1. Osteoporosis in the HIV-infected Patient: Update on Pathogenesis and Treatment
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, Theratechnologies, Gilead Sciences, Inc, GlaxoSmithKline, Merck & Co, Inc, and ViiV Healthcare.

3. The HIV Treatment Revolution
Pre-HAART Era
HAART Era
1996

4. The Impact of Highly Active Antiretroviral Therapy (HAART) on HIV Morbidity
Palella, NEJM, 1998

5. Projected
For years , data is based on 33 states and U.S. dependent areas with confidential name-based HIV infection reporting, Centers for Disease Control: HIV/AIDS Surveillance Report, 2005.
For years , data is based on 34 states and 5 U.S. dependent areas with confidential name-based HIV infection
reporting, Centers for Disease Control: HIV/AIDS Surveillance Report, 2007
*Data from 2008, onward projected based on trends (calculated by author), data from CDC Surveillance Reports Slide Courtesy of Amy Justice, MD, PhD

6. 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

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

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

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

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

11. Early Reports Suggested that ART was Good for the Bone
JCEM, 1999

12. BMD Loss with ART-initiation: ~2-6% at 48-96 weeks
Author, y N
Wks
ART-type
Study outcomes
Gallant, 2004
602
144
TDF vs. d4T
Spine :TDF-2.2% ; d4T:-1.0%
Hip : TDF: -2.8%; d4T:-2.4%
Tebas, 2007
157 96
NFV vs EFV
2.5% decrease in total BMC
Bonnet, 2007 74 36
PI vs non-PI
0.8% decrease in lumbar BMD
Brown, 2009
106
LPV/r vs AZT/3TC/EFV
2.5% loss in total BMD
Duvivier, 2009 71 48
PI vs Non-PI
Spine: -4.1% , Hip: -2.8%
van Vonderen, 2009 50
104
AZT/3TC/LPV/r v NVP/LPVr
Fem Neck: -6.3% v -2.3%
Spine: v -2.6 %
Moyle, 2009
385
TDF v ABC
Hip: ABC:-1.9%; TDF: -3.6%
Spine:ABC: -1.6%; TDF -2.4%
McComsey, 2010
258
ATV/r vs EFV
Hip: ABC:-2.2%; TDF: -4.0%
Spine:ABC: -1.8%; TDF -3.8%
Hip: ATV/r:-3.5%; EFV: -3.5%
Spine:ATV/r:-3.0%; EFV: -2.0%
Huang, 2010
753
TDF v AZT v d4T
LPV/r v EFV
Total BMD: TDF: -3%; v AZT: -1.75% v d4T: -2%Difference LPV/r vs EFV: -0.5%
Qaqish, 2011
160
LPV/r+RAL v LPV/r+TDF/FTC
Total BMD: v -2.5%
Tebas, 2011
349
RPV vs EFV (+NRTI)
Total BMD: -1.5% vs -1.5%
Moyle, 2011
224
ATV/r v LPV/r (+TDF/FTC)
Total BMD: -3% v -4%

13. 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

14. Estimated Mean 96-week % Total BMD Change (95% Confidence Interval)
Lower CD4 cell count prior to ART initiation is associated with greater decreases in BMD
Baseline CD4
(cells/ul)
Estimated Mean 96-week % Total BMD Change
(95% Confidence Interval) p
<50
-2.3 (-3.4, -1.3)
<0.001
50-199
-0.8(-1.8, 0.2)
-0.7 (-1.6, 0.3)
-0.6 (-1.7, 0.4)
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. IAS-USA: Guidelines for Initial ARV Regimens
Dual NRTI
Key 3rd Drug
Recommended
TDF/FTC
EFV or RPV
ATV/r or DRV/r
RAL or EVG or DTG
ABC/3TC
EFV
ATV/r
DTG +
Note the following details from the IAS-USA Guidelines:
TDF/FTC:
Available as fixed-dose combination alone and with efavirenz
Once daily
Low genetic barrier to resistance (emtricitabine)
Renal dysfunction, decreased bone mineral density associated with tenofovir influence choice
EFV: NNRTI class
Available in fixed-dose combination with tenofovir/emtricitabine, which has become standard-of-care comparator regimen in most clinical trials
Low genetic barrier
Major psychiatric illness, first trimester of pregnancy, or intention to become pregnant influences choice
Atazanavir/r
PI/r class
Widely prescribed when PI/r is chosen for initial therapy
Leaves options for future regimens
Less lipidogenic potential than lopinavir/r
Hyperbilirubinemia, need for acid-reducing agents, and risk of nephrolithiasis influence choice
Darunavir/r:
Once daily in treatment-naive patients
Limited experience in treatment-naive patients, presence of other options in most naive patients, and efficacy inpatients with treatment experience and multidrug resistant virus influence choice
Raltegravir
INSTI class (only 1 FDA approved at present time)
Twice daily
Low drug interaction potential
Rapid decline in HIV-1 RNA slope after initiation
Limited experience in naive patients, presence of other options in most naive patients, and efficacy in treatment-experienced patients with multidrug resistant virus influence choice
Gunthard, JAMA, 2014

