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Reply to osteogenesis imperfecta calls for caution

Nature Medicine volume 5, pages 466–467 (1999)Cite this article

Horwitz replies—We fully agree that interpretation of clinical benefit in any pilot study must be made cautiously. In our study1, we reported engraftment of marrow-derived mesenchymal cells in the bones of children with severe OI undergoing an allogeneic bone marrow transplant, and correlated this engraftment with evidence of improvement in the specified clinical parameters. Bishop correctly indicates the technical difficulty of performing bone biopsies in infants with OI. However, the specimens we obtained showed obvious differences in osteocyte arrangement with the formation of lamellar bone after transplant. Tetracycline labeling was smeared throughout the specimen before transplant, which we attribute to abnormal bone formation, and became much more crisp after the transplant. We agree that in an uncontrolled pilot study of this type, measurement of any single clinical parameter before and after transplant may produce misleading results. However, we found improvements in every parameter measured. In particular, fracture rates declined sharply compared with both the preceding 6 months and the first 6 months of life.

Marini is concerned that there was no measurable increase in lumbar bone density. However, bone mineralization is not uniform throughout the skeleton. Furthermore, bone density measurements may not be the most appropriate means to express bone mineralization in pediatrics7. For this reason, we chose to measure changes in total bone mineral content with dual energy X-ray absorptiometry. This is a more sensitive assay of overall bone mineralization than measurements of the spine, which is only a small portion of the skeleton. Marini also confirms the presence of mesenchymal engraftment, but questions how so low a level of engraftment can produce the profound changes seen. We agree that this is puzzling, and in our article and the accompanying News & Views article8, several possible mechanisms were proposed. Marini discounts many of these based on the fact that they are not consistent with predictions made after studying mosaic carriers of OI. It is an equally valid argument, however, that mosaic carriers of OI simply fail to accurately model the effects of normal osteoblasts in children with severe disease.

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References

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Authors and Affiliations

  1. Cell & Gene Therapy Program St. Jude Children's Research Hospital, 332 N. Lauderdale, Room D-4026, Memphis, 38101, Tennessee, USA

    Edwin M. Horwitz, Jeffrey C. Marx & Malcolm K. Brenner

  2. Allegheny University of the Health Sciences, 15th and Vine Streets, Philadelphia, 19102, Pennsylvania , USA

    Darwin J. Prockop

  3. Mayo Clinic, 200 First Street SW, Rochester, 55905, Minnesota, USA

    Lorraine A. Fitzpatrick

  4. Wayne State University, 4707 St. Antoine Boulevard, Detroit, 48201, Michigan, USA

    Winston W.K. Koo

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Horwitz, E., Prockop, D., Fitzpatrick, L. et al. Reply to osteogenesis imperfecta calls for caution. Nat Med 5, 466–467 (1999). https://doi.org/10.1038/8327

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