Todd T. Brown, MD, PhD Division of Endocrinology, Diabetes, and Metabolism

1. Management of Osteoporosis and Vitamin DDeficiency in the HIV Infected Patient: Current Concepts and Controversies Todd T. Brown, MD, PhD Division of Endocrinology, Diabetes, and Metabolism Johns Hopkins University

2. Disclosure • Dr Brown has served as a consultant for Bristol-Myers Squibb, Abbott Laboratories, EMD-Serono, Gilead Sciences, Inc, GlaxoSmithKline, Merck & Co, Inc, and ViiV Healthcare.

3. Objectives • To understand the multifactorial pathogenesis of osteoporosis in HIV-infected patients • To know the optimal screening and treatment of osteoporosis in HIV-infected patients

4. Prevalence of Osteoporosis in HIV-infected Patients vs HIV-uninfected Controls: A Meta-analysis Overall prevalence of osteoporosis in HIV-infected patients 15% Odds ratio (95% CI) Study Amiel (2004) Brown (2004) Bruera (2003) Dolan (2004) Huang (2002) Knobel (2001) Loiseau-Peres (2002) Madeddu (2004) Tebas (2000) Teichman (2003) Yin (2005) Overall (95% CI) 5.03 (1.47,17.27) 4.26 (0.22,82.64) 4.51 (0.26,79.27) 2.11 (0.54,8.28) 3.52 (0.15,81.92) 5.13 (1.80,14.60) 4.28 (0.46,39.81) 29.84 (1.80,494.92) 3.40 (0.19,61.67) 17.41 (0.97,313.73) 2.37 (1.09,5.16) 3.68 (2.31,5.84) .01 1 100 Odds ratio Brown, AIDS, 2006

5. Fracture Prevalence in HIV-infected and non-HIV-infected Persons in MGH/Partners Healthcare System: 1996-2008 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 20-29 30-39 40-49 50-59 60-69 HIV HIV Non-HIV Non-HIV 7.0 P=0.002 P<0.0001 6.0 (overall comparison) (overall comparison) 5.0 4.0 3.0 Fracture Prevalence/100 Persons Fracture Prevalence/100 Persons 2.0 1.0 0.0 30-39 40-49 50-59 60-69 70-79 Women Men 8,525 HIV-infected 2,208,792 non HIV-infected patients Triant, JCEM, 2008

6. Multifactorial Etiology of Reduced Bone Mineral Density in HIV Host Medication Disease

7. Pathophysiology and Risk Factors Host Factors Low Body Weight Smoking Alcohol Use Opiate Use Hepatitis C Co-infection Physical Inactivity Hypogonadism Low Vitamin D

8. Pathophysiology and Risk Factors HIV Disease Factors Inflammation and Viral Proteins ↑bone resorption ↓ bone formation

9. Pathophysiology and Risk Factors HIV Disease Factors Inflammation and Viral Proteins ↑bone resorption ↓ bone formation Medication Factors ART initiation

10. BMD Loss with ART-initiation: ~2-6% at 48-96 weeks

11. Average 2-year Percent Change in BMD in Healthy Women Lumbar Spine Total Body n=336 3.8 1.2 0.5 0.6 -0.6 -0.4 -0.9 -2.1 Warming, Osteo Int, 2002

12. Bone Loss in Patients Initiating Glucocorticoid Treatment • 120 patients initiating GCs (≥7.5 mg/day of prednisone or equivalent ) • All patients received 500 mg calcium/day • ↓ 3%/year at all sites in placebo group

13. BMD Loss with ART-initiation: ~2-6% at 48-96 weeks Lower CD4 cell count prior to ART initiation is associated with greater decreases in BMD

14. Combined Analysis of ART-initiation Studies in the ACTG 500 cell/ul reference; adjusted for age, sex, race, BMI, baseline HIV RNA, protease inhibitor use, tenofovir use n=796 Grant, CID, 2013

15. High Dose Vitamin D and Calcium Attenuates Bone Loss with Initiation of TDF/FTC/EFV Overton, CROI, 2014

16. What about specific ART agents?

17. Randomized, Controlled Trials Comparing BMD in PI vs Non-PI Regimens Remaining Questions: • Which PIs? • What is the mechanism? • What is the clinical significance? • Should this alter our prescribing practices? Monitoring?

