Bone Loss and Antiretroviral Therapy in HIV and HCV

Among the numerous comorbidities that affect people living with HIV (PLWH), an increased prevalence of osteopenia and osteoporosis has been observed across a range of studies.¹ The etiology of reduced bone mineral density (BMD) in this population has been linked to various factors, including those associated with HIV infection and treatment, as well as unrelated factors. As a result, PLWH have a greater prevalence of fractures compared with the general population, with one study showing rates of 2.87 vs 1.77 per 100 people per year, especially involving the spine, hip, and wrist.²

Findings increasingly point to antiretroviral therapy (ART) as a key contributing factor to low bone density and fracture risk in those with HIV. In a study published in May 2019 in Frontiers in Endocrinology, researchers at the University of Verona in Italy investigated low bone density and fracture risk in 83 patients receiving ART, including 55 with HIV, 11 with HIV and hepatitis C virus (HCV) coinfection, 12 with hepatitis B virus (HBV), and 4 with HCV.¹ On the basis of various measures of bone metabolism, densitometry (DXA), and lateral spine X-rays, results were varied for the overall sample. The prevalence of hypovitaminosis D, osteopenia, and osteoporosis was 53%, 48%, and 14%, respectively. There was a 41% prevalence of at least 1 vertebral fracture and a 30.4% prevalence of multiple fractures compared with 17% in a sample of 40 noninfectious control individuals. Among patients with fractures, grade 1 fractures were found in 44% of patients, grade 2 fractures in 41% of patients, and grade 3 fractures in 15% of patients. A higher prevalence and greater severity of vertebral fractures was observed in patients >60 years of age.

A higher mean number of fractures were discovered in patients treated with tenofovir, protease inhibitors, or both compared with those not receiving these medications (1.4±0.9 vs 0.7±0.5; P <.05), and a higher median Spine Deformity Index in the former vs the latter group (2.2±1.1 vs 0.86±1.00; P <.05). “The use of these drugs was also associated with lower levels of vitamin D and higher bone turnover levels compared to other antiretroviral drugs,” according to the researchers. Patients with comorbid HIV and HCV coinfection showed a significantly lower mean T-score compared with those with HIV alone (−2.2±0.8 vs −1.6±1.2; P <.05).

In addition, the “viral load and the CD4+ cell count were respectively, directly, and inversely correlated with the number and severity of vertebral fractures,” the authors wrote.¹ The results also indicate that “measurement of bone mineral density alone cannot exclude the risk of fragility fractures, since many of these fractures occur in patients with normal BMD,” the authors wrote.

“For this reason, it would be indicated to perform an X-ray of the spine in order to detect vertebral deformities even in patients with a normal or slightly reduced bone mineral density,” they concluded.

To further discuss the effects of ART on bone health in PLWH, Infectious Disease Advisor interviewed the following experts: Jessica Rachel Starr, MD, an endocrinologist at the Hospital for Special Surgery, New York City, who specializes in bone health; Emmanuel Biver, MD, PhD, a researcher in the Division of Bone Diseases at the University of Geneva, Switzerland; and Todd T. Brown, MD, PhD, a clinical investigator and professor of medicine in the Division of Endocrinology, Diabetes, and Metabolism at Johns Hopkins University School of Medicine, Baltimore, Maryland.

Infectious Disease Advisor: What is known about the effects of ART on bone health in HIV, and what are the underlying mechanisms?

Dr Starr: We know the inflammatory state of HIV predisposes patients with HIV to a higher risk for osteoporosis irrespective of ART use. Patients with HIV have lower bone density scores at the spine, hip, and wrist, as well as higher bone turnover.^1,2 The rates of bone loss each year are higher as well at each of these sites compared with HIV-negative people.

ART, when given intermittently vs continuously, has a better effect on BMD decline, meaning bone density is less negatively affected when patients take breaks from the antiretroviral agents.³

Certain medications are more clearly implicated than others; namely, tenofovir has been shown to lead to BMD decline by causing a Fanconi anemia and phosphate wasting. The protease inhibitor class, in general, is the one most closely linked to BMD decline.⁴

This is a complex topic and highlights how HIV has become a chronic disease, meaning patients with HIV are living long enough to develop chronic age-related conditions such as osteoporosis, although they are perhaps developing these conditions at an earlier time in life and with a higher degree of severity than their HIV-negative peers.

