With the aging of the HIV-infected population, identifying individuals at higher risk of fracture to address modifiable risk factors for fracture prevention is an increasingly important focus of long-term outpatient care. In unadjusted analyses, the risk of fragility fracture is approximately 35% higher in HIV-infected than in uninfected controls 1,2 and increases with age.3 HIV primary care guidelines recommend the performance of dual energy x-ray absorptiometry (DXA) for bone mineral density (BMD) assessment in HIV-infected individuals >50 years4,5 and risk stratification using FRAX starting at the age of 40.5 FRAX is an assessment tool for the prediction of fractures (10-year probability of major osteoporotic and hip fracture) validated primarily in men and women >50 years. FRAX includes 11 clinical risk factors for fractures, as well as femoral neck BMD, although the latter is not a necessary component.6
In Europe, FRAX is commonly used for risk prognostication in the general population to identify individuals >40 years who should undergo a screening DXA, and those at high-enough risk of fracture to receive pharmacologic therapy without BMD evaluation.7 In the United States, where DXA is considered the preferred screening modality for older individuals, FRAX is used primarily in individuals who do not meet the criteria for osteoporosis by DXA but have low bone density/osteopenia (T score <−1.0 but >−2.5) to determine the appropriateness of pharmacologic therapy.8 There are no definitive data on similar use of FRAX for HIV-infected patients. Recent studies suggest that FRAX underestimates the fracture rates in HIV-infected men9,10; however, both studies included men <50 years and compared the FRAX score to either the BMD outcomes or prevalent rather than incident fractures.
The goal of this study was to compare the performance of a modified-FRAX among HIV-infected and uninfected men >50 years. We hypothesized that the modified-FRAX would underestimate the actual fracture rates more in HIV-infected than in uninfected men. We evaluated whether inclusion of HIV as a cause of secondary osteoporosis in the FRAX calculation would improve the accuracy of FRAX estimates in HIV-infected men. Chronic liver disease is among the conditions listed as a cause of secondary osteoporosis in the FRAX calculator; however, hepatitis C virus (HCV) infection without hepatic decompensation is not usually included in the calculation. Since HCV coinfection is fairly prevalent among HIV-infected individuals and has been associated with significant fracture risk,11,12 we also evaluated whether inclusion of HCV as a cause of secondary osteoporosis would improve the accuracy of FRAX estimates in HIV-infected men.
The Veterans Aging Cohort Study Virtual Cohort (VACS-VC)13 is a prospective observational cohort of HIV-infected veterans matched with uninfected veterans by age, sex, race ethnicity, and geographic region who enrolled for care at the Veterans Health Administration in the same calendar year. Our analysis included all male HIV-infected and uninfected veterans at the VACS-VC who were aged 50–70 years in the year 2000 and have data available to approximate the risk factors necessary for calculation of FRAX. In VACS-VC, 42,924 males met these inclusion criteria, including 25,720 with data to approximate all but 2 of the FRAX variables (parental history of hip fracture and secondary osteoporosis). Among these subjects, 1269 whose weight exceeded the 125-kg limit for the FRAX calculation were excluded, resulting in 24,451 subjects with valid FRAX calculations. Each subject had at least 1 clinic visit recorded within the Veterans Health Administration database during the period 2000–2010.
Estimated Fracture Risk by Modified-FRAX
A “modified-FRAX” fracture risk estimate was calculated for each subject using the following 9 variables available at the VACS-VC to approximate FRAX calculator variables: age, sex, race/ethnicity limited to the categories used in FRAX (white, black, Asian, and Hispanic), weight (kilograms), height (square centimeters), history of previous fragility fracture, ever glucocorticoid use, rheumatoid arthritis, and alcohol use. A subject was determined to be a current smoker if current smoking status was listed as a health factor in the year 2000; therefore, prevalence is lower than that in previous VACS-VC analyses in which current smoking status was listed as a health factor in any year within the study period.3 The presence of the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code for alcohol use/abuse was used to approximate the 3 or more units of alcohol per day threshold used by FRAX. Rheumatoid arthritis was also determined by the ICD-9-CM codes. Parental history of hip fracture and secondary osteoporosis (ie, type 1 diabetes, osteogenesis imperfecta, untreated hyperthyroidism, hypogonadism or premature menopause <45 years, chronic malnutrition, malabsorption, and chronic liver disease) were not used in the calculation of the modified-FRAX because the data were either not collected or not validated at the VACS-VC. By convention, parental history of hip fracture and secondary osteoporosis were entered as “No” for all subjects, but we also performed a sensitivity analysis for the test characteristics of the modified-FRAX by entering “Yes” for the parental history of hip fracture and secondary osteoporosis (see Methods). HCV infection status was also defined for subjects by positive HCV antibody, HCV RNA, or ICD-9-CM codes.
