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Prospective evaluation of bone markers, parathormone and 1,25-(OH)2 vitamin D in HIV-positive patients after the initiation of tenofovir/emtricitabine with atazanavir/ritonavir or efavirenz
- Emanuele Focà1,
- Davide Motta1,
- Marco Borderi2,
- Daria Gotti1,
- Laura Albini1,
- Alessandra Calabresi1,
- Ilaria Izzo1,
- Rita Bellagamba3,
- Pasquale Narciso3,
- Laura Sighinolfi4,
- Alberto Clò5,
- Davide Gibellini5,
- Eugenia Quiros-Roldan1,
- Nigritella Brianese1,
- Bruno Mario Cesana6,
- Maria Carla Re5 and
- Carlo Torti1, 7Email author
© Focà et al; BioMed Central Ltd. 2012
Received: 21 September 2011
Accepted: 14 February 2012
Published: 14 February 2012
Increased risk of fractures and osteoporosis have been associated with the use of antiretroviral drugs. There is a paucity of prospective evaluations of bone markers after the initiation of drugs currently recommended to treat HIV infection and results on the evolution of these markers are conflicting. Lastly, the effect of tenofovir on 1,25-(OH)2 vitamin D is uncertain.
We performed a prospective study on the evolution of bone markers, parathormone and 1,25-(OH)2 vitamin D before and after standard antiretroviral regimens. This was a sub-study of a trial conducted in antiretroviral-naïve patients randomized to tenofovir + emtricitabine in combination with either atazanavir/ritonavir (ATV/r) or efavirenz (EFV). Follow-up lasted 48 weeks. The following bone markers were analyzed: C-terminal cross-laps (CTx), osteocalcin (OC), osteoprotegerin (OPG), and receptor activator of nuclear factor κB ligand (RANKL). Mixed-factorial analysis of variance with random-coefficient general linear model was used to compare their trends over time and linear multivariable regression was performed with a backward selection method to assess predictors of their variations from baseline to week 48. Trends of parathormone and 1,25-(OH)2 vitamin D were also evaluated.
Seventy-five patients were studied: 33 received EFV and 42 ATV/r. Significant increases were found for all markers except for RANKL. There was a significant direct association between CTx and OC increases. Multivariable analysis showed that higher glomerular filtration rate (estimated through cystatin C clearance) predicted greater OPG increase, while older age, higher HIV RNA at baseline and use of ATV/r predicted greater CTx increase. A significant increase of parathormone accompanied the evolution of the study markers. 1,25-(OH)2 vitamin D remained stable, though a seasonality variation was demonstrated.
These data demonstrate CTx increase (bone resorption marker) corresponding to OC increase (bone formation marker) early upon HAART initiation. Moreover, predictors of bone marker increases have been suggested, possibly indicating that a stricter monitoring of bone health and pro-active interventions are needed in older patients, those with higher HIV RNA, prescribed ATV/r rather than EFV, and with decreased renal function at baseline. Further studies are needed to clarify the mechanisms responsible for up-regulation of bone turnover markers, as well as to understand if and what markers are best correlated or predictive of pathological fractures.
KeywordsHIV Antiretroviral therapy Bone turnover Osteoporosis Vitamin D
Highly active antiretroviral therapy (HAART) consisting of 2 nucleoside reverse transcriptase inhibitors (NRTI) (i.e., nucleoside backbone) combined with either a protease inhibitor (PI) or a non nucleoside reverse transcriptase inhibitor (NNRTI) (i.e., anchor drugs) have dramatically reduced opportunistic infections and death in HIV infected patients. However, despite these benefits, several co-morbidities, including osteoporosis , have emerged. In HIV-infected patients, osteoporosis is present with an overall prevalence of about 15%, and fragility fractures are becoming more frequent than in the general population [2, 3]. Therefore, screening and prevention strategies should be implemented to diagnose bone alterations.
Several biochemical markers of bone turnover have been proposed to detect early-onset modifications in bone formation (such as osteocalcin, OC) or bone resorption (C-terminal cross-laps, CTx) . These markers could also help to evaluate the effectiveness of anti-osteoporotic therapy . Moreover, although osteoprotegerin (OPG) and receptor activator of nuclear factor κB ligand (RANKL) are not proper osteoporotic markers since their levels in blood do not entirely reflect those present inside bone, they are considered major regulators of bone remodeling, so we studied them to explore osteoclastogenesis .
