Stimulation of the Growth of Femoral Trabecular Bone in Ovariectomized Rats by the Novel Parathyroid Hormone Fragment, hPTH-(1-31)NH 2 (Ostabolin)

Abstract

The human parathyroid hormone, hPTH-(1-84), and its hPTH-(1-34) fragment are promising anabolic agents for treating osteoporosis because they can strongly stimulate the production of biomechanically effective cortical and trabecular bone in osteopenic ovariectomized (OVX) rats and trabecular bone in osteoporotic postmenopausal humans. The ideal PTH fragment for treating osteoporosis would be the smallest and functionally simplest fragment that activates only one signal mechanism and still strongly stimulates trabecular bone growth. A new PTH fragment, hPTH-(1-31)NH2, which only stimulates adenylyl cyclase instead of stimulating both adenylyl cyclase and phospholipase-C as do hPTH-(1-84) and hPTH-(1-34), is this minimum, high-potency anabolic fragment. hPTH-(1-31)NH2 (which we have named Ostabolin) can greatly thicken trabeculae and increase the dry weight and calcium content of trabecular bone in the distal femurs of osteopenic, young, sexually mature OVX Sprague-Dawley rats when injected subcutaneously each day for 6 weeks at doses between 0.4 and 1.6 nmole/100 g of body weight.

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

“…Daily injections of PTH(1-34) or PTH(1-31) produced an equivalent anabolic effect in rats; however, whereas PTH(1-34) activates both cAMP production and PKC, PTH (1-31) only activates cAMP production [41]. On the other hand, PTH(3-38), which activates PKC but not cAMP production, did not cause an anabolic effect [42].…”

Prolonged low-dose infusion of human parathyroid hormone does not increase femoral cancellous bone volume in ovariectomized rats

“…The high dose, 0.5 nmole/100 g BW/day, is within the osteogenic range when given in once-daily boluses (13,16). Blood calcium concentrations were measured every 2 weeks to determine whether the hPTH analog infusions were causing bone resorption and hence hypercalcemia.…”

“…This model is widely used because it combines the easy manageability of rats with the main features of postmenopausal osteoporosis in women such as rapid and selective loss of cancellous bone and skeletal responsiveness to bisphosphonates and PTH fragments (5, 14,16). It is also one of the two animal models required by the United States Food and Drug Administration for the preclinical assessment of drugs for treating osteoporosis (17 The experiment was a restorative experiment designed to compare the abilities of the fragments to increase the volume of the cancellous bone remaining in the severely depleted cancellous bone of rats several weeks after ovariectomy (OVX).…”

“…Although hPTH fragments can stimulate cortical bone growth in still-growing young rats such as those used in these experiments (14, 18), we focused on distal femoral cancellous bone because its responses to OVX and PTH fragments are proportionally much larger and therefore more easily and accurately measured (13,14,16,19). Femurs were removed from euthanized rats and cleaned.…”

Osteogenic PTHs and vascular ossification—Is there a danger for osteoporotics?

“…One of these is the full-length, recombinant(r) human (h) rhPTH-(1-84)OH which has completed its phase III clinical trial and is called Preos TM by its manufacturer NPS pharmaceuticals (Salt Lake City, UT) [reviewed by Whitfield et al, 2002;Whitfield, 2005]. The next in order of size is Lilly's rhPTH-(1-34)OH (also known as teriparatide) which is being used under the name Forteo TM [reviewed by Whitfield et al, 2002;Whitfield, 2005] [Whitfield et al, 1996Barbier et al, 1997].…”