Slide 1. Management of Osteoporosis: Seizing the Opportunity to Prevent Adverse Outcomes
Dr. Burke: Hello. I am Dr. Susan Burke. Dr. Ellen Miller and I are pleased that you can join us in our discussion on how best to seize the opportunities we have in our everyday practices to identify and treat osteoporosis effectively.
Slide 2. Osteoporosis Definition: NIH Consensus Conference
Dr. Burke: Let us first go with the definition of osteoporosis. According to the National Institutes of Health (NIH) consensus conference, osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. Bone strength is comprised of bone density (something that we can easily measure) and bone quality (a very important aspect but not something that is directly measurable -- at least not easily).
Slide 3.
Dr. Burke: I think this is a better definition of osteoporosis. Here is a woman with kyphosis because of multiple vertebral compression fractures. She has also had a hip fracture and is condemned to use a walker for her remaining life because of that hip fracture. This is what we are here to learn how to prevent.
Slide 4. Epidemiology and Prevalence of Osteoporosis
Dr. Burke: Let us look at the epidemiology and prevalence of osteoporosis.
Slide 5. Epidemiology of Osteoporosis in the US
Dr. Burke: Osteoporosis presently affects 8 million women and 2 million men. An additional 34 million Americans currently have low bone mass, defined as a bone mineral density (BMD) measurement between -1 and -2.5 standard deviations below the mean. Approximately half of women and a quarter of men over the age of 50 will suffer an osteoporotic fracture within their remaining lifetime.
Slide 6. Osteoporosis Fracture Incidence vs Incidence of Heart Attack, Stroke, Breast Cancer, and Prostate Cancer
Dr. Burke: This slide puts in perspective the osteoporosis fracture risk compared to other common diseases that we see in our practices. Currently we have 1.5 million cases of osteoporotic-related fractures in the United States annually. Compare that in particular to the right side of the slide. You can see breast cancer at about 211,000 annual incidents and prostate cancer at about 232,000 annual incidents. Osteoporotic fractures are clearly higher than a lot of these common diseases.
Slide 7. Economic Burden of Osteoporosis in the US
Dr. Burke: The economic burden of osteoporosis is not insignificant either. For example, we presently spend about $20 billion on congestive heart failure: the number 1 admission diagnosis for patients over age 65. Osteoporotic-related expenses are not far behind, at $17 billion. This number is expected to increase dramatically as our baby boomers hit retirement age, and in the next 20 years or so, this expenditure could be upwards of $60 billion, unless we do something now to help prevent these fractures.
Slide 8. Risk of Another Vertebral Fracture Is Higher in the Year Following a New Fracture
Dr. Burke: Once the patient has a vertebral fracture, the risk of another fracture is significantly higher in the year following that fracture. In this analysis of patients from various clinical trials for whom baseline vertebral fracture status was known, Lindsay found that, overall, 20% of patients will have a new fracture within 1 year of their baseline vertebral fracture.
Slide 9. Mortality Following Clinical Fractures: Fracture Intervention Trial (FIT)
Dr. Burke: So, you might think: So what is the big deal about an osteoporotic fracture? What is the big deal -- it is just a fracture; it is not a stroke; it is not a heart attack. Well, unfortunately, mortality following clinical fractures is also quite high.
In this analysis from the Fracture Intervention Trial, we can see that the relative risk of dying is 6.7 times higher after a hip fracture -- something that many clinicians may have heard about. What is not as well appreciated, is that mortality is increased even after a vertebral fracture: up to 8.6 times increased risk of dying after a vertebral fracture. So, osteoporosis, unfortunately, is not without its significant sequelae.
Slide 10. Morbidity and Mortality Associated With Hip Fracture
Dr. Burke: Fewer than half of hospitalized hip fracture patients recover prefracture competence in their activities. Mortality after a hip fracture is actually higher in men than in women in the year following fracture. And, one final sobering statistic: a 50-year-old woman's lifetime risk of dying from a hip fracture is actually equal to her risk of dying from breast cancer. Think of the effort that we presently put into screening women for breast cancer. We should also be putting this same amount of effort into targeting women at risk for fracture.
Slide 11. Osteoporosis Often Goes Unrecognized in the Clinical Setting
Dr. Burke: Unfortunately, though, osteoporosis continues to go unrecognized in a clinical setting. This study, looking at 934 patients who were admitted to a hospital who also had a chest X-ray done, found that 132 of them had a fracture identified by the study radiologist. However, only half of those fractures were noted in the radiology report, and only 23 of those fractures were noted in the medical record. So overall, only 18% of women with fracture were receiving treatment, and this has been borne out in other recent studies as well.
Slide 12. Identifying Individuals at Risk for Osteoporotic Fractures
Dr. Burke: Let us turn to how to best identify individuals at risk for osteoporotic fractures. What I would like to do is to present 2 cases for you to think about as we go through the rest of the information, and then we will come back to these cases at the end.
Slide 13. Case 1
Dr. Burke: The first case is a 60-year-old woman who is postmenopausal, who has not taken hormone therapy, has not done much in the way of calcium supplementation, and has had 2 or 3 weeks of intermittent steroid use, because of asthma exacerbations. Her BMD results show a lumbar spine T-score of -2.6 and a hip T-score of -2.8.