The mechanisms responsible for osteopenia and osteoporosis are uncertain but exposure to certain antiretroviral drugs (in particular a NRTI: tenofovir--TDF--and the PI class), aging, HIV by itself, parathormone (PTH) increase, and vitamin D deficiency may be implicated [7–10].
Discordant results regarding levels and evolution of bone turnover markers in HIV patients on HAART have been demonstrated [11–16]. Moreover there is a paucity of data on predictors of changes in these parameters [11–16]. In particular, discordant results regarding the possible impact of different types of antiretroviral drugs on changes in bone turnover markers currently exist.
Therefore, the main objective of this study was to describe the evolution of bone markers in HIV infected patients starting the HAART regimens currently recommended [17, 18]. We also aimed to evaluate possible predictors of the evolution of these markers (including class of antiretroviral therapy used as anchor).
This was a sub-study of a pilot open-label, multicenter, randomized controlled trial conducted in 91 patients without chronic kidney diseases to evaluate renal function after TDF + emtricitabine (FTC) plus either atazanavir boosted by ritonavir (ATV/r) or efavirenz (EFV) in HIV-infected patients naive to antiretroviral therapy (EudraCT number: 2007-007934-21) .
Seventy-five patients who remained in the randomized treatment arms were included. Baseline data included clinical history, CD4+ T-cell count, HIV RNA (branched chain DNA-enhanced label amplification assay, Quantuplex 2-0; Chiron, with a 50 copies/mL cut-off) and HBV/HCV serostatus. Clinical examination, HIV RNA, CD4+ T-cell count and routine laboratory tests (including creatinine and electrolytes) were assessed during follow-up. Plasma samples were taken and stored at -80°C until they were de-frozen for the present analyses.
Enzyme immunoassay techniques were used for all markers: OC (inter-assay and intra-assay coefficients of variation--CV--4.0% and 1.8%, respectively), CTx (inter-assay CV 7.7%, intra-assay CV 2.2%) and 1,25-(OH)2 vitamin D (inter-assay CV 6.6%, intra-assay CV 5.9%) were determined with EIA kits by IDS (Boldon, UK); OPG (inter-assay CV 6.9%, intra-assay CV 3.8%) and RANK-L (inter-assay CV 7.5%, intra-assay CV 5.7%) were determined with EIA kits by Peprotech (London, UK); lastly, PTH was determined with a DIAsource ImmnoAssays S.A. EIA kit (Nivelles, Belgium; inter-assay CV 5.0%, intra-assay CV 1.6%). Manufacturers' procedures were followed as indicated in the instruction manuals. All analyses were performed at the Microbiology Section, University of Bologna, Bologna, Italy. The following ranges of normality were considered: OC in women 8.4-33.9 ng/mL, in men 9.6-40.8 ng/mL; CTx in women 0.112-0.738 ng/mL, in men 0.115-0.748 ng/mL. Hyperparathyroidism cut-off was 65 pg/ml, and vitamin D deficiency was defined as < 11 pg/mL. Clinically validated ranges of normality for OPG and RANKL currently do not exist.
Glomerular filtration rate (GFR) was estimated by the CKD-EPI formulae since they are more suitable for patients without chronic kidney disease using both creatinine  and cystatin C  values, corrected for body surface area (BSA) by the DuBois method .
The study was conducted in accordance with good clinical practice (ICH-E6) . The protocol and amendments were approved by the institutional review boards and the patients gave written informed consent before screening at each study site. The enrolment period lasted from June 2007 to April 2009.
Descriptive statistics was calculated for quantitative variables (mean, standard deviation--SD, median, minimum and maximum) and qualitative variables (absolute and percentage frequencies). Ninety-five percent confidence intervals (95%CI) were calculated as appropriate. The unpaired Student's t test was used to compare quantitative variables (Wilcoxon's Rank Sum test for variables that were not Gaussianly distributed) and the χ2 test (Fisher's exact test) for qualitative variables.
The overall time-variation of the markers was evaluated by a mixed-factorial analysis of variance (ANOVA) with random-coefficient general linear model.
Differences between week-48 and baseline values were calculated as delta (Δ[wk 48-bl]) for each marker. Pearson's correlation coefficient was used to assess the relationship of the markers' Δ[wk 48-bl] between each other.
