Bone Loss and Fracture Risk in Patients With HIV: What We Know So Far

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The initiation of ART is associated with a decrease in BMD in the first 48 to 96 weeks.
The initiation of ART is associated with a decrease in BMD in the first 48 to 96 weeks.

Due to significant advances in the treatment of human immunodeficiency virus (HIV) infection in the past few decades, the life expectancy of patients infected with HIV is quickly approaching that of the general population.1 A longer life expectancy brings on the extra burden of living with HIV-related complications such as liver disease, cardiovascular disease, diabetes, cancer, renal dysfunction, and fractures.2

The correlation between HIV infection, low bone mineral density (BMD), and fragility fracture has been established in a number of studies.3-5 Although the role of HIV infection itself in low BMD remains unclear,6 research has shown that the initiation of  antiretroviral therapy (ART) is associated with a 2% to 6% reduction in BMD in the first 1 to 2 years of treatment.2 However, not all treatments have the same effect on BMD —  there are indicators that certain ARTs may have greater effects on osteoporosis and fracture risk in patients with HIV.

In an interview with Infectious Disease Advisor, Todd T. Brown, MD, PhD, professor of medicine and epidemiology, division of endocrinology, diabetes, and metabolism, Johns Hopkins University, Baltimore, Maryland, discussed the effects of HIV infection and ART on BMD, as well as management strategies for HIV patients at risk for fragility fracture. 

Infectious Disease Advisor: Could you please explain how HIV infection and ART influence bone metabolism? Do certain ARTs increase the likelihood of osteoporosis and bone fracture in individuals infected with HIV?

Todd T. Brown, MD, PhD:  With the initiation of ART there is a decrease in BMD over the first 48 to 96 weeks. This drop in BMD appears to be mediated by an acceleration in bone turnover with activation of osteoclasts and osteoblasts, and a favoring of osteoclast activity, leading to net bone loss. Furthermore, this effect is related to the specific ART used. In multiple studies, tenofovir disoproxil fumarate (TDF) has been associated with larger decreases in BMD compared with other nucleoside analog regimens.7-9 The protease inhibitors (PIs) have also been associated with larger decreases in BMD in that first period of ART initiation.  Conversely, switching off TDF or a PI tends to improve BMD.   

Infectious Disease Advisor: What are the main risk factors for fragility facture in individuals infected with HIV, and how are they assessed?

Dr Brown:  Some of the important risk factors for osteoporosis and fragility facture in individuals infected with HIV are similar to those present in the general population and not unique to the HIV population. They include low body weight, low muscle mass, corticosteroid use, and hypogonadism. There are also important behavioral risk factors such as smoking and alcohol use which are prevalent in HIV-infected populations. Risk factors unique to the HIV population are the use ARTs; specifically the effects of TDF and PIs mentioned earlier. There also risk factors associated with the effects of HIV infection itself, independent of ART, but these have been less well-documented in clinical studies.

Infectious Disease Advisor: Are there any specific guidelines for diagnosing and following up patients infected with HIV at risk for osteoporosis and fragility fracture?

Dr. Brown: The important thing to recognize is that osteoporosis is a silent disease, so the prevention and identification of osteoporosis are important. The only way to determine if a patient has osteoporosis is to do a bone density scan — a dual-energy x-ray absorptiometry (DXA) scan. Current recommendations call for screening in men 50 and older with HIV and all postmenopausal women infected with HIV with a DXA scan. This is a large population, so priority should be given to those patients who have additional risk factors for osteoporosis and fracture. So, identifying osteoporosis is the first important step. In addition, there are precautions that should be taken in all patients to maintain or improve bone health. 

Infectious Disease Advisor: What type of prevention/management strategies are recommended in patients with HIV at risk for fragility fracture?

Dr Brown: Smoking cessation and the reduction of alcohol consumption are important. Regular physical activity is critical, since strong muscles lead to strong bones. Fall risk is also important — more than 90% of fractures occur when people fall, so if we can keep people on their feet, we'll decrease the risk of fracture. Therefore, it is important to ask patients about falling and to intervene if they have repeated falls, don't feel comfortable on their feet, or are worried about falling. Regarding vitamin D supplementation, I recommend a universal supplementation approach with 800 to 1000 IU of vitamin D daily. Making sure that people have calcium in their diets is also important.

