Childhood hypothyroidism causes delayed bone development and adult thyrotoxicosis is associated with a 3-fold increase in osteoporotic fracture. To investigate underlying mechanisms we characterised the skeletal phenotypes of mice harbouring dominant-negative mutations (TRa1PV/+, TRa1R384C/+, TRbPV/PV) or deletions (TRa0/0, TRb-/-) of the genes encoding TRa and TRb. Endochondral ossification, growth and bone mineralisation were retarded in TRa0/0 mice and more severely delayed in TRa1 dominant-negative mutants. In contrast, these parameters were advanced in TRb knockout and PV-mutant mice. Bone microarchitecture and mineralisation were analysed by quantitative backscattered electron scanning electron microscopy. TRa mice displayed increased cortical bone width and trabecular bone volume with thicker trabeculae and greater microarchitectural complexity. In contrast, these parameters revealed TRb mutants were osteoporotic. Analysis of downstream signalling pathways revealed a phenotype of skeletal hypothyroidism in all TRa mutant mice but skeletal thyrotoxicosis in TRb mutants. TRa was expressed at 15-fold higher levels in bone than TRb, whereas TRb is predominantly expressed in hypothalamus and pituitary and controls negative feedback regulation of TSH. Accordingly, TRa mutant mice were euthyroid whereas TRbPV/PV and TRb-/- displayed pituitary resistance to thyroid hormone with elevated circulating thyroid hormones. Analysis of TR mutant mice with differing genetic backgrounds unequivocally demonstrates that TRa is the predominant TR expressed in bone, and shows that the skeletal response to disrupted TRb signalling results from effects on systemic thyroid status. The maintenance of increased trabecular bone mass in TRa mutant mice reveals potential for therapeutic targeting of TRa in the treatment of osteoporosis.