Smith, Alice MMS, PA-C; Shaw, Brittany MMS, PA-C; Laliberte, Danielle MMS, PA-C; Langston, Jennifer MMS, PA-C; Bushardt, Reamer L. PharmD, PA-C
According to the National Osteoporosis Foundation, about 9 million Americans have osteoporosis.1 Bone Health and Osteoporosis from the US Surgeon General reports that an estimated 1.5 million Americans suffer a bone disease-related fracture each year.2 Data from the 2010 National Hospital Discharge Survey revealed 306,000 hospital discharges with hip fractures as the first listed-diagnosis, with an average patient length of stay of 5.8 days.3 In fact, direct care costs for osteoporotic fractures in the United States are estimated at $18 billion annually.4 Whether it is the prevalence of osteoporosis or the high cost of related fractures that grabs your attention, the bottom line is that physician assistants (PAs) need to be prepared to diagnose and manage it. The standard of care for osteoporosis diagnosis, prevention, and treatment is changing. Questions linger about the long-term safety and efficacy of some of the most commonly prescribed drug therapies for prevention and treatment. The once straightforward approach to the use of bone mineral density (BMD) screening is now complicated by better understanding of influential clinical risk factors. This article reviews pertinent epidemiologic and etiologic features of osteoporosis as well as offers practical answers to questions percolating in the minds of practicing PAs. The clinical bottom line will be a guide for appropriate treatment, but not overtreatment. In the discussion of drug therapy, this article presents non-estrogen medications for the prevention and treatment of osteoporosis and osteoporosis-related fractures.
PATHOPHYSIOLOGY IN OSTEOPOROSIS
Osteoporosis is characterized by decreased bone mass, diminished bone strength, and alterations in bone architecture that culminate in greater bone fragility and fracture risk.5 Although bone loss is expected with aging and menopause, the severity of losses varies widely, and this influences the clinical significance. Other factors also contribute to reduced bone density, including failure to achieve an optimal peak bone mass by the second decade of life, accelerated loss due to certain chronic diseases or medication toxicities, bone loss related to nutritional deficiencies, or genetic variables.
GENDER AND JOINT SPECIFIC DIFFERENCES
Osteoporosis is more common in women than men, but both groups are affected.2 The previously mentioned Surgeon General's report also describes high-risk populations.2 For example, a White woman over age 50 years has greater than a 40% chance of suffering a fracture during the rest of her life. The lifetime risk for fracture (hip, spine, or forearm) in the US for adults at age 50 is estimated at 40% in women and 13% in men.6 Osteoporosis-related fractures, especially hip fractures, can be devastating to quality of life and affect mobility. According to the North American Menopause Society, hip fractures result in up to a 25% increase in mortality within one year of the fracture.7 For Americans age 50 years and older, osteoporosis of the hip affects 2% of men (0.8 million) and 10% of women (4.5 million).3 Despite numerous advances in the surgical and medical management of patients with hip fracture, patients continue to experience high rates of complications. One in four postmenopausal women suffering hip fracture will require long-term care after the fracture, and half experience some form of long-term loss of mobility.7 Furthermore, mortality is 12% to 20% higher in the first year following a hip fracture than that in individuals of similar age and gender without hip fractures.8 Although osteoporosis is typically a condition found among older adults, PAs should be suspicious in younger patients when comorbidities that are known secondary causes of osteoporosis are identified.
ASSESS BASELINE RISK FOR FRACTURE
According to the FDA, 44 million Americans are at risk for osteoporosis. Prescribers are reacting by frequently turning to drug therapies to prevent this condition. FDA surveillance revealed 150 million prescriptions for bisphosphonates, the most commonly used class of osteoporosis medication, between 2005 and 2009. The decision to prescribe a medication for osteoporosis or fracture prevention in patients with low bone mass generally should be based on more than just a T-score. When the manufacturers of bisphosphonate osteoporosis treatments describe how a drug can reduce fractures by up to 50% in high-risk women, they are referring to results showing relative risk reduction among women who were, as a group, already at increased risk of fracture before randomization in the trials. Direct-to-consumer advertisements have frequently emphasized these relative risk reduction effects. Providers can improve the quality of decision making by establishing a patient's baseline risk before considering the potential benefit of drug treatments. A 50% relative risk reduction in a population of patients with a relatively high baseline risk will yield more clinically significant reductions than the same relative risk reduction in a population of patients who have minimally increased risk.
