Osteopetrosis is a rare inherited bone disorder characterized by increased bone density owing to failure in bone resorption by the osteoclasts. The disease is genetically and histologically heterogeneous with a wide spectrum of microscopic findings. The histology varies from cases with a total absence of osteoclasts to bone biopsies characterized by high numbers of enlarged multinucleated osteoclasts on a background of sclerotic cancellous bone with or without additional defect of mineralization of the bone matrix. Here we present typical cases of human osteopetrosis on the basis of bone biopsies with four distinct genotypes (mutations of TNFRSF11A, TCIRG1, CNCL7, KINDLIN-3 genes) and discuss genotype-phenotype relationships. Analyzing human bone biopsies of rare skeletal disorders might improve our understanding of bone metabolism with possible implications for the clinical management of other bone diseases.
