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HIV infection and its association with an excess risk of clinical fractures and: a nation-wide case-control study
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"In summary, our study suggests that HIV-infected adults are at an highly increased risk of hip and other bone fractures, compared to the general population. This finding 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."
"We report a significantly increased prevalence of HIV infection of almost 3-fold among fracture cases, compared to gender and age-matched controls from the Danish health registries. This is, in our data, independent of potential confounders, including fracture history, alcoholism, use of potentially involved medications (sedatives, opioids, antidepressants, anticonvulsants, antipsychotics, and corticosteroids), and annual income. Even more importantly, we demonstrate an age and gender-adjusted 9-fold higher risk of hip fractures in HIV-infected patients. Similarly, risk of clinical spine fractures appears to be 9 times higher in patients diagnosed with HIV. A lower effect size (but still significant) effect was observed for the association between forearm fractures and HIV status, with a 3.5-fold increase among the HIV-infected patients. The latter were though attenuated and became non-significant after multivariable adjustment for potential confounders."
"As high active antiretroviral therapy (HAART) for HIV infection allows patients to live longer, many are being confronted with additional health challenges related to aging.......a number of studies have reported a decrease in bone mineral density (BMD) among HIV-infected patients .......However, the consequences of low bone mass on fracture risk among patients diagnosed with HIV infection are not well known, as data is still limited and in some cases contradictory. We have therefore used the nation-wide Danish health registries to explore the existing association between HIV clinical diagnosis and fracture risk using a case-control design..........The excess risk associated with HIV infection increased with time from diagnosis: for the HIV infected for up to 2 (median 0.84) years, adjusted OR 1.20 [0.53-2.73]; for 2.1 to 4 (median 3.11) years OR 2.30 [1.12-4.72]; for 4.1 to 6 (median 4.98) years 2.10 [1.06-4.16]; for 6.1 to 7.5 (median 6.64) years OR 2.5 [1,14-5,67]; and for >7.5 (median 9.62) years OR 3.00 [1.39-6.47]. According to the smooth spline produced, the effect increases rapidly in the first 2-3 years after the diagnosis of HIV infection to then continue increasing less steeply [Figure 1]."
".........we report for the first time a time-varying association between HIV infection and fracture risk: the excess risk associated with HIV infection appears to increase rapidly in the first 2-3 years after diagnosis, and then continues increasing more slowly. Other studies like the one by Yin et al have found that fracture risk is highest in the first 2 years after HAART initiation [13]. Again, whether bone deterioration is consequence of HIV itself or TAR remains controversial."
"the pathogenesis responsible for this excess risk remains unclear........many studies show.......use of certain antiretroviral therapies......chronic immune activation produced by HIV infection......increased production of pro-inflammatory cytokines ....... altered vitamin D metabolism in untreated HIV patients.......interaction between the virus and the patient's immunological status is indeed relevant, as an association between nadir CD4 counts and fractures has been consistently shown...... Our study has many limitations[see below]......"
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HIV infection and its association with an excess risk of clinical fractures and : a nation-wide case-control study
JAIDS Journal of Acquired Immune Deficiency Syndromes: Publish Ahead of Print
POST ACCEPTANCE, 21 January 2014
Prieto-Alhambra, Daniel; Guerri-Fernandez, Robert; De Vries, Frank; Lalmohamed, Arief; Bazelier, Marloes; Starup-Linde, Jakob; Diez-Perez, Adolfo; Cooper, Cyrus; Vestergaard, Peter
Preliminary results from this work were reported as a Plenary Poster at the last American Society of Bone and Mineral Research (ASBMR) annual meeting, held in Minneapolis (Minnessotta, USA) in October/2012.
Abstract
Background: Different studies have reported an association between HIV infection, antiretroviral therapies and impaired bone metabolism, but data on their impact on fracture risk are scarce. We studied the association between a clinical diagnosis of HIV infection and fracture risk.
Methods: We conducted a case-control study using data from the Danish National Health Service registries, including 124,655 fracture cases and 373,962 age-gender-matched controls. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression.
Results: A total of 50 (0.40/1,000) patients in the fracture group and 52 (0.14/1,000) controls had a HIV diagnosis. The risk of any fracture was thus significantly increased among HIV-infected patients (age and gender-matched OR = 2.89, 95% CI 1.99-4.18). Similarly, significant increases in the risk of hip (OR=8.99, 95% CI 1.39-58.0), forearm (OR=3.50, 95 CI 1.26-9.72), and spine fractures (OR=9.00, 95% CI 1.39-58.1) were observed.
Conclusions: HIV infection is associated with an almost 3-fold increase in fracture risk compared to that of uninfected age and gender-matched uninfected patients. HIV patients are also at an almost 9-fold higher risk of hip fracture.
