osteoporosis establishing treatment strategies

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Osteoporosis—Establishing Treatment Strategies Statement of Need Osteoporosis is an underdiagnosed and undertreated condition with serious consequences for patients and the health care system as a whole. The cost of treating osteoporosis-related fractures was estimated to be $19 billion in 2005. As the percentage of the population older than age 65 years increases, these costs are expected to increase accordingly. Primary care practitioners play a critical role in testing and identifying patients at risk for osteoporosis-related fracture and in treating them to reduce this risk. In order for health care professionals to be able to reduce the burden posed by this condition, they must be aware of the epidemiology and risk factors involved in osteoporosis, as well as the guidelines and current data on appropriate treatment. Introduction Treatment of osteoporosis is an essential strategy for preventing fractures. Fifty percent of women and as many as 25% of men aged older than 50 years will experience an osteoporosis-related fracture during their remaining lifetime.1 The hip is one of the most common sites for an osteoporosis-related fracture, and the consequences of this type of fracture can be devastating. Twenty-four percent of patients who experience a hip fracture die within the first year, and 20% require long-term care afterward.1 Therefore, testing of patients at risk to identify osteoporosis and initiation of appropriate treatment are critical to improving patient outcomes. The National Osteoporosis Foundation (NOF) published the Clinician’s Guide to Prevention and Treatment of Osteoporosis. NOF recommendations for patients that should receive pharmacologic treatment for osteoporosis are summarized in Table 1.2


Table 1. National Osteoporosis Foundation Guidelines on Pharmacologic Therapy for Osteoporosis Postmenopausal women and men aged 50 years and older presenting with the following should be considered for treatment:

A hip or vertebral (clinical or morphometric) fracture

T-score ≤–2.5 at the femoral neck or spine by dual-energy x-ray absorptiometry (DXA) after appropriate evaluation to exclude secondary causes

Low bone mass (T-score between –1.0 and –2.5 [osteopenia] at the femoral neck or spine) and a 10-year probability of a hip fracture ≥3% or a 10-year probability of a major osteoporosis-related fracture ≥20% based on the US-adapted WHO FRAX® algorithm

WHO=World Health Organization The goal of treatment is to prevent fractures and the associated pain, disability, and reduction in quality of life (QOL).2 Nonpharmacologic Interventions for the Prevention of Osteoporosis A number of recommendations may be applied to the general population and to those at risk for osteoporosis with the intention of preventing the development of osteoporosis. These recommendations may also be applied to those with existing osteoporosis. Most of the interventions are focused on promoting good overall health and wellness. They include an adequate intake of calcium and vitamin D, lifelong participation in regular exercise, and avoidance of smoking and excessive consumption of alcohol.2 Vitamin D deficiency is common and occurs in as many as 90% of older adults.3 The optimal level of serum 25-hydroxyvitamin D [25(OH)D], however, is unclear. A serum level of at least 30 ng/mL, particularly in older people who have low bone mass or osteoporosis, has been recommended by organizations such as NOF and The Endocrine Society. Vitamin D intoxication does not occur until levels of serum 25(OH)D reach 150 ng/mL or higher and is rare even with supplementation.3 Importantly, a study conducted in postmenopausal North American women who were receiving osteoporosis therapy found that serum 25(OH)D was less than 20 ng/mL in 18% of the women; less than 25 ng/mL in 36%; and less than 30 ng/ml in 52%.4 This study also noted that vitamin D deficiency, defined as serum levels of 25(OH)D of less than 30 ng/mL, was more likely to be found in those receiving less than 400 international units (IU) vitamin D supplementation daily.4 Factors associated with vitamin D deficiency included age older than 80 years; a body mass index higher than 25 kg/m2; use of medications known to affect vitamin D metabolism (eg, corticosteroids, cholestyramine, and anti-epilepsy medications including carbamazepine and phenytoin5); vitamin D supplementation of


