Short- and long-term effects of a single dose of bisphosphonates on retinoid-induced bone resorption in thyroparathyroidectomized rats

Stutzer, A.; Fleisch, H.; Trechsel, U.

doi:10.1007/bf02556639

Cited by 32 publications

(7 citation statements)

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“…Given these limitations, the present short-term study shows profound effects of both zoledronate and pamidronate on bone comparable to those reported for other bisphosphonates. This is particularly true for the inhibition of bone resorption which is the main pharmacological effect of bisphosphonates and has been repeatedly observed in various experimental models in a variety of species (Miller and Jee, 1979;Schenk et al, 1986;de Vernejoul et al, 1987;Stutzer et al, 1988;Wronski et al, 1989;Mü hlbauer et al, 1991;Seedor et al, 1991).…”

Section: Discussionmentioning

confidence: 92%

Effects of short-term treatment with the bisphosphonates zoledronate and pamidronate on rat bone: A comparative histomorphometric study on the cancellous bone formed before, during, and after treatment

et al. 1997

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To study the anti-resorptive effects of zoledronate and pamidronate on growing long bones we have performed a histomorphometric analysis of the three regions of the proximal tibial cancellous bone of bone formed before, during, and after drug treatment. Male rats (190-220 g) were treated subcutaneously for 10 days with zoledronate (0.028-2.8 g/kg) or pamidronate (3.7-370 g/kg) and sacrificed 5 days later. To delineate the three regions of cancellous bone, and for dynamic bone histomorphometry, calcein and demeclocycline were injected at various times. Both bisphosphonates caused a dose-dependent suppression of cancellous bone turnover and resorption to produce an increase in cancellous bone, but zoledronate was 100 times more potent than pamidronate. The increase in the bone amount and connectivity was more pronounced in the bone formed during treatment where transient bone resorption and normal bone formation led to a positive bone balance. In the bone formed before treatment, inhibition of bone resorption associated with reduced bone formation produced a net gain in amount of bone. Although both bone regions showed a positive bone balance, more bone accumulated in the bone formed during treatment probably because its trabecular bone surface was three times greater. In the primary spongiosa formed after treatment, a moderate increase in the bone amount and connectivity was observed only at the highest dose of both bisphosphonates. The bone formed before, during, and after treatment with bisphosphonates responds differently due to differences in bone architecture, rates of modeling and remodeling, and period of drug exposure. Anat. Rec. 249:458-468, 1997. 1997 Wiley-Liss, Inc. Key words: pamidronate; zoledronate; bisphosphonate; rat; bone histomorphometryThe bisphosphonate compound zoledronate (CGP 42446) is a very potent antiresorptive agent in several pharmacological models (Green et al., 1994). In a previous pilot experiment we studied the effects of zoledronate and pamidronate on static histomorphometric parameters of cancellous bone in rat tibia (Pataki et al., 1990). We reported that zoledronate and pamidronate induce a dose-dependent increase in the proximal tibial metaphyseal cancellous bone and that zoledronate was at least 100 times more potent than pamidronate in accumulating bone mass. Both compounds caused a dose-dependent decrease in osteoid perimeter and serum levels of osteocalcin, alkaline phosphates, and tartrate-resistant acid phosphates, suggesting that the increase in bone resulted from depression of bone resorption and formation. In the present study, both static and dynamic morphometric parameters were investigated after administration of zoledronate and compared to the effects of the reference drug pamidronate. In addition to morphometric investigations, the effects on cortical and cancellous bone were also analyzed chemically.Previous investigators characterized the effects of bisphosphonates on the entire metaphysis in growing rats. This is the first report that analyzes the his...

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Section: Discussionmentioning

confidence: 92%

Effects of short-term treatment with the bisphosphonates zoledronate and pamidronate on rat bone: A comparative histomorphometric study on the cancellous bone formed before, during, and after treatment

et al. 1997

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“…BPs also suppress resorption induced by many other agents such as calcitriol, vitamin D, and retinoids. The effect on retinoid‐induced hypercalcemia has been used to develop a powerful and rapid‐screening assay for new compounds 34,35 . In growing intact rats, the BPs block the removal of both bone and cartilage, thus retarding the remodeling of the metaphysis, which becomes club‐shaped and radiologically denser than normal 36 .…”

