Manage Osteoporosis

Posted on Dec 7, 2010 in Expired CME | 1 comment

Managing Your Patients With Osteoporosis

 

 

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CME Information

Learning Objectives

After completing this activity, the learner should be able to

• Utilize National Osteoporosis Foundation consensus recommendations regarding risk evaluation and treatment for patients who have or are at risk of osteoporosis
• Recognize the risk factors for osteoporosis and identify patients for appropriate use of evaluation tools such as dual-energy x-ray absorptiometry and FRAX^®
• Identify safety, efficacy, dosing, and administration profiles of agents used to prevent and treat osteoporosis

Introduction

Osteoporosis, the most common bone disease, is characterized by reduced bone mass and loss of normal skeletal architecture, which results in an increased risk of fracture. Clinically, osteoporosis may remain silent for many years, until the occurrence of fracture. The most common sites of osteoporosis-related fracture are the lumbar vertebrae, the proximal femur, and the distal forearm.[1] Fractures and other clinical sequelae of osteoporosis are associated with considerable mortality and morbidity. Particularly in older patients, osteoporotic fractures are frequently life-changing events, reducing or curtailing patients’ ability to live independently.

Rates of osteoporosis diagnosis and treatment are disappointingly low,[2,3] even in patients with a sentinel event such as a hip fracture. In recent years, efforts to address this situation have seen the development of standardized screening tools, treatment guidelines, and campaigns to increase public awareness of osteoporosis. Given the availability of effective lifestyle measures and pharmacologic treatments, increased levels of intervention could produce dramatic improvements in the outlook for patients with osteoporosis. This article, which is based on a live presentation given at Best Practices in Primary Care™ in June 2010, reviews current strategies for osteoporosis management, guidelines on who to screen and treat, and barriers to overcome for improved patient outcomes.

Epidemiology and Impact

Osteoporosis is a major burden on society.[4] According to a review produced by the US National Institutes of Health Osteoporosis and Related Diseases National Resource Center, approximately 10 million individuals have osteoporosis and approximately 34 million have low bone mass.[5] After age 50, osteoporosis-related fractures affect about 1 in 2 women and 1 in 4 men.[5] In patients with osteoporosis, hip fracture carries the worst prognosis; mortality is increased 10% to 20% overall within 1 year of a hip fracture,[6] and only about 40% of affected patients fully regain their prefracture level of independence.[7] Although it is most common in postmenopausal women, osteoporosis also has a substantial impact in men: 80,000 men experience hip fractures annually in the United States; one-third die within the following year.[5] The pain, disability, and dependency commonly associated with osteoporosis-related fractures can dramatically impair quality of life and social functioning. Psychological effects include anger, depression and anxiety, and significant impairment of personal relationships.[8]

Osteoporosis is underdiagnosed
primarily because of highly inadequate screening.

In women, the annual incidence of osteoporosis is several times higher than the annual incidence of other common morbidities such as stroke, myocardial infarction, and breast cancer[9-12] (Figure 1) The healthcare costs associated with osteoporosis are substantial. US data for 2005 show a direct cost of osteoporosis of $16.9 billion, of which 72% was related to hip fractures.[9] Inpatient care accounted for 57% of spending, long-term care for 30%, and outpatient care for 13%.[9]

Shortcomings of Current Care

Clearly, reduction of the societal burden of osteoporosis and related conditions requires identification of at-risk individuals and use of preventive and therapeutic interventions. However, healthcare providers frequently fail to diagnose and treat osteoporosis.

Screening

Osteoporosis is underdiagnosed primarily because of highly inadequate screening. Sampling of Medicare insurance data for people 65 years or older for the years 1999 to 2005 showed that approximately 30% of women and 4.4% of men received a bone mineral density (BMD) test in the previous 5 to 7 years.[13] Repeat central dual-energy x-ray absorptiometry (DXA) varied considerably in patients who received initial testing from 1999 to 2002; between 40% and 73% of people had a repeat determination.[13]