Patients' characteristics at baseline
Age, years [mean (SD)]
Risk factor IVDU
BMI (< 25 Kg/m2)
Viral load > 100.000 copies/mL
CD4 T cell count < 200 cells/mm3
CD4/CD8 ratio < 0.4
HCV Ab positive
CDC 93 clinical class A
• TDF/FTC + EFV
• TDF/FTC + ATV/r
Phosphoraemia < 2.7 mg/dL
1,25 (OH)2 Vitamin D < 11 pg/mL
Hyperparathyroidism (> 65 pg/mL)
eGFR creatinine * < 90 mL/min
eGFR cystatin C * < 90 mL/min
OC, ng/mL [mean (SD)]
CTx, ng/mL [mean (SD)]
OPG, ng/mL [mean (SD)]
RANKL at baseline was not dosable in 86% of patients
To account for possible seasonal variations in 1,25-(OH)2 vitamin D, we stratified patients into two groups according to the month of HAART initiation (sunny-period between May and October and not-sunny-period between November and April). All patients resided in a region between 41° and 45° latitude North; these periods were selected because 1,25-(OH)2 vitamin D production is impossible during the not-sunny months owing to the solar zenith angle, which influences the incident UVB radiation .
All analyses were performed using the statistical software package SAS® (SAS Istitute Inc., Cary NC, USA) version 9.13. All p values were considered significant if < 0.05 or according to Bonferroni's significance adjustment. With 38 patients in each group, there is a power of 0.80 of demonstrating an effect size of about 0.65 at an unpaired Student's t test with a significance level of 0.05 (two tailed).
Patients' characteristics at baseline
Among 91 patients enrolled in the trial, 75 remained on follow-up with the randomized HAART regimens and had plasma samples available, so they were included in this sub-study (33/75 receiving EFV and 42/75 ATV/r). All patients achieved HIV RNA < 50 copies/mL by week 24 and maintained virological success up to the end of the follow-up. CD4+ T-cell count increased from baseline to week 48 by a mean of 202 (SD: 172) cells/mm3. One patient withdrew the informed consent after week 48 for the main trial but not for this sub-study. Sixteen patients discontinued the study, none of them for renal failure or bone alterations.
Patients' characteristics are shown in Table 1. Most patients were males and acquired HIV infection through sexual intercourse, 77.3% had CD4+ T-cell count > 200/mm3 and more than half had not experienced any HIV-related events. A quarter of patients (19/75) showed hypophosphoremia (< 2.7 mg/dL) and a considerable proportion (22.6%) of patients had serious 1,25-(OH)2 vitamin D deficiency (i.e., < 11 pg/mL) at baseline. Mean PTH at baseline was 31.04 (SD: 17.7) pg/mL; considering 65 pg/mL as a cut-off, 4/75 (5.3%) patients had hyperparathyroidism. Most patients initiated antiretroviral therapy with normal kidney function calculated using either creatinine or cystatin C clearance. These characteristics were similar to those of the main trial including 91 patients .
All patients had normal serum calcium levels at baseline. In 30 patients in whom FRAX™ scores  could be calculated because age was > 40 years the mean score was 3.12 (SD: 0.87).
Values of bone turnover markers at baseline are shown in Table 1. Of note, RANKL was undetectable (< 0.0063 pg/mL) in 86% patients. As for the other markers, we found that, at baseline, 2/75 patients exceeded the OC cut-off, while 8/75 (10.6%) exceeded the CTx cut-off.
Trends of the bone turnover markers
RANKL remained or became undetectable in 87% patients throughout the follow-up. Linear correlation analysis to explore relationship between Δ[wk 48-bl] of the study markers showed that OC increased with increasing CTx (correlation coefficient: 0.26; p = 0.026), while no other significant correlations between each other were found.
Trends of PTH and 1,25-(OH)2 vitamin D
PTH increased significantly by a mean (Δ[wk 48-bl]) of 15.05 (SD: 35.76) pg/mL (Figure 1d). At week 48 there were 9 (12%) patients with an elevated PTH.