Dr Biver: A decline in BMD after ART initiation occurs within the first year independent of ART regimen, with more pronounced bone loss when starting a regimen containing tenofovir disoproxil fumarate (TDF), and potentially boosted with protease inhibitors. Bone loss seems lower with abacavir, integrase inhibitor, or the alternative tenofovir prodrug tenofovir alafenamide (TAF).⁵

The effect of ART on bone loss is transient (within the first 1-2 years after initiation) and mainly associated with an increase of bone resorption during the immune reconstitution. TDF-related bone loss has also been associated with renal phosphate wasting caused by the toxicity of high tenofovir plasma concentrations toward renal proximal tubular cells.⁵

Finally, HIV infection and ART also interfere with vitamin D metabolism. For instance, the first-line nonnucleoside reverse transcriptase inhibitor efavirenz is associated with a decline of vitamin D levels that might be linked to the modulation of various cytochromes and enzymes involved in the activation or deactivation of vitamin D or vitamin D-binding protein.⁵

Dr Brown: We know from multiple studies that PLWH have a higher fracture risk than people who don’t have HIV. There are many contributing factors, such as low body weight and demographic factors such as age, as well as factors specific to HIV populations. BMD decreases by 2% to 6% over the course of 96 weeks with initiation of ART, in part as a result of reconstitution of the immune system, when levels of bone turnover are high on resorption but low on formation.⁷

It also depends on which medications are used: the 2 main drugs associated with fracture risk are TDF and protease inhibitors. Protease inhibitors probably have an independent effect on bone mass density, but in combination with TDF, there may be augmentation of bone loss. The newer TAF, which is increasingly used in the United States, has fewer bone adverse effects than TDF.

Infectious Disease Advisor: How should this be managed in clinical practice in terms of screening and treatment, including when and how to collaborate with rheumatologists?

Dr Starr: Screening ART patients for osteoporosis with DXA is important, especially if they have other risk factors such as a body mass index <18 kg/m², older age, and female sex. I would screen at the outset of therapy and consider using the newer TAF vs the older TDF, as the TAF was shown to lead to lower tenofovir blood levels and less reduction in bone density than TDF.

Collaborating with rheumatologists comes into play if these patients are being seen for rheumatic conditions because the rheumatologists should also be aware of the detrimental effect of HIV and ART on bone density, so a rheumatology appointment is an opportunity to screen patients with DXA testing.

Dr Biver: Preventive measures against osteoporosis should be implemented in all PLWH as soon as ART is initiated to target the critical first 2 years: regular physical activity; balanced diet containing sufficient amounts of calcium and proteins; cessation of toxic habits, such as smoking and alcohol abuse; and if necessary, vitamin D±calcium supplements.

Screening for osteoporosis with DXA should be performed in patients with high risk for fragility fracture; that is, all men who are HIV-positive aged ≥50 years and women who are postmenopausal, and PLWH with risk factors, such as history of low-trauma fracture (after a fall from standing height or lower), evidence of vertebral fracture from previous thoracic and abdominal X-rays or computed tomography scans, clinical hypogonadism, oral glucocorticoid use of at least 2.5 mg once per day of prednisone equivalent for >3 months, malabsorption, inflammatory bowel disease, or primary hyperparathyroidism.

Basically, treatment of osteoporosis in PLWH should follow the recommendations for the general population, using bisphosphonates as first-line treatment. Rheumatologists can help to validate the indication for an antiresorptive drug and to choose and manage the treatment in case of osteoporosis or prior fragility fracture. ART regimens should be reviewed, if possible, in patients with osteoporosis and high bone turnover.

Dr Brown: The strongest risk factor for fractures is age, which really drives the guidelines regarding who should be screened for osteoporosis. It’s generally men aged ≥70 years and women aged ≥65 years, and there’s a whole list of factors, including HIV, to be considered for potential screening at younger ages.

For PLWH, screening is recommended for all women who are postmenopausal and all men aged >50 years. The challenge is, that’s a lot of people [Editor’s note: An estimated half of PLWH in the United States are >50 years.⁸], and there are a lot of competing concerns that primary care physicians have to deal with, DXA among them. I would suggest using age as the primary indicator, but certainly stratify on the basis of other factors, such as low body weight, family history of fractures, and other diseases that may be associated with fracture, including rheumatoid arthritis and chronic obstructive pulmonary disease.

Treatment of osteoporosis does not really differ for people living with HIV and those in the general population. Bisphosphonates represent the first-line treatment strategy; there are fewer data pertaining to other agents. With denosumab, there is some concern that immunodeficient patients may be more at risk for infection, although this is more of a theoretical concern, as there are no data to support this.

As demonstrated in a 2016 study by Ofotokun et al, for patients who haven’t yet started ART, you can administer a dose of intravenous zoledronic acid (5 mg) when ART is initiated to attenuate the bone loss associated with treatment.⁹ [Editor’s note: Compared with placebo, the group treated with zoledronic acid showed a 65% reduction in bone resorption at 24 weeks and a 57% reduction at 48 weeks (P <.001).]

Infectious Disease Advisor: What are other key considerations for clinicians regarding this topic?

Dr Starr: Osteoporosis and osteopenia are more common in women, older patients, and those with lower body weight. All patients with HIV should have BMD screening before initiating treatment with ART.

