Objectives Discuss bone health and the consequences of osteoporosis on patients medical and disability status. Discuss the pathophysiology of osteoporosis and major risk factors. Assess the major diagnostic procedures and discuss overall management principles for the prevention and treatment. Discuss the role of the healthcare professional in prevention, treatment, and counseling strategies relevant to good bone health. Module 1- An Overview of Bone Health will Discuss bone health and the consequences of osteoporosis on patients medical and disability status. Discuss the pathophysiology of osteoporosis and major risk factors. Assess the major diagnostic procedures and discuss overall management principles for the prevention and treatment. Discuss the role of the healthcare professional in prevention, treatment, and counseling strategies relevant to good bone health. 2
Supported through an educational grant from Merck & Co, Inc. This activity has been supported through an educational grant from Merck & Co, Inc. 3
Speaker Kelly Krohn, MD Director of Clinical Research Medical Director, Mercy Osteoporosis Program Mercy Hospital Department of Medicine Clinical Associate Professor of Pharmacy Duquesne University, Pittsburgh, PA Today s presentation is presented by Dr. Kelly Krohn. Dr. Kelly Krohn is Director of Clinical Research and Medical Director for the Mercy Osteoporosis Program in the Department of Medicine at Mercy Hospital of Pittsburgh. 4
Pre-Test Instructions Prior to beginning this activity, please take a few moments to complete a brief pre-test. For each question, choose your answer by checking the box left of that answer. Post-Test Instructions Upon completion of this activity, visit www.bonehealthcme.com and use the CME Activities link to log in and take the post-test to receive CME credit. Prior to beginning the program, please read and answer the self-assessment questions that follow. After viewing the full presentation you will have the opportunity to submit a brief posttest and evaluation in order to receive CME/CE credit. 5
Self-Assessment Question 1 The definition of osteoporosis incorporates bone density as well as bone quality. A person can have osteoporosis without a prevalent fracture. A. True B. False 6
Self-Assessment Question 2 Bone remodeling occurs on the bone surface. In postmenopausal women, the rate of bone loss is higher in long bones (cortical) compared to cancellous (trabecular) bone such as the spine. A. True B. False 7
Self-Assessment Question 3 The following techniques have been shown to be valuable in estimating bone density and predicting fracture risk: A. Heel ultrasound B. DXA of the hip and spine C. Quantitative CT D. All of the above 8
Self-Assessment Question 4 T-scores are defined as the number of standard deviations above or below the mean bone density for young healthy adults. A. True B. False 9
Self-Assessment Question 5 The WHO criteria for the definition of osteoporosis based upon T-score values using central DXA should only be applied to postmenopausal women. A. True B. False 10
Self-Assessment Question 6 Which of the following agents have proven efficacy in the reduction of spinal fractures in postmenopausal women? A. Raloxifene B. Alendronate C. Teriparatide D. Risedronate E. HRT F. All of the above 11
Osteoporosis Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. Bone strength reflects the integration of two main features: bone density and bone quality. A fracture occurs when a failureinducing force is applied to osteoporotic bone. Thus, osteoporosis is a significant risk factor for fracture. 1 1. NIH Consensus Development Conference Statement March 2000 As we develop strategies to reduce the development of osteoporosis and the subsequent development of osteoporotic fractures, it is important that we define osteoporosis. Over the last 30 years, the definition of osteoporosis has changed significantly. In the year 2000, a consensus conference was held by the NIH, and the definition of osteoporosis was agreed upon to be a skeletal disorder characterized by compromised bone strength, predisposing to an increased risk of fracture. Bone strength is an integration of two features bone density and bone quality. A fracture occurs when a failure-inducing force is applied to osteoporotic bone. Osteoporosis is a significant risk factor for fracture; therefore, you can have patients who have osteoporosis who do not have fractures. In this example of osteoporosis, we see a beautiful picture of normal trabecular bone on the right side, which is very strong because of both the amount of bone as well as the bone quality. On the left, we see osteoporotic trabecular bone, and it is obvious that there is less bone, and there is significant loss of connectivity between the bone. Therefore, this combination of decreased bone density and inferior quality reduces the bone strength and increases the risk for fracture. 12
