February 9, 2004
Stephano Mora from Milan gave us a good introduction this afternoon to the problem of bone metabolism in HIV-infected children. As you know, osteopenia and osteoporosis are frequent among HIV-infected patients. It is still not clear if this problem is related to HIV infection itself, its treatment or both. It is easy to imagine that if this is a serious problem in adults with HIV, because there is a potential risk of increasing fractures in the future, it is even more serious in children with HIV. Children stay in a period of development before reaching their peak bone mass, something that happens at approximately 25 years of age.
Mora's summary was taped and can be heard in webcast. You may want to consider listening to the talk, since it was a nice introduction to the current issues in the field. (Click for audio and slides or video and slides.)
Dr. Mora started with an overall introduction to the topic. He defined osteoporosis as a problem of bone mineralization and architecture that predispose one to fractures. The World Health Organization (WHO) defines osteoporosis as based in bone mineral density (BMD) as measured by DEXA. The bone mineral density of a given individual is compared to the bone mineral density of an average 30-year-old. The result is expressed as the number of standard deviations from that measurement (the t score). A t score of less than -1 and greater than -2.5 defines osteopenia and a t score of less than -2.5 defines osteoporosis.
BMD can be measured using different techniques. The most popular of them is the already mentioned DEXA, but using plain XR, QCT scan or Q ultrasound are alternative ways to look at bone mineralization. Each technique has its advantages and disadvantages. There are normalized data for adults using these techniques, so it is easy to calculate t scores. However, it is much more difficult with children because there are no normalized data for children since they grow so rapidly. Children's bone mineral density cannot be expressed by comparison to the typical adult who at 30 years old has reached his or her peak bone mass. This markedly complicates any type of study in this population.
Although there are multiple predictors for a person's final bone mass, genetics is by far the most important factor and explains probably more than 75% of an individual's final bone mass. Other factors that are associated with low BMD include: chronic diseases such as celiac, renal, and now, HIV infection; hormones (testosterone, estrogen, growth hormone, thyroid, etc.); behavioral factors such as exercise, alcohol abuse and tobacco use; and, finally, the use of certain drugs such as diuretics, anticonvulsants and maybe antiretrovirals.
The most classic approach to discover what is happening to the bone is to perform bone biopsies. But the use of biopsies is complicated for the study of bone metabolism, especially in children. Nowadays, if we want to know the status of the bone, we tend to use markers of bone metabolism. The bone is a live tissue in a continuous status of remodelation, with a delicate equilibrium between bone formation (done by a particular group of cells in the bone called osteoblasts) and resorption (done by a different group of cells called osteoclasts).
Osteocalcin and bone alkaline phosphatase are used to measure the activity of osteoblasts, and pyridinolines and telopeptides are used for the measurement of bone destruction. HIV infection, in the absence of treatment, is characterized by a status of low bone turnover (especially in advanced disease). After the initiation of antiretroviral therapy, there is a switch to a state of high bone turnover that is maintained over time. This has been well characterized in adults over the last few years. Dr. Mora presented data suggesting that the same phenomenon is going on in children. He also presented data suggesting that the use of antiretroviral therapy is associated with an increase in RANK-L, a cytokine that increases the activity of osteoclasts, and a decrease in osteopetregin, a cytokine responsible for osteoblast activity.
In summary, deficits of bone mineralization are quite common in children with HIV, especially if they are on antiretroviral treatment, and this is an important issue that clinicians taking care of these patients will have to face.
What about treatment? In adults who have developed this problem, we recommend supplementation with vitamin D and calcium as well as lifestyle changes that tend to improve bone mineralization (such as regular exercise and discontinuing tobacco and alcohol use).
If the osteoporosis is severe enough to warrant treatment, then alendronate is a potential option. During last year's Retrovirus conference, my colleagues and I presented data on the use of alendronate in patients with HIV infection.1 During this meeting, Guraladi (Poster 742) presented some preliminary data with similar (but less dramatic results). The ACTG is currently performing a larger study called A5163 that will also evaluate the utility of this drug, focusing especially on women.
Unfortunately, the use of alendronate in children cannot be recommended because it might increase the fragility of bone. So, for the treatment of children with deficits in bone mineralization, we are left with "classic measures" such as adequate intake of calcium and vitamin D and adequate exercise and sun exposure (to increase the synthesis of endogenous vitamin D).
Abstract: Disorders of Bone Mass and Bone Metabolism (Symposium 47)
Authored by: S. Mora, I. Zamproni, M. Sciannamblo, V. Giacomet, A. Viganò
Affiliations: Sci. Inst. H. S. Raffaele, Milan, Italy; Univ. of Milan, Hosp. L. Sacco, Italy