Dr Biver: Musculoskeletal health is highly influenced by nutritional status and lifestyle habits, which should be targeted first. Low BMI, which is more prevalent in PLWH, accounts for a substantial proportion of low BMD in this population.

In elderly patients with long-term HIV infection, an emerging population, the risk for falls should be considered in the prevention of fragility fractures.

Dr Brown: In the osteoporosis world, we tend to focus on skeletal risk factors for fractures, but there are also nonskeletal risk factors, including the risk of falling. PLWH have more factors associated with increased fall risk, such as peripheral neuropathy and cognitive impairment, and data show that fall risk is higher in this population.¹ It is important to identify people at risk for falls or who have fallen previously and to refer them for physical therapy to include strength and balance training.

The prevalence of frailty is also higher in PLWH. The best approach to address frailty in the general population is physical activity; this is the only thing that’s been shown to work, and it can reduce fracture risk as well.¹⁰

HCV is another important risk factor for fractures in HIV populations.¹ It is unclear whether low bone density seen in HCV is associated with the virus itself or other factors such as illicit drug use. One key strategy to tease this apart is to treat the HCV and see whether BMD improves. We have a study currently looking at whether BMD improves after eradication of HCV.

Infectious Disease Advisor: What are remaining research needs regarding this topic?

Dr Starr: Additional research is needed to tease out the relative contribution of the HIV itself to low BMD vs the medications used to control the virus. There is also a need to determine whether ART affects bone metabolism or vitamin D metabolism or both. A recent Columbia University study attempted to explore this and found that giving women who were HIV-positive 3000 IU vitamin D did not affect bone density when compared with 1000 IU vitamin D daily.⁶

Dr Biver: Epidemiological data on fractures in elderly PLWH with a long history of ART are lacking, especially at the age when fracture risk becomes particularly high.

There are currently no data showing that initiating or switching to a bone-protective ART regimen lowers fracture incidence in PLWH. It is unknown whether the magnitude of the transient BMD change is clinically significant in terms of actual increased fracture risk beyond the traditional underlying risk factors of bone fragility, which are highly prevalent in PLWH.

Dr Brown: In terms of the big picture view, most people living with HIV do not live in this United States. There is increasing chronic disease burden in regions such as sub-Saharan Africa and the Indian subcontinent, and osteoporosis is going to increase as these populations age. How will treatment of HIV change the trajectory of fracture risk in these countries?

Studies investigating contributors to fracture risk relative to HIV and inflammatory states are also needed, as some data suggest that chronic inflammation is a factor influencing bone loss in HIV.¹¹

References

1. Dalla Grana E, Rigo F, Lanzafame M, et al. Relationship between vertebral fractures, bone mineral density, and osteometabolic profile in HIV and hepatitis B and C-infected patients treated with ART [published online May 14, 2019]. Front Endocrinol (Lausanne). 2019;10:302.

2. 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.

3. Grund B, Peng G, Gibert CL, et al. Continuous antiretroviral therapy decreases bone mineral density. AIDS. 2009;23(12):1519-1529.

4. Moran CA, Weitzmann MN, Ofotoku I. The protease inhibitors and HIV-associated bone loss. CurrOpinHIVAIDS. 2016;11(3):333-342.

5. Biver E, Calmy A, Rizzoli R. Bone health in HIV and hepatitis B or C infections. Ther Adv Musculoskelet Dis. 2017;9(1):22-34.

6. Yin MT, RoyChoudhury A, Bucovsky M, et al. A randomized placebo-controlled trial of low- versus moderate-dose vitamin D3 supplementation on bone mineral density in postmenopausal women with HIV. J Acquir Immune Defic Syndr. 2019;80(3):342.349.

7. McComsey GA, Tebas P, Shane E, et al. Bone disease in HIV infection: A practical review and recommendations for HIV care providers. Clin Infect Dis. 2010;51(8):937-994.

8. HIV and older adults. US Department of Health and Human Services website. https://aidsinfo.nih.gov/understanding-hiv-aids/fact-sheets/25/80/hiv-and-older-adults Reviewed September 29, 2019. Accessed September 5, 2019.

9. Ofotokun I, Titanji K, Lahiri CD, et al. A single-dose zoledronic acid infusion prevents antiretroviral therapy–induced bone loss in treatment-naive HIV-infected patients: a phase IIb trial. Clin Infect Dis. 2016;63(5):663-671.

10. McPhee JS, French DP, Jackson D, Nazroo J, Pendleton N, Degens H. Physical activity in older age: perspectives for healthy ageing and frailty. Biogerontology. 2016;17(3):567-580.

11. Hileman CO, Labbato DE, Storer NJ, Tangpricha V, McComsey GA. Is bone loss linked to chronic inflammation in antiretroviral-naive HIV-infected adults? A 48-week matched cohort study. AIDS. 2014;28(12):1759-1767.