Vitamina D e saúde óssea em adultos: uma revisão sistemática e metanálise

Segheto, Kátia Josiany; Pereira, Marcos; Silva, Danielle Cristina Guimarães da; Carvalho, Cristiane Junqueira de; Massardi, Felipe Ribeiro; Kakehasi, Adriana Maria; Juvanhol, Leidjaira Lopes; Longo, Giana Zarbato

doi:10.1590/1413-81232021268.15012020

Kátia Josiany Segheto

Departamento de Nutrição e Saúde, Universidade Federal de Viçosa (UFV). Ed. Centro de Ciências Biológicas II s/n, Campus Universitário. 36570-900 Viçosa MG Brasil. kaseghetto@gmail.com

http://orcid.org/0000-0003-4605-0823

Marcos Pereira

Instituto de Saúde Coletiva, Universidade Federal da Bahia. Salvador BA Brasil.

http://orcid.org/0000-0003-3766-2502

Danielle Cristina Guimarães da Silva

Centro das Ciências Biológicas e da Saúde, Universidade Federal do Oeste da Bahia. Barreiras BA Brasil.

http://orcid.org/0000-0001-5456-0853

Cristiane Junqueira de Carvalho

Departamento de Medicina e Enfermagem, UFV. Viçosa MG Brasil.

http://orcid.org/0000-0001-8574-6669

Felipe Ribeiro Massardi

Departamento de Medicina e Enfermagem, UFV. Viçosa MG Brasil.

http://orcid.org/0000-0003-4630-6948

Adriana Maria Kakehasi

Faculdade de Medicina, Universidade Federal de Minas Gerais. Belo Horizonte MG Brasil.

http://orcid.org/0000-0001-9411-7493

Leidjaira Lopes Juvanhol

Departamento de Nutrição e Saúde, Universidade Federal de Viçosa (UFV). Ed. Centro de Ciências Biológicas II s/n, Campus Universitário. 36570-900 Viçosa MG Brasil. kaseghetto@gmail.com

http://orcid.org/0000-0001-8012-6006

Giana Zarbato Longo

Departamento de Nutrição, Universidade Federal de Santa Catarina. Florianópolis SC Brasil.

http://orcid.org/0000-0001-7666-5007

Collaborations

KJ Segheto: responsible for writing the article, collecting data, analyzing and interpreting the results. M Pereira: responsible for writing the article, analyzing and interpreting the results. DCG Silva: responsible for writing the article and critical review. CJ Carvalho: responsible for writing the article, responsible for data collection and analysis and interpretation of results. FR Massardi: responsible for data collection and analysis and interpretation of results. AM Kakehasi: responsible for writing the article and critical review. LL Juvanhol: responsible for writing the article and critical review. GZ Longo: responsible for writing the article and critical review.

Chief editors:

Romeu Gomes, Antônio Augusto Moura da Silva

Database	Search Strategy	Items Found
PubMed http://www.ncbi.nlm.nih.gov/pubmed	“vitamin D “[MeSH Terms] AND “Bone Density”[MeSH Terms] AND “Adult”[MeSH Terms] AND ((“2000/01/01”[PDAT]: “3000/12/31”[PDAT]) AND “humans”[MeSH Terms])	1980
Web of science http://apps-webofknowledge.ez	#1 (TI= (bone density AND vitamin D AND adult)) AND TIPOS DE DOCUMENTO: (Article) Índices=SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI Tempo estipulado=2000-2018 = 12#2 TI= (TI = (vitamin D AND bmd OR bmc AND adult)) AND TIPOS DE DOCUMENTO: (Article)Índices=SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI Tempo estipulado=2000-2018 =15 #2 OR #1=26	26
Scopus http://www.scopus.com/	TITLE-ABS-KEY ( “vitamin D “ AND “bone density” OR bmd OR bmc AND adult AND “ Observational Study” ) AND ( LIMIT-TO ( PUBYEAR , 2018 ) OR LIMIT-TO ( PUBYEAR , 2017 ) OR LIMIT-TO ( PUBYEAR , 2016 ) OR LIMIT-TO ( PUBYEAR , 2015 ) OR LIMIT-TO ( PUBYEAR , 2014 ) OR LIMIT-TO ( PUBYEAR , 2013 ) OR LIMIT-TO ( PUBYEAR , 2012 ) OR LIMIT-TO ( PUBYEAR , 2011 ) OR LIMIT-TO ( PUBYEAR , 2010 ) OR LIMIT-TO ( PUBYEAR , 2009 ) OR LIMIT-TO ( PUBYEAR , 2008 ) OR LIMIT-TO ( PUBYEAR , 2007 ) OR LIMIT-TO ( PUBYEAR , 2006 ) OR LIMIT-TO ( PUBYEAR , 2005 ) OR LIMIT-TO ( PUBYEAR , 2004 ) OR LIMIT-TO ( PUBYEAR , 2003 ) OR LIMIT-TO ( PUBYEAR , 2002 ) OR LIMIT-TO ( PUBYEAR , 2001 ) OR LIMIT-TO ( PUBYEAR , 2000 ) )	214
Science Direct http://www.sciencedirect.com/	“vitamin D “ AND “Bone Density” AND “Adult” AND “Observational Study”	222
LILACS http://lilacs.bvsalud.org/	(tw:(Vitamin D)) OR (tw:(Vitamina D)) AND (tw:(Bone Density)) OR (tw:(Densidad Ósea)) OR (tw:(Densidad Ósea)) AND (tw:(Adult)) OR (tw:(Adult))	120

