Many people with HIV are at risk of osteoporosis – a progressive thinning of the bones that can lead to breakage. Derek Thaczuk looks at who is at risk and what preventive steps can be taken.
Several years ago, people with HIV and their doctors began to notice that bones were breaking suspiciously often. Studies soon confirmed that osteoporosis – the thinning, brittle bones traditionally associated with women past the age of menopause – was in fact common among those living with the virus.
We are continuing to gather insights into who is most at risk. More importantly, these insights suggest steps HIV-positive people may be able to take to protect their bones.
Bones are basically the body’s scaffolding, a rigid support system that houses and protects more delicate organs and tissues. Although bones are largely made of calcium and other minerals, they are living organs nonetheless. Like most bodily organs, they are in a constant state of replacement – simultaneously being built up from, and eroding back into, the components from which they are made.
In healthy adults, breakdown and build-up are roughly balanced. Overall bone mass reduces slowly as we age, but sometimes, however, the rate of breakdown greatly outpaces replacement, so that bone minerals erode away much more quickly over time. A significant amount of bone mineral density (BMD) can be lost without posing a significant risk of bone breakage: this moderate amount of BMD loss is called osteopenia. If the loss continues, bones become porous, spongy, fragile and easily broken – a more serious condition known as osteoporosis. Loss of bone density often produces no noticeable symptoms, at least in the early stages, and can easily go undetected until a bone breaks.
In the population at large, osteoporosis occurs most frequently in women past the age of menopause. It is less common in men because men have larger skeletons, their bone loss starts later and progresses more slowly, and they have no period of rapid hormonal change and bone loss. However, by 65 or 70, men and women are losing bone mass at the same rate, as well as having a decreased ability to absorb calcium.1
Studies have also found osteoporosis to be common amongst HIV-positive men of all ages, as well as in some younger HIV-positive women. In 2006, Todd Brown and colleagues at Johns Hopkins combined data from eleven smaller studies in the United States. This large analysis found osteoporosis in 15% of the HIV-positive participants overall – three and a half times the rate in similar HIV-negative people.2 Researchers have noted that the rates of bone loss seen in HIV-positive men in their mid-40s are substantial, similar to the significant rates of loss in women aged 55 to 75 years.3 Other studies have produced both higher and lower estimates of osteoporosis rates, owing maybe to variations between study groups, such as how long people had been HIV-positive or on therapy. Yet one thing is consistent: osteopenia, at least, is extremely common in people with HIV, being seen in up to half of study participants.4,5,6
Sticks and stones
Given how common bone loss is amongst people with HIV, how often does it actually lead to breakage? In answering this question, investigators need to be clear about what they are looking for, since many fractures are unrelated to osteoporosis. Some studies have looked at all fractures, regardless of cause or type, but many researchers choose to disregard so-called traumatic fractures – those caused by high-force impacts, such as breaking an arm in a fall downstairs. The risk of traumatic fractures should be largely unaffected by bone density: if you fall hard enough, even a perfectly healthy bone is going to break.
Therefore, many studies look only at fragility fractures, the type most associated with osteoporosis. Typically seen at the wrist, spine or hip, fragility fractures can result from very light impacts – such as a fall to the floor from a standing position – and generally do not occur in healthy bones.
Studies are finding that HIV-positive individuals are generally more prone to fragility fractures than their HIV-negative counterparts. However, they do not all agree on exactly who is most at risk, or to what extent. In the HIV Outpatient Study (a large and largely male US cohort), fragility fractures were nearly two and a half times more likely than estimated rates in the general US population.7
Who is most at risk?
Many factors have long been known to heighten the risk of osteoporosis in older women, and many of these are proving true for people with HIV as well. Studies have consistently found that ‘traditional’ risk factors including smoking, heavy alcohol intake, low body weight, and low testosterone levels all increase the risk of bone loss in people with HIV, and that risk increases with age.
