Osteoblastic Bone Metastases Research Articles

Early (mucosal) gastric cancer with synchronous osteosclerotic bone metastases: a case report

Early gastric cancer (EGC) is defined as an adenocarcinoma confined to the gastric mucosa or submucosa, regardless of the presence of lymph node metastases. Early gastric cancer carries an excellent prognosis, with a 5-year survival rate at least 85% in most series. However, there are rare cases where distant metastases exist. Bone metastases are rare in gastric cancer; osteoblastic bone metastases are even rarer. We report a patient with EGC (mucosal) and synchronous osteosclerotic bone metastasis. To our knowledge, this is the first reported case of submucosal EGC with synchronous bone metastases. The patient was operated and he received adjuvant chemotherapy and radiotherapy. He died 18 months after gastric surgery from generalized disease.

Pancreatic cancer's initial presentation: back pain due to osteoblastic bone metastasis

Pancreatic cancer may cause osteolytic metastases, but the osteoblastic ones are extremely rare. In addition, it almost always presents with symptoms related to the invasion of the structures in the abdomen. Symptoms from bone metastases are rare and, if seen, are in the late phase of the course. We present a case of cancer of the body of the pancreas, which presented with severe back pain due to an osteoblastic lesion to L3 vertebra. Biopsy of the vertebra led to the diagnosis. Radiographs, computed tomography, magnetic resonance and scintigraphic images as well as pathology slices are shown. The present case raises the issue that pancreatic cancer, as a cause of an osteolytic bone lesion, should not be overlooked in an unknown primary investigation.

A 70-year-old male having advanced prostate cancer presenting with hypercalcemia and diffuse osteoblastic bone metastases: a case report

BackgroundBony metastases were occasionally the initial presentations of malignancy. Overlooking of bony changes on radiographs in cancer patients with non-specific clinical symptoms may lead to delayed diagnosis.Case presentationWe presented a 70-year-old male having hypercalcemia and diffuse osteoblastic bone metastases on routine plain films. Finally, prostate cancer was diagnosed with a prostate needle biopsy.ConclusionAlthough the modern radionuclide bone scanning is useful in diagnosis, osteoblastic bone changes are occasionally seen in plain films, which are frequently overlooked. To avoid delayed diagnosis, bony structures should be carefully examined in all plain-film radiographs.

Bone-Targeted Therapy

Bone-targeted therapy that combines strontium-89 (Sr-89) with alternating weekly chemohormonal therapy may improve clinical outcomes in patients with metastatic hormone-refractory prostate cancer. This phase II study investigated the addition of Sr-89 to an alternating weekly regimen of doxorubicin and ketoconazole with paclitaxel and estramustine in patients with progressive prostate cancer and bone involvement. Twenty-nine patients with progressive adenocarcinoma of the prostate and osteoblastic bone metastases who failed conventional hormonal therapy were registered for the study. Of those, 27 were treated with Sr-89 on day 1 of week 1. On weeks 1, 3, and 5, patients received doxorubicin (20 mg/m on day 1) and oral ketoconazole (400 mg 3 times a day for 7 days). On weeks 2, 4, and 6, patients received paclitaxel (100 mg/m(2)) and oral estramustine (280 mg 3 times a day for 7 days). No treatment was given during weeks 7 and 8. Cycles were repeated every 8 weeks. A > or =50% reduction in prostate-specific antigen level was maintained for at least 8 weeks in 77.7% of the patients (21 patients) at 16 weeks and in 66.6% (18 patients) at 32 weeks. The median progression-free survival was 11.27 months (range, 1.83-29.53), and the median overall survival was 22.67 months (1.83-57.73+). Two patients died during study because of disease progression. Overall, the chemotherapy combined with Sr-89 was well tolerated. Our results demonstrate that the combination of alternating weekly chemohormonal therapies with Sr-89 demonstrates a prolonged progression-free and overall survival with acceptable toxicity. Further investigation of combination therapies with Sr-89 is warranted.

