Pharmacological diversity among drugs that inhibit bone resorption

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ScienceDirect Pharmacological diversity among drugs that inhibit bone resorption R Graham G Russell1,2 Drugs that inhibit bone resorption (‘anti-resorptives’) continue to dominate the therapy of bone diseases characterized by enhanced bone destruction, including Paget’s disease, osteoporosis and cancers. The historic use of oestrogens for osteoporosis led on to SERMs (Selective Estrogen Receptor Modulators, e.g. raloxifene and bazedoxifene). Currently the mainstay of treatment worldwide is still with bisphosphonates, as used clinically for over 40 years. The more recently introduced anti-RANK-ligand antibody, denosumab, is also very effective in reducing vertebral, non-vertebral and hip fractures. Odanacatib is the only cathepsin K inhibitor likely to be registered for clinical use. The pharmacological basis for the action of each of these drug classes is different, enabling choices to be made to ensure their optimal use in clinical practice. Addresses 1 The Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, United Kingdom 2 The Mellanby Centre for Bone Research, University of Sheffield Medical School, Sheffield S10 2RX, United Kingdom Corresponding author: Russell, R Graham G ([email protected], [email protected])

Current Opinion in Pharmacology 2015, 22:115–130 This review comes from a themed issue on Musculoskeletal Edited by James Gallagher and Graham Russell

http://dx.doi.org/10.1016/j.coph.2015.05.005 1471-4892/# 2015 Published by Elsevier Ltd.

Introduction and overview This chapter will focus on drugs that inhibit bone resorption, but also refer to recent developments with other bone-active drugs. The term ‘anti-resorptive’ when applied to the treatment of bone diseases is used to describe pharmacological agents that inhibit bone resorption. There are alternative terms, which are sometimes used, such as ‘anti-catabolic’ agents. The term ‘anabolic’ is commonly used to describe agents that stimulate bone formation [1]. A simpler and perhaps preferable nomenclature would to talk about ‘bone resorption inhibitors’ and ‘bone forming agents’. www.sciencedirect.com

Bone resorption is accomplished by highly specialized multi-nucleated osteoclasts, which dissolve the bone mineral phase of bone by secreting acid, and degrade collagen and other bone matrix proteins utilizing a battery of secreted or intracellular enzymes. There are many ways in which drugs can influence osteoclast development and action, directly or indirectly. Even though their individual pharmacological actions may involve different biochemical and molecular mechanisms, the net result of reducing bone destruction makes them very useful in the therapy of bone diseases, many of which are characterized by enhanced bone resorption. Indeed the use of drugs that inhibit bone resorption continues to dominate the treatment of not just osteoporosis, but also Paget’s disease of bone, myeloma and bone metastases secondary to breast, prostate and other cancers, as well as many less common acquired or inherited skeletal disorders, such as osteogenesis imperfecta, inflammatory bone loss, and glucocorticoid-associated osteoporosis. There are now several different classes of drugs approved for treating osteoporosis. Historically treatment options have included hormones, such as estrogens, as well as calcitonins. These have now been replaced by more effective treatments, which have convincingly been shown to reduce the occurrence of fractures in welldesigned prospective clinical trials. Considerable effort was devoted to developing SERMs (Selective Estrogen Receptor Modulators) as substitutes for classical estrogens, but among these only raloxifene and bazedoxifene continue to be used. Other drugs such as strontium salts have been introduced in some but not all countries. The bisphosphonates have been used clinically for more than 40 years and emerged as effective drugs for osteoporosis in the 1990s, first with etidronate, which was soon superseded by alendronate. Currently the bisphosphonate group of drugs remains the mainstay of treatment worldwide, based on their overall efficacy and safety. The therapeutic options have been much enhanced by the introduction of a biological therapy, the anti-RANKligand antibody, denosumab, which like the best bisphosphonates, can reduce the occurrence of fractures at all major skeletal sites, vertebral and non-vertebral sites, including hips. There has been a flurry of new developments in the past couple of years. The long awaited results from the Phase Current Opinion in Pharmacology 2015, 22:115–130

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3 trials of a cathepsin K inhibitor, odanacatib, have been announced and regulatory approval is expected soon. Furthermore intriguing results are emerging from studies of anti-sclerostin antibodies, such as romosozumab, which show that these bone-forming strategies may be accompanied by a significant anti-resorptive component. It is fascinating to note how the study of rare diseases has led to the identification of potential drug targets, and thence to several of the drugs now used for or being developed for treating skeletal diseases [2]. Even the bisphosphonates were first studied as analogues of pyrophosphate for their inhibitory effects on mineralization, as had been revealed in studies of hypophosphatasia, which is now treated by enzyme replacement with alkaline phosphatase [3]. The development of denosumab and cathepsin K inhibitors can both be traced back to the study of rare skeletal diseases. Among other potential anti-resorptive agents derived from studies of various osteopetrotic disorders are src inhibitors, chloride channel blockers, and ATP proton pump inhibitors. Similarly new bone forming agents such as anti-sclerostin antibodies and dkk antagonists have their origin in studies of the genetics of Wnt pathway modulators. Although the many genetic discoveries underlying the osteopetroses and other high bone mass disorders have inspired many pharmacological approaches, the treatment of osteopetrotic syndromes themselves remains challenging, but marrow transplantation, or interferons, can be helpful in selected cases [4]. There is a vast published literature about osteoporosis and its treatment, and many good recent reviews are available [5,6]. This chapter will discuss further some of the current pharmacological and clinical issues concerning the use of the established and emerging drugs.

Calcitonin and calcitonin gene-related peptides (CGRP) Calcitonin is a peptide hormone secreted by the C-cells of the thyroid gland, which inhibits bone resorption and lowers blood calcium by directly but transiently inhibiting osteoclast activity. Although salmon calcitonin turned out to be more potent than porcine or human calcitonin, it only showed weak anti-fracture effects in osteoporosis, and its use was quickly superseded by the bisphosphonates as more effective treatments. The nasal forms of calcitonin have been recently withdrawn by the CHMP because of concerns about cancer risk [7]. Efforts to develop oral forms of calcitonin have proved disappointing, both in osteoporosis and osteoarthritis. Calcitonin is still sometimes used for pain relief after vertebral fracture, and the neural effects of related peptides continue to be actively studied. Calcitonin generelated peptide (CGRP) is a 37-amino acid neuropeptide, produced by alternative RNA processing of the calcitonin Current Opinion in Pharmacology 2015, 22:115–130

gene. CGRP has two major forms (a and b), which belong to a group of peptides that all act on an unusual receptor family [8]. These receptors consist of calcitonin receptorlike receptor (CLR) linked to an essential receptor activity modifying protein (RAMP) that is necessary for its full function [9]. RAMPs are being studied as potential pharmacological targets in relation to cancer [10]. CGRP is a highly potent vasodilator and antagonists are being developed for migraine [11]. Other new aspects of calcitonin biology include its role in fetal development [12]. Recent studies suggesting that it may function physiologically as an inhibitor of bone formation, via effects on sphingosine-1-phosphate locally within bone [13,14]. Assays of procalcitonin are being used as a biomarker for sepsis [15].