18. Protease Inhibitors ART initiation Effect on Fracture
↑ lumbar spine BMD loss ATV/r v EFV; similar effect at total hip (ACTG 5224s)
↑ lumbar spine and total hip BMD loss with ATV/r or DRV/r vs RAL (ACTG 5260s)
No difference b/t ATV/r and DRV/r (ACTG 5260s)
Effect on Fracture

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. Protease Inhibitors ART initiation Effect on Fracture
ART Switch: Switch from PI to RAL leads to modest increases in BMD (SPIRAL)

21. TDF ART initiation Effect on Fracture
1-2% additional loss at lumbar spine and hip vs other NRTIs (Gilead 903, A5224s, ASSERT, TAF studies)
Effect on Fracture

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. TDF ART initiation Effect on Fracture Effect of Switch
1-2% additional loss at lumbar spine and hip vs other NRTIs (Gilead 903, A5224s, ASSERT, TAF studies)
Effect on Fracture
Effect of Switch

24. 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

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

26. 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 years, if there is concern based on risk factor profile

27. 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

28. 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

29. Secondary Causes of Low BMD
Vitamin D deficiency 25 OH Vit D
Phosphate wasting Fractional Excretion of Phosphate 29

30. 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

31. Case
50 y/o Caucasian male dx’d with HIV in 1985, started ART in CD4 236, VL<50 on TDF/FTC/LPV/r
Referred to Endocrine Clinic for HIV Lipodystrophy

32. “Is there anything else that is bothering you?”
Left hip pain for the past 2 weeks. No antecedent trauma

33. Femoral Neck Fracture

34. Femoral Neck Fracture Surgical Repair Osteoporosis Risk Factors:
Steroid exposure
Hypogonadism
? Lactic acidosis/NRTI exposure
Smoking
Past heavy EtOH use

35. DXA Results Spine T-score -2.6 Right femoral neck T-score -5.2
Right total hip T-score

36. Secondary work-up: 25 OH Vit D 61 ng/mL PTH 15 pg/ml Ca++ 10 mg/dL
TSH mU/L
Testosterone ng/dl
Serum Phosphate 0.8 mg/dl
Fractional Excretion of Phosphate of 53% 1,25 dihydroxy Vitamin D 150 (nl 6-62)

37. Case: Treatment Tenofovir  Abacavir Phosphate 500 mg qid
Calcium 1 gram tid

38. DXA Follow Up Spine T-score -2.6 -0.9 R femoral neck T-score -5.2 -2.0
Aug 06
May 07
Change:
↑ 8.9%
↑ 5.5%
↑ 14.6%
Spine T-score
R femoral neck T-score
R total hip T-score

39. Management Options General recommendations Rx options
Calcium/vitamin D supplementation
Smoking cessation, Alcohol reduction
Weight-bearing exercise
Assess fall risk (Are you worried about falling?)
Strength/Balance Training
Rx options
Change ART: Switch off TDF or PI
Bone Specific Meds:
Bisphosphonates
Selective estrogen receptor modulator
PTH analogue 39

40. Conclusions Bone loss in HIV is multifactorial
ART-initiation is associated with clinically significant bone loss which is more pronounced in those with low pre-treatment CD4
Protease inhibitors and TDF have independent detrimental effects on bone. In persons at increased fracture risk, consider avoiding for ART initiation or switching off for those on ART
DXA screening recommended in HIV-infected patients in men > 50 yrs and post-menopausal women
Remember secondary causes (Vit D def and phosphate wasting)
Treatment guidelines should follow those established for the general population