In this prospective study of older men with or at risk for HIV infection, we found that the combination of heroin use and AIDS diagnosis was associated with a substantial decline in BMD. This was evident at both the femoral neck and total hip, as well as in analyses of the greatest decline in BMD at any of the femoral neck, total hip, or lumbar spine. Hepatitis C seropositivity and methadone use, factors that are prevalent among HIV-infected opioid users, were also associated with bone loss in this cohort. Taken together, these data suggest that HIV-infected opioid-using men may be at particular risk of bone loss as they age, as a result of comorbid disease such as hepatitis C infection, opioid substitution treatment with methadone, ongoing heroin use, progression to AIDS, or a combination of these factors. The lack of an independent association of BMD loss with cigarette smoking might be due in part to the fact that nearly 90% of participants in the cohort were current or former smokers.
These longitudinal data extend the cross-sectional findings previously reported in this cohort , and in a similar cohort of middle-aged women with or at risk for HIV infection , which reported an association between reduced BMD in the lumbar spine and methadone use. To our knowledge, this is the first longitudinal study in HIV-infected men to evaluate the association of opioid use with changes in BMD. Like HIV-infected individuals, opioid users possess multiple risk factors for osteopenia, including hypogonadism, tobacco use, alcohol use, lack of physical activity, and malnutrition. Yet BMD in patients with opioid dependence has received limited attention. Prescription opioid users had reduced total hip BMD compared with nonusers in the third National Health and Nutrition Examination Survey, with a nonsignificant trend toward longer term opioid users having lower BMD than shorter term users. Data on illicit opioid use were not available in that study . A cross-sectional study  in a methadone maintenance treatment program found that more than three quarters of the patients met the WHO criteria for osteoporosis or osteopenia despite a median age of only 42 years, including an unexpectedly high proportion of the 33 men studied having osteopenia (36%) and osteoporosis (61%). Many participants had risk factors for osteoporosis including history of tobacco use (95%), heavy alcohol use (52%), persistent amenorrhea (32% of women), and HIV infection (28%), which likely contributed to the high prevalence of low BMD.
Multiple endocrine and metabolic abnormalities have been described in patients infected with HIV, and opiate use may contribute to these problems. Opioid use has been associated with central hypogonadism, resulting in diminished secretion of gonadotropin-releasing hormone, luteinizing hormone (LH), estrogen, and testosterone . Cross-sectional studies [18–20] in HIV-negative heroin and methadone users have shown decreased levels of gonadotropins, which may be dose dependent , and partially reversible with the administration of naltrexone, an opiate antagonist . Hypogonadism is also common in men with AIDS-related wasting syndrome , and has been reported in 21% of men with HIV-related weight loss on HAART . Androgen deficiency is prevalent in our cohort; previously, we reported that among this cohort, HIV infection was not associated with androgen deficiency, whereas IDU, hepatitis C virus seropositivity, high BMI, and use of psychotropic medications were . To date, most studies examining hypogonadism in HIV infection have used non-IDU HIV patients, and HIV-infected drug users remain a largely understudied group . Osteoporosis in men often has secondary causes, the most common of which are alcohol abuse, glucocortoicoid excess, and hypogonadism . In our cohort, despite the high prevalence of hypogonadism, we did not find an association between serum testosterone level and loss of BMD over time. Although history of testosterone replacement was associated with a lower rate of bone loss in univariate analyses; compared with those men who did not report testosterone use, this association was no longer significant in multivariable analyses. Thus, although hypogonadism has been associated with both HIV infection and opioid use, as well as osteoporosis, this association was not significant in our cohort and does not explain the combined effect of HIV clinical status and heroin use on BMD observed.
Opioids may contribute to lowered BMD by directly interfering with bone formation. Studies [26,27] have documented large concentrations of opioid receptors in osteoblasts; inhibition of the growth of human osteoblast tissue cultures by small concentrations of opioids ; prevention of this inhibition by opioid antagonists ; lowered serum levels of osteocalcin, a bone formation marker, in heroin addicts ; and inhibition of osteocalcin production by morphine in osteoblast tissue cultures, which was abolished when osteoblastic cells were incubated simultaneously with naloxone . An effect of opiates on calcium-regulating hormones has also been reported, in addition to other mechanisms relating to altered bone metabolism. Pedrazzoni et al.  found a reduction in lumbar BMD in heroin users compared with nondrug-dependent control participants and former drug addicts. Heroin users had higher levels of serum calcium, urinary excretion of calcium, and urinary excretion of hydroxyproline and lower levels of parathyroid hormone, LH, and testosterone. Levels of bone-specific alkaline phosphatase and osteocalcin were normal . Of note, although 60% of current and former heroin users were HIV infected, the contribution of HIV serostatus to bone and mineral metabolism and bone mass was not evaluated. Prior to that study, reports [30–33] on calcium-regulating hormones in opioid users focused on the finding of higher levels of serum calcitonin.