Bone Strength: NIH Consensus Statement 2000 Bone Strength Bone Quality Bone Density Architecture Turnover Mineralization Damage Accumulation Geometry Standard BMD measurements JAMA 2001: 285; 785-795 Bone strength, as defined by the NIH Consensus Statement, is a combination of both bone quality and bone density. We have a number of standard ways to measure bone density. Most typically we measure bone density with DXA scans or other ways to noninvasively measure bone density such as CT scan. Bone quality is the other major feature that contributes to bone strength, and as we have learned more about risks of fracture as well as the reduction of fractures through our clinical research, it becomes apparent that issues of bone quality may be even more important than bone density in some situations. Bone quality is much more difficult to measure. It is a combination of a number of factors, which include bone architecture, rate of bone turnover, mineralization of bone, damage accumulation within the bone, and the geometry of the bone. For example, larger bones with increased diameter have different strengths than smaller diameter bones. As we move forward with our clinical research both in the understanding of fracture risk and the reduction of fracture, it s apparent that we have to look at many other aspects of bone strength besides standard bone density measurement. 13
Lifetime Representation of Bone Mass and Fracture Risk in Women High Low BONE MASS FRACTURE RISK Low 10 20 30 40 50 60 70 80 High PHASE CLINICAL GOAL Skeletal Maturation Build Maximum Peak Bone Mass Bone Loss Slow Bone Loss Osteoporosis Build New Bone Adapted from Wasnich Primer on Metabolic Bone Disease If we look at the lifetime representation of bone mass and follow a young healthy female skeleton through the natural history of a woman s life up to the mid-80s, we can divide this lifetime representation of bone mass into three distinct areas. For the first 30 years or so, the phase that we see is skeletal maturation. This is a very important time if we are to optimize bone health. It is during this time that our clinical goal will be to build maximum peak bone mass. Increasing peak bone mass in children may have an impact upon their fracture risk as elderly adults. The next phase of bone life is the perimenopausal and early postmenopausal years of the woman s life. During this time, there is bone loss, and our primary clinical goal would be to slow down bone loss throughout this time period. Finally, unfortunately when we see many of our patients in their 70s and 80s, they already have very low bone mass, and our clinical goal at this point would be to build new bone and to strengthen the bone that they have in order to reduce their fracture risk. 14
Normal Bone Remodeling 1 2 Osteoclast Resorption Osteoblast Recruitment 3 4 New Bone Formation Osteoblast Apoptosis As we go forward with our understanding of treatments for osteoporosis, it is important that we understand normal bone remodeling. In normal bone remodeling, the osteoclast is recruited to resorb or to remove damaged bone. The osteoclasts dig a deep resorption pit on the bone surface, and subsequently the osteoblast is recruited to lay down new bone. The osteoblast lays down new bone that is called osteoid. If the right environment with adequate calcium and vitamin D is available, the bone becomes mineralized, and the new healthy bone is formed to replace the void. The net result is no gain or loss of bone. 15
Postmenopausal Bone Loss 1 2 Increased Osteoclast Resorption Increased Osteoblast Recruitment 3 4 Inadequate Osteoblast Osteoid Production Net Bone Loss In postmenopausal women, there is increased activity of the osteoclasts. Bone resorption is enhanced, and there is a deeper resorption pit and an increased number of resorption pits on the bone surface. Because of this increased osteoclastic resorption, there is an attempt to lay down more new bone. This is done in part by increasing the number of osteoblasts through recruitment. Unfortunately, the osteoblasts in general are unable to keep up with the very rapid bone resorption, and there is a net bone loss. 16