Authors/Year	Question Numbers				Overall Judgment on Risk of Bias
Authors/Year	Q1	Q2	Q3	Q4	Q5	Q6	Q7
Sherman et al., 1992	+	+	+	+	+	+	-	High
Brot et al., 1999	+	+	+	+	+	+	-	High
Güller et al., 2007	-	-	+	-	+	+	-	High
Lamberg-Allardt et al., 2001	+	+	+	+	+	+	-	High
Guzel et al., 2001	+	+	+	+	+	+	-	High
Tandon et al 2003	-	-	+	-	+	+	+	High
Bischoff- Ferrari et al., 2004	-	-	+	+	+	+	+	High
Saadi et al., 2006	+	+	+	-	+	+	-	High
Islam et al., 2008	+	+	+	-	+	+	-	High
Marwaha et al., 2009	+	+	+	-	+	+	+	High
Allali et al., 2009	+	+	+	-	+	+	+	High
Adami et al., 2009	+	+	+	+	+	+	+	Low
Multani et al., 2010	+	+	+	-	+	+	+	High
Gutiérrez et al., 2011	+	+	+	+	+	+	+	Low
Sadat-Ali et al., 2011	+	+	+	-	+	+	-	High
Harinarayan et al., 2011	+	+	+	-	+	+	-	High
Powe et al., 2011	-	-	+	+	+	+	+	High
Nakamura et al., 2001	-	-	+	-	+	+	+	High
Shivane et al., 2012	+	+	+	+	+	+	+	Low
Lim et al., 2012	+	+	+	+	+	+	+	Low
Kassi et al., 2015	+	+	+	-	+	+	+	High
Khashayar et al., 2016	+	+	+	+	+	+	-	High
Sayed-Hassan et al., 2014	+	+	+	-	+	+	+	High
Hannan et al., 2008	+	+	+	+	+	+	+	High
Arya et al., 2004	+	?	+	+	+	+	+	Moderate
Högström et al., 2006	+	+	+	+	-	+	+	High
Frost et al., 2010	+	+	+	+	+	+	+	Low
Boot et al., 2011	+	+	+	+	-	+	+	High
Kull et al., 2012	+	+	+	+	+	+	+	Low
Joo et al., 2013	+	+	+	+	+	+	+	Low
George et al., 2014	-	+	+	+	+	+	+	High
Wei et al., 2015	+	+	+	+	+	+	+	Low
Zhang et al., 2016	-	+	+	+	+	+	+	High
Callegari et al., 2017	-	+	+	+	+	+	+	High
Ardawi et al., 2012	+	+	+	+	+	+	+	Low

