New Treatments Needed to Prevent Fractures in Osteoporosis

Sclerostin inhibits Wnt signaling, which causes inhibition of osteoblast function. Sclerostin antibody stimulates osteoblast function by allowing for increased Wnt signaling. Following a single dose of sclerostin antibody, there may be marked increases in markers of bone formation compared with markers of bone resorption.

Bone and cartilage loss in RA is measured by X-ray, ultrasound and MRI.

Animal studies with knockout mice (SOST-/-) demonstrate greater than a 50% increase in BMD (lumbar spine and femur) with sclerostin antibody. Micro CT studies show increases in both trabecular and cortical bone. Histomorphometric analyses demonstrate greater than a nine-fold increase in the osteoblast surfaces, with no change in the osteoclast surface (uncoupling). Increased strength is demonstrated via mechanical testing. In ovariectomized rats, there was complete reversal of one year of estrogen-deficiency-induced bone loss. Bone mass and strength increased to levels that exceeded the results found in nonovariectomized controls.

Osteocytes

Osteocytes are derived from the osteoblast and are buried inside the bone. They are responsible for sensing mechanical loads in bone and sending signals to the surface and the interior of the bone via long projections from the cell body through the matrix and to the surface osteoblasts. They can synthesize matrix proteins. It has been documented that in the presence of steroids, there is increased apoptosis of the osteocyte.⁵ Ultimately, osteocytes may control remodeling through signaling to the bone surface and directing osteoclasts when and where to resorb, and osteoblasts where to form bone.

Metabolic Bone Effects of Biologics

Bone and cartilage loss in rheumatoid arthritis (RA) is measured by X-ray, ultrasound and magnetic resonance imaging. Disease modifying antirheumatic drugs and biologics can halt or retard the progression of joint destruction. IL-1 and tumor necrosis factor alpha (TNFα) have significant effects on bone remodeling.¹⁴

Focal bone loss in RA occurs through multiple mechanisms, including matrix metalloproteinase (MMP) via osteoclast precursor cells. Osteoclasts are the major cell types that mediate focal bone loss in RA.14 Patients with RA or inflammatory arthritis have more osteoclasts around the joint and in the bone than individuals with no arthritis, which causes resorption of bone and bony erosions, as well as bone loss in inflamed joints.¹⁵ Osteoclasts produce TRAP and cathepsin K, which work to degrade bone matrix. The expression of calcitonin receptors coincides with the differentiation of the osteoclast into a fully competent resorbing cell. Multinucleated cells expressing messenger RNA (mRNA) for TRAP, cathepsin K and the calcitonin receptor were found in resorption lacunae where pannus invaded bone. Other cell types, including activated synovial fibroblasts or macrophages, may contribute to focal bone erosions. RANKL is necessary for osteoclast differentiation and activation. Osteoprotegerin (OPG) acts as a decoy receptor to block RANKL and, ultimately, osteoclastogensis.