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Decreased Bone Mineral Density Due to Time with HIV, not ART
  "Decreased bone mineral density in HIV-infected patients is independent of antiretroviral therapy"
AIDS 2003; 17(13):1917-1923
Dario Bruera and colleagues. Endocrinology Department and Endocrinology Laboratory. Hospital Nacional de Clínicas. Medical Science School. National University of Cordoba. Cordoba and STD/AIDS Unit. Rawson Hospital. Cordoba, Argentina.
ABSTRACT Objective: To describe the alterations in the bone metabolism of HIV-seropositive patients and evaluate the effects of antiretroviral therapies.
Design: Cross-sectional analytical study.
Method and materials: A total of 142 subjects (113 male, 29 female), aged 20-45 years were divided into four groups: group A, 33 HIV-seropositive antiretroviral-naive patients; group B1, 36 HIV-seropositive patients on antiviral therapy for over 1 year, without protease inhibitors (PI); group B2, 42 HIV-seropositive patients on combined therapy containing PI for over 1 year; and group C, 15 healthy, HIV-seronegative subjects. Bone mineral density (BMD) were determined by dual energy X-ray absorptiometry in total body, lumbar spine and proximal femur; and evaluation of serum osteocalcin, D-pyridinoline, parathyroid hormone (THP), calcium and phosphate, and urine calcium.
Results: BMD was significantly lower in HIV-seropositive patients in comparison with healthy controls, in all sites studied. However, no statistical differences were observed among all groups of HIV-infected patients, independently of the antiretroviral therapy. There was a significantly higher occurrence of osteopenia and osteoporosis in HIV-infected patients in comparison with controls (P < 0.0001), with no differences among treatment-naive patients and either of the treatment groups. Bone formation and resorption markers were similar among all studied groups. There was a significant correlation in all bone sites between time of infection and BMD (P < 0.02).
Conclusions: BMD was significantly lower in HIV-seropositive patients in comparison with controls in lumbar spine, proximal femur and total body, without significant differences among treatment-naive patients and either of the treatment groups. Only time with HIV infection and not specific therapy was associated with BMD decreases.
BACKGROUND The advances in the treatment of HIV-infected individuals, particularly with the use of highly active anti-retroviral therapy (HAART), have significantly decreased the morbility and mortality caused by this infection. The long-term survival of the treated patients has revealed several metabolic complications, such as lipodystrophy, insulin resistance, diabetes, dyslipidemia and, more recently, alterations in phosphocalcic metabolism.
Paton et al. showed, for the first time, a decrease in bone mineral density (BMD); since then a growing number of authors have reported different alterations in the bone mineral metabolism in HIV patients. Today, there is reasonable agreement about the frequent association between osteopenia and HIV infection.
A variable pattern for the biochemical parameters controlling bone formation and resorption have been described: a study by Teichmann et al. showed in HIV-seropositive patients a decrease in the formation markers with an increase in the bone resorption markers, regardless of variables such as the type and duration of treatment therapy. Tebas et al. reported an increase in the bone formation and resorption markers in patients on protease inhibitor (PI) therapies, suggesting an increased bone turnover. Non-PI treated patients, however, were not included in this study. The role of PIs in the metabolism of phosphocalcic markers is also controversial, several authors have found a significant increase in bone formation markers in patients treated with PI, suggesting a beneficial effect of this therapy.
In a recently published study, Nolan et al. concluded that there is an increase in BMD in patients taking indinavir or nelfinavir, suggesting that the osteopenia observed in treatments that use different PI may be due to their own metabolism. In a study where neither therapeutic regimens nor administration times were considered, Huang et al. found a relationship, in HIV-infected men, between the decrease of BMD and the increase in abdominal visceral fat (lipodystrophy).
Carr et al. did not find a relation between decreased BMD and use of PIs or therapy duration, linking osteopenia to both lactic acidosis and low patient weight at the beginning of therapy.
The etiology and pathogenesis of osteopenia in HIV infection has not been fully elucidated. Multiple factors have been involved, including the direct effect of the virus upon osteogenic cells; persistent activation of pro-inflammatory cytokines, especially the tumor necrosis factor-alpha (TNF-[alpha]); alterations in the metabolism of vitamin D and its derivatives; opportunistic and/or chronic diseases associated with HIV; and mitochondrial abnormalities related to lactic acidemia.
In a study carried out at the Massachusetts General Hospital, a relation was established between the decreased BMD at the lumbar spine and the increased abdominal fat in men with lipodystrophy. This finding was not confirmed by Cooper's team, who compared HIV-seropositive patient groups with and without lipodystrophy, and found similar BMD values in both groups.
Although the scope of these findings is still uncertain, there are few reports of pathologic fractures associated with osteopenia in HIV-infected patients. The role of HAART, especially regimens containing PI, on bone metabolism and on BMD in HIV-seropositive patients is controversial. In one of the first studies, Tebas et al., showed a relationship between the use of PIs and a decrease in BMD, and other authors have found Pis linked to the diagnose of osteopenia. However, these findings still need to be confirmed by other groups. When studying a patient with lipodystrophy, Hoy et al. found that BMD remained unaltered after replacing PI-containing regimens with a non-PI therapy during 48 weeks. Moyle et al. studied HIV-seropositive patients on PI and non-PI therapies, and found similar BMD values in both groups, which suggests a direct effect of the HIV infection on BMD. More recent studies have found a frequent occurrence of osteopenia among HIV-infected patients, but no significant differences among groups treated with different therapeutic regimens; thus, the alterations found could not be attributed to the regimens themselves. Moreover, in a longitudinal study, Nolan et al. did not find significant BMD changes in patients on HAART, and pointed out that indinavir therapy can be linked to an increase of BMD over time.