RANK ligand/RANK, and the RANKL antibody (denosumab) RANK ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) are the two key cytokines that are essential for generating osteoclasts. Ablation of either results in osteopetrosis due to absence of functional osteoclasts. The discovery of these regulatory pathways has transformed bone biology and therapeutics. M-CSF binds to c-Fms, a single transmembrane domain receptor of the tyrosine kinase family, and RANKL binds to RANK, a single transmembrane receptor of the tumour necrosis factor (TNF) receptor family, which forms trimers upon ligand binding. M-CSF and RANKL are both secreted by bone marrow stromal cells and osteoblasts, whereas RANKL is also secreted by T cells and to a lesser extent by B cells. Osteocytes have recently been recognized as an important source of RANKL. Another component of the RANKL/RANK system is osteoprotegerin (OPG). OPG is a shed extracellular portion of the RANK receptor, which acts as a decoy-RANK receptor. OPG can act as an antagonist to RANK signaling and osteoclastogenesis by scavenging RANKL in the extracellular environment. OPG is also a regulated molecule, and it is the ratio between RANKL and OPG, which determines the level of activation of RANK, and therefore the extent to which osteoclast production and function is stimulated. The overall endocrine regulation of skeletal homeostasis involves interactions between systemic hormones and the RANKL/RANK/OPG system acting locally. Thus, several calcium-regulating hormones, including estrogens, parathyroid hormone (PTH), and vitamin D3 regulate the expression and secretion of both RANKL and OPG. Early attempts to develop drugs based on these pathways utilized a chimeric OPG-Fc fusion protein to antagonise RANKL, but this was thwarted by the formation of neutralising antibodies against OPG. This setback led www.sciencedirect.com

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to the more attractive strategy of inhibiting RANKL directly, and the introduction of denosumab. Denosumab is a fully human monoclonal antibody against RANK ligand (RANKL), which has now been marketed for several years under the name of Prolia1 (Pralia1 in Japan) for osteoporosis and Xgeva1 for the prevention of skeletal complications in patients with bone metastases from breast, prostate or other cancers. The clinical use of denosumab in osteoporosis is based on the results from the FREEDOM pivotal phase 3 clinical trial, which demonstrated a significant reduction in vertebral, nonvertebral and hip fractures compared with placebo [16]. FREEDOM is the acronym for the Fracture Reduction Evaluation of Denosumab in Osteoporosis every 6 Months study, which has now been extended

out to 8 years of treatment. These further studies have confirmed the ongoing efficacy and overall safety of denosumab [17–19,20]. Treatment with denosumab increases BMD and reduces markers of bone turnover to a significantly greater extent than oral bisphosphonates in women who had not received bisphosphonates at all or in the recent past, or in those who had switched from alendronate to denosumab treatment. It is becoming apparent the several key pharmacological differences between denosumab and the bisphosphonates may have important practical consequences. The drugs differ in their uptake and retention within bone, and in their effects on precursors and mature osteoclasts (Figure 1) [21]. This may explain differences in the degree and rapidity of reduction of bone resorption, their potential differential effects on trabecular and cortical bone, and

Figure 1

Osteoclasts Are Inhibited in Different Ways by Denosumb, Cathepsin K inhibitors, and Bisphosphonates

Bisphosphonates

Denosumab

Cathepsin K inhibitors RANKL RANK

Bisphosphonates (BPs) can also inhibit osteoclast differentiation

OPG Denosumab

Cat K inhibitors do not directly affect osteoclast differentiation

Denosumab blocks RANKL

BP BP BP

BP

BP BP BP

BP BP

Bone Bisphosphonates (BPs) bind to bone mineral. Nitrogen-containing BPs inhibit the resorptive function of osteoclasts via inhibition of FPPS and prenylation of GTP-ases, but ‘disabled’ osteoclasts may persist

Bone Denosumab binds to RANKLand blocks osteoclast differentiation and reduces osteoclast numbers to near zero

Bone Osteoclasts persist in the presence of Cat K inhibitors and may continue to produce ‘clastokines’ that stimulate osteoblasts

Current Opinion in Pharmacology

Scheme to illustrate differences in the way denosumab, cathepsin K inhibitors, and bisphosphonates act on osteoclast differentiation and function. Denosumab inhibits osteoclast production, whereas cathepsin K inhibitors do not. Bisphosphonates act both on osteoclast differentiation and function, resulting in impaired resorptive activity, and persistence of ‘crippled’ osteoclasts.

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the reversibility of their actions. The effects of denosumab on cortical bone are important and have been substantiated by elegant imaging studies of the upper femur [22,23]. The effects of denosumab rapidly reverse when treatment is stopped, which means that ensuring compliance is important if potential benefits are to be sustained. The effects of denosumab produces continuous increases in BMD on prolonged treatment, whereas the effects of bisphosphonate treatment appear to plateau earlier, after about three years. Another difference is the potential use of denosumab in patients with impaired renal function, in whom use of bisphosphonates is contra-indicated.

Oestrogens/estrogens and selective estrogen receptor modulators (SERMs) The decline in oestrogen production at the menopause has long been known to be associated with bone loss. The use of oestrogens as HRT (ERT or hormone replacement therapy) in postmenopausal women was therefore a logical approach towards alleviating not only the symptoms and consequences of the menopause, but also bone loss leading to osteoporosis. In recent years the use of oestrogens for osteoporosis is no longer advocated, not only because more selective and effective drugs have been developed, but also because of associated adverse events revealed in the Women’s Health Initiative (WHI), which showed an increase in heart attacks and breast cancer [24]. The overall benefits and risks of oestrogens continue to be re-appraised [25–27] and their reputation has been somewhat restored. The problems associated with HRT/ ERT provided an impetus to the development of selective oestrogen receptor modulators (SERMs), with the aim of retaining the beneficial effects of oestrogens while minimizing their adverse effects. The mechanisms by which oestrogens and oestrogen-like compounds act on bone and indeed on other tissues are complex. Oestrogens exert many of their cellular effects by binding to oestrogen receptors (a and b), which are members of the large family of nuclear hormone receptors that regulate the transcription of specific genes [28]. Oestrogens may have direct effects on bone cells, but many of their effects may be indirect, mediated for example by reducing the actions of the RANK-ligand system on osteoclast differentiation. Oestrogens can also exert rapid cellular responses by nongenomic mechanisms [29], for example by binding to another type of receptor, called the G protein-coupled estrogen receptor 1 (GPER), formerly referred to as G protein-coupled receptor 30 (GPR30). GPER is an integral membrane protein with high affinity for estradiol, and is a member of the rhodopsin-like family of G proteincoupled receptors. Selective estrogen receptor modulators (SERMs) are a diverse group of naturally occurring or synthetic Current Opinion in Pharmacology 2015, 22:115–130

non-steroidal compounds that exhibit tissue-specific estrogen receptor (ER) agonist or antagonist activity, that is, they can act as estrogens on some tissues but anti-estrogens on others. The biochemical basis for differential actions on various target tissues is most likely to be due to the different conformation changes induced in the receptor after binding to individual ligands. These conformational changes in the ER in turn result in different patterns of binding to various co-activators and co-repressor molecules, thereby leading to distinctive patterns of gene transcription and protein expression in the various target tissues. The pharmacological profile of each individual SERM is therefore determined by the effects observed on the key target tissues that are important for human health. An ideal SERM would therefore have positive effects on the cardiovascular system and bone, without stimulating breast or endometrial tissue and raising the risk of cancer. Attempts to meet this ideal profile have been partially successful with currently approved SERMs such as raloxifene and bazedoxifene. However, it has so far proved impossible to wean out the adverse effects of provoking hot flushes or venous thrombosis from any of the individual SERMs in current clinical use. There are several recent and comprehensive reviews of estrogens and SERMs available [30,31]. Many different molecules with oestrogen agonist or antagonist activity have been identified. Some occur naturally in nature, for example, isoflavones. Others have been synthesized and evaluated experimentally, and several have been examined for their clinical potential. Most have failed to progress on account of unacceptable side effects or lack of desired efficacy. These include droloxifene, idoxifene, and arzoxifene. Overall there have been more failures than successes in clinical development. There are currently only two SERMs approved for use of osteoporosis namely raloxifene and bazedoxifene. Lasofoxifene is another SERM that was effective in reducing fractures in clinical trials [32]. However, it has never been marketed, despite the encouraging clinical results and fracture data compared with other SERMs, and despite it receiving approval for use in the European Union countries. Raloxifene is approved for the prevention of invasive breast cancer as well as treatment of osteoporosis. Bazedoxifene is also approved in many counties either as a single agent but also as a combined preparation with conjugated equine estrogens, denoted as a tissue selective estrogen complex (TSEC). This pairing is designed to reduce the risk of endometrial hyperplasia that can occur with the estrogenic component of the TSEC without the need for a progestogen in women with a uterus. The combination also allows for the oestrogen to control hot flushes and to prevent bone loss without stimulating the breast or the endometrium. Although bisphosphonates remain first-line therapy for most patients, SERMs such www.sciencedirect.com

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as raloxifene and bazedoxifene can provide an acceptable alternative [33–36].