Corticosteroid Effect on Remodeling 1 2 Increased Osteoclast Resorption Decreased Osteoblast Recruitment 3 4 Premature Osteoblast Apoptosis Net Bone Loss In corticosteroid bone remodeling, there is also a slight increase in osteoclast resorption, but the predominant impact of corticosteroids on bones is to result in decreased osteoblast recruitment and unfortunately to encourage osteoblast apoptosis (also known as programmed cell death). The net result in patients on corticosteroids is dramatic bone loss, which can occur in a very short time period. 17
Cancellous and Cortical Bone Loss Occurs at Different Times and Rates 100 Percent of Peak Bone Mass 90 80 Wrist fractures Cancellous Bone Cortical bone 70 60 Vertebral fractures Hip fractures 40 50 60 70 80 Age Used with Permission Watts NB. Am Fam Phys 1988;38:193-207 Since bone remodeling occurs primarily on the bone surface, the bone that has the most surface area will be the bone that is affected soonest and in a more dramatic fashion relative to the bone that has less surface area; therefore, cancellous or trabecular bone is generally impacted at a much greater rate compared to cortical bone. An example of this would be vertebral bone and distal bone of the wrist which have a substantial component of trabecular bone. We see this with the development early on in clinical spectrum of osteoporotic fractures that are predominantly cancellous bone in nature. These would include fractures of the wrists and the vertebrae. Many years down the road in the 70s and 80s, we start seeing a significant increase in hip fractures, which has a substantial component of cortical bone. 18
Fractures as a Function of Age Used with Permission Cooper et al. JBMR 1992 Feb 7(2):221-7 This slide represents the epidemiology of osteoporotic fractures in women, and we can see the fractures are divided up into distal forearm or wrist fractures, vertebral fractures, and hip fractures. These fractures occur at different ages. Wrist fractures tend to start in women in the mid to late 40s and have a fairly consistent incidence over the next 20 years. Vertebral fractures tend to start slightly later in the mid-50s and continue to rise throughout the life span of the woman. Hip fractures usually do not occur until the mid-60s or early 70s and continue to increase at a fairly high rate into the 7 th, 8 th, and 9 th decades. What we see on this graph by Cooper et al. published in the Journal of Bone and Mineral and Research in 1992 compares the incidence of osteoporotic fractures in women and in men as a function of age. You can see in men, there is a shift to the right in the age at which fractures begin to occur. Vertebral and hip fractures occur at a high rate in men, but it is generally 10 to 15 years later than compared to women. Men also have a much lower rate of Colles fractures or fractures of the wrist. Wrist fractures perhaps occur less in men because of differences in falls as well as differences in the geometry of the male wrist, which might be more suited to resist a trauma to the wrist. 19
Assessing the Risk for Hip Fracture STRENGTH OF BONE Bone Turnover Bone Mass Fall-Related Trauma Risk of Fall Neuromuscular Function Environmental Hazards Time Spent at Risk Bone Quality Force of Impact Type of Fall Protective Responses Energy Absorption As we look at the risk for hip fractures, which is the primary fracture that we are trying to reduce in our elderly population, we have to look at two aspects that are equally important in assessing the risk for hip fractures. We ve talked a lot about the strength of the bone and defined bone strength as being made up of components of bone mass as well as bone quality and bone turnover. The other side of the equation is related to falls, and here we see the risk of fall is very important in terms of assessing someone s risk for hip fracture. The type of fall, as well as the ability to absorb the energy of a fall, has a tremendous impact on whether or not the individual will fracture their hip. Our interventions, if they are to be successful, have to address both issues of bone strength as well as issues related to falls and trauma. 20
Determinants of Hip Fracture Risk Used with Permission: Cummings et al. NEJM 1995;332 No 12:767-73 We have very strong data that low bone density is a strong predictor of the risk of hip fractures. We also have very strong data that there are a number of additional risk factors that help us predict the risk of hip fracture. If we are able to combine these two aspects, both low bone density and additional risk factors for fracture, we are much more able to predict the risk of subsequent fractures in an individual patient. This is shown very nicely in a threedimensional diagram by Cummings et al. that looks at the relative risk of hip fractures when we incorporate both low bone density and other risk factors. Individuals with low bone density have a relatively higher risk for fractures when compared to a population with normal bone density. Individuals with low bone density and multiple additional risk factors for fracture have the highest risk for hip fracture. 21
