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Bone Disease and HIV/AIDS: More Common Than You Think -- This Month in HIV
An Interview With Todd Brown, M.D., Ph.D., and Ben Young, M.D., Ph.D.

By Bonnie Goldman

January 2010

Dr. Todd Brown
Dr. Ben Young

Introduction

Hello and welcome to This Month in HIV. My name is Bonnie Goldman.

With the remarkable success of HIV treatment comes a renewed focus on other health issues that plague people with HIV. You've probably heard a lot about heart disease and HIV and certainly lipodystrophy and HIV, but bone disease may affect up to 50 percent of HIV-positive people and it is little talked about.

With me to explore this issue is Todd Brown, M.D., Ph.D. Dr. Brown is an endocrinologist and an assistant professor of medicine at Johns Hopkins School of Medicine. He's also one of the top researchers when it comes to bone disease in HIV-positive peoples and has been researching this issue since 2004.

Also with me is one of TheBody.com's online experts, Ben Young, M.D., Ph.D. Dr. Young is an assistant clinical professor of medicine at the University of Colorado. He is also a consultant physician at Denver Infectious Disease Consultants, and as such he'll be able to speak to what he's seeing in what is one of Denver's largest private practices.

"I think the biggest issues now are how to best screen, diagnose and optimally manage people who may have bone disease and HIV."

-- Ben Young, M.D., Ph.D.

Bonnie Goldman: Welcome, Dr. Young and Dr. Brown to This Month in HIV. I want to start with you, Dr. Young. What is the biggest issue you're seeing in your practice today?

Ben Young: Our patients are living much longer, and are much healthier than they were in the earlier pre-HAART [highly active antiretroviral therapy] and early HAART eras. This means that they are now beginning to worry about long-term survival and issues related to aging -- all of which are good things.

In the midst of all of this, though, about four or five years ago, we started seeing one or two patients a year with unexplained fractures. Compression fractures of the vertebrae were the sentinel symptoms of this problem.

At first, we thought that they were just outliers, unusual people with unusual problems, and not part of a larger trend. It was Dr. Brown's analysis in 20061 that brought the magnitude and the frequency of this problem to a head.

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The biggest issues now are how to best screen, diagnose and optimally manage people who may have bone disease and HIV. I think this is going to be a very important topic, particularly as our patients age into the next decade of their lives, and so on.

Bonnie Goldman: What percentage of patients in your practice have bone disease?

Ben Young: We'll probably touch on this later, but it was really because of Dr. Brown's meta-analysis that we became concerned about silent bone disease in our practice. That is to say, thinning of the bones and brittle bones -- osteopenia and osteoporosis, respectively. What we detect in patients are fractures.

Obviously, from a preventive medicine standpoint, we like to identify patients who are at risk of having very serious fractures, or fracture risk, before they fracture. So we embarked on a program to try to do just this, namely doing dual energy X-ray absorptiometry, or DXA scanning.

"I've screened about 80 percent of the patients in our practice. ... Over 50 percent of our patients have one form or another of abnormally thin bones. This is a really striking number, much greater than many, many of the other complications that we worry about."

-- Ben Young, M.D., Ph.D.

I've screened about 80 percent of the patients in our practice. What we find is entirely sanguine with Dr. Brown's earlier analysis, which is: Over 50 percent of our patients have one form or another of abnormally thin bones. This is a really striking number, much greater than many, many of the other complications that we worry about.

Bonnie Goldman: When you say "silent," what do you mean? Do you mean no one is experiencing any symptoms?

Ben Young: This is similar to hardening of the arteries, which doesn't cause symptoms until something bad happens. A patient who has osteopenia, for example, should have no symptoms whatsoever. A patient who has osteoporosis frequently doesn't have fractures, right up until the point that he or she fractures a hip or a vertebral body. The real problem is recognizing risk and trying to improve bone health before this fracture.


Figuring Out Bone Disease Prevalence in the HIV-Positive Population

Bonnie Goldman: Dr. Brown, what made you initiate your investigations into bone disease in the HIV-positive population?

Todd Brown: There had been scattered reports of low bone density among HIV-positive patients. There's some question regarding whether or not it was related to HIV itself, or antiretroviral therapy.

When I was in training at Georgetown University, we had conducted a study2 but it wasn't large enough to be able to draw firm conclusions about the most severe losses in bone mineral density.

"We did find about a 15 percent prevalence of osteoporosis -- the average age was probably the low 40s -- across the various studies that we looked at. Compared to the respective HIV-negative control population, this was about three and a half times the prevalence that was seen in those populations."

-- Todd Brown, M.D., Ph.D.

That's why the meta-analysis was an effective way to do this. We could look at osteoporosis, rather than a combined category of osteopenia, which is a lower than normal bone mineral density, and osteoporosis.

We did find about a 15 percent prevalence of osteoporosis -- the average age was probably the low 40s -- across the various studies that we looked at.

