As consultant pharmacists are called to review and evaluate more and more admissions to nursing homes, the frequency with which

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1 Clinical Review Series Fall 2016 Topic: New and Emerging Treatments for Osteoporosis By Dana Saffel, PharmD, CGP, CPh, FASCP The Clinical Review Series includes peer-reviewed articles written by leading experts in senior care. Each article includes a companion slide set that corresponds to the article. Slide numbers are noted in parentheses. This article summarizes the main substantive content of the educational program on new and emerging treatments for osteoporosis that was presented at the Senior Care Conference and Exhibition in June As consultant pharmacists are called to review and evaluate more and more admissions to nursing homes, the frequency with which they are asked to evaluate patients with osteoporosis continues to increase. As part of the health care team, consultant pharmacists play a critical role in the management and monitoring of the medications and care strategies for patients with osteoporosis. (SLIDE 1) Osteoporosis is the most common metabolic bone disease in the United States and can result in devastating physical, psychosocial, and economic consequences. It is often overlooked and undertreated, however, in large part because it is clinically silent before manifesting as fracture. Consultant pharmacists can play a critical role in the management and monitoring of the medications and the medication strategy for patients with osteoporosis, both before and after fracture. Dana Saffel, Pharm D CPh, CGP, FASCP President, CEO Objectives New and Emerging Treatments for Osteoporosis Recognize and screen at-risk patients to reduce the burden of osteoporosis-related fractures Identify candidates for pharmacologic therapy for osteoporosis to reduce fracture risk Explain recent changes to guidelines for osteoporosis treatment Describe risks associated with long-term use of medications for the treatment of osteoporosis Osteoporosis: Definition Osteoporosis A skeletal disorder characterized by reduced bone strength predisposing a person to an increased risk of fracture. Bone strength primarily reflects the integration of bone mineral density and bone quality. 1 Normal Bone Moderate Osteoporosis Severe Osteoporosis 1. JAMA. 2001;285: BMC Musculoskelet Disord. 2011; 12(209). Diagnostic Categories for Osteoporosis Category Definition by Bone Mineral Density T Score Normal BMD = 0 to -1 Osteopenia BMD = -1 to -2 Osteoporosis BMD > -2.5 and greater Severe or Established Osteoporosis BMD > -2.5 and greater with one or more fragility fractures Slide 2 Slide (SLIDE 2) Upon completion of this activity, the reader should be able to: Recognize and screen at-risk patients to reduce the burden of osteoporosis-related fractures. Identify candidates for pharmacologic therapy for osteoporosis to reduce fracture risk. Explain recent changes to guidelines for osteoporosis treatment. Describe risks associated with long-term use of medications for the treatment of osteoporosis. (SLIDE 3) Osteoporosis is a skeletal disorder characterized by reduced bone strength predisposing a person to an increased risk of fracture. Bone strength primarily reflects the integration of bone mineral density and bone quality. These images illustrate the microarchitecture of vertebrae of normal bone, moderate osteoporosis, and severe osteoporosis, showing the progressive loss of bone over time. (SLIDE 4) Dual-energy x-ray absorptiometry (DXA) is currently the criterion standard for the evaluation of BMD. DXA provides the patient s T-score, which is the BMD value compared with that of control subjects who are at their peak BMD. World Health Organization (WHO) criteria define a normal T-score value as within 1 standard deviation (SD) of the mean BMD value in a healthy young adult. Osteopenia and Osteoprosis are identified when T-scores reach the following: T-score of 1 to 2.5 SD indicates osteopenia T-score of less than 2.5 SD indicates osteoporosis T-score of less than 2.5 SD with fragility fracture(s) indicates severe osteoporosis T-score refers to a standard deviation below the mean BMD value for young adult white females. Prevalence of low BMD in the U.S. is high: Osteoporosis 10 million Osteopenia 43 million Osteoporos Int DOI.1007/s June BMD bone mineral density Slide 4 4

2 Two Major Types of Bone Major types of bones Cortical Trabecular Cortical, or compact, bone The outside of the bone Dense and hard Comprises 75% to 80% of the skeleton Turnover rate: 10 years Trabecular, or cancellous, bone Highly vascularized and spongy Comprises the inner portions of vertebrae and ends of long bones Turnover rate: 4 years Vertebra Fractures and their complications are the relevant clinical sequelae of osteoporosis. Recognize Patients at Risk of Osteoporosis Non-modifiable Risk Factors Age Caucasian or Asian Female gender Personal history of dementia, poor health or frailty Personal or family history of fracture as an adult Small body frame (</= 127 lb) Trabecular Bone Cortical Bone Femur Slide 5 Modifiable Risk Factors Alcohol abuse Diseases associated with secondary osteoporosis Functional impairment Inadequate exercise Inadequate intake of calcium and vitamin D Medications that adversely affect bone metabolism Smoking Society for Post Acute and Long Term Care Medicine.. Osteoporosis Guideline. Columbia (MD): American Medical Directors Association (AMDA); Incidence of Osteoporotic Fractures in Women 1 Annual incidence per 1000 women Vertebrae Hip Wrist Age (Years) 1 out of every 2 Caucasian women will experience an osteoporosis-related fracture at some point in her lifetime 2 1. Wasnich RD, Osteoporos Int 1997;7 Suppl 3: Osteoporos Int DPI /s August Don t Overlook Male Patients Slide 6 Slide 7 Up to 2 million American men have osteoporosis Another 8-13 million are at risk 20% - 25% of hip fractures in people aged >50 years are in men Morbidity and mortality from hip fractures are higher in men than in women 20.7% mortality after hip fracture among men aged >75 years Men fracture ~10 years later in life than women Risk factors for osteoporosis in men include: History of non-traumatic fracture Hypogonadism Advanced age 5 7 (SLIDE 5) There are 2 major types of bone: cortical and trabecular. Cortical, or compact, bone comprises the hard external portion of every bone and is also referred to as the cortical envelope. Although it contains some vascularization, cortical bone appears uniformly dense and hard. Approximately 75% to 80% of the skeleton is cortical bone; however, a relatively higher amount is found in the appendicular skeleton. Trabecular bone (also called spongy or cancellous bone) is highly vascularized and spongy in appearance. It comprises the inner portion of the vertebrae and epiphyseal portions of long bones. Found in relatively high amounts in the axial skeleton, trabecular bone is less dense than cortical bone and has an increased rate of remodeling. This increased rate of remodeling is, in part, what contributes to a higher incidence of osteoporosis in trabecular bone as compared to cortical bone (SLIDE 6) The first step in appropriately managing osteoporosis consists of identifying patients at risk of osteoporosis. All new admissions (women and men) should be screened for osteoporosis risks. Patients who have low bone mass are at risk for osteoporosis, and postmenopausal women are at greater risk because of bone loss due to lack of estrogen. At menopause, the risk of osteoporosis may be increased due to low bone mass. Other factors such as cigarette smoking, excessive alcohol intake, and inadequate calcium intake also may increase risk. The risk of osteoporosis increases with age. Bones become less dense and weaker, regardless of gender, as one ages and calcium absorption becomes less efficient. Other risk factors for osteoporosis include: Early menarche Estrogen deficiency Ethnicity (Caucasian or Asian) History of excessive exercise resulting in amenorrhea Low testosterone in men Use of certain medications, eg, glucocorticoids, chemotherapy, anticonvulsants, lithium, antacids, excess thyroid replacement, excess vitamin A, GnRH agonists/ antagonists, and heparin Conditions, (eg, chronic liver failure, chronic obstructive lung disease, chronic renal failure, Cushing s syndrome, type 1 diabetes, vitamin D deficiency, multiple myeloma, lymphoma, hyperthyroidism or excess thyroid hormone replacement, disuse or immobilization, hypogonadism, malabsorption syndrome, cirrhosis, and inflammatory bowel disease.) (SLIDES 7-9) Osteoporosis and low bone mass are currently estimated to be a major public health threat for almost 44 million U.S. women and men aged 50 and older. In 2010, 52 million people suffered from either osteoporosis or low bone mass, representing over 50 percent of the people aged 50 and older in the United States. By the year 2020, if current trends continue, the figure will climb to more than 61 million by Endocrinol Metab Clin N Am. 2007;36: Incidence of Osteoporotic Fractures in Men Slide 8 8 Osteoporotic fractures in women begin to occur after the ago of 50 and corresponding to a reduction in estrogen due to menopause. The rate of vertebral fractures is higher than hip or wrist through the course of the disease, with hip fracture incidence rising as the women approaches 75 years of age. Annual incidence per 100,000 men Vertebrae Hip Wrist Age (Years) Age (Years) 1 out of every 5 Caucasian men will experience an osteoporosis-related fracture at some point in his lifetime 2 1. Wasnich RD, Osteoporos Int 1997;7 Suppl 3: Osteoporos Int DPI /s August Slide 9 While approximately eighty percent of people with osteoporosis are women, osteoporosis in men is now recognized as an increasingly important public health issue. It is estimated that the lifetime risk of experiencing an osteoporotic fracture in men over the age of 50 is 30% similar to the lifetime risk of developing prostate cancer. 30% of hip fractures and 20% of vertebral fractures occur in men. As with women, vertebral fractures occur with higher incidence than wrist or hip fracture, however men general begin fracturing about a decade later than women. Similar to women,