Strontium Strontium, as a ranelate salt, emerged in the 1990s as a potential treatment for osteoporosis, after prospective clinical trials had shown its efficacy in reducing fractures [37]. Strontium was initially depicted as an uncoupling agent, which stimulated bone formation while decreasing bone resorption. This was an attractive profile for a new drug for osteoporosis, and led to the concept of ‘DABAs’ (Dual Acting Bone Agents). Despite its apparent efficacy in reducing fractures, how this is achieved remains unclear [38]. The effects of strontium on bone resorption and formation are small, but there are substantial changes in BMD measurements, largely due to substitution of strontium for calcium in bone mineral. A plausible explanation for its effects on bone are that it changes the material properties of bone by altering composition of the mineral phase, thereby conferring resistance to fractures. Recent safety concerns about sensitivity reactions, venous thrombosis and adverse cardiovascular effects are now limiting its use.

Bisphosphonates Bisphosphonates have been used in clinical medicine for more than 40 years, and continue to be the main group of drugs used worldwide for treating the whole spectrum of bone resorption disorders. A search in PubMed using the term ‘bisphosphonates’ reveals over 20 000 references. The biological effects of the bisphosphonates (BPs), then called diphosphonates, were first reported in 1969 [39]. They were originally studied as inhibitors of calcification as well as of bone resorption, and the history of their development and clinical uses has been recently reviewed [40,41]. Their early use for bone scintigraphy has continued to the present day, and they also remain the standard of care for the treatment of Paget’s disease, and for the prevention of skeletal-related events in patients with myeloma or bone metastases. Their use in osteoporosis only became possible in the 1990s, when bone densitometry became widely available and enabled quantitative diagnosis and evaluation of osteoporosis, and their development as the leading drugs for the treatment of osteoporosis. Over the years many hundreds of different bisphosphonates have been made, and there are naturally many chemical, biochemical, and pharmacological differences among them. Several of these have been studied as clinical candidates in man, and more than a dozen have been registered for clinical use for various indications in various countries. www.sciencedirect.com

One of the gratifying advances is recent years has been the elucidation of the molecular mechanisms of action through which bisphosphonates act. The pharmacological effects of BPs as inhibitors of bone resorption appear to depend upon two key properties; their affinity for bone mineral, and their inhibitory effects on osteoclasts [42]. When bisphosphonates are administered they are rapidly cleared from the circulation by ‘first pass’ uptake into bone. There are differences in binding affinities for hydroxyapatite bone mineral among the clinically used BPs, which may influence their distribution within bone, their biological potency, and their duration of action. Within bone, bisphosphonates are internalised selectively by osteoclasts and appear in intracellular vesicles. Within osteoclasts they interfere with specific biochemical processes, by acting as analogues of naturally occurring pyrophosphate enzyme substrates. The nitrogen-containing BPs (including alendronate, risedronate, ibandronate, minodronate and zoledronate) act as strong and selective inhibitors of farnesyl pyrophosphate synthase (FPPS), a key enzyme in the mevalonate pathway of cholesterol biosynthesis. This pathway generates isoprenoid lipids utilized for the post-translational modification (prenylation) of small GTP-binding proteins that are essential for osteoclast function. The inhibition of farnesyl pyrophosphate synthase (FPPS) in the mevalonate pathway has other biochemical consequences. One of these is the accumulation of the upstream metabolite, isopentenyl pyrophosphate (IPP), which may be responsible for immunomodulatory effects on gamma delta (gd) T cells, specifically Vg9Vd2 T cells, via interaction with a putative ancestral phosphoantigen receptor [43]. Accumulation of IPP can also lead to production of another ATP metabolite called ApppI, which has intracellular actions, including induction of apoptosis in osteoclasts. Some of the simpler older BPs such as etidronate, clodronate, and tiludronate, which do not contain nitrogen groups, act in a different manner, by being incorporated into ATP by specific reversal of t-RNA synthases involved in amino acid activation during protein synthesis [44]. BPs may have other biologically important cellular effects, on inhibiting osteoclast differentiation, on decreasing tumour cell viability, and on preventing osteocyte apoptosis, the latter possibly through other pathways, for example, connexin channels [45]. The extensive knowledge about how BPs work explains why different BPs share many pharmacological properties, but also why every BP has a specific and often unique profile based on its mineral binding affinity and IC50 on its enzyme targets such as FPPS. Clinicians should be aware that these pharmacological differences may be of practical importance [46], for example Current Opinion in Pharmacology 2015, 22:115–130

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in the degree and duration of reduction of bone turnover, which may influence how long to treat patients with individual drugs. For many years the ‘big’ four bisphosphonates (alendronate, risedronate, zoledronate, ibandronate) have been the leading drugs used worldwide for the treatment of osteoporosis. This has been based on the results from randomized controlled trials (RCTs), in which alendronate, risedronate, and zoledronate were shown to reduce the risk of vertebral, nonvertebral, and hip fractures. Bisphosphonates are also indicated for treating glucocorticoid induced osteoporosis [47]. Several other bisphosphonates also have been used in osteoporosis and other disorders, but have not achieved broad indications and been licensed in fewer countries. Etidronate was approved in most countries in the early 1990s, and these other BPs include clodronate, pamidronate, tiludronate, neridronate, minodronate, and olpadronate. Pamidronate has been extensively used off-label for osteoporosis as it was the only intravenous bisphosphonate available before zoledronate. It is still used in the management of osteogenesis imperfecta [48,49]. Pamidronate also has been used in children with severe burns to retard bone and muscle loss presumed to be mediated by inflammatory cytokines [50]. Interestingly minodronate has emerged as probably the most potent bisphosphonate, but is only used in Japan [51,52]. There are several currently debated issues regarding the use of bisphosphonates. In the case of osteoporosis some of these topical issues include deciding whom to treat and for how long, which bisphosphonate to use, and how to manage poor compliance [53,54]. In general bisphosphonates have proved to be not only highly effective but also very safe drugs. Nonetheless, issues of side effects and adverse events continue to attract attention, as with osteonecrosis of the jaw (ONJ), and atypical femoral (subtrochanteric) fractures (AFFs) and have been the subject of several reports by task forces, and of many reviews [55,56]. Despite the associations the possible causative role of bisphosphonates remains unclear and the potential mechanisms unexplained [57]. The disproportionate attention paid to these issues and the ‘fear of side effects’ has probably contributed to the declining use of drugs to treat osteoporosis despite its increasing prevalence as populations age. These are rare events and the overall risk to benefit profile remains highly favorable. All of the bisphosphonates in current use were developed more than a decade ago, and many of their key patents have therefore expired. Most bisphosphonates have therefore now become generic drugs, and are therefore less expensive than branded drugs. One outcome may be a greater use of iv zoledronate, as cost becomes less of a deterrent. This has attractions because Current Opinion in Pharmacology 2015, 22:115–130

it ensures compliance compared with oral alternatives. Zoledronate is exceptional among the bisphosphonates for its long duration of action enabling once yearly treatment [58]. Remarkably, a single dose may even reduce bone turnover for up to 5 years [59,60]. Bisphosphonates are likely to remain major drugs for treating bone diseases for some time to come. Advances continue to be made, such as producing formulations to overcome interference of intestinal absorption by food [61]. The detailed molecular understanding about the interactions of bisphosphonates with the FPPS enzyme has enabled structure-based design of novel bisphosphonates with even greater potency and selectivity. Sadly none of these are being very actively developed.