Diagnosis and Treatment

Patients at high risk of fractures and other bone disorders are underdiagnosed and undertreated.[14] Over 50% of women and 75% of men with osteoporosis are undiagnosed; by the age of 85, the rate of undiagnosed disease rises to over 80%.[2] Perhaps of greatest concern is the finding that even after a fracture occurs, less than 30% of patients with osteoporosis are diagnosed.[3] Similarly, treatment rates are unsatisfactory, with the majority of patients not started on appropriate treatment. After a fracture, only 30% of patients receive treatment with calcium and vitamin D, and fewer than 15% of patients receive bisphosphonates.[3] This is in contrast to the situation with other common diseases: for example, 94% of patients receive a beta-adrenoceptor blocker following myocardial infarction and 88% of patients with coronary artery disease receive low density lipoprotein screening measurement.[3]

Obstacles to Effective Intervention

Various obstacles to optimal care in osteoporosis have been identified (Table 1). A fundamental barrier to diagnosis of osteoporosis is the lack of obvious clinical signs prior to fracture. Moreover, certain fractures, such as vertebral fracture, may remain symptomless for some time after the initial event.

There appears to be a significant problem in identifying patients at risk of osteoporosis in the setting of a primary care consultation. There are also practical barriers to initiating screening and intervention for a condition for which the patient has no symptoms. Differences between guidelines as to screening criteria can be confusing to clinicians and can contribute to inadequate screening practices, with the result being a screening frequency that is haphazard. Many clinicians are also not clear regarding which patients require treatment based on the results of screening. Other barriers to optimal care are time limitations and the need to manage more acute illnesses.

A fundamental barrier to diagnosis of osteoporosis is
the lack of obvious clinical signs prior to fracture.

Dr. Levine comments on why screening for osteoporosis is suboptimal.
Jeffrey Levine, MD, MPH

Recommendations for Screening

The National Osteoporosis Foundation (NOF) recommends bone density testing by DXA, regardless of risk factors, for women 65 and older and men 70 and older.[4] Age is a major independent risk factor for fracture. Thus, for a T-score of -2.5, the 10-year probability of symptomatic fracture in women doubles between the ages of 50 and 70 (11.3% vs 22.8%).[15] Although, in general, men are at lower risk for osteoporosis-related fracture than women, it is becoming increasingly apparent that osteoporosis is also a major problem in men. Although both genders undergo age-related loss of BMD, men do not undergo the rapid bone loss associated with menopause.

Dr. Levine explains the relationship between age and risk for osteoporosis.

Additional Risk Factors

The main categories of patients who should receive BMD testing are summarized in Table 2. In postmenopausal women younger than 65 and men younger than 70, the clinical decision about who to screen is made by individual risk factor assessment. A number of risk factors for osteoporosis have been established. These include older age, family history of osteoporosis or adult fracture, body weight under 127 lb (for women), history of a low-trauma fracture after age 40, women with premature or surgically induced menopause and men who are hypogonadal, smoking or excessive use of alcohol, treatment with certain medications (eg, steroids, anticonvulsants, aromatase inhibitors), and presence of certain diseases (eg, rheumatoid arthritis [regardless of steroid use] hyperparathyroidism, celiac sprue).[4]

 

Clinical Pearl: Low bone mass (osteopenia) is not a disease in healthy premenopausal women.
World Health Organization (WHO) guidelines for diagnosing osteoporosis are based on data from postmenopausal white women who have already lost bone tissue, thereby weakening the internal structure of the bone. Low bone density (osteopenia) occurs in about 15% of premenopausal women and usually does not represent a disease. These are typically individuals who simply have not reached a high bone mass during childhood and adolescence. In general, it is not necessary to screen premenopausal women for osteoporosis unless other risk factors are present.

Medicare Reimbursement

Federal regulations established in 1998 (Bone Mass Measurement Act) provide a national coverage policy for reimbursement of BMD tests in Medicare beneficiaries. Medicare insurance covers BMD testing in women 65 and older. It also covers evaluation for certain other patients, such as estrogen-deficient women at clinical risk for osteoporosis, individuals with vertebral abnormalities or primary hyperparathyroidism, individuals receiving chronic glucocorticoid therapy, and individuals being monitored to assess the response to or efficacy of a US Food and Drug Administration (FDA)-approved osteoporosis drug therapy (every 2 years). Although the stipulated interval for testing is 2 years, more frequent testing may qualify for coverage if deemed to be medically necessary by the treating clinician, such as for monitoring patients who are receiving long-term glucocorticoid therapy or in cases where a previous test was different from the current proposed testing method.

