Oestrogen and thyroid hormone interactions in the regulation of bone mass

Osteoporosis is characterised by low bone mass, reduced bone mineral density and a deterioration of bone microarchitecture, resulting in increased susceptibility to fragility fractures. Oestrogen deficiency and thyrotoxicosis are established risk factors for osteoporosis. Oestrogen and thyroid hormone have opposing actions on adult bone and I hypothesise that accelerated bone loss at the menopause is due to unopposed actions of thyroid hormone on the skeleton. To test this hypothesis, I investigated the effect of altered thyroid status on the skeleton in adult sham-operated and ovariectomised wild type and thyroid hormone receptor (TR) α and β knockout mice (TRα0/0 and TRβ-/-). Skeletal phenotype analysis included determination of structural, densitometric, histomorphometric and biomechanical parameters. Skeletal phenotypes of euthyroid wild type mice were compared to hypothyroid and thyrotoxic wild type as well as TRα0/0and TRβ-/- mice. Bone mass was elevated in TRα0/0and reduced in TRβ-/- mice despite similar bone formation rates. These data suggest that the differences in bone mass are due to differing osteoclast activity. The skeletal phenotypes of TRα0/0 and TRβ-/- mice following manipulation of thyroid status were then described in detail. TRβ-/- and wild type mice rendered hypothyroid, had significantly lower bone formation than hypothyroid TRα0/0 mice suggesting that, in the absence of thyroid hormone, TRα may inhibit bone formation. Finally, the effect of oestrogen withdrawal in each of these groups of mice was also investigated. These studies demonstrate oestrogen deficiency bone loss was greater in hypothyroid compared to hyperthyroid mice, indicating that accelerated bone loss following oestrogen withdrawal cannot result from unopposed actions of thyroid hormones. Nevertheless, the studies contained in this thesis provide new insight regarding the roles of TRα and TRβ in bone maintenance and the effects of interactions between oestrogen and thyroid hormones on the regulation of bone mass.