Introduction

Although hormone replacement therapy has fallen out of favor because of its dangerous side effects, there are still plenty of ways women (and men) can try to avoid osteoporosis. First, the selective estrogen-receptor modulators (e.g. raloxifene or Evista®) have been shown to slow the reabsorption of bone that occurs with advancing age; they represent a modified estrogen in their effect on bone. The bisphosphonate drugs (e.g. alendronate or Fosamax®, risedronate or Actonel®) have the same sort of action on bone reabsorption. And just recently, parathyroid hormone has been introduced (Forteo®); this hormone actually stimulates bone formation, and is therefore a new approach to severe osteoporosis (see first link below).

At first glance, it would seem logical to combine a drug that slows reabsorption of bone with one that stimulates new bone growth. This would be hitting osteoporosis with a 'double whammy'. This idea was tested in two studies recently reported in the New England Journal of Medicine.

What was done?

In the first study, 238 postmenopausal women were given alendronate, or parathyroid hormone, or both together, for one year. In the second study, 83 men were given the same three types of treatment, except the parathyroid hormone was started after 6 months, so the combination group had already had alendronate for 6 months when the parathyroid hormone was begun. This study lasted 30 months.

Both studies measured the bone mineral density (BMD) in the spine and in the 'neck' of the femur at the end of the trial period.

What was found?

All the treatments resulted in an increase in BMD to a certain degree, varying with the site and type of bone examined - cortex (the outer solid layer) or trabecular (the net-like inside) bone. The findings can be summarized:

	1st Study		2nd Study
	BMD in spine	BMD in femur	BMD in spine	BMD in femur
Alendronate	+	+	++	++
Parathyroid	+++	+/-	+++	++
Combination	++	+	++	++

Different sorts of bone density were measured - the above results for the spine apply to the trabecular bone studied, while the femur results were for cortical bone. It must be remembered that the results in the 1st study were obtained after 12 months of treatment, while those in the 2nd study were after 30 months of treatment (12 months of those with parathyroid hormone).

In addition to the effect on BMD, parathyroid hormone was found to increase the volume of the cortical bone in the femur, while alendronate lessened this effect.

What does this mean?

Taken together, these studies show that, in both men and women, combination of alendronate with parathyroid hormone reduces the benefits of parathyroid hormone given alone. This is clearly one drug combination that shouldn't be used.

Parathyroid hormone (Forteo®) is expensive, and has to be given by daily injection. It's therefore usually reserved for patients with severe osteoporosis - those with a T score¹ of less than -2.5, or with one or two fractures due to their condition.

For those patients with severe osteoporosis already on bisphosphonates, a switch to parathyroid hormone should be considered; however, this approach hasn't been studied in clinical trials. And it might be reasonable to add back alendronate, or another bisphosphonate, once the volume-increasing effect of parathyroid hormone has been achieved (probably after a year).

Finally, these two studies show that one shouldn't just accept that if one drug is good, adding another will be better. Combinations of drugs need to be clinically tested before they can be widely recommended.