Bone Density Risk Factors in People With HIV: A Long, Familiar List
Abstract: A list of osteoporosis risk factors compiled by the National Osteoporosis Foundation is long and detailed, yet it omits two factors confirmed by research and highly prevalent in people with HIV: HCV or HBV infection and opioid substance abuse or opioid substitution therapy. The National Osteoporosis Foundation does count HIV infection as a risk factor, a determination confirmed by plentiful research. Numerous classical risk factors are prevalent in some HIV populations, including low weight, smoking, heavy alcohol drinking, diabetes, kidney disease, stroke, depression, steroid use, and low testosterone. Bone mineral density drops 2% to 6% in the first 2 years of antiretroviral therapy, but continuing treatment does not appear to pose a further threat to bone health. New HIV bone guidelines suggest avoiding tenofovir disoproxil fumarate and protease inhibitors in people with a high fracture risk (previous fragility fracture, DXA-derived T score at or below -2.5, FRAX at or above 20%).
If you consult the National Osteoporosis Foundation web site (www.nof.org), you can count no fewer than 69 osteoporosis risk factors, including six uncontrollable risks, seven controllable risks, 16 medications, and 40 diseases or conditions (Tables 1, 2, and 3). Thorough, but hardly a handy checklist you can keep at your fingertips. And if you consult the HIV literature, you learn this 69-item tally has a few holes. The uncontrollable-risk list does not include white or Asian race (which the CDC and the Mayo Clinic do count). The controllable-risk list overlooks opioids and substance use. And the menu of diseases mentions liver disease but does not specify hepatitis C or B infection (HCV, HBV), amply documented as low bone mineral density risk factors in studies of people with and without HIV.
Does HIV Alone Heighten Low Bone-Density Risk?
More than a few major risk factors highly prevalent in many HIV populations show up in the National Osteoporosis Foundation inventory, including smoking, heavy alcohol drinking, low weight, steroid use, diabetes, kidney disease, liver disease, stroke, depression, and low testosterone in men. And the Foundation cites HIV infection as a risk factor. Almost a dozen studies over the past decade implicate HIV infection as an independent risk factor for low bone mineral density (BMD) or fracture. Three other studies also found HIV an independent predictor -- until weight got factored into the analysis.
A meta-analysis scrutinizing 11 cross-sectional studies published from 2000 through 2004 (five in the United States and the rest in Western Europe or Argentina) calculated that HIV infection independently bolstered chances of osteoporosis 3.7-fold (95% confidence interval [CI] 2.3 to 5.9).1 The pooled analysis involved 884 people with HIV and 654 without HIV, about two thirds of them men and most in their mid-30s to mid-40s.
Ten studies published after the meta-analysis figured that HIV infection independently raised chances of lower BMD or fracture.2-11 These studies include prospective and cross-sectional cohort surveys and case-control analyses. Eight of them took place in the United States,2-8,10 one in Switzerland,9 and one in Ireland.11 Ages usually averaged in the 40s, though two studies involved postmenopausal U.S. women6,7 and one involved U.S. men 49 or older.3 Two other studies assessed only women.4,5
What explains the higher bone-thinning risk in HIV-positive people in these studies? Two factors leap out as key contributors because adjustment for those factors dimmed the impact of HIV on risk: shifts in bone metabolism and low weight. The bone-metabolism study involved 474 HIV-positive and negative people with similar demographic backgrounds in Dublin's UPBEAT Study Group.11 Many study participants were women, 41%, with HIV and 56% without HIV; 40% and 25% with and without HIV were African, and median ages stood at 39 and 42. Among people with HIV, the largest proportion, 47%, got infected during heterosexual sex, 25% during gay sex, and 19% while injecting drugs.
Statistical analysis adjusted for body mass index and demographic and lifestyle factors independently linked HIV infection to lower BMD at the femoral neck (-0.62 g/cm2, P < 0.0001), total hip (-0.078 g/cm2, P < 0.0001), and lumbar spine (-0.060 g/cm2, P = 0.0002).11 HIV remained independently associated with reduced BMD after further adjustment for bone biomarkers, though the impact dwindled. People with HIV had significantly higher bone turnover rates than HIV-negative controls (P < 0.0001).
