Clinical Insights on HIV-Related Bone Disease Risk, Screening and Care

Featuring Michael T. Yin, M.D., M.S.

Michael T. Yin, M.D., M.S.
Dr. Yin is well recognized for research on bone disease and other metabolic complications of HIV infection and antiretroviral therapy. The coauthor of several dozen publications on these issues, he is also a member of the Osteo Renal Exchange Program, which issued the 2015 recommendations for evaluating and managing bone disease in people with HIV. Dr. Yin is principal investigator of a NIAID-funded initiative to study the impact of menopause on bone and muscle in the Women's Interagency HIV Study (WIHS). And he is co-principal investigator of a NICHD-funded study examining bone health in antiretroviral-treated children in South Africa. Dr. Yin is also a member of Bone and Metabolic Working Groups for the WIHS, the Veterans Aging Cohort Study (VACS), and the AIDS Clinical Trials Group (ACTG). He earned his M.D. at the Columbia College of Physicians and Surgeons and added a Masters in Epidemiology at the Columbia University Mailman School of Public Health.

Focusing on Modifiable Risk Factors

Aside from age, what are the most important bone risk factors in people with HIV?

The biggest risks are prior fracture, white race, and low body weight.

You can't do anything about fracture history or race, but what about low weight? Should HIV clinicians aggressively try to get underweight people to add pounds?

I think that's a reasonable approach. You hit upon an important point. There are some modifiable risk factors and some that are not. Controlling body weight, gaining muscle mass with exercise, quitting smoking, and limiting alcohol drinking to moderate amounts are all things that are modifiable and are probably important in people who are at high risk of bone disease. For people who have really low body weight, especially if they are prone to falls, strength training and improvement in muscle mass function would be helpful.

For the majority of patients who are in a reasonable weight range, we don't know how much benefit they'll get from strength training and other exercise. But in older folks, frailer folks, those who are more prone to falls, that kind of intervention is probably going to be beneficial.

The lifestyle risk factors you just mentioned -- smoking, heavy alcohol drinking, and lack of exercise -- those are all habits that are pretty hard for people to change. Do you have any advice on how HIV clinicians can motivate people to address those factors?

Changing ingrained habits can be difficult, but many people do find the motivation to change. The United States, for example, now has more former smokers than current smokers.1 For some patients, understanding and seeing the short-term benefits of modifying their behavior are strong motivators. Clinicians can help patients find this motivation by mapping out and tracking gains from changed behavior.

Gray Zones in Interpreting DXA and FRAX

When are DXA scans and the FRAX algorithm appropriate screening tooling for low bone mineral density in people with HIV?

DXA screening is recommended for all HIV-positive people over 50.2 It's a logical extrapolation from screening guidelines in the general population, but I think it will result in lots of test results that are in the gray area. Interpreting results will require a discussion between patient and provider about whether to monitor with a follow-up DXA in 1 year after lifestyle modification, or to switch antiretrovirals and monitor, or to start bisphosphonates or other bone-specific therapy. The thresholds for each of those decisions are not clearly defined, and we hope research will provide results to help guide us in the future. FRAX -- the algorithm based on a list of clinical factors3 -- can be used in HIV patients. Guidelines from the European AIDS Clinical Society (EACS) recommend FRAX for men in their 40s and premenopausal women over 40 without fragility fracture risk.4 This is an extrapolation from screening guidelines for the general population in Europe, which differ from those followed in the United States. Available data suggest that FRAX underestimates risk in HIV-infected individuals.5 Some of that underestimation can be corrected if you consider HIV a cause of secondary osteoporosis in the FRAX calculation, but whether it is an accurate enough predictor of fracture risk in HIV to use it as a screening tool is still not clear.

You pointed out that recent HIV bone guidelines call for FRAX screening starting at age 40,2,4 but one of your studies found that young men with HIV have lower peak bone mass than young HIV-negative men.6 [See "Substance Use, Old Age, Young Age" in this issue] Should HIV clinicians be on the lookout for signs of bone problems in people in their 20s and 30s?

