Bone Fracture Facts: Prevalence and Incidence Higher With HIV

Fall 2015

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Abstract: Bone disease has affected people with HIV since the early days of the epidemic. Over the years, low bone mineral density has proved frequent in HIV-positive people, who bear a high burden of traditional bone loss risk factors. Accumulated evidence from the United States, Canada, and Western Europe indicates that people with HIV run a higher risk of fracture than comparison groups. Five cross-sectional studies confirmed significantly higher fracture prevalence in people with HIV than in comparison groups. Ten longitudinal comparative studies all found higher fracture incidence in HIV populations, and the higher fracture rate with HIV proved significant in seven of these studies, independently of certain classical risk factors. In one U.S. study, fracture incidence rose steadily over the years in people with HIV but not in the general population.

It all started with a bad tooth. A very bad tooth. In November 1989 -- a scant 5 years after researchers discovered the AIDS virus -- specialists in Copenhagen described what appears to be the first published case of bone disease in an HIV-positive person: tooth loss and necrosis of the alveolar (tooth socket) bone in a patient with trigeminal herpes zoster.1

Alveolar necrosis (bone death) did not emerge as a prominent complication of HIV infection, but over the next several years groups in the UK and France reported avascular necrosis of the hip2 and femoral head3 in people with HIV. In 1993 researchers in Spain compared 16 HIV-positive people with 27 healthy HIV-negatives and charted significantly lower levels of osteocalcin -- a bone formation marker -- in the HIV group.4 Bone mass also proved lower in the group with HIV. Although that difference lacked statistical significance, scores of later studies would confirm significantly lower bone mineral density (BMD) in people with HIV than in HIV-negative comparison groups.

BMD offers a convenient signal of bone health, but HIV clinicians and the people they see care more about the ultimate consequence of waning bone density: fractures. And plenty of research, detailed in this article, records higher fracture rates in people with than without HIV. The published history of broken bones in HIV-positive people dates back at least to 2001, when Italian clinicians reported fractures "after trivial trauma" in two men with AIDS -- one with osteopenia, the other with osteoporosis.5 One man was 49 and the other 51, and both had central and peripheral lipodystrophy. Both men had taken indinavir plus stavudine/lamivudine, both had well-controlled HIV infection, and neither had abnormal lipids.

Twelve years later meta-analysis of seven studies comparing fracture incidence in people with and without HIV calculated a 58% higher incidence of all fractures in the HIV group (pooled incidence rate ratio [IRR] 1.58, 95% confidence interval [CI] 1.25 to 2.00) and a 35% higher incidence of fragility fractures (pooled IRR 1.35, 95% CI 1.10 to 1.65).6 (Fragility fractures are those following minimal trauma and usually affecting the hip, spine, or wrist.7) Published from 2007 through 2012, these studies confirmed several traditional fracture risk factors in people with HIV -- older age, white race, low weight, alcohol or substance use, diabetes, and liver disease.6 Six of seven studies in the meta-analysis figured that hepatitis C virus (HCV) infection inflated fracture risk.

Researchers who ran the meta-analysis rate the 58% higher all-fracture risk and the 35% higher fragility-fracture risk "modest" surges in risk with HIV.6 A review of five cross-sectional studies (Table 1) and new longitudinal studies published since the meta-analysis (Table 2) add weight to the conclusion that HIV makes broken bones more likely.

Table 1. Cross-Sectional Studies of Fracture With Versus Without HIV
First AuthorYear(s), Site(s), Study Typen HIV+/HIV-Risk Factors HIV+/HIV-Fracture Prevalence HIV+/HIV-

Higher Fx prevalence with HIV
2007, Canada, cross-sectional case-control138/402 women matched for age and region; 100/138 HIV+ on ARTAge 37.7/38.0, BMI 25.0/26.2, Aboriginal 12.5%/2%, black 16.2%/1%; HIV+ smoked, injected drugs, used steroids moreFragility Fx prevalence 26.1%/17.3%,* OR 1.7 (1.1-2.6);* BMD similar HIV+/HIV

Higher Fx prevalence with HIV
1996-2008, Boston, population-based comparison8525/2,208,792; female 34.9%/55.8%; male 65.2%/44.1%Female:
Age 27.5%/32.4% >50; 39.3%/62.5% white, 30.6%/6.4% black

Age 36.3%/25.4% >50; 55.1%/64.3% white, 17.9%/6.1% black
Vertebral, wrist, hip fracture prevalence 2.87/1.77 per 100 persons;* overall Fx 2.49/1.72 female,* 3.08/1.83 male*