Practical method for radioactivity distribution analysis in small-animal PET cancer studies

We present a practical method for radioactivity distribution analysis in small-animal tumors and organs using positron emission tomography imaging with a calibrated source of known activity and size in the field of view. We reconstruct the imaged mouse together with a source under the same conditions, using an iterative method, Maximum likelihood expectation-maximization with system modeling, capable of delivering high-resolution images. Corrections for the ratios of geometrical efficiencies, radioisotope decay in time and photon attenuation are included in the algorithm. We demonstrate reconstruction results for the amount of radioactivity within the scanned mouse in a sample study of osteolytic and osteoblastic bone metastasis from prostate cancer xenografts. Data acquisition was performed on the small-animal PET system, which was tested with different radioactive sources, phantoms and animals to achieve high sensitivity and spatial resolution. Our method uses high-resolution images to determine the volume of organ or tumor and the amount of their radioactivity has the possibility of saving time, effort and the necessity to sacrifice animals. This method has utility for prognosis and quantitative analysis in small-animal cancer studies, and will enhance the assessment of characteristics of tumor growth, identifying metastases, and potentially determining the effectiveness of cancer treatment. The possible application for this technique could be useful for the organ radioactivity dosimetry studies.

BMP7: A New Bone Metastases Prevention?

Prostate cancer is the most frequently diagnosed cancer in men and a leading cause of cancer death. More than 218,000 cases will occur in 2007, and prostate cancer will lead to more than 27,000 deaths.1 Although the 5-year survival rate is excellent for localized stages (100%), the relative survival rapidly decreases to 33% when prostate cancer metastasizes.1 Cancer cells from prostate primary tumors commonly colonize bones, and postmortem analyses show that 65 to 75% of patients with advanced disease have bone metastases.2 Scientific knowledge of bone metastasis pathophysiology has increased in recent years, but effective therapy for this devastating complication of cancer remains suboptimal. In this issue of The American Journal of Pathology, Buijs and colleagues3 shed more light into pathophysiology of bone metastases. More importantly, they apply this knowledge to develop novel therapy for bone metastases using bone morphogenetic protein 7 (BMP7).

Dickkopf homolog 1 mediates endothelin-1-stimulated new bone formation.

Tumor-produced endothelin-1 (ET-1) stimulates osteoblasts to form new bone and is an important mediator of osteoblastic bone metastasis. The anabolic actions of ET-1 in osteoblasts were investigated by gene microarray analyses of murine neonatal calvarial organ cultures. Targets of ET-1 action were validated by real-time RT-PCR in murine primary osteoblast cultures. IL-6, IL-11, the CCN (CYR61, CTGF, NOV) family members cysteine-rich protein 61 and connective tissue growth factor, inhibin beta-A, serum/glucocorticoid regulated kinase, receptor activator of nuclear factor kappaB ligand, snail homolog 1, tissue inhibitor of metalloproteinase 3, and TG-interacting factor transcripts were increased by ET-1. ET-1 decreased the transcript for the Wnt signaling pathway inhibitor, dickkopf homolog 1 (Dkk1). Calvarial organ cultures treated with ET-1 had lower concentrations of DKK1 protein in conditioned media than control cultures. High DKK1 concentrations in bone marrow suppress bone formation in multiple myeloma. We hypothesized that the converse occurs in osteoblastic bone metastasis, where ET-1 stimulates osteoblast activity by reducing autocrine production of DKK1. Recombinant DKK1 blocked ET-1-mediated osteoblast proliferation and new bone formation in calvarial organ cultures, whereas a DKK1-neutralizing antibody increased osteoblast numbers and new bone formation. ET-1 directed nuclear translocation of beta-catenin in osteoblasts, indicating activation of the Wnt signaling pathway. The data suggest that ET-1 increases osteoblast proliferation and new bone formation by activating the Wnt signaling pathway through suppression of the Wnt pathway inhibitor DKK1.

Basic Mechanisms Responsible for Osteolytic and Osteoblastic Bone Metastases

Certain solid tumors metastasize to bone and cause osteolysis and abnormal new bone formation. The respective phenotypes of dysregulated bone destruction and bone formation represent two ends of a spectrum, and most patients will have evidence of both. The mechanisms responsible for tumor growth in bone are complex and involve tumor stimulation of the osteoclast and the osteoblast as well as the response of the bone microenvironment. Furthermore, factors that increase bone resorption, independent of tumor, such as sex steroid deficiency, may contribute to this vicious cycle of tumor growth in bone. This article discusses mechanisms and therapeutic implications of osteolytic and osteoblastic bone metastases.

