I västvärlden idag är benskörhet och dess följder ett växande hälsoproblem. Maximal
benmassa uppnås i ung vuxen ålder och denna påverkas bl.a. av genetik, motion och kost. Den maximala benmassan har betydelse för utveckling av benskörhet senare i livet. För att
optimera benmassan och motverka benskörhet är det av största vikt att identifiera faktorer tidigt i livet som gynnar bentillväxten.
Faktum är att forskare under de senaste decennierna har intresserat sig mer och mer för hur den tidiga nutritionen påverkar sjukdomsutfall långt senare. Djurstudier har visat att
avkommans tillgång på fettsyror under sen graviditet och första levnadsveckor påverkar benkvalitet i vuxenlivet. Detta tillräknas fettsyrors förmåga att modifiera genuttryck som har med metabolism och tillväxt att göra. Exempelvis spelar fleromättade fettsyror såsom omega-3 och omega-6 roll, där omega-omega-3 tros främja nybildning av ben medan omega-6 tros påverka nedbrytning av ben. Eftersom benskörhet är ett resultat av en obalans mellan bennybildning och bennedbrytning är kvoten mellan omega-6 och omega-3-fettsyror av betydelse. Denna studie syftar till att undersöka hur kostens sammansättning av fettsyror i spädbarnsåren påverkar benformationen under samma tidsperiod och även bentäthet senare i barndomen.
Mellan år 2008 och 2009 inkluderades 398 nyfödda barn på Halmstads sjukhus till studien.
Blodprover togs vid födelse samt vid 4 månaders ålder och fettsyror och benformations-markörerna osteocalcin och P1NP analyserades. Föräldrarna besvarade frågeformulär angående amningsvanor och barnen delades in i två grupper beroende på om de blivit ammade eller fått mjölkersättning (Nestlé NAN) vid 4 månaders ålder. Vid 8 års ålder
genomfördes en mätning av benmineraldensitet (BMD) av ländryggen med dual-energy X-ray absorptiometry (DEXA) på 167 av barnen från ursprungspopulationen. DEXA innebär en lågdos-röntgen och passar sig väl för barn.
Resultaten visade att ammade barn hade högre nivåer av 3- och lägre nivåer av omega-6-fettsyror vid 4 månaders ålder jämfört med barn som fått ersättningsmjölk. Ammade hade även högre nivåer av benmarkören osteocalcin men inte P1NP. Ett antal fettsyror korrelerade med osteocalcin men sambanden försvann efter att ha justerat för störande faktorer. Inte heller sågs korrelationer mellan fettsyror, benmarkörer och BMD av ländryggen vid 8 års ålder.
Istället var vikt och kvinnligt kön associerat till högre BMD.
Slutsatsen av denna studie är därför att amning, men inte specifikt fettsyror, påverkar benformationsmarkören osteocalcin under spädbarnstiden men har troligen ingen bestående effekt på bentäthet vid 8 års ålder. För att med säkerhet uttala sig i frågan behövs
kompletterande studier.
Acknowledgements
I am greatly thankful to the following people:
Jovanna Dahlgren for her outstanding supervision, her wonderful companionship and general wisdom. She introduced me to the world of research, in which I have found great joy.
The nurses Monica and Eivor at Halmstad Hospital for their contagious enthusiasm and diligent job that made this study possible.
Senior researchers Josefine Roswall and Emma Kjellberg for their great support and help in data collection.
Mats Andersson for his kindness and incredible job in the lab, spending many hours analysing fatty acids.
The Seidal family for letting me stay in their guest house and for providing with food and good company during my weeks in Halmstad.
REFERENCES
1. Barker DJ, Clark PM. Fetal undernutrition and disease in later life. Rev Reprod. 1997 May;2(2):105–12.
2. Barker DJ. Fetal origins of coronary heart disease. BMJ. 1995 Jul 15;311(6998):171–4.
3. Godfrey K. The ‘developmental origins’ hypothesis: Epidemiology. In: Developmental origins of health and disease. New York, NY, US: Cambridge University Press; 2006. p. 6–32.
4. Woodall SM, Johnston BM, Breier BH, Gluckman PD. Chronic Maternal Undernutrition in the Rat Leads to Delayed Postnatal Growth and Elevated Blood Pressure of Offspring. Pediatr Res. 1996 Sep;40(3):438–43.
5. Persson E, Jansson T. Low birth weight is associated with elevated adult blood pressure in the chronically catheterized guinea-pig. Acta Physiol Scand. 145(2):195–6.
