT data to larger populations of patients and offer an opportunity to examine the relationship of different agents on selected outcomes. Data from a recent observational study44 suggest that patients receiving risedronate have an 18% lower rate of hip fractures and a 43% lower rate of NVFs during their first year of therapy than patients receiving alendronate. Although the individual cohort results were consistent with the treatment effects demonstrated for each individual agent from the previously published RCTs, it is important to recognize that observational data are limited by potential biases that cannot be systematically controlled and these analyses can only report associations, not cause and effect. Additional clinical trial and observational studies and meta-analyses will help to better define the similarities and differences that may be associated with the observed differences of in vitro potency in the bisphosphonates.

Safety Profiles

• Osteoporosis management should include institution of the basic preventive strategies including adequate intake of calcium and vitamin D, exercise, smoking cessation, and limited use of alcohol. These are the foundation for good bone health; however, in patients at higher risk for osteoporosis, disease management may also call for initiation of pharmacologic intervention.

• There are a variety of dosage options, frequencies, and administration requirements within the bisphosphonate class of drugs. The individual bisphosphonates differ in binding affinity and potency. Whether these in vitro changes affect NVF risk reduction or time to onset of action is not known.

• Although generally well-tolerated, the bisphosphonates have been associated with gastrointestinal symptoms (oral bisphosphonates) or acute flulike symptoms (IV bisphosphonates). Recent data suggest that bisphosphonate therapy is associated with a very low risk of ONJ.


Treatment Challenges

• The DXA shows a lumbar spine T-score of −2.1 and a left femoral neck T-score of −1.3, consistent with a diagnostic classification of low bone mass (osteopenia)

Use currently available tools (bone density measurement and clinical risk factors for fracture) to estimate the likelihood of future fracture.

(2) Fracture risk reporting

Combine the fracture risk findings with other clinically relevant information to determine whether pharmacologic treatment is indicated.

(4) Treatment decisions

Patients who sustain an osteoporosis-related fracture are at very high risk for future fracture, and usually warrant aggressive treatment. In the absence of a fracture, measurement of BMD by DXA is the only method for diagnosing osteoporosis, and is a robust predictor of fracture risk. As BMD in the untreated patient decreases, fracture risk increases, with an approximate doubling of fracture risk for every 1 standard deviation (SD) decrease in BMD. With treatment using an FDA-approved agent, stability or an increase in BMD may be associated with reduction in fracture risk, while a significant decrease in BMD is cause for clinical concern, suggesting poor adherence to therapy or the presence of other factors having adverse skeletal effects.

The results of the DXA test are expressed as a Tscore, which represents the SD difference between the patient’s BMD and that of a young-adult reference population. Based on the T-score value, the WHO diagnostic criteria classify patients as being normal or having low bone mass (osteopenia), osteoporosis, or severe osteoporosis.52 Ironically, despite major federal initiatives identifying osteoporosis as a major public health concern and recognizing that DXA is an underutilized clinical tool,2 the US government has severely decreased reimbursement for DXA in free-standing facilities. If scheduled cuts in reimbursement continue, by 2010 the payment for a BMD test will drop to about $35. This drop in payment is far below the cost of doing the procedure,53 and is likely to limit patient access to osteoporosis care, reduce the already low number of patients being treated for osteoporosis, and increase the burden of osteoporosis- related fractures, in terms of personal suffering and costs to society.

BMD combined with clinical risk factors for fracture is a better predictor of fracture risk than BMD or clinical risk factors alone. The WHO is developing a model to quantitatively assess fracture risk based on femoral neck T-score by DXA and the following clinical risk factors for fracture 54:

• Age

• Current cigarette smoking

• High alcohol intake (greater than 2 units/day)

• Prior or current glucocorticoid use

Fracture Risk Reporting

The anticipated new NOF guidelines will help healthcare professionals manage patients with low BMD by identifying those with the highest risk for fracture who are most likely to benefit from therapy. If a patient’s 10-year fracture probability exceeds the intervention threshold, then treatment may be cost-effective. Evaluations of cost-effectiveness for osteoporosis treatments have used Markov state transition models characterized by health states, transition probabilities, Markov cycles, and a time horizon.56

These models require the use of country-specific fracture data and economic assumptions that include societal willingness to pay (usually expressed as cost per quality-adjusted life-year [QALY] gained), costs of morbidity and mortality associated with fractures, and costs of treatment. In 2002, it was suggested that a value of $60 000 per QALY gained was appropriate in developed countries.57 With inflation and possible changes in economic priorities, this value may now be different. In Sweden, using a threshold for cost-effectiveness of $45 000 per QALY gained, a simulation determined that it was cost-effective to treat a woman 50 years of age with a 10-year hip fracture probability of 1.2% and a woman 80 years of age with a probability of 7.5%. US cost-effectiveness analyses are being conducted by the NOF, with the results expected to be published in association with the release of the WHO technical report on fracture risk assessment and intervention thresholds. Ultimately, treatment decisions for each individual patient involve consideration of many factors in addition to cost-effectiveness.

Treatment Decisions

• Age, sex, and menopausal status

• Affordability of the medication

• Beliefs about medications and osteoporosis

When determining how to treat, considerations include:

• Patient’s fracture probability

• Patient’s nonskeletal risks and benefits

• Patient’s expected adherence to therapy

• Patient’s previous medication experience

• Provider’s knowledge of each of the treatments

Treatments approved by the FDA for osteoporosis are 3 bisphosphonates, salmon calcitonin, raloxifene, and teriparatide. The currently approved bisphosphonates are listed in Table 3.

Safety, Efficacy, and Administration RequirementsThe safety and efficacy profiles of the bisphosphonates are addressed in the previous section titled Overview: The Bisphosphonate Class of Drugs. The dosing options and administration requirements for each drug are also covered in that section.

Selecting the Appropriate Therapy

• Although clinical practice guidelines provide helpful information, current osteoporosis treatment recommendations and risk-factor definitions are not consistent across these guidelines.

• Treatment decisions in individual patients require clinical judgment with consideration of factors that include: fracture risk assessment with estimation of fracture probability, comorbidities, and other factors specific to the individual patient; skeletal and nonskeletal risks and benefits; complexity of drug administration; and cost.


Roundtable Participants led by Gary Owens, MD (Moderator)

• Clinical outcomes, including fractures, and BMD test scores

• Potential burden or adverse events associated with an oral or infusion therapy

• Longevity of the member with the health plan

The participants agreed that the current clinical practice guidelines for the diagnosis and management of osteoporosis form the foundation for the other decision points. Also discussed was the need for better data on the number of patients at risk within a specific population and the hope that a 10-year probability index would help to better discriminate which health plan members require osteoporosis treatments and which members do not.

In addition to creating the list of the most important factors, the group generated a comprehensive list of the key considerations and clinical decision points, which are shown in Table 4.

The experts then created a policy algorithm for bisphosphonate management. This policy algorithm is highlighted in the Figure.

Clear,Targeted Communications:

• Developing an integrated medical/pharmacy policy is an essential step toward managing the bisphosphonate category. Proactive policy development should be considered when similar drugs can be administered by multiple routes of administration.

• A policy should be reassessed, and possibly revised if the clinical value of a product increases in relationship to the other products, or if the clinical values remain equivalent and there is a cost shift resulting in a product being more or less favorably priced than the other.

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