Table 2.

Characteristics of included randomized controlled trials with Vitamin D and Calcium supplementation.

Authors	Country	Study Design	n	Sex (WM %)	Age (Mean)	Sample (at Baseline)	Groups	Duration of Intervention	Follow-Up	Dose of Vitamin D, Frequency	Effects on BMD	Effects on 25(OH)D and PTH	Effects on Bone Turnover Indices	Effects on Falls	Secondary Results
[21]	Australia	Randomized placebo-controlled doubled-blind RCT	54	n/a	32	Overweight or obese vitamin D-deficient (25OHD < 50 nmol/L) adults	Vitamin D n = 28 placebo group n = 26	16 weeks	16 weeks	Loading dose of 100.000 IU cholecalciferol, followed by 4000 IU cholecalciferol/d or a matching placebo	ns changes in BMD	↑25(OH)D ↓ PTH	ns changes in FGF-23	ns change in OF
[24]	China	randomized controlled trial	420	81.4	>60	bone mineral density (BMD) at lumbar vertebra or hip ≤ −2.5	Inactive vitamin group (n = 98) Inactive vitamin with exercise group (n = 97) Active vitamin group (n = 99) Active vitamin and exercise group (n = 98)	12 m	3,6,12 m 12 m  BMD	Inactive VitD group: 800 mg Ca and 800 IU inactive VitD/day. Inactive VitD + exercise group: 800 mg Ca and 800 IU VitD/day + instructions to improve muscle strength and balance Active VitD group: 800 mg Ca and 0.5 µg active VitD/day Active VitD + exercise group: 800 mg Ca and 0.5 µg of active VitD/day + instructions for improving muscle strength and balance	↑Lumbar BMD of the A VitD group and the P-A VitD group   Ns change in hip, femur neck BMD	↑25(OH)D		ns change in OF   ns change in falls	-
[25]	Turkey	Prospective, open-label, controlled clinical trial.	120	100	50	Pre- and postmenopausal women diagnosed with vitamin D deficiency	Group A (cholecalciferol + Ca) n = 43 Group B (calcitriol + cholecalciferol + Ca) n = 77	6 m	6 m	Group A (1000 IU of Vitamin D3 and 1 g of Ca/D) Group B (0.5 μg calcitriol in addition to 400 IU of cholecalciferol and 1 g of Ca/D)	Ns in total BMD ↑ Lumbar spine BMD in group B	↑25(OH)D ↓PTH	↓ ALP (Group B) ↑ CTx, NTx, deoxypyridinoline, OC (Group A and Group B, no difference between groups)	ns change in OF	-
[26]	USA	Randomized double-blind, controlled trial	222	99	71	Elderly (>65 years), overweight with a serum 25(OH)D between 10–30 ng/m	High dose group (n = 110) Low dose group (n = 112)	6, 12 m	6,12 m	Supplementation with 1000 mg of elemental Ca citrate/day, and the daily equivalent of 3750 IU/day or 600 IU/day of vitamin D3	↑BMD at the total hip and lumbar spine, but not the femoral neck, in both study arms.   ↑ subtotal body BMD in the high-dose group at 1 year.   Subjects with 25OHD < 20 ng/mL and PTH level > 76 pg/mL ↑ hip BMD	↑25(OH)D ↑ calcitriol in the high dose group   ↓ PTH but ns change between groups	↓OC, CTX ns difference between groups	↑ in OF
[27]	India	Randomized, open-labeled, comparative, controlled clinical study	65	66	40	Osteopenic adults	Treatment group: 32 Control group: 33	0, 6, 12m	6, 12 m	Treatment group received two tablespoons of PG (10mL in lukewarm milk), along with Ca and vitamin D3 supplements (containing elemental Ca 1200 mg and vitamin D3 [cholecalciferol] 800 IU/day) twice a day, whereas control group received only Ca and vitamin D3 supplements twice a day	↑BMD scores at 6 months, which was sustained at 12 months in both the study groups. Maximal improvement was observed in the lumbar spine and left forearm regions.	↑vitamin D3 in the PG group than in the SOC group at 6 and 12 months, which was statistically significant at 12 months (30.3 ng/mL vs. 22.3 ng/mL)	Improvement in OC, TRAP-5b in the PG-treated group	ns change in OF
