Markers of bone turnover for the management of patients with bone metastases from prostate cancer

British Journal of Cancer (2000) 82(4), 858–864 © 2000 Cancer Research Campaign DOI: 10.1054/ bjoc.1999.1012, available online at http://www.idealibrary.com on Markers of bone turnover for the management of patients with bone metastases from prostate cancer P Garnero1,2, N Buchs3, J Zekri4, R Rizzoli3, RE Coleman4 and PD Delmas1 1 INSERM Research Unit 403, Hôpital E Herriot, Pav F, 69437 Lyon cedex 03, France; 2SYNARC, Lyon, France; 3Division of Bone Disease, University Hospital, Geneva, Switzerland; 4YCR Department of Clinical Oncology, Sheffield, UK Summary Although increased bone formation is a prominent feature of patients with osteosclerotic metastases from prostate cancer, there is also some evidence for increased bone resorption. The aim of this study was to compare the clinical utility of new bone resorption markers to that of bone formation in patients with bone metastases from prostate cancer before and after bisphosphonate treatment. Thirty-nine patients with prostate cancer and bone metastasis, nine patients with prostate cancer without bone metastases, nine patients with benign prostatic hyperplasia and 355 healthy age-matched men were included. Urinary non-isomerized (α CTX) and β isomerized (β CTX) type I collagen C-telopeptides (CTX) and a new assay for serum CTX were used to assess bone resorption. Bone formation was determined by serum osteocalcin, serum total (T-ALP) and bone (BAP) alkaline phosphatase and serum type I collagen C-terminal propeptide (PICP). Fourteen patients with bone metastases were also evaluated 15 days after a single injection of the bisphosphonate pamidronate (120 mg). Levels of all bone formation and bone resorption markers were significantly (P < 0.006–0.0001) higher in patients with prostate cancer and bone metastasis than in patients with benign prostatic hyperplasia, patients with prostate cancer without bone metastases and healthy controls. In patients with bone metastases the median was increased by 67% for serum osteocalcin, 128% for T-ALP, 138% for BAP, 79% for PICP, 220% for urinary α CTX, 149% for urinary β CTX and 214% for serum CTX. After bisphosphonate treatment all three resorption markers significantly decreased by an average of 65% (P = 0.001), 71% (P = 0.0010) and 61% (P = 0.0015) for urinary α CTX, urinary β CTX and serum CTX, respectively, whereas no significant change was observed for any bone formation markers. Patients with prostate cancer and bone metastases exhibit a marked increase in bone resorption, which decreases within a few days of treatment with pamidronate. These findings suggest that these new resorption markers may be useful for the management of these patients. © 2000 Cancer Research Campaign Keywords: bone markers; prostate cancer; bone metastases; type I collagen; bisphosphonate Prostate cancer is the most common malignancy in elderly men and is often complicated by osteosclerotic metastases. Bone scintigraphy is commonly used to assess the extent of bone metastases; its use is limited in monitoring of treatment efficacy because it is an expensive, time-consuming technique that does not reflect the rapid skeletal response to therapy (Coleman, 1998). The bone scan flare response following successful therapy also reduces the value of bone scanning in the early monitoring of treatment in prostate cancer (Pollen et al, 1984). The serum level of prostatespecific antigen is the most sensitive index of disease progression in most but not all patients, but does not reflect the effects of palliative treatments such as bisphosphonates for bone metastases in patients that escape from antihormonal therapy. The marked increase of osteoblastic activity in patients with osteosclerotic metastases is reflected by increased levels of serum total and bone-specific alkaline phosphatase (Pecherstorfer et al, 1995; Lorente et al, 1996). There is, however, biochemical (Myamoto et al, 1994, Sano et al, 1994; Kylmala et al, 1995; Berruti et al, 1996; Ikeda et al, 1996; Takeuchi et al, 1996; Maeda et al, 1997; Nguyen-Pamart et al, 1997, Pelger et al, 1998) and histological (Urwin et al, 1985; Clarke et al, 1991) evidence of Received 22 March 1999 Revised 20 September 1999 Accepted 20 September 1999 Correspondence to: P Garnero 858 increased bone resorption in these patients even in the absence of overt osteolytic bone metastases. This increased bone resorption is of clinical relevance as it is the rationale for using bisphosphonates, a palliative treatment that has been shown to reduce bone pain in patients with progressive metastatic prostate cancer who no longer respond to hormonal therapy (Adami et al, 1985; Carey and Lippert, 1988; Clarke et al, 1992; Kylmala et al, 1993, Taube et al, 1994; Pelger et al, 1998). In this study we assessed the level of bone resorption in patients with osteosclerotic metastases from prostate cancer before and after bisphosphonate treatment by using new sensitive and specific biochemical markers of bone resorption including a serum assay for type I collagen C-telopeptide breakdown products; and values were compared to those of bone formation markers. PATIENTS AND METHODS Forty-eight patients with carcinoma of the prostate (age 71.7 ± 9.6 years, mean ± 1 s.d.) and nine with benign prostatic hyperplasia (BHP) (age 69.8 ± 4.2 years) were enrolled. All patients with cancer had a prostatic biopsy and tissue diagnosis of adenocarcinoma. Bone involvement and its extent was evaluated by bone scintigraphy using Technetium-99m labelled methylene bisphosphonate. When bone metastases were suspected, confirmation was obtained with standard radiographs, computerized tomography (CT) and/or magnetic resonance imaging. The metastatic load in Bone turnover in prostate cancer 859 bone, defined by the number and size of the metastatic lesions, was graded using the scoring and stratification proposed by Soloway et al (1988) in a subset of 32 patients with prostate cancer. Patients were classified into two groups: score < 2 (i.e. 0 and 1) corresponding to fewer than six malignant bone lesions; score ≥ 2 (from 2 to 4) corresponding to six and more lesions. Among the subjects with prostate cancer, 39 had proven bone metastases (age 71.8 ± 9.6 years), whereas nine (age 71.1 ± 9.8 years) had no detectable metastatic diseases. The nine patients with BPH had no previous history of malignancy and the biopsy specimen did not reveal any evidence of cancer. Forty-eight out of the 57 patients had no previous treatment for their prostate disease. Five subjects with skeletal metastases had undergone orchidectomy 4–56 months before the study (23 ± 4 months) and two had a previous hormonal therapy (cyproterone acetate for 3 months, flutamide for 8 months). Fourteen patients with endocrine-resistant bone metastases were also assessed 15 days after a single intravenous injection of the bisphosphonate pamidronate (120 mg). All these 14 patients had apparently sclerotic disease with no radiographical evidence of ly (...truncated)