6. Korotkova M, Ohlsson C, Gabrielsson B, Hanson LA, Strandvik B. Perinatal essential fatty acid deficiency influences body weight and bone parameters in adult male rats. Biochim Biophys Acta. 2005 Jan 5;1686(3):248–54.
7. Godfrey KM, Lillycrop KA, Burdge GC, Gluckman PD, Hanson MA. Epigenetic Mechanisms and the Mismatch Concept of the Developmental Origins of Health and Disease. Pediatr Res. 2007 May 1;61(5 Part 2):5R-10R.
8. Hochberg Z, Feil R, Constancia M, Fraga M, Junien C, Carel J-C, et al. Child Health, Developmental Plasticity, and Epigenetic Programming. Endocr Rev. 2011 Apr 1;32(2):159–224.
9. Zhang X, Ho S-M. Epigenetics meets endocrinology. J Mol Endocrinol. 2011 Feb;46(1):R11–32.
10. Eriksson JG, Forsén T, Tuomilehto J, Winter PD, Osmond C, Barker DJP. Catch-up growth in childhood and death from coronary heart disease: longitudinal study. BMJ. 1999 Feb 13;318(7181):427–31.
11. Singhal A, Fewtrell M, Cole TJ, Lucas A. Low nutrient intake and early growth for later insulin resistance in adolescents born preterm. The Lancet. 2003 Mar 29;361(9363):1089–97.
12. Davidson S, Hod M, Merlob P, Shtaif B. Leptin, insulin, insulin-like growth factors and their binding proteins in cord serum: insight into fetal growth and discordancy. Clin Endocrinol (Oxf).
65(5):586–92.
13. Karaolis-Danckert N, Buyken AE, Kulig M, Kroke A, Forster J, Kamin W, et al. How pre- and postnatal risk factors modify the effect of rapid weight gain in infancy and early childhood on subsequent fat mass development: results from the Multicenter Allergy Study 90. Am J Clin Nutr.
2008 May 1;87(5):1356–64.
14. Socha P, Grote V, Gruszfeld D, Janas R, Demmelmair H, Closa-Monasterolo R, et al.
Milk protein intake, the metabolic-endocrine response, and growth in infancy: data from a randomized clinical trial. Am J Clin Nutr. 2011 Dec 1;94(suppl_6):1776S-1784S.
16. AGROGIANNIS GD, SIFAKIS S, PATSOURIS ES, KONSTANTINIDOU AE.
Insulin-like growth factors in embryonic and fetal growth and skeletal development (Review). Mol Med Rep. 2014 Aug;10(2):579–84.
17. Baird J. Being big or growing fast: systematic review of size and growth in infancy and later obesity. BMJ. 2005;331(7522):929.
18. Sørensen TI. The changing lifestyle in the world. Body weight and what else? Diabetes Care. 2000 Apr;23 Suppl 2:B1-4.
19. Berquin IM, Edwards IJ, Chen YQ. Multi-targeted Therapy of Cancer by Omega-3 Fatty Acids. Cancer Lett. 2008 Oct 8;269(2):363–77.
20. Lau BYY, Cohen DJA, Ward WE, Ma DWL. Investigating the Role of Polyunsaturated Fatty Acids in Bone Development Using Animal Models. Molecules. 2013 Nov 15;18(11):14203–27.
21. Strandvik Birgitta. Perinatal programming by diets with essential fatty acid
deficient/high saturated fatty acids or different n‐6/n‐3 ratios for diseases in adulthood. Eur J Lipid Sci Technol. 2015 Jul 30;117(10):1513–21.
22. Hartl J, Herrmann R. Do they always say no? German consumers and second-generation GM foods. Agric Econ. 40(5):551–60.
23. Bioactive fatty acids: role in bone biology and bone cell function. Prog Lipid Res. 2001 Mar 1;40(1–2):125–48.
24. Neuringer M, Connor WE. n-3 Fatty acids in the brain and retina: Evidence for their essentiality. Nutr. Rev. 1986.
25. Pham-Huy LA, He H, Pham-Huy C. Free Radicals, Antioxidants in Disease and Health.
Int J Biomed Sci IJBS. 2008 Jun;4(2):89–96.
26. Simopoulos AP. The importance of the omega-6/omega-3 fatty acid ratio in
cardiovascular disease and other chronic diseases. Exp Biol Med Maywood NJ. 2008 Jun;233(6):674–
88.