less than 400 IU daily; poor general health; limitation in daily activities; exercise less than 6 times per week; the lack of a discussion with a physician regarding the importance of vitamin D to bone health; lower education level; lower annual income; and fewer weekly servings of vitamin D-rich foods.4 The NOF Guide recommends 800 to 1000 IU of vitamin D per day for adults aged 50 years and older; some older patients, however, may need higher levels.2 Dietary sources of vitamin D include vitamin D-fortified milk and cereals, salt-water fish, egg yolks, and liver. Vitamin D is also included in some calcium supplements and in most multivitamins.2 The NOF recommends that all individuals be advised to obtain an adequate intake of dietary calcium of at least 1,200 mg per day – lifelong intake of adequate calcium levels is important for attainment of peak bone mass and maintenance of healthy bone.2 Ideally, the calcium should come from consumption of calcium-rich foods—usually this means dairy foods—with supplements in pill form only to bring the total to the recommended daily amount. However, the majority of American women and men older than forty to fifty years of age consume ≤ 600 to 700 mg/d of calcium in their diets, and therefore many will require supplementation.2,6,7 Dietary sources of calcium include dairy products—milk, cheese, yogurt—some vegetables—spinach, kale, bok choy, mustard or turnip greens—and some fortified cereals and juices.6,7 Calcium is a threshold nutrient, so taking in more than the threshold is not necessary and may even be harmful. Higher levels of calcium supplementation have been associated with increased risk for kidney stones, and there is some evidence that higher amounts of supplements may be associated with an increase in the risk for cardiovascular disease including myocardial infarction.2,6,8,9 The EPIC-Heidelberg study found a significantly increased risk for myocardial infarction (hazard ratio [HR]=1.86; 95% CI 1.17 to 2.96) among those taking calcium supplements as compared with non-users of any supplements.8 A meta-analysis of placebo-controlled trials of calcium supplements (≥500 mg/day) also found an increased risk of myocardial infarction among those taking calcium supplements without coadministered vitamin D (HR=1.31; 95% CI 1.02 to 1.67).9 However, it is important to note that the ability of the body to absorb calcium decreases with age. In addition, high levels of sodium increase urinary calcium excretion.7 Smoking and excessive alcohol intake (defined as 3 or more units of alcohol per day—30 mL of spirits, 285 mL of beer, or 120 mL of wine) have been implicated as risk factors for the development of osteoporosis.10-12 Therefore, smoking cessation and limiting alcohol consumption are advisable.13 Exercise is another important element of an osteoporosis prevention and treatment regimen. Weight-bearing and muscle-strengthening exercise done on a regular basis can reduce the risk of falls and fractures by improving balance, agility, strength, and posture.2 Patients who have already developed osteoporosis,


though, should be evaluated by a clinician before engaging in exercise because some types of exercise can increase the risk of fracture.2 The NOF Clinician’s Guide on the Prevention and Treatment of Osteoporosis includes recommendations for nonpharmacologic interventions for the prevention and treatment of osteoporosis, which are summarized in Table 2. Table 2. National Osteoporosis Foundation Guidelines on Nonpharmacologic Interventions for the Prevention and Treatment of Osteoporosis2

Adequate calcium and vitamin D intake

Calcium at least 1200 mg/d, including supplements if necessary

Vitamin D 800 to 1000 IU/d for adults aged 50 years and older and for patients with malabsorption (eg, celiac disease), chronic renal insufficiency, for housebound patients, the chronically ill, and others with limited sun exposure at high risk for deficiency

Serum 25(OH)D levels should be measured in those at risk of deficiency

Regular weight-bearing exercise and muscle strengthening to reduce risk of falls and fractures

Improves agility, strength, posture, and balance

Fall prevention

Checking and correcting vision and hearing

Evaluating neurological problems

Reviewing prescription medications for side effects

Providing a checklist for improving safety at home

Avoidance of tobacco use and excessive alcohol intake

Fall prevention is essential to reducing the fractures associated with osteoporosis. Table 3 lists risk factors for falls. Important strategies to reduce the risk of falling include installing grab bars and other assistive devices in bathrooms, and securing loose throw rugs, and removing obstacles from walking paths. Adequate lighting should be used, where possible, to improve visibility. In addition, medications should be reviewed and those that may increase the risk for falls due to neurologic, sedative or other effects discontinued or changed to an alternative if possible/appropriate.14