Veterans Aging Cohort Study (VACS) investigators compared incident fragility fractures in male veterans with and without HIV.12 More than half of the group, 55%, was black or Hispanic, and 34% were 50 or older. Statistical analysis adjusted for demographics, comorbid disease, smoking, and alcohol abuse figured that vets with HIV had a 24% higher fracture risk (adjusted hazard ratio [aHR] 1.24, 95% CI 1.11 to 1.39). But further adjustment for body mass index rendered the risk difference nonsignificant (aHR 1.10, 95% CI 0.97 to 1.25).
A 2007 meta-analysis considered 10 studies comparing HIV-positive adults with HIV-negative controls of comparable age and gender, all with weight or body mass index data.13 HIV-positive people averaged 5.1 kg lower in weight than negative controls, a highly significant difference (P < 0.001). Unadjusted analyses found significantly lower BMD at all skeletal sites, ranging from 4.4% to 7.0% lower, in people with HIV (P < 0.01). After adjustment for weight, those differences became nonsignificant for the total body and lumbar spine and were smaller though still significant at the total hip (-0.02 g/cm2, 95% CI -0.04 to 0.00, P = 0.031) and femoral neck (-0.04 g/cm2, 95% CI -0.07 to -0.01, P = 0.013).
A 2015 study in the Netherlands compared osteoporosis rates in 581 people with HIV and 520 HIV-negative people with similar demographics, all of them 45 or older.14 Prevalent osteoporosis proved significantly more frequent in the HIV group, 13.3% versus 6.7% (P < 0.001). But statistical adjustment for body weight and smoking diluted this difference to nonsignificance.
Impact of Antiretrovirals on Weak-Bone Risk
Volumes could be written -- indeed, volumes have been written -- on whether antiretrovirals individually or en masse directly lower BMD. The bottom line: some do, but no one suggests avoiding or delaying antiretroviral therapy because it sends people to the hospital with fragility fractures.
The National Osteoporosis Foundation pointedly omits antiretrovirals from its 16-drug list of medications that make osteoporosis more likely (Table 2). And new HIV bone guidelines advise following national protocols on when to start antiretroviral therapy because treatment benefits "far outweigh the potential negative long-term effects on bone mass and metabolism, and fracture risk."15 For people with a high fracture risk (previous fragility fracture, T score at or below -2.5, FRAX at or above 20%), the guidelines suggest avoiding tenofovir disoproxil fumarate (TDF) and protease inhibitors (PIs) in first-line regimens and switching from those drugs if treatment has begun. (For findings on tenofovir alafenamide -- TAF -- and BMD, see "Antiretrovirals: PIs, TDF and TAF").
Perhaps because many people start therapy with TDF, a PI, or both, BMD does drop 2% to 6% in the first 2 years of treatment, the bone guidelines acknowledge.15 But after that not much happens, according to a 6-year study comparing 44 men with HIV and 37 without HIV.16 The HIV group averaged 49 years in age and the control group 46. The groups did not differ significantly in weight or body mass index, but a significantly higher proportion of the HIV group smoked (37% versus 3%, P < 0.001). Men with HIV had been infected for an average 8 years.
HIV-positive men had DXA scans when antiretrovirals began and 2 and 6 years later. HIV-negative controls also had three DXA scans over 6 years. Six-year change in total body BMD did not differ significantly between men with and without HIV (+0.3% and +0.5%, P = 0.15), and the same proved true for total hip BMD (-0.6% and -0.1%, P = 0.8). Men with HIV gained significantly more lumbar spine BMD than did seronegative men through 6 years (+5.3% versus +0.3%, P < 0.001).