[28]	USA	Randomized, double-blind controlled study	58	100	58	overweight/obese healthy, postmenopausal women (age 50–70 years old; BMI 25–40 kg/m2)	A: 600 IU/day (n = 19), B: 2000 IU/day (n = 20), C:4000 IU/day (n = 19)	12 m	12 m	Vitamin D 600, 2000, 4000 IU   Ca 1.2 g/day during weight control	↓ cortical thickness in the 600-IU group but not in the higher vitamin D groups	↑25(OH)D ↓ PTH	↑ CTX, P1NP ns difference between groups	ns change in OF	3 % weight reduction
[29]	USA	Randomized trial	135	100	55.8	Overweight/obese Caucasian, early–postmenopausal women	Placebo n = 62 Dairy n = 64 Supplement (Ca + vitamin D) n = 62	6 m	6 m	Moderate energy restriction (~85% of energy needs) for all participants. All subjects complemented with low-fat dairy foods (4–5 servings/day), or Ca + vitamin D supplements a total of ~1500 mg/day and 600 IU/day of Ca and vitamin D, respectively, or placebo pills	Supplement group: lower decrease or slight increase in BMD in measured skeletal sites.	↑25(OH)D ↓ PTH	ns change in OF	ns change in OC, NTx   ↓ Urinary CTx in the supplement group and ↑ in the control group	dairy group: better body composition outcomes, higher decrease in fat and lower decrease in lean mass.
[30]	USA	Randomized placebo controlled trial	273 (Caucasian n = 163 African American n = 110)	100	Caucasian 67 African American 65	Elderly women with vitamin D insufficiency, (serum 25(OH)D levels ≤50 nmol/ L)	8 intervention groups D3 doses of: 400 IU/d, n = 20 800 IU/d, n = 22 1600 IU/d, n = 23 2400 IU/d, n = 24 3200 IU/d, n = 21 4000 IU/d, n = 20 4800 IU/d, n = 21 Placebo group n = 22	12 m	12 m	Vitamin D3 400, 800, 1600, 2400, 3200, 4000, or 4800 IU daily   Ca 200 mg as to maintain a total Ca intake of ~1200 mg	ns change in total BMD and hip, lumbar spine BMD   No association between change in BMD and the 12-month values for serum total 25(OH)D, serum free 25(OH)D or serum 1,25(OH)2D	↑25(OH)D ↓PTH		ns change in OF	Results for Caucasian and African American women were similar. ↑ in total body Ca in the treated women with higher baseline serum PTH.
[51]	USA and Lebanon	Double-blind, randomized controlled trial	221	55.2	>65   71.1	Overweight, with a baseline serum 25(OH)D of between 10 and 30 ng/mL	High-dose group: 1000 mg elemental Ca and 3750 IU/day vitamin D. Low-dose group: 1000 mg elemental Ca and 600 IU/day vitamin D	6, 12 m	6, 12 m	All subjects received 1000 mg elemental Ca and oral vitamin D3 (600 IU/ day or 3750 IU/day) supplementation	ns change in spine and hip BMD at 12 months   ↑ subtotal body BMD with the high dose.	No increase in total, bioavailable, and free 25(OH)D levels was found at 12 months (p < 0.001) for low dose and high-dose supplementation. Vitamin D supplementation at a dose of 3750 IU/day resulted in serum levels of total, bioavailable, and free 25(OH)D, that were 1.28–1.38 higher than levels reached with 600 IU/day dose.			Weak but significant relationship between 25(OH)D and % BMD change at femoral neck only (p = 0.033), and only mild significant correlation between the free and bioavailable 25(OH)D, and the total body BMD at 12 months.

Ca = calcium; BMD = bone mineral density; PTH = parathormone; OC = osteocalcin; CTX = C-terminal telopeptide; NTx: N-terminal telopeptide; TRAP-5b = Tartrate-resistant acid phosphatase; FGF-23 = Fibroblast growth factor 23; y = year; m = month; w = week; WM: women.