Zoledronic acid (ZOL) is a highly potent heterocyclic bisphosphonate which has been shown to inhibit bone resorption in short-term experiments in young growing animals. In this investigation we have evaluated the effects of a 1-year administration to mature, ovariectomized (OVX) rats as a model for postmenopausal osteoporosis in order to elucidate (1) the temporal changes in urinary biochemical markers of bone turnover and femoral bone mineral density (BMD), (2) to measure changes of static and dynamic histomorphometric parameters and mechanical strength, and (3) to assess the preventive effects of chronic treatment with ZOL on these parameters. In urine, deoxypyridinoline increased after OVX and was significantly reduced by ZOL administration, indicative of a reduced bone collagen turnover. These changes were accompanied by alterations of tibial cancellous bone: trabecular bone volume and parameters of bone architecture were significantly augmented by ZOL and bone formation rates fell as a consequence of suppressed bone turnover, but were still measurable. No signs of "frozen bone" or osteomalacia could be detected. BMD of the whole femurs rose in sham-operated control animals (SHAM) during the entire experimental period, whereas in OVX animals, BMD plateaued after 32 weeks at a lower level. ZOL at a low dose (0.3 mg/kg/week s.c.) did not alter whole femur BMD, but at higher doses (1.5 and 7.5 mg/kg/week s.c.) BMD increased to the level of the SHAM group. A distinct pattern was noted for the distal quarter of the femur, a region rich in cancellous bone: BMD initially increased in all treatment groups except the OVX group, and at a later stage fell again at a comparable rate irrespective of treatment. Mechanical stability, as assessed by a 3-point bending test, was significantly increased by all doses of ZOL and exceeded OVX and sham-operated controls. The effects on mechanical properties were observed at a low dose which did not measurably increase femoral BMD after 1-year treatment. Multiregression analysis revealed a significant positive correlation between maximum load and BMD, and a significant negative correlation of maximum load with labeled perimeter, a marker of bone formation and turnover. No significant correlation was found with urinary deoxypyridinoline, a marker of bone resorption. The data show that mechanical testing detects improvements of functional bone quality following low dose bisphosphonate treatment which are not identified by standard DXA measurements of BMD.

This study investigated the protective effect of long-term treatment with the bisphosphonate zoledronic acid on bone mass, structure, and strength in adult, estrogen-deficient rats. Rats were ovariectomized (OVX) at the age of 4 months and divided into four groups of 20 rats: one group of saline-treated OVX controls, and three groups of OVX rats treated with 0.3, 1.5, or 7.5 microg/kg/week s.c. zoledronic acid (ZOL). An additional group of sham-operated, saline-treated rats served as normal controls. Biochemical assays were performed after 16 and 51 weeks, respectively, and bone mineral density (BMD) determinations after 17 and 52 weeks, respectively. Before the end of the experiment animals were injected with tetracyclines for the determination of dynamic bone indexes. Finally, animals were sacrificed after 52 weeks, and vertebral bones (LV5) were subjected to mechanical compression testing. LV4 were used for histology and LV2 for microcomputed tomography. ZOL treatment abolished the rise of osteocalcin and reduced urinary deoxypyridinoline excretion. BMD was reduced in the OVX group in comparison to sham controls, and the decline was dose-dependently prevented by ZOL treatment. Tetracycline labeling showed a significant increase in bone formation rate (BFR) in OVX rats which was abolished by ZOL treatment. The same was observed for osteoid perimeter (Os.Pm) suggesting that ZOL diminished the high bone turnover associated with estrogen deficiency. Architectural parameters (BV/TV, Tb.Th*, Tb.N*, Tb.Sp*, SMI, CD) underwent the expected changes toward structural deterioration which was completely prevented by ZOL administration at doses of 1.5 and 7.5 microg/kg/week s.c. Similar results were obtained in compression testing: maximum stress fell significantly after OVX, and this effect was effectively prevented by ZOL treatment. Regression analysis suggests that in this rat model, SMI and Tb.Th* significantly contribute to compressive strength, albeit to a smaller degree than total cross-sectional area. The data further suggest that in the aged OVX rat, SMI and TB.Th* change in an interdependent way. ZOL prevents this process by inhibiting plate thinning and the transition into rod-shaped trabeculae.

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Recent data indicate that the catechol estrogen, 2-hydroxyestrone (2-OHE 1 ), has no effect on any target tissue including bone, whereas 16 -hydroxyestrone (16 -OHE 1 ) exerts tissue-selective estrogen agonist activity. The effect of the catechol estrogen, 4-hydroxyestrone (4-OHE 1 ), putatively associated with tumorigenesis, has not been studied in the skeleton. The purpose of this study was to assess the effect of 4-OHE 1 on tibia, uterine and mammary gland histology and blood cholesterol in ovariectomized (OVX'd) growing rats. Ten-week-old female Sprague-Dawley rats were injected subcutaneously with 200 µg/kg BW per day with 4-OHE 1 , 17 -estradiol (E 2 ) or vehicle for three weeks. OVX resulted in uterine atrophy, increased body weight, radial bone growth and cancellous bone turnover, and hypercholesterolemia. E 2 prevented these changes with the expected exception that the subcutaneous infusion of this high dose of estrogen did not prevent the hypercholesterolemia. 4-OHE 1 prevented the increase in blood cholesterol and the increase in body weight. 4-OHE 1 appeared to have partial estrogen activity in the uterus; uterine weight and epithelial cell height were significantly greater than the OVX rats but significantly less (twofold) than the E 2 animals. Analysis of variance indicated that 4-OHE 1 slightly decreased the periosteal mineral apposition rate (P<0·05) compared with vehicletreated rats but had no effect on double-labeled perimeter or bone formation rate. Similarly, 4-OHE 1 was a partial estrogen agonist on cancellous bone turnover. The data suggest that the catechol estrogen, 4-OHE 1 , unlike 2-OHE 1 , has estrogen activity. Furthermore, the profile of activity differs from that of 16 -OHE 1 . Our results suggest that estrogen metabolites may selectively influence estrogen-target tissues and, concomitantly, modulate estrogen-associated disease risk.

Aseptic loosening is the major cause of failure in primary total hip replacements. Loss of bone stock occurs in both cementless and cemented implants. Impaction of morsellised allograft represents a major advance in the restoration of bone loss at revision hip surgery. This study was designed to test the early stability of the femoral impaction construct. Polished double tapered stems were inserted into neomedullary canals within impacted allograft in fibreglass femora. Subsidence was measured during cyclical loading. Four methods of impaction grafting were tested: allograft alone; allograft and heparinised blood; allograft/cement/heparinised blood; allograft/cement/clotted blood. Uncemented impaction grafting failed at low loads and few cycles. The cemented technique supported higher loads. Heparinised blood reduced the strength of the composite. Initial stability was achieved with allograft, cement and clotted blood. There is need for caution in the early post-operative period due to the wide variation in initial stability of the allograft composite. The reliability of this technique has been increased by the use of specialised instruments. Experimental studies and clinical experience suggest that this approach to revision surgery is technique dependent.