INSERM U349 Hopital Lariboisiere Paris France Email: martine.cohen-solal{at}inserm.lrb.ap-hop-paris.fr
Sir,
We read with interest the reply by De Broe and D'Haese concerning our article on accumulation of fluoride and strontium in dialysis patients. We fully agree with the first conclusion that we provided evidence that strontium may accumulate in patients dialyzed in developed countries.
However, De Broe and his colleague have a different interpretation of our results. We agree that the role of each element in the development of osteomalacia cannot be provided by such a study. Bone strontium content is significantly higher in patients with osteomalacia, but fluoride content is significantly higher as well. The originality of the present study is to provide evidence that these two metals may have accumulated together, suggesting that both and perhaps some unmeasured other metals may contribute to the development of osteomalacia. Indeed, high levels of strontium or fluoride do not establish a causeeffect relationship with osteomalacia. We agree with De Broe and D'Haese that associations between bone content and osteoid indices do not reflect a causal relationship in human biopsies, but they may provide some explanation about the pathophysiology involved. Indeed, such analysis has been performed by the group of D'Haese et al. in a previous report [1]. Therefore, we still think that the title of our article supports the conclusions we reached and stresses the lack of evidence for a direct responsibility of strontium or fluoride in this type of renal osteodystrophy.
We chose the criteria of Sherrard et al. [2] to classify the different patterns of renal osteodystrophy. It is well known that the skeletal expression of hyperparathyroidism may display a moderate increase of osteoid, because under physiological conditions osteoid mineralization is delayed compared with osteoid apposition [3]. This does not mean that there is a mineralization defect in the group of patients with hyperparathyroidism since bone formation rate is high. Therefore, this may not neutralize the association between strontium and osteoid accumulation. Moreover, we found no correlation between osteoid volume and fluoride content in patients with hyperparathyroidism (r=0.12, P=0.58), osteomalacia (r=0.49, P=0.17) or adynamic bone disease (r=0.14, P=0.50), nor was there a correlation between osteoid volume and strontium content in patients with hyperparathyroidism (r=0.13, P=0.57), osteomalacia (r=0.56, P=0.15) or adynamic bone disease (r=0.18, P=0.39). We believe that if strontium and fluoride were responsible for mineralization defect, correlation should have been statistically significant between osteoid volume and metal content.
We feel that De Broe and his colleague misunderstood our statement between metal deposition and bone turnover. Indeed, in no part of the article did we perform a correlation analysis between strontium content and bone formation rate. The adynamic bone disease and hyperparathyroidism groups were used as controls for low and high turnover, indicating that strontium deposition is not related to the level of bone turnover.
We are still convinced that the bone strontium concentration is crucial for the development of osteomalacia. De Broe and his colleague wrote that the bone strontium content mentioned in the discussion section of our article was not correct. We found that osteomalacic patients had a 1.5-fold increase compared with both healthy normal patients and with any type of renal osteodystrophy. De Broe and D'Haese found that bone strontium content was 0.91x10-3 µg/g in their patients with osteomalacia and 0.30x10-3 µg/g in their control subjects with normal bone histology, corresponding to a 3-fold increase in the patients [1]. However, the effect of low doses of strontium in chronic renal failure rats will be of interest and we look forward to reading the submitted paper.
Finally, some interesting points have been raised in this reply. Again, and as discussed in our paper, no firm conclusion can be drawn about the responsibility of a unique metal because a causeeffect relationship is missing. However, we understand that such results are not directly in line with De Broe's previous work, which was mainly focused on the toxicity of strontium, emphasizing again the need of further investigations on the role of this and other metals.
References