Table 3. Risk Factors for Falls2

Environmental Risk Factors

Lack of assistive devices in bathrooms

Loose throw rugs

Low level lighting

Obstacles in the walking path

Slippery outdoor conditions

Medical Risk Factors

Age

Anxiety and agitation

Arrhythmias

Dehydration

Depression

Female sex

Impaired transfer and mobility

Malnutrition

Medications causing oversedation (narcotic analgesics, anticonvulsants, psychotropics)

Orthostatic hypotension

Poor vision and use of bifocal eyeglasses

Previous fall

Reduced problem-solving or mental acuity and diminished cognitive skills

Urgent urinary incontinence

Vitamin D deficiency

Neuro and Musculoskeletal Risk Factors

Kyphosis

Poor balance

Reduced proprioception

Weak muscles

Pharmacologic Interventions for the Prevention and Treatment of Osteoporosis A number of pharmacologic interventions are available for the prevention or treatment of osteoporosis, including the bisphosphonates, calcitonin, denosumab, raloxifene, and teriparatide. Treatment with each of these agents has been found to prevent one or more types of fractures. The most commonly used agents are the oral bisphosphonates; two bisphosphonates are available in intravenously administered formulations.


Pharmacologic treatments approved for the treatment and/or prevention of osteoporosis are summarized in Table 4.

Table 4. Pharmacologic Interventions for the Treatment of Osteoporosis

Drug Indication Route Dose Evidence

Alendronate15,16 Indicated for prevention and treatment of postmenopausal osteoporosis, for treatment to increase bone mass in men with osteoporosis, and for treatment of glucocorticoid-induced osteoporosis

Oral 5 mg/d tablet 10 mg/d tablet 35 mg/wk tablet 70 mg/wk tablet or liquid formulation 70 mg/wk tablet + 2800 IU or 5600 IU vitamin D

Reduces the risk for spinal and hip fractures over 3 yrs

Ibandronate17 Indicated for prevention (oral only) and treatment of postmenopausal osteoporosis

Oral or IV 2.5 mg/d tablet 150 mg/mo tablet 3 mg/every 3 mo IV

Reduces the risk for vertebral fractures over 3 yrs

Risedronate18 Indicated for prevention and treatment of postmenopausal osteoporosis, for treatment to increase bone mass in men with osteoporosis, and for prevention and treatment of glucocorticoid-induced osteoporosis

Oral 5 mg/d tablet 35 mg/wk tablet 35 mg/wk tablet + 6 tablets of 500 mg calcium carbonate 150 mg/mo tablet 35 mg tablet with delayed release coating and chelating agent for once weekly use

Reduces the risk for vertebral and nonvertebral fractures over 3 yrs

Zoledronic acid19

Indicated for prevention and treatment of postmenopausal osteoporosis, for treatment to increase bone mass in men with osteoporosis, and for prevention and treatment of glucocorticoid-induced osteoporosis

IV 5 mg IV over at least 15 min once every year for treatment and once every 2 years for prevention

Reduces the risk for vertebral fractures, hip fractures and nonvertebral fractures

Calcitonin20,21 Indicated for treatment Nasal 200 IU in single 200 IU intranasally reduces


of osteoporosis in women more than 5 years’ postmenopausal with low bone mass relative to healthy premenopausal females

spray or SC injection

daily intranasal spray 100 IU every 1 to 2 day SC or IM

the risk for new vertebral fractures at 5 yrs22 Recently there have been concerns about cancer risk with calcitonin; the European Medicines Agency has recommended withdrawal of approval for osteoporosis23

Raloxifene24 Indicated for prevention and treatment of osteoporosis in postmenopausal women

Oral 60 mg/d tablet Reduces the risk of vertebral fractures over 3 years

Teriparatide25 Indicated for treatment of osteoporosis in postmenopausal women at high risk for fracture, for treatment to increase bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture, for treatment of men and women with osteoporosis associated with sustained systemic glucocorticoid therapy at high risk for fracture