Compared to the respective HIV-negative control population, this was about three and a half times the prevalence that was seen in that population.


Defining Low Bone Mineral Density

Bonnie Goldman: Could you explain what osteopenia and osteoporosis are?

Todd Brown: Bone density is probably the best way, or the most available way, of measuring and evaluating fracture risk using DXA, or dual X-ray energy absorptiometry. Osteoporosis and osteopenia are really designations, or classifications, based on [the bone density of] postmenopausal women. A lot of this research has been done in postmenopausal women just for the simple fact that this is where the burden of fractures lies.

When you look at bone density tests, DXA scans, the measure that most people use is something called the "T-score." This is the number of standard deviations that a person's bone mineral density is away from that of a gender-matched, young, normal population.

If your T-score is more than two-and-a-half standard deviations lower than that of a young, normal population, then you have osteoporosis. You have osteopenia if your T-score is between one standard deviation and 2.5 standard deviations less than that of the young, normal population.

Bonnie Goldman: When you say bone mineral density, are you simply referring to the thickness of someone's bones?

Todd Brown: That's right: the amount of mineral that's in your bones. This designation, as I mentioned, has mostly been validated in postmenopausal women, but has been applied to other populations, as well.

Bonnie Goldman: Postmenopausal women are the most likely to lose bone because of the hormonal changes that occur after they stop menstruating, is that right?

Todd Brown: That's right.

Bonnie Goldman: So, it's really not common in the general population.

Todd Brown: There's not a lot of good, standard data to understand what the bone mineral density is in the average person.

Bonnie Goldman: Dr. Young, is it a challenge to explain bone disease to patients?

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Ben Young: Actually, I think that people get it. Osteoporosis is common enough in the general population that people have heard about it.

My mother, for example, had osteoporosis. That's a precise term: a brittle bone. Often we'll use the terminology of abnormal, but not diseased, bones -- much analogous to HIV without AIDS, for example. It's not particularly complicated for people to understand.

Sometimes the T-score/Z-score standard deviation language can confuse people. But it just indicates how far away from the expected bone density you are. Once you're two-and-a-half standard deviations below that, then we define that as having osteoporosis.

What people should realize is that these scores, the standard deviations, are a continuous variable, in a way, so that the risk of fractures is continuous. It's a function of both the strength of the bones, if you will, and the likelihood that one is going to fall -- a larger component that also influences the risk of having a fracture.

In general, people do understand this. Explaining to them why I'm concerned about assessing them for bone health is not as complicated as some of the other things that we do in HIV medicine.

Causes of Low Bone Density or Osteoporosis in HIV-Positive People

Bonnie Goldman: I was reviewing the causes of bone problems in people with HIV. I found a long, long, long list of people who were at risk for bone disease. It included: long-term survivors; people who are thin; women; people who took protease inhibitors; people who are taking Viread [tenofovir] (the drug that's in Truvada [tenofovir/FTC] and Atripla [efavirenz/tenofovir/FTC]); people who have low testosterone; people who have no subcutaneous fat; people who have kidney disease; people who smoke; people who drink alcohol; diabetics; older people; smokers. I mean, it kind of included everybody.

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Dr. Brown, what do we know now? Who is at risk?

Todd Brown: When thinking about the causes of low bone density or osteoporosis in HIV-positive patients, it's useful to separate things into three categories.

It's an amalgam, or a combination, of these factors, which lead to the decreases in bone density that we see.

Bonnie Goldman: What about the long list of categories of people that I detailed? If you're a drinker who also smokes, does that put you at greater risk?

Todd Brown: Absolutely. Both of those are risk factors for osteoporosis in the general population, and may be more common in some HIV populations, as well. Those are people who you may be more concerned about, in terms of screening recommendations, for example.

As for some of the other people that you listed: People who are thinner tend to have lower bone density; males who have not enough testosterone will also have lower bone density.

The kidney disease issue is complicated, because the low bone density that you measure by DXA in someone with kidney disease may not represent osteoporosis. There are other reasons why patients with kidney disease may have low bone density.

Bonnie Goldman: What about the theory that Viread might be causing some bone density issues?

"It's pretty clear from a whole bunch of studies that bone density drops in the first two years of antiretroviral therapy, but those drops are larger if you're on certain medications . . . and Viread is one of them."

-- Todd Brown, M.D., Ph.D.

Todd Brown: There is pretty good evidence that Viread is associated with lower bone density. I should say that a lot of the best studies come from people who are HIV positive who have never seen antiretroviral therapy before they start treatment; these studies look at what happens to their bone mineral density when they start treatment.

It's pretty clear from a whole bunch of these studies that bone density drops in the first two years of antiretroviral therapy, but those drops are larger if you're on certain medications, and Viread is one of them.

Why that is is not entirely clear at this point. It might be due to some of the effects that Viread has on the kidney.

