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Supplement Article  |   February 2013
Reducing the Risk of Osteoporotic Fracture
Author Notes
  • From the Department of Obstetrics and Gynecology at the University of South Carolina School of Medicine in Greenville (Dr Forstein); Bryn Mawr Hospital in Bryn Mawr and Main Line Woman's Health Care in Rosemont, Pennsylvania (Dr Bernardini); the Department of Internal Medicine at Michigan State University College of Osteopathic Medicine in East Lansing (Dr Cole); the University of California, San Francisco School of Medicine (Dr Harris); and the departments of medicine and obstetrics and gynecology at MedStar Georgetown University Hospital and Georgetown University Medical Center (Dr Singer) 
  • Address correspondence to David A. Forstein, DO, Greenville Hospital System University Medical Center, Department of Obstetrics and Gynecology, 890 W Faris Rd, Suite 470, Greenville, SC 29605-4281. E-mail: dforstein@ghs.org  
Article Information
Emergency Medicine / Neuromusculoskeletal Disorders
Supplement Article   |   February 2013
Reducing the Risk of Osteoporotic Fracture
The Journal of the American Osteopathic Association, February 2013, Vol. 113, S5-S24. doi:
The Journal of the American Osteopathic Association, February 2013, Vol. 113, S5-S24. doi:
Abstract

Osteoporosis is a major cause of morbidity in the United States, resulting in approximately 2 million fractures and contributing to 65,000 deaths annually. Organizations have published guidelines for the diagnosis and management of the disease. However, a degree of conflict exists among some of the recommendations. Several screening tools have been developed to identify fracture risk, and although the Fracture Risk Assessment tool developed by the World Health Organization has been widely adopted, other screening tests are also potentially useful. A range of medications are available for the prevention of osteoporosis in individuals who are at high risk for the disease and for the treatment of individuals who already have osteoporosis. Although some of these medications are highly effective, all have adverse-effect profiles and other caveats that require both familiarity with the characteristics of the medication and detailed knowledge of patient needs and preferences. Effective therapy is only possible with strong patient adherence to the regimen, which in turn requires that the patient have an understanding of the risks and benefits and can participate in the treatment-selection process.

The Demographic Characteristics and Public Health Burden Associated With Osteoporosis
What burden does osteoporosis place on our health system?
Dr Cole: Osteoporosis is a substantial public health problem in the United States. Approximately 10 million US adults have osteoporosis, and another 34 million have low bone mineral density (BMD), which increases the risk for fractures.1 Approximately 15% of the US population is at risk for disability or even death as a result of osteoporotic fractures. Osteoporosis occurs more frequently in women than in men, developing in 80% of women vs 20% of men.1 As many as 1 in 2 women vs 1 in 4 men older than 50 years will incur an osteoporosis-related fracture in their lifetime. The mortality rate associated with osteoporosis is high, with approximately 65,000 deaths due to complications of osteoporotic fractures occurring annually.2 In 2005, a total of 2 million fractures of all types were associated with osteoporosis, and this number is expected to exceed 3 million by 2025.2 The prevalence of the disease is increasing despite advances in prevention and treatment, and it is predicted to increase as the population ages. 
One of the most serious complications of osteoporosis is hip fracture. Hip fractures are particularly common in patients who are in their late 70s and older. Approximately 300,000 hip fractures occur each year, and they can be extremely serious; 1 in 5 ambulatory individuals who incur a hip fracture subsequently require long-term care.3 Approximately one-fourth of patients aged 50 years or older who have a hip fracture die within 1 year of incurring the fracture.3 Hip fractures account for approximately 180,000 nursing home admissions and 432,000 hospital admissions per year, in addition to 2.5 million visits to physician offices.3 
What benefits could be expected if the burden of osteoporosis is substantially reduced?
Dr Singer: The 20% of patients with osteoporosis who require long-term care represent a substantial cost. In addition, 6 months after sustaining a hip fracture, only 15% of patients are able to walk across a room unaided, thus potentially placing a burden on family members who must assist them with their daily activities.4 There are other, less visible costs associated with patients having reduced function as a result of nonvertebral fractures and possibly being unable to return to work. Therefore, the goal should be to provide treatment to reduce costs, to reduce the need for assistance, and to maintain the highest possible level of functioning. 
We need to examine the potential savings that can be achieved by the prevention and treatment of osteoporosis, particularly in light of the current economic climate. When we see cutbacks, such as cuts in reimbursement for bone densitometry, it may be enlightening to put the costs of screening and treatment in perspective in terms of the amount saved compared with the resulting increased expenditures for hip fracture. 
What are the realities of osteoporosis in terms of its effect on patient quality of life?
Dr Harris: Many older patients with fractures will have substantial impairment of their quality of life. Literature exists concerning the limitations that osteoporotic fractures can impose on activities of daily living, especially the effects on self-image and self-esteem, which is an indisputably important issue for patients. However, although the literature addresses quality of life, I do not believe that it fully captures the day-to-day impact that this debilitating condition can have on patients. Some patients who do not have fractures constantly worry about the threat of decrepitude, which leaves them permanently uneasy and gives them an underlying sense of foreboding about their future. This worry about a gradual physical decline occurring over the years takes a considerable toll on their quality of life. 
Dr Cole: Some patients have a constant level of fear—fear that they are going to fall, fear that they will break a bone, and fear that they will possibly have to live in a nursing home one day. Particularly for patients who have already experienced 1 or more fractures, this fear can be strong enough to prevent them from carrying out their family activities. Basic daily tasks, such as cleaning the house, running a vacuum cleaner, lifting and carrying items from place to place, fetching the groceries, and so on, become perceived as potential hazards that could cause a life-changing injury. Although some patients have obvious disabilities resulting from either a compression fracture of a vertebra or a hip fracture, which can result in severe limitations because of associated pain, there are others who become psychologically imprisoned. These patients can become frustrated because they cannot get out and do the things that they want to do. For them, it is not a question of self-esteem or depression, but one of intense frustration because they fear performing their normal activities. 
Dr Harris: There is a danger that the medical community may generate disproportionate or inappropriate concerns for patients who are being tested for osteoporosis. I have encountered many patients who are far more concerned than their situation warrants because of the information acquired in the course of medical consultations and testing. When patients are counseled about risk and benefit based on their densitometry and Fracture Risk Assessment (FRAX) scores, it is apparent that many who are at a lower risk are frightened by the technology, focusing on the T score and being given a diagnosis of osteoporosis. They are not receiving enough information to balance those findings with a solid, understandable assessment of the actual risks of fracture in their particular situation. 
One of the more valuable actions a clinician can take is persuade patients not to take the diagnosis too seriously. The clinician should explain that the available diagnostic and therapeutic tools are extremely helpful and that more helpful tools and techniques will be available in the future. No patient should feel hopeless in this situation or believe that life is effectively over and that residing in a nursing home is their destiny. We have important therapies that work for patients with osteoporosis and more are emerging. 
Risk Factors for Osteoporosis
What are the risk factors for osteoporosis and fractures?
Dr Bernardini: If you look carefully, it seems that every patient has at least 1 or 2 of the many risk factors associated with osteoporosis. Age is a factor, thus the US Preventive Services Task Force recommends that women undergo screening at age 65 years. In addition to age, other possible risk factors include family medical history, race, tobacco smoking, alcohol consumption of more than 3 drinks per day, small physical frame, thyroid disease, premature onset of menopause, antiestrogen treatment for breast or other cancers, and the presence of malabsorption syndromes, such as celiac disease. Upon further investigation, some young patients with severe osteoporosis have been found to have undiagnosed celiac disease. Other risk factors include weight loss surgery (which is frequently associated with osteoporosis), the use of certain medications (such as steroids, aromatase inhibitors, proton pump inhibitors, and even selective serotonin-reuptake inhibitors), and a sedentary lifestyle. There are many risk factors, and clinicians need to be aware of the possibility of osteoporosis and screen for it when appropriate. 
What are some of the secondary causes of osteoporosis?
Dr Singer: Disorders of calcium and vitamin D metabolism, including hypercalciuria and hyperparathyroidism, are very common. In addition to hyperparathyroidism, other endocrine disorders that may be responsible for secondary osteoporosis include diabetes mellitus, which of course is very prevalent, and hyperthyroidism, which may be an innate disease or may result from overreplacement occurring during management of hypothyroidism. Any hypogonadal state can also be a cause of osteoporosis, including premature menopause in women and conditions causing low testosterone levels in men. 
