Osteoporosis 2012 Update and Review of Current Controversies

Osteoporosis 2012 Update and Review of Current Controversies
Thomas Repas DO FACP FACOI FNLA FACE CDE Clinical Assistant Professor, Dept. of Internal Medicine, University of South Dakota, Sanford School of Medicine Board Certified: Endocrinology, Diabetes and Metabolism Clinical Lipidology Nutrition Internal Medicine Regional Medical Clinic Aspen Centre- Endocrinology 640 Flormann Street Rapid City, South Dakota

Objectives Brief review of pathophysiology, diagnosis and prevalence of osteoporosis Understand the concept of fracture risk and how it should be applied to therapeutic decision-making Identify current treatment options: Non-pharmacologic Medications Discuss controversies in osteoporosis Adverse events: ONJ, Atypical femur fractures Bisphosphonate Holidays? Use of bone turnover markers? How often should follow-up DXAs be performed?

Pathophysiology and prevalence
Osteoporosis Pathophysiology and prevalence

Osteoporosis: Definition
“Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture.” Osteoporosis: Definition The hallmark of osteoporosis is microarchitectural degeneration of bone tissue.1,2 The rate of bone resorption exceeds the rate of bone formation in older adults, particularly in postmenopausal women. Osteoporosis results from this imbalance between bone resorption and formation. Bone mass is lost, density is reduced, and bones become fragile, thin, and brittle. In the United States, a National Institutes of Health (NIH) consensus conference developed a definition of osteoporosis that embraced similar concepts3: “Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture.” References Eastell R. Treatment of postmenopausal osteoporosis. N Engl J Med. 1998;338: Follin SL, Hansen LB. Current approaches to the prevention and treatment of postmenopausal osteoporosis. Am J Health Syst Pharm. 2003;60: NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001;285: NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy.. JAMA. 2001;285:

Fracture Risk Depends on Bone Strength
Decreased bone mass Increased cortical porosity Reduced bone strength/ Increased fracture risk Increased bone turnover Disrupted trabecular connectivity Fracture Resistance Depends on Bone Strength As we saw earlier, fracture resistance depends on bone strength, which is highly dependent on bone turnover. An often unrecognized factor influencing bone turnover is vitamin D insufficiency. Vitamin D insufficiency increases bone turnover.1 Is there a gap in nutrition for bone health? Calcium is widely recognized as essential, but… vitamin D is necessary for calcium absorption; the role of vitamin D in bone health is being increasingly recognized. The few sources of vitamin D include fortified milk, fortified orange juice, salmon and other fatty fish, and vitamin supplements.2 References: 1. Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Endocr Rev. 2001;22:477–501. 2. National Academy of Sciences. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: Institute of Medicine, National Academy Press, 1997. Decreased mineralization Lips P. Endocr Rev. 2001;22(4):477–501.

Clinical Presentation of Osteoporosis
Usually asymptomatic until fracture occurs Clinical signs and symptoms: Low-trauma fragility fractures of spine, wrist or hip Loss of height Kyphosis Acute or chronic pain Diagnostic studies Bone mineral density assessment X-rays or morphometry Clinical Presentation of Osteoporosis Osteoporosis is usually asymptomatic until fractures occur. Common presenting signs and symptoms of osteoporosis are provided here, along with the key tests used in diagnosis ReferenceBone Health and Osteoporosis: A Report of the Surgeon General. Rockville, Md: US Department of Health and Human Services; 2004: Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, Md: US Department of Health and Human Services; 2004:

Bone Remodeling Cycle in Normal Bone
Resorption Osteoclasts digest bone within a sealed resorption vacuole Bone Resting Reversal Apoptotic osteoclasts Preosteoblasts Bone Bone Mature osteoblasts building osteoid tissue Mineralization Formation Bone Lining cells Illustration Copyright ©2009 Nucleus Medical Art, All rights reserved.

Why Bone Remodeling? Allows skeleton to Respond to mechanical loading
Repair and prevent microdamage (“wear & tear”) Maintains quality control Release growth factors and minerals (calcium and phosphate) stored in matrix into circulation All bone cells participate in remodeling Considerable energy expended to remodel the skeleton

Osteoporosis: Factors that increase risk of fracture
Genetic or nonmodifiable Age Female sex Asian or white ethnic origin Previous fragility fracture Family history of hip fracture Small frame Potentially modifiable Estrogen deficiency and menopause Low body weight Calcium and vitamin D deficiency Inadequate physical activity Excessive alcohol intake Cigarette smoking Long-term glucocorticoid use Risk Factors for Osteoporotic Fractures Genetic or nonmodifiable risk factors for osteoporotic fractures include: Age Female sex Asian or white ethnic origin Previous fragility fracture Family history of hip fracture Small frame Major risk factors for osteoporosis that are potentially modifiable include: Menopause-related estrogen deficiency Low body weight Calcium and vitamin D deficiency Inadequate physical activity Excessive alcohol intake Cigarette smoking Long-term glucocorticoid use Factors demonstrated to confer additional fracture risk independent of BMD include age, previous fragility fracture, family history of hip fracture, neuromuscular disorders, low body weight, poor visual acuity, cigarette smoking, and long-term glucocorticoid use. Reference National Osteoporosis Foundation. Fast facts on osteoporosis. Available at: Accessed August 13, 2007. National Osteoporosis Foundation. Fast facts on osteoporosis. Available at: Accessed August 13, 2007.

Annual Incidence of Osteoporotic Fractures in US
Osteoporosis is a major public health threat with serious clinical consequences 1.5 million fractures annually in the United States One hip fracture increases the risk of a second hip fracture fourfold. Annual Incidence (US) of Osteoporotic Fractures Osteoporosis leads to more than 1.5 million fractures each year in the United States alone. These include At least 300,000 hip fractures About 700,000 vertebral fractures Approximately 250,000 wrist fractures An estimated 300,000 fractures at other sites One hip fracture increases the risk of a second hip fracture by a factor of 4. Osteoporosis is a major public health threat with serious clinical consequences. Reference National Osteoporosis Foundation. Fast Facts on Osteoporosis. Available at: Accessed February 7, 2007. National Osteoporosis Foundation. Fast facts on osteoporosis. Available at: Accessed February 7, 2007.

Consequences of Fractures
Vertebral fractures Severe back pain Kyphosis and height loss Hip fracture Loss of ambulatory status (30%) Admission to chronic care facility Death All fractures are associated with increased risk for future fractures Burden on society in terms of public health, health care resources, direct and indirect costs This slide shows an aging woman with osteoporosis suffering from dorsal kyphosis – note that she used to stand taller than her daughter, who is standing behind her in this photograph. Vertebral fractures have significant consequences for patients, including increased mortality risk. Collapsed vertebrae may initially present in the form of severe back pain, loss of height, or spinal deformities such as kyphosis or stooped posture.1 Fragility fractures of the vertebrae are associated with significant disability, pain, deformity, increased morbidity and mortality, and a greatly increased risk for future fracture at any skeletal site.2 These consequences of vertebral, nonvertebral, and hip fractures have a significant impact on the patient’s health and quality of life. In addition, they place a significant burden on society in terms of public health, health care resources, direct medical costs such as surgical procedures, and indirect medical costs such as lost productivity.1-3 References National Osteoporosis Foundation. Fast Facts on Osteoporosis. Available at: Accessed August 13, 2007. Delmas PD, van de Langerijt L, Watts NB, for the IMPACT Study Group. Underdiagnosis of vertebral fractures is a worldwide problem: the IMPACT study. J Bone Miner Res. 2005;20: Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, Tosteson A. Incidence and economic burden of osteoporosis-related fractures in the United States, J Bone Miner Res. 2007;22: . National Osteoporosis Foundation. Fast Facts on Osteoporosis. Available at: Accessed August 13, 2007. Delmas PD, van de Langerijt L, Watts NB, J Bone Miner Res. 2005;20: Burge R, Dawson-Hughes B, et al .. J Bone Miner Res. 2007;22:

1-Year Risk of Refracture in Patients With Incident Vertebral Fracture
Lindsay and colleagues performed an analysis on placebo patients from one of the pivotal clinical trials in the risedronate development program to quantify the subsequent fracture and cost outcomes in patients with a prevalent vertebral fracture. Using Kaplan-Meier time-to-event models, they determined the cumulative incidence or probabilities of all fractures within one year of an incident vertebral fracture. Results of their analysis revealed that 26.1% of the overall population (mean age, 74 years) refractured at any site within 1 year. 17.4% of patients experienced a new vertebral fracture. 3.6% experienced a hip fracture. 1.6% experienced a fracture of the forearm or wrist. 3.6% experienced a fracture at another site, such as the humerus or leg. Because of the significance of incidence of subsequent fractures at any site following an incident vertebral fracture, the authors stress the importance of providing interventions for patients that can provide proven, rapid efficacy in the prevention of future fragility fractures. Reference Lindsay R, Burge RT, Strauss DM. One year outcomes and costs following a vertebral fracture. Osteoporos Int. 2005;16:78-85. Lindsay R, Burge RT, Strauss DM. One year outcomes and costs following a vertebral fracture. Osteoporos Int. 2005;16:78-85.

Osteoporosis: Prevalence
10 million in the US have established osteoporosis. 34 million additional people have low bone mass (osteopenia) Epidemiology of Osteoporosis in the US According to the National Osteoporosis Foundation, 44 million Americans, 80% of whom are women, are threatened by osteoporosis. This includes 55% of people aged 50 years and older.1 10 million have established osteoporosis.2 34 million additional people have osteopenia (low bone mass), which places them at increased risk for osteoporosis.2 By 2010, more than 52 million men and women will likely be affected by osteoporosis or osteopenia.2 12 million will have established osteoporosis. 40 million will have osteopenia. By 2020, 61 million may have osteoporosis/osteopenia.2 14 million will have established osteoporosis. 47 million will have osteopenia. Osteoporosis leads to more than 1.5 million fractures annually in the United States, and it is anticipated that this number will continue to increase as the population ages.1 References National Osteoporosis Foundation. Fast facts on osteoporosis. Available at: Accessed February 7, 2007. National Osteoporosis Foundation. Advocacy: news & updates. Available at: Accessed February 7, 2007. National Osteoporosis Foundation. Fast facts on osteoporosis. Available at: Accessed February 7, 2007.

