Current Pharmaceutical Design - Volume 16, Issue 27, 2010

Bisphosphonates are stable analogues of the naturally-occuring inorganic pyrophosphate and unlike PPi, they are resistant to hydrolysis due to a carbon atom bridging the two phosphonate groups. Whether the first bisphosphonates formerly termed diphosphonates were synthesized in the late 1800s, their clinical applications have been relatively recent. In the 1960s, H. Fleisch and R.G.G. Russell identified the inorganic pyrophosphate as an important physiological regulator of calcification and with M.D. Francis demonstrated that bisphosphonates inhibit the pathological calcifications in vivo [1]. These three distinguished researchers will become the leaders of international research on bisphosphonates. The first medical use of the bisphosphonate, etidronate disodium, was in 1968 to treat a young patient suffering from myositis ossificans progressiva. Bisphosphonates have been widely used during the last 3 decades in the treatment of diseases involving excessive bone resorption which include post-menopausal osteoporosis, Paget's disease of bone, tumour-associated bone disease, and hypercalcaemia of malignancy. However, it is only in recent years that major advances have been made in our understanding of the cellular and molecular mechanisms of action of this class of drugs. The present issue of Current Pharmaceutical Design, for which I have the honour to be the Executive Guest Editor, will give an overview of the past, the present and the future of bisphosphonates. This special issue prepared by specialists of bisphosphonates addresses all aspects of bisphosphonates including their pharmacology and chemical evolution, their recent elucidated mechanisms of action (in bone and non bone cells), the assessment of their biological activities, their main pre-clinical use and in fine their main clinical applications. The specific pharmacology of nitrogen-containing bisphosphonates (N-BPs) is mainly attributable to their calcium adsorption and chelating properties. In agreement with this specificity, they primarily affect the function of resorbing osteoclasts but recent advances gave some evidences that other cell types (osteoblasts, osteocytes, monocytes, T lymphocytes, etc) could be the targets of these drugs. In this context, A.Roelof, K. Thompson, F.H. Ebetino, M.J. Rogers, and F.P. Coxon give an overview of the pharmacology of bisphosphonates covering their development, molecular mechanisms of action, bone mineral binding properties and cellular actions [2]. Once bound to bone the N-BPs can be internalized by osteoclasts where the drug can then interact with its molecular target, the Farnesyl Pyrophosphate Synthase (FPPS), a key enzyme in the mevalonate pathway. This targeting then prevents the prenylation process, disrupts vital signaling and induces the loss of osteoclast activities and their death. Recent investigations summarized by J.E. Dunford [3] clarified the biochemistry of FPPS and its inhibition by the N-BPs but also identified many other targets for this drugs (other FPPS enzymes, Matrix Metalloproteinases, Protein Tyrosine Phosphatases, etc). These targets lead to the development of a new generation of N-BPs characterized by a low affinity to the bone mineral and then can be available to extraosseous targets. These observations opened novel clinical applications. FPPS is the main targets of N-BPs, however these drugs exert consequently very large effects on cell metabolism affecting cell adhesion, migration, division and death. To identify the mechanisms of actions of bisphosphonates, novel methodologies have been set up. L.M. Mitrofan, S. Auriola, H. Monkkonen and J. Monkkonen [4] present an original review which highlights the main methodologies used to monitor the action of BPs in in vitro cell models, with a special emphasis on the detection of BP-induced ATP-analogues by mass spectrometry. Cell death monitoring, immunomodulatory effects and inhibition of growth/proliferation are also described. Bisphosphonates have been used successfully for many years to reduce the skeletal complications associated with the benign and malignant bone diseases that are characterized by enhanced osteoclastic bone resorption. Until recently, it was thought that the clinical efficacy of bisphosphonates in the treatment of cancer patients with bone metastases was purely a result of the inhibition of osteoclast-mediated bone resorption. However, recent studies have demonstrated that bisphosphonates inhibit the growth, attachment and invasion of cancer cells in culture and promote their apoptosis. These results suggest that these drugs are also anti-cancer agents, raising the possibility that they could inhibit cancer-cell colonization in visceral organs. Thus, a series of complementary reviews addressing the clinical interest of bisphosphonates in oncology is proposed in the present issue. The first is proposed by G. Moriceau, B. Ory, B. Gobin, F. Verrecchia, F. Gouin, F. Blanchard, F. Redini and Heymann D. and describes