WEIGH RISK AND BENEFIT OF TREATMENT
BMD testing is widely available, and several osteoporosis risk assessment tools facilitate early recognition of patients with and at risk for osteoporosis. The challenge for some providers is that the tests do not adequately distinguish between risk factors for osteoporosis, such as delineated by BMD, and risk factors for osteoporotic fractures. Refer to Table 1 for risk factors for osteoporotic fracture. Early recognition of patients at risk for osteoporosis and appropriate risk reduction strategies are important, but providers need to also consider the risk and benefits of osteoporosis medications. In recent years, increased concerns have arisen about the long-term safety of several medications used in the prevention and treatment of osteoporosis. Reduced prescribing of estrogen-based preventive therapies among women at risk for osteoporosis has been influenced by highly publicized estrogen-associated toxicities, including thromboembolic complications, breast cancer, and cardiovascular disease.9 Subsequently, alternative therapies, such as bisphosphonates, emerged as gold-standard treatments. Nearly 2 decades after the approval of alendronate, rare but serious toxicities have been linked to bisphosphonates in post-marketing reports. Effects described include atypical femoral shaft fractures, osteonecrosis of the jaw, esophageal cancer, and several complications in patients with end-stage renal disease.10–12 Providers who are considering drug therapy for patients at risk for osteoporosis face a couple key questions. When does the risk of a drug outweigh its benefit, and what is an optimal duration of therapy? This article attempts to bring clarity to these two important questions based on current evidence.
COMBINE BMD TESTING AND CLINICAL RISK FACTOR SCREENING
Providers should understand what T-scores tell us, and what they do not tell us. The World Health Organization (WHO) offered a classification system for osteoporosis based on BMD in 1994. The BMD is typically reported as a T-score. According to the WHO system, BMD is classified in postmenopausal women as either normal (T-score of -1.0 or higher), osteopenia (T-score of -1.1 to -2.4), or osteoporosis (T-score of -2.5 or less).13 The National Osteoporosis Risk Assessment (NORA) study demonstrated the value of BMD measures in predicting fracture risk.14 Data collected from nearly 164,000 patients about 1 year into the study showed that women with osteoporosis experienced a fourfold increase in fracture rates compared to women with normal BMD. Women with osteopenia had a 1.8-fold higher rate of fracture. When controlling for other risk factors, the clinical bottom line was that osteopenia was associated with a 1.7 higher fracture risk and osteoporosis was associated with a 2.7 higher fracture risk within one year.14 A challenge with using BMD measurements to predict fracture risk is that they have a high specificity but low sensitivity. Most postmenopausal women presenting with a fragility fracture, for example, have a T-score higher than -2.5.15 The Study of Osteoporotic Fractures found that 54% of postmenopausal women with incident hip fractures did not have a baseline T-score at the hip that met the definition of osteoporosis.16 T-scores do not predict all patients at risk for fracture, so they cannot be the only means of screening employed.
