| |
HiV+ & HiV/HCV(tripled) Have Higher Fracture Rates Compared to General Population in Denmark
|
| |
| |
Download the PDF here
"The risk of fractures is determined by a combination of bone strength and a relevant trauma....... Chronic HiV-infection is associated with immune-activation, chronic inflammation, and low body mass index (BMi), which are all established risk factors for low bone mineral density (BMD)......increased fracture risk in HiV/HCV-coinfected patients may be associated with consequences of intravenous drug use or increased alcohol use including increased fall or trauma risk.....[in this study] HiV-monoinfected and HiV/HCV-coinfected patients had increased risk of low-energy fracture, iRR of 1.6 (95% Ci; 1.4-1.8) and 3.8 (95% Ci; 3.0-4.9). However, only HiV/HCV-coinfected patients had increased risk of high-energy fracture, iRR of 2.4 (95 %Ci; 2.0-2.9). Among HiV-monoinfected patients the risk of low-energy fracture was only significantly increased after HAART-exposure, iRR of 1.8 (95% Ci; 1.5-2.1). The increased risk in HAART-exposed patients was not associated with CD4 cell count, prior AiDS, tenofovir or efavirenz exposure, but with comorbidity and smoking."
"Temporal trends in incidence rates of low-energy fractures
For HiV-monoinfected subjects the iR increased from 3.5/1000 PYR (95% Ci; 2.2-5.7) for the pre-HAART period (1996-1997) to 8.3/1000 PYR (95% Ci; 7.2-9.7) for the period 1997-2003 and 7.5/1000 PYR (95% Ci; 6.5-8.6) for the period 2004-2009.
For HiV/HCV-infected subject the iR remained stable during the three periods, 16.7/1000 PYR (11.1-25.3), 17.9/1000 PYR (14.4-22.2) and 17.8/1000 PYR (14.1-22.4), respectively.
For the population control cohort the iR were 6.2/1000 PYR (5.4-7.1) for 1995-1996, 4.6/1000 PYR (4.3-4.9) for 1997-2003, and 4.7/1000 PYR (4.4-5.0) for 2004-2009."
"As in all observational studies we can identify associations but cannot attribute causality. We found an association between HAART-exposure and increased risk of low-energy fracture but cannot determine whether this increased risk is induced by the alterations in BMD
observed after HAART initiation or by differences between HAART-treated and HAART-naive patients. Use of HAART may be a marker of duration and/or severity of HiV-infection, and the two groups may therefore have different immunological profiles and response to HiV-infection. Previous studies have shown association between low CD4 cell count and increased BMD loss after start of HAART [3,7]. While one study [14] found an association between low CD4 cell count and fracture risk others did not [13,16]. in our study, neither pre-HAART CD4 cell count nor pre-HAART AiDS defining diagnosis were significantly associated with subsequent fracture risk."
"we defined low-energy fractures as fractures possibly due to osteoporosis, typically those caused by low-energy trauma.....High-energy fractures were defined as fractures unlikely to be due to osteoporosis, typically those caused by high-energy trauma....We used a wider definition of low-energy fractures than the major osteoporotic fractures at spine, forearm, hip and shoulder [32], and therefore we also present relative risks for each type of low-energy fracture.The risk of fractures is determined by a combination of bone strength and a relevant trauma [13]. The fracture risk in HiV/HCV-coinfected patients with considerably increased risk of both low-energy and high-energy fractures was substantially different from that observed in HiV-monoinfected patients We have previously shown that HiV/HCV-coinfected patients had a poorer prognosis irrespective of recorded HiV transmission group [29], and further that HCV co-infection was a very sensitive marker of past or ongoing intravenous drug use and of lifestyle-related risk factors [25,30]. Thus the markedly increased fracture risk in HiV/HCV-coinfected patients may be associated with consequences of intravenous drug use or increased alcohol use including increased fall or trauma risk [16]. To reduce confounding by lifestyle-related factors and more precisely explore the influence of HiV-infection and HAARTexposure on risk
of fracture we therefore performed analyses restricted to HiV-monoinfected patients."
