Consequences of Neoplasia Induced Bone-Resorption and the Use of Clodronate (Review)

Kanis, JA; O’Rourke, N.; McCloskey, EV

doi:10.3892/ijo.5.4.713

Cited by 11 publications

(7 citation statements)

References 103 publications

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“…It has been suggested that the relatively long skeletal half‐life of bisphosphonates may account for the long duration of response in Paget's disease of bone and osteoporosis 4 , 40. This seems unlikely since in disorders where skeletal retention is increased, such as hypercalcaemia and metastatic bone disease, the rate of reversal of the therapeutic effect is relatively rapid after stopping treatment 41 , 42. For these reasons, it seems unlikely that alendronate buried in mineralized bone is of clinical importance.…”

Section: Discussionmentioning

confidence: 99%

Elimination and Biochemical Responses to Intravenous Alendronate in Postmenopausal Osteoporosis

Khan

Kanis

Vasikaran

et al. 1997

Journal of Bone and Mineral Research

262

135

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Postmenopausal women with established vertebral osteoporosis were studied for 2 years to determine the terminal elimination half-life and the duration of response to treatment with intravenous alendronate (30 mg) given over 4 days. The urinary excretion of alendronate followed a multiexponential decline. Approximately 50% of the total dose was excreted over the first 5 days, and a further 17% was excreted in the succeeding 6 months. Thereafter, there was a much slower elimination phase with an estimated mean terminal half-life of greater than 10 years (n ‫؍‬ 11). Urinary excretion of hydroxyproline and calcium decreased significantly from pretreatment values by day 3, reaching a nadir by 1 week (40% and 67% decrease, respectively). Thereafter, hydroxyproline remained suppressed for the following 2 years. In contrast, urinary calcium excretion returned gradually toward pretreatment values over the first year and during the second year was comparable to pretreatment values. Serum activity of alkaline phosphatase activity decreased over 3 months (23% reduction), increased gradually thereafter, and returned to pretreatment values at month 24. Bone mineral density measured at the spine increased by approximately 5% during the first year and remained significantly higher than pretreatment values at 2 years. We conclude that a short course of high doses of intravenous alendronate is associated with a prolonged skeletal retention of the agent. This open study also suggests that this regimen has a sustained effect on bone turnover persisting for at least 1

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Section: Discussionmentioning

confidence: 99%

Elimination and Biochemical Responses to Intravenous Alendronate in Postmenopausal Osteoporosis

Khan

Kanis

Vasikaran

et al. 1997

Journal of Bone and Mineral Research

262

135

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“…C LODRONATE (dichloromethylenebisphosphonate) is a synthetic analog of pyrophosphate1 and is widely used in the treatment of metabolic bone diseases that involve excessive bone resorption such as hypercalcemia of malignancy and osteolytic disease resulting from bone metastases1–3 and Paget's disease 4 , 5. Like alendronate and other bisphosphonates (BPs) that all have a P‐C‐P backbone,6 clodronate has high affinity for bone mineral and inhibits bone resorption in vitro and in vivo through effects on osteoclasts 1 , 7.…”

Section: Introductionmentioning

confidence: 99%

Clodronate and Liposome-Encapsulated Clodronate Are Metabolized to a Toxic ATP Analog, Adenosine 5′-(β,γ-Dichloromethylene) Triphosphate, by Mammalian Cells In Vitro

Frith

Mönkkönen

Blackburn

et al. 1997

Journal of Bone and Mineral Research

407

211

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Clodronate, alendronate, and other bisphosphonates are widely used in the treatment of bone diseases characterized by excessive osteoclastic bone resorption. The exact mechanisms of action of bisphosphonates have not been identified but may involve a toxic effect on mature osteoclasts due to the induction of apoptosis. Clodronate encapsulated in liposomes is also toxic to macrophages in vivo and may therefore be of use in the treatment of inflammatory diseases. It is generally believed that bisphosphonates are not metabolized. However, we have found that mammalian cells in vitro (murine J774 macrophage-like cells and human MG63 osteosarcoma cells) can metabolize clodronate (dichloromethylenebisphosphonate) to a nonhydrolyzable adenosine triphosphate (ATP) analog, adenosine 5-(␤,␥-dichloromethylene) triphosphate, which could be detected in cell extracts by using fast protein liquid chromatography. J774 cells could also metabolize liposome-encapsulated clodronate to the same ATP analog. Liposome-encapsulated adenosine 5-(␤,␥-dichloromethylene) triphosphate was more potent than liposome-encapsulated clodronate at reducing the viability of cultures of J774 cells and caused both necrotic and apoptotic cell death. Neither alendronate nor liposome-encapsulated alendronate were metabolized. These results demonstrate that the toxic effect of clodronate on J774 macrophages, and probably on osteoclasts, is due to the metabolism of clodronate to a nonhydrolyzable ATP analog. Alendronate appears to act by a different mechanism.

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“…Response rates were lower than that reported by O'Rourke et al (1993) of 80% for 1500 mg clodronate. This may be because of a relatively high proportion of patients with humoral hypercalcaemia (Kanis et al, 1990(Kanis et al, , 1994. Only 54% of patients in this study were known to have bone metastases and all patients with haematological malignancies (including myeloma and lymphoma) were excluded.…”

Section: Discussionmentioning

confidence: 99%

Is there a dose response relationship for clodronate in the treatment of tumour induced hypercalcaemia?

et al. 2002

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Eighty-six patients with tumour induced hypercalcaemia were randomised to 600, 900, 1200 or 1500 mg of intravenous clodronate, according to post hydration serum calcium levels. Sixty-seven were evaluable for response. The overall response rate was 49.3% (95% CI: 36.8 -61.8) with no significant difference in response rates, i.e. achievement of normocalcaemia at days 6 -9 (corrected serum calcium 42.6 mmol l 71 ) across all groups.

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Consequences of Neoplasia Induced Bone-Resorption and the Use of Clodronate (Review)

Cited by 11 publications

References 103 publications

Elimination and Biochemical Responses to Intravenous Alendronate in Postmenopausal Osteoporosis

Elimination and Biochemical Responses to Intravenous Alendronate in Postmenopausal Osteoporosis

Clodronate and Liposome-Encapsulated Clodronate Are Metabolized to a Toxic ATP Analog, Adenosine 5′-(β,γ-Dichloromethylene) Triphosphate, by Mammalian Cells In Vitro

Is there a dose response relationship for clodronate in the treatment of tumour induced hypercalcaemia?

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