Osteoporosis is a common, yet underrecognized, problem in men, whether or not they are infected with HIV. Although several longitudinal studies [39–47] of BMD have been conducted in HIV-infected, HAART-treated patients, they have generally lacked a suitable comparison group of HIV-negative persons with similar risk factors for osteoporosis, and either have used healthy controls [39,40] did not include HIV-uninfected controls [41–46], or focused on specific groups such as premenopausal women  or men with normal or above average BMD . A recent meta-analysis  found that compared with HIV-uninfected controls, HIV-infected patients had a 6.4-fold increased odds of reduced BMD. Studies [49,50] in the general population indicate that for each SD reduction in BMD as measured by DEXA, the risk of fracture doubles. The gradient of risk between BMD and fracture is continuous, suggesting that men with osteopenia may be at increased risk of developing osteoporosis when compared with men with higher BMD [13,51]. In the general population, it is estimated that the lifetime risk of experiencing an osteoporotic fracture in men over the age of 50 years is 30% , similar to the lifetime risk of developing prostate cancer . Studies [54–56] have shown that the fracture-related mortality rate is higher in men than in women, and that fractures occur at higher BMD levels in men than in women [57–60]. Considering the risk of fracture in men with low BMD and the increased prevalence of low BMD in HIV-infected adults at younger than expected ages, HIV-infected men may be at even greater risk for fragility fractures as they age. In fact, recent data suggest that fractures may occur more frequently in HIV-infected individuals  and that continuous ART may be associated with higher fracture risk .
Our study is subject to some limitations. We had no evidence regarding the mechanism of the observed associations, including that of opioid use on BMD. We did not include measures of vitamin D, calciotropic hormones, or biochemical markers of bone formation or resorption. Additionally, data collection and analyses were structured on patient interview data. Information about drug use was obtained by self-report, which may be subject to bias; however, drug-use behaviors were queried using ACASI technique, which has been shown to enhance collection of potentially stigmatizing information . Finally, because of the limited number of incident cases of osteopenia and osteoporosis, we were unable to do multivariable analysis regarding factors affecting differences in these outcomes by HIV status. Our study also has several strengths. Our cohort represents a large, ethnically diverse group of older, HIV-infected men and a control group of HIV-uninfected men with similar behavioral risk factors. The inclusion of a comparison group with similar drug use, in particular, allowed us to demonstrate the potential role of opioid use in bone loss, in contrast to other studies of BMD in HIV-infected men, which lacked comparison groups that could address the novel role of drug use in bone disease.
Our findings suggest that there is an association of heroin use and AIDS with decreased BMD, and that heroin users with AIDS may be at particular risk for bone loss. An improved understanding of factors associated with ongoing bone loss and fracture risk is needed to help guide thresholds for assessment of BMD and for osteopenia treatment in HIV-infected persons and opioid users. The degree to which opioid use and advanced HIV disease affect the risk of osteopenia will inform the need for treatment efforts and programs to prevent bone loss among drug users with HIV infection. Furthermore, for drug users who are treated with methadone, it is imperative to determine whether treatment adversely affects BMD, and if so, to develop ways to prevent or attenuate any adverse effect of opioids on BMD.
This study was supported by the National Institute on Drug Abuse (#R01 DA14998), grant to R.S.K. A.S. is supported by the Robert Wood Johnson Foundation Physician Faculty Scholars Program and SUNY Downstate Medical Center Dean's Initiative in Research Investment.
There are no conflicts of interest.
1. Mocroft A, Ledergerber B, Katlama C, Kirk O, Reiss P, d'Arminio Monforte A, et al
, EuroSIDA study group. Decline in the AIDS and death rates in the EuroSIDA study: an observational study. Lancet 2003; 362:22–29.
