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Abstract
Postmenapausal osteoporosis is the most common cause of inadequate bone strength in the Western World. In Europe, 72 million women over 50 years old will suffer 1 or more osteoporotic fractures during their remaining life. The pathogenesis of this often severely disabling disease is poorly understood. We suggest that postmenopausal osteoporosis is best explained as a failure of the adaptive response of bone to mechanical loading, which normally maintains bone structure to withstand everyday forces without fracture. Based on in vitro data, we hypothesise that estrogen receptor a (ERa) is involved in this adaptive response and that it is a decline in ERa in bone at the menopause that leads to postmenopausal osteoporosis. To investigate this hypothesis we determined the response of ERa knockout (aERKO) mice to mechanical loading. A non-invasive technique for mechanical loading of the mouse ulna by dynamic axial compression in vivo was validated. Loading the left ulna of adult CD1 mice for 10 minutes 5 days/week for 2 weeks using a 4Hz trapezoidal wave engendering high physiological strains and strain rates, resulted in a peak strain-related osteogenic response in the cortical bone of the ulnar diaphysis. Refinement studies revealed that: 1) alternate day loading was no less osteogenic than everyday loading; and 2) 40 loading cycles/day separated by 14.9s rest periods were sufficient to create a osteogenic response over 2 weeks. The left ulnae of adult female aERKO mice and their wild type littermates were loaded 3days/week for 2 mice the osteogenic response to loading was only 30% of that in wild types. This result is consistent with the hypothesis that functional ERa number is an important determinant of the capacity of bone to adapt to mechanical loading in vivo.
