Osteoporosis International

, Volume 19, Issue 2, pp 157–167 | Cite as

Intrauterine programming of bone. Part 2: Alteration of skeletal structure

  • S. A. LanhamEmail author
  • C. Roberts
  • M. J. Perry
  • C. Cooper
  • R. O. C. Oreffo
Original Article



Osteoporosis is believed to be partly programmed in utero. Rat dams were given a low protein diet during pregnancy, and offspring were studied at different ages. Old aged rats showed site-specific strength differences. In utero nutrition has consequences in later life.


Epidemiological studies suggest skeletal growth is programmed during intrauterine and early postnatal life. We hypothesize that age-related decrease in bone mass has, in part, a fetal origin and investigated this using a rat model of maternal protein insufficiency.


Dams received either 18% w/w (control) or w/w 9% (low protein) diet during pregnancy, and the offspring were studied at selected time points (4, 8, 12, 16, 20, 47, 75 weeks).


Using micro-CT, we found that at 75 weeks of age female offspring from mothers fed a restricted protein diet during pregnancy had femoral heads with thinner, less dense trabeculae, femoral necks with closer packed trabeculae, vertebrae with thicker, denser trabeculae and midshaft tibiae with denser cortical bone. Mechanical testing showed the femoral heads and midshaft tibiae to be structurally weaker, whereas the femoral necks and vertebrae were structurally stronger.


Offspring from mothers fed a restricted protein diet during pregnancy displayed significant differences in bone structure and density at various sites. These differences result in altered bone characteristics indicative of significantly altered bone turnover. These results further support the need to understand the key role of the nutritional environment in early development on programming of skeletal development and consequences in later life.


Density DEXA In utero Micro computed tomography Programming Structure 



This work was supported by a programme grant from Research into Ageing. We acknowledge useful discussion with Professors Mark Hanson, Nicholas Clarke and Dr Trudy Roach and the support of the Biomedical Research Facility. We thank statistician Karen Jameson from the MRC Epidemiology Resource Centre for helpful assistance with statistical analysis.

Conflict of interest statement

All authors have no conflicts of interest.


  1. 1.
    NIH Consensus development panel on osteoporosis prevention DaT (2001) Osteoporosis prevention, diagnosis, and therapy. JAMA 285:785–795Google Scholar
  2. 2.
    Ralston SH (1998) Do genetic markers aid in risk assessment? Osteoporos Int 8(Suppl 1):S37–S42PubMedGoogle Scholar
  3. 3.
    Cooper C, Cawley M, Bhalla A et al (1995) Childhood growth, physical activity, and peak bone mass in women. J Bone Miner Res 10:940–947PubMedCrossRefGoogle Scholar
  4. 4.
    Cooper C, Fall C, Egger P et al (1997) Growth in infancy and bone mass in later life. Ann Rheum Dis 56:17–21PubMedCrossRefGoogle Scholar
  5. 5.
    Cooper C, Javaid MK, Taylor P et al (2002) The fetal origins of osteoporotic fracture. Calcif Tissue Int 70:391–394PubMedCrossRefGoogle Scholar
  6. 6.
    Fall C, Hindmarsh P, Dennison E et al (1998) Programming of growth hormone secretion and bone mineral density in elderly men: a hypothesis. J Clin Endocrinol Metab 83:135–139PubMedCrossRefGoogle Scholar
  7. 7.
    Godfrey KM, Barker DJ (2000) Fetal nutrition and adult disease. Am J Clin Nutr 71(Suppl):1344S–1352SPubMedGoogle Scholar
  8. 8.
    Barker DJ (1992) The fetal origins of diseases of old age. Eur J Clin Nutr 46(Suppl 3):S3–S9PubMedGoogle Scholar
  9. 9.
    Mehta G, Roach HI, Langley-Evans S et al (2002) Intrauterine exposure to a maternal low protein diet reduces adult bone mass and alters growth plate morphology in rats. Calcif Tissue Int 71:493–498PubMedCrossRefGoogle Scholar
  10. 10.
    Aihie S, Dunn R, Langley-Evans SC et al (2001) Prenatal exposure to a maternal low protein diet shortens life span in rats. Gerontology 47:9–14CrossRefGoogle Scholar
  11. 11.
    Langley-Evans SC, Welham SJ, Sherman RC et al (1996) Weanling rats exposed to maternal low-protein diets during discrete periods of gestation exhibit differing severity of hypertension. Clin Sci (Lond) 91:607–615Google Scholar
  12. 12.
    Musha Y, Itoh S, Hanson MA et al (2006) Does estrogen affect the development of abnormal vascular function in offspring of rats fed a low-protein diet in pregnancy? Pediatr Res 59:784–789PubMedCrossRefGoogle Scholar
  13. 13.
    Franco MdC, Arruda RM, Dantas APV et al (2002) Intrauterine undernutrition: expression and activity of the endothelial nitric oxide synthase in male and female adult offspring. Cardiovasc Res 56:145–153CrossRefGoogle Scholar
  14. 14.
    Sun L, Peng Y, Sharrow AC et al (2006) FSH Directly regulates bone mass. Cell 125:247–260PubMedCrossRefGoogle Scholar
  15. 15.
    Tobias JH, Cooper C (2004) PTH/PTHrP Activity and the programming of skeletal development in utero. J Bone Miner Res 19:177–182PubMedCrossRefGoogle Scholar
  16. 16.
    Bourrin S, Toromanoff A, Ammann P et al (2000) Dietary protein deficiency induces osteoporosis in aged male rats. J Bone Miner Res 15:1555–1563PubMedCrossRefGoogle Scholar
  17. 17.
    Gluckman PD, Hanson MA (2004) Living with the past: evolution, development, and patterns of disease. Science 305:1733–1736PubMedCrossRefGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2007

Authors and Affiliations

  • S. A. Lanham
    • 1
    • 3
    Email author
  • C. Roberts
    • 1
  • M. J. Perry
    • 2
  • C. Cooper
    • 1
  • R. O. C. Oreffo
    • 1
  1. 1.Bone and Joint Research Group, Developmental Origins of Health and DiseaseUniversity of SouthamptonSouthamptonUK
  2. 2.Department of AnatomyUniversity of BristolBristolUK
  3. 3.Bone and Joint Research Group, MP887, Institute of Developmental SciencesSouthampton General HospitalSouthamptonUK

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