All five cross-sectional studies, which span 1996 through 2010, found significantly higher fracture prevalence with HIV than in comparison populations.8-12 Two of these cross-sectional studies took place in Italy and one each in Canada, the UK, and the U.S. Three focused on fragility fractures8-10? and two on all fractures.11,12 The Canadian study included only women,8 one Italian study included only men,10 and the remaining three studies considered both women and men. The Canadian8 and U.S.9 studies found 60% to 70% higher fragility fracture prevalence in HIV populations than in comparison groups -- rates close to the 58% higher all-fracture incidence calculated in the meta-analysis.6
These cross-sectional analyses involve almost 12,000 people with HIV and over 2 million controls. The largest review -- a population-based comparison in Boston's Partners HealthCare System -- focused on 8525 people with HIV and 2.2 million without an HIV diagnosis (Table 1).9 Women made up one third of the HIV group, and 72.5% of them were younger than 50. Among men, 64% were under 50. Whites, who run a higher fracture risk than blacks, accounted for 39% of women with HIV and 55% of men.
Prevalence of vertebral, wrist, and hip fractures (all fragility fracture sites) stood at 2.87 per 100 persons in the HIV group, 62% higher than the 1.77 per 100 rate in the HIV-negative comparison group.9 In both women and men, fracture prevalence was higher with than without HIV in every 10-year age group analyzed, starting with 20 to 29 for men and with 30 to 39 for women, though these differences were not always statistically significant. Fracture prevalence remained higher with than without HIV when the researchers looked at three nonoverlapping periods, 1997-1999, 2001-2003, and 2005-2007.
As one would expect, fracture prevalence rose with age in the Boston study.9 But the relative difference between people with and without HIV also rose with age (see Figure 2). Among 60- to 69-year-old women and men with HIV, prevalence exceeded 5.5 per 100 people, compared with rates of 2.15 per 100 for women and 1.58 for men the same age in the general population. With more HIV-positive people surviving into their 60s and beyond, these findings suggest HIV clinicians will be spending more time helping older patients recover from debilitating fractures.
The 10 studies of fracture incidence ran from 1993 through 2009 (Table 2),13-22 and four were not in the 2013 fracture incidence meta-analysis.6 Seven studies took place in the United States, two in Denmark,20,21 and one in Spain.19 One study involved only children in the Pediatric AIDS Clinical Trials Group (PACTG),13 two involved only men in the New York CHAMPS cohort14 or the U.S. Veterans Aging Cohort Study (VACS),17 one included only women in the U.S. Women's Interagency HIV Study (WIHS),15 and the rest studied both men and women.
Of these 10 fracture incidence analyses, three did not find a significantly higher fracture rate with than without HIV, five did find a significantly higher fracture rate with HIV, and three found a higher fracture rate with HIV/HCV or HIV/HBV than without infection. Of the three studies that saw no more incident fractures with than without HIV, a 1993-2007 study involved 5- to 10-year-old U.S. children with or exposed to HIV,13 a 2002-2006 U.S. study involved only men (n = 559),14 and a 2002-2008 U.S. study involved only women (n = 2391).15 In all three of these studies, fracture incidence was higher in the HIV group (from 9% to 29% higher) but not significantly higher.
In the 1997-2009 all-male VACS analysis, only 34% of veterans with or without HIV were older than 50, and 55% were black or Hispanic (whites have a higher fracture risk).17 Median body mass index (BMI) measured 25 kg/m2 in the HIV group, significantly lower than the 28 kg/m2 in the HIV-negative group but still on the lower end of the overweight spectrum. An analysis adjusted for demographics, comorbid disease, smoking, and alcohol abuse determined that men with HIV had a 24% higher fragility fracture rate than men without HIV (Table 2). After further adjustment for BMI, veterans with HIV had a 10% higher fragility fracture rate, but now the difference from the comparison group fell short of statistical significance.
HIV Outpatient Study (HOPS) investigators measured all-fracture incidence in 5826 people with HIV from 2000 through 2008 and indirectly standardized those numbers to a general-population cohort by age and sex through 2006.18 The HIV group had a median age of 40 (interquartile range [IQR] 34-46), 79% were men, and half were white. Standardized all-fracture incidence proved higher with HIV in every year analyzed from 2000 to 2006 and significantly higher with HIV in 2001, 2002, 2003, 2004, 2005, and 2006 (Figure 1). Incidence rose significantly from 2000 to 2008 in the HIV group but not in the comparison group. The HOPS team noted that the rising fracture incidence through the years could reflect improved fracture record keeping as providers became more aware of bone problems in people with HIV, it could reflect a true jump in incidence as people lived longer with HIV, or it could reflect both factors.
Figure 1. Standardized all-fracture incidence per 10,000 population proved consistently higher in HIV-positive men and women in the HIV Outpatient Study (HOPS) than in the general population from 2000 through 2006 and significantly higher in every year after 2000.18
Among reports not included in the meta-analysis, a nationwide case-control study in Denmark compared 124,655 people with a new fracture from January through December 2000 and 373,962 people without fractures in that period.21 With matching for age and gender, age averaged 43.4 in both cases and controls and 52% were women. People with fractures included a significantly higher proportion who abused alcohol (7.1% versus 2.5%) or ever used steroids (54.3% versus 50.7%).
In this age- and gender-matched comparison, HIV prevalence stood significantly higher among people who had a fracture during the study year than among no-fracture controls (0.04% versus 0.01%, P < 0.01).21 Odds of any fracture stood almost 3 times higher with HIV, while HIV raised chances of breaks at fragility-fracture sites even higher: 9 times at the hip, 3.5 times at the forearm, and 9 times at the spine (Table 2). All of these analyses factored in fracture history, alcoholism, use of medications affecting fracture risk, and annual income. The strength of these associations held true in men and women and in younger and middle-aged populations. The Danish team concluded their overall result "is in line with other recent publications and adds to a growing body of evidence suggesting that HIV-infected patients should be assessed for fracture risk as part of their routine care."21
Research in the general population indicates that every 1 standard deviation lower bone mineral density measure approximately doubles fracture risk.23 Together, findings from these cross-sectional and longitudinal comparisons of HIV-positive and negative people confirm that lower bone density with HIV does mean a higher fracture rate. In 2015 recommendations for evaluating and managing bone disease in people with HIV (see "When to Use FRAX and DXA -- and What They Mean" in this issue), eight experts concur that "patients with HIV infection have a higher risk of low bone mineral density and fragility fracture than the general population."24
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