Slide 14. Case 2
Dr. Burke: The second case for you to think about is a frail, 77-year-old woman who in 2002 had a history of a 3-inch height loss and also presented with acute back pain associated with 2 vertebral fractures. Her dual-energy X-ray absorptiometry (DXA) at that time showed a lumbar spine T-score of -3 and a femoral neck T-score of -2.8. She was started on a weekly bisphosphonate and also received a calcium plus vitamin D combination supplement. In 2004, she had another vertebral fracture and now her follow-up BMD showed a lumbar spine T-score of -3.5 and a femoral neck T-score of -3.2. So, think about those cases.
And now let us turn to the evaluation of at-risk patients.
Slide 15. Fracture Risk vs Bone Density/Fracture Risk With Aging
Dr. Burke: As we evaluate our patients, there are 2 important concepts to keep in mind. The first is that fracture risk increases exponentially with decreasing bone mass. You can see the mean BMD, in the center of the graph on the left side of this slide. As we move to a BMD of -1, the incidence of fracture in a population doubles and then doubles again at a T-score of -2.
The other important correlation is on the right side of the slide, and that is that fracture risk increases with aging. Generally, the first fractures to occur are wrist fractures -- starting at around age 45 or 50, you can see them starting to increase. These, although they are associated with some morbidity, are not associated with an increase in mortality; but, they can be useful to help us target patients in this age group who are at risk for other fractures, since having a wrist fracture is associated with a decreased BMD.
The next fractures to peak are vertebral fractures, starting at age 55 to 60. Then hip fractures begin to rise around age 60 to 65. This pattern of fractures increasing with increasing age underlies the reasoning behind the United States Preventive Services Task Force recommendation to begin BMD screening starting at age 65 and to screen at age 60 or older if other risk factors are present besides being postmenopausal and Caucasian.
Slide 16. Risk Factors for Osteoporosis in Women
Dr. Burke: The risk factors for osteoporosis in women are shown here, with some of the more common ones highlighted in yellow. I would also like to point out some of the other important ones that have been identified more recently, and that is poor health status, frailty, and low physical activity. This generally leads to an increase in falls and is associated with a decrease in mobility in these patients, predisposing those patients to fracture risk.
Slide 17. Risk Factors for Osteoporosis in Men
Dr. Burke: The risk factors for men with osteoporosis are shown here, and you can see a lot of similarities to the risks in women. Men generally have a higher likelihood to have a secondary cause for osteoporosis; so in men, look particularly for hypogonadism, excess alcohol use, or perhaps steroid use.
Slide 18. Medical Conditions That May Increase Risk
Dr. Burke: There are a number of medical conditions that can increase a person's risk for osteoporosis, and many of them are shown here. These numbers are really growing by the day, and I will just point out hyperthyroidism, hyperparathyroidism -- I think we are aware of some of the risks associated with those diseases. More recently, bariatric surgery has emerged as an increasing risk, very similar to gastrectomy, predisposing those patients to malabsorption or other problems. Celiac disease, again coming to the fore per a recent article in Archives of Internal Medicine -- something to be aware of in your low-weight patients or patients who have diarrhea, who have osteoporosis beyond what you would expect them to have, or if they also have a family history of osteoporosis. Keep in mind some of these diseases.
Slide 19. Medications Predisposing Patients to Bone Loss
Dr. Burke: There are also numerous medications to be mindful of. We are very familiar with steroids increasing osteoporosis risk. Aromatase inhibitors are also coming to the fore in women with breast cancer. Adjuvant therapy with aromatase inhibitors is generally taking over -- where we used to use tamoxifen in these patients. Tamoxifen can be bone protective in some patients who are postmenopausal. Now, the aromatase inhibitors are better for breast cancer, but they have been associated with an increased fracture rate.
In men, similarly, the gonadotropin-releasing hormone (GnRH) agonists can be associated with an increased risk of fracture, so we need to be mindful, as we treat our patients with cancer, to pay attention to their bone health as well. Long-acting progesterone has been also in the press recently as decreasing BMD, and this can be an important factor in our younger age population. It is not yet known how this is going to affect bone later on, but the present recommendation is not to use these agents for longer than 2 years, if at all possible. Fortunately, BMD tends to recover with cessation of the long-acting progesterone in these patients.
Slide 20. Glucocorticoid Use and Fracture Risk in Users 18 Years and Older
Dr. Burke: I would like to just show one slide to highlight how glucocorticoid use can markedly increase fractures. Fracture risk increases with increasing doses of steroids, with high-dose here defined as only 7.5 mg or greater. Think of how often we use even higher doses than this in our at-risk patients. You can see here that vertebral fractures are particularly affected, reflecting the action of corticosteroids on the trabecular bone of the vertebrae, which has a higher bone-turnover rate than cortical bone does.
Slide 21. Vitamin D Deficiency
Dr. Burke: There is also a growing awareness that vitamin D deficiency is much more common than originally thought. Deficiency can occur secondary to a variety of reasons including inadequate exposure to sunlight, secondary to use of sunscreens, which block the absorption of vitamin D; also wearing of clothing; living in northern latitudes; and dark-skinned individuals have a decreased conversion of vitamin D in the skin. Aging also decreases vitamin D production in the skin, as does inadequate dietary intake, impaired renal conversion, and intestinal resistance or disease. We talked about bariatric surgery and celiac disease: one of the problems there is impaired vitamin D absorption.
The normal level of vitamin D was established in 1997, but several recent studies have shown that the present definition of normal is not high enough to optimize calcium absorption and that normal levels should actually be greater than 32 nanograms/milliliter (ng/mL) or greater than 80 nanomoles/liter (nmol/L).
