Prevention of Postmenopausal Bone Loss by Tiludronate

Reginster, Jacques; Lecart, Marie-Paule; Deroisy, Rita; Sarlet, Nathalie; Denis, Danielle; Ethgen, D; Collette, Jean-Paul; Franchimont, P

doi:10.1097/00006254-199006000-00014

Cited by 23 publications

(34 citation statements)

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“…They have been established as therapeutic agents in many bone disorders characterDr. Collin ized by increased resorption, such as Paget's disease (see review [2 ]), tumoral bone disease (see review [31), and recently, osteoporosis as well (4)(5)(6)(7). The mechanisms by which bisphosphonates inhibit bone resorption, however, remain to be clarified.…”

Section: Introductionmentioning

confidence: 99%

Bisphosphonates act on rat bone resorption through the mediation of osteoblasts.

Sahni¹,

Guenther²,

Fleisch³

et al. 1993

J. Clin. Invest.

387

170

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Bisphosphonates are generally considered to act on bone resorption by binding to bone mineral and subsequently inhibiting the activity of the osteoclasts which ingest them. This has been supported by the fact that bisphosphonates adsorbed on mineralized tissue inhibit the resorbing activity of isolated osteoclasts in vitro. However, the effectiveness of different bisphosphonates determined in this system does not reflect their relative potencies in vivo. Employing the well-described isolated osteoclast resorption pit assay, with ivory as the resorption substrate, we show here that this lack of correlation prevails only when the bisphosphonates are added to the mineral before addition of osteoclasts, but not when the cells are treated for a short time (5 min) before allowing them to adhere onto ivory. By using this approach with five different bisphosphonates, a stringent correlation of relative potencies was obtained with those found, both in the rat and in the human, in vivo. Furthermore, by using an osteoblastic cell line (CRP 10/30 ) which is a powerful promoter of osteoclastic resorption in vitro, we obtained evidence that the inhibitory effect of bisphosphonates was the result of an action on osteoblasts rather than on osteoclasts. Thus, in experiments in which the osteoblastic cells were pretreated for 5 min with bisphosphonates and then cocultured with osteoclasts, inhibition ofosteoclastic resorbing activity was obtained. Moreover, it was found that this treatment resulted in a decrease of the stimulatory effect found in CRP 10/30-conditioned medium. In conclusion the present study shows that part of the osteoclast inhibiting action of the bisphosphonates is mediated through an action on osteoblasts. (J.

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Section: Introductionmentioning

confidence: 99%

Bisphosphonates act on rat bone resorption through the mediation of osteoblasts.

Sahni¹,

Guenther²,

Fleisch³

et al. 1993

J. Clin. Invest.

387

170

View full text Add to dashboard Cite

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“…The main biological effect is a decrement in bone resorption through inhibition of osteoclast activity. The bisphosphonates have been used to treat a variety of disorders characterized by increased bone resorption, including Paget's disease, hypercalcemia, metastatic bone disease, and recently osteoporosis [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. Presently, only etidronate and alendronate are approved for osteoporosis treatment.…”

Section: Introductionmentioning

confidence: 99%

A 2-Year Phase II Study with 1-Year of Follow-up of Risedronate (NE-58095) in Postmenopausal Osteoporosis

