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Thomas Repas DO FACP FACOI FNLA FACE CDE Board Certified: Endocrinology, Diabetes and Metabolism Clinical Lipidology Nutrition Internal Medicine Regional.

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Presentation on theme: "Thomas Repas DO FACP FACOI FNLA FACE CDE Board Certified: Endocrinology, Diabetes and Metabolism Clinical Lipidology Nutrition Internal Medicine Regional."— Presentation transcript:

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

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

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4 Osteoporosis: Definition Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy.. JAMA. 2001;285:

5 Fracture Risk Depends on Bone Strength Increased bone turnover Reduced bone strength/ Increased fracture risk Decreased bone mass Decreased mineralization Increased cortical porosity Disrupted trabecular connectivity Lips P. Endocr Rev. 2001;22(4):477–501.

6 Clinical Presentation of Osteoporosis Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, Md: US Department of Health and Human Services; 2004: 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

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

8 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

9 Osteoporosis: Factors that increase risk of fracture Genetic or non- modifiable Age Female sex Asian or white ethnic origin Previous fragility fracture Family history of hip fracture Small frame National Osteoporosis Foundation. Fast facts on osteoporosis. Available at: Accessed August 13, 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

10 Annual Incidence of Osteoporotic Fractures in US National Osteoporosis Foundation. Fast facts on osteoporosis. Available at: Accessed February 7, Osteoporosis is a major public health threat with serious clinical consequences Osteoporosis is a major public health threat with serious clinical consequences 1.5 million fractures annually in the United States 1.5 million fractures annually in the United States One hip fracture increases the risk of a second hip fracture fourfold. One hip fracture increases the risk of a second hip fracture fourfold.

11 Consequences of Fractures 1.National Osteoporosis Foundation. Fast Facts on Osteoporosis. Available at: Accessed August 13, 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: 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

12 1-Year Risk of Refracture in Patients With Incident Vertebral Fracture Lindsay R, Burge RT, Strauss DM. One year outcomes and costs following a vertebral fracture. Osteoporos Int. 2005;16:78-85.

13 Osteoporosis: Prevalence 10 million in the US have established osteoporosis. 10 million in the US have established osteoporosis. 34 million additional people have low bone mass (osteopenia) 34 million additional people have low bone mass (osteopenia) National Osteoporosis Foundation. Fast facts on osteoporosis. Available at: Accessed February 7, 2007.

14 Osteoporosis: Prevalence By 2020, 61 million may have osteoporosis or low bone mass 14 million with established osteoporosis. 14 million with established osteoporosis. 47 million with low bone mass. 47 million with low bone mass. National Osteoporosis Foundation. Fast facts on osteoporosis. Available at: Accessed February 7, 2007.

15 Osteoporosis is underdiagnosed Morris CA, Carrino JA, Lang P, et al. Incidental vertebral fractures on chest radiographs. Recognition, documentation, and treatment. J Gen Intern Med. 2006;21: 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

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17 ISCD: Indications for Bone Mineral Density (BMD) Testing 2007 ISCD Official Positions AdultandPediatric.pdf 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.

18 ISCD: Indications for BMD Testing -continued ISCD Official Positions AdultandPediatric.pdf. 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

19 Bone Density Criteria for Diagnosing Osteoporosis Prevention and Management of Osteoporosis. Report of a WHO Scientific Group. WHO Technical Report Series 921. Geneva: World Health Organization, T-score = units of standard deviation (SD) that a patients 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 persons fracture risk by 1.5 to 2.5-fold.

20 Bone Density Criteria for Diagnosing Osteoporosis Prevention and Management of Osteoporosis. Report of a WHO Scientific Group. WHO Technical Report Series 921. Geneva: World Health Organization, Normal BMD: T-score of -1 or above. Normal BMD: T-score of -1 or above. Low bone mass (osteopenia) : T-score between 1 and 2.5. Low bone mass (osteopenia) : T-score between 1 and 2.5. Osteoporosis: T-score lower than 2.5. Osteoporosis: T-score lower than 2.5. Severe, or established, osteoporosis: T- score lower than 2.5 with fragility fractures Severe, or established, osteoporosis: T- score lower than 2.5 with fragility fractures.

21 Fragility Fracture and Osteoporosis Prevention and Management of Osteoporosis. Report of a WHO Scientific Group. WHO Technical Report Series 921. Geneva: World Health Organization, 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 ones standing height or less.

22 BMD Reporting in Females Prior to Menopause and in Males < 50 yrs 2007 ISCD Official Positions AdultandPediatric.pdf 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 Osteoporosis cannot be diagnosed in men under age 50 on the basis of BMD alone.

