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Background: Skeletal metastases are often accompanied by bone pain. To investigate the clinical meaning of bone pain associated with skeletal metastasis in breast cancer patients after surgery, we explored whether the presence of bone pain was due to skeletal-related events (SREs) or survival (cause specific death, CSD), retrospectively., Methods: Consecutive breast cancer patients undergoing surgery between 1988 and 1998 were examined for signs of skeletal metastasis until December 2006. Patients who were diagnosed as having skeletal metastasis were the subjects of this study. Bone scans were performed annually for 5, 7 or 10 years; they were also conducted if skeletal metastasis was suspected. Data concerning bone pain and tumor markers at the time of skeletal metastasis diagnosis, and data relating to various factors including tumors, lymph nodes and hormone receptors at the time of surgery, were investigated. The relationships between factors such as bone pain, SRE and CSD were analyzed using the Kaplan-Meier method and Cox's analysis., Results: Skeletal metastasis occurred in 668 patients but the pain status of two patients was unknown, therefore 666 patients were included in the study. At the time of skeletal metastasis diagnosis 270 patients complained of pain; however, 396 patients did not. Analysis of data using Cox's and Kaplan-Meier methods demonstrated that patients without pain had fewer SREs and better survival rates than those with pain. Hazard ratios regarding SRE (base = patients without pain) were 2.331 in univariate analysis and 2.243 in multivariate analysis. Hazard ratios regarding CSD (base = patients without pain) were 1.441 in univariate analysis and 1.535 in multivariate analysis. Similar results were obtained when analyses were carried out using the date of surgery as the starting point., Conclusion: Bone pain at diagnosis of skeletal metastasis was an indicator of increased SRE and CSD. However, these data did not support recommendations of follow-up bone surveys in breast cancer patients.

Transforming growth factor (TGF)-beta is known to promote tumor invasion and metastasis. Although bone morphogenetic proteins (BMPs), members of the TGF-beta family, are expressed in a variety of human carcinoma cell lines, their roles in tumor progression have not been fully clarified. In this study, we sought to determine the roles of BMPs in the progression of breast cancer bone metastasis using human breast cancer samples and a mouse xenograft model. Immunohistochemical analysis of samples from breast cancer patients as well as a mouse xenograft model of MDA-231-D, highly metastatic human breast cancer cells, revealed phospho-Smad2 and phospho-Smad1/5/8 staining in the nuclei of cancer cells in primary tumor and/or bone metastasis. Using a functional in vivo bioluminescence imaging system, we showed that TGF-beta- and BMP-induced transcriptional pathways are active in bone metastatic lesions in vivo. In addition, both TGF-beta3 and BMP-2 promoted the motility and invasiveness of the MDA-231-D cells in vitro. Moreover, expression of dominant-negative receptors for TGF-beta and/or BMPs in the MDA-231-D cells inhibited invasiveness in vitro and bone metastasis in the xenograft model. These results suggest that BMPs as well as TGF-beta promote invasion and bone metastasis of breast cancer.

Transforming growth factor (TGF)-beta signaling has been shown to promote tumor growth and metastasis in advanced cancer. Use of inhibitors of TGF-beta signaling may thus be a novel strategy for treatment of patients with such cancers. In this study, we investigated the effects of a novel TGF-beta type I receptor (TbetaR-I) kinase inhibitor, Ki26894, on bone metastasis of a highly bone-metastatic variant of human breast cancer MDA-MB-231 cells, termed MDA-MB-231-5a-D (MDA-231-D). Ki26894 blocked TGF-beta signaling in MDA-231-D cells, as detected by suppression of phosphorylation of Smad2 and inhibition of TGF-beta-responsive reporter activity. Moreover, Ki26894 decreased the motility and the invasion of MDA-231-D cells induced by TGF-beta in vitro. Ki26894 also suppressed transcription of plasminogen activator inhibitor-1 (PAI-1), parathyroid hormone-related protein (PTHrP), and interleukin-11 (IL-11) mRNA of MDA-231-D cells, which were stimulated by TGF-beta. X-ray radiography revealed that systemic Ki26894 treatment initiated 1 day before the inoculation of MDA-231-D cells into the left ventricle of BALB/cnu/nu female mice resulted in decreased bone metastasis of breast cancer cells. Moreover, Ki26894 prolonged the survival of mice inoculated with MDA-231-D cells compared to vehicle-treated mice. These findings suggest that TbetaR-I kinase inhibitors such as Ki26894 may be useful for blocking the progression of advanced cancers.