Risk Factors Associated with Hip Fracture Relative risk Age (per 5 yrs) 1.4 Hx maternal hip fx 1.8 Any fracture since 50 1.5 Calcaneal BMD (1 SD decrease) 1.6 On feet < 4 hrs/day 1.7 Inability to rise from chair 1.7 Reduced depth perception 1.4 Current use benzodiazepine 1.6 Walk for exercise 0.7 Cummings et al. NEJM 1995;332 No 12:767-73 The risk factors associated with hip fracture have become very clear over the last 20 years. Things that are important in terms of determining someone s risk for hip fracture included advancing age, history of maternal fracture, any fracture since the age of 50, low bone density, and a number of other risk factors that really have to do with the patient s risk of falling things like inability to get up from the chair, poor vision, and use of medications that might make a person at higher risk for falling. 22
Osteoporosis Detection BMD Radiography Subjective, insensitive Vertebral QCT Expensive, higher radiation dose, high CV Primarily used for spine measurements Dual energy x-ray absorptiometry (DXA) Accurate, safe, multiple sites, low CV Machines for all sites: spine, hip, radius, calcaneus, phalanx Ultrasound Safe, low CV, no radiation, estimate of structure? Machines for calcaneus, tibia, phalanges We have a number of ways to determine bone density. This has gone through several advances over the last 20 years, and we continue to have improvements in the methods to measure bone density as an objective measurement of risk for osteoporotic fractures. Plain radiographs are valuable to evaluate for fractures, but they are very subjective and very insensitive to determine if somebody has osteoporosis. Quantitative CT scans have been used for many years and are very valuable, particularly when looking at the spine, as well as looking at newer components of bone quality such as bone geometry. The primary modality in most clinical settings for determining bone mineral density is known as DXA. DXA stands for Dual energy X-ray Absorptiometry. The newer DXA machines are very accurate, very fast, and can measure a number of anatomical sites, including the spine, the hip, the distal radius, and whole body bone mineral density. Ultrasound is another modality that is being used to estimate bone density primarily at sites such as the heel. Ultrasound can be done without any radiation exposure. 23
Measuring BMD at Any Site Can Predict the Risk of Hip Fracture Relative Risk of Hip Fracture per 1 SD Decrease Below Age-Adjusted Mean 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Risk of Hip Fracture Approximately Doubles for Each 1 SD Below the Age-Adjusted Mean 2.6 1.6 Adapted From Marshall D et al. BMJ. 1996;312:1254 1259 2.1 Hip Lumbar Spine Proximal Radius BMD Measurement Site 1.8 Distal Radius 2.0 Heel It is important to note that low bone density at any anatomical site has been well documented to be a risk factor for hip fractures. Therefore, whether we measure the spine, the heel, or the hip, if a person has low bone density at any site, it can help us predict the risk of hip fracture. It makes sense that the best place to determine the risk of hip fracture is to do a measurement of the hip itself. And indeed the hip has the strongest correlation in terms of relative risk per standard deviation below age-adjusted mean BMD for hip fracture compared to the other anatomical sites. 24
Calcaneal Ultrasound Inexpensive screening device Cannot be used to follow patients T-scores are not equivalent to DXA of hip/spine (T-Score of -1 on a heel ultrasound represents low bone mass) No radiation safety requirements Ultrasound has a lot of potential in that it can be used as a very inexpensive screening device. Ultrasound can be used in settings where there are no issues about radiation safety. It can be used in health fairs in urban settings or as a screening device in rural areas where quantitative CT scans or DXA machines are not available. It is important that we acknowledge peripheral machines such as heel ultrasound should not be used for following patients. The error on most peripheral devices is too high to allow us to use them to compare a baseline to a follow-up study down the road. It is also important to know that the T-scores that are reported on the various peripheral machines do not correlate to the equivalent of the T-score of a DXA machine, which is traditionally done of the hip and the spine. Most clinicians feel that peripheral devices such as ultrasound machines should be used primarily as a screening device, and those patients who are low should be potentially referred for central DXA of the hip or the spine or quantitative CT scan of the spine if that is what is available locally. 25