"HiV-monoinfected individuals had increased risk of low-energy fractures compared with population controls, and importantly this risk was only increased in HAART-exposed patients.....Our study is the first to highlight an association between HAART exposure and subsequent fracture risk.....Yin et al found no association with cumulative use of HAART and fracture risk [16]; Young et al found that HAART exposure was associated with a hazard rate of 1.39 for fracture [14], but their result was not statistically significant......As in all observational studies we can identify associations but cannot attribute causality. We found an association between HAART-exposure and increased risk of low-energy fracture but cannot determine whether this increased risk is induced by the alterations in BMD observed after HAART initiation or by differences between HAART-treated and HAART-naiŽve patients. Use of HAART may be a marker of duration and/or severity of HiV-infection, and the two groups may therefore have different immunological profiles and response to HiV-infection. Previous studies have shown association between low CD4 cell count and increased BMD loss after start of HAART [3,7]. While one study [14] found an association between low CD4 cell count and fracture risk others did not [13,16]. in our study, neither pre-HAART CD4 cell count nor pre-HAART AiDS defining diagnosis were significantly associated with subsequent fracture risk....increased prevalence of smoking among HiV-infected patients [31] may explain part of the excess risk. Concerns have been raised about the long-term effect of tenofovir on bone strengths. However, similar to three other studies we found no association between use of tenofovir and fracture risk [4,13,16]. As in most other studies, Caucasian race and increasing age were associated with increased fracture risk."
incidence of low- and high-energy fractures in persons with and without HiV-infection: a Danish population-based cohort study
AiDS Dec 2011 advance pub
Hansen, Ann-Brit E.; Gerstoft, Jan; Kronborg, Gitte; Larsen, Carsten S.; Pedersen, Court; Pedersen, Gitte; Obel, Niels
aDepartment of infectious Diseases, Copenhagen University Hospital Rigshospitalet, bDepartment of infectious Diseases, Copenhagen University Hospital Hvidovre Hospital, Copenhagen, cDepartment of infectious Diseases, Aarhus University Hospital, Skejby, dDepartment of infectious Diseases, Odense University Hospital, Odense, and eDepartment of infectious Diseases, Aarhus University Hospital, Aalborg, Denmark.
Abstract
Objective: To compare fracture risk in persons with and without HiV-infection and to examine the influence of HAART initiation on risk of fracture.
Design: Population-based nationwide cohort study using Danish registries.
Methods: Outcome measures were time to first fracture at any site, time to first low-energy and high-energy fracture in HiV-infected patients (n = 5,306) compared with a general population control cohort (n = 26,530) matched by sex and age during the study period 1995 to 2009. Cox regression analyses were used to estimate incidence rate ratios (iRR).
Results: HiV-infected patients had increased risk of fracture [iRR: 1.5 (95% Ci; 1.4-1.7)] compared with population controls. The relative risk was lower in HiV-monoinfected patients [iRR: 1.3 (95% Ci; 1.2-1.4)] than in HiV/HCV-coinfected patients [iRR: 2.9 (95% Ci; 2.5-3.4)].
Both HiV-monoinfected and HiV/HCV-coinfected patients had increased risk of low-energy fracture, iRR of 1.6 (95% Ci; 1.4-1.8) and 3.8 (95% Ci; 3.0-4.9). However, only HiV/HCV-coinfected patients had increased risk of high-energy fracture, iRR of 2.4 (95 %Ci; 2.0-2.9). Among HiV-monoinfected patients the risk of low-energy fracture was only significantly increased after HAART-exposure, iRR of 1.8 (95% Ci; 1.5-2.1). The increased risk in HAART-exposed patients was not associated with CD4 cell count, prior AiDS, tenofovir or efavirenz exposure, but with comorbidity and smoking.