Section: Early Studies On Ppi and Bpsmentioning

confidence: 99%

Bisphosphonates

Russell

2006

Annals of the New York Academy of Sciences

383

275

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The discovery and development of the bisphosphonates (BPs) as a major class of drugs for the treatment of bone diseases has been a fascinating journey that is still not over. In clinical medicine, several BPs are established as the treatments of choice for various diseases of excessive bone resorption, including Paget's disease of bone, myeloma and bone metastases, and osteoporosis. Bisphosphonates are chemically stable analogues of inorganic pyrophosphate, and are resistant to breakdown by enzymatic hydrolysis. Bisphosphonates inhibit bone resorption by being selectively taken up and adsorbed to mineral surfaces in bone, where they interfere with the action of the bone-resorbing osteoclasts. Bisphosphonates are internalized by osteoclasts and interfere with specific biochemical processes. Bisphosphonates can be classified into at least two groups with different molecular modes of action. The simpler non-nitrogen-containing bisphosphonates (such as clodronate and etidronate) can be metabolically incorporated into nonhydrolyzable analogues of adenosine triphosphate (ATP) that may inhibit ATP-dependent intracellular enzymes. The more potent, nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, ibandronate, and zoledronate) are not metabolized in this way but can inhibit enzymes of the mevalonate pathway, thereby preventing the biosynthesis of isoprenoid compounds that are essential for the posttranslational modification of small GTP-binding proteins (which are also GTPases) such as rab, rho, and rac. The inhibition of protein prenylation and the disruption of the function of these key regulatory proteins explain the loss of osteoclast activity and induction of apoptosis. The key target for bisphosphonates is farnesyl pyrophosphate synthase (FPPS) within osteoclasts, and the recently elucidated crystal structure of this enzyme reveals how BPs bind to and inhibit at the active site via their critical N atoms. In conclusion, bisphosphonates are now established as an important class of drugs for the treatment of many bone diseases, and their mode of action is being unraveled. As a result their full therapeutic potential is gradually being realized.

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“…Furthermore, young growing rats can provide useful information on the short-term effects of drugs on bone resorption, such as in the retinoidinduced bone resorption model [118,119], calcium kinetics and balance [120], or calciotropic hormone levels. They can also be used to evaluate the effects of interventions aimed at increasing osteoblastic recruitment and bone formation [121].…”

Section: Specific Considerationmentioning

confidence: 99%

Importance of Preclinical Studies in the Development of Drugs for Treatment of Osteoporosis: A Review Related to the 1998 WHO Guidelines

Bonjour

Ammann

Rizzoli

1999

Osteoporosis International

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Osteoporosis, which is defined as a disease characterized by low bone mass and microarchitectural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture risk, is a major health issue worldwide. Among the various strategies to prevent and cure this devastating ailment, an important objective is the development of new efficacious and safe drugs. This situation prompted the World Health Organization (WHO) to provide a comprehensive statement of guiding principles for the design, implementation and interpretation of both preclinical testing and clinical trials in osteoporosis. These guidelines, which are now available, underline the crucial importance of the preclinical evaluation, particularly for assessing the effect of an intervention on bone strength. This concept is heightened by the lack of a validated technique for noninvasively evaluating bone strength in humans and the multiple difficulties and heavy burden inherent in the evaluation of fracture rate in clinical trials. The WHO guidelines emphasize that a comprehensive and adequate preclinical program is expected to provide key information on the relationship between bone mass and strength and thus attenuate the burden of clinical studies. The present report provides a review of experimental evidence in support of the preclinical program as proposed in the WHO guidelines. This program is based on the recent development and refinement of animal models of osteoporosis that mimic the human condition according to the conceptual definition of the disease. Many preclinical studies carried out in appropriate animal models with agents that exert either antiresorbing or anabolic effects on bone indicate that they have been highly predictive of the drug action in humans in terms of both bone mass and remodeling, as well as of bone strength whenever fracture rate has been documented in clinical trials. Based on this evidence the WHO guidelines propose strategies according to which the results of preclinical evaluation will determine the end-points required in the different phases of the clinical development of the drug. Such a distribution of task assignment between preclinical and clinical programs should optimize the progress of research available to patients already suffering from or at risk of osteoporosis.

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Short- and long-term effects of a single dose of bisphosphonates on retinoid-induced bone resorption in thyroparathyroidectomized rats

Cited by 32 publications

References 14 publications

Effects of short-term treatment with the bisphosphonates zoledronate and pamidronate on rat bone: A comparative histomorphometric study on the cancellous bone formed before, during, and after treatment

Effects of short-term treatment with the bisphosphonates zoledronate and pamidronate on rat bone: A comparative histomorphometric study on the cancellous bone formed before, during, and after treatment

Bisphosphonates

Importance of Preclinical Studies in the Development of Drugs for Treatment of Osteoporosis: A Review Related to the 1998 WHO Guidelines

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