Skip to main content

Advertisement

SpringerLink
Log in

Bone Loss Among Women Living With HIV

  • Behavioral-Bio-Medical Interface (JL Brown and RJ DiClemente, Section Editors)
  • Published:
Current HIV/AIDS Reports Aims and scope Submit manuscript

Abstract

Clinical data accumulated over the past two decades attests to a significant decline in bone mineral density (BMD) in patients infected by HIV, which does not remit but may actually intensify with anti-retroviral therapy (ART). Long generally perceived as an aberration without clinical consequences in relatively young HIV-infected cohorts, recent studies have documented marked increases in fracture incidence in HIV-infected men and women over a wide age continuum. Fractures are associated with chronic pain, crippling morbidity, and increased mortality, undermining the gains in quality of life achieved though ART. As bone loss and resulting increases in fracture incidence are a natural consequence of aging, there is now concern regarding the long-term consequences of HIV/ART-associated premature bone loss, given the transition of the HIV/AIDS population into an older age demographic. The development of guidelines for diagnosis and treatment of bone disease within the context of HIV and ART has been an important recent step in raising awareness of the problem and the implications of bone fracture for patient health. Significant progress has also been made in recent years in dissecting the complex and multifactorial mechanisms driving bone loss in HIV/ART and the role of underlying immunological disruption in skeletal dysmorphogenesis. This review examines recent progress in the field and studies by Women’s Interagency HIV Study (WIHS)-associated investigators, inside and outside of the WIHS cohort, aimed at identifying skeletal abnormalities, quantifying facture incidence, management, and understanding underlying mechanisms in people living with HIV in the context of chronic ART.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Riggs BL, Khosla S, Melton 3rd LJ. Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev. 2002;23(3):279–302.

    Article  CAS  PubMed  Google Scholar 

  2. Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev. 2000;21(2):115–37.

    CAS  PubMed  Google Scholar 

  3. Eisman JA, Bogoch ER, Dell R, Harrington JT, McKinney Jr RE, McLellan A, et al. Making the first fracture the last fracture: ASBMR task force report on secondary fracture prevention. J Bone Miner Res. 2012;27(10):2039–46.

    Article  PubMed  Google Scholar 

  4. Bass E, French DD, Bradham DD, Rubenstein LZ. Risk-adjusted mortality rates of elderly veterans with hip fractures. Ann Epidemiol. 2007;17(7):514–9.

    Article  PubMed  Google Scholar 

  5. Khosla S. Minireview: the OPG/RANKL/RANK system. Endocrinology. 2001;142(12):5050–5.

    Article  CAS  PubMed  Google Scholar 

  6. Teitelbaum SL. Bone resorption by osteoclasts. Science. 2000;289(5484):1504–8.

    Article  CAS  PubMed  Google Scholar 

  7. Yun TJ, Chaudhary PM, Shu GL, Frazer JK, Ewings MK, Schwartz SM, et al. OPG/FDCR-1, a TNF receptor family member, is expressed in lymphoid cells and is up-regulated by ligating CD40. J Immunol. 1998;161(11):6113–21.

    CAS  PubMed  Google Scholar 

  8. Li Y, Toraldo G, Li A, Yang X, Zhang H, Qian WP, et al. B cells and T cells are critical for the preservation of bone homeostasis and attainment of peak bone mass in vivo. Blood. 2007;109(9):3839–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Weitzmann MN, Ofotokun I. Physiological and pathophysiological bone turnover—role of the immune system. Nat Rev Endocrinol. 2016. In Press.

  10. 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):3499–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Vikulina T, Fan X, Yamaguchi M, Roser-Page S, Zayzafoon M, Guidot DM, et al. Alterations in the immuno-skeletal interface drive bone destruction in HIV-1 transgenic rats. Proc Natl Acad Sci U S A. 2010;107(31):13848–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Titanji K, Vunnava A, Sheth AN, Delille C, Lennox JL, Sanford SE, et al. Dysregulated B cell expression of RANKL and OPG correlates with loss of bone mineral density in HIV infection. PLoS Pathog. 2014;10(10):e1004497. This was the first study to link an immunoskeletal defect to bone loss in humans with HIV infection and to show a correlation between the B cell RANKL/OPG ratio and BMD in humans with HIV infection.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lencel P, Magne D. Inflammaging: the driving force in osteoporosis? Med Hypotheses. 2011;76(3):317–21.

    Article  CAS  PubMed  Google Scholar 

  14. Indridason OS, Franzson L, Sigurdsson G. Serum osteoprotegerin and its relationship with bone mineral density and markers of bone turnover. Osteoporos Int. 2005;16(4):417–23.

    Article  CAS  PubMed  Google Scholar 

  15. Khosla S, Arrighi HM, Melton 3rd LJ, Atkinson EJ, O’Fallon WM, Dunstan C, et al. Correlates of osteoprotegerin levels in women and men. Osteoporos Int. 2002;13(5):394–9.