Osteoporosis: Prevalence
By 2020, 61 million may have osteoporosis or low bone mass 14 million with established osteoporosis. 47 million with low bone mass. Epidemiology of Osteoporosis in the US According to the National Osteoporosis Foundation, 44 million Americans, 80% of whom are women, are threatened by osteoporosis. This includes 55% of people aged 50 years and older.1 10 million have established osteoporosis.2 34 million additional people have osteopenia (low bone mass), which places them at increased risk for osteoporosis.2 By 2010, more than 52 million men and women will likely be affected by osteoporosis or osteopenia.2 12 million will have established osteoporosis. 40 million will have osteopenia. By 2020, 61 million may have osteoporosis/osteopenia.2 14 million will have established osteoporosis. 47 million will have osteopenia. Osteoporosis leads to more than 1.5 million fractures annually in the United States, and it is anticipated that this number will continue to increase as the population ages.1 References National Osteoporosis Foundation. Fast facts on osteoporosis. Available at: Accessed February 7, 2007. National Osteoporosis Foundation. Advocacy: news & updates. Available at: Accessed February 7, 2007. National Osteoporosis Foundation. Fast facts on osteoporosis. Available at: Accessed February 7, 2007.

Osteoporosis is underdiagnosed
Among 10,291 hospitalized women with chest radiographs, 142 (1.4%) had vertebral fractures. 41% had fracture noted in the x-ray report. 16% had fracture noted on discharge summary. 13% were given an initial prescription for osteoporosis therapy at discharge Osteoporosis is Underdiagnosed Osteoporosis is not recognized often enough in clinical practice In fact, many patients who receive chest x-rays for any reason have signs of vertebral fractures that are often missed by their physicians. Recognition of osteoporosis is also suboptimal in the hospital setting. In a 2006 study, hospital and outpatient records were reviewed for patients who had vertebral fractures on inpatient chest x-ray. Among 10,291 women with chest radiographs, 142 (1.4%) had vertebral fractures. Of these, 58 (41%) had their fracture noted in the findings section but not in the final x-ray summary. Only 23 (16%) discharge summaries documented a vertebral fracture. At discharge, only 13% of these patients were given an initial prescription for osteoporosis therapy. Reference Morris CA, Carrino JA, Lang P, et al. Incidental vertebral fractures on chest radiographs. Recognition, documentation, and treatment. J Gen Intern Med. 2006;21: Morris CA, Carrino JA, Lang P, et al. Incidental vertebral fractures on chest radiographs. Recognition, documentation, and treatment. J Gen Intern Med. 2006;21:

Diagnosis, fracture risk assessment and therapeutic decision-making
Osteoporosis Diagnosis, fracture risk assessment and therapeutic decision-making

ISCD: Indications for Bone Mineral Density (BMD) Testing
Women aged 65 and older Postmenopausal women under age 65 with risk factors for fracture. Women during the menopausal transition with clinical risk factors for fracture, such as low body weight, prior fracture, or high-risk medication use. Men aged 70 and older. Men under age 70 with risk factors for fracture. 2007 ISCD Official Positions 2007 ISCD Official Positions

ISCD: Indications for BMD Testing -continued-
Adults with a fragility fracture. Adults with a disease or condition associated with low bone mass or bone loss. Adults taking medications associated with low bone mass or bone loss. Anyone being considered for pharmacologic therapy. Anyone being treated, to monitor treatment effect. Anyone not receiving therapy in whom evidence of bone loss would lead to treatment 2007 ISCD Official Positions 2007 ISCD Official Positions .

Bone Density Criteria for Diagnosing Osteoporosis
T-score = units of standard deviation (SD) that a patient’s BMD is above or below mean peak bone mass for a young adult, measured at the spine or hip. Reduction in T-score by 1 SD is equivalent to a 10% to 12% decrease in BMD. Generally, a change in T-score by 1 SD increases a person’s fracture risk by 1.5 to 2.5-fold. This slide depicts the criteria for diagnosing osteoporosis developed by the World Health Organization, categorized according to bone mineral density Four general diagnostic categories for women are generally recognized, based on the results of BMD scanning. The BMD is categorized as normal when the BMD value is within 1 standard deviation (SD) of the young adult reference mean, denoted as a T-score of -1 or above. A patient is said to have osteopenia, or low bone mass, if the BMD is more than 1 SD below the young adult mean but less than 2.5 SD below this value, denoted as a T-score between 1 and 2.5. Osteoporosis is diagnosed when a BMD value of 2.5 SD or more below the young adult mean is present, denoted as T-score lower than 2.5. Severe, or established, osteoporosis is the diagnosis when a patient has a BMD of 2.5 SD or more below the young adult mean and/or one or more fragility fractures. Reduction in T-score by 1 SD is equivalent to a 10% to 12% decrease in BMD. Generally, a change in T-score by 1 SD increases a person’s fracture risk by 1.5 to 2.5-fold. T-score = units of standard deviation (SD) that a patient’s BMD is above or below mean peak bone mass for a young adult woman, measured at the spine or hip. However, if a patient develops a fragility fracture, it is diagnostic for osteoporosis regardless of the T-score. Reference Prevention and Management of Osteoporosis. Report of a WHO Scientific Group. WHO Technical Report Series 921. Geneva: World Health Organization, 2003. Prevention and Management of Osteoporosis. Report of a WHO Scientific Group. WHO Technical Report Series 921. Geneva: World Health Organization, 2003.

Bone Density Criteria for Diagnosing Osteoporosis
Normal BMD: T-score of -1 or above. Low bone mass (osteopenia) : T-score between 1 and 2.5. Osteoporosis: T-score lower than 2.5. Severe, or established, osteoporosis: T- score lower than 2.5 with fragility fractures. This slide depicts the criteria for diagnosing osteoporosis developed by the World Health Organization, categorized according to bone mineral density Four general diagnostic categories for women are generally recognized, based on the results of BMD scanning. The BMD is categorized as normal when the BMD value is within 1 standard deviation (SD) of the young adult reference mean, denoted as a T-score of -1 or above. A patient is said to have osteopenia, or low bone mass, if the BMD is more than 1 SD below the young adult mean but less than 2.5 SD below this value, denoted as a T-score between 1 and 2.5. Osteoporosis is diagnosed when a BMD value of 2.5 SD or more below the young adult mean is present, denoted as T-score lower than 2.5. Severe, or established, osteoporosis is the diagnosis when a patient has a BMD of 2.5 SD or more below the young adult mean and/or one or more fragility fractures. Reduction in T-score by 1 SD is equivalent to a 10% to 12% decrease in BMD. Generally, a change in T-score by 1 SD increases a person’s fracture risk by 1.5 to 2.5-fold. T-score = units of standard deviation (SD) that a patient’s BMD is above or below mean peak bone mass for a young adult woman, measured at the spine or hip. However, if a patient develops a fragility fracture, it is diagnostic for osteoporosis regardless of the T-score. Reference Prevention and Management of Osteoporosis. Report of a WHO Scientific Group. WHO Technical Report Series 921. Geneva: World Health Organization, 2003. Prevention and Management of Osteoporosis. Report of a WHO Scientific Group. WHO Technical Report Series 921. Geneva: World Health Organization, 2003.

Fragility Fracture and Osteoporosis
The presence of a fragility fracture is diagnostic for osteoporosis regardless of the T-score. Definition: A fracture that occurs spontaneously or with minimal trauma, such as due to a fall of one’s standing height or less. This slide depicts the criteria for diagnosing osteoporosis developed by the World Health Organization, categorized according to bone mineral density Four general diagnostic categories for women are generally recognized, based on the results of BMD scanning. The BMD is categorized as normal when the BMD value is within 1 standard deviation (SD) of the young adult reference mean, denoted as a T-score of -1 or above. A patient is said to have osteopenia, or low bone mass, if the BMD is more than 1 SD below the young adult mean but less than 2.5 SD below this value, denoted as a T-score between 1 and 2.5. Osteoporosis is diagnosed when a BMD value of 2.5 SD or more below the young adult mean is present, denoted as T-score lower than 2.5. Severe, or established, osteoporosis is the diagnosis when a patient has a BMD of 2.5 SD or more below the young adult mean and/or one or more fragility fractures. Reduction in T-score by 1 SD is equivalent to a 10% to 12% decrease in BMD. Generally, a change in T-score by 1 SD increases a person’s fracture risk by 1.5 to 2.5-fold. T-score = units of standard deviation (SD) that a patient’s BMD is above or below mean peak bone mass for a young adult woman, measured at the spine or hip. However, if a patient develops a fragility fracture, it is diagnostic for osteoporosis regardless of the T-score. Reference Prevention and Management of Osteoporosis. Report of a WHO Scientific Group. WHO Technical Report Series 921. Geneva: World Health Organization, 2003. Prevention and Management of Osteoporosis. Report of a WHO Scientific Group. WHO Technical Report Series 921. Geneva: World Health Organization, 2003.