Introduction
As high active antiretroviral therapy (HAART) for HIV infection allows patients to live longer, many are being confronted with additional health challenges related to ageing [1]. Apart from the classical risk factors, there are morbidities not classically considered to be HIV-related that have been associated with ongoing HIV replication, chronic immune activation, and long-term high activity antiretroviral therapy [ 1, 2 ]. In these lines, a number of studies have reported a decrease in bone mineral density (BMD) among HIV-infected patients [1, 3, 4 ]. A meta-analysis [1] of twelve cross-sectional studies in HIV infected adults found that the probabilities of osteopenia and osteoporosis were 6.4 and 3.7 times higher respectively in HIV-infected than in uninfected patients. However, the consequences of low bone mass on fracture risk among patients diagnosed with HIV infection are not well known, as data is still limited and in some cases contradictory.
We have therefore used the nation-wide Danish health registries to explore the existing association between HIV clinical diagnosis and fracture risk using a case-control design.
Potential confounders
Using The National Hospital Discharge Register [6], we gathered information on the number of days spent in hospital the year preceding fracture [year 1999] and history of a prior fracture in the period 1977-2000. Similarly, data from the National Bureau of Statistics was obtained for a more accurate patient characterisation including: income, social status, working status, and educational status in 1999. The National Health Organisation Register information was then used to study number of contacts to general practitioners and practising specialists for the period 1996 to 2000.
Information on alcoholism was collected as appearance of a diagnosis of alcoholism in the National Hospital Discharge Register or in the Psychiatric Central Register [6], or a prescription of disulfiram in the Prescriptions database. Data on use of drugs with a potential effect on bone metabolism and/or fracture risk [corticosteroids, sedatives, opioids, antidepressants, anticonvulsants, and antipsychotics) were gathered from the Prescriptions database.
RESULTS
124,655 fracture cases were identified in 2000 in Denmark, and 373,962 controls were matched on age and gender. Hence, both cases and controls had similar age (mean (SD) 43.4 (27.4) years), and 51.8% of both populations were women.
Controls had significantly higher annual income, were more likely to be married and actively working, less likely to suffer alcoholism, and to use antiepileptic drugs, sedatives/hypnotics, and corticosteroids. In addition, controls had also less co-morbidities and less commonly a previous fracture history [Table 1].
Prevalence of HIV infection was 0.04% (n=50) among cases and 0.01% (n=52) among controls (p<0.01), equivalent to an overall unadjusted (age and gender-matched) OR of 2.89 (1.99-4.18). Similarly, 3/10,530 (0.03%) hip fracture cases had a previous HIV infection, compared to 1/31,535 (<0.01%) matched controls: OR 8.99 (1.39-58.0). The prevalence of HIV infection among forearm and spine fracture cases was 7/20,035 (0.03%) and 3/3,364 (0.09%), whilst the proportions of HIV infected matched controls were 6/60,030 (0.01%) and 1/10,079 (0.01%) respectively, equivalent to age and gender matched ORs 3.50 (1.26-9.72) and 9.00 (1.39-58.1) respectively. Adjustment for previous fracture history, alcoholism, use of corticosteroids, use of sedatives and annual income attenuated the observed associations for all but for overall fracture (multivariate adjusted OR 1.99 [1.31-3.03]) [Table 2]. This latter association stood for further adjustment for use of opioids, antidepressants, anticonvulsants, and antipsychotics: OR 1.76 [1.14-2.71].
Stratified analysis by gender demonstrated similarly increased prevalence of HIV among fracture cases in men and women: 45 (0.07%) male and 5 (0.01%) female cases had a history of HIV infection, compared to 48 (0.03%) and 4 (<0.01%) controls. Estimated Ors were therefore 2.73 (1.78-4.19) for HIV-infected men and 3.75 (1.48-9.50) for women with a clinical diagnosis of HIV. Age-stratified analyses offered comparable results in the young and middle-aged populations (OR 2.76 [1.57-4.86] and OR 3.12 [1.80-5.41] respectively), but no significant increase in HIV prevalence amongst elderly fracture cases: 1(<0.01%) cases aged 60 or older had a history of HIV infection, and 2(<0.01%) controls had an equivalent HIV infection status (OR 1.50 [0.14-16.5]).
The excess risk associated with HIV infection increased with time from diagnosis: for the HIV infected for up to 2 (median 0.84) years, adjusted OR 1.20 [0.53-2.73]; for 2.1 to 4 (median 3.11) years OR 2.30 [1.12-4.72]; for 4.1 to 6 (median 4.98) years 2.10 [1.06-4.16]; for 6.1 to 7.5 (median 6.64) years OR 2.5 [1,14-5,67]; and for >7.5 (median 9.62) years OR 3.00 [1.39-6.47]. According to the smooth spline produced, the effect increases rapidly in the first 2-3 years after the diagnosis of HIV infection to then continue increasing less steeply [Figure 1].
