Ward 86 Management Recommendations
Contributors: Carina Marquez, MD, MPH
Dolores Shoback, MD
Mark Jacobson, MD
Meredith Greene, MD
Annie Luetkemeyer, MD
HIV-infected patients are at an increased risk of osteoporosis and fragility fractures of the hip, vertebrae, humerus, and forearm. Those at highest risk should undergo screening by dual-energy x-ray absorptiometry (DEXA) scan.
Multiple studies have now documented that HIV patients have lower bone mineral density (BMD) and higher rates of osteoporosis and fragility fractures than age-matched controls.(1,2,3,4) In several recent population-based studies, the rate of fragility fractures (defined as fractures of the hip, spine, proximal humerus, or forearm) has been reported to be 2- to 4-fold higher in HIV patients compared with age- and gender-matched controls and remains significantly higher after adjusting for confounding risk factors for osteoporosis such as smoking, body mass index, and alcohol and glucocorticoid use.(2,4) In a large cohort of HIV-infected and HIV-uninfected men, the increase in incidence of osteoporotic fractures occurred at a younger age in HIV-infected men.(3) Although the etiology of osteoporosis is often multifactorial in HIV patients (see list of risk factors highlighted below), HIV alone is associated with an increased prevalence of osteoporosis and fractures, especially among patients with lower CD4 cell count nadirs.(5,6,7)
Initiation of antiretroviral therapy (ART) has been associated with a 2-6% decrease in BMD in the first 48 weeks of therapy.(8,9,10) The effect of ART on fracture risk has not been prospectively studied. The relative losses in BMD with ART initiation depend in part on the antiretroviral regimen.
Initiation of a tenofovir disoproxil fumarate (TDF)-containing regimen in a randomized controlled trial was associated with greater loss in BMD during the first 96 weeks of treatment, compared with a regimen that contained abacavir.(10) In this study, changes from baseline in spine BMD were 1.3% (abacavir) and 3.3% (TDF) (p = .004) and in hip BMD 2.6% (abacavir) and 4.0% (TDF) (p = .024). There was less BMD decline in tenofovir alafenamide (TAF)-containing regimens compared with TDF-containing regimens in both treatment-naive studies and switch studies.(11,12,13)
Protease inhibitors (PIs) also have been associated with declines in BMD.(10,11,12,(13,14) The ACTG 5260 study compared loss in BMD in patients randomized to TDF/emtricitabine plus atazanavir/ritonavir or darunavir/ritonavir or raltegravir.(14) There was no difference in 96-week loss in BMD between the PI arms; however, patients randomized to raltegravir experienced less BMD loss in the spine and hip compared with those on PIs. In another randomized trial, switching to raltegravir was also associated with less BMD loss than continuing a PI.(15) Additional data are needed to assess the impact of dolutegravir on BMD.
There are fewer data on the long-term effects of ART on BMD. A recent study found that, up to 7.5 years after ART initiation, the lumbar BMD continued to decline at a faster rate among HIV-infected patients compared with matched HIV-uninfected controls.(16) Patients were on either TDF/emtricitabine or abacavir/lamivudine plus a PI or efavirenz.
We recommend DEXA screening for osteoporosis for HIV-infected men and postmenopausal women age 50 years and older, in settings in which DEXA is routinely available. This recommendation is based on a large number of studies that suggest HIV is an additional risk factor for osteoporosis and osteoporotic fracture. Though this screening recommendation is consistent with expert opinion, it is not strongly evidence based.(1,17,18)
In settings in which DEXA is not routinely available, patients can be triaged for DEXA screening based on fall history, a Fracture Risk Assessment Tool (FRAX) score of ≥9.3%, or additional risk factors for osteoporosis, such as:
Active use of glucocorticoids or a history of taking the equivalent of ≥5 mg prednisolone daily for ≥3 months
Active use of proton pump inhibitors, aromatase inhibitors, or androgen deprivation therapy
Active tobacco use
History of a parent with a hip fracture
Intake of >3 ounces of alcohol per day
Severe renal or liver disease
Other known causes of secondary osteoporosis, including malnutrition, thyrotoxicosis, and hyperparathyroidism (18)
DEXA should be repeated at an interval based on the baseline BMD measurements, age of the patient, and overall risk profile as determined by the treating clinician.