Bisphosphonates as modulators of mevalonate metabolism (‘MMMs’), and their non-skeletal effects There is an increasing realization that bisphosphonates have an extensive range of biological actions in addition to their well-established effects on bone resorption. Examples of observed clinical benefits outside the field of bone diseases include a reduction in mortality observed with zoledronate in the Horizon trial [62,63]. Other observational studies report a reduction in mortality after hip fracture in patients receiving oral bisphosphonates [64] and a reduction of myocardial infarctions in rheumatoid arthritis patients treated with bisphosphonates [65]. Administration of oral bisphosphonates may also be associated with a reduction in deaths from colon cancer [66,67], and bisphosphonates now feature alongside vitamin D, aspirin and statins in lists of potential chemoprotective agents [68]. The pharmacology underlying these potential effects of bisphosphonates needs to be understood, but in theory they could all result from the known inhibitory effects of bisphosphonates on the mevalonate pathway and the consequent effects on protein prenylation and intracellular signaling pathways in key tissues. Statins and bisphosphonates are both modulators of mevalonate metabolism (‘MMMs’), and it is therefore not surprising that they may have synergistic effects under certain conditions. A dramatic example is the extension of life span that occurs when zoledronate is given in combination with statins in a mouse model of Hutchinson–Gilford Progeria syndrome [69]. The underlying defect in Hutchinson–Gilford Progeria Syndrome (HGPS) arises from a series of point mutations in the LMNA gene, which encodes lamin A. Lamin A is a major protein of the nuclear lamina, which is a complex molecular structure located between the inner membrane of the nuclear envelope and chromatin, and is important for many cellular functions. The genetic mutations in HGPS produce an increase in the use of an internal splice site resulting in translation of an abnormal lamin A protein www.sciencedirect.com

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called progerin. Progerin lacks the proteolytic cleavage site required for removal of its posttranslationally attached farnesyl moiety, and the farnesylated form of progerin accumulates. This is thought to be ultimately responsible for the clinical features of accelerated ageing and cardiovascular disease, and provides the rationale for using inhibitors of farnesylation to treat HGPS. There have been encouraging results [70] indicating improved survival in a large cohort of HGPS patients utilizing treatments that interfere with the posttranslational farnesylation of lamin A proteins. These treatments include use of a farnesyltransferase inhibitor, lonafarnib, or a combination of a bisphosphonate (zoledronate), which inhibits the synthesis of farnesyl-pyrophosphate, and a statin (pravastatin), which inhibits 3-hydroxy-3methylglutaryl coenzyme A reductase. Collectively these effects of bisphosphonates on increasing longevity in animal progeroid models, and in clinical studies, raise the possibility that they may have more general effects on ageing processes, which are currently being intensively studied [71,72]. Emerging results suggest that bisphosphonates may enhance human stem cell life span, DNA repair and tissue regeneration [73], all by processes that appear to involve modulation of protein prenylation. Bisphosphonates appear to affect signaling via mTOR (TOR = target of rapamycin) dependent pathways known to be involved in ageing and cancer, as well as in bone metabolism [74,75]. Many other non-skeletal effects of bisphosphonates have been recorded over the years, many of which involve inhibition of the mevalonate pathway. These include effects on T cells, on several protozoan parasites and even on plants as herbicides. There may also be effects that are independent of the mevalonate pathway. This clearly happens with the non-nitrogen bisphosphonates like clodronate, which act via production of P-C-P containing ATP metabolites, but N-bisphosphonates may have other actions too. An interesting example is the anti-tumour effect apparently mediated via effects on the EGF-receptor [76,77]. Bisphosphonates have an overall excellent safety profile, and new and even more potent compounds with lower bone affinity are under study for these novel applications. One interesting example are phosphonocarboxylate analogues of bisphosphonates, in which one of the phosphonate groups is replaced by a carboxylate moiety which results in reduced affinity for bone mineral. Some such compounds inhibit other enzymes in the mevalonate pathways such as RAB prenyl transferases [78]. Prenyl transferases are attractive potential targets in cancer therapy [79].

Cathepsin K protease inhibitors, including odanacatib Cathepsins are lysosomal proteases that belong to a large family of papain-like cysteine proteases, of which there www.sciencedirect.com

are eleven different types (B, C, F, H, K, L, O, S, V, X, and W). Cathepsin K is highly expressed by activated osteoclasts and is one of the primary enzymes involved in degrading type I collagen, the major component of the organic bone matrix. The concept of using inhibitors of cathepsin K to prevent bone loss arose from the discovery that loss-of-function mutations in the cathepsin K gene lead to pycnodysostosis, a disorder characterized by osteosclerosis, bone fragility, and decreased bone turnover. Cathepsin K therefore became an attractive therapeutic target in osteoporosis, and also potentially in other conditions, such as osteoarthritis and bone cancers. This led to flurry of research activity, particularly in the 1990s, and medicinal chemists designed and synthesized many inhibitors with varying degrees of selectivity [80] and many patents have been issued [81]. However many hurdles have been encountered during the discovery and development of cathepsin K inhibitors as drugs [82]. The key requirements for a clinically viable inhibitor include high selectivity over related cathepsins, oral bioavailability, optimal pharmacokinetic and pharmacodynamic (PK/PD) profiles, and minimal off target effects on skin, lungs and other tissues to ensure safety. Despite the involvement of several major pharmaceutical companies, there have been more failures than successes in this field so far, with several ‘failures’ in the development of cathepsin K inhibitors. Three of the cathepsin K inhibitors that did not progress beyond phase I and phase II clinical trials are balicatib (AAE-581), relacatib (SB462795), and ONO-5334 [83–85]. Odanacatib is the only cathepsin K inhibitor for which both Phase 2 and 3 studies have been completed, and fracture reduction has been demonstrated [86]. Odanacatib (MK-0822) is a non-basic and non-lysosomotropic nitrile-based molecule, cleverly designed to avoid uptake by lysosomes, with the aim of minimizing off target effects [87]. It is highly selective for cathepsin K, compared with other cathepsins (B, L and S). It has a long half-life (>60 hours) in humans, enabling once weekly treatment. The pivotal Phase 3 fracture trial was called LOFT, (The Long-Term Odanacatib Fracture Trial), which was a randomized, double-blind, placebo-controlled, eventdriven trial. LOFT enrolled 16 713 women with osteoporosis, 65 years of age or older (mean age 73), from 40 countries, studied over 5 years with the mean duration of therapy was 34 months. The results were presented in 2014 [88,89] but are still not fully published. The results announced so far reveal that the LOFT trial demonstrated a significant reduction in the risk of three types of osteoporotic fracture (hip, spine and non-vertebral Current Opinion in Pharmacology 2015, 22:115–130