18. Protease Inhibitors vs Raltegravir: BMD Change 96 weeks after ART initiation Brown, CROI, 2014

19. Antiretroviral Exposure and Risk of Osteoporotic Fractures in VA Study: HAART Era Hazard Ratio MV Model 1: Controlling for CKD, age, race, tobacco use, diabetes and BMI; MV Model 2: Controlling for Model 1 variables + concomitant exposure to other ARVs. Bedimo, AIDS, 2012

20. Exposure to Specific Protease Inhibitors and OF Risk: HAART Era Hazard Ratio MV Model 1: Controlling for CKD, age, race, tobacco use, diabetes and BMI; MV Model 2: Controlling for Model 1 variables + concomitant exposure to other ARVs.

21. Randomized, Controlled Trials Comparing BMD in TDF vs Non-TDF Regimens Remaining Questions: • What is the mechanism? • What is the clinical significance? • Should this alter our prescribing practices? Monitoring? • Special populations • Pregnant women • children/adolescents • Older • HIV-uninfected (prophylaxis) • HBV co-infected

22. Antiretroviral Exposure and Risk of Osteoporotic Fractures in VA Study: HAART Era Hazard Ratio MV Model 1: Controlling for CKD, age, race, tobacco use, diabetes and BMI; MV Model 2: Controlling for Model 1 variables + concomitant exposure to other ARVs. Bedimo, AIDS, 2012

23. Case Presentation: AD 62 year old white male referred to LD clinic for body fat changes HIV dx’d 1987, nadir CD4 22, currently TDF/FTC/EFV H/O hypogonadism on transdermal T H/O COPD (60 pk-yr tobacco hx), multiple steroid courses No h/o fracture, no height loss

24. To Screen or Not to Screen…. No DXA DXA DXA

25. 2013 US National Osteoporosis Foundation (NOF) Guidelines for DXA Screening Those with a history of fragility fracture Women ≥ 65 yrs, Men ≥ 70 Postmenopausal women and men 50-70 years, if there is concern based on risk factor profile

26. Case Presentation: AD Dual X-ray Absorptiometry

27. Definitions Functional Definition (DXA)- WHO Definition Osteoporosis: T-score < -2.5 Osteopenia: T-score= -1.0 to -2.5 Normal: T-score > -1.0 ↑ Risk of fracture by 1.5-3.0 x for each SD decrease Caveats: Z-score ( <-2.0) used in men < 50 years and premenopausal women BMD explains only about 50% of fracture risk

28. What is the next step? • Treat with a bisphosphonate • Treat with calcium and vitamin D • Work-up secondary causes of low BMD • Treat with a bisphosphonate, calcium, vitamin D, and work-up secondary causes of low BMD

29. 2013 US NOF Guidelines: Who to Treat* Those with hip or vertebral fractures Those with BMD T-scores ≤ -2.5 at the femoral neck, total hip, or spine by DXA Those with T-score b/t -1 and -2.5 (osteopenia) at above sites AND 10-year hip fracture probability ≥ 3% or 10-year all major osteoporosis-related fracture ≥ 20% based on FRAX model *applies to post-menopausal women and men ≥ 50 years

30. http://www.shef.ac.uk/FRAX/

32. Secondary Causes of Low BMD • Vitamin D deficiency 25 OH Vit D • Hyperparathyroidism PTH, Ca++ • Subclinical Hyperthyroidism TSH • Hypogonadism Males: Free Testosterone • Phosphate wasting Fractional Excretion of Phosphate • Idiopathic Hypercalciuria 24 hr Urinary Calcium • Celiac Sprue Tissue Transglutaminase • Multiple Myeloma Serum Protein Electrophoresis • Mastocytosis  Serum Tryptase • Cushing’s Syndrome  24 hr Urinary Free Cortisol

