High Affinity For Bone Research Articles

The Osteoclast as a New Target in the Treatment of Rheumatoid Arthritis: A Role for the Bisphosphonates?

There is a lot of evidence that osteoclasts have a pivotal role in the subchondral, periarticular and general bone loss in rheumatoid arthritis. Bisphosphonates have a high affinity for bone where they are strong inhibitors of osteoclast mediated bone resorption. There is no doubt that bisphosphonates are useful in patients with postmenopausal or glucocorticoid induced osteoporosis certainly if these patients also suffer from RA. Bisphosphonates appear to have beneficial effects on subchondral bone loss and joint destruction in animal models of arthritis. However in human studies these effects remain largely unclear although some antiinflammatory influence seems to be confirmed. An explanation for this discrepancy might be the possibility that more potent agents, or higher doses of existing agents, need to be used. Additional research is necessary to reveal if bisphosphonates possess disease-modifying properties in RA. Keywords: rheumatoid arthritis, osteoporosis, joint destruction, bisphosphonates, osteoclasts, cytokines

生体活性チタン合金のin vivo骨界面強度(J10-2 チタン系材料の展開と応用技術,J10 チタン系材料の力学・強度特性と応用技術)

Pure titanium and titanium alloy are generally used as orthopaedic implants like total hip arthroplasty because of its high strength and high biocompatibility. Stability of bone-implant interfacial bonding is a critical factor for successful total hip arthroplasty. Because of the problems of loosening and dissolution of harmful ion with cemented techniques, alternative cement-less fixation of the total hip arthroplasty has been developed. Plasma spray coating of bone-like apatite is an example to add strong bonding capability with bone to metallic materials. However, this physical coating treatment shows weak base-coating bonding strength and difficult to apply on irregular surface. Chemical treatments do not have such drawbacks. The alkali-heat treatment method, developed by Kokubo et al, is a kind of chemical treatment to enhance the bone-bonding strength of pure titanium. This technique involves soaking the implant in an alkali solution and subsequent heating, resulting in a strong bone-bonding ability and a high bone affinity. This study transplants alkali heat treated titanium alloy on the rabbit femoral bone and examined in vivo interfacial bonding strength.

Bone histology at autopsy and matched bone scintigraphy findings in patients with hormone refractory prostate cancer: the effect of bisphosphonate therapy on bone scintigraphy results: Roudier MP, Vesselle H, True LD, Higano CS, Ott SM, King SH, Vessella RL, Department of Urology, University of Washington, Seattle, WA. Clin Exp Metastasis 2003;20:171–180

Bisphosphonates (BisP) are nonmetabolized compounds with high-bone affinity used in bone metastasis diagnosis and treatment. Currently, BisP are used to treat hypercalcemia of malignancy as well as to prevent, minimize, or delay skeletal morbidity. These compounds have a long half-life in bone. Thus, long-term BisP treatment might saturate bone and interfere with a single-dose scanning agent used for bone scintigraphy when visualizing bone metastases. In an effort to answer this question, this study evaluated the concordance of histology and Technetium99 methylene diophosphonate (Tc99 MDP) bone scintigraphy in the diagnosis of bone metastases in prostate cancer patients. We assessed the concordance of findings between bone scintigraphy and histology using 188 bone biopsies from 11 autopsied patients who died with metastatic prostate cancer, 5 of whom were treated with pamidronate for 2 to 13 months before death. Overall agreement between histology and bone scintigraphy was 84%, 86% in nonpamidronate-treated patients and 82% in pamidronate-treated patients. Scintigraphic bone metastases without histological metastasis (false negatives = 12.7%) were observed in 24 anatomic locations; half of these were in one patient who had been treated with pamidronate and had no histological bone response to the carcinoma. There were only 4 sites where a positive bone scan was not associated with histologic metastasis (false positives = 2.21%). There was no statistical difference between the treated and nontreated group for concordance, specificity, sensitivity, positive and negative predictive values of bone scintigraphy and prevalence of histological abnormality. Long-term pamidronate treatment of prostate cancer bone metastases does not generally affect the ability to detect bone metastases with Tc99 MDP bone scintigraphy.

Dentin matrix protein 1 is expressed in human lung cancer.