the clinical applications of bisphosphosnates in the primary bone tumors (giant cell tumor of bone, osteosarcoma, Ewing's sarcoma, chondrosarcoma, etc.) [5]. Thus, these drugs have been used as a carrier for radio nucleotides to develop novel approaches of bone imaging. They exert also indirect anti-tumour activities in vivo by interfering with the bone microenvironment and target osteoclasts, endothelial cells and immune cells (tumour-associated macrophages, γ9δ2 T cells). They induce tumour cell death in vitro and similar activity is suspected in vivo explaining why clinical trials assessing the combination conventional chemotherapy with bisphosphonates are actually in progress. In contrast to primary bone tumors for which the clinical impact of bisphosphonates is currently in progress, bisphosphonates are now a standard treatment for bone metastases. Pre-clinical data demonstrated the anti-tumor effects of bisphosphonates alone and to combine theses drugs with other anti-cancer agents. S.P. Syddall, P.D. Ottewell and I. Holen give an overview of these pre-clinical studies and of the main clinical studies which aimed to determine whether adding bisphosphonates to standard anticancer therapy will improve outcome for patients [6]. E.J. Woorward and R.E. Coleman have perfectly completed this last review and compelled the most recent reported randomised clinical studies to support the use of bisphosphonates in clinical practice at earlier stages of the disease to prevent bone metastases [7]. Recent data revealed that N-BPs are able to stimulate human γδ T cells and pastes N-BPs at the crossroad of innate and adaptive immunity. This new activity of N-BPs strengthens their interest as anti-tumour agents through the modulation of immune system. This novel activity of N-BPs is summarized by P. Clezardin and M. Massaia in an exhaustive review on the molecular and cellular mechanisms by which N-BPs stimulate the expansion and cytotoxic activity of human γδ T cells [8]. They also discuss the emerging clinical evidence that N-BPs can have a role in cancer immunotherapy. It will be not objective to focus all reviews of this issues to discard the other therapeutic options for the treatment of bone metastases excepted N-BPs. The recent better understanding of bone biology lead to the elaborations of newer and more and more efficient drugs with requires very stringent clinical studies to prove their clinical interest and to determine the long term side-effects. J.T. Buijs, CC.H. Kuijpers and G. van der Pluijm described in details the molecular process of metastasis from primary tumor to bone through which the novel drugs have been elaborated [9]. These authors have checked the novel therapeutic targets (bisphosphonates, RANKL, TGFβ, Wnt pathway, MMPs, Cathepsin K, integrins, calcium sensing receptor, CXXR5/CXCL12 axis, ET-1 pathway, glcycoprotein nonmetastatic B, Src, etc) and the strategies developed for the treatment of bone metastases. To complete this very large panel of review on bisphosphonate and cancers, M.A. Lawson, J. Ashcroft and P.I. Croucher have proposed a specific review on multiple myeloma and bisphosphosnates [10]. Indeed, multiple myeloma is an incurable B cell neoplasm often resulting in devastating osteolysis. Bisphosphonates have been successfully used to treat the tumour-induced bone disease associated with multiple myeloma. Their review focus on preclinical studies and clinical investigations of patients suffering from multiple myeloma which have contributed to a better under understanding of the mechanisms of action of bisphosphonates in this pathology. Because bisphosphonates currently remain the principle drugs used to treat excessive bone resorption, they have extensively used in rheumatology. The first review on this topic, prepared by B. Le Goff, P. Guillot, J. Glemarec, J.M. Berthelot and Y. Maugars summarize the use of bisphosphonates for the treatment of osteoporosis and compared their clinical effects with other treatment [11]. They have done an evaluation of the cost of all treatments, topic particularly important in the actual health politics. The second review presented by B. Le Goff, J.M. Berthelot, Y. Maugars and E. Romas focuses on the new potential alternative indications for bisphosphonate in rheumatic diseases [12]. Indeed, bisphosphonates could also have others properties through a specific analgesic or anti-inflammatory effect. Thus, rheumatic diseases like rheumatoid arthritis, spondylarthritis or SAPHO syndrome that are associated with bone loss could be good candidates for bisphosphonate therapy similarly to other non-inflammatory rheumatic diseases like bone osteonecrosis, algodystrophy, fibrous dysplasia or neuropathic osteoarthropathy. I wish to thank all the authors and co-authors for their commitments and to give their expertise to our colleagues, clinician and researchers, to the students and to all readers. I would like to thank the anonymous reviewers who contributed by their constructive remarks to the excellence of this issue.