Anyone still wavering on whether to start (or continue) antiretroviral therapy in someone with a high fracture risk should consider the plentiful reports linking low CD4 count or high viral load to lower bone density or fracture. At least two studies tied higher viral load to lower BMD. The older study involved 161 consecutive HIV-positive people in Italy who completed a rigorous demographic questionnaire and testing for bone-related disease.17 Twenty-two of 48 antiretroviral-naive people (46%) and 58 of 113 taking antiretrovirals (51%) had osteopenia or osteoporosis -- a slim difference. Three classic risk factors -- female gender, older age, and lower body mass index -- independently predicted osteopenia or osteoporosis. And every 10-fold higher viral load at DXA scanning doubled chances of osteopenia or osteoporosis (adjusted odds ratio [aOR] 1.97, 95% CI 1.16 to 3.34, P = 0.01) (Figure 1). Compared with antiretroviral-naive people, the treated group did not run a higher risk of low bone density. A more recent analysis pooled data from 796 participants in AIDS Clinical Trials Group (ACTG) studies in which everyone had whole-body DXA before starting first-line therapy and 96 weeks later.18 Participants lost an average 2% of BMD through 96 weeks of treatment. The same three classic risk factors identified in the Italian study17 -- female gender, older age, and lower body mass index -- emerged as independent predictors of a greater 96-week BMD drop. Higher pretreatment viral load independently predicted greater BMD loss (-0.56% lower per 10-fold higher viral load, P = 0.02) (Figure 1). Treatment with TDF or a PI also made losing more BMD more likely.
A half-dozen studies link lower baseline18,19 or nadir20-23 CD4 count to low BMD or fracture. In a single-center Australian case-control study of HIV patients with and without fractures, a current CD4 count below 500 cells/mm3 doubled the risk of fragility fracture.19 A count below 200 cells/mm3 (versus above 500) inflated fracture risk almost 7-fold. In the U.S. HIV Outpatient Study (HOPS), a nadir CD4 count below 200 raised the risk of incident fracture 60%.20 Together these studies show that uncontrolled HIV infection -- signaled by high viral loads or low CD4 counts -- threaten bone health more than antiretroviral therapy.
Neither the National Osteoporosis Foundation nor the CDC counts hepatitis virus infection as an osteoporosis risk factor, though the Foundation more broadly lists "liver disease." But plentiful evidence from recent meta-analyses and other studies confirms that either HCV or HBV adds to the bone-thinning risk with HIV. Testing for these viruses should be routine for people with HIV, regardless of bone risk, because both can be treated and HBV can be prevented by vaccination. The added bone risk with hepatitis virus infection should offer an extra prod to test HIV patients for these viruses.
Two recent meta-analyses established a tie between HCV/HIV coinfection and osteoporosis or fracture compared with HIV alone or no infection. The more recent analysis considered studies published up to April 2013 that assessed endpoints of BMD or incident fracture in HCV/HIV-coinfected people compared with HIV-monoinfected people or HCV/HIV-negative individuals.24 The investigators found 13 studies -- six considering BMD and seven fracture -- involving 427,352 people. Compared with HIV-monoinfected individuals (but not uninfected people), HCV/HIV-coinfected people had a doubled chance of low bone density (pooled OR 1.98, 95% CI 1.18 to 3.31). Fracture risk proved more than 50% higher with coinfection than with HIV alone (pooled relative risk [RR] 1.57, 95% CI 1.33 to 1.86). Fractures were more than twice as likely with HCV/HIV coinfection than with neither infection in cohort studies (pooled RR 2.46, 95% CI 1.03 to 3.88) or in cross-sectional studies (pooled OR 2.30, 95% CI 2.09 to 2.33).
Exploring 15 studies presented through 2013 -- nine focused on BMD and six on fracture -- another team reached similar conclusions.25 HCV/HIV-coinfected people had 63% higher odds of osteoporosis than HIV-monoinfected people (OR 1.63, 95% CI 1.27 to 2.11). Coinfected individuals had a 77% higher overall fracture incidence than HIV-monoinfected people (pooled incidence rate ratio [IRR] 1.77, 95% CI 1.44 to 2.18) and almost a tripled fracture incidence compared with uninfected people (pooled IRR 2.95, 95% CI 2.17 to 4.01). This analysis confirmed the importance of classical bone risk factors in these populations -- older age, lower BMI, smoking, and alcohol and substance abuse.