FRAX is a web-based calculator tool available free of charge here. The FRAX calculation of risks for having a major osteoporosis-associated fracture or a hip fracture in the next 10 years is based on data from women and men and is currently the best available method for quantifying this risk. HIV infection should be considered a cause of secondary osteoporosis in using this calculator, though FRAX may underestimate fracture risk in HIV-infected adults, even after adding HIV as a secondary risk factor.(19) Of note, risk can be calculated without entering BMD as a factor.
Screening of the serum 25-hydroxyvitamin D levels for vitamin D deficiency in the absence of osteoporosis confirmed by DEXA or fragility fractures is controversial. It is important to realize, however, that HIV-infected patients often have concomitant conditions (eg, malabsorption, weight loss, poor nutritional status) or take medications (efavirenz, tenofovir) that can affect vitamin D metabolism and therefore should be considered for assessment of vitamin D status.(20)
HIV patients (age 50 or over) diagnosed with osteopenia (a DEXA T-score of 1 to 2.49) or osteoporosis (T-score of less than 2.5) should have potential secondary causes and lifestyle risk factors investigated and addressed as follows:
A workup for secondary causes of osteoporosis should include serum morning testosterone levels in men and serum 25-hydroxyvitamin D, parathyroid levels, complete blood count, creatinine, thyroid stimulating hormone, serum calcium, and liver function tests in men and women. The risk-benefit profile for testosterone replacement should be considered and only if it is favorable should that treatment be prescribed. Low vitamin D levels should be replaced. There is controversy as to whether the lower limit of normal for serum 25-hydroxyvitamin D should be considered 20 or 30 ng/mL. Optimal replacement therapy for vitamin D deficiency is vitamin D3 (1,000 IU daily).(20)
For patients who take TDF, there are many options for substitution of ART, including the newly approved modified TDF congener tenofovir alafenamide fumarate (TAF) and the nucleoside analogue abacavir (but only if the patient has tested negative for HLA-B*5701 haplotype and has a virus that is susceptible to abacavir). Substitution with an agent from another antiretroviral class also may be an option. There are no data that show an ART switch results in a decreased incidence of fractures in HIV-infected patients with osteoporosis or osteopenia.
Cessation of alcohol use and smoking should be encouraged.
In patients with osteoporosis for whom the contributing causes mentioned above cannot be reversed or treated, bisphosphonate therapy (eg, weekly alendronate) should be administered, particularly for those at risk of falls.
Initiating bisphosphonate therapy also should be strongly considered for any HIV patient who already has sustained a fragility fracture (ie, of hip, vertebrae, humerus, or forearm).
All HIV-infected patients should be encouraged to maintain a diet that provides adequate calcium and vitamin D intake. In the United States, the Institute of Medicine (IOM) publishes age- and gender-specific recommendations for dietary calcium and vitamin D intake.(21) The recommended dietary allowance of calcium is 1,000 mg/day and 600 IU/day of vitamin D for adults up to the age of 70. For those 70 years and older, the IOM recommends 1,200 mg/day of calcium and 800 IU/day of vitamin D. Those who cannot consume sufficient calcium through their diet should be offered calcium supplementation. If, however, there is a history of renal stones, calcium supplements may need to be avoided and further evaluation should be conducted for the presence of additional stones in the kidneys and elevated calcium in the urine.
Patients who are receiving a regimen that includes TDF should have serum phosphorus, serum creatinine, and urine protein monitored at 6-month intervals. For those who have serum phosphorus levels below the lower limit of normal, serum creatinine levels above the upper limit of normal, or 2+ or greater protein or persistent 1+ protein detected in urine, substitution of TDF in the ART regimen should be strongly considered as described above in the Treatment section.
Efavirenz/emtricitabine/TDF (Atripla) is no longer first-line therapy for treatment-naive patients in the United States; however, for HIV-infected patients initiating efavirenz/emtricitabine/TDF, supplementation with daily vitamin D3 (4,000 IU) and daily calcium carbonate (1,000 mg) should be considered on the basis of results from a randomized trial that reported HIV-infected patients initiating efavirenz/emtricitabine/TDF in the active vitamin D/calcium treatment arm had significantly less BMD loss after 48 weeks of ART than those assigned to placebo.(22)
Studies on the use of pharmacologic interventions to prevent BMD loss from ART treatment initiation are ongoing. A small Phase 2b randomized placebo controlled study found that a single dose of zoledronic acid given at the time patients started a TDF-containing ART regimen resulted in a 65% reduction in bone resorption compared with placebo at 24 weeks; larger multicenter randomized trials are under way.(23)
- 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 Oct 15;51(8):937-46.
- Prieto-Alhambra D, Güerri-Fernández R, De Vries F, et al. HIV infection and its association with an excess risk of clinical fractures: a nationwide case-control study. J Acquir Immune Defic Syndr. 2014 May 1;66(1):90-5.
- Gonciulea, AR, Wang R, Althoff KN, et al. Fractures occur at a younger age in HIV+ men in the Multicenter AIDS Cohort Study. In: Program and abstracts of the 2016 Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston. Abstract 699.
- Triant VA, Brown TT, Lee H, et al. 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 Sep;93(9):3499-504.
- Yong MK, Elliott JH, Woolley IJ, et al. Low CD4 count is associated with an increased risk of fragility fracture in HIV-infected patients. J Acquir Immune Defic Syndr. 2011 Jul 1;57(3):205-10.
- Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS. 2006 Nov 14;20(17):2165-74.
- Young B, Dao CN, Buchacz K, et al, HIV Outpatient Study (HOPS) Investigators. Increased rates of bone fracture among HIV-infected persons in the HIV Outpatient Study (HOPS) compared with the US general population, 2000-2006. Clin Infect Dis. 2011 Apr 15;52(8):1061-8.
- Stellbrink HJ, Orkin C, Arribas JR, et al. Comparison of changes in bone density and turnover with abacavir-lamivudine versus tenofovir-emtricitabine in HIV-infected adults: 48-week results from the ASSERT study. Clin Infect Dis. 2010 Oct 15;51(8):963-72.
- Duvivier C, Kolta S, Assoumou L, et al; ANRS 121 Hippocampe study group. Greater decrease in bone mineral density with protease inhibitor regimens compared with nonnucleoside reverse transcriptase inhibitor regimens in HIV-1 infected naive patients. AIDS. 2009 Apr 27;23(7):817-24.
- McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: Aids Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis. 2011 Jun 15;203(12):1791-801.
- Sax PE, Wohl D, Yin MT, et al; GS-US-292-0104/0111 Study Team. 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. 2015 Jun 27;385(9987):2606-15.
- Wohl D, Oka S, Clumeck N, et al; GS-US-292-01040111 and Study Team. Brief report: a randomized, double-blind comparison of tenofovir alafenamide versus tenofovir disoproxil fumarate, each coformulated with elvitegravir, cobicistat, and emtricitabine for initial HIV-1 treatment: week 96 results. J Acquir Immune Defic Syndr. 2016 May 1;72(1):58-64.
- Mills A, Arribas JR, Andrade-Villanueva J, et al; GS-US-292-0109 team. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, non-inferiority study. Lancet Infect Dis. 2016 Jan;16(1):43-52.
- Brown TT, Moser C, Currier JS, et al. Changes in bone mineral density after initiation of antiretroviral treatment with tenofovir disoproxil fumarate/emtricitabine plus atazanavir/ritonavir, darunavir/ritonavir, or raltegravir. J Infect Dis. 2015 Oct 15;212(8):1241-9.
- Curran A, Martinez E, Saumoy M, et al. Body composition changes after switching from protease inhibitors to raltegravir: SPIRAL-LIP substudy. AIDS. 2012 Feb 20;26(4):475-81.
- Grant PM, Kitch D, McComsey GA, et al. Long-term bone mineral density changes in antiretroviral-treated HIV-infected individuals. J Infect Dis. 2016 Aug 15;214(4):607-11.
- Brown TT, Hoy J, Borderi M, et al. Recommendations for evaluation and management of bone disease in HIV. Clin Infect Dis. 2015 Apr 15;60(8):1242-51.
- Cosman F, de Beur SJ, LeBoff MS, et al; National Osteoporosis Foundation. Clinician's guide to prevention and treatment of osteoporosis. Osteoporos Int. 2014 Oct;25(10):2359-81.
- Yin MT, Shiau S, Rimland D, et al. Fracture prediction with modified-FRAX in older HIV-infected and uninfected men. J Acquir Immune Defic Syndr. 2016 Aug 15;72(5):513-20.
- Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Guidelines for preventing and treating vitamin D deficiency and insufficiency revisited. J Clin Endocrinol Metab. 2012 Apr;97(4):1153-8.
- Institute of Medicine of the National Academies. Dietary Reference Intakes for Calcium and Vitamin D.
- Overton ET, Chan ES, Brown TT, et al. Vitamin D and calcium attenuate bone loss with antiretroviral therapy initiation: a randomized trial. Ann Intern Med. 2015 Jun 16;162(12):815-24.
- 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 Off. 2016 Sep 1;63(5):663-71.