At one point, this led some experts to suggest that HIV itself did not play a direct role in bone loss – rather, that the loss was purely due to factors commonly associated with HIV, such as low body weight.8
But at least one recent study, after carefully accounting for the effects of body mass and other factors, found that simply being HIV-positive does make bone fractures about 40% more likely – at least in men.9 In women, HIV seems to be an additional risk factor for bone loss after the age of menopause.10 Below that age, HIV does not appear to make broken bones any more likely11 except in women with other risk factors such as low body weight and low testosterone.12
Antiretrovirals: bad for bones?
Does antiretroviral treatment (ART) affect the risk of osteoporosis and bone fracture? Not everyone agrees: at least one sizeable study, of both men and women, found that being on or off ART made no difference to bone mineral loss.13 Most investigations, however, have found that bone damage is indeed more likely in people on ART, and that the risk increases the longer one is on treatment.14,15 Most experts now believe that HIV infection and antiretroviral treatment each play some role in bone loss.
Ritonavir-boosted protease inhibitors (PIs) and the nucleotide reverse transcriptase inhibitor (NRTI) tenofovir (Viread) have often been cited as the drugs most likely to lead to bone loss, but not all evidence from clinical studies agrees. For instance, one recent comparison of efavirenz (Sustiva, also in the combination pill Atripla) to boosted lopinavir (Kaletra) found that people on either drug (with a standard two-nucleoside combination) lost nearly equal amounts of BMD after two years.16 However, a similar study from France found almost twice the degree of bone loss in people taking boosted PIs than in those on non-nucleoside reverse transcriptase inhibitors (NNRTIs).17 Differences between individual PIs are also unclear: most studies so far have not been large enough to separate out the different drugs, but have looked at the class of PIs as a whole. Similarly, many but not all studies have found tenofovir to be linked to bone loss. Test-tube studies have shown that tenofovir can affect bone metabolism, and one large study found twice as much spinal bone mineral loss with tenofovir than with d4T (stavudine, Zerit) over three years, in combination with efavirenz and 3TC (lamivudine, Epivir).18
Why does bone loss occur?
Although the exact causes of HIV-related bone loss are still poorly understood, several clues are emerging. Some experts believe that the growing list of metabolic problems common in people with HIV – from bone loss to cardiovascular risk to kidney failure – are part of an overall pattern of ‘accelerated ageing’. The ongoing immune activation (inflammation) caused by chronic HIV infection is often seen as driving this process, so that younger HIV-positive people experience problems normally seen in older adults.
A wave of recent studies has also found that vitamin D – a vitamin crucial for bone formation – is very widely deficient among people with HIV,19 as it is in the general population. But it is unlikely that vitamin D deficiency alone is enough to explain the degree of bone loss being seen, as osteoporosis and fragility fractures have been observed in people (with or without HIV) who have a normal vitamin D level.
There may be a link between antiretroviral treatment and vitamin D deficiency. Several bodily hormones, including one known as parathyroid hormone (PTH), control how much calcium is released from bones. If more calcium is needed elsewhere in the body (for instance by the nervous system, where it regulates nerve signals), PTH levels go up, which stimulates more calcium to be released from the bones into the bloodstream. Once enough calcium is released, the hormone levels usually drop, signalling ‘enough’ and causing the bones to retain calcium again.
However, several other factors may drive up PTH levels in people with HIV. One is the low vitamin D levels now known to be common. Secondly, tenofovir may also increase PTH, creating a ‘false signal’ that causes calcium to be continually leached from the bones.20 While this is still a preliminary theory, it may pave the way for a more extensive understanding of how HIV drives bone loss – and how to correct it.
Beating the breaks
One of the first steps in prevention is adequate screening. Bone mineral density can be measured painlessly with a diagnostic scan known as DEXA (for Dual Energy X-ray Absorptiometry). DEXA scans usually assess bone density at the hip joint and a representative segment of the spine. Forthcoming BHIVA (British HIV Association) guidelines will make recommendations on when DEXA scans should be used in people with HIV.
Setting the scales
Bone mineral density (BMD) is expressed as a ‘T-score’, which compares an individual's bone density values to the average for the overall population. A T-score of zero would mean that the person's BMD is exactly equal to the population average; negative T-scores indicate lower-than-average BMD.