Bisphosphonates are widely used in the treatment of diseases involving excessive bone resorption, such as osteoporosis, cancer- associated bone disease, and Paget’s disease of bone. They target to the skeleton due to their calcium-chelating properties, where they primarily act by inhibiting osteoclast-mediated bone resorption. The simple bisphosphonates, clodronate, etidronate and tiludronate, are intracellularly metabolised to cytotoxic ATP analogues, while the more potent, nitrogen-containing bisphosphonates act by inhibiting the enzyme FPP synthase, thereby preventing the prenylation of small GTPases that are necessary for the normal function and survival of osteoclasts. In recent years, these concepts have been refined, with an increased understanding of the exact mode of inhibition of FPP synthase and the consequences of inhibiting this enzyme. Recent studies further suggest that the R2 side chain, as well as determining the potency for inhibiting the target enzyme FPP synthase, also influences bone mineral binding, which may influence distribution within bone and duration of action. While bisphosphonates primarily affect the function of resorbing osteoclasts, it is becoming increasingly clear that bisphosphonates may also target the osteocyte network and prevent osteocyte apoptosis, which could contribute to their anti-fracture effects. Furthermore, increasing evidence implicates monocytes and macrophages as direct targets of bisphosphonate action, which may explain the acute phase response and the anti-tumour activity in certain animal models. Bone mineral affinity is likely to influence the extent of any such effects of these agents on non-osteoclast cells. While alternative anti-resorptive therapeutics are becoming available for clinical use, bisphosphonates currently remain the principle drugs used to treat excessive bone resorption.

The nitrogen containing bisphosphonates (N-BP) are the drug of choice for treating disease characterised by resorption of bone such as osteoporosis and metastatic bone disease. The overall mechanism of action is achieved through a combination of precise targeting to the bone environment and an extremely potent inhibition of a vital enzyme in an essential metabolic pathway. This targeting to bone is achieved through the phosphate-carbon-phosphate backbone of the drug which gives a high affinity for bone mineral. Once bound to bone the N-BP can be internalised by osteoclasts as they resorb bone where the drug can then interact with its molecular target. The enzyme target of these drugs, FPP synthase, is at a branch point in the mevalonate pathway. This pathway is principally used for the manufacture of cholesterol but also many other biochemicals including farnesyl pyrophosphate and geranylgeranyl pyrophosphate. These prenyl groups are used in the post-transcriptional modification of proteins such as small GTPases that require a lipid membrane anchor to function. The main cellular effect of the blockade of FPP synthase by N-BP is to prevent protein prenylation resulting in disruption to vital signalling pathways and loss of osteoclast function. This review will examine the biochemistry of FPP synthase, inhibition by the NBP and and other potential uses of prenyl synthase inhibitors.

Bisphosphonates are a class of drugs developed over the past three decades for the treatment of metabolic bone diseases with high bone turnover, such as Paget's disease, tumor associated osteolysis and osteoporosis. The exceptional pharmacokinetic profile of bisphosphonates makes them very suitable and safe drugs for the treatment of bone diseases, because, by conventional administration, osseous tissue and bone resorbing osteoclasts are the targets for these drugs as a result of the very high affinity of bisphosphonates for bone mineral. Several recent studies have demonstrated; however, that bisphosphonates decrease tumor burden in bone in rodent models of myeloma and metastatic bone disease, with suggestions of antitumor effects also in patients. Although, decreased tumor burden could be a consequence of inhibition of bone resorption, there is increasing evidence that bisphosphonates might also have direct effects on tumor cell in vivo, since effects on tumors outside of skeleton or at doses not inhibiting bone resorption have been reported. Recent studies also suggest that bisphosphonates have inhibitory effect also on endothelial cell function and angiogenesis in tumor tissue. These findings suggest that the target cells for bisphosphonates as well as their molecular mechanism of action may be more diverse and complex than realized so far. This review highlights the main methodologies used to monitor the action of BPs in vitro cell models, with a special emphasis on the detection of BP-induced ATP-analoques by mass spectrometry. In addition, cell death monitoring, immunomodulatory effects and inhibition of growth/proliferation are described.