These investigators noted that people with HCV/HIV may run a higher fracture risk because of behaviors that boost chances of bone-breaking trauma.25 But they doubted such dangerous behavior completely explains the inflated risk because adjustment for alcohol and substance use did not eliminate the higher fracture risk with HCV. Rather, they observed, research shows that chronic liver disease upsets healthy bone remodeling.26-28 Other research suggests chronic inflammation resulting from HIV infection promotes bone resorption (breakdown).29 Reason suggests that the added inflammation due to HCV coinfection would compound that process.
Less work addresses the interplay between HBV infection -- with or without HIV -- and bone risk. A recent study compared incident hip fracture in four U.S. Medicaid populations -- 4156 people dually treated for HBV and HIV, 2015 treated only for HBV monoinfection, 96,253 treated for HIV monoinfection, and 746,794 HBV/HIV-negative people.30 Through 5 years the HBV/HIV group had a 37% higher risk of hip fracture (aHR 1.37, 95% CI 1.03 to 1.83) than HIV-monoinfected people and a 35% higher risk than uninfected people (aHR 1.35, 95% CI 1.03 to 1.84).
Apart from drinking too much alcohol and smoking, substance use -- particularly with opioids or opioid substitutes -- figures prominently in bone-risk research but has not earned a place on the 69-item National Osteoporosis Foundation risk list. Here's some of the evidence:
A prospective study of 245 middle-aged women with HIV and 219 women without HIV -- about half of them opioid or cocaine users -- determined that methadone therapy independently predicted waning BMD at the femoral neck.5 Current methadone use also predicted falling BMD (at the total hip) in a study of 230 men with HIV and 159 without HIV, all of them 49 or older and nearly all of them opioid or cocaine users.31 This prospective study linked heroin use plus AIDS to falling BMD at the total hip or femoral neck. Two other studies tied methadone treatment to lower spine BMD in 495 middle-aged women with or without HIV2 and 559 men 49 or older and with or without HIV.3
Incidence of diverse major chronic diseases ratchets relentlessly upward with age, and osteoporosis is no exception. As prevalence of predisposing comorbid diseases climbs and bone mass dwindles with age, risk of osteoporosis and osteoporotic fracture grows apace. And fracture risk with age appears to climb faster with age in people with HIV than in HIV-negative people, suggest results of a large cross-sectional study at Boston's Partners HealthCare System.32 The analysis compared 8525 HIV-positive adults with 2.2 million HIV-negative people in the same system, all of them seen at some point between October 1996 and March 2008. Fragility fracture prevalence rose steeply starting at age 40 in both the HIV-positive and negative groups, but the climb was steeper among both women and men with HIV than in their HIV-negative counterparts (Figure 2).
The risk imbalance between people with and without HIV may begin early in life -- even before people reach peak bone mass in their early 20s -- if children are infected at birth or in adolescence. The impact of early HIV infection came clear in a three-way comparison involving perinatally and behaviorally HIV-infected young men and healthy controls.33
The researchers cited five previous studies that recorded lower BMD in perinatally and behaviorally infected children and adolescents than in HIV-negative controls, even after adjustment for sexual maturation stage, height, and weight. But they noted that DXA has limitations in growing children that may make comparisons between HIV-positive and negative youngsters unreliable. Thus they used both DXA and high-resolution peripheral quantitative CT (HR-pQCT) to measure BMD in this cross-sectional study of 15 perinatally HIV-infected men, 15 men infected during adolescence, and 15 healthy HIV-negative controls.33 Everyone was between 20 and 25 years old, everyone had reached Tanner stage 5, and all HIV-positive men were on antiretroviral therapy. People usually attain peak bone mass by age 20. Among men with HIV, 60% were black and 40% Hispanic. Among controls, 20% were black and 80% Hispanic. Height, weight, body mass index, smoking status, and alcohol use did not differ significantly between study participants with and without HIV.
