Author name (year) Ref Country Study design Comparison source N HIV+/ Control/ Total HIV+ sex (%M) HIV+ Age (years) HIV+ race/ ethnicity Measurements Key Findings
Mora (2001) [33] Italy Cross sectional Recruited healthy control group (N=314) 40/314/354 45 Range: 6-17 100% W DXA (Lunar): WB BMD, LS BMD   •Children on ART had lower WB BMD, LS BMD compared to control, adjusted for sex, age, bone area, weight, and height.
•WB BMD was lower in children on ART with lipodystrophy than children not on treatment
O’Brien (2001) [21] USA Cross sectional Single site database of healthy children (Ellis 1996, Children’s Nutrition Research Center database) (N=483) 19/483/502 0 Mean (SD): 9.2 (2.6) Range: 5.9-15.2 89% B 11% W DXA (Hologic): WB BMC, WB BMD •Lower WB BMC compared to control (age, race, and height matched).
•Low dietary calcium intake and elevated renal excretion.
•Calcitropic hormone (1,25 OH vitamin D and PTH) alterations related to increased bone resorption (NTx)
Arpadi (2002) [22] USA Cross sectional HIV-uninfected children enrolled in body composition study at the same site (N=262) 51/262/313 51 Range: 4.2-14.7 51% H 41.5% B 7.5% W DXA (Lunar): WB BMC   •Lower WB BMC compared to controls, adjusted for age, sex, race, height and weight.
•Magnitude of difference between HIV+ and controls increased with age
Gaughan (2002) [32] USA Longitudinal Exposed but uninfected children (N=849) 2014/849/2863 50 Median: 5.3 10th, 90th: 1, 12 16% W 52% B 31% H 1% O Legg-Calve-Perthes disease (LCPD) •Six cases of LCPD including 4 cases reported at study entry and 2 diagnosed during 5837 person-years of follow-up
Zamboni (2003) [34] Italy Cross sectional Normal prepubertal population (N=198) 13/198/211 31 Range: 4-12 Not specified DXA (Lunar): LS BMD, calculated vBMD •Densitometry results not compared with controls
•Negative vBMD Z-score (Z-score <0.0) in 6/13
•Spontaneous clavicular fracture in 1 child with low vBMD z-score
•Low bone formation and high bone resorption markers (e.g. low OCN, high NTX, low IGF in children with low CD4 and high IL-6)
Mora (2004) [35] Italy Longitudinal Recruited control group of healthy volunteers of comparable ages (N=381) 32/381/413 53 Mean (SD): 12.4 (0.5) Range: 6.3-17.7   100% W DXA (Lunar): WB BMD, LS BMD •Lower WB BMD and LS BMD compared to control at baseline, adjusted for sex, age, Tanner stage, and weight
•Lower annual increment for WB BMD compared to control
•Higher bone turnover rate compared to controls (BSAP and NTx)
Stagi (2004) [36] Italy Cross-sectional Recruited control group matched by age, pubertal stage, and sex (N=55) and also used normative database (CUBA for age 5-15 years, Falcini 2003 for under age 5 years) 44/55/99 48 Median: 8.4 Range: 4.6-12.4 100% W QUS (McCue Ultrasonics): heel BUA       •Children with severe clinical symptoms had lower BUA compared to controls (age, sex, and pubertal-stage sex matched)
•BUA related to free IGF-1
Giacomet (2005) [37] Italy Longitudinal Recruited control group of healthy white volunteers (N=166) 16/166/182 Not reported Mean 13.3 Range 6.4-17.9 100% W DXA (Lunar): LS BMC, LS BMD, WB BMC, WB BMD •During treatment with tenofovir, WB BMC, WB BMD, LS BMC, LS BMD changes did not differ from expected