Bone tumours can be dissociated in two main categories: i) primary bone tumours (benign or malignant) including mainly osteosarcoma and other sarcomas. ii) and giant cell tumour and bone metastases originate from others cancer (Breast, prostate, kidney cancer, etc). These tumours are able to destroy or/and induce a new calcified matrix. However, the first step of bone tumour development is associated with an induction of bone resorption and the establishment of a vicious cycle between the osteoclasts and the tumour growth. Indeed, bone resorption contributes to the pathogenesis of bone tumour by the release of cytokines (IL6, TNFα) which govern the bone tumour's development and which are trapped into the bone matrix. Bisphosphonates (BPs) are chemical compounds of P-C-P structure with a high affinity for bone hydroxyapatite crystals. Thus, they have been used as a carrier for radio nucleotides to develop novel approaches of bone imaging. BPs exert also indirect anti-tumour activities in vivo. Indeed, BPs directly interfere with the bone microenvironment and target osteoclasts, endothelial cells and immune cells (tumour-associated macrophages, γ9δ2 T cells). BPs induce tumour cell death in vitro and same activity is suspected in vivo. The present review summarizes the mechanisms of actions of BPs as well as their clinical interests in bone primary tumours.

Bisphosphonates are standard treatment for cancer-induced bone disease, a common feature of many advanced malignancies. Traditionally used to inhibit bone turnover and reduce the risk of skeletal-related events, there is now increasing pre-clinical evidence that these agents may also affect tumour burden and disease progression. In particular, combining bisphosphonates with chemotherapeutic agents has been demonstrated to cause substantially increased anti-tumour effects compared to giving the single agents. Clinical studies are in progress to determine whether adding bisphosphonates to standard anti-cancer therapy results in improved outcome for patients. Here we give an overview of the key pre-clinical studies of anti-tumour effects of bisphosphonates, alone and in combination with other agents, and introduce some of the ongoing clinical trials that aim to determine the clinical relevance of bisphosphonates in combination therapy.

Certain primary tumours including breast and prostate cancers have a particular propensity for metastasis to bone. Metastatic bone disease can have significant impact on morbidity and mortality of cancer patients. Skeletal-morbidity (spinal cord compression, hypercalcaemia, fracture, need for radiotherapy and surgery to bone) can be effectively reduced by bisphosphonates, a class of antiresorptive drugs. They are also effective in relieving pain from bone metastases, and may improve survival in patients with accelerated bone resorption. Additionally, there is an exciting body of evidence that suggests these drugs may have anti-tumour effects that may be exploited to prevent or delay the development of bone metastases. Reported effects include inhibition of cancer cell migration, adhesion and invasion as well as anti-angiogenic and immunomodulating effects. The pre-clinical evidence is compelling, and some recently reported randomised clinical studies go part way to support their use in clinical practice at earlier stages of the disease to prevent bone metastases. However, further results are awaited before routine clinical use in the adjuvant setting can be recommended.

Bisphosphonates, especially nitrogen-containing bisphosphonates (N-BPs), are widely used to block bone destruction in cancer patients with bone metastasis because they are effective inhibitors of osteoclast-mediated bone resorption. In addition to their antiresorptive effects, preclinical evidence strongly suggests that N-BPs have anticancer activity. Some of the activities associated with N-BPs are observed in human γδ T cells that straddle the interface of innate and adaptive immunity and have potent anti-tumour activity. This review examines the molecular and cellular mechanisms through which N-BPs stimulate the expansion and cytotoxic activity of human γδ T cells. In addition, we discuss the emerging clinical evidence that N-BPs have a role in cancer immunotherapy.