Conclusions: HiV-infected patients had increased risk of fracture compared with population controls. Among HiV-monoinfected patients the increased risk was observed for low-energy but not for high-energy fractures, and the increased risk of low-energy fracture was only observed in HAART-exposed patients.
introduction
increased prevalence of osteopenia and osteoporosis is well documented in both antiretroviral naive and antiretroviral treated HiV-infected persons [1]. Chronic HiV-infection is associated with immune-activation, chronic inflammation, and low body mass index (BMi), which are all established risk factors for low bone mineral density (BMD). Antiretroviral treatment may also cause accelerated bone loss. A number of randomized controlled trials have demonstrated accelerated bone loss in the initial six to twelve months after highly active antiretroviral therapy (HAART) initiation followed by stabilization of BMD hereafter [2-4].
Further, prospective studies of patients on established HAART showed stable or increasing BMD [5,6]. Although there are drug and drug class differences, especially tenofovir causes a larger initial bone loss [2,4], the initial BMD loss after HAART initiation has been observed for all combinations of major drug classes in the HAART regimen [3,7-9]. Recent studies have also shown low BMD in MSM with primary HiV-infection [10] and in HiV-negative MSM at high risk of HiV-infection [11] thus suggesting importance of risk factors associated with both risk of HiV-infection and with low BMD.
The clinical impact of the changes in BMD remains uncertain. Most studies have found increased fracture rates among HiV-infected individuals compared with HiV-negative controls [12-15] whereas a study of premenopausal women did not [16]. Especially the influence of the short-term bone loss associated with HAART initiation on long-term risk of fracture is not well described. Only few studies have specifically addresses the influence of HAART treatment on subsequent fracture risk. Two American studies found no association between HAART exposure and risk of fracture [14,16]; recently Bedimo et al found increased fracture risk in the HAART era compared with the pre-HAART era but primarily ascribed the increased risk to non HiV-related risk factors [17]. Some of the published studies have been hampered by small study
populations, absence of information on hepatitis C status, included mainly intravenous drug users, or did not conduct separate analyses for low-energy and high-energy fractures.
We aimed to compare the overall incidence of fractures and the incidence of low-energy and high-energy fractures in antiretroviral-naive and HAART-treated HiV-infected patients with the general population during the period January 1 1995 to January 1 2010. Linking data from the population-based Danish HiV Cohort Study with the Danish Civil Registration System and Danish National Hospital Registry allowed us to capture all fractures diagnosed at hospital admissions and at outpatient or emergency visits for both HiV-infected persons and matched general population controls.
Results
Characteristics of the study population.
The study population included 5306 HiV-infected patients and 26,530 individuals in the general population control cohort (Table 1). Patients and population controls were well matched in terms of age at index date and sex, and furthermore, they were equally distributed in terms of emigration and loss to follow-up. Median age was 37 years and the male-to-female ratio was 3:1. Almost two thirds of the HiV-infected patients (62%) had received a diagnosis of HiV-infection after 1 January 1995, and 78% percent of the HiV-infected patients started HAART during the study period. Co-infection with HCV was observed in 851 (16%) of the HiV-infected patients.
Total number of fractures
We observed 806 fractures in the HiV-infected cohort during 38,456 person-years (PYR) [iR of 21.0/1000 PYR (95% Ci; 19.8-22.2)], and 3312 fractures in the general population control cohort during 245,315 PYR [iR of 13.5/1000 PYR (95% Ci; 13.1-13.9)]. HiV-infected patients had increased fracture risk compared with population controls, iRR of 1.5. Fracture risk was increased in both HAART-naive (iRR of 1.4) and HAART-exposed patients (iRR of 1.6). Compared with corresponding population controls both HiV monoinfected patients (iRR of 1.3) and HiV/HCV-coinfected patients (iRR of 2.9) had increased risk of fracture. Table 2 displays iRRs with 95% Ci.
Low-energy fractures
For HiV-monoinfected patients the iR of low-energy fracture was 7.4/1000 PYR (95% Ci; 6.7-8.2), for HiV/ HCV-coinfected patients the iR was 17.7/1000 PYR (15.3-20.5), and for the population controls cohort the iR was 4.8/1000 PYR (4.6-5.0). Compared with the population controls both HiV-monoinfected patients (iRR of 1.6) and HiV/HCV-coinfected patients (iRR of 3.8) had increased risk of low-energy fracture. Figure 1 displays cumulative incidence of low-energy fractures for the three groups.
