Oral dosing of pentoxifylline, a pan-phosphodiesterase inhibitor restores bone mass and quality in osteopenic rabbits by an osteogenic mechanism: A comparative study with human parathyroid hormone.

The non-selective phosphodiesterase inhibitor pentoxifylline (PTX) is used for the treatment of intermittent claudication due to artery occlusion. Previous studies in rodents have reported salutary effects of the intraperitoneal administration of PTX in segmental bone defect and fracture healing, as well as stimulation of bone formation. We determined the effect of orally dosed PTX in skeletally mature ovariectomized (OVX) rabbits with osteopenia. The half-maximal effective concentration (EC50) of PTX in rabbit bone marrow stromal cells was 3.07 ±â€¯1.37 nM. The plasma PTX level was 2.05 ±â€¯0.522 nM after a single oral dose of 12.5mg/kg, which was one-sixth of the adult human dose of PTX. Four months of daily oral dosing of PTX at 12.5 mg/kg to osteopenic rabbits completely restored bone mineral density, bone mineral content (BMC), microarchitecture and bone strength to the level of the sham-operated (ovary intact) group. The bone strength to BMC relationship between PTX and sham was similar. The bone restorative effect of PTX was observed in both axial and appendicular bones. In osteopenic rabbits, PTX increased serum amino-terminal propeptide, mineralized nodule formation by stromal cells and osteogenic gene expression in bone. PTX reversed decreased calcium weight percentage and poor crystal packing found in osteopenic rabbits. Furthermore, similar to parathyroid hormone (PTH), PTX had no effect on bone resorption. Taken together, our data show that PTX completely restored bone mass, bone strength and bone mineral properties by an anabolic mechanism. PTX has the potential to become an oral osteogenic drug for the treatment of post-menopausal osteoporosis.

Odanacatib Restores Trabecular Bone of Skeletally Mature Female Rabbits With Osteopenia but Induces Brittleness of Cortical Bone: A Comparative Study of the Investigational Drug With PTH, Estrogen, and Alendronate.

Cathepsin K (CK), a lysosomal cysteine protease, is highly expressed in mature osteoclasts and degrades type 1 collagen. Odanacatib (ODN) is a selective and reversible CK inhibitor that inhibits bone loss in preclinical and clinical studies. Although an antiresorptive, ODN does not suppress bone formation, which led us to hypothesize that ODN may display restorative effect on the osteopenic bones. In a curative study, skeletally mature New Zealand rabbits were ovarectomized (OVX) and after induction of bone loss were given a steady-state exposure of ODN (9 mM/d) for 14 weeks. Sham-operated and OVX rabbits treated with alendronate (ALD), 17b-estradiol (E2), or parathyroid hormone (PTH) served as various controls. Efficacy was evaluated by assessing bone mineral density (BMD), bone microarchitecture (using micro-computed tomography), fluorescent labeling of bone, and biomechanical strength. Skeletal Ca/P ratio was measured by scanning electron microscopy (SEM) with X-ray microanalysis, crystallinity by X-ray diffraction, and bone mineral density distribution (tissue mineralization) by backscattered SEM. Between the sham and ODN-treated osteopenic groups, lumbar and femur metaphyseal BMD, Ca/P ratio, trabecular microstructure and geometric indices, vertebral compressive strength, trabecular lining cells, cortical parameters (femoral area and thickness and periosteal deposition), and serum P1NP were largely comparable. Skeletal improvements in ALD-treated or E2-treated groups fell significantly short of the sham/ODN/PTH group. However, the ODN group displayed reduced ductility and enhanced brittleness of central femur, which might have been contributed by higher crytallinity and tissue mineralization. Rabbit bone marrow stromal cells expressed CK and when treated with ODN displayed increased formation of mineralized nodules and decreased apoptosis in serum-deficient medium compared with control. In vivo, ODN did not suppress remodeling but inhibited osteoclast activity more than ALD. Taken together, we show that ODN reverses BMD, skeletal architecture, and compressive strength in osteopenic rabbits; however, it increases crystallinity and tissue mineralization, thus leading to increased cortical bone brittleness.