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2 OSTEOPOROSIS REVIEW AND UPDATE Boca Raton Regional Hospital Internal Medicine Conference 2017 Benjamin Wang, M.D., FRCPC Division of Rheumatology Mayo Clinic Jacksonville, FL

3 Disclosures Nothing to disclose

4 Topics A bit of bone biology Screening for osteoporosis Fracture risk assessment Prevention of fracture Atypical femoral fractures and osteonecrosis of the jaw Glucocorticoid-induced osteoporosis Long term management and treatment failures

5 Definition Osteoporosis is characterized by Low bone density and low bone mass Disruption of microarchitecture Skeletal fragility Increased fracture risk Accounts for 1.5M fractures per year in the U.S. 300,000 hip fractures 40 million women with low BMD Fracture risk is multifactorial and not just a function of BMD

6 Definition World Health Organization definition Osteoporosis: T-score -2.5 standard deviations Osteopenia: -2.5 T -1.0 standard deviations Severe osteoporosis T-score -3.5 standard deviations, OR T-score -2.5 standard deviations with fragility fracture (esp. hip, spine, wrist, humerus, rib, pelvis) May be a candidate for anabolic treatment T-score: young-adult reference population Z-score: age-matched reference population Premenopausal women and men <50 years old Do not use WHO criteria (fracture risks differ) Use Z-score; if <-2.0 standard deviations, diagnose BMD lower than expected for age and look for secondary causes of osteoporosis (drugs, cancer, thyroid, calcium metabolic defects, etc.)

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9 Bone remodeling physiologic conditions and osteoporosis Normal coupled Osteoporosis uncoupled BMU-basic metabolic unit; OC-osteoclast; OB-osteoblast; LC-lining cell; OCY-osteocyte Adapted from Baron R and Hesse E 2012; J Clin Endocrinol Metab; 97(2):

10 Action of antiresorptive drugs Bisphosphonates Denosumab Raloxifene Teriparitide

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14 Serial DXA Scans

15 Age contributes significantly to fracture risk Kanis JA et al. 2001; Osteoporos Int 12:

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17 FRAX Considerations Data derived from 11 unique national cohorts use the one that s right for the patient Data derived from untreated postmenopausal women ages only don t extrapolate Uses hip BMD (not spine) FRAX cannot account for changes in risk as a result of drug treatment don t use for serial measurement Candidates for therapy based on FRAX: 10-year risk of hip fracture 3.0 percent 10-year risk of major osteoporotic fracture 20 percent

18 Trabecular Bone Score has better prognostic ability for spine fracture Silva BC et al. J Bone Miner Res. 2014;29(3):

19 Risk assessed by TBS is independent of BMD Hans D et al. JBMR 2011; 26(11):

20 Quantitative CT (qct) visualizes and quantifies bone microarchitecture

21 Management Strategy Overview Thorough clinical evaluation: history and physical exam Family history Risk factors e.g. smoking, medications Height and posture Diet: adequate dietary levels of calcium, vitamin D Physical activity, esp. weight-bearing exercise Avoid harmful lifestyle factors, e.g. smoking Fall prevention measures including home assessments Pharmacological therapy for patients at high risk for fracture

22 Currently available anti-resorptive agents for osteoporosis Anti remodeling agents Bisphosphonates: alendronate, risedronate, ibandronate, zoledronic acid Selective estrogen agonist/antagonist: raloxifene RANKL inhibitor (denosumab) Remodeling stimulating (anabolic) agent: teriparatide (PTH 1 34)

23 Considerations with Drug Therapy All drugs provide effective protection from fractures Vertebral fracture by 60% 70% Multiple vertebral fractures by 75% 96% Hip fracture by 40% 50% Non vertebral fracture by 20% 35% Fracture protection is rapidly acquired: within 12 months, sometimes within 6 months Fracture risk reduction (>50%) is disproportionate to increases in BMD (5-6% maximal at hip, 10% at spine) Not all agents are proven to reduce fracture risk at the hip: ibandronate and raloxifene do not! Oral bisphosphonates are a good first-line treatment if possible (except with esophageal stricture, dysphagia, GI ulcer disease, severe GI intolerance, chronic kidney disease) An temporary inflammatory response is sometimes seen with bisphosphonates, esp. zoledronic acid

24 Reduction in hip fracture risk occurs rapidly

25 Reduction in hip and vertebral fracture risk is rapid with zoledronic acid

26 Atypical Femoral Fractures (AFF) Incidence 1.78/100,000 patient years in first 2 years 113/100,000 patient years in years Possible risk factors Genetic associations PPI use Anatomic configuration Prodromal thigh pain Evaluate the other hip Look for sclerotic reaction on xray or DXA Dell RM et al. 2012; JBMR 27(12):

27 Drug Holidays Discontinuation of bisphosphonate therapy may be considered in postmenopausal women with low fracture risk After treatment for 5 years with alendronate After treatment for 3 years with zoledronic acid Reassessment at 2 to 3 years with DXA Restart treatment if DXA score declines May use denosumab although AFF has also been reported Reserve teriparatide for patients with severe osteoporosis (T<-3.5 or <-2.5 and fracture)

28 Osteonecrosis of the Jaw (ONJ) Mainly seen in cancer patients receiving IV bisphosponates for hypercalcemia of malignancy 1-2% of cancer patients receiving zoledronic acid in trials General population incidence <<1% Reported with other bisphosphonates (e.g. pamidronate) and denosumab Oral health-associated risk factors Dentoalveolar surgery Concomitant oral disease and other local risk factors

29 ONJ improved with teriparatide Cheung A and Seeman E. N Engl J Med 2010; 363:

30 Long Term Management 5% decrease in BMD is a reason to consider a change in drug therapy Combination therapy with antiresorptives is not recommended Following teriparatide (2 year maximum) with bisphosphonate or denosumab is acceptable There is no established guideline regarding frequency or need for serial BMD measurements Alternative monitoring methods such as use of bone turnover markers are being evaluated

31 Monitoring markers of bone turnover McClung MR et al. N Engl J Med 2006;354:

32 Denosumab is the first biologic drug for osteoporosis: RANKL inhibitor J. Brent Richards JB, Zheng H-F, Spector TD. Nature Rev Genetics 2012; 13:

33 Anabolic effects on bone by two pathways Use of rhpth (teriparitide) Wnt signalling pathway sclerostin inhibition

34 Biologic effects of PTH in relation to continuity of exposure

35 Wnt signalling promotes osteoblast production and has an anabolic effect on bone Wnt signalling promotes Sclerostin (Sost) inhibits Adapted from Baron R and Rawadi G. Endocrinology 2007;148:

36 Rochefort GY. Ther Adv Musculoskelet Dis Jun;6(3):79-91

37 Romosozumab: sclerostin inhibitor McClung MR et al. N Engl J Med 2014;370:

38 Abaloparatide binds the PTH receptor more specifically and is more potent to reduce fractures Miller PD et al. JAMA 2016;316(7):

39 Abaloparatide causes less bone resorption than teriparatide one reason for its potency Miller PD et al. JAMA 2016;316(7):

40 Novel Therapies for Osteoporosis Makras P et al. Metabolism 2015; 64:

41 Summary Osteoporosis remains a significant public health issue, yet it is still undertreated Comprehensive assessment of risk factors and BMD are needed to diagnose osteoporosis and determine candidacy for treatment Drug treatment is safe and effective for those at highest risk for fracture Optimal long term management strategies are being studied Novel effective methods of diagnosing and treating osteoporosis are close at hand

42 Thank you