SC injection

20 mcg once daily Reduces the risk for vertebral fractures and nonvertebral fracture after 18 mos

Denosumab26 Indicated for treatment of postmenopausal women with osteoporosis at high risk for fracture, for treatment to increase bone mass in men with osteoporosis at high risk for fracture and in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer, and for treatment to increase bone mass in women at

SC injection

60 mg once every 6 mo

Reduces the risk for vertebral fractures, hip fractures and nonvertebral fractures


high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer

BMD=bone mineral density; d=day; mo=month(s); IU=international units; IV=intravenous; SC=subcutaneous; wk=week(s); yr=year. Bisphosphonates Bisphosphonates have proven efficacy for treatment of osteoporosis and have been widely used for many years. Bisphosphonates approved for the treatment of osteoporosis in the United States are alendronate, risedronate, ibandronate, and zoledronate. Information on each drug, their indications, routes of administration, and doses are included in Table 4. It is essential that patients are educated about the importance of following specific instructions for taking oral bisphosphonates for adequate absorption and to minimize the risk for esophageal irritation. Alendronate, risedronate and oral ibandronate must be taken on an empty stomach first thing in the morning with 8 oz of plain water. No food, liquid (other than water), or other medication should be taken after that for at least 30 minutes (60 minutes for ibandronate), and the patient should remain upright. Ibandronate is also available in an intravenous (IV) formulation, and zoledronic acid is only given intravenously. Serum calcium and creatinine should be checked before each dose of IV zoledronic acid, and bisphosphonate treatment discontinued if serum creatinine levels are increased,15-19 Ibandronate and risedronate are not recommended in patients with a creatinine clearance of less than 30 mL/minute, while alendronate is not recommended in patients with a creatinine clearance of less than 35 mL/minute.15-18 Zoledronic acid is contraindicated in patients with a creatinine clearance of less than 35 mL/minute and in those with evidence of acute renal impairment.19 The optimal duration of bisphosphonate therapy has not been established. The US Food and Drug Administration (FDA) recently completed a review of data on bisphosphonate use from 3 major long-term extension trials—the Fracture Intervention Trial (FIT) Long-Term Extension (FLEX), the Reclast Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT), and the Actonel Vertebral Efficacy with Risedronate Therapy-Multinational Trial (VERT-MN) extension. Concerns about atypical subtrochanteric fractures as well as osteonecrosis of the jaw during prolonged bisphosphonate therapy prompted the investigations (this is discussed in more detail in the section on oral bisphosphonates).27,28 The evidence to date for identifying subgroups of patients more likely to benefit from continuing bisphosphonate therapy beyond 3 to 5 years is unclear. Although data suggest that bisphosphonate therapy may be discontinued in some patients without losing the therapeutic gains already made, robust clinical trials have yet to establish the duration of drug benefit after cessation of therapy.28 Nonetheless, patients at low risk for fracture, such as younger patients without a history of fracture and with a near normal BMD, may be


good candidates for discontinuation of bisphosphonate therapy after 3 to 5 years, while those at increased risk for fracture, such as older patients with a history of fracture and a BMD still within the osteporotic range, may derive benefit from continued therapy.28 Making decisions about how long to treat patients requires careful consideration of all the factors involved, including the patient’s age, T-score, response to treatment, history of fractures, comorbidities, use of concomitant medication, and patient preference.27 Table 5 presents one possible approach to duration of treatment with bisphosphonates for patients with low, mild, moderate, and high fracture risk. In all cases, if therapy is stopped, continued assessment of the patient for the development of new clinical risk factors and periodic monitoring of BMD is essential as re-institution of treatment may be necessary in some patients over time. Table 5. Suggested Duration of Bisphosphonate Therapy in Osteoporosis Based on Watts and Diab 201029

Fracture Risk and Recommendations

Example Explanation

Low Treatment not needed

53-yr-old woman, menopause at age 50; lowest T-score –1.6, no risk factors, bisphosphonate therapy for 2 yrs

