Resource-limited settings (RLS) that constitute low- and middle-income countries  continue to bear the greatest burden of the HIV epidemic globally . Advantageously, the expanding access to highly active antiretroviral therapy has resulted in dramatically increased survival of HIV-infected individuals in the last 2 decades . With more HIV-infected individuals living longer, it is expected that medical comorbidities such as osteoporosis and fragility fractures will increase. Data from developed countries estimate that up to two-thirds of HIV-infected antiretroviral therapy (ART)-treated and ART-naïve individuals exhibit osteopenia or osteoporosis at the time of low bone mineral density (BMD) diagnosis, with those on ART at increased risk . Importantly, studies in resource rich settings (RRS) are reporting increased evidence of fracture rates in the HIV-infected population, with fracture rates 30–70% higher than those among matched uninfected controls [5,6▪,7▪,8,9]. Fragility fractures are associated with significant loss of physical function, independence, and quality of life , as well as an increased risk of short-term and long-term mortality [11–13]. These data call for more strategic clinical management of HIV individuals that includes prevention or minimization of long-term metabolic complications of HIV infection and its treatment in addition to treating opportunistic infections. In this review, we summarize recently published and presented studies that inform the discussion on bone health among HIV-infected persons in RLS. We highlight the epidemiology of HIV and bone loss in RLS, and among special populations, including HIV-infected young women and perinatally infected adolescents. We focus on three main areas of interest in HIV metabolic bone disease in RLS: effects of HIV and ART, vitamin D insufficiency and other risk factors for bone loss, and fracture risk assessment. We further identify important gaps in research and clinical management as well as make recommendations for future research priorities that would help address these HIV-related, bone health comorbidities in RLS.
Bone mass and HIV in resource-limited settings
The World Health Organization has categorized low BMD into osteopenia and osteoporosis. In postmenopausal women and men, 50 years and above, osteoporosis is defined as a T-score at or below 2.5 SD whereas osteopenia is defined as a T-score between 1 and 2.5 SD below the young adult mean value. Premenopausal women, men below 50 years or children who have a BMD Z-score at or below 2.0 of the age and sex-matched population are classified as having low bone mass. . In the general population, a decline in BMD, assessed by dual-energy X-ray absorptiometry (DXA), is associated with an increased risk of subsequent fractures . Data from RRS consistently show that HIV infection is associated with low BMD and increased fracture risk [5,6▪,7▪,8,9]. A meta-analytic review of 11 studies by Brown et al. involving 884 HIV-infected individuals and 654 controls estimated the prevalence of low BMD among HIV-infected individuals to be as high as 67%, 15% of whom had osteoporosis. The magnitude of low BMD was 6.4 times greater and that of osteoporosis 3.7 times greater than in HIV-uninfected controls . Further, in a recent meta-analysis, fracture risk was 1.35-fold higher in HIV-positive compared to HIV-negative controls [7▪]. Although underlying mechanisms leading to reduced BMD in HIV-infected persons are still unclear, they are believed to be multifactorial and include both traditional and HIV-specific risk factors [4,16–25]. Owing to physiological, psychological, and lifestyle factors, HIV-infected persons are likely to have many of the traditional risk factors for low BMD such as physical inactivity, low body weight, nutritional deficiencies (including inadequate calcium and vitamin D intake), depression, smoking, heavy alcohol use, oligo-/amenorrhoea, and hypogonadism [26–35]. Among the nontraditional causes, a direct effect of HIV and its treatment have been most often quoted; chronic inflammation induced by HIV may impact bone metabolism [36–39]. In addition, ART significantly contributes to bone loss among HIV-infected persons . Among individuals on ART, studies in RRS consistently report a 2–6% decline in BMD over the first few years after treatment initiation [25,41], regardless of ART choice .
In RLS with a disproportionately high burden of HIV and background nutritional deficiencies , known risk factors for low BMD remain similar to those in RRS [25,43,44]. However, some of these risk factors such as low BMI, malnutrition, advanced disease, longer duration since HIV diagnosis and higher HIV viral load are more common in HIV-infected populations in RLS [45▪,46,47▪,48]. These risk factors coupled with more widespread use of non-BMD sparing ART-like tenofovir disoproxil fumarate (TDF) and efavirenz (EFV) make the extremely high prevalence of low BMD in some RLS almost inevitable. Unfortunately, data on BMD among HIV-infected individuals are currently scanty and subject to methodological concerns such as cross-sectional design, lack of appropriate control groups, and local BMD reference data. The majority of the studies did not use local noninfected controls for comparison; the United States National Health and Nutrition Examination Survey reference data being used instead and comparisons were not adjusted for differences in body composition and size. Our review revealed overlapping prevalence of low BMD in RLS and RRS, with a generally higher prevalence of low BMD in RLS overall compared to RRS (Table 1 and Fig. 1). Data from both low-income countries such as Uganda [45▪], Nigeria [47▪], India , Indonesia  and middle-income countries (South Africa , Brazil , Turkey , China [51,52], Israel , and Thailand ) as well as mixed settings (South Africa, India, Thailand, Malaysia, and Argentina ) show varying levels of low BMD with some studies reporting a high prevalence of low BMD in HIV-positive individuals of up to 85% . However, a few authors such as Hamill et al. from South Africa have reported comparable BMD levels between HIV-infected women and appropriate uninfected controls regardless of disease severity. The high BMI of participants in this study may have had a sparing effect on bone loss. In contrast, a study comparing ART-naïve to ART-experienced patients on long-term suppressive ART in western India found extremely high prevalence of low BMD, 80.4% among ART-experienced, and 67% among ART-naïve patients, but no local uninfected controls were used . Another cross-sectional study among young HIV-infected Israeli women of Ethiopian and Caucasian origin found a higher prevalence of low BMD, 85% among Ethiopians compared to 40% seen in the Caucasians  which the authors attributed to poorer vitamin D status among Ethiopian women . Similar proportions of low BMD have been reported by recently published data from RRS [56▪,57–60] with the exception of a few studies [61–63].