Increased appreciation has occurred in recent years for the importance of clinical risk factors that affect fracture risk independent of BMD. The WHO developed the Fracture Risk Assessment Tool (FRAX) in 2008 to offer providers a predictive tool for assessing a patient's fracture risk over 10 years, and to provide guidance for clinical decision-making. A major driver for the development of FRAX was the need for a clinical risk factor assessment model that could be used independent of BMD for predicting fracture risk. The instrument can be used with or without knowledge of the patient's BMD, and has been validated using BMD at the hip (Table 1). FRAX has not been validated in patients already treated with osteoporosis medication. If a patient has prior treatment with an osteoporosis medication but has been off therapy for at least a year for most drugs, or 2 years for bisphosphonates, then use of the FRAX is appropriate.17 Several organizations, including the North American Menopause Society (NAMS) and the National Osteoporosis Foundation (NOF), offer guidelines for appropriate use of osteoporosis medication that integrate the FRAX score. The concept is simple—assess the patient's baseline risk before prescribing. These guidelines attempt to guide clinical decision-making with consideration of risk and benefit as well as a cost-effective approach to pharmacologic intervention.1,7,18,19 Providers should also understand how ongoing monitoring and testing is conducted. Indications for initial and follow-up BMD testing for osteoporosis are presented in Table 2. The clinical bottom line is that combining BMD measurements with clinical risk factors is better for estimating fracture risk than looking just at BMD or risk factors alone.20
REDUCE FRACTURE RISK WITH LIFESTYLE INTERVENTIONS
Effective strategies to prevent bone loss include several lifestyle recommendations, which should be a foundation of treatment. Providers should encourage patients to follow these guidelines, which are derived from universal recommendations for all patients from the NOF as well as dietary intake recommendations from the Institute of Medicine.21,22
1. Maintain adequate calcium and vitamin D intake. Ensuring adequate daily intake of calcium and vitamin D is a safe, effective and low-cost strategy for reducing osteoporotic fracture risk. Obtaining calcium and vitamin D from a balanced, healthful diet is the best option. Over-the-counter supplements or prescription vitamin products should be used to reach targets when diet alone is inadequate. Men ages 50 to 70 should consume 1,000 mg calcium per day. Women age 51 and older and men age 71 and older should consume 1,200 mg calcium per day. In the US, adults age 50 and older consume 600 to 700 mg of dietary calcium per day on average. The NOF recommends that adults age 50 and older should intake of 800 to 1,000 international units (IU) of vitamin D per day.21 The Institute of Medicine Dietary Reference Intake for vitamin D differs slightly with recommendations for 600 IU daily until age 70, then 800 IU per day at age 71 and older.22 Laboratory monitoring can help ensure adequate vitamin D intake. Vitamin D supplements are recommended in amounts to achieve and maintain a serum 25(OH) vitamin D level of about 30 ng/mL (75 nmol/L).
2. Exercise and take steps to prevent falls. Weight-bearing and muscle-strengthening exercise is recommended to reduce fall risk and likelihood of subsequent fracture. Although exercise may result in modest increases in bone density, the most significant benefits include weight loss as well as improved agility, posture, balance, and strength. In addition to exercise, fall prevention strategies are essential preventive measures. Examples of effective strategies include individualized fall risk assessment screening, correction of vision, interventions to improve home or workplace safety, and management of polypharmacy including excessive use of psychotropic agents. Consultation with a physical or occupational therapist for an individualized plan can be beneficial, such as through education to promote proper body mechanics and improve strength. Other patients who will likely benefit from referral to a rehabilitative specialist include patients with severe kyphosis, back pain, or gait instability. Limited evidence supports the use of hip protectors, which may reduce the impact of hip injury if worn at the time of a fall.
3. Eliminate tobacco use and excessive alcohol intake. Tobacco damages the skeleton. The safest amount of tobacco products to use is none. Moderate intake of alcohol is unlikely to adversely affect bone health. Providers should screen, however, for patients consuming three or more drinks per day, as excessive use can damage bone health and increase risk of injury.
4. Reduce the fall risk for patients at high risk for falls (older patients, frail patients, those who have had a stroke, and those on medications that decrease mental alertness). Advise patients to anchor rugs and use nonskid mats; minimize household clutter, especially on floors; wear sturdy, low-heeled shoes; install handrails in bathrooms, halls, and stairways; keep entrances, stairwells, and hallways well-lit; and to use appropriate hearing and vision aids. Providers can adjust the patient's medication list to minimize medication-associated dizziness or increase mental alertness.
TO PRESCRIBE OR NOT TO PRESCRIBE, THAT IS THE QUESTION
A management approach that emphasizes lifestyle modifications may be all that is necessary for patients at low risk for osteoporotic fracture. There are clear indications, however, for prescribing medication therapy for preventing and treating osteoporosis in higher-risk patients. See Figure 1 for a schematic that summarizes the diagnostic and management approach. Adapted from guidance from the NOF and NAMS, drug therapy should be considered in postmenopausal women and men age 50 and older who present with the following7,19,21:
* An osteoporotic hip or vertebral fracture
* Osteoporosis as defined by a T-score ≤ -2.5 at the femoral neck, total hip, or lumbar spine
* Low bone mass (T-score between -1 and -2.5) and a 10-year probability, based on FRAX, of a major osteoporosis-related fracture of 20% or greater or hip fracture of 3% or greater.