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fractures) compared to placebo in the primary efficacy analysis, and also reduced the risk of the secondary endpoint of clinical vertebral fractures by 72%. Specifically, there was a 54% relative risk reduction of new and worsening morphometric (radiographically assessed) vertebral fractures, and a reduction of 23% in non-vertebral fractures. A total of 237 hip fractures occurred in this event-driven trial, and odanacatib produced a 47% reduction in hip fractures compared with placebo. Treatment with odanacatib led to progressive increases over five years in bone mineral density (BMD) at the lumbar spine and total hip, compared to placebo. The change in BMD from baseline at five years with odanacatib for lumbar spine was 11.2% and for total hip was 9.5%. The rates of adverse events overall in LOFT were generally balanced between patients taking odanacatib and placebo, but have yet to be published in full. Morphea-like skin lesions and atypical femoral fractures occurred rarely but more often in the odanacatib group than in the placebo group. There were no adjudicated cases of osteonecrosis of the jaw. The underlying pharmacology and cellular actions of cathepsin K inhibitors differ from other bone active drugs. There had therefore been an expectation that the responses to a cathepsin K inhibitor might be different from other anti-resorptive drugs, based on the notion that inhibition of cathepsin K may partially uncouple the link between reduction in bone resorption and bone formation, allowing bone formation to continue while bone resorption is reduced [90,91]. This has been borne out with results from both preclinical and clinical studies with odanacatib showing that the extent of reduction in biochemical markers of bone resorption was dose-dependent, but the effects on bone formation biomarkers were less than with other drugs such as bisphosphonates or denosumab. This suggested that it might be possible to dissociate inhibition of bone resorption from a reduction in bone formation favoring a better response the terms of potential fracture reduction. An interesting possibility is that the effects of cathepsin K inhibition on cortical bone may be mediated by reduced breakdown of periostin, which in turn suppresses sclerostin, thereby allowing increased bone formation [92]. Because cathepsin K inhibitors act on a protease and affect matrix degradation rather than osteoclast differentiation or apoptosis, the number of osteoclasts and their function should not be reduced. This may allow osteoclast to osteoblast communication, for example, via ‘clastokine’ signaling, that contributes to maintaining bone formation, while suppressing bone resorption (See Figure 1). The persistence of large numbers on non-resorbing osteoclasts may also explain why the rebound bone loss seems to be rapid and possibly excessive, when a patient discontinues treatment. Current Opinion in Pharmacology 2015, 22:115–130

Assuming that FDA approval and registration of odanacatib is successful, it will be the first cathepsin K inhibitor to enter the market, but will have to compete with cheap generic drugs especially bisphosphonates, as well as with denosumab.

Other pharmacological agents that may act as resorption inhibitors There are many other ways in which osteoclasts might be targeted to inhibit bone resorption and a number of other potential drugs have been and are being explored as resorption inhibitors. Most of these are being derived from knowledge of the genetic basis of osteoclast dysfunction in animal models and inherited human diseases. Some examples are mentioned below, particularly where there is data from clinical studies. However none of these are yet approved for treating osteoporosis or other bone diseases. Src kinase inhibitors have generated interest as inhibitors of osteoclast activity, particularly in relation to cancer [93]. Src belongs to a family of non-receptor proto-oncogene tyrosine kinases. Mice deficient in src develop osteopetrosis due to impairment of osteoclast function. Among many src inhibitors, three (dasatinib, saracatinib (AZD0530), and bosutinib) are currently still undergoing clinical studies in patients with bone metastases, but not apparently osteoporosis. Glucagon-like peptide (GLP)-2 is a mediator of the fall in bone resorption that occurs after feeding, and the circadian fall in (GLP)-2 may contribute to the increase in bone resorption that occurs at night, suggesting that administration of GLP-2 might modify bone loss. This is of interest in relation to the bone changes and increased fracture rates that occur in diabetes, and whether therapies used in diabetes such as DPP-4 inhibitors might avert the bone changes [94]. This is a complex topic and has been well reviewed recently [95]. Adhesion and acidification and other osteoclast functional targets. There are several theoretical targets for inhibiting bone resorption based on blocking key processes in osteoclast activity. For example, bone resorption can be inhibited by using antibodies and peptide inhibitors directed against the avb3 integrin, the adhesion molecule involved in the attachment of the osteoclast to bone and the formation of the sealing zone. Other experimental strategies involve inhibition of Atp6v0d2, a subunit of vATPase that is required for acidification by the osteoclast, and the voltage-gated chloride channel ClC-7, for which an inhibitor NS3736 has been shown to prevent bone loss in ovariectomized rats. None of these seem to be being pursued currently as serious drug candidates. Nitrates and nitric oxide. Nitric oxide is one of the many locally active mediators produced endogenously in bone www.sciencedirect.com

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that appears to modulate bone resorption and formation. It is therefore a potential target for intervention, and this appeared to be a promising approach since several organic nitrates, which can act as nitric oxide donors, have been used in medicine for many years for the treatment of angina. The potential value of nitrates in osteoporosis has been studied by epidemiological approaches, as well as in clinical trials [96]. Nitrates appear to increase BMD, but effects on fractures are so far inconclusive, and their use may be further limited by adverse events such as headaches.

Inflammatory bone loss. Role of anti-cytokine therapies and anti-resorptives Bone loss is a common and important feature of many inflammatory diseases affecting the skeleton, including infection, arthritis and periodontal disease [97–99]. The study of osteoimmunology reveals the role of many cytokines in promoting bone destruction [100,101]. In rheumatoid arthritis the RANK/RANKL/OPG system plays a role in local activation of osteoclasts. Anti-cytokine therapy, for example, with anti-TNFs appears to attenuate bone loss, and bisphosphonates and denosumab block bone erosions although they have not been formally approved for these uses [102,103].

The use of drug combinations and sequential treatments With the increasing numbers of drugs becoming available for the treatment of osteoporosis, there are more choices for patients. This raises many questions. Which drugs should be used first for treatment and how long should they be given? Should cost influence choice? If drugs are changed, is there is any preferred sequence? Will any of the drugs given interfere with the action of the next? Which if any drugs might be used concurrently [104]? A few examples will illustrate some of the issues. Several clinical studies indicate that prior or concurrent treatment with raloxifene or with bisphosphonates such as alendronate may interfere with the subsequent anabolic response to parathyroid hormone (PTH). Interestingly this seems not to occur with zoledronate. Giving two anti-resorptive drugs concurrently seems unnecessary unless they have additive effects, but switching to a different drug during sequential treatment may produce an added response. For example, an additional reduction of bone turnover can be attained when denosumab is given after a bisphosphonate. Combining an anti-resorptive drug with a bone-forming agent has attractions [105], and there are several examples of success with such combinations, such as the combination of estrogens with PTH, or of zoledronate or denosumab with PTH [106]. Such combinations can achieve greater changes in BMD than with either drug www.sciencedirect.com

alone, but remain experimental and have not so far been shown to produce added reductions in fractures. An important example of combined use of drugs in sequence is the use of bone resorption inhibitors, particularly bisphosphonates or denosumab, to preserve the bone gain achieved during finite courses of treatment with bone forming agents such as teraparatide and PTH analogues [107]. This is also likely to be a useful strategy in the future to maintain bone mass after courses of antisclerostin treatment.

Fracture healing, bone repair and orthopaedics There continues to be great interest in finding therapeutic strategies to improve bone healing and fracture repair [108]. The biology of fracture healing is now well understood [109], involving a temporal sequence of events of vascular invasion, production of a cartilaginous callus, and its subsequent ossification. It has often been assumed that anti-resorptive drugs will impair fracture healing, but this has not been borne out in animal studies, nor in clinical practice. In the major clinical studies with the anti-resorptive drugs there has been no evidence of delayed fracture healing or malunion [110,111]. Theoretically, there is no early stage in fracture repair at which anti-resorptive drugs would be expected to impair the process. However one might expect anti-resorptive drugs to have an impact during the latter stages of remodelling of the calcified callus by osteoclasts, and this is what is observed in experimental studies with BPs and denosumab. This suggests that that they may have positive rather than negative effects on fracture repair [112], by stabilizing the fracture callus [113]. There may be other potential applications of bisphosphonates in orthopaedics [114]. These include protection against loosening of prostheses [115], better integration of biomaterials and implants [116], improved healing in distraction osteogenesis, and conserving bone architecture in hips affected by Perthes disease or osteonecrosis [117].