Slide 22. Complications of Vitamin D Insufficiency/Deficiency
Dr. Burke: Complications of vitamin D insufficiency and deficiency include suboptimal calcium absorption and resultant mild secondary hyperparathyroidism to help to compensate for this -- and we will often see that in some of our older patients. This leads to a mild elevation in alkaline phosphatase, and a decrease in BMD, and then osteoporosis and, in very severe cases, osteomalacia. What is not as well appreciated is that vitamin D receptors are also located on the muscle, and deficiency can result in a subclinical myopathy and an increased risk of falling, again predisposing that patient to fractures.
Slide 23. Diagnosis of Osteoporosis
Dr. Burke: Now let us turn to the diagnosis of osteoporosis.
Slide 24. Laboratory Assessment
Dr. Burke: Routine laboratory assessment should include a complete blood cell (CBC) count, serum chemistries to evaluate renal and liver function, and thyroid-stimulating hormone. A 25 hydroxy-D level should also be obtained in patients now found with osteoporosis, because of the rampant vitamin D deficiency that is seen in patients over the age of 50. This is the best form of vitamin D to measure, not the 1,25 form. Twenty-four-hour urine for calcium and creatinine and, in men, gonadal function should also be evaluated.
Slide 25. Laboratory Assessment: Specialized Testing for Secondary Osteoporosis
Dr. Burke: Specialized testing for secondary osteoporosis is shown here and would be indicated depending on whatever results you get out of the routine testing. For example, if the patient has high calcium, it would be reasonable to check parathyroid hormone (PTH) levels. If a patient is suspected of having celiac disease -- especially if he or she has a slightly elevated PTH or a very markedly decreased vitamin D level -- you could do a tissue transglutaminase antibody IgA and other investigations to rule out that disorder.
Slide 26. Who Should Have a BMD Test?
Dr. Burke: So, who should have a BMD test? As I mentioned before, all women age 65 and older, regardless of risk factors, should have a BMD test. And I tell my residents: if you think of the patient needing a flu shot or a pneumonia shot and qualifying for those, then they also probably qualify to have a BMD test done; and that can help everyone remember to obtain that at age 65 and older. Younger postmenopausal women with 1 or more risk factors (other than being white and postmenopausal) should also be considered for a BMD test.
And finally, men and women who present with low-trauma fractures, such as any fall from a standing position that results in a fracture -- that is a low-trauma fracture. And you would obtain a BMD test in those cases not to diagnose osteoporosis but just to confirm the diagnosis and to determine disease severity, because those patients are actually osteoporotic by definition, regardless of what their BMD is.
Slide 27. Frequency of BMD Testing
Dr. Burke: The frequency of BMD testing is outlined here. Patients found to have a normal BMD -- that is, a T-score greater than -1.0 -- can have a BMD test performed in follow-up approximately every 3 to 5 years, depending on the risk in that patient.
Patients in an osteoporosis-prevention or treatment program should have testing every 1 to 2 years, with every 2 years being acceptable in most cases -- and every year (or even in 6 months in special cases, such as patients on steroids or patients with hyperparathyroidism) to monitor their disease.
Slide 28. International Society for Clinical Densitometry (ISCD) Recommendations for Diagnosis
Dr. Burke: The International Society for Clinical Densitometry (ISCD) recommends the gold standard of BMD testing to be central technology, most commonly DXA testing. What is tested here is the posterior-anterior (PA) of the spine, and in the hip various sites are looked at: total proximal femur, femoral neck, or trochanter of either hip. Forearm BMD of the nondominant arm can also be used, especially if the spine or hip cannot be interpreted. For example, if the patient has had hip replacements or if the patient has already had multiple compression fractures, that is going to alter the DXA results, and a forearm BMD may be more useful. The lowest T-score at any site should be used for diagnosis. Peripheral measurements, for example, ultrasound, finger, DXA, etc., are useful screening devices for lower-risk patients but should not be used alone for diagnosis or follow-up. A peripheral test may prompt you to obtain central technology because that's the best technology to use for follow-up in your patients.
Slide 29. BMD Considerations in Disease Monitoring
Dr. Burke: Now, what are some BMD considerations with regard to disease monitoring? In populations of patients, various meta-analyses have demonstrated that increases in BMD are associated with a decrease in fracture risk. However, the exact relationship in individuals is not as clear. In other words, it is not well defined how much fractures are reduced with a certain increase in BMD or whether just any maintenance or increase in BMD reduces fractures similarly. What is known, however, is that a loss of BMD is associated with an increase in fracture rate compared to those who maintain or increase BMD. For the loss to be meaningful, it has to be greater than the least significant change of the machine, which is usually not more than 2% to 3%. Ideally the patient should also be tested on the same machine. Loss of BMD is an important finding and should prompt a reevaluation of the patient to confirm compliance with the medication prescribed or to consider reinvestigating whether the patient may have a secondary cause for his or her continued bone loss.
Slide 30. Utility of Biochemical Markers (BCM) in Osteoporosis Assessment
Dr. Burke: Let us look briefly at the utility of biochemical markers in osteoporosis assessment.
