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Bisphosphonates - Dr. Plotkin

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Questions and Answers from Dr. Plotkin about Bisphosphonates

1. Can pamidronate or any other bisphosphonate be given by injection?

Pamidronate is given by slow intravenous infusion (during the course of approximately three hours). In South America and Europe it is also available for oral administration. Risedronate is given by mouth, as well as Alendronate. Ibandronate can be given by mouth or intravenously, and Zoledronate is given by a rapid intravenous injection. Protocols for infusion vary among different centers.

2. Explain the "new" quick or 5 minute pamidronate treatment.

It is not actually Pamidronate. This new drug is called Zoledronate, and belongs to the same family (bisphosphonates). Zoledronate is 850 times more potent than pamidronate, and therefore can be given in only one short infusion (about 30 minutes), instead of dividing the dose in two or three days. This drug has been used to treat patients with cancer, and there are currently studies administering it to adult women with osteoporosis. We are part of an international multicenter study to test the efficacy of the drug in children with osteogenesis imperfecta. No results are available yet.

3. Explain the once a week dose for Fosamax. What is it and how does it work?

Alendronate (Fosamax) and Risedronate (Actonel) were once administered once a day. There is strong evidence that it has similar effect given once a week. This schedule has been tried in adult patients with good results, and it is the current tendecy to give them once a week to children too. It does increase the compliance. People taking alendronate or risedronate have to wait 30 minutes before having breakfast. This sometimes makes it difficult for children who have to go to school in the morning. The weekly pill can, for example, be taken during the weekend.

4. How long will an infant, child, teen or adult need to stay on bisphosphonates to achieve normal bone density? Is the new level of bone density permanent?

Each child is different. There is no way to predict how fast normal bone density values will be reached. Furthermore, bone density is just one aspect that is modified by the treatment. Relief of pain and reduction in fracture rate are probably more important. There is not enough experience with patients off treatment to be able to say for how long the treatment has to be given before reaching an "steady state" in bone density.

5. Do bisphosphonates cause/contribute to dental problems?

There is no evidence that bisphosphonates cause dental problems. They certainly do not improve dentinogenesis imperfecta when the treatment is started after three years of age. We are in the process of evaluating whether there is any improvement when the treatment is started before that age.

6. List all side effects for these drugs. Do people who have OI experience different side effects than people in the general population?

The side effects that we have seen after treating more than 300 children with bisphosphonates are: A flu-like syndrome with fever and discomfort the first time they receive the treatment. We give now Tylenol to our patients to prevent this reaction. Some babies have a reaction with decrease of blood cells, recovering normal values in 48-72 hours. A few patients have had a skin reaction with rendness that resolves very fast without treatment, and redness of the eyes that also resolves without treatment. Patients taking alendronate can have gastric discomfort or even severe burning of the esophagus (the tube that connects the mouth with the stomach) if the drug is not taking properly. Other problems that have been seen in adults and described in the literature include muscle pain, and headaches. Patients receiving radiation of the jaw for cancer may have problems in the ares (called "osteonecrosis") An article was published showing the effects of an overdose of pamidronate in a child (click
for my comments on that article)

7. How does a bisphosphonate actually work?

There are two main cell groups in the bone. The osteoblasts, that make bone; and the osteoclasts, that "eat" bone. Both types of cells are very active, even in adults, and work together to keep the bone intact and responding to stress. For example, when astronauts go to space, where there is no gravity, the bones do not "feel" the mechanical stress of weight bearing, and get weaker very fast. The same happens when a person is immobilized after a fracture. The current knowledge on bisphosphonates suggests that they shorten the life of the osteoclasts, and prolong the life of the osteoblast, tilting the balance towards the production of bone. But they may also interfere with the osteoclast function. They are certainly not a cure for OI, as the basic genetic defect is still present.

8. Will bisphosphonate therapy improve any of the other problems (such as loose joints etc.) experienced by an OI person due to the collagen defect?

In our experience, bisphosphonates do not improve loose joints in patients with OI. It does make sense, as the drug acts on bone and not in ligaments.

9. What is the role of PT or exercise for a person who is taking a bisphosphonate? Are calcium and/or vitamin D supplements necessary when taking a bisphosphonate?

Bisphosphonate treatment is one leg of a tripod. The other two legs are calcium intake and exercise. It is clear that when a patient has a fracture and is immobilized for a certain period, the bone density drops dramatically. The bisphosphonates will protect the patient from bone loss, but there will be little or no gain. On the other hand, physiotherapy should be administered by professionals with experience with people with OI. An adequate Calcium intake is warranted, as well as vitamin D, particularly if there is not much sunlight where you live. Vitamin D requirements are 400 IU per day, and calcium requirements vary with age.

10. Will everyone benefit from treatment, regardless of age, sex or type?

Our experience shows that all children with OI benefit from the treatment. Some have dramatic improvement (particularly when they start before age 3), some progress somewhat slowly, but all show signs of improvement in bone density and pain relief.

11. Has an optimum age for treatment been determined?

Our experience shows that the sooner, the better. We have patients that started the treatment before one month of age, and responding very well.