| 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
|