Cancer is a major leading cause of death in the western world (following heart diseases). It poses an enormous burden on patients and society with a major impact on healthcare and economy. Once cancers have spread to the skeleton, treatment options are predominantly limited to palliation, treatment of hypercalcemia and prevention of pathological fractures. Despite the elaborate efforts of modern medicine to improve treatment, novel therapies for the treatment of solid tumors in patients with advanced disease, including metastatic bone disease, have generally failed to improve patient overall survival. However, initial beneficial responses on metastatic tumor burden are frequently followed by re-growth of therapy resistant, malignant metastatic bone lesions. Cancer relapse in bone coincides with devastating consequences and causes considerable morbidity. Bisphosphonates represent the current gold standard in bone metastasis therapies. Because of the progress made in our understanding of the pathogenesis of skeletal metastasis using preclinical models, newer and more efficacious compounds and therapies have been developed that are being evaluated (or will soon be) in clinical trails. In this chapter, we discuss novel therapeutic targets and strategies for the treatment of metastatic bone disease. Future, successful treatment of skeletal metastasis will rely on targeting critical molecular mediators/processes in both metastasisinitiating subpopulations of osteotropic cancers (“the seed”) together with their supportive, cellular and extra-cellular surrounding bone/bone marrow stroma (“the soil”).

Multiple myeloma is an incurable B cell neoplasm caused by the monoclonal expansion of malignant plasma cells in the bone marrow, often resulting in devastating bone disease. For over 2 decades bisphosphonates have been successfully used to treat the tumourinduced bone disease associated with multiple myeloma. This review will focus on preclinical studies and investigations in patients with multiple myeloma that have led to our current understanding of the mechanisms of action of bisphosphonates in myeloma bone disease. Major advances in the use of bisphosphonates, including findings that they may have additional benefits such as anti-tumour effects and promoting patient survival will be discussed.

Since their development 30 years ago, bisphosphonates are now one of the standard therapy in the management of osteoporosis. Improvements in terms of anti-resorptive potency have leaded to new molecules available either orally or intravenously, from weekly to yearly administration. Overall tolerance of bisphosphonates is good with regards to the risk of mandibular necrosis, not comparable with those observed in cancer treatment, and with no causal link yet established in osteoporotic patients. Compliance remains poor and should be improved by a better education of the patients about their treatment. Other treatments like teriparatide, raloxifene or strontium ranelate are now also available and give more therapeutic options but also more questions on the best molecule to choose for each patient. There is currently no valid basis for distinguishing in a formal and objective manner the different new-generation bisphosphonates, in terms of efficacy against either vertebral, peripheral or hip fractures. In a same way, comparison between bisphosphonates and the other treatments available for osteoporosis is hard in absence of proper randomised controlled study. This review gives an overview of the recent data on the efficacity and tolerance of bisphosphonates in the different forms of osteoporosis and compares them to the other treatments currently available.

Bisphosphonates are widely use for pathologies such as osteoporosis, Paget's disease or bone metastasis. However, their potent antiresorptive properties open new therapeutic opportunities for other conditions associated with an increased focal or systemic bone remodelling. Moreover, apart from their antiresorptive activity, bisphosphonates could also have others properties through a specific analgesic or anti-inflammatory effect. Thus, rheumatic diseases like rheumatoid arthritis, spondylarthritis or SAPHO syndrome (acronym for synovitis, acne, pustulosis, hyperostosis and osteitis) that are associated with systemic and sometimes focal bone loss could be good candidates for bisphosphonate therapy. Other non-inflammatory rheumatic diseases like bone osteonecrosis, algodystrophy, fibrous dysplasia or neuropathic osteoarthropathy are also associated with pain and an increase of focal bone remodelling. Several studies have shown that bisphosphonate could have promising therapeutic potential in these inflammatory or non-inflammatory diseases where therapeutic options are usually few. This review will focus on the new potential alternative indications for bisphosphonate in rheumatic diseases