Case Study: Roberta

Roberta is a 59-year-old woman, 8 years postmenopausal, who seeks advice regarding her osteoporosis risk after viewing consumer television advertisements. She believes she has a healthy lifestyle, performing weight-bearing exercise 3 times weekly, and she is a nonsmoker and nondrinker. She takes a calcium supplement each day. However, she does not consume dairy products, is not taking vitamin D supplementation, and avoids sun exposure. Her mother suffered an osteoporosis-related hip fracture in her 70s.

Discussion

Although Roberta, being younger than 65, does not qualify for testing based on age alone, she should undergo BMD testing on the basis of her family history of osteoporosis-related hip fracture. This should involve at least 2 sites, preferably the hip and spine (unless contraindicated), with the wrist as an additional surrogate.

BMD scanning of the spine and hip was performed. Evaluation of L1 through L4 revealed a T-score of -2.1, indicating low bone mass rather than osteoporosis. Total hip T-scores were -1.5 (left) and -1.7 (right), for a mean of -1.6, confirming that Roberta does not have osteoporosis. Guidelines from the NOF,[4] the American Association of Clinical Endocrinologists,[16] and the North American Menopause Society[8] provide BMD cutoff criteria for initiation of treatment according to whether or not risk factors for osteoporosis and osteoporotic fracture are present. For patients with low bone mass (osteopenia), recommendations differ regarding testing methodology and interpretation and evaluation of risk, potentially creating confusion for clinicians. Roberta’s BMD results indicated that further fracture risk evaluation was necessary to decide whether or not to initiate pharmacologic treatment.

Dr. Levine’s insights on the confusion surrounding patients with low bone mass.

Who to Treat

Demographic Considerations

The relationship between fracture risk and BMD was evaluated in the National Osteoporosis Risk Assessment (NORA) study, an analysis of a large population of postmenopausal women (N=149,524).[17] Although fracture rate increases at T-scores at or below the threshold for osteoporosis (T-score <-2.5), the absolute number of fractures is greatest in the range above the WHO-designated osteoporosis threshold (Figure 2).[17] In fact, the majority of fractures occurred in women with low bone mass (T-score between -2.5 and -1.0).[17] Fracture risk is a continuum; however, it would not be financially viable to treat all patients with low bone mass. Clinical tools providing additional risk evaluation can be used to identify the most appropriate candidates for treatment.

National Osteoporosis Foundation Guidelines

According to the NOF guidelines, pharmacologic treatment is clearly indicated in patients with a hip or vertebral compression fracture and/or a T-score at or below -2.5 at the femoral neck, total hip, or spine after evaluation to exclude secondary causes.[4] For patients with low bone mass (ie, T-scores in -1.0 to -2.5), the WHO fracture risk assessment tool (FRAX^®) should be used to assist in the treatment decision.

In postmenopausal women younger than 65
and men younger than 70,
the clinical decision about who to screen
is made by individual risk factor assessment.

Applying FRAX® in Clinical Practice

FRAX^® is analogous to the Framingham Heart Study 10-year coronary heart disease risk predictor. It generates the 10-year probability of a hip fracture or major osteoporotic fracture based on race/ethnicity and the country of practice. FRAX^® recommendations are based on absolute fracture risk, calculated from the T-score at the femoral neck (total hip T-score can be used in place of femoral neck T-score if this is unavailable) in combination with the following risk factors[3]:

• Age
• Personal history of a low-trauma fracture as an adult
• Parental history of hip fracture
• Current or prior glucocorticoid usage
• Current smoking
• Alcohol consumption
  • >3 units (drinks) per day for men
  • >2 units per day for women
• Diagnosis of rheumatoid arthritis

FRAX^® can be used in patients aged 40 to 90, and in both women and men. In the United States, treatment is recommended in patients with a FRAX^®-based 10-year probability of a hip fracture of 3% or greater or 10-year probability of a major osteoporotic fracture of 20% or greater.[4] Moving to the use of FRAX^® rather than T-scores should improve the appropriateness of targeting treatment to patients who are at greatest risk of fracture. It removes systematic errors that result from the fact that risk factors are not always intuitive (eg, past steroid use is a contributing risk but past smoking is not).