27. Simopoulos AP. Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr. 2002 Dec;21(6):495–505.
28. Eriksson S, Mellström D, Strandvik B. Fatty acid pattern in serum is associated with bone mineralisation in healthy 8-year-old children. Br J Nutr. 2009 Jan;102(3):407–12.
29. Faulkner RA, Bailey DA. Osteoporosis: A Pediatric Concern? Optim Bone Mass Strength. 2007;51:1–12.
30. Bonjour J-P, Rizzoli R. Chapter 25 - Bone Acquisition in Adolescence. In: Marcus R, Feldman D, Kelsey J, editors. Osteoporosis (Second Edition) [Internet]. San Diego: Academic Press;
2001 [cited 2018 Jul 6]. p. 621–38. Available from:
http://www.sciencedirect.com/science/article/pii/B978012470862450026X
31. Cole ZA, Gale CR, Javaid MK, Robinson SM, Law C, Boucher BJ, et al. Maternal dietary patterns during pregnancy and childhood bone mass: a longitudinal study. J Bone Miner Res Off J Am Soc Bone Miner Res. 2009 Apr;24(4):663–8.
32. Jones G, Riley MD, Dwyer T. Maternal diet during pregnancy is associated with bone
33. Poulsen RC, Moughan PJ, Kruger MC. Long-Chain Polyunsaturated Fatty Acids and the Regulation of Bone Metabolism. Exp Biol Med. 2007 Nov 1;232(10):1275–88.
34. Ilich JZ, Kerstetter JE. Nutrition in bone health revisited: a story beyond calcium. J Am Coll Nutr. 2000 Dec;19(6):715–37.
35. Koren N, Simsa-Maziel S, Shahar R, Schwartz B, Monsonego-Ornan E. Exposure to omega-3 fatty acids at early age accelerate bone growth and improve bone quality. J Nutr Biochem.
2014 Jun 1;25(6):623–33.
36. Calcium metabolism, osteoporsis and essential fatty acids: A review. Prog Lipid Res.
1997 Sep 1;36(2–3):131–51.
37. Watkins BA, Li Y, Allen KGD, Hoffmann WE, Seifert MF. Dietary Ratio of (n-6)/(n-3) Polyunsaturated Fatty Acids Alters the Fatty Acid Composition of Bone Compartments and
Biomarkers of Bone Formation in Rats. J Nutr. 2000 Sep 1;130(9):2274–84.
38. Gao Q, Xu M, Alander CB, Choudhary S, Pilbeam CC, Raisz LG. Effects of
prostaglandin E2 on bone in mice in vivo. Prostaglandins Other Lipid Mediat. 2009 Jun 1;89(1):20–5.
39. Lau BYY, Ward WE, Kang JX, Ma DWL. Vertebrae of developing fat-1 mice have greater strength and lower n-6/n-3 fatty acid ratio. Exp Biol Med Maywood NJ. 2009 Jun;234(6):632–
8.
40. Högström M, Nordström P, Nordström A. n-3 Fatty acids are positively associated with peak bone mineral density and bone accrual in healthy men: the NO2 Study. Am J Clin Nutr. 2007 Mar;85(3):803–7.
41. Harvey N, Dhanwal D, Robinson S, Kim M, Inskip H, Godfrey K, et al. Does maternal long chain polyunsaturated fatty acid status in pregnancy influence the bone health of children?
Osteoporos Int. 2012 Sep 1;23(9):2359–67.
42. CDC. 2018 Breastfeeding Report Card [Internet]. Centers for Disease Control and Prevention. 2018 [cited 2018 Dec 2]. Available from:
https://www.cdc.gov/breastfeeding/data/reportcard.htm
43. Muniz LC, Menezes AMB, Buffarini R, Wehrmeister FC, Assunção MCF. Effect of breastfeeding on bone mass from childhood to adulthood: a systematic review of the literature. Int Breastfeed J. 2015;10:31.
44. Andres A, Casey PH, Cleves MA, Badger TM. Body fat and bone mineral content of infants fed breast milk, cow’s milk formula, or soy formula during the first year of life. J Pediatr. 2013 Jul;163(1):49–54.
45. Foley S, Quinn S, Jones G. Tracking of bone mass from childhood to adolescence and factors that predict deviation from tracking. Bone. 2009 May;44(5):752–7.
