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The Three Ages of Woman Gustav Klimt, 1905

Osteoporosis 2013 – Where Are We Now?. Mary Zoe Baker, M.D. The Three Ages of Woman Gustav Klimt, 1905. Disclosures. Industry Research Support to Institution – VM BioPharma, Novo Nordisk, Merck Sharp & Dohme Corp., Boehringer-Ingelheim, Corcept Therapeutics, Inc., Pfizer, Inc.

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The Three Ages of Woman Gustav Klimt, 1905

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  1. Osteoporosis 2013 – Where Are We Now? Mary Zoe Baker, M.D. The Three Ages of Woman Gustav Klimt, 1905

  2. Disclosures • Industry Research Support to Institution – VM BioPharma, Novo Nordisk, Merck Sharp & Dohme Corp., Boehringer-Ingelheim, Corcept Therapeutics, Inc., Pfizer, Inc. • Consultancies, Financial Holdings or Speaker’s Bureau – None • Discussion of unlabeled use of drugs - None

  3. Objectives • To identify the optimal treatment plans and duration of treatment for common osteoporosis (OP) drugs. • To describe how to apply the FRAX fracture assessment tool to clinical practice. • To recognize the risk factors for atypical femoral shaft fractures.

  4. Incidence of Osteoporotic Fractures in Women 40 30 20 10 Vertebrae Annual incidence per 1000 women Hip Wrist 50 60 70 80 Age (Years) Wasnich RD, Osteoporos Int 1997;7 Suppl 3:68-72

  5. Osteoporotic Fractures:Comparison with Other Diseases Annual incidence all ages 2000 1 500 000 1500 250 000hip Annual incidence x 1000 250 000forearm 1000 annual estimate women 29+ 250 000 other sites 513 000 annual estimate women 30+ 500 1996 new cases, all ages 750 000 vertebral 228 000 184 300 0 Osteoporotic Fractures Heart Attack Stroke Breast Cancer American Heart Association,1996 American Cancer Society,1996 Riggs BL & Melton LJ 3rd, Bone, 1995;17(5 suppl):505S-511S

  6. All fractures are Associated With Morbidity Unable to carry out at least one independent activity of daily living 80% One year after an hip fracture: Patients (%) Unable to walk independently 40% Permanent disability Death within one year 30% 20% Cooper C, Am J Med, 1997;103(2A):12S-17S

  7. Vertebral Fractures • Most common fracture type • Often silent • Insidious, progressive nature • Associated with significant morbidity • Predict future spine and hip fractures • Associated with 2-fold increase in risk of death

  8. WHO Criteria for Diagnosis of Bone Status Diagnostic criteria*Classification T is above or equal to -1 Normal T is between -1 and -2.5 Osteopenia (low bone mass) T is -2.5 or lower Osteoporosis T is -2.5 or lower + fx = Severe or est. osteoporosis *Measured in "T scores." T score indicates the number of standard deviations below or above the average peak bone mass in young adults.

  9. 10-Year Fracture Risk: Age and BMD AGE 20 For a given BMD, risk increases with age 80 15 70 10 Hip fracture risk (% per 10 Years) 60 5 50 0 -3 -2.5 -2 -1.5 -1 -0.5 0 0.5 1 BMD T-score Kanis JA et al, Osteoporos Int, 2001;12:989-995

  10. WHO Absolute Fracture Risk Model FRAX • Estimates absolute fracture risk using epidemiology of osteoporosis, risk factors and therapeutic data. • By basing treatment decisions on fracture probability, therapy can be targeted to those who would receive the greatest benefit. • Calculation tool is online and calculates the 10 year risk for hip fractures and any osteoporosis related fracture. • Using a series of clinical questions, BMD data, weight and height the tool calculates these risks for individual patients. • Treatment is recommended for a 10 year hip fracture risk over 3% and a 10 year osteoporotic fracture risk over 20%.

  11. Screening for Osteoporosis: U.S. Preventive Services Task ForceRecommendation Statement • Recommendations: The USPSTF recommends screening for osteoporosis in women aged 65 years or older and in younger women whose fracture risk is equal to or greater than that of a 65-year-old white woman who has no additional risk factors. (Grade B recommendation). • The USPSTF recommends using a 10-year fracture risk threshold of 9.3% to screen women aged 50 to 64 years. Ann Intern Med. 2011;154:356-364.