Case Study: Follow-Up

FRAX^® can be a useful clinical tool for evaluating absolute risk in a patient for whom T-score data does not clarify whether or not treatment is indicated. Patients with an established diagnosis of osteoporosis, pre-existing hip fracture, vertebral fracture, or a T-score of -2.5 or below do not require a FRAX^® assessment and should receive pharmacologic treatment. FRAX^® is not appropriate for patients on existing treatment.

Dr. Levine’s comments on use of the FRAX^® tool.

Clinical Evaluation

Clinical evaluation for osteoporosis risk should be undertaken in all postmenopausal women and men 50 and older to determine whether or not BMD testing is needed. Although a clinical diagnosis can be made in at-risk individuals who sustain a low-trauma fracture, confirmation of the diagnosis requires measurement of BMD, which can also be useful for monitoring purposes.

Abnormal laboratory findings in uncomplicated postmenopausal osteoporosis warrant further investigation. In patients with recent fractures, laboratory studies are useful in evaluating secondary causes of osteoporosis and to establish the presence of renal or liver disease. In addition, biochemical testing should be considered in patients with documented osteoporosis prior to initiation of treatment.

Laboratory Tests

Before initiation of pharmacologic treatment for osteoporosis, renal function testing is appropriate, since renal impairment (glomerular filtration rate <35 mL/min) can be a contraindication to use of bisphosphonates.[18-21] It is important to establish the presence of both renal and liver disease. If calcium is elevated, causes such as secondary hyperparathyroidism must be investigated. Complete blood chemistry testing can provide evidence of malnutrition and/or malignancy. A 24-hour urine collection, although inconvenient for patients, can provide useful diagnostic information for detecting secondary causes of osteoporosis, particularly with regard to calcium excretion. In a study that included 173 postmenopausal women, Tannenbaum et al[22] reported that the addition of 24-hour urine analysis to parathyroid hormone, serum calcium measurement, and 25-hydroxyvitamin D testing improved the detection rate of new diagnoses from 66% to 98% (55 vs 37 disorders).

Serum 25-hydroxyvitamin D should be routinely measured in patients at risk for osteoporosis. It is important that this form of vitamin D—the storage form—is measured rather than the active derivative 1,25-dihydroxyvitamin D, as the former is a better indicator of true vitamin D deficiency. The recommended optimal serum level of 25-hydroxyvitamin D to lower risk of fracture is greater than 30 ng/mL (70–80 nmol/L).[23] It is difficult to overdose on vitamin D; patients with levels less than 30 ng/mL should receive vitamin D3, whereas more aggressive intervention may be required in those with levels less than 10 ng/mL.

Optimizing Treatment for Osteoporosis

The traditional management of osteoporosis involves supplementation of calcium and vitamin D, weight-bearing exercise, and, in the case of frail patients, fall-prevention techniques. All adults should receive adequate calcium (approximately 1000 mg/d for those 49 and younger and 1200 mg/d for those 50 and older).[24] It is important to note that for patients who are taking proton pump inhibitors, or for patients who are older, calcium citrate rather than calcium carbonate is recommended. Absorption of calcium declines with increasing age beginning at approximately 60 and reaching significant malabsorption over 80 years.[25] The citrate formulation is more easily absorbed and is recommended for individuals who have conditions associated with malabsorption.[26] In addition, proper intake of vitamin D (400–800 IU/d for patients 49 and younger and 800–1000 IU/d for those 50 and older) is recommended. Calcium and vitamin D recommendations represent total intake, and allowance is made for normal dietary content when determining the amount to supplement. These measures are relatively inexpensive and highly cost-effective.

Modifiable risk factors should also be addressed, and main measures include encouraging weight-bearing exercise for inactive patients, smoking cessation, moderating alcohol and caffeine intake, and evaluating the risk-benefit ratio of medications in terms of osteoporosis.

