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 paddy.mallon@ucd.ie 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?

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; 20:2165-2174

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 “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 2010. Abstract 747. Bonjoch A et al. 18th IAC 2010. Abstract THPDB104.

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?

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;93:3499-3504 7

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 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

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?

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): 1367-1376

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: 176 134 117 182 141 125 TDF/FTC: 180 156 138 183 165 143 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) Stellbrink HJ et al., EACS 2009

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

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

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

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; 36:482–490 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.

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

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= 114 134 112 130 114 134 113 134 In a multivariate analysis, differences between arms were statistically significant for P1NP, Osteocalcin and BSAP 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) Or Consider DXA if ≥ 1 of following: History of low-impact fractures High falls risk Post-menopausal women Men >50 yrs Hypogonadism Steroid Exposure http://www.europeanaidsclinicalsociety.org/guidelines.asp

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’

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

HIV+ patients are getting older Most of the age increase is in the 50-60 age group Patient age in Brighton cohort: 1996-2009 The increase in the over 50s is greater than the overall cohort Personal communication, M. Fisher

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