Slide 31. The Role of Bone Turnover
Dr. Burke: Bone remodeling is a physiologic reparative process in which small areas of bone are resorbed through the action of osteoclasts and new bone is filled in with osteoblast activity. This process occurs constantly and is an important contributor to bone quality. There are various factors that influence the bone remodeling process and the balance between normal bone resorption and normal bone formation. For example, at the time of menopause or with aging, resorption can exceed formation and result in a net loss of bone. This imbalance can affect bone quality by disrupting microarchitecture and connectivity of the trabeculae, increasing cortical porosity, and decreasing mineralization and mass of bone.
Slide 32. Commonly Used Markers of Bone Turnover
Dr. Burke: The process can be assessed by measuring markers of bone turnover. Common resorption markers are shown here and include pyridinoline, deoxypyridinoline, and the amino-terminal and the carboxy-terminal telopeptides. The commonly used formation markers are osteocalcin and bone-specific alkaline phosphatase.
Slide 33. Realities of Biochemical Markers of Bone Turnover
Dr. Burke: There are certain realities of measuring markers of bone turnover that you should be aware of. Biochemical markers cannot be used to diagnose osteoporosis, but they can play a role in monitoring response to therapy. They are excellent in clinical trials because the changes that occur are significant and meaningful in those trials, reflecting a drug's effect on a population of patients. However, an individual patient may or may not show a significant change with therapy.
Unfortunately, the measurement of bone turnover can be complicated by several factors including that it is a biologic agent subject to degradation, as well as having both seasonal and circadian variability. So, although they have utility in some patients, they are not presently considered a routine assessment outside of the clinical trial setting.
Slide 34. Treatment
Dr. Burke: We will now turn the podium over to Dr. Miller, who will discuss treatment options in the management of osteoporosis.
Dr. Miller: My name is Dr. Ellen Miller, and I am a Clinical Assistant Professor of Medicine at the Albert Einstein College of Medicine.
Slide 35. Your Clinical Goals Include...
Dr. Miller: Your clinical goals in treating patients with osteoporosis include reducing the likelihood of fractures. We do this by decreasing bone loss, restoring bone turnover to premenopausal levels, and preserving or increasing bone strength.
Slide 36. Universal Treatment Strategies
Dr. Miller: All patients should be advised on universal treatment strategies, most importantly, fall prevention (good lighting and no area rugs); and if patients still have a propensity to fall, they should be outfitted with hip protectors. Certainly all of our patients should be advised of the importance of smoking cessation. We should advise them on weight-bearing exercises, as well as a well-balanced diet enriched with calcium and vitamin D.
Slide 37. Reduction in Hip and Other Nonvertebral Fractures: Calcium and Vitamin D Supplementation in Elderly, Institutionalized Patients
Dr. Miller: How important are calcium and vitamin D in preventing fractures? This is a study that looked at elderly institutionalized patients, who tend to have low levels of vitamin D. In this study, the patients who were treated with calcium and vitamin D had significantly fewer hip fractures, as well as other nonvertebral fractures, when compared to patients who were treated with placebo.
Slide 38. Recommended Calcium Intake
Dr. Miller: What is the recommended intake of calcium? For men up to the age of 65 as well as women up to the time of menopause, they should supplement their diet with 1000 mg of calcium daily. Men over the age of 65 and menopausal women should supplement with 1500 mg of calcium daily.
Slide 39. Vitamin D Supplementation Decreases Fracture Risk
Dr. Miller: What about vitamin D supplementation? This was a clinical study that looked at elderly patients living in the community, both men and women, between the ages of 65 and 85. Over the course of 5 years, these patients were randomized to receive either a dose of 100,000 IU of vitamin D every 4 months or a placebo, which was mailed to them. The patients who received the vitamin D supplementation had 33% reduction in the relative risk of fractures that we typically attribute to osteoporosis.
Slide 40. Recommendations for Treatment of Vitamin D Deficiency/Insufficiency
Dr. Miller: What do we do with our patients once we identify that they have low levels of vitamin D? Those patients who were found to be deficient in vitamin D -- defined at the level below 50 nmol/L -- should be supplemented with 50,000 IU weekly for a total of 8 weeks. After the vitamin D level is corrected, they should be given 1000 IU daily. For patients who have normal or insufficient levels of vitamin D -- between 50 and 80 nmol/L -- they should receive a supplemented 800 to 1000 IU daily. Our goal would be to aim for a level of vitamin D of at least 80 nmol/L. Patients, of course, who have impaired intestinal absorption will have greater benefit from sunlight with its ultraviolet light B wavelength (UVB) rays, since vitamin D is a fat-soluble vitamin. Once the levels are stable, the levels should be monitored annually.
Slide 41. Pharmacologic Treatment Recommendations Based on BMD Score
Dr. Miller: Now, let us turn to pharmacologic treatment recommendations for osteoporosis. Here we see the recommendations from the two major organizations: the National Osteoporosis Foundation and the American Association for Clinical Endocrinologists. They both agree that patients who have a T-score less than -1.5 with risk factors should be treated for their osteoporosis. Where they differ is in the patients who do not have risk factors. The American Association of Clinical Endocrinologists recommends treating these patients at a T-score of -2.5 or lower, but the National Osteoporosis Foundation is a little more aggressive and recommends treating at a T-score of -2 or lower.
What is important to remember is that the most important predictor of which patients are going to fracture is age. So, for any given T-score, any given bone density, age is a very important independent risk factor. So, an 80-year-old patient with a T-score of -2 has a much greater risk of fracturing than a 60-year-old woman with the same T-score, and we should certainly take this into consideration when deciding whom to treat.