Previously mentioned risk factors that are known causes of secondary osteoporosis include celiac disease and other forms of malabsorption, as well as gastrointestinal surgery (in particular, gastric bypass surgery) and some bowel diseases (such as Crohn disease and ulcerative colitis). Pancreatic disease may also be associated with secondary osteoporosis as well as genetic disorders, including hemochromatosis. Rheumatologic or autoimmune diseases may cause osteoporosis, with the greatest risk associated with rheumatoid arthritis. Osteoporosis can also develop secondary to solid organ transplantation, alcoholism, and depression. 
Dr Cole: Smoking is one of the most common risk factors for osteoporosis, other than vitamin D deficiency. Smokers cannot improve their BMD until they quit smoking, even if alendronate or other medications are taken. Cigarette smoking increases metabolism of estrogen to inactive 2-hydroxyestrone in the liver, which may explain why it has a deleterious effect in patients with osteoporosis. 
Dr Forstein: In my reproductive endocrinology practice, I encounter young patients with unique risk factors such as anorexia, amenorrhea in female athletes, and hyperprolactinemia. Although gynecologic textbooks may suggest that it is acceptable not to treat patients with hyperprolactinemia if they are not concerned about galactorrhea, I think that they are overlooking the risk of hypoestrogenemia, leading to failure to build bone mass, which may in turn later lead to osteoporosis. 
How much caffeine intake is required to increase the risk of osteoporosis?
Dr Harris: Heaney5 investigated caffeine and its effect on calcium metabolism, and he found that the effect is minor and is not sufficient to have a deleterious effect in patients who receive adequate calcium from their diet. The consumption of soft drinks has also been found to have no adverse effects on bone, with the possible exception of colas consumed in excess.6 
These findings are important to consider when counseling patients about lifestyle changes. The more changes patients are asked to make, the more resistant they become. By disregarding activities with no proven effect on osteoporosis, it may be possible to improve the chances that patients will comply with more beneficial recommendations. If patients are allowed to consume coffee, sodas, and small amounts of alcohol, they are more likely to improve modifiable risk factors, such as smoking and exercise. 
Dr Cole: Although from a cognitive perspective moderate amounts of coffee may actually be beneficial, it has long been believed that consumption of large amounts of caffeine (that is, in excess of 400 mg/day, or the equivalent of more than 4 cups of coffee) has the potential to produce serious adverse symptoms and may place a patient at risk for osteoporosis. Barger-Lux and Heaney7 attempted to quantify this hypothesis in 1995, and they concluded that for every 6-fl oz (177.5-mL) serving of coffee containing caffeine, an approximately 40-mg increase in calcium consumption is required. If this conclusion is correct, a person who consumes 1 L (perhaps 4 cups) of caffeinated coffee each day requires an additional 225 mg of dietary calcium to offset the effect of the caffeine. A degree of caution in terms of the quantity consumed each day would be prudent. Because the effect of such factors as body mass on caffeine levels has not been studied, there may be considerable variation between individuals regarding the amount of coffee that can be consumed without untoward effects occurring. 
Screening for Osteoporosis
What criteria should be used in determining who should be screened for osteoporosis and fracture risk?
Dr Singer: Several groups have published guidelines for screening, including the National Osteoporosis Foundation (NOF),8 the International Society for Clinical Densitometry,9 the US Preventive Services Task Force,10 and the American Association of Clinical Endocrinologists.11 These guidelines contain a number of points of general agreement. Age-based criteria recommend screening for women aged 65 years or older who have not previously been screened, as well as for men aged 70 years or older. Postmenopausal women younger than 65 years who have 1 or more risk factors should be screened, and it is common to find that many of these patients have at least 1 risk factor. Men between the ages of 50 and 70 years who have 1 or more additional risk factors should also be considered for screening. 
Perimenopausal women with significant risk factors can be considered for screening. In the years since publication of the results from the Women's Health Initiative, many women have discontinued hormone therapy. Women who have chosen to discontinue estrogen therapy should be considered for screening, because discontinuation of estrogen often results in a decline in BMD that parallels the loss that occurs when women reach natural menopause. 
Patients aged 40 years or older who have a low-trauma or fragility fracture should be screened to obtain a baseline BMD measurement. Screening should also be performed for patients who have conditions—or are taking medications—associated with a high risk of secondary osteoporosis. Clinicians should screen any patient for whom the results of a bone density scan might influence treatment decisions. 
Several screening tools are available to assist in identifying patients who are at risk. How useful are these tools in practice?
Dr Harris: I find FRAX very useful and use it every day. Developed by the World Health Organization, FRAX is an online fracture risk calculation tool.12 It is accessible via the Internet, is available as a downloadable application for smartphones, and is incorporated into the software of a number of different densitometers (Figure 1). 
Figure 1.
The online FRAX (Fracture Risk Assessment) tool from the World Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield website.12 Abbreviations: BMD, bone mineral density; DXA, dual-energy x-ray absorptiometry.
Figure 1.
The online FRAX (Fracture Risk Assessment) tool from the World Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield website.12 Abbreviations: BMD, bone mineral density; DXA, dual-energy x-ray absorptiometry.
A number of well-established risk factors, including BMD, are used by FRAX to calculate an estimated risk of fracture over the next decade. After the user selects the country and ethnicity of the patient, he or she inputs a number of variables, including age, sex, height, and weight. Medical variables include a history of previous fracture after the age of 45 or 50 years (albeit with fractures of the fingers, toes, face, or skull excluded), parental history of hip fracture, use of glucocorticoids, rheumatoid arthritis, secondary osteoporosis, smoking, and alcohol consumption of 3 or more drinks per day. Finally, the femoral neck BMD measurement is entered, and the FRAX tool calculates the estimated risk of hip fracture over the next decade, as well as a separate estimate of the risk of any major osteoporotic fracture. The estimates that are produced by FRAX are invaluable. They provide a tangible risk profile that can be used as a basis for further discussion with a patient. 
I typically perform the FRAX calculation interactively with the patient, sharing the laptop screen to allow the patient to observe and participate in the process. When the result appears, I can say to the patient, “What do you think? If you do nothing over the next 10 years, your risk of hip fracture is X; your risk of having a major osteoporotic fracture is Y. If you were to start taking a medication, you could demonstrably reduce those risks. Do you think it makes sense, given your particular situation, to think more seriously about this?” This is an oversimplified version of what would be a more nuanced discussion, but I do find FRAX to be extremely helpful on a daily basis. 
Using FRAX can be much more beneficial than providing a typical BMD report alone. Regrettably, a BMD report will often conclude with an impression such as “osteoporosis: 4-fold increased risk of fracture,” which is not very informative and may result in an unnecessarily high level of concern for the patient, as discussed previously. The ability to provide a contextual risk value, such as “The risk of hip fracture in the next decade is 4%,” with the implied corollary that there is a 96% chance that there will not be a hip fracture—even without medication—is very reassuring to the patient. This type of perspective facilitates a more balanced discussion of the risks and benefits of treatment. 
Dr Bernardini: The FRAX tool calculation is built into our dual-energy x-ray absorptiometry (DXA) scan program. The data provide an excellent stepping stone to a real discussion about risk and treatment recommendations. For some patients, the FRAX tool can alleviate fear, and it helps them to understand the benefits of treatment vs nontreatment. In addition, FRAX can help to individualize the approach to a patient-specific profile; for example, one might be inclined to provide more aggressive treatment to a patient who is unstable on his or her feet. Conversely, one might be inclined to take a less aggressive approach to someone who exercises several times a day and is in excellent physical condition. The FRAX tool is very helpful in providing a framework to address these issues and making treatment a joint decision with the patient. 
Dr Forstein: I have found that the ability to show the 10-year probability of hip fracture and other major fractures has improved treatment adherence tremendously. 
However, there are some limitations to the use of FRAX. For instance, it is not applicable to patients who are already receiving treatment. Other patient characteristics have to be considered in addition to the FRAX score. For example, for a patient who is physically unstable and likely to fall, treatment should not be based solely on the FRAX results; a more aggressive approach will be needed. 
In addition, FRAX has not yet been validated for women younger than 40 years. 
Dr Singer: I find FRAX to be a wonderful tool, and it certainly is a step in the right direction. However, I also find that it has limitations. Many aspects of a patient's history and risk cannot be adequately quantified using a simple yes-or-no approach; quantification of such variables as duration of smoking, duration and dose of steroid treatment, and the number of fractures that a patient has cannot be captured by FRAX. This dichotomous input for continuous variables can sometimes limit the usefulness of the FRAX tool, but that is clearly where clinicians must use their judgment and experience to work with the patient to make the best possible decisions. 