et al. 1997

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This paper presents the results of a two-center, double-masked, placebo-controlled, randomized, oral-dose study of risedronate treatment in postmenopausal osteoporosis. Patients had at least one, but no more than four prevalent vertebral fractures at baseline. They received either 2.5 mg continuous risedronate, 2.5 mg cyclic risedronate, or placebo for 2 years. Both risedronate and placebo were formulated as hard gelatin capsules. All women furthermore received a daily calcium supplement of 1 g which was taken separately from the study drug. During the 1-year of follow-up, all women received only a daily calcium supplement of 1 g. A total of 132 patients were enrolled (44 in each treatment group), of which 73% completed the 2-year treatment period and 70% all 3 years. Generally the outcome of the study was negative. Lumbar spine bone mineral density (BMD) increased 1.2% (NS) and 0.8% (NS) and after 2 and 3 years in the group treated with continuous risedronate, 1.7% (NS) and 2.3% (p < 0.05) in the group treated with cyclic risedronate, and 0.6% (NS) and 1.7% (NS) in the placebo group. BMD in the femoral neck increased 2.9% (p < 0.05) and 0.9% (NS) after 2 and 3 years in the group treated with continuous risedronate, 1.3% (NS) and 2.4% (p < 0.01) in the group treated with cyclic risedronate, and 1.3% (NS) and 2.6% (p < 0.01) in the placebo group. The differences between all three groups in spinal and femoral BMD after 2 years were not statistically significant, but reached statistical significance after 3 years (p < 0.01) in the femoral neck. Only minor changes were observed in the measured markers of bone turnover. Both the incidence and rate of new vertebral fractures showed no overall differences between the groups. The distribution of adverse events was similar across treatment groups. None of the serious adverse events were considered causally related to risedronate. The lack of effect shown in the present study may be explained by insufficient dose regimen and/or impaired absorption from the intestinal tract. Further investigations (ongoing phase III trials) are needed to define future dose regimens in order to validate the effect on bone mass, fracture rate and biochemical markers. In these studies another formulation of the drug and other dosing instructions are used.

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“…They have been used to treat metabolic bone disorders such as postmenopausal bone loss [3][4][5] and osteoporosis [6][7][8][9][10][11] that are characterized by excessive bone resorption. Although their bioavailability is limited, oral bisphosphonates have been proven to be effective in preventing bone loss [4,5] and have even been reported to increase bone mass [6,7,[9][10][11] in postmenopausal women with low bone mass or osteoporosis. Some of these studies have used cyclic [4][5][6][7][8][9] and the others used continuous [10] regimens.…”

mentioning

confidence: 99%

“…Although their bioavailability is limited, oral bisphosphonates have been proven to be effective in preventing bone loss [4,5] and have even been reported to increase bone mass [6,7,[9][10][11] in postmenopausal women with low bone mass or osteoporosis. Some of these studies have used cyclic [4][5][6][7][8][9] and the others used continuous [10] regimens. The optimal method of administration has not been clearly established.…”

mentioning

confidence: 99%

The Effectiveness of Cyclic and Continuous Oral Clodronate Therapy on Bone Density and Markers in Osteopenic Postmenopausal Women

et al. 1999

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Bisphosphonates have been used effectively to treat established osteoporosis and prevent postmenopausal bone loss. However, the optimal manner of its administration-whether cyclic or continuous-has not been well established. This study investigated the efficacy of cyclic and continuous oral administration of clodronate in 54 newly identified osteopenic postmenopausal women in a randomized, double-blind, crossover fashion. The participants were randomly separated into two groups. The cyclic group (n = 29) received 800 mg twice daily of oral clodronate for 2 weeks every 3 months for the first 12 months followed by placebo for the second 12 months. The continuous group (n = 25) received placebo in the first 12 months and ingested 400 mg of clodronate once daily for the second 12 months. The urinary amino-terminal (NTXtrade mark) and carboxy-terminal (CrossLapstrade mark) cross-linked fragments of type I collagen, both markers of bone resorption, showed a marked decrease (25-50%) with both regimens during the period of active treatment. In the cyclic group, the levels of these two markers increased in the second 12 months with placebo, but did not return to the baseline completely. However, bone mineral density (BMD), determined by dual-energy X-ray absorptiometry (DXA), showed no significant change of BMD at various sites after 1 year of active treatment in both groups. Thoracic and lumbar spine X-ray showed no new vertebral fracture in either group after 2 years of treatment. With the two treatment protocols in this study, oral clodronate was effective in decreasing postmenopausal bone resorption, causing no significant changes in BMD at various sites.

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Prevention of Postmenopausal Bone Loss by Tiludronate

Cited by 23 publications

References 0 publications

Bisphosphonates act on rat bone resorption through the mediation of osteoblasts.

Bisphosphonates act on rat bone resorption through the mediation of osteoblasts.

A 2-Year Phase II Study with 1-Year of Follow-up of Risedronate (NE-58095) in Postmenopausal Osteoporosis

The Effectiveness of Cyclic and Continuous Oral Clodronate Therapy on Bone Density and Markers in Osteopenic Postmenopausal Women

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