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Lilly Announces New Data Further Exploring Mechanistic Differences Between FORTEO and Zoledronic Acid

Eli Lilly and Company (NYSE: LLY) today presented data comparing the effects of FORTEO and zoledronic acid on transiliac crest bone biopsies at six months in postmenopausal women with osteoporosis, based on additional analysis of data from the SHOTZ trial. Results, which were presented in an oral presentation at the 2012 Annual Meeting of the American Society for Bone and Mineral Research (ASBMR) in Minneapolis, MN, clearly differentiate the mechanism of action of FORTEO as anabolic and that of zoledronic acid as antiresorptive.

The data show that the contrasting effects of FORTEO and zoledronic acid on bone remodeling are evident on all three bone surfaces: cancellous, endocortical and periosteal. The effects on mineralizing surface (MS/BS) and bone formation rate (BFR/BS) – dynamic indices of bone formation and turnover – provided clear differentiation of the mechanism of action of the two drugs at six months.1

"This study continues to differentiate these two established osteoporosis treatments with different mechanisms of action and further contrasts the anticatabolic action of zoledronic acid and the anabolic action of teriparatide on all three bone surfaces," said David W. Dempster, PhD, professor of clinical pathology, Columbia University. "It is important to understand the effect of antifracture drugs on cortical bone, which makes up 80 percent of the adult skeleton."

Previously, researchers used dynamic histomorphometry, a technique to measure cellular activities of remodeling at the bone tissue level, to explore the mechanisms of action of FORTEO and zoledronic acid in the cancellous compartment of bone biopsies. In this study, researchers extended their observations to the outer and inner surfaces of cortical bone.

In a typical bone sample, the internal meshwork, or cancellous bone, is surrounded with cortical bone. The cortical bone has two surfaces; the endocortical (inner) surface is adjacent to cancellous bone, and the periosteal (outer) surface forms the external bone surface.

These study results showed that the contrasting effects of FORTEO and zoledronic acid on bone remodeling were evident on all three bone envelopes measured. The dynamic index of bone formation, mineralizing surface (MS/BS), was a striking differentiator between the drugs:

cancellous (median: 5.6 percent [FORTEO] vs. 0.16 percent [zoledronic acid]); endocortical (median: 18.64 percent [FORTEO] vs. 0.30 percent [zoledronic acid]); and periosteal (median: 0.71 percent [FORTEO] vs. 0.0 percent [zoledronic acid]). Similar results were observed for other histomorphometric indices such as bone formation rate (BFR), mineral apposition rate (MAR), osteoid surface (OS/BS), osteoid thickness (O.Th) and wall thickness (W.Th); all of which were significantly higher in the FORTEO than the zoledronic acid group in both cancellous and endocortical envelopes. Conversely, in both envelopes, eroded surface (ES/BS) was lower in the zoledronic acid than the teriparatide group. Periosteal MS/BS and BFR/BS were greater with FORTEO than with zoledronic acid treatment.1

Although the effect of FORTEO was smaller on the periosteal surface than the endocortical surface, the greater values for dynamic indices relative to the zoledronic acid group suggests the possibility of periosteal expansion, and possibly an increase in bone size with FORTEO treatment. Further, in FORTEO samples, MS/BS and BRF/BS were higher in the endocortical than the cancellous envelope which, coupled with an increase in wall thickness, provides a mechanism for cortical thickening with FORTEO treatment.1

In the study, the overall safety profile was consistent with the known FORTEO safety profile seen in this patient population. The overall incidence of serious adverse events, treatment-emergent adverse events and adverse events leading to discontinuation were similar between the FORTEO and zoledronic acid treatment groups.1

"We believe these data help further explain the growing body of evidence supporting the mechanism of action of FORTEO," said Anthony Beardsworth, M.D., senior medical director, Eli Lilly and Company. "The results may help healthcare professionals better determine osteoporosis treatment for their individual patients."

FORTEO is used in both men and postmenopausal women with osteoporosis who are at high risk for having broken bones (fractures). FORTEO is used in both men and women with osteoporosis due to use of glucocorticoid medicines, such as prednisone, for several months, who are at high risk for having broken bones (fractures). FORTEO can be used by people who have had a fracture related to osteoporosis, or who have several risk factors for fracture, or who cannot use other osteoporosis treatments.2

During the drug testing process, the medicine in FORTEO caused some rats to develop

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