Dr Cole: Another limitation of FRAX involves patients who have low BMD of the spine. Although FRAX is very effective for patients who have low BMD of the hip, it is not very helpful for those with a problem involving the spine. 
Is there a hip fracture or major osteoporotic fracture risk percentage that is used to recommend initiation of treatment?
Dr Harris: The NOF guidelines8 from 2010 suggested that, from a pharmacoeconomic perspective, treatment should be initiated for patients who have either a hip fracture risk of 3% or greater or a global osteoporotic fracture risk of 20% or greater. I do not necessarily follow these recommendations literally, but I find them to be helpful as a platform for discussion. The principal value of FRAX is that it helps in the counseling of individual patients as well as in providing a framework for constructing discussions of the arguments for and against treatment. 
Describe the Osteoporosis Self-Assessment Tool.
Dr Forstein: For quick in-office screening, this test is simple in that it uses only weight and age. Age in years is subtracted from weight in kilograms, and the resulting value is divided by 5. The score is used to assign a high, moderate, or low risk of osteoporosis. This test has been shown to be as sensitive as, or more sensitive than, some considerably more complex multifactoral tools.13,14 
What is the current status of markers?
Dr Harris: Markers are a source of contention. Physicians divided firmly into 2 camps more than a decade ago. One group consisted of physicians who use markers all the time in every patient, whereas the other group included physicians who use markers occasionally. 
Markers provide a sense of whether bone remodeling is occurring at a relatively higher or lower rate. A bone density measurement is inherently static and provides a snapshot of the skeleton at 1 moment in time. Markers, however, are more dynamic and can help predict whether BMD is likely to increase, decrease, or remain relatively static. I do not think that markers are well-established clinical tools to be used in every patient. Rather, they should be used primarily by the specialist in challenging circumstances where it is unclear what changes might be occurring in the bone. 
Dr Cole: I have performed tests of fasting serum levels of C-terminal telopeptide of type I collagen in the past, and I have found that they posed a number of difficulties, 1 of which is ensuring that patients fast before testing, as required. There were also problems with securing reimbursements for the tests. Occasionally, I do test markers as I deem appropriate in certain circumstances, but I do not use test markers routinely. 
Diagnosing Osteoporosis
What are the key diagnostic criteria for osteoporosis?
Dr Bernardini: Central DXA is the primary tool used in my practice. Peripheral DXA is used in many areas, often by podiatrists. It can be a practical screening tool, but if any findings are out of the ordinary, I send patients for central DXA. 
Dual-energy x-ray absorptiometry measures BMD by comparing the absorption by bone of very small doses of low- and high-energy x-rays. The DXA result is compared with a reference standard based on the BMD measurement of a healthy 30-year-old person who is of the same sex and race as the subject. The difference between these 2 measurements, expressed in standard deviations, is known as the T score. A T score of -2.5 or lower is consistent with osteoporosis; a score higher than -1 is normal, and a score between -1 and -2.5 is designated as osteopenia, or low bone mass.8,15 
Dual-energy x-ray absorptiometry has a number of limitations, such as the lack of insurance coverage for this technique in many parts of the country. Where coverage is not available, peripheral DXA may be used as a screening tool, but its accuracy is not sufficient for reliable diagnostic use. Ultrasound heel densitometry is inexpensive, portable, and quick, and it has a high negative predictive value, making it excellent for screening. However, DXA is the diagnostic standard, both for a definitive diagnosis and for following treatment.16 
Dr Cole: Peripheral DXA was widely used in the 1990s. The machines were inexpensive, and initially most clinicians used them for screening. However, central DXA screening of the hip and lumbar spine has become so refined and precise that it is now recognized as the diagnostic standard. 
Dr Singer: Using BMD measurement is an appropriate and valuable approach to diagnosing osteoporosis. When a patient presents with a fragility fracture and no other underlying cause—in particular, a hip or vertebral fracture—that fracture confers a diagnosis of osteoporosis regardless of T score. Unfortunately, we miss the opportunity to evaluate and diagnose many of these patients when they present, and without an appropriate diagnosis, treatment options generally are not offered. 
Dr Forstein: The NOF uses both of these criteria for the diagnosis of osteoporosis: a clinical diagnosis for patients with low-trauma fracture and a diagnosis made on the basis of DXA measurement. 
What is the Z score, and why is it important?
Dr Singer: The Z score compares the BMD of the patient with the BMD of a group of age- and sex-matched controls.8 The Z score should be used when the World Health Organization T-score criteria, which are intended for use with postmenopausal women and men older than 50 years, do not apply—for example, for premenopausal women, younger men, and children. When a patient has a BMD score that is below the expected range for age and sex (as defined by a Z score of 2.0 or lower), this may be an indication of an underlying secondary cause or other factors contributing to the osteoporosis. For such a patient, an evaluation for underlying causes should be considered. 
Are there any other reasons why DXA has become the diagnostic standard?
Dr Harris: When the World Health Organization attempted to systematize the approach to diagnosis approximately 20 years ago, the largest data set available was obtained by DXA. Large epidemiologic studies used by the World Health Organization were based on DXA measurement. Although there had been a great deal of prior experience with other technologies, nothing was as far-reaching on an international scale as were the DXA-based studies available at that time. 
What is your opinion of dual-femur vs single-femur BMD tests?
Dr Cole: I conducted a study comparing the 2 techniques in 313 postmenopausal women.17 Inclusion of the bilateral hip in BMD testing resulted in a change in classification to a more severe diagnosis for 9% of patients—a change from diagnosis of a normal condition to osteopenia for 5.7% of patients and a change from osteopenia to osteoporosis for 3.3% of patients. 
The dual-femur test clearly provided a more accurate diagnostic evaluation of these patients than the single-femur test and should be considered the standard. 
Is there a role for peripheral quantitative computed tomography?
Dr Harris: Peripheral quantitative computed tomography is a very useful research tool that enables one to look at the cortical and trabecular envelopes in a differential manner, but there are no recognized diagnostic criteria for making an initial diagnosis, nor is there a standardized set of criteria for evaluating long-term response. Therefore, although this tool has value in the research setting, it is not presently a useful clinical tool and is quite expensive. Peripheral quantitative computed tomography uses relatively high levels of radiation, but because the radiation is directed to relatively radioinsensitive areas—the tibia and the wrist—radiation exposure is not considered a serious concern. 
How and when do you use quantitative ultrasound densitometry?
Dr Harris: Quantitative ultrasound densitometry may be useful for screening. When cost is a factor, low-cost peripheral technologies, such as ultrasonography, can be used for screening patients at relatively low risk. When the risk is higher, I would not use quantitative ultrasound densitometry as the initial test. Dual-energy x-ray absorptiometry should be used, if possible. 
Are other diagnostic tests considered to be useful in osteoporosis?
Dr Cole: After DXA, the most important diagnostic test—one that is widely used—is vertebral fracture assessment. It should be considered a standard test because it detects so many fractures and provides an immediate diagnosis. Vertebral fracture assessment is performed with a DXA machine and is incorporated into most current models. 
Dr Bernardini: Electronic medical records facilitate the regular recording of vital signs. It is now becoming standard procedure to record certain vital signs for all patients, such as height, weight, blood pressure, pulse, etc, thereby creating a reference history. Height loss is a concern for osteoporosis and is an indication for DXA. 
How much height loss is cause for concern?
Dr Harris: The criteria in the literature vary between 3 and 6 cm for postmenopausal women.18,19 Siminoski et al18 quantified these height changes as historical height loss. Height alone is not a useful indicator, but change in height can be useful. On the basis of the work by Siminoski et al, I consider a change in height of 1.5 in for women and 2 in for men to be clinically significant. 
Prevention
What prophylactic measures are available to prevent fractures?
Dr Cole: To make it easy to remember, I call my approach the CDEFFs of treatment: calcium intake, vitamin D intake, exercise (load-bearing muscle strengthening and balance), fall prevention, and factors for risk elimination (eg, smoking, alcohol, other modifiable risk factors). 
I recommend that patients have a total calcium intake of 1200 mg per day. The average person obtains approximately 700 mg of calcium from his or her diet, so he or she needs to take an additional 500-mg calcium supplement. I usually recommend calcium citrate. I recommend a vitamin D intake of 800 to 1000 IU per day for most patients and up to 2000 IU per day for elderly or shut-in patients to maintain a 25-hydroxyvitamin D level greater than 30 ng/mL, and patients should have limited exposure to sunlight, if possible, for approximately 15 minutes per day. Also, I suggest that my patients take a multivitamin with trace minerals to ensure that they receive sufficient magnesium, manganese, zinc, vitamin C, vitamin K, etc, for good bone and general health. I think that ensuring adequate magnesium intake, in particular, is very important for the formation of strong bone. 
