SUPPLEMENT ARTICLE

Emerging 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 and 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 ( and ) 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 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 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 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 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 , 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 that rate of 0.5%–1% per year. Women also lose bone at an accel- would favor and the development of osteo- erated rate after . 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 , chronic jects did not show alterations in BMD or biochemical differ- illness, and concurrent 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. Men receiving PIs had lower median t scores Additional prospective, longitudinal studies are necessary to for the lumbar spine BMD compared with the other 2 groups. determine the exact role of each of these factors in the path- On the basis of lumbar spine BMD t scores, 50% of the subjects ogenesis of HIV-related bone mineral loss. on PIs were classified as osteopenic or osteoporotic according to the WHO classification. The relative risk for osteoporo- sis in these subjects was 2.19 (95% CI, 1.13–4.23) when com- ASSESSMENT AND RECOMMENDATIONS pared with HIV-infected subjects not receiving PIs. Sub- Current diagnosis and treatment of osteopenia/osteoporosis in jects with more prolonged use of PIs tended to have more HIV-infected individuals is primarily based on recommenda- negative t scores in the lumbar spine (Pearson correlation tions used for management of disease in HIV-seronegative coefficient p Ϫ0.19,P p .14 ), but this correlation did not adults. Measurement of BMD as a routine test in HIV-infected reach statistical significance. patients is not recommended. Rather, a detailed history and We also performed an assessment of bone metabolism in a physical examination to assess an individual’s fracture risk is different cohort of 73 HIV-infected subjects receiving therapy advised, in addition to an evaluation of nutritional status and with 2 nucleosides and a PI [33]. Ninety-five percent of the potential secondary causes of osteoporosis. Abnormal labora- cohort had an undetectable virus load, and the median CD4 tory values obtained during the course of HIV treatment (i.e., cell count was 1540 cells/mm3, thus representing a group that elevated alkaline phosphatase or low testosterone) should also had responded remarkably well to HAART. Forty-three percent prompt consideration of further testing for osteoporosis [36]. of the subjects were osteopenic/osteoporotic according to the As noted above, the primary diagnoses of osteopenia or os- WHO definition. There was no association of osteopenia with teoporosis are based on the WHO definitions according to regard to specific PIs. A significant proportion of subjects had measurements of BMD. The most widely used technique for both increased markers of bone resorption and bone formation, determining BMD is DXA. DXA scanning measures bone mass including elevations in pyridinolines, bone alkaline phos- and density in central regions of interest (hip and spine) as phatase, and osteocalcin. This is in sharp contrast with the well as appendicular regions (wrist, forearm, heel). It has be- previous observations of low osteocalcin levels in subjects with come the gold standard to which all other bone densitometry advanced disease. The levels of bone alkaline phosphatase and technologies are compared [37–39]. DXA studies are also useful pyridinolines in urine correlated with BMD. Testosterone and to define fracture risk as well as to measure the effectiveness thyroid-stimulating hormone levels were normal in this pop- of various therapies on bone mass [21]. Biochemical markers ulation, and they did not correlate with BMD, either in the of bone turnover can provide complementary information to lumbar spine or in the hip. More than 50% of the patients had DXA scans, including changes in bone remodeling that can be 1 1 urinary calcium levels 200 mg/24 h, and 25% had 300 mg/ identified before changes in BMD [21]. However, the use of 24 h. Another more recent study looking at similar bone met- such markers in predicting future changes in bone mass and abolic parameters in HIV-infected children also found HAART- fracture risk remains controversial. associated losses in BMD that were associated with an increased Until studies are completed that specifically address the treat- rate of bone turnover [34]. ment of low BMD in HIV-infected patients, it seems reasonable Other studies have shown a more accelerated loss of BMD to pursue osteoporosis treatment strategies that have been in individuals receiving potent antiretroviral therapy, but the proven effective in the general population. A careful search for association with PI use remains speculative [13–14]. Most pa- reversible causes of secondary osteoporosis should be per- tients have also received nucleoside analog reverse transcriptase formed, and vitamin D and calcium intake should be optimized inhibitors (NRTIs) at the time of PI therapy. The use of NRTIs to meet recommended dietary levels. For calcium, the rec- has been associated with mitochondrial toxicity and lactic ac- ommended intake from all sources is 1500 mg/d, and for vi- idosis. Preliminary data have been presented correlating osteo- tamin D, the recommended intake is 400–1000 IU/d. These penia/osteoporosis, total duration of NRTI therapy, and mag- recommendations have been in place for years, but only ∼50% nitude of NRTI-related lactic acidemia [35]. of American adults meet them. Other nutrients are also im- Unfortunately, given the cross-sectional nature of these re- portant in relation to . Diets with very high protein cent studies, it is impossible to attribute cause and effect and content, excess caffeine, phosphorus, and sodium can increase to measure the cumulative effects of other important but com- calcium losses, but their contribution does not appear to be mon risk factors for BMD loss in HIV-infected individuals. very important if the individual has an adequate intake of These include history of wasting or poor nutrition, past steroid calcium. Moderate physical activity is also recommended to usage (i.e., for pneumocystis carinii pneumonia or myopathy), help preserve bone mass. hormonal deficiencies, or the potential contribution of HIV- For more severe cases, the use of hormone replacement ther- related immune system activation and immune reconstitution. apy (if otherwise indicated), , , or

Emerging Bone Problems in HIV Disease • CID 2003:36 (Suppl 2) • S103 is recommended [21]. These agents have not been the case in several patients from the National Institutes of tested specifically in HIV-infected individuals, but there are no Health cohort. Changing antiretroviral therapy to a non- good biological reasons to think that these treatments would PI–containing regimen does not appear to help, but treating fail. Although all of these agents have shown efficacy with BMD concomitant predisposing conditions that might cause further as the primary outcome, only the bisphosphonates have con- osteonecrosis seems to be a reasonable approach. sistently shown strong efficacy in reducing the risk of vertebral Clearly, long-term prospective studies are needed to further and nonvertebral fractures [21]. These agents typically reduce evaluate the effects of antiretroviral therapies, immune recon- the risk of vertebral fractures by 30%–50%. No significant in- stitution, and duration of HIV infection on bone metabolism. teractions are expected with PIs or other antiretroviral therapies Further in vitro and in vivo studies can also provide additional (J. Gerber, personal communication), although no studies have information about the specific effects on bone of both indi- been conducted yet. vidual and various combinations of antiretroviral drugs. Pre- liminary studies reveal that different PIs have different effects on bone metabolism, vitamin D metabolism, and the differ- OSTEONECROSIS entiation and function of and osteoclasts [41, 42]. In the meantime, HIV-infected patients with low BMD Another emerging bone-related problem in HIV-infected in- should be treated similarly to seronegative patients with the dividuals is osteonecrosis, a relatively rare occurrence that is appropriate use of nutritional supplements, exercise, hormone usually the result of lack of an adequate arterial blood supply replacement, and antiresorptive therapies. Data are lacking with to the bone. The femoral head is most commonly affected, and regard to the effects on bone of switching or discontinuing patients usually present with pain. 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