BMD Reporting in Females Prior to Menopause and in Males < 50 yrs
Z-scores, not T-scores, are preferred. This is particularly important in children. Z-score of -2.0 or lower is defined as “below the expected range for age” Z-score above -2.0 is “within the expected range for age.” Osteoporosis cannot be diagnosed in men under age 50 on the basis of BMD alone. This slide depicts the criteria for diagnosing osteoporosis developed by the World Health Organization, categorized according to bone mineral density Four general diagnostic categories for women are generally recognized, based on the results of BMD scanning. The BMD is categorized as normal when the BMD value is within 1 standard deviation (SD) of the young adult reference mean, denoted as a T-score of -1 or above. A patient is said to have osteopenia, or low bone mass, if the BMD is more than 1 SD below the young adult mean but less than 2.5 SD below this value, denoted as a T-score between 1 and 2.5. Osteoporosis is diagnosed when a BMD value of 2.5 SD or more below the young adult mean is present, denoted as T-score lower than 2.5. Severe, or established, osteoporosis is the diagnosis when a patient has a BMD of 2.5 SD or more below the young adult mean and/or one or more fragility fractures. Reduction in T-score by 1 SD is equivalent to a 10% to 12% decrease in BMD. Generally, a change in T-score by 1 SD increases a person’s fracture risk by 1.5 to 2.5-fold. T-score = units of standard deviation (SD) that a patient’s BMD is above or below mean peak bone mass for a young adult woman, measured at the spine or hip. However, if a patient develops a fragility fracture, it is diagnostic for osteoporosis regardless of the T-score. Reference Prevention and Management of Osteoporosis. Report of a WHO Scientific Group. WHO Technical Report Series 921. Geneva: World Health Organization, 2003. 2007 ISCD Official Positions

WHO Fracture Risk Assessment Tool
AgeThe model accepts ages between 40 and 90 years. If ages below or above are entered, the programme will compute probabilities at 40 and 90 year, respectively.SexMale or female. Enter as appropriate.WeightThis should be entered in kg.HeightThis should be entered in cm.Previous fractureA previous fracture denotes more accurately a previous fracture in adult life occurring spontaneously, or a fracture arising from trauma which, in a healthy individual, would not have resulted in a fracture. Enter yes or no (see also notes on risk factors).Parent fractured hipThis enquires for a history of hip fracture in the patient's mother or father. Enter yes or no.Current smokingEnter yes or no depending on whether the patient currently smokes tobacco (see also notes on risk factors).GlucocorticoidsEnter yes if the patient is currently exposed to oral glucocorticoids or has been exposed to oral glucocorticoids for more than 3 months at a dose of prednisolone of 5mg daily or more (or equivalent doses of other glucocorticoids) (see also notes on risk factors).Rheumatoid arthritisEnter yes where the patient has a confirmed diagnosis of rheumatoid arthritis. Otherwise enter no (see also notes on risk factors).Secondary osteoporosisEnter yes if the patient has a disorder strongly associated with osteoporosis. These include type I (insulin dependent) diabetes, osteogenesis imperfecta in adults, untreated long-standing hyperthyroidism, hypogonadism or premature menopause (<45 years), chronic malnutrition, or malabsorption and chronic liver diseaseAlcohol 3 or more units/dayEnter yes if the patient takes 3 or more units of alcohol daily. A unit of alcohol varies slightly in different countries from 8-10g of alcohol. This is equivalent to a standard glass of beer (285ml), a single measure of spirits (30ml), a medium-sized glass of wine (120ml), or 1 measure of an aperitif (60ml) (see also notes on risk factors).Bone mineral density (BMD)(BMD) Please select the make of DXA scanning equipment used and then enter the actual femoral neck BMD (in g/cm2). Alternatively, enter the T-score based on the NHANES III female reference data. In patients without a BMD test, the field should be left blank (see also notes on risk factors) (provided by Oregon Osteoporosis Center). WHO Fracture Risk Assessment Tool

Risk Factors used in the WHO FRAX® tool
Enter Age, gender, height (cm), weight (kg). Previous fracture? a fracture in adult life occurring spontaneously, or arising from trauma which, in a healthy individual, would not have resulted in a fracture. Parent fractured hip? history of hip fracture in the patient's mother or father. Current smoking? This slide depicts the criteria for diagnosing osteoporosis developed by the World Health Organization, categorized according to bone mineral density Four general diagnostic categories for women are generally recognized, based on the results of BMD scanning. The BMD is categorized as normal when the BMD value is within 1 standard deviation (SD) of the young adult reference mean, denoted as a T-score of -1 or above. A patient is said to have osteopenia, or low bone mass, if the BMD is more than 1 SD below the young adult mean but less than 2.5 SD below this value, denoted as a T-score between 1 and 2.5. Osteoporosis is diagnosed when a BMD value of 2.5 SD or more below the young adult mean is present, denoted as T-score lower than 2.5. Severe, or established, osteoporosis is the diagnosis when a patient has a BMD of 2.5 SD or more below the young adult mean and/or one or more fragility fractures. Reduction in T-score by 1 SD is equivalent to a 10% to 12% decrease in BMD. Generally, a change in T-score by 1 SD increases a person’s fracture risk by 1.5 to 2.5-fold. T-score = units of standard deviation (SD) that a patient’s BMD is above or below mean peak bone mass for a young adult woman, measured at the spine or hip. However, if a patient develops a fragility fracture, it is diagnostic for osteoporosis regardless of the T-score. Reference Prevention and Management of Osteoporosis. Report of a WHO Scientific Group. WHO Technical Report Series 921. Geneva: World Health Organization, 2003. WHO Fracture Risk Assessment Tool

Glucocorticoids? is patient currently exposed to oral glucocorticoids or has been exposed to oral glucocorticoids for more than 3 months at a dose of prednisolone of 5mg daily or more (or equivalent doses of other glucocorticoids)? This slide depicts the criteria for diagnosing osteoporosis developed by the World Health Organization, categorized according to bone mineral density Four general diagnostic categories for women are generally recognized, based on the results of BMD scanning. The BMD is categorized as normal when the BMD value is within 1 standard deviation (SD) of the young adult reference mean, denoted as a T-score of -1 or above. A patient is said to have osteopenia, or low bone mass, if the BMD is more than 1 SD below the young adult mean but less than 2.5 SD below this value, denoted as a T-score between 1 and 2.5. Osteoporosis is diagnosed when a BMD value of 2.5 SD or more below the young adult mean is present, denoted as T-score lower than 2.5. Severe, or established, osteoporosis is the diagnosis when a patient has a BMD of 2.5 SD or more below the young adult mean and/or one or more fragility fractures. Reduction in T-score by 1 SD is equivalent to a 10% to 12% decrease in BMD. Generally, a change in T-score by 1 SD increases a person’s fracture risk by 1.5 to 2.5-fold. T-score = units of standard deviation (SD) that a patient’s BMD is above or below mean peak bone mass for a young adult woman, measured at the spine or hip. However, if a patient develops a fragility fracture, it is diagnostic for osteoporosis regardless of the T-score. Reference Prevention and Management of Osteoporosis. Report of a WHO Scientific Group. WHO Technical Report Series 921. Geneva: World Health Organization, 2003. WHO Fracture Risk Assessment Tool

Rheumatoid arthritis? Secondary osteoporosis? Does the patient have a disorder strongly associated with osteoporosis. This includes type I (insulin dependent) diabetes, osteogenesis imperfecta in adults, untreated long-standing hyperthyroidism, hypogonadism or premature menopause (<45 years), chronic malnutrition, or malabsorption and chronic liver disease Alcohol 3 or more units/day Enter yes if the patient takes 3 or more units of alcohol daily. A unit of alcohol varies slightly in different countries from 8-10g of alcohol. This is equivalent to a standard glass of beer (285ml), a single measure of spirits (30ml), a medium-sized glass of wine (120ml), or 1 measure of an aperitif (60ml) (see also notes on risk factors). Bone mineral density (BMD) (BMD) Please select the make of DXA scanning equipment used and then enter the actual femoral neck BMD (in g/cm2). Alternatively, enter the T-score based on the NHANES III female reference data. In patients without a BMD test, the field should be left blank (see also notes on risk factors) (provided by Oregon Osteoporosis Center). This slide depicts the criteria for diagnosing osteoporosis developed by the World Health Organization, categorized according to bone mineral density Four general diagnostic categories for women are generally recognized, based on the results of BMD scanning. The BMD is categorized as normal when the BMD value is within 1 standard deviation (SD) of the young adult reference mean, denoted as a T-score of -1 or above. A patient is said to have osteopenia, or low bone mass, if the BMD is more than 1 SD below the young adult mean but less than 2.5 SD below this value, denoted as a T-score between 1 and 2.5. Osteoporosis is diagnosed when a BMD value of 2.5 SD or more below the young adult mean is present, denoted as T-score lower than 2.5. Severe, or established, osteoporosis is the diagnosis when a patient has a BMD of 2.5 SD or more below the young adult mean and/or one or more fragility fractures. Reduction in T-score by 1 SD is equivalent to a 10% to 12% decrease in BMD. Generally, a change in T-score by 1 SD increases a person’s fracture risk by 1.5 to 2.5-fold. T-score = units of standard deviation (SD) that a patient’s BMD is above or below mean peak bone mass for a young adult woman, measured at the spine or hip. However, if a patient develops a fragility fracture, it is diagnostic for osteoporosis regardless of the T-score. Reference Prevention and Management of Osteoporosis. Report of a WHO Scientific Group. WHO Technical Report Series 921. Geneva: World Health Organization, 2003. WHO Fracture Risk Assessment Tool