We have previously shown that breast and prostate cancers express bone matrix proteins. DMP1 expression was evaluated in 59 human lung cancer samples at the protein and mRNA levels. It was detectable in 80% of the cases, suggesting a potential role for DMP1 in tumor progression and bone metastasis. Previously, we and others have shown that bone extracellular matrix proteins such as bone sialoprotein (BSP) and osteopontin (OPN) are expressed in various types of cancer that are characterized by a high affinity for bone including breast, prostate, and lung adenocarcinoma. Based on biochemical and genetic features, BSP, OPN, dentin matrix protein 1 (DMP1), and dentin sialophosphoprotein (DSPP) have been recently classified in a unique family named SIBLING (small integrin-binding ligand, N-linked glycoprotein). Therefore, we investigated whether DMP1 could also be detected in osteotropic cancers. We first used a cancer array for evaluating the relative abundance of DMP1 transcript in a broad spectrum of human cancer tissues. This screening showed that DMP1 was strongly detectable in lung tumors compared with normal corresponding tissue. In a second step, we used an immunophosphatase technique and a specific polyclonal antibody directed against DMP1 to examine the expression of DMP1 in 59 human non-small cell lung cancer samples, including 29 squamous carcinoma, 20 adenocarcinoma, and 10 bronchioloalveolar carcinoma. Student's t-test was used to determine the statistical significance of immunostaining scores between the lung cancer histological groups studied and between cancer and normal lung tissues. Our results show that DMP1 is detectable in 90% of the adenocarcinoma and squamous carcinoma analyzed while 8 of 10 bronchioloalveolar specimens were negative. DMP1 immunostaining intensity and extent scores were significantly higher in adenocarcinoma (p = 0.0004) and squamous carcinoma (p < 0.0001) samples compared with adjacent normal lung tissue. In situ hybridization experiments confirmed that DMP1 mRNA is localized in lung cancer cells. In this study, we show that a third SIBLING protein is ectopically expressed in lung cancer. The role of DMP1 in lung cancer is largely unknown. Further studies are required to determine the implication of this protein, next to its sisters SIBLING proteins, in tumor progression and bone metastasis development.

Bone as an effect compartment : models for uptake and release of drugs.

"Bone-seeking agents" are drugs characterised by high affinity for bone, and are disposed in bone for prolonged periods of time while maintaining remarkably low systemic concentrations. As a consequence, the bone becomes a reservoir for bone-seeking agents, and a site of both desirable and adverse effects, depending on the pharmacological activities of the specific agent. For some agents, significant systemic effects may also be produced following their prolonged release from bone, a process that is governed mostly by the rate of bone remodelling. This review covers the pharmacokinetic and pharmacodynamic features of bone-seeking agents with different pharmacological properties, including drugs (bisphosphonates, drug-bisphosphonate conjugates, radiopharmaceuticals and fluoride), bone markers (tetracycline, bone imaging agents) and toxins (lead, chromium, aluminium). In addition, drugs that do not possess bone-seeking properties but are used for therapy of bone diseases (such as antibacterials for treatment of osteomyelitis) are discussed, along with targeting of these drugs to the bone by conjugation to bone-seeking agents, local delivery systems, and other approaches. The pharmacokinetic and pharmacodynamic behaviour of bone-seeking agents is extremely complex due to heterogeneity in bone morphology and physiology. This complexity, accompanied by difficulties in human bone research caused by ethical and other limitations, gave rise to modelling approaches to study bone drug disposition. This review describes the pharmacokinetic models that have been proposed to describe the pharmacokinetic behaviour of bone-seeking agents and predict bone concentrations of these agents for different doses and patient populations. Models of different types (compartmental and physiologically based) and of different complexity have been applied, but their relevance to drug effects in the bone tissue is limited since they describe the behaviour of the "average" drug molecule. Understanding of the cellular and molecular processes responsible for the heterogeneity of bone tissue will provide better comprehension of the influence of microenvironment on drug bone disposition and the resulting pharmacological response.

Bone affinity of a bisphosphonate-conjugated protein in vivo.

