Cells Affected by Fosamax and Other Bisphosphonate

Some visitors to this site have asked which cells are affected by Fosamax and other bisphosphonates. Since all bisphosphonates act on the same fundamental cells, we can look at them as a whole and apply what we know about bisphosphonates in general to Fosamax in particular and vice-versa.

Osteoblasts Versus Osteoclasts

We have two basic types of cells that regulate bone growth and loss. Osteoblasts, of which there are three kinds, are responsible for bone-growth. Since they are not acted upon by bisphosphonates, we won't go into the different types of osteoblast and how they behave. Osteoclasts, on the other hand, are responsible for bone resorption. That is, they cause bone to break down and cause bone loss. In a healthy young person, these two types of cells stay in balance and bone formation happens as fast or faster than bone resorption. This bone turnover is necessary for healthy bones.

Where things go wrong is when the balance gets tipped for one reason or another in favor of the osteoclasts and bone loss occurs faster than bone formation. This is the process that leads to osteopenia and osteoporosis and that's where bisphosphonates come into play.

Role of Bisphosphonates

Bisphosphonates are derivatives of inorganic pyrophosphate (PPi), a naturally occurring compound in the body. Early studies showed that PPi inhibits calcification and also have the effect of suppressing bone resorption by preventing hydroxyapatite crystal breakdown. In short, they both inhibit mineralization of the bones (which makes them stronger) and they also inhibit bone breakdown. This is the main function of bisphosphonates and primarily responsible for their effect in the bones. By modifying the chemical structure of bisphosphonates, it has been possible change the relative strength of these contrary effects and to emphasize the effects that inhibit bone breakdown. These modifications can increase the ability of bisphosphonates to inhibit bone loss from ten fold (for alendronate, that is Fosamax) to 10,000 fold (for Zoledronic acid).

Bisphosphonates inhibit osteoclast activity. This is decidedly beneficial for people at risk of osteoporosis or other conditions caused by bone loss. There is some worry, though, that this slows bone turnover too much and could lead to bone fragility.

If this all sounds a bit vague, in fact it is. According to Weinstein et al. the effect of bisphosphonates on their target cells remains enigmatic, since in patients benefiting from therapy, little change, if any, has been observed in the number of osteoclasts, which are the cells responsible for bone resorption.

Dr Weinstein and his team set out to find out just what was happening to the osteoclasts. It may seem counter-intuitive, but in fact patients on relatively high doses of Fosamax (10mg per day) actually have 2.6 times as many osteoclasts as those on lower doses or on a placebo. High levels of calcium apparently send a signal to osteoclasts that cause them to die off. Since Fosamax suppresses calcium loss, the osteoclasts receive a weaker signal and live longer, which results in there being more of them. Nevertheless, even normal-appearing osteoclasts have trouble doing their normal job when the patient is being treated with alendronate (Fosamax) and bone loss is slowed, despite the large number of osteoclasts.

Conclusion

So in brief, bisphosphonates bind to certain minerals common in the bones, and also have effects on both the bone-producing osteoblasts and the bone-wasting osteoclasts. Modern bisphosphonates like Fosamax and more recent drugs have a much stronger effect on osteoclasts, inhibiting their action and slowing bone loss. Interestingly, the very act of inhibiting the effectiveness of these cells allows them to live much longer and thus increase in numbers, but that does not seem to have any negative effects based on the knowledge currently available as of January, 2009. These are, however, results of a single study and further investigation may modify those conclusions.

References

• Robert S. Weinstein, M.D., Paula K. Roberson, Ph.D.,
  and Stavros C. Manolagas, M.D., Ph.D, "Giant Osteoclast Formation and Long-Term
  Oral Bisphosphonate Therapy," The New England Journal of Medicine, January 1, 2009, v. 360:1, pp. 53–62.
• Matthew T. Drake, Bart L. Clarke and Sundeep Khosla, "Bisphosphonates: Mechanism of Action and Role in Clinical Practice" (review article), Mayo Clinic Proceedings, September, 2008; 80(9):1032–1045.