The estimated 10-year probability of major osteoporotic and hip fracture was calculated for each subject using a program that automated data entry and retrieval from the FRAX web site calculator for the United States stratified by race/ethnicity (http://www.shef.ac.uk/FRAX/index.aspx).
Fracture outcomes were defined using codes from the ICD-9-CM to match FRAX-defined osteoporotic fractures of the hip, shoulder, and forearm and clinical vertebral fractures; hip: 820.0X, 820.1X, 820.2X, 820.3X, 820.8, 820.9; shoulder/upper arm: 812.X, 812.1X; radius and ulna: 813.0X, 813.1X, 813.2X, 813.3X, 813.4X, 813.5X, 813.8X, 813.9X; and vertebrae: 805.2, 805.3, 805.4, 805.5, 805.6, 805.7; 805.8; 805.9. These codes were previously validated by a chart review of 400 randomly selected radiology reports. Overall agreement between the chart review and ICD-9-CM codes was 97%. Agreement beyond chance (kappa) was substantial [0.77, 95% confidence interval (CI): 0.62 to 0.90].14 Analyses using these fracture outcomes have been published previously.3,15 Only the first fractures occurring for each subject during the study period 2001–2010 were included in the analyses.
Descriptive analyses included means and SDs for the continuous variables, and frequency and percentages for the categorical variables. Variables were compared across groups using t tests for the continuous variables and χ2 or Fisher exact tests for the categorical variables. Incident fracture risk was calculated based on the occurrence of a new fracture at a major osteoporotic fracture site (ie, hip, upper arm, radius/ulna, and vertebrae) and hip alone for each subject between 2001 and 2010 so as to fit the 10-year fracture estimate calculated by the modified-FRAX. We also conducted a sensitivity analysis restricted to the 15,876 subjects who had clinic data beyond 2010 to rule out the possibility that fractures did not occur because subjects had died during follow-up.
Assessment of Accuracy
Calibration was our measure of accuracy because thresholds for the numeric probability of fracture determined by FRAX have been established for BMD screening and pharmacologic treatment. Calibration assesses how well the observed fractures compare with the estimated (predicted) probabilities of fracture across the entire spread of the data.16 The number of individuals observed to sustain a fracture vs the number of individuals expected to sustain a fracture by modified-FRAX, the observed/expected (O/E) ratio, at a major osteoporosis site or at the hip was calculated for HIV-infected and uninfected groups. Chi-square tests were used to test the differences between the O/E ratios between groups, and the Hosmer–Lemeshow χ2 statistic was used to compare the O/E ratios over deciles of estimated risk.
To assess whether the accuracy of the modified-FRAX improves when HIV is included as a cause of secondary osteoporosis, the modified-FRAX was recalculated for each subject after entering “Yes” for secondary osteoporosis. Similarly, the accuracy of modified-FRAX was assessed when HCV infection was considered a cause of secondary osteoporosis. Note that only one cause of secondary osteoporosis can be entered into the FRAX calculator; therefore, in this analysis, secondary osteoporosis was entered as “Yes” for all HCV-infected subjects without consideration of the HIV status.
We evaluated the sensitivity/specificity of the modified-FRAX for prediction of incident fracture among HIV-infected men using FRAX thresholds for pharmacologic therapy endorsed by osteoporosis guidelines in the United States and Europe.7,17 In addition, we performed a sensitivity analysis for the test characteristics of the modified-FRAX for prediction of incident fracture by entering “Yes” for the 2 FRAX variables that were not available in the VACS data set (parental history of hip fracture and secondary osteoporosis) and recalculating the modified-FRAX.
Analyses were performed using SAS version 9.4 (Cary, NC) and the R package “rmap.”18 All tests were 2-tailed, and a P value <0.05 was considered significant.