Your bones are made up mostly of collagen, which is sort of the glue that holds them together. They are also made up of the minerals phosphate and calcium.

Part of the problem with Viread might be that your body loses phosphate, and the place where the body goes to get the phosphate back is the bones. That may thin the bones in that way. But there's a lot of research that needs to be done to really understand what's going on.

Bonnie Goldman: What about protease inhibitors? There was some thought that it might have been protease inhibitors causing some of the bone density issues.

Todd Brown: If you look at studies where people start antiretroviral therapy, some have shown that patients who start antiretrovirals with certain protease inhibitors have a more profound decrease in bone density.

Most likely, there are differences among the protease inhibitors regarding their effect on bone density. It's something that really needs to be looked at in more detail.

A Note About Low Bone Density in People With HIV

HIV-positive people who are found to have low bone density by a DXA scan should have other causes investigated. These are conditions that are associated with low bone density and are often called "secondary causes" of low bone density. They each have specific treatments which will also help to build back bone.

If you are told you have low bone density, Dr. Brown advises that you be sure to have your health care provider investigate if you have the following conditions:

  • Hyperparathyroidism
  • Hyperthyroidism
  • Hypogonadism
  • Vitamin D deficiency
  • Phosphate Wasting

Screening for Bone Disease

Bonnie Goldman: Let's go back to the basics about bone health. Dr. Young, you said that you're looking at all the patients in your practice. How can someone find out if he or she has healthy bones? You mentioned DXA scans. Are there any symptoms that someone might have? Is there something else that would tell someone that he or she might have bone disease?

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Ben Young: The key part here is that for the most part, bones don't cause symptoms until they fracture. Probably, the most important thing to stress to patients is that you largely don't have symptoms, and could have bone disease.

In fact, there's a lot of interest in trying to determine which specific risk factors may place one person or another at greater risk of having bone disease. Obviously, there's a lot of research interest in trying to sort out the specific mechanisms of this.

The large surveys suggest that this is a common enough problem that in a way I don't really care what's the specific matrix of risk factors that puts one individual at risk or not; it's common enough in our practice that we see this with quite a bit of frequency.

Indeed, it was with a collaboration with Dr. Brown in a CDC-sponsored study called SUN that we really first became aware of the specific problems in our patients.3 Namely, in our practice, about 50 percent of our patients have bone disease. About 10 percent have osteoporosis. Virtually all of these patients were living their lives just fine before we did the specific testing to look for it.

What You Can Do to Improve Your Bone Health

  • Ask your health care provider to give you a baseline DXA scan.
  • Next time you get your blood count, ask them to check your vitamin D levels.
  • Try to exercise (particularly with weights) at least three times a week for 20 minutes each time. This will not only keep your heart healthy, but will help build and maintain your bones.
  • Stop smoking and you'll help not only your heart and lungs, but your bones.
  • Avoid drinking an excessive amount of alcohol. Excessive drinking can cause bone loss.
  • Be sure to eat a balanced diet rich in calcium and vitamin D. Browse this for foods that may help.
  • Talk to your health care provider about adding vitamin D and calcium supplements to your daily regimen.

So, to your point: There are methodologies to measure the calcium content and the density of the bones. The best and most quantitative way to do that is with these DXA scans.

In fact, that's what we are now embarking on doing for all the patients in our practice. As we expand the number of patients we have screened, from the initial 100 that were in the clinical study to in the neighborhood of 400 or 500 individuals, the numbers remain just that: About 50 percent of our patients have abnormal bone mineral density. And it's quite a bit of a concern.

The problem is that one really needs to do that test to have the best measure of it. There are probably some alternative strategies that are worth mentioning.

For one, many people do get X-rays, for one reason or another. The information in those X-rays can often reveal abnormally low bone mineral density. But one has to be mindful to ask the radiologist. We have occasionally picked up abnormal bone density on chest X-rays that were done not looking for bone density, but rather for pneumonia.

A fracture that is unexplained from a not-so-traumatic event should not just be written off as just an unfortunate fall, or a weird step off the curb that broke your ankle. One should ask the question: Is that a patient who might actually have abnormal bone density?

Bonnie Goldman: Are DXA scans generally covered by insurance and Medicaid?

Ben Young: To my surprise, they are actually covered by most insurance companies. I should add that patients who have other significant risk factors (for example, patients who have been on long-term corticosteroid therapies, patients who have abnormally low testosterone levels or patients who have had abnormal fractures in the past) have access to DXA scans, both by insurance companies and by Medicaid.

The Medicaid question and HIV is a problematic one, because it's not well covered, if at all. Medicaid is variable. It depends a little bit on state funding and such, but it is usually not covered. There are people trying to improve that. But if one has third party insurance, it's pretty easy to get a DXA scan. The doctor just needs to know what to ask for.


