1. Top 10 Questions About Bobo Tanner MD Director, Osteoporosis Clinic Division of Rheumatology & Allergy Vanderbilt University Medical Center Nashville TN April 21, 2016

2.  1. Describe the evaluation of osteoporosis  2. Formulate a patient-centered and evidence- based treatment plan  3. Focus on issues of particular importance to the PCP such as prevention, therapeutic lifestyle changes and health maintenance

3.  70 yo w female  Fell at home ( tripped over dog)  Left femur fracture  Hospitalized: open reduction, internal fixation  2 weeks rehab hospital  3 months home care, walker, forgetful  4 months assisted living, does not recognize family  Hospitalized, UTI, pneumonia, sepsis  expired

4. 1 Consensus Development Conference: Diagnosis, Prophylaxis, and Treatment of Osteoporosis. Am J Med 1991;90:107-110 2 Kanis JBMR 1994 Defining Osteoporosis: Most common metabolic bone disease in adults Functional definition: A systemic skeletal disease characterized by low bone mass and micro-architectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture (fragility fracture). 1 Fragility fracture: Fracture after fall from a standing height Quantitative Definition: WHO T-score <-2.5 2 Normal Bone Osteoporotic Bone

5. 1. Death 2,6 Mortality rate same as breast cancer 2. Disability 1,2 50% incapacitation 3. Dependence 1,2 20% of females need assisted living or nursing home 4. Delirium & dementia 3,4,5 40% to 60% risk of delirium 41% higher rate of dementia 1 www.share.iofbonehealth.org/WOD/2012 2 Cooper C, et. al., Am J Epidemiol 1993;137:1001 3 Gustafson et al.. J Am Geriatr Soc 1988;36:525–530. 3 Givens et al J Am Geriatr Soc. 2008 Jun;56(6):1075-9 4 Tsai C et al, Medicine 2014 93(26) :1-7 5 Marcantonio et al J Am Geriatr Soc. 2011 Nov;59 Suppl 2:S282-8 6 Panula et al BMC Musculoskeletal Disorders 2011, 12:105

6. www.slideshare.net/clarityproducts/clarity-2007- aging-in-place-in-america-2836029 Phone survey: ~800 older US adults in 2007 What do you fear most? Loss of independence: 26% Moving out of home into nursing home: 13% Giving up driving: 11% Loss of family/friends: 11% Death: 3% Diagnosis & Treatment Goal: Reduce the Risk of Fracture

7. The Osteoporotic Event: Hip Fracture Prevention: Understand the Causes

8. Haddad JG, Kaplan FS Journal of Clinical Rheumatology 2(1):33-40 1996 …trending on Twitter #osteoporosis

9. #1. When Should Bone Density Testing Be Performed?

11.  Multiple sites  Spine  Hip  Forearm  Total body  Considered the clinical standard “Gold Standard”

13. Osteoporosis : T-score World Health Organization (WHO) Classification Postmenopausal Caucasian with DXA measure WHO Study Group JBMR 1994

14. 1. Women with estrogen deficiency 2. Spine x-ray evidence of fracture or OP 3. Glucocorticoid therapy (3mos, >5mg/d) 4. Primary Hyper-PTH 5. Follow-up treatment (23 months unless medical reason for sooner e.g. steroids)

16. Which Woman is at Higher Fracture Risk? 54 year old smoker with a T-score of -2.0 or 81 year old with no prior fracture with a T- score of -1.4 10 year risk of hip fracture = 2.5%; major osteoporotic fracture = 10% 10 year risk of hip fracture = 3.2%; major osteoporotic fracture = 26%

17.  Frequency of falls  Inability to arise from sitting w/out hands  Bifocals  Diabetes mellitus  Chronic use of PPI  Chronic Use of SSRI  Chronic use of anti-seizure medications

18. #2. Which Lab tests should you order ?

19. 1. CBC 2. Liver Function Tests 3. Creatinine 4. Calcium 5. Phos 6. TSH 7. PTH 8. 25-OH Vitamin D 9. (24 hr. urine calcium, magnesium, phos, creatinine)

20.  In 664 peri/postmenopausal♀, T-score < –2.5  53% had secondary osteoporosis by history With lab testing:  12% had previously unrecognized factors including low vitamin D ( < 20 ng/ml)*  Conclusion: Previously undiagnosed disorders are common 20 Tannenbaum C. J Clin Endocrinol Metab. 2002;87(10):4431. *Luckey, personal communication

21. #3. Reducing the Risk of Fracture : Is estrogen therapy effective after age 65?

