The aim of the present work was to investigate birefringence and morphology of the secretory-stage enamel organic extracellular matrix (EOECM), and structural and mechanical properties of mature enamel of upper incisors from adult rats that had been treated with pamidronate disodium (0.5 mg/kg/week for 56 days), using transmitted polarizing and bright-field light microscopies (TPLM and BFLM), energy-dispersive X-ray (EDX) analysis, scanning electron microscopy (SEM) and microhardness testing. BFLM showed no morphological changes of the EOECM in pamidronate and control groups, but TPLM revealed a statistically significant reduction in optical retardation values of birefringence brightness of pamidronate-treated rats when compared with control animals (p<0.01). EDX analysis showed that pamidronate-induced statistically significant decrease in phosphorus’ quantity in outer mature enamel (p<0.01) and an increase in the calcium/phosphorus ratio in that structure (p<0.05). Pamidronate did not induce ultra-structural alterations in mature enamel as revealed by SEM and did not cause a reduction in its microhardness (p>0.05). The present study indicates that pamidronate can affect birefringence of the secretory-stage EOECM, which does not seem to be associated with significant changes in morphological and/or mechanical properties of mature enamel.

The proton-translocating inorganic pyrophosphatases (H+-PPases) are primary electrogenic H+ pumps that derive energy from the hydrolysis of inorganic pyrophosphate (PPi). They are widely distributed among most land plants and have also been found in several species of protozoan parasites. Here we describe, for the first time, the molecular cloning and functional characterization of a gene encoding an H+-pyrophosphatase in the protozoan scuticociliate parasite Philasterides dicentrarchi, which infects turbot. The predicted P. dicentrarchi PPase (PdPPase) consists of 587 amino acids of molecular mass 61·7 kDa and an isoelectric point of 5·0. Several motifs characteristic of plant vacuolar H+-PPases (V–H+-PPases) were also found in the PdPPase, which contains all the sequence motifs of the prototypical type I V–H+-PPase from Arabidopsis thaliana vacuolar pyrophosphatase type I (AVP1) plant. The PdPPase has a characteristic residue that determines strict K+-dependence, but unlike AVP1, PdPPase contains an N-terminal signal peptide (SP) sequence. Antibodies generated by vaccination of mice with a genetic or recombinant protein containing a partial sequence of the PdPPase and a common motif with the polyclonal antibody PABHK specific to AVP1 recognized a single band of about 62 kDa in western blots. These antibodies specifically stained both vacuole and the alveolar membranes of trophozoites of P. dicentrarchi. H+ transport was partially inhibited by the bisphosphonate pamidronate (PAM) and completely inhibited by NaF. The bisphosphonate PAM inhibited both H+-translocation and gene expression. PdPPase and PAM also inhibited in vitro growth of the ciliates. The apparent lack of V–H+-PPases in vertebrates and the parasite sensitivity to PPI analogues may provide a molecular target for developing new drugs to control scuticociliatosis.

Background: Osteoporosis causes much morbidity and mortality among elderly people. Older inpatients with severe mental illness may be at particular risk of osteoporosis because of factors including immobility, vitamin D deficiency and psychotropic medication.

Method: We screened predominantly older inpatients with severe mental illness for osteoporosis using a peripheral DEXA scanner. Associations were examined between patient variables and osteoporosis as detected by DEXA scan, Z-scores and history of fragility fractures. Patients were followed up to see how many subsequently received drug treatment for osteoporosis. Patient acceptability of the scanning technique was also assessed.

Results: It was possible to scan 72/89 (81%) of patients. Mean T-score was −2.79 (SD 1.50) and mean Z-score −0.76 (SD 1.34). Forty-two (58%) patients had osteoporosis and 23 (32%) osteopenia. Twelve (17%) patients with a history of fragility fractures had osteoporosis on DEXA scan. A scan suggestive of osteoporosis and a history of fragility fractures were both associated with age of 75 years and over and thoracic kyphosis. Low Z-scores were associated with longer hospital stay and osteoporosis-predisposing drugs. Patient acceptability of scanning was high. At follow-up, only 7/16 (44%) patients were suitable for central scanning and 9/40 (23%) for bisphosphonates.

Conclusion: Older institutional patients with severe mental illness are likely to be at high risk of developing osteoporosis. Peripheral DEXA scanning is acceptable to these patients and identifies those at high risk of fractures. Some behaviorally disturbed patients are not suitable for central scans or for some osteoporosis drug treatments.

Most patients present with disease that appears to be confined to the breast. However, a significant proportion of women will go on to develop metastatic breast cancer with bone being the most frequent site of distant relapse. The bone microenvironment provides a fertile soil for circulating metastatic cells as resorbing bone releases growth factors that are thought to attract circulating cancer cells to the bone surface and facilitate their growth and proliferation. These infiltrating tumour cells in turn produce bone cell-activating factors, which lead to increased bone resorption and further release of growth factors in a ‘vicious cycle’. The third-generation bisphosphonate zoledronic acid is a potent inhibitor of osteoclast-mediated bone resorption. It also has effects on numerous processes in the metastatic cascade, with in vitro and animal studies showing synergistic antitumour effects with a range of cytotoxic and endocrine treatments. The addition of zoledronic acid to adjuvant therapy could therefore be a therapeutic strategy of potential importance.

To investigate this, the AZURE trial was designed to determine whether adjuvant zoledronic acid improves the disease-free and bone metastasis-free survival of women with stage II/III breast cancer. Recruitment of 3300 subjects was completed in January 2006. First efficacy data are expected in 2008. There is a potential for synergistic action with chemotherapy to manifest as enhanced toxicity. Reassuringly, initial safety data show that zoledronic acid is well tolerated and can be safely combined with adjuvant chemotherapy without any increase in myelotoxicity or effect on dose intensity.

Endocrine adjuvant therapy for breast cancer has been associated with a decrease in bone mineral density (BMD) and bone loss. For aromatase inhibitors, this bone loss is likely to be the most significant limitation to their long-term use. Treatments traditionally used to counteract his effect include exercise and supplementation with calcium and vitamin D. A newer treatment is the use of bisphosphonates, a class of drugs that reduce osteoclast activity. Clinical trials currently underway to examine the effect of bisphosphonate treatment on breast cancer patients have shown improvement in bone strength. Additional benefits of bisphosphonates, currently under study, give this class of drugs an important role to play in the treatment of cancer treatment-induced bone loss.

Bone metastases frequently occur in advanced breast cancer patients and once incorporated into bone have profound effects on bone physiology. Bisphosphonates are potent inhibitors of osteoclastic function and are becoming increasingly important for the management of patients with breast cancer. They affect the ability of cancer cells to accelerate bone turnover and as a result control pain and reduce the risk of pathological fracture.

Furthermore ongoing clinical trials are investigating the role of bisphosphonates as an adjuvant therapy in high-risk breast cancer patients with an aim to prevent bone metastasis.

This article reviews the mechanisms of bone metastasis and will discuss present and future developments for the monitoring and treatment of metastatic bone disease.