Long‐Term Effect of Strontium Ranelate Treatment on BMD

It is remarkable to consider that the successful treatment of osteoporosis is a recent phenomenon. Despite the earlier availability of etidronate, bisphosphonates only became firmly established as the treatment of choice after the publication in 1996 of the Fracture Intervention (FIT) alendronate trial. Now the treatment options available are mainly with antiresorptive agents that prevent bone breakdown. Most studies with these agents show good antifracture efficacy with regard to the spine, whereas the more potent nitrogen-containing bisphosphonates also show a reduction in nonvertebral fractures. For patients with previous fractures, treatment with an anabolic agent that enhances bone formation may be desirable, and this is now possible since the introduction of 1-34 recombinant PTH. However, the use of PTH is limited by its high cost and the fact that it is given by subcutaneous self-injection. Recently, a new agent, strontium ranelate, has been licensed in Europe for the treatment of osteoporosis. Whereas the mechanism of action of strontium ranelate is not yet fully understood, compared with other treatments, it seems to have the unique effect of both inhibiting bone resorption and stimulating bone formation. Two recent trials, the Spinal Osteoporosis Therapeutic Intervention (SOTI) and Treatment of Peripheral Osteoporosis (TROPOS) studies, have shown its efficacy at preventing vertebral and nonvertebral fractures, respectively. In a subset of high-risk women, strontium ranelate was also shown to prevent hip fractures. In this editorial, we discuss the unusual effect of strontium treatment on BMD, and in particular, the likely persistence of this effect once treatment has stopped. Strontium ranelate is composed of two atoms of stable strontium combined with organic ranelic acid. Ranelic acid is a carrier that makes the treatment more palatable, whereas strontium is the active component with regard to the skeleton. As an alkaline earth element, strontium is similar to calcium in its absorption in the gut, incorporation in bone, and elimination from the body through the kidneys. Strontium is naturally present in trace amounts, with around 100 g in every gram of bone, so treatment with strontium ranelate is simply making more strontium available for incorporation into bone. In the short term, the strontium atoms are adsorbed onto the surface of hydroxyapatite crystals, whereas in the longer term, some strontium will exchange with calcium in the bone mineral and remain bound in the skeleton. A great deal of information about the long-term retention of strontium in the skeleton is available from early radionuclide tracer studies. In particular, a task group set up by the International Commission on Radiological Protection (ICRP) published a report on alkaline earth metabolism in adult humans that included a detailed model of the whole body kinetics of strontium. The ICRP model predicts that at 3 months, 1 year, and 3 years after a single oral dose of strontium, the skeleton retains 20%, 15%, and 11%, respectively, of the strontium absorbed by the gut. Three-year treatment with strontium ranelate at 2 g/day corresponds to a total strontium intake of 750 g. Assuming 25% absorption by the gut and using the ICRP model to calculate the average long-term retention, we find that after a 3-year treatment, there is ∼30 g of strontium in the skeleton. Expressed as a molar fraction of the total calcium content in bone, this is about 1% (i.e., after 3 years of treatment with strontium ranelate, there is ∼1 strontium atom for every 100 calcium atoms in bone tissue). There is always interest in the size of the BMD changes for any therapeutic agent used to treat osteoporosis. Figure 1A shows results for raloxifene, risedronate, alendronate, and PTH. In the SOTI trial, there were impressive BMD increases in the spine (12.7%) and total hip (8.6%) (Fig. 1B), with the spine curve similar to that for PTH (Fig. 1A). However, some caution is necessary in interpreting these results because much of this effect is caused by the higher atomic number of strontium (Z 38) compared with calcium (Z 20). When BMD is measured by DXA, strontium atoms in bone attenuate X-rays more strongly than calcium atoms. However, when the DXA scanner software calculates BMD from the measured X-ray transmission factors, the increased attenuation caused by bone strontium content (BSC) is interpreted as increased calcium content and will cause an artifactual increase in BMD. This effect was studied by Pors Nielsen et al., who constructed a set of phantoms containing mixtures of calcium and strontium hydroxyapatite with varying molar fractions of strontium that were scanned on several different models of a DXA bone densitometer. They concluded that the same adjustment factor (a 1% molar fraction of strontium causing a 10% overestimation of BMD) applied to all makes of densitometer studied. Taken with the estimate of a 1% molar fraction of strontium in bone after the 3-year treatment given above, this figure is clearly compatible with the SOTI trial BMD data. The correction of the BMD changes found in the stronGuy’s, King’s and St Thomas’ School of Medicine, London, United Kingdom. The authors have no conflict of interest. JOURNAL OF BONE AND MINERAL RESEARCH Volume 20, Number 11, 2005 Published online on August 8, 2005; doi: 10.1359/JBMR.050810 © 2005 American Society for Bone and Mineral Research