3 hip fracture incidence begins to rise around the age of 75. Although the overall prevalence of fragility fractures is higher in women, men generally have higher rates of fracture related mortality. (SLIDE 10) Fractures are associated with morbidity. Within one year after a hip fracture, 80% of patients will be unable to carry out at least one independent activity of daily living, 40% will be unable to walk independently, 30% will have a permanent disability, 20% will have a nursing home placement, and 20% will die. (SLIDE 11) Vertebral fractures are frequently asymptomatic many are only discovered by chance and less than one third are actually diagnosed. Fracture of the spine may lead to crowding of internal organs and intestinal dysfunction or restrictive lung disease. Increased mortality and morbidity are associated with limited physical activity, back pain, skeletal deformity, height loss, and kyphosis. Vertebral fractures are associated with an increased risk for additional vertebral fractures and are predictive for the future development of non-vertebral fractures. Vertebral fractures remain undetected in clinical practice and are a major cause of mortality and morbidity. Almost 20% of patients with a prevalent vertebral fracture experience an additional fracture within a year. Early detection is critical. (SLIDE 12) Previous vertebral fracture confers a higher risk of developing a new fracture, compared with patients with no previous fracture1 In a prospective cohort study (Dubbo Osteoporosis Epidemiology Study) in Australia of 2245 community-dwelling women and 1760 men aged 60 years or older followed up for 16 years from July 1989 through April Main Outcome Measure Incidence of first (initial) fracture and incidence of subsequent fracture according to sex, age group, and time since first fracture. Relative risk was determined by comparing risk of subsequent fracture with risk of initial fracture. There were 905 women and 337 men with an initial fracture, of whom 253 women and 71 men experienced a subsequent fracture. Relative risk (RR) of subsequent fracture in women was 1.95 (95% confidence interval [CI], ) and in men was 3.47 (95% CI, ). As a result, absolute risk of subsequent fracture was similar in women and men and at least as great as the initial fracture risk for a woman 10 years older. Thus, women and men aged 60 to 69 years had absolute re-fracture rates of 36/1000 person-years (95% CI, 26-48/1000) and 37/1000 person years (95% CI, 23-59/1000), respectively. The increase in absolute fracture risk remained for up to 10 years, by which time 40% to 60% of surviving women and men experienced a subsequent fracture. All fracture locations apart from rib (men) and ankle (women) resulted in increased subsequent fracture risk, with highest RRs following hip (RR,9.97; 95% CI, ) and clinical vertebral (RR,15.12; 95% CI, ) fractures in younger men. In multivariate analyses, femoral neck bone mineral density, age, and smoking were predictors of subsequent fracture in women and femoral neck bone mineral density, physical activity, and calcium intake were predictors in men. Conclusion After an initial low-trauma fracture, absolute risk of subsequent fracture was similar for men and women. This increased risk occurred for virtually all clinical fractures and persisted for up to 10 years (SLIDES 13-14) The FRAX tool has been developed by WHO to evaluate fracture risk of patients. It is based on individual patient models that integrate the risks associated with clinical risk factors as well as bone mineral density (BMD) at the femoral neck. The FRAX algorithms give the 10-year probability of fracture. The output is a 10-year probability of hip fracture and the 10-year probability of a major osteoporotic fracture (clinical spine, forearm, hip or shoulder fracture). Knowing fracture risk is valuable since the United States Prevention Services Task Force currently recommends testing BMD on all women 65 and older and All Fractures are Associated with Morbidity Death within one year 20% Nursing home placement 20% Permanent disability 30% 1. Cooper C, Am J Med, 1997;103(2A):12S-17S 2. Osteoporos Int DPI /s August Vertebral Fractures 1. Osteoporos Int DPI /s August Unable to walk independently 40% Unable to carry out at least one independent activity of daily living 80% Most common fracture type Often silent Insidious, progressive nature Associated with: Impaired breathing (restrictive lung disease) Altered abdominal anatomy (constipation, pain, distention, reduced appetite, premature satiety) Predict future spine and hip fractures Prior Vertebral Fracture Increases the Risk of New Fracture Incidence (%)* year Risk of New Fracture 1* Hip Pelvis Humerus Leg Spine Fracture Site 1.58 Wrist Overall *Based on Kaplan-Meier analyses. 1. Osteoporos Int. 2005;16: JAMA. 2001;285: J Bone Miner Res. 1999;14: Prior vertebral fracture increases fracture risk: Vertebral - 5-fold 2 Hip - 2-fold 3 FRAX WHO Fracture Risk Assessment Tool FRAX Tool Accessed 5/16/16. Interpreting the FRAX Results USPSTF recommends testing BMD on all women 65 and older and younger women whose fracture risk is =/> than that of a 65 year old white woman with no additional risk factors. FRAX Tool Accessed 5/16/ Slide 10 Slide Slide Slide USPSTF United States Prevention Services Task Force 14 Slide 14

4 The Impact of Untreated Osteoporosis For the patient 1 Increased risk of fracture 1 Reduced quality of life 1 Increased dependency 1 Pain and suffering 1 For the caregiver 2 Increased need to provide supervision and assistance if a fracture occurs For the facility 3 Increased costs Legal and regulatory issues 1. JAMWA. 