Higher Fx prevalence with HIV
1998-2010, Italy, case-control160/163 men matched for age Vertebral Fx prevalence 26.9%/12.9%;* any Fx 29.6%/12.9%* on ART, 17.1%/12.9%*

Higher Fx prevalence with HIV
2002-2009; Italy, case-control2854 HIV+/8562 general population; 37% women; all HIV+ on ARTAge 46 overallAll Fx prevalence 10.8%/0.7% <40 y,* 15.2%/0.9% 41-50 y,* 14.8%/1.3% 51-60 y;* 12.5%/2.5% >60*; higher prevalence with HIV independent of age, sex, hypertension

Higher Fx prevalence with HIV
2009-2010, London, case-control222/222 matched for age; 133/44 men, 89/178 womenFemale:
Age 44.6/45.2; BMI 27.9/25.1*; smokers 12.4%/19.7%; heavy alcohol 1.1%/1.1%

Age 46.2/46.9; BMI 24.3/26.9*; smokers 35.3%/22.7%; heavy alcohol 18%/0%* Overall:48% white, 38% black
Osteoporosis prevalence 17.6%/3.6%;* Fx prevalence 20.3%/7%,* OR 3.27

* Statistically significant.

ART, antiretroviral therapy; BMD, bone mineral density; BMI, body mass index; Fx, fracture; OR, odds ratio; py, person-years.

Table 2. Longitudinal Studies of Fracture With Versus Without HIV
First AuthorYear(s), Site(s), Study Typen HIV+/HIV-Risk Factors HIV+/HIV-Fracture Prevalence HIV+/HIV-

No higher Fx risk with HIV

(Not in meta-analysis6)
1993-2007, U.S. PACTG 219/219C, prospective cohort; 4.97 y F/U1326 HIV+/649 HIV-exposed; 51% female in both groups; all HIV+ on ARTAge 7.1/5.8 y; 11%/11% white, 62%/53% black; 24%/35% Hispanic; steroids ever 2%/1%Fx incidence 1.2/1.1 per 1000 py (NS), IRR 1.1 (0.2-5.5); no difference by BMI or steroid use

11% higher incidence with HIV

No higher Fx risk with HIV
2002-2006, NYC, CHAMPS cohort328/231 men; 87% of HIV+ with ART experienceAll 49+ years, median 55; 12%/19% white, 61%/50% black, 23%/28% Hispanic; 52%/70% overweight or obese; 61%/75% smokers; 86%/94% ever drug useFx incidence 3.1/2.6 per 100 py (NS); femoral neck and lumbar BMD significantly lower in HIV+

19% higher incidence with HIV

No higher Fx risk with HIV
2002-2008, U.S. prospective WIHS cohort, 5.4 y F/U1728/663 women; 66% HIV+ on ART at index visitAge 40.4/36.1;* post-menopause 19.6%/11.2%;* 13.3%/10.7% white, 56.3%/58.4% black, 27.2%/27.0% Hispanic; BMI 28.5/30.0;* 45.3%/50.8% smokers;* 2.1%/3.9% heavy drinkers;* HCV 25.4%/14.5%;*Fx incidence 1.8/1.4 per 100 py (NS); fragility Fx incidence 0.58/0.53 per 100 py (NS)

29% higher all-Fx incidence with HIV; 9% higher fragility Fx incidence
Lo Re16

Higher Fx risk with HCV/HIV vs no infection
1999-2005; U.S. Medicaid system; F/U 5.2 y HCV/HIV+, 2.3 y HCV+ only; 3.7 y HIV+ only, 2.2-2.7 y HCV/HIV-36,950 HCV/HIV+, 276,901 HCV+ only, 95,827 HIV+ only, 3,110,904 HCV/HIV-; women 29.3% HCV/HIV+, 46.4% HCV+ only, 36.9% HIV+ only, 29.3-46.5% HCV/HIV-Age 42 HCV/HIV+, 47 HCV+ only, 39 HIV+ only, 42-48 HCV/HIV-; 27.8% HCV/HIV+, 46.1% HCV+ only, 27.3% HIV+ only, ~39% HCV/HIV- white; respective % black 39.8%, 21.3%, 44.4%, ~18%, respective % smoker 10.1%, 11.6%, 4.6%, ~3%Hip Fx incidence 3.06 per 1000 py HCV/HIV+, 2.69 HCV+ only, 1.95 HIV+ only, 1.29 HCV/HIV-; HCV/HIV+ aHR 1.38 vs HCV+ only,* 1.76 vs HIV+ females only, 1.36 vs HIV+ males only,* 2.65 vs HCV/HIV- females,* 2.20 vs HCV/HIV- males*