Slide 42. US FDA-Approved Pharmacologic Options
Dr. Miller: These are the current Food and Drug Administration (FDA)-approved treatment options available to us. They include the 3 bisphosphonates: alendronate, ibandronate, and risedronate, as well as calcitonin, raloxifene, and teriparatide.
Slide 43. Calcitonin
Dr. Miller: Let us start with calcitonin. This is an antiresorptive medication that is specifically indicated for women who are 5 or more years postmenopausal and unable to tolerate or refuse other osteoporosis medications. It is very easy to administer as a nasal spray (200 IU daily), and it is still available as a subcutaneous injection (100 IU 3 times a week). It is fairly well tolerated; the only adverse event is from local nasal irritation from the nasal spray.
Slide 44. Nasal Calcitonin: Effect on Lumbar Spine BMD (PROOF: 5-Year Analysis)
Dr. Miller: Let us look at the effect on bone density with nasal calcitonin. It had a very modest increase in bone density in the spine compared to placebo at the end of 5 years.
Slide 45. Nasal Calcitonin: Effect on Hip and Vertebral Fractures (PROOF 5-Year Analysis)
Dr. Miller: This resulted in a reduction of 33% of vertebral fractures. However, no significant reduction was seen in hip fractures.
Slide 46. Teriparatide (Parathyroid Hormone)
Dr. Miller: Now, let us turn to teriparatide, or PTH. This agent is different from all the other agents we are discussing today in that this is an anabolic agent that builds new bone. It is only available as a subcutaneous injection in a dose of 20 mcg daily. It is contraindicated in patients who have hypercalcemia, hyperparathyroidism, unexplained elevations in their alkaline phosphatase, exposure to external beam radiation, or prior history of radiation therapy of the skeleton.
Slide 47. Teriparatide
Dr. Miller: Teriparatide is indicated for men and postmenopausal women who have osteoporosis and are at high risk for fracture. We define high risk as those men and women who have had previous osteoporotic fractures, those with multiple risk factors for fracture, as well as those who have failed or are intolerant of other osteoporosis treatments. We must remember that the FDA assigned a black box warning to teriparatide because of the findings of osteosarcoma in the rodent studies. The adverse events are hypercalcemia, nausea, leg cramps, and dizziness.
Slide 48. Teriparatide: Effect on Lumbar Spine and Hip BMD in Postmenopausal Women
Dr. Miller: Let us look at the effect of teriparatide on bone density. It increased bone density in the lumbar spine by 9.7% and in the total hip by 2.6% compared to placebo at the end of 18 to 24 months. This study, as I mentioned earlier, was cut off sooner than it was expected because of the findings in the rodent studies.
Slide 49. Teriparatide: Effect on Fractures
Dr. Miller: This resulted in a 65% reduction in vertebral fractures and a 53% reduction in nonvertebral fragility fractures -- with teriparatide compared to placebo.
Slide 50. Raloxifene
Dr. Miller: Now, let us turn to raloxifene. Raloxifene is a selective estrogen-receptor modulator that acts like an estrogen on the bone but, unlike estrogen, does not stimulate the estrogen receptors in the breast or the uterus. It is indicated at a dose of 60 mg daily for both the prevention and treatment of postmenopausal osteoporosis. The adverse events we see in the studies are vasomotor flushes, venous thromboembolic events similar to that seen with estrogen therapy, and leg cramps.
Slide 51. Raloxifene: Effect on Lumbar Spine and Femoral Neck BMD in Postmenopausal Women
Dr. Miller: What is the effect of raloxifene on the bone density? It increased the bone density in the lumbar spine by 2.6% and in the femoral neck by 2.1% compared to placebo at the end of 3 years.
Slide 52. Raloxifene: Effect on Radiographic Vertebral Fractures (MORE)
Dr. Miller: This resulted in a 50% reduction in vertebral fractures in patients who had osteoporosis but no preexisting vertebral fractures. It also looked at patients who had preexisting vertebral fractures, and it showed a 30% reduction in new vertebral fractures.
Slide 53. Raloxifene: Effect on Nonvertebral and Hip Fracture
Dr. Miller: However, there was no effect in the reduction of hip fractures or nonvertebral fractures with raloxifene compared to placebo at the end of 3 years.
Slide 54. Bisphosphonates
Dr. Miller: Now, let us turn to the bisphosphonates. All 3 of the currently approved bisphosphonates are indicated for the prevention and treatment of osteoporosis in our postmenopausal women.
Alendronate and risedronate are indicated for the treatment of glucocorticoid-induced osteoporosis in men and women. Only risedronate is indicated for the prevention of glucocorticoid-induced osteoporosis, and alendronate is the only agent indicated for the treatment of osteoporosis in men.
Slide 55. Alendronate: Effect on Lumbar Spine and Femoral Neck BMD in Postmenopausal Women
Dr. Miller: Let us start with alendronate. Alendronate increased the bone density in the lumbar spine by 8.8% and in the femoral neck by 5.9% compared to placebo at the end of 3 years.
Slide 56. Alendronate: Clinical Trial Data
Dr. Miller: It also resulted in a 48% reduction in vertebral fractures and a 56% reduction in hip fractures at the end of 4 years in patients who had low bone density but no baseline vertebral fractures. In patients with baseline vertebral fractures, there was a 47% reduction in new vertebral fractures and a 51% reduction in hip fractures at the end of 3 years.