Prescribing information and practical points of discussion will be provided for the following medications or drug classes used in patients with or at risk for osteoporosis: bisphosphonates, calcitonin, denosumab, raloxifene, and teriparatide. Although the vast majority of clinical studies have been conducted in postmenopausal women with osteoporosis, limited data demonstrating the effects of therapy in men and individuals with glucocorticoid-induced osteoporosis have been incorporated into this discussion.23–25 When a provider determines that an osteoporosis medication is warranted, selection should be based on an individual assessment of risks and benefits. This practice is supported by the American College of Physicians in a 2008 guideline, which evaluated 76 randomized, controlled trials and 24 meta-analyses to determine comparative benefits and risks among available osteoporosis medications.26 This guideline also reported the need for more head-to-head trials for fracture prevention and further research on the appropriate duration of treatment for osteoporosis. Further discussion by drug or drug class follows.
Bisphosphonates work by inhibiting the activity and shortening the half-life of osteoclasts, which reduces bone turnover. These drugs are generally considered a first-line drug therapy for prevention and treatment of osteoporosis. Three orally available agents (alendronate, risedronate, and ibandronate) and an intravenous infusion product (zoledronic acid) are used for patients with or at risk for osteoporosis. All four of these agents have been shown to prevent vertebral fractures in good quality studies. Additional evidence demonstrates hip fracture prevention with alendronate, risedronate, and zoledronic acid.23,26
The most common adverse effects associated with bisphosphonates are gastrointestinal. To help reduce the risk for serious gastrointestinal injury, the oral products are contraindicated in patients who cannot sit upright or stand for 30 minutes after a dose. Before initiating therapy, patients should be screened for renal impairment which can be worsened by bisphosphonates. These drugs are contraindicated in patients with estimated glomerular filtration rate less than 30 to 35 mL/min. Zoledronic acid infusion is associated with a risk for an acute phase reaction, which can produce arthralgia, myalgia, fever, and headache. Acetaminophen is sometimes administered before the infusion to reduce the risk of this adverse reaction.21 As previously mentioned, doubts about the long-term safety of bisphosphonate therapy have been reported in recent years. Rare adverse effects reported include osteonecrosis of the jaw, inflammatory symptoms affecting the eye, as well as low trauma atypical subtrochanteric and diaphyseal femoral fractures.11 The optimal duration of bisphosphonate therapy for osteoporosis is controversial. Trial data to guide prescribing of bisphosphonates beyond 5 years are limited, consisting of one trial with alendronate and one with zoledronic acid, both involving postmenopausal women.27,28 Researchers involved with these studies made these recommendations based on trial results:
* Continue bisphosphonate in patients with low BMD at femoral neck (T-score less than -2.5) after 3 to 5 years of treatment
* Consider continuation of therapy in patients with an existing vertebral fracture who have reduced bone density (T-score of -2.0 or less)
* Consider discontinuation of therapy in patients with femoral neck T-score greater than -2.0
* Recommendations regarding discontinuation of therapy after 3 to 5 years should be limited to alendronate and zoledronic acid.
A more detailed discussion of duration of therapy for bisphosphonates, including the use of laboratory monitoring for bone turnover markers, is discussed in an accompanying Special Topics article by Ott on page 64.
Calcitonin inhibits bone resorption; however, the reduction in bone turnover is lower than with other commercially available osteoporosis medications. This drug is FDA-approved for the treatment of osteoporosis in women who are at least 5 years postmenopausal. Fair-quality research demonstrated about a 30% reduction in vertebral fracture rates and no data have shown significant reductions in nonvertebral fractures.21 The drug is not a first-line treatment. Recently, both the FDA and European regulators have questioned the use of long-term calcitonin for osteoporosis, stating that risks may outweigh benefits. Calcitonin is available in two forms—nasal spray and injectable formulation. Common adverse reactions include rhinitis, nasal congestion, and epistaxis with the nasal form; and gastrointestinal reactions with the injectable form. Calcitonin may offer benefits in short-term approaches in select patients due to a reported analgesic effect.9
Denosumab is FDA-approved for the treatment of osteoporosis in postmenopausal women at high risk for fracture. The drug also is approved for increasing BMD in men who are at high risk for fracture as well as other high-risk patients including men receiving androgen deprivation therapy for non-metastatic prostate cancer and women receiving adjuvant aromatase inhibitor therapy for breast cancer. Denosumab is a fully human monoclonal antibody to receptor activator of nuclear factor kappa-B ligand (RANKL), which inhibits bone resorption by osteoclasts. The drug is administered every 6 months as a subcutaneous injection. Denosumab is associated with skin infection and skin rash; it may cause hypocalcemia.21 Bisphosphonates continue to be generally preferred over denosumab as a first-line consideration, but denosumab offers a relatively convenient, effective alternative in patients who are at high risk for fracture and for patients who have failed or do not tolerate other therapies.