Growth factors capable of stimulating bone formation are potential therapeutic agents for osteoporosis treatment. It is essential, however, that a targeting mechanism is incorporated into the growth factors to deposit them at osseous tissue with minimal distribution to extraskeletal sites. To this end, a strategy has been developed in which a bone-seeking molecule, 1-amino-1,1-diphosphonate methane (aminoBP), was chemically conjugated to a model protein, bovine serum albumin (BSA). This study was carried out to assess the bone affinity of the conjugates in a tibia injection model. Using ovariectomized (OVX) rats, initial (3 h) retention of BSA and aminoBP-BSA were found to be equivalent when injected into the medullary cavity of tibia. After 1 day, an 8- and 12-fold higher tibiae retention of the protein was obtained in normal and OVX rats as a result of aminoBP conjugation. A similar result ( approximately 12-fold difference) was also obtained in OVX rats after 3 days. We concluded that aminoBP conjugation to BSA imparted a high bone affinity and enhanced bone retention of proteins in normal and OVX rats.

Bisphosphonate conjugation to proteins as a means to impart bone affinity.

Growth factors are endogenous proteins capable of stimulating new bone formation, but their clinical benefit for systemic stimulation of bone mass has not been demonstrated. The critical challenge is to deliver a significant dose of the proteins to bone after intravenous injection. This challenge may be overcome by derivatizing proteins with ligands that exhibit a high bone affinity (e.g., bisphosphonates). To demonstrate the feasibility of this approach, 1-amino-1,1-diphosphonate methane (aminoBP) was conjugated to a model protein, albumin. The conjugation was performed by (1) converting the amino group of aminoBP to a thiol group using 2-iminothiolane, (2) derivatizing the albumin amino groups with a thiol-reactive sulfosuccinimidyl-4-(N-maleimidomethyl)-1-cyclohexane carboxylate, and (3) reacting the derivatized albumin with thiolated aminoBP. Typically, 1-4 aminoBP molecules per albumin were obtained. The conjugated albumin exhibited a high affinity to hydroxyapatite that was proportional to the extent of conjugation. The conjugates were shown to exhibit a high affinity to bone matrix in vitro in a serum-containing medium. Once bound to bone matrix, the conjugates were found to desorb more slowly than the unmodified albumin, especially from bone whose organic matrix was removed by ashing. In conclusion, conjugation of bisphosphonates to albumin was shown to impart a high bone affinity to the protein, and such conjugates can be potentially targeted to bone.

Bisphosphonates in development for metabolic bone disease

Bisphosphonates are analogues of endogenous pyrophosphate and exhibit profound effects on bone metabolism. These compounds have been shown to inhibit the recruitment and/or activity of osteoclasts (bone-resorbing cells) and to increase bone mass by reducing both the activation frequency of new bone remodelling units and the depth to which osteoclasts resorb bone. In animal studies, several bisphosphonates (etidronate, tiludronate, pamidronate, and cimadronate (YM-175) have also produced beneficial biomechanical effects on bone (increases in bone strength, stiffness and fracture load) in conjunction with increases in bone mass. Because of the bisphosphonates' high affinity for bone, very few soft-tissue effects or toxicities are observed. Bisphosphonates have shown clinical efficacy in metabolic bone diseases such as Paget's disease, metastatic hypercalcaemia and postmenopausal osteoporosis, and their use is under investigation in other diseases of abnormal bone turnover such as glucocorticoid-induced oste...

Comparison of biological characteristics of EDTMP complexes with 99mTc, 111In and 153Sm in rats

The pharmacokinetics and elimination of EDTMP chelates with different radionuclides ( 99mTc, 111In and 153Sm) has been investigated in rats. The biodistribution of the complexes under study was similar and two main processes, namely bone uptake and the elimination of glomerular filtration, take part in their rapid blood clearance. A substantially slower blood clearance of 111In-EDTMP in comparison with the other complexes suggests partial indium exchange between the chelate and transferrin. All the complexes exhibited high affinity for bone and the radionuclide uptake into the skeleton was in the order 153Sm 111In 99mTc. No specific extra-skeletal uptake was found.