Age range
1. Saliba W, Barnett-Griness O, Rennert G. Obesity and Association of Serum 25(OH)D Levels with All-Cause Mortality. Calcif Tissue Int 2014; 95(3):222-228. 2. Viljakainen HT, Saarnio E, Hytinantti T, Miettinen M, Surcel H, Mäkitie O, Andersson S, Laitinen K, Lamberg-Allardt C. Maternal Vitamin D Status Determines Bone Variables in the Newborn. J Clin Endocrinol Metab 2010; 95(4):1749-1757. 3. McConda DB, Boukhemis KW, Matthews LJ. Watkins CM. Bone mineral density and vitamin D level compared to lifestyle in resident physicians. W V Med J 2016; 112(4):32-37. 4. Hamson C, Goh L, Sheldon P, Samanta A. Comparative study of bone mineral density, calcium, and vitamin D status in the Gujarati and white populations of Leicester. Postgrad Med J 2003; 79(931):279-283. 5. Diamond TH, Levy S, Smith A, Day P. High bone turnover in Muslim women with vitamin D deficiency. Med J Aust 2002; 177(3):139-141. 6. Ahuja M. Normal variation in the density of selected human bones in north India: a necropsy study. J Bone Joint Surg Br 1969; 51(4):719-735. 7. Kim BK, Choi YJ, Chung YS. Other than daytime working is associated with lower bone mineral density: the Korea National Health and Nutrition Examination Survey 2009. Calcif Tissue Int 2013; 93(6):495-501. 8. Goswami R, Gupta N, Goswami D, Marwaha RK, Tandon N, Kochupillai N. Prevalence and significance of low 25-hydroxyvitamin D concentrations in healthy subjects in Delhi. Am J Clin Nutr 2000; 72(2):472-475. 9. Yeum K-J, Song BC, Joo N-S. Impact of Geographic Location on Vitamin D Status and Bone Mineral Density. Int J Environ Res Public Health 2016; 13(2):184.
Associated diseases
10. Kantorovich V, Gacad MA, Seeger LL, Adams JS. Bone mineral density increases with vitamin D repletion in patients with coexistent vitamin D insufficiency and primary hyperparathyroidism. J Clin Endocrinol Metab 2000; 85(10):3541-3543. 11. Dietrich T, Joshipura KJ, Dawson-Hughes B, Bischoff-Ferrari HA. Association between serum concentrations of 25-hydroxyvitamin D3 and periodontal disease in the US population. Am J Clin Nutr 2004; 80(1):108-113. 12. Silva BCC, Camargos BM, Fujii JB, Dias EP, Soares MMS. Prevalence of vitamin D deficiency and its correlation with PTH, biochemical bone turnover markers and bone mineral density, among patients from ambulatories. Arq Bras Endocrinol Metabol 2008; 52(3):482-488. 13. Wöfl C, Englert S, Moghaddam AA, Zimmermann G, Schmidt-Gayk G, Höner B, Hogan A, Lehnhardt M, Grützner PA, Kolios L. Time course of 25(OH)D3 vitamin D3 as well as PTH (parathyroid hormone) during fracture healing of patients with normal and low bone mineral density (BMD). BMC Musculoskelet Disord 2013; 14:6. 14. Perry HM 3rd, Horowitz M, Morley JE, Fleming S, Jensen J, Caccione P, Miller DK, Kaiser FE, Sundarum M. Aging and bone metabolism in African American and Caucasian women. J Clin Endocrinol Metab 1996; 81(3):1108-1117. 15. Hwang S, Choi HS, Kim KM, Rhee Y, Lim SK. Associations between serum 25-hydroxyvitamin D and bone mineral density and proximal femur geometry in Koreans: the Korean National Health and Nutrition Examination Survey (KNHANES) 2008-2009. Osteoporos Int 2015; 26(1):163-171.
Age range
16. Zhang M, Li Y, Ma Q, Mao W, Gao Y, Liu Y, Liang B. Relevance of parathyroid hormone (PTH), vitamin 25(OH)D3, calcitonin (CT), bone metabolic markers, and bone mass density (BMD) in 860 female cases. Clin Exp Obstet Gynecol 2015; 42(2):129-132. 17. Fradinger EE, Zanchetta JR. Vitamin D and bone mineral density in ambulatory women living in Buenos Aires, Argentina. Osteoporos Int 2001; 12(1):24-27. 18. del Puente A, Esposito A, Savastano S, Carpinelli A, Postiglione L, Oriente P. Dietary calcium intake and serum vitamin D are major determinants of bone mass variations in women. A longitudinal study. Aging Clin Exp Res 2002; 14(5):382-388. 19. Chandran M, Hoeck HC, Wong HC, Zhang RF, Dimai HP. Vitamin D status and Its Relationship with Bone Mineral Density and Parathyroid Hormone in Southeast Asian Adults with Low Bone Density. Endocr Pract 2011; 17(2):226-234. 20. Zhou W, Langsetmo L, Berger C, Poliquin S, Kreiger N, Barr SI, Kaiser SM, Josse RG, Prior JC, Towheed TE, Anastassiades T, Davison KS, Kovacs CS, Hanley DA, Papadimitropoulos EA, Goltzman D, CaMos Research Group. Longitudinal changes in calcium and vitamin D intakes and relationship to bone mineral density in a prospective population-based study: the Canadian Multicentre Osteoporosis Study (CaMos). J Musculoskelet Neuronal Interact 2013; 13(4):470-479. 21. Joo N-S, Dawson-Hughes B, Kim Y-S, Oh K, Yeum K-J. Impact of calcium and vitamin D insufficiencies on serum parathyroid hormone and bone mineral density: Analysis of the fourth and fifth Korea National Health and Nutrition Examination Survey (KNHANES IV-3, 2009 and KNHANES V-1, 2010). J Bone Miner Res 2013; 28(4):764-770. 22. Kota S, Jammula S, Kota S, Meher L, Modi K. Correlation of vitamin D, bone mineral density and parathyroid hormone levels in adults with low bone density. Indian J Orthop 2013; 47(4):402-407. 23. Rocha AKS, Bos AJG, Carnenaz G, Machado DC. Bone mineral density, metabolic syndrome, and vitamin D in indigenous from south of Brazil. Arch Osteoporos 2013; 8:134. 24. Mosele M, Coin A, Manzato E, Sarti S, Berton L, Bolzetta F, et al. Association between serum 25-hydroxyvitamin d levels, bone geometry, and bone mineral density in healthy older adults. J Gerontol Biol Sci Med Sci 2013; 68(8):992-998. 25. Sohl E, Jongh RT, Swart KMA, Enneman AW, van Wijngaarden JP, van Dijk SC, Ham AC, van der Zwaluw NL, Brouwer-Brolsma EM, van der Velde N, Groot CPGM, te Velde SJ, Lips P, van Schoor NM. The association between vitamin D status and parameters for bone density and quality is modified by body mass index. Calcif Tissue Int 2015; 96(2):113-122. 26. Choi S-W, Kweon S-S, Choi J-S, Rhee J-A, Lee Y-H, Nam H-S, Jeong S-K, Park K-S, Ryu S-Y, Song H-R, Shin M-H. The association between vitamin D and parathyroid hormone and bone mineral density: The Dong-gu Study. J Bone Miner Metab 2016; 34(5):555-563. 27. Olmos JM, Hernandez JL, Garcia-Velasco P, Martinez J, Llorca J, Gonzalez-Macias J. Serum 25-hydroxyvitamin D, parathyroid hormone, calcium intake, and bone mineral density in Spanish adults. Osteoporos Int 2016; 27(1):105-113. 28. Kudlacek S, Schneider B, Peterlik M, Leb G, Klaushofer K, Weber K, Woloszczuk W, Willvonseder R, Austrian Study Group on Normative Values of Bone Metabolism. Assessment of vitamin D and calcium status in healthy adult Austrians. Eur J Clin Invest 2003; 33(4):323-331. 29. Pasco JA, Henry MJ, Nicholson GC, Brennan SL, Kotowicz MA. Behavioural and physical characteristics associated with vitamin D status in women. Bone 2009; 44(6):1085-1091. 30. Khaw KT, Sneyd MJ, Compston J. Bone density parathyroid hormone and 25-hydroxyvitaminD concentrations in middle aged women. BMJ1992; 305(6848):273-277. 31. Budak N, Çiçek, B, Sahin, H, Tutus, A. Bone mineral density and serum 25-hydroxyvitamin D level: is there any difference according to the dressing style of the female university students. Int J Food Scie Nutr 2004; 55(7):569-575. 32. Ghannam NN, Hammami MM, Bakheet SM, Khan BA. Bone mineral density of the spine and femur in healthy Saudi females: relation to vitamin D status, pregnancy, and lactation. Calcif Tissue Int 1999; 65(1):23-28. 33. Kota S, Jammula S, Kota S, Meher L, Modi K. Correlation of vitamin D, bone mineral density and parathyroid hormone levels in adults with low bone density. Indian J Orthop 2013; 47(4):402-407. 34. Overgaard K, Nilas L, Johansen JS, Christiansen C. Lack of seasonal variation in bone mass and biochemical estimates of bone turnover. Bone 1988; 9(5):285-258.
Age range
35. Kadam N, Chiplonkar S, Khadilkar A, Divate U, Khadilkar V. Low bone mass in urban Indian women above 40 years of age: prevalence and risk factors. Gynecol Endocrinol 2010; 26(12):909-917. 36. Scharla SH, Scheidt-Nave C, Leidig G, Woitge H, Wüster C, Seibel MJ, Ziegler R. Lower serum 25-hydroxyvitamin D is associated with increased bone resorption markers and lower bone density at the proximal femur in normal females: a population-based study. Exp Clin Endocrinol Diabetes 1996; 104(3):289-292. 37. Wei QS, Chen ZQ, Tan X, Su HR, Chen XX, He W, Deng WM. Relation of Age, Sex and Bone Mineral Density to Serum 25-Hydroxyvitamin D Levels in Chinese Women and Men. Orthop Surg 2015; 7(4):343-349. 38. Araujo AB, Travison TG, Esche GR, Holick MF, Chen TC, McKinlay JB. Serum 25-hydroxyvitamin D and bone mineral density among Hispanic men. Osteoporos Int 2009; 20(2):245-255. 39. Garg MK, Tandon N, Marwaha RK, Menon AS, Mahalle N. The relationship between serum 25-hydroxy vitamin D, parathormone and bone mineral density in Indian population. Clin Endocrinol 2014; 80(1):41-46. 40. Nguyen HT, Von Schoultz B, Nguyen TV, Dzung DN, Duc PT, Thuy VT, Hirschberg AL. Vitamin D deficiency in northern Vietnam: prevalence, risk factors and associations with bone mineral density. Bone 2012; 51(6):1029-1034. 41. van Ballegooijen AJ, Robinson-Cohen C, Katz R, Criqui M, Budoff M, Li, D, de Boer IH. Vitamin D metabolites and bone mineral density: The multi-ethnic study of atherosclerosis. Bone 2015; 78:186-193.
Pregnancy
42. Shao H, Tao M, Fan Y, Jing J, Lu J. Vitamin D levels and other factors related to bone mineral density during pregnancy. Aust N Z J Obstet Gynaecol 2012; 52(6):571-575.
Revision
43. Bell NH. Bone and mineral metabolism in African Americans. Trends Endocrinol Metab 1997; 8(6):240-245. 44. Pérez-López FR, Cano A, Calaf J, Vázquez F, Barriendos JF. Factores reguladores del recambio óseo: estrógenos y vitamina D. Progresos de obstetricia y ginecología 2009; 52(2)99-108. 45. Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc 2006; 81(3):353-373. 46. Pérez-López FR. Vitamin D and its implications for musculoskeletal health in women: an update. Maturitas 2007; 58(2):117-137.
Bone evaluation by methods other than DXA
47. Garton M, Martin J, New S, Lee S, Loveridge N, Milne J, Reid D, Reid I, Robins S. Bone mass and metabolism in women aged 45-55. Clin Endocrinol 1996; 44(5):563-570.
Letter to the Editor
48. Boucher BJ, Mannan N, Cunningham J. Vitamin D status and bone mass in UK South Asian women. Bone 2007; 40(4):1182.
Did not evaluate 25(OH)D
49. Högström M, Nordström A, Nordström P. Relationship between vitamin D metabolites and bone mineral density in young males: a cross-sectional and longitudinal study. Calcif Tissue Int 2006; 79(2):95-101.