Compared with HIV-uninfected men, those with HIV infection were similar in age but differed in all other FRAX variables. HIV-infected men were more likely to be black, have previous fractures, glucocorticoid use, and alcohol use/abuse than uninfected men, but had lower weight/body mass index and were less likely to be current smokers or have rheumatoid arthritis than uninfected men (Table 1). HIV-infected men were also more likely to have HCV infection than HIV-uninfected men (33.2% vs 7.9%, P < 0.0001).
The 10-Year Observed and Estimated Fracture Risks by Modified-FRAX
During an observation period of 10 years, the mean estimated 10-year risk of fracture by modified-FRAX was higher for HIV-infected than uninfected men at the major osteoporosis sites (2.9% ± 1.5% vs 2.7% ± 1.4%, P < 0.0001) and at the hip (0.3% ± 0.4% vs 0.3% ± 0.2%, P < 0.0001) (Fig. 1). When HIV is included as a cause of secondary osteoporosis in the calculation of the modified-FRAX, the estimated rate of fracture in HIV-infected men increased 31% for major osteoporotic fractures, from 2.9% ± 1.5% to 3.8% ± 2.1%, and increased 67% for hip fractures, from 0.3% ± 0.4% to 0.5% ± 0.6%.
Accuracy of Modified-FRAX in HIV-Infected Men
Among all participants, the modified-FRAX consistently underestimated the true fracture risk: the O/E ratio for fractures was 1.39 (95% CI: 1.30 to 1.48) (Table 2). The modified-FRAX was less accurate in HIV-infected than in uninfected men for the major osteoporotic fractures (O/E: 1.62 vs 1.29, P = 0.03) but did not differ for hip fractures (O/E: 4.52 vs 3.56, P = 0.43). Figure 2 shows the goodness of fit of observed and expected fractures in HIV-infected and uninfected men. Of note, the accuracy of the modified-FRAX for HIV-infected men seems to worsen with higher estimated risk for major osteoporotic fractures. In the sensitivity analysis that limited the sample to those men who had data after 2010 (N = 15,876), the O/E ratios were similarly higher in HIV-infected (O/E = 1.81; 95% CI: 1.56 to 2.09) than in uninfected men (O/E = 1.22; 95% CI: 1.11 to 1.35).
Accuracy of Modified-FRAX With Consideration of HIV or HCV as a Cause of Secondary Osteoporosis
We recalculated the O/E ratios for HIV-infected men using the modified-FRAX and including HIV as a cause of secondary osteoporosis. As a result, the O/E ratio among HIV-infected men decreased from 1.62 (95% CI: 1.45 to 1.81) to 1.20 (95% CI: 1.08 to 1.34) for major osteoporotic fractures and from 4.52 (95% CI: 3.68 to 5.53) to 2.66 (95% CI: 2.17 to 3.26) at the hip (Table 2). With this adjustment, the O/E ratios were closer to the O/E ratios in uninfected men: 1.29 (95% CI: 1.19 to 1.40) at major osteoporotic sites and 3.56 (95% CI: 3.03 to 4.18) at the hip.
When we recalculated the O/E ratios including HCV as a cause of secondary osteoporosis without consideration for HIV, the O/E ratio among HIV-infected men decreased from 1.62 (95% CI: 1.45 to 1.81) to 1.48 (95% CI: 1.33 to 1.65) for major osteoporotic fractures and from 4.52 (95% CI: 3.68 to 5.53) to 3.87 (95% CI: 3.16 to 4.75) for fracture at the hip (Table 2). The O/E ratios were also closer to the O/E ratios in uninfected men: 1.27 (95% CI: 1.17 to 1.37) at major osteoporotic site and 3.44 (95% CI: 2.93 to 4.04) at the hip. Overall, the accuracy improved more with consideration of HIV than HCV as a cause of secondary osteoporosis in the modified-FRAX calculation.
