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We evaluated the effects of suppressed bone remodeling caused by bisphosphonate on microdamage accumulation and degree of mineralization of bone (DMB) for the dog rib in two independent studies. Study 1: 36 female beagles, 1-2 years old, were treated daily for 1 year with saline vehicle, risedronate at 0.5 mg/kg/day, or alendronate at 1.0 mg/kg/day. Study 2: 29 beagles, 1 year old, were given lactose, or incadronate at 0.3 mg/kg/day or 0.6 mg/kg/day for 3 years. In both studies, the ninth rib was harvested. Intracortical remodeling was significantly suppressed following either 1 year or 3 years of bisphosphonate treatment without impairment of primary mineralization, although the remodeling rate was obviously lower in study 2 than in study 1 because of the aging of animals. Microdamage accumulation was significantly increased following any bisphosphonate treatment in response to the extent of remodeling suppression. One-year treatment with risedronate or alendronate did not significantly affect the mean DMB or osteonal distribution based on DMB. In contrast, mean DMB was significantly increased following 3 years of incadronate treatments, and osteonal distributions based on DMB showed a dose-dependent shift toward the higher values in incadronate-treated animals when compared with controls. Our results demonstrated that DMB was increased following only 3 years but not 1 year of bisphosphonate treatment. This finding suggests that suppressed remodeling induced by long-term bisphosphonate treatment increased DMB by increasing the population of old, highly mineralized osteons; however, the expression of this phenomenon depends on duration of the treatment because the secondary mineralization is a very slow process.

Bicyclo[2.2.1]hepta-2,5-diene (2,5-norbornadiene) dimerizes in the presence of a catalytic amount of Ru(1-2:5-6-η-cyclooctadiene)(1-6-η-cyclooctatriene) (Ru(cod)(cot)) and an electron-deficient olefin such as N,N-dimethylacrylamide, dimethyl fumarate, or dimethyl maleate in toluene or tetrahydrofuran (THF) to give a new compound, pentacyclo[6.6.0.02,6.03,13.010,14]tetradeca-4,11-diene (PCTD), in high yield along with a small amount of a known endo − endo dimer, heptacyclo[6.6.0.02,6.03,13.04,11.05,9.010,14]tetradecane (HCTD), which is a major product in the reaction in DMSO. Ru(cod)(cot)-dimethyl fumarate in THF was the most efficient catalyst, and the yield of PCTD was 96% even at 40 °C. The structure of PCTD was determined by X-ray analysis of its derivative, [AgOTf(PCTD)] n . PCTD was found to be derived via endo − endo dimerization of 2,5-norbornadiene. Formation of PCTD from two molecules of 2,5-norbornadiene involves the cleavage of two carbon−carbon bonds. Dimerization of 7-tert-butoxy-2,5-norbornadiene gave the corresponding exo- and endo-4,9-disubstituted PCTD derivatives. Ru(cod)(cot) reacts with dimethyl fumarate to give a novel complex, Ru(cot)(dmfm)2 (dmfm = dimethyl fumarate), in high yield. The structure of the complex was determined by X-ray analysis. At 40 °C in toluene, Ru(cot)(dmfm)2 itself catalyzes the dimerization of 2,5-norbornadiene to give PCTD in excellent yield in the absence of olefinic additives. The mechanisms of the formation of PCTD are discussed.