MORE ON THE NORA TRIAL

The experts we spoke to while preparing the documentary had differing opinions on the NORA trial.

Effectiveness of Testing Equipment
Some argued that the testing equipment used in the trial led to misleading results

A lot of the bone testing for the NORA trial was done on the finger, wrist and ankle using ultra sound equipment designed for 'peripheral testing'. This equipment is most effective when there is little fat or muscle between the machine and the bone which is being tested which is why  ultra sound equipment is usually used on the finger wrist or ankle.

The critics of the study rightly claim that peripheral testing of this sort underestimates bone loss.
In other words, they argue, if the more sophisticated bone densitometry machines had been used more of the women surveyed would have been diagnosed with osteoporosis (a T score of less than minus 2.5).  As a result, the critics claim that the group defined as having osteoporosis by these peripheral tests was too small – it was underestimated – in reality the group should have been bigger and then the results would have shown that a greater number of the fractures would have occurred in this group.

Those who support the study argue that the fact that the peripheral (ultra sound) machines underestimate bone loss cuts both ways
They argue that if the peripheral machines underestimate bone loss then those who did have T scores of less than -2.5 on the ultra sound equipment were in fact worse off than those machines indicated. It would then follow that their incidence of fracture should have been higher given the even greater severity of their bone loss.

Nature of Fractures Reported
A second argument used against the study is that when the women were asked to complete the questionnaires they were asked to record any fracture that had occurred – no attempt was made to distinguish between osteoporotic fractures – the ones attributable to a weakness of the bone – and fractures that came about because of the force or impact involved.

Those who support the study claim that this argument is highly ironic. They point to the fact that most of the fracture statistics used to promote the incidence of osteoporosis use exactly this sort of methodology to establish fracture rates ie all fractures that occur in post menopausal women are counted. So on one hand the all in figures are considered admissable when counting fractures, but thought to be inappropriate when used in the NORA Trial.

That said, we have to accept that many of the fractures counted in the study were probably not osteoporotic fractures in the sense that weak bone was responsible for the fracture. Many could have been impact fractures. That doesn't seem to us to detract from a study that clearly indicated that low bone density by itself was a poor indicator of future fracture.

Exclusion of Younger Women
A third argument is also advanced, but to our knowledge the analysis has not yet been done to prove or disprove this assertion. This argument asserts that if you remove from the study all the women under 60 or under 65, the predictive validity of the bone density test used would improve ie we would see that more women with low bone density had fractured.

We don't doubt this assertion, however as the documentary indicates, bone density is only one of the risk factors involved in fractures and numerous other risk factors need to be considered if an accurate picture of the likelihood of future fracture is to be obtained – and one of those risk factors is age, so this argument has some merit. But while the percentage of those who fractured might be increased by excluding younger women we doubt that it would confirm the sort of link between bone density loss and fracture rates that has has been promoted around the world for a number of years.

The documentary was particularly interested in this study precisely because it included the younger group of women – the 50 to 65 year olds. These are the women who seem to be being targeted by companies involved in selling bisphosphonates. These are women who might have low bone density and to whom it is often suggested that a bisphosphonate might prevent a future fracture because these drugs increase bone density. It is apparent from this study that the link between low bone density and fracture, particularly in this group of younger women, is difficult if not impossible to sustain.

More to the point, the documentary clearly indicates through the NNT (Numbers Needed to Treat) figures and the opinions of the experts interviewed, that treating younger well women with bisphosphonates is an expensive, wasteful and largely useless endeavour with possibly debilitating side effects. The NORA study supports that observation.

General
There is one other relevant observation related to the use of ultra sound equipment.
This equipment is small and easily transportable compared to the larger bone densitometry machines. As a result they are often used in Bone Testing buses and trucks that offer free bone testing in many large cities. These free tests are used to funnel women into the medical system. A lowish score on these ultrasound machines is likely to result in a recommendation that the individual goes on for further testing. So when these machines are used as a stepping stone onto a path that may lead to prescription medicine, the machines are thought to be acceptable and useful  – but those same machines are critcised as providing misleading information when used in the NORA Trial.

ZOLEDRONIC ACID AND ATRIAL FIBRILLATION

In the documentary we talk about the injectable bisphosphonate Zoledronic Acid (Reclast). This form of the drug has found favour in some medical circles. With the oral form of the bisphosphonate drug patients forgot to take it or didn't like the way it had to be taken. To avoid the drug damaging the oesophagus the patient was instructed not to lie down for about half an hour after taking the medication. These problems were circumvented with this annual injectable form of the drug.

The documentary refers to a study that indicated that there was a connection between atrial fibrillation (rapid and irregular heart beats) and Zoledronic Acid in a small percentage of women. Our purpose was to indicate that the risk of a serious side effect might be about the same as the chance that the drug might prevent a fracture. We based this conclusion on the high NNT (Numbers Needed to Treat) figures particularly for younger women.

The point we perhaps did not labour hard enough in the documentary is that if drugs are to be prescribed as a preventative measure then we believe it is incumbent on the manufacturers to test them thoroughly and ensure they are safe before they are used.

We really know very little about the long term effectiveness of these drugs - or what long term adverse effects they may have when administered to patients who have a relatively low risk of fracture. We believe that a drug being widely prescribed as a preventative measure should be proven to be safe in long term trials before being released on the public - otherwise there may be unanticipated adverse effects - or a collection of them.

In the case of the relationship between atrial fibrillation and Zoledronic Acid the jury may still be out. There have been two recent studies one supporting the connection (Arch Intern Med 2008;168(8)826-831) and the other claiming there is no connection at all (British Medical Journal 2008 April 12;336(7648); 813-816

Either way we believe our case still stands - with bisphosphonates the numerous risks related to the drug may outweigh the benefits for many women.