Treatment was not indicated in the first place and can be discontinued

Mild Treat with bisphosphonate for 3-5 yr, then stop

65-yr-old woman, menopause at age 52; initial lowest T-score –2.6, no risk factors, bisphosphonate therapy for 5 yr; BMD stable over that time

Treatment was indicated, but after 5 yr of treatment, a drug holiday might be considered

Moderate Treat with bisphosphonate for 5-10 yr, then offer drug holiday of 3-5 yr unless significant loss of BMD or fracture occurs

70-yr-old woman, menopause at age 49; lowest initial T-score –2.7, no risk factors, bisphosphonate therapy for 8 yr, BMD increased over that time, so lowest T-score now –2.3

Treatment was indicated, but after 8 yr of treatment a drug holiday of 3-5 yr might be considered

High Treat with bisphosphonate for 10 yr, offer drug holiday of 1-2 yr until significant loss of BMD or fracture occurs. Nonbisphosphonate may be offered during holiday

72-yr-old woman, menopause at age 43; lowest initial T-score –3.8, rheumatoid arthritis requiring ongoing corticosteroid therapy for 12 yr, 3-in height loss and 2 vertebral fractures by VFA; treatment with bisphosphonate for 10 yr

Treatment was indicated. After 10 yr, she remains at high risk of fracture. If a holiday from bisphosphonates is considered, interval treatment with teriparatide or raloxifene would be prudent

VFA=vertebral fracture assessment


The oral bisphosphonates may cause gastrointestinal effects, including esophageal burning and ulceration.3,30 Among side effects associated with bisphosphonate treatment of osteoporosis, osteonecrosis of the jaw (ONJ) and atypical femur fractures are of greatest concern to patients. ONJ was first reported in 2003 in patients receiving very high IV doses of bisphosphonates for skeletal malignancies. Later reports emerged of patients experiencing ONJ at lower doses of bisphosphonates; more than 90% of cases, however, occurred in patients with malignancies receiving higher doses.29 Reports in the media have led to false impressions among medical and dental professionals and the public about the incidence of ONJ and the risk associated with bisphosphonate treatment. In some cases patients have decided to stop their treatment despite being at high risk for fracture and at low risk for ONJ.29 The actual incidence of ONJ is difficult to pinpoint, but epidemiological data indicate that it ranges from 1 in 10,000 to 1 in 160,000.29 Evidence also suggests that the risk is very small in the first 5 years of therapy.2 Although the mechanisms involved are not understood,29 recommendations are that patients receiving bisphosphonates should undergo oral examination and should receive all necessary dental treatment. Patients should be instructed about the possibility of developing ONJ and the importance of good oral hygiene, particularly among those receiving IV bisphosphonates.31 Atypical fractures of the femoral shaft have been associated with bisphosphonate use, according to case reports and series. A meta-analysis of data from the FIT, FLEX, and HORIZON PFT trials involving a total of 14,195 women found that 12 fractures occurred in the subtrochanteric or diaphyseal femur, for a rate of 2.3 per 10,000 patients-years.32 A Swedish study of 12,777 women aged 55 years or older who had sustained a fracture of the femur found an increase in absolute risk of 5 cases per 10,000 patient-years for bisphosphonate-associated atypical fractures.33 In 2010, the FDA announced that an increased risk for these fractures has been added to the Warnings and Precautions section of bisphosphonate labels.34 Nonetheless, the risk for these fractures is small, even in those receiving the drugs for as long as 10 years, and is outweighed by the beneficial effects of the drugs in patients at high risk for fracture.32,33