Debate: DXA Scans for Everyone With HIV?

Bonnie Goldman: Would you say that everyone with HIV should get a baseline DXA?

Ben Young: This will be controversial, but in our practice, that's our standard. There are no U.S.-based guidelines for this.

"From a knowledge gained and a preventive medicine perspective, the information I get from doing $100 test to look at bone health, is probably more valuable than doing a fourth or fifth viral load test in a patient who is otherwise doing well."

-- Ben Young, M.D., Ph.D.

I summarize it this way: One out of every two patients in my practice probably has abnormal bone density. The cost of doing a scan is roughly $100. It's about half the price of doing a viral load test. From a knowledge gained and a preventive medicine perspective, the information I get from doing a $100 test to look at bone health is probably more valuable than doing a fourth or fifth viral load test in a patient who is otherwise doing well.

Todd Brown: I differ a little bit here. I think that a bone density test is a decent way to assess fracture risk. But the problem that you get into is that people who are younger than 50 really don't fracture all that often. If we were talking about universal screening of HIV-infected patients, I would suggest screening people over the age of 50.

Even if someone has low bone density by DXA and may be at increased risk of having a fracture compared to someone of a similar age who has normal bone density, the chances that he or she is going to have a fracture are just so low, because young people generally don't have fragility fractures.

Ben Young: This is something that is a nice point of debate, Todd. I'll differ with you again a little bit, to make just a couple of points.

Number one is that the largest study regarding this comes from the Massachusetts Study Group, comparing HIV negatives to HIV positives, in which the fracture rate for sub-40-year-olds who are HIV positive approximates that of an HIV-negative 50-year-old. You were an author on this, I believe.4 That analysis suggests that the fracture frequency of HIV positives who are young approximates the fracture frequency for HIV negatives aged greater than 50.

Moreover, to me, the biggest concern is that young people are still in a period where they can improve their bone health with improvements in modifiable risk factors, including calcium supplementation and normalizing vitamin D levels and such.

So there's an opportunity -- if we identify those people earlier. I'd hate to miss the opportunity to improve their bone health before they reach their bone density maximum at age 40 or so.

From a cost benefit analysis, while I think the fracture absolute frequency is, yes, relatively low, there's still an opportunity to intervene with a preventive medicine strategy.

Todd Brown: The counterargument to that is that a lot of the strategies that can be taken to improve bone health should be undertaken in everyone. This means maintaining adequate vitamin D intake and adequate calcium intake, refraining from smoking, refraining from excessive alcohol use; all those things you want to be doing in everyone.

The concern that I have in screening people who are at low fracture risk is that they might be inappropriately put on medications that have long-term side effects for their bones, and they may not actually benefit from them.

Supplementation With Vitamin D and Calcium

Bonnie Goldman: Let's turn to supplementation, since you both mentioned it just now. What is the role for vitamins? Which vitamins would you recommend? Dr. Brown, I know you have done some studies on vitamin D, and the importance of vitamin D.

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Todd Brown: Vitamin D deficiency is very common in the general population, and in HIV-positive patients, as well. It's associated with all kinds of medical problems. Bone density and fractures is one of them.

The current recommendations are that everyone should be getting at least 800 international units of vitamin D daily. That's probably not enough, given the high prevalence of vitamin D deficiency. There is some work being done in the general population to change those guidelines. I think 1,000 or 1,500 international units would be more appropriate to get to adequate vitamin D levels.

Bonnie Goldman: Some people take prescription vitamin D weekly, or monthly. Is there a difference between taking it daily or weekly or monthly? Or taking prescription versus non-prescription vitamin D?

Todd Brown: Not really. They are different formulations of a similar compound: vitamin D. You could either get it by prescription (something called ergocalciferol) or over-the-counter (generally something called cholecalciferol). Either of them can be used.

The problem with big dose supplementation of vitamin D is that there is a risk of overdoing it, and becoming toxic on vitamin D. So if you are giving yourself large doses of vitamin D -- more than about 2,000 international units a day -- you probably want to talk to your doctor or provider about that.

"The problem with big dose supplementation of vitamin D is that there is a risk of overdoing it, and becoming toxic on vitamin D."

-- Todd Brown, M.D., Ph.D.

Bonnie Goldman: What are the risks?

Todd Brown: If you have very high levels of vitamin D, you can get too much calcium absorption. We should back up a little bit to say what vitamin D does.

Vitamin D's main job is to allow calcium and phosphate to be brought in from the gut. If you have too much vitamin D on board, your calcium levels can go too high. That's the real problem.

Bonnie Goldman: Do you recommend most people take calcium pills with their vitamin D?

Todd Brown: Most people do require calcium. The current recommendation is to take between 1,000 and 1,200 milligrams of calcium. Depending on people's diets, they may get close to that; if they are a big milk drinker, they could be able to get that in their diet alone. But most people need somewhere between 600 and 1,000 milligrams of calcium supplementation a day.