Dr. Greenspan discusses vitamin D supplementation.
Susan L. Greenspan, MD

 

Pharmacologic Treatments

A range of medications are approved for use in osteoporosis, including bisphosphonates, calcitonin, denosumab, raloxifene, and teriparatide. Estrogen/hormone therapy is no longer used for the chronic management of osteoporosis alone. Glucocorticoid-induced disease in women or men can be treated with alendronate, risedronate, zoledronic acid, or teriparatide.

Case Study, Reassessment of Fracture Risk

With inclusion of a nontraumatic wrist fracture in her history, the FRAX^® result for Roberta is a 25% 10-year probability of major osteoporotic fracture and 1.4% for hip fracture. Since her risk of major osteoporotic fracture is greater than 20%, she is a candidate for treatment. Roberta’s 25-OH vitamin D level was also checked.

The main preventive measures for Roberta are calcium supplementation to achieve a daily intake of 1200 mg, vitamin D supplementation (800–1000 IU/d), reinforcement of the benefit of weight-bearing exercise, and instruction in fall prevention. Pharmacologic therapy was selected based on her individual situation. After discussion of the options, it was decided to use weekly bisphosphonate treatment, based on cost, convenience, and side effects.

Bisphosphonates

Bisphosphonates have become a mainstay of pharmacologic treatment for osteoporosis. The oral agents, alendronate and risedronate, can be taken daily but in most patients will be used once weekly. Risedronate and ibandronate can also be dosed in a less frequent monthly regimen. Two agents are available as IV formulations: ibandronate is administered every 3 months, and zoledronic acid is administered every year for treatment and every 2 years for prevention.[4,24]

Efficacy

The efficacy of bisphosphonates in fracture prevention has been evaluated in multicenter, randomized, placebo-controlled trials in postmenopausal women with osteoporosis treated for up to 36 months[27-30] (Table 3). In these studies, the active treatments increased spine BMD by approximately 5% to 7% and total hip BMD by 3% to 6%, highly significant benefits compared with placebo. Bisphosphonate treatment substantially reduced the 3-year relative risk of vertebral fracture by approximately 40% to 70% in various studies (Table 3). In addition, alendronate, risedronate, and zoledronic acid reduced the risk of nonvertebral fractures by 25% to 40%, and of hip fractures by 40% to 50%.[27,28,30] However, treatment with ibandronate had no overall effect on rates of nonvertebral or hip fractures[29] (Table 3).

Route of Administration

Oral bisphosphonates are poorly absorbed and thus they have specific requirements for administration. They need to be taken with water first thing in the morning on an empty stomach; after taking the bisphosphonate, the patient should remain upright for either 30 or 60 minutes depending on the particular agent used. Oral bisphosphonate therapy is associated with tolerability problems, particularly gastrointestinal intolerance, often expressed as exacerbation of gastroesophageal reflux disease (GERD) or reflux. In patients unable to tolerate bisphosphonate therapy or comply with the procedure for oral administration, the injectable route may be considered. The oral route is contraindicated in patients with delayed esophageal emptying and in those with an inability to stand or sit upright. Intravenous administration may also be required in patients who do not obtain a BMD response, causes of which include malabsorption and poor adherence and/or persistence.

Safety

The more commonly encountered adverse effects of oral bisphosphonates are upper gastrointestinal symptoms, whereas influenza-like symptoms and abdominal, bone, joint, and/or muscle pain are also encountered with oral and intravenous administration.[4,24] There have been conflicting data on the association of oral bisphosphonate use and esophageal cancer. Reports of 54 cases of esophageal cancer in the United States, Japan, and Europe by the FDA in 2009[31] prompted further studies. Although two of these studies examined data from the UK General Practice Research Database, one study did not find a significantly elevated risk for esophageal cancer in patients who were taking bisphosphonates compared with control patients (HR=1.07; 95% confidence interval [CI], 0.74-1.49),[32] whereas another study found increased risk as compared with matched controls (relative risk [RR]=1.30; 95% CI, 1.02-1.66; P<.02).[33] Interestingly, there was an even stronger association in patients who had longer duration of bisphosphonate therapy.[33] Osteonecrosis of the jaw[34] and atypical femoral shaft fractures—the latter under FDA investigation—have been reported on rare occasions in patients receiving bisphosphonate treatment. A recent analysis of 3 large placebo-controlled trials involving over 14,000 women found no significant excess risk of subtrochanteric or diaphyseal fracture in patients receiving bisphosphonates for up to 10 years, although these events were very rare (12 fractures in 10 patients) and the confidence intervals for risk estimates were large.[35]