There are 5 components of a good exercise program: walking, weight training, balance, posture, and flexibility. Load-bearing is, of course, very important to maintain hip and femoral neck BMD as well as for overall strength and fitness. Also, lightweight muscle-strengthening exercise is valuable. As a former fitness trainer, I have found that balance is very important to maintain and that it reduces the risk of falls; we really need to focus on this aspect of exercise. Balance can be improved by exercises, and it should be incorporated into the routines of elderly patients. Postural exercises can help reduce kyphosis, which often develops in elderly patients.20 Exercise that contracts the rhomboid muscles and encourages good posture can be very beneficial. Stretching exercises, such as yoga, can also be beneficial to reduce the stiffness that increases with age and to help maintain flexibility. 
Dr Bernardini: For several reasons, reduction of alcohol consumption should be considered. Aside from causing damage to bones, alcohol can impair the sense of balance and lead to falls. A patient's other medications should be assessed to identify those that have sedative effects or those that will exacerbate the effects of alcohol. Smoking cessation is extremely important as well. 
An association between calcium supplementation and an increased risk for myocardial infarction has caused considerable concern among patients, as reported by Li et al.21 My own opinion is that the goal should still be a calcium intake of 1200 mg per day, with as much calcium as possible obtained from dietary sources. 
Dr Singer: We also need to be attentive to the effect that reducing supplements and increasing dietary calcium can have on vitamin D intake. If patients eliminate supplements that were also providing vitamin D, they should increase their vitamin D intake with a separate supplement because they are not likely to obtain sufficient vitamin D from dietary sources and sunlight alone. The bulk of calcium should come from diet; we really do not know what other cofactors may be obtained by patients from dietary sources but may not be included in a supplement. 
The Institute of Medicine published age-specific recommendations for vitamin D supplementation in 2010. Do you follow these recommendations or take a different approach?
Dr Harris: I think that vitamin D deficiency is very common, and I often advocate empirical vitamin D supplementation. This approach may be somewhat controversial, but it avoids the need for measurement of 25-hydroxyvitamin D, which is an expensive procedure. If supplementation is given universally, then vitamin D measurement should be performed only for those patients who fail to respond as expected or in special cases, such as after bariatric surgery. The recommendation by the Institute of Medicine (IOM)22 of 600 to 800 IU of supplemental vitamin D per day is rather conservative, and I believe that somewhat higher levels of supplementation—perhaps 1000 to 2000 IU of vitamin D3 (cholecalciferol) per day—may be more reasonable. 
Dr Singer: We should bear in mind that the recommendations of the IOM are based on a normal, healthy population; the recommended vitamin D level is based on the amount required to achieve adequate levels in 97.5% of the healthy population. This recommendation is of concern for the osteoporotic population, which is a very different group of patients. I generally prefer the recommendation of the American Association of Clinical Endocrinologists, which is 1000 to 2000 IU of vitamin D per day.11 
I agree that every patient should receive vitamin D supplementation and that testing is best reserved for patients with a higher risk. The guidelines from the International Osteoporosis Foundation suggest that the patient who is at average risk need not undergo testing before receiving routine supplementation. Testing to determine 25-hydroxyvitamin D levels should be considered for patients who are obese; those who have osteoporosis; those who, for various reasons, have little exposure to the sun; and those receiving antiseizure medications, which increase the metabolism of vitamin D. The desired range for 25-hydroxyvitamin D is 30 to 60 ng/mL,8 although some clinicians consider 30 ng/mL to be too low and although some laboratories use a normal range that begins at 20 ng/mL, which is definitely too low for the population, that concerns us. I recommend targeting the high-normal range, to allow a margin for fluctuation. 
Treatment Options in Osteoporosis
Who should be considered for treatment?
Dr Singer: The NOF guidelines recommend treatment for postmenopausal women and men aged 50 years or older who present with a hip or vertebral fracture; a T score of −2.5 or less at the femoral neck or spine, if there are no secondary causes; low bone mass (osteopenia), as determined by a T score between −1.0 and −2.5 at the femoral neck or spine, with a FRAX-derived 10-year probability of hip fracture of 3% or more; or a 10-year probability of a major osteoporosis-related fracture of 20% or more.8 The guidelines are not all encompassing, however, and there is room for interpretation and decision making by the clinician. The FRAX tool is ideal for assessing the patient who has low bone mass, because there is a wide range of risk levels in this group. Clinical judgment must be the final arbiter. 
The NOF guidelines do not address younger patients whose Z scores indicate low bone mass. Should these patients be considered for treatment?
Dr Harris: I think that we tend to take a very individualized approach with these patients. An abnormal Z score is a clue to aggressively search for secondary causes. The FRAX tool is not useful for younger patients. In fact, there are no firm treatment guidelines for this group, and assessment is more difficult. These patients are best placed under the care of a specialist. 
What is the role of osteopathic manipulative medicine in the management of osteoporosis and the prevention of fracture?
Dr Cole: DiGiovanna et al23(p229) summarize the role of osteopathic manipulative medicine as follows in their definitive book, An Osteopathic Approach to Diagnosis and Treatment:
 

A significant concern in treating patients with osteoporosis is that bones may fracture. While this is certainly a concern, it does not indicate that a person with osteoporosis should not receive manipulation. Gentleness is the key. No significant force should be exerted on fragile bone, especially the ribs. Gentle stretching of soft tissues, positioning techniques such as counterstrain and proper exercises are very helpful in decreasing back pain. Often the pain experienced is not the result of the osteoporosis, but rather from tense soft tissues. Somatic dysfunctions can be treated with balanced ligamentous tension techniques or counterstrain. Osteopathy in the cranial field is non-traumatic for these patients.

 

In the presence of new compression fractures, no manipulation should be performed in the area, but manipulation of distant areas is still possible. Once the fracture heals, the manipulation can be performed near that vertebra.

 

Older individuals, especially menopausal women, should be carefully screened before the use of any type of compressive force.

 
Dr Bernardini: There are a number of techniques that can be used for patients with severe osteoporosis to achieve the goal of normalizing joint motion and balance, including soft-tissue and strain and counterstrain techniques, some craniosacral techniques, and the muscle-energy technique. The importance of hands-on therapy should not be underestimated. The downside of such therapy is minimal, and it can improve balance, flexibility, and strength, as well as reduce pain. 
Pharmacotherapy for Osteoporosis
How do you use the estrogen agonists/antagonists?
Dr Bernardini: Estrogen agonists/antagonists are a very interesting class of drugs. They inhibit bone resorption in the same way that estrogen does, but without an associated increased risk of breast and uterine cancer. Using raloxifene, for example, may confer additional benefit to patients with an elevated risk of invasive breast cancer. However, a May 2012 update from the Agency for Healthcare Research and Quality concluded that, although raloxifene reduces the incidence of vertebral fracture, it is not effective in reducing other fracture types, including hip fracture.24 Because of the limited effectiveness of raloxifene, I would be more inclined to consider using it in a preventive role rather than as a treatment. However, it does increase the risk of venous thromboembolic disease,25 making it an unsuitable choice for patients with a history of cerebrovascular accident, a factor V Leiden disorder, or other clotting disturbances, or for patients with prolonged immobilization. Raloxifene also increases vasomotor symptoms,26 especially in newly menopausal patients. As a result of the increase in symptoms, as well as the high cost of raloxifene, patients may discontinue use of this drug. 
Patients who receive tamoxifen (another of the estrogen agonists/antagonists) after breast cancer will derive some benefit, although tamoxifen does not have a primary indication as an antiresorptive agent. 
What is the role of hormone replacement therapy in the management of osteoporosis?
Dr Singer: Purely from the perspective of effects on bone, estrogen looks very beneficial. Concerns exist regarding the extraskeletal effects of estrogen, particularly the potential risks involved. Estrogen was never approved by the US Food and Drug Administration for osteoporosis treatment, although it is indicated for prevention. The Women's Health Initiative provided prospective randomized data showing a fracture risk benefit for both the hip and the spine in patients treated with either estrogen in combination with progesterone or estrogen alone.27 Benefits incidental to fracture prevention include a reduction in colon cancer. 