Slide 57. Alendronate: Evidenced-Based Review of Osteoporosis Trials -- Vertebral Fractures
Dr. Miller: Here we see a meta-analysis of studies that looked at alendronate and its reduction in vertebral fractures. When we look across multiple studies, we see that there was a 48% reduction in the risk of vertebral fractures in patients treated with alendronate compared to those treated with placebo, demonstrating to us that this is a consistent finding across multiple studies.
Slide 58. Ibandronate: Effect on Lumbar Spine and Femoral Neck BMD in Postmenopausal Women (BONE)
Dr. Miller: Now, let us turn to ibandronate. Ibandronate at a dose of 2.5 mg daily -- it is also available at a dose of 150 mg once monthly -- was found, in this daily-dose study, to increase the bone density by 6.5% in the lumbar spine and by 2.8% in the femoral neck compared to placebo at the end of 3 years.
Slide 59. Ibandronate: Effect on New Morphometric Fractures (BONE)
Dr. Miller: It also resulted in a reduction of new vertebral fractures at the end of 3 years. There was no significant decrease seen, however, in nonvertebral fractures.
Slide 60. Risedronate: Effect on Lumbar Spine and Femoral Neck BMD in Postmenopausal Women
Dr. Miller: Let us turn to risedronate. Risedronate increased the bone density in the lumbar spine by 5.4% and in the femoral neck by 1.6% when compared to placebo at the end of 3 years.
Slide 61. Risedronate: Clinical Trial Data
Dr. Miller: It also resulted in a reduction in vertebral fractures, in patients who had baseline vertebral fractures, of 33% to 46% at the end of 3 years.
In this study, looking at hip fractures, it resulted in a reduction in hip fractures of 40% in patients between the ages of 70 and 79 and a 20% reduction in patients who were over the age of 80.
Slide 62. Risedronate: Evidenced-Based Review of Osteoporosis Trials -- Vertebral Fractures
Dr. Miller: Just as we looked at in the first meta-analysis, we can look at a meta-analysis with risedronate that looked at multiple clinical trials with vertebral fractures reported as an endpoint. And here we see, across multiple clinical trials, overall a 36% reduction in vertebral fractures with risedronate compared to placebo.
Slide 63. Estrogen Therapy: Women's Health Initiative Fracture Outcomes Data
Dr. Miller: No discussion of osteoporosis would be complete without a discussion of estrogen therapy. We have known since the early days of the Postmenopausal Estrogen/Progestin Interventions (PEPI) trials that estrogen therapy has a favorable effect on BMD and bone health in general. However, it was not until the Women's Health Initiative that we had the evidence that it actually reduced the risk of both hip and vertebral fractures. However, because of the outcome of the Women's Health Initiative, the recommendations were that estrogen therapy should not be used as a primary treatment for bone health.
Slide 64. Comparison Trials and Combination Studies
Dr. Miller: How do we compare the available agents for osteoporosis? Well, we have looked at a lot of studies today comparing each of these agents individually to placebo. However, we cannot compare those studies to each other unless we have a head-to-head study comparing these agents individually and together.
Now, the best head-to-head study, of course, would have fractures as the primary outcome. However, if we wanted to compare the bisphosphonates in terms of efficacy for fracture reduction, there is only about a 10% or 20% difference that we are looking for between alendronate and risedronate. In order to see such a difference at a statistically significant level in comparing these agents, we would have to do a very large study enrolling a large number of patients over a long period of time.
Slide 65. 2004 Surgeon General's Report on Osteoporosis
Dr. Miller: The Surgeon General recognized that and in his report in 2004 stated, "Although the most important study outcome is fracture risk reduction, changes in bone density or markers of bone turnover can be used [in the conduct of clinical studies] as supportive evidence of the effectiveness of treatment."
Slide 66. Head-to-Head Comparison of Alendronate and Risedronate (FACT)
Dr. Miller: That is what we see here: a head-to-head comparison of the two bisphosphonates, alendronate and risedronate. These were two studies -- one done in the United States and one international study -- where the patients were randomized to receive either a once weekly dose of alendronate 70 mg with a placebo that looked like the 35 mg of risedronate once weekly, or an active pill of 35 mg of risedronate with a dummy pill that looked like 70 mg of alendronate. These pills were taken on an empty stomach, with a full glass of water, 30 minutes before breakfast. The entrance criteria was a bone density T-score of less than or equal to -2 at any central location. No patients with gastrointestinal (GI) problems were excluded unless they had abnormalities of the esophagus that delayed emptying, specifically stricture or achalasia. The primary endpoint of this study was the mean change in bone density in the trochanter. The secondary endpoints were the changes in bone density in the other sites: the spine, the lumbar spine, the femoral neck, and the total hip. They also looked at the percentage of patients who responded, as well as the bone turnover markers and the GI tolerability.
Slide 67. Summary of BMD Endpoint Results
Dr. Miller: This is a summary of the BMD endpoints, and what we see here from the US Fosamax Actonel Comparison Trial (FACT) is that both agents -- we see alendronate on the left of each pair of bar graphs; and on the right of each pair of bar graphs we see risedronate -- increased bone density in each site tested. But in each site tested, alendronate increased bone density to a greater extent than risedronate did.
Slide 68. Summary of BMD Endpoint Results
Dr. Miller: Similar findings were seen in the international study.