Denosumab Denosumab is an inhibitor of receptor activator of nuclear factor kappa-B ligand (RANKL) and the first fully human monoclonal antibody to be approved for the treatment of osteoporosis. Given in a subcutaneous injection once every 6 months, denosumab is indicated for the treatment of postmenopausal women at high risk for fracture to reduce this risk.26 It is also indicated to increase bone mass in women at high risk of fracture who are receiving adjuvant aromatase inhibitor therapy for breast cancer and in men at high risk for fracture who are receiving androgen-deprivation therapy for nonmetastatic prostate cancer. Recently, it has received approval as treatment to increase bone mass in men with osteoporosis at high risk for fracture.26 Denosumab inhibits the development and activity of osteoclasts, decreases bone resorption, and increases bone density.2,35 A study in more than 7800 women found that denosumab


therapy reduced the risk of vertebral, hip, and nonvertebral fracture.36 Five-year data from the FREEDOM Extension trial indicate that bone density measurements continue to increase, while bone turnover markers are maintained at lower than pretreatment levels, but are no lower than levels achieved early during the core trial.37 According to the package insert, ONJ and atypical femur fractures have been reported in clinical trial participants during the extension study.The incidence of these side effects with denosumab is not yet known.26,37 Raloxifene Raloxifene, a selective estrogen receptor modulator (SERM), is approved by the FDA for the prevention and treatment of osteoporosis, and there is also an approval for the reduction in risk for invasive breast cancer in postmenopausal women with osteoporosis or who are at high risk for breast cancer.24 Four-year data from the Multiple Outcomes of Raloxifene Evaluation (MORE) study, conducted in more than 7000 postmenopausal women, demonstrated a favorable risk-benefit safety profile.38 In this study, raloxifene was also associated with a significant reduction in the risk for breast cancer.39 New or worsening hot flashes or muscle cramps may occur or increase with raloxifene therapy, and this therapy is associated with an approximate 3-fold increase in venous thromboembolic events.2,30,39 Calcitonin Calcitonin is a hormone produced by the specialized cells in the thyroid gland that plays a role in calcium metabolism. Synthetic salmon calcitonin is available in injectable and nasal spray formulations and is approved by the FDA for the treatment of postmenopausal osteoporosis.30 At a dose of 200 IU/d given intranasally, calcitonin produced a reduction in the incidence of vertebral fractures, but it has not demonstrated efficacy for hip and other nonvertebral fractures. It does not increase BMD in areas other than the spine.30 Calcitonin is generally considered safe, though some patients may experience rhinitis and, rarely, epistaxis.2 Recently, however, the European Medicines Agency has recommended withdrawing the indication for osteoporosis for calcitonin and reserving its use for Paget’s disease because of concerns about an increased risk for cancer.23 Teriparatide Teriparatide, human recombinant PTH 1-34, is a parathyroid hormone fragment and the only anabolic agent available for the treatment of osteoporosis. It is approved for use in postmenopausal women and men at high risk for fracture, and for men and women at high risk of fractures who are receiving long-term glucocorticoid therapy. It reduces the risk of spine and nonvertebral fractures, and is given subcutaneously in a daily dose of 20 mcg.25


Teriparatide is generally well tolerated, although some patients experience nausea, light-headedness or leg cramps. Because it has been shown to increase the incidence of osteosarcoma in rats, those at increased risk for osteosarcoma, such as patients with a history of skeletal radiation or Paget disease, should not receive teriparatide.25 Two years is considered the maximum duration of this therapy because the safety of this agent has not been demonstrated beyond that time period. It is common to follow teriparatide with one of the anti-bone resorbing agents.2

New and Emerging Therapies Progress continues to be made in our understanding of the mechanisms involved in the pathogenesis of osteoporosis, and new therapies for the condition are in development. Among these are the cathepsin K inhibitors, which inhibit protease breakdown of the protein matrix of bone.40 Of the drugs in this class, odanacatib has just concluded Phase 3 clinical trials and is the closest to seeking approval for treatment of osteoporosis. Odanacatib has been found to increase bone mass and bone strength at the hip.41.42 Other osteoporosis therapies under investigation include vitamin K and the sclerostin inhibitors, agents that are anabolic for bone, such as AMG-785.40,43 The Issues of Monitoring Osteoporosis is a chronic condition, and treatment may be long term in some patients. Although the utility of serial BMD testing for monitoring therapeutic efficacy has been debated,44 monitoring the progress of patients to determine if treatment is effective is important. Patients in clinical practice differ considerably from populations in clinical trials, and it cannot be assumed that the efficacy demonstrated in trials will be achieved in patients in clinical practice. One study found that approximately 80% of patients with osteoporosis seen in clinical practice would be excluded from participating in trials because of comorbidities or use of concomitant medications.45 Furthermore, compliance/persistence in clinical practice is much poorer than in trials. Adherence in the FIT trial, for example, was greater than 85%; in clinical practice, adherence is about 43% based on refills.44,46 In one study, only 20% of patients continued bisphosphonates over 24 months.46 As adherence drops below 90%, fracture risk increases significantly.47

