Endocrine Abstracts

Bone remodeling is a fine tuned process optimizing bone biomechanical properties. Peak bone mass is reached in early adult life, where after bone mass declines in both sexes leading to an increasing risk for low energy fractures. The understanding of bone remodeling has led to pharmacologic treatment of osteoporosis, being different antiresorptive modalities or anabolic treatment with PTH - or analogues. Inherited osteosclerotic bone disorders have been diagnosed since the introduction of radiography. Interestingly, some disorders were prone to pathological fractures, some not. The most severe forms were typically found to be autosomal recessive, whereas mild types were dominantly inherited. Early systematic studies of different osteosclerotic disorders indicated defective bone resorption as a common radiogrammetric and histomorphometric finding, whereas bone formation seemed to be relatively normal. The high bone mass phenotype was described in the Nineties based on family studies of index cases with high BMD. Further genetic studies revealed gain of function mutations in the LRP5 gene in several different family forms, pointing to the Wnt signaling pathway as pivotal for bone remodeling. The opposite picture, the Osteoporosis Pseudo-Glioma Syndrome was at the same time found to be caused by a loss of function mutation in LRP5. The regulation of the Wnt signaling pathway was discovered to be even more complicated by studies of van Buchem’s disease and Sclereosteosis in the early Zero’es, discovering Sclerostin produced by the osteocytes as yet another important player in the bone remodeling mosaic. Defective Sclerostin leads to a constitutive activation of Wnt with bone formation activation, followed indirectly by inhibition of bone resorption – a new dual concept by Nature. Monoclonal antibodies towards Sclerostin (Romososumab) are by now close to the clinic (approved by FDA) as a new treatment modality for osteoporosis. Fracture prevention seems promising, whereas potential cardiovascular side effects are investigated.