Raloxifene

Efficacy

The estrogen agonist/antagonist raloxifene provides some of the benefit of estrogen on bone metabolism, preserving bone density, and reducing the incidence of vertebral fractures by up to 50%. In the randomized, placebo-controlled Multiple Outcomes of Raloxifene Evaluation (MORE) trial in 7705 postmenopausal women with osteoporosis, the incidence of new vertebral fractures at 36 months was significantly reduced, with raloxifene 60 mg/d (6.6%) and 120 mg/d (5.4%) compared with placebo (10.1%).[36] The corresponding values for relative risk (95% CI) were 0.7 (0.5–0.8) for raloxifene 60 mg/d and 0.5 (0.4–0.7) for raloxifene 120 mg/d. However, neither raloxifene treatment arm reduced nonvertebral or hip fractures compared with placebo. A further study of the MORE cohort reported a significant reduction in new cases of breast cancer in postmenopausal osteoporotic women receiving raloxifene (RR=0.24; 95% CI, 0.13–0.44; P<.001), which reflected a 90% reduction in risk of estrogen receptor-positive cancer and no benefit in estrogen receptor-negative disease.[37] A 4-year follow up study also demonstrated reduced risk for breast cancer in patients at low and high risk who received raloxifene.[38]

Safety

The main adverse events of raloxifene are hot flashes, venous thrombosis, and leg cramps.[36,37] Raloxifene treatment increased the frequency of thromboembolic disease 3.1 times.[36,37] Given the dual disease targets of this agent, it could be considered for use in older patients that require treatment for osteoporosis who have a family history of breast cancer. In younger patients who are going through menopause, raloxifene would normally be avoided because of the potential for exacerbation of hot flashes. The small but finite risks of venous thromboembolism and fatal stroke associated with raloxifene treatment are the subject of an FDA black box warning.[39]

Calcitonin

Calcitonin is usually administered at a dose of 200 IU/d by nasal spray. In a 5-year randomized, placebo-controlled trial in 1255 postmenopausal women with established osteoporosis, intranasal salmon calcitonin 200 IU/d increased bone density at the spine by a modest extent (1.0%–1.5%) and reduced the risk of new vertebral fractures by 33% (RR=0.67; 95% CI, 0.47–0.97; P=.03) (36% reduction in patients with prevalent vertebral fractures at baseline) but had no effect on nonvertebral or hip fractures.[40] Higher and lower doses of calcitonin had no significant effects on fracture rates. Intranasal calcitonin may be associated with allergic reactions, rhinitis, and epistaxis.[41]

Clinical Pearl: BMD and Antiresorptive Therapy
Antiresorptive drugs prevent bone loss and preserve bone architecture while improving the overall quality of bone. Controlled trials of bisphosphonate agents have shown that reduction in fracture rate occurs early in the treatment course (within about 6 months), and is sustained during ongoing administration. It is important to realize that patients receiving antiresorptive agents do not need to exhibit increased BMD for a reduction in fracture to be achieved; fracture protection is produced even in patients whose BMD is stable. Thus, an unchanged result on a BMD repeated after 2 years is a good result and indicates that the treatment is providing fracture protection. In this scenario, changes in other properties related to bone turnover and metabolism (not reflected in BMD) presumably account for the balance of the improvement in bone strength.

Dr. Greenspan comments on the benefits of antiresorptive therapy.

Teriparatide

Teriparatide (parathyroid hormone [1-34]) is a fragment of parathyroid hormone and the only anabolic agent currently available for the treatment of osteoporosis. This agent has beneficial effects on bone density, size, and microarchitecture and is given daily as a subcutaneous injection. Teriparatide is indicated for both men and women with osteoporosis who are at high risk of fracture, including patients who have already sustained one or more fragility fractures, those who are intolerant of other approved therapies, and those who continue to fracture on other approved therapies. Teriparatide treatment is used for up to 2 years, after which patients would normally be started or restarted on antiresorptive therapy.[42]