Alcohol 3 or more units/day? A unit of alcohol is equivalent to a standard glass of beer (285ml), a single measure of spirits (30ml), a medium-sized glass of wine (120ml), or 1 measure of an aperitif (60ml) Bone mineral density (BMD): select the make of DXA scanning equipment used and then enter the actual femoral neck BMD (in g/cm2) or the T-score This slide depicts the criteria for diagnosing osteoporosis developed by the World Health Organization, categorized according to bone mineral density Four general diagnostic categories for women are generally recognized, based on the results of BMD scanning. The BMD is categorized as normal when the BMD value is within 1 standard deviation (SD) of the young adult reference mean, denoted as a T-score of -1 or above. A patient is said to have osteopenia, or low bone mass, if the BMD is more than 1 SD below the young adult mean but less than 2.5 SD below this value, denoted as a T-score between 1 and 2.5. Osteoporosis is diagnosed when a BMD value of 2.5 SD or more below the young adult mean is present, denoted as T-score lower than 2.5. Severe, or established, osteoporosis is the diagnosis when a patient has a BMD of 2.5 SD or more below the young adult mean and/or one or more fragility fractures. Reduction in T-score by 1 SD is equivalent to a 10% to 12% decrease in BMD. Generally, a change in T-score by 1 SD increases a person’s fracture risk by 1.5 to 2.5-fold. T-score = units of standard deviation (SD) that a patient’s BMD is above or below mean peak bone mass for a young adult woman, measured at the spine or hip. However, if a patient develops a fragility fracture, it is diagnostic for osteoporosis regardless of the T-score. Reference Prevention and Management of Osteoporosis. Report of a WHO Scientific Group. WHO Technical Report Series 921. Geneva: World Health Organization, 2003. WHO Fracture Risk Assessment Tool

WHO Fracture Risk Assessment Tool
AgeThe model accepts ages between 40 and 90 years. If ages below or above are entered, the programme will compute probabilities at 40 and 90 year, respectively.SexMale or female. Enter as appropriate.WeightThis should be entered in kg.HeightThis should be entered in cm.Previous fractureA previous fracture denotes more accurately a previous fracture in adult life occurring spontaneously, or a fracture arising from trauma which, in a healthy individual, would not have resulted in a fracture. Enter yes or no (see also notes on risk factors).Parent fractured hipThis enquires for a history of hip fracture in the patient's mother or father. Enter yes or no.Current smokingEnter yes or no depending on whether the patient currently smokes tobacco (see also notes on risk factors).GlucocorticoidsEnter yes if the patient is currently exposed to oral glucocorticoids or has been exposed to oral glucocorticoids for more than 3 months at a dose of prednisolone of 5mg daily or more (or equivalent doses of other glucocorticoids) (see also notes on risk factors).Rheumatoid arthritisEnter yes where the patient has a confirmed diagnosis of rheumatoid arthritis. Otherwise enter no (see also notes on risk factors).Secondary osteoporosisEnter yes if the patient has a disorder strongly associated with osteoporosis. These include type I (insulin dependent) diabetes, osteogenesis imperfecta in adults, untreated long-standing hyperthyroidism, hypogonadism or premature menopause (<45 years), chronic malnutrition, or malabsorption and chronic liver diseaseAlcohol 3 or more units/dayEnter yes if the patient takes 3 or more units of alcohol daily. A unit of alcohol varies slightly in different countries from 8-10g of alcohol. This is equivalent to a standard glass of beer (285ml), a single measure of spirits (30ml), a medium-sized glass of wine (120ml), or 1 measure of an aperitif (60ml) (see also notes on risk factors).Bone mineral density (BMD)(BMD) Please select the make of DXA scanning equipment used and then enter the actual femoral neck BMD (in g/cm2). Alternatively, enter the T-score based on the NHANES III female reference data. In patients without a BMD test, the field should be left blank (see also notes on risk factors) (provided by Oregon Osteoporosis Center). WHO Fracture Risk Assessment Tool

NOF Criteria for Initiating Medical Therapy for Low Bone Mass and Osteoporosis
A hip or vertebral (clinical or morphometric) fracture T-score ≤ -2.5 at the femoral neck or spine after evaluation excluding secondary causes Low bone mass (T-score -1.0 to-2.5 at the femoral neck or spine) AND a 10-year probability of a hip fracture ≥ 3% OR a 10-year probability of a major osteoporosis-related fracture ≥ 20% Clinicians judgment and/or patient preferences also must also be taken into consideration NOF Clinician's Guide to Prevention and Treatment of Osteoporosis: NOF Clinician's Guide to Prevention and Treatment of Osteoporosis:

Current therapeutic options
Osteoporosis Current therapeutic options

Preventing and Treating Osteoporosis
Pharmacotherapy (antiresorptives and anabolics) Address Secondary Factors (drugs and diseases) Lifestyle Changes (nutrition, physical activity, and fall prevention) Osteoporosis Prevention and Treatment US Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. US Dept of Health and Human Services, Office of the Surgeon General; 2004.

Measures to Prevent Bone Loss
Maintain adequate calcium intake; use calcium supplements, if needed, to meet minimal required intake Maintain adequate vitamin D intake; supplement vitamin D, if needed, to maintain serum levels of 25- OH vit D between 30 and 60 ng/mL Limit alcohol intake to no more than 2 servings/day Limit caffeine intake Avoid or stop smoking Maintain an active lifestyle, including weight bearing exercises for at least 30 minutes daily American Association of Clinical Endocrinologists Guidelines for Clinical Practice for the Diagnosis and Treatment of Postmenopausal Osteoporosis © 2010 .

Non-Pharmacologic Treatment of Osteoporosis
All the previous measures plus the following: Maintain adequate protein intake Use proper body mechanics Consider the use of hip protectors in individuals with a high risk of falling Take measures to reduce the risk of falling Consider referral for physical therapy and occupational therapy American Association of Clinical Endocrinologists Guidelines for Clinical Practice for the Diagnosis and Treatment of Postmenopausal Osteoporosis © 2010 .

Measures to Prevent Falls
Anchor rugs, use nonskid mats, remove loose wires and minimize clutter Install handrails in bathrooms, halls, and long stairways Light hallways, stairwells, and entrances Encourage patient to wear sturdy, low-heeled shoes Recommend hip protectors for patients who are predisposed to falling American Association of Clinical Endocrinologists Guidelines for Clinical Practice for the Diagnosis and Treatment of Postmenopausal Osteoporosis © 2010 .

Before Starting Medication Consider…
Basic laboratory work up: Complete blood count Serum chemistry, including calcium, phosphorus, total protein, albumin, liver enzymes, alkaline phosphatase, creatinine, and electrolytes Serum 25-hydroxyvitamin D American Association of Clinical Endocrinologists Guidelines for Clinical Practice for the Diagnosis and Treatment of Postmenopausal Osteoporosis © 2010 .

If reasons to suspect secondary causes of bone loss:
TSH Erythrocyte sedimentation rate PTH for possible primary or secondary hyperparathyroidism 24-hour urine calcium Tissue transglutaminase antibodies for suspected celiac disease Urinary free cortisol or other tests for suspected Cushings Serum tryptase or other tests for mastocytosis Serum protein electrophoresis and free kappa and lambda light chains for suspected myeloma In men, testosterone Other? Bone marrow biopsy? Iliac crest bone biopsy? American Association of Clinical Endocrinologists Guidelines for Clinical Practice for the Diagnosis and Treatment of Postmenopausal Osteoporosis © 2010 .

Ultimate Goal of Osteoporosis Pharmacotherapy
To minimize fracture risk by achieving “normal” bone strength Ideally therapy should be safe, well-tolerated, easy to administer, and inexpensive Slide by Dr. David Dempster

Medications for treating low bone mass and osteoporosis
Antiresorptives Bisphosphonates Anti-RANK ligand antibody (denosumab) Calcitonin SERMs (selective estrogen receptor modulators) Anabolic Therapy Teriparatide Estrogen and HRT For prevention only Classes of Pharmacologic Agents for the Treatment of Osteoporosis Available therapies for the treatment for osteoporosis include antiresorptive agents (bisphosphonates, calcitonin, and selective estrogen receptor modulators [SERMs]) and the anabolic agent parathyroid hormone [rhPTH(1-34)].1 Anti-resorptive medications act directly on the resorption portion of the bone-remodeling cycle. The bisphosphonates alendronate, ibandronate, and risedronate bind tightly to the major bone mineral, hydroxyapatite. Once attached to bone, the bisphosphonates inhibit the metabolic pathway that is responsible for production of proteins that are critical to osteoclast functioning.2 Because resorption and formation are tightly coupled, decreases in the rate of resorption are followed by secondary, slower decreases in formation.3 Bone mineral density may therefore increase over time. 1 Calcitonin, a naturally occurring hormone, is involved in calcium regulation and bone metabolism. In women who are more than 5 years beyond menopause, calcitonin slows bone loss, increases spinal bone density, and reduces the risk of spinal fractures.1 SERMs bind to estrogen receptors, thereby activating certain estrogenic pathways and blocking others.1 Parathyroid hormone stimulates osteoblast activity to directly increase the rate of bone formation.1 Estrogen therapy (ET) and hormone therapy (HT) are approved for prevention of osteoporosis, but not for treatment. They are effective at preventing bone loss that occurs after menopause. However, the US FDA recommends that other osteoporosis medications be considered first before ET and HT because of the associated increased risk of breast cancer, strokes, and heart attacks. References National Osteoporosis Foundation. Medications to prevent & treat osteoporosis. Available at: Accessed February 7, 2007. Rogers MJ, Frith JC, Luckman P, et al. Molecular mechanisms of action of bisphosphonates. Bone. 1999;24(suppl):73S-79S. Papapoulos S, Frölich M. Prediction of the outcome of treatment of Paget’s disease of bone with bisphosphonates from short-term changes in the rate of bone resorption. J Clin Endocrinol Metab. 1996;81: National Osteoporosis Foundation.. Available at: Accessed February 7, 2007. Rogers MJ, Frith JC, Luckman P, et al. Bone. 1999;24(suppl):73S-79S. Papapoulos S, Frölich M. J Clin Endocrinol Metab. 1996;81:

Stabilize or improve microarchitecture Decrease in fracture risk
Antiresorptive Therapy Mechanism of Fracture Risk Reduction Antiresorptive therapy REDUCE bone turnover Stabilize or improve microarchitecture Increase BMD Decrease in fracture risk From presentation given by Dr. Paul Miller.