DISCUSSION
We report a significantly increased prevalence of HIV infection of almost 3-fold among fracture cases, compared to gender and age-matched controls from the Danish health registries. This is, in our data, independent of potential confounders, including fracture history, alcoholism, use of potentially involved medications (sedatives, opioids, antidepressants, anticonvulsants, antipsychotics, and corticosteroids), and annual income. Even more importantly, we demonstrate an age and gender-adjusted 9-fold higher risk of hip fractures in HIV-infected patients. Similarly, risk of clinical spine fractures appears to be 9 times higher in patients diagnosed with HIV. A lower effect size (but still significant) effect was observed for the association between forearm fractures and HIV status, with a 3.5-fold increase among the HIV-infected patients. The latter were though attenuated and became non-significant after multivariable adjustment for potential confounders.
The strength of the associations observed between HIV status and fractures is similar for men and women, as well as in younger and middle-aged populations. By contrast, no such relationship was seen among patients aged 60 years or older, possibly because of a reduced number of HIV-infected cases and controls in this strata. In a study by Bonjoch et al male gender was reported as an independent factor for bone loss in HIV patients [11].. Triant et al. where the authors analyzed fracture prevalence amongst HIV and non HIV patients. Instead, we compared the prevalence of HIV in fractured patients versus matched controls [12] .Despite of this, the general conclusions of the study are similar to our findings, where HIV infection and fracture appear to be associated
Most previous reports on the association between HIV infection and fractures studied exclusively American patients. In contrast, our data comes from a Northern European population, with different representation of ethnic groups and probably different risk factors. Nonetheless, the results highlighting an association between HIV infection and fractures, even, once adjusting for diferent risk factor, are similar.
Finally, we report for the first time a time-varying association between HIV infection and fracture risk: the excess risk associated with HIV infection appears to increase rapidly in the first 2-3 years after diagnosis, and then continues increasing more slowly. Other studies like the one by Yin et al have found that fracture risk is highest in the first 2 years after HAART initiation [13]. Again, whether bone deterioration is consequence of HIV itself or TAR remains controversial.
Despite the evidence of an association between fractures and HIV infection was inconclusive until recently, a number of studies have now consistently pointed to an increased risk in the HIV-infected patients. A just published retrospective cohort study carried out by our group reported similar results, with age and gender-adjusted HRs of 6.2 [95%CI 3.5-10.9; p<0.001] and 2.7 [2.01-3.5; p<0.001] for hip and clinical major fractures respectively among patients from Catalonia (Spain) [14] . Other population-based studies support these findings [12, 15, 16].
Although the causal pathways for such associations remain obscure, different potential factors have been described in the literature. Collin et al demonstrated an increased incidence of all fractures in a cohort of HIV-infected men and women on HAART for ten years [17], raising concerns of undesired effects of HAART on bone metabolism. In a recent study by Womack et al [18] a similar association between fractures and HIV was described, but this was no longer significant after adjustment for body mass index and comorbidities, suggesting that these might explain the increased risk of fractures in HIV populations. Smaller studies, with more restricted samples [4, 19] have suggested that HIV infection is independently associated with BMD reductions in aging men, as well as with increased fracture risk in these patients.
There is therefore a growing body of evidence that indicates that people with HIV are at high risk for osteoporosis and fractures. However, the pathogenesis responsible for this excess risk remains unclear. Many studies show that the early bone loss seen in HIV patients can be attributed to the use of certain antiretroviral therapies such as protease inhibitors and/or tenofovir [20, 21,22]. In a substudy of 214 patients included in the SMART trial BMD decreased further in the group receiving continous HAART when compared to those on intermittent therapy. More recently, Bedimo et al. have reported on the cumulative effect of continuous tenofovir and lopinavir / ritonavir were on osteoporotic fracture risk [23]. Notwithstanding this, other studies have suggested that the chronic immune activation produced by HIV infection might also play an important role in the development of osteoporotic fractures amongst HIV-infected populations [24, 25]. Various mechanisms might explain the effects of the virus on bone metabolism, including increased production of pro-inflammatory cytokines such as tumor necrosis factor alpha [26] or interleucin 6 [27, 28], and altered vitamin D metabolism in untreated HIV patients, which lead to excessive bone resorption [29]. This narrow interaction between the virus and the patient's immunological status is indeed relevant, as an association between nadir CD4 counts and fractures has been consistently shown [15, 21, 23]. Our study has many limitations, the main one being the scarcity of detailed information on HIV infection and antiretroviral therapies. In addition, we could not investigate other potential confounders such as bone mineral density, smoking, or body mass index. And, HAART medications are not available in this dataset, as these drugs are not dispensed in community pharmacies but in hospital settings. However, we have used highly validated nation-wide data, and our study includes a big and representative sample of patients, with information gathered during routine clinical practice. We also expect low recall bias, as HIV infection is likely to be accurately registered due to the relevant consequences that the coding of this disease has for patients' access to appropriate therapies.
In summary, our study suggests that HIV-infected adults are at an highly increased risk of hip and other bone fractures, compared to the general population. This finding 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.
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