Neer et al[43] randomized 1637 postmenopausal women with previous vertebral fractures to daily subcutaneous injections of teriparatide 20 or 40 µg or placebo. After a median of 21 months, the 20 µg dose of teriparatide produced a 65% reduction in vertebral fractures compared with placebo (5% vs 14%; RR=0.35; 95% CI, 0.22–0.55; P<.001), whereas nonvertebral fractures were reduced by 35% (34 vs 53 fractures; P=.04). Teriparatide 20 µg increased BMD by 9.7% in the lumbar spine, 2.8% at the femoral neck, and 2.6% for the total hip, all significantly superior to the effects of placebo (P<.001). Hip fractures were not assessed separately, due to low numbers. The higher dose of teriparatide (40 µg/d) produced similar effects on fracture but had a tendency toward increased side effects. Teriparatide appears to be well tolerated. However, the package insert contains a black box warning regarding the potential risk for osteocarcinoma.[42]

Novel Agents

Denosumab, an inhibitor of RANK ligand which affects the activation, function, and survival of osteoclasts, was approved by the FDA in June 2010 for treatment of postmenopausal women with osteoporosis who are at high risk of fracture.[44] Denosumab is administered by subcutaneous injection every 6 months. In a 36-month study of 7393 women with postmenopausal osteoporosis, treatment with denosumab (60 mg) reduced the relative risk of vertebral fracture by 68% (P<.001) compared with placebo.[45] Relative risk of nonvertebral and hip fractures was also reduced by 20% and 40%, respectively, in denosumab-treated patients as compared with those who received placebo.[45]

Several investigational agents are being developed for osteoporosis. Among the more promising antiresorptive agents are novel estrogen agonist-antagonist agents and cathepsin K inhibitors. In addition, calcium-sensing receptor antagonists and new forms of parathyroid hormone have shown potential and are worthy of further evaluation.

Patient-Related Treatment Barriers

Clinical Pearl: Adherence and Persistence
A large proportion of patients do not take their medication properly. It is common for patients to stop medications for bone disease altogether within a few months of treatment initiation. Adherence and persistence are gauges of patient compliance with therapeutic regimens. Adherence refers to the proportion (percentage) of prescribed medication being taken, maintenance of the correct dosage regimen (eg, following important instructions such as once weekly, on an empty stomach and the need to stay upright), and the medication possession ratio (the proportion of days the patient has medications, typically calculated based on the frequency of prescriptions collected). A common problem with osteoporosis treatments is the need to avoid taking oral medication with food; if this is not followed, absorption can be impaired, resulting in loss of therapeutic efficacy.

Persistence involves the continued taking of prescribed medication, expressed as a percentage of patients at a certain time point. A number of factors tend to favor patients’ discontinuing medication in the setting of osteoporosis, the most important being the silent nature of the disease and the lack of obvious benefit, treatment side effects, and the ongoing financial cost of medication. Ongoing contact and communication from the physician can be a major influence on persistence.

Role of Adherence and Persistence

Adherence rates of 80% or higher have been shown to be associated with the best treatment outcomes.[46] This level of adherence is typically observed in clinical trials where studies are designed to minimize dropout of patients.[47] Studies of “real-world” adherence have reported much lower adherence rates than controlled trials, with 25% to 50% of patients nonadherent with prescribed treatments for osteoporosis.[48-50] As would be expected, poor adherence is associated with reduced efficacy, as revealed in lower than expected risk reduction for fractures[51] and suboptimal improvements in bone turnover markers and BMD.[48]

Studies of “real-world” adherence have reported
much lower adherence rates than controlled trials.

Health plan data for 18,822 patients starting pharmacologic treatment for postmenopausal osteoporosis showed an initial rapid drop in adherence (medication days <80% of possible) over the first few months—reflecting patients not accepting the treatment, with less than 50% of those initiated on bisphosphonate treatment remaining adherent after 6 months.[51] Subsequently, persistence continued to decline but at a slower rate until 12 months and beyond, presumably due to various other factors such as a lack of obvious benefit and side effects.

Case Study, postscript

After adhering fairly well to her medication for the first 3 months, Roberta fails to refill her prescription for several weeks. Over the next several months, she often misses her weekly bisphosphonate dose.