Estrogen: Women’s Health Initiative Fracture Data
5.2 years average follow-up Writing Group for the Women’s Health Initiative. JAMA. 2002; 288 (3):

Estrogen: Women’s Health Initiative
Over one year, 10,000 women taking estrogen plus progestin compare to placebo experienced: 7 more CHD events 8 more strokes 18 more thromboembolic events 8 more invasive breast cancers 6 fewer colorectal cancers 5 fewer hip fractures Writing Group for the Women’s Health Initiative. JAMA. 2002; 288 (3):

Estrogen: FDA Recommendations
When prescribing medications to prevent osteoporosis, clinicians should consider all non-estrogen preparations first. When prescribing estrogen, clinicians should prescribe lowest dose for shortest time possible. Clinicians should prescribe estrogen containing products only when benefits outweigh the risks for a specific patient. US Food and Drug Administration. FDA News. January 8,2003

Selective estrogen receptor modulators (SERMs)
Raloxifene: a selective estrogen receptor modulator: Acts as estrogen agonist on bone Acts as estrogen antagonist on breast and uterus ↓ Bone turnover ↑ BMD but to lesser degree than bisphosphonates ↓ Vertebral fractures Does not reduce hip or other non-vertebral fractures Ettinger B, et al. JAMA. 1999;282:

Effect of Raloxifene in Women with or Without Pre-Existing Fractures MORE Trial—3 Years
25 RR 0.7a (95% CI = 0.6–0.9) Placebo Raloxifene 60 mg/d 20 30% Incident Vertebral Fractures % of Women with 15 10 RR 0.5a (95% CI = 0.3–0.7) 5 55% Without Pre-Existing Vertebral Fracture With Pre-Existing Vertebral Fracture aWomen who completed the study and had evaluable radiographs at 36 months. Ettinger B, et al. JAMA. 1999;282:

Raloxifene and Breast Cancer
4 years with raloxifene 72% relative risk reduction in incidence of new breast cancer compared to placebo 8-year extension trial data showed 66% relative risk reduction in incidence of new onset breast cancer in raloxifene treated patients compared to placebo Vogel VG, et al. JAMA. 2006;295:

Side effects and adverse events
Raloxifene: Side effects and adverse events Hot flashes Deep vein thrombosis Leg cramps Small increase in risk of fatal stroke Barret-Connor E, et al. N Enlg J Med Jul 13; 355 (2):

Calcitonin Derived from parafollicular cells of the thyroid gland
Inhibits bone resorption Available in nasal and subcutaneous formulations Excellent safety profile Ability to reduce pain with injectable formulations Indicated for women at least 5 years postmenopausal who are unable to tolerate other osteoporosis medications.

Calcitonin: Effects on Fracture
Nasal formulation’s reduction in vertebral fracture occurred only in the 200 IU/spray formulation Lower and higher doses had no effect No dose has shown nonvertebral fracture risk reduction N=1255 postmenopausal women with osteoporosis. Chesnut CH 3rd, et al. Am J Med. 2000; Sep; 109 (4):

Bisphosphonates Analogs of naturally occurring pyrophosphates
High affinity for bone at the calcium-phosphorus interface surface and stabilizes the crystal Reduce osteoclast activity by inhibiting the enzyme farnesyl pyrophosphate synthetase (FPPS) Differences among bisphosphonates are related to differences in the physiochemical and cellular effects Bisphosphonates are not metabolized. The molecule released from bone retains biologic activity

Bisphosphonates: Effects
↓ Bone turnover ↑ BMD at lumbar spine and hip ↓ Vertebral and non-vertebral fractures Sustained effects with continued treatment Best studied class of medications used to treat osteoporosis. Long term record of safety and adverse events Black DM et al. Lancet. 1996; Body J-J, et al. J Clin Endocrinol Metab. 2002; 87: Chestnut CH III et al J Bone Miner Res. 2004; 19: 1241 – 1249 Harris ST et al. JAMA 1999; 282:

Available Bisphosphonates for Osteoporosis
Oral Alendronate (daily, weekly) Risedronate (daily, weekly, monthly) Ibandronate (daily, monthly) Intravenous Ibandronate (quarterly) Zoledronic acid (annual) Off-label Pamidronate (IV quarterly)

Effects of Bisphosphonates on Osteoclast Function
Effect of Bisphosphonates on Osteoclast Function A reduction in osteoclast activity and viability is desirable in a number of disease states, including osteoporosis and Paget’s disease of bone. Nitrogen-containing bisphosphonates impair osteoclast function by inhibiting farnesyl pyrophosphate synthase (FPPS), thereby preventing the prenylation of small GTPase proteins.1,2 This results in disruption of cytoskeletal organization,3 loss of the ruffled membrane border,3 and altered vesicular trafficking.4 In addition, while osteoclasts naturally undergo apoptosis, this process is accelerated in osteoclasts exposed to bisphosphonates.5 References 1. Rogers MJ, Frith JC, Luckman SP, et al. Molecular mechanisms of action of bisphosphonates. Bone. 1999;24(suppl 5):73S-79S. 2. Fleisch H. Bisphosphonates: mechanisms of action. Endocr Rev. 1998;19: 3. Sato M, Grasser W, Endo N, et al. Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure. J Clin Invest. 1991;88: 4. Rogers MJ. New insights into the molecular mechanisms of action of bisphosphonates. Curr Pharm Des. 2003;9(32): 5. Hughes DE, Wright KR, Uy HL, et al. Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo. J Bone Miner Res. 1995;10: Normal Osteoclast Osteoclast after uptake of bisphosphonate Rogers MJ, Frith JC, Luckman SP, et al.. Bone. 1999;24(suppl 5):73S-79S. 2. Fleisch H.. Endocr Rev. 1998;19: 3. Sato M, Grasser W, Endo N, et al.. J Clin Invest. 1991;88: 4. Rogers MJ Curr Pharm Des. 2003;9(32): 5. Hughes DE, Wright KR, Uy HL, et al. J Bone Miner Res. 1995;10:

Administration guidelines for oral bisphosphonates
Must take medication first thing in AM after arising before eating or drinking with 8 oz of water. Must be NPO for at least ½ hour Ibandronate must be taken at least 1 hour before eating or drinking Patients must remain upright by walking, standing or sitting for ½ hour. Remind patients that this includes not lying down of going back to bed. Exception: AtelviaTM

Poor Compliance and Persistence Lead to Compromised Fracture Risk Reduction
Siris and colleagues demonstrated that poor adherence to therapy compromises the level of fracture risk reduction achievable with bisphosphonates Most patients do not comply fully with the dosing regimen for antiresorptive therapy, which has an adverse impact on fracture rates in the real-world setting. In a 2006 study, Siris et al performed a retrospective analysis of 2 US claims databases that included records from 45 employers and 100 health plans over a 5-year period (January 1, December 31, 2003). The analysis included 35,537 women aged 45 years or more who received a prescription for a bisphosphonate. Persistence was defined as continuous therapy without a gap in refills of 30 days or more in the 24-month study period. Over 24 months, relative risk reductions among persistent patients were 29% for non-vertebral fractures (P < .001). Reference Siris ES, Harris ST, Rosen CJ, et al. Adherence to bisphosphonate therapy and fracture rates in osteoporotic women: relationship to vertebral and nonvertebral fractures from 2 US claims databases. Mayo Clin Proc. 2006;81: Siris ES, Harris ST, Rosen CJ, et al. Mayo Clin Proc. 2006;81:

Refill Compliance and Fracture Protection Over 24 Months for Bisphosphonate-Treated Patients
The data in this slide demonstrate that patients who comply with their bisphosphonate treatment regimen less than half of the time achieve no improvements in fracture reduction over 2 years, and those who comply 75% of the time achieve modest fracture risk reductions, but those who have 90% or better compliance achieve the most benefit from bisphosphonate therapy Siris and colleagues calculated the probability of a fracture as a function of medication possession ratio (MPR). MPR was calculated as the sum of the days’ supply divided by the follow-up time. A patient who was given a prescription for 3 months of medication and sought 2 additional 3-month refills would be considered 75% compliant with her medication during a 1-year period. As seen on this slide, there is virtually no fracture protection effect until MPR has reached 50% or more. Fracture risk decreases modestly for MPRs between 50% and 74%, and decreases sharply for patients with MPRs of 75% or more. For a patient on a weekly bisphosphonate regimen, 50% compliance is equivalent to missing 1 dose out of every 2 weeks. According to this model, such a patient will have a risk of fracture that is similar to that of a patient who has not received any therapy. Only 43% of patients were refill compliant (defined as MPR ≥80%). Relative risk reductions among these patients were 21% for all fracture, 37% for hip fracture, and 37% for vertebral fracture vs non-compliant group (all P < .001). Reference Siris ES, Harris ST, Rosen CJ, et al. Adherence to bisphosphonate therapy and fracture rates in osteoporotic women: relationship to vertebral and nonvertebral fractures from 2 US claims databases. Mayo Clin Proc. 2006;81: Siris ES, Harris ST, Rosen CJ, et al. Mayo Clin Proc. 2006;81:

Advantages of IV Bisphosphonates
Oral bisphosphonates have fastidious absorption patterns (exception: AtelviaTM ) Oral bisphosphonates may induce GI intolerability Oral bisphosphonate may be contraindicated in patients with GI diseases (achalasia, scleroderma, Barrett’s, etc) Serum levels of bisphosphonate cannot be measured, creating uncertainties around oral absorption and bone bioavailability in certain clinical scenarios

Bisphosphonates: Side effects, contraindications and other concerns
Upper GI (oral) Musculoskeletal pain First phase reactions (IV) Contraindicated in renal insufficiency Other concerns (these will be discussed more later): Osteonecrosis of the jaw? Atypical femur fractures?