		n	%	Reference
Year of publication
	1992-2005	8	22.86	[18,28-34]
	2006-2010	10	28.57	[17,20,35-42]
	2011-2015	13	37.14	[43-55]
	2016-2017	4	11.43	[56-59]
Location
	United States	5	14.28	[28,34,37,44,46]
	Europe (Denmark, Finland, Turkey, Italy, Greece, Estonia, Germany, Sweden)	8	22.86	[29,30,31,35,38,41,49,54]
	Asia (India, Bangladesh, United Arab Emirates, Japan, Korea, Syria, China, Iran, Saudia Arabia)	17	48.57	[17,18,20,32,33,40,42,45,47,48,50-52,55-58]
	Africa (Morocco, South Africa)	2	5.72	[39,53]
	Oceania (Australia)	1	2.85	[59]
	No location	2	5.72	[36,43]
Sample size
	<100	7	20	[18,30,32,33,35,36,46]
	100-500	15	42.86	[17,20,28,31,40,42,43,45,47,49,53-55,57,59]
	>500	13	37.17	[29,34,37-39,41,44,48,50-52,56,58]
Gender
	Both	18	51.43	[28,31-34,42-44,46,47,49,50-55,57]
	Women	10	28.57	[17,18,20,29,30,36,38,39,45,59]
	Men	7	20	[35,37,40,41,48,54,58]
Evaluated bone sites
	BMC	9	25.71	[17,18,29,35,43,44,49,53,59]
	LS-BMD	30	85.71	[17,20,28-30,32,33,35-43,46-52,54-59]
	H-BMD	23	65.71	[20,29,32,34-42,45,47,49-53,56-59]
	FN-BMD	28	80	[17,28-30,32,36-43,45,47-59]
	T-BMD	15	42.86	[17,29,32,33,36,37,39,40,42,45,47,49-51,56]
	IT-BMD	6	17.14	[32,33,42,45,47,51]
	WT-BMD	5	14.29	[17,32,33,36,45]
	R-BMD	8	22.86	[18,28,31-33,37,40,45]
Adjustment Variables
	Age	14	40	[29, 34, 35, 37-41,44,46,49,52,55,58]
	Gender	9	25.71	[28,31,32,34,43,44,46,51,57]
	Height	7	20	[28,35,37,40,52,57,59]
	Total Body Mass	7	20	[18,29,35,37,40,52,57]
	Body Mass Index	6	17.14	[34,38,40,41,46,49]
	Physical Activity	6	17.14	[34,35,41,49,57,59]
	Smoking	4	11.42	[34,41,49,58]
	Season of the Year	4	11.42	[34,37,49,52]
	Race/skin color	3	8.57	[34,37,46]
	Drinking Alcohol	2	5.72	[41,49]
	Latitude/Longitude	2	5.72	[38,59]
	Lean mass	1	2.85	[59]
	Fat %	1	2.85	[49]
	Fat Free Mass	1	2.85	[49]
	Socioeconomic level	1	2.85	[34]
	Solar Exposure	1	2.85	[38]
	Use of Hormones (estrogen, birth control)	1	2.85	[34]
	Others (age of menarche, total caloric intake, calcium intake, supplements, milk and coffee consumption, creatine level, chronic diseases, number of children and breastfeeding)	7	20	[34,40,41,43,49,52,58]

