The present experiments were carried out to test the hypothesis that artery calcification is linked to bone resorption by determining whether the selective inhibition of bone resorption with the bisphosphonates alendronate and ibandronate will inhibit artery calcification. Artery calcification was first induced by treatment of 42-day-old male rats with warfarin, a procedure that inhibits the gamma-carboxylation of matrix Gla protein and has been shown to cause extensive calcification of the artery media within 2 weeks. These experiments revealed that ibandronate (0.05 mg. kg(-1). d(-1)) and alendronate (0.1 mg x kg(-1) x d(-1)) completely inhibited calcification of all arteries and heart valves examined after 2 and 4 weeks of warfarin treatment. A 10-fold lower dose of alendronate reduced artery calcification by 50% (P<0.005). These bisphosphonate doses are comparable to those that inhibit bone resorption in rats of this age. More rapid artery calcification was induced by treatment with warfarin together with high doses of vitamin D, a procedure that causes extensive artery calcification by 84 hours. Alendronate and ibandronate again completely inhibited calcification of all arteries and heart valves examined. The subcutaneous doses of alendronate and ibandronate necessary to inhibit artery calcification are comparable to the daily subcutaneous doses of these drugs that have previously been shown to inhibit bone resorption in rats of the same age, with 50% inhibition of artery calcification at 20 microg alendronate x kg(-1) x d(-1) and at 1 microg ibandronate x kg(-1) x d(-1) x Bisphosphonate treatment did not affect serum calcium and phosphate, and so the inhibition of artery calcification cannot be due to a simple lowering of the serum calcium phosphate ion product. We conclude that bisphosphonates inhibit the calcification of arteries and heart valves at doses comparable to the doses that inhibit bone resorption. These results support the hypothesis that artery calcification is linked to bone resorption. The mechanism of this linkage remains to be established, however, and an alternative explanation for the present results is also considered.

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Bisphosphonates Alendronate and Ibandronate Inhibit Artery Calcification at Doses Comparable to Those That Inhibit Bone Resorption

http://labs.biology.ucsd.edu/pprice/Calcification%20Papers/fetuin%201.pdf

Discovery of a High Molecular Weight Complex of Calcium, Phosphate, Fetuin, and Matrix γ-Carboxyglutamic Acid Protein in the Serum of Etidronate-treated Rats

Common herbs, essential oils, and monoterpenes potently modulate bone metabolism

Prevention of low bone mass is important to reduce the incidence of osteoporotic fractures. In man, the consumption of fruits and vegetables is associated with greater bone mineral density (BMD), an effect that is claimed to be caused by their base excess buffering metabolic acid, thought to dissolve bone. We showed previously that in the rat the consumption of several vegetables, salads, and herbs inhibits bone resorption and that onion increases bone mass. In this study we show that, although the intake of onion is associated with a decrease in urinary noncarbonic acid excretion and a concomitant inhibition of bone resorption of similar magnitude, the two findings are not causally related. Onion retains its bone resorption inhibitory activity in the rat even when added to a vegetarian diet with typical base excess. Onion and a mixture of vegetables, salads, and herbs retain their inhibitory activity even when metabolic acid is buffered with potassium citrate. In addition, neither the pH nor the potassium content of individual ashed vegetables, salads, and herbs correlates with inhibition of bone resorption. The effect of vegetables, salads, and herbs, which inhibit bone resorption in the rat, therefore is not mediated by their base excess but possibly by a pharmacologically active compound(s).

Onion and a mixture of vegetables, salads, and herbs affect bone resorption in the rat by a mechanism independent of their base excess

Interference with the microenvironmental growth support is an attractive therapeutic strategy for repressing metastatic tumor growth. Bone is a highly dynamic tissue that is continuously remodeled by bone resorption and subsequent bone formation. Growth factors supporting bone metastatic growth are released especially during bone resorption. Differently from most other tissues, drugs that can limit local turnover, such as bisphosphonates, are available for bone. In the present study, we tested the hypothesis that inhibition of bone turnover can affect development and growth progression of experimental bone metastasis. Whole-body bioluminescent reporter imaging was used for the detection, monitoring, and quantification in vivo of the growth progression of bone metastases induced by intracardiac or intraosseous injection of luciferase-transfected breast cancer cells (MDA-231-B/luc+) to nude mice. Suppression of bone turnover by bisphosphonates, before bone colonization by cancer cells, inhibited by a great extent the number of developing bone metastasis. Tumor growth in the few, but still developing, bone metastases was affected only transiently. Reduction of bone turnover had no effect on growth progression of bone metastases, which were already established when bisphosphonate treatment was initiated, despite a substantial reduction in osteolysis. Therefore, cancer cells metastatic to bone, after an initial growth phase that depends on the interaction with the local stroma, become independent of microenvironmental growth factor support and progress autonomously. Inhibition of bone turnover may represent a useful adjuvant therapy especially for cancer patients at risk to develop bone metastasis.

https://cancerres.aacrjournals.org/content/canres/65/17/7682.full.pdf

Interference with the Microenvironmental Support Impairs the De novo Formation of Bone Metastases In vivo

This study investigates whether bisphosphonate-treated rats are still able to adapt to low calcium supply through an increase in bone resorption assessed by measuring the urinary excretion of [3H]-tetracycline from chronically prelabeled rats. First it was shown that in this model, parathyroid hormone was responsible for the increase in bone resorption on the low calcium diet. In the second part, animals were treated with the three bisphosphonates—clodronate, alendronate, and ibandronate—given in two doses. Animals receiving a dose that already strongly inhibits bone resorption were still able to respond to a low calcium diet by increasing bone resorption, showing the potency of the latter as a stimulator of bone resorption. Higher doses were, however, able to blunt this response. As soon as the treatment was discontinued, this increase in bone resorption resumed with clodronate but not with alendronate or ibandronate.

V. N. Antic

Papers

Effect of bisphosphonates on the increase in bone resorption induced by a low calcium diet