Although direct comparisons are not available, key fracture reduction data with denosumab versus bisphosphonate agents does offer an indirect opportunity for comparison. The FREEDOM Trial found a number-needed-to-treat (NNT) of 58 for clinical vertebral fracture prevention and 200 for hip fracture prevention in patients treated with denosumab versus placebo. The NNTs for the same measures with bisphosphonate agents versus placebo ranged from 23 to 37 for clinical vertebral fracture prevention; the NNT was 91 for hip fracture prevention, based on data from the Fracture Intervention Trial, VERT Trial, HIP Trial, and HORIZON Trial.29
Discontinuation of denosumab has been associated with transient increases in bone remodeling and losses in BMD. Little evidence describes the effect on fracture risk following treatment cessation. One study suggests providers can safely discontinue therapy without significant increases in fracture risk for the next 2 years.30 Serious adverse effects reported with denosumab include eczema or skin infection, hypocalcemia, pancreatitis, osteonecrosis of the jaw, and atypical femoral fractures. More common adverse effects include pain (arthralgia, back pain, pain in an extremity), hypercholesterolemia, and cystitis.
Raloxifene is an estrogen agonist/antagonist FDA-approved for the prevention and treatment of osteoporosis in postmenopausal women. This drug also is useful for risk reduction of invasive breast cancer in postmenopausal women with osteoporosis.
Clinical studies over 3 years of treatment reveal about a 30% relative risk reduction in vertebral fracture in women with a prior vertebral fracture and a 55% reduction in patients without a prior fracture. Based on the Multiple Outcomes of Raloxifene Evaluation trial, the NNT for vertebral fracture prevention over 3 years ranged from 15 to 46, with the greater benefit seen in higher risk patients.23
Common adverse reactions to raloxifene include hot flashes and leg cramps. Raloxifene is also associated with an increased risk of thromboembolic events and is contraindicated in patients at high risk for these complications.
Teriparatide is an anabolic (bone-building) drug FDA-approved for treatment of osteoporosis in postmenopausal women and men at high risk for fracture. In clinical practice, teriparatide generally is used in patients for whom bisphosphonate therapy has been ineffective, including patients who had osteoporotic fracture while on treatment.31 Teriparatide is also used to prevent glucocorticoid-related osteoporosis, and to increase bone mass in men who are at high risk for fracture related to primary or hypogonadal osteoporosis.
Good-quality evidence demonstrates vertebral fracture prevention with teriparatide and limited data demonstrate hip fracture prevention. In a recent meta-analysis of trials that reported fracture as an outcome, treatment was associated with a 70% risk reduction in vertebral fractures (risk ratio 0.30, 95% CI: 0.21-0.44; three trials, n=1452) and 38% risk reduction in non-vertebral fractures (risk ratio 0.62, 95% CI: 0.44-0.87; three trials, n=1,842).32 An area of ongoing study is the combination of anabolic therapy with teriparatide with denosumab for fracture prevention. Prior studies combining teriparatide with bisphosphonates offered little to no improvements in efficacy. In a recent trial with teriparatide and denosumab, however, the combination approach increased BMD more than either agent alone and to a greater extent than has been reported with approved therapies. Combination treatment may be useful to treat patients at high risk of fracture, but further study is needed.33
Teriparatide is administered as a daily subcutaneous injection. Bone loss can be rapid following discontinuation and alternative agents may be considered to maintain bone density. Adverse effects include leg cramps, nausea, and dizziness. Limited evidence exists regarding the long-term safety of this agent beyond the 2 years evaluated during clinical trials.