Denosumab Human monoclonal antibody-IgG2 isotype
High affinity and specificity for human RANK ligand Does not bind to TNFα, TNFβ, TRAIL, or CD40L Pharmacokinetics (SC): similar to other fully human IgG2 monoclonal antibodies Absorption is rapid and prolonged (Cmax ≈1–4 wks postdose) Long half-life ≈34 days with maximum dose Distribution ≈ intravascular volume Clearance ≈ reticuloendothelial system No kidney filtration or excretion of intact molecule Abbreviations: TNF, tumor necrosis factor; TRAIL, TNF-related apoptosis-inducing ligand. Bekker PJ, et al. J Bone Miner Res. 2004;19: Boyle WJ, et al. Nature. 2003;423:

Denosumab: Mechanism of Action
RANKL RANK OPG CFU-M Dmab Pre-Fusion Osteoclast Growth Factors Hormones Cytokines Multinucleated Osteoclast RANKL Osteoclast Osteoblast Lineage Bone Abbreviation: CFU-M, colony forming unit macrophage.

Denosumab: Serum Levels (1 mg/kg SC)
3 5 9 Study Month 2 4 6 10 Serum Level (ng/mL) EC50 Bekker PJ, et al. J Bone Miner Res. 2004;19:

Denosumab: Effects 68% decrease in vertebral fractures
2.3% vs 7.2%, P <.0001 41% decrease in hip fractures 0.7% vs 1.2%, P = .036 20% decrease in nonvertebral fractures 6.5% vs 8.0%, P = .011 Denosumab increases BMD and reduces bone turnover markers compared with placebo AEs and SAEs generally similar to placebo No increased risk of cancer, infection, cardiovascular disease, delayed fracture healing, hypocalcemia, no osteonecrosis of the jaw Increased risk of cellulitis, eczema, flatulence; decreased risk of falls, concussion Cummings SR, et al. N Engl J Med. 2009;361:1-10.

Denosumab: Discontinuation
Lumbar Spine BMD Serum CTx Miller PD et al. . Bone. 2008; 43:

Denosumab: Retreatment
Lumbar Spine BMD Serum CTx Miller PD et al. . Bone. 2008; 43:

Anabolic Therapy Mechanism of Fracture Risk Reduction
INCREASE bone turnover Stabilize or improve microarchitecture Increase in BMD Decrease Fracture Risk From presentation given by Dr. Paul Miller.

Teriparatide First in class of anabolic (bone-building) agents
Human PTH has 84 amino acids, teriparatide is the active 1-34 amino acid portion Approved by the FDA in 2002. Approximately doubles rate of bone formation in patients with osteoporosis Neer RM, et al. N Eng J Med. 2001; 344: Forteo (teriparatide [rDNA origin] injection) prescribing information. Eli Llly and Co; September 2004.

Teriparatide Stimulates osteoblast activity and overall bone remodeling, resulting in new bone formation. ↑ bone mass ↓ vertebral and non-vertebral fractures Improves trabecular microarchitecture and increases cortical thickness Requires daily SC injections. Neer RM, et al. N Eng J Med. 2001; 344: Forteo (teriparatide [rDNA origin] injection) prescribing information. Eli Llly and Co; September 2004.

Effect of Teriparatide on Risk of Vertebral Fractures in Postmenopausal Women
16 RR 0.35 (95% CI = 0.22–0.55)a 14 12 10 % of Patients with ≥1 Fracture 8 65%  6 4 2 Placebo Teriparatide 20 µg aP <.001 vs placebo. Neer RM, et al. N Engl J Med. 2001;344: Adapted from graphic by Dr. Paul Miller.

Nonvertebral and Hip Fractures Teriparatide
20 Control Teriparatide 20 µg 15 Percent with New Fractures 10 RR = 0.5 (0.3,0.9) 5 NS Nonvertebral Fractures Hip Fractures 5 fragility hip fractures (control + primary treatment group). Nonvertebral fractures = fragility fractures, otherwise not specified. Neer R, et al. N Engl J Med. 2001;344:1434–1441. Adapted from graphic by Dr. Paul Miller.

Teriparatide Subcutaneous injections every day
Treatment duration = 2 years Patient must be initiated on antiresorptive therapy after course of teriparatide completed or will rapidly lose any gains in BMD Cannot be used in patients with contraindications Neer RM, et al. N Eng J Med. 2001; 344: Forteo (teriparatide [rDNA origin] injection) prescribing information. Eli Llly and Co; September 2004.

Contraindications to Teriparatide
Unexplained hypercalcemia Unexplained elevated alkaline phosphatase Paget’s disease Prior skeletal (therapeutic) radiation Metastatic cancer Unfused epiphysis GFR <30 mL/min

Teriparatide: Side Effects and Adverse Events
Leg cramps Dizziness Use currently limited to 2 years Long term effects unknown Initial PTH trials were stopped early due to finding of osteosarcoma in animals No excess osteosarcoma reported in humans FDA assigned boxed warning because of osteosarcoma in animal studies US Food and Drug Administration. FDA Talk Paper. November 2002

AACE Postmenopausal Osteoporosis Guidelines 2010: Choosing a drug
First line agents: alendronate, risedronate, zoledronic acid, and denosumab Use ibandronate as a second-line agent Use raloxifene as a second- or third-line agent Use calcitonin as the last line of therapy Use teriparatide for patients with very high fracture risk or patients in whom bisphosphonate therapy has failed Do not use combination therapy •American Association of Clinical Endocrinologists Guidelines for Clinical Practice for the Diagnosis and Treatment of Postmenopausal Osteoporosis © 2010

Follow-up of Patients on Medication for the Treatment of Osteoporosis
Minimal follow-up Verify that patient is taking the medication Verify appropriate dosing procedure for oral bisphosphonates Verify that patient is taking sufficient calcium and vitamin D Other Bone density – not usually before 2 years Bone turnover markers – role uncertain- may be useful for confirming compliance with therapy and/or effect of therapy Creatinine, Other labs? 25-OH vitamin D level?

Current controversies
Osteoporosis Current controversies

Current controversies in osteoporosis
Safety and adverse events Osteonecrosis of the jaw Atypical or mid-shaft femoral fractures Bisphosphonate holidays? Assessment of bone turnover markers? How often should follow-up DXAs be performed?

Osteonecrosis of the jaw: Background
Reports of ONJ have primarily been in patients with advanced malignancies and skeletal metastases (>90% of cases) Etiology and pathogenesis are not well characterized Role of bisphosphonates uncertain The clinical diagnosis of ONJ is usually made on the basis of visual inspection (eg, presence of exposed bone) and/or radiographic appearance1 No uniform diagnostic criteria currently applied Ruggiero S, et al. J Oncol Practice. 2006;2:7-14.

Osteonecrosis of the jaw: Signs and symptoms
- “Heavy jaw”, a dull aching sensation - Numbness/tingling of the jaw - Tooth pain - Undiagnosed oral pain Signs - Rough area on the jawbone - soft tissue swelling, drainage or infection - exposed bone in the oral cavity - sudden change in the health of periodontal tissue - Failure of oral mucosa to heal - Loosening of teeth Ruggiero S, et al. J Oncol Practice. 2006;2:7-14.

Osteonecrosis of the jaw: Clinical Presentation
Exposed bone in maxillofacial area that occurs in association with dental surgery or occurs spontaneously, with no evidence of healing No evidence of healing after 6 to 8 weeks of appropriate evaluation and dental care No evidence of metastatic disease in the jaw or osteoradionecrosis Ruggiero S, et al. J Oncol Practice. 2006;2:7-14.

Osteonecrosis of the jaw: Prevalence
190 million prescriptions in the United States for oral alendronate, risedronate, and ibandronate Over 6 million patients treated with iv bisphosphonates for cancer worldwide ONJ in oral bisphosphonate users ranges from 1:10,000 (from Australia and Israel) to 1:250,000 (from Germany) to 1:160,000 worldwide. These figures are rough approximations because of difficulties in case finding (not all cases of ONJ are reported and not all cases reported are really ONJ) Watts N et al. J Clin Endocrinol Metab, April 2010, 95(4):1555–1565.

Osteonecrosis of the jaw: Bisphosphonates
Several different sources of retrospective data on ONJ incidence are available ONJ incidence varies widely in retrospective studies Risk factors vary for different disease states ONJ was not identified prospectively in any of the clinical trials that included more than 60,000 patient-years in studies of osteoporosis or Paget’s disease Black DM, et al. N Engl J Med. 2007;356: Grbic J, et al. J Am Dent Assoc.2008;139 (1):32-40. Watts N et al. J Clin Endocrinol Metab, April 2010, 95(4):1555–1565. .

Osteonecrosis of the jaw: Bisphosphonates
Only 1 study was prospectively designed to look at adjudicated incidence of ONJ1,2 HORIZON-PFT examined efficacy of zoledronic acid in patients with postmenopausal osteoporosis: Only two cases of ONJ identified: 1 case in the active treatment group, 1 case in the placebo group Both cases healed with conservative treatment of debridement and antibiotics No difference in rate of ONJ was observed in treatment vs placebo group over 6 years Black DM, et al. N Engl J Med. 2007;356: Grbic J, et al. J Am Dent Assoc.2008;139 (1):32-40.

Osteonecrosis of the jaw: Prevention
Patients who are starting or taking bisphosphonates should be informed that there are risks of treatment, including a low risk of ONJ. Regular dental visits and maintenance of good oral hygiene are important for everyone. Routine dental cleaning and restorative procedures should be strongly encouraged. Watts N et al. J Clin Endocrinol Metab, April 2010, 95(4):1555–1565 American Association of Oral and Maxillofacial Surgeons 2007 Position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 65:369–376

Patients on bisphosphonates who are considering surgery should be advised of the risks and alternatives. Invasive surgical procedures should be avoided, if possible, especially in patients receiving iv bisphosphonates for cancer. If dental treatment is needed, it should progress stepwise, if possible. Watts N et al. J Clin Endocrinol Metab, April 2010, 95(4):1555–1565 American Association of Oral and Maxillofacial Surgeons 2007 Position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 65:369–376

Patients with periodontal disease should receive appropriate non-surgical therapy first. Patients starting oral bisphosphonates who need invasive dental procedures should have procedures done and healing complete before starting, if circumstances permit. Patients already taking a bisphosphonate may elect to take some time off therapy, however there is no evidence that this will prevent ONJ. Watts N et al. J Clin Endocrinol Metab, April 2010, 95(4):1555–1565 American Association of Oral and Maxillofacial Surgeons 2007 Position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 65:369–376

Atypical femur fractures Background
Case reports of unusual low-energy subtrochanteric femoral fractures and pelvic insufficiency fractures, which exhibited problems with healing, in patients on long term bisphosphonate therapy Watts N et al. J Clin Endocrinol Metab, April 2010, 95(4):1555–1565.