Bonnie Goldman: Is there any way to monitor your vitamin D levels and your calcium levels?

Todd Brown: There is a relatively easy blood test to measure vitamin D called the 25-hydroxy vitamin D level. It's a test that can easily be done. This is what really tells you whether or not someone has an adequate amount of vitamin D.

Bonnie Goldman: I was looking at different recommendations, and some said vitamin D levels should be over 30, and some said over 25 was enough. Which one is it?

Todd Brown: There's a lot of controversy as to what constitutes adequate vitamin D. Right now, above 30 is considered vitamin D sufficient. Between 20 and 30 is considered insufficiency, and less than 20 is considered deficiency.

Some people bring the lower number down, saying that there's a severe deficiency state of less than 10. Some people think -- from looking at big studies in large populations -- that the optimal level of vitamin D is somewhere around 40 to 50. But generally, people whose levels are less than 30 probably should get their vitamin D levels up.

Bonnie Goldman: What would be the best way to do that?

Todd Brown: With vitamin D replacement, as you had mentioned, either by prescription or by over-the-counter vitamin D.

Bonnie Goldman: I understand that that doesn't work for everybody. There was a small study where it worked for only 49 percent of the participants. Although, of course, we don't know if they were taking it; we don't know a lot of things.

"If you take vitamin D, generally, you'll be able to see a response. Some people are more resistant to supplementation, meaning they need more vitamin D to get their vitamin D levels up. Some antiretroviral medications may chew up vitamin D. Efavirenz [Sustiva or Stocrin, which is one of the drugs in Atripla], ... has been associated with lower vitamin D levels."

-- Todd Brown, M.D., Ph.D.

Todd Brown: The biggest issue is compliance. I think there was a study -- and this may be the one that you're speaking about -- that was presented at the retrovirus meeting last year, where they looked at various doses of vitamin D, and how much they change your vitamin D level. The main issue that I saw with that study is that the compliance was not very good.

So, if you take vitamin D, generally, you'll be able to see a response. Some people are more resistant to supplementation, meaning they need more vitamin D to get their vitamin D levels up. Some antiretroviral medications may chew up vitamin D.

Efavirenz [Sustiva or Stocrin, which is one of the drugs in Atripla], in a study that we were working on, has been associated with lower vitamin D levels. Why that is, isn't entirely clear. But people on efavirenz may need more vitamin D.

Bonnie Goldman: Does this mean that people taking efavirenz or Atripla should be taking a greater supplementation of vitamin D, above the recommendation?

Todd Brown: We don't know that exactly, now. But it looks like people who are on those medications are more likely to be vitamin D deficient. So, extending that, they may need more vitamin D to reach the same vitamin D level as someone who is not on those drugs.

Ben Young: We have been talking about vitamin D, but I'd like to get your thoughts as to whether checking a vitamin D level should be something that should be part of baseline, or annual, laboratory assessment for people living with HIV.

Todd Brown: Probably. The real problem with the vitamin D question is that we know that a lot of people are deficient, even in the general population. What we don't have a great sense of is whether or not replacing vitamin D can really improve your health. We think that that's true. I think that that's true. But we don't know that for sure. I think that's why people are reluctant to recommend universal testing of vitamin D levels.

Personally, I have a very low threshold for testing vitamin D levels in my patients. It's relatively inexpensive. You get information that you can't get from other sources and the treatment, although we did mention the potential problems of vitamin D replacement, it's relatively well tolerated and relatively inexpensive. I think that for those reasons, the threshold to test vitamin D levels in patients should be pretty low.

Bonnie Goldman: Isn't it true that certain people are at greater risk for low vitamin D, such as people who live in the North and people with dark skin?

Todd Brown: That's absolutely true. There's a big seasonal variation with vitamin D. Vitamin D levels go down by about 10 points in the winter, compared to the summer.

There's a big variation depending on the color of your skin. Patients with darker skin will invariably have lower vitamin D -- again, about 10 to 15 points lower than patients who have lighter skin. Those are very important factors, as well.

Bonnie Goldman: I guess one easy way to increase your vitamin D levels, besides supplementation, is to just find 15 minutes a day to be in the sun.

Todd Brown: That is a good one. We probably do not spend enough time in the sun and when we do, oftentimes, especially in the summer, we put sunscreen on. We're trying to protect our skin, but it is important [to get some sun exposure]. And winter sun, up in the North, may not be enough to really increase your body's ability to make the vitamin D.

Bonnie Goldman: Let's just remind people what's the bad thing about having low vitamin D.

Todd Brown: The biggest issue, and that's why we're talking today, is the effect on your bone health. If vitamin D levels are low, your body won't be able to absorb the building blocks of bone -- that is, calcium and phosphate. And your body doesn't like this very much.