46. Harvey NC, Robinson SM, Crozier SR, Marriott LD, Gale CR, Cole ZA, et al. Breast-feeding and adherence to infant Breast-feeding guidelines do not influence bone mass at age 4 years. Br J Nutr. 2009 Sep;102(6):915–20.
47. Young RJ, Antonson DL, Ferguson PW, Murray ND, Merkel K, Moore TE. Neonatal
(Current Clinical Practice). Available from: https://link.springer.com/chapter/10.1007/978-1-59745-211-3_3
49. Pietrobelli A, Peroni DG, Faith MS. Pediatric body composition in clinical studies:
which methods in which situations? Acta Diabetol. 2003 Oct 1;40(1):s270–3.
50. Goran MI. Measurement Issues Related to Studies of Childhood Obesity: Assessment of Body Composition, Body Fat Distribution, Physical Activity, and Food Intake. Pediatrics. 1998 Mar 1;101(Supplement 2):505–18.
51. Ott SM, O’Hanlan M, Lipkin EW, Newell-Morris L. Evaluation of vertebral volumetric vs. areal bone mineral density during growth. Bone. 1997 Jun;20(6):553–6.
52. Eriksson S, Mellström D, Strandvik B. Volumetric bone mineral density is an important tool when interpreting bone mineralization in healthy children. Acta Paediatr. 2009 Feb 1;98(2):374–
9.
53. Kučukalić-Selimović E, Valjevac A, Hadžović-Džuvo A. The utility of procollagen type 1 N-terminal propeptide for the bone status assessment in postmenopausal women. Bosn J Basic Med Sci. 2013 Nov;13(4):259–65.
54. Cox G, Einhorn TA, Tzioupis C, Giannoudis PV. Bone-turnover markers in fracture healing. J Bone Joint Surg Br. 2010 Mar 1;92-B(3):329–34.
55. Nakamura A, Dohi Y, Akahane M, Ohgushi H, Nakajima H, Funaoka H, et al.
Osteocalcin secretion as an early marker of in vitro osteogenic differentiation of rat mesenchymal stem cells. Tissue Eng Part C Methods. 2009 Jun;15(2):169–80.
56. Sabel K-G, Lundqvist-Persson C, Bona E, Petzold M, Strandvik B. Fatty acid patterns early after premature birth, simultaneously analysed in mothers’ food, breast milk and serum
phospholipids of mothers and infants. Lipids Health Dis. 2009 Jun 10;8:20.
57. Peng YM, Zhang TY, Wang Q, Zetterström R, Strandvik B. Fatty acid composition in breast milk and serum phospholipids of healthy term Chinese infants during first 6 weeks of life. Acta Paediatr. 2007 Nov 1;96(11):1640–5.
58. Nilsson AK, Löfqvist C, Najm S, Hellgren G, Sävman K, Andersson MX, et al. Long-chain polyunsaturated fatty acids decline rapidly in milk from mothers delivering extremely preterm indicating the need for supplementation. Acta Paediatr. 2018 Jun 1;107(6):1020–7.
59. Cole TJ, Bellizzi MC, Flegal KM, Dietz WH. Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ. 2000 May 6;320(7244):1240.
60. Bonnet N, Ferrari SL. Effects of long-term supplementation with omega-3 fatty acids on longitudinal changes in bone mass and microstructure in mice. J Nutr Biochem. 2011 Jul
1;22(7):665–72.
61. Bouillon R, Prodonova A. Growth Hormone Deficiency and Peak Bone Mass. J Pediatr Endocrinol Metab. 2014;13(Supplement):1327–1342.
62. Mizokami A, Kawakubo-Yasukochi T, Hirata M. Osteocalcin and its endocrine functions. Biochem Pharmacol. 2017 May 15;132:1–8.
63. Wei J, Ferron M, Clarke CJ, Hannun YA, Jiang H, Blaner WS, et al. Bone-specific insulin resistance disrupts whole-body glucose homeostasis via decreased osteocalcin activation. J
64. Karsenty G, Oury F. Regulation of male fertility by the bone-derived hormone osteocalcin. Mol Cell Endocrinol. 2014 Jan 25;382(1):521–6.
65. Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, et al. Endocrine Regulation of Energy Metabolism by the Skeleton. Cell. 2007 Aug 10;130(3):456–69.
66. Boucher-Berry C, Speiser PW, Carey DE, Shelov SP, Accacha S, Fennoy I, et al.
Vitamin D, osteocalcin, and risk for adiposity as comorbidities in middle school children. J Bone Miner Res Off J Am Soc Bone Miner Res. 2012 Feb;27(2):283–93.
