CORRESPONDENCE

Re: A Randomized, Placebo-Controlled Trial of Zoledronic Acid in Patients With Hormone-Refractory Metastatic Prostate Carcinoma

Alfredo Berruti, Marcello Tucci, Carlo Terrone, Roberto Mario Scarpa, Alberto Angeli, Luigi Dogliotti

Correspondence to: Luigi Dogliotti, M.D., Oncologica Medica, Azienda Ospedaliera San Luigi, Regione Gonzole 10, 10043 Orbassano, Italy (e-mail: luigi.dogliotti{at}unito.it).

We read with interest the article by Saad et al. (1) showing that the administration of zoledronic acid can substantially decrease the risk of skeletal-related complications in hormone-refractory prostate cancer patients with blastic bone metastases. The monitoring of bone turnover markers stimulates questions that were not addressed by the authors in the discussion and suggest some further analyses. As expected, zoledronic acid administration led not only to a prompt reduction in bone collagen breakdown markers (N-telopeptide of type 1 collagen [NTX]) but also to a decrease in bone alkaline phosphatase (BALP), with the lowest levels attained after 3 months. Because the target of bisphosphonates is not osteoblasts, the delayed BALP reduction with respect to urinary NTX suggests a maintenance, at least to a certain degree, of the coupling phenomenon (osteoclastic bone resorption followed by osteoblastic bone formation) in metastatic bone lesions. There is, however, an alternative hypothesis. Zoledronic acid could have favored the repair of the osteolytic component of bone lesions. It is well known that disease response in bone to systemic treatment is preceded by a transient rise in bone formation markers shortly after the start of treatment (24). The transient rise in serum BALP in a number of cases could have delayed the decrease in mean BALP values with respect to urinary NTX levels. If this hypothesis is true, monitoring BALP serum levels could be useful in predicting early who would benefit from zoledronic acid. This raises two questions: 1) how many patients who received zoledronic acid had a transient rise in BALP levels within the first 2 months? and 2) was this transient rise related to the probability of subsequent skeletal-related complications?

Saad et al. (1) also showed that zoledronic acid administration led to a rise in parathyroid hormone (PTH) serum levels, which persisted throughout the study. The osteoblastic nature of bone lesions from prostate cancer and the high potency of zoledronic acid could have contributed to the increased levels. It is important to note that a proportion of prostate cancer patients with bone metastases already have elevated PTH values before the zoledronic acid administration, resulting from an increased calcium demand related to increased bone formation (5). Secondary hyperparathyroidism may stimulate osteoclast activity at sites distant from those involved with the tumor. Recently, it was suggested (5) that the administration of bisphosphonates in prostate cancer patients with bone metastases may be contraindicated because these drugs may potentially worsen the pre-existing hyperparathyroidism. This hypothesis is not supported by our results obtained with pamidronate in a prostate cancer patient with bone metastases and associated hypocalcemia and hyperparathyroidism (6). Pamidronate treatment achieved an improvement in bone metabolism, leading to a reduction in bone remodelling markers. The reduction in bone formation improved the hyperparathyroidism (PTH serum levels decreased after an initial rise and serum calcium increased). In the study by Saad et al. (1), BALP significantly decreased, as in our experience, but serum PTH still remained elevated after many months, probably because zoledronic acid is 1000 times more potent than pamidronate. It would be interesting to know how many patients in the study by Saad et al. (1) had baseline elevated PTH and what the outcome of these patients was according to the randomization arms in terms of incidence of adverse skeletal events, bone pain, changes in bone turnover markers, and PTH.

REFERENCES

1 Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002;94:1458–68.[Abstract/Free Full Text]

2 Coleman RE, Withaker KB, Moss DW, Mashiter G, Fogelman I, Rubens RD. Biochemical prediction of response of bone metastases to treatment. Br J Cancer 1988;58:205–10.[Medline]

3 Berruti A, Cerutti S, Fasolis G, Sperone P, Tarabuzzi R, Bertetto O, et al. The osteoblastic flare assessed by serum alkaline phosphatase activity is an index of short duration of response in prostate cancer patients with bone metastases submitted to systemic therapy. Anticancer Res 1997;17:4697–702.[Medline]

4 Mackintosh J, Simes J, Raghavan D, Pearson B. Prostatic cancer with bone metastases: serum alkaline phosphatase (SAP) as a predictor of response and the significance of the SAP "flare." Br J Urol 1990;66:88–93.[Medline]

5 Murray RM, Grill V, Crinis N, Ho PW, Davison J, Pitt P. Hypocalcemic and normocalcemic hyperparathyroidism in patients with advanced prostatic cancer. J Clin Endocrinol Metab 2001;86:4133–8.[Abstract/Free Full Text]

6 Berruti A, Sperone P, Fasolis G, Torta M, Fontana D, Dogliotti L, et al. Pamidronate administration improves the secondary hyperparathyroidism due to "bone hunger syndrome" in a patient with osteoblastic bone metastases from prostate cancer. Prostate 1997;33:252–5.[CrossRef][Medline]


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