Concerns associated with estrogen therapy include an increased risk of thromboembolic disease; an increased risk of stroke related to the use of both combination therapy and monotherapy; and the potential for increased cardiovascular events. There is also a small increase in the risk of breast cancer. Because of these concerns, and because we now have other effective options for osteoporosis therapy, we do not consider first-line use of estrogen for this indication. If estrogen or a combination of estrogen and progesterone are used to treat other problems, such as vasomotor symptoms, the patient will also benefit from a reduced fracture risk. 
Dr Harris: Estrogen still has a role in the treatment of patients who have important quality-of-life issues that would respond well to this treatment. I encounter patients who are struggling with alternative treatments and should be receiving estrogen, because they have disruptive symptoms of estrogen deficiency. The antifracture efficacy of estrogen appear comparable to that of other treatments discussed. 
Dr Cole: Many women take phytoestrogens, or isoflavones, in the belief that these chemicals will help to protect their bone; however, I am not aware of any reliable evidence that supplementation with these chemicals is beneficial to bone. Some studies have indicated that high doses of phytoestrogens relieve vasomotor symptoms, although systematic reviews have failed to detect consistent benefits.28 
Dr Forstein: The results of the Kronos Early Estrogen Prevention Study (KEEPS) trial29 are now in the process of being published. Hopefully, this trial will refute some of the concerns about heart disease that were raised in the Women's Health Initiative and confirm a benefit for osteoporosis treatment. 
There appears to be considerable confusion surrounding bisphosphonate therapy. How do these drugs work?
Dr Cole: Bisphosphonates have become the mainstay of osteoporosis treatment. There are 4 bisphosphonates that are widely used for osteoporosis: alendronate, risedronate, ibandronate, and zoledronic acid (Table 1). Approximately 3 of 4 prescriptions written for osteoporosis treatment are for a bisphosphonate. The bisphosphonates are antiresorptive agents that reduce the rate of bone turnover. The bisphosphonate molecule binds to the bone mineral on the surface of the bone and blocks the action of an enzyme called farnesyl diphosphate synthase. This reduces the rate at which osteoclasts resorb bone tissue. The bone-forming activity of osteoblasts is not affected, so there is an increase in bone mass over time. 
Table 1.
Effectiveness of Medications to Reduce Fracture Risk by Body Regiona
Medication Vertebral Nonvertebral Hip Wrist
Bisphosphonates
Alendronate Yes Yes Yes Yesb
Risedronate Yes Yes Yes Yesb,c
Zoledronic acid Yes Yes Yes Not specified
Ibandronate Yes Not specified Not specified Not specified
Denosumab Yes Yes Yes Not specified
Teriparatide Yes Yesd Not specified Not specified
Raloxifene Yes No No No
  a Strength of evidence is high (there are consistent results from good-quality studies and further research is very unlikely to change the conclusions) except where otherwise noted.
  b Low strength of evidence (there are very few studies, or existing studies are flawed).
  c Risedronate-mediated reduction in wrist fracture did not reach the conventional level of statistical significance.
  d Moderate strength of evidence (findings are supported, but further research could change the conclusions).
  Source: John M. Eisenberg Center for Clinical Decisions and Communications Science. Treatment To Prevent Osteoporotic Fractures: An Update. Rockville, MD: Agency for Healthcare Research and Quality; 2012.
Table 1.
Effectiveness of Medications to Reduce Fracture Risk by Body Regiona
Medication Vertebral Nonvertebral Hip Wrist
Bisphosphonates
Alendronate Yes Yes Yes Yesb
Risedronate Yes Yes Yes Yesb,c
Zoledronic acid Yes Yes Yes Not specified
Ibandronate Yes Not specified Not specified Not specified
Denosumab Yes Yes Yes Not specified
Teriparatide Yes Yesd Not specified Not specified
Raloxifene Yes No No No
  a Strength of evidence is high (there are consistent results from good-quality studies and further research is very unlikely to change the conclusions) except where otherwise noted.
  b Low strength of evidence (there are very few studies, or existing studies are flawed).
  c Risedronate-mediated reduction in wrist fracture did not reach the conventional level of statistical significance.
  d Moderate strength of evidence (findings are supported, but further research could change the conclusions).
  Source: John M. Eisenberg Center for Clinical Decisions and Communications Science. Treatment To Prevent Osteoporotic Fractures: An Update. Rockville, MD: Agency for Healthcare Research and Quality; 2012.
×
The first bisphosphonate to become available was alendronate. The Fracture Intervention Trial (Table 2) showed that, over the course of 3 years, alendronate reduced vertebral fractures by more than 47%, hip fractures by 51%, and wrist fractures by 48%.30 Alendronate also produced significant increases in BMD in the lumbar spine and the femoral neck. 
Table 2.
New Vertebral Fractures in a Fracture Intervention Triala
Vertebral Fractures, No. (%)
Fracture Placebo Alendronate Relative Risk (95% CI)
Morphometric
≥1 145 (15.0) 78 (8.0) 0.53 (0.41-0.68)
≥2 47 (4.9) 5 (0.5) 0.10 (0.05-0.22)
Clinical Vertebral 50 (5.0) 23 (2.3) 0.45b (0.27-0.72)
  a Among 965 women in the placebo group, there were 240 morphometric fractures in 145 women. Among 981 women in the alendronate group, there were 86 morphometric fractures in 78 women.
  b Relative hazard.
  Source: Black DM, Cummings SR, Karpf DB, et al; Fracture Intervention Trial Research Group. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet. 1996;348(9041):1535-1541.30 Reprinted with permission.
Table 2.
New Vertebral Fractures in a Fracture Intervention Triala
Vertebral Fractures, No. (%)
Fracture Placebo Alendronate Relative Risk (95% CI)
Morphometric
≥1 145 (15.0) 78 (8.0) 0.53 (0.41-0.68)
≥2 47 (4.9) 5 (0.5) 0.10 (0.05-0.22)
Clinical Vertebral 50 (5.0) 23 (2.3) 0.45b (0.27-0.72)
  a Among 965 women in the placebo group, there were 240 morphometric fractures in 145 women. Among 981 women in the alendronate group, there were 86 morphometric fractures in 78 women.
  b Relative hazard.
  Source: Black DM, Cummings SR, Karpf DB, et al; Fracture Intervention Trial Research Group. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet. 1996;348(9041):1535-1541.30 Reprinted with permission.
×
Alendronate is not easily absorbed from the gut (>1% of an oral dose is absorbed) and may cause gastrointestinal irritation. Patients are required to take alendronate with plain water on an empty stomach upon waking in the morning and then remain upright for 30 to 60 minutes. Nothing else should be taken by mouth for at least 30 minutes. This rather complex treatment regimen has led to some problems with adherence. The treatment regimen associated with newer bisphosphonates is less problematic, and dosing occurs as infrequently as once monthly. Intravenous zoledronic acid is effective when administered in just an annual dose.31 
Risedronate has demonstrated a 41% reduction in the recurrence of vertebral fractures and a 39% reduction in nonvertebral fractures, as well as notably increased BMD in the lumbar spine.32 
Dr Singer: There is a delayed-release chelated form of risedronate that can be taken immediately after breakfast, although it is necessary to remain upright afterward. There is also a new, effervescent dissolving tablet of alendronate. 
Dr Harris: Ibandronate has been demonstrated to reduce vertebral fracture.33 The evidence of benefit for patients with other types of fracture is contentious because it was demonstrated that protection against nonvertebral fracture was observed primarily in a subgroup of patients who were at higher risk. 
Although there is considerable debate about the relative benefits of bisphosphonates for different patient types, I am not convinced that the differences are clinically significant, although there may be differences in pharmacokinetics in terms of the speed of onset of action and, perhaps, in terms of dissipation when the drug is discontinued. The bisphosphonates all have a very similar mechanism of action, and although there are slight differences from one study to another in terms of demonstrating fracture protection, I suspect that this is probably more a function of particular study populations and study designs than a reflection of any fundamental difference in the medications themselves. Therefore, I suggest that practitioners regard bisphosphonates as largely interchangeable in terms of their antifracture efficacy. 
Is there any basis for choosing one bisphosphonate over another?
Dr Bernardini: Cost is an important consideration, especially as we move further into the world of managed care. Alendronate is the only bisphosphonate for which there is an available generic form, which can reduce costs. Sometimes it is possible to help patients by using intravenous zoledronic acid, which is billed under Medicare Part B, rather than under patients' drug plans, which are billed under Medicare Part D. Compliance is particularly important when taking bisphosphonates, and the annual dosing of zoledronic acid is certainly helpful in ensuring compliance. 