Hazra (2005) [23]   USA Longitudinal Databases Bachrach 1999, Faulkner 1996   18/NS/18 61 Mean (SD): 12 (2.5) Range: 8.3-16.2 33% W 55% B 6% H 6% O DXA (Hologic): LS BMD •Baseline median LS BMD z-score was -1.18, adjusted for age, ethnicity, and sex
•5 of 15 subjects experienced decrease in LS BMD at week 48 after starting tenofovir
Jacobson (2005) [24] USA Longitudinal  Siblings (N=9) and single site multiethnic database (Ellis 2001, Children’s Nutrition Research Center database) 37/9/46 49 Median: 11.6 Range: 9.6-13.8 40% B 27% H 24% W DXA (Lunar or Hologic): WB BMC, WB BMD   •Lower WB BMD than population but not in comparison to sibling controls, adjusted for height and weight z-scores
•All controls had stable or increased repeat WB BMD but only 44% of HIV+ (p=0.09)
Mora (2005) [38]   Italy Cross-sectional Recruited control group of healthy children (N=119) 16/119/135 38 Mean (SD): 9.3 (3.9) Range: 4.4-16.0 100% W DXA (Lunar): LS BMC & WB BMC •LS BMC and WB BMC not significantly lower than controls, adjusted for sex, weight, and bone area
Pitukcheewanont (2005) [25] USA Cross sectional Recruited control group matched for age, gender, ethnicity (N=58) 58/58/116 45 Mean (SD): 12.03 (3.88) Range: 5-19.39 “of multiple ethnicities” DXA (Hologic): LS bone area, LS BMC, LS BMD, WB bone area, WB BMC, WB BMD QCT (General Electric Hilite Advantage): vertebral BD, vertebral height, vertebral CSA •Less LS bone area, LS BMC, LS BMD, WB bone area, WB BMC, WB BMD compared to controls (unadjusted).
•Variance in bone area, BMC, and BMD largely accounted for by height and weight
•Similar volumetric BMD by QCT in HIV+ compared to controls but smaller vertebral height and CSA
Rosso (2005) [39]   Italy Cross sectional Recruited control group from schools (N=1227) 44/1227/1271 48 Median: 10.7 Mean (SD): 10.4 (4.0) Range: 3-17 100% W QUS: phalangeal SOS, BTT •Lower SOS and BTT compared to control, adjusted for age, bone age, and body size
Gafni (2006) [26]   USA Longitudinal For children >9 years: single site multi-ethnic longitudinal database (N=423) (Bachrach 1999) For children <8 years old: single site longitudinal database (Faulkner 1996) 15/NS/15 67 Range: 4-18 NS DXA (Hologic): LS BMD, FN  BMD, TH BMD, LS BMAD •Baseline median z-scores were: LS BMD -1.2, TH BMD -1.0, FN BMD -1.4, LS BMAD -0.9
•Decrease in BMD and BMD z-score at LS, FN, and TH from baseline to 24 weeks and 48 weeks after tenofovir initiation and then stabilized
Mora (2007) [40] Italy Longitudinal Control group of healthy children (N=336) 27/336/363 48 Range: 4.9-17.3 100% W DXA (Lunar): LS BMD, WB BMD •Lower WB BMD and LS BMD compared to controls, adjusted for sex, age, weight, and height
Purdy (2008) [27] USA Longitudinal None 6/NA/6 67 Median: 12.8 Range: 11.3-17.5 N/A DXA (Hologic): LS BMD •5/6 children had decreases in LS BMD after receiving tenofovir as part of new regimen
Mora (2009) [41] Italy Cross sectional Manufacturer’s software (DXA: DPX-L version, version 1.5; QUS: BeamMed) 88/NS/88 49 Range: 4.8-22.1 78/88 W 10/88 B DXA (Lunar): LS BMC & BMD, WB BMC & BMD QUS (BeamMed): tibia, radius SOS •SoS associated with LS BMC, LS BMD, WB BMC, WB BMD, adjusted for sex, weight, and height
