Calcium compounds Bisphosphonates

The bisphosphonates are the most effective compounds available to treat hypercalcemia of malignancy. Pamidronate (Aredia) and zoledronic acid (Zometa) can be infused intravenously and are the most effective compounds available for rapid reduction of serum calcium levels. 

Once bone loss is sufficient to result in a compression fracture, pharmacological therapy is much less effective. However, even after fractures have occurred, the use of the bisphosphonates and rPTH has been shown to increase bone densities and reduce the rate of subsequent fractures. Nasal calcitonin (200 units daily) is effective in promoting fracture healing and also exhibits an analgesic effect by reducing pain in persons with acute lumbar compression fractures. Whatever compound is used for prophylaxis or treatment of osteoporosis, calcium and Ds supplementation are required for maximum benefit. 

Clinical trials have demonstrated that the use of the bisphosphonates, nasal calcitonin, or human rPTH combined with calcium and vitamin D supplementation is effective in preventing drug-induced osteoporosis. Thus, individuals receiving over the long term any medication that can induce osteomalacia should also take one of these compounds and have periodic bone density determinations. 

Actions. These compounds are effective calcium chelators that rapidly target exposed bone mineral surfaces in vivo, where they can be released by bone-resorbing osteoclasts, resulting in inhibition of osteoclast function and osteoclast apoptosis. The bisphosphonates (alendronate, clodronate, etidronate, pamidronate, risedronate, tiludronate and zoledronate) inhibit the activation and function of osteoclasts and possibly directly stimulate formation of bone by the osteoblasts. They also bind strongly to hydroxyapatite crystals and, in high doses, can inhibit the mineralisation of bone. The doses at which effects on mineralisation occur are not related to antiresorptive efficacy. There is wide variation between these compoimds in terms of their capacity to inhibit... 

Bisacylphosphonates (50) and bishydroxyiminophosphonates (51) were found to be the first examples of non-geminal bisphosphonates biologically active in calcium metabolism disorders such as pathological calcification and bone resorption These compounds showed less toxic side-effects and improved bioavailability than bisphosphonates approved for clinical use. ... 

For the same purpose of targeting bone tumors with boron-containing phosphonates, carbabora-nylbis- and -polyphosphonic acids were described by Benedict in a patent application. Two examples of the prepared compounds (37, 38) are shown in Figure 2.4. The gcm-bisphosphonate 37 was subjected to a crystal growth inhibition test to determine its potential to reduce calcium phosphate deposition. This showed that the capability of 37 to retard the formation of calcium phosphate is on the same order as the known inhibitor dichloromethylene diphosphonate. Furthermore, it was found to exhibit high skeletal affinity in an animal skeletal uptake test. 

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