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Clinical Science

Brief Report: Aging Attenuates the Association Between Coronary Artery Calcification and Bone Loss Among HIV-Infected Persons

Escota, Gerome MDa; Baker, Jason MDb; Bush, Tim BAc; Conley, Lois MPHc; Brooks, John T. MDc; Patel, Pragna MDc; Powderly, William MDa; Presti, Rachel MD, PhDa; Overton, Edgar T. MDd; for the CDC (Centers for Disease Control and Prevention)-SUN (Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy) Investigators

Author Information
JAIDS Journal of Acquired Immune Deficiency Syndromes: September 1, 2019 - Volume 82 - Issue 1 - p 46-50
doi: 10.1097/QAI.0000000000002092

Abstract

INTRODUCTION

With the advent of potent antiretroviral therapy (ART), people with HIV are living longer and non–AIDS-defining illnesses (NADIs) are becoming more prevalent. The incidence of acute myocardial infarction and low bone mineral density (BMD) among people with HIV is significantly greater than among people in the general population.1,2 HIV infection is also independently associated with the occurrence of these comorbid illnesses even after adjustment for traditional risk factors.3,4

Studies derived from the general population suggest a biologic and epidemiologic link between cardiovascular and bone disease that cannot be accounted for by age alone. Large prospective5,6 and cross-sectional studies7 have found that cardiovascular disease (CVD) predicts the occurrence of fracture and greater BMD loss independent of multiple risk factors. Similarly, several epidemiologic studies show that markers of subclinical atherosclerosis (eg, abdominal aortic calcification) are also independently associated with incident fracture8,9 and bone loss over time.8–15 Although most studies have demonstrated a link between cardiovascular and bone disease, there are also studies in the general population that failed to show an age-independent association between the 2 disorders.16–20

In the general population, it is posited that the association between CVD and osteoporosis is mediated by a common pathogenesis and shared risk factors. CVD and osteoporosis have certain risk factors in common, including advanced age, smoking, physical inactivity, hypertension, estrogen deficiency, and chronic inflammation.21,22 Evidence suggests that factors involved in osteogenesis may also impact vascular calcification.23,24 Recent studies have identified certain biomarkers that contribute to the pathogenesis of cardiovascular and bone disease, including osteoprotegerin, receptor activator of nuclear factor-κβ (RANK), and RANK ligand.23,24

The link between CVD and osteoporosis has not been well investigated among people with HIV. In this analysis, we assessed data from the Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy (SUN Study) to evaluate the relationship between coronary artery calcium (CAC) and low BMD among younger to middle-aged people with HIV before and after adjustments for important HIV-related and traditional risk factors.

MATERIALS AND METHODS

The SUN Study

The SUN Study was a prospective, observational cohort funded by the US Centers for Disease Control and Prevention (CDC) that monitored the clinical course of people with HIV treated with ART at 7 HIV clinics in 4 cities in the United States: St. Louis, Missouri; Providence, Rhode Island; Minneapolis, Minnesota; and Denver, Colorado. Seven hundred people with HIV were enrolled between March 2004 and June 2006 and were followed until June 2012. Participants were ART-naive or on combination ART at enrollment. Informed consent was obtained from all study participants, and the study was approved and renewed annually by the institutional review boards of all participating institutions and the CDC. The SUN Study cohort and detailed study methodology have been described elsewhere.25

Briefly, at baseline, comprehensive clinical and behavioral data were collected on all subjects, including height and weight for calculating body mass index; use of medications; behavioral risk data including use of alcohol, tobacco, and illicit drugs; as well as data on comorbidities and a range of fasting laboratory values.

CAC and BMD Measurements

CAC was measured using computed tomography scans performed at baseline and at the year 2 visit. Thirty to 40 contiguous tomographic slices were obtained at 3-mm intervals beginning 1 cm below the carina and progressing caudally to include the entire coronary tree. All scans were analyzed with a commercially available software package (Neo Imagery Technologies, City of Industry, CA). An attenuation threshold of 130 Hounsfield units and a minimum of 3 contiguous pixels were used to identify a calcific lesion. Each focus was scored using the algorithm developed by Agatston et al,26 and the total CAC score was determined by summing individual lesion scores from each of 4 arteries: the left main, left anterior descending, left circumflex, and right coronary arteries.27 An expert reader, blinded to all clinical and demographic information, read each case for total and per-vessel CAC score.