All subgroups of low-energy fractures contributed to the increased risk of low-energy fracture observed in HiV-monoinfected patients. For HiV/HCV-coinfected patients the relative risk of hip fractures was substantially higher than risk of other low-energy fractures, iRR of 16.0, while vertebral fractures seemed under-represented (Table 2).
High-energy fractures
For HiV-infected patients the iR of high-energy fracture was 9.5/1000 PYR (95% Ci; 8.7-9.5), for HiV/HCV-monoinfected patients the iR was 22.7/1000 PYR (19.9-25.9), and for population controls the iR was 8.7/1000 PYR (8.4-9.0). Thus HiV-monoinfected patients and population controls had comparable risks of high-energy fractures, while HiV/HCV-coinfected patients had increased risk of high-energy fractures compared with population controls, iRR of 2.4 (Fig. 1). Low-energy fractures in HAART-naive versus HAART treated HiV-monoinfected patients
Figure 2 displays cumulative incidence of low-energy fractures stratified by time before and after HAART exposure in HiV-monoinfected patients and corresponding population controls. As illustrated, there was no significant difference in fracture risk between HAART-naive patients and population controls. in contrast, HAART-exposed patients had increased risk of low-energy fracture [iRR of 1.8 (95% Ci; 1.5-2.1)]
compared with population controls. After adjusting for comorbidity the iRR was 1.6 (95% Ci: 1.36-1.87). A plot of Schoenfeld residuals proved that the risk of low-energy fracture was constant over time after HAART initiation (data not shown).
Risk-factors for low-energy fractures in HAARTexposed HiV-monoinfected patients
For HiV-monoinfected patients, we estimated the effect of age, gender, an AiDS defining diagnosis prior to HAART, CD4 cell count and race in univariate and multivariate analyses restricted to time after HAART initiation (Table 3). We found no significant association between CD4 cell count, prior AiDS diagnosis or gender and risk of low-energy fracture. Caucasian race, increasing age and medium or high comorbidity score was associated with increased fracture risk in both univariate and multivariate analyses. We had only information on smoking in 69% of the patients (of whom 67% were current or former smokers) and therefore evaluated the effect of smoking in a separate model. Smoking was associated with increased fracture risk, unadjusted iRR of 2.0 and adjusted iRR of 2.0. Use of tenofovir did not increase the risk of fracture, iRR of 1.2 (95% Ci; 0.8 -1.7); neither did the use of efavirenz, iRR of 1.1 (0.8-1.4). The iRR for use of abacavir was 0.9 (0.7-1.2).
Temporal trends in incidence rates of low-energy fractures
For HiV-monoinfected subjects the iR increased from 3.5/1000 PYR (95% Ci; 2.2-5.7) for the pre-HAART period (1996-1997) to 8.3/1000 PYR (95% Ci; 7.2-9.7) for the period 1997-2003 and 7.5/1000 PYR (95% Ci; 6.5-8.6) for the period 2004-2009.
For HiV/HCV-infected subject the iR remained stable during the three periods, 16.7/1000 PYR (11.1-25.3), 17.9/1000 PYR (14.4-22.2) and 17.8/1000 PYR (14.1-22.4), respectively.
For the population control cohort the iR were 6.2/1000 PYR (5.4-7.1) for 1995-1996, 4.6/1000 PYR (4.3-4.9) for 1997-2003, and 4.7/1000 PYR (4.4-5.0) for 2004-2009.