Type of Association	Linear Correlation (n=27)					Linear Regression (n=15)
	Women (n=21)
	BMC (n=2)	LS-BMD (n=12)	H-BMD (n=11)	FN-BMD (n=12)	T-BMD (n=8)	BMC (n=2)	LS-BMD (n=7)	H-BMD (n=4)	FN-BMD (n=5)	T-BMD (n=5)
Positive	---	3 [39*; 47; 56]	3 [39*; 47; 56]	3 [39*; 47; 56]	3 [39*; 47; 56]	2 [18; 29]	5 [17; 29; 36; 38; 39*]	3 [36; 38; 39*]	4 [17; 36; 38; 39*]	5 [17; 29; 36; 38; 39*]
Negative	---	1 [36]	1 [36]	1 [36]	1 [36]	---	1 [36]	1 [36]	1 [36]	---
Null	2 [29; 59]	9 [28*; 29; 30; 32; 36; 39; 42; 55; 59]	8 [29; 32; 36; 39; 42; 45; 57; 59]	11 [28*; 29; 30; 32; 36; 39; 42; 45; 55; 57; 59]	6 [29; 32; 36; 39; 42; 45]	---	2 [20; 28*]	1 [20]	1 [28*]	---
	Men (n=10)
	BMC (n=0)	LS-BMD (n=7)	H-BMD (n=5)	FN-BMD (n=6)	T-BMD (n=1)	BMC (n=2)	LS-BMD (n=1)	H-BMD (n=0)	FN-BMD (n=1)	T-BMD (n=0)
Positive	---	4 [37; 41; 52; 58]	4 [37; 41; 52; 58]	4 [37; 41; 52; 58]	1 [37]	---	1 [48]	---	1 [48]	---
Negative	---	2 [20; 40]	1 [20]	---	---	2 [18; 35]	---	---	---	---
Null	---	2 [40; 54]	---	2 [40; 54]	---	---	---	---	---	---
	Both genders (n=8)
	BMC (n=4)	LS-BMD (n=11)	H-BMD (n=7)	FN-BMD (n=10)	T-BMD (n=6)	BMC (n=2)	LS-BMD (n=3)	H-BMD (n=3)	FN-BMD (n=1)	T-BMD (n=1)
Positive	4 [43; 49*; 50; 53]	7 [33; 43; 46; 49; 51*; 53; 55]	4 [49; 50; 51; 53]	7 [33; 43; 49; 50; 51; 53; 55]	4 [33; 49; 50; 51]	2 [44; 49*]	3 [46; 49; 51*]	3 [34; 49; 51]	2 [49; 51]	2 [49; 51]
Negative	---	3 [42; 56; 57]	3 [42; 56; 57]	3 [42; 56; 57]	2 [42; 56]	---	---	---	---	---
Null	---	---	---	---	---	---	---	---	---	---

Bone sites	n	I² (%)	Meta-regression p-values
Bone sites	n	I² (%)	Mean age	Sample size	Gp	Mean 25(OH)D	Lat	Long	Risk of bias
Z BMC	7	85.4	0.64	0.81	0.95	0.68	0.43	0.80	0.03*
Z LS-BMD	11	97.8	0.64	0.20	0.75	0.27	0.85	0.98	0.29
Z H-BMD	14	87.3	0.50	0.01*	0.80	0.03*	0.14	0.66	0.71
Z FN-BMD	19	84.0	0.30	<0.01*	0.32	0.07	0.15	0.49	0.36
Z T-BMD	8	87.2	0.13	0.16	0.60	0.78	0.16	0.32	0.29