33. Secondary Causes of Low BMD Vitamin D deficiency 25 OH Vit D Phosphate wasting Fractional Excretion of Phosphate

34. Osteomalacia Impaired bone mineralization Accompanied by weakness, fracture, pain, anorexia, and weight loss Treated with Vitamin D, Ca++, +/- phosphate, not bisphosphonates Most important differential diagnosis for low BMD

35. RB • 51 y/o WM with HIV dx’d in 2001, nadir CD4 30, VL< 50 on TDF/FTC/EFV, but CD4 cell count 150-250 • Drinks 3-4 glasses wine/day, former smoker • Sister with osteoporosis, no fx • H/O two traumatic fractures (boating and glade skiing)

36. Case Presentation: RB Dual X-ray Absorptiometry FRAX (femoral neck): 10 y all osteoporotic fx 4.7%/hip fx 0.5%

37. Secondary work-up: 25 OH Vit D 15 ng/mL PTH 44 pg/ml Ca++ 9.5 mg/dL TSH 1.8 mU/L Free Testosterone 61pg/ml Serum Phosphate 3.0 mg/dl Fractional Excretion Phos 10%

38. 20 30 40 50 60

39. Change in 25OHD with ART-initiation: EFV vs non-EFV Adjusted* Mean Difference(SEM): -5.1 ± 1.5 ng/mL, p=0.001 *Adjusted for baseline 25(OH)D, race, season Brown, Antiviral Therapy, 2010

40. What is the optimal Vitamin D replacement regimen for this pateint? • D3 400 IU/d • D3 2000 IU/d • Ergocalciferol 50,000 units q week x 8 weeks • The optimal replacement regimen is unclear

41. Treatment of Vitamin D Deficiency Replacement • Ergocalciferol (D2) 50K units 1-2 times/week for 8-12 weeks OR • Cholecalciferol (D3) 2000 IU/d Maintenance • Ergocalciferol 50K units 1-2 times/month OR • Cholecalciferol 1000-2000 IU/d Rule of Thumb: 100 IU D3/d will increase 25 OH D by 1 ng/mL

42. Does it matter how 25OHD is increased into the target range?: A Recent Randomized Trial • 2256 women ≥ 70 years • Randomized to 500,000 IU D3 orally each fall • Followed 3-5 years 50 ng/mL 30 ng/mL Sanders, JAMA, 2010

43. Annual high dose vitamin D associated with increased falls and fractures Sanders, JAMA, 2010

44. Dealing with Vitamin D: My Strategy • If BMD is low or history of falls, check 25OHD: • >30 ng/mL: 1000 IU/d • 20-30 ng/mL: 2000 IU/d • 15-20 ng/mL: Ergocalciferol 50K units weekly x 8 weeks, then D3 2000 IU/d • <15 ng/mL: Ergocalciferol 50K units once or twice a week x 8-12 weeks, then D3 2000 IU/d, recheck 25OHD after ergo course • More aggressive replacement if PTH is high or s/s of osteomalacia

45. Management: RB • Plain films of thoracic and lumbar spine • Vitamin D replacement • D2 50K q week x 12 weeks • 2000 IU D3 daily • Ca++ 1000 mg • Continue exercise

46. RB • 71 y/o WM with HIV dx’d in 2001, nadir CD4 30, VL< 50 on TDF/FTC/EFV, but CD4 cell count 150-250 • Drinks 3-4 glasses wine/day, former smoker • Sister with osteoporosis, no fx • H/O two traumatic fractures (boating and glade skiing)

47. Management Options • General recommendations • Calcium/vitamin D supplementation • Smoking cessation, Alcohol reduction • Weight-bearing exercise • Assess fall risk (Are you worried about falling?) • Strength/Balance Training • Rx options • Bisphosphonates • Selective estrogen receptor modulator • Estrogen • PTH analogue

48. Considerations When Choosing Between Bisphosphonates

49. Bisphosphate Holiday How long? How to monitor? What medications after the holiday? McClung, Am J Medicine, 2013

50. Effect of Switching off TDF in those with Low BMD TDF ABC TDF RAL Percentage Change over 48 Weeks Negredo, CROI, 2013 Bloch, CROI, 2012