There are very limited data in any RLS regarding BMD longitudinal changes among HIV-infected persons. In a 48-week, multisite, second-line trial in South Africa, India, Thailand, Malaysia, and Argentina , HIV-infected patients who initiated a second-line regimen experienced additional bone loss. We did not find any longitudinal data on the effect of ART initiation on BMD among ART-naïve cohorts, or any data on fractures among HIV-infected individuals in RLS.
Role of tenofovir
A strong body of evidence from longitudinal data in RRS shows that among the different antiretroviral drugs, the potential effect of TDF on bone health is particularly concerning [64–70]. In ART-naïve HIV-positive individuals, initiating TDF-containing ART was associated with greater bone loss over the first few years compared to TDF-sparing regimens [67,69–71]. With ART-initiation, there is a rapid acceleration of bone turnover; bone resorption outstrips bone formation, likely accounting for the decrease in BMD [72,73]. Consistent with these findings, Brown and others [66,67,74] have shown that ART initiation is associated with a 2–6% loss of BMD over the first 48–96 weeks of therapy that does not return to baseline after prolonged HIV RNA suppression and also reoccurs after reinitiation of ART after treatment failure. In another adult study comparing TDF-containing and noncontaining regimens, Gallant et al. observed increased bone resorption and loss in the TDF-containing arm compared to patients receiving an alternate NRTI (stavudine), at both the LS (−3.3 vs. −2.0%) and hip (−3.2 vs. −1.8%). Importantly, the majority of BMD loss was observed within the first 24–48 weeks of treatment, and thereafter, BMD loss slowed, but BMD did not recover over the 144 weeks of the study. Similarly, a study comparing TDF to abacavir an NRTI revealed a greater loss of BMD at total hip (−3.6 vs. −1.9%) and LS (−2.4 vs. −1.6%) in the TDF group. Again, BMD loss occurred closer to initiation of therapy and was maximal in the spine at 24 weeks and in the hip at 48 weeks . More interestingly, switching from a TDF-containing regimen to an alternative NRTI leads to an increase in BMD . Though the mechanism through which TDF reduces bone mass is not clear, there is more evidence suggesting that TDF induces renal dysfunction [75–87]. TDF has been shown to induce proximal renal tubular dysfunction that results in excessive glomerular filtration, renal tubular acidosis phosphate loss  and possible impairment in vitamin D hydroxylation [75,76,80,86–94].
In RLS, the two WHO recommended first line ART treatment regimens for adults and children above 15 years contain TDF; TDF, lamivudine (3TC) and EFV or TDF, emtricitabine (FTC), and EFV, which exposes many HIV-infected individuals to the negative impact of TDF on bone health [3,95]. Conversely, there are scarce data on the effect of TDF-based ART on BMD in these settings. Martin et al. reported that HIV-infected patients who initiated a second-line regimen had a greater bone loss if they were on TDF for longer duration during the 48 weeks of the study. For every 1 year of TDF use, the femur BMD reduced by 1.58% and spine BMD by 1.65% (P < 0.001).
Vitamin D and bone health in HIV
Worldwide, it's estimated that more than one billion people are characterized as having vitamin D deficiency (<20 ng/ml), or insufficiency (<30 ng/ml) regardless of the economic setting. According to a recent review by Mansueto et al. the prevalence of vitamin D deficiency among HIV-infected individuals in both RLS and RRS varies widely across studies ranging from 25 to 93%, with an overall prevalence of 70.3 to 83.7%. Similarly, our review yielded high but similar prevalence of low vitamin D among HIV individuals regardless of ART use in both RLS [50,53,97–102] and RRS [61,103–109] with insufficient levels of up to 90% in Turkey  and the USA , Belgium , Spain  (Table 2 and Fig. 2). The authors ascribed the high prevalence of vitamin D deficiency seen among Turkish , and Israeli  to skin coverage with resultant reduced sunlight exposure. Among individuals on ART, several cross-sectional studies from both RRS and RLS have shown an association between EFV use and low 25-hydroxyvitamin D (25(OH)D) [30,97,104,110–113]. NNRTIs, especially EFV which are widely used to treat HIV infection in RLS are hypothesized to enhance 25(OH)D catabolism through the induction of cytochrome P450 enzymes (CYP24A)  which reduce 25(OH)D concentrations. Among HIV-infected individuals, vitamin D insufficiency has been associated with a higher risk of HIV disease progression, death and virologic failure after ART [96,114]. In addition, vitamin D deficiency has been reported to independently increase the risk of low BMD . In view of this, supplementation with vitamin D has been reported to mitigate bone loss [61,105]. In a recent randomized trial Overton et al. found that BMD loss in the first year after ART initiation may be minimized by calcium and vitamin D supplementation D. By way of contrast, none of the studies we reviewed supported an association between vitamin D insufficiency and low BMD . Though a cross-sectional study by Shahar et al. among HIV-infected Israeli women of Ethiopian and Caucasian origin reported lower levels of BMD among vitamin D deficient individuals, there findings were limited by the small sample size in addition to lack of an HIV-uninfected control group. Larger studies with a suitable comparison of HIV-uninfected controls are needed to quantify the association between vitamin D status and BMD or fracture risk in HIV populations in RLS, and whether vitamin D supplementation mitigates bone loss.
Bone health among HIV-infected young adult women
In RLS, the HIV burden among young adult women is high . Women account for approximately 57% of the 34 million people living with HIV/AIDS. Most women living with HIV are of reproductive age , and the provision of reproductive health services is a crucial part of their HIV care. However, certain types of hormonal contraception have been associated with long-term metabolic dysregulation, particularly low BMD. In RLS with the highest unmet need for contraception, depot medroxyprogesterone acetate (DMPA) is the preferred contraceptive option across the different age groups  with approximately 15 million current users in the sub-Saharan African region alone . Among HIV-infected women in particular, DMPA remains effective  because of its lack of interactions with antiretroviral drugs [119–121]. However, owing to its hypoestrogenemic effects , DMPA has also been associated with reduced BMD [123–130]. The few published observational studies on the association between DMPA and fracture risk in RRS suggest increased risk of fractures among DMPA users [131,132]. For example, a large population-based control study by Meier et al. showed a 50% increased risk of incident fractures among 20 to 44-year-old European DMPA users receiving 10 or more injections compared to nonhormonal users, among those who had received 10 or more injections. It must also be noted that all the above studies were conducted among HIV-negative individuals. Our review did not yield any published data on the effect of DMPA on BMD or fracture risk among HIV-infected women either in RRS or RLS. This presents a critical gap in policy and clinical management guidelines for HIV infected women.