2004;59: Arch Intern Med. 2002;162: Report of the Surgeon General. Available at: Accessed: December 7, Non-Pharmacological Approaches to Managing Osteoporosis Counsel on risk of osteoporosis and related fractures Advise on a diet that includes adequate total daily intake of calcium 1000mg daily for men years 1200mg daily for women 51+ years and men 71+ years Advise on Vitamin D intake 800 IU 1000 IU daily for individuals 50+ years Recommend regular weight-bearing and muscle-strengthening exercise to: Improve agility, strength, posture and balance Maintain or improve bone strength Reduce risk of falls and fractures Non-Pharmacological Approaches to Managing Osteoporosis Assess risk factors for falls and offer appropriate modifications Home safety assessment Balance training Avoidance of CNS depressant medications Careful monitoring of antihypertensive medications Visual correction when needed Advise on cessation of tobacco smoking and excessive alcohol Medications Associated with Adverse Effects on Bone Metabolism Aluminum (in antacids) Anticoagulants (heparin) Anticonvulsants Aromatase inhibitors Depo-medroxyprogesterone (premenopausal contraception) Lithium cyclosporine A and tacrolimus Proton pump inhibitors Tamoxifine (premenopausal use) Barbiturates Glucocorticoids (> 5mg/day prednisone or equivalent for > 3 months) Methotrexate Selective serotonin reuptake inhibitors Thiazolidinediones Risk Factors for Falling Lack of assistive devices in bathrooms Loose throw rugs Low level lighting Environment Risk Factors Cancer chemotherapeutic drugs GnRH (gonadotropinreleasing hormone) agonists Parenteral nutrition Thyroid hormones (in excess) Obstacles in the walking path Slippery conditions Medical Risk Factors Slide 15 Age Medications causing sedation (narcotic Anxiety and agitation analgesics, anticonvulsants, psychotropics) Arrhythmias Orthostatic hypotension Dehydration Poor vision Depression Previous falls or fear of falling Vitamin D insufficiency (<30 ng/ml) Reduced problem solving or mental acuity Malnutrition and diminished cognitive skills Urgent urinary incontinence Neurological and Musculoskeletal Risk Factors Kyphosis Reduced proprioception Poor balance Weak muscles/sarcopenia Impaired transfer and mobility Deconditioning Disease 16 Slide Slide Slide 18 younger women whose fracture risk is equal to or greater than that of a 65 year old white woman with no additional risk factors. (SLIDE 15) Osteoporosis can not only negatively impact patient s health, but also may increase demands on the senior care facility s staff and administration. For the resident, untreated osteoporosis increases the risk of fractures, which may reduce the quality of life. Increased falls are associated with increased fractures. For the facility, any fall or fracture may expose the facility to litigation and regulatory oversight issues, with the potential for increased costs Osteoporotic fractures, particularly vertebral fractures, can be associated with disabling pain. Quality of life issues include adverse effects on physical health (eg, skeletal deformity) and on financial resources. An osteoporotic hip fracture is associated with increased difficulty with the activities of daily life, as only one third of fracture patients regain their pre-fracture level of function and one third require placement in a nursing home. After a fall, patient performance of activities of daily living (ADLs) may decline (SLIDES 16-17) Non-pharmacological management of osteoporosis is a broad concept. It must be viewed as an essential part of the prevention of fractures from childhood through adulthood and the old age. A number of non-pharmacological approaches have been found to be effective in managing osteoporosis, including nutrients such as calcium and Vitamin D, physical exercise, lifestyle changes, fall prevention, and hip protectors. Diets deficient in calcium, proteins or vitamin D impair skeletal integrity. The effect of other nutriments is less clear, although an excessive consumption of sodium, caffeine, or fiber exerts negative effects on calcium balance. The deleterious effects of tobacco, excessive alcohol consumption and a low BMI are well accepted. Physical activity is of primary importance to reach optimal peak bone mass but, if numerous studies have shown the beneficial effects of various types of exercise on bone mass, fracture data as an endpoint are scanty. Fall prevention strategies are especially efficient in the community setting, but less evidence is available about their effectiveness in preventing fall-related injuries and fractures. The efficacy of hip protectors remains controversial. (SLIDE 18) Many drugs can affect bone metabolism. Examples listed in this slide such as heparin, warfarin, cyclosporine, glucocorticoids, medroxyprogesterone acetate, cancer drugs and thyroid hormone can cause bone loss through various methods. Whenever possible these drugs should be avoided or minimized when managing osteoporosis. (SLIDE 19) Most falls are caused by the interaction of multiple risk factors. The more risk factors a person has, the greater their chances of falling. Consultant pharmacists can lower a person s risk by reducing or minimizing that individual s risk factors. To prevent falls, pharmacists should focus FIRST on these modifiable risk factors: Lower body weakness Difficulties with gait and balance Use of psychoactive medications Postural dizziness Poor vision Problems with feet and shoes Home hazards 19 Slide 19

