Bones of Contention – HIV and Bone Disease
Dr Paddy MallonMB BCh BAO FRACP FRCPI PhD
School of Medicine and Medical SciencesMater Misericordiae University Hospital
University College DublinIreland
UCD School of Medicine & Medical Science
Scoil an Leighis agus Eolaíocht An Leighis UCD
What are the ‘bones of contention’?
• Is low BMD more common in HIV?
• Are fractures more common in HIV?
• What’s the best measure – the ‘T’ score or the ‘Z’ score?
• Is it ARV, BMI or vitamin D?
• Which patients should I screen?
What are the ‘bones of contention’?
• Is low BMD more common in HIV?
• Are fractures more common in HIV?
• What’s the best measure – the ‘T’ score or the ‘Z’ score?
• Is it ARV, BMI or vitamin D?
• Which patients should I screen?
Publication Number of patients
% BMD
HIV+ HIV– HIV+ HIV–
Amiel et al 2004 148 81 82.5 35.8Brown et al 2004 51 22 63 32Bruera et al 2003 111 31 64.8 13Dolan et al 2004 84 63 63 35Huang et al 2002 15 9 66.6 11Knobel et al 2001 80 100 87.5 30Loiseau-Peres et al 2002
47 47 68 34
Madeddu et al 2004 172 64 59.3 7.8Tebas et al 2000 95 17 40 29Teichman et al 2003 50 50 76 4Yin et al 2005 31 186 77.4 56
Adapted from Brown TT & Qaqish RB. AIDS 2006; 20:2165-2174
Low BMD is common in HIV+ patients
Cazanave C et al. 17th CROI 2010. Abstract 747. Bonjoch A et al. 18 th IAC 2010. Abstract THPDB104.
Progression of BMD is common
Spain. N=391.49% osteopenic, 22% osteoporosis.Progression after 2.5 years:
- 12.5% to osteopenia- 15.6% to osteoporosis
Aquitaine cohort. N=255. 68% men. Age 44 yrs. All on ART.72% osteopenic (osteoporosis excluded)Progression after 2.3 years:
- 7.8% to osteopenia- 11.4% to osteoporosis
What are the ‘bones of contention’?
• Is low BMD more common in HIV?
• Are fractures more common in HIV?
• What’s the best measure – the ‘T’ score or the ‘Z’ score?
• Is it ARV, BMI or vitamin D?
• Which patients should I screen?
Frac
ture
pre
vale
nce
in w
omen
/100
per
sons
Healthcare Registry study8,525 HIV-infected patients2,208,792 non HIV-infected patientsFracture rates in women demonstrated
Overall comparison p=0.002
HIV+
HIV-
30-39 40-49 50-59 60-69 70-79
Years
Triant VA et al, JCEM 2008;93:3499-3504
7
6
5
4
3
2
1
0
Fractures are more common in HIV+ patients
What are the ‘bones of contention’?
• Is low BMD more common in HIV?
• Are fractures more common in HIV?
• What’s the best measure – the ‘T’ score or the ‘Z’ score?
• Is it ARV, BMI or vitamin D?
• Which patients should I screen?
Osteoporosis / osteopenia
T score = standard deviation (SD) difference from BMD of white women at peak bone density (aged 30 years)1,2
Z score = SD difference from BMD of individuals of the same age, race and gender 2
Disorder T scoreNormalOsteopeniaOsteoporosis
> –1.0–2.5 to –1.0
< –2.5Disorder Z scoreOsteoporosis < –2.0
1. World Health Organ Tech Rep Ser 1994; 843:1–1292. NIH consensus development panel on osteoporosis prevention, diagnosis and therapy. JAMA 2001; 285:785–795
<50 yrs – Z score>50 yrs – T score
What are the ‘bones of contention’?
• Is low BMD more common in HIV?
• Are fractures more common in HIV?
• What’s the best measure – the ‘T’ score or the ‘Z’ score?
• Is it ARV, BMI or vitamin D?
• Which patients should I screen?