Patients harboring cancer and other tumors frequently exhibit such bone morbidity as metabolic bone diseases and bone metastases. Cancers produce and secrete cytokines and growth factors for their growth and survival. Cytokines are also produced by reacting immune systems. Those humoral factors, when produced in a sizable quantity, enter into the general circulation and become a causative principle for paraneoplastic syndrome. An example is parathyroid hormone-related protein (PTHrP) for humoral hypercalcemia of malignancy, and fibroblast growth factor 23 (FGF23) for oncogenic osteomalacia. In animal models, PTHrP appear to produce cancer-associated cachexia as well. Some particular cancers such as those of lung, prostate, breast and thyroid are prone to metastasize into bone resulting in metastatic bone disease. Interactions between these cancers and inhabitant bone cells and bone matrices constitute a favorable condition where particular cancer cells deposit and survive. A variety of principle factors, mostly signal materials, were identified that are responsible for these interactions and these principle factors can be a target for the development of new chemotherapeutic agents.

Background: Parathyroid hormone-related protein (PTHrP) has been implicated in bone metastasis. However, the effects on bone metastasis of blocking the PTHrP function have not been tested in the clinic. Here, the effects of a humanized anti-PTHrP monoclonal antibody (mAb) on bone metastasis in a human xenograft model are shown., Materials and Methods: Subline MDA-5a, with high bone metastatic activity, was established from the human breast cancer cell line MDA-MB-231. Mice were injected with MDA-5a and an anti-PTHrP monoclonal antibody (mAb) raised against human PTHrP (1-34); bone metastasis was evaluated by X-ray photography., Results: MDA-5a produced elevated levels of PTHrP, Interleukin 8 (IL-8), IL-6 and matrix metalloproteinase 1 (MMP-1) and frequently metastasized to the bone. Administration of the humanized anti-PTHrP mAb significantly suppressed osteolytic bone metastasis of MDA-5a and caused osteogenesis at the sites of metastasis., Conclusion: The humanized anti-PTHrP mAb was effective against bone metastasis by inducing osteogenesis and, therefore, will provide a new treatment option for bone metastasis in breast cancer.

Background: There are several bone resorption markers which are generated by different mechanisms. The serum level of 3 different bone resorption markers in cancer patients with or without skeletal metastasis was compared to see whether the markers exhibit clinically significant differences useful for metastatic screening., Patients and Methods: Serum bone metabolic markers were measured in 75 cancer patients with and 201 cancer patients without skeletal metastasis. The 3 bone resorption markers, N-terminal cross-linked telopeptide of type I collagen (NTx), pyridinoline cross-linked carboxy-terminal telopeptides of type I collagen (ICTP) and tartrate-resistant acid phosphatase type 5b (TRAP 5b), and two bone formation markers, procollagen type I C-terminal peptide (PICP) and procollagen type I N-terminal peptide (PINP), were measured in the single sample. Each marker serum level was compared with the menopausal and the osseeous metastatic status assessed using Soloway's method for each patient., Results: Bone resorption marker serum levels, except for ICTP, were about 16% larger in postmenopausal patients than in premenopausal patients. All 3 bone resorption marker serum levels were 3-4 times greater in patients with extensive skeletal metastasis (extent of disease III; EOD = III) than in patients with no osseous metastasis. Although ROC analysis indicated each bone resorption marker had a similar sensitivity and specificity regarding the ability to detect osseous metastasis, some differences were detectable. The T-score of TRAP 5b was elevated, but not significantly so, in patients with a small bone metastatic burden (EOD = I). In contrast, although the T-score of NTx was not elevated in patients with a small metastatic burden (EOD = I), it was significantly elevated in patients with extensive osseous metastasis (EOD = III)., Conclusion: Three bone resorption markers with different generation mechanisms showed a difference in menopause and osseous metastasis status. The level of ICTP was not elevated in postmenopausal patients, but the levels of NTx and TRAP 5b. In osseous metastasis, even though not statistically significant, TRAP 5b increased in patients with a small bone metastatic burden and NTx increased in patients with extensive bone metastatic burden.

Background: Breast cancer has been the subject of many recent studies because it is a significant cause of death in women. This study was performed to clarify whether solitary skeletal metastasis has clinical significance compared with multiple skeletal metastasis., Patients and Methods: Seven hundred and three patients who developed metastatic bone lesions up to September 2002 after beginning treatment for breast cancer from 1988 to 1998 were included. The lesions were classified first as solitary or multiple based on bone scan results and then according to anatomical distribution. Next, solitary-to-multiple conversion was investigated in patients with solitary skeletal metastasis. Then factors related to solitary or multiple skeletal metastasis were analyzed. The prognosis of skeletal metastasis was compared between patients with solitary or multiple metastatic bone lesions. A Cox proportional hazards model was used to test whether solitary skeletal metastasis compared with multiple skeletal metastasis was an independent factor of survival., Results: Two hundred and eighty-nine patients (41%) had solitary skeletal metastasis and 414 patients (59%) showed multiple skeletal metastasis. The sternum was a frequent site for solitary skeletal metastasis (98 of 289, 34%), while other skeletal sites were more frequent in patients with multiple metastatic bone lesions (P <0.001). Solitary sternal metastatic lesions remained solitary longer than solitary metastatic bone lesions to places other than the sternum (P <0.001), but did not lengthen patient survival times (P = 0.871). The factors related to solitary skeletal metastasis are TNM stage (tumor-node-metastasis) and histology. The patients with earlier stage and favorable histology tend to have solitary skeletal metastasis. The patients with solitary skeletal metastasis lived longer than those with multiple metastatic bone lesions (P <0.001). Multivariate analysis revealed that a solitary metastatic bone lesion (P = 0.002) is an independent favorable prognostic factor in patients with skeletal metastasis., Conclusions: Solitary skeletal metastasis has a different anatomical distribution and is an independent prognostic factor in patients with skeletal metastasis.

The use of bisphosphonates for skeletal metastasis of breast cancer is now well established. Although clinical judgement for treating skeletal metastasis is based on symptoms and imaging studies, accurate or quantitative means are few. Various bone metabolic markers have been developed and these were evaluated in patients with metastasis to bone. Bone metabolic markers, especially resorption markers, have been shown to be a good tool for the monitoring the response to therapy for skeletal metastasis. This is also true for bisphosphonate treatment for skeletal metastasis. Bone metabolic markers are produced by different mechanisms. There are some different classes of resorption markers; tartrate-resistant acid phosphatase (TRAP) is secreted by osteoclast, N- and C-terminal cross-linking telopeptide of type I collagen (NTx and CTx) are the degradation the products of type I collagen, mainly produced by cathepsin K, and pyridinoline cross-linked carboxyl-terminal telopeptides of type I collagen (I CTP) is also a degradation product of type I collagen, by matrix metalloproteases. Even though bone resorption markers are a good tool to monitor response to bisphosphonate therapy, there remains the question of which class of bone resorption markers is best suited to the task.

Currently, imaging techniques are the leading methods used to diagnose of metastasis to bone. However, these techniques are expensive, expose patients to toxic and radioactive compounds, and monitor response to treatment poorly; these drawbacks have prompted the search for alternative screening methods. Therefore, bone metabolic markers have been evaluated as possible methods to diagnose and monitor the development and progression of metastatic bone disease. Although bone metabolic markers are often grouped as either resorption or formation markers, studies have revealed that each marker has its own biologic meaning and clinical relevance. Recent milestones in the use of bone metabolic markers as screening methods for metastatic bone disease and as evaluation methods for treatment response are shown in the following lists. 1. Bone metabolic marker measurements provide insight into mechanisms of metastasis to bone. 2. Although promising data have been reported, bone metabolic markers are not yet considered to be reliable screening methods for metastasis to bone. 3. Bone metabolic markers are reliable indicators of response to both conventional and bisphosphonate therapies. 4. Preliminary results indicate bone metabolic markers might be an independent prognostic factor in patients whose tumors metastasize to bone. 5. New or refined assays for bone metabolic markers are expected to improve the sensitivity and specificity of bone metabolic marker use in diagnosing and monitoring metastasis to bone.

Purpose: Although skeletal metastasis is a common complication associated with prostate cancer, assessment of the response of osseous metastasis to therapy is still difficult. To remedy this situation a study of bone formation metabolic markers gaps in patients with prostate cancer and osseous metastasis was done to determine these gaps as clinical markers for the efficacy of therapy against osseous metastasis., Materials and Methods: The activities of the bone formation markers amino terminal propeptide of type I procollagen (PINP), bone alkaline phosphatase (BAP) and osteocalcin (OC) were measured in 57 and 60 patients with prostate cancer without and with osseous metastasis, respectively. Of the 60 patients with osseous metastasis serial measurements were performed in 31. The status of osseous metastasis at the time of marker measurement was categorized, and the BAP-to-PINP, OC-to-PINP and OC-to-BAP ratios were calculated., Results: The BAP-to-PINP ratio did not change. However, the OC-to-PINP and OC-to-BAP ratios were significantly different depending on osseous metastasis status. The ratios were high in patients with no osseous metastasis or with metastasis shrinkage (improvement) but low in those in whom metastases were growing and/or spreading (progression). Cutoff levels of OC-to-PINP and OC-to-BAP ratios were determined by comparing ratios with clinical judgment on the response to treatment in all patients. When these cutoffs were applied to the 31 patients, the OC-to-PINP ratio agreed with clinical judgment in 29 (94%) and the OC-to-BAP ratio agreed in 28 (90%)., Conclusions: Different bone formation markers seem to be sensitive clinical markers for judging the response to therapy of prostate cancer metastasized to bone.

Cachexia often causes deterioration in the quality of life in cancer patients; however, its mechanism remains poorly understood. Cachexia has often been observed in experimental animals with bone metastases, and parathyroid hormone-related protein (PTHrP) plays an important role in the formation of such metastases. We therefore investigated the possible involvement of PTHrP in an experimental cachexia model using human lung-cancer cells (HARA-B). HARA-B cells produce a high amount of PTHrP but no TNF-alpha, IL-6 or leukemia inhibitory factor. The s.c. inoculation of HARA-B cells into nude mice caused reductions in body weight, adipose tissue weight, muscle weight and serum glucose levels. Serum levels of calcium and PTHrP increased. Neutralization of PTHrP with antibody caused rapid weight gain along with a rapid decrease in serum calcium levels. Our findings suggest that PTHrP plays an important role in the development of cancer cachexia. PTHrP therefore is a possible target molecule for the treatment of cancer cachexia., (Copyright 2001 Wiley-Liss, Inc.)

Background: A review and analysis of breast cancer treatment records were conducted to establish criteria for performing disease staging by bone scintigraphy in Japanese breast cancer patients., Methods: Records from 5538 consecutive Japanese breast cancer patients from January 1988 to December 1998 were reviewed and analyzed to determine bone metastasis status at the time of initial treatment. Correlation between metastasis to bone and factors known before and after surgery was analyzed using logistic regression., Results: The overall incidence of metastasis to bone was 2.13% [95% confidence interval (CI): 1.77-2.55%, 118/5538]. Multivariate logistic analysis revealed that tumor size, nodal involvement and histopathology correlated with metastasis to bone. Patients with tumors larger than 30 mm had a significantly higher probability of metastasis to bone, as did patients with lymph node evaluation results N > or = 1. The incidence of metastasis to bone was 0% in patients with stage 0 disease, 0.08% in stage I patients, 1.09% in stage II patients, 9.96% in stage III patients and 34.04% in stage IV patients. Stage II patients were sub-classified by tumor size T (small, 21-30 mm; and large, 31-50 mm), nodal involvement N and histopathology. The incidence of metastasis to bone in stage II patients was higher in patients with large tumors, scirrhous carcinoma or invasive lobular carcinoma or both., Conclusion: Bone metastasis correlated with tumor size (T), lymph node involvement (N) and histopathology. Using the criteria that bone scintigraphy is not necessary in populations with a < 1% incidence of bone metastasis, but is recommended at incidence > 3%, the following conclusions were drawn. Staging by bone scintigraphy provided no benefit to patients whose disease was stage I or less, stage II with small tumors or stage II with large tumors marked by low-grade histopathology (papillotubular cancer). Bone scintigraphy is recommended in patients whose disease is stage II with large tumors marked by high-grade histopathology (scirrhous or invasive lobular cancer), stage III or stage IV. Consequently, staging by bone scintigraphy could be avoided in 71% (3943/5538) of Japanese breast cancer patients.

Objective: To assess the level of a bone-formation marker, the amino-terminal propeptide of type I procollagen (PINP), for its utility in indicating bone metastasis in patients with prostate cancer., Patients and Methods: Several bone formation markers, i.e. PINP, the carboxy-terminal propeptide of type I procollagen (PICP), bone-specific alkaline phosphatase (BALP), and bone Gla protein (BGP), a bone resorption marker (pyridinoline cross-linked carboxy-terminal telopeptide, ICTP), and prostate specific antigen (PSA) were measured in 40 patients without and 25 patients with bone metastasis. No patient had undergone previous treatment, except for six who developed bone metastasis while undergoing hormone therapy., Results: All markers except BGP were significantly higher in patients with bone metastasis than in those without. The levels of PINP correlated best with the extent of disease, although the levels of PSA, BALP and ICTP also correlated well. While PINP had the largest area under the receiver-operator characteristic curve, PSA, BALP and ICTP also produced useful curves., Conclusion: The bone formation marker PINP seems to be useful for discriminating patients with and without bone metastasis. PINP may help in the early and accurate diagnosis of bone metastasis in such patients.

Cancer cells metastasized to bone induce osteoclastogenesis for bone destruction. Coculture of either mouse melanoma B16 or breast cancer Balb/c-MC cells with mouse bone marrow cells (BMCs) induced osteoclast-like cells, which were not observed when cancer cells were segregated from BMCs. Osteoclast differentiation factor (ODF), also known as receptor activator of NF-kappaB ligand (RANKL), is a direct mediator of many osteotropic factors. Neither BMCs, B16 nor Balb/c-MC cells alone expressed ODF mRNA. However, coculture of these cancer cells with BMCs induced ODF expression, which was prevented by indomethacin. Moreover, the coculture with cancer cells inhibited secretion of osteoprotegerin/osteoclastogenesis inhibitory factor (OPG/OCIF), an inhibitory decoy receptor for ODF, from BMCs. Thus, enhanced osteoclastogenesis in the presence of cancer cells might be due to an increase in ODF activity. These results suggest that interactions between cancer cells and BMCs induce ODF expression and suppress OPG/OCIF level in metastatic foci resulting in pathological osteoclastogenesis for bone destruction., (Copyright 2000 Academic Press.)

Bone scan flare seriously complicates evaluations of the therapeutic response of bone metastases. The value of bone metabolic markers in monitoring the therapeutic response for bone metastases in breast cancer was assessed. Twenty-three breast cancer patients with bone metastases treated by combined chemotherapy of cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF) were monitored using bone scans; a bone resorption marker, pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen (ICTP); a bone formation marker, bone-specific alkaline phosphatase (BAI-p); and a tumor-specific marker (CA15-3). Bone scans were performed before and 3 or 4 months after therapy. After CAF therapy, markers were measured monthly. As a control, the markers of nine patients without bone metastases who received adjuvant CAF therapy were also measured monthly. The therapeutic effect on bone metastases was assessed after the study. Five patients had progression of disease (PD), three had no change (NC), and 15 patients had partial responses (PR). Bone scan flare-up was seen in five PR patients. In patients who received adjuvant therapy, ICTP, BAI-p, and CA15-3 did not change. ICTP increased significantly in PD patients. ICTP did not increase in either NC or PR, including bone scan flare patients. BAI-p and CA15-3 did not show any discernible pattern among PD, PR, flare, and NC patients. Thus measuring ICTP could distinguish PD from NC or PR patients' responses to CAF therapy. This was true also for patients who showed bone scan flare-up. Measuring a bone resorption marker, ICTP, allows clinicians to monitor patients' responses to CAF therapy and may prevent prolonged ineffective therapy or unnecessary changes in therapy as a result of the flare phenomenon.

A breast cancer patient with bone metastases showed a marked response to treatment with a bisphosphonate, an inhibitor of osteoclastic bone resorption. The patient was admitted to our hospital with hypercalcemia, widespread bone metastases and severe disseminated intravascular coagulation (DIC). We treated her conservatively with pamidronate and gabexate mesilate, because the patient had refused any anti-cancer chemotherapy. She showed marked improvement in performance status, hypercalcemia, DIC and tumor markers, whereas splenomegaly due to metastasis progressed. These results suggest that pamidronate has the potential to suppress metastatic tumor growth selectively in bone.

Purpose: We examined the correlation between bone metabolic markers and bone scintigraphy in prostatic cancer., Materials and Methods: Osteoblastic and osteoclastic markers, prostate specific antigen (PSA) and bone scans were investigated in 83 specimens from 70 patients with prostatic cancer, including 32 with and 38 without bone metastasis., Results: All markers except for osteocalcin were significantly greater in patients with than without bone metastasis. Pyridinoline cross-linked carboxyterminal telopeptide, an osteoclastic marker, reflected the extent of bone metastasis more accurately than PSA and other bone markers., Conclusions: Pyridinoline cross-linked carboxyterminal telopeptide might assist PSA and bone scintigraphy in monitoring metastatic bone activity of prostatic cancer.

Ninety-one lung cancer patients were evaluated to determine the usefulness of bone metabolic markers in the diagnosis and follow-up of bone metastases and also to investigate their clinical usefulness as an adjunct to bone scintigraphy. Both bone resorption markers, ICTP and fDPD, and bone formation markers, Al-p, BAL, PICP and BGP, were evaluated in 47 patients with and 44 without bone metastasis. The patients with bone metastasis were classified according to the bone metastatic burden, and they were also separately classified into groups according to the course of the bone metastasis. ICTP, fDPD, Al-p and BAL were significantly elevated (P < 0.001) in patients with bone metastasis, but PICP and BGP were not. Receiver-operating characteristic (ROC) curves of these markers revealed that ICTP was most highly correlated with the diagnosis of bone metastasis. The sensitivity of ICTP (71.4%) and fDPD (61.0%) were good with high specificity. T scores of ICTP, fDPD and BAL tended to be higher at higher grades of bone metastasis. T-scores of ICTP, fDPD and BAL were elevated in the newly diagnosed cases and progressed cases, but the T-scores of ICTP and fDPD in those cases were higher than that of BAL. In the follow-up study, ICTP was well correlated with uncontrolled or controlled bone metastasis. Thus, bone resorption markers, especially ICTP, could be a good indicator of the progression and multiplicity of disease, and it could help in the follow-up and in the monitoring of therapy for bone metastasis from lung cancer.

To clarify the meaning and clinical value of bone formation markers in bone metastasis from prostate cancer, we investigated the bone formation markers carboxy-terminal propeptide of type I procollagen (PICP), bone-specific alkaline phosphatase (BA1-p) and osteocalcin, so-called bone gla protein (BGP) in 43 prostate cancer patients with and 46 patients without overt bone metastasis. Patients with bone metastasis were evaluated repeatedly by bone scan at intervals of 3-6 months. The expression patterns of bone formation markers in patients with progression of bone metastasis became dissociated; BA1-p and PICP were elevated in patients with progression of bone metastasis but BGP was not. Instead, BGP showed slight elevation in patients with improvement and complete remission of bone metastasis. PICP, BA1-p and BGP are all bone formation markers, but each marker appears in a different phase of bone formation: PICP appears in proliferation phase, BA1-p appears in matrix maturation phase and BGP appears in late bone formation phase. Our findings that BGP was not elevated in progression of bone metastasis and that it increased slightly with improvement and complete remission of bone metastasis may imply that the bone formation that occurs in blastic bone metastasis is different from normal bone formation.

Recently discovered bone metabolic markers are expected to play an additional role in the diagnosis of bone metastasis. We measured bone metabolic markers, serum pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen (ICTP) and carboxyterminal propeptide of human type I procollagen (PICP) in 224 patients with breast cancer (106 with bone metastases), 61 patients with prostatic cancer (30 with bone metastases), 45 patients with lung cancer (17 with bone metastases) and 13 patients with miscellaneous cancers (7 with bone metastasis) and compared the values in the presence and absence of bone metastasis. ICTP and PICP increased significantly in patients with bone metastases. By the analysis of sensitivity and specificity, the cut-off levels were considered to be 5.0 ng/ml for ICTP and 140 ng/ml for PICP. In lung cancer (bone metastases are mostly of osteolytic), ICTP was excellent marker in detecting bone metastasis. In breast cancer (bone metastases are mostly of mixed type), ICTP was good in detecting bone metastases. In prostatic cancer (bone metastases are mostly of osteoblastic), ICTP and PICP were good markers in detecting high grade of bone metastases. Over all, ICTP was more sensitive in the diagnosis of bone metastases than PICP. However, both markers were not effective in detecting low grade bone metastases. ICTP and PICP should play a supportive role to imaging modalities in the diagnosis of bone metastases.