Bone health among HIV-infected adolescents
With the scale up of ART, more HIV-infected children are surviving into adolescence. In 2012, an estimated 2.1 million adolescents (10–19 years) were living with HIV in RLS [2,133], constituting over 95% of all HIV infections in this age group . Although global data on ART coverage for adolescents are not available, the WHO ‘Early Release Guideline’ recommending initiation of ART in all individuals living with HIV, regardless of CD4 cell count raises further the number of adolescents in need of treatment. Perinatally infected individuals have the greatest cumulative life-time exposure to HIV and its treatment which results in increased risk of associated comorbidities, including possible reduced bone mass at a critical time of peak bone mass (PBM) accrual. Data show that a lower PBM in the young is a major determinant of subsequent osteoporosis and fracture in older adults [134–137]. Several studies from RRS support an independent, dose–response relationship between BMD and risk of osteoporotic fractures [135,138–148]. For example, a 10% increase in PBM in young women is associated with an estimated 50% reduction in fracture risk after menopause . Although there have been a few controversies among HIV individuals on ART [133,149], the general conclusion from a number of studies in RRS is that TDF treatment decreases BMD with stronger associations being seen in children and adolescents than in adults [64,150–152]. Thus, BMD may be more affected during the active period of bone growth and development. Among HIV-infected adolescents living in RLS, additional highly prevalent factors, including protein and energy malnutrition, micronutrient deficiencies, and childhood infections that are known to adversely affect bone mass accrual may pose additional threats to bone acquisition. To date, there are currently no published data in RLS where over 90% of infected adolescents live. This has inadvertently lead to lack of prevention and clinical management guidelines for this unique age group who may be at considerable risk of bone complications during a critical period of PBM attainment and subsequent lifelong ART exposure.
Constraints to diagnosis and management of bone loss in resource-limited settings
In 2015, 11 out of the 16 million people receiving ART globally were in the WHO Africa region alone . However, unlike RRS where medications such as EFV are no longer preferred, and alternatives to TDF with less bone toxicity are likely to be more frequently used, there are currently no strategies in RLS for minimizing bone loss among HIV-infected individuals. The already limited funding, poor healthcare infrastructures, and sparse personnel pose tremendous challenges toward prevention and management of metabolic bone complications in RLS. As the standard assessment tool for BMD, DXA has only limited value as a single assessment. Serial assessments during HIV patient monitoring while on ART provide more information on the pattern of BMD changes . In RLS, use of DXA scans in assessing BMD is limited by availability, cost, and training. In addition, once the diagnosis is obtained, the current cost of treatment medications for osteoporosis, for example, bisphosphonates is prohibitive. Furthermore, most healthcare personnel in most RLS lack the expertise to make appropriate diagnoses and provide relevant care.
With more people starting ART  and living longer with HIV than ever before, more individuals will continue to experience osteoporosis and its sequelae, including fragility fractures . Given low clinical and research capacity for metabolic bone disease in RLS, there is urgent special need for building capacity in bone healthcare and research. Expanding knowledge about bone health in RLS will not only provide significant insights into the burden of HIV-related bone loss in RLS but also predictors, and evolution of bone metabolic comorbidities in the time course of HIV infection and its lifelong treatment. An initial focus is needed to establish the epidemiology of metabolic bone diseases in both the general and HIV populations. We recommend prioritization of the following research agenda in RLS:
- Cost-effective and feasible strategies to prevent osteoporosis for both HIV-infected and noninfected populations.
- Identification of simple-low cost tools to detect early osteopenia.
- Strategies to minimize or avoid ARV-associated bone loss such as ART choice, dose optimization, and ARV switching.
- Research among HIV-infected populations focusing on women of reproductive age and special populations such as perinatally infected children and adolescents.
To successfully conduct research addressing the above mentioned gaps in bone health comorbidities in RLS, there is need to work through several existing research networks either regionally or globally. This will ensure effective design and quality implementation approaches are employed. Importantly, involving key policy makers both domestically and regionally upfront will make the future policy implementation more successful.
The review reveals overlapping prevalence of low BMD in RLS and RRS, with a generally higher prevalence of low BMD in RLS overall compared to RRS. We highlight important gaps in our knowledge about HIV-associated bone health comorbidities in RLS. In particular, there are scarce data on bone health mainly from cross-sectional studies that call for urgent need for research that can inform management guidelines in metabolic bone complications in RLS.
F.K.M. would like to thank Professors Todd T Brown and Mary Glenn Fowler, Dr Francis Kiweewa, MU-JHU Research Collaboration, Consortium for Advanced Research and Training in Africa, Makerere University School of Public Health and University of the Witwatersrand.
Financial support and sponsorship
F.K.M. has received an R01 grant from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH) under Award Number R01AI118332NIH for bone health-related work as the Principal Investigator, and support as a site investigator on NIH funded microbicide trials network protocols. K.R. has received support from Senior Research Scholar, Thailand Research Fund (TRF) for his work.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
1. The World Bank. World Bank list of economies. 2015. http://data.worldbank.org/about/country-classifications/country-and-lending-groups
. [Accessed 8 December 2015]
2. UNAIDS, Report on the global AIDS epidemic 2013.
Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection, Accessed November 2015. Geneva, World Health Organization 2013.
4. Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS 2006; 20:2165–2174.
5. Güerri-Fernandez R, Vestergaard P, Carbonell C, et al HIV infection is strongly associated with hip fracture risk, independently of age, gender, and comorbidities: a population-based cohort study. J Bone Miner Res 2013; 28:1259–1263.
6▪. 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; 66:90–95.
