1. Bones of Contention – HIV and Bone Disease
Dr Paddy Mallon
MB BCh BAO FRACP FRCPI PhD
School of Medicine and Medical Sciences
Mater Misericordiae University Hospital
University College Dublin
Ireland
UCD School of Medicine
& Medical Science
Scoil an Leighis agus
Eolaíocht An Leighis UCD

2. 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?

3. 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?

4. Low BMD is common in HIV+ patients
Publication
Number of patients
%  BMD
HIV+
HIV–
Amiel et al 2004
148 81
82.5
35.8
Brown et al 2004 51 22 63 32
Bruera et al 2003
111 31
64.8 13
Dolan et al 2004 84 35
Huang et al 2002 15 9
66.6 11
Knobel et al 2001 80
100
87.5 30
Loiseau-Peres et al 2002 47 68 34
Madeddu et al 2004
172 64
59.3
7.8
Tebas et al 2000 95 17 40 29
Teichman et al 2003 50 76 4
Yin et al 2005
186
77.4 56
“A silent epidemic”?
The prevalence of reduced BMD (osteopenia or osteoporosis) in patients with HIV has been examined in a number of studies. Many of these were reviewed by Brown and Qaqish (2006), some of their key findings are summarised in this table [1].
Reduced BMD was commonly found in HIV patients in all studies (40–87.5%) and was less frequent in HIV negative individuals (4–56%).
The extent of the problem of bone pathology in HIV-infected individuals is clearly significant and has been described as “a silent epidemic”.
If physicians do not address this problem, the consequences for their patients in terms of fracture risk, morbidity and mortality are likely to be high.
References
Brown TT & Qaqish RB. AIDS 2006; 20:2165–2174.
Adapted from Brown TT & Qaqish RB. AIDS 2006; 20:

5. 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= % men. Age 44 yrs. All on ART.
72% osteopenic (osteoporosis excluded)
Progression after 2.3 years:
- 7.8% to osteopenia
- 11.4% to osteoporosis
“A silent epidemic”?
The prevalence of reduced BMD (osteopenia or osteoporosis) in patients with HIV has been examined in a number of studies. Many of these were reviewed by Brown and Qaqish (2006), some of their key findings are summarised in this table [1].
Reduced BMD was commonly found in HIV patients in all studies (40–87.5%) and was less frequent in HIV negative individuals (4–56%).
The extent of the problem of bone pathology in HIV-infected individuals is clearly significant and has been described as “a silent epidemic”.
If physicians do not address this problem, the consequences for their patients in terms of fracture risk, morbidity and mortality are likely to be high.
References
Brown TT & Qaqish RB. AIDS 2006; 20:2165–2174.
Cazanave C et al. 17th CROI Abstract 747. Bonjoch A et al. 18th IAC Abstract THPDB104.

6. 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?

7. Fracture prevalence in women
Fractures are more common in HIV+ patients
Healthcare Registry study
8,525 HIV-infected patients
2,208,792 non HIV-infected patients
Fracture rates in women demonstrated
HIV+
HIV- 7 6
Overall comparison p=0.002 5 4
Fracture prevalence in women
/100 persons 3 2 1
40-49
50-59
60-69
70-79
30-39
Years
Triant VA et al, JCEM 2008;93: 7

8. 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?

9. 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 score
Normal
Osteopenia
Osteoporosis
> –1.0
–2.5 to –1.0
< –2.5
Z score
< –2.0
<50 yrs – Z score
>50 yrs – T score
1. World Health Organ Tech Rep Ser 1994; 843:1–129
2. NIH consensus development panel on osteoporosis prevention, diagnosis and therapy. JAMA 2001; 285:785–795

10. 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?

11. Within group and between-group differences all P<0.05
ART initiation is associated with bone loss
Greater loss in BMD with ART containing NRTI
-0.2
Lumbar spine Z score
Within group and between-group differences all P<0.05
-0.3
ZDV/3TC/LPV/r
-0.4
NVP/LPV/r
-0.5 # *
-0.6
-0.7
-0.8
-0.9 3 12 24
month
Changes in BMD accompanied by increases in markers of bone turnover
von Voderen M. et al. AIDS 2009; 23(11):