Slide 69. Percentage of Patients With Response by BMD Gains/Losses at 12 Months in FACT
Dr. Miller: When we look at the percentage of patients who responded with increases in their bone density -- if we look at the far side of the chart here -- we see that those patients who had a BMD increase of at least 5% were 31% of the patients in the alendronate group and 20% of the patients in the risedronate group. By the same token, we can look at the percentage of patients who lost bone, who lost at least 3% of their bone: 5% of the patients in the alendronate arm, and 11% of the patients in the risedronate arm lost at least 3% of bone.
Slide 70. Secondary Endpoint Results: Biochemical Markers of Bone Resorption
Dr. Miller: We also looked at the bone turnover markers, and here we see the markers of bone resorption. With both agents there was a rapid reduction in bone turnover seen as early as 3 months, but there was a greater reduction in bone resorption with alendronate than with risedronate.
Slide 71. Secondary Endpoint Results: Biochemical Markers of Bone Formation
Dr. Miller: Similarly, we saw a reduction in the markers of bone formation with both agents: again a greater reduction with alendronate than with risedronate.
Slide 72. Safety and Tolerability Results
Dr. Miller: When we compare the safety and the tolerability of the two agents, we find they are very similar. We see that about 20% to 22% of the patients in both arms of the study complained of upper GI side effects, but when we looked down at the bottom in the number of patients who discontinued due to their upper GI side effects, it was a very small percentage -- 2.5% to 3.0% -- and no difference between the two agents.
Slide 73. Incidence of Fracture Adverse Events
Dr. Miller: As I mentioned earlier, fractures were not a primary or even a secondary endpoint of this study, but in all osteoporosis studies we always track fractures as adverse events. And here we see the number of fractures that occurred in the two arms of the study. In the US arm of the study, there were 26 fractures in the alendronate arm and 20 fractures in the risedronate arm. In the international study, there were 18 fractures in the alendronate arm and 20 fractures in the risedronate arm. None of these differences are statistically significant, and I would also like to add that these were not adjudicated as osteoporotic fractures. They included every fracture the patient reported, including fractures of the fingers and toes.
Slide 74. Combined or Sequential Use of Therapies
Dr. Miller: What about using combined therapies for osteoporosis? We have looked at a lot of different treatments for osteoporosis -- and it would be nice if we could give combinations of therapy to patients in hopes of having an even added benefit -- and over the years many studies have been done looking at various combinations. There were studies looking at combining hormone therapy and the bisphosphonates, and it was found that the combination increased bone density better than either agent alone. There was one study that combined raloxifene with alendronate and found that bone density increases were better than with raloxifene alone. PTH when added to hormone replacement therapy (HRT), increases bone density better than the hormone therapy alone. What is not clear at this point, however, is if bisphosphonates should be used concurrently or sequentially with PTH.
Slide 75. Case Studies
Dr. Miller: Now I would like to turn the podium back to Dr. Burke, who is going to discuss the cases with you.
Dr. Burke: We will return to the cases we brought up earlier.
Slide 76. Recap: Case 1
Dr. Burke: Remember, the first case was a 60-year-old woman who was postmenopausal, without hormone therapy, not on calcium supplementation, and who had intermittent steroid use. Her DXA showed a -2.6 T-score at the lumbar spine and -2.8 at the hip.
Slide 77. Question: What Would You Do Next?
Dr. Burke: Let me put a question forward to you: What would you do next? Would you start raloxifene in this patient; start estrogen therapy; prescribe a bisphosphonate; do a work-up for secondary osteoporosis; start teriparatide; or not give her any treatment because the BMD is not significant?
Actually, this BMD is significant and consistent with osteoporosis. What we did in this patient was to begin a bisphosphonate; we also started the patient on 1500 mg of calcium and 800 IU of additional vitamin D. She did very well, and on repeat BMD testing a year later, she did show improvement in her BMD.
Slide 78. Recap: Case 2 Dr. Burke: The second case, as you recall, was a little bit more complicated. A 77-year-old woman had a 3-inch height loss associated with vertebral fractures and, in 2002, had a lumbar spine T-score of -3 and a femoral neck T-score of -2.8. She had been started on a weekly bisphosphonate and took a calcium-plus-D combination supplement. Unfortunately, she had another vertebral compression fracture 2 years later; and now her DXA lumbar spine T-score was -3.5, and her femoral neck T-score was -3.2.
Slide 79. Question: What Would You Do Next? Dr. Burke: What would you do next for this patient? Would you discontinue the bisphosphonate and start raloxifene? Would you increase her dose of bisphosphonate? Would you do a work-up for secondary osteoporosis? Would you add teriparatide? Or would you not change her regimen because the BMD change was not significant?
This BMD decrease was, in fact, significant, and this patient was found, on secondary work-up, to be significantly vitamin D deficient. She was given 50,000 IU of vitamin D weekly for 8 weeks and then given 1000 IU daily. She was initially switched to another bisphosphonate, but her urine biomarkers did not significantly decrease in 3 months' time, so she was then switched again, to teriparatide. After 1 year of teriparatide therapy, she did show a very nice increase in lumbar spine BMD and has not had any additional fractures.
Slide 80. Summary Dr. Burke: In closing, I would like to summarize that osteoporosis is a disease with serious consequences, and patients at risk for osteoporotic fractures should receive BMD testing. A patient's BMD T-score and their age are two important contributors to their fracture risk. All patients should be counseled on nonpharmacologic treatment strategies, including reducing fall risk, ingesting adequate calcium and vitamin D, exercising, and not smoking. Various pharmacologic options are, fortunately, available that have been shown to reduce fractures beyond what is seen with calcium and vitamin D supplementation alone. These agents should be prescribed to all appropriate patients to reduce the devastating sequelae of this disease.