"Patients with low vitamin D levels -- and this is particularly older patients -- are more likely to fall than those who have normal vitamin D levels. That's probably due to vitamin D that's working on the muscle."

-- Todd Brown, M.D., Ph.D.

If it doesn't have enough calcium and phosphate, your body goes to the bones to try to maintain the calcium and phosphate levels, because the bones are the biggest store of calcium and phosphate that we have. As a result, the calcium and phosphate get leached out of the bones, and the bone density decreases. That's the biggest concern.

There are some other issues that are related to vitamin D. Patients with low vitamin D levels -- and this is particularly older patients -- are more likely to fall than those who have normal vitamin D levels. That's probably due to vitamin D that's working on the muscle.

Bonnie Goldman: Is that a balance problem then?

Todd Brown: It's probably a muscular strength problem, rather than balance. We know from many studies -- this is outside of the HIV realm -- that supplementation with vitamin D can decrease the risk of falling.

Bonnie Goldman: I understand there are also heart disease risks in people with low vitamin D levels.

Todd Brown: There have been a lot of studies that have shown that the risk of cardiovascular disease is higher in people who have low vitamin D.

The risk of diabetes is higher with people who have low vitamin D levels. The risk of some infections is higher in people with low vitamin D levels.

So there is a whole host of bad outcomes that have been associated with low vitamin D levels. What's missing -- with the exception of bone health and falls -- are good studies to say that, if you replace vitamin D, you're going to decrease those outcomes.

We've been fooled in the past by trying to use information gathered by the observational studies to make recommendations about treatment. Hormone replacement therapy is a common example.

Bonnie Goldman: So, we should wait before ...

Todd Brown: Specifically, in that population. For example, there's not any great evidence that someone who has a heart attack should be tested for vitamin D.

Having said that, the risks of treatment with vitamin D are relatively low, and it's relatively inexpensive. So I think the threshold to treat is somewhat lower.

Bonnie Goldman: What's the role of exercise, and weight-bearing exercise? Does that help build bones?

Todd Brown: Absolutely. Your muscles pulling on the bone will cause bone to grow. Anytime you exercise your muscles and your muscles pull on the bone, it's going to be good for the bone. Weight-bearing exercise -- weight training or even just walking or jogging, or any time your muscles flex against the bone -- would be helpful.

Bonnie Goldman: Would walking around with a five-pound weight be a nice first step?

Todd Brown: I think any level of activity would be nice; maintaining your level of activity is really important. What you don't want to do is be sedentary. It doesn't necessarily need to be something that you would consider exercise. For example, there have been some studies showing that gardening, an activity that's relatively physical, is actually quite good for the bones. It doesn't necessarily need to be dedicated exercise.

Bonnie Goldman: How often should this be done during one week?

Todd Brown: Probably three or four times a week for at least a half hour.

Bonnie Goldman: Does exercise help build bone by a certain amount? Is there some measurable effect?

Todd Brown: There is. It depends on what exercise you're talking about. You get this information (i.e., trying to see what the effect is) by looking at studies. Oftentimes, the studies really aren't long enough to see a big effect, or the types of exercises are quite different. I wouldn't be able to put a number on exactly how much bone you can build. But there's no question that maintaining your level of physical activity is a really important part of bone health.

Shining a Brighter Light on the Problem of Bone Disease in HIV-Positive People

Bonnie Goldman: Why do you think so little attention is being paid to the issue of bone disease in HIV-positive people? Dr. Young?

Ben Young: The short answer is: I don't know. I think that there has been a compelling amount of evidence, starting maybe even in 1999/2000, that certainly the bone mineral density issue was very common in our patients.

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I think there are two points. Number one is that the fracture frequencies to date have been low and, in part, owing to the relative younger age of our patients.

It takes a large patient population to see sufficient numbers of fractures to begin to connect the dots, in terms of fracture risk. I think that there's a disconnect between the recognition of a common, let's say, laboratory abnormality and the potentially very serious clinical event, meaning fractures.

"A lot of the continuing medical education that we receive is often sponsored by pharmaceutical companies. And pharmaceutical companies have largely not connected their bone health franchises with their HIV franchises."

-- Ben Young, M.D., Ph.D.

Even in our clinic, where we had these fractures, it took us a number of years to begin to realize there was some connection between the fractures and the abnormal bone mineral density.

The second one is a little more challenging, I think. It speaks to the idea that, for better or worse, a lot of the continuing medical education that we receive is often sponsored by pharmaceutical companies. And pharmaceutical companies have largely not connected their bone health franchises with their HIV franchises.

That's not to say that everything in the world was driven by pharma, but it is a large component of the drum beating, so to speak.

So that we've heard a lot about heart disease that was amplified by medical education sponsored by pharmaceutical companies. I think that bone disease in the HIV-positive population has fallen between the cracks.

However, there is a palpable increase in the number of scientific articles and posters at conferences and such related to bone health. I think that people's awareness of it is starting to very significantly increase, and I'm grateful for that.

