Calcitonin has been in use for decades, and many millions of individuals have been exposed to pharmaceutical doses of sCT; it remains in use in many countries throughout the world, including the USA. An association with cancer, particularly a causal relationship, would clearly be important information.
Our meta-analysis is consistent with a small increased risk of cancer in calcitonin recipients when combining all types of malignancies; however, the data are not strongly persuasive of such an association in our opinion; the evidence of a causal relationship is even weaker. This interpretation is consistent with others who have also found the evidence to be of poor quality . A large nested case-control study of the use of calcitonin nasal spray in women with postmenopausal osteoporosis found that there was no association with “all cancer” but that there was a positive association (increased risk) for liver cancer and a negative association (decreased risk) for breast cancer in calcitonin users . In our opinion, these results are likely due to chance given the many types of cancer for which a possible association was sought. The authors concluded that that the results “did not completely support” the decision to discontinue use of calcitonin.
For many years, the criteria proposed by Bradford Hill in 1965 have been used to differentiate a cause and effect relationship from a noncausal association with respect to epidemiologic and environmental factors and disease . The same criteria have been useful in the pharmacovigilance arena . These criteria include strength, consistency, specificity, temporality, biological gradient, plausibility, coherence, and analogy.
With respect to the strength of association, the signal is weak and not statistically significant for any individual study. The lower bound of the 95 % CI of the RD is close to 0, and specificity and biological plausibility are absent.
The data are inconsistent on a number of levels, including results of formal preclinical toxicology data, in which calcitonin administration resulted in a lack of tumors in tissues of rodent species/strains which have a background incidence of spontaneous tumors. Therefore, the postulate of nonspecific tumor promotion is inconsistent with basic experimental carcinogenicity findings. Furthermore, no signal was noted in the largest study (Fig. 1, A2303) with the greatest patient-years of exposure. No temporality was observed; i.e., time to onset was not different in the intranasal group compared to placebo recipients. No signal is apparent in postmarketing surveillance data despite many years of use.
Specificity is entirely absent; the original NVS meta-analysis of 17 intranasal trials included 19 different types of tumors. The concept of nonspecific, multisite tumor promoters is inconsistent with the fundamental principle that tumor promoters are organ specific, based on several decades of experimental carcinogenesis studies elucidating the mechanism of tumor formation.
A biological gradient is not apparent, as no dose-response was evident in the FDA’s analysis . In PROOF, there was an inverse relationship between total exposure and development of the two most commonly reported malignancies, BCC and breast cancer.
There are no experimental data that show a cause and effect relationship, aside from prostate cancer data from the Shah lab. Ironically, prostate cancer is the only cancer for which a systematic evaluation was performed in the clinic, in two large OA trials. For this tumor type, the thesis of increased risk was ultimately refuted.
We are not aware of an analogy, e.g., in which a drug substance serves as a nonspecific oncogen or tumor promoter and whose effects are not observed in formal carcinogenicity studies.
None of these factors alone can disprove a causal relationship, but together, they provide a compelling argument against causality. Based on the preclinical literature, the known mechanism of action of calcitonin, and the receptor distribution, there is no real biological plausibility for a “pan cancer” causal association, nor for any single cancer type.
Our analysis, like those preceding it, has important limitations. None of the 22 trials included in the meta-analysis was designed specifically to identify an increased risk of malignancy, nor were cancer cases adjudicated in blinded fashion. In all cases, the analyses refer to adverse events reported as malignancy or consistent with a malignant adverse event. Furthermore, the enrolment criteria and duration of use varied in these trials. The exposure to sCT afforded by the various routes of administration and investigational oral formulations may not be comparable.