Jacobson (2010) [6] USA Cross sectional Recruited control group of uninfected children into 3 Tanner strata with similar overall distribution for sex and race/ethnicity as the HIV+ 236/143/379 53 Median: 12.6 Range: 7-24   13.1% W 54.7% B 32.2% H DXA (Lunar or Hologic): LS BMC & BMD, WB BMC & BMD   •HIV-infected males had lower WB BMC and WB BMD and LS BMD at Tanner 5 than controls, adjusted for DXA scanner, race, HIV, Tanner group, interaction of HIV and Tanner group, age, height, lean body mass. No differences in girls
•Use of NNRTI associated with higher LS BMC and LS BMD
•Ritonavir-boosted protease inhibitors associated with lower BMC and WB and LS BMD
•No effect of cumulative time on ART and bone measures 
•Conclusions with spinal BMAD same as LS BMD
Rosso (2010) [42] Italy Longitudinal Manufacturer software (not specified) 8/NS/8 75 Median: 11.2 Range: 3.8-18.2 NS QUS (not specified): SOS and BTT •SOS and BTT z-score values did not show differences during tenofovir treatment
Vigano (2010) [43] Italy Longitudinal Manufacturer software (enCORE software, version 13, GE medical systems) 21/NS/21 48 At baseline: Median: 12.1 Range: 4.9-17.9 100% W DXA (Lunar): WB BMD and LS BMD •LS BMD and WB BMD did not change during 60 month period after starting tenofovir treatment
Zuccotti (2010) [44] Italy Cross sectional Recruited healthy controls of comparable age (N=194) 86/194/280 45 Range: 4.8-22.1 NS DXA (Lunar): LS BMC & BMD, WB BMC & BMD •Lower WB BMC, LS BMC and BMD in children receiving PI-based treatment compared to healthy
•LS BMC lower in children receiving stavudine or ritonavir compared to healthy and treatment naïve or those on other ART.
•Lower WB BMD in children on ART compared to healthy
•No differences between ART naïve and healthy children
•All models adjusted for age, sex, pubertal stage, weight, height
Arpadi (2012) [28] USA Longitudinal Multicenter study of healthy children (Bone Mineral Density of Childhood Study Kalkwarf 2007) 59/NS/59 NS Range: 6-16 63% B 37% H DXA (Hologic): WB BMC and WB BMD •WB BMC WB BMD LS BMC and LS BMD increased at 1 year and 2 year for both randomized groups in the study. No group differences.
Della Negra (2012) [50] USA, Brazil, Panama Longitudinal Manufacturer software (not specified but used age-matched, sex-matched, and race-matched healthy controls) 90/NS/90 44 Mean (SD): 14 (1.5) 100% H DXA (Lunar or Hologic): LS BMD, WB BMD •Median WB BMD Z-score decreased -0.2 and LS BMD Z-score decreased -0.2 for TDF group and WB BMD Z-score -0.1 and LS BMD Z-score -0.1 for placebo group in first 24 weeks
Mulligan (2012) [7] USA Cross sectional Recruited control group of seronegative men from the same age range at same sites as HIV+ (N=53) 199/53/252 100 Median: 21 Range 14-25 59.8% B 28.1% H 12.1% O DXA (Lunar or Hologic): TH BMD, LS BMD, WB BMD, TH BMC, LS BMC, WB BMC •WB BMD and WB BMC Z-scores lower among HIV-infected on ART, in particular for those on PI, compared to controls, adjusted for race, BMI, type of DXA scanner
•FN BMD and FN BMD Z-scores only lower for those on PI compared to ART-naïve HIV+ and controls
Puthanakit (2012) [47] Thailand Cross sectional Data from cohort of 199 HIV-uninfected children aged from 12–18 years (N=199) 101/199/300 51 Median: 14.3 IQR: 13.0-15.7 100% Thai DXA (Lunar or Hologic): LS BMD   •24% of HIV-infected have low LS BMD (Z score ≤ -2)