Todd Brown: I agree. I think that more and more attention has been paid, and as the understanding gets better, more people will become interested.

"HIV-infected patients may be at higher risk for falling, for reasons that aren't related to bone density at all. For example, peripheral neuropathy is a big risk factor for falling and we know that HIV-infected populations have a high risk of peripheral neuropathy."

-- Todd Brown, M.D., Ph.D.

The other issue that we haven't really talked about -- I think Ben might have mentioned it earlier -- is the non-skeletal risk factors for fracture.

Most fractures occur when people fall. HIV-infected patients may be at higher risk for falling, for reasons that aren't related to bone density at all. For example, peripheral neuropathy is a big risk factor for falling and we know that HIV-infected populations have a high risk of peripheral neuropathy.

So I think that those issues also need to be addressed, and also need to come out in consultations with patients who are concerned about bone health.

There are some practical things that people can do to decrease their risk of falling: for example, wearing certain shoes; making environmental changes, such as picking up piles of paper, making sure that there are no rugs that slip; really watching themselves while walking on slippery surfaces. All these things are also very important in preventing fractures.

Bonnie Goldman: Dr. Brown, can you explain why peripheral neuropathy would make someone more likely to fall?

Todd Brown: You rely on your feet. When we walk around, we don't really realize what we're doing, but we have a sense of where our feet are in space. So we can walk down the street, and we can talk to people while we're walking down the street, and we will automatically bring our foot up to go over the curb. But it's because we have a sense of where our feet are in space.

People with peripheral neuropathy may not have that sense as well, and so they might be more likely to stumble and fall as a result.

Bonnie Goldman: So that, compounded with low bone density, would cause the fracture?

Todd Brown: Absolutely.

Bonnie Goldman: The European HIV guidelines just came out, and they have a whole section about bone disease diagnosis, prevention and management. [Click here to view.] Yet there are no such recommendations in the U.S. guidelines. Are you hoping that the U.S. guidelines will include something like that in the future?

Ben Young: Yes. I actually went to the European AIDS Clinical Society meetings in Cologne, Germany, where they did, indeed, present what I believe to be the first management guidelines for bone health, prevention and such, in HIV patients.

They speak specifically about issues relating to the screening for bone disease, vitamin D and calcium supplementation, and so on. I think that these are a very welcome advance, and provide good guidance for clinicians as to how to take care of people for their long-term health.

I'll point out as well that the Europeans were, I think, quite prescient, including guidelines for managing other health issues in their compendium, such as diabetes and lipid problems [click to view], cardiovascular disease [click to view] and cancer [click to view].

People can go to the European AIDS Clinical Society Web site and look at these guidelines.

Todd Brown: I haven't seen the published version, or the presented version, of the guidelines, but I did see an earlier draft. One important thing to realize is that, even in the general population, European recommendations for screening for osteoporosis are different than the U.S. guidelines. I think it's important to keep this in mind when you're trying to apply the European guidelines to U.S. populations.

Ben Young: Good point, Todd. Actually, I'd love to hear your thoughts. The principal screening tool that they recommend is the use of the FRAX equation, which is available through online calculators, and is adjusted for both race and country. I want to get your thoughts as to whether that's a reasonable tool for us to be using, absent DXA scans.

Bonnie Goldman: Just a note: FRAX is a fracture risk assessment tool.

Todd Brown: This is a way of trying to figure out for a given person what is his or her risk of having a fracture in the next 10 years.

This gets at this idea that I mentioned before between your risk in relation to someone your own age versus your absolute risk of having a fracture.

You plug risk factors into this Web-based algorithm [click here to view]. Anyone can do it themselves. If you Google "FRAX" and log on to the site in Sheffield, England, you can plug in risk factors. At the end, you press a button and you get the 10-year risk of fracture. It's broken down in two ways: either all osteoporotic fracture or hip fracture, specifically.

You can look to see what your risk of fracture is. You could either use it in conjunction with a bone density test (that's how FRAX is used in the U.S.) or use it without a bone density test to determine who should get a screening DXA scan -- you use just your body weight and height as a surrogate.

There are differences in how people in the U.S. and how people in Europe use this tool. The concern that I have is that most of the data that FRAX is built on -- and a lot of work went into trying to figure out the factors that are associated with fractures, and the various populations -- but most of the data is in people older than 50. I have some reservations about using those data in making clinical decisions, because the reference database from which FRAX calculates the fracture risk really wasn't very robust at low ages. That's my general concern with using FRAX.

Bonnie Goldman: How do we get health care providers to add the prevention and management of bone disease to the long list of things they are already doing as part of primary care in people with HIV?

