SUPPLEMENT ARTICLE Emerging Bone Problems in Patients Infected with Human Immunodeficiency Virus Kristin Mondy and Pablo Tebas Division of Infectious Diseases, AIDS Clinical Trials Unit, Washington University School of Medicine, St. Louis, Missouri Recently, a high incidence of osteopenia and osteoporosis has been observed in individuals infected with human immunodeficiency virus (HIV). This problem appears to be more frequent in patients receiving potent antiretroviral therapy. Other bone-related complications in HIV-infected individuals, including avascular ne- crosis of the hip and compression fracture of the lumbar spine, have also been reported. People living with HIV have significant alterations in bone metabolism, regardless of whether they are receiving potent antiret- roviral therapy. The underlying mechanisms to account for these observations remain unknown, although studies are underway to examine the relationship between the bone abnormalities and other complications associated with HIV and antiretroviral therapy. HIV-infected patients with osteopenia or osteoporosis should be treated similarly to HIV-seronegative patients with appropriate use of nutritional supplements (calcium and vitamin D) and exercise. Hormone replacement and antiresorptive therapies might be also indicated. The introduction of highly active antiretroviral therapy nificantly higher incidence of osteopenia and osteo- (HAART) with the use of protease inhibitors (PIs) has porosis in individuals receiving combination therapy resulted in significant reductions in morbidity and mor- that included nucleoside analogs and PIs compared tality from HIV infection in recent years [1, 2]. Al- with both HIV-infected individuals not receiving PIs though initial strong enthusiasm for HAART led to its and seronegative individuals [12]. This study needs fur- widespread use early in HIV infection, practitioners ther confirmation. There have been several reports of have now become more cautious in early initiation of other bone-related complications in HIV-infected in- HAART in light of reports concerning serious and po- dividuals, including avascular necrosis of the hip and tentially irreversible toxicities associated with numerous compression fracture of the lumbar spine [11, 15–20]. antiretroviral drugs [3–10]. These toxicities include the Clearly, people living with HIV have significant alter- development of diabetes mellitus, insulin resistance, hy- ations in bone metabolism, regardless of whether they perlipidemia, lipodystrophy, and lactic acidosis [4–9]. are receiving potent antiretroviral therapy. The under- Recently, a high incidence of osteopenia and osteo- lying mechanisms to account for these observed effects porosis has been observed in HIV-infected individuals. remain unknown, although studies are underway to This problem seems to be more frequent in patients examine the relationship between the bone abnormal- receiving potent antiretroviral therapy, although a spe- ities and other complications associated with HIV and cific contribution (if any) of the drugs used in com- antiretroviral therapy. bination regimens has yet to be established [11–14]. Our group, in a cross-sectional study, observed a sig- OSTEOPOROSIS Reprints or correspondence: Dr. Pablo Tebas, Washington University School of Worldwide, osteoporosis is a significant cause of mor- Medicine, Division of Infectious Diseases, Campus Box 8051, 660 S. Euclid, St. bidity and mortality, with an estimated 10 million peo- Louis, MO 63110 ([email protected]). ple in the United States already living with this disease Clinical Infectious Diseases 2003;36(Suppl 2):S101–5 ᮊ 2003 by the Infectious Diseases Society of America. All rights reserved. [21]. It is a skeletal disorder characterized by compro- 1058-4838/2003/3607S2-0009$15.00 mised bone strength predisposing to an increased risk Emerging Bone Problems in HIV Disease • CID 2003:36 (Suppl 2) • S101 of fracture. Bone strength refers to a combination of bone count, HIV virus load, and BMD among our cohort. Most quantity and quality. Bone quantity is measured by means of recently, at the 2001 Conference on Retroviruses and Oppor- bone mineral density (BMD), a commonly used surrogate tunistic Infections, additional studies were presented that marker for bone strength. In a consensus statement from 1994, showed a significant prevalence of low BMD in HAART-naive the World Health Organization (WHO) agreed to standard patients compared with the general population [26–28]. In the definitions of osteoporosis according to normalized measure- larger of these studies, the prevalence of osteopenia/osteopo- ments of BMD. By WHO criteria, a t score is defined as the rosis was 28%, compared with the 16% that one would expect number of SDs above or below