Trials have found, however, that patients whose BMD is stabilized while on therapy for osteoporosis do as well in regard to the rates of new vertebral fractures as those whose BMD increases.44 Thus, the purpose of monitoring BMD in patients undergoing treatment is to identify those who experience a significant decrease in BMD while being treated,44 as they are at increased risk for fracture. These patients should be further evaluated to determine if the cause is poor compliance, calcium or vitamin D deficiency, malabsorption, comorbidities, or true failure to respond to the drug.44

Follow-up should be conducted approximately 1 year after starting therapy, and thereafter at intervals determined by the patient’s circumstances.44 The NOF Guide suggests monitoring patients by asking them about adherence and encouraging them to


continue adhering to their regimen, as well as by performing serial central DXA BMD.2 Peripheral sites do not respond to the same degree as do the spine and hip, and therefore are not appropriate for monitoring treatment effects. Biochemical markers of bone turnover may provide valuable information, but the changes seen in individuals must be large because of biological and analytical variability. Serial measurements should be made at the same time of day.2 For resorption markers, it is important to obtain fasting measurements in the morning; for formation markers, however, timing of measurement is less important.2

An Undertreated Condition Osteoporosis is an undertreated condition.48 Identification of those at risk, diagnosis of osteoporosis, and treatment of those who have developed the condition is important for preventing its potentially devastating consequences. Possible barriers to effective treatment include patient fear of side effects, insurance issues, and among patients who receive treatment, inadequate adherence.49

Adherence is essential to efficacy. An analysis of medical claims databases found that in the United States between 2001 and 2008, an estimated 144,670 fractures were prevented among women aged 45 years or older with oral bisphosphonate use at adherence levels of 50% or more based on medication possession ratios. The best results occurred when adherence rates were 80% or more.49 These data suggest that more fractures could be prevented with improvements in diagnosis of patients at risk, treatment of such patients, and improvement in adherence once a treatment is initiated. Poor adherence may result from a failure to understand the risks involved. Most postmenopausal women with risk factors do not realize their risk for fracture.11 Patients need to recognize this in order to appreciate the importance of adhering to their medication regimen and of receiving adequate amounts of vitamin D and calcium in their diet or as supplements.4

Improving adherence requires good patient communication and education about osteoporosis, fall prevention, and side effects of therapy.2 Patients should receive training for performance of safe movement and safe activities of daily life; steps should be implemented to improve posture and balance and to strengthen quadriceps muscles to allow patients to rise unassisted from a chair. The use of assistive devices to help with ambulation balance, lifting, and reaching should be promoted and recommendations for a complete exercise program should be provided.2

Conclusions Prevention of fracture is the goal of therapy in osteoporosis. Achieving this goal requires both nonpharmacologic and pharmacologic interventions. Among the former are use of vitamin D and calcium supplements; appropriate exercise programs to improve strength, balance, and agility; fall prevention programs; and good patient education to


improve understanding of the condition and adherence to the prescribed regimen. Bisphosphonates remain the most commonly used pharmacologic therapy; other agents include antiresorptive therapies such as denosumab, raloxifene and calcitonin and the anabolic compound teriparatide. Although the optimal duration of bisphosphonate therapy has yet to be definitively determined, patients at low risk for fracture may be candidates for discontinuing bisphosphonate therapy after 3 to 5 years. In contrast, patients at increased risk for fracture may receive benefit from continued therapy with bisphosphonates.28


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