Dr Harris: The choice of which bisphosphonate to use is influenced by cost, which is in turn determined by the complexities of Medicare Part B and Medicare Part D coverage, as well as by the Medicare Part D coverage gap; the negotiated formulary status of each of the drugs; the dosing regimen, be it daily, weekly, monthly, quarterly intravenous, or annual intravenous administration; and concerns about adverse effects, because the intravenous formulations have a different adverse effect profile than the oral preparations. Selection of an agent is not straightforward. 
All of the oral bisphosphonates have the potential for causing contact irritation of the gastrointestinal tract. This effect can be avoided by implementing the medication intravenously. However, intravenously administered bisphosphonates can cause an acute-phase reaction, or influenza-like illness, in a minority of patients.31 The intravenous formulation also has the potential to cause direct renal toxic effects, so it has to be infused slowly and should not be given to patients who have impaired renal function. More troubling than these adverse effects are the development of osteonecrosis of the jaw (ONJ) and atypical femoral fracture, both of which have occurred with bisphosphonate use and often cause concern to patients. When bisphosphonates are given in the doses used for osteoporosis therapy, ONJ occurs in the range of 1 in 10,000 and 1 in 100,000 patients receiving therapy each year, so it is relatively rare.34 Atypical femoral fractures, which are strange subtrochanteric fractures that occur after years of therapy, are somewhat more common, with an estimated incidence in the range of 1 in 1000 to 1 in 10,000 patients receiving treatment with bisphosphonate each year.35 
The exact pathophysiologic profile of these conditions is not understood. They are believed to be the consequence of oversuppression of bone remodeling in particularly susceptible patients. Until more is known about the causes of these adverse outcomes and how they might be avoided, clinicians should acknowledge the risks in discussions with patients and should balance them against the substantial benefits in fracture reduction that bisphosphonates are known to provide. 
Dr Cole: Adverse effects related to bisphosphonates are among the most serious issues in the field of osteoporosis.36 Because of the possibility of ONJ developing, many patients are now apprehensive to take even oral bisphosphonates, despite the excellent benefits that they provide, and many physicians are apprehensive to prescribe them. 
A September 2012 article37 discussed the risk of malpractice suits against physicians who fail to warn patients about the risks of ONJ and atypical femoral fracture. The same article also warned that “the failure to diagnose and treat osteoporosis may amount to a negligent omission—with implications for legal liability.”37(p36) This dilemma must be considered by the physician, and great care must be taken when counseling patients on bisphosphonate use. 
Although the reported occurrence of ONJ was low when alendronate first became available, statistics are showing a higher incidence. An Australian study38 in 2007 estimated that the frequency of ONJ in osteoporotic patients—mainly those receiving oral alendronate weekly—was 1 in 2260 to 8470 patients (0.01% to 0.04%). If extractions were performed, the calculated frequency was 1 in 296 to 1130 patients (0.09% to 0.34%).38 These figures are not consistent with previous estimates of ONJ incidence. 
The American Association of Oral and Maxillofacial Surgeons has published guidelines for the treatment of patients who are considering dental implants and taking bisphosphonates.39 The guidelines include a recommendation to obtain informed consent from these patients, in which they acknowledge the risk of possible future implant failure and development of ONJ. The guidelines further recommend that patients who are taking corticosteroids concomitantly and patients who have been taking bisphosphonates for more than 3 years should take a drug holiday beginning 3 months before surgery, if systemic conditions permit, and should not resume bisphosphonate therapy until osseous healing has occurred. Furthermore, in dentists' offices, notices have begun to appear instructing patients to tell the dentist if they are taking a bisphosphonate. Dentists are instructing their patients to discuss with their physician the possibility of changing their medication because of the risk of ONJ. 
The inevitable result is that the public is becoming increasingly and disproportionately fearful of bisphosphonates. We are all encountering patients who are very concerned about these warnings from the oral surgery and dental communities. 
There clearly is a need for more definitive data so that we can understand the true extent of ONJ in patients treated with bisphosphonates and so that we can provide patients and clinicians with accurate information. There needs to be a consensus about the amount of risk and the way in which patients are counseled concerning that risk. 
What is your opinion of the calcitonin nasal spray?
Dr Singer: In the Prevent Recurrence of Osteoporotic Fractures (PROOF) trial, calcitonin reduced vertebral fractures, but there was no reduction in nonvertebral or hip fractures.40 Interestingly, the reduction in vertebral fracture was not dose dependent; a significant reduction was seen with the use of 200 IU of calcitonin per day but not with 400 IU per day. 
To my knowledge, there has been no head-to-head comparison of calcitonin nasal spray with bisphosphonates or other agents, but I do not consider the fracture data for calcitonin to be particularly robust. It is, however, an option for those who are unable to tolerate other medications. Guidelines generally relegate calcitonin to the position of a last line of therapy. There is some evidence, however, that injectable calcitonin may help with pain reduction, so it can be considered for painful fractures. 
Dr Harris: A few of my patients have benefitted from pain reduction associated with calcitonin, given in injectable and nasal spray form, although the evidence supporting this analgesic effect is not very robust. Administration is easy, and it has been considered a safe medication, but it really has not been very effective. Within the past year, concerns about a possible slight elevation in the cancer risk have led European regulatory authorities to review the indication for calcitonin in osteoporosis.41 If the indication is removed, it is probable that the US Food and Drug Administration will follow suit. In any event, I do not think that calcitonin will be used much longer for the long-term management of osteoporosis. 
Discuss the use of parathyroid hormone.
Dr Harris: Parathyroid hormone is available in the United States only as teriparatide, a recombinant fragment of human parathyroid hormone. Parathyroid hormone is the only true anabolic agent, and it is the only one that can be considered as a true bone formation–stimulating agent. As a result, there is a belief that parathyroid hormone is more effective as an antifracture drug than are other available modalities. I think that this is true, but it is admittedly speculative, because there are few direct comparison studies involving the antifracture drugs used to treat osteoporosis. 
Parathyroid hormone is largely reserved for relatively high-risk patients: those for whom treatment with bisphosphonates has failed or those who are intolerant of bisphosphonates; patients who are at high risk at initial presentation; and patients who have continued to have fractures occur despite receiving other forms of therapy. Parathyroid hormone therapy should be used only for a limited time. The US Food and Drug Administration does not recommend treatment for more than 2 years. When parathyroid hormone is discontinued, it is normally replaced with an antiresorptive agent. 
Dr Bernardini: Teriparatide has a black box warning about an increased risk of osteosarcoma.42 It should not be used for patients with Paget disease or for patients with previous exposure to skeletal radiation. 
Have you prescribed osteoclast inhibitors?
Dr Singer: Denosumab, the first drug in this class, is a human monoclonal antibody to receptor activator of nuclear factor κ-B ligand (RANKL). This antibody prevents RANKL from binding to receptor activator of nuclear factor κ-B (RANK) receptors on osteoclast precursors, inhibiting their maturation, function, and survival. Denosumab is thus an antiresorptive agent. 
The pivotal trial for denosumab was the Fracture Reduction Evaluation of Denosumb in Osteoporosis Every 6 Months (FREEDOM) trial, which enrolled 7868 postmenopausal women. The trial demonstrated that denosumab offers an alternative approach to the treatment of osteoporosis by decreasing bone resorption and increasing BMD through the inhibition of RANKL. Denosumab was associated with a significant reduction in the risk of vertebral, hip, and nonvertebral fractures in postmenopausal women with osteoporosis.43 On September 20, 2012, the US Food and Drug Administration approved a new indication for denosumab (Prolia) as a treatment to increase bone mass in men with osteoporosis at high risk for fracture (Figure 2). 
Figure 2.
Incidence of new vertebral, nonvertebral, and hip fractures in the Fracture Reduction Evaluation of Denosumb in Osteoporosis Every 6 Months (FREEDOM) trial. The primary end point was the incidence of new vertebral fractures at 36 months (A, left), which is shown for each study year (A, right). Risk ratios (RRs) are for participants in the group receiving denosumab, compared with those receiving placebo. Kaplan-Meier curves of the time to the first nonvertebral fracture (B) and the first hip fracture (C) were determined based on the number of participants who did not have a fracture or who did not leave the study before the time point of interest. The participants at risk at 36 months included all those who completed end-of-study visits at or after the start of the window for the 36-month visit. From Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756-765.43 Copyright ©2009 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
Figure 2.
