The human skeleton is continuously remodeling during growth and in response to mechanical stress and hormonal regulation. The maintenance of normal bone mass during adult life depends on a precise balance between osteoblastic bone formation and osteoclastic bone destruction, implicating tight coupling between these two cellular activities. In various skeletal diseases associated with bone loss, including osteoporosis, hypercalcemia of malignancy, tumor metastases or Paget's disease, increased osteoclastic bone resorption exceeds formation resulting in low bone mass, skeletal fragility and increased risk of fracture. When considering therapeutic approaches to manage these diseases, inhibitors of bone resorption such as bisphosphonates or estrogen-like compounds have been proven effective. In this review, we will discuss new insights into osteoclast differentiation and activity which offer the potential new therapeutic targets for blocking bone resorption.

Osteoclasts are multinucleated, terminally differentiated cells which degrade mineralized tissues during normal and pathological bone turnover [1±3]. The rate of bone resorption is tightly regulated through the control of osteoclast differentiation and activation. Osteoclast maturation involves the proliferation and homing to bone of the hemopoietic progenitors, which are shared with the monocyte-macrophage lineage. On the bone surface, osteoclast progenitors differentiate and fuse to form multinucleated cells, which migrate from one resorption site to the next. During resorption, osteoclasts attach firmly to the bone surface and form a tight sealing zone (or``clear zone'') which encloses the resorption lacuna, frequently compared to a giant lysosome. Insertion of secretory vesicles into the bone-facing membrane forms a highly convoluted structure called the``ruffled border'', a characteristic feature of active osteoclasts.