Higher Fx risk with HIV
1997-2009; U.S. VACS-VC prospective cohort; F/U 6.0/6.9 y*40,115/79,203 men; 75% HIV+ with ART experienceAge at enrollment 34%/34% over 50; age at fracture 54/53;* 55%/55% black/Hispanic; BMI 25/28;* alcohol abuse 16%/15%;* smoker 61%/54%;* steroid use 5%/3%*aHR for fragility Fx 1.24 (1.11-1.39);† aHR after further adjustment for BMI 1.10 (0.97-1.25) (NS)

Higher Fx risk with HIV
2000-2008; U.S. HOPS prospective cohort compared with age- and sex-matched general-population cohort; F/U 3.8 y5826 HIV+; 79% men; 73% with ART experienceAge 40 y; 51.8% white, 33.0% black, 11.7% Hispanic; BMI 24.4Standardized all-Fx incidence per 10,000 HIV+/HIV- 57.7/29.1 in 2000; 84.8/38.1 in 2002:* 81.1/26.0 in 2004;* 83.2/35.9 in 2006;* in HIV+ (but not HIV-) incidence rose significantly from 2000 to 2008

Higher Fx risk with HIV

(Not in meta-analysis6)
2007-2009; Catalonia, Spain; population-based cohort comparison; F/U 3.0 y2489/1,115,667 40 y or older; 75.3%/47.8% male*Age 50.0/61.3;* BMI 24.5/28.4;* smoker 53.3%/18.9%;* heavy alcohol 2.7%/1.8%*Fx incidence 8.03/7.93 per 1000 py; aHR 4.7 (2.4-9.5) for hip Fx,* aHR 1.8 (1.2-2.5) for osteoporotic Fx*

Higher Fx risk with HIV or HIV/HCV
1995-2009; Denmark; population-based matched cohort comparison; F/U 6.5 y HIV+, 9.6 y population controls5306/26,530; 76%/76% male; 78% of HIV+ started ART in study periodAge 36.7/36.7; 80% HIV+ white; 16% HIV+ also HCV+Fx incidence 21.0/13.5 per 1000 py;* for all Fx IRR 1.5 (1.4-1.7) for HIV+, 1.3 (1.2-1.4) for HIV+ only, 2.9 (2.5-3.4) for HIV/HCV+, 1.6 (1.4-1.8) for low-energy Fx in HIV+ and 3.8 (3.0-4.9) HIV/HCV+ (all comparisons vs population controls)

Higher Fx risk with HIV

(Not in meta-analysis6)
Jan-Dec 2000; Denmark; nationwide case-control study124,655 Fx cases/373,962 age- and gender-matched controls without FxAge 43.4 Fx cases and no-Fx controls; 48.2% cases and controls men; Charlson comorbidity index 1-2 in 16.8% of cases and 12.8% of controls,* 3-4 in 4.4% of cases and 2.4% of controls;* alcoholism 7.1% vs 2.5%;* ever use steroid 54.3% vs 50.7%*0.40 per 1000 with Fx had HIV vs 0.14 per 1000 without Fx; OR for any Fx with vs without HIV 2.89 (1.99-4.18)*, for hip Fx OR 8.99 (1.39-58.0)*, forearm Fx OR 3.5 (1.26-9.72)*, spine Fx OR 9.00 (1.39-58.1)*

Higher Fx risk with HIV/HBV vs no infection

(Not in meta-analysis6)
1997-2007; U.S. Medicaid cohort comparison; F/U 5 y4156 Medicaid patients treated for HBV/HIV, 2053 treated with HBV only, 96,253 treated with HIV only, 746,794 randomly sampled Medicaid clientsMedicaid clientsHip Fx incidence HBV/HIV vs HIV only aHR 1.37 (1.03-1.83)*; vs HBV only aHR 2.62 (0.92-7.51, NS), vs no infection aHR 1.35 (1.03-1.84)*

* Statistically significant.

† After adjustment for demographics, comorbid disease, smoking, alcohol abuse. aHR, adjusted hazard ratio; ART, antiretroviral therapy; BMD, bone mineral density; BMI, body mass index; F/U, follow-up; HOPS, HIV Outpatient Study; IRR, incidence rate ratio; NS, not significant; OR, odds ratio; PACTG, Pediatric AIDS Clinical Trials Group; py, person-years; VACS-VC, Veterans Aging Cohort Study Virtual Cohort; WIHS, Women's Interagency HIV Study.

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This article was provided by The Center for AIDS Information & Advocacy. It is a part of the publication Research Initiative/Treatment Action!. Visit CFA's website to find out more about their activities and publications.

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