22.  Bone benefit occurs even late in life  10-20% non-responders  But “wash out” effect when discontinued  Overshadowed by Women’s Health Initiative results : risks of C-V dz, breast cancer

23. #4. Since the FDA recommends estrogens for short term use only, what are the options for osteoporosis and osteopenia treatment?

24. 2–4 weeks 3–4 months Resting Stage Reversal Phase Formation Remodeling Completed ActivationResorption Lining cells Osteoclast precursors Activated Osteoclasts Osteoblasts Bone remodeling unit 1. Marcus R. In: Hardman JG et al. Goodman & Gillman’s The Pharmacologic Basis of Therapeutics. 10 th ed. McGraw-Hill; 2001:1715–1743. 2. Tanaka Y et al. Curr Drug Targets Inflamm Allergy. 2005;4:325–328. 3. Rosen CJ. Available at: http://www.endotext.org/parathyroid/index.htm. Accessed March 15, 2006.http://www.endotext.org/parathyroid/index.htm Lining cells Treatment Targets

25. DrugPost Menopausal OPSteroid OPMale OP PreventionTreatmentPreventionTreatment Alendronate Risedronate Ibandronate Zoledronic acid Raloxifene Estrogen Calcitonin* * Under review Denosumab Teriparatide

26. #5. How long should a patient stay on treatment?

27.  Monitor with repeat DXA scans q 1-2 years  Monitor Bone Turnover Markers (N-telopeptide, Procollagen 1 N-terminal Peptide (P1NP) Osteocalcin, Alkaline Phosphatase)  7-10 year bisphosphonate data:  “ Drug Holiday” after 5 yrs?  10 year Denosumab data  3 year Teriparatide data Safety Concerns with bisphosphonates & denosumab:  Osteonecrosis of the jaw (ONJ)?  Atypical subtrochanteric fractures?

28.  Signs &Symptoms: 1  Asymptomatic or  Facial pain, jaw pain  Soft-tissue swelling,drainage  Exposed,necrotic bone  Cultures: actinomyces 2  Risk factors  Cancer & concomitant therapies  Poor oral hygiene  Smoking  Pre-existing dental disease, anemia, coagulopathy, and infection  Management  Povidone-iodine & 0.12% chlorhexidine mouthwash  Oral antibiotics and anti-inflammatory drugs  Conservative debridement for necrotic tissue Ruggiero SL, Hehrotra B, Rosenberg TJ, et al. J Oral Maxillofac Surg. 2004;62:527-34. 1. Expert Panel Recommendations for the Prevention, Diagnosis, and Treatment of Osteonecrosis of the Jaws: June 2004 2. Naveau A. Joint Bone Spine 2005. Melo MD, Obeid G. J Can Dent Assoc 2005;71: 11-3.

29. Kanis JA et al. Osteoporos Int. 2001;12:417-427. Pharmcoepidemiol Drug Saf. 2003;12:195-202. National Center for Health Statistics. JADA. 2006;137:1144-1150. www.nssl.noaa.gov/papers/techmemos/NWS-SR-193/techmemo-sr193-4.html (1) Women age 65-69 (from Swedish National Bureau of Statistics and database of Olmsted County, MN, USA.) 0.6 0.7 6 11 32 387 2668 0102030405060708090100 Death by Lighting Strike ONJ- Osteoporosis Patient Death by Murder Death by MVA Anaphylaxis from Penicillin Shot Hip Fracture (1) Any Fragility Fracture (1) Risk per 100,000 People per Year

30.  Rare  Low energy or spontaneous  Subtrochanteric,arbitrarily 5cm below l. troch  Thickened lateral cortex (often bilat.)  Transeverse or spiral fracture  “beak” assoc. with stress fracture  Thigh pain before fracture  Often 5-10 years of bisphos. use Goh JBJS 2007, Nevaiser J Ortho Truama 2008, Somford JBMR 2009, Capeci JBJS 2009, Lenart Osteoporosis International 2009, Koh J Ortho Trauma 2010 Bukata S ISCD Ann Mtg San Antonio 2010

31. Goh SK. JBJS 2007;89:349

33. #6. What should be done if a patient does not respond to treatment?