A case–control study using data from the Danish National Health Service registries which show that HIV infection is associated with an almost three-fold increase in fracture risk compared with that of age and sex-matched uninfected patients.
7▪. Shiau S, Broun EC, Arpadi SM. Incident fractures in HIV-infected individuals: a systematic review and meta-analysis. AIDS (London, England) 2013; 27:1949.
A systematic review and meta-analysis which shows that HIV infection is associated with a modest increase in incident fracture.
8. Battalora LA, Young B, Overton ET. Bones, fractures, antiretroviral therapy and HIV. Curr Infect Dis Rep 2014; 16:1–6.
9. Compston J. Osteoporosis and fracture risk associated with HIV infection and treatment. Endocrinol Metab Clin North Am 2014; 43:769–780.
10. Burge R, Dawson-Hughes B, Solomon D H, et al Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025. J Bone Miner Res 2007; 22:465–475.
11. Cauley JA. Public health impact of osteoporosis. J Gerontol A Biol Sci Med Sci 2013; 68:1243–1251.
12. Morin S, Lix LM, Azimaee M, et al Mortality rates after incident nontraumatic fractures in older men and women. Osteoporos Int 2011; 22:2439–2448.
13. Johnell O, Kanis JA. An estimate of the worldwide prevalence, mortality and disability associated with hip fracture. Osteoporos Int 2004; 15:897–902.
14. Kanis JA, Melton LJ 3rd, Christiansen C, et al The diagnosis of osteoporosis. J Bone Miner Res 1994; 9:1137–1141.
15. Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 1996; 312:1254–1259.
16. Tebas P, Powderly WG, Claxton S, et al Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy. AIDS 2000; 14:F63–F67.
17. Knobel H, et al Osteopenia in HIV-infected patients: is it the disease or is it the treatment? AIDS 2001; 15:807–808.
18. Arnsten JH, Freeman R, Howard AA, et al HIV infection and bone mineral density in middle-aged women. Clin Infect Dis 2006; 42:1014–1020.
19. Amorosa V, Tebas P. Bone disease and HIV infection. Clin Infect Dis 2006; 42:108–114.
20. McDermott AY, Terrin N, Wanke C, et al CD4+ cell count, viral load, and highly active antiretroviral therapy use are independent predictors of body composition alterations in HIV-infected adults: a longitudinal study. Clin Infect Dis 2005; 41:1662–1670.
21. Mondy K, Yarasheski K, Powderly WG, et al Longitudinal evolution of bone mineral density and bone markers in human immunodeficiency virus-infected individuals. Clin Infect Dis 2003; 36:482–490.
22. Mondy K, Tebas P. Emerging bone problems in patients infected with human immunodeficiency virus. Clin Infect Dis 2003; 36 (Suppl 2):S101–S105.
23. Bongiovanni M, Fausto A, Cicconi P, et al Nonnucleoside-reverse-transcriptase-inhibitor-based HAART and osteoporosis in HIV-infected subjects. J Antimicrob Chemother 2006; 58:485–486.
24. Brown TT. HIV: an underrecognized secondary cause of osteoporosis? J Bone Miner Res 2013; 28:1256–1258.
25. Yin MT, Overton ET. Increasing clarity on bone loss associated with antiretroviral initiation. J Infect Dis 2011; 203:1705–1707.
26. 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; 51:937–946.
27. Neto LFP, Ragi-Eis S, Vieira Nilo FR, et al Low bone mass prevalence, therapy type, and clinical risk factors in an HIV-infected Brazilian population. J Clin Densitom 2011; 14:434–439.
28. Mdodo R, Frazier EL, Dube SR, et al Cigarette smoking prevalence among adults with HIV compared with the general adult population in the United States: cross-sectional surveys. Ann Intern Med 2015; 162:335–344.
29. Wunder DM, Bersinger NA, Fux CA, et al Hypogonadism in HIV-1-infected men is common and does not resolve during antiretroviral therapy. Antivir Ther 2007; 12:261.
30. Welz T, Childs K, Ibrahim F, et al Efavirenz is associated with severe vitamin D
deficiency and increased alkaline phosphatase. AIDS 2010; 24:1923–1928.
31. Rietschel P, Corcoran C, Stanley T, et al Prevalence of hypogonadism among men with weight loss related to human immunodeficiency virus infection who were receiving highly active antiretroviral therapy. Clin Infect Dis 2000; 31:1240–1244.
32. Guadalupe-Grau A, Fuentes T, Guerra B, Calbet JA. Exercise and bone mass in adults. Sports Med 2009; 39:439–468.
33. Michelson D, Stratakis C, Hill L, et al Bone mineral density in women with depression. N Engl J Med 1996; 335:1176–1181.
34. Schweiger U, Deuschle M, Korner A, et al Low lumbar bone mineral density in patients with major depression. Am J Psychiatry 1994; 151:1691–1693.
35. Cotter AG, Powderly WG. Endocrine complications of human immunodeficiency virus infection: hypogonadism, bone disease and tenofovir-related toxicity. Best Pract Res Clin Endocrinol Metab 2011; 25:501–515.
36. Hernandez-Vallejo SJ, Beaupere C, Larghero J, et al HIV protease inhibitors induce senescence and alter osteoblastic potential of human bone marrow mesenchymal stem cells: beneficial effect of pravastatin. Aging Cell 2013; 12:955–965.
37. Vikulina T, Fan X, Yamaguchi M, et al Alterations in the immuno-skeletal interface drive bone destruction in HIV-1 transgenic rats. Proc Natl Acad Sci U S A 2010; 107:13848–13853.
38. Titanji K., Vunnava K., Sheth A.. B cell dysregulation promotes HIV-induced bone loss. In Journal of Bone and Mineral Research. 2013. Wiley-Blackwell 111 River St, Hoboken 07030–5774, NJ USA.
39. Ofotokun I, Titanji K, Vikulina T, et al Role of T-cell reconstitution in HIV-1 antiretroviral therapy-induced bone loss. Nat Commun 2015; 6:8282.
40. Walker Harris V, Brown TT. Bone loss in the HIV-infected patient: evidence, clinical implications, and treatment strategies. J Infect Dis 2012; 205 (Suppl 3):S391–S398.
