Maintenance of Increased Bone Mass After Recombinant Human Parathyroid Hormone (1-84) With Sequential Zoledronate Treatment in Ovariectomized Rats

Abstract

The concept of lose, restore, maintain (LRM) for reversing existing osteoporosis was tested in rats. The withdrawal of PTH results in the loss of the acquired bone mass, but sequential therapy with zoledronate quite effectively maintained the PTH(1-84)-acquired bone quantity and quality.Introduction: Because antiresorptive agents against osteoporosis are presently quite limited, strong anabolic agents such as human parathyroid hormone (hPTH) are quite helpful. However, because hPTH(1-34) is available only through injection and has a critical side effect of causing bone tumors during life-long administration in the rat, it would be practical to use PTH for the shortest possible duration to obtain the maximal effect. To determine the effectiveness of the osteoporosis-reversing concept of lose, restore, and maintain (LRM), recombinant hPTH(1-84) ] and the respective antiresorptive agents were sequentially studied. Materials and Methods: Thirty-six, 20-week-old Sprague-Dawley rats were used. Treatment started at the 25th week after ovariectomy, which was performed at 20 weeks of age, with 5 weeks of rhPTH(1-84) 100 g/kg/day, 5 days/week, followed by the respective sequential therapies for 5 weeks as follows: (1) ovariectomized rats (OVX; n ϭ 6), (2) sham-operated rats (SHAM; n ϭ 6), (3) OVX rats with PTH maintenance (PTH-M; n ϭ 6), (4) OVX rats treated with PTH and then PTH was withdrawn (PTH-W; n ϭ 6), (5) PTH-treated OVX rats treated with 17␤-estradiol (PTH-E; 10 g/day SC, 5 days/week; n ϭ 6), and (6) PTH-treated OVX rats treated with zoledronate (PTH-Z; 12.5 g/kg SC weekly; n ϭ 6). BMD of the right femora was measured by DXA. CT was used to measure the structural parameters of the second lumbar vertebrae. Three-point bending test of the femora and compressive tests of vertebrae were also performed. Results: Bone quantity data showed that the BMD and most of the microstructural parameters were significantly higher in the PTH-M and PTH-Z groups than in the OVX and PTH-W groups (p Ͻ 0.05). Measurement of the cortical thickness revealed that only the PTH-M group showed a significant increase (p ϭ 0.001). The ultimate force (F u ) at the midshaft of the femora was similar in the treated groups and stronger than in the OVX group (p Ͻ 0.05). However, in the vertebrae, the F u of the PTH-M and PTH-Z groups was significantly higher, by ϳ44 -47%, than in the OVX and PTH-E groups and showed a higher tendency than in the PTH-W group. Conclusion: PTH withdrawal resulted in the loss of acquired BMD, and sequential therapy with antiresorptives prevented further loss (17␤-estradiol versus zoledronate). The zoledronate after rhPTH(1-84) as a sequential regimen was quite consistently effective.

Systemically Administered Bone Morphogenetic Protein-6 Restores Bone in Aged Ovariectomized Rats by Increasing Bone Formation and Suppressing Bone Resorption

“…After discontinuation of BMP-6 therapy animals maintained the BMD value for another 12 weeks. In comparative studies utilizing aged rats with a similar post-OVX time period, PTH withdrawal results in a loss of acquired BMD within 5 weeks (44). Unlike PTH, which circulates in serum, BMP-6 circulates when bone regenerates, like in patients with multiple bone fractures.…”

Biochemical markers in preclinical models of osteoporosis

“…Labor-Internationalensive (Parfitt et al 1987a;Baddeley et al 1986;Eriksen 1986;Gundersen et al 1988;Vesterby et al 1987;Hauge et al 1999;Hauge et al 2001 (Barbier et al 1999;Rhee et al 2004;Schaller et al 2004;Bollerslev & Andersen Jr. 1989;Tuukkanen et al 2000;Munns et al 2004;Moisio et al 2003 , Ylipahkala et al 2005a). Finally, the major advantage of the markers is that they can be measured dynamically during resorption experiments and therefore provide additional information, such as reversibility of an effect, loss of sensitivity to a treatment and fast responses to treatment, when compared to endpoint measurements of pit area, number and volume.…”

Short-term continuous infusion of human parathyroid hormone 1–34 fragment is catabolic with decreased trabecular connectivity density accompanied by hypercalcemia in C57BL/J6 mice

“…Regarding the anabolic action, it has been well established that intermittent treatment with PTH, both N-terminal 1-34 fragment and intact 1-84 peptide, is anabolic in a range of species including mice (Jilka et al 1999, Alexander et al 2001, Andersson et al 2001, Iida-Klein et al 2002, Fukata et al 2004, Rhee et al 2004, Seebach et al 2004. However, there are very few studies that demonstrate the catabolic effects of continuously elevated PTH on bone in mice.…”