Todd Brown: I personally would take an age-stratified approach. For older HIV-infected patients -- and I use 50 as a cut point -- I think that there should be an emphasis on obtaining a baseline bone density test, in addition to talking about other issues related to bone health -- calcium intake, vitamin D intake, activity level, smoking cessation, making sure that the alcohol intake is not excessive.

These latter factors, not the bone density issues, would also be a discussion that could be had with younger patients. But other people have different strategies, in terms of screening.

Ben Young: I agree with all of the points, except for -- and again, I accept the uncertainty regarding -- the age threshold at which you deploy screening methodology. The prevalence of abnormal bone mineral density in the HIV population is greater than it is in the general population and there is at least some data that suggest that it's also prevalent in younger individuals.

I certainly caution people from drawing too many conclusions from individual anecdotes -- but through these earlier studies, we identified people who were under age 25, who had no obvious risk factors, who had osteoporosis.

Thinking prospectively -- from this perspective of how much harm is done by trying to screen and address secondary or reversible causes versus the harm done by ignoring the potential risk in having fractures -- I will err, at the moment, on the side of more aggressive screening and prevention. But I accept that the data set and the national guidelines to date don't address the risk/benefit equation for men with bone disease and people of either gender who have HIV and bone risk.

There are a lot of unknowns and a lot that needs improvement, but at least for the moment, this clinician's view is to try to address the concerns with as many patients as possible and, if appropriate and relevant, DXA scan the patients.

Todd Brown: Just to follow up on one idea, which hasn't come out: We all reach our peak bone mass at around age 30 and bone density declines thereafter. Your bone density at, say, age 55 or 65 in part depends on whether or not you've reached your peak bone mass.

For people who are younger than age 30, it's a really crucial time to build bone. There's concern, as well as some studies, showing that there may be a failure in HIV-infected children and adolescents to get up to that peak bone mass.

I think that the approaches, in terms of calcium and vitamin D, are really important. There are some concerns about using DXA in this population. It can be difficult to interpret clinically. So that's one of the big drawbacks.

Bonnie Goldman: Dr. Brown, is there any ongoing or future research regarding bone disease in HIV-positive people that you're particularly excited about?

Todd Brown: There are a couple of areas of research that are important -- the first is really trying to nail down the actual risk of fractures.

At this year's retrovirus meeting there are going to be some studies that will look at this in more detail, and I know Ben is part of one of them. I think that it is crucial to try to understand what the risk of fracture is. We can talk about bone density and DXA scans, but what we really care about at the end of the day is whether people are breaking bones, and what the risk factors are for breaking bones.

The next thing is looking at some of the mechanisms of why HIV-infected patients may be more likely to have lower bone density and have an increased fracture risk.

I had mentioned that there is a drop in bone mineral density in the first two years of antiretroviral therapy. Why that is, really, is not clear. Generally, inflammation is considered to be bad for the bone. With antiretroviral therapy, markers of inflammation invariably go down. So why would you get a decrease in bone density? And this has been seen consistently in many, many studies. I think that that's a very interesting thing to look at.

Of course, the goal here would be to try to prevent this drop in bone density. To see if there are various agents that may be less associated with this drop in bone mineral density is another important goal.

Also, can we do things to mitigate, or decrease, this loss? For example, if we supplement people with calcium and vitamin D, can we decrease the amount of bone that's lost in the first two years of antiretroviral therapy?

Then, I think that trying to understand bone disease for aging HIV-infected patients is crucial. I had talked briefly about non-skeletal risk factors -- so, not related to bone density -- that are very important in fractures, and mostly, fall risk. I think that those issues need to be clearly studied in HIV patients.

Also, I think that getting more data to try to make better decisions about who should be screened would be very important, and to go through some of these cost benefit type analyses, to see if it makes sense on a population level to screen people with HIV infection across the board with DXA scans.

Bonnie Goldman: I guess we'll get some more information at the end of February, after CROI [Conference on Retroviruses and Opportunistic Infections].

Todd Brown: That's right.

Bonnie Goldman: Thank you both for taking the time to talk with me, and for providing such a terrific update on bone disease and HIV.

This transcript has been lightly edited for clarity.

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References

  1. Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS. November 14, 2006; 20(17):2165-74.
  2. Brown TT, Ruppe MD, Kassner R, et al. Reduced Bone Mineral Density in Human Immunodeficiency Virus-Infected Patients and Its Association with Increased Central Adiposity and Postload Hyperglycemia. J Clin Endocrinol Metab. March 2004;89(3):1200-6.
  3. Overton T, Mondy K, Bush T, et al, and SUN Study Investigators. Factors associated with low bone mineral density in a large cohort of HIV-infected US adults: baseline results from the SUN study. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstract 836.
  4. Triant VA, Brown TT, Lee H, Grinspoon SK. Fracture prevalence among human immunodeficiency virus (HIV)-infected versus non-HIV-infected patients in a large U.S. healthcare system. J Clin Endocrinol Metab. 2008;93(9):3499-3504.




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