Incidence of new vertebral, nonvertebral, and hip fractures in the Fracture Reduction Evaluation of Denosumb in Osteoporosis Every 6 Months (FREEDOM) trial. The primary end point was the incidence of new vertebral fractures at 36 months (A, left), which is shown for each study year (A, right). Risk ratios (RRs) are for participants in the group receiving denosumab, compared with those receiving placebo. Kaplan-Meier curves of the time to the first nonvertebral fracture (B) and the first hip fracture (C) were determined based on the number of participants who did not have a fracture or who did not leave the study before the time point of interest. The participants at risk at 36 months included all those who completed end-of-study visits at or after the start of the window for the 36-month visit. From Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756-765.43 Copyright ©2009 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
Denosumab is associated with a number of dermatologic skin reactions, such as eczema and rashes, as well as infections, including cellulitis. It is generally well tolerated. There have been a small number of cases of ONJ reported, as well as 2 cases of atypical femoral fractures. Care should be taken to individualize therapy, balancing potential risks and benefits, as with all of the medications used for osteoporosis. 
Dr Cole: Denosumab can be used in patients with renal insufficiency. This can be very useful for elderly patients with diabetes mellitus and poor creatinine clearance, for whom bisphosphonates are not an option. Also, administration is by twice-yearly subcutaneous injection, so adherence is not a problem. 
Dr Harris: Although it is true that denosumab is not directly toxic to the kidney, there is still a need for caution when considering its use for patients who have significantly impaired renal function. Patients with severe grade 4 or grade 5 chronic kidney disease may have mixed renal osteodystrophy. If the adynamic form of renal osteodystrophy is present and an antiresorptive agent is given, there is the potential of exacerbating the condition.44 There is no direct evidence that denosumab causes kidney damage, but it may nevertheless be prudent to avoid its use in patients who have bone disease associated with substantial renal impairment. More studies are needed to clarify the extent of the risk. 
Are other significant approaches to the treatment of osteoporosis in use or under investigation?
Dr Singer: Strontium ranelate, which is approved for use in Europe, has been shown to reduce fracture risk and increase BMD.45 
How does the management of osteoporosis differ in men vs women and in younger vs older postmenopausal women?
Dr Harris: The general approach to a man with osteoporosis is very similar to that for a woman: we first look for underlying causes. The major distinction is the recognition that testosterone deficiency is a major risk factor for bone loss and fracture in men. This may be either iatrogenic due to androgen deprivation therapy, or it may be endogenous testosterone deficiency. Hypogonadism is a real concern. We must be aware that height loss in men older than 50 years may be the result of unrecognized vertebral compression. Patients with vertebral compression are at high risk and therefore require evaluation and appropriate treatment. 
Dr Cole: Men should be evaluated for secondary risk factors such as smoking, chronic obstructive pulmonary disease, and gastrointestinal disease, as well as testosterone deficiency. 
How do you select a treatment for patients?
Dr Bernardini: We have to be aware of the vasomotor issues associated with the use of estrogen agonists or antagonists for younger, newly postmenopausal patients. Also, we must be aware of the nature of risk changes with increasing age. A younger postmenopausal woman with a higher T score may be at lower risk than an older woman because she does not have the same risks of falling. For a younger, newly postmenopausal patient with trouble-some symptoms, hormone replacement should be a strong consideration, particularly given the potential to derive multiple benefits from a single medication. Of course, it will be necessary to re-evaluate this patient on a regular basis and to decide when and if it is time to change to a different treatment plan. 
Dr Singer: With older patients or those who have other clinical factors that place them at high risk, we may be more inclined to use medications that are more potent antiresorptives. Younger patients who have not sustained a fracture and do not have severe disease may be appropriate candidates for estrogen or raloxifene, and these medications may be used initially. Later in life, these patients may be switched to denosumab or a bisphosphonate. 
How do you use the DXA scan to monitor therapy?
Dr Bernardini: Most clinicians perform DXA every 2 years, unless the patient is losing bone mass at a rapid rate or is receiving medications associated with a high risk of osteoporosis, such as high-dose steroids. 
Dr Cole: I may perform DXA more frequently on patients who are receiving chemotherapy or taking drugs such as leuprolide, as well as patients who are smokers or who are at high risk. 
Dr Harris: When reading scan results, we look for an absence of significant loss, rather than large increases in BMD. This distinction is important because the therapies improve bone quality, thereby causing the reduction in fracture risk to occur earlier and to a greater extent than would be predicted from the change in BMD alone. 
I think many practitioners consider the goal of therapy to be an increased T score, but this is not the case. The ultimate goal is the prevention of fracture, and patients who have only a stable BMD while receiving therapy are likely to experience an improvement in bone quality. There is no specific test for bone quality, so patients have to be persuaded that although they do not necessarily feel better while receiving treatment, and although their BMD may not have increased very much, we believe that they are benefitting from the therapy in terms of having a reduction in fracture risk. 
Dr Singer: I receive many referrals of patients who are considered to have therapy failure because their BMD has not increased but, rather, has remained stable. Treatment has succeeded for these patients because further bone loss has been prevented. Explaining this distinction to patients and to other providers is critical. 
Which drugs are associated with a particularly high risk for osteoporosis?
Dr Harris: There are many drugs associated with an elevated risk of osteoporosis (Figure 3). Steroid-induced osteoporosis is the most significant secondary cause of osteoporosis that we see. Any patient who is receiving any dose of systemic steroids for more than 3 to 6 months should have a bone density measurement performed. 
Figure 3.
Drugs associated with an elevated risk of osteoporosis.
Figure 3.
Drugs associated with an elevated risk of osteoporosis.
Dr Bernardini: Drugs that reduce stomach acid also reduce calcium absorption. Proton pump inhibitors tend to be under-recognized because they are available over the counter. Patients should be asked about any nonprescription medications that they may be taking. 
Dr Singer: Depot medroxyprogesterone acetate is generally used in a younger population. It has a black box warning about use for more than 2 years, and there is some concern about bone loss occurring with long-term use.46 Although testing and treatment often are not warranted in this generally healthy young group of women, clinicians should consider the duration of use of medroxyprogesterone and whether to use alternative forms of birth control. If a patient discontinues this drug while still relatively young, most of the bone loss incurred is generally reversible. 
Adherence to Therapy
What strategies have you found to be most effective in ensuring treatment adherence and lifestyle change among your patients?
Dr Singer: Involve the patient in shared decision making and discuss not only the risks of medication but also the benefits, as well as the risks of not treating. Educational materials can be helpful. Follow-up is crucial. To evaluate how they are doing, I see most of my patients at 3 months, particularly those who are receiving oral agents, for whom there is a risk of poor adherence. When there is little or no follow-up between scans, compliance rates are very poor. Even if the patient has been given a 1-time dose of a medication, the patient should return to discuss calcium and vitamin D intake, exercise, and progress in making lifestyle changes. 
Dr Cole: Adherence is an extremely serious issue (Figure 4). One study47 showed that after 1 year, 50% of patients stopped taking their osteoporosis medication, with most discontinuing therapy within the first 3 months. At 3 years, adherence decreased to 23%.47 One reason for this outcome is that patients do not feel any better when taking these preventive drugs, so they lack the motivation to persevere with their treatment. If their next scan shows no increase in BMD, they consider that as proof that the drugs are not helping. Persuading patients that the treatment is helping to prevent fractures is difficult. 
Figure 4.
Impact of medication nonadherence on the clinical effectiveness (expressed as the number of fractures prevented and the number of quality-adjusted life-years [QALYs] gained) of oral bisphosphonates. Reprinted from Hiligsmann M, Rabenda V, Bruyère O, Reginster JY. The clinical and economic burden of non-adherence with oral bisphosphonates in osteoporotic patients. Health Policy. 2010;96(2):170-177. Copyright 2010, with permission from Elsevier.
Figure 4.
Impact of medication nonadherence on the clinical effectiveness (expressed as the number of fractures prevented and the number of quality-adjusted life-years [QALYs] gained) of oral bisphosphonates. Reprinted from Hiligsmann M, Rabenda V, Bruyère O, Reginster JY. The clinical and economic burden of non-adherence with oral bisphosphonates in osteoporotic patients. Health Policy. 2010;96(2):170-177. Copyright 2010, with permission from Elsevier.
Many patients also fear the adverse effects of osteoporosis drugs, and they dislike the often awkward methods of administration. Some patients do not perceive osteoporosis to be a very serious condition, which also reduces motivation. They may consider it sufficient to supplement their calcium and vitamin D intake, not understanding that although this helps, it will not rebuild structurally damaged bone. Even with these supplements, persistence is not good. Many older patients are already taking multiple medications; they do not want to increase their medication burden, and they do not want to pay additional copay amounts. 