67. Wang J-W, Tang Q-Y, Ruan H-J, Cai W. Relation between serum osteocalcin levels and body composition in obese children. J Pediatr Gastroenterol Nutr. 2014 Jun;58(6):729–32.
68. Wang G, Johnson S, Gong Y, Polk S, Divall S, Radovick S, et al. Weight Gain in Infancy and Overweight or Obesity in Childhood across the Gestational Spectrum: a Prospective Birth Cohort Study. Sci Rep [Internet]. 2016 Jul 15 [cited 2018 Dec 22];6. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4945912/
69. Kalra SP, Dube MG, Iwaniec UT. Leptin increases osteoblast-specific osteocalcin release through a hypothalamic relay. Peptides. 2009 May;30(5):967–73.
70. Ferron M, Wei J, Yoshizawa T, Del Fattore A, DePinho RA, Teti A, et al. Insulin Signaling in Osteoblasts Integrates Bone Remodeling and Energy Metabolism. Cell. 2010 Jul 23;142(2):296–308.
71. Krall EA, Dawson‐Hughes B. Heritable and life-style determinants of bone mineral density. J Bone Miner Res. 1993;8(1):1–9.
72. Boot AM, de Ridder MAJ, Pols HAP, Krenning EP, de Muinck Keizer-Schrama SMPF.
Bone Mineral Density in Children and Adolescents: Relation to Puberty, Calcium Intake, and Physical Activity. J Clin Endocrinol Metab. 1997 Jan 1;82(1):57–62.
73. Stagi S, Cavalli L, Cavalli T, de Martino M, Brandi ML. Peripheral quantitative computed tomography (pQCT) for the assessment of bone strength in most of bone affecting conditions in developmental age: a review. Ital J Pediatr [Internet]. 2016 Sep 26 [cited 2018 Dec 8];42. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037897/
74. Jimenez Avila JM. Vertebral Destruction Syndrome: From Knowledge to Practice. J Spine [Internet]. 2015 [cited 2018 Dec 9];04(04). Available from:
http://www.omicsgroup.org/journals/vertebral-destruction-syndrome-from-knowledge-to-practice-2165-7939-1000251.php?aid=59237
75. Matkovic V, Jelic T, Wardlaw GM, Ilich JZ, Goel PK, Wright JK, et al. Timing of peak bone mass in Caucasian females and its implication for the prevention of osteoporosis. Inference from a cross-sectional model. J Clin Invest. 1994 Feb 1;93(2):799–808.
76. Newton-John HF, Morgan DB. The loss of bone with age, osteoporosis, and fractures.
Clin Orthop. 1970;71:229–52.
77. Singh S, Kumar D, Lal AK. Serum Osteocalcin as a Diagnostic Biomarker for Primary Osteoporosis in Women. J Clin Diagn Res JCDR. 2015 Aug;9(8):RC04–7.
Appendix
TABLE A. Drop-put analysis showing early demographic characteristics of the follow-up study population (n=167) versus dropouts (n=231) included at birth but not at DEXA.
Follow-up cohort Dropouts p-value
TABLE B. Summary of correlation between monounsaturated fatty acids (MUFA) and polysaturated fatty acids (PUFA), BMDL1-L4 and BMADspine.
Fatty acids
Note. p<0.02 was considered statistically significant. r= correlation coefficient. ALA=alpha linolenic acid; EPA=eicosapentaenoic acid;
DHA=docosahexaenoic acid; LA=linoleic acid; AA=arachidonic acid. P-values of BMD= bone mineral density and BMAD= bone mineral apparent density.
TABLE C. Summary of correlations between bone formation markers and BMDL1-L4 and BMADspine
Bone formation markers
r
BMDL1-L4
p
BMDL1-L4
r
BMADspine
p
BMADspine
P1NPb 0.059 0.463 0.007 0.933
OCb 0.042 0.606 0.029 0.726
P1NP4m -0.014 0.859 -0.049 0.546
OC4m -0.071 0.387 -0.116 0.155
Note. r= correlation coefficient; p<0.05 was considered statistically significant. P1NP = procollagen type 1 amino-terminal propeptide. OC = osteocalcin. Bone formation markers were measured in cord blood at birth (b) and 4 months of age (4m). BMD= bone mineral density and BMAD= bone mineral apparent density.