Author/Year	Country/City	Sample (n)	Age (Years) Mean (+SD)	25(OH)D (ng/ml) Mean (+SD)	BMC (g)/BMD (g/cm²) Mean (+SD)
Sherman et al., 1992*	United States - Baltimore	Men and Women, White (n=312)	---	---	---
Brot et al., 1999	Denmark - Copenhagen	Women Perimenopausa (n=510)	50.6+2.8	----	BMC: 2,294+363; LS-BMD: 1.021+0.142; H-BMD: 0.906+0.115; FN-BMD: 0.792+0.114; T-BMD: 0.682+0.094.
Güller et al., 2007		Group 1: typical garments (n=40); Group 2: only the skin of the hands and face is not covered (n=40)	Group 1: 36.1±3.2; Group 2: 34.8±3.3 (p>0.05)	Group 1: 25.43±11; Group 2: 13.7 ±9.83 (p<0.05)	Group 01: LS-BMD: 1.02+0.12; T-BMD: 0.68+0.12; TW-BMD 0.80+0.18; FN-BMD: 0.87+0.17; H-BMD: 0.90+0.11. Group 02: LS-BMD: 0.99+0.11; T-BMD: 0.68+0.10; TW-BMD: 0.76+0.13; FN-BMD: 0.88+0.14; H-BMD: 0.91+0.13. (p>0.05)
Lamberg-Allardt et al., 2001⁺	Finland	Men: (n=126); Women (n=202)	Men: 37.0+4; Women:38.0+.3 (p>0.05)	Men: 18.02+14.02; Women: 17.62+13.62 (p>0.05)	---
Guzel et al., 2001	Turkey	Women (n=60) Group 1: Veiled (n=30) Group 2: Unveiled (n=30)	Group 1: 24.6+5.1; Group 2: 24.9+6.2. (p>0.05)	Group 1: 33.1+16; Group 2: 53.9+27.3 (p<0.001)	Group 1: LS-BMD: 0.960+0.140; FN-BMD: 0.810+0.130. Group 2: LS-BMD: 1.010+0.090; FN-BMD: 0.850+0.090. (p>0.05)
Tandon et al., 2003	India	Men (n=40) Women (n=50).	Men: 22.7+2.8; Women: 23.4+3.1 (p>0.05)	Men: 18.4+5.3; Women: 25.3+7.4 (p <0.001)	Men: LS-BMD: 0.947+0.086; FN-BMD: 0.911+0.129; H-BMD: 1.016+0.133; T-BMD: 0.740+0.117; TW-BMD: 0.798+0.146; FIT-BMD: 1.167+0.159; DR-BMD: 0.619+0.072. Women: LS-BMD: 0.981+0.092; FN-BMD:0.850+0.101; H-BMD: 0.957+0.103; T-BMD: 0.707+0.121; TW-BMD: 0.769+0.121; FIT-BMD: 1.137+0.122; DR-BMD: 0.541+0.034.
Bischoff- Ferrari et al., 2004*⁺	United States	White (n=2,482) Mexican-American: (n=2,516) Black (n=2,517).	White: 34.8+8.1; Mexican-American: 32.6+8.4; Black: 33.5+8.0	White: 33.17+12.25; Mexican-American: 24.63+9.17; Black: 18.45+7.97	White: H-BMD: 0.97+0.14. Mexican-American: H-BMD: 1.00+0.14. Black: H-BMD: 1.07+0.17.
Saadi et al., 2006*⁺	United Arab Emirates	Women (n=259): Pre-Menopause (n=175)	Pre-Menopause: 37.5+9.5	Pre-Menopause 9.73±4.16	Pre-Menopause LS-BMD: 1.1+0.13; H-DMB: 0.970+0.13.
Islam et al., 2008*⁺	Bangladesh	Women (n=200)	22.6+3.7	14.7+4.48	FN-BMD: 0·788+0·106; T-BMD: 0.624+0.0893; TW-BMD: 0.645+0.118; LS-BMD: 0.894+0·116.
Marwaha et al., 2009*⁺	Indian-Deli	Men (n=473)	---	13.66+6.33	TR-BMD: 0.605+0.061; DR-BMD: 0.451+0.080; H-BMD: 1.129+0.130; FN-BMD: 1.115+0.134; T-BMD: 0.926+0.126; LS-BMD: 1.170+0.137
Allali et al., 2009*	Morocco-Rabat	Women (n=415) Pre-Menopause (n=108)	Women: 50+9.3; Pre-Menopause 42.8+6.2	Women: 18.1+7.9 Pre-Menopause; 18.6+7.7	Women: LS-BMD: 1.1+0.13; FN-BMD: 0.97+0.6; T-BMD: 0.79+0.11; H-BMD: 1.02+0.16.
Adami et al., 2009	Italy (North, Center and South)	Women, white, pre-menopause (n=608) North (n=364) Center (n=111) South (n=133)	North: 35.9+8.3 Center: 36.5+8.2 South: 35.7+8.3 (p>0.05)	North: 27.6+11.1 Center: 28.9+11.3 South: 24.8+11.2 (p>0.05)	25(OH)D Suf (>20ng/ml): LS-BMD: 1.028±0.121; FN-BMD: 0.907±0.128; H-BMD; 0.791±0.116*. 25(OH)D Insuf (<20ng/ml).: LS-BMD: 1.061±0.122; FN-BMD: 0.923±0.115; H-BMD: 0.810±0.128. (p=0.002; p=0.089; *p= 0.063)
Multani et al., 2010	Indian-Mumbai	Resident Physicians (n=214) Men (n=174); Women (n=40)	Men: 26.87+1.6; Women: 26.33+1.58.	Men: 12.80±7.94 Women: 10.94±4.54	Men: LS-BMD: 0.907+0.112; FN-BMD: 0.800+0.116; T-BMD: 0.662+0.099; FIT-BMD: 1.087+0.167; H-BMD 0.094+0.120. Women: LS-BMD: 0.899+0.101; FN-BMD: 0.740+0.106; T-BMD: 0.610+0.091; FIT-BMD: 0.971+0.203; H-BMD: 0.830+0.115.
Gutiérrez et al., 2011	United States	White (n=2,239); Mexican-American (n=989); Black (n=978); both sexes	White:45.3+0.5; Mexican-American: 37.0+0.7; Black 41.3+0.6	White: 25.6±0.4. Mexican-American: 19.5±0.5. Black: 14.8±0.4	White: 25(OH)D Suf. (>30 ng/ml): BMC: 1.03+0.01; 25(OH)D Insuf. (<30 ng/ml e >10ng/ml): BMC:1.03+0.01; 25(OH)D Def. (<10ng/ml): BMC:1.02+0.01; (p=0.79) Mexican-American: 25(OH)D Suf. (>30 ng/ml): BMC:1.03+0.01; 25(OH)D Insuf. (<30 ng/ml e >10ng/ml): BMC: 1.03+0.01; 25(OH)D Def. (<10ng/ml): BMC: 1.01+0.01; (p<0.01) Black: 25(OH)D Suf. (>30 ng/ml): BMC:1.08+0.02; 25(OH)D Insuf. (<30 ng/ml e >10ng/ml): BMC: 1.09+0.01; 25(OH)D Def. (<10ng/ml): BMC:1.09+0.01; (p=0.21)