#
#
*
Lumbar spine Z score
month0 3 12 24
-0.9
-0.8
-0.7
-0.6
-0.5
-0.3
-0.2
ZDV/3TC/LPV/rNVP/LPV/r
von Voderen M. et al. AIDS 2009; 23(11): 1367-1376
Within group and between-group differences all
P<0.05
• Changes in BMD accompanied by increases in markers of bone turnover
Greater loss in BMD with ART containing NRTI
ART initiation is associated with bone loss
-0.4
ABC/3TC: -1.90%TDF/FTC: -3.55%D = -1.68 ; 95% CI (-2.26, -1.09)
ABC/3TC: -1.59%TDF/FTC: -2.41%D = -0.84 ; 95% CI (-1.61, -0.06)
0
-1
- 2
- 3
- 4
0 24 48
Hip
0
-1
- 2
- 3
- 4
0 24
P<0.001
Lumbar Spine
48
P=0.036
week week
% c
hang
e in
BM
D
% c
hang
e in
BM
D
SubjectsABC/3TC: 176 134 117 182 141 125TDF/FTC: 180 156 138 183 165 143
ART and bone Loss -ABC/3TC vs TDF/FTC
Stellbrink HJ et al., EACS 2009
Lumbar Spine
McComsey GA et al. CROI 2010
Hip
ART and bone loss - ABC/3TC vs TDF/FTCACTG A5224s
PI/NNRTI
NNRTI/NRTI
PI/NRTI
-4.4
-5.81
-1.48
-7
-6
-5
-4
-3
-2
-1
0
Lumbar Spine
-2.35
-3.86
-2.73
-7
-6
-5
-4
-3
-2
-1
0
PI/NNRTI
NNRTI/NRTI
PI/NRTI
Hip
Duvivier, et al., AIDS 2009; 27:817-24
PI: LPV/r (40-74%) NNRTI: EFV (55-60%) NRTIs: AZT/3TC (85%) IDV/r (25-47%) NVP (37-45%)
ART and bone loss - PI vs NNRTI
ART and bone loss - PI vs NNRTI
Lumbar Spine
McComsey GA et al. CROI 2010
HipACTG A5224s
• Consistently associated with low BMD in HIV1-7
• In one meta-analysis, low BMI explained much of the difference in BMD between HIV+ and HIV- 8
• Association between weight loss and BMD loss observed in HIV- male populations9
• Usually associated with negative health implications• Lower BMI in HIV+ patients associated with greater loss of
BMD in prospective studies10
• Low BMI does not explain loss of BMD with ARV initiation
1. Mondy K, et al. CID 2003; 36:482–490 2. Fausto A et al. Bone 2006;38:893-7 3. Carr A et al. AIDS 2001;15:703-9 4. Nolan D et al. AIDS 2001;15:1275-80 5. Arnsten JH et al. AIDS 2007;21:617-23 6. Arnsten
JH et al. CID 2006;42:1014-20 7. Dolan SE et al. JCEM 2006;91:2938-45 8. Bolland MJ et al. JCEM 2007;92:4522-8. 9. Shen Y et al. J Bone Mineral Res 2009;24:1290-1298. 10. Bonjoch A et al. 18th IAC
2010. Abstract THPDB104.
Body Mass Index and BMD….
Vitamin D…..
• High prevalence of low vitamin D in HIV+ patients1-3
• High prevalence of low vitamin D in general population4
• Associations with EFV exposure and low 25-OH vitamin D (but not 1,25-OH vitamin D)2,5
• N=33. PHI. 45% osteopenia, 6% osteoporosis but none had vitamin D deficiency (25-OH and 1,25-OH)6
• Seasonal variation important4
• EFV use not associated with accelerated bone loss7
• High bone turnover state in HIV+ patients8
1. Jacobson D, et al. JAIDS 2008; 49:298–308, 2. Dao, CN et al, CROI 2010 #750. 3. 2. Fux et al. CROI 2010t #749. 4. Stephensen CB, et al. Am J Clin Nutr 2006; 83:1135–41. 5. Muller N. et al. CROI 2010 #752. 6. Grijsen ML et al. AIDS 2010;24
7. McComsey GA et al. CROI 2010. 8. Stellbrink HJ et al., EACS 2009
In a multivariate analysis, differences between arms were statistically significant for P1NP, Osteocalcin and BSAP
N= 114 134 112 130 114 134 113 134
81%
44%
72%
44%
92%
75%
97%
80%
0
20
40
60
80
100
P1NP Osteocalcin BSAP CTX
Una
djus
ted
% c
hang
e fr
om b
asel
ine
ABC/3TCTDF/FTC
Biomarkers and ART initiation…
Stellbrink HJ et al., EACS 2009
What are the ‘bones of contention’?
• Is low BMD more common in HIV?
• Are fractures more common in HIV?
• What’s the best measure – the ‘T’ score or the ‘Z’ score?
• Is it ARV, BMI or vitamin D?
• Which patients should I screen?
Who should be screened?EVERYBODY!
>40 years old use FRAX (www.shef.ac.uk/FRAX)
History of low-impact fracturesHigh falls risk
Post-menopausal womenMen >50 yrs
HypogonadismSteroid Exposure
http://www.europeanaidsclinicalsociety.org/guidelines.asp
Or
Consider DXA if ≥ 1 of following:
BMD and the ‘Double Edged Sword’
‘Main Entry: double–edged swordFunction: noun Date: 15th century: something that has or can have both favorable and unfavorable consequences’
Patient age in Brighton cohort: 1996-2009
Personal communication, M. Fisher
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
<50 >50
HIV+ patients are getting older
0
100
200
300
400
500
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
>50
>60
>70
Personal communication, M. Fisher
Most of the age increase is in the 50-60 age groupPatient age in Brighton cohort: 1996-2009
HIV+ patients are getting older
The increase in the over 50s is greater than the overall cohort
Acknowledgements
Grants / research support: Science Foundation Ireland, Molecular Medicine Ireland, European Union (NEAT), Irish Lung Foundation, Mater College, GlaxoSmithKline, PfizerSpeaker Bureau / Honoraria: GlaxoSmithKline, ViiV Healthcare, Merck, Gilead, Abbott, Tibotec, BMS