Potential role of anti-resorptive drugs in osteoarthritis Osteoarthritis remains a challenging condition to manage [118]. Apart from pain management, there have been more disappointments than successes with attempts at pharmacological therapy. The potential use of anti-resorptive drugs in osteoarthritis remains an attractive option [119], based on the notion that modulating the excessive subchondral bone remodelling might be beneficial. Several studies have been conducted with bisphosphonates [120], and there are recent positive studies with strontium [121]. Interestingly, a reduction in the cartilage resorption marker, CTX-II derived from type 2 collagen, has been Current Opinion in Pharmacology 2015, 22:115–130

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noted with several bone anti-resorptives, including bisphosphonates, calcitonin and even strontium. Since it seems unlikely that all of this diverse group of drugs would affect cartilage destruction directly, a more plausible explanation is that it represents blockade of osteoclastmediated resorption of calcified cartilage, which would be expected to contain residual type 2 collagen. It remains to be determined whether anti-resorptive and other bone directed therapies are of real clinical benefit in osteoarthritis.

Bone marrow lesions The increasing use of magnetic resonance and other imaging in clinical practice has led to the recognition of a new entity, bone marrow lesions (BMLs). These lesions are characterized by excessive water signals in the marrow space and have emerged as a common feature of many different diseases of the musculoskeletal system. BMLs have been associated with a wide variety of inflammatory and non-inflammatory rheumatologic conditions, and can be significant sources of pain. Interestingly the pain often responds to the use of anti resorptive drugs including calcitonin or bisphosphonates and to antiTNFs in arthritis [122]. The origin and management of skeletal pain remains a topic of active research, and anti-resorptives and other bone-active drugs have a role to play [123].

Vitamin D and calcium The importance of vitamin D and calcium for bone health is well known, and many populations, not just the elderly, appear to lack sufficient vitamin D. Ensuring adequate calcium intake and vitamin D has been part of the routine management of patients at risk of fracture when they are given any of the bone active drugs currently available. However, the routine use of vitamin D and calcium supplementation has recently been questioned as a result of studies suggesting that there may be an increased risk of cardiovascular and other adverse events in patients receiving high intakes of calcium [124]. This issue remains controversial, but is already having an impact on recommendations about how patients should be managed [125].

Pharmacogenomics There is currently much interest in ‘personalised’ medicine and in using pharmacogenomics to identify patients who may respond better to one type of drug rather than another. Despite encouraging advances being made in other fields, such as cancer therapy, these concepts have not yet been successfully applied to osteoporosis. Many genes contribute to osteoporosis, and there is some evidence that responses to some drugs such as SERMs and bisphosphonates might be influenced by genetics. These interesting possibilities have been reviewed recently [126]. Current Opinion in Pharmacology 2015, 22:115–130

Some current issues, future prospects, and conclusions Many impressive advances have taken place in recent years in understanding bone biology and skeletal diseases. Anti-resorptive agents are still the principal therapeutics used for preventing bone loss and fractures in osteoporosis, and reductions of 40–70% can be achieved for vertebral fractures and up to 40% for non-vertebral fractures. The best of current treatments can reduce hip fractures by 40% or more in certain groups of patients, which is encouraging in terms of its impact on individuals and on health care costs [127] (see (Figure 2) for comparison of current treatments). Despite this, we are still a long way from being able to offer a ‘cure’ to patients. Is it possible to do better? Many patients with osteoporosis who might benefit do not get treated, so there is a need for improved identification of patients at risk. Ensuring compliance with oral therapies in particular is still sub-optimal. Even with newer therapies it may not be possible to achieve better anti-fracture efficacy than already reported for the bisphosphonates or denosumab, so will the development of new drugs overcome these obstacles [128]? It has long been hoped that bone-forming drugs would eventually outperform anti-resorptives, and achieving that aspiration now depends on the outcome of trials with antisclerostin antibodies [129,130]. Sclerostin is an inhibitor of the Wnt signaling pathway [131], and is a physiological regulator of bone formation. Genetic deficiencies in sclerostin lead to marked increases in bone mass in the inherited disorders of von Buchem’s disease and sclereostosis. Romosozumab and blosozumab are anti-sclerostin antibodies, which produce rapid and marked increases in BMD. These biological therapies are being evaluated in clinical trials and early data looks promising [132,133], but has generated some surprises. Firstly, the anabolic responses in terms of biomarkers wear off within the first year of treatment, and secondly there was a substantial fall in bone resorption markers within the early phase of treatment. Thus, contrary to expectation, there seemed to be an ‘uncoupling’ between formation and resorption, with these anti-sclerostin antibodies displaying ‘anti-resorptive’ properties. Interestingly, a similar initial fall is resorption also occurs with PTH [134], which is currently the only approved bone formation stimulator used for treating osteoporosis. Alternate forms of PTH are being developed for osteoporosis, and promising results have recently been reported for abaloparatide. Abaloparatide (also known as BA058) is a novel synthetic peptide analogue of PTHrelated protein that has subtle but significant pharmacological differences from PTH and teraparatide [135], and reduces both vertebral and non-vertebral fractures. What will the future hold for the discovery and development of drugs for bone diseases? Drug discovery is a www.sciencedirect.com

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Figure 2

Non-Vertebral Fracture

Hip Fracture

Calcium Vitamin D

Bisphosphonates

Calcium + vitamin D

Alendronate Risedronate Ibandronate Zoledronate Raloxifene Strontium Denosumab Odanacatib Teriparatide PTH (1-84)

0.2

0.5 Favours treatment

1

2 Favours control

0.06

0.2 0.5 Favours treatment

1

2 4 8 Favours control

Current Opinion in Pharmacology

Scheme to show the efficacy of treatments for the prevention of non-vertebral and hip fractures. Figure adapted from Reid [136]. Note that these results come from different studies with different entry criteria and patient characteristics, and are not head-to-head comparisons. Data for strontium, odanacatib and PTH1–84 are relative risks; other data are odds ratios from various sources. Values are shown as 95% confidence intervals.

challenging process. The rewards of success can be great, but sadly more drugs fail than succeed during clinical development. The costs of developing drugs for osteoporosis are particularly high and may approach $1 billion to successfully complete the necessary Phase 3 studies, and to show fracture reduction in populations of 10 000– 20 000 patients studied over several years. So will the pharmaceutical industry have the appetite for any more clinical development programs that may take at least 5 years to complete, and incur huge costs? The current approach to drug discovery is to start with defined molecular targets. For bone active drugs, several trace their origins back to discovering the genetic basis of rare inherited skeletal disorders. New potential targets continue to be discovered by genetic and other approaches. There are obvious advantages for new drugs that have additional applications in the management of bone diseases beyond osteoporosis. In addition, new drugs will have to have added benefits if they are to compete with cheaper generics, especially with the increasingly draconian approach taken towards restricting the use of costly drugs. www.sciencedirect.com

Extending the use of drugs to new areas is well illustrated by using ‘anti-resorptives’ to prevent skeletal-related events in cancer. This has developed into a major area of therapeutics, with zoledronate and denosumab representing the ‘standard of care’ for many patients with cancer. There are many other unmet medical needs for such drugs, not only in cancer, but also in fracture healing, implant fixation and osteoarthritis to name just a few. There is currently much emphasis based on the management of rare diseases, despite the usually extremely high costs of such treatments. Finally there are opportunities for the ‘re-purposing’ of old drugs for new indications. Bisphosphonates offer an excellent example with a wide range of new potential medical uses, including effects on T cells, tissue regeneration, radioprotection, and extension of life span. Bisphosphonates have an excellent safety profile established over many decades, and new and even more potent compounds with lower bone affinity could be developed for these novel non-skeletal applications.

Conflict of interest Consultancy: Amgen, UCB. Share holder: Episynesis, Biscardia. Legal work for Merck, Lilly and Novartis. Current Opinion in Pharmacology 2015, 22:115–130

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References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as:  of special interest  of outstanding interest 1.