2. Lima VD, Hogg RS, Harrigan PR, Moore D, Yip B, Wood E, et al
. Continued improvement in survival among HIV-infected individuals with newer forms of highly active antiretroviral therapy. AIDS 2007; 21:685–692.
3. Walensky RP, Paltiel AD, Losina E, Mercincavage LM, Schackman BR, Sax PE, et al
. The survival benefits of AIDS treatment in the United States. J Infect Dis 2006; 194:11–19.
4. Lohse N, Hansen AE, Pedersen G, Kronborg G, Gerstoft J, Sorensen HT, et al
. Survival of persons with and without HIV infection in Denmark, 1995–2005. Ann Intern Med 2007; 146:87–95.
5. Bhaskaran K, Hamouda O, Sannes M, Boufassa F, Johnson AM, Lambert PC, et al
, CASCADE Collaboration. Changes in the risk of death after HIV seroconversion compared with mortality in the general population. JAMA 2008; 300:51–59.
7. Hartel DM, Schoenbaum EE, Lo Y, Klein RS. Gender differences in illicit substance use among middle-aged drug users with or at risk for HIV infection. Clin Infect Dis 2006; 43:525–531.
8. Arnsten JH, Freeman R, Howard AA, Floris-Moore M, Lo Y, Klein RS. Decreased bone mineral density and increased fracture risk in aging men with or at risk for HIV infection. AIDS 2007; 21:617–623.
9. Klein RS, Lo Y, Santoro N, Dobs AS. Androgen levels in older men who have or who are at risk of acquiring HIV infection. Clin Infect Dis 2005; 41:1794–1803.
10. Mayfield DG, McCleod G, He YD. The CAGE questionnaire: validation of a new alcoholism screening instrument. Am J Psych 1974; 131:1121–1123.
11. Radloff LS. The CES-D scale: a self-report depression scale for research in the general population. Appl Psychol Meas 1977; 1:385–401.
12. Metzger DS, Koblin B, Turner C, Navaline H, Valenti F, Holte S, et al
. Randomized controlled trial of audio computer-assisted self-interviewing: utility and acceptability in longitudinal studies. HIVNET Vaccine Preparedness Study Protocol Team. Am J Epidemiol 2000; 152:99–106.
13. World Health Organization. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: report of WHO study group
. World Health Org Tech Rep Ser
14. Arnsten JH, Freeman R, Howard AA, Floris-Moore M, Santoro N, Schoenbaum EE. HIV infection and bone mineral density in middle-aged women. Clin Infect Dis 2006; 42:1014–1020.
15. Kinjo M, Setoguchi S, Schneeweiss S, Solomon DH. Bone mineral density in subjects using central nervous system-active medications. Am J Med 2005; 118:1414e7–1414e12.
16. Kim TW, Alford DP, Malabanan A, Holick MF, Samet JH. Low bone density in patients receiving methadone maintenance treatment. Drug Alcohol Depend 2006; 85:258–262.
17. Cooper OB, Brown TT, Dobs AS. Opiate drug use: a potential contributor to the endocrine and metabolic complications in human immunodeficiency virus disease. Clin Infect Dis 2003; 37(2 Suppl):S132–S136.
18. Brambilla F, Sacchetti E, Brunetta M. Pituitary–gonadal function in heroin addicts
19. Celani MF, Carani C, Montanini V, Baraghini GF, Zini D, Simoni M, et al
. Further studies on the effects of heroin addiction on the hypothalamic–pituitary–gonadal function in man. Pharmacol Res Commun 1984; 16:1193–1203.
20. Mendelson JH, Meyer RE, Ellingboe J, Mirin SM, McDougle M. Effects of heroin and methadone on plasma cortisol and testosterone. J Pharmacol Exp Ther 1975; 195:296–302.
21. Mendelson JH, Ellingboe J, Kuehnle JC, Mello NK. Heroin and naltrexone effects on pituitary–gonadal hormones in man: interaction of steroid feedback effects, tolerance, and supersensitivity. J Pharmacol Exp Ther 1980; 214:503–506.
22. Dobs AS, Dempsey MA, Ladenson PW, Polk BF. Endocrine disorders in men infected with human immunodeficiency virus. Am J Med 1988; 84:611–616.
