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Marked improvements in milk production, health and reproduction have resulted from manipulations of the pre-calving diet. An understanding of the underlying physiological changes resulting from manipulation of late gestational diets is needed in order to refine and enhance these responses. The physiology of late gestation and early lactation of the dairy cow is examined in the context of exploring the hypothesis that changes in physiology occur not only through homeostatic, but also homeorhetic change. Studies in mice and man have identified a pivotal role for skeleton, particularly through production of active forms of osteocalcin, in integrating energy metabolism. Skeleton appears to particularly influence lipid metabolism and vice versa. Further insights into the factors influencing skeletal function and calcium (Ca) metabolism are emerging, including the potential for negative dietary cation anion difference (DCAD) diets to upregulate the responses of the skeleton in metabolism through increased bone mobilisation and in enhancing responses to parathyroid hormone. The rumen appears to be an important site of absorption of Ca, but physiological mechanisms influencing this uptake are not clear. We provide quantitative evidence of the magnitude of responses that reflect relationships linking Ca metabolism, skeleton and production, using meta-analytic methods. Negative DCAD diets increase milk production in multiparous cattle, but not in heifers. Further, examination of concentrations of metabolites related to energy metabolism obtained from cattle exposed to a negative DCAD diet over calving identified a dominant role for Ca concentrations, which were associated with blood-free fatty acids (NEFA), blood 3-hydroxybutyrate, glucose and cholesterol. These relationships were homeostatic, occurring on the same day, but also homeorhetic with concentrations of Ca and NEFA being significantly associated over 21 days. The findings in cattle are consistent with those in the murine models. However, Ca and the skeleton are not the only significant factors in the transition period influencing future performance as hormonal treatments, metabolic demands and sex of the conceptus, and inflammation and the factors controlling this play a role in future performance. Homeorhetic, longer-term, adaptive responses are critical to achieving orchestrated longer-term adaptive responses to calving and lactation. We consider that the teleological question ‘why would a bone-specific hormone (osteocalcin) regulate energy metabolism?’ is answered by the specific needs for integrated metabolism to address the extreme metabolic demands of lactation in many species.