Link to protease inhibitors and metabolic disorders?

Several studies have found that protease inhibitor (PI) treatment has been associated with a significantly greater incidence of osteoporosis.

For example, one study found that 21% of a group of 64 men receiving PIs, compared with 6% of an age-matched HIV-negative control group, had severe osteoporosis. There was no significant relationship between osteoporosis and fat redistribution.1 Fifty percent of the PI group had some evidence of reduced bone mass, compared to 29% of the control group. Although some researchers have speculated that reduced level of the male sex hormone testosterone might be linked to reduced bone mass, no link was found in this study.

An Australian group has also reported reduced bone mass in 28% of 80 patients with lipodystrophy. However, researchers do not know what is causing this high prevalence of osteoporosis given that the proportion with reduced bone mass did not increase during six months of follow-up, and switching from a PI-containing regimen to a PI-sparing regimen did not improve bone mass.2 The loss of bone mass was most pronounced in the legs and spine, increasing the possibility of broken bones among PI recipients.

One test-tube study has shown that PIs interfere with vitamin D metabolism through their influence on the cytochrome P450 system.3 While vitamin D is crucial for bone formation, there is no evidence that people taking PIs have reduced levels of vitamin D. On the other hand, another test tube study has shown that some PIs may contribute to the manufacture of new bone cells which contradicts the theory that PIs are weakening bones.4

An analysis of more than 10,000 patients enrolled in 13 randomised studies of PIs found no difference between patients receiving PIs and patients receiving other regimens in the rate of fractures. Approximately 2% in each group reported fractures, and very few of these were compression fractures, the type associated with osteoporosis.5

References

  1. Tebas P et al. Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy. AIDS 14:4, F63-F67, 2000
  2. Hoy J et al. Osteopenia in a randomised multicenter study of protease inhibitor substitution in patients with the lipodystrophy syndrome and well-controlled HIV viremia. Seventh Retroviruses Conference, San Francisco, abstract 208, 2000
  3. Dusso A et al. Protease inhibitors inhibit in vitro conversion of 25 (OH)-vitamin D to 1,25 (OH)2-vitamin D. Antiviral Therapy 5: S19, 2000
  4. Nolan D et al. Stable or increasing bone mineral density in HIV-infected patients treated with nelfinavir or indinavir. AIDS 15(10): 1275-1280, 2001
  5. Struble K et al. Bone fracture rates in HIV+ patients receiving PI vs non-PI containing regimens. 41st Interscience Conference on Antimicrobial and Antiviral Chemotherapy, Chicago, abstract I-1329, 2001
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