    Article  CAS  PubMed  Google Scholar 

  16. Li Y, Terauchi M, Vikulina T, Roser-Page S, Weitzmann MN. B Cell Production of Both OPG and RANKL is Significantly Increased in Aged Mice. Open Bone J. 2014;6:8–17. It has been shown in humans that OPG increases with age and likely protects against more aggressive bone loss. This mouse study showed that B cells are the likely source of compensatory OPG.

    PubMed  PubMed Central  Google Scholar 

  17. Eghbali-Fatourechi G, Khosla S, Sanyal A, Boyle WJ, Lacey DL, Riggs BL. Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J Clin Invest. 2003;111(8):1221–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Adeel S, Singh K, Vydareny KH, Kumari M, Shah E, Weitzmann MN, et al. Bone loss in surgically ovariectomized premenopausal women is associated with T lymphocyte activation and thymic hypertrophy. J Investig Med. 2013;61(8):1178–83.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Cenci S, Weitzmann MN, Roggia C, Namba N, Novack D, Woodring J, et al. Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-alpha. J Clin Invest. 2000;106(10):1229–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lam J, Takeshita S, Barker JE, Kanagawa O, Ross FP, Teitelbaum SL. TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest. 2000;106(12):1481–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhang YH, Heulsmann A, Tondravi MM, Mukherjee A, Abu-Amer Y. Tumor necrosis factor-alpha (TNF) stimulates RANKL-induced osteoclastogenesis via coupling of TNF type 1 receptor and RANK signaling pathways. J Biol Chem. 2001;276(1):563–8.

    Article  CAS  PubMed  Google Scholar 

  22. Fuller K, Murphy C, Kirstein B, Fox SW, Chambers TJ. TNFalpha potently activates osteoclasts, through a direct action independent of and strongly synergistic with RANKL. Endocrinology. 2002;143(3):1108–18.

    CAS  PubMed  Google Scholar 

  23. Brown TT, McComsey GA, King MS, Qaqish RB, Bernstein BM, da Silva BA. Loss of bone mineral density after antiretroviral therapy initiation, independent of antiretroviral regimen. J Acquir Immune Defic Syndr. 2009;51(5):554–61.

    Article  CAS  PubMed  Google Scholar 

  24. Ofotokun I, Titanji K, Vikulina T, Roser-Page S, Yamaguchi M, Zayzafoon M, et al. Role of T-cell reconstitution in HIV-1 antiretroviral therapy-induced bone loss. Nat Commun. 2015;6:8282. This study shows a proof of concept that T cell reconstitution/immune activation associated with ART may underlie the bone loss common to all ART types.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ofotokun I, Titanji K, Vunnava A, Roser-Page S, Vikulina T, Villinger F, et al. Antiretroviral therapy induces a rapid increase in bone resorption that is positively associated with the magnitude of immune reconstitution in HIV infection. AIDS. 2016;30(3):405–14. This study shows a significant correlation between the magnitude of T cell reconstitution following ART-initiation and bone resorption.

    Article  CAS  PubMed  Google Scholar 

  26. Ofotokun I, Titanji K, Lahiri CD, Vunnava A, Foster A, Sanford SE 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--71. This study demonstrates that a single prophylactic dose of zoledronic acid can completely prevent bone loss associated with ART over 48 weeks.

  27. Anastos K, Lu D, Shi O, Mulligan K, Tien PC, Freeman R, et al. The association of bone mineral density with HIV infection and antiretroviral treatment in women. Antivir Ther. 2007;12(7):1049–58.

    CAS  PubMed  Google Scholar 

  28. Arnsten JH, Freeman R, Howard AA, Floris-Moore M, Santoro N, Schoenbaum EE. HIV infection and bone mineral density in middle-aged women. Clin Infect Dis. 2006;42(7):1014–20.

    Article  CAS  PubMed  Google Scholar 

  29. Dolan SE, Huang JS, Killilea KM, Sullivan MP, Aliabadi N, Grinspoon S. Reduced bone density in HIV-infected women. AIDS. 2004;18(3):475–83.

    Article  PubMed  Google Scholar 

  30. Prior J, Burdge D, Maan E, Milner R, Hankins C, Klein M, et al. Fragility fractures and bone mineral density in HIV positive women: a case-control population-based study. Osteoporos Int. 2007;18(10):1345–53.

    Article  CAS  PubMed  Google Scholar 

  31. Teichmann J, Stephan E, Lange U, Discher T, Friese G, Lohmeyer J, et al. Osteopenia in HIV-infected women prior to highly active antiretroviral therapy. J Infect. 2003;46(4):221–7.