  12. New England Journal of Medicine. 366(3):225-33, 2012 Jan 19.

  13. Management of PMO: Goals of Therapy • Prevent first fragility fracture or future fractures if one has already occurred • Stabilize/increase bone mass • Relieve symptoms of fractures and/or skeletal deformities • Improve mobility and functional status • Initiate lifestyle changes to enhance prevention of fractures • Smoking • Alcohol

  14. Osteoclast Osteoblast Inhibition of resorption Stimulation of formation Pharmacologic TreatmentTargets

  15. Inhibit bone resorption Maintain or increase bone mass Reduce fracture risk Increase bone formation Maintain or increase bone mass Reduce fracture risk Pharmacologic Treatment of OP: Overview Treatment Action Estrogen replacement therapy Selective estrogen receptor modulators (SERMs) Calcitonin Bisphosphonates Denosumab Parathyroid hormone

  16. Pharmacologic Treatment of PMO: Overview

  17. Pharmacologic Treatment of PMO: Overview Denosumab Strong evidence Strong evidence Strong evidence Treatment Ann Intern Med. 2008;149:404-415

  18. Osteoporosis TreatmentsFracture Reduction • Alendronate 52% • Risedronate 49% • Ibandronate 56% • Evista 50% • Calcitonin 36%

  19. Monitoring Response to Therapy • BMD • May not tell the whole story • Remember rate of change must be greater than the precision of the densitometric method • Unclear if bone density changes reflect the whole picture • May want to repeat BMD in another year before changing therapy • Bone Markers • High variability make use in individual patients risky • May have a role in younger women

  20. It’s Not All Bone Density • Similar changes in BMD may not translate into consistent efficacy for reduction in fracture risk when comparing agents eg. Fluoride • Patients with higher bone turnover may be at higher risk of fracture eg. glucocorticoids even with a normal bone mineral density • Bone density may not capture all aspects of fracture reduction eg. Sensory or drug effects

  21. Bisphosphonate Therapy - Risks • Initial studies taken to the FDA to gain approval for these drugs identified a lower than expected risk of GI side effects • No unexpected side effects were seen in these studies • However, about 15 years ago, cases of osteonecrosis of the jaw which dentists had not seen for a least a century, began to appear • Subsequently, the possibility of an increased risk of atypical femur fractures in patients treated with these drugs was proposed.

  22. ONJ • Exposed necrotic bone in the maxillo-facial region • Not healing after 6-8 weeks in patients with no hx of craniofacial radiation • Exposed yellow-white hard bone with smooth or ragged borders, often in the site of dental extraction or other invasive dental procedure with poorly fitting dentures • Over 90% of reported cases in cancer patients receiving BP doses 10X higher than used to treat osteoporosis • Estimated incidence in OP: 1:10,000-1:100,000 Khosla et al. ASBMR Rask Force, JBMR 2008;23:159. Woo S-B et al, Ann Intern Med 2006;144:753-761.

  23. Femoral Shaft Fractures • In 2005, Odvina et al reported a series of nine patients with spontaneous, atypical fractures, all on bisphosphonate therapy for a period of time ranging from 3 to 8 years. • Four with fractures in the subtrochanteric region and one each with fractures of the sacrum, rib, ischium, pubic rami and lumbar spine. • 6/9 had delayed or absent healing during management. • Histology revealed over suppression of bone turnover, possibly linked to bisphosphonate usage, but other factors, i.e.. estrogens and glucocorticoid use left much room for debate. Odvina et al JCEM2005;90:1294–1301

  24. Figure 1 Figure 1 . Radiographs of Fractures of the Femoral Shaft Showing the "Simple with Thick Cortices" Pattern Panel A shows a fracture of the femoral shaft in an 83-year-old woman with a 9-year history of alendronate use. Panel B shows a similar fracture in a 77-year-old woman with a 5-year history of alendronate use. Atypical Fractures of the Femoral Diaphysis in Postmenopausal Women Taking Alendronate. Lenart, Brett; Lorich, Dean; Lane, Joseph New England Journal of Medicine. 358(12):1304-1306, March 20, 2008.