23. Rietschel P, Corcoran C, Stanley T, Basgoz N, Kilbanski A, Grinspoon S. Prevalence of hypogonadism in men with weight loss related to human immunodeficiency virus infection who were receiving highly active antiretroviral therapy. Clin Infect Dis 2000; 31:1240–1244.
24. Wahlstrom JT, Dobs AS. Acute and long term effects of AIDS and injection drug use on gonadal function. J Acquir Immune Defic Syndr 2000; 25(Suppl 1):S27–S36.
25. Ebeling PR. Osteoporosis in men: new insights into aetiology, pathogenesis, prevention and management. Drugs Aging 1998; 13:421–434.
26. Elhassan AM, Lindgren JU, Hultenby K, et al
. Methionine–enkephalin in bone and joint tissues. J Bone Miner Res 1998; 13:88–95.
27. Pérez-Castrillón JL, Olmos JM, Gómez JJ, Barrallo A, Riancho JA, Perera L, et al
. Expression of opioid receptors in osteoblast-like MG-63 cells, and effects of different opioid agonists on alkaline phosphatase and osteocalcin secretion by these cells. Neuroendocrinology 2000; 72:187–194.
28. Rico H, Costales C, Cabranes JA, Escudero M. Lower serum osteocalcin levels in pregnant drug users and their newborns at the time of delivery. Obstet Gynecol 1990; 75:998–1000.
29. Pedrazzoni M, Vescovi PP, Maninetti L, Michelini M, Zaniboni G, Pioli G, et al
. Effects of chronic heroin abuse on bone and mineral metabolism. Acta Endocrinol 1993; 129:42–45.
30. Tagliaro F, Capra F, Dorizzi R, Luisetto G, Accordini A, Renda E, et al
. High serum calcitonin levels in heroin addicts. J Endocrinol Invest 1984; 7:331–333.
31. Tagliaro F, Dorizzi R, Lafisca S, Maschio S, Marigo M. Calcitonin serum levels in heroin addicts: effects of methadone and clonidine detoxication treatments. Drug Alcohol Depend 1987; 70:181–183.
32. Spagnolli W, Torboli P, Mattarei M, De Venuto G, Marcolla A, Miori R. Calcitonin and prolactin serum levels in heroin addicts: study on a methadone treated group. Drug Alcohol Depend 1987; 70:143–148.
33. Spagnolli W, De Venuto G, Mattarei M, Dal Piaz A, Merz O, Miori R. Immunoheterogeneity of serum calcium in heroin addicts. Drug Alcohol Depend 1988; 32:1960–1966.
34. Shorr RI, Griffin MR, Daugherty JR, Ray WA. Opioid analgesics and the risk of hip fracture in the elderly: codeine and propoxyphene. J Gerontol 1992; 47:M111–M115.
35. Guo Z, Wills P, Viitanen M, Fastbom J, Winblad B. Cognitive impairment, drug use, and the risk of hip fracture in persons over 75 years old: a community-based prospective study. Am J Epidemiol 1998; 148:887–892.
36. Ensrud KE, Blackwell T, Mangione CM, Bowman PJ, Bauer DC, Schwartz A, et al
, Study of Osteoporotic Fractures Research Group. Central nervous system active medications and risk for fractures in older women. Arch Intern Med 2003; 163:949–957.
37. Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk associate with the use of morphine and opiates. J Intern Med 2006; 260:76–87.
38. Ensrud KE, Blackwell TL, Mangione CM, Bowman PJ, Whooley MA, Bauer DC, et al
, Study of Osteoporotic Fractures Research Group. Central nervous system active medications and risk for falls in older women. J Am Geriatr Soc 2002; 50:1629–1637.
39. Bolland MJ, Grey AB, Horne AM, Briggs SE, Thomas MG, Ellis-Pegler RB, et al
. Bone mineral density remains stable in HAART-treated HIV-infected men over 2 years. Clin Endocrinol (Oxf) 2007; 67:270–275.
40. Dolan SE, Kanter JR, Grinspoon S. Longitudinal analysis of bone density in human immunodeficiency virus-infected women. J Clin Endocrinol Metab 2006; 91:2938–2945.
41. Fernández-Rivera J, García R, Lozano F, Macías J, García-García JA, Mira JA, et al
. Relationship between low bone mineral density and highly active antiretroviral therapy including protease inhibitors in HIV-infected patients. HIV Clin Trials 2003; 4:337–346.