5 (SLIDE 20-22) It is important to have adequate calcium and vitamin D supplementation in osteoporosis treatment. The National Osteoporosis Foundation recommends elemental calcium dietary intake of 1200 mg per day in split daily dosing for postmenopausal women (those over 50 years old) and men over 70 years old. The recommended intake for vitamin D for this group is IU per day with a target 25(OH) Vitamin D level of at least 30 ng/ml. For women younger than 50 years old and for me younger than 70 years old, daily calcium intake of 1000ng and Vitamin D intake of IU is recommended. The Institute of Medicine (IOM) and the USPSTF have slightly different recommendations. Strategies for attaining target Vitamin D levels of ng/ml can vary based on the initial 25(OH)D levels. If current supplementation has levels < 20mg/ml, Vitamin D supplementation should be increased to 50,000 IU D2 three times weekly for 4 weeks, and increase supplemental D3 by 2000 IU daily. If 25(OH)D levels range from ng/ ml, increase D3 supplementation by 2000 IU daily. If 25(OH)D levels range from ng/ml, increase D3 supplementation by 1000 IU daily. Serum 25(OH)D levels should be reevaluated every 3 to 6 months. Calcium & Vitamin D Requirements Total daily calcium intake (in divided doses < 500mg at a time: Women: < 50 years Men: < 70 years 1000 mg Women: 50 years and older Men: 71 years and older 1200 mg Maximum of 2000mg/day Total daily vitamin D intake: Below 50 years: IU Above 50 years: IU up to 4000 IU IOM Vitamin D should be < 70yo 600iu > 71yo 800iu USPSTF current evidence does not support supplementation with D or Calcium to prevent fractures Elemental Calcium in Selected Supplements 20 Slide 20 Reasonable Approaches to Vitamin D Repletion Target serum 25(OH)D: ng/ml ng/ml; increase supplemental D 3 by 1,000 IU/day ng/ml; increase supplemental D 3 by 2,000 IU/day < 20 ng/ml; 50,000 IU D 2 3 times per week for 4 weeks and increase supplemental D 3 by 2,000 IU per day, repeat 25(OH)D ~3-6 months later For Faster Results: 50,000 IU D 2 once per week for eight weeks, or 50,000 IU D 2 three times per week for four weeks 21 Slide 21 Slide 22 Pepper, et. al, Endocrine Pract, 15;95-103, (SLIDE 23) All patients being considered for treatment of osteoporosis should also be: Counseled on risk factor reduction Importance of calcium, Vitamin D and exercise as part of treatment Evaluated for secondary causes of osteoporosis Have BMD measurements by central DXA when available and vertebral imaging when appropriate Biochemical markers when monitoring treatment effects is planned Considerations for Pharmacologic Therapy All patients being considered for treatment of osteoporosis should also be: Counseled on risk factor reduction Importance of calcium, Vitamin D and exercise as part of treatment Evaluated for secondary causes of osteoporosis Have BMD measurements by central DXA when available and vertebral imaging when appropriate Biochemical markers when monitoring of treatment effects is planned Slide (SLIDE 24) There are two basic approaches to treating osteoporosis; drugs that preserve existing bones (i.e., antiresorptive) or drugs that rebuild bone (i.e., anabolic). Antiresorptive medications slow bone loss by inhibiting the function of s. The main antiresorptive medications include bisphosphonates, denosumab and selective oestrogen receptor modulators. Teriparatide, a parathyroid hormone (PTH) analogue, is the first anabolic medication approved to treat osteoporosis. The choice of which approach to take for treatment should be based on T-score, history of previous fractures, and intolerance to or significant bone loss while on antiresorptive therapy. Normal Bone Remodeling: A Balance of Bone and Stage Osteoclast precursors O st eoclast s O st eoblast s Bone remodeling unit Activation Secondary mineralization Remodeling Completed 2 4 week s 3 4 months Adapted from: Rosen CJ. Available at: Accessed December 7, Slide 24

6 Normal Bone Remodeling: A Balance of Bone and Stage Osteoclast precursors Activation O st eoclast s O st eoblast s Bone remodeling unit Secondary mineralization Remodeling Completed 2 4 week s 3 4 months Adapted from: Rosen CJ. Available at: Accessed December 7, Osteoporosis: Exceeds Osteoclast precursors O st eoclast s Pits develop that weaken bone O st eoblast s 2 4 week s 3 4 months 1. Adapted from: Rosen CJ. Available at: Accessed December 7,2007. Bone remodeling unit Stage Activation Secondary Remodeling Mineralization Completed 25 Slide Slide 26 Bisphosphonates Block Osteoclasts: Reduce Bisphosphonate attaches to exposed bone mineral surfaces Stage Activation Bisphosphonate 1. Adapted from: Osteoporosis Int. 1999;Suppl 2:S66-S80. Bisphosphonates Medication Class Mechanism of Action Osteoclast takes up bisphosphonate loss of ruffled border, inactivation, detachment O st eoclast precursors Consider for O st eoclast New bone formation by osteoblasts renders bisphosphonate inert, inaccessible Secondary Remodeling Mineralization Completed I nact ivat ed ost eoclast Avoid in patients with O st eoblast Comments Bisphosphonate Antiresorptive First line Inability to remain Daily, weekly, or monthly (oral) Binds to therapy for upright for at least dosing Alendronate D,W hydroxyapatite most patients 30 minutes GI side effects: crystals in Prevention & Esophageal or esophagitis, dysphagia, Ibandronate D,M bone Treatment of swallowing abdominal pain, Risedronate D,W,M Inhibits postmenopausal or Inability or stomach, heartburn disorder diarrhea, upset activity corticosteroidinduced OP follow directions musculoskeletal pain unwillingness to May cause Inhibits resorption of Treatment of Hypocalcemia Associated rarely with bone and OP in men Renal Insufficiency jaw osteonecrosis and increases atypical thigh fracture bone density May reduce risk of Reduces breast cancer fracture risk Consider stopping after 5 years unless high risk (femoral neck T-score < -2.5 or previous vertebral fracture and femoral neck T-score -2 or lower D daily dosing, W weekly dosing, M monthly dosing OP - Osteoporosis 28 Bisphosphonates Medication Class Bisphosphonate (IM,IV) Ibandronate (Boniva) Zoledronic Acid (Reclast) Mechanism of Action Antiresorptive Binds to hydroxyapatite crystals in bone Inhibits activity Inhibits resorption of bone and increases bone density Reduces fracture risk Consider for patients Unable to take oral bisphosphonates due to GI issues Unwilling to follow oral bisphosphonate dosing instructions Avoid in patients with Hypocalcemia Renal Insufficiency 27 Slide 27 Slide 28 Comments Zoledronic acid given once a year for treatment, once every 2 years for prevention Ibandronate given once every 3 months for treatment (postmenopausal) Associated rarely with jaw necrosis and atypical thigh fracture Consider stopping after 3 years unless high risk (femoral neck T-score < -2.5 or previous vertebral fracture and femoral neck T-score -2 or lower Acute renal failure reported Acute flu-like reaction May cause musculoskeletal pain. (SLIDES 25-27) Normal bone remodeling is a homeostatic, coupled process comprised of bone resorption by s and bone formation by osteoblasts. The bone remodeling cycle is a tightly coupled process whereby bone is resorbed at approximately the same rate as new bone is formed. Basic multicellular units (BMUs) compose the remodeling unit of bone and include: s which stimulate bone resorption, and osteoblasts, which are responsible for new bone formation, The bone remodeling cycle begins with activation of resting osteoblasts on the surface of bone and marrow stromal cells. This is followed by a cascade of signals originating from the activated osteoblasts, to s and their precursors. The osteoblast functions not only to signal s during remodeling, but also to lay down collagen and orchestrate mineralization of previously resorbed lacunae in the skeletal matrix. In healthy adults as many as two million remodeling sites may be active at any given time, and it is estimated that nearly one fourth of all trabecular bone is remodeled each year. In general resorption takes only days, while formation is much more deliberate and can take upwards of three months. Under ideal circumstances, by the end of the cycle, the amount of bone resorbed equals the amount reformed. Osteoporosis is a disorder characterized by reduced bone mass, impaired bone quality and a propensity to fracture. Osteoporosis occurs when the balance between bone removal and replacement is altered, resulting in greater bone removal than replacement. The pathogenesis of primary osteoporosis centers on uncoupling of the remodeling sequence. Alterations at any stage along the process of recruitment, activation, differentiation or cell death can lead to imbalances in remodeling which eventually would result in bone loss or reduced bone mass Bone formation may be normal, suppressed, or slightly reduced in relation to an acceleration of resorption. When the remodeling process is uncoupled so that resorption exceeds formation, bone is lost. Bone loss as a result of aging/and or estrogen deficiency in menopause is the predominant pathophysiologic disorder of primary osteoporosis Frequent use of glucocorticoids in both men and women, contribute dramatically to the total number of individuals with very low BMD and/or osteoporotic fractures. In general resorption takes only days, while formation is much more deliberate and can take upwards of three months. Under ideal circumstances, by the end of the cycle, the amount of bone resorbed equals the amount reformed. (SLIDES 28-29) Bisphosphonates inhibit the differentiation or recruitment of precursors. Because mature s resorb bone, their inhibition slows bone resorption. Bisphosphonates: Inhibit metabolism Disrupt the cytoskeleton and ruffled border of s so that they cannot function to resorb bone Induce apoptosis of s Osteoblasts proceed with new bone formation, covering over the bisphosphonate and rendering it inert and inaccessible to s. Due to concerns about atypical femur fractures and the development of osteonecrosis of the jaw, which are relatively raw effects of bisphosphonate therapy related to dose and duration of therapy, a drug holiday may be considered after 3 5 years of bisphosphonate therapy in patients with moderate or low risk off fracture, because stopping bisphosphonates for a short period of time poses minimal risk to the patient Slide 29 29

7 (SLIDES 30-31) Estrogen actions on bone are complex. The major physiological effect of estrogen is to inhibit bone resorption. Bone cells have two kinds of intracellular steroid receptors for estrogen. When estrogen binds to the receptors, various genes become active. Estrogen also has effects that do not depend on activating the DNA. Estrogen effects may be mediated in part by growth factors and interleukins. For example, interleukin 6 is a potent stimulator of bone resorption, and estrogen blocks the osteoblast s synthesis of interleukin 6. Estrogen may also antagonize the interleukin 6 receptors. Transgenic mice without interleukin 6 do not develop osteoporosis after oophorectomy Estrogen and SERMS: Mechanism of Action in Bone Precursor (Osteoblast) osteoblast Cytokines IL-1, TNF-a IL-6, TGF-b Estrogens apoptosis Increase TNF-α TGF-β + Cytokines RANK-L Precursor (Osteoclast) Osteoclast apoptosis is regulated by estrogens. With estrogen deficiency, the s live longer and are therefore able to resorb more bone. In response to the increased