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Effects of Glycomacropeptide, Amino Acid & Casein Diets on Osteopenia in PKU Mice

Effects of Glycomacropeptide, Amino Acid & Casein Diets on Osteopenia in PKU Mice . Denise M. Ney, PhD, RD Professor of Nutritional Sciences Waisman Center University of Wisconsin-Madison . Disclosure.

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Effects of Glycomacropeptide, Amino Acid & Casein Diets on Osteopenia in PKU Mice

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  1. Effects of Glycomacropeptide, Amino Acid & Casein Diets on Osteopenia in PKU Mice Denise M. Ney, PhD, RD Professor of Nutritional Sciences Waisman Center University of Wisconsin-Madison

  2. Disclosure • D Ney is a co-inventor on US Patent Application US-2010-0317597, GMP Medical Foods for Nutritional Management of PKU, which is held by the Wisconsin Alumni Research Foundation and licensed to Cambrooke Foods, LLC. A percentage of all royalty payments is awarded to the inventors. • D Ney has received consulting income from Cambrooke Foods and BioMarin.

  3. Funding: National PKU Alliance & USDA Hatch Grant UW-Madison PKU Bone Research Team Denise Ney Robert Blank Sangita Murali Patrick Solverson

  4. Background • PKU is associated with low bone mass, or osteopenia, and fractures in early adulthood. • 57% of 28 patients had osteopenia/osteoporosis • Perez-Dueñas et al. ActaPaediatr 91:800, 2002 • Reduced bone mineral density (BMD) in PKU is present from an early age onward and it cannot be predicted by plasma phe levels. • 20% of 53 patients studied had osteoporosis • de Groot et al. Mol Genet Metab 101:566, 2012

  5. What causes skeletal fragility in PKU? • The fundamental question is whether reduced BMD is inherent to PKU or secondary to its dietary management. • In order to isolate the contributions of the PKU genotype itself and dietary treatment of PKU we have conducted a factorial experiment in PKU mice.

  6. Objective & Design • To determine how the PKU genotype and the source of dietary protein affect growth, body composition and bone development. Casein High Phe ♂ ♀ • WT • PKU AA Low Phe GMP

  7. PKU & WT Mice Housed With Same Sex Littermates ↓pheGMP ↓pheAA ↑phe Casein

  8. GMP is a natural whey protein produced when making cheese. Pure GMP contains no phe.

  9. Growth Solverson, P et al Am J PhysiolEndocrinolMetab302:E885-95, 2012

  10. Metabolic Phenotyping Platform ●Food & water intake ●O2 consumption & CO2 production

  11. PKU mice show increased energy expenditure with casein diet

  12. GMP Diet Normalizes Food Intake in PKU Mice Values with different letter superscripts are significantly different, p<0.05

  13. AA Diet Increases Kidney Workload in both WT and PKU Mice Values with different letter superscripts are significantly different, p<0.05

  14. Does PKU increase energy needs? • Resting energy expenditure is ~5-10% higher in adolescent females with PKU than that predicted by standard equations. • J Am Diet Assoc 110:922-25, 20101 • Am J Clin Nutr 62:797-804, 1995 • Reduced growth occurs in children with PKU • Mol Genet Metab 101:99-109, 2010 • J Pediatr 26:1-11, 2002

  15. Dual Energy X-Ray Absorptiometry(DXA)

  16. PKU mice show reduced whole-body bone mineralization compared to WT mice

  17. Load (F) Femur Strength: 3 Point Loading Test Loading force being applied to a mouse femur Displacement

  18. Yield Point Post-Yield Displacement Fracture Elastic Deformation Load-Displacement Curve Max Load 16 14 12 10 8 Load, N 6 4 2 -0.1 0.1 0.2 0.4 0.5 0.6 0.7 0.8 0.3 -2 Displacement, mm

  19. PKU mice show bones that are brittle and break easily

  20. PKU mice show reduced femoral bone mineralization compared to WT mice

  21. How the casein, AA and GMP diets affect bone size and strength?

  22. GMP Increases Bone Size in PKU & WT Mice Casein AA GMP

  23. GMP Improves Bone Strength in PKU and WT Mice Compared with AA Diet

  24. Summary • PKU mice have femora that are brittle and weak. This suggests defects in both collagen synthesis and mineralization. • GMP increases bone size and strength; femora tolerate a higher max load before fracture compared with the AA diet. • How does GMP work to improve bone strength in mice?

  25. What causes skeletal fragility in PKU? • Inherent to PKU genotype and/or • Secondary to management with an AA diet. • Answer = both genotype and diet

  26. Conclusion • Skeletal fragility is inherent to the PKU genotype and is attenuated by a GMP compared with an AA diet in mice. • Future research is needed to determine if improved low-phe diets containing GMP reduce skeletal fragility in human PKU.

  27. Take Home Message: How can bone health be improved in PKU? • Follow a low-phe diet to improve growth and bone development • Include weight bearing exercise each day

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