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Bone Density and HIV Infection
David Alain Wohl, MD
University of North Carolina AIDS Treatment and Research Unit
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Individuals infected with HIV have been observed to have bone densities that are lower than expected based on age. Some studies suggest BMD loss may be more common for patients on ART, while other studies find equal rates of BMD loss for HIV+ persons with no treatment experience. However, the causes and significance of lower bone mineral density (BMD) in the setting of HIV remain unclear. Fortunately, despite the data demonstrating lower bone densities in HIV-infected persons, severe osteoporosis and non-traumatic bone fractures in this population are rare. Confounding any attempts to identify causative factors of bone loss are the presence of other risk factors for low bone density among many HIV-infected persons including corticosteroid use, low testosterone levels, alcohol abuse, weight loss and lack of exercise, among others. (The science of bone density has its own lingo. Those who think a t-score has something to do with sports should check out a nice website created by Susan Ott, MD at http://uwcme.org/courses/bonephys/index.html.)
"Osteopenia & HIV", written for NATAP by Andrew Carr, MD:
www.natap.org/2000/lipo/osteopenia011501.htm
Editorial note: There wasn't much interesting at this Retrovirus Conference on bone problems in HIV. There was much more of interest at last year's Retrovirus Conference. Before reporting Dr Wohl's review of 2 studies from this year's conference, here is a summary review of bone loss in HIV from studies reported over the last 2 years.
Review of Bone Studies Prior to Retrovirus 2002
There have been numerous studies conducted and reported over the last 2 years finding various different potential explanations, potential causative factors, or associations related to bone mineral density loss in HIV including: prior corticosteroid use, nukes & elevated lactate (mitochondrial toxicity), lower weight prior to starting HAART, a greater rise in CD4 count on therapy, fat loss in leg, duration of HIV therapy, PI therapy, not associated with PI use, having lower body weight, age, total body fat, lean body mass, and immune changes. It remains unclear what's causing bone loss in HIV. Other viral diseases can be associated with manifestations such as this; for example, liver disease is associated with bone loss and it is not understood why, or what the cause may be. It might be the change in the immune system that occurs from disease. In HIV, partial immune restoration may be one of a number of things associated with bone loss. Perhaps, the various HIV drugs have specific and different effects on bones or the cytokines affecting bones. Actions you can take that might help prevent bone loss include: weight-bearing exercise, better diet, vitamin supplementation (calcium), stop smoking & excessive alcohol use.
1. Moyle reported at the Lipodystrophy Wksp 2000 that viral control with therapy may diminish risk of osteopenia. BMD was greater in the PI-treated than the NRTI-treated and HIV+ never treated.
2. In a switch study where patients with osteopenia and on a PI were switched to a PI-sparing regimen, there was no apparent improvement; this could mean either the PI had nothing to do with causing osteopenia or the damage was irreversible. (ICAAC 2000)
3. McGowen at Gilead (study 903) reported 24% osteopenia among naives (Retro 2001)
4. Knobel of Spain - although not significant, found osteopenia in 25% of therapy-naives, in 40% of protease inhibitor treated, in 33% of non-protease inhibitor treated and in 16% of healthy adults (Retro 2001)
4. Chang of Korea reported on 100 Asians and found no difference in osteoporosis and osteopenia in a HAART-experienced group vs a HAART-naive group of patients (abstract 630). Yet in this study of 109 Asians (Korean), rates of decreased bone mineral density in the lumbar spine (low back) were quite similar when comparing HIV negative controls, HIV-positive, HAART-naive and HAART-experienced patients (18-24% range). (Retro 2001)
5. Lawal of St. Luke's-Roosevelt Hospital Center in New York City found HAART did not cause osteopenia but HIV did. He reported that the rate of osteopenia among HIV positive men in 1993 was similar to the rate among HIV positive men taking HAART in 1998. DEXA scanning was used. However, bone mineral density in both groups was significantly lower than HIV negative, control patients. (Retro 2000
6. Arpadi of Columbia University reported significant reductions in BMD among children with HIV which increased with age but it was not associated with PI use. It could have been HIV, nukes, therapy or both. (Retro 2001)
7. "Avascular Necrosis" (Bone Death Due to Inadequate Blood)
Dr. J.C. Keruly of Johns Hopkins University reported 15 cases of "avascular hip necrosis" in their HIV Clinic Cohort. This condition may have no symptoms (diagnosed by x-ray or other imaging study) or may be painful. If required, the treatment is hipbone replacement with a metal "prosthesis" during surgery. The "incidence" rate in the current study was 47-fold higher than in the general HIV negative population. There was a significant trend in that the annual number of cases increased from 1995 through 2000 at their institution. Risk factors associated with this specific adverse event included steroid drug (prednisone, cortisone, others) use, low CD4 count (less than 200 cells per microliter) and a longer time since HIV diagnosis, but not treatment for HIV. Nearly half of the cases had never taken a PI or NNRTI drug.
Similarly, Dr. D.M. Gaughan of Harvard School of Public Health reported 5 cases of "avascular necrosis" in HIV-infected children. The incidence rate was much higher in this cohort than in the HIV negative, general pediatric population. (Retro 2001).