At enrollment and annually for the following 4 years, whole-body and site-specific (femoral neck, total hip, and lumbar spine) dual X-ray absorptiometry scans for each participant were obtained by each study site, and the dual X-ray absorptiometry files were transmitted to central readers for interpretation.

Definitions

Detectable CAC was defined as CAC >0 Agatston score. We used the World Health Organization (WHO) classification of BMD using the difference between an individual's BMD and that of a young-adult reference population (T-score). A T-score that is within 1 SD of the reference BMD is classified as normal, 1–2.5 SD below the reference BMD as osteopenia and greater than 2.5 SD below the reference BMD as osteoporosis.28 The classification of low BMD includes all persons with either osteopenia or osteoporosis.

Statistical Analysis

CAC was used as a categorical variable (present or absent) while BMD was expressed both as a categorical (based on the presence or absence of osteopenia or osteoporosis according to the WHO categorization of T-score) and as 2 continuous variables (actual T-scores and bone mass expressed in g/cm2). We used the Mantel-Haenszel χ2 test for categorical variables and the Student t test for continuous variables to measure associations between participant characteristics and CAC. We performed logistic regression analysis to assess the relationship between BMD and CAC. The odds ratio was adjusted according to age alone (model 1), traditional risk factors other than age (model 2; male sex, black race, history of tobacco use, presence of diabetes mellitus, and presence of hypertension), and HIV-associated factors (model 3; current HIV RNA < 400 copies/mm3, nadir CD4 cell count, duration of tenofovir use, duration of protease inhibitor use, and duration of HIV diagnosis). These variables were included in the models based on previous studies that demonstrated an association between BMD and detectable CAC among people with and without HIV.29,30

RESULTS

Baseline Characteristics

There were 472 participants with baseline CAC and BMD measurements (Table 1). The median age was 41 years, 358 (76%) were men, and 273 (58%) were non-Hispanic white. Two-thirds of the participants were either current or former smokers, and two-thirds were current alcohol users. The majority of participants (71%) had HIV RNA <400 copies/mm3, and the median CD4 cell count was 433 cells/mm3. Participants with detectable CAC were older, more likely to be male, less likely to be non-Hispanic black, and more likely to have hypertension and longer duration of HIV infection and use of tenofovir or protease inhibitor.

T1
TABLE 1.:
Characteristics of Participants and Associations With Baseline CAC, the Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy, 2004–2012, United States (n = 472)

The majority of participants had baseline osteopenia or osteoporosis [250 (53%) and 47 (10%), respectively] while only 84 (18%) had CAC >0 Agatston score.

Association Between CAC and BMD

In univariate analyses, detectable CAC was significantly associated with decreased femoral neck and total hip T-scores and decreased femoral neck, total hip, and lumbar spine BMD (Table 2). Having either osteoporosis or osteopenia is also associated with a 90% greater odds of having a detectable CAC (vs. none).

T2
TABLE 2.:
Association Between Detectable CAC and BMD in the Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy, 2004–2012, United States (n = 472)

After adjustment for age alone (model 1), the association between detectable CAC and the measures of BMD was no longer significant. However, adjustment for traditional risk factors other than age (model 2) maintained the association between detectable CAC and lower femoral neck T-score and lower femoral neck, total hip, and lumbar spine BMD. Similarly, adjustment for HIV-associated risk factors (model 3) did not fully eliminate the associations between detectable CAC and decreased femoral neck BMD and having either osteopenia or osteoporosis.

We also performed a separate analysis exploring the association of detectable CAC and BMD stratified according to age (see Table 1, Supplemental Digital Content, https://links.lww.com/QAI/B333). We also did not find any association between CAC >0 and BMD after age stratification.