Riggs BL, Parfitt AM: Drugs used to treat osteoporosis: the critical need for a uniform nomenclature based on their action on bone remodeling. J Bone Miner Res 2005, 20:177-184.

2. 

Brommage R: Genetic approaches to identifying novel osteoporosis drug targets. J Cell Biochem 2015 http:// dx.doi.org/10.1002/jcb.25179. A thoughtful review of how targets for drug discovery can be identified.

3. 

Whyte MP, Greenberg CR, Salman NJ, Bober MB, McAlister WH, Wenkert D, Van Sickle BJ, Simmons JH, Edgar TS, Bauer ML, Hamdan MA, Bishop N, Lutz RE, McGinn M, Craig S, Moore JN, Taylor JW, Cleveland RH, Cranley WR, Lim R, Thacher TD, Mayhew JE, Downs M, Milla´n JL, Skrinar AM, Crine P, Landy H: Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med 2012, 366:904-913. This paper describes the remarkable clinical responses to enzyme replacement in hypophosphatasia.

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Sobacchi C, Schulz A, Coxon FP, Villa A, Helfrich MH: Osteopetrosis: genetics, treatment and new insights into osteoclast function. Nat Rev Endocrinol 2013, 9:522-536. An excellent review of the multiple genetic mechanisms underlying human osteopetrotic syndromes.

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Appelman-Dijkstra NM, Papapoulos SE: Prevention of incident fractures in patients with prevalent fragility fractures: current and future approaches. Best Pract Res Clin Rheumatol 2013, 27:805-820.

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Lems WF, Geusens P: Established and forthcoming drugs for the treatment of osteoporosis. Curr Opin Rheumatol 2014, 26:245-251.

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Overman RA, Borse M, Gourlay ML: Salmon calcitonin use and associated cancer risk. Ann Pharmacother 2013, 47: 1675-1684.

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Russell FA, King R, Smillie SJ, Kodji X, Brain SD: Calcitonin generelated peptide: physiology and pathophysiology. Physiol Rev 2014, 94:1099-1142. A comprehensive review of current knowledge of CGRP. 9.

Kuwasako K, Hay DL, Nagata S, Murakami M, Kitamura K, Kato J: Functions of third extracellular loop and helix 8 of Family B GPCRs complexed with RAMPs and characteristics of their receptor trafficking. Curr Protein Pept Sci 2013, 14:416-428.

10. Desai AJ, Roberts DJ, Richards GO, Skerry TM: Role of receptor activity modifying protein 1 in function of the calcium sensing receptor in the human TT thyroid carcinoma cell line. PLOS ONE 2014, 9:e85237. 11. Bell IM: Calcitonin gene-related peptide receptor antagonists: new therapeutic agents for migraine. J Med Chem 2014, 57:7838-7858. 12. Kovacs CS: Bone development and mineral homeostasis in the fetus and neonate: roles of the calciotropic and phosphotropic hormones. Physiol Rev 2014, 94:1143-1218. 13. Martin TJ, Sims NA: Calcitonin physiology, saved by a  lysophospholipid. J Bone Miner Res 2015, 30:212-215. New data on an old hormone, calcitonin. 14. Keller J, Catala-Lehnen P, Huebner AK, Jeschke A, Heckt T, Lueth A, Krause M, Koehne T, Albers J, Schulze J, Schilling S, Haberland M, Denninger H, Neven M, Hermans-Borgmeyer I, Streichert T, Breer S, Barvencik F, Levkau B, Rathkolb B, Wolf E, Calzada-Wack J, Neff F, Gailus-Durner V, Fuchs H, de Angelis MH, Klutmann S, Tsourdi E, Hofbauer LC, Kleuser B, Chun J, Schinke T, Amling M: Calcitonin controls bone formation by inhibiting the release of sphingosine 1-phosphate from osteoclasts. Nat Commun 2014, 5:5215. 15. Henriquez-Camacho C, Losa J: Biomarkers for sepsis. Biomed Res Int 2014, 2014:547818 http://dx.doi.org/10.1155/2014/ 547818. Current Opinion in Pharmacology 2015, 22:115–130

16. Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR et al.: Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009, 361:756-765. 17. Boonen S, Adachi JD, Man Z, Cummings SR, Lippuner K, To¨rring O, Gallagher JC, Farrerons J, Wang A, Franchimont N, San Martin J, Grauer A, McClung M: Treatment with denosumab reduces the incidence of new vertebral and hip fractures in postmenopausal women at high risk. J Clin Endocrinol Metab 2011, 96:1727-1736. 18. Papapoulos S, Chapurlat R, Libanati C, Brandi ML, Brown JP, Czerwin´ski E, Krieg MA, Man Z, Mellstro¨m D, Radominski SC, Reginster JY, Resch H, Roma´n Ivorra JA, Roux C, Vittinghoff E, Austin M, Daizadeh N, Bradley MN, Grauer A, Cummings SR, Bone HG: Five years of denosumab exposure in women with postmenopausal osteoporosis: results from the first two years of the FREEDOM extension. J Bone Miner Res 2012, 27:694-701. 19. Scott LJ: Denosumab: a review of its use in postmenopausal women with osteoporosis. Drugs Aging 2014, 31:555-576. 20. Bone HG, Chapurlat R, Brandi ML, Brown JP, Czerwinski E,  Krieg MA, Mellstro¨m D, Radominski SC, Reginster JY, Resch H, Ivorra JA, Roux C, Vittinghoff E, Daizadeh NS, Wang A, Bradley MN, Franchimont N, Geller ML, Wagman RB, Cummings SR, Papapoulos S: The effect of three or six years of denosumab exposure in women with postmenopausal osteoporosis: results from the FREEDOM extension. J Clin Endocrinol Metab 2013, 98:4483-4492. Important follow-up study of denosumab from the FREEDOM trial. 21. Baron R, Ferrari S, Russell RG: Denosumab and  bisphosphonates: different mechanisms of action and effects. Bone 2011, 48:677-692. A review of the differential effects of denosumab compared with bisphosphonates. 22. Poole KE, Treece GM, Gee AH, Brown JP, McClung MR, Wang A, Libanati C: Denosumab rapidly increases cortical bone in key  locations of the femur: a 3D bone mapping study in women with osteoporosis. J Bone Miner Res 2015, 30:46-54. A novel approach to studying changes in hip cortical bone in response to therapy. 23. Whitmarsh T, Treece GM, Gee AH, Poole KE: Mapping bone changes at the proximal femoral cortex of postmenopausal women in response to alendronate and teriparatide alone, combined or sequentially. J Bone Miner Res 2015 http:// dx.doi.org/10.1002/jbmr.2454. 24. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J, Writing Group for the Women’s Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 2002, 288:321-333. 25. Wells G, Tugwell P, Shea B, Guyatt G, Peterson J, Zytaruk N, Robinson V, Henry D, O’Connell D, Cranney A, Osteoporosis Methodology Group and The Osteoporosis Research Advisory Group: Meta-analyses of therapies for postmenopausal osteoporosis. V. Meta-analysis of the efficacy of hormone replacement therapy in treating and preventing osteoporosis in postmenopausal women. Endocr Rev 2002, 23:529-539. 26. Santen RJ, Allred DC, Ardoin SP, Archer DF, Boyd N, Braunstein GD, Burger HG, Colditz GA, Davis SR, Gambacciani M, Gower BA, Henderson VW, Jarjour WN, Karas RH, Kleerekoper M, Lobo RA, Manson JE, Marsden J, Martin KA, Martin L, Pinkerton JV, Rubinow DR, Teede H, Thiboutot DM, Utian WH, Endocrine Society: Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab 2010, 95(Suppl 1):s1-s66. 27. Sarrel PM, Njike VY, Vinante V, Katz DL: The mortality toll of estrogen avoidance: an analysis of excess deaths among hysterectomized women aged 50 to 59 years. Am J Public Health 2013, 103:1583-1588. 28. Nelson ER, Wardell SE, McDonnell DP: The molecular  mechanisms underlying the pharmacological actions of www.sciencedirect.com

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estrogens, SERMs and oxysterols: implications for the treatment and prevention of osteoporosis. Bone 2013, 53:42-50. An excellent review of how oestrogens and their analogues work. 29. Manolagas SC, O’Brien CA, Almeida M: The role of estrogen and androgen receptors in bone health and disease. Nat Rev Endocrinol 2013, 9:699-712. 30. Komm BS, Chines AA: An update on selective estrogen receptor modulators for the prevention and treatment of osteoporosis. Maturitas 2012, 71:221-226. 31. Komm BS, Mirkin S: An overview of current and emerging  SERMs. J Steroid Biochem Mol Biol 2014, 143C:207-222. An excellent review of SERMS and their actions.