Predictors of increase in bone turnover markers
multivariable regression analysis
ATV/r vs. EFV
Age (for one year older)
Log10 HIV RNA (for 1 log10 higher)
eGFR cystatin C (< 90 vs. > 90 L/min)
CTx Δ[wk 48-bl] was associated at univariate analysis with increasing OC Δ[wk 48-bl] (r2 = 0.07, p = 0.026), lower CD4+/CD8+ T-cell ratio at baseline (r2 = 0.07, p = 0.038), smaller eGFR Creatinine Δ[wk 48-bl] (r2 = 0.1, p = 0.009), older age (r2 = 0.05, p = 0.05), and higher HIV RNA at baseline (r2 = 0.04, p = 0.06). At multivariable analysis including treatment group as clinically significant variable, older age, higher HIV RNA at baseline, and the use of ATV/r were significantly associated with CTx increase. Particularly, as for treatment received, patients prescribed ATV/r had a mean of 0.22 ng/mL CTx increase, independently from the other two factors.
For OC Δ[wk 48-bl], no significant associations besides that with CTx Δ[wk 48-bl] were found.
There is a paucity of data on bone turnover markers in HIV-infected patients after HAART. Some studies demonstrated an increase in OC and CTx [14, 15] and these increases correlated with reduction of bone mineral density (BMD) . By contrast, other authors found significant decreased levels of OC in patients treated with HAART [12, 13]. Our data confirm a parallel increase of soluble markers indicating bone formation (OC) and resorption (CTx) upon initiation of HAART and this effect appeared to be maximal at week 24.
We found a significant increase of OPG after HAART, differently from the study by Brown et al.  who found a decrease of this marker. The authors hypothesized that decreased inflammation after HAART could reduce OPG. In the present study, inflammation was not assessed, but all patients achieved sustained undetectable HIV RNA (the main driver of inflammation), therefore other factors may be implicated.
Higher eGFR at baseline (measured by cystatin C using the CKD-EPI formula) predicted OPG increase from baseline to week 48. Glomerular filtration rate estimated through cystatin C may be a reliable method to assess renal function in HIV infected patients because it is less influenced by muscle mass and liver function than the methods based on creatinine [26, 27]. Therefore, our data suggest that patients with better eGFR are protected since OPG by itself is known to counteract osteoclastic activation by antagonism to RANKL . However, since cystatin C is increased by inflammation [29, 30], it has to be seen whether the pro-inflammatory status at baseline or the actual kidney damage is a better predictor OPG evolution.
Older age and increasing HIV RNA at baseline were independently predictive of CTx increase during the follow-up. Since the increase in CD4+ T-cells is greater in patients with higher HIV RNA at baseline [31, 32] the correlation between higher HIV RNA and CTx increase could be mediated by immune-reconstitution, as recently suggested . However, no significant correlation between Δ[wk 48-bl] of the CD4+ T-cell count and CTx increase was found in our study (data not shown), and this seems to contradict the previous hypothesis . Therefore, greater increase of CTx could be due to the fact that bone health is already impaired in older patients and in those with higher HIV RNA due to a damaging effect of HIV on bone health [34, 35]. However, the underlying mechanisms should be investigated.
Notably, the use of ATV/r was associated with greater CTx increase in our study. Brown et al.  found that OC increase, but not CTx increase, was associated with PI use. Notwithstanding this apparent inconsistency, both studies suggest that PIs are associated with up-regulation of bone remodeling. Although we could not provide reliable explanations, McComsey et al.  already demonstrated a deeper impact of ATV/r on lumbar vertebral BMD than EFV when co-administered with TDF. Our results are in line with--and may explain--this observation.
We found a significant PTH increase after HAART, confirming previous studies [8, 37, 38]. This increase could be due to low 25(OH) vitamin D levels. However, we did not evaluate 25(OH) vitamin D, so this hypothesis could not be proven. Rather, we were interested in 1,25-(OH)2 vitamin D in order to assess the availability of the final product exerting biological activity. We found that 1,25-(OH)2 vitamin D remained stable, while in other studies TDF seemed to increase it [11, 39]. This stability was observed independently from variations due to seasonality, a finding that was not confirmed by others . Therefore, the effect of TDF on 1,25 (OH)2 vitamin D needs further considerations.
This study suffers from several limitations. First of all, BMD was not assessed; therefore the early activation of bone markers could not be coupled with BMD reduction. Second, 1,25-(OH)2 vitamin D levels are unstable and its values are of difficult interpretation . Third, our study is descriptive, so we did not provide any data on possible mechanisms. For instance, it is impossible to infer whether the increase in bone markers was due to PTH increase or to a direct effect of antiretroviral drugs on bone metabolism. Fourth, the number of patients was small, but the study provided statistically significant results. Lastly, we studied a sub-group of patients from the randomized cohort based on the availability of stored samples and maintenance of the initial HAART regimen. Although we could not exclude a selection bias, this is unlikely because no patients dropped out of the study for bone complications and they were not systematically selected for inclusion in the study. Notwithstanding these limitations we believe that our results add interesting information given the paucity of the current literature data.
The rapid and significant increase in bone markers observed in the present study reinforce that a strict monitoring is necessary to detect early signs of bone damage as already stated by recent guidelines . Moreover, we identified possible predictors of bone turnover changes (such as age, HIV RNA, ATV/r co-administration and kidney function) which may help identify most-at-risk patients. Since a correlation between increase of soluble bone markers and reduction of BMD has already been found, our results can be clinically significant. Moreover, it has been hypothesized that bone turnover markers may offer additional or complementary information with respect to BMD assessment through DXA scan . However, more powerful studies are needed to correlate changes in bone turnover markers with bone mineral density and risk of fractures, so as to understand if these markers (and what) should be monitored in clinical practice . Our results, however, suggest that OC and CTx are good candidates.
The authors would like to thank all patients enrolled in the trial, all investigators in the participant Centers, all nurses, and especially Cristina Minardi and Anna Brozzoni, who managed and processed the blood samples.
Special thanks to Francesca Brognoli for the help and advice in administrative procedures and legal management of the protocol, and to Dr Giuseppe Lapadula, who participated in the design of the main trial protocol, enrolment and patients' follow-up.
This work was partially supported by NEAT (Network for Excellence in Antiretroviral Treatment) funded by the European Commission (Project number: LSHP-CT-2006-037570).
Funding for this study was obtained from the University of Brescia ("ex-60%").
- Brown TT, Qaqish RB: Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS. 2006, 20: 2165-2174. 10.1097/QAD.0b013e32801022eb.View ArticlePubMedGoogle Scholar
- Young J, Bucher HC, Guenthard HF, Rickenbach M, Fux CA, Hirschel B, Cavassini M, Vernazza P, Bernasconi E, Battegay M: Virological and immunological responses to efavirenz or boosted lopinavir as first-line therapy for patients with HIV. Antivir Ther. 2009, 14: 771-779. 10.3851/IMP1291.View ArticlePubMedGoogle Scholar
- Womack JA, Goulet JL, Gibert C, Brandt C, Chang CC, Gulanski B, Fraenkel L, Mattocks K, Rimland D, Rodriguez-Barradas MC, Tate J, Yin MT, Justice AC: Increased risk of fragility fractures among HIV infected compared to uninfected male veterans. PLoS One. 2011, 6: e17217-10.1371/journal.pone.0017217.View ArticlePubMedPubMed CentralGoogle Scholar
- Borderi M, Gibellini D, Vescini F, De Crignis E, Cimatti L, Biagetti C, Tampellini L, Re MC: Metabolic bone disease in HIV infection. AIDS. 2009, 23: 1297-1310. 10.1097/QAD.0b013e32832ce85a.View ArticlePubMedGoogle Scholar
- Watts NB, Bilezikian JP, Camacho PM, Greenspan SL, Harris ST, Hodgson SF, Kleerekoper M, Luckey MM, McClung MR, Pollack RP, Petak SM: American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of postmenopausal osteoporosis. Endocr Pract. 2010, 16 (Suppl 3): 1-37.View ArticlePubMedPubMed CentralGoogle Scholar
- Vega D, Maalouf NM, Sakhaee K: CLINICAL Review: the role of receptor activator of nuclear factor-kappaB (RANK)/RANK ligand/osteoprotegerin: clinical implications. J Clin Endocrinol Metab. 2007, 92: 4514-4521. 10.1210/jc.2007-0646.View ArticlePubMedGoogle Scholar
- Rivas P, Górgolas M, García-Delgado R, Díaz-Curiel M, Goyenechea A, Fernández-Guerrero ML: Evolution of bone mineral density in AIDS patients on treatment with zidovudine/lamivudine plus abacavir or lopinavir/ritonavir. HIV Med. 2008, 9: 89-95. 10.1111/j.1468-1293.2007.00525.x.View ArticlePubMedGoogle Scholar
- van Vonderen MGA, Lips P, van Agtmael MA, Hassink EAM, Brinkman K, Geerlings SE, Sutinen J, Ristola M, Danner SA, Reiss P: First line zidovudine/lamivudine/lopinavir/ritonavir leads to greater bone loss compared to nevirapine/lopinavir/ritonavir. AIDS. 2009, 23: 1367-1376. 10.1097/QAD.0b013e32832c4947.View ArticlePubMedGoogle Scholar
- Moyle G, Newey C, Baldwin C, Torti C, Mandalia S, Gazzard B: Osteopenia: a consequence of HIV not HAART?. Antivir Ther. 2000, 5: 43-Google Scholar
- Fernández-Rivera J, García R, Lozano F, Macías J, García-García JA, Mira JA, Corzo JE, Gómez-Mateos J, Rueda A, Sánchez-Burson J, Pineda JA: Relationship between low bone mineral density and highly active antiretroviral therapy including protease inhibitors in HIV-infected patients. HIV Clin Trials. 2003, 4: 337-46. 10.1310/4X0H-UVMJ-BHYW-CPFB.View ArticlePubMedGoogle Scholar
- Aukrust P, Haug CJ, Ueland T, Lien E, Müller F, Espevik T, Bollerslev J, Frøland SS: Decreased bone formative and enhanced resorptive markers in human immunodeficiency virus infection: indication of normalization of the bone-remodeling process during highly active antiretroviral therapy. J Clin Endocrinol Metab. 1999, 84: 145-150. 10.1210/jc.84.1.145.PubMedGoogle Scholar
- Hernández Quero J, Ortego Centeno N, Muñoz-Torres M, Martinez Pérez MA, Higuera Torres-Puchol JM: Alterations in bone turnover in HIV-positive patients. Infection. 1993, 21: 220-222. 10.1007/BF01728893.View ArticlePubMedGoogle Scholar
- Serrano S, Mariñoso ML, Soriano JC, Rubiés-Prat J, Aubia J, Coll J, Bosch J, Del Rio L, Vila J, Goday A: Bone remodelling in human immunodeficiency virus-1-infected patients. A histomorphometric study. Bone. 1995, 16: 185-191. 10.1016/8756-3282(94)00028-X.View ArticlePubMedGoogle Scholar
- Brown TT, Ross AC, Storer N, Labbato D, McComsey G: Bone turnover, osteoprotegerin/RANKL and inflammation with antiretroviral initiation: tenofovir versus non-tenofovir regimens. Antivir Ther. 2011, 16: 1063-1072. 10.3851/IMP1874.View ArticlePubMedGoogle Scholar
- Stellbrink H-J, Orkin C, Arribas JR, Compston J, Gerstoft J, Van Wijngaerden E, Lazzarin A, Rizzardini G, Sprenger HG, Lambert J, Sture G, Leather D, Hughes S, Zucchi P, Pearce H: 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. 10.1086/656417.View ArticlePubMedGoogle Scholar
- Piso RJ, Rothen M, Rothen JP, Stahl M: Markers of bone turnover are elevated in patients with antiretroviral treatment independent of the substance used. J Acquir Immune Defic Syndr. 2011, 56: 320-4. 10.1097/QAI.0b013e31820cf010.View ArticlePubMedGoogle Scholar
- Panel on Antiretroviral Guidelines for Adults and Adolescents: Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. 2011, Department ofHealth and Human Services, 1-167. Available at [http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf]. Accessed December 15th, 2011Google Scholar
- Antinori A, Marcotullio S, Ammassari A, Andreoni M, Angarano G, Carosi G, Cinque P, d' Arminio Monforte A, Di Perri G, Ensoli B, Ferrazzi E, Galli M, Mastroianni C, Matteelli A, Mazzotta F, Moroni M, Palù G, Puoti M, Puro V, Rizzardini G, Sagnelli E, Suter F, Vella S, Lazzarin A: Italian guidelines for the use of antiretroviral agents and the diagnostic-clinical management of HIV-1 infected persons. New Microbiol. 2011, 34: 109-46.PubMedGoogle Scholar
- Albini L, Cesana BM, Motta D, Focà E, Gotti D, Calabresi A, Izzo I, Bellagamba R, Fezza R, Narciso P, Sighinolfi L, Maggi P, Quiros-Roldan E, Manili L, Guaraldi G, Lapadula G, Torti C: A randomized, pilot trial to evaluate glomerular filtration rate by creatinine or cystatin C in naïve HIV-infected patients after tenofovir/emtricitabine in combination with atazanavir/ritonavir or efavirenz. J Acquir Immune Defic Syndr. 2012, 59: 18-30. 10.1097/QAI.0b013e31823a6124.View ArticlePubMedGoogle Scholar
- Stevens LA, Schmid CH, Greene T, Zhang YL, Beck GJ, Froissart M, Hamm LL, Lewis JB, Mauer M, Navis GJ, Steffes MW, Eggers PW, Coresh J, Levey AS: Comparative performance of the CKD Epidemiology Collaboration (CKD-EPI) and the Modification of Diet in Renal Disease (MDRD) Study equations for estimating GFR levels above 60 mL/min/1.73 m2. Am J Kidney Dis. 2010, 56: 486-95. 10.1053/j.ajkd.2010.03.026.View ArticlePubMedPubMed CentralGoogle Scholar
- Stevens LA, Coresh J, Schmid CH, Feldman HI, Froissart M, Kusek J, Rossert J, Van Lente F, Bruce RD, Zhang YL, Greene T, Levey AS: Estimating GFR using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 3,418 individuals with CKD. Am J Kidney Dis. 2008, 51: 395-406. 10.1053/j.ajkd.2007.11.018.View ArticlePubMedPubMed CentralGoogle Scholar
- Dubois D, Dubois E: A formula to estimate the approximate surface area if height and weight be known. Arch Intern Med. 1916, 17: 863-871.View ArticleGoogle Scholar
- European Medicines Agency (EMEA): ICH Topic E 6 (R1) Guideline for Good Clinical Practice. 2002, CPMP/ICH/135/95Google Scholar
- Webb AR, Kline L, Holick MF: Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. J Clin Endocrinol Metab. 1988, 67: 373-378. 10.1210/jcem-67-2-373.View ArticlePubMedGoogle Scholar
- Kanis JA, the World Health Organization Scientific Group: Assessment of osteoporosis at the primary healthcare level. Technical Report. 2007, University of Sheffield, Sheffield: WHO Collaborating CentreGoogle Scholar
- Odden MC, Scherzer R, Bacchetti P, Szczech LA, Sidney S, Grunfeld C, Shlipak MG: Cystatin C level as a marker of kidney function in human immunodeficiency virus infection: the FRAM study. Arch Intern Med. 2007, 167: 2213-2219. 10.1001/archinte.167.20.2213.View ArticlePubMedPubMed CentralGoogle Scholar
- Filler G, Bökenkamp A, Hofmann W, Le Bricon T, Martínez-Brú C, Grubb A: Cystatin C as a marker of GFR-history, indications, and future research. Clin Biochem. 2005, 38: 1-8. 10.1016/j.clinbiochem.2004.09.025.View ArticlePubMedGoogle Scholar
- van Vonderen M, Mallon P, Murray B, Doran P, van Agtmael M, Danner S, Lips P, Reiss S, MEDICLAS Study Group: Changes in Bone Biomarkers in ARV-naïve HIV + Men Randomized to NVP/LPV/r or AZT/3TC/LPV/r Help Explain Limited Loss of Bone Mineral Density over the First 12 Months after ART Initiation. 18th Conference on Retroviruses and Opportunistic Infections, Boston MA Feb 24-Mar 2. 2011, 833-Google Scholar
- Keller C, Katz R, Cushman M, Fried LF, Shlipak M: Association of kidney function with inflammatory and procoagulant markers in a diverse cohort: a cross-sectional analysis from the Multi-Ethnic Study of Atherosclerosis (MESA). BMC Nephrol. 2008, 9: 9-10.1186/1471-2369-9-9.View ArticlePubMedPubMed CentralGoogle Scholar
- Barraclough K, Er L, Ng F, Harris M, Montaner J, Levin A: A comparison of the predictive performance of different methods of kidney function estimation in a well-characterized HIV-infected population. Nephron Clin Pract. 2009, 111: c39-c48. 10.1159/000178978.View ArticlePubMedGoogle Scholar
- Bennett KK, DeGruttola VG, Marschner IC, Havlir DV, Richman DD: Baseline predictors of CD4 T-lymphocyte recovery with combination antiretroviral therapy. J Acquir Immune Defic Syndr. 2002, 31: 20-26. 10.1097/00126334-200209010-00003.View ArticlePubMedGoogle Scholar
- Collaboration of Observational HIV Epidemiological Research Europe (COHERE) Study Group, Sabin CA, Smith CJ, d' Arminio Monforte A, Battegay M, Gabiano C, Galli L, Geelen S, Gibb D, Guiguet M, Judd A, Leport C, Dabis F, Pantazis N, Porter K, Raffi F, Thorne C, Torti C, Walker S, Warszawski J, Wintergerst U, Chene G, Lundgren J: Response to combination antiretroviral therapy: variation by age. AIDS. 2008, 22: 1463-73.View ArticleGoogle Scholar
- Ofotokun I, Weitzmann N, Vunnava A, Sheth A, Villinger F, Zhou J, Williams E, Sanford S, Rivas M, Lennox J: HAART-induced Immune Reconstitution: A Driving Force Behind Bone Resorption in HIV/AIDS. 18th Conference on Retroviruses and Opportunistic Infections, Boston MA. 2011, 78-Google Scholar
- Onen NF, Overton ET, Seyfried W, Stumm ER, Snell M, Mondy K, Tebas P: Aging and HIV infection: a comparison between older HIV-infected persons and the general population. HIV clin trials. 2010, 11: 100-109. 10.1310/hct1102-100.View ArticlePubMedGoogle Scholar
- Fausto A, Bongiovanni M, Cicconi P, Menicagli L, Ligabò EV, Melzi S, Bini T, Sardanelli F, Cornalba G, d' Arminio Monforte A: Potential predictive factors of osteoporosis in HIV-positive subjects. Bone. 2006, 38: 893-897. 10.1016/j.bone.2005.11.001.View ArticlePubMedGoogle Scholar
- McComsey GA, Kitch D, Daar ES, Tierney C, Jahed NC, Tebas P, Myers L, Melbourne K, Ha B, Sax PE: 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. J Infect Dis. 2011, 203: 1791-1801. 10.1093/infdis/jir188.View ArticlePubMedPubMed CentralGoogle Scholar
- Rosenvinge MM, Gedela K, Copas AJ, Wilkinson A, Sheehy CA, Bano G, Hay PE, Pakianathan MR, Sadiq ST: Tenofovir-linked hyperparathyroidism is independently associated with the presence of vitamin D deficiency. J Acquir Immune Defic Syndr. 2010, 54: 496-499. 10.1097/QAI.0b013e3181caebaa.View ArticlePubMedGoogle Scholar
- Masià M, Padillla S, Robledano C, López N, Ramos JM, Gutiérrez F: Early changes in parathyroid hormone concentrations in patients initiating antiretroviral therapy with tenofovir. AIDS Res Hum Retrovir.Google Scholar
- Haug CJ, Aukrust P, Haug E, Mørkrid L, Müller F, Frøland SS: Severe deficiency of 1,25-dihydroxyvitamin D3 in human immunodeficiency virus infection: association with immunological hyperactivity and only minor changes in calcium homeostasis. J Clin Endocrinol Metab. 1998, 83: 3832-3838. 10.1210/jc.83.11.3832.View ArticlePubMedGoogle Scholar
- Mueller NJ, Fux CA, Ledergerber B, Elzi L, Schmid P, Dang T, Magenta L, Calmy A, Vergopoulos A, Bischoff-Ferrari HA: High prevalence of severe vitamin D deficiency in combined antiretroviral therapy-naive and successfully treated Swiss HIV patients. AIDS. 2010, 24: 1127-1134. 10.1097/QAD.0b013e328337b161.View ArticlePubMedGoogle Scholar
- Hollis BW: Assessment and interpretation of circulating 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D in the clinical enviroment. Endocrinol Metab Clin North Am. 2010, 39: 271-286. 10.1016/j.ecl.2010.02.012.View ArticlePubMedPubMed CentralGoogle Scholar
- Vasikaran S, Eastell R, Bruyère O, Foldes AJ, Garnero P, Griesmacher A, McClung M, Morris HA, Silverman S, Trenti T, Wahl DA, Cooper C, Kanis JA: Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int. 2011, 22: 391-420. 10.1007/s00198-010-1501-1.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/12/38/prepub
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