New therapeutics for osteoporosis.

Two new approaches for the treatment of osteoporosis are summarized, each having arisen out of important new discoveries in bone biology. Odanacatib (ODN) inhibits the enzyme, cathepsin K, that is essential for the resorbing activity of osteoclasts. It is effective in preventing ovariectomy-induced bone loss in preclinical studies, and a phase II clinical study has shown inhibition of resorption sustained over five years.

Implications of osteoblast-osteoclast interactions in the management of osteoporosis by antiresorptive agents denosumab and odanacatib.

Antiresorptive agents, used in the treatment of osteoporosis, inhibit either osteoclast formation or function. However, with these approaches, osteoblast activity is also reduced because of the loss of osteoclast-derived coupling factors that serve to stimulate bone formation. This review discusses how osteoclast inhibition influences osteoblast function, comparing the actions of an inhibitor of osteoclast formation [anti-RANKL/Denosumab (DMAB)] with that of a specific inhibitor of osteoclastic cathepsin K activity [Odanacatib (ODN)].

Potential role of odanacatib in the treatment of osteoporosis.

Cathepsin K is a key enzyme involved in the degradation of organic bone matrix by osteoclasts. Inhibition of bone resorption observed in human and animal models deficient for cathepsin K has identified this enzyme as a suitable target for intervention by small molecules with the potential to be used as therapeutic agents in the treatment of osteoporosis. Odanacatib (ODN) is a nonbasic selective cathepsin K inhibitor with good pharmacokinetic parameters such as minimal in vitro metabolism, long half-life, and oral bioavailability.

Regulation of glucose metabolism and the skeleton.

Complex interactions occur among adipose tissue, the central nervous system, bone and pancreas to integrate bone remodelling, glucose, lipid and energy metabolism. Data obtained largely from the judicious use of gain-of-function and loss-of-function genetic mouse models show that leptin, an adipocyte-secreted product, indirectly inhibits bone accrual through a central pathway comprising the hypothalamus and central nervous system. Increased sympathetic output acting via β2-adrenergic receptors present in osteoblasts decreases bone formation and causes increased bone resorption.

Lack of sustained response to teriparatide in a patient with adult hypophosphatasia.

Introduction: Hypophosphatasia (HPP) is a rare genetic disorder characterized by low serum alkaline phosphatase (ALP) and defective bone mineralization predisposing to poorly healing pseudofractures and fractures. Experience with teriparatide in HPP is limited.

Methods: A 53-yr-old woman was diagnosed with HPP on the basis of repeatedly low serum ALP (6-8 IU/liter; normal, 30-120 IU/liter), high urine phosphoethanolamine (PEA) and serum pyridoxal 5'-phosphate (PLP) concentrations, and pseudofractures on the lateral aspect of both proximal femurs.

Periprosthetic bone remodeling using a triple-taper polished cemented stem in total hip arthroplasty.

The triple-taper cemented femoral stem was developed to promote proximal femoral and calcar loading to minimize periprosthetic bone loss and aseptic loosening. Periprosthetic changes in bone mineral density in Gruen zones 1 to 7 were analyzed in 103 patients over a 2-year period using dual x-ray absorptiometry. There was a statistically significant decrease in bone mineral density in all Gruen zones, but was most marked in zones 1 and 7.

Is Wnt signalling the final common pathway leading to bone formation?

Since the discovery of the link between mutations in the LRP5 gene and human bone mass, considerable progress has been made in our understanding of Wnt signalling and bone formation. The connection between canonical Wnt signalling and bone formation is convincing, and there is evidence of interaction between the Wnt signalling pathway and key growth factors, transcriptional factors and systemic hormones. More recently, the role of the non-canonical pathway in bone metabolism has also started to be explored as well as potential bone-gut interactions.

Osteoclast inhibitory lectin, an immune cell product that is required for normal bone physiology in vivo.

Osteoclast inhibitory lectin (OCIL or clrb) is a member of the natural killer cell C-type lectins that have a described role mostly in autoimmune cell function. OCIL was originally identified as an osteoblast-derived inhibitor of osteoclast formation in vitro. To determine the physiological function(s) of OCIL, we generated ocil(-/-) mice.

Osteoclast inhibitory lectin (OCIL) inhibits osteoblast differentiation and function in vitro.

Osteoclast inhibitory lectin (OCIL) is a type II C-type lectin and binds NK cell-associated receptor Nkrp1d and sulfated glycosaminoglycans. OCIL is expressed by several cell types found in bone and inhibits osteoclast differentiation. To determine whether OCIL may have wider effects on bone metabolism, we examined the effects of recombinant soluble OCIL on cultured osteoblasts and pre-osteoblastic KUSA O cells.

Stretch-induced PTH-related protein gene expression in osteoblasts.

Unlabelled: Mechanical forces play a critical role in regulating skeletal mass and structure. We report that mechanical loading induces PTHrP in osteoblast-like cells and that TREK-2 stretch-activated potassium channels seem to be involved in this induction. Our data suggest PTHrP as a candidate endogenous mediator of the anabolic effects of mechanical force on bone.

Cell lines and primary cell cultures in the study of bone cell biology.

Bone is a metabolically active and highly organized tissue consisting of a mineral phase of hydroxyapatite and amorphous calcium phosphate crystals deposited in an organic matrix. Bone has two main functions. It forms a rigid skeleton and has a central role in calcium and phosphate homeostasis.

Characterization of sugar binding by osteoclast inhibitory lectin.

Osteoclast inhibitory lectin (OCIL) is a membrane-bound C-type lectin that blocks osteoclast differentiation and, via binding to its cognate receptor NKRP1D, inhibits natural killer cell-mediated cytotoxicity. OCIL is a member of the natural killer cell receptor C-type lectin group that includes CD69 and NKRP1D. We investigated carbohydrate binding of soluble recombinant human and mouse OCIL in enzyme-linked immunosorbent assay-based assays.

Isolation of a human homolog of osteoclast inhibitory lectin that inhibits the formation and function of osteoclasts.

Unlabelled: Osteoclast inhibitory lectin (OCIL) is a newly recognized inhibitor of osteoclast formation. We identified a human homolog of OCIL and its gene, determined its regulation in human osteoblast cell lines, and established that it can inhibit murine and human osteoclast formation and resorption. OCIL shows promise as a new antiresorptive.

Osteoclast inhibitory lectin, a family of new osteoclast inhibitors.

We have identified two novel type II membrane-bound C-lectins, designated mOCILrP1 and mOCILrP2, of 218 and 217 amino acids, respectively, that share substantial identity with the murine osteoclast inhibitory lectin (OCIL). The extracellular domains of mOCILrP1 and mOCILrP2 share 83 and 75% identity, respectively, with the extracellular domain of mOCIL. When the extracellular domains were expressed as recombinant proteins, each inhibited osteoclast formation in murine bone marrow cultures treated with M-CSF and RANKL with similar potencies to mOCIL (IC(50) of 0.