Analysis of a large US managed care database involving 38,120 women treated for osteoporosis (mean age, 66 years) for the years 1997–2003 found that low treatment compliance contributed to a 17% increase in fracture rate.[53] The medication possession ratio (MPR) was below 80% in three-quarters of patients (average follow-up, 1.7 years). In addition, decreasing compliance resulted in progressive and significant impairment of fracture risk reduction (Figure 4). Similarly, 2-year fracture risk data for a large sample of bisphosphonate-treated women enrolled in workplace health plans (n=35,537) showed a progressive inverse relationship between MPR and fracture risk. An MPR of approximately 50% was required for a treatment benefit to be observed; above this level, fracture probability was reduced with increasing MPR, the association becoming more pronounced with MPR above 75%.[54]

Overcoming Barriers to Adherence and Persistence

Patient convenience is a major predictor of treatment success. Some osteoporosis treatments have restrictive dosage requirements, which may constitute a barrier to compliance. In addition, lower frequency of administration is associated with improved adherence to treatment regimens. Analysis of health claims data for patients prescribed daily (n=2010) and weekly (n=731) bisphosphonate treatment showed that those on a weekly regimen had a substantially higher median time to discontinuation (269 vs 134 days; P<.0001) and significantly higher, but still suboptimal, persistence rate at 12 months (44.2% vs 31.7%; P<.0001).[55] These findings suggest that less frequent dosage regimens would be more effective in practice by increasing persistence with treatment. Other measures that improve patient convenience should be applied wherever possible in the treatment of osteoporosis.

Increased communication and contact with patients
is a key strategy for promoting adherence.

Increased communication and contact with patients is a key strategy for promoting adherence. Ongoing follow-up assists with patient motivation and improves the quality of care. The effect of monitoring on adherence and persistence with antiresorptive therapy was evaluated in 75 postmenopausal women prescribed raloxifene for osteopenia, who were randomized to nurse monitoring (involving several open-ended questions at 12, 24, and 36 weeks) with or without marker monitoring (feedback based on urinary N-telopeptide of type I collagen testing) or no monitoring.[56] Kaplan-Meier curves showed that, compared with no monitoring, nurse monitoring increased adherence by 57% (P=.04) and persistence by 25% (P=.07); the addition of marker monitoring did not improve on the results with nurse monitoring. Adherence increased the efficacy of treatment according to surrogate end points: adherence after 1 year was significantly correlated with change in hip BMD (r=0.28; 95% CI, 0.051–0.480; P=.01) and urinary N-telopeptide of type I collagen (r= -0.36; 95% CI, -0.549–0.141; P=.002).

Dr. Greenspan remarks on adherence and fracture reduction.

Conclusions

Osteoporosis results in considerable morbidity and mortality and is likely to increase its toll on society as the population ages. This situation could be improved dramatically if available measures for screening and treatment were implemented more effectively. Unfortunately, even when pharmacologic treatment is initiated, adherence to therapy is often poor and drops off substantially within a few months. The low rates of diagnosis and treatment of osteoporosis represent an urgent public health issue.

Key practical messages to improve osteoporosis management can be summarized as follows:

• Implement bone density testing by DXA regardless of other risk factors for women 65 and older and men 70 and older, at a minimum
• Consider pharmacologic treatment for patients with low bone mass and a FRAX^®-determined 10-year risk for hip fracture of 3% and greater or major osteoporotic fracture of 20% and greater
• Improve clinician-patient communication, in order to increase patient adherence with treatment
• Osteoporosis is truly a silent disease to many clinicians and patients. Patients may be unaware of its presence until a fracture, and clinicians fail to screen and manage the disease appropriately. There is a compelling case for more active management of this disease. It is hoped that improved clarity and relevance of guidelines for screening and treatment algorithms, together with more aggressive implementation, can improve the current state of osteoporosis care

 

John O’Brien, BPharm
Published on December 7, 2010

References

1. National Osteoporosis Foundation. Fast facts on osteoporosis. www.nof.org/osteoporosis/diseasefacts.htm. 2008. Accessed May 6, 2010.
2. US Department of Health and Human Services. Bone Health and Osteoporosis. A Report of the Surgeon General. Rockville, MD: US Department of Health and Human Services; January 2004.
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