Bisphosphonates for Bone Disease in HIV -- and Advice on Antiretrovirals, Calcium, Vitamin D and Glitazones

New bone health guidelines for HIV providers offer straightforward advice on when to use bisphosphonates, when to use antiretrovirals, and which antiretrovirals to use, based on dual-energy x-ray absorptiometry (DXA)-derived bone mineral density (BMD) and FRAX osteoporotic fracture prediction scores.¹ The guidelines say one of four variables indicates fracture risk in people with HIV and should encourage clinicians to consider bisphosphonate therapy (Figure 1): (1) previous fragility fracture, (2) DXA-derived T score at or below -2.5 at the lumbar spine, total hip, or femoral neck in postmenopausal women or older men, (3) T score between -2.5 and -1.0 and a FRAX major osteoporotic fracture score at or above 20% or a FRAX hip fracture score at or above 3% for postmenopausal women or older men, or (4) a FRAX osteoporotic fracture score (without DXA-derived BMD) at or above 20%.

HIV-positive people with one of those traits should be checked for secondary causes of osteoporosis and such causes (Table 5 in guidelines¹), if identified, should be treated. Otherwise, clinicians should optimize calcium and vitamin D intake (discussed below), encourage physical activity (Table 1), smoking cessation, and moderate alcohol drinking, and they should consider starting bisphosphonates.

Antiretrovirals: PIs, TDF and TAF

Bone variables should not dissuade clinicians from starting or continuing antiretroviral therapy (ART), the guidelines say. As with any patient, "local or national guidelines for initiation and choice of ART regimen should be followed."¹ But, the guidelines advise, people who meet one of the fracture risk criteria described above should not start tenofovir disoproxil fumarate (TDF) or a ritonavir-boosted protease inhibitor (PI), and those already taking TDF or a boosted PI should switch. The guidelines list abacavir and raltegravir as switch options for TDF and raltegravir as a switch option for PIs. What about other integrase inhibitors? For now, these experts say, evidence supporting use of other integrase agents remains too scant.

Will tenofovir alafenamide (TAF) sidestep the bone and kidney trouble seen with TDF? Forty-eight-week results of a randomized trial suggest it will,²˒³ though some wary clinicians reserve judgment until TAF builds a record in clinical practice. Combined results of identical phase 3, double-blind, double-dummy trials found TAF virologically noninferior to TDF when either came packed in a single tablet with elvitegravir, cobicistat, and emtricitabine.³ The trials involved 1733 people starting their first regimen, all with an estimated glomerular filtration rate at or above 50 mL/min and none with hepatitis B or C. Concentrations of tenofovir in plasma -- where it spells toxicity trouble for people -- were 91% lower with TAF than with TDF. Tenofovir levels inside cells -- where it spells trouble for HIV -- were 4 times higher with TAF.³

Average hip bone mineral density (BMD) fell marginally in the TAF group through 48 weeks (-0.66%) while dropping 4.5-fold more in the TDF arm (-2.95%), a significant difference (P < 0.001).² Average spine BMD fell 1.30% with TAF plus the other drugs versus 2.86% with TDF and the other drugs (P < 0.001). Almost half of study participants randomized to TDF (45%) endured a 3% or greater decline in spine BMD, compared with 26% randomized to TDF. Respective proportions of participants who lost 3% or more hip BMD were 50% and 17%. Two bone turnover markers -- Ctelopeptide and P1NP -- rose significantly less with TAF than TDF. Signals of kidney toxicity also significantly favored TAF. Results of a trial in which people switch from TDF to TAF will be presented in 2015.

Guidance on Bisphosphonates, Calcium, Vitamin D

Do bisphosphonates work in people with HIV? A 2014 meta-analysis of eight randomized controlled trials showed they boost BMD at the spine and hip through 96 weeks, though the trials did not last long enough to figure whether treatment prevents fracture.⁴ The analysis involved five trials of oral alendronate and three trials of intravenous zoledronate (zoledronic acid). Pooled results showed a mean difference in spine BMD of 6.76% favoring the bisphosphonates over placebo or no treatment and a mean difference of 3.2% in hip BMD favoring the bisphosphates. No one dropped out of alendronate trials because of drug-related side effects, while 2 of 104 taking zoledronate dropped out for that reason. Guideline-recommended doses are 70 mg orally once weekly for alendronate (plus 1000 mg of calcium carbonate and 400 IU vitamin D daily) and 5 mg of zoledronate intravenously yearly.¹ These guidelines also advise reviewing bisphosphonate therapy after the first 3 to 5 years because of concerns over suppressing bone turnover that long.¹ In the interview in this issue, Michael Yin discusses two other bone-preserving agents, teriparatide (Forteo) and denosumab (a monoclonal antibody against RANK-ligand).

The new HIV bone guidelines urge clinicians to ensure adequate daily calcium for postmenopausal women and for men 50 or older.¹ Men 51 to 70 years old should get 1000 mg of calcium daily, while women 51 or older and men 71 or older should get 1200 mg daily, which are the Recommended Dietary Allowances (RDAs) in the United States. The guidelines suggest first advising people on sources of dietary calcium (Table 2) and turning to calcium supplements if the dietary approach fails.