DXA: Gold Standard for BMD Measurement Low Radiation Exposure Fast Scan Time Patient Comfort with single position Ability to assess vertebral morphometry to determine if prevalent vertebral fractures exist Dual energy X-ray absorptiometry, or DXA, is the gold standard at this time for bone mineral density measurement. It is used both as a diagnostic tool to help guide treatment decisions as well as being used in the majority of clinical research in osteoporosis. The advantages of DXA on the newer machines include low radiation exposure, very fast scan time, and relative patient comfort with the scan being able to be done in a single position. The error on most DXA machines is probably 1% to 3% if they are well calibrated and performed in a center that does considerable volume of studies with an excellent technician. 26
Vertebral Morphometry + + + + + + One of the newer advances in osteoporosis diagnosis and treatment is the ability to look at vertebral morphometry. The DXA machines that are equipped with this additional ability are able to give us a digital image of the thoracic and lumbar spine, and we are able to determine if the individual patient has a prevalent vertebral fracture. This information is digitalized and quantified by careful measurements of the vertebral body in the posterior, mid, and anterior portions of the vertebral body. The importance of prevalent vertebral fractures has become very apparent in our clinical practice. We know that if an individual with osteoporosis already has one vertebral fracture, the risk of acquiring a second vertebral fracture within the next year is approximately 20% if they are not placed on osteoporosis treatment. Therefore, this piece of information, coupled with the bone density result, can be a very valuable tool in assessing clinical risk factors for subsequent fractures in an individual patient. This slide shows us an example of a vertebral morphometry technique, known as instant vertebral assessment, in a patient with prevalent fracture of L1. 27
BMD Reference Curve Employing T- and Z-Scores Young adult peak BMD value Reference curve BMD Age-matched BMD value T-Score Z-Score Measured BMD value Age Bone density values are reported using standard deviations away from the mean of either an age-matched population or a population of young adults who have achieved a normal peak bone mass. When we compare our elderly patients to other patients of their same age, we call this a Z-score. When we compare anybody s bone mass to a healthy 30-year-old mean bone mass, we call this a T-score. In general, the majority of our references in terms of fracture risk are related to a T-score, which is comparing our patients to a population of healthy, young, 30-year-olds with normal bone mass. 28
Relationship of Age to Fracture Risk Any Low-trauma Non-spine Fracture 5-Year Fracture Risk, % 40 35 30 25 20 15 10 5 0 50 55 60 65 70 75 80 85-3.5-3.0-2.5-2.0-1.5-1.0 Age Used with Permission Cummings SR et al, JAMA 2002;288:1889-1897 It is important to note that the relationship of fracture risk to T-score is not a constant, and it changes with different ages. For example, a patient who has a T-score of 2.5 who is 80 years old has approximately a 23% five-year fracture risk. On the other hand, the patient who is 60 years old with the same score of 2.5 has approximately a 14% five-year fracture risk; therefore, it is very difficult to assign specific fracture risk to a T-score without considering age. 29
WHO Osteoporosis Classification for DEXA of Hip and Spine (T-scores) Standard deviations From Young Normals -1-2.5 Normal Osteopenia Osteoporosis WHO definition Applies only to PM Women and Central DXA results 20 60 80 40 Age (yrs) Kanis, JA. Osteoporosis Int. 1994 Nov;4(6):368-91 The World Health Organization has developed a classification for bone densities of the hip and the spine to define osteoporosis on the basis of bone density. Any patient who has a T-score within one standard deviation from the young, healthy, peak normal bone mass would be considered normal; and any patient who is more than 2.5 standard deviations below the young, healthy mean bone mineral density value would be considered to have osteoporosis. It is important to note