bone resorption, there is increased bone formation and a high turnover state develops which leads to bone loss and perforation of the trabecular plates. Estrogen and SERMS Medication Mechanism of Consider for Avoid in patients Class Action with Selective Antiresorptive Prevention and Treatment Hot flashes Estrogen Blocks in women who are: History of venous osteoblast s Postmenopausal at high thromboembolism Receptor synthesis of IL6 risk of breast cancer Hip fracture is the Modulator which reduces Postmenopausal who primary concern. (SERM) cannot take activity bisphosphonate therapy Regulates In their 50s or 60s with concerns about longterm bisphosphonate apoptosis Inhibits bone therapy resorption Slide 30 Comments Analgesic effect May reduce risk of breast cancer Higher risk of vertebral fractures than hip fractures in women in their 50s and 60s Estrogen/HRT Antiresorptive Prevention of osteoporosis Tissueselective osteoporosis Antiresorptive Prevention of Estrogen Complex (conjugated estrogen/baze doxifene) Intended only for post-menopausal women with intact uterus. Use should be for the shortest duration consistent with treatment goals and risks. Side effects include: muscle spasms, nausea diarrhea, dyspepsia, pain, and dizziness (SLIDES 32-33) Teriparatide is currently the only FDA-approved anabolic agent that forms new bone. The mechanisms of action by which antiresorptive drugs confer protection against fractures differ fundamentally from the mechanism of fracture protection of teriparatide. Teriparatide preferential stimulates osteoblastic activity over ic activity stimulatating new bone formation on trabecular and cortical (periosteal and/or endosteal) bone surfaces. New bone is formed on surfaces that have not undergone a prior phase of bone resorption as well as at sites where remodeling is taking place. The bone-forming effects of teriparatide are manifest as an increase in skeletal mass, an increase in markers of bone formation and resorption, and an increase in bone strength. 31 Slide 31 Teriparatide [rdna origin] injection) Stimulates Osteoblasts: Rebuilds Bone 1. Stimulates formation of new bone independent of bone remodeling cycle O st eoclast s Stage 2. Increases bone turnover O st eoblast s Bone remodeling unit Activation 3. Stimulates osteoblast activity Secondary mineralization Remodeling Completed 2 4 week s 3 4 months Information regarding mechanisms of action does not provide evidence of comparative fracture protection. Adapted from: Rosen CJ. Available at: Accessed December 7, Slide 32 Parathyroid Affect Hormone Medication Mechanism Consider for Avoid in Comments Class of Action patients with Calcitonin Antireorptive Treatment in postmenopausal women of hip fracture flushing, and runny nose Primary concern Side effects include nausea, nasal spray Inhibits s Who cannot take Less than 5 years Not a first-line drug for OP. Reduces bone bisphosphonates postmenopausal Does not have strong resorption With bone pain from (not proven) fracture efficacy and has less vertebral compression effects on BMD than other fractures osteoporosis meds. Clinical significance of its relief of vertebral fracture pain unclear. Teriparatide Anabolic Treatment in patients Metabolic bone Daily SQ injection Stimulates with high fracture risk disease Side effects include nausea, osteoblasts With post-menopausal Paget s disease dizziness, headache, and leg over OP Previous skeletal cramps s With primary or irradiation Use for max of 2 years Builds new hypogonadal OP (men) Elevated alkaline Treatment course may be bone With cortico-steroidinduced OP unknown etiology Associated with osteo- phosphatase of followed by bisphosphonate Increases BMD and Especially those who Severe renal sarcoma in rats bone quality have failed or cannot impairment Analgesic effect take other agents Caution use in moderate renal impairment Expensive ($15,000 yr) 33 Slide 33

8 RankL Inhibition: Mechanism of Action in Bone Precursor (Osteoblast) osteoblast Cytokines IL-1, TNF-a IL-6, TGF-b RankL Cytokines RANK-L apoptosis TNF-α + Precursor (Osteoclast) (SLIDES 34-35) Denosumab, the first biologic introduced for osteoporosis treatment, is a fully human monoclonal RANKL antibody, and by binding to RANKL, it prevents the binding of RANKL to RANK; this leads to inhibition of activation and function. RANKL is a member of the tumor necrosis factor (TNF) superfamily, and both RANKL and RANK are expressed on T lymphocytes, B cells and dendritic cells. There is a theoretical risk that denosumab, in combination with other biologic agents, may increase the risk of infection. Most phase 2 and phase 3 trials of denosumab have not shown an increased risk of infection. 