Letters

Recombinant human parathyroid hormone

BMJ 2002; 324 doi: https://doi.org/10.1136/bmj.324.7347.1218 (Published 18 May 2002) Cite this as: BMJ 2002;324:1218

Preclinical data on rat osteosarcoma were not dismissed

  1. Gemma Kuijpers, clinical pharmacology reviewer,
  2. Bruce Schneider, medical officer,
  3. Bruce Stadel, medical officer,
  4. Eric Colman (colmane{at}cder.fda.gov), medical officer
  1. US Food and Drug Administration, Center for Drug Evaluation and Research, Division of Metabolic and Endocrine Drug Products, 5600 Fishers Lane, Rockville, MD 20857, USA
  2. University Department of Medicine, Box 157, Addenbrooke's Hospital, Cambridge CB2 2QQ

    EDITOR—As members of the United States Food and Drug Administration's division of metabolic and endocrine drug products responsible for the review of Eli Lilly's teriparatide (PTH1-34) application, we would like to respond to Reeve's editorial on recombinant human parathyroid hormone.1 Although the administration's advisory committee concluded that the company provided sufficient evidence to support the efficacy of teriparatide in the treatment of postmenopausal osteoporosis and idiopathic and hypogonadal osteoporosis in men, the committee did voice concern about osteosarcomas that developed in rats treated with the drug.

    In contrast to Reeve's assertion that rats received huge doses of teriparatide, some animals developed osteosarcomas when treated with doses that were approximately three times the expected daily human exposure—a small safety margin by conventional standards of drug development. Although several factors limit the ability to extrapolate the rat findings to humans, we did not dismiss the preclinical data as clinically irrelevant and believe that they should be factored into the drug's profile of benefits versus risks. A complete discussion of teriparatide's efficacy and safety can be found in the transcript of the July 2001 meeting of the advisory committee of the Food and Drug Administration.2

    Footnotes

    • This letter expresses the views of the authors and does not necessarily reflect the official position of the US Food and Drug Administration.

    References

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    Author's reply

    1. Jonathan Reevehead, bone research group (MRC)
    1. US Food and Drug Administration, Center for Drug Evaluation and Research, Division of Metabolic and Endocrine Drug Products, 5600 Fishers Lane, Rockville, MD 20857, USA
    2. University Department of Medicine, Box 157, Addenbrooke's Hospital, Cambridge CB2 2QQ

      EDITOR—Kuijpers et al are right to correct my editorial, which left my desk on 13 September 2001, when I was still relying on verbatim accounts of the Food and Drug Administration's hearing. The editorial's publication was a surprise: I had thought that, in the event of delayed publication, I would be allowed to correct and update it.

      Osteosarcoma is an uncommon human tumour (up to 1500 cases annually in the United States), usually occurring before the age of 30, more often in males.1 It can also occur in Pagetic bone at older ages. Having asked the makers of teriparatide and those investigating related compounds, I know of no case of osteosarcoma being reported among around 2000 patients treated so far with parathyroid hormone or parathyroid hormone related protein analogue. Clearly, if teriparatide becomes licensed, patients should be followed clinically and through cancer registries to be sure that this carcinogenic effect in rats really is absent in patients. The low background incidence of osteosarcoma, especially in the age group likely to receive teriparatide, may make it more difficult for any carcinogenic effect to be detected. The opposite is likely to be the case for strictly mathematical reasons (since the variance in the observed difference between two quantities described by Poisson statistics is the sum of those quantities).

      Since last year further information has emerged implying that the protective effect of teriparatide against fractures extends to men and that some protection in men and women continues after treatment is discontinued. 2 3 There is reason at this stage to be hopeful about the prospects for controlling the effects of osteoporosis with this and other already established treatments. This is necessary because osteoporosis currently leads to the occurrence of one or more spine fractures in 40% of women and 20% of men by the age of 80.4 Only about 10% of these, by interpolation from a recent survey,5 become known in NHS primary care. This rate is unsatisfactory, not only because spine fractures can sometimes be exquisitely painful when they first occur but also because of their deleterious long term effects on quality of life and their prediction of future hip fractures.

      References

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      View Abstract

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