12. ART and bone Loss -ABC/3TC vs TDF/FTC
Hip
Lumbar Spine
P<0.001
P=0.036 -1  -1  
% change in BMD
- 2
% change in BMD
- 2   
- 3
- 3  
- 4
- 4 24 48 24 48
Differences in BMD blinded and read by central laboratory
We have checked that the shape of the spine graph is not being caused by dropouts, the majority of patients in the study at both timepoints showed an increase from Week 24 to Week 48. There is not a lot consistency within individual subjects between Hip and Spine i.e some of those with the largest increases in spine continued to decrease in Hip. It could be that we are seeing a restoration in the spine earlier than it is seen in the hip and week 96 data should help us understand if that is the case.
week
week
Subjects
ABC/3TC:
TDF/FTC:
ABC/3TC: %
TDF/FTC: %
D = ; 95% CI (-2.26, -1.09)
ABC/3TC: %
TDF/FTC: %
D = ; 95% CI (-1.61, -0.06)
Stellbrink HJ et al., EACS 2009

13. ART and bone loss - ABC/3TC vs TDF/FTC
ACTG A5224s
Lumbar Spine
Hip
McComsey GA et al. CROI 2010

14. ART and bone loss - PI vs NNRTI
Lumbar Spine
Hip
PI/
NNRTI
PI/
NRTI
NNRTI/
NRTI
PI/
NNRTI
PI/
NRTI
NNRTI/
NRTI
PI: LPV/r (40-74%) NNRTI: EFV (55-60%) NRTIs: AZT/3TC (85%)
IDV/r (25-47%) NVP (37-45%)
Duvivier, et al., AIDS 2009; 27:817-24

15. ART and bone loss - PI vs NNRTI
ACTG A5224s
Hip
Lumbar Spine
McComsey GA et al. CROI 2010

16. Body Mass Index and BMD….
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– Fausto A et al. Bone 2006;38: Carr A et al. AIDS 2001;15: Nolan D et al. AIDS 2001;15: Arnsten JH et al. AIDS 2007;21: Arnsten JH et al. CID 2006;42: Dolan SE et al. JCEM 2006;91: Bolland MJ et al. JCEM 2007;92: Shen Y et al. J Bone Mineral Res 2009;24: Bonjoch A et al. 18th IAC Abstract THPDB104.

17. 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 # Fux et al. CROI 2010t # Stephensen CB, et al. Am J Clin Nutr 2006; 83:1135– Muller N. et al. CROI 2010 # Grijsen ML et al. AIDS 2010;24 7. McComsey GA et al. CROI Stellbrink HJ et al., EACS 2009

18. significant for P1NP, Osteocalcin and BSAP
Biomarkers and ART initiation…
97%
100
92%
80%
81% 80
75%
72% 60
ABC/3TC
Unadjusted % change from baseline
44%
44%
TDF/FTC 40 20
At W24 differences in CTx were statstically significant
Bone formation
Osteocalcin
A specific marker of osteoblast function
Relatively low within-person variation
Bone Specific Alkaline Phosphatase (BSAP)
Enzyme located on the outer surface of osteoblasts
Procollagen type 1 Amino-terminal propeptide (P1NP)
Type 1 collagen is the most abundant protein of bone matrix in osteoblasts, cleaved to P1NP during metabolism of procollagen, released into the blood. Most serum P1NP originates from bone
Bone Resorption
C-terminal telopeptide of type I collagen (CTx)
Marker of collagen degradation
P1NP
Osteocalcin
BSAP
CTX N=
In a multivariate analysis, differences between arms were statistically
significant for P1NP, Osteocalcin and BSAP
Stellbrink HJ et al., EACS 2009

19. 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?

20. Who should be screened? EVERYBODY!
>40 years old use FRAX ( Or
Consider DXA if ≥ 1 of following:
History of low-impact fractures
High falls risk
Post-menopausal women
Men >50 yrs
Hypogonadism
Steroid Exposure

21. BMD and the ‘Double Edged Sword’
‘Main Entry: double–edged sword
Function: noun
Date: 15th century
: something that has or can have both favorable and unfavorable consequences’

22. Patient age in Brighton cohort: 1996-2009
HIV+ patients are getting older
Patient age in Brighton cohort:
Personal communication, M. Fisher

23. HIV+ patients are getting older
Most of the age increase is in the age group
Patient age in Brighton cohort:
The increase in the over 50s is greater than the overall cohort
Personal communication, M. Fisher

24. Acknowledgements
Grants / research support: Science Foundation Ireland, Molecular Medicine Ireland, European Union (NEAT), Irish Lung Foundation, Mater College, GlaxoSmithKline, Pfizer
Speaker Bureau / Honoraria: GlaxoSmithKline, ViiV Healthcare, Merck, Gilead, Abbott, Tibotec, BMS