DISCUSSION

In this cohort of younger to middle-aged participants with mostly well-controlled HIV infection, we found a high rate of osteopenia or osteoporosis (63%) and a low proportion of detectable CAC (18%). We identified an association between decreased BMD and detectable CAC that was attenuated by age but not by other traditional risk factors or HIV-specific risk factors.

Our findings were inconsistent with that of Bellasi et al31 that showed that prevalent atherosclerosis (defined as CAC > 100 Agatston score) was associated with decreased femoral neck BMD (defined as BMD < 25th percentile) independent of traditional and HIV-associated risk factors. The use of different definitions for the outcome variables may in part explain the discordant findings. We defined detectable CAC as >0 Agatston score due to the low prevalence of CAC >100 Agatston score in the SUN Study (n = 27, 6%). Of note, when we ran an analysis using CAC > 100 Agatston score as cutoff, the results were essentially similar in that associations disappeared after adjustment for age alone (see Table 2, Supplemental Digital Content, https://links.lww.com/QAI/B333). We also used more widely accepted definitions of BMD using absolute values of T-score and BMD at not only the femoral neck site, but at the lumbar spine and hip, as well. Furthermore, we used the WHO classification to define decreased BMD as osteopenia or osteoporosis, which are more clinically relevant definitions of BMD.

Our findings fail to corroborate previous studies that demonstrated an association between CAC and low BMD independent of age in the general population. These studies have typically included participants in the sixth or seventh decade of life who are at much greater risk of CVD and low BMD. Because CVD and osteoporosis are both driven by chronic inflammation, one would expect to find an independent association between the 2 among people with HIV. Our findings suggest that aging continues to mediate this relationship especially among younger to middle-aged persons. The aging process results in a chronic inflammatory state characterized by elevated levels of cytokines that are at least two- to four-fold higher compared with younger individuals,32 and HIV infection exhibits similar patterns of chronic inflammation as in the aging process33 that are only partially reduced by ART.34

Aging remains a universal risk factor for CVD and osteoporosis.35,36 As people with HIV age, the prevalence of these diseases will increase. Whether traditional risk factors or the residual inflammation that persists after ART drives the increasing burden of these diseases in the aging HIV-infected population is difficult to determine. Our analysis suggests that among people with HIV, aging drives the accrual of both cardiovascular and bone disease. Although we cannot stop our patients from aging, we can work to identify interventions that can reduce persistent inflammation and slow the progression of these diseases. For example, statins have emerged as a leading candidate drug to reduce HIV-associated inflammation. In a trial of rosuvastatin therapy, markers of inflammation were significantly reduced and progression of common carotid artery intima-media thickness slowed, but researchers observed no significant effect on BMD.37,38 Future studies should explore additional interventions for salutary effects on heart and bone health.

Our study was subject to several limitations. Our data may not be generalizable to all people with HIV. Moreover, we did not have robust information on clinical cardiovascular events and fracture, and hence, participants who might have had these prevalent conditions at baseline were not excluded in our cross-sectional study. Also, our cohort was heterogeneous in terms of the type of antiretroviral medications used, which could have influenced development of low BMD. In addition, we did not have complete information on bisphosphonate, vitamin D, and calcium use. The uncertain clinical implication of the cutoff value we used to categorize a positive or a negative CAC and the low prevalence of detectable CAC as defined in our study further limits interpretation of our data. However, it is important to note that studies in the general population show that any detectable CAC (CAC > 0) remains a risk factor for coronary artery disease, especially in the younger population.39,40

In conclusion, we found that aging attenuates the association between detectable CAC and BMD in this cohort of younger to middle-aged people with HIV. Aging remains an important contributor to NADIs, and these data reinforce the importance of developing screening and prevention strategies for older people with HIV given their excess risk across a wide spectrum of end-organ complications.