Samarium for osteoblastic bone metastases and osteosarcoma

Samarium-153 lexidronam (153Sm-EDTMP) is FDA approved for painful osteoblastic bone metastases that image on bone scan. 153Sm-EDTMP decay has a therapeutic β-emission and a γ-photon for bone scan imaging. Monitoring of osteosarcoma radiation treatment effectiveness was performed with bone, CT, MRI and PET/CT fusion imaging. Bone scan and PET/CT improved in 5 out of 9 and 16 out of 18 osteosarcoma sites, respectively. 153Sm-EDTMP targets multiple sites of disease, with a single administration. Side effects of 153Sm-EDTMP (0.5 – 2.5 mCi/kg) have been minimal and include transient thrombocytopenia and neutropenia. 153Sm-EDTMP can be combined with radiation therapy, bisphosphonates and/or chemotherapy to synergistically improve palliation. This article reviews the rationale, indications and monitoring of standard-dose samarium and investigational high-dose 153Sm-EDTMP treatment of cancer involving bone.

Mechanism of osteoblastic bone metastasis of prostate cancer

The high prevalence of osteoblastic bone metastasis in prostate cancer is thought to be attributable to the production of osteoblast-stimulating factors by prostate cancer cells. Prostate-specific antigen (PSA) expression is arguably the most distinctive features of prostate cancer. PSA is a serine protease and an important serological marker for prostate cancer. Expression, secretion, and activation of transforming growth factor-beta (TGF-beta) is induced by PSA, and PSA-induced osteoblastic changes in bone were caused by an autonomous increase in mature osteoblasts and by depletion of the osteoclast population. Osteoblastic changes result from an imbalance between the rate of bone resorption and formation.

Prostate-specific antigen induces apoptosis of osteoclast precursors: Potential Role in osteoblastic bone metastases of prostate cancer

Prostate cancer is frequently associated with bone metastases with marked osteoblastic changes and low osteoclastic activity but its mechanism is not well understood. We previously reported that prostate-specific antigen (PSA) stimulated the proliferation and the activation of osteoblasts. In this study, we investigated the effect of PSA on osteoclastogenesis. Two human prostate cancer cell lines and PSA were directly injected into human adult bone (HAB) implanted into NOD/SCID mice, followed by morphological analysis. RAW 264.7 cells, murine osteoclast precursor, were treated with PSA. PSA-producing LNCaP and PSA caused a significant decrease of osteoclast precursors and osteoclasts in HAB accompanied by osteoblast proliferation and new bone formation, while PSA-nonproducing PC3 showed increasing osteoclasts with osteolysis. PSA induced apoptosis of RAW 264.7 cells in vitro. PSA-induced apoptosis was dependent of enzymatic activity of PSA and was specific to immature tartrate-resistant acid phosphatase-negative mononuclear RAW 264.7 cells. PSA plays a crucial role for osteoblastic bone metastasis by promoting both osteoblasts proliferation and apoptosis of osteoclast precursors.

Osteoblastic bone metastases in breast cancer: is not seeing believing?

Osteoblastic bone metastases in breast cancer: is not seeing believing?

Palliative and pain medicine: radiation oncology

Radiation therapy is an effective palliative treatment for incurable cancer. Radiation can be used to palliate pain, bleeding, or obstruction. Pain resulting from bone metastases can be controlled with external localized or wide field radiotherapy. Healing of bone fracture can be influenced by the use of radiation therapy. Radiopharmaceuticals such as 89 Sr and 153 Sm are considered forms of systemic radiation therapy that can be used in the presence of generalized osteoblastic bone metastases. Spinal cord compression can be fatal if not diagnosed and treated in a timely fashion. Radiation therapy plays a role in the management of brain metastases using traditional whole brain radiation therapy or stereotactic radiosurgery, offering a faster and easier way of palliation. Visceral metastases can be treated with external beam, brachytherapy, or radionuclides. Brachytherapy allows the safe delivery of high doses over short time intervals with minimal doses to the surrounding structures. The use of yttrium-90 microspheres is a new intraarterial therapy consisting of beta-irradiating microspheres that can be delivered directly to the tumors. 90 Y microspheres, which carry the radiation, are selectively taken up by the tumors, thus preserving normal liver. Radiation therapy is part of a multimodality approach to deal with cancer patients with serious conditions.