Comparison of non-invasive approaches to red marrow dosimetry for radiolabelled monoclonal antibodies

Red marrow is usually the dose-limiting organ during radioimmunotherapy. Several non-invasive approaches to calculate the red marrow dose have been proposed. We compared four approaches to analyse the differences in calculated red marrow doses. The data were obtained from immunoscintigraphy of two antibodies with different red marrow kinetics [iodine-131-16.88 IgM and indium-111-OV-TL-3 F(ab')2]. The approaches are based on, respectively, homogeneously distributed activity in the body, a red marrow-blood activity concentration ratio of 0.3, scintigraphic quantification, and a combination of the second and third approaches. This fourth approach may be more adequate because of its independence from the chosen antibody. In addition, the influence of activity accumulation in liver, kidneys or cancellous bone on red marrow dose was studied. The calculated red marrow dose varied between 0.14 and 0.42 mGy/MBq for 111In-OV-TL-3 and between 0.13 and 0.68 mGy/MBq for 131I-16.88. If the radiopharmaceutical shows high affinity for cancellous bone or another organ situated near the red marrow, the activity in these organs must be included in dose calculations. This study shows a large variation in calculated red marrow dose and selection of the definitive non-invasive approach awaits validation.

Ｈｕｍｏｒａｌ ｈｙｐｅｒｃａｌｃｅｍｉａ ｏｆ ｍａｌｉｇｎａｎｃｙを合併した有きょく細胞癌

We reported a case of humoral hypercalcemia of malignancy (HHM) in association with squamous cell carcinoma of the skin. The term HHM describes the condition in which the hypercalcemia is due to the production by the cancer of some substance which acts generally upon the skelton to increase bone resorption.The patient was a 51-year-old man. He became aware of asymptomatic tumor, on his lower back, measured about 2×2cm in 1971. From June, 1992, the lesion enlareged rapidly and ulcerlated. At the same time, both inguinal lymph nodes metastases were found. When he was addmitted our hospital on September, 1992, the size of the lesion on the lower back was 18×10cm. Histopathological examination of the lower back and inguinal lymph nodes revealed an infiltrating, well differentiated squamous cell carcinoma of the skin with involvement of the lymph nodes. The cell masses showed keratinization, horn pearls were present.Laboratory studies on admission showed as following: the WBC count was 8, 600/ mm3, with a normal differential cell count. The hemoglobin level was 15.6g/dl, and the hematocrit reading was 45.7%. The liver function tests, urinalysis were normal. The total protein level was 7.3g/dl and an albumin level was 4.0mg/dl. The serum calcium level was 13.4mg/dl, the phosphate value was 2.1mg/dl. The serum parathyroid hormone (PTH) level was lower than 100 pg/ml (normal: 180-560pg/ml) . The serum calcitonin level was 5lpg/ml (normal: 0-100pg/dl) . Bone scintigram, computed tomography (CT), and X-ray examination showed no evidence of metastatic bone lesion. Culture from his wound revealed Staphylococcus aureus.We treated him for hypercalcemia with sodium chloride infusion and calcitonin. However, the serum calcium level was not significantly decreased. Then, we treated with aminohydroxyprolidene diphosphonate (APD) 30mg. Two days after this treatment, the serum calcium level fell to normal (10mg/dl) . APD is a kind of bisphosphonates which are analogues of pyrophosphate. They have high affinity for bone. The precise effects of bisphosphonates on bone and bone cells are not known in detail, however, they are thought to be taken up by osteoclasts and appear to inhibit the action of these cells.The tumor of lower back and inguinal lymph nodes were excised and skin graft wasapplied. And we administered doxorubicin hydrochloride and cisplatin. However, because of recurence, the serum calcium level rose again and his condition deteriorated. He died on Jan. 23, 1992.Parathyroid hormone related protein (PTH-rP) is one of the substance which cause HHM. Recently, cDNAs coding for a PTH-rP has been cloned. PTH-rP shares 80% homology with the first 13 amino acids of PTH in the resion responsible for binding to the PTH receptor. Whether PTH-rP has a physiological role is uncertain, but the compound seems to be primary associated with epithelium. Very high concentrations have been found in breast milk, and immunocytochemical studies have demonstrated high concentrations of PTH-rP in mammary epithelium. It is also abundant in skin, and most squamous cell carcinomas contain PTH-rP. During his hospitalization, we studied his serum level of PTH-rP. The normal level was from 13.8 to 55.3pmol/l. The patient's was 728.4pmol/l. So, we thought the secretion of PTH-rP from SCC was responsible for his hypercalcemia.

Anticancer-agent-linked phosphonates with antiosteolytic and antineoplastic properties: a promising perspective in the treatment of bone-related malignancies?