Men with and without HIV had similar bone size, but DXA-derived BMD Z scores proved significantly lower in HIV-positive men than in healthy controls at the spine, hip, and radius. HR-pQCT showed significantly lower total and trabecular volumetric BMD at the radius (forearm) and tibia (shin) in men with HIV. Cortical and trabecular thickness were also significantly lower in men with HIV at the radius and tibia. Other bone measures also favored men without HIV. No DXA or HR-pQCT results differed significantly between perinatally and behaviorally infected men with HIV.
The investigators believe their data "suggest that men infected with HIV early in life have lower peak bone mass, a thinner cortical shell, markedly abnormal trabecular bone microstructure with deficiencies in trabecular plates and axial bone volume fraction, and reduced bone strength."33 They proposed that "these deficits may place them at higher risk of fractures as they age than uninfected individuals and HIV-infected individuals who were infected later in life, after acquisition of peak bone mass."
Osteoporosis Risk Pieces Not So Puzzling
With the National Osteoporosis Foundation 69-item risk lists (Table 1, 2, and 3) as a starting point, findings outlined in this article suggest a simpler schema for judging and lowering risk in people with HIV. The blueprint hinges on six immutable risk factors (Figure 3, center), with the understanding that low weight can be improved if its cause is poor nutrition or eating disorders. Six lifestyle changes (Figure 3, left) can lower chances of poor bone health regardless of fixed risk factors. Six comorbidities prevalent in people with HIV (Figure 3, top right) add to the risk of osteoporosis, but all these diseases can be prevented or treated. Five types of nonantiretroviral medications often taken by people with HIV (Figure 3, bottom right) can hike the risk of bone disease and should be considered in the risk equation.
The Figure 3 framework abridges the National Osteoporosis Foundation risk factor list by focusing on those most often pinpointed in studies of people with HIV. Still, it remains too lengthy for most to memorize. But anyone can keep in mind the three prime risk factors HIV bone guidelines list for fragility fracture:15
- History of fragility fracture
- Glucocorticoids for more than 3 months (≥5 mg of prednisone daily or equivalent)
- High risk for falls
The following article in this issue covers fragility fracture risk assessment according to the new guidelines.15
- Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS. 2006;20:2165-2174.
- 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.
- 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.
- Anastos K, Lu D, Shi O, et al. The association of bone mineral density with HIV infection and antiretroviral treatment in women. Antivir Ther. 2007;12:1049-1058.
- Sharma A, Cohen HW, Freeman R, Santoro N, Schoenbaum EE. Prospective evaluation of bone mineral density among middle-aged HIV-infected and uninfected women: association between methadone use and bone loss. Maturitas. 2011;70:295-301.
- Yin MT, Zhang CA, McMahon DJ, et al. Higher rates of bone loss in postmenopausal HIV-infected women: a longitudinal study. J Clin Endocrinol Metab. 2012;97:554-562.
- Yin MT, Shu A, Zhang CA, et al. Trabecular and cortical microarchitecture in postmenopausal HIV-infected women. Calcif Tissue Int. 2013;92:557-565.
- Peters BS, Perry M, Wierzbicki AS, et al. A cross-sectional randomised study of fracture risk in people with HIV infection in the Probono 1 study. PLoS One. 2013;8:e78048.
- Calmy A, Chevalley T, Delhumeau C, et al. Long-term HIV infection and antiretroviral therapy are associated with bone microstructure alterations in premenopausal women. Osteoporos Int. 2013;24:1843-1852.
- Hileman CO, Labbato DE, Storer NJ, Tangpricha V, McComsey GA. Is bone loss linked to chronic inflammation in antiretroviral-naive HIV-infected adults? A 48-week matched cohort study. AIDS. 2014;28:1759-1767.
- 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.
- Womack JA, Goulet JL, Gibert C, et al. Increased risk of fragility fractures among HIV infected compared to uninfected male veterans. PLoS One. 2011;6:e17217.
- Bolland MJ, Grey AB, Gamble GD, Reid IR. Low body weight mediates the relationship between HIV infection and low bone mineral density: a meta-analysis. J Clin Endocrinol Metab. 2007;92:4522-4528.