34.  The International Osteoporosis Foundation recommends changing treatment if : 1. Two or more incident fragility fractures occur 2. One fracture occurs, there is a significant decrease in Bone Density and/or no reduction in Bone Turnover Markers (BTMs) 3. Both a significant decrease in Bone Density and no significant decrease Bone Turnover Markers (BTMs) BTMs = serum P1NP or C-Telopeptide Diez-Perez, et. al, Osteoporos Int, 23:2769-, 2012

35.  Stable BMD or BMD is a good response  Review compliance /adherence  Review the diagnosis  Lab work : CBC, Chemistry, Phos, TSH, PTH, 25-OH Vitamin D, 24 hr. urine calcium,magnesium,phos,protein immunoelectropheresis  Switch treatment : IV? subcutaneous? anabolic?  New agents under study:  anti-cathepsin K ( odanacatib)  anti- sclerostin (romosozumab )

36. Prefusion osteoclast Adapted from Boyle et al. Nature. 2003;423:337. CFU-M Multinucleated osteoclast RANKL BONE RANKL DenosumabRANK Active Osteoclast Osteoblast

37. Anabolic agent Daily injection for two years Safety issues: 2-year rat study: developed osteosarcomas Teriparatide not for patients with: 1. Paget’s disease 2. Prior radiation therapy 3. Immature skeleton

38. #7. When should combination therapy be used?

39.  2 antiresorptive drugs may be additive (BMD)  Alendronate + estrogen  Alendronate + raloxifene  Risedronate + estrogen  Caveat  No fracture data  Increased cost  Possible increased side effects  Combination of antiresorptive and anabolic agents theoretically attractive: but data is specific for certain agents  No advantage to alendronate + teriparatide combination  Synergy with denosumab + teriparatide combination Black DM, et al. New Engl J Med. 2003;349:1207. Leder BZ, et al. J Clin Endocrinol Metab 2014; 99: 1694–700.

40. #8. What is the role of Calcium supplementation?

41.  Evidence suggests that calcium + vitamin D supplementation reduces bone loss and fractures  Some studies suggest that calcium supplements (not dietary) may increase vascular disease risk  Effects on vascular disease are controversial and expert opinion is divided  Calcium is a simple first step in promoting bone health;  consume 1000-1200 mg daily preferably from food sources,  supplements should be used when an adequate dietary intake cannot be achieved Institute of Medicine. 1997. Washington, DC, Academy Press

42. Ettinger Annals Int Med 1988 Calcium is necessary but not sufficient for treatment of Post Menopausal Osteoporosis See also N Engl J Med Volume 354;7:669-683 February 16, 2006

43. #9. What is the role of Vitamin D supplementation?

44. Critical for normal calcium absorption & mineralization of osteoid (type I collagen) Storage form measured as 25-OH Vitamin D Goal : 32ng/ml: ↓ PTH, ↑ calcium absorption Also affects muscle strength Risk factors for deficiency: – Inadequate diet, sunlight, high BMI – Anticonvulsant therapy, liver dz, – Malabsorption (celiac disease)

45. Storage form

46.  Aging  skin less effective as a source  dietary intake reduced  GI tract less effective absorption  Renal activation declines  Replenish with 50,000 International Units once a week for 8 weeks  Maintenance with 1,000 units daily  Vitamin D 3 is more ”potent” than D2  Other vitamins and minerals may be helpful; Magnesium, K, B12  but excessive Vitamin A appears to increase fracture risk Bischoff-Ferrari H. et al. JAMA. 2005;293(18):2257-2264 Janssen HCJP, et al. Am J Clin Nutr. 2002;75:611

47. #10. How does one treat an elderly patient with severe, established osteoporosis?

48. 0.0 1.0 2.0 036912 Months % of Patients with Fractures Control Risedronate * * * 69%. Watts N, et al. J Bone Miner Res. 2001;16(suppl 1):S407..

49.  Insert needle into vertebral body  Inflate balloon  Create a cavity, deflate & withdraw balloon  Inject methyl methacrylate

50. Cumulative Hazard of Hip Fractures Months 54% reduction* Kannus P, et al. N Engl J Med 2000; 343:1506-1513 Hip Protectors *P=0.008 1801 elderly men and women in long stay or supported home care

51. 1. Early death is associated with fragility fractures 2. DXA scans predict fracture risk & monitor response to treatment 3. Therapeutic intervention can reduce fracture risks & mortality 4. Calcium & Vitamin D are essential but may not be sufficient