that the WHO definition of osteoporosis truly only applies to post-menopausal women and only applies when using DXA of the hip and the spine. The very large category of patients who fall within the mid range of osteopenia between a T-score of 1 and 2.5 are probably some of the most difficult patients for us to make clinical decisions about. Someone who has a bone mineral density of 1.1 for instance should be looked at much differently than somebody who has a bone density result of 2.4. Additionally, someone who has a mid-range bone density but has many clinical risk factors for fracture would be looked at differently than someone who has no additional risk factors for fracture. It is important that we use bone mineral density values from our DXA reports in our clinical decision making, but make sure we understand the additional risk factors, which are also predictive of fracture risk. 30
Who to Treat with Pharmacologic Therapy? Fracture or T-score -2.5 or below T-score -1.5 to -2.5 T-score above -1.5 Treat with prescription medication Consider treatment if there are risk factors General preventive measures Based on Hodgson SF and Watts NB. AACE Osteoporosis Guidelines Endocrine Practice 2003: Who we treat with pharmacologic therapy is a very challenging area. A number of organizations have come out with good clinical guidelines. The American Association of Clinical Endocrinologists has come up with very reasonable clinical guidelines about recommendations for treatment with pharmacological therapy for patients depending on their bone density values as determined by central DXA. The recommendations include that anybody who has a bone density of 1.5 or above should be treated with general preventive measures such as encouragement of adequate calcium, vitamin D, and weight-bearing exercises. Any patient who has already had an osteoporotic fracture or whose T-score is below 2.5 should be recommended to start pharmacologic therapy to stabilize their bone mass and to potentially reduce their risks of subsequent fractures. Again, the range from approximately 1.5 to 2.5 is the more challenging range, and it is here where the clinician has to be very tuned in to additional risk factors to determine if this individual patient should be considered for pharmacological therapy. 31
Fracture Risk Reduction in Women with Postmenopausal Osteoporosis Agent Calcitonin (Miacalcin ) Raloxifene (Evista ) Alendronate (Fosamax ) Risedronate (Actonel ) Teriparatide (Forteo ) HRT (Prempro ) Vertebral Fx Nonvert Fx X X Hip Fx??? We have a number of pharmacologic therapies that have been approved and that have been validated in large clinical trials to reduce the subsequent rate of fractures in high-risk, postmenopausal osteoporotic women. These agents that have shown efficacy in reducing vertebral fractures include calcitonin, raloxifene, alendronate, teriparatide, and estrogen replacement therapy most recently as evidenced by the Women s Health Initiative in the form of estrogen and progesterone. At least three agents have been shown to reduce the subsequent development of hip fractures, and these include the two bisphosphonates, alendronate and risedronate, and again estrogen, as evidenced by the reduction in hip fractures in the Women s Health Initiative. 32
Conclusion Optimizing bone health and reducing the development of osteoporosis and osteoporotic fractures requires an approach that incorporates adequate nutritional support for the growing skeleton and the mature skeleton. Determining risk for fracture by measuring bone density and by incorporating additional risk factors for osteoporosis will allow us to appropriately identify patients at highest risk for fracture for pharmacologic therapy. When properly prescribed, pharmacologic therapies for osteoporosis are both effective and safe. As we develop more pharmacologic therapies, we will be able to individualize the choice of therapy based on the patient s needs. Optimizing bone health and reducing the development of osteoporosis and osteoporotic fractures requires an approach that incorporates adequate nutritional support for the growing skeleton and the mature skeleton. Determining risks for fracture by measuring bone density and incorporating additional risk factors for osteoporosis will allow us to appropriately identify patients at highest risk for fracture for pharmacologic therapy. When properly prescribed, pharmacologic therapies for osteoporosis are both effective and safe. As we develop more pharmacologic therapies for osteoporosis, we will be able to individualize the choice of therapy based on the patient s needs. 33