Several emerging therapies, not yet approved in the United States, may offer benefits for patients with or at risk for osteoporosis and osteoporotic fractures.19,21
Strontium ranelate has reduced the incidence of vertebral fractures compared to placebo in postmenopausal women evaluated in Europe and Australia. Strontium appears to have an anti-remodeling effect on bone. It is approved for the treatment and prevention of osteoporosis outside of the United States.
Tibolone is a synthetic steroid hormone that has been used outside of the United States for the prevention of osteoporosis as well as the treatment of menopausal symptoms. A 2012 systematic review evaluated the effectiveness and safety of tibolone in postmenopausal women.34 The authors reported safety concerns related to the use of tibolone, specifically citing increased risk for breast cancer in women with a prior history of breast cancer and an increase in stroke risk in older women.
New therapies under investigation for the treatment of osteoporosis include sclerostin inhibitors, integrin antagonists, and cathepsin-K inhibitors. These drugs are in various stages of research and development and offer unique mechanisms of action. Inhibiting sclerostin, which is produced by osteocytes and inhibits bone formation, has been shown to increase bone mass in a phase I trial in healthy adults.35 Integrin antagonists prevent bone resorption by inhibiting integrin-mediated adhesion of osteoclasts to the bone surface. Cathepsin-K inhibitors inhibit bone matrix dissolution by preventing the action of the cathepsin-K protease, which plays a role in osteoclast-mediated bone resorption, thus leading to decreased bone resorption and improved bone mineral density.36
Nutritional factors such as vitamin K and isoflavones also may play a potential role in the prevention and treatment of osteoporosis. Low vitamin K status has been associated with an increased risk of fracture in older adults, and clinical trial data suggest that vitamin K supplementation may decrease fracture risk and bone loss.37 Isoflavones are micronutrients with estrogenic properties that have been reported to have a beneficial effect on BMD and fracture risk. They are found in foods such as soybeans, chickpeas, and lentils. As of yet, however, there are no randomized controlled trials that assess the effects of isoflavones on BMD or fracture risk.
Osteoporosis and osteoporosis-related fractures can be devastating in the life of a patient, with well-described morbidity, including loss of independence and mobility, as well as mortality. Identifying at-risk patients with early adoption of preventive strategies is critical to improving health and avoiding the costly complications of fracture. The question of when to start an osteoporosis medication requires clinical reasoning, a critical analysis of risk and benefit, and an approach individualized for the patient. Several steps can be adopted by providers to promote best practices for optimizing benefits and minimizing risk of osteoporosis and osteoporosis-related fractures. Assess a patient's baseline risk. This assessment should incorporate a survey of clinical risk factors as well as radiologic screening, such as with BMD screening. These authors recommend the use of a validated tool for clinical risk factor assessment, such as FRAX. Interpretation requires integration of these results weighed against the relative risks and benefits of available therapies. Target risk reduction with proven lifestyle interventions in all patients.
Bisphosphonate agents remain the primary choice for prevention and treatment of osteoporosis in men and women, but questions about long-term risk remain. Although multiple bisphosphonate agents—including oral and an intravenously infused product—are proven efficacious for prevention and treatment of osteoporosis, their safety profiles and availability of long-term safety data differ. More will likely be learned from ongoing research that is attempting to refine how follow-up radiologic monitoring and laboratory assays, including biochemical markers of bone turnover, are used to improve safety and prescribing decisions. When a bisphosphonate is not an appropriate option or an optimal duration of use has been met, understanding the safety profiles of other non-estrogen treatments facilitates decision making. A clear presentation of anticipated benefits (including a description of the magnitude of those benefits presented in a way that patients and caregivers can understand) and discussion of potential short-term and long-term adverse effects are essential. A collaborative approach between patients and providers can achieve optimal therapeutic results with significantly decreased fracture risk, ultimately lessening the burden of osteoporosis and greatly increasing patients' quality of life.
When the potential risk of drug therapy outweighs anticipated benefit, not prescribing is likely the best choice for your patients. Emphasis could then be placed on lifestyle interventions and monitoring for disease progression.
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© 2013 American Academy of Physician Assistants.