IGF‐I‐Deficient Mice: Role in Skeletal Adaptation to Load

Bikle et al. recently reported the skeletal structure of insulin-like growth factor I (IGF-I)-deficient mice. Interestingly, IGF-I–deficient mice had relatively higher bone mass of the proximal tibia compared with their wild-type littermates when the difference in size of bone was taken into account, that is, the cortical thickness of the proximal tibia in IGF-I–deficient mice was approximately 80% of that in the wild-type littermates, although body weight and fat-free bone weight of IGF-I–deficient mice were only less than 30% of those of the wild-type littermates; and the trabecular bone volume/total volume of the proximal tibia in IGF-I– deficient mice was higher than that in the wild-type littermates. By contrast, these changes were either less or not observed in the first lumbar vertebra. We accept several of the reasons discussed by the authors and would like to comment on these results from a different angle. Bone strain generated by mechanical loads is an important factor to control bone mass. The adaptation of bone to mechanical loads may be related to the skeletal structure of IGF-I–deficient mice as follows. One explantation is the impairment of bone material properties (bone tissue quality) in IGF-I–deficient mice. We previously suggested that IGF-I could influence bone material properties through the modulation of carboxylated osteocalcin synthesis. This is consistent with the evidence that decreased serum IGF-I concentration was strongly associated with an increased risk of osteoporotic fractures independently of bone mass. Impairment of bone material properties could induce a gain of bone mass resulting from an increase of bone strain from mechanical loads. A second explantation is the change of bone threshold strain for bone modeling in IGF-I–deficient mice. Some hormones such as estrogen and parathyroid hormone have been suggested to sensitize bone to mechanical stimuli, and growth hormone (GH) could be also permissive for skeletal adaptation to mechanical loads. We agree with the suggestion by Bikle et al. that GH level may be elevated in IGF-I–deficient mice, which could induce bone gain by decreasing the threshold strain for bone modeling. The above concept of skeletal adaptation to mechanical loads is supported by the surprisingly well-preserved periosteal bone formation at the tibiofibular junction in IGF-I– deficient mice, when the smaller size of bone was factored. Degree of bone strain from mechanical loads under standard laboratory conditions is higher at the tibia than at the vertebra, and this may be associated with the difference in skeletal structure between the proximal tibia and first lumbar vertebra in IGF-I–deficient mice.