Bisphosphonate structure
The bisphosphonates are all related to pyrophosphate (PPi), which is a byproduct of cellular metabolism.
When nucleotides are formed, then:
ATP -> AMP + PPi
Pyrophosphate is a natural circulating inhibtor of mineralization in the blood and urine which can't get inside the bones because the lining cells destroy it with alkaline phosphatase. People with genetic problems of alkalline phosphatase have osteomalacia, because the pyrophoshate can get into the bone and it prevents mineralization.
If a carbon is substituted for the oxygen, then a bisphosphonate is formed. The bisphosphonates not only get inside the bone, but they attach very strongly to the bone mineral. The different strengths of the bisphosphonates depend on the variations in the side chains. Notice how similar some of these drugs are to each other.
Click  to see a more formal image of bisphosphonate structures.
Anti-resorptive potency
of different bisphosphonates
| | Drug |
Potency
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| etidronate | 1
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| clodronate | 10
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| tiludronate | 10
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| pamidronate | 100
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| alendronate | 1000
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| risedronate | 5000
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| ibandronate | 10000
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Physiological effects
| The bisphosphonates increase bone mass in both cortical and trabecular bone. In this slide from the FIT study, the dose was doubled at year 2.
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| The biochemical markers of both bone resorption (N-telopeptide) and bone formation (Bone specific alkaline phosphatase) show decreases with the bisphosphonates.
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| This study by Bauer shows that in women treated with alendronate the change in biochemical markers predicts the incidence of spine fractures as well or better than the change in bone density. Shown is the relative risk of a fracture for each standard deviation decrease in the markers or increase in the DEXA values.
 Move your mouse over the image to see the results for hip fractures, in which only the bone alkaline phosphatase change predicted fracture outcome.
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| The bisphosphonates cause dramatic reductions in the bone formation. This is seen on bone biopsies labelled with tetracycline. It is not clear if this is a direct effect of bisphosphonates or if it is just secondary to the inhibition of bone resorption. The graph shows the mineralizing surface as a percentage of the trabecular bone surface. With higher doses only 0.16% of the surface is still forming bone (Chavassieux). Below is seen a graph of published studies that report mineralization surfaces in normals and in patients treated with bisphosphonates. |
 | EFFECTS OF BLOCKING RESORPTION
Bisphosphonates block resorption, but formation continues for a forming period (6-12 months). During that interval the bone volume (and bone mass) will increase. This is a one-time increase, and afterwards the bone volume will plateau.
The slight increases seen after a year probably represent increased mineralization within each newly formed bone remodeling unit. The mineral is more densely packed and so the bone density will increase even though the bone volume does not. The major effect is to increase bone strength, and this is seen in clinical trials up to five years duration. After prolonged usage or with high doses the bone could potentially become more brittle.
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Overall, the major way that bisphosphonates improve bone strength is that they prevent trabecular perforations that lead to weakened micro-structure. While the bone volume may increase a small amount, most studies of human bone biopsies have not been able to demonstrate this. The following diagram shows a summary of the bisphosphonate actions, with question marks showing mechanisms that are still uncertain. More information about bone perforations is on the page about bone quality.
The best way to understand the effects of bisphosphonates on the bone is to watch the animations on this page , and compare the end result of normal bone turnover, estrogen deficiency, and bisphosphonate administration.
Cellular mechanisms of action
Etidronate may act by causing chemical changes to the mineral itself, inhibiting crystal formation and making the mineral resistant to resorption. These effects depend on the amount of drug given. This is why etidronate can be used to treat heterotopic calcifications, or prevent vascular calcifications in animal models. The trouble is that prolonged use results in osteomalacia. With the newer bisphosphonates, the dose is so small that the effects cannot be caused by physical-chemical changes in the mineral, and osteomalacia is a rare side effect.
Possible cellular actions of bisphosphonates
- Interfere with osteoclast cytoskeleton
- Inhibit mevalonate pathway enzymes
- Decrease protein-tyrosine phosphatases
- Stimulate apoptosis of osteoclasts
- Inhibit osteoclast attachment to bone
- Inhibit proton pump of osteoclasts
- Inhibit secretion of matrix metalloproteinases
- Act on osteoblasts to inhibit stimulator of osteoclast recruitment
- Act on osteoblast to stimulate inhibitor of osteoclast recruitment
- Act on osteoblasts to inhibit osteoclast activity
Osteoclasts are the cells which mediate the effects of the bisphosphonates. There is evidence for both direct and indirect effects, which may depend on whether the cells are exposed to external drug or whether they ingest it along with the bone. The bisphosphonates also act on the osteoblasts, to either increase inhibitors or decrease promoters of osteoclast action or recruitment. There is no general consensus about which mechanism is predominant in vivo, and the mechanisms may be different for each bisphosphonate.
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| These figures from van Beek show the mevalonate pathway of cholesterol synthesis. HMG CoA reductase inhibitors such as mevastatin, used to treat hypercholesterolemia, had been shown to reduce bone resorption. Ibandronate inhibited bone resorption (shown as the lower dotted line). When geranylgeraniol was added, the inhibition was reversed. This was seen in the nitrogen-containing bisphosphonates (risedronate, alendronate, olpadronate, & ibandronate). GeranylgeranylPP modifies (prenylates) a small GTP-binding protein called rho21, which regulates the cytoskeleton. Thus, inhibition of geranlygeranylPP leads to abnormalies in the cytoskeleton, so osteoclasts don't have a ruffled border and are unable to resorb bone.
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Updated 5/31/07
to see a more formal image of bisphosphonate structures.