Altered Bone and Mineral Metabolism in Patients Treated with Imatinb.

Imatinib is a tyrosine kinase that effectively inhibits the bcr-abl fusion protein in Philadelphia (Ph) chromosome positive CML and c-kit, which is overexpressed in gastrointestinal stomal tumors (GIST). We identified a group of patients treated with Imatinib at Memorial Hospital who developed low phosphate (PO4) levels and studied metabolic bone and mineral parameters associated with this finding. A total of 61 patients who received a prescription for Imatinib from the hospital pharmacy were screened to determine whether a PO4 level had ever been drawn. Of these, 26 had at least one PO4 level, and 10 of these (38%) had a low value (<2.5 mg/dL).Patients samples were then studied for calcium (Ca++), parathyroid horme (PTH), 25-(OH)-vitamin D and 1,25-(OH)2-vitamin D, as well as serum markers of bone formation (bone alkaline phosphatase and osteocalcin) and resorption (N-telopeptide). Urinary calcium and PO4 were measured and fractional excretion of PO4 (FEPO4) was calculated as well. A total of 10 patients (8 men, 2 women) median age 47 (range 32–60) with CML (n=8) or GIST (n=2) were studied. The median time interval between diagnosis and starting Imatinib was 3.8 mos (range 0.4–161) and the median interval between starting Imatinib and first low PO4 was 3.9 mos (range 0.3–23).Results of Bone MetabolismUPINPO4CalciumPTHFePO4N-TelopepOsteocalcinBone Alk phos2.5–4.2mg/dL8.5–10.5mg/dL10–65pg/mL< 5%5.5–19.5nM3.1–12.7ng/ml15–441U/L12.08.78425NDNDND21.78.69724NDNDND32.39.46844NDNDND41.99.584257.13.71851.88.985176.2NMA1562.19.38323NDNDND71.78.757165.6NMA1781.38.11363810.1NMA5392.39.2811013.4NMA17102.18.941175.82.615ND: Not done: NMA: No measurable amount; 25-(OH)-vitD levels were low to mid-normal, and 1,25-(OH)2 vit D levels were typically borderline high or elevated (data not shown)Two patients who temporarily stopped Imatinib had normalization of their PO4, which again decreased upon resumption of the drug. In summary, patients who develop hypophosphatemia while on Imatinib have low-normal to mildly low serum Ca++ but elevated PTH, elevated FEPO4, low-normal levels of N-telopeptide, very low levels of osteocalcin, and low levels of bone alkaline phosphatase. These values distinctly differ from patients with either inherited or tumor induced forms of hypophosphatemia with renal phosphate wasting (X-linked hypophosphatemic rickets, adult dominant hypophosphatemic rickets, and tumor-induced osteomalacia). Our preliminary data suggest that in some patients, Imatinib results in profound suppression of bone formation and mild suppression of bone resorption, leading to a state of hypodynamic bone remodeling. Further investigation is planned comparing patients on Imatinib who become hypophosphatemic and those who do not. Better characterization of bone and mineral metabolism in this setting is important for several reasons: (1) myalgias from Imatinb, a common side effect, may be related to hyphophosphatemia and correctible with appropriate replacement; (2) while these data are premature, it is conceivable that Imatinib might be useful in situations where suppression of bone formation and turnover is desirable, such as in osteoblastic bone metastases, osteopetrosis, and other diseases of abnormally increased bone formation.