That's a good question. If we look, we're going to find evidence of bone deficiency in younger people with HIV, just as we did in that study. The problem with using a risk factor measure such as the FRAX -- and even bone mineral density (BMD) by DXA -- is that they are useful for predicting fracture only in older individuals. FRAX is well validated for people older than 50, although the calculator itself lets you go down to age 40. Those tools are less useful in younger people because fracture risks are generally low in younger individuals; even if a younger person has low BMD, their fracture risk is still much lower than that of an older person with the same BMD value. So the question is, in HIV-infected people who are infected at a very early age, including those infected perinatally, whether another kind of screening measure is indicated. We don't have good data to answer that question yet. The study that you pointed out and some others are just starting to assemble that data.

Your Veterans Aging Cohort Study analysis found that FRAX underestimates fracture risk in HIV-positive men 50 and older.5 Does that finding also raise concerns about the predictive power of FRAX in men in their early or later 40s?

That's an issue that we really wanted to address with that analysis. It's not a perfect analysis because we didn't have all the risk factors that are necessary to calculate FRAX. So the data we presented are illustrative but not definitive of how accurate FRAX could be in the HIV-infected population if you had all the variables. From our analysis, it appears that a modified-FRAX (calculated with all but two of the FRAX variables) has poor predictive value for fracture using commonly accepted thresholds for pharmacologic therapy (greater than 3% 10-year fracture risk at the hip). However, defining the true predictive value of FRAX in people with HIV still requires a definitive study in which all the variables are utilized. Bisphosphonates -- and before -- and beyond

What are the strongest indications for bisphosphonate therapy in people with HIV?

Prior fracture is the strongest indication. In the general population when someone has a prior fracture, you don't even need to get a FRAX. A fracture alone is indication enough that a patient should be on bisphosphates or some other bone-specific medication. Otherwise, bisphosphonate therapy should be considered for a patient with very low bone density. The osteoporosis cutoff is bone density at 2.5 standard deviation below that of a person the same sex and race at a young age. If a patient is below that cutoff, then the fracture risk is relatively high and the patient should be on therapy.

The issue is that now, with the guidelines to screen early,2 we see a lot of relatively young people -- around age 50 -- who have a bone density right around that osteoporosis cutoff. And if you look at their risk prediction by FRAX, which we understand is not perfect, the FRAX score is relatively low, suggesting they're not at high risk for fracture. And because they're in their early 50s, you don't know whether you want to begin a bisphosphonate that you might have to use for a relatively long time.

For such patients, one strategy that has emerged is to look at the patient's other modifiable risk factors -- such as low weight, low vitamin D, exercise, et cetera -- and see if we can modify those factors. Switching their antiretrovirals could be an option, if they're taking antiretrovirals that may contribute to low bone density risk. The data on switching off tenofovir suggest that you can gain 1% to 3% in bone density within a year just by trading tenofovir for abacavir or raltegravir.

Addressing some of these factors first and seeing if bone density has stabilized a year or 2 later could allow you to defer bisphosphonate therapy. That's something we're beginning to explore. We think it's a safe strategy for relatively young patients who just received DXA screening and who are not at a significant risk for fracture within 1 year, and we're trying to do some studies to validate that approach.

How long do HIV-negative people typically take bisphosphonates before the drugs start to cause problems?

The data indicate that bisphosphonate-related toxicities are quite rate. Atypical femoral fractures are devastating because they don't repair well, but they're very rare.7 Data on who gets these fractures indicate that very few people with less than 5 years of exposure to bisphosphonates have this problem. That's why the recommendation is that around the 5-year point you can consider having a drug holiday or switching off the bisphosphonates.2 The practice of giving a bisphosphonate drug holiday has become recognized only in the last few years. Before that, people who started bisphosphonates stayed on them for life.

When switching from bisphosphonates to another medication is an option, what are the switch possibilities for people with HIV?

