Mammalian sirtuins (SIRT1–7) are members of the nicotine adenine dinucleotide (NAD+)-dependent family of enzymes critical for histone deacetylation and posttranslational modification of proteins. Sirtuin family members regulate a wide spectrum of biological processes and are best known for maintaining longevity. Sirtuins are well characterized in metabolic tissues such as the pancreas, liver and adipose tissue (AT). They are regulated by a diverse range of stimuli, including nutrients and metabolic changes within the organism. Indeed, nutrient-associated conditions, such as obesity and anorexia nervosa (AN), were found to be associated with bone fragility development in osteoporosis. Interestingly, it has also been demonstrated that sirtuins, more specifically SIRT1, can regulate bone activity. Various studies have demonstrated the importance of sirtuins in bone in the regulation of bone homeostasis and maintenance of the balance between bone resorption and bone formation. However, to understand the molecular mechanisms involved in the negative regulation of bone homeostasis during overnutrition (obesity) or undernutrition, it is crucial to examine a wider picture and to determine the pancreatic, liver and adipose tissue pathway crosstalk responsible for bone loss. Particularly, under AN conditions, sirtuin family members are highly expressed in metabolic tissue, but this phenomenon is reversed in bone, and severe bone loss has been observed in human subjects. AN-associated bone loss may be connected to SIRT1 deficiency;​ however, additional factors may interfere with bone homeostasis. Thus, in this review, we focus on sirtuin activity in the pancreas, liver and AT in cases of over- and undernutrition, especially the regulation of their secretome by sirtuins. Furthermore, we examine how the secretome of the pancreas, liver and AT affects bone homeostasis, focusing on undernutrition. This review aims to lead to a better understanding of the crosstalk between sirtuins, metabolic organs and bone. In long term prospective it should contribute to promote improvement of therapeutic strategies for the prevention of metabolic diseases and the development of osteoporosis.