The Correlation Between Palliation of Bone Pain by Intravenous Strontium-89 and External Beam Radiation to Linked Field in Patients With Osteoblastic Bone Metastases

We studied the correlation between the efficacy of local external beam radiotherapy and the efficacy of strontium-89 in the palliation of osteoblastic metastatic bone pain in 43 patients with cancer. All 43 had been treated with hormonal or chemotherapy according to the primary malignancies and analgetic pharmacotherapy as needed, 36 received local external beam radiotherapy as a palliative before strontium-89 injection, and all 43 were ultimately treated with strontium-89 as salvage therapy. Responses to the first strontium treatment, and to the first radiation treatment if given, were taken from patient files. Pain was evaluated by Karnofsky performance status, analgesic dosage, and duration of response to treatment translated into numeric scores on a pain duration scale and an integrated response scale. The efficacy of limited field external radiation in metastatic bone pain palliation was 80.6% versus 58.1% for strontium-89. Patients treated with both external radiation and strontium had a positive correlation of 0.4 with a probability of P = 0.0158 between the responses to the 2 treatments, indicating that response to external radiotherapy could be viewed as an indicator of strontium-89 efficacy in metastatic osteoblastic bone pain palliation in the same patient. No significant correlation was found between strontium efficacy and gender, location of metastases to weight-bearing bones, duration of hormonal therapy or chemotherapy, or type of primary neoplasm.

Analysis of three-dimensional microarchitecture and degree of mineralization in bone metastases from prostate cancer using synchrotron microcomputed tomography

Bone architecture and mineralization are generally considered to be important components of bone quality, and determine bone strength in conjunction with bone mineral density. Although the features of bone quality have recently been studied under conditions in which bone density decreases, such as osteoporosis, little is known in osteosclerotic diseases. In this study, we compared the trabecular bone microarchitecture and degree of mineralization between osteoblastic bone metastasis and degenerative osteosclerosis using synchrotron radiation microcomputed tomography (SR-μCT). Small cubes of lumbar vertebrae were excised postmortem from the sites of osteoblastic metastasis, degenerative osteosclerosis, and comparative sites of normal subjects without skeletal lesions. The samples were imaged at high spatial resolution (voxel size = 6 μm) using the SR-μCT system developed at the synchrotron facility (SPring-8), Hyogo, Japan. The three-dimensional (3D) image data were then analyzed for the morphological parameters and the degree of mineralization of bone (DMB). Trabecular bone in metastatic lesions showed a highly connected and isotropic network pattern compared with the normal samples. Although the trabecular surface was markedly irregular in osteoblastic metastases, no significant difference was found in the mean trabecular thickness (Tb.Th) between osteoblastic metastases and normal tissue. The DMB of trabeculae in metastatic lesions had a broader range and lower mean than that of the normal tissue. In contrast, trabecular bone in degenerative osteosclerotic lesions showed a similar degree of anisotropy (DA) and connectivity to the normal tissue, whereas the trabecular thickness was greater in the degenerative osteosclerotic lesions. No significant difference in DBM between degenerative osteosclerosis and normal tissue was detected. These results characterize the difference in bone quality between osteoblastic bone metastasis and degenerative osteosclerosis. Further study on the relationship between bone quality and bone strength in these osteosclerotic lesions would improve our understanding of the pathogenesis of bone fragility.

Pulmonary adenocarcinoma with osteoblastic bone metastases in a cat

A 12-year-old male cat with depression and dyspnoea was presented for investigation. Radiography and computed tomography revealed hydrothorax and solid masses involving the sternum, ribs and thoracic vertebrae. The cat died two days after first presentation, and postmortem examination revealed lung masses and proliferative bony lesions. Histologically, a neoplastic proliferation of epithelial cells was seen in the lungs, with a large amount of collagen and deposits of cholesterin. The bone lesions were also composed of neoplastic epithelial cells and abundant calcified osteoid, without atypia. A diagnosis of pulmonary adenocarcinoma with osteoblastic bone metastases was made. This is the first reported case of osteoblastic metastases in the cat.