To overcome patient resistance, it is necessary to show patients what is in it for them. For example, patients may understand that they are at risk of bone loss, but they do not view bone loss as a problem. However, if you convey this in concrete terms, pointing out the possibility of fracturing a hip or developing kyphosis (better known as a dowager's hump), it gives the patient an image that makes the consequences more real. 
I agree with Dr Singer that it is important to perform a follow-up at 3 months. The patient's physician should also regularly monitor the patient's adherence to drug therapy and supplementation. 
Dr Bernardini: Communication is a theme that we have heard repeatedly in this discussion; it is truly a cornerstone of osteoporosis management. Ensure that you communicate with your patients and that you perform follow-ups, obtain feedback, and listen to them. If you do not listen when they tell you why they are not taking their medications or what their problems and concerns are, you will not succeed in having them follow their treatment regimen. Their bones will not improve, and you will not be able to prevent fracture. 
   This article is based on a roundtable discussion held on Monday, September 24, 2012, and led by Dr Forstein.
 
   Financial Disclosures: Drs Forstein and Bernardini have no relevant financial relationships to disclose. Dr Cole is on the speakers' bureaus for Amgen, Eli Lilly and Company, Novartis, and Roche. Dr Harris is on the speakers' bureaus for Amgen, Eli Lilly and Company, Genentech, Gilead Sciences, Novartis, and Warner Chilcott. In addition, Dr Harris is a consultant for Amgen, Eli Lilly and Company, Gilead Sciences, Merck, and Roche. Dr Singer is a consultant and is on the speakers' bureaus for Amgen and Medtronic. Dr Singer is also on the advisory board for Amgen.
 
   Vindico Medical Education was involved in the preparation of this article. The staff involved in this project have no relevant financial relationships to disclose. Steve Pridgeon, who was a medical writer for this article, has no relevant financial relationships to disclose.
 
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Figure 1.
The online FRAX (Fracture Risk Assessment) tool from the World Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield website.12 Abbreviations: BMD, bone mineral density; DXA, dual-energy x-ray absorptiometry.
Figure 1.
The online FRAX (Fracture Risk Assessment) tool from the World Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield website.12 Abbreviations: BMD, bone mineral density; DXA, dual-energy x-ray absorptiometry.
Figure 2.
Incidence of new vertebral, nonvertebral, and hip fractures in the Fracture Reduction Evaluation of Denosumb in Osteoporosis Every 6 Months (FREEDOM) trial. The primary end point was the incidence of new vertebral fractures at 36 months (A, left), which is shown for each study year (A, right). Risk ratios (RRs) are for participants in the group receiving denosumab, compared with those receiving placebo. Kaplan-Meier curves of the time to the first nonvertebral fracture (B) and the first hip fracture (C) were determined based on the number of participants who did not have a fracture or who did not leave the study before the time point of interest. The participants at risk at 36 months included all those who completed end-of-study visits at or after the start of the window for the 36-month visit. From Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756-765.43 Copyright ©2009 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
Figure 2.
Incidence of new vertebral, nonvertebral, and hip fractures in the Fracture Reduction Evaluation of Denosumb in Osteoporosis Every 6 Months (FREEDOM) trial. The primary end point was the incidence of new vertebral fractures at 36 months (A, left), which is shown for each study year (A, right). Risk ratios (RRs) are for participants in the group receiving denosumab, compared with those receiving placebo. Kaplan-Meier curves of the time to the first nonvertebral fracture (B) and the first hip fracture (C) were determined based on the number of participants who did not have a fracture or who did not leave the study before the time point of interest. The participants at risk at 36 months included all those who completed end-of-study visits at or after the start of the window for the 36-month visit. From Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756-765.43 Copyright ©2009 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
Figure 3.
Drugs associated with an elevated risk of osteoporosis.
Figure 3.
Drugs associated with an elevated risk of osteoporosis.
Figure 4.
Impact of medication nonadherence on the clinical effectiveness (expressed as the number of fractures prevented and the number of quality-adjusted life-years [QALYs] gained) of oral bisphosphonates. Reprinted from Hiligsmann M, Rabenda V, Bruyère O, Reginster JY. The clinical and economic burden of non-adherence with oral bisphosphonates in osteoporotic patients. Health Policy. 2010;96(2):170-177. Copyright 2010, with permission from Elsevier.
Figure 4.
Impact of medication nonadherence on the clinical effectiveness (expressed as the number of fractures prevented and the number of quality-adjusted life-years [QALYs] gained) of oral bisphosphonates. Reprinted from Hiligsmann M, Rabenda V, Bruyère O, Reginster JY. The clinical and economic burden of non-adherence with oral bisphosphonates in osteoporotic patients. Health Policy. 2010;96(2):170-177. Copyright 2010, with permission from Elsevier.
Table 1.
Effectiveness of Medications to Reduce Fracture Risk by Body Regiona
Medication Vertebral Nonvertebral Hip Wrist
Bisphosphonates
Alendronate Yes Yes Yes Yesb
Risedronate Yes Yes Yes Yesb,c
Zoledronic acid Yes Yes Yes Not specified
Ibandronate Yes Not specified Not specified Not specified
Denosumab Yes Yes Yes Not specified
Teriparatide Yes Yesd Not specified Not specified
Raloxifene Yes No No No
  a Strength of evidence is high (there are consistent results from good-quality studies and further research is very unlikely to change the conclusions) except where otherwise noted.
  b Low strength of evidence (there are very few studies, or existing studies are flawed).
  c Risedronate-mediated reduction in wrist fracture did not reach the conventional level of statistical significance.
  d Moderate strength of evidence (findings are supported, but further research could change the conclusions).
  Source: John M. Eisenberg Center for Clinical Decisions and Communications Science. Treatment To Prevent Osteoporotic Fractures: An Update. Rockville, MD: Agency for Healthcare Research and Quality; 2012.
Table 1.
Effectiveness of Medications to Reduce Fracture Risk by Body Regiona
Medication Vertebral Nonvertebral Hip Wrist
Bisphosphonates
Alendronate Yes Yes Yes Yesb
Risedronate Yes Yes Yes Yesb,c
Zoledronic acid Yes Yes Yes Not specified
Ibandronate Yes Not specified Not specified Not specified
Denosumab Yes Yes Yes Not specified
Teriparatide Yes Yesd Not specified Not specified
Raloxifene Yes No No No
  a Strength of evidence is high (there are consistent results from good-quality studies and further research is very unlikely to change the conclusions) except where otherwise noted.
  b Low strength of evidence (there are very few studies, or existing studies are flawed).
  c Risedronate-mediated reduction in wrist fracture did not reach the conventional level of statistical significance.
  d Moderate strength of evidence (findings are supported, but further research could change the conclusions).
  Source: John M. Eisenberg Center for Clinical Decisions and Communications Science. Treatment To Prevent Osteoporotic Fractures: An Update. Rockville, MD: Agency for Healthcare Research and Quality; 2012.
×
Table 2.
New Vertebral Fractures in a Fracture Intervention Triala
Vertebral Fractures, No. (%)
Fracture Placebo Alendronate Relative Risk (95% CI)
Morphometric
≥1 145 (15.0) 78 (8.0) 0.53 (0.41-0.68)
≥2 47 (4.9) 5 (0.5) 0.10 (0.05-0.22)
Clinical Vertebral 50 (5.0) 23 (2.3) 0.45b (0.27-0.72)
  a Among 965 women in the placebo group, there were 240 morphometric fractures in 145 women. Among 981 women in the alendronate group, there were 86 morphometric fractures in 78 women.
  b Relative hazard.
  Source: Black DM, Cummings SR, Karpf DB, et al; Fracture Intervention Trial Research Group. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet. 1996;348(9041):1535-1541.30 Reprinted with permission.
Table 2.
New Vertebral Fractures in a Fracture Intervention Triala
Vertebral Fractures, No. (%)
Fracture Placebo Alendronate Relative Risk (95% CI)
Morphometric
≥1 145 (15.0) 78 (8.0) 0.53 (0.41-0.68)
≥2 47 (4.9) 5 (0.5) 0.10 (0.05-0.22)
Clinical Vertebral 50 (5.0) 23 (2.3) 0.45b (0.27-0.72)
  a Among 965 women in the placebo group, there were 240 morphometric fractures in 145 women. Among 981 women in the alendronate group, there were 86 morphometric fractures in 78 women.
  b Relative hazard.
  Source: Black DM, Cummings SR, Karpf DB, et al; Fracture Intervention Trial Research Group. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet. 1996;348(9041):1535-1541.30 Reprinted with permission.
×