Supplementary Data S2a: Summary of Evidence Table Primary Outcome (BMD)

Supplementary Data S2a: Summary of Evidence Table Primary outcome (BMD)

Study (first Study design Study population Test used O Compared to Results author, year) ut c o m e s Numbe Sex Age r Doulgeraki Cross- 14 8 male 13.16 (6.17-16.58) yrs BMD Z-score BMD Z-scores (median, 2014 sectional 6 range): study female Lumbar spine, total body Lumbar spine: -0.65 (-2.5 to 1.4) Total body: -0.3 (-1.7 to 0.6)

Overall, median BMD Z- scores within normal range.

5 patients low-normal lumbar spine Z-score (between -1 and -2), whereas total body Z-scores were normal.

BMD Z-scores (mean±SD) Lumbar spine: -0.58 ±1.29 Total body: -0.6 ±0.9

1 Study (first Study design Study population Test used O Compared to Results author, year) ut c o m e s Panis 2004 Cross- 40 13 3.0-17.3 yrs Absolute BMD, BMD Z-score BMD Z-score femoral neck sectional male (mean±SD): study 27 Mean: Lumbar spine, femoral neck -0.3±0.9 (-1.6 to 1.4) female 8.9±4.1 yrs BMD Z-score lumbar spine (mean±SD): -0.6±0.8 (-2.2 to 1.4)

Mean BMD Z-score of lumbar spine significantly decreased when compared to reference data (p<0.001). Rubio- Cross- 11 5 male 2.5-18.0 yrs BMD Z-score BMD Z-score total body Gozalbo sectional 6 (mean, range): 2002 study female Total body -0.99 (-0.5 to -1.4) (p<0.05).

2 Study (first Study design Study population Test used O Compared to Results author, year) ut c o m e s Tan 2014 Retrospectiv 25 15 5-41 yrs BMD Z-score 70% of patients >10 yrs of e case series male age had a normal bone (conference 10 Mean: 13.5±7.1 yrs Lumbar spine, total hip density. abstract) female BMD Z-score entire cohort (mean±SD): Lumbar spine: -0.80 ±0.99 Total hip: -0.76 ±1.19 BMD Z-score children (mean±SD): Lumbar spine: -0.78 ±1.04 Total hip: -0.84 ±1.18 BMD Z-score adults (mean±SD): Lumbar spine: -1.00 ±0.60 Total hip: -0.20 ±1.35 BMD Z-score adult males (mean±SD): Lumbar spine: -0.70 ±0.42 Total hip: 0.35±1.35

3 Study (first Study design Study population Test used O Compared to Results author, year) ut c o m e s Waisbren Cross- 33 17 18-59 yrs BMD Z-score Bone density on average 2012 sectional male greater than one SD below study 16 Mean: Hip, femoral neck, spine the mean (Z-score= -1.1). female 32.6±11.7 yrs 8/33 (24%) had Z-score greater than 2 SD below the mean.

15 subjects (45%) had history of fractures; 6 during childhood, 9 at ages 20-46 yrs.

BMD Z-score adults (mean±SD): Lumbar spine: -0.91 ±1.26 Total hip: -0.94 ±0.86 Femoral neck: -0.97 ±0.82 BMD Z-score males (mean±SD): Lumbar spine: -0.80 ±1.28 Total hip: -0.81 ±0.70 Femoral neck: -0.89 ±0.66 BMD Z-score females (mean±SD):

4 5 Supplementary Data S2b: Summary of Evidence Table Secondary outcomes (BMC, BTM, vitamins, minerals and hormones)

Abbreviation list

1.25OHD = 1,25-dihydroxy vitamin D Mg = magnesium 25-OH-D vitamin = 25-hydroxycholecalciferol NA = not applicable AP = alkaline phosphatase NTX = amino terminal telopeptide of type I collagen BAP = bone-specific alkaline phosphatase OC = osteocalcin Ca= calcium P = phosphate cOC = carboxylated osteocalcin PTH = parathormone CTX = carboxy-terminal telopeptide of type 1 collagen ucOC =under-carboxylated osteocalcin ERT = estrogen replacement therapy Z= zinc IGF-1 = insulin-like growth factor-1

Study (first Study design Study population Outcomes Compared to Results author, year) Numbe Sex Age r Gajewska Cross- 35 17 1-10 yrs Serum Ca, P, 25(OH)D, AP, CTX 20% lower than controls, 2006 sectional male OC, BAP, CTX p<0.001. study 18 Mean: female 5.0 yrs All other values similar to controls or within reference range.

6 Study (first Study design Study population Outcomes Compared to Results author, year) Gajewska Cross- 62 32 2-20 yrs Serum Ca, P, 25(OH)D, OC, Substantial overlap in 2008 sectional male BAP, CTX-I patients with 2006 study. study 30 Group female children: CG children: CTX-I is about N=32 20% lower than in controls 17 male (p<0.001). BAP and OC not 15 female significantly different. 2-9 yrs CG adolescents: BAP is about Group 30% higher than in controls adolescents (p<0.05), OC is about 35% : higher than in controls N=30 (p<0.02). CTX-I not 15 male significantly different. 15 female 10-20 yrs Healthy adolescents have significantly lower levels of CTX-I, BAP and OC than healthy children.

Ca, P, 25(OH)D in CG patients within normal ranges. Panis 2004 Cross- 40 13 3.0-17.3 yrs Serum Ca, P, Mg, Zn, Significantly decreased: cOC, sectional male 1.25OHD, PTH, 17-beta NTX, CTX, IGF-1 Z-scores. study 27 Mean: estradiol, IGF-1 Z-score, female 8.9±4.1 yrs CTX, BAP, cOC, ucOC, All other outcomes within ucOC/cOC ratio, NTX reference range.

7 Study (first Study design Study population Outcomes Compared to Results author, year) Panis 2006 Randomized- 40 13 3-17 yrs DXA Pediatric reference data controlled male trial on effect 27 of calcium, female vitamin K1 and D3 supplementat ion on bone mineral content Rubio- Cross- 11 5 male 2.5-18.0 yrs Serum Ca, P, PTH, AP, NTX significantly lower than in Gozalbo sectional 6 25(OH)D, 1.25OHD, cOC, controls (p<0.001). 2002 study female ucOC, NTX, BAP There was no correlation between BMD results and dietary calcium intake.

Sirrs 2010 Retrospectiv 16 9 male 17-55 yrs 25(OH)D 9 patients had 25(OH)D levels e case series 7 in insufficient range, 1 patient (conference female Mean: in deficient range, despite half abstract) 26.6±9 yrs of them having moderate- good compliance to supplements (total daily vitamin D intake ≥400 IU).

8 Study (first Study design Study population Outcomes Compared to Results author, year) Waisbren Cross- 33 17 18-59 yrs Plasma 25(OH)D 80% has 25(OH)D level below 2012 sectional male the sufficient range. study 16 mean: female 32.6±11.7 Mean plasma 25(OH)D 27±11 yrs ng/mL, reference range 32- 100 ng/mL.