the average BMD for race- and in the general population. These studies suggest that HIV in- sex-adjusted population norms determined at peak bone mass fection itself has a significant impact on bone metabolism and (which occurs at ∼30 years of age). A z score compares the may be a contributing factor in the pathogenesis of reduced patient to population norms adjusted for age, race, and sex. BMD. Currently, WHO defines osteoporosis as a t score 1Ϫ2.5 SDs. Other studies have examined biochemical markers of bone Osteopenia is defined as a BMD between Ϫ1 and Ϫ2.5 SDs. metabolism and bone biopsy specimens of therapy-naive HIV- Osteoporosis without a history of fracture carries a 4–5-fold infected individuals in comparison with healthy seronegative increase in fracture risk compared with individuals with normal controls. The most characteristic finding was a marked decrease BMD. A history of fracture and diagnosis of osteoporosis carries in the concentration of osteocalcin (a marker of bone for- a 20-fold increased risk, and osteopenia alone carries a 2-fold mation) and an increase in C-telopeptide (a marker of bone increase in fracture risk [22–24]. resorption) that correlated with enhanced activation of the tu- Gradual bone loss is a common occurrence with aging and mor necrosis factor system and increasing severity of HIV dis- is often referred to as primary osteoporosis. Men and women ease [29–31]. Because numerous cytokines are known to induce naturally begin to lose bone around the age of 35 years, at a differentiation of bone marrow precursors into osteoclasts that rate of 0.5%–1% per year. Women also lose bone at an accel- would favor bone resorption and the development of osteo- erated rate after menopause. In addition to female sex and age, porosis, it seems that immune system activation could play a additional risk factors include white race, low weight, smoking, role in the development of bone abnormalities associated with excessive alcohol use, and history of fracture. A number of HIV. secondary causes of osteoporosis are also well known, including To date, the only published study of assessments of bone corticosteroid use, hypogonadism, hyperthyroidism, prolonged samples from antiretroviral therapy–naive HIV-infected sub- immobility, nutritional deficiencies or malabsorption, chronic jects did not show alterations in BMD or biochemical differ- illness, and concurrent medications such as anticonvulsants or ences in bone metabolism compared with healthy controls, anticoagulants. All of these potential confounding factors must except for decreased levels of osteocalcin in individuals with be accounted for in studying the relationships between bone lower CD4 counts [32]. The number of osteoclasts was found abnormalities, HIV, and antiretroviral therapies. to be significantly lower in HIV-infected individuals rather than higher, as previously predicted. These findings suggest that pro- gression of HIV may promote a decline in activity of bone BONE METABOLISM IN HIV-INFECTED metabolism and that the low-BMD “phenotype” observed in INDIVIDUALS treated individuals is unlikely to be the result of HIV disease alone. The strength of this conclusion is limited because of the Before the era of HAART, studies indicated that bone mineral cross-sectional nature of the studies. Larger prospective studies metabolism was only minimally affected in HIV-infected in- are currently underway to try and answer some of these dividuals. In one study, Paton et al. [25] reported that 45 HIV- questions. infected patients had marginally lower BMD at the lumbar spine than HIV-seronegative controls (P p .04 ). The subjects and controls did not differ in total body or hip BMD. At BONE IN HIV-INFECTED PATIENTS RECEIVING longitudinal follow-up (15 months), a small decrease in total ANTIRETROVIRAL THERAPY body BMD (Ϫ1.6%;P p .02 ) was observed, but there was no significant reduction in spine and hip BMD. We conducted a As part of our ongoing studies of metabolic complications as- similar cross-sectional analysis in 20 HIV-infected subjects na- sociated with HAART, we performed a cross-sectional analysis ive to antiretroviral therapy to evaluate whether osteopenia was of whole-body, lumbar spine (L1–L4), and proximal femur a manifestation of HIV infection itself. Total body, hip, and BMD in 112 male subjects (HIV-infected patients receiving spine BMD were measured by dual X-ray absorptiometry HAART that included a PI, HIV-infected patients not receiving (DXA), with no significant differences from the general pop- a PI, and healthy HIV-seronegative adults) using DXA scans ulation. There was also no significant correlation between CD4 [12]. The median exposure to PIs in the group receiving PIs S102 • CID 2003:36 (Suppl 2) • Mondy and Tebas was 104 weeks.