Bisphosphonates
Bisphosphonates are compounds characterized chemically by two C-P bonds giving them an affinity for bone through rapid and strong binding to hydroxyapatite crystals with preferential localization in areas of increased bone resorption and regeneration. In bone chelated with bisphosphonates there is a reduction in the number and activity of osteoclasts which appears to be the result of a direct effect on osteoclasts as well as an indirect effect through inter-relating osteoblasts and possibly macrophages. The intimate mechanism of action is complex and still uncertain in many respects but the net effect, at specific concentrations, is a reduction in excessive bone turnover with preservation of bone structure and materialization in otherwise osteopenic states. The decrease in bone resorption is also accompanied by increased intestinal absorption of calcium in the presence of raised 1,25-(OH)2 vitamin D which contributes further to the increased calcium balance, and this, in addition to the need to counter the effects of secondary hyperparathyroidism, is the reason associating calcium and vitamin D supplementation to these patients when receiving bisphosphonates. In addition to their effect on bone metabolism, there is evidence that bisphosphonates can inhibit the potential of tumor cells to metastase to, and develop in, bone through reduced adhesion, reduced metalloproteinase-mediated bone-matrix degradation and other mechanisms entering into the metastatic cascade.
Side-effects of bisphosphonates differ according to whether administration is oral or intravenous. Bisphosphonates are poorly bioavailable reaching only a few percent even with oral bisphosphonates such as clodronate, the result of their low lipophilicity and chelation by calcium. Gastrointestinal side-effects are frequent with nausea, dyspepsia, vomiting, gastric pain, diarrhea and even ulceration. These can be alleviated by taking water and remaining upright to minimize esophageal reflux. The major risk with intravenous bisphosphonate administration is that of renal failure consequent to the formation of deposits after an over-rapid injection. Renal side-effects can be avoided by slow intravenous infusion with adequate fluid volumes. A transient low-grade fever accompanied sometimes by flu-like symptoms can initially accompany the parenteral administration of nitrogen-containing bisphosphonates. Given in excessive amounts bisphosphonates will inhibit normal calcification. The therapeutic window and modalities of administration are an important feature defining the use of the different bisphosphonates.