Discussion
in this nationwide population-based cohort study we found that HiV-monoinfected patients had increased risk of low-energy fractures driven by the period after HAARTexposure compared with population controls. in contrast, we observed similar risks of high-energy fractures in HiV-monoinfected patients and controls. The risk of fractures is determined by a combination of bone strength and a relevant trauma [13]. The fracture risk in HiV/HCV-coinfected patients with considerably increased risk of both low-energy and high-energy fractures was substantially different from that observed in HiV-monoinfected patients We have previously shown that HiV/HCV-coinfected patients had a poorer prognosis irrespective of recorded HiV transmission group [29], and further that HCV co-infection was a very sensitive marker of past or ongoing intravenous drug use and of lifestyle-related risk factors [25,30]. Thus the markedly increased fracture risk in HiV/HCV-coinfected patients may be associated with consequences of intravenous drug use or increased alcohol use including increased fall or trauma risk [16]. To reduce confounding by lifestyle-related factors and more precisely explore the influence of HiV-infection and HAARTexposure on risk of fracture we therefore performed analyses restricted to HiV-monoinfected patients.
HiV-monoinfected individuals had increased risk of low-energy fractures compared with population controls, and importantly this risk was only increased in HAART-exposed patients. Our study is the first to highlight an association between HAART exposure and subsequent
fracture risk. Only few previous studies have analyzed data on HAART initiation and subsequent fracture risk; Yin et al found no association with cumulative use of HAART and fracture risk [16]; Young et al found that HAART exposure was associated with a hazard rate of 1.39 for fracture [14], but their result was not statistically significant.
As in all observational studies we can identify associations but cannot attribute causality. We found an association between HAART-exposure and increased risk of low-energy fracture but cannot determine whether this increased risk is induced by the alterations in BMD observed after HAART initiation or by differences between HAART-treated and HAART-naive patients. Use of HAART may be a marker of duration and/or severity of HiV-infection, and the two groups may therefore have different immunological profiles and response to HiV-infection. Previous studies have shown association between low CD4 cell count and increased BMD loss after start of HAART [3,7]. While one study [14] found an association between low CD4 cell count and fracture risk others did not [13,16]. in our study, neither pre-HAART CD4 cell count nor pre-HAART AiDS defining diagnosis were significantly associated with subsequent fracture risk.
Adjusting for comorbidity attenuated the difference in fracture risk between HiV-infected patients and controls. We were not able to adjust for other traditional risk factors for osteoporosis such as low BMi, smoking and steroid exposure that may also be more common in HiV-infected patients than in general population controls. Among HAART-exposed patients smoking was associated with a two-fold increased risk of low-energy fracture. Thus, increased prevalence of smoking among HiV-infected patients [31] may explain part of the excess risk. Concerns have been raised about the long-term effect of tenofovir on bone strengths. However, similar to three other studies we found no association between use of tenofovir and fracture risk [4,13,16]. As in most other studies, Caucasian race and increasing age were associated with increased fracture risk.
The strengths of our study include the use of population-based nationwide cohorts; long and nearly complete follow-up; access to detailed data on fracture and comorbidity in DNHR; and for the HiV-patients clinical information on use of antiretroviral treatment, AiDS defining events, CD4 cell count and viral load. Our study also had limitations. Fracture data were incomplete before 1995 as the DNHRonly included data on outpatients and emergency patients since 1995. Therefore we could not exclude persons with low-energy fracture before the index date.
We used a wider definition of low-energy fractures than the major osteoporotic fractures at spine, forearm, hip and shoulder [32], and therefore we also present relative risks for each type of low-energy fracture. Another potential shortcoming is inaccuracies in fracture diagnoses reported to DNHR. However, the positive predictive value of the registry diagnoses is generally high (70% to 99%) [33], and the positive predictive value of hip fractures inDNHRhas been shown to be as high as 93% [34].
in conclusion, we found that HiV-infected patients had increased risk of fracture at any site. HiV-infected patients without HCV-coinfection had increased risk of low-energy fractures but not of high-energy fractures. The risk of low-energy fracture was associated with HAART-exposure but also with traditional risk factors such as age, comorbidity and smoking. The risk associated with HAART was moderate and did not increase over time. Future research should explore mechanisms behind the HAART-associated initial BMD loss and investigate possible interventions in patients at high risk of osteoporosis.
| |
| |
| |
|
|
|