Atypical femur fractures Clinical features
Fractures are typically associated with prodromal pain in the region of the fracture Frequently bilateral Characteristic radiographic findings include cortical hypertrophy, a transverse fracture pattern, and medial cortical spiking Watts N et al. J Clin Endocrinol Metab, April 2010, 95(4):1555–1565.

Atypical femur fractures
Bone biopsies in such patients often (but not always) show severely suppressed bone turnover Thought to be due to long term over-suppression of bone turnover leading to impaired bone remodeling, accumulation of micro-damage in bone and increased skeletal fragility Several retrospective studies suggest an association between bisphosphonate use and atypical fractures Watts N et al. J Clin Endocrinol Metab, April 2010, 95(4):1555–1565.

However the observed association between long-term bisphosphonate use and atypical fractures does not prove causality A register-based national cohort study from Denmark showed that the ratio of classical to atypical hip fractures was identical in the alendronate treated subjects vs. matched untreated controls Atypical fractures may be due to osteoporosis rather than the bisphosphonate therapy itself Watts N et al. J Clin Endocrinol Metab, April 2010, 95(4):1555–1565. Abrahamsen B, Eiken P, Eastell R 2009 Subtrochanteric and diaphyseal femur fractures in patients treated with alendronate: a registerbased national cohort study. J Bone Miner Res 24:1095–1102

“Concern about oversuppression of bone turnover resulting in atypical fractures should not lead to stopping bisphosphonate therapy in the vast majority of postmenopausal women at the present time” Watts N et al. J Clin Endocrinol Metab, April 2010, 95(4):1555–1565.

Bisphosphonate “Drug Holiday”
Not a topic of discussion when bisphosphonates first launched Became a consideration after July 9, (WHI JAMA publication) Became more widely discussed after FLEX (Black et al, JAMA 2004) and better science defining bisphosphonate PK/PD became available FRAXTM also drove the “drug holiday” discussion in women (untreated) who had been at low risk before bisphosphonates were started Not yet standard of care in the United States Miller PD. Best Prac Res Clin Endocrinol Metab. 2008;22:849–868.

Watts N et al. J Clin Endocrinol Metab, April 2010, 95(4):1555–1565.

“Duration based largely on personal opinion”
Bisphosphonate “Drug Holiday” “Duration based largely on personal opinion” Watts N et al. J Clin Endocrinol Metab, April 2010, 95(4):1555–1565.

Low risk of fracture: treatment is not needed. If bisphosphonate has been prescribed, it should be discontinued and not restarted unless/until the patient meets treatment guidelines. Watts N et al. J Clin Endocrinol Metab, April 2010, 95(4):1555–1565.

Example- Low risk of fracture: 53-yr-old woman, menopause at age 50 yr, lowest T-score -1.6, no risk factors, bisphosphonate therapy for 2 yr. Treatment was never indicated in the first place and can be discontinued. Watts N et al. J Clin Endocrinol Metab, April 2010, 95(4):1555–1565.

Mild risk of fracture: treat with bisphosphonate for 3–5 yr and then stop. Continue drug holiday until there is significant loss of BMD (i.e. more than the LSC) or the patient has a fracture, whichever comes first. Watts N et al. J Clin Endocrinol Metab, April 2010, 95(4):1555–1565.

Example- Mild risk of fracture: 65-yr old woman, menopause at age 52 yr, initial lowest T-score -2.6, no risk factors, bisphosphonate treatment for 5 yr, BMD stable over that time. Treatment was indicated, but after 5 yr of treatment, a drug holiday might be considered. Watts N et al. J Clin Endocrinol Metab, April 2010, 95(4):1555–1565.

Moderate risk of fracture: treat with bisphosphonate for 5–10 yr Offer a drug holiday of 3–5 yr or until there is significant loss of BMD or the patient has a fracture, whichever comes first. Watts N et al. J Clin Endocrinol Metab, April 2010, 95(4):1555–1565.

Example- Moderate risk of fracture: 70-yr-old woman, menopause at age 49 yr, lowest initial T score -2.7, no risk factors, bisphosphonate therapy for 8 yr, BMD increased over that time so lowest T-score now is -2.3. Treatment was indicated, but after 8 yr of treatment, a drug holiday might be considered. Watts N et al. J Clin Endocrinol Metab, April 2010, 95(4):1555–1565.

High risk of fracture: treat with bisphosphonate for 10 yr Offer a drug holiday of 1–2 yr until there is significant loss of BMD or the patient has a fracture, whichever comes first. A non-bisphosphonate treatment (e.g. raloxifene, teriparatide) may be offered during the holiday from the bisphosphonate. Watts N et al. J Clin Endocrinol Metab, April 2010, 95(4):1555–1565.

Example - High risk of fracture: 72-yr-old woman, menopause at age 43 yr, lowest initial T-score -3.8, rheumatoid arthritis requiring ongoing corticosteroid therapy for 12 yr, 3-in. height loss and two vertebral fractures by VFA, treatment with bisphosphonate therapy for 10 yr Treatment was indicated. After 10 yr, she remains at high risk of fracture. If a holiday from the bisphosphonate is considered, interval treatment with teriparatide or raloxifene would be prudent. Watts N et al. J Clin Endocrinol Metab, April 2010, 95(4):1555–1565.

Biochemical Markers of Bone Turnover
AACE 2010 Guidelines: “Bone turnover markers may be used at baseline to identify patients with high bone turnover and can be used to follow the response to therapy” Commonly Used Biochemical Markers of Bone Turnover Mature bone is constantly undergoing remodeling.1 Osteoclasts mature and then dissolve (or “resorb”) old bone tissue. This resorption phase lasts an average of 27 days2 and is followed by a brief “reversal,” phase lasting about 9 days,3 during which macrophage-like cells appear on the surface of resorbed bone. The reversal phase is followed by bone formation, when osteoblasts fill the resorption cavity with mineralized osteoid,1 a phase that lasts an average of 89 days.2 Usually, bone resorption and bone formation are coupled so that they occur in close sequence and remain balanced. An imbalance in the bone remodeling cycle causes bone loss that eventually leads to osteoporosis and fracture risk.3 Biochemical markers of bone turnover are dynamic assessments that reveal changes in bone metabolism that have occurred in the previous weeks or months.3 In research, the most commonly used markers of bone formation are bone-specific alkaline phosphatase (BSAP), osteocalcin (OC), and propeptide of type I collagen (P1NP).3 Commonly used markers of bone resorption in research include N-telopeptide of type I collagen (NTX), and C-telopeptide of type I collagen (CTX).3 References Domon T, Suzuki R, Takata K, et al. The nature and function of mononuclear cells on the resorbed surfaces of bone in the reversal phase during remodeling. Ann Anat. 2001;183: Agerbaek MO, Eriksen EF, Kragstrup J, et al. A reconstruction of the remodeling cycle in normal human cortical iliac bone. Bone Miner. 1991;12: Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, Md: US Department of Health and Human Services; 2004: American Association of Clinical Endocrinologists Guidelines for Clinical Practice for the Diagnosis and Treatment of Postmenopausal Osteoporosis © 2010

Biochemical Markers of Bone Turnover
Formation Bone-specific alkaline phosphatase (BSAP) Osteocalcin (OC) Propeptide of type I collagen (P1NP) Resorption N-telopeptide of type I collagen (NTX) C-telopeptide of type I collagen (CTX). Commonly Used Biochemical Markers of Bone Turnover Mature bone is constantly undergoing remodeling.1 Osteoclasts mature and then dissolve (or “resorb”) old bone tissue. This resorption phase lasts an average of 27 days2 and is followed by a brief “reversal,” phase lasting about 9 days,3 during which macrophage-like cells appear on the surface of resorbed bone. The reversal phase is followed by bone formation, when osteoblasts fill the resorption cavity with mineralized osteoid,1 a phase that lasts an average of 89 days.2 Usually, bone resorption and bone formation are coupled so that they occur in close sequence and remain balanced. An imbalance in the bone remodeling cycle causes bone loss that eventually leads to osteoporosis and fracture risk.3 Biochemical markers of bone turnover are dynamic assessments that reveal changes in bone metabolism that have occurred in the previous weeks or months.3 In research, the most commonly used markers of bone formation are bone-specific alkaline phosphatase (BSAP), osteocalcin (OC), and propeptide of type I collagen (P1NP).3 Commonly used markers of bone resorption in research include N-telopeptide of type I collagen (NTX), and C-telopeptide of type I collagen (CTX).3 References Domon T, Suzuki R, Takata K, et al. The nature and function of mononuclear cells on the resorbed surfaces of bone in the reversal phase during remodeling. Ann Anat. 2001;183: Agerbaek MO, Eriksen EF, Kragstrup J, et al. A reconstruction of the remodeling cycle in normal human cortical iliac bone. Bone Miner. 1991;12: Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, Md: US Department of Health and Human Services; 2004: Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, Md: US Department of Health and Human Services; 2004:

Biochemical Markers of Bone Turnover: Benefits
Elevated bone turnover markers (BTMs) predict more rapid rates of bone loss in certain groups of patients Increased BTMs are associated with increased fracture risk independent of BMD at menopause and in elderly women BTM markers respond quickly to therapeutic intervention Changes in BTMs have been associated with bone response to therapy and reduction in fracture risk Commonly Used Biochemical Markers of Bone Turnover Mature bone is constantly undergoing remodeling.1 Osteoclasts mature and then dissolve (or “resorb”) old bone tissue. This resorption phase lasts an average of 27 days2 and is followed by a brief “reversal,” phase lasting about 9 days,3 during which macrophage-like cells appear on the surface of resorbed bone. The reversal phase is followed by bone formation, when osteoblasts fill the resorption cavity with mineralized osteoid,1 a phase that lasts an average of 89 days.2 Usually, bone resorption and bone formation are coupled so that they occur in close sequence and remain balanced. An imbalance in the bone remodeling cycle causes bone loss that eventually leads to osteoporosis and fracture risk.3 Biochemical markers of bone turnover are dynamic assessments that reveal changes in bone metabolism that have occurred in the previous weeks or months.3 In research, the most commonly used markers of bone formation are bone-specific alkaline phosphatase (BSAP), osteocalcin (OC), and propeptide of type I collagen (P1NP).3 Commonly used markers of bone resorption in research include N-telopeptide of type I collagen (NTX), and C-telopeptide of type I collagen (CTX).3 References Domon T, Suzuki R, Takata K, et al. The nature and function of mononuclear cells on the resorbed surfaces of bone in the reversal phase during remodeling. Ann Anat. 2001;183: Agerbaek MO, Eriksen EF, Kragstrup J, et al. A reconstruction of the remodeling cycle in normal human cortical iliac bone. Bone Miner. 1991;12: Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, Md: US Department of Health and Human Services; 2004: American Association of Clinical Endocrinologists Guidelines for Clinical Practice for the Diagnosis and Treatment of Postmenopausal Osteoporosis © 2010

Biochemical Markers of Bone Turnover: Limitations
Limited by high in vivo and assay variability (resorption markers) Poor predictive ability in individual patients Lack of evidence-based threshold for clinical decision making Commonly Used Biochemical Markers of Bone Turnover Mature bone is constantly undergoing remodeling.1 Osteoclasts mature and then dissolve (or “resorb”) old bone tissue. This resorption phase lasts an average of 27 days2 and is followed by a brief “reversal,” phase lasting about 9 days,3 during which macrophage-like cells appear on the surface of resorbed bone. The reversal phase is followed by bone formation, when osteoblasts fill the resorption cavity with mineralized osteoid,1 a phase that lasts an average of 89 days.2 Usually, bone resorption and bone formation are coupled so that they occur in close sequence and remain balanced. An imbalance in the bone remodeling cycle causes bone loss that eventually leads to osteoporosis and fracture risk.3 Biochemical markers of bone turnover are dynamic assessments that reveal changes in bone metabolism that have occurred in the previous weeks or months.3 In research, the most commonly used markers of bone formation are bone-specific alkaline phosphatase (BSAP), osteocalcin (OC), and propeptide of type I collagen (P1NP).3 Commonly used markers of bone resorption in research include N-telopeptide of type I collagen (NTX), and C-telopeptide of type I collagen (CTX).3 References Domon T, Suzuki R, Takata K, et al. The nature and function of mononuclear cells on the resorbed surfaces of bone in the reversal phase during remodeling. Ann Anat. 2001;183: Agerbaek MO, Eriksen EF, Kragstrup J, et al. A reconstruction of the remodeling cycle in normal human cortical iliac bone. Bone Miner. 1991;12: Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, Md: US Department of Health and Human Services; 2004: American Association of Clinical Endocrinologists Guidelines for Clinical Practice for the Diagnosis and Treatment of Postmenopausal Osteoporosis © 2010

Biochemical Markers of Bone Turnover: Possible Uses
Assessment of fracture risk in elderly patients when elevated levels would influence the decision to begin pharmacotherapy Early indicator of therapeutic response to anabolic or antiresorptive therapy Evaluation of patients losing BMD despite antiresorptive therapy Assessment of medication compliance, drug absorption, or therapeutic efficacy Commonly Used Biochemical Markers of Bone Turnover Mature bone is constantly undergoing remodeling.1 Osteoclasts mature and then dissolve (or “resorb”) old bone tissue. This resorption phase lasts an average of 27 days2 and is followed by a brief “reversal,” phase lasting about 9 days,3 during which macrophage-like cells appear on the surface of resorbed bone. The reversal phase is followed by bone formation, when osteoblasts fill the resorption cavity with mineralized osteoid,1 a phase that lasts an average of 89 days.2 Usually, bone resorption and bone formation are coupled so that they occur in close sequence and remain balanced. An imbalance in the bone remodeling cycle causes bone loss that eventually leads to osteoporosis and fracture risk.3 Biochemical markers of bone turnover are dynamic assessments that reveal changes in bone metabolism that have occurred in the previous weeks or months.3 In research, the most commonly used markers of bone formation are bone-specific alkaline phosphatase (BSAP), osteocalcin (OC), and propeptide of type I collagen (P1NP).3 Commonly used markers of bone resorption in research include N-telopeptide of type I collagen (NTX), and C-telopeptide of type I collagen (CTX).3 References Domon T, Suzuki R, Takata K, et al. The nature and function of mononuclear cells on the resorbed surfaces of bone in the reversal phase during remodeling. Ann Anat. 2001;183: Agerbaek MO, Eriksen EF, Kragstrup J, et al. A reconstruction of the remodeling cycle in normal human cortical iliac bone. Bone Miner. 1991;12: Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, Md: US Department of Health and Human Services; 2004: American Association of Clinical Endocrinologists Guidelines for Clinical Practice for the Diagnosis and Treatment of Postmenopausal Osteoporosis © 2010

How often should Follow-up DXA be obtained?
AACE Guidelines 2010: Obtain a baseline DXA Repeat DXA every 1 to 2 years until findings are stable. Continue with follow-up DXA every 2 years or at a less frequent intervals. Follow-up of patients should be in the same facility, with the same machine, and, if possible, with the same technologist Commonly Used Biochemical Markers of Bone Turnover Mature bone is constantly undergoing remodeling.1 Osteoclasts mature and then dissolve (or “resorb”) old bone tissue. This resorption phase lasts an average of 27 days2 and is followed by a brief “reversal,” phase lasting about 9 days,3 during which macrophage-like cells appear on the surface of resorbed bone. The reversal phase is followed by bone formation, when osteoblasts fill the resorption cavity with mineralized osteoid,1 a phase that lasts an average of 89 days.2 Usually, bone resorption and bone formation are coupled so that they occur in close sequence and remain balanced. An imbalance in the bone remodeling cycle causes bone loss that eventually leads to osteoporosis and fracture risk.3 Biochemical markers of bone turnover are dynamic assessments that reveal changes in bone metabolism that have occurred in the previous weeks or months.3 In research, the most commonly used markers of bone formation are bone-specific alkaline phosphatase (BSAP), osteocalcin (OC), and propeptide of type I collagen (P1NP).3 Commonly used markers of bone resorption in research include N-telopeptide of type I collagen (NTX), and C-telopeptide of type I collagen (CTX).3 References Domon T, Suzuki R, Takata K, et al. The nature and function of mononuclear cells on the resorbed surfaces of bone in the reversal phase during remodeling. Ann Anat. 2001;183: Agerbaek MO, Eriksen EF, Kragstrup J, et al. A reconstruction of the remodeling cycle in normal human cortical iliac bone. Bone Miner. 1991;12: Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, Md: US Department of Health and Human Services; 2004: American Association of Clinical Endocrinologists Guidelines for Clinical Practice for the Diagnosis and Treatment of Postmenopausal Osteoporosis © 2010

NEJM: Jan 19, 2012 4957 women, 67 years of age or older, with normal BMD (T score at the femoral neck and total hip, −1.00 or higher) or osteopenia (T score, −1.01 to −2.49) followed prospectively for up to 15 years. No history of hip or clinical vertebral fracture No treatment for osteoporosis Gourlay M et al. NEJM 366;3.

NEJM: Jan 19, 2012 Found that osteoporosis would develop in less than 10% of older, postmenopausal women with DXA rescreening intervals of : 15 years for women with normal BMD or mild osteopenia (T score greater than −1.49) 5 years for women with moderate osteopenia (T score −1.50 to −1.99) 1 year for women with advanced osteopenia (T score, −2.00 to −2.49). Gourlay M et al. NEJM 366;3.

Osteoporosis Conclusion

Pharmacotherapy for osteoporosis Summary
Antiresorptive and anabolic therapies are available to manage osteoporosis All have unique mechanisms to reduce fracture risk Individual clinical trials may show differences in efficacy, however, the lack of head-to- head fracture trials prevents claiming superiority of one therapy over another

Both oral as well as intravenous bisphosphonates are available. Bisphosphonates can reduce the risk for vertebral, nonvertebral, and hip fractures IV bisphosphonates allow delivery without GI side effects, and assures drug delivery to bone in circumstances where absorption of oral bisphosphonates is uncertain

Denosumab is an human monoclonal antibody which is an antiresorptive through a different mechanism than bisphosphonates Teriparatide stimulates bone formation and is especially useful in patients at high risk for fractures or who have not “responded” to alternative osteoporosis pharmacologic agents

The future of osteoporosis therapy
Improved understanding of the regulators of bone remodeling and mediators of bone resorption and formation Modulate bone remodeling in ways that optimize skeletal health New agents that prevent bone loss and/or restore lost bone mass and bone quality that occurs due to age and disease

Thank You! Thomas Repas DO FACP FACOI FNLA FACE CDE
Regional Medical Clinic- Endocrinology Aspen Centre 640 Flormann Street- 3rd Floor Rapid City, South Dakota 57701 Office: Blog:

Osteoporosis 2012 Update and Review of Current Controversies

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Osteoporosis 2012 Update and Review of Current Controversies

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