Marketing and Medicine

On September 9, 2011 a federal advisory panel from the Food and Drug Administration (FDA) released a statement advising that, after an investigation of claims that drugs for osteoporosis, such as Fosamax, Actonel, Boniva, and Reclast (Bisphosphonates) may increase a person’s risk of jaw decay and fractures of the femur, there is still insufficient evidence for them to make recommendations about whether their use should be restricted. This is of course, not even taking into account the reports of increased irregular heart beat, muscle pain, kidney impairment, and severe esophageal problems with use of these drugs.

Why all the side effects? An analysis of bone physiology and the mechanism of action of bisphosphonates will be enlightening. Bones are part of an elegant system designed to accomplish two goals. First, the bones themselves provide a strong and pliable framework for support of muscles and protection of organs, not to mention housing for the synthesis of blood cells. Bones are kind of like flexible steel-reinforced concrete: they are made of collagen (stringy protein=steel) and hydroxyapatite (concrete), a mineral made of calcium and phosphate.

But bones are also a “bank.” That is, calcium is not just part of bones and is not just stored in them. Calcium, a chemical that is important for mediating reactions within cells, vital for normal muscle function, and essential for regulation of heart rhythm, is also deposited and withdrawn from bones. Blood levels of calcium are carefully fine-tuned by a delicate interplay of hormones and cells known as osteoclasts (which break down bone to release calcium into the blood when more is needed) and osteoblasts (which sequester calcium into the bone when there is too much in the blood). This regulatory system enables the body to remodel bones depending on the stress put on them, keeping them at optimum shape and rigidity, but is also extremely important for proper heart and muscle function.

According to Merck, Fosamax works by inhibiting “osteoclast-mediated bone reabsorption.” That is, it prevents calcium from being withdrawn from the bone bank. The result is that calcium builds up in the bones, increasing their density by packing in more and more hydroxyapatite (cement) between the collagen fibers. Osteoporosis does decrease, but the bones inevitably become brittle. And, as the channels that provide vital nutrients to the osteocytes become blocked with mineral deposits, the cells die; the bones may even become necrotic. Thus, fractures in a weight-bearing bone such as the femur and osteonecrosis of the jaw bone should not come as a surprise.

But remember, calcium is vital for function of muscle, the heart, and more. It has been shown that taking bisphosphonates may result in hypocalcemia, that is reduced levels of blood calcium, which is bound to mean the these drugs will have serious side effects–and they do. Calcium is vital for normal skeletal muscle function; low levels cause twitching and cramps, both of which have been reported as side effects of bisphosphonates.

In the heart, calcium is important for regulating the heart beat, which is why calcium channel blockers are prescribed for arrhythmia and high blood pressure. Therefore, it should come as no surprise that bisphosphonates have been implicated in doubling the risk of atrial fibrillation.

The effect of hypocalcemia on the kidneys is more complex. Low blood calcium levels stimulate the hypothyroid to release parathyroid hormone, which in turn stimulates the kidneys to retain calcium and the bones to release it. But perhaps when this is not possible due to the actions of a drug such as Reclast, a bisphosphonate, then the kidneys become over-stressed and may even fail. Novartis recently released a warning about the relationship between Reclast and kidney failure.

Finally, there appears to be a significant relationship between use of bisphosphonates and severe esophageal disease. Again, we come to the natural function of calcium in the body–prevention of hyperacidity and its effects: gastric reflux, esophageal damage, and even cancer. Calcium levels must be carefully regulated; interference with that regulation by preventing calcium reabsorption is like fighting crime by imprisoning everyone between the ages of 15 and 25. Effective, but perhaps a little excessive?

This issue of bisphosphonate side effects has been under investigation for some years. It is a fact that these drugs do reduce the incidence of wrist, hip and vertebral fractures in postmenopausal women with osteoporosis or Parkinson’s disease (Dynamed). However, direct evidence for their benefit is lacking in men with osteoporosis and anyone who does not have osteoporosis. In June 2008 the FDA “requested information from all bisphosphonate drug manufacturers regarding this potential safety signal [fibrillation]. All available case reports and clinical trial data were requested. FDA’s review of these data did not show an increase in this risk in women using these medications.” Interestingly, their report on the unusual thigh fractures, which admittedly have only been reported in 300 women, reads the same.

But notice, who did the FDA ask for information about the drugs? The manufacturers. Who made $3.2 billion in 2005 alone. So, is taking them to be recommended? It seems that the FDA still thinks it is. Whether you agree is up to you. Think about it, discuss it with your physician, and decide for yourself. As for me, I’m going to eat my 5-10 servings of fruit and vegetables a day and get some exercise.