34 Slide 34 RankL Inhibitor Medication Mechanism Consider for Class of Action Denosumab Antiresorptive Treatment in patients Inhibits with high risk of RANKL which fracture (e.g., previous inhibits fracture, multiple risk factors) formation. With postmenopausal OP, especially those who have failed or can t/won t take bisphosphonates, such as those with renal insufficiency With prostate cancer, receiving androgen deprivation therapy With breast cancer, receiving an aromatase inhibitor Avoid in patients with Hypocalcemia Comments Subcutaneous injection every 6 months Dermatologic reactions and cellulitis reported Potential for jaw osteonecrosis and atypical fractures unknown Expensive (about $2000 per year) 35 Slide 35 Emerging Treatments for Osteoporosis Ospemifene Lasofoxifene Arzoxifene Odanacatib Monoclonal antibody cathepsin K inhibitor, the primary protease in s. Inhibits bone resorption without killing the, therefore signaling greater osteoblast activity. Carvacrol Potentiates apoptosis in mature s by caspase-3 activation and DNA fragmentation Strontium ranelate SERMS Increases collagen & noncollagen protein systhesis, enhances preosteoblast differentiation, reduces function Abaloparatide recombinant PTH Increases bone formation Osteoporosis Pearls Bisphosphonates have the best evidence for preventing spine or hip fractures. But some patients are reluctant to take them long-term due to news about possible atypical femur fractures and jaw osteonecrosis. Reassure patients that these problems are very rare. Continue to suggest a bisphosphonate first-line in most patients. Suggest stopping an oral bisphosphonate after 5 years in low-risk patients. Women who stop alendronate after 5 years have a similar risk of nonvertebral fractures as those who take it for 10 years. Suggest taking it longer for patients who still have osteoporosis...or those with a previous spine fracture and low bone density. Suggest another osteoporosis med when necessary. Raloxifene prevents spine fractures...but hasn't been shown to prevent hip fractures. Suggest raloxifene for women in their 50s or 60s. They're at low risk for hip fractures...and raloxifene reduces breast cancer risk. 36 Slide Slide 37 (SLIDE 36) Several novel medications utilizing different mechanisms of action are in development for the treatment of osteoporosis. Besides several monoclonal antibiodies and selective estrogen reuptake inhibitors on the horizon, new approaches include Cathepsin K, the main protease involved in ic degradation of protein bone matrix. Odanacatib is a selective inhibitor of Cathepsin K, thus inhibiting bone resorption, and has been found to significantly increase BMD and decrease incident fractures as compared with controls.[63] With odanacatib use, there may be uncoupling of bone remodelling as well. Carvacrol potentiates apoptosis in mature s by caspase-3 inhibition and DNA fragmentation. Strontium ranelate increases collagen and non-collagen protein synthesis to enhance preosteoblast differentiation and reduce function. Abaloparatide will be a second anabolic therapy based on PTH activity to increase bone formation. These medications, with unique mechanisms of action, not only increase the options for osteoporosis treatment but also open the door to potential improvements in treatment efficacy. (SLIDES 37-38) Bisphosphonates have the best evidence for preventing spine or hip fractures, but some patients are reluctant to take them long-term due to concerns about possible atypical femur fractures and jaw osteonecrosis. Reassure patients that these problems are very rare. Continue to suggest a bisphosphonate first-line in most patients. Suggest stopping an oral bisphosphonate after 5 years in low-risk patients. Suggest taking bisphosphonates longer for patient who still have osteoporosis or those with a previous spine fracture and low BMD. Raloxifene prevents spine fractures, but hasn t been shown to prevent hip fractures. Suggest raloxifene for women in their 50s and 60s.

9 Estrogen prevents spine and hip fractures, but at the risk of more strokes and breast cancer for women taking estrogen and progestin. Suggest using in women with postmenopausal symptoms. Calcitonin is often used for painful vertebral fractures, but it is not very effective for pain or fracture prevention. Denosumab seems to work about as well as bisphosphonates for spine fracture. The concern about increase infection risk seems to be less. Osteoporosis Pearls Estrogen prevents spine and hip fractures...but at the risk of more strokes and breast cancer for women taking estrogen plus progestin. Suggest saving estrogen for women who need it for menopausal symptoms...not just to prevent fractures. Calcitonin is often used for painful vertebral fractures. Explain that it's not very effective for pain or preventing fractures. Denosumab seems to work about as well as a bisphosphonate for spine fractures...but may increase infection risk. Teraparitide is likely the most effective med for spine fractures...but is not recommended for use beyond 2 years. Recommend for patients at high fracture risk. Continue to suggest adequate calcium and vitamin D. Teriparatide is likely the most effective medication for spine fractures, but is not recommended for use beyond two years. Continue to suggest adequate calcium and Vitamin D intake. 38 Slide 38 Goal-directed treatment of osteoporosis has been proposed on the basis of consideration of a certain BMD or fracture-free period as a defined treatment goal. Treatment goals could be potentially adopted to allow clinicians both to intensify therapy if treatment targets are not met and to reduce patient exposure to unnecessary duration of therapy. Dana Saffel, PharmD is President and CEO of PharmaCare Strategies, Inc., a market development firm that specializes in assisting pharmaceutical manufacturers, pharmacy providers, and pharmacists in positioning key products in specialty channels such as long-term care, managed care, Medicaid/Medicare and hospital markets. As a part of this role, Dr. Saffel provides disease management education specifically focused on the geriatric patient and their management in the long-term care environment. Dr. Saffel may be contacted at dana@pharmacarestrategies.com.