U.S. authorities call for 1000 mg of calcium daily starting at age 4, and that quota jumps to 1300 mg from ages 9 through 18.⁵ For adults 19 to 50 years old, the RDA stands at 1000 mg (and at 1300 mg for pregnant or lactating women 14 to 18 years old).

Most people do not eat enough calcium to meet these requirements, and daily calcium consumed drops with age. A survey of 9475 U.S. adults figured median daily dietary calcium intakes of 968 mg for 31- to 40-year-olds, 852 mg for 41- to 50-year-olds, 777 mg for 51- to 60-year-olds, and 735 mg for 71- to 80-year-olds.⁶ A comparison of 112 HIV-positive adults in Italy and 76 HIV-negative people matched for age and gender measured an average daily calcium consumption of only 454 mg in the HIV group as recorded in weekly food-frequency questionnaires.⁷ Daily total calcium did not correlate with DXA-measured BMD, but in multivariate analysis weekly yoghurt intake emerged as a significant predictor of lumbar spine BMD (P = 0.04). When the researchers grouped participants into milk drinkers and milk-plus-yoghurt imbibers, they measured significantly higher rates of osteopenia and osteoporosis in the milk-only group. These findings may reflect yoghurt's status as the highest single-food source of calcium (Table 2).

A study of 89 HIV-positive and 95 HIV-negative postmenopausal U.S. women found that three quarters had a vitamin D level below 30 ng/mL, the cutoff indicating insufficient vitamin D.⁸ Insufficiency prevalence proved higher in African-American women (33% of participants) than in Hispanic women (67% of participants). Regardless of HIV status, vitamin D levels were significantly higher in women who took both multivitamins and calcium supplements than in women who took neither (mean 31.5 versus 21.0 ng/mL, P < 0.0001), but only 1 in 5 women took both multivitamins and calcium.

A 1778-woman analysis of the Women's Interagency HIV Study (WIHS) found that most women with or without HIV had vitamin D deficiency (25(OH)D < 25 ng/mL), though deficiency prevalence proved significantly lower with than without HIV (60% versus 72%, P < 0.001).⁹ Compared with white race, African American race tripled odds of deficiency (adjusted odds ratio [aOR] 3.02, 95% confidence interval [CI] 2.30 to 3.97), while Hispanic ethnicity tended to raise the odds (aOR 1.40, 95% CI 0.99 to 1.96). Every additional 10 years of age cut deficiency risk 16% (aOR 0.84, 95% CI 0.73 to 0.96), a finding contrary to results in the general population. Among the 1268 women with HIV, an undetectable viral load independently trimmed chances of deficiency 31% (aOR 0.69, 95% CI 0.50 to 0.95), while a CD4 count below 200 cells/mm³ versus above 500 cells/mm³ raised chances (aOR 1.66, 95% CI 1.11 to 2.48).

The new HIV bone guidelines recommend measuring vitamin D (25-hydroxy vitamin D) in people with a history of low BMD or fracture.¹ Clinicians may also consider checking vitamin D in people with risk factors for low levels -- dark skin, dietary insufficiency, avoidance of sun exposure, malabsorption, obesity, chronic kidney disease, or efavirenz use. These experts recommend vitamin D supplementation for people with quotients below 20 ng/mL with a dose that yields 25-hydroxy vitamin D levels of about 30 ng/mL, followed by "a suitable maintenance dose."¹

The guidelines stress that vitamin D deficiency can stifle responses to bisphosphonates, so people with HIV should get levels up to 30 ng/mL before starting bisphosphonate therapy.¹ But guideline writers caution that research has not firmly established any "health benefit" to spotting low D levels and pumping them up.¹ One exception may be a lower risk of hip fracture or nonvertebral fracture in people 65 or older in the general population (mean age 76, 91% women) taking about 800 IU daily, according to results of an 11-study meta-analysis.¹⁰ Fewer falls may be another benefit of vitamin D supplementation by elderly people. A meta-analysis of eight trials found that high-dose vitamin D cut the risk of falls about 20% in older people in the general population (mean age 65).¹¹

Do Glitazones or Statins Make a Bone Difference?

Two other drug classes often used by people with HIV -- glitazones and statins -- may or may not affect BMD, depending on which studies you consult and how you interpret them. New bone guidelines for HIV clinicians suggest avoiding or stopping drugs linked to bone loss -- glitazones, corticosteroids, proton pump inhibitors, and antiepileptics -- in people who need bisphosphonates, "if appropriate alternatives are available."¹

A placebo-controlled trial of daily rosiglitazone involved 71 HIV-positive people with lipoatrophy who had stopped stavudine and zidovudine for at least 24 weeks.¹² The researchers found no significant change in total BMD in either arm through 48 weeks. The bone formation marker P1NP dropped significantly at weeks 24 and 48 in rosiglitazone takers, but the difference between the rosiglitazone group and the placebo group was statistically significant only at week 24. Osteocalcin, another bone formation marker, also dropped significantly through 24 weeks in the rosiglitazone arm, but the fall did not differ significantly from the placebo group. Another placebo-controlled trial of rosiglitazone in 63 people taking antiretroviral therapy found that the diabetes drug did not affect BMD through 48 weeks.¹³

The HIV bone guidelines do not mention statins.¹ Some evidence suggests statins improve BMD and lower fracture risk, but other research finds no such benefits. At week 48 of an ongoing 147-person placebo-controlled trial of rosuvastatin in HIV-positive people with normal low-density lipoprotein cholesterol, researchers measured small gains in trochanter BMD (mean 0.9%) and total hip BMD (mean 0.6%) with the statin that differed significantly from BMD changes in the placebo arm (P < 0.05).¹⁴ Total hip BMD improvement with rosuvastatin remained significant after adjustment for age, sex, race, and smoking (P = 0.02).

Meta-analysis of eight observational studies in the general population independently linked statin use to 57% lower odds of hip fracture and 31% lower odds of nonspine fracture.¹⁵ But combined analysis of two clinical trials found no protective benefit with statins. Analysis of 3601 HIV-positive people starting or not starting a statin in an AIDS Clinical Trials Group longitudinal cohort found no evidence that statin therapy prevented nontraumatic fracture.¹⁶ And after a median of 1.9 years in a double-blind placebo-controlled trial of daily rosuvastatin involving almost 18,000 men over 50 and women over 60 in the general population, fracture incidence was nearly identical in statin takers and placebo takers.¹⁷

A note on the New HIV Bone Guidelines

This issue of RITA! reviews key advice in the 2015 "Recommendations for evaluation and management of bone disease in HIV."¹ But these guidelines have much more to offer. HIV clinicians should get their hands on a copy and read it from start to finish. These comprehensive yet concise recommendations run for only 7 pages, including two algorithms and six tables (and excluding references). Eight HIV-bone experts authored the guidelines with input from 34 specialists working in 16 countries. At this point Clinical Infectious Diseases has not made the guidelines freely accessible online, but they are available elsewhere.¹

References

1. 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.

2. Sax PE, Saag MS, Yin MT, et al. Renal and bone safety of tenofovir alafenamide vs tenofovir disoproxil fumarate. CROI 2015. February 23-26, 2015. Seattle, Washington. Abstract 143LB.

3. 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.

4. Pinzone MR, Moreno S, Cacopardo B, Nunnari G. Is there enough evidence to use bisphosphonates in HIV-infected patients? A systematic review and meta-analysis. AIDS Rev. 2014;16:213-222.

5. National Institutes of Health. Calcium. Dietary supplement fact sheet.

6. Mangano KM, Walsh SJ, Insogna KL, Kenny AM, Kerstetter JE. Calcium intake in the United States from dietary and supplemental sources across adult age groups: new estimates from the National Health and Nutrition Examination Survey 2003-2006. J Am Diet Assoc. 2011;111:687-695.

7. Li Vecchi V, Soresi M, Giannitrapani L, et al. Dairy calcium intake and lifestyle risk factors for bone loss in HIV-infected and uninfected Mediterranean subjects. BMC Infect Dis. 2012;12:192.

8. Stein EM, Yin MT, McMahon DJ, et al. Vitamin D deficiency in HIV-infected postmenopausal Hispanic and African-American women. Osteoporos Int. 2011;22:477-487.

9. Adeyemi OM, Agniel D, French AL, et al. Vitamin D deficiency in HIV-infected and HIV-uninfected women in the United States. J Acquir Immune Defic Syndr. 2011;57:197-204.

10. Bischoff-Ferrari HA, Willett WC, Orav EJ, et al. A pooled analysis of vitamin D dose requirements for fracture prevention. N Engl J Med. 2012;367:40-49.

11. Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, et al. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ. 2009;339:b3692.

12. Ross AC, Hileman CO, Brown TT, et al. Bone effects of rosiglitazone in HIV-infected patients with lipoatrophy. HIV Clin Trials. 2012;13:212-221.

13. Schindler K, Rieger A, Tura A, et al. The effect of rosiglitazone on insulin sensitivity, beta cell function, bone mineral density, and body composition in HIV-positive patients on highly-active antiretroviral therapy (HAART). Horm Metab Res. 2009;41:573-579.

14. Erlandson KM, Jiang Y, Debanne SM, McComsey GA. Effects of randomized rosuvastatin compared with placebo on bone and body composition among HIV-infected adults. AIDS. 2015;29:175-182.

15. Bauer DC, Mundy GR, Jamal SA, et al. Use of statins and fracture: results of 4 prospective studies and cumulative meta-analysis of observational studies and controlled trials. Arch Intern Med. 2004;164:146-152.

16. Overton ET, Kitch D, Benson CA, et al. Effect of statin therapy in reducing the risk of serious non-AIDS-defining events and nonaccidental death. Clin Infect Dis. 2013;56:1471-1479.

17. Peña JM, Aspberg S, MacFadyen J, Glynn RJ, Solomon DH, Ridker PM. Statin therapy and risk of fracture: results from the JUPITER randomized clinical trial. JAMA Intern Med. 2015;175:171-177.