8. At the Lipodystrophy Wksp in 2000, Andrew Carr looked at 221 HIV+ men and found 20% had osteopenia & 3% osteoporosis. The only factors independently associated with osteopenia or osteoporosis were higher lactate and lower weight prior to commencing antiretroviral therapy. There was no independent association with any other parameter, including type or duration of any antiretroviral drug or drug class, or with lipodystrophy at any site. Low spinal (but not low total) BMD was associated with both lactic acidemia and duration of nucleoside analogue therapy. Carr suggests that duration and magnitude of lactic acidemia are linked somehow to low BMD, especially in the spine. He hypothesized that the cause may be a direct effect of nucleoside analogs on osteoblast mitochondria. The other possibility is that hydroxyapatite (the principle bone salt that provides the compressional strength vertebrate bone) is being leached from bone to buffer the acid load of chronic lactic acidemia. Carr cautioned this study has limitations, as all these studies in bone loss & lipodystrophy do. The study did not look at women, children, various racial groups, or abacavir. Previously, several researchers including the group at Washington University reported an association between PI therapy and bone loss. I believe they have since recanted this proposition.
These studies suggest that there is no clear relationship between HAART and reduced bone mineral density. Also, there appears to be increasing information that HIV by itself might increase the risk of losing of bone mineral content. However, the cross-sectional design of many of these studies represents a major limitation. The preliminary results require therefore confirmation in longitudinal, prospective, well-controlled trials. Additionally, people with HIV may also have increased incidence of risk factors for osteopenia. Potential confounding cofactors that can contribute to developing osteopenia include being sedentary, cigarette smoking, nutrition (including inadequate calcium intake), current or past steroid hormones (prior exposure to steroid treatment for PCP, use of Megesterol acetate for appetite stimulation, post-menopausal hormone deficiency), excessive alcohol intake, genetics, elevated lipids, possibly lower body mass, diseases such as kidney failure & thyroid overactivity, and long-term treatment with cortisone (but not anabolic steroids, which if anything increase BMD).
Dr Wohl's Review of Retrovirus 2002
The prevalence and history of BMD was examined in a longitudinal study of 128 patients receiving combination antiretroviral therapy who received DEXA scans and provided blood and urine specimens for bone markers every 24 weeks (K. Mondy, et al. Abstr 718-T). Subjects were mostly male (85%), white (82%), taking protease inhibitor based regimens (68%), smokers (40%), occasional alcohol drinkers (41%) and 44% had moderate to high levels of physical activity. Median body mass index (BMI) was 24 (IQR 22-28). Interestingly, 61% were taking less than 1000 mg/d (RDA) of calcium and only 9% were taking calcium supplements at baseline but this rose to 35% at week 48 (suggesting that when people find out about their bone densities they start downing the calcium and milk). Almost half the subjects (46%) met DEXA criteria for osteopenia (mild to moderately low BMD) or osteoporosis (severely low BMD). Median lumbar and hip t-scores were -0.90 (IQR -0.3 to -1.7) and -0.93 (IQR -0.2 to -1.6), respectively. A link between a specific antiretroviral class and low BMD could not be made when other factors for osteopenia were considered. During the 48 week follow-up, there was a small but statistically significant increase in BMD (lumbar 2.3% ± 0.5% p <0.0001, hip 2.2% ± 0.5% p <0.0001). Bone markers, which indicated high bone turnover at baseline, did not change appreciably during the course of the study. These data indicate that low BMD is common among treated HIV-infected patients. The lack of progression of bone loss during treatment is somewhat reassuring but may indicate that the damage done by therapy occurs early. Conversely, the contributory role played by therapy may be small. Although, previous data indicating lower osteopenia rates in those who are treatment naive indicate therapy is associated with lower BMD.
Osteopenia and Osteoporosis More Prevalent in HIV+ Persons. This study found low BMD in the treatment naive and even more profound BMD abnormalities in those on treatment were reported in a similar prospective study involving treatment naive and protease inhibitor receiving subjects (C. Amiel, et al. Abstr 715-T). In this study 150 men aged 25-55 years on either stable HIV therapy (50 with PI; 50 without PI (25 with 2 NRTI+1 NNRTI and 25 with 3 NRTI), or not treated (50) were compared to 119 HIV-uninfected controls with DEXA scans and biochemical blood and urine assays. Depending on which bone was scanned, osteopenia was seen in 7-11% of HIV-uninfected subjects but in 45-55% of HIV positive patients. Osteoporosis was observed in less than 2% of HIV-unifected but in 7-11% of HIV-infected subjects. Rates of osteopenia and osteoporosis seemed to be lower in HIV-infected subjects not receiving antiretroviral treatment compared to those on therapy and there was little difference between those on protease inhibitor and non-nucleoside based regimens.
HIV, Immune Changes May Cause Bone Loss. The authors in this study hypothesize that the types of cytokines that affect T-cells and are predominant in HIV disease and persist or accelerate after ART are critical to bone loss in HIV. As factors other than antiretroviral toxicity emerge as a potential contributor to bone loss in the setting of HIV, immunologic factors are being explored. Laurence and Fakruddin from New York presented laboratory data supporting their hypothesis that hyperactive osteoclasts under the influence of TRANCE, a cytokine associated with T-cell activation that increases during antiretroviral treatment, play a key role in HIV associated bone disease (Abstr 714-T). TRANCE and its receptor were found to be overproduced by the T-cells of 9 of 12 HIV-infected patients compared to controls and T-cells of controls infected with HIV. When osteoclast precursor cells were added to a mix of T-cells infected with HIV, the activity of these cells doubled. The investigators theorize that TNF-alpha, which rises in response to antiretroviral induced immune restoration, may synergize with TRANCE and in the test tube the combination of both increased HIV replication.
The studies presented help move us in small steps toward a greater understanding of the cause of bone demineralisation among HIV-infected individuals. The spotlight is now focused on factors other than direct antiretroviral toxicity. Patient factors, immune responses and drug effects may all act in concert. As we are learning with other metabolic complications, it is not a simple as it first seems.
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