41. Bolland MJ, Grey A, Horne AM, et al Stable bone mineral density over 6 years in HIV-infected men treated with highly active antiretroviral therapy (HAART). Clin Endocrinol 2012; 76:643–648.
42. Navarro MC, Sosa M, Saavedra P, et al Poverty is a risk factor for osteoporotic fractures. Osteoporos Int 2009; 20:393–398.
43. Bonjoch A, Figueras M, Estany C, et al High prevalence of and progression to low bone mineral density in HIV-infected patients: a longitudinal cohort study. AIDS 2010; 24:2827–2833.
44. Kim H-S, Chin BS, Shin H-S. Prevalence and risk factors of low bone mineral density in Korean HIV-infected patients: impact of abacavir and zidovudine. J Korean Med Sci 2013; 28:827–832.
45▪. Wandera B., Agnes K., Fred S. Low bone mineral density among Ugandan HIV infected patients on failing first line antiretroviral therapy; a sub-study of the EARNEST trial. 21st Conference on Retroviruses and Opportunistic Infections Boston, MA March 3-6, 2014. in Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections. 2007.
This is one of only a few studies which investigated the prevalence of osteoporosis among HIV-infected persons in sub-Saharan Africa.
46. Dravid A, Kulkarni M, Borkar A, Dhande S. Prevalence of low bone mineral density among HIV patients on long-term suppressive antiretroviral therapy in resource limited setting of western India. J Int AIDS Soc 2014; 17:19567.
47▪. Alonge T, Okoje-Adesomoju V, Atalabi O, et al Prevalence of abnormal bone mineral density in HIV-positive patients in Ibadan, Nigeria. J West Afr Coll Surg 2013; 3:1–14.
The largest cross-sectional study in a cohort of HIV-infected adults in low and low–middle-income countries revealing a high prevalence of low bone mineral density.
48. Masyeni S, Utama S, Somia A, et al Factors influencing bone mineral density in ARV-naive patients at Sanglah Hospital, Bali. Acta Med Indones 2013; 45:175–179.
49. Hamill M, Ward K, Pettifor J, et al Bone mass, body composition and vitamin D
status of ARV-naïve, urban, black South African women with HIV infection, stratified by CD4 count. Osteoporos Int 2013; 24:2855–2861.
50. Aydin OA, Karaosmanoglu HK, Karahasanoglu R, et al Prevalence and risk factors of osteopenia/osteoporosis in Turkish HIV/AIDS patients. Braz J Infect Dis 2013; 17:707–711.
51. Zhang L, Su Y, Hsieh E, et al Bone turnover and bone mineral density in HIV-1 infected Chinese taking highly active antiretroviral therapy–a prospective observational study. BMC Musculoskelet Disord 2013; 14:224.
52. Wang Q, Liu J, Ding H, et al Reduced bone mineral density among ART-naive male patients with HIV in China. Future Virol 2015; 10:827–833.
53. Shahar E, Segal E, Rozen GS, et al Vitamin D
status in young HIV infected women of various ethnic origins: Incidence of vitamin D
deficiency and possible impact on bone density. Clin Nutr 2013; 32:83–87.
54. Wattanachanya L, Jantrapakde J, Avihingsanon A, et al. Bone Mineral Density and Vitamin D
Status in Antiretroviral-naïve HIV-infected Thais: A Preliminary Result from a Five-Year Prospective Cohort Study. American Society for Bone and Mineral Research (ASBMR) 2014 Annual Meeting, George R. Brown Convention Center September 12–15, 2014.
55. Martin A, Moore C, Mallon PW, et al Bone mineral density in HIV participants randomized to raltegravir and lopinavir/ritonavir compared with standard second line therapy. AIDS (London, England) 2013; 27:2403.
56▪. Battalora L, Buchacz K, Armon C, et al Low bone mineral density and risk of incident fracture in HIV-infected adults. Antivir Ther 2015; [Epub ahead of print].
The first study demonstrating that low BMD was associated with incident fracture in HIV populations.
57. Short C-ES, Shaw SG, Fisher MJ, et al Prevalence of and risk factors for osteoporosis and fracture among a male HIV-infected population in the UK. Int J STD AIDS 2014; 25:113–121.
58. Mazzotta E, Ursini T, Agostinone A, et al Prevalence and predictors of low bone mineral density and fragility fractures among HIV-infected patients at one Italian center after universal DXA screening: sensitivity and specificity of current guidelines on bone mineral density management. AIDS Patient Care STDS 2015; 29:169–180.
59. Kooij KW, Wit FW, Bisschop PH, et al Low bone mineral density in patients with well suppressed HIV infection is largely explained by body weight, smoking and prior advanced HIV disease. J Infect Dis 2014; 211:539–548.
60. Kinai E, Nishijima T, Mizushima D, et al Long-term use of protease inhibitors is associated with bone mineral density loss. AIDS Res Hum Retroviruses 2014; 30:553–559.
61. 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; 162:815–824.
62. Cotter AG, Sabin CA, Simelane S, et al Relative contribution of HIV infection, demographics and body mass index to bone mineral density. AIDS 2014; 28:2051–2060.
63. Carr A, Grund B, Neuhaus J, et al International Network for Strategic Initiatives in Global HIV Trials (INSIGHT) START Study Group. Prevalence of and risk factors for low bone mineral density in untreated HIV infection: a substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial. HIV Med 2015; 16 (Suppl 1):137–146.
64. Gallant JE, Staszewski S, Pozniak AL, et al Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA 2004; 292:191–201.
65. Martin A, Bloch M, Amin J, et al Simplification of antiretroviral therapy with tenofovir-emtricitabine or abacavir-Lamivudine: a randomized, 96-week trial. Clin Infect Dis 2009; 49:1591–1601.
66. 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; 51:963–972.
67. 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; 203:1791–1801.
68. Bernardino JI, Mocroft A, Mallon PW, et al Bone mineral density and inflammatory and bone biomarkers after darunavir–ritonavir combined with either raltegravir or tenofovir–emtricitabine in antiretroviral-naive adults with HIV-1: a substudy of the NEAT001/ANRS143 randomised trial. Lancet HIV 2015; 2:e464–e473.
