Review
HIV and bone disease

https://doi.org/10.1016/j.abb.2010.07.029Get rights and content

Abstract

Advances in management have resulted in a dramatic decline in mortality for individuals infected with human immunodeficiency virus (HIV). This decrease in mortality, initially the result of improved prophylaxis and treatment of opportunistic infections but later mediated by the use of highly-active antiretroviral therapy (HAART) has led to the need to consider long-term complications of the disease itself, or its treatment. Bone disease is increasingly recognised as a concern.

The prevalence of reduced BMD and possibly also fracture incidence are increased in HIV-positive individuals compared with HIV-negative controls. There are many potential explanations for this – an increased prevalence of established osteoporosis risk factors in the HIV-positive population, a likely direct effect of HIV infection itself and a possible contributory role of ARV therapy. At present, the assessment of bone disease and fracture risk remains patchy, with little or no guidance on identifying those at increased risk of reduced BMD or fragility fracture. Preventative and therapeutic strategies with bone specific treatments need to be developed. Limited data suggest bisphosphonates may be beneficial in conjunction with vitamin D and calcium supplementation in the treatment of reduced BMD in HIV-infected patients but larger studies of longer duration are needed. The safety and cost-effectiveness of these and other treatments needs to be evaluated.

Research highlights

► HIV is associated with increased fracture risk but mechanisms remain unclear. ► Lifestyle factors need to be addressed. ► Vitamin D deficiency is common but role of replacement needs evaluation. ► The direct impact of anti-retroviral therapy on bone loss remains contentious.

Introduction

Advances in anti-retroviral therapy have resulted in a dramatic decline in mortality for individuals infected with human immunodeficiency virus (HIV)1 and have ensured HIV-positive individuals are living longer [1]. A fall in the incidence of new HIV infections has been offset by the dramatic decline in the mortality associated with acquired immune deficiency syndrome (AIDS), so that the prevalence of HIV infection continues to increase globally, with an estimated 42 million people infected worldwide [2]. A Danish population-based cohort study has estimated the median survival for a young person diagnosed with HIV infection between 2000 and 2005 to be more than 35 years [3]. A multinational collaboration of HIV cohort studies in Europe and North America has estimated the average number of years remaining to be lived in a 20 year old infected with HIV to be at least two-thirds that of the general population and this figure will likely continue to rise with advances in therapy [4].

The decrease in mortality in HIV-infected persons initially was the result of improved prophylaxis and treatment of opportunistic infections but was considerably accelerated with the introduction of highly-active antiretroviral therapy (HAART) – the use of combinations of three or more anti-retroviral (ARV) agents – in the mid-1990s [1].

In the post-HAART era, opportunistic infections have been replaced by long-term complications of HIV infection itself and of HAART, resulting in cardiovascular, renal or hepatic toxicity [5], or in a range of metabolic complications [6]. Over the past decade, reduced bone mineral density (BMD) has emerged as one of these complications (as reviewed by Amorosa et al. [7]). There is an increasing concern that this could lead to a fragility fracture epidemic in an ageing cohort of individuals living with HIV infection, with related consequences for HIV-associated morbidity and mortality. The surveillance and treatment of these complications will increasingly be a focus of HIV care as the HIV-positive population ages.

In this review we discuss evidence linking metabolic bone disease to HIV infection and its treatment, with an emphasis on the extent of the problem, the risk factors, the pathogenic mechanisms, clinical assessment and management.

Section snippets

Prevalence

Heterogeneous cross-sectional cohort studies, performed over the past ten years, have described a significantly higher prevalence of bone disease in HIV-positive individuals when compared to age-, race- and sex-matched HIV-negative individuals (see Table 1) [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27]. The prevalence of reduced BMD in HIV-infected individuals – defined as a T-score <−1 when measured by Dual X-ray

HIV-independent risk factors

Validated risk factors for reduced BMD and fragility fracture are well established for the general population [35]. In addition to previous fragility fracture and low BMD at the femoral neck, these include: increasing age; low BMI; parental history of hip fracture; glucocorticoid exposure; rheumatoid arthritis; current smoking; alcohol consumption ⩾3 units per day; hypogonadism, including post-menopausal status in women; prolonged immobility; malabsorption and liver cirrhosis [35]. In addition,

Fracture risk assessment in HIV-positive individuals

As stated previously, the HIV-positive population has a high prevalence of risk factors for metabolic bone disease and increased fracture risk. To date, however, there have been no published studies on the use of osteoporosis risk or fracture risk assessment tools in HIV-positive individuals.

Recently, the WHO Collaborating Centre for Metabolic Bone Diseases in Sheffield has undertaken a comprehensive review and a number of meta-analyses of published risk factors within the general population.

Conclusions

The prevalence of reduced BMD and possibly also fracture incidence are increased in HIV-positive individuals compared with HIV-negative controls. There are many potential explanations for this – an increased prevalence of established osteoporosis risk factors in the HIV-positive population, a likely direct effect of HIV infection itself and a possible contributory role of ARV therapy – with potential mechanisms identified for both HIV infection and ARV therapies. At present there is no adequate

References (133)

  • S. Loiseau-Peres et al.