An authorative account of the cellular mechanisms of bisphosphonate action. 45. Plotkin LI, Bellido T: Beyond gap junctions: Connexin43 and bone cell signaling. Bone 2013, 52:157-166. 46. Russell RG, Watts NB, Ebetino FH, Rogers MJ: Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int 2008, 19:733-759. 47. Warriner AH, Saag KG: Prevention and treatment of bone changes associated with exposure to glucocorticoids. Curr Osteoporos Rep 2013, 11:341-347. 48. Hald JD, Evangelou E, Langdahl BL, Ralston SH: Bisphosphonates for the prevention of fractures in osteogenesis imperfecta: meta-analysis of placebocontrolled trials. J Bone Miner Res 2014 http://dx.doi.org/ 10.1002/jbmr.2410.

32. Cummings SR, Ensrud K, Delmas PD, LaCroix AZ, Vukicevic S, Reid DM, Goldstein S, Sriram U, Lee A, Thompson J,  Armstrong RA, Thompson DD, Powles T, Zanchetta J, Kendler D, Neven P, Eastell R, PEARL Study Investigators: Lasofoxifene in postmenopausal women with osteoporosis. N Engl J Med 2010, 362:686-696 Erratum in: N Engl J Med 2011 20;364:290. The results of the Phase 3 trial with lasofoxifene, a SERM that was not registered for clinical use despite promising clinical effects

49. Shapiro JR, Byers PH: Osteogenesis imperfecta. In A  Translational Approach to Brittle Bone Disease. Edited by Glorieux , Sponseller PD.. USA: Elsevier; 2014978-0-12-397165-4. An excellent contemporary multiauthor book on osteogenesis imperfecta and its management.

33. Pinkerton JV, Thomas S: Use of SERMs for treatment in postmenopausal women. J Steroid Biochem Mol Biol 2014, 142:142-154.

50. Børsheim E, Herndon DN, Hawkins HK, Suman OE, Cotter M, Klein GL: Pamidronate attenuates muscle loss after pediatric burn injury. J Bone Miner Res 2014, 29:1369-1372.

34. Santen RJ, Kagan R, Altomare CJ, Komm B, Mirkin S, Taylor HS: Current and evolving approaches to individualizing estrogen receptor-based therapy for menopausal women. J Clin Endocrinol Metab 2014, 99:733-747.

51. Sakai A, Ikeda S, Okimoto N, Matsumoto H, Teshima K, Okazaki Y, Fukuda F, Arita S, Tsurukami H, Nagashima M, Yoshioka T: Clinical efficacy and treatment persistence of monthly minodronate for osteoporotic patients unsatisfied with, and shifted from, daily or weekly bisphosphonates: the BPMUSASHI study. Osteoporos Int 2014, 25:2245-2253 http:// dx.doi.org/10.1007/s00198-014-2756-8 Erratum in: Osteoporos Int 2014 25:2505–6.

35. Silverman SL, Chines AA, Kendler DL, Kung AW, Teglbjærg CS, Felsenberg D, Mairon N, Constantine GD, Adachi JD, Bazedoxifene Study Group: Sustained efficacy and safety of bazedoxifene in preventing fractures in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled study. Osteoporos Int 2012, 23:351-363. 36. Kaufman JM, Palacios S, Silverman S, Sutradhar S, Chines A: An evaluation of the Fracture Risk Assessment Tool (FRAXW) as an indicator of treatment efficacy: the effects of bazedoxifene and raloxifene on vertebral, nonvertebral, and all clinical fractures as a function of baseline fracture risk assessed by FRAXW. Osteoporos Int 2013, 24:2561-2569. 37. Bolland MJ, Grey A: A comparison of adverse event and fracture efficacy data for strontium ranelate in regulatory documents and the publication record. BMJ Open 2014, 4. 38. Stepan JJ: Strontium ranelate: in search for the mechanism of action. J Bone Miner Metab 2013, 31:606-612.  A recent review of possible mechanisms of action of strontium. 39. Fleisch H, Russell RGG, Francis MD: Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone resorption in tissue culture and in vivo. Science 1969, 165:1262-1264. 40. Russell RG: Bisphosphonates: the first 40 years. Bone 2011,  49:2-19. A detailed review of the history and development of bisphosphonates from bench to bedside. 41. Burr D, Russell RG: Special issue of Bone to mark the 40th anniversary of bisphosphonates. Bone 2011, 49:1. 42. Ebetino FH, Hogan AM, Sun S, Tsoumpra MK, Duan X, Triffitt JT,  Kwaasi AA, Dunford JE, Barnett BL, Oppermann U, Lundy MW, Boyde A, Kashemirov BA, McKenna CE, Russell RG: The relationship between the chemistry and biological activity of the bisphosphonates. Bone 2011, 49:20-33. This is probably the most comprehensive review available of the structure and activity of bisphosphonates. 43. Thompson K, Roelofs AJ, Jauhiainen M, Mo¨nkko¨nen H, Mo¨nkko¨nen J, Rogers MJ: Activation of gd T cells by bisphosphonates. Adv Exp Med Biol 2010, 658:11-20 http:// dx.doi.org/10.1007/978-1-4419-1050-9_2. 44. Rogers MJ, Crockett JC, Coxon FP, Mo¨nkko¨nen J: Biochemical  and molecular mechanisms of action of bisphosphonates. Bone 2011, 49:34-41. www.sciencedirect.com

52. Iwamoto J, Okano H, Furuya T, Urano T, Hasegawa M, Hirabayashi H, Kumakubo T, Makita K: Patient preference for monthly bisphosphonate versus weekly bisphosphonate in a cluster-randomized, open-label, crossover trial: Minodronate Alendronate/Risedronate Trial in Osteoporosis (MARTO). J Bone Miner Metab 2015. (Epub ahead of print). 53. Eriksen EF, Dı´ez-Pe´rez A, Boonen S: Update on long-term  treatment with bisphosphonates for postmenopausal osteoporosis: a systematic review. Bone 2014, 58:126-135. An excellent review by three experts on bisphosphonates and osteoporosis. 54. McClung M, Harris ST, Miller PD, Bauer DC, Davison KS, Dian L,  Hanley DA, Kendler DL, Yuen CK, Lewiecki EM: Bisphosphonate therapy for osteoporosis: benefits, risks, and drug holiday. Am J Med 2013, 126:13-20. A good discussion of bisphosphonate therapy. 55. Khan AA, Morrison A, Hanley DA, Felsenberg D, McCauley LK, O’Ryan F, Reid IR, Ruggiero SL, Taguchi A, Tetradis S, Watts NB, Brandi ML, Peters E, Guise T, Eastell R, Cheung AM, Morin SN, Masri B, Cooper C, Morgan SL, Obermayer-Pietsch B, Langdahl BL, Al Dabagh R, Davison KS, Kendler DL, Sa´ndor GK, Josse RG, Bhandari M, El Rabbany M, Pierroz DD, Sulimani R, Saunders DP, