Bone Health in Human Immunodeficiency Virus Infection - Infectious Disease Advisor

Bone Health in Human Immunodeficiency Virus Infection

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  • In a meta-analytic review that included 884 patients with HIV, 67% were found to have reduced BMD.2 Of these individuals, 15% had osteoporosis. When compared with a pooled analysis of HIV-negative uninfected controls from 11 other studies, individuals who were HIV positive were found to be 3.7 times more likely to have osteoporosis develop. Risk for reduced BMD was increased with ART, with ART-treated patients having a 2.5-fold increased risk for reduced BMD compared with patients who had never received ART. Protease inhibitor-treated patients also had an increased risk for reduced BMD vs those not treated with protease inhibitors.2

    Prevalence of Low Bone Mineral Density in HIV

    In a meta-analytic review that included 884 patients with HIV, 67% were found to have reduced BMD.2 Of these individuals, 15% had osteoporosis. When compared with a pooled analysis of HIV-negative uninfected controls from 11 other studies, individuals who were HIV positive were found to be 3.7 times more likely to have osteoporosis develop. Risk for reduced BMD was increased with ART, with ART-treated patients having a 2.5-fold increased risk for reduced BMD compared with patients who had never received ART. Protease inhibitor-treated patients also had an increased risk for reduced BMD vs those not treated with protease inhibitors.2

  • Patients with HIV have been found to have reduced bone size, mass, and strength.1 HIV is known to affect cells in the bones directly and to alter vitamin D and phosphate metabolism, which contribute to impaired mineralization and low BMD. HIV is also thought to interrupt the cross-talk between osteoblasts and osteoclasts, impairing bone remodeling and resulting in reduced bone mass.3 Despite HIV having a direct impact on bone health, the pathogenesis of bone perturbations in this population is thought to be multifactorial, likely resulting from a complex interaction among HIV infection, traditional osteoporosis risk factors that are amplified in the setting of chronic HIV infection (eg, poor nutrition, low body mass index), high rates of alcohol and tobacco use, low vitamin D levels, advancing age, and treatment-related factors.1,3,4

    Etiology of Bone Perturbations in HIV

    Patients with HIV have been found to have reduced bone size, mass, and strength.1 HIV is known to affect cells in the bones directly and to alter vitamin D and phosphate metabolism, which contribute to impaired mineralization and low BMD. HIV is also thought to interrupt the cross-talk between osteoblasts and osteoclasts, impairing bone remodeling and resulting in reduced bone mass.3 Despite HIV having a direct impact on bone health, the pathogenesis of bone perturbations in this population is thought to be multifactorial, likely resulting from a complex interaction among HIV infection, traditional osteoporosis risk factors that are amplified in the setting of chronic HIV infection (eg, poor nutrition, low body mass index), high rates of alcohol and tobacco use, low vitamin D levels, advancing age, and treatment-related factors.1,3,4

  • Vitamin D is essential for maintaining normal bone structure and increasing the bioavailability of phosphorus, ensuring adequate mineralization. Vitamin D deficiency is a common problem, but it is particularly pervasive among HIV-positive individuals, with prevalence rates reaching 85%.5 Many non-HIV- and HIV-related risk factors can contribute to low vitamin D levels in these patients. Common non-HIV-related risk factors include limited sun exposure, low dietary intake of vitamin D, and advanced age. HIV-related risk factors may include use of highly active ART, which has been shown to exacerbate vitamin D deficiency, and HIV-related chronic kidney inflammation, which inhibits conversion of calcifediol, a prehormone produced in the liver by hydroxylation of vitamin D3, to calcitriol, the hormonally active metabolite of vitamin D. Subsequently, vitamin D status should be assessed regularly in HIV-infected patients and vitamin D supplementation given when needed.6

    Vitamin D Deficiency in HIV

    Vitamin D is essential for maintaining normal bone structure and increasing the bioavailability of phosphorus, ensuring adequate mineralization. Vitamin D deficiency is a common problem, but it is particularly pervasive among HIV-positive individuals, with prevalence rates reaching 85%.5 Many non-HIV- and HIV-related risk factors can contribute to low vitamin D levels in these patients. Common non-HIV-related risk factors include limited sun exposure, low dietary intake of vitamin D, and advanced age. HIV-related risk factors may include use of highly active ART, which has been shown to exacerbate vitamin D deficiency, and HIV-related chronic kidney inflammation, which inhibits conversion of calcifediol, a prehormone produced in the liver by hydroxylation of vitamin D3, to calcitriol, the hormonally active metabolite of vitamin D. Subsequently, vitamin D status should be assessed regularly in HIV-infected patients and vitamin D supplementation given when needed.6

  • Osteomalacia is a softening of the bones as a result of defective bone mineralization. It is often caused by severe vitamin D deficiency, and in patients with HIV, it has also been associated with use of tenofovir disoproxil fumarate (TDF), an adenine analogue reverse transcriptase inhibitor that is often combined with other ART to treat HIV.3,7,8 TDF use can result in hypophosphatemia, Fanconi syndrome, and nephrotoxicity, including proximal tubulopathy, all of which can contribute to the development of osteomalacia.8 TDF-related osteomalacia has been observed in adult and pediatric patients, with risk increased in those also receiving a boosted protease inhibitor.8 Patients with severe osteomalacia may have bone pain, muscle weakness, and stiffness. Laboratory abnormalities include low calcium and phosphorus levels, low calcifediol levels, and elevated alkaline phosphatase and parathyroid hormone levels. TDF-related osteomalacia can often be reversed with TDF withdrawal.8 Photo Credit: Biophoto Associates/Science Source

    Osteomalacia in HIV

    Osteomalacia is a softening of the bones as a result of defective bone mineralization. It is often caused by severe vitamin D deficiency, and in patients with HIV, it has also been associated with use of tenofovir disoproxil fumarate (TDF), an adenine analogue reverse transcriptase inhibitor that is often combined with other ART to treat HIV.3,7,8 TDF use can result in hypophosphatemia, Fanconi syndrome, and nephrotoxicity, including proximal tubulopathy, all of which can contribute to the development of osteomalacia.8 TDF-related osteomalacia has been observed in adult and pediatric patients, with risk increased in those also receiving a boosted protease inhibitor.8 Patients with severe osteomalacia may have bone pain, muscle weakness, and stiffness. Laboratory abnormalities include low calcium and phosphorus levels, low calcifediol levels, and elevated alkaline phosphatase and parathyroid hormone levels. TDF-related osteomalacia can often be reversed with TDF withdrawal.8 Photo Credit: Biophoto Associates/Science Source

  • Osteopenia is a reduction in BMD, with a T-score between −1 and −2.49.4 Because individuals with osteopenia are at increased risk for progression to osteoporosis, it is recommended that the World Health Organization Fracture Risk Assessment Tool (FRAX) be used to calculate the 10-year risk for major osteoporotic fracture and hip fracture in these patients.4 If the 10-year risk for major osteoporotic fracture is ≥20% or the risk of hip fracture is ≥3%, initiation of pharmacologic therapy may be warranted.4 In HIV-positive patients, the bisphosphonates alendronate and zoledronic acid have been associated with increased BMD and good tolerability.4,9 However, the impact of bisphosphonates on fracture risk in this setting remains unclear.9

    Osteopenia in HIV

    Osteopenia is a reduction in BMD, with a T-score between −1 and −2.49.4 Because individuals with osteopenia are at increased risk for progression to osteoporosis, it is recommended that the World Health Organization Fracture Risk Assessment Tool (FRAX) be used to calculate the 10-year risk for major osteoporotic fracture and hip fracture in these patients.4 If the 10-year risk for major osteoporotic fracture is ≥20% or the risk of hip fracture is ≥3%, initiation of pharmacologic therapy may be warranted.4 In HIV-positive patients, the bisphosphonates alendronate and zoledronic acid have been associated with increased BMD and good tolerability.4,9 However, the impact of bisphosphonates on fracture risk in this setting remains unclear.9

  • Osteoporosis is a reduction in BMD significant enough to greatly increase fracture risk, with a T-score of −2.5 or lower.4 The disease is asymptomatic, with the first indication often being a fracture. Subsequently, patients who experience a fragility fracture secondary to minimal trauma should also be considered to have osteoporosis.10 Because HIV and its treatments are known to induce bone loss, BMD investigations should be considered for these patients.10 Such investigations are especially important in the setting of additional risk factors for osteoporosis and fractures. In patients living with HIV, the most frequent risk factors associated with bone loss, even in the setting of long-duration infection, include advanced age, smoking, white race, low weight, and low body mass index.10

    Osteoporosis in HIV

    Osteoporosis is a reduction in BMD significant enough to greatly increase fracture risk, with a T-score of −2.5 or lower.4 The disease is asymptomatic, with the first indication often being a fracture. Subsequently, patients who experience a fragility fracture secondary to minimal trauma should also be considered to have osteoporosis.10 Because HIV and its treatments are known to induce bone loss, BMD investigations should be considered for these patients.10 Such investigations are especially important in the setting of additional risk factors for osteoporosis and fractures. In patients living with HIV, the most frequent risk factors associated with bone loss, even in the setting of long-duration infection, include advanced age, smoking, white race, low weight, and low body mass index.10

  • Osteonecrosis occurs when there is a loss of blood supply to the bones, starving the cells needed to create new bone. This causes the shape of the bone to change and impairs joint movement, which can lead to debilitating pain. Osteonecrosis usually affects the hips, but the shoulders and knees may also be affected.11 A study conducted by the National Institutes of Health found that people living with HIV have a 100-fold greater risk for osteonecrosis than the general population.12 The etiology of osteonecrosis in people with HIV is thought to be multifactorial, including factors such as impaired fat metabolism and/or impaired coagulation from increased inflammation, both of which can lead to blood clots that can reduce or cut off blood supply; long-term use of anti-inflammatory agents such as prednisone or hydrocortisone; and lifestyle factors such as heavy smoking and alcohol use.11 Thus far, no evidence has linked any specific anti-HIV drugs to the condition.11 Photo Credit: James Cavallini/Science Source

    Osteonecrosis in HIV

    Osteonecrosis occurs when there is a loss of blood supply to the bones, starving the cells needed to create new bone. This causes the shape of the bone to change and impairs joint movement, which can lead to debilitating pain. Osteonecrosis usually affects the hips, but the shoulders and knees may also be affected.11 A study conducted by the National Institutes of Health found that people living with HIV have a 100-fold greater risk for osteonecrosis than the general population.12 The etiology of osteonecrosis in people with HIV is thought to be multifactorial, including factors such as impaired fat metabolism and/or impaired coagulation from increased inflammation, both of which can lead to blood clots that can reduce or cut off blood supply; long-term use of anti-inflammatory agents such as prednisone or hydrocortisone; and lifestyle factors such as heavy smoking and alcohol use.11 Thus far, no evidence has linked any specific anti-HIV drugs to the condition.11 Photo Credit: James Cavallini/Science Source

  • Dual energy x-ray absorptiometry (DEXA) is the gold-standard for determining loss of BMD, and its use is appropriate to assess the risk for fragility fracture and low BMD in all adults with HIV.1 Major risk factors for fragility fracture include a history of fragility fracture, use of glucocorticoid treatment for >3 months (or ≥5 mg of prednisone daily or equivalent), and the presence of risk factors for falls.13 People with HIV who have these risk factors should receive a baseline DEXA, which should be repeated every 1 to 2 years for advanced osteopenia (T-score, −2.00 to −2.49) and every 5 years for mild to moderate osteopenia (T-score, −1.01 to −1.99).13 Patients started on bisphosphonates should undergo repeat DEXA in 2 years. 13 Adult patients with HIV with no risk factors for fragility facture or osteoporosis should have their 10-year risk for fracture assessed using the FRAX. Patients with a FRAX score ≤10% can be reassessed in 2 to 3 years.13 A FRAX score ≥10% warrants DEXA.13

    Monitoring Bone Health in HIV

    Dual energy x-ray absorptiometry (DEXA) is the gold-standard for determining loss of BMD, and its use is appropriate to assess the risk for fragility fracture and low BMD in all adults with HIV.1 Major risk factors for fragility fracture include a history of fragility fracture, use of glucocorticoid treatment for >3 months (or ≥5 mg of prednisone daily or equivalent), and the presence of risk factors for falls.13 People with HIV who have these risk factors should receive a baseline DEXA, which should be repeated every 1 to 2 years for advanced osteopenia (T-score, −2.00 to −2.49) and every 5 years for mild to moderate osteopenia (T-score, −1.01 to −1.99).13 Patients started on bisphosphonates should undergo repeat DEXA in 2 years. 13 Adult patients with HIV with no risk factors for fragility facture or osteoporosis should have their 10-year risk for fracture assessed using the FRAX. Patients with a FRAX score ≤10% can be reassessed in 2 to 3 years.13 A FRAX score ≥10% warrants DEXA.13

  • Patients with HIV should be counseled about HIV’s impact on bone health and about dietary and lifestyle changes they can undertake to protect their bone health. Important dietary considerations include ensuring adequate calcium and vitamin D intake.13 Those with a low BMD or a history of fracture should undergo assessment of vitamin D levels, and those with vitamin D insufficiency (<20 ng/mL) should receive supplementary vitamin D.13 Important lifestyle measures for those with osteopenia and osteoporosis include engaging in regular physical activity, particularly weight-bearing and muscle-strengthening exercises; smoking cessation; and avoiding excessive alcohol consumption.13 Individuals at risk for fragility fractures should also be advised to take steps to prevent falls.13

    Protecting Bone Health in HIV

    Patients with HIV should be counseled about HIV’s impact on bone health and about dietary and lifestyle changes they can undertake to protect their bone health. Important dietary considerations include ensuring adequate calcium and vitamin D intake.13 Those with a low BMD or a history of fracture should undergo assessment of vitamin D levels, and those with vitamin D insufficiency (<20 ng/mL) should receive supplementary vitamin D.13 Important lifestyle measures for those with osteopenia and osteoporosis include engaging in regular physical activity, particularly weight-bearing and muscle-strengthening exercises; smoking cessation; and avoiding excessive alcohol consumption.13 Individuals at risk for fragility fractures should also be advised to take steps to prevent falls.13

  • In people living with HIV, anti-osteoporosis treatment should be initiated following guidelines for the general population.13 In those with concomitant vitamin D insufficiency, vitamin level should be restored to ≥30 ng/dL before bisphosphonate therapy is started, as research has shown that patients with these levels are more likely to achieve improved BMD with bisphosphonate therapy. 13,14 Oral (alendronate, risedronate, or ibandronate) or intravenous bisphosphonates (ibandronate or zoledronic acid) can be considered, with the latter preferred for patients who do not tolerate or who are not compliant with oral bisphosphonate therapy. Bisphosphonate treatment should be assessed after 3 to 5 years to determine whether its use should continue, as there are concerns about adverse effects with long-term bisphosphonate use, such as osteonecrosis of the jaw. 13

    Managing Osteoporosis in HIV

    In people living with HIV, anti-osteoporosis treatment should be initiated following guidelines for the general population.13 In those with concomitant vitamin D insufficiency, vitamin level should be restored to ≥30 ng/dL before bisphosphonate therapy is started, as research has shown that patients with these levels are more likely to achieve improved BMD with bisphosphonate therapy. 13,14 Oral (alendronate, risedronate, or ibandronate) or intravenous bisphosphonates (ibandronate or zoledronic acid) can be considered, with the latter preferred for patients who do not tolerate or who are not compliant with oral bisphosphonate therapy. Bisphosphonate treatment should be assessed after 3 to 5 years to determine whether its use should continue, as there are concerns about adverse effects with long-term bisphosphonate use, such as osteonecrosis of the jaw. 13

Bone Health in HIV

People living with HIV have a higher prevalence of low bone mineral density (BMD), osteomalacia, osteopenia, osteoporosis, and osteonecrosis than age-matched individuals without HIV.1 Although highly active antiretroviral therapy (ART) has enabled people infected with HIV to achieve normal life expectancies, its use has been associated with reduced BMD and other bone health problems. Subsequently, as the HIV-positive population continues to age, screening for low BMD and addressing bone health will become increasingly important to prevent fractures and other injuries and to improve their overall quality of life.

Compiled by Christina T. Loguidice

References

  1. Kruger MJ, Nell TA. Bone mineral density in people living with HIV: a narrative review of the literature. AIDS Res Ther. 2017;14:35.
  2. Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS. 2006;20(17):2165-2174.
  3. Borderi M, Gibellini D, Vescini F, et al. Metabolic bone disease in HIV infection. AIDS. 2009;23(11):1297-1310.
  4. 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):937-946.
  5. Jiménez-Sousa MÁ, Martínez I, Medrano LM, Fernández-Rodríguez A, Resino S. Vitamin D in human immunodeficiency virus infection: influence on immunity and disease. Front Immunol. 2018;9:458.
  6. Conesa-Botella A, Florence E, Lynen L, Colebunders R, Menten J, Moreno-Reyes R. Decrease of vitamin D concentration in patients with HIV infection on a non nucleoside reverse transcriptase inhibitor-containing regimen. AIDS Res Ther. 2010;7:40.
  7. Matovu FK, Wattanachanya L, Beksinska M, Pettifor JM, Ruxrungtham K. Bone health and HIV in resource-limited settings: a scoping review. Curr Opin HIV AIDS. 2016;11(3):306-325.
  8. Lucey JM, Hsu P, Ziegler JB. Tenofovir-related Fanconi’s syndrome and osteomalacia in a teenager with HIV. BMJ Case Rep. 2013;2013:bcr2013008674.
  9. 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(4):213-222.
  10. Lima ALLM, de Oliveira PRD, Plapler PG, et al. Osteopenia and osteoporosis in people living with HIV: multiprofessional approach. HIV/AIDS (Auckl). 2011;3:117-124.
  11. International Association of Providers of AIDS Care. Osteonecrosis. Fact Sheet 559. aidsinfonet.org. Reviewed September 30, 2014. Accessed September 29, 2018.
  12. Morse CG, Mican JM, Jones EC, et al. The incidence and natural history of osteonecrosis in HIV-infected adults. Clin Infect Dis. 2007;44(5):739-748.
  13. 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.
  14. Derk CT, Patel R, Rhee RL, et al. Determination of vitamin D level prior to the initiation of bisphosphonate therapy. Presented at: 2013 American College of Rheumatology (ACR)/Association of Rheumatology Health Professionals (ARHP) Annual Meeting; October 25-30, 2013; San Diego, CA. Abstract 1217.
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