REFERENCES

1. Althoff KN, McGinnis KA, Wyatt CM, et al. Comparison of risk and age at diagnosis of myocardial infarction, end-stage renal disease, and non-AIDS-defining cancer in HIV-infected versus uninfected adults. Clin Infect Dis. 2015;60:627–638.
2. Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS. 2006;20:2165–2174.
3. Cotter AG, Sabin CA, Simelane S, et al. Relative contribution of HIV infection, demographics and body mass index to bone mineral density. AIDS. 2014;28:2051–2060.
4. Freiberg MS, Chang CC, Kuller LH, et al. HIV infection and the risk of acute myocardial infarction. JAMA Intern Med. 2013;173:614–622.
5. Collins TC, Ewing SK, Diem SJ, et al. Peripheral arterial disease is associated with higher rates of hip bone loss and increased fracture risk in older men. Circulation. 2009;119:2305–2312.
6. Sennerby U, Melhus H, Gedeborg R, et al. Cardiovascular diseases and risk of hip fracture. JAMA. 2009;302:1666–1673.
7. Pouwels S, Lalmohamed A, Leufkens B, et al. Risk of hip/femur fracture after stroke: a population-based case-control study. Stroke. 2009;40:3281–3285.
8. Bagger YZ, Tankó LB, Alexandersen P, et al. Radiographic measure of aorta calcification is a site-specific predictor of bone loss and fracture risk at the hip. J Intern Med. 2006;259:598–605.
9. Szulc P, Kiel DP, Delmas PD. Calcifications in the abdominal aorta predict fractures in men: MINOS study. J Bone Miner Res. 2008;23:95–102.
10. Hak AE, Pols HA, van Hemert AM, et al. Progression of aortic calcification is associated with metacarpal bone loss during menopause: a population-based longitudinal study. Arterioscl Throm Vas. 2000;20:1926–1931.
11. Hyder JA, Allison MA, Wong N, et al. Association of coronary artery and aortic calcium with lumbar bone density: the MESA Abdominal Aortic Calcium Study. Am J Epidemiol. 2009;169:186–194.
12. Jørgensen L, Joakimsen O, Rosvold Berntsen GK, et al. Low bone mineral density is related to echogenic carotid artery plaques: a population-based study. Am J Epidemiol. 2004;160:549–556.
13. Kim SH, Kim YM, Cho MA, et al. Echogenic carotid artery plaques are associated with vertebral fractures in postmenopausal women with low bone mass. Calcif Tissue Int. 2008;82:411–417.
14. Naves M, Rodriguez-Garcia M, Diaz-Lopez JB, et al. Progression of vascular calcifications is associated with greater bone loss and increased bone fractures. Osteoporos Int. 2008;19:1161–1166.
15. Schulz E, Arfai K, Liu X, et al. Aortic calcification and the risk of osteoporosis and fractures. J Clin Endocrinol Metab. 2004;89:4246–4253.
16. Aoyagi K, Ross PD, Orloff J, et al. Low bone density is not associated with aortic calcification. Calcif Tissue Int. 2001;69:20–24.
17. Bakhireva LN, Barrett-Connor EL, Laughlin GA, et al. Differences in association of bone mineral density with coronary artery calcification in men and women: the Rancho Bernardo Study. Menopause. 2005;12:691–698.
18. Montalcini T, Emanuele V, Ceravolo R, et al. Relation of low bone mineral density and carotid atherosclerosis in postmenopausal women. Am J Cardiol. 2004;94:266–269.
19. Samelson EJ, Cupples LA, Broe KE, et al. Vascular calcification in middle age and long-term risk of hip fracture: the Framingham Study. J Bone Miner Res. 2007;22:1449–1454.
20. von Muhlen D, Allison M, Jassal SK, et al. Peripheral arterial disease and osteoporosis in older adults: the Rancho Bernardo Study. Osteoporos Int. 2009;20:2071–2078.
21. den Uyl D, Nurmohamed MT, van Tuyl LH, et al. Sub clinical cardiovascular disease is associated with increased bone loss and fracture risk; a systematic review of the association between cardiovascular disease and osteoporosis. Arthritis Res Ther. 2011;13:R5.