Management of Metastatic Bone Disease and Hypercalcemia of Malignancy

Thirty years of research have established bisphosphonates as the most effective agents for the inhibition of osteoclast-mediated bone resorption, and they play an important role in the management of malignant bone disease. Bisphosphonates have been systematically improved through chemical engineering, and the newest nitrogen-containing compounds, including zoledronic acid and ibandronate, are 1000-fold more potent than first-generation compounds. Consequently, they can be administered at low molar doses via short intravenous infusions without compromising renal safety. Bisphosphonates have a variety of metabolic effects on osteoclasts. Nitrogen-containing bisphosphonates inhibit protein prenylation via the mevalonate pathway, thereby inhibiting osteoclast activation and inducing apoptosis. Preclinical studies suggest that bisphosphonates also have direct and indirect antitumor activity. In animal models, bisphosphonates reduced skeletal tumor burden and bone metastases. Currently, intravenous bisphosphonates are the standard therapy for hypercalcemia of malignancy, and they have become an integral part of the treatment of bone metastases in conjunction with standard antineoplastic agents. Intravenous bisphosphonates quickly normalize serum calcium, reduce skeletal complications, and palliate bone pain in patients with bone metastases. Intravenous pamidronate (90mg via 2-hour infusion every 3–4 weeks) has, until recently, been the international standard for the treatment of osteolytic bone lesions from breast cancer or multiple myeloma. However, 4mg zoledronic acid (via 15-minute infusion) is quickly becoming the new standard based on evidence that it is as safe and effective as 90mg pamidronate in patients with breast cancer and multiple myeloma and significantly more effective for hypercalcemia of malignancy. Consequently, the American Society of Clinical Oncology guidelines for breast cancer and multiple myeloma recommend pamidronate or zoledronic acid for patients with radiographic evidence of osteolytic bone destruction. Moreover, 4mg zoledronic acid is the only bisphosphonate that has demonstrated significant clinical benefit in patients with other solid tumors, including lung cancer, and prostate cancer patients with primarily osteoblastic bone metastases. Bisphosphonates also may have activity in the adjuvant setting to prevent or delay the development of bone metastases. Studies with oral clodronate in early breast cancer have provided clinical evidence that bone metastases can be inhibited, and the studies are ongoing with more potent bisphosphonates. Bisphosphonates have also been shown to prevent cancer treatment-induced bone loss. These and other studies continue to redefine the role of bisphosphonates in the treatment of malignant bone disease and the management of bone health in cancer patients.

The role of zoledronic acid in cancer: Clinical studies in the treatment and prevention of bone metastases

Preclinical studies with zoledronic acid (Zometa; Novartis Pharmaceuticals Corp, East Hanover, NJ) have shown its potential in malignant bone disease. Clinical studies in the treatment of hypercalcemia of malignancy have been completed, as have phase I and II trials in patients with cancer and pre-existing bone metastases. Three randomized, double-blind, controlled phase III trials are ongoing to establish the efficacy and safety of zoledronic acid in the treatment of osteolytic and osteoblastic bone metastases. In one study, 4 mg zoledronic acid is compared with the standard therapy, 90 mg pamidronate, in treatment of osteolytic lesions in patients with breast cancer and multiple myeloma. Two other studies, one in patients with prostate cancer and bone metastases and another in patients with nonsmall cell lung cancer and other tumor types, are placebo-controlled. The primary end point in all three studies is the frequency of skeletal complications resulting from bone metastases. Adjuvant trials that assess the ability of zoledronic acid to prevent or reduce the incidence of bone metastases in patients at high risk for future skeletal metastasis are also planned or ongoing. The rationale and design of these ongoing and planned studies is discussed.

Placental bone morphogenetic protein (PLAB) gene expression in normal, pre-malignant and malignant human prostate: relation to tumor development and progression.

The second most common target of prostate-cancer metastasis is bone, and the phenomenon of skeletal metastasis represents the incurable stage of disease. Histologically, skeletal metastasis from prostate cancer is distinctive due to its osteoblastic nature. The osteoblastic bone metastasis shows extensive new bone formation, with possible involvement of the soluble growth factors secreted by tumor cells, such as bone morphogenetic proteins (BMPs). In the present study, we analyzed the gene expression of one of the new members of the BMP family, placental bone morphogenetic protein (PLAB). In situ hybridization studies showed high levels of this gene in normal prostate. However, the gene is down-regulated during the progression of cancer at the primary site. The most significant finding was re-expression of the PLAB gene in osseous metastatic lesions. Our results demonstrate that tumor cells, when released from the primary site and after re-growth elsewhere, are capable of re-expressing specific genes that may play a different role at metastatic sites than at the primary site.