23 WHO Fracture Risk Assessment Tool WHO Fracture Risk Assessment Tool

24 Risk Factors used in the WHO FRAX® tool WHO Fracture Risk Assessment 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?

25 Risk Factors used in the WHO FRAX® tool 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)?

26 Risk Factors used in the WHO FRAX® tool 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).

27 Risk Factors used in the WHO FRAX® tool 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

28 WHO Fracture Risk Assessment Tool WHO Fracture Risk Assessment Tool

29 NOF Criteria for Initiating Medical Therapy for Low Bone Mass and Osteoporosis NOF Clinician's Guide to Prevention and Treatment of Osteoporosis: 1.A hip or vertebral (clinical or morphometric) fracture 2.T-score -2.5 at the femoral neck or spine after evaluation excluding secondary causes 3.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 Clinicians judgment and/or patient preferences also must also be taken into consideration

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31 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; Pharmacotherapy (antiresorptives and anabolics) Address Secondary Factors (drugs and diseases) Lifestyle Changes (nutrition, physical activity, and fall prevention) Osteoporosis Prevention and Treatment Preventing and Treating Osteoporosis

32 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.

33 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.

34 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.

35 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.

36 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.

37 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

38 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 National Osteoporosis Foundation.. Available at: Accessed February 7, Rogers MJ, Frith JC, Luckman P, et al. Bone. 1999;24(suppl):73S-79S. Papapoulos S, Frölich M. J Clin Endocrinol Metab. 1996;81:

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

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

41 Estrogen: Womens 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 Womens Health Initiative. JAMA. 2002; 288 (3):

42 Estrogen: FDA Recommendations When prescribing medications to prevent osteoporosis, clinicians should consider all non-estrogen preparations first. 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. 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. 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

43 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:

44 Effect of Raloxifene in Women with or Without Pre-Existing Fractures MORE Trial3 Years a Women who completed the study and had evaluable radiographs at 36 months. Ettinger B, et al. JAMA. 1999;282: % of Women with Incident Vertebral Fractures Raloxifene 60 mg/d Placebo Without Pre-Existing Vertebral Fracture RR 0.5 a (95% CI = 0.3–0.7) With Pre-Existing Vertebral Fracture RR 0.7 a (95% CI = 0.6–0.9) 30% 55%

45 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:

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

47 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.

48 Calcitonin: Effects on Fracture Nasal formulations 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 Chesnut CH 3rd, et al. Am J Med. 2000; Sep; 109 (4): N=1255 postmenopausal women with osteoporosis.

49 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

50 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 1.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 – Harris ST et al. JAMA 1999; 282:

51 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)

52 Effects of Bisphosphonates on Osteoclast Function 1.Rogers MJ, Frith JC, Luckman SP, et al.. Bone. 1999;24(suppl 5):73S-79S. 2. Fleisch H.. Endocr Rev. 1998;19: Sato M, Grasser W, Endo N, et al.. J Clin Invest. 1991;88: Rogers MJ Curr Pharm Des. 2003;9(32): Hughes DE, Wright KR, Uy HL, et al. J Bone Miner Res. 1995;10: Normal Osteoclast Osteoclast after uptake of bisphosphonate

53 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: Atelvia TM

54 Poor Compliance and Persistence Lead to Compromised Fracture Risk Reduction Siris ES, Harris ST, Rosen CJ, et al. Mayo Clin Proc. 2006;81:

55 Refill Compliance and Fracture Protection Over 24 Months for Bisphosphonate-Treated Patients Siris ES, Harris ST, Rosen CJ, et al. Mayo Clin Proc. 2006;81:

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

57 Bisphosphonates: Side effects, contraindications and other concerns Side effects: 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?

58 Denosumab Human monoclonal antibody-IgG 2 isotype Human monoclonal antibody-IgG 2 isotype High affinity and specificity for human RANK ligand High affinity and specificity for human RANK ligand Does not bind to TNFα, TNFβ, TRAIL, or CD40L Does not bind to TNFα, TNFβ, TRAIL, or CD40L Pharmacokinetics (SC): similar to other fully human IgG 2 monoclonal antibodies Pharmacokinetics (SC): similar to other fully human IgG 2 monoclonal antibodies Absorption is rapid and prolonged (C max 1–4 wks postdose) Absorption is rapid and prolonged (C max 1–4 wks postdose) Long half-life 34 days with maximum dose Long half-life 34 days with maximum dose Distribution intravascular volume Distribution intravascular volume Clearance reticuloendothelial system Clearance reticuloendothelial system No kidney filtration or excretion of intact molecule No kidney filtration or excretion of intact molecule Bekker PJ, et al. J Bone Miner Res. 2004;19: Boyle WJ, et al. Nature. 2003;423: Abbreviations: TNF, tumor necrosis factor; TRAIL, TNF-related apoptosis-inducing ligand.

