New Treatments Needed to Prevent Fractures in Osteoporosis

Denosumab increases bone mineral density (BMD) and reduces bone turnover markers (BTM) in postmenopausal women with low BMD and osteoporosis.^6,7 These effects are reversible after discontinuation, and retreatment does produce as significant a response as before. Vertebral, hip and nonvertebral fractures are significantly reduced by treatment with denosumab.⁸ Studies demonstrate increases in BMD and decreases in BTMs with denosumab more so than with alendronate.⁹ Patients who switch therapy from alendronate to denosumab increase BMD more than those continuing on alendronate.¹⁰

When the osteoclast attaches to the bone surface, it releases acid, which demineralizes bone, releasing proteins that degrade nonmineralized tissue. Cathepsin K is a lysosomal cysteine protease with an important role in the function of osteoclasts. It acts to degrade bone collagen. By inhibiting cathepsin K, the removal of bone matrix is reduced. Clinical trials have demonstrated that cathepsin K has no effect on the function, formation or survival of the osteoclast.

Osteoblasts

Preosteoblasts, which are derived from mesenchymal stromal cells, differentiate into osteoblasts. These cells may get buried into bone and become osteocytes, or they can be lining cells on the surface of the bone or differentiate into mature osteoblasts. These bone formation cells stimulate matrix mineralization, make type I collagen, alkaline phosphatase, osteocalcin, fibronectin and collagenase. Receptors on the osteoblast surface, crucial for control of bone turnover and calcium homeostasis, include parathyroid hormone (PTH) receptors, vitamin D and TGF-β. RANKL is also expressed on the surface of the osteoblast and is essential to bone remodeling pathways, most specifically for osteoclastogenesis.

The Wnt signaling pathway is critical for regulation of cell growth, differentiation, function and death, and this is especially true in bone metabolism.¹¹ The Wnt pathway has a frizzled and LDL receptor-related protein (LRP-5/6) co-receptor. The Wnt protein signals after attaching to its receptors, through beta catenin, genes that direct osteoblast maturation to turn on.

Wnt/LRP5/β-Catenin Pathway in Bone Formation

The Wnt/LRP5/β catenin pathway is essential for osteoblast proliferation, differentiation and survival.¹² Loss of function mutations in LRP5 cause severe osteoporosis and fracture as seen in the osteoporosis pseudoglioma syndrome (OPPG), while gain of function mutation in LRP5 produces the high bone-mass “trait.”12 LRP5 in bone formation may be directed by signals from the gut (small intestine).¹³

Upregulation of serotonin acting vita receptors (subtype Htr1b) inhibits bone formation. Loss of signaling or production has a net bone remodeling effect and stimulates high bone mass.¹³

Natural inhibitors of the Wnt/LRP5/β catenin pathway include dickkopf (DKK) made by myeloma cells; soluble decoy receptors, such as Wnt inhibitory factor (WIF); secreted frizzled-related protein (sFRP); and sclerostin (SOST) a product of osteocytes.