69. Assoumou L, Katlama C, Viard J-P, et al Changes in bone mineral density over a 2-year period in HIV-1-infected men under combined antiretroviral therapy with osteopenia. AIDS 2013; 27:2425–2430.
70. Taiwo BO, Chan ES, Fichtenbaum CJ, et al Less bone loss with maraviroc-compared to tenofovir-containing antiretroviral therapy in the ACTG A5303 study. Clin Infect Dis 2015; 61:1179–1188.
71. Bianco C, Rossetti B, Gagliardini R, et al Bone mineral density improvement after 48 weeks of switch to maraviroc+ darunavir/ritonavir 300/800/100 mg QD, preliminary results of GUSTA study. J Int AIDS Soc 2014; 17 (4Suppl 3):19816.
72. Brown TT, Ross AC, Storer N, et al Bone turnover, osteoprotegerin/RANKL and inflammation with antiretroviral initiation: tenofovir versus nontenofovir regimens. Antivir Ther 2011; 16:1063–1072.
73. Rey D, Treger M, Sibilia J, et al Bone mineral density changes after 2 years of ARV treatment, compared to naive HIV-1-infected patients not on HAART. Infect Dis 2015; 47:88–95.
74. Brown TT, McComsey GA, King MS, et al Loss of bone mineral density after antiretroviral therapy initiation, independent of antiretroviral regimen. J Acquir Immune Defic Syndr 2009; 51:554–561.
75. Fux CA, Rauch A, Simcock M, et al Tenofovir use is associated with an increase in serum alkaline phosphatase in the Swiss HIV Cohort Study. Antivir Ther 2008; 13:1077–1082.
76. Kohler JJ, Hosseini SH, Hoying-Brandt A, et al Tenofovir renal toxicity targets mitochondria of renal proximal tubules. Lab Invest 2009; 89:513–519.
77. Earle KE, Seneviratne T, Shaker J, Shoback D. Fanconi's syndrome in HIV+ adults: report of three cases and literature review. J Bone Miner Res 2004; 19:714–721.
78. Parsonage MJ, Wilkins EG, Snowden N, et al The development of hypophosphataemic osteomalacia with myopathy in two patients with HIV infection receiving tenofovir therapy. HIV Med 2005; 6:341–346.
79. Williams J, Chadwick DR. Tenofovir-induced renal tubular dysfunction presenting with hypocalcaemia. J Infect 2006; 52:e107–e108.
80. Nelson MR, Katlama C, Montaner JS, et al The safety of tenofovir disoproxil fumarate for the treatment of HIV infection in adults: the first 4 years. AIDS 2007; 21:1273–1281.
81. Labarga P, Barreiro P, Martin-Carbonero L, et al Kidney tubular abnormalities in the absence of impaired glomerular function in HIV patients treated with tenofovir. AIDS 2009; 23:689–696.
82. Woodward CL, Hall AM, Williams IG, et al Tenofovir-associated renal and bone toxicity. HIV Med 2009; 10:482–487.
83. Perrot S, Aslangul E, Szwebel T, et al Bone pain due to fractures revealing osteomalacia related to tenofovir-induced proximal renal tubular dysfunction in a human immunodeficiency virus-infected patient. J Clin Rheumatol 2009; 15:72–74.
84. Calmy A, Fux CA, Norris R, et al Low bone mineral density, renal dysfunction, and fracture risk in HIV infection: a cross-sectional study. J Infect Dis 2009; 200:1746–1754.
85. Di Biagio A, Rosso R, Monteforte P, et al Whole body bone scintigraphy in tenofovir-related osteomalacia: a case report. J Med Case Rep 2009; 3:8136.
86. Zimmermann AE, Pizzoferrato T, Bedford J, et al Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions. Clin Infect Dis 2006; 42:283–290.
87. Schaaf B, Aries SP, Kramme E, et al Acute renal failure associated with tenofovir treatment in a patient with acquired immunodeficiency syndrome. Clin Infect Dis 2003; 37:e41–e43.
88. Gupta SK. Tenofovir-associated Fanconi syndrome: review of the FDA adverse event reporting system. AIDS Patient Care STDS 2008; 22:99–103.
89. Castillo AB, Tarantal AF, Watnik MR, Martin RB. Tenofovir treatment at 30 mg/kg/day can inhibit cortical bone mineralization in growing rhesus monkeys (Macaca mulatta). J Orthop Res 2002; 20:1185–1189.
90. Peyriere H, Reynes J, Rouanet I, et al Renal tubular dysfunction associated with tenofovir therapy: report of 7 cases. J Acquir Immune Defic Syndr 2004; 35:269–273.
91. Fux CA, Christen A, Zgraggen S, et al Effect of tenofovir on renal glomerular and tubular function. AIDS 2007; 21:1483–1485.
92. Verhelst D, Monge M, Meynard JL, et al Fanconi syndrome and renal failure induced by tenofovir: a first case report. Am J Kidney Dis 2002; 40:1331–1333.
93. Rollot F, Nazal EM, Chauvelot-Moachon L, et al Tenofovir-related Fanconi syndrome with nephrogenic diabetes insipidus in a patient with acquired immunodeficiency syndrome: the role of lopinavir-ritonavir-didanosine. Clin Infect Dis 2003; 37:e174–e176.
94. Izzedine H, Launay-Vacher V, Deray G. Renal tubular transporters and antiviral drugs: an update. AIDS 2005; 19:455–462.
National ART Rx Guidelines Dec 2013.pdf Addendum to the national ART guidelines, Uganda, Ministry of Heath, December 2013. Accessed November 2015.
96. Mansueto P, Seidita A, Vitale G, et al Vitamin D
deficiency in HIV infection: not only a bone disorder. Biomed Res Int 2015; 2015:735615.
97. Steenhoff AP, Schall JI, Samuel J, et al Vitamin D3
supplementation in Batswana children and adults with HIV: a pilot double blind randomized controlled trial. PLoS One 2015; 10:e0117123.