The objective of this work was to identify and describe possible bone metabolic alterations in HIV-infected patients, and to evaluate the effects of different therapeutic regimens on such changes.
Body mass index (BMI) and weight were slightly lower in HIV-infected patients than in controls. The antiretroviral-naive patient group (group A) had the shorter infection time and slighter elevated plasma HIV RNA than patients on treatment (groups B1 and B2).
The BMD, expressed both in absolute values and standard deviation score (t and z score), was statistically lower, in every case, in HIV-seropositive patients in comparison with the healthy controls. Different treatment therapies revealed similar BMD results. The percent of calcium (calciuria) present in HIV-seropositive patients was lower than in controls; again no differences were observed among groups A, B1 and B2. Comparable results were obtained for the rest of the measurements.
There was a significantly higher percentage of osteopenia and osteoporosis in HIV-patients than in controls (P < 0.0001), with no differences among patient groups. When categorizing subjects using the z-score (adjusted for same sex and age subjects), the percentage of patients with osteopenia and osteoporosis remained significantly higher in HIV-seropositive patients than in controls (P < 0.002).
There was significant correlation between years of infection and BMD in femoral neck (r = -0.26; P = 0.01), lumbar spine (r = -0.25; P = 0.02) and total body (r = -0.26, P = 0.01). The rest of the variables did not correlate with BMD.
The odds ratio was significantly higher for the years of infection, without differences against the other variables.
At the present time, osteopenia is frequently linked to HIV infection. Its etiology is not fully understood. Similarly to the phenomenon of fat redistribution (lipodystrophy), osteopenia was initially attributed to the use of PIs; however, additional research efforts did not prove this relationship. These days, the role of the many antiretroviral regimens used in the treatment of HIV-infected individuals on the metabolism of phospho-calcium is controversial, to such an extent that some authors believe these regimens are responsible for the decreased BMD observed, whereas others suggest the opposite.
Tebas et al. studied a population of 112 HIV-infected men on HAART, divided into two groups (on PI and non-PI therapy), and compared both with a third group of non-HIV-infected individuals, concluding that those on PI had a higher incidence of osteopenia and osteoporosis. They did not find any relation between ostopenia and osteoporosis and fat redistribution, suggesting that they are independent adverse effects. However, Tebas et al. did not compare them with a group that were not receiving antiretroviral therapy; in addition the densitometries were not performed at the same time, some were done at the beginning of therapy and other during treatment; furthermore the lumbar spine BMD data was extrapolated from total body densitometries and the minimum exposure time to PIs was 16 weeks, which might not have been enough to evaluate the impact of PI on BMD. All these issues and especially the length of the PI treatment could explain the differences found in our study. In our research, one of the patient inclusion criterion was a minimum of 24 months on PI therapy, which would enable us to evaluate the effects of the therapy.
The fat distribution analysis, demonstrated that the relationship between appendiceal to/central fat mass index was higher in patients on treatment, regardless of treatment type. The naive group's response was similar to that of groups on treatment.
In April, 2001, Knobel et al. found osteopenia and osteoporosis both in patients on HAART treatment and in therapy-naive patients. The HIV-patients group showed significant differences from the non-HIV, healthy control group with respect to BMD, with a similar percentage of osteopenia and osteoporosis in HIV-infected individuals, both on therapy and therapy-naive. These findings match the results of our research. However, Knobel's team did not find a positive correlation between the years of infection and the BMD. A minimum infection time was not considered, though, which may mask the direct effect of the HIV infection on phosphocalcic metabolism.
These differences regarding the role of therapeutic agents in BMD could be attributed to the use of different regimens, without considering - in some cases - minimum disease evolution time and minimum therapy duration.
In this study, we did an exhaustive selection of patients to avoid patients with other risks that would have masked the results of the phospho-calcium metabolism. All HIV-infected patients had a documented time of infection, 2 years or more, and a well-controlled therapy duration, 1 year as a minimum. We also included no treated HIV-infected (treatment naive) and healthy, HIV seronegative individuals. The lack of statistically significant differences in BMD between patient groups may suggest that the decrease may not be due to the effect of the drugs used. However, the positive correlation between years of infection and BMD in all bone sites under study suggests a direct or indirect effect of the virus. The activation of pro-inflammatory factors, indirect effect of HIV, with known effects on phosphocalcic metabolism would be one of the proposed mechanisms. In this study these cytokines and/or chemokines were not studied; therefore, we can not make any inference about the etiology of the alterations found in bone metabolism.
In summary, we have found that the BMD was significantly lower in HIV-seropositive patients when compared with healthy seronegative individuals, with no significant differences among patient groups on different therapeutic regimens. Therefore, the alterations found could not be attributed to the therapeutic therapies themselves. Bone formation and resorption markers were similar among all the groups studied. The positive correlation between years of infection and BMD in all bone sites studied, suggests a deleterious effect of the virus on bone metabolism, independent of antiretroviral therapy.
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