Osteoporosis is defined as a T-score of -2.5 or lower, corresponding to a BMD in the bottom 0.62% of the population. Osteopenia is defined as a T-score in the range from -1 to -2.5, which includes one-sixth of the population as a whole.
Some experts have argued that these definitions, especially that of osteopenia, are arbitrary and more statistical than medical. In fact, a recent African study of pre-exposure prophylaxis (PrEP) in healthy, HIV-negative men and women found that almost half had osteopenia by the standard, US-based definition,21 leading the researchers to question whether these ‘normal’ values apply to everyone. Our notions of risk levels may require some questioning as we continue to investigate BMD in HIV-positive populations.
What can I do?
Currently, recommendations for treating or avoiding bone mineral density loss are based on many years of experience treating osteoporosis in older women. The approach is basically threefold: diet and supplements, exercise, and addressing ‘secondary factors’.
As calcium and vitamin D are essential to bone formation, people at risk of bone loss should make sure to get plenty of both. Many dietary foods are rich in calcium, including milk & other dairy products, leafy green vegetables such as kale and broccoli, beans such as soy and baked beans, nuts, sesame seeds, and many types of fish like salmon and sardines. Vitamin D is found in oily fish and eggs, as well as in foods that are specially fortified, such as breakfast cereals. However, to guarantee adequate amounts you may want to consider taking supplement tablets, particularly if your diet does not include many of these foods.
As calcium and vitamin D are essential to bone formation, people at risk of bone loss should make sure to get plenty of both.
How much supplementation is appropriate is still a bit of an open question. Recommendations generally run in the range of 1000 to 1200mg calcium and 10 to 30µg (micrograms - 0.01mg) or 400 to 1200 international units (IU) vitamin D. These are largely based on experience with osteoporosis in HIV-negative older women, so there is no guarantee that they are appropriate for people with HIV – for instance, we do not yet know for sure whether supplements at this level can correct HIV-related vitamin D deficiency. However, given what we do know, supplementation seems a wise step for anyone at risk. Taking too much of a supplement can be harmful, so it is a good idea to talk to someone at your HIV clinic, or your GP, before you start. You could also ask to talk to a dietician, to find out if you can adapt your diet to increase the calcium and vitamin D it provides.
The body produces its own vitamin D when the skin is exposed to ultraviolet-containing sunlight. People with brown or black skin may have lower levels of vitamin D than people with fairer skin, and the British climate can also lead to levels being low, especially during the winter. When sun is scarce and much of life happens indoors, getting extra vitamin D is all the more essential.
Another reason to quit
Many factors besides HIV contribute to risk of bone loss, and while some of these cannot be changed, others can. Smoking and heavy alcohol consumption are well-known risks, not only for bone loss, but for a host of other health problems including lung and other cancers, heart attack and stroke. Although it may be difficult, quitting smoking is probably one of the best things an HIV-positive person can do to better their all-around health prospects.
In the ‘healthy lifestyle’ discussion, exercise usually follows hot on the heels of the ‘quit smoking/watch your drinking’ advice, and this is no exception. Specifically, weight-bearing exercise is recommended for those at risk of or diagnosed with osteoporosis. This means any type of exercise in which your muscles are forced to work against gravity. If that definition seems rather abstract: swimming and cycling don't count; weight-lifting, running and walking, stair climbing and aerobics do. While non-weight-bearing exercise like swimming is certainly good for your health in other ways – nobody says you shouldn’t do it! – only weight-bearing exercise actually stimulates the growth of new bone. (People who are actually at risk of bone fracture due to low bone mineral density should clearly use caution and seek expert advice before attempting any possibly risky exercise.)
Finally, several of the other risk factors discussed above may also be addressable. Low testosterone – in men and women – is detectable, treatable, and may address a number of other problems: regular screening is useful for people with HIV and, if no-one in your healthcare team suggests it, you may want to raise it as a possibility. People with low body mass (i.e. possibly underweight) may require concerted effort on the right kinds of diet and exercise, and some people with HIV find it very challenging to gain weight in the form of muscle mass rather than unwanted fat. However, each pound gained – up to a point - is a pound of protection against osteoporosis and other problems.
Finally, there are drug treatments available. A once-weekly dose of alendronate (Fosamax) has been shown to help HIV-positive people gain bone mineral density more effectively than calcium and vitamin D supplements alone, without significant side-effects.22 Other drugs in the same class as alendronate (called bisphosphonates) are also available and have been used to treat post-menopausal osteoporosis; some of these are being studied for people with HIV-related bone loss and may also prove to be safe and effective.
References
1. www.niams.nih.gov/Health_Info/Bone/Osteoporosis/men.asp
2. Brown T, Qaqish R Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS 20(17):2165-74, 2006.
3. Grund B et al. Continuous antiretroviral therapy decreases bone mineral density. AIDS 23:1519–1529, 2009.
4. Cazanave et al. Reduced bone mineral density in HIV-infected patients: prevalence and associated factors. AIDS 22: 395–402, 2008.
5. Duvivier C et al. Greater decrease in bone mineral density with protease inhibitor regimens compared with nonnucleoside reverse transcriptase inhibitor regimens in HIV-1 infected naïve patients. AIDS 23: 817-24, 2009.
6. Calmy A et al. Low bone mineral density, renal dysfunction, and fracture risk in HIV infection: a cross-sectional study. J Infect Dis 200: 1746-54, 2009.
7. Dao C et al. Higher and increasing rates of fracture among HIV-infected persons in the HIV Outpatient Study compared to the general US population, 1994 to 2008. 17th Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 128, 2010.
8. Bolland MJ et al. Low body weight mediates relationship between HIV infection and low bone mineral density: a meta-analysis. J Clin Endrocrin Metab (online edition), 2007.
9. Womack J et al. HIV-infection and fragility fracture risk among male veterans. Seventeenth Conference on Retroviruses and Opportunistic Infections, abstract 129, San Francisco, 2010.
10. Yin MT et al. Low bone mass and high bone turnover in postmenopausal HIV-infected women. J Clin Endocrinol Metab (advance online publication, January 2010) doi:10.1210/jc.2009-0708.
11. Yin M et al. Fracture rates are not increased in younger HIV-positive women. Seventeenth Conference on Retroviruses and Opportunistic Infections, abstract 130, San Francisco, 2010.
12. Dolan SE at al. Effects of weight, body composition, and testosterone on bone mineral density in HIV-infected women. J Acquir Immune Defic Syndr 45: 161-67, 2007.
13. Cazanave, op. cit.
14. Bongiovanni M et al. Osteoporosis in HIV-infected subjects: combined effect of highly active antiretroviral therapy and HIV itself? J Acquir Immune Defic Syndr 40: 503–504, 2005.
15. Grund B et al. Op. cit.
16. Brown T et al. Loss of bone mineral density after antiretroviral therapy initiation, independent of antiretroviral regimen. J Acquir Immune Defic Syndr 51(5):554-561, 2009.
17. Duvivier C et al. Greater decrease in bone mineral density with protease inhibitor regimens compared with nonnucleoside reverse transcriptase inhibitor regimens in HIV-1 infected naïve patients. AIDS 23: 817-24, 2009.
18. Gallant 2004, cited in Brown 2006, op. cit.
19. Several studies: see www.aidsmap.com/en/news/A17781D3-3857-455D-B13B-D7628DF427C7.asp
20. Childs K et al. Vitamin D and calcium supplements reverse the secondary hyperparathyroidism that commonly occurs in HIV patients on TDF-containing HAART.Fifteenth BHIVA Conference, Liverpool, poster P89, 2009.
21. Buliva E et al. Bone mineral density (BMD) in a population of healthy HIV-negative young African adults enrolling in a pre-exposure prophylaxis (PrEP) trial in Botswana. 5th IAS Conference on HIV Treatment, Pathogenesis and Prevention, Cape Town, abstract WECA103, 2009.
22. McComsey G et al. Alendronate with calcium and vitamin D supplementation is superior to calcium and vitamin D alone in the management of decreased bone mineral density in HIV-infected patients: results from ACTG 5163. Fourteenth Conference on Retroviruses and Opportunistic Infections, Los Angeles, abstract 42, 2007.