- Kooij KW, Wit FW, Bisschop PH, et al. Low bone mineral density in patients with well-suppressed HIV infection: association with body weight, smoking, and prior advanced HIV disease. J Infect Dis. 2015;211:539-548.
- Brown TT, Hoy J, Borderi M, et al. Recommendations for evaluation and management of bone disease in HIV. Clin Infect Dis. 2015;60:1242-1251.
- Bolland MJ, Grey A, Horne AM, et al. Stable bone mineral density over 6 years in HIV-infected men treated with highly active antiretroviral therapy (HAART). Clin Endocrinol (Oxf ). 2012;76:643-648.
- Fausto A, Bongiovanni M, Cicconi P, et al. Potential predictive factors of osteoporosis in HIV-positive subjects. Bone. 2006;38:893-897.
- Grant PM, Kitch D, McComsey GA, et al. Low baseline CD4+ count is associated with greater bone mineral density loss after antiretroviral therapy initiation. Clin Infect Dis. 2013;57:1483-1488.
- Yong MK, Elliott JH, Woolley IJ, Hoy JF. Low CD4 count is associated with an increased risk of fragility fracture in HIV-infected patients. J Acquir Immune Defic Syndr. 2011;57:205-210.
- Young B, Dao CN, Buchacz K, Baker R, Brooks JT; HIV Outpatient Study (HOPS) Investigators. Increased rates of bone fracture among HIV-infected persons in the HIV Outpatient Study (HOPS) compared with the U.S. general population, 2000-2006. Clin Infect Dis. 2011;52:1061-1068.
- Negredo E, Domingo P, Ferrer E, et al. Peak bone mass in young HIV-infected patients compared with healthy controls. J Acquir Immune Defic Syndr. 2014;65:207-212.
- Li Vecchi V, Soresi M, Giannitrapani L, et al. Dairy calcium intake and lifestyle risk factors for bone loss in HIV-infected and uninfected Mediterranean subjects. BMC Infect Dis. 2012;12:192.
- Cazanave C, Dupon M, Lavignolle-Aurillac V, et al. Reduced bone mineral density in HIV-infected patients: prevalence and associated factors. AIDS. 2008;22:395-402.
- O'Neill TJ, Rivera L, Struchkov V, Zaheen A, Thein HH. The effect of HIV-hepatitis C co-infection on bone mineral density and fracture: a meta-analysis. PLoS One. 2014;9:e101493.
- Dong HV, Cortés YI, Shiau S, Yin MT. Osteoporosis and fractures in HIV/hepatitis C virus coinfection: a systematic review and meta-analysis. AIDS. 2014;28:2119-1131.
- Rouillard S, Lane NE. Hepatic osteodystrophy. Hepatology. 2001;33:301-307.
- Pignata S, Daniele B, Galati MG, et al. Oestradiol and testosterone blood levels in patients with viral cirrhosis and hepatocellular carcinoma. Eur J Gastroenterol Hepatol. 1997;9:283-286.
- Hay JE. Bone disease in cholestatic liver disease. Gastroenterology. 1995;108:276-283.
- Aukrust P, Haug C, Ueland T, et al. Decreased bone formative and enhanced resorptive markers in human immunodeficiency virus infection: indication of normalization of the bone-remodeling process during highly active antiretroviral therapy. J Clin Endocrinol Metab. 1999;84:145-150.
- Byrne DD, Newcomb CW, Carbonari DM, et al. Increased risk of hip fracture associated with dually treated HIV/hepatitis B virus coinfection. J Viral Hepat. 2015 Mar 6. doi: 10.1111/jvh.12398. Epub ahead of print.
- Sharma A, Flom PL, Weedon J, Klein RS. Prospective study of bone mineral density changes in aging men with or at risk for HIV infection. AIDS. 2010;24:2337-2345.
- 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.
- Yin MT, Lund E, Shah J, et al. Lower peak bone mass and abnormal trabecular and cortical microarchitecture in young men infected with HIV early in life. AIDS. 2014;28:345-353.