    Joint Bone Spine

    (2002)
  • J. Teichmann et al.

    J. Infect.

    (2003)
  • A. Fausto et al.

    Bone

    (2006)
  • E.M. Haney et al.

    Bone

    (2010)
  • G. Meintjes et al.

    Lancet Infect. Dis.

    (2008)
  • A.S. Dobs et al.

    Am. J. Med.

    (1988)
  • M. Clerici et al.

    Immunol. Today

    (1993)
  • J.M. Fakruddin et al.

    J. Biol. Chem.

    (2003)
  • Y.Y. Kong et al.

    Immunol. Today

    (2000)
  • J.P. Herbeuval et al.

    Blood

    (2005)
  • S. Srivastava et al.

    J. Biol. Chem.

    (2001)
  • B.R. Wong et al.

    Mol. Cell.

    (1999)
  • A.P. Malizia et al.

    Antiviral. Res.

    (2007)
  • R.G. Jain et al.

    J. Biol. Chem.

    (2002)
  • R. Modarresi et al.

    Am. J. Pathol.

    (2009)
  • I.F. Grigsby et al.

    Biochem. Biophys. Res. Commun.

    (2010)
  • I.F. Grigsby et al.

    Biochem. Biophys. Res. Commun.

    (2010)
  • F.J. Palella et al.

    N. Engl. J. Med.

    (1998)
  • UNAIDS/WHO, AIDS Epidemic Update,...
  • N. Lohse et al.

    J. Antimicrob. Chemother.

    (2007)
  • R. Hogg, K. Lima, J.A.C. Sterne et al. for the Antiretroviral Therapy Cohort Collaboration, Life expectancy of...
  • W.M. El-Sadr et al.

    N. Engl. J. Med.

    (2006)
  • S. Grinspoon et al.

    N. Engl. J. Med.

    (2005)
  • V. Amorosa et al.

    Clin. Infect. Dis.

    (2006)
  • A. Carr et al.

    AIDS

    (2001)
  • H. Knobel et al.

    AIDS

    (2001)
  • A.L. Moore et al.

    AIDS

    (2001)
  • D. Nolan et al.

    AIDS

    (2001)
  • D. Bruera et al.

    AIDS

    (2003)
  • J. Fernandez-Rivera et al.

    HIV Clin. Trials.

    (2003)
  • K. Mondy et al.

    Clin. Infect. Dis.

    (2003)
  • F. Vescini et al.

    J. Acquir. Immune Defic. Syndr.

    (2003)
  • C. Amiel et al.

    J. Bone Miner. Res.

    (2004)
  • T.T. Brown et al.

    J. Clin. Endocrinol. Metab.

    (2004)
  • S.E. Dolan et al.

    AIDS

    (2004)
  • G. Madeddu et al.

    Q. J. Nucl. Med. Mol. Imaging

    (2004)
  • M. Konishi et al.

    AIDS

    (2005)
  • M. Yin et al.

    Osteoporos. Int.

    (2005)
  • A.M. Garcia Aparicio et al.

    Clin. Rheumatol.

    (2006)
  • C. Cazanave et al.

    AIDS

    (2008)
  • A. Calmy et al.

    J. Infect. Dis.

    (2009)
  • P. Tebas et al.

    AIDS

    (2000)
  • T.T. Brown et al.

    AIDS

    (2006)
  • J. Womack, J. Goulet, C. Gibert, C. Brandt, K. Mattocks, D. Rimland, M. Rodriguez-Barradas, J. Tate, M. Yin, J. Amy,...
  • J.H. Arnsten et al.

    AIDS

    (2007)
  • C. Dao, B. Young, K. Buchacz, R. Baker, J. Brooks, Higher and increasing rates of fracture among HIV-infected persons...
  • V.A. Triant et al.

    J. Clin. Endocrinol. Metab.

    (2008)
  • S.R. Cummings et al.

    N. Engl. J. Med.

    (1995)
  • J.A. Kanis et al.

    Osteoporos. Int.

    (2005)
  • M. Pedrazzoni et al.

    Acta. Endocrinol. (Copenh.)

    (1993)
  • Cited by (59)

    • Hemin activation of innate cellular response blocks human immunodeficiency virus type-1-induced osteoclastogenesis

      2015, Biochemical and Biophysical Research Communications
      Citation Excerpt :

      These cells release calcium and growth factors from bone to maintain normal bodily functions and contribute to physiological bone remodeling, as well as pathological bone destruction in osteoporosis and rheumatoid arthritis; thus, they represent a pharmacological target for drug development [1–5]. Extensive evidence points convincingly towards increased activity of osteoclasts and impaired activity of osteoblasts in cancer and HIV-infected patients, leading to a significant increase in the prevalence of osteoporosis [6–16]. HIV-infected patients show bone loss and osteopenia/osteoporosis during the course of the disease [17–22].

    • Contribution of viral and bacterial infections to senescence and immunosenescence

      2023, Frontiers in Cellular and Infection Microbiology
    View all citing articles on Scopus
    View full text