    Article  CAS  PubMed  Google Scholar 

  32. Yin M, Dobkin J, Brudney K, Becker C, Zadel JL, Manandhar M, et al. Bone mass and mineral metabolism in HIV+ postmenopausal women. Osteoporos Int. 2005;16(11):1345–52.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Yin MT, Lu D, Cremers S, Tien PC, Cohen MH, Shi Q, et al. Short-term bone loss in HIV-infected premenopausal women. J Acquir Immune Defic Syndr. 2010;53(2):202–8.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Yin MT, Zhang CA, McMahon DJ, Ferris DC, Irani D, Colon I, et al. Higher rates of bone loss in postmenopausal HIV-infected women: a longitudinal study. J Clin Endocrinol Metab. 2012;97(2):554–62.

    Article  CAS  PubMed  Google Scholar 

  35. Yin MT, Shu A, Zhang CA, Boutroy S, McMahon DJ, Ferris DC, et al. Trabecular and cortical microarchitecture in postmenopausal HIV-infected women. Calcif Tissue Int. 2013;92(6):557-65.

  36. Sharma A, Tian F, Yin MT, Keller MJ, Cohen M, Tien PC. Association of regional body composition with bone mineral density in HIV-infected and HIV-uninfected women: Women’s Interagency HIV Study. J Acquir Immune Defic Syndr. 2012;61(4):469–76.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Sharma A MY, Scherzer R, Wheeler AL, Cohen M, Gustafson D, Yin MT, Tien PC, editors. Association of adipokines with bone mineral density in HIV+ and HIV women. Program and Abstracts of 22nd Conference on Retroviruses and Opportunistic Infections; Seattle, WA; 2015.

  38. Yin MT, Shi Q, Hoover DR, Anastos K, Sharma A, Young M, et al. Fracture incidence in HIV-infected women: results from the Women’s Interagency HIV Study. AIDS. 2010;24(17):2679–86.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Sharma A, Shi Q, Hoover DR, Anastos K, Tien PC, Young MA, et al. Increased fracture incidence in middle-aged HIV-infected and HIV-uninfected women: updated results from the Women’s Interagency HIV Study. J Acquir Immune Defic Syndr. 2015;70(1):54–61. This follow up study revealed a two-fold increase in fracture incidence in the 5 years since the previous study in the WIHS. Just 5 years of aging of the WIHS women had a dramatic effect on fracture prevalence.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Sharma A HD, Shi Q, Holman S, Plankey MW, Wheeler AL, Weber K, Golub ET, Holstad MK, Yin MT, editors. Prevalence of falls among older women in the Women’s Interagency HIV Study. Program and Abstracts of 23rd Conference on Retroviruses and Opportunistic Infections; Boston, MA; 2016.

Download references

Author information

Authors and Affiliations

  1. The Atlanta Department of Veterans Affairs Medical Center, 1670 Clairmont Road, Decatur, GA, 30033, USA

    M. Neale Weitzmann

  2. Department of Medicine, Division of Endocrinology and Metabolism and Lipids, Emory University School of Medicine, 101 Woodruff Circle, 1305 WMB, Atlanta, GA, 30322, USA

    M. Neale Weitzmann & Kehmia Titanji

  3. Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, 49 Jesse Hill Jr Drive, Atlanta, GA, 30303, USA

    Ighovwerha Ofotokun

  4. Grady Healthcare System, 80 Jesse Hill Jr Drive SE, Atlanta, GA, 30303, USA

    Ighovwerha Ofotokun

  5. Divisions of General Internal Medicine and Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave, Block Bldg #305, Bronx, NY, 10461, USA

    Anjali Sharma

  6. Division of Infectious Diseases, Columbia University Medical Center, 630 West 168th Street, PH8-876, New York, NY, 10032, USA

    Michael T. Yin

Authors
  1. M. Neale Weitzmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ighovwerha Ofotokun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kehmia Titanji
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anjali Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael T. Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Neale Weitzmann.

Ethics declarations

Conflict of Interest

M. Neale Weitzmann is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) under award numbers R01AR059364 and R01AR070091 and by the National Institute on Aging (NIA) under award number R01AG040013 and is supported by a grant from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development (5I01BX000105).

Ighovwerha Ofotokun is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) under award numbers R01AR059364 and R01AR070091 and by the National Institute on Aging (NIA) under award number R01AG040013.

Kehmia Titanji is supported by a grant from the Emory University Research Council (URC); has received a grant from the National Heart, Lung, and Blood Institute (NHLBI) under award number K01HL131333; and has received travel support from NIH.

Anjali Sharma is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) under award number K23AR061993.

Michael T. Yin is supported by a grant from the National Institute of Allergy and Infectious Diseases (NIAID) under award number R01AI095089 and has received travel support for WIHS meetings.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Behavioral-Bio-Medical Interface

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Weitzmann, M.N., Ofotokun, I., Titanji, K. et al. Bone Loss Among Women Living With HIV. Curr HIV/AIDS Rep 13, 367–373 (2016). https://doi.org/10.1007/s11904-016-0336-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11904-016-0336-6

Keywords

Search

Navigation