Bone problems and HIV: an interview with Steven Petak.

RITA:

Certainly for the past 10 years, almost since the beginning of widespread use of highly active antiretroviral therapy (HAART), we have known about changes in fat metabolism in the setting of HIV/AIDS that result in a cluster of symptoms commonly called lipodystrophy. What we have not heard as much about are HIV-related bone disturbances, but these are well-documented in the clinical literature. Are these bone problems also related to metabolic disturbances or irregularities?

SP:

We have not seen any direct evidence that these bone problems are related to the metabolic disturbances observed in HIV-positive people. However, HIV-positive patients with dyslipidemia, insulin resistance, and central adiposity appear to be more vulnerable to having decreased bone mineral density (BMD). In fact, these patients don't have to be very ill to experience bone problems--it isn't just patients with AIDS-related wasting. There are also some data suggesting that the hormone leptin, which is involved in regulating body weight and appetite, increases bone resorption (the process of losing bone). This hormone could provide a link between lipodystrophy and bone problems in HIV-positive people, but there is no direct evidence yet. To complicate matters, several studies have used a variety of different methodologies to assess BMD. For example, studies using quantitative computed tomography (QCT) report somewhat disparate findings from studies using dual X-ray absorptiometry (DXA) to measure BMD. CT is somewhat affected by marrow fat and this may complicate the findings further. This is a fascinating controversy, and much research is being done to figure out which method is the most accurate.

RITA:

In your opinion as a researcher and clinician, is there any direct relationship between these bone changes and the changes in fat metabolism?

SP:

At this point, it isn't clear whether there is a direct relationship. As mentioned earlier, one interesting area of research focuses on the hormone leptin. In addition, cytokines may be involved in inhibiting new bone formation and stimulating bone resorption, therefore resulting in decreased BMD. People with HIV have elevated levels of certain cytokines, such as tumor necrosis factor (TNF) and interleukin-1 (IL-1), and these elevated levels may be partly responsible. Because both healthy HIV-positive patients and patients with AIDS-related wasting have increased levels of cytokines, all HIV-positive patients are at risk.

RITA:

So are bone changes in HIV disease caused by HIV medications, HIV itself, both of these, or some other factors (eg, host factors or risk factors)?

SP:

The majority of studies indicate that these bone problems are not caused by HIV medications. While it is common to see a loss of BMD in patients when they initially start taking HIV medications, especially protease inhibitors, this loss is typically transient and stabilizes over time. Instead, researchers believe that HIV disease itself leads to an imbalance between bone formation and bone resorption, possibly via increased cytokine levels.

RITA:

What are the clinical manifestations or symptoms of these types of bone changes?

SP:

Decreased BMD as shown by DXA (or another methodology) is an obvious feature. Unfortunately, osteoporosis is typically asymptomatic until a patient experiences a bone fracture. Malnourished patients, such as those with a calcium and/or vitamin D deficiency, can experience osteomalacia. In this situation, the bone mass is present, but the bone tissue is soft. Patients with osteomalacia frequently experience bone aches. Fragility fractures are also a common symptom and can be a strong predictor of recurrent fractures.

RITA:

Are there any warning signs of these types of bone problems? If so, what are they? What should patients look for and when should they discuss any signs or symptoms with their doctor?

SP:

Warning signs include bone aches, fragility fractures, or bone fractures. In addition, patients with calcium and/or vitamin D deficiencies will have muscle weakness and balance problems. Any patient with signs of AIDS-related wasting should definitely be assessed for loss of BMD. However, even healthy HIV-positive patients are at risk for these bone problems, especially if they have a low body weight and a low body mass index (BMI). Patients having any of these symptoms or risk factors should discuss these issues immediately with their doctor.

RITA:

As an endocrinologist, how have you become involved or interested in the issues around HIV and bone disease? Are HIV-positive patients with these types of bone problems referred to you?

SP:

I am part of a specialty practice that focuses on general endocrine and nonsurgical reproductive system disorders affecting men and women. Approximately 60% of the patients in my practice have bone disease. In addition to seeing HIV-positive patients with bone disease, I also see patients whose bone disease is caused by other factors such as renal disease, steroid use, or unknown factors. Unfortunately, while the HIV-positive population is extremely vulnerable to bone disease, bone health status is often overlooked in clinical exams. As a result, these problems are not being addressed adequately. Since many of these patients are young, their fractures risks may be offset by their age in part--but there is much we don't know.

RITA:

What are the standard treatments or interventions for these types of bone problems?

SP:

First, patients must be assessed for a calcium and/or vitamin D deficiency and be treated with the appropriate supplements. Surprisingly, vitamin D insufficiency is common even in developed countries. In addition, patients can also be treated off-label with bisphosphonates like alendronate (Fosamax) if risk factors indicate that they have a high fracture risk.

RITA:

Are there any preventive measures an HIV-positive person can take to stop or delay the onset of these symptoms?

SP:

Good nutrition is imperative. As discussed earlier, deficiencies in calcium and/or vitamin D are well-documented risk factors. Maintaining a proper body weight is also important because being underweight is a risk factor. Patients have to control their HIV disease with available medications that suppress viral replication. In particular, minimizing irregularities in cytokine levels is important because there is strong evidence that cytokines affect bone resorption. Also, HIV-positive patients with hypogonadism are at increased risk for bone disease, and patients should be tested for this. In addition, I would recommend that any HIV comorbidities, such as liver or kidney disease, be treated or controlled as best as possible. There are also some data to suggest that smoking and alcohol use can increase a patient's risk for developing bone problems. Overall, I would recommend that HIV-positive patients do their best to stay as healthy as possible and focus on the conventional risk factors, in addition to controlling their disease.

RITA:

What are the hot areas of research now in this field? Is it applicable or specific to HIV?

SP:

Cytokines are a very interesting area of research. In addition, looking at new ways to measure or assess bone loss is another fertile area of research. These would include micro-magnetic resonance imaging (micro-MRI), micro-computed tomography (microCT), and ways to actually assess bone structure. Also, in 2007, the World Health Organization will be publishing an updated set of guidelines to assess fracture risk that will help identify at-risk populations in older men and women, but will not be directly applicable to secondary causes for low bone density such as HIV. Clearly, there is a need for further research.

RITA:

As an endocrinologist, what interested you in disorders related to HIV?

SP:

In the past, I would see these patients as part of a consultation and I realized that not a lot of information was known about this particular condition. I also believe that this condition is often overlooked in the HIV-positive population. Today, with the use of HIV medications, HIV-positive patients are living more normal lives. Unfortunately, these patients are getting other diseases now, including bone disease. We need to keep their bones healthy, especially those patients with risk factors.

Suggested resources:

* Amorosa V, Tebas P. Clin Infect Dis. 2006;42(1): 108-114.

* Brown TT, Ruppe MD, Kassner R, et al. J Clin Endocrinol Metab. 2004;89(3): 1200-1206.

* The Surgeon General Report on Bone Health and Osteoporosis at www.surgeongeneral.gov

* The International Society for Clinical Densitometry (ISCD) website for updates and guidelines on densitometry at www.iscd.org

* The American Association of Clinical Endocrinologists (AACE) website for AACE guidelines at www.aace.com

Steven Petak MD, JD, FACE, FCLM is an Associate at the Texas Institute for Reproductive Medicine and Endocrinology in Houston and President of the American Association of Clinical Endocrinologists.