98. Chokephaibulkit K, Saksawad R, Bunupuradah T, et al Prevalence of vitamin D
deficiency among perinatally HIV-infected Thai adolescents receiving antiretroviral therapy. Pediatr Infect Dis J 2013; 32:1237–1239.
99. Avihingsanon A, Kerr SJ, Ramautarsing RA, et al The association of gender, age, efavirenz use, and hypovitaminosis D among HIV-infected adults living in the tropics. AIDS Res Hum Retroviruses 2015; 31: [Epub ahead of print].
100. Aurpibul L, Sricharoenchai S, Wittawatmongkol O, et al Vitamin D
status in perinatally HIV-infected Thai children receiving antiretroviral therapy. J Pediatr Endocrinol Metab 2015; [Epub ahead of print].
101. Sales SH, da Matta Sandra, da Silva DC, et al High frequency of deficient consumption and low blood levels of 25-hydroxyvitamin D in HIV-1-infected adults from São Paulo city, Brazil. Sci Rep 2015; 5:12990.
102. Canuto JMP, Canuto VMP, Lima MHAd, et al Risk factors associated with hypovitaminosis D in HIV/aids-infected adults. Arch Endocrinol Metab 2015; 59:34–41.
103. Schwartz JB, Moore KL, Yin M, et al Relationship of vitamin D
, HIV, HIV treatment, and lipid levels in the women's interagency HIV study of HIV-infected and uninfected women in the United States. J Int Assoc Provid AIDS Care 2014; 13:250–259.
104. Hidron AI, Hill B, Guest JL, Rimland D. Risk factors for vitamin D
deficiency among veterans with and without HIV infection. PLoS One 2015; 10:e0124168.
105. Lake J., Hoffman R., Tseng C, et al. Success of standard dose vitamin D
supplementation in treated HIV infection. in Open forum infectious diseases. 2015. Oxford University Press.
106. Klassen KM, Fairley CK, Kimlin MG, et al Vitamin D
deficiency is common in HIV-infected southern Australian adults. Antiviral therapy 2015; [Epub ahead of print].
107. Gedela K, Edwards SG, Benn P, Grant AD. Prevalence of vitamin D
deficiency in HIV-positive, antiretroviral treatment-naïve patients in a single centre study. Int J STD AIDS 2014; 25:488–492.
108. Theodorou M, Sersté T, Van Gossum M, Dewit S. Factors associated with vitamin D
deficiency in a population of 2044 HIV-infected patients. Clin Nutr 2014; 33:274–279.
109. Bañón S, Rosillo M, Gómez A, et al Effect of a monthly dose of calcidiol in improving vitamin D
deficiency and secondary hyperparathyroidism in HIV-infected patients. Endocrine 2014; 49:528–537.
110. Dao CN, Patel P, Overton ET, et al Low vitamin D
among HIV-infected adults: prevalence of and risk factors for low vitamin D
Levels in a cohort of HIV-infected adults and comparison to prevalence among adults in the US general population. Clin Infect Dis 2011; 52:396–405.
111. Doroana Wohl, D., Orkin M. C., et al. Change in vitamin D
levels smaller and risk of development of severe vitamin D
deficiency lower among HIV-1-infected, treatment-naive adults receiving TMC278 compared with EFV: 48-week results from the phase III ECHO trial. in 18th Conference on Retroviruses and Opportunistic Infections. 2011.
112. Brown TT, McComsey GA. Short communications-association between initiation of antiretroviral therapy with efavirenz and decreases in 25-hydroxyvitamin D. Antivir Ther 2010; 15:425.
113. Wiboonchutikul S, Sungkanuparph S, Kiertiburanakul S, et al Vitamin D
insufficiency and deficiency among HIV-1-infected patients in a tropical setting. J Int Assoc Physicians AIDS Care 2012; 11:305–310.
114. Havers F, Smeaton L, Gupte N, et al 25-Hydroxyvitamin D insufficiency and deficiency is associated with HIV disease progression and virological failure postantiretroviral therapy initiation in diverse multinational settings. J Infect Dis 2014; 210:244–253.
115. Paul T, Asha H, Thomas N, et al Hypovitaminosis D and bone mineral density in human immunodeficiency virus-infected men from India, with or without antiretroviral therapy. Endocr Pract 2010; 16:547–553.
116. U.N.W.C.U.c.M., Available from: http://www.un.org/esa/population/publications/contraceptive2011/contraceptive2011.htm
. Accessed August 2014. Contraception 2011; 77:84–90.
118. World Health Organization Department of Reproductive Health and Research (WHO/RHR) and Johns Hopkins Bloomberg School of Public Health/Center for Communication Programs (CCP), I.P., Family planning: a global handbook for providers. Baltimore, MD: CCP and WHO; 2007.
119. Cohn SE, Park JG, Watts DH, et al Depo-medroxyprogesterone in women on antiretroviral therapy: effective contraception and lack of clinically significant interactions. Clin Pharmacol Ther 2007; 81:222–227.
120. Watts DH, Park JG, Cohn SE, et al Safety and tolerability of depot medroxyprogesterone acetate among HIV-infected women on antiretroviral therapy: ACTG A5093. Contraception 2008; 77:84–90.
121. Nanda K, Amaral E, Hays M, et al Pharmacokinetic interactions between depot medroxyprogesterone acetate and combination antiretroviral therapy. Fertil Steril 2008; 90:965–971.
122. Hergenroeder AC. Bone mineralization, hypothalamic amenorrhea, and sex steroid therapy in female adolescents and young adults. J Pediatr 1995; 126:683–689.
123. Albertazzi P, Bottazzi M, Steel SA. Bone mineral density and depot medroxyprogesterone acetate. Contraception 2006; 73:577–583.
124. Scholes D, LaCroix AZ, Ichikawa LE, et al Injectable hormone contraception and bone density: results from a prospective study. Epidemiology 2002; 13:581–587.
125. Clark MK, Sowers M, Levy B, Nichols S. Bone mineral density loss and recovery during 48 months in first-time users of depot medroxyprogesterone acetate. Fertil Steril 2006; 86:1466–1474.