The other potential approaches include switching off the ARTs that are associated with lower BMD, such as TDF and PIs, if other ART regimens are available.  In older patients who are initiating ART, particularly patients with osteoporosis, we know that a single dose of the intravenous bisphosphonate, zoledronic acid, will eliminate the decrease in BMD that we see with ART initiation, so I think that this is a powerful strategy in older people or people at risk for fracture.

The treatment thresholds for bone-specific medications used to treat osteoporosis are similar to those in the general population and are country-specific.

Infectious Disease Advisor: One of your recent studies demonstrated that BMD at the hip declines twice as quickly in women infected with HIV than in men. Are these findings directly related to the general predisposition of women to osteoporosis or are other mechanisms at play that in women infected with HIV that increase their risk for bone loss?

Dr Brown: With the design in that study we really could not answer that question, because there was no equivalent HIV-uninfected comparison group. So, it's difficult to say whether this finding is different compared with the natural history of bone loss by gender. The other difficult thing with the data is that most studies relating to BMD in patients infected with HIV are focused on men, so we know relatively little about BMD in women infected with HIV compared with men.

Infectious Disease Advisor: Which other important questions still remain to be answered about the influence of HIV infection and ART on bone loss?

Dr. Brown: I think that finding optimal regimens to decrease the risk of osteoporosis and fragility fracture is really important. Trying to identify people at risk for fracture and instituting proper therapies and focusing on fall risk and risk factors for falls are also important areas that will become even more important as the population with HIV ages and as the first wave of people aging get into their 60s and 70s, when there is a dramatic risk for fragility fracture in the general population.

The other important issue is whether BMD is the best assessment of fracture risk. DXA is used widely, but only explains about a half of fracture risk. There are other modalities such as computed tomography (CT) and ultrasound that are more direct measures of bone material properties and bone turnover markers. A related question is whether a combination of these modalities to assess bone health is better than DXA alone.

Other critical questions are what is the best osteoporosis medication to prevent fractures in the HIV-infected population?; what is the best sequence of medications to optimize bone health?; and whether osteoporosis treatment should differ in people living with HIV compared with the general population. Finally, it's important to better understand the relationship between inflammation/immune activation and osteoporosis and determine whether treatment of inflammation can decrease fracture risk.

Disclosures

Dr Brown has served as a consultant to Gilead, Merck, BMS, ViiV Healthcare, and Theratechnologies.

References

  1. van Sighem AI, Gras LA, Reiss P, et al. Life expectancy of recently diagnosed asymptomatic HIV-infected patients approaches that of non-infected individuals. AIDS. 2010;24(10):1527-1535.
  2. Compston J. HIV infection and bone disease. J Intern Med. 2016;280(4):350-358.
  3. Cazanave C, Dupon M, Lavignolle-Aurillac V, et al. Reduced bone mineral density in HIV-infected patients: prevalence and associated factors. AIDS. 2008;22(3):395-402.
  4. Rivas P, Górgolas M, García-Delgado R, et al. Evolution of bone mineral density in AIDS patients on treatment with zidovudine/lamivudine plus abacavir or lopinavir/ritonavir. HIV Med. 2008;9(2):89-95.
  5. Gonciulea A, Wang R, Althoff KN, et al. An increased rate of fracture occurs a decade earlier in HIV+ compared to HIV- men. AIDS. 2017;31(10):1435-1443.
  6. Brown TT, Hoy J, Borderi M, et al. Recommendations for evaluation and management of bone disease in HIV. Clin Infect Dis. 2015;60(8):1242-1251.
  7. Güerri-Fernández R, Molina-Morant D, Villar-García J, et al. Bone density, microarchitecture, and tissue quality after long-term treatment with tenofovir/emtricitabine or abacavir/lamivudine. J Acquir Immune Defic Syndr. 2017;75(3):322-327.
  8. Taiwo BO, Chan ES, Fichtenbaum CJ, et al. Less bone loss with maraviroc- versus tenofovir-containing antiretroviral therapy in the AIDS clinical trials group A5303 study. Clin Infect Dis. 2015;61(7):1179-1199.
  9. Bianco C, Rossetti B, Gagliardini R, et al. Bone mineral density improvement after 48 weks of switch to maraviroc=darunavir/ritonavir 300/800/100 mg QD, preliminary results of GUSTA study. J Int AIDS Soc. 2014;(4 Suppl 3):19816.  
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