42. Grund B, Peng G, Gibert CL, Hoy JF, Isaksson RL, Shlay JC, et al
, INSIGHT SMART Body Composition Substudy Group. Continuous antiretroviral therapy decreases bone mineral density. AIDS 2009; 23:1519–1529.
43. Jacobson DL, Spiegelman D, Knox TK, Wilson IB. Evolution and predictors of change in total bone mineral density over time in HIV-infected men and women in the nutrition for healthy living study. J Acquir Immune Defic Syndr 2008; 49:298–308.
44. Madeddu G, Spanu A, Solinas P, Calia GM, Lovigu C, Chessa F, et al
. Bone mass loss and vitamin D metabolism impairment in HIV patients receiving highly active antiretroviral therapy. Q J Nucl Med Mol Imaging 2004; 48:39–48.
45. Mondy K, Yarasheski K, Powderly WG, Whyte M, Claxton S, DeMarco D, et al
. Longitudinal evolution of bone mineral density and bone markers in HIV-infected individuals. Clin Infect Dis 2003; 36:482–490.
46. Nolan D, Upton R, McKinnon E, John M, James I, Adler B, et al
. Stable or increasing bone mineral density in HIV-infected patients treated with nelfinavir or indinavir. AIDS 2001; 15:1275–1280.
47. Yin MT, Lu D, Cremers S, Tien PC, Cohen MH, Shi Q, et al
. Short-term bone loss in HIV-infected premenopausal women
. J Acquir Immune Defic Syndr
48. Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS 2006; 20:2165–2174.
49. Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 1996; 312:1254–1259.
50. Johnell O, Kanis JA, Oden A, Johansson H, De Laet C, Delmas P, et al
. Predictive value of BMD for hip and other fractures. J Bone Miner Res 2005; 20:1185–1194.
51. Kanis JL, Melton LJ, Christiansen C, Johnston CC, Khaltaev N. The diagnosis of osteoporosis. J Bone Miner Res 1994; 9:1137–1141.
52. Melton LJ 3rd, Chrischilles EA, Cooper C, Lane AW, Riggs BL. Perspective. How many women have osteoporosis? J Bone Miner Res 1992; 7:1005–1010.
53. Merrill RM, Weed DL, Feuer EJ. The lifetime risk of developing prostate cancer in white and black men. Cancer Epidemiol Biomarkers Prev 1997; 6:763–768.
54. Center JR, Nguyen TV, Schneider D, Sambrook PN, Eisman JA. Mortality after all major types of osteoporotic fracture in men and women: an observational study. Lancet 1999; 353:878–882.
55. Hasserius R, Karlsson MK, Nilsson BE, Redlund-Johnell I, Johnell O, European Vertebral Osteoporosis Study. Prevalent vertebral deformities predict increased mortality and increased fracture rate in both men and women: a 10-year population-based study of 598 individuals from the Swedish cohort in the European Vertebral Osteoporosis Study. Osteoporos Int 2003; 14:61–68.
56. Olszynski WP, Shawn Davison K, Adachi JD, Brown JP, Cummings SR, Hanley DA, et al
. Osteoporosis in men: epidemiology, diagnosis, prevention, and treatment. Clin Ther 2004; 26:15–28.
57. Greenspan SL, Myers ER, Maitland LA, Resnick NM, Hayes WC. Fall severity and bone mineral density as risk factors for hip fracture in ambulatory elderly. JAMA 1994; 271:128–133.
58. Greenspan SL, Myers ER, Maitland LA, Kido TH, Krasnow MB, Hayes WC. Trochanteric bone mineral density is associated with type of hip fracture in the elderly. J Bone Miner Res 1994; 9:1889–1894.
59. Karlsson MK, Johnell O, Nilsson BE, Sernbo I, Obrant KJ. Bone mineral mass in hip fracture patients. Bone 1993; 14:161–165.
60. Nguyen T, Sambrook P, Kelly P, Jones G, Lord S, Freund J, et al
. Prediction of osteoporotic fractures by postural instability and bone density. BMJ 1993; 307:1111–1115.
61. Triant VA, Brown TT, Lee H, Grinspoon SK. Fracture prevalence among human immunodeficiency virus (HIV)-infected versus non-HIV-infected patients in a large U.S. healthcare system. J Clin Endocrinol Metab 2008; 93:3499–3504.