  25. Femoral Shaft Fractures • Usually occur in the proximal third of the femoral shaft • May have a prodrome of thigh pain • Often bilateral or sequential • X-rays prior to fracture may reveal some beaking of the cortex and cortical thickening of the proximal femoral shaft. • Early identification may require intervention – but exactly what is unclear

  26. Atypical Femoral Fracture A B C D Conventional AP radiograph of the pelvis (A) shows bilateral focal cortical thickening from periosteal new bone formation (arrows). Corresponding bone scintigraphy (B) demonstrates focal increased radionuclide uptake in the proximal lateral femoral cortices (arrows). MRI images of the femurs (C) demonstrate subtle decreased signal on T1-weighted and increased signal on T2-weighted images only of the right femur on this section. Similar findings on AP DXA hip images (D) show focal bilateral cortical thickening consistent with early, evolving femoral insufficiency fractures. Shane et al, JBMR 25:2010;25:2267–2294.

  27. Bisphosphonate Use and the Risk of Subtrochanteric or Femoral Shaft Fractures in Older Women L. Park-Wyllie, PharmD, MS, M. Mamdani, PharmD, MA, MPH, D. Juurlink, MD, PhD, G. Hawker, MD, MSc, N. Gunraj, MPH, P. Austin, PhD, D. Whelan, MD, MSc, P. Weiler, MD, MASc, P Eng. Laupacis, MD, MSc Population-based, nested case-control study in a cohort of women aged 68 years or older from Ontario, Canada treated with oral bisphosphonate between April 1, 2002, and March 31, 2008. Primary analysis - association between hospitalization for a subtrochanteric or femoral shaft fracture and duration of bisphosphonate exposure Secondary analysis - association of bisphosphonate use and classic intertrochanteric or femoral neck fractures JAMA. 2011;305(8):783-789

  28. Summary • 716 (0.35%) suffered a subtrochanteric or femoral shaft fracture after receiving bisphosphonate therapy. • Cases were matched with 3580 controls • Bisphosphonate treatment to prevent typical femoral fractures should last at least 5 years. • Bisphosphonate treatment for more than 5 years begins to increase the risk for atypical femoral shaft fractures which are still extremely rare. JAMA. 2011;305(8):783-789

  29. Atypical Fractures • Can occur in BP naïve patients • 6% of cases reviewed by ASBMR Task Force had no BP exposure • Most case series include a minority with no BP exposure • Occur in other bone diseases

  30. Bisphosphonates: Decreased Mortality • IV – Post-hip fracture: 28% Decreased RR • PO - Post-hip fracture: 63% decreased relative risk/year of Rx • Dubbo OP Study: Decreased Mortality in women, possibly in men • Institutionalized elders:HR [0.7390.56-0.940] Lyles, NEJM 357:1799,2007 Beaupre OI 22:983,2011 Center JCEM 96:1006,2011 Sambrook OI 22:2551,2011

  31. Bisphosphonate Therapy Benefits • Decreased risk of breast cancer • Decreased risk of colorectal cancer • Decreased risk of stroke • Decreased risk of gastric cancer • Decreased overall mortality Nelson Watts – Endocrine Society National Meeting - 2012

  32. Bisphosphonates for Osteoporosis — Where Do We Go from Here? • The available data do not identify patients likely to benefit from treatment beyond 3-5 years. • … decisions to continue treatment must be based on individual assessment of risks and benefits and on patient preference. NEJM 366:2048, 2012

  33. How Long to Treat With Bisphosphonates? • Patients who did not need treatment in the first place • Discontinue Treatment • Lower risk patients, if DXA is stable/increasing • Consider a drug holiday after 3-5 years of treatment • Higher risk patients (fractures, corticosteroid Rx, very low BMD) • Consider a drug holiday after 10 years of therapy • May use teriparatide or raloxifene (but not another potent antiresorptive agent – ie. denosumab) during the holiday from bisphosphonates Watts and Diab JCEM, 2010 95:1555.

