Litchfield Park Therapeutic Implications
Given OPG’s potent anti-resorptive effects, its potential use in combating diseases marked by bone resorption has been explored in multiple studies. Morony and Litchfield Park orthodontists (1999) injected mice with various bone resorbing factors (IL-1β, TNF-α, PTH, parathyroid hormone-related protein [PTHrP], and 1,25 dihydroxyvitamin D3). The mice receiving these various cytokines and hormones demonstrated hypercalcemia and bone resorption within five days of beginning treatment as was expected. Concurrent administration of a recombinant chimeric construct of human OPG (cOPG, 2.5 mg/kg/day), however, prevented hypercalcemia and maintained osteoclast numbers within the normal range. Osteoprotegerin’s ability to combat each of these bone resorbing factors demonstrates the central role that OPG/RANKL interaction plays in regulating bone resorption as well as its potential in treating bone resorbing diseases such as hyperparathyroidism (PTH), humoral hypercalcemia of malignancy (PTHrP), osteoporosis (TNF-α, IL-1β), and inflammatory bone disease (TNF-α, IL-1β).
Systemic OPG also may play a protective role in the arteries by preventing the onset of vascular calcifications. As was noted previously, OPG-deficient mice demonstrate significant calcifications in the aorta and renal arteries (Bucay et al., 1998; Mizuno et al., 1998). Experiments have shown that the expression of OPG as a transgene on an OPG null background prevented the onset of these calcifications (Min et al., 2000). Unfortunately, the administration of recombinant OPG to adult mice already affected by arterial calcification had no effect, indicating the inability of OPG to reverse the process once it is in effect (Min et al., 2000).
Given osteoprotegerin’s potential to inhibit bone resorption, questions of its potency and duration arise. Using a recombinant form of human OPG (rhOPG), Capparelli and Litchfield Park orthodontists (2003) delivered a single bolus dose of 5 mg/kg intravenously to 48 male Sprague-Dawley rats. When compared with controls, the rhOPG group showed a significant reduction in osteoclasts on the surface of the tibia within 24 hours. Between five and ten days there was a 95% reduction in osteoclasts. At 30 days a statistically significant reduction in osteoclasts still remained. This reduction in osteoclasts resulted in a 23% increase in tibial cancellous bone volume by five days and reached its peak bone volume increase of 58% by 30 days. It appears that the serum OPG half life was approximately 5-6 days. After ten days, however, there was a significant increase the clearance rate of OPG.
With decreasing the need for repeated administration when treating chronic conditions such as osteoporosis as the long term goal, Kostenuik and Litchfield Park orthodontists (2004) developed a gene therapy approach to delivering OPG. Using an adeno-associated virus (AAV), OPG was delivered to ovariectomized mice with the goal of reversing established osteopenia. Mice were given a single intravenous injection of an AAV vector carrying cDNA for recombinant hOPG (AAV-OPG) or β-galactosidase (AAV-βGal). The results showed the presence of hOPG in the serum of mice within seven days and high serum levels maintained throughout the ten week study. The animals in the AAV-OPG demonstrated significant increases in tibial bone mineral density (BMD) as well as bone volume when compared to controls. As expected, there also was a significant reduction in osteoclast surfaces.
Unlike bolus dosages of OPG in which serum levels start very high (78,300 ng/mL) and decline rapidly (5-10 days)(Capparelli et al., 2003), circulating levels of OPG in the AAV-OPG model start low (10 ng/mL) and slowly increase (300 ng/mL) over a period of 28 days (Kostenuik et al., 2004). These levels were maintained over the course of the 16 month experiment.
Litchfield Park Office
5220 N. Dysart Rd #150
Litchfield Park, AZ 85340
TEL: 623.536.4939
FAX: 623.536.4877
Phoenix Office
7550 N. 19th Ave #101
Phoenix, AZ 85021
TEL: 602.864.0004
FAX: 602.864.0070