Bisphosphonates are compounds with a high affinity for bone and other calcified tissues. They inhibit tumor-induced bone destruction and the associated hypercalcemia by hindering the activity of the osteoclasts. Owing to a long biological half-life of bisphosphonates in the bone, a treatment using a prophylactic regimen seems possible. This paper summarizes preclinical studies with the bisphosphonate 3-amino-1-hydroxypropylidene-1,1-diphosphonic acid and two methyl derivatives; 3-N,N-dimethylamino-1-hydroxypropylidene-1,1-diphosphonic acid and 4-N,N-dimetyhlamino-1-hydroxybutylidene-1,1-diphosphonic acid with respect to their bone-protecting activity in therapy as well as in prophylaxis. To find substances that are useful for the treatment of primary tumor, as well as bone metastasis, we synthesized and tested cis-diammine[nitrilotris(methylphosphonato)(2-)-O1,N1]platin um(II) and cis-diammine[( bis-(phosphonatomethyl)amino]acetato(2-)-O1,N1)platinum(II), which contain both an osteotropic and an antineoplastic moiety. Experiments were carried out: (a) in the intratibial transplanted Walker carcinosarcoma 256B of the rat, which mimics osteolytic bone metastasis, and (b) in the transplantable osteosarcoma of the rat, which shows a histology and metastatic pattern similar to that found in man. These investigations indicate that it is possible to effect adjuvant therapy of bone metastases by combination of two compounds with different properties into one structure without losing the therapeutic characteristics of the parent compounds. They thus provide evidence that it may be possible to design compounds well suited for the therapeutic or prophylactic treatment of bone-related malignancies.

Bisphosphonates: a new class of drugs in diseases of bone and calcium metabolism.

The geminal bisphosphonates are characterized by a PCP bond and are therefore analogs of pyrophosphate. They bind strongly to hydroxyapatite crystals and in vitro inhibit both crystal formation and dissolution. In vivo they inhibit soft tissue calcification and when given in large amounts also normal calcification. This effect is due to the inhibition of calcium phosphate crystal growth. Furthermore, the bisphosphonates are very potent inhibitors of bone resorption. The mechanism(s) of action is not yet known but is likely to be at a cellular level. The extent of the biological activity of each compound depends on the specific chemical structure, so that each individual bisphosphonate must be considered as a separate compound. The only common characteristic is the PCP group, which gives the compound its high affinity to bone. The individual effects, however, are determined by the side groups on the carbon atom. This opens interesting possibilities for the development of new compounds. No bisphosphonate analyzed so far can be degraded in vivo; all are either deposited in the skeleton, where they remain for years until the bone is destroyed, or are excreted in the urine. The high affinity for bone explains the specificity of the compounds for bone and the fact that they have relatively few nonosseous effects. Bisphosphonates are used in man to inhibit ectopic calcification, including dental tartar and ectopic ossification. Furthermore, they are used to inhibit bone resorption, especially in diseases such as Paget's disease and tumoral osteolysis. Finally, when linked to 99nTc, bisphosphonates are employed as bone scanning agents.

The development and in-vivo behavior of tin containing radiopharmaceuticals—I. Chemistry, preparation, and biodistribution in small animals

Tin is an essential ingredient of most technetium-99 m radiopharmaceutical preparations but its in-vivo distribution and long-term fate are not well understood. Tin-117 m ( t 1 2 l4 d; y 159 keV, 86% ) is an ideal Tracer for studying biological behavior of tin compounds as well as for developing clinically-useful radiopharmaceuticals. This work describes the preparation and in-vivo distribution in mice of a number of tin-117 m labeled compounds with commonly used ligands. High bone uptake of most compounds studied as well as the unexpectedly high bone uptake of Sn 4+-DTPA indicates a high bone affinity of tin bound to chemically diverse ligands. Various compounds show subtle but significant differences in blood clearance, excretion, and soft-tissue uptake. Differences among Sn 2+ and Sn 4+ compounds with the same ligand are particularly noteworthy. For stannic chelates, higher bone uptake, faster blood clearance, and reduced soft-tissue concentration were observed. It appears that tin compounds bind to bone predominantly through the tin atom and that the differences in biodistribution depend on factors such as the net charge on the complex, the oxidation state of tin, and hydrolytic and kinetic stabilities of the complexes. The results indicate that the favorable half-life and decay characteristics of tin-117 m in various stannic compounds, especially stannic-DTPA, make it potentially useful as.an agent for skeletal scintigraphy and radiotherapy of bone tumors.