•LS BMD lower compared to controls (age and sex-matched)
•Advanced clinical disease prior to initiation of ART and short stature associated with low LS BMD
Siberry (2012) [29] USA Longitudinal Exposed but uninfected children 1326/649/1975 49 Mean: 7.1 Range: 5.0, 10.0 62% B 11% W 24% H 2% O Fractures •No increased risk of fracture in HIV-infected compared to HIV-exposed but uninfected children
Schtscherbyna (2012) [49] Brazil Cross sectional Manufacturer software (Prodigy software version 11.4) 74/NS/74 45 Mean (SD): 17.3 (1.8) 36.5% W 63.5% not W DXA (Lunar WB, LS BMD   •Low WB and/or LS BMD (Z score <-2) in 32.4% of population
•Children on tenofovir had lower LS BMD and WB BMD
•Time on TDF inversely correlated to LS BMD
Bunders (2013) [46] Netherlands Longitudinal Manufacturer software (unspecified) 66/NS/66 45 Median: 6.7 IQR: 4.4-10.3 62% B DXA (Hologic): LS BMD, left FN BMD •Low LS BMD (Z score <-2.0) in 8% of HIV+ children
•Lower LS BMD compared to controls at baseline; median LS BMD z-score was -0.9
DiMeglio (2013) [30] USA and Puerto Rico Cross sectional Exposed uninfected children (N=160) 350/160/510 46 Median: 12.6 IQR: 10.2, 14.4 26% H 66% B 8% O/W DXA (Lunar or Hologic): WB BMD, LS BMD •Lower TB and LS BMD Z-scores adjusted for sex, race/ethnicity and puberty stage compared to control
•No differences with further adjustment for weight and height.
•WB BMD lower with use of lamivudine and ritonavir-boosted protease inhibitor
Lima (2013) [48] Brazil Cross sectional Database from NHANES (Kelly 2009) 48/NS/48 50 Mean (SD): 12.7 (2.7) Range: 7-17 53.3% W 43.8% B DXA (Hologic): WB BMD, LS BMD •16.7% of HIV+ had low bone mass for age
•WB BMD Z-scores greater in adolescence compared to children.
•No difference by sex once height accounted for.
•Association between ritonavir-boosted protease inhibitors and lower WB BMD Z-score
MacDonald (2013) [45] Canada Longitudinal Healthy controls who were participants in the University of British Columbia Healthy Bones III follow-up study (N=883) 31/883/914 61 Median: 13.6 IQR: 11.6, 16.0 32.2% Mixed 25.8% B 22.6% Aboriginal 12.9% W 6.5% A DXA (Hologic): WB BMC, LS BMC, femur BMC Peripheral QCT (Norland/Stratec XCT): muscle CSA, total and cortical bone area, cortical BMD, thickness and strength strain index at tibial shaft •WB BMC and femur BMC lower among HIV+, adjusted for height and lean mass
•CD4% positively associated with WB BMD z-score
•Muscle CSA lower in HIV+
•Tibial total and cortical bone area not different than controls.
•Cortical BMD positively associated with NNRTI use
•Cortical thickness negatively associated with PI use
Yin (2014) [31] USA Cross-sectional Recruited control group of HIV-uninfected controls (N=15) 30/15/45 100 Mean (SD): 22.5 (0.3) 60% B 40% H DXA (Hologic): LS BMC, LS BMD, FN BMC, FN BMD, TH BMC, TH BMD, R13 BMC, R13 BMD, UD BMC, UD BMD HR peripheral QCT (XtremeCTScanco): radius CSA, radius vBMD, radius microarchitecture, tibia CSA, tibia vBMD, tibia microarchitecture •DXA BMD Z-scores lower at the LS, TH, and R13 than controls
•HR peripheral QCT total and trabecular vBMD and cortical and trabecular thickness lower than controls
Table 2: Results of the systematic review on bone health in HIV-infected children, adolescents, and young adults