126. Berenson AB, Breitkopf CR, Grady JJ, et al Effects of hormonal contraception on bone mineral density after 24 months of use. Obstet Gynecol 2004; 103:899–906.
127. Curtis KM, Martins SL. Progestogen-only contraception and bone mineral density: a systematic review. Contraception 2006; 73:470–487.
128. Clark MK, Sowers M, Nichols S, Levy B. Bone mineral density changes over two years in first-time users of depot medroxyprogesterone acetate. Fertil Steril 2004; 82:1580–1586.
129. Berenson AB, Radecki CM, Grady JJ, et al A prospective, controlled study of the effects of hormonal contraception on bone mineral density. Obstet Gynecol 2001; 98:576–582.
130. Wanichsetakul P, Kamudhamas A, Watanaruangkovit P, et al Bone mineral density at various anatomic bone sites in women receiving combined oral contraceptives and depot-medroxyprogesterone acetate for contraception. Contraception 2002; 65:407–410.
131. Meier C, Brauchli YB, Jick SS, et al Use of depot medroxyprogesterone acetate and fracture risk. J Clin Endocrinol Metab 2010; 95:4909–4916.
132. Lopez LM, Chen M, Mullins S, et al Steroidal contraceptives and bone fractures in women: evidence from observational studies. Cochrane Database Syst Rev 2012; 8:CD009849.
133. Purdy JB, Gafni RI, Reynolds JC, et al Decreased bone mineral density with off-label use of tenofovir in children and adolescents infected with human immunodeficiency virus. J Pediatr 2008; 152:582–584.
134. Heaney RP, Abrams S, Dawson-Hughes B, et al Peak bone mass. Osteoporos Int 2000; 11:985–1009.
135. Bonjour JP, Chevalley T, Ferrari S, Rizzoli R. The importance and relevance of peak bone mass in the prevalence of osteoporosis. Salud Publica Mex 2009; 51 (Suppl 1):S5–S17.
136. Tandon N, Fall CH, Osmond C, et al Growth from birth to adulthood and peak bone mass and density data from the New Delhi Birth Cohort. Osteoporos Int 2012; 23:2447–2459.
137. Bachrach LK. Acquisition of optimal bone mass in childhood and adolescence. Trends Endocrinol Metab 2001; 12:22–28.
138. Siris ES, Brenneman SK, Miller PD, et al Predictive value of low BMD for 1-year fracture outcomes is similar for postmenopausal women ages 50-64 and 65 and older: results from the National Osteoporosis Risk Assessment (NORA). J Bone Miner Res 2004; 19:1215–1220.
139. Cummings SR, Black D. Bone mass measurements and risk of fracture in Caucasian women: a review of findings from prospective studies. Am J Med 1995; 98:24S–28S.
140. Stone KL, Seeley DG, Lui LY, et al BMD at multiple sites and risk of fracture of multiple types: long-term results from the study of osteoporotic fractures. J Bone Miner Res 2003; 18:1947–1954.
141. Sarkar S, Reginster JY, Crans GG, et al Relationship between changes in biochemical markers of bone turnover and BMD to predict vertebral fracture risk. J Bone Miner Res 2004; 19:394–401.
142. Robbins JA, Schott AM, Garnero P, et al Risk factors for hip fracture in women with high BMD: EPIDOS study. Osteoporos Int 2005; 16:149–154.
143. Nguyen TV, Center JR, Eisman JA. Femoral neck bone loss predicts fracture risk independent of baseline BMD. J Bone Miner Res 2005; 20:1195–1201.
144. Johansson H, Kanis JA, Oden A, et al BMD, clinical risk factors and their combination for hip fracture prevention. Osteoporos Int 2009; 20:1675–1682.
145. Tremollieres FA, Pouilles JM, Drewniak N, et al Fracture risk prediction using BMD and clinical risk factors in early postmenopausal women: sensitivity of the WHO FRAX tool. J Bone Miner Res 2010; 25:1002–1009.
146. Albertsson D, Mellstrom D, Petersson C, et al Hip and fragility fracture prediction by 4-item clinical risk score and mobile heel BMD: a women cohort study. BMC Musculoskelet Disord 2010; 11:55.
147. BMD change predicts bone fracture risk due to zoledronate treatment. Bonekey Rep 2012; 1:205.
148. Krege JH, Wan X, Lentle BC, et al Fracture risk prediction: importance of age, BMD and spine fracture status. Bonekey Rep 2013; 2:404.
149. Vigano A, Zuccotti GV, Puzzovio M, et al Tenofovir disoproxil fumarate and bone mineral density: a 60-month longitudinal study in a cohort of HIV-infected youths. Antivir Ther 2010; 15:1053–1058.
150. Purdy JB, Gafni RI, Reynolds JC, et al Decreased bone mineral density with off-label use of tenofovir in children and adolescents infected with human immunodeficiency virus. J Pediatr 2008; 152:582–584.
151. Hazra R, Gafni RI, Maldarelli F, et al Tenofovir disoproxil fumarate and an optimized background regimen of antiretroviral agents as salvage therapy for pediatric HIV infection. Pediatrics 2005; 116:e846–e854.
152. Gafni RI, Hazra R, Reynolds JC, et al Tenofovir disoproxil fumarate and an optimized background regimen of antiretroviral agents as salvage therapy: impact on bone mineral density in HIV-infected children. Pediatrics 2006; 118:e711–e718.
153. Global health sector response to HIV, 2000–2015: focus on innovations in Africa: progress report. World Health Organization 2015. Accessed 8 December 2015. Available from: http://hesp-news.org/2015/12/06/global-health-sectorresponse-to-hiv-2000-2015-focus-on-innovations-in-africa/
154. Hileman CO, Eckard AR, McComsey GA. Bone loss in HIV: a contemporary review. Curr Opin Endocrinol Diabetes Obes 2015; 22:446–451.
155. Mirani G, Williams PL, Chernoff M, et al Changing trends in complications and mortality rates among US youth and young adults with HIV infection in the era of combination antiretroviral therapy. Clin Infect Dis 2015; 61:1850–1861.