Table 2.

Results of the systematic review on bone health in HIV-infected children, adolescents, and young adults

Ref (Year)	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 (XtremeCT Scanco): 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

Abbreviations: A, asian; ART, antiretroviral therapy; B, black; BD, bone density; BTT, bone transmission time; CSA, cross sectional area; BMC, bone mineral content; BMD, bone mineral density; BUA, broadband ultrasound attenuation; DXA, dual X-ray absorptiometry; FN, femoral neck; H, hispanic/latino; HR, high-resolution; IQR, interquartile range; LS, lumbar spine; NA, not applicable; NHANES, national health and nutrition examination survey; NNRTI, non-nucleoside reverse transcriptase inhibitor; NS, not specified; O, other; QCT, quantitative computed tomography; QUS, quantitative ultrasound; PI, protease inhibitor; PTH, parathyroid hormone; R13, 1/3 distal radius; SD, standard deviation; SOS, speed of sound; TH, total hip; UDR, ultradistal radius; WB, whole body; W, white