There are several other agents. One is injectable teriparatide, or Forteo, which is an anabolic agent that stimulates osteoblasts to increase bone formation. So its mechanism is completely different from that of bisphosphonates, which work by inhibiting bone resorption by osteoclasts. There are reports of Forteo being used in HIV patients with good success without toxicity,8 so that is probably the second-line agent for HIV-infected individuals whose BMDs do not improve with bisphosphonates..

There are newer agents, such as injectable denosumab,9 a monoclonal antibody against RANK- ligand that has been approved for use in postmenopausal osteoporosis and is also being studied for corticoid-induced osteoporosis. Denosumab, however, has not been used in HIV patients because of a concern about increased infectious risks, since the treatment arm had more cases of skin and soft tissue infection in one of the pivotal approval trials for use in postmenopausal women.

Switching Antiretrovirals, Supplementing With Calcium or Vitamin D

When is it appropriate to switch from tenofovir disoproxil fumarate (TDF) or a ritonavir-boosted protease inhibitor (PI) because of low bone density?

Evidence is emerging for avoidance of TDF and possibly PIs in favor of raltegravir in patients with prior fracture and osteoporosis.2 Clinicians might also consider avoiding or switching from these antiretrovirals in certain high-risk patients -- those with fractures, older patients, and potentially those with HCV coinfection.

BMD data in people starting tenofovir alafenamide (TAF), the investigational tenofovir prodrug, are encouraging,10 so TAF may become an option for patients in whom TDF is not indicated. Data on the potential merits of switching from TDF to TAF are pending.11,12 Data on antiretroviral initiation with raltegravir or switching from TDF to raltegravir are also very encouraging. There are no data yet on changes in BMD with dolutegravir, but bone turnover marker findings are encouraging.

The new HIV bone guidelines are clear in suggesting when to switch people off TDF or boosted protease inhibitors in favor of other drugs.2 How strong is that evidence?

I think data are strong for less bone loss with initiation of certain regimens and improvements with switches to other regimens. But I don't think those antiretroviral switches are necessarily indicated for everybody. I think we should consider switches in patients already at higher fracture risk -- older people, certainly people who've already had a fracture, certainly those with low bone density. Those are the types of scenarios in which clinicians might want to get a patient off these antiretrovirals.

With the new antiretrovirals coming into use, and with the awareness of risk posed by TDF, in the future we are probably going to be prescribing first-line regimens that don't contain TDF. That change, in and of itself, may help prevent low bone density in some people with HIV. But right now there are a lot of patients taking TDF and doing quite well. We shouldn't switch everyone off TDF without a strong indication, because we probably would not see any benefit from doing that. But in select populations who are at higher risk for fracture or bone loss, I think we have good data to make that switch.

Where do calcium and vitamin D supplementation fit into the management picture?

We have clear data from a recently published study showing that supplementation with 4000 IU of vitamin D3 daily and 500 mg of calcium carbonate twice daily decreased bone loss with initiation of TDF/FTC/efavirenz (Atripla) in antiretroviral-naive individuals.13 However, we're not certain what the ideal doses are, whether both vitamin D and calcium supplementation are necessary, whether supplementation will have the same effect when used with other antiretroviral regimens, or how long you have to supplement for maximal impact. Aside from supplementation during antiretroviral initiation, it is prudent to supplement during puberty and older age or after the menopause.

When to Get an Endocrinologist's Help

What we've been talking about so far -- screening and basic management of bone loss -- are things most HIV clinicians will handle on their own. What are the scenarios in which clinicians should think about referring to a specialist?

When patients are not responding to straightforward interventions, you should consider referral. Let's say you switch someone off an antiretroviral and their bone density doesn't improve, and you're concerned and want to start a bone-specific therapy. That's not a bad indication for having an endocrinologist evaluate the patient to select the most appropriate therapy, such as which particular bisphosphonate to prescribe. Many primary care providers are comfortable making that first choice, and that's perfectly fine, but others will want an endocrinologist's help.

Most referrals involve people who don't respond to the bisphosphonates or who fracture while taking a bisphosphonate. Other scenarios in which an endocrinologist can help involve patients with bisphosphonate toxicity, or patients who have taken a bisphosphonate for a number of years and may be a candidate for a drug holiday.

What else do you see looking ahead?

Management of low bone density and fracture risk is an area that will continue to evolve as new agents become available and as we gain a better sense of what risk factors are truly specific for HIV patients. One HIV-related risk factor we haven't talked about is hepatitis C coinfection. Some observational studies make it clear that hep C is a very strong additive risk for fractures in HIV patients.14,15 [See "Heightened Bone Risk With HCV or HBV" in this issue] Whether treatment of hepatitis C will diminish that risk is still unclear. I think that will be a very interesting area to watch over the next few years as we begin to treat more patients with the new oral hep C agents.

References

  1. U.S. Department of Health and Human Services. The Health Consequences of Smoking -- 50 Years of Progress: A Report of the Surgeon General. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2014.
  2. Brown TT, Hoy J, Borderi M, et al. Recommendations for evaluation and management of bone disease in HIV. Clin Infect Dis. 2015;60:1242-1251.
  3. The FRAX calculator is online at www.shef.ac.uk/FRAX (click Calculation Tool tab, click appropriate region, then click country). Variables that should be indicated are age, sex, race, geographic region, weight, height, previous fracture, parental hip fracture, current smoking, glucocorticoid use, rheumatoid arthritis, secondary cause of osteoporosis, and alcohol use.
  4. EACS European AIDS Clinical Society. Guidelines. Version 7.1. November 2014.
  5. Yin MT, Skanderson M, Shiau S, et al. Fracture prediction with modified FRAX in older HIV+ and HIV- men. CROI 2015. February 23-26, 2015. Seattle, Washington. Abstract 141.
  6. Yin MT, Lund E, Shah J, et al. Lower peak bone mass and abnormal trabecular and cortical microarchitecture in young men infected with HIV early in life. AIDS. 2014;28:345-353.
  7. Unnanuntana A, Saleh A, Mensah KA, Kleimeyer JP, Lane JM. Atypical femoral fractures: what do we know about them? J Bone Joint Surg Am. 2013;95(2):e8.
  8. Wheeler AL, Tien PC, Grunfeld C, Schafer AL. Teriparatide treatment of osteoporosis in an HIV-infected man: a case report and literature review. AIDS. 2015;29:245-246.
  9. Dempster DW, Lambing CL, Kostenuik PJ, Grauer A. Role of RANK ligand and denosumab, a targeted RANK ligand inhibitor, in bone health and osteoporosis: a review of preclinical and clinical data. Clin Ther. 2012;34:521-536.
  10. Sax PE, Wohl D, Yin MT, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials. Lancet. Published Online 16 April 2015.
  11. ClinicalTrials.gov. Switch study to evaluate the safety and efficacy of emtricitabine/rilpivirine/tenofovir alafenamide (FTC/RPV/TAF) fixed dose combination (FDC) in HIV-1 positive adults who are virologically suppressed on emtricitabine/rilpivirine/tenofovir disoproxil fumarate (FTC/RPV/TDF). ClinicalTrials.gov Identifier NCT02345252.
  12. ClinicalTrials.gov. Study to evaluate switching from a regimen consisting of efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) fixed dose combination (FDC) to emtricitabine/rilpivirine/tenofovir alafenamide (FTC/RPV/TAF) FDC in virologically-suppressed, HIV-1 infected adults. ClinicalTrials.gov Identifier NCT02345226.
  13. Overton ET, Chan ES, Brown TT, et al. High-dose vitamin D and calcium attenuates bone loss with antiretroviral therapy initiation: a prospective, randomized placebo-controlled trial for bone health in HIV-infected individuals. Ann Intern Med. 2015;162:815-824.
  14. O'Neill TJ, Rivera L, Struchkov V, Zaheen A, Thein HH. The effect of HIV-hepatitis C co-infection on bone mineral density and fracture: a meta-analysis. PLoS One. 2014;9:e101493.
  15. Dong HV, Cortés YI, Shiau S, Yin MT. Osteoporosis and fractures in HIV/hepatitis C virus coinfection: a systematic review and meta-analysis. AIDS. 2014;28:2119-1131.