Modified-FRAX and Thresholds for Pharmacologic Treatment
Since the clinical utility of FRAX is based on accepted thresholds for pharmacologic intervention, we compared the sensitivity/specificity of the modified-FRAX for fracture prediction using accepted FRAX thresholds for pharmacologic interventions in HIV-infected and uninfected groups. For HIV-infected men, the modified-FRAX calculated was with HIV as the cause of secondary osteoporosis. As none met the threshold (>20%) for major osteoporotic fracture endorsed by the National Osteoporosis Foundation (NOF),17 we used the age-specific thresholds for major osteoporotic fractures endorsed by European osteoporosis societies (6.3%–13.4% in 50- to 70-year-olds).7 At the hip, we used the threshold (>3%) endorsed by the NOF.17 Using these thresholds, only 21/326 (6.4%) HIV-infected men with fractures at major osteoporotic sites and 3/93 (3.2%) at the hip were correctly predicted (Table 3). The sensitivity was similarly poor among uninfected men: only 16/609 (2.6%) with fractures at the major osteoporotic sites and 0/148 (0%) at the hip were correctly predicted. These analyses were meant only to illustrate the test characteristics of the modified-FRAX. Use of a FRAX score with complete risk factors and/or with BMD may greatly improve the sensitivity/specificity at these thresholds.
Sensitivity Analyses for Missing FRAX Variables
When we recalculated the modified-FRAX by entering “Yes” for the 2 variables that were not available in the VACS (parental history of hip fracture and secondary osteoporosis), it overestimated the incident fracture rates for both HIV-infected and uninfected individuals at the major osteoporotic sites (7.3% ± 3.7% vs 7.0% ± 3.5%, P < 0.0001) and at the hip (0.7% ± 1.0% vs 0.6% ± 0.8%, P < 0.0001). As a result, O/E ratios were lower with this modified-FRAX calculation. Accuracy was better in HIV-infected than in uninfected men for major osteoporotic fractures (O/E: 0.63 vs 0.50, P = 0.009), but did not differ for hip fractures (O/E: 1.86 vs 1.48, P = 0.29). Using the modified-FRAX calculation with “Yes” for the 2 variables that were not available in the VACS, fracture prediction using pharmacologic thresholds improved only slightly. Only 14/93 (15%) HIV-infected men and 9/148 (6.1%) uninfected men with fractures at the hip were correctly predicted.
In this study of men aged 50–70 years, 10-year fracture rates calculated using modified-FRAX without BMD underestimated the true fracture rates at the major osteoporosis sites and the hip in HIV-infected compared with uninfected men. The accuracy of the modified-FRAX for HIV-infected men was improved when HIV was considered as a cause of secondary osteoporosis in the calculation; however, it still underestimates the observed fracture rates. Similarly, the accuracy of the modified-FRAX improved when HCV infection was considered a cause of secondary osteoporosis, but to a lesser degree than with HIV infection.
The greatest limitation of this study was the fact we did not have data on 2 predictors (secondary cause of osteoporosis and family history of hip fracture) used in the FRAX calculator and therefore, we have been careful to present our outcomes in terms of the use of a “modified-FRAX.” Fracture risk from causes of secondary osteoporosis may vary. Given the lack of sufficient fracture risk data for specific secondary osteoporosis conditions, Kanis et al6 assigned the same risk ratio for the presence of secondary osteoporosis as history of rheumatoid arthritis in the FRAX algorithm. Family history of hip fracture had the least weight among all clinical risk variables for the determination of hip fracture, but had a strong weight in the determination of major osteoporotic fracture.6 Also, our sensitivity analyses in which the modified-FRAX was recalculated with “Yes” entered for both missing predictors revealed that fracture prediction was improved only slightly. Aside from the 2 missing variables, the other FRAX variables were approximated based on availability in the database of health factors and ICD-9 coding, which may not accurately reflect thresholds used by the FRAX. For example, the ICD-9 code for alcohol use/abuse and ever use of glucocorticoids may not accurately capture the thresholds for exposure (3 or more units of alcohol per day and current or more than 3 months at prednisolone 5 mg daily or more, respectively) validated in FRAX. Given these limitations, the accuracy of the modified-FRAX results in this study cannot be readily compared with test performance characteristics in other studies using complete data for FRAX calculation. Similarly, it would be inappropriate to compare the sensitivity/specificity of modified-FRAX using pharmacologic treatment thresholds to other studies. The objective of this analysis was to compare the test characteristics for FRAX within this cohort of subjects, and not to compare the test characteristics with an external population or sample; therefore, we are of the opinion that our primary comparisons between HIV-infected and uninfected groups are valid.
Other factors may have also contributed to the poor performance of the modified-FRAX in both the HIV-infected and uninfected groups. FRAX models are calibrated to the epidemiology of death and fracture for each country with available data.19 Our study was based entirely on a US population, and similar results were found using all eligible subjects as well as when the sample was restricted to those who were alive and not lost to follow-up beyond the 10-year observation period for fracture. However, FRAX has been criticized for not accurately reflecting the fracture incidence and mortality rate for nonwhite study populations, because the US database for development of FRAX was derived from the Rochester cohort in Olmsted County Minnesota, which is predominantly white.20,21 Since over half of the VACS are nonwhite, the accuracy of FRAX may not be comparable to its performance in other predominantly white populations. In addition, there may be risk factors related to fragility fractures that are prevalent in male veterans that are not captured in FRAX. Addition of BMD to FRAX may have improved the accuracy; however, the improvement in other studies is usually modest and is not always predictable. In an analysis of FRAX performance in the Osteoporotic Fractures in Men (MrOS) Study, Ettinger et al22 found that FRAX without BMD overestimated the observed incidence of fracture (O/E ratios 0.7–0.9) and the addition of BMD neither improved the calibration (O/E ratios 0.7–1.1) nor consistently improved discrimination. Several smaller studies in HIV-infected individuals have found that FRAX calculated with the addition of BMD underestimated prevalent fractures9,10; however, none have evaluated the prediction of incident fracture.
In the majority of published cohort studies, HCV infection is associated with increased fracture risk in both HIV-infected and uninfected individuals, and HCV infection remains a significant predictor of fracture risk after adjustments in multivariate 23–26 or stratified analyses.11,27 From a meta-analysis, HIV/HCV coinfection increases the risk of fragility fracture by 77% over HIV monoinfection.28 Therefore, it is not surprising that the modified-FRAX improves when HCV is considered a cause of secondary osteoporosis. Since the FRAX algorithm does not adjust for risk from multiple causes of secondary osteoporosis, the underestimation of risk in HIV/HCV coinfection is likely to be much more than that of HIV or HCV monoinfection. For the modified-FRAX, the O/E ratio in HIV/HCV-coinfected individuals was 2.20 (95% CI: 1.84 to 2.63) for major osteoporotic sites and 6.63 (95% CI: 4.71 to 9.33) at the hip. This finding may be unique to this cohort with such a high prevalence of HCV coinfection, and will require corroboration in other populations.
Our analyses demonstrate that the modified-FRAX is a poor case-finding tool for HIV-infected men using the pharmacologic therapy thresholds for HIV-infected men aged 50–70 years, even when considering HIV infection as a cause of secondary osteoporosis in the calculation. The sensitivity of the modified-FRAX in this situation was only 3% at the hip using the NOF guidelines and did not improve with the age-specific thresholds endorsed by the European guidelines. Our findings cannot be generalized to suggest that the actual FRAX with all clinical factors available would be a poor case-finding tool in HIV-infected men. However, despite these caveats, our data suggest that we that cannot assume that FRAX would be a good case-finding tool in the HIV-infected population, and additional studies are necessary to assure that widespread implementation is indicated.
Aside from lacking complete data on clinical risk factors for FRAX calculation, use of approximated variables for the clinical risk factors, and lack of BMD data, there were other limitations to this analysis. Fracture events were identified by the ICD-9 codes; however, fragility fracture codes have been validated previously in VACS, demonstrating excellent agreement between the administrative codes and chart review. In addition, our study was only conducted in men, which limits the generalizability of our results to women.
FRAX is a readily available calculator of fracture risk that can be used in HIV-infected individuals. In HIV-infected individuals, fracture estimates calculated using FRAX without BMD likely underestimates the true fracture risk. The accuracy can be improved when HIV is considered a cause of secondary osteoporosis in the FRAX calculation; however, it still may be a poor case-finding tool for HIV-infected men aged between 50 and 70 years. Given the increased fracture risk among HIV-infected individuals, dietary and lifestyle modifications, antiretroviral modifications, and screening DXAs are indicated in higher risk older individuals.29 However, further studies are necessary to determine the role of FRAX in screening and risk stratification for pharmacologic therapy in older HIV-infected individuals.
We would like to thank Melissa Skanderson for her help in data acquisition and Dr. Ethel Siris for reviewing the manuscript.
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