Slide 81. Does an Increase in BMD After Treatment Correlate With a Reduced Fracture Rate?
Speaker: Does an increase in BMD after treatment correlate with a reduced fracture rate?
Dr. Miller: The answer is yes. Probably the bigger question, however, is: Do greater increases in bone density result in a greater decrease in fracture? This is a little trickier -- with some meta-analyses indicating that it does and others showing that any increase in bone density results in fracture reduction and that the amount of increase is not really important. What is important, though, is that loss of BMD beyond the least significant change of the machine is worrisome and should prompt a reevaluation of the patient for compliance or a secondary cause for that loss.
Slide 82. How Long Should You Continue Bisphosphonate Treatment?
Speaker: How long should you continue bisphosphonate treatment?
Dr. Miller: There is no finite time limit to the use of bisphosphonates for osteoporosis. Alendronate has been studied for up to 10 years with continued maintenance or increases seen in BMD. Risedronate data for at least 5 years also show continued positive BMD effects. If the patient normalizes his or her BMD on therapy, it might be reasonable to consider stopping the agent and monitoring that patient periodically with bone density testing although there are no studies specifically evaluating this.
Slide 83. Do You Treat All Patients With Osteopenia With Bisphosphonate?
Speaker: Do you treat all patients with osteopenia with bisphosphonate?
Dr. Miller: No. There are some patients with osteopenia who need to be treated, though. For example, those with a history of a low-trauma fracture have osteoporosis by definition, regardless of what their BMDs show. And these patients deserve to be treated.
Dr. Burke: In addition, the NORA (National Osteoporosis Risk Assessment) study identified osteopenic women who were at higher risk for fractures. They included patients with a prior fracture, as Dr. Miller just said; those with a T-score of -1.8 or less; and those with poor mobility and poor overall health status. So, women with these risk factors could also be considered for therapy.
Slide 84. If a Patient's BMD Is Still Not "Normal" After 2 Years of Teriparatide Treatment, What Would You Recommend?
Speaker: If a patient's BMD is still not "normal" after 2 years of teriparatide treatment, what would you recommend?
Dr. Miller: Presently, teriparatide should not be used for longer than 2 years, so I would stop it at that time and switch the patient to a bisphosphonate to help maintain or increase the BMD gains achieved with teriparatide.
Dr. Burke: Remember, though, that any BMD gain is associated with a decrease in fracture risk even though the patient might not have normalized their BMD.
Slide 85. How Much Sunlight Is Needed to Meet Vitamin D Requirements?
Speaker: How much sunlight is needed to meet vitamin D requirements?
Dr. Burke: Fifteen minutes between 11:00 am and 2:00 pm should provide adequate sunlight, except in northern latitudes in the winter. Here, supplementation would be necessary.
Slide 86. Do We Need to Be Concerned About Vitamin D Toxicity?
Speaker: Do we need to be concerned about vitamin D toxicity?
Dr. Miller: No. It takes massive doses of vitamin D given chronically to induce toxicity. Some say greater than 10,000 IU daily. Others estimate even higher doses are necessary for toxicity.
Dr. Burke: What we do know is that it is really very difficult to induce toxicity, and we should not be afraid to offer appropriate supplementation. For example, patients on anticonvulsant therapy may need 4000 IU daily to achieve adequate vitamin D levels.
Slide 87. What Is the Rationale for Waiting Until Age 65 for Dual Energy X-Ray Absorptiometry (DXA) Scan?
Speaker: What is the rationale for waiting until age 65 for DXA scan?
Dr. Miller: Fortunately, fracture risk at the time of menopause is less than at older ages, regardless of bone density. Age is one of the most important predictors of fracture risk, with the incidents of spine and hip fractures beginning to increase starting at the age of 60 or 65.
Dr. Burke: Certain women at menopause may benefit from earlier screening, however. Women with several lifestyle risk factors -- those on steroid therapy, with breast cancer on treatment, and so forth -- should be screened earlier than age 65 to identify those who would benefit from pharmacologic treatment. All women should be counseled on lifestyle strategies: calcium, vitamin D, exercise, and nonsmoking.
Slide 88. Are There Specific Findings Other Than Osteoporosis That Might Trigger a Clinician to Think a Patient Has Vitamin D Deficiency?
Speaker: Are there specific findings other than osteoporosis that might trigger a clinician to think a patient has vitamin D deficiency?
Dr. Burke: We're just starting to realize that there are many things that we have attributed to other problems in the past -- especially in elderly patients, for example -- that may actually be due to vitamin D deficiency: postural instability, trouble walking, and increased body sway. All of those will increase a patient's risk of falling. Also, general aches and persistent musculoskeletal pain. Patients with significant vitamin D deficiency and osteomalacia have achy bone and muscular pain, and vitamin D repletion will help these patients. In one study of patients presenting with general aches to a specialty clinic, 88% of these patients ended up having vitamin D deficiency. So, in patients like this, before attributing their aches to old age or fibromyalgia, think of making sure that these patients are not vitamin D deficient.
Contemporary Management of Osteoporosis: Seizing the Opportunity to Prevent Adverse Outcomes
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