22. Farhat GN, Cauley JA. The link between osteoporosis and cardiovascular disease. Clin Cases Miner Bone Metab. 2008;5:19–34.
23. Hofbauer LC, Brueck CC, Shanahan CM, et al. Vascular calcification and osteoporosis—from clinical observation towards molecular understanding. Osteoporos Int. 2007;18:251–259.
24. Mody N, Tintut Y, Radcliff K, et al. Vascular calcification and its relation to bone calcification: possible underlying mechanisms. J Nucl Cardiol. 2003;10:177–183.
25. Vellozzi C, Brooks JT, Bush TJ, et al. The study to understand the natural history of HIV and AIDS in the era of effective therapy (SUN Study). Am J Epidemiol. 2009;169:642–652.
26. Agatston AS, Janowitz WR, Hildner FJ, et al. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol. 1990;15:827–832.
27. Budoff MJ, Achenbach S, Blumenthal RS, et al. Assessment of coronary artery disease by cardiac computed tomography: a scientific statement from the American heart association committee on cardiovascular imaging and intervention, council on cardiovascular radiology and intervention, and committee on cardiac imaging, council on clinical cardiology. Circulation. 2006;114:1761–1791.
28. Czerwinski E, Badurski JE, Marcinowska-Suchowierska E, et al. Current understanding of osteoporosis according to the position of the World health organization (WHO) and international osteoporosis foundation. Ortop Traumatol Rehabil. 2007;9:337–356.
29. Baker JV, Hullsiek KH, Singh A, et al. Immunologic predictors of coronary artery calcium progression in a contemporary HIV cohort. AIDS. 2014;28:831–840.
30. Escota GV, Mondy K, Bush T, et al. High prevalence of low bone mineral density and substantial bone loss over 4 years among HIV-infected persons in the era of modern antiretroviral therapy. AIDS Res Hum Retrov. 2016;32:59–67.
31. Bellasi A, Zona S, Orlando G, et al. Inverse correlation between vascular calcification and bone mineral density in human immunodeficiency virus-infected patients. Calcified Tissue Int. 2013;93:413–418.
32. Brüünsgaard H, Pedersen BK. Age-related inflammatory cytokines and disease. Immunol Allergy Clin North Am. 2003;23:15–39.
33. Deeks SG. HIV infection, inflammation, immunosenescence, and aging. Annu Rev Med. 2011;62:141–155.
34. Hearps AC, Maisa A, Cheng WJ, et al. HIV infection induces age-related changes to monocytes and innate immune activation in young men that persist despite combination antiretroviral therapy. AIDS. 2012;26:843–853.
35. Ferket BS, van Kempen BJ, Hunink MG, et al. Predictive value of updating Framingham risk scores with novel risk markers in the U.S. general population. PLoS One. 2014;9:e88312.
36. Kanis JA, Borgstrom F, De Laet C, et al. Assessment of fracture risk. Osteoporos Int. 2005;16:581–589.
37. Erlandson KM, Jiang Y, Debanne SM, et al. Effects of 96 weeks of rosuvastatin on bone, muscle, and fat in HIV-infected adults on effective antiretroviral therapy. AIDS Res Hum Retrov. 2016;32:311–316.
38. Longenecker CT, Sattar A, Gilkeson R, et al. Rosuvastatin slows progression of subclinical atherosclerosis in patients with treated HIV infection. AIDS. 2016;30:2195–2203.
39. Carr JJ, Jacobs DR Jr, Terry JG, et al. Association of coronary artery calcium in adults aged 32-46 years with incident coronary heart disease and death. JAMA Cardiol. 2017;2:391–399.
40. Shaw LJ, Giambrone AE, Blaha MJ, et al. Longterm prognosis after coronary artery calcification testing in asymptomatic patients: a cohort study. Ann Intern Med. 2015;163:14–21.
Keywords:

HIV; coronary artery calcium; bone mineral density; bone health; cardiovascular disease; aging

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