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

60 Denosumab: Serum Levels (1 mg/kg SC) Bekker PJ, et al. J Bone Miner Res. 2004;19: Study Month Serum Level (ng/mL) EC 50

61 Denosumab: Effects 68% decrease in vertebral fractures 2.3% vs 7.2%, P < % decrease in hip fractures 0.7% vs 1.2%, P = % 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.

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

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

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

65 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 Approximately doubles rate of bone formation in patients with osteoporosis 1.Neer RM, et al. N Eng J Med. 2001; 344: Forteo (teriparatide [rDNA origin] injection) prescribing information. Eli Llly and Co; September 2004.

66 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. 1.Neer RM, et al. N Eng J Med. 2001; 344: Forteo (teriparatide [rDNA origin] injection) prescribing information. Eli Llly and Co; September 2004.

67 Effect of Teriparatide on Risk of Vertebral Fractures in Postmenopausal Women PlaceboTeriparatide 20 µg % of Patients with 1 Fracture RR 0.35 (95% CI = 0.22–0.55) a 65% a P <.001 vs placebo. Neer RM, et al. N Engl J Med. 2001;344: Adapted from graphic by Dr. Paul Miller.

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

69 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 1.Neer RM, et al. N Eng J Med. 2001; 344: Forteo (teriparatide [rDNA origin] injection) prescribing information. Eli Llly and Co; September 2004.

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

71 Teriparatide: Side Effects and Adverse Events Side effects: 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

72 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

73 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?

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75 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?

76 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 appearance 1 No uniform diagnostic criteria currently applied Ruggiero S, et al. J Oncol Practice. 2006;2:7-14.

77 Osteonecrosis of the jaw: Signs and symptoms 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.

78 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.

79 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.

80 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 Pagets disease Black DM, et al. N Engl J Med. 2007;356: Grbic J, et al. J Am Dent Assoc.2008;139 (1): Watts N et al. J Clin Endocrinol Metab, April 2010, 95(4):1555–1565..

81 Osteonecrosis of the jaw: Bisphosphonates Only 1 study was prospectively designed to look at adjudicated incidence of ONJ 1,2 HORIZON-PFT examined efficacy of zoledronic acid in 7736 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.

82 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

83 Osteonecrosis of the jaw: Prevention 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

84 Osteonecrosis of the jaw: Prevention 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

85 Atypical femur fractures Background Case reports of unusual low-energy sub- trochanteric 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.

86 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.

87 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.

88 Atypical femur fractures 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

89 Atypical femur fractures 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.

90 Bisphosphonate Drug Holiday Not a topic of discussion when bisphosphonates first launched Became a consideration after July 9, 2002 (WHI JAMA publication) Became more widely discussed after FLEX (Black et al, JAMA 2004) and better science defining bisphosphonate PK/PD became available FRAX TM 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.

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

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

93 Bisphosphonate Drug Holiday. 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.

94 Bisphosphonate Drug Holiday. 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.

95 Bisphosphonate Drug Holiday. 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.

96 Bisphosphonate Drug Holiday. 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.

97 Bisphosphonate Drug Holiday. 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.

98 Bisphosphonate Drug Holiday. 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 Treatment was indicated, but after 8 yr of treatment, a drug holiday might be considered.

99 Bisphosphonate Drug Holiday. 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.

100 Bisphosphonate Drug Holiday. 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.

101 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 American Association of Clinical Endocrinologists Guidelines for Clinical Practice for the Diagnosis and Treatment of Postmenopausal Osteoporosis © 2010

102 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). Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, Md: US Department of Health and Human Services; 2004:

103 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 American Association of Clinical Endocrinologists Guidelines for Clinical Practice for the Diagnosis and Treatment of Postmenopausal Osteoporosis © 2010

104 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 American Association of Clinical Endocrinologists Guidelines for Clinical Practice for the Diagnosis and Treatment of Postmenopausal Osteoporosis © 2010

105 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 American Association of Clinical Endocrinologists Guidelines for Clinical Practice for the Diagnosis and Treatment of Postmenopausal Osteoporosis © 2010

106 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 American Association of Clinical Endocrinologists Guidelines for Clinical Practice for the Diagnosis and Treatment of Postmenopausal Osteoporosis © 2010

107 How often should Follow-up DXA be obtained? NEJM: Jan 19, 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.

108 How often should Follow-up DXA be obtained? 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.

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110 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

111 Pharmacotherapy for osteoporosis Summary 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

112 Pharmacotherapy for osteoporosis Summary human monoclonal antibody 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

113 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

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


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