  34. Proposed Guidelines for Use of Bisphosphonates • Patients with bone density T-scores of -2.5 or lower at femoral neck after 3 to 5 years of treatment at highest risk for vertebral fractures and appear to benefit most from continued therapy (for up to 10 years). • Patients with an existing vertebral fracture and T-scores up to −2.0 may also benefit from continued therapy. • Patients with femoral neck T-scores above −2.0 have low risk of vertebral fractures and are unlikely to benefit from continued treatment after 3-5 years. Black et al. 2012, NEJM 366:2051

  35. * *Use FRAX to estimate risk Watts and Diab JCEM, 2010 95:1555.

  36. When Should the Holiday End?* • Arbitrary* - Longer for drugs with highest skeletal affinity (zoledronic acid), shorter for drugs with lowest skeletal affinity (risedronate)? Many patients will have been on more than one - complicating matters. • Some use bone turnover markers (measure degree of active bone resorption) – but which ones and what cut off values to use is unclear. There is no good evidence here. • BMD – If significant decrease seen with annual testing * To quote Dr. Watts himself, this is an evidence free zone. Watts and Diab JCEM, 2010 95:1555.

  37. Bisphosphonates for Osteoporosis - Summary • Risk/Benefit Ratio – favorable for most high risk patients • Length of treatment depends upon fracture risk • Risks of ONJ and AFF may increase after 5 years but risk is low • What to do about ONJ and AFF? • ONJ: Look in the mouth • AFF: Instruct patient to report thigh/groin pain and investigate if clinically indicated. • Review films of any reported femur fx

  38. 10 Year Probabilities • Major OP fracture in untreated 72 year-old woman with FN T- score of -3.0 = 25% • Major OP fracture in treated 72 year-old woman with FN T- score of -3.0 = 12.5% • Fatal MVA = 0.11% • Murder = 0.06 % • ONJ = 0.01% • Atypical Femur Fracture = 0.50% Shane – Endocrine Society Annual Meeting - 2012

  39. www.hormone.org

  40. A systematic review of persistence and compliance with bisphosphonates for osteoporosis Percentages of daily and weekly bisphosphonate users persistent with therapy after 1 year based on prior bisphosphonate usage Osteoporos Int (2007) 18:1023–1031

  41. The Endocrine Society Recommends Patient-Centered Approach to Long-Term Bisphosphonate Use for the Treatment of Osteoporosis - A review of the May 2012 FDA Analysis - May 16, 2012 • “The Endocrine Society is concerned that a superficial reading of the FDA analysis will result in an inappropriate abandonment of bisphosphonates for both short- and long-term use in patients with osteoporosis. Therefore, the Society urges its members to engage in a patient-specific dialogue about the appropriateness of long-term bisphosphonate use...

  42. Prolia – A Word • Antiresorptive agent anti RANK ligand ab • IV twice a year • Evidence for prevention of vertebral, non-vertebral and hip fractures • Risk of significant hypocalcemia – particularly in renal failure • May be safer in renal failure (key word is may) • Not any safer than bisphosphonates with regards to ONJ and atypical femur fractures.

  43. Vitamin D • 400 I.U. in usual multivitamins • Found in combination with calcium supplements • Can be found as a single component • Not in yogurt, cheese etc. unless noted on packaging. • Monitor using 25(OH) vitamin levels aiming for 25 ng/ml (recently adjusted normals) • May need larger doses for replacement – 50,000 IU weekly, biweekly or monthly

  44. IOM Report - 2010

  45. Associations of dietary calcium intake and calcium supplementation with myocardial infarction and stroke risk and overall cardiovascular mortality in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition study • EPIC-Heidelberg cohort • 25,540 local residents aged 35-64 years • Excluded diagnosis of MI, stroke, or transient ischemic attack at baseline (n = 1322) • Self-administered food questionnaire • Interview to assess ever use of vitamins and calcium supplements • Incident cardiovascular events during follow-up were reported by participants or their next of kin in follow-up surveys. • Reported cardiovascular events were verified by tracking medical records or official death certificates. Heart 2012;98:920-925.

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