Sadat-Ali et al., 2011*	Saudi Arabia -Al Khobar	Men and women (n=400): 100 men e 100 women for each (age group 25 and 35 years and ≥50 years)	25(OH)D Suf. (>30 pg/ml): Men: 27.96+3.5; Women: 29.81+3.8; 25(OH)D Insuf. (21-29 pg/m): Men: 28.89+4.28; Women: 28.05+3.13; 25(OH)D Def. (<20 pg/ml): Men: 28.5+4.5.; Women: 23.9+1.87.	---	LS-BMD Men: 25(OH)D Suf. (>30 pg/ml): 1.100+0.09; 25(OH)D Insuf. (21-29 pg/mLl): 0.903+0.13; 25(OH)D Def. (<20 pg/ml): 0.612+0.25. LS-BMD Women: 25(OH)D Suf. (>30 pg/ml): 0.844+0.14; 25(OH)D Insuf. (21-29 pg/ml): 0.747+0.09; 25(OH)D Def. (<20 pg/ml): 0.618+0.13 (p <0.001)
Harinarayan et al., 2011*	Indian	Hospital staff and patients (n=191) Pre-menopause (n=55); Post- menopause (n=136)	Pre-Menopause: 37.42+0.72 Post-menopause: 53.29+0.72 (p<0.001)	Pre-menopause (20-30 years): 24.08+1.12.	Pre-menopause (20-30anos): FR-BMD: 0.645+0.021; PR-BMD: 0.533+0.018; R-BMD: 0.403+0.012; TR-BMD: 0.527+0.016; T-BMD: 0.641+0.019; FIT-BMD: 1.058+0.021; FN-BMD: 0.757+0.015; TW-BMD 0.639+0.025; H-BMD: 0.886+0.017.
Powe et al., 2011*⁺	United States -Boston	Men (n=27); Women (n=22)	23.5+3.4	Men: 21.14+7.73. Women: 31.36+12.13 (p<.001)	Men: LS-BMD: 1.040+0.14; Women: LS-BMD 1.070+0.13. (p=0.371)
Nakamura et al., 2001*⁺	Japan	Women (n=77)	32.9+11.3	16.86+6.04	---
Shivane et al., 2012	Indian	Men (n=558); Women (n=579)	Men: 30.11+3.53; Women: 30.52+3.57	Men: 18.93+8.93; Women: 15.85+9.07	Men: FN-BMD: 0.827+0.125; T-BMD: 0.642+0.103; FIT-BMD: 0.986+0.140; H-BMD: 0.887+0.122; LS-BMD: 0.912+0.123 Women: FN-BMD: 0.755+0.108; T-BMD 0.595+0.109; FIT-BMD: 0.904+0.130; H-BMD: 0.814+0.111; LS-BMD: 0.899+0.120
Lim et al., 2012***	Korea	Men (n=1,926); Women (n=2,350)	Men: 28.61+8.34; Women: 29.24+7.98	Men: 18.85+6.67; Women: 16.74+5.74	Men: LS-BMD: 0.97+0.14; T-BMD: 0.70+0.09; FN-BMD: 0.87+0.13; H-BMD: 1.00+0.13. Women: LS-BMD: 0.97+0.13; T-BMD: 0.65+0.08; FN-BMD: 0.77+0.11; H-BMD: 0.90+0.11
Kassi et al., 2015	Greece - Athens	Men (n=181)	34.69+7.38	19.81+6.96	LS-BMD: 1.220 +0.13; H-BMD: 1.020+ 011
Khashayar et al., 2016	Iran - Tehran; Tabriz; Mashhad; Shiraz; Bandar; Busher	Men (n=1,900); Women (n=2,2250)	42.6+13.9	Osteoporosis: 42.03+34.59 Osteoponics: 35.97±26.49 Normal: 33.04±23.78 (p<0.001)	---
Sayed-Hassan et al., 2014	Syria - Damascus	Men (n=156); Women (n=64)	Men: 32.2±9.2; Women: 36.9±10 (p=0.006)	Men: 13.5+7.4 Women: 8+5.1 (p<0.001)	Men: LS-BMD: 0.938±0.12; FN-BMD: 0.861±0.13; H-BMD: 0.989±0.12*. Women: LS-BMD: 0.954±0.12; FN-BMD: 0.766±0.11; H-BMD: 0.872±0.12. (p=0.392; p<0.001; p<0.001*).
Hannan et al., 2008	United States - Massachusetts	Men: Black (n=331), Hispacnic (n=362); White (n=421).	Black: 48.0+12.5; Hispacnic: 44.4+10.9 White: 48.3+13.1 (p<0.001)	Black: 25.0 +14.7; Hispacnic: 32.9+13.9; White: 37.4+14.0 (p<0.001)	Black: FN-BMD: 0.94+0.15; T-BMD: 0.81+0.14; H-BMD: 1.09+0.15; LS-BMD: 1.10+0.15; TR-BMD: 0.80+0.07; DR-BMD: 0.56+0.08. Hispacnic: FN-BMD: 0.88+0.14; T-BMD: 0.76+0.12; H-BMD: 1.02+0.15; LS-BMD: 1.00+0.13; TR-BMD: 0.75+0.06; DR-BMD: 0.52+0.07. White: FN-BMD: 0.84+0.12; T-BMD: 0.75+0.12; H-BMD: 1.00+0.14; LS-BMD: 1.03+0.15; TR-BMD: 0.76+0.06; DR-BMD: 0.52+0.07. (p<0.001, comparing the same bone site between groups)
Arya et al., 2004	Indian - Lucknow	Hospital worker: Men (n=35); Women (n=67)	34.2± 6.7	12.3±10.9	---
Högström et al., 2006⁺	Sweden - Umea	Men, White (n=73)	22.6+0.7	39.26+13.82	BMC: 1.31+0.08; H-BMD: 1.26+0.15; LS-BMD: 1.27+0.12.
Frost et al., 2010*⁺	Denmark - Odense	Men (n=700)	25(OH)D Suf.: 25.6+2.9 25(OH)D Insuf.: 25.6+2.8 25(OH)D Def.: 25.3+2.8 (p>0.05))	Spring: 23.75+10.85 Summer: 24.27+11.17 Autum: 30.04+7.85 Winter: 28.20+11.81g (p<0.001)	25(OH)D Suf. LS-BMD: 1.08+0.12; FN-BMD: 0.95+0.13; H-BMD: 1.09+0.14. 25(OH)D Insuf. LS-BMD: 1.09+0.13; FN-BMD: 0.97+0.14; H-BMD: 1.10+0.14. 25(OH)D Def. LS-BMD:1.06+0.12; FN-BMD: 0.93+0.13; H-BMD: 1.05+0.14. (p=0.024; p=0.004; p=0.032*)
Boot et al., 2011⁺	---	Men (n=117); Women (n=347)	Men: 24.8+3.0; Women: 24.1+2.8	Men: 28.44+10.81; Women: 35.65+12.62	Men: BMC: 1.276+0.09; LS-BMD: 1.272+0.15; FN-BMD: 1.139+0.16. Women: BMC: 1.182+0.07; LS-BMD: 1.248+0.13; FN-BMD:1.063+0.13.
Kull et al., 2012⁺	Estônia - Lääne-Viru County	Men (n=122); Women (n=151).	Men: 48.3+11.8; Women: 49.2+12.9. (p=0.41)	Measured in winter: Men: 17.1+5.0; Women: 17.58+6.08 Measured in summer: Men: 24.63+7.57; Women: 23.35+7.13 (p=0.19)	Men: LS-BMD: 1.202+0.175; FN-BMD: 1.017+0.127; T-BMD: 0.965+0.155; H-BMD: 1.102+0.134; BMC: 1.264+0.086. Women: LS-BMD: 1.127+0.191; FN-BMD: 0.969+0.150; T-BMD: 0.848+0.136; H-BMD: 763.5+142.6; BMC: 1.032+0.149. (p=0.08; p=0.003; p<0.0001; p<0.0001; p<0.0001, comparing the same bone site between groups)
Joo et al., 2013*⁺	Korea	22-29 years Men (n=574); Women (n=775)	Men: 25.5+0.1; Women: 25.6+0.1	Men: 17.78+0.04; Women: 15.5+0.2	Men: FN-BMD: 5.06+0.04; H-BMD: 42.76+0.32; LS-BMD: 68.82+0.49. Women: FN-BMD: 3.47+0.02; H-BMD: 28.70+0.18; LS-BMD: 57.26+0.36. (Results presented in grams)
George et al., 2014*⁺	South African - Johannesburg	Women: Black African (n=187); Indian Asian (n=187) Men: Black African (n=181); Indian Asian (n=160)	Women: Black African: 41.7+13.1; Asian Indian: 43.8+12.7 (p=0.08) Men: Black African: 41.7+13.2; Asian Indian 43.0+13.2 (p=0.36)	Women: Black African: 23.35 (17.18-34.29) Asian Indian: 14.30 (9.21-21-83) (p<0.0001) Men: Black African: 29.12 (20.47-37-70) Asian Indian: 18.18 (13.46-25.12) (p<0.0001)	Men: Black African: ST-BMD 0.695(0.683-0.707); H-BMD: 1.068(0.934-1.162); FN-BMD: 0.938(0.826-1.026)*. Asian Indian: ST-BMD 0.671(0.659-0.683); H-BMD: 0.946(0.882-1.051)*; FN-BMD: 0.793(0.723-0.873). (p=0.02; p<0.0001; p<0.0001) Women: Black African: ST-BMD 0.702(0.691-0.713); H-BMD: 0.998(0.909-1.088); FN-BMD: 0.919(0.830-0.995). Asian Indian: ST-BMD 0.648(0.636-0.659); H-BMD: 0.887(0.803-0.978); FN-BMD: 0.777(0.692-0.859). (p<0.0001; p<0.0001; p<0.0001*)
Wei et al., 2015*	China - Guangzhou	Men (122); Women (n=188).	Men: 43.89+21.29 Women: 49.67+17.61 (p<0.05)	Men: 27.25+7.94 Women: 25.35+6.59 (p<0.05)	Men: LS-BMD: 1.17+0.18; FN-BMD: 0.97+0.18. Women: LS-BMD: 1.04+0.17; FN-BMD: 0.84+0.15. (p<0.001, for all bone sites)
Zhang et al., 2016*⁺	China - Guiyang	Men: Young (n=346); Middle-age (n=182)	Young: 30+6.4 (p<0.05) Middle-age: 49.2+5.8 (p<0.01)	Young: 17.46+9.49 (p<0.01) Middle-age: 23.59+8.04 (>0.05)	Young: FN-BMD: 0.95+0.12; (p<0.001); H-BMD: 1.000+0.12 (p<0.001); LS-BMD: 1.10+0.12. Middle-age: FN-BMD: 0.88+0.12; (p<0.01); H-BMD: 0.95+0.14 (p<0.01); LS-BMD: 1.10+0.14.
Callegari et al., 2017⁺	Canada - Victoria	Women (n=400)	22+3	27.64+11.21	BMC: 1.527+236; LS-BMD: 1.04+0.13; H-BMD: 0.93+0.12; FN-BMD: 0.87+0.13.
Ardawi et al., 2012*⁺	Saudi Arabia - Jeddah,	Men (<50 years) (n=550)	35.7+10.6	12.52+7.02	LS-BMD: 1.116+0.143; FN-BMD: 1.029+0.168.

[1] Collaborations

KJ Segheto: responsible for writing the article, collecting data, analyzing and interpreting the results. M Pereira: responsible for writing the article, analyzing and interpreting the results. DCG Silva: responsible for writing the article and critical review. CJ Carvalho: responsible for writing the article, responsible for data collection and analysis and interpretation of results. FR Massardi: responsible for data collection and analysis and interpretation of results. AM Kakehasi: responsible for writing the article and critical review. LL Juvanhol: responsible for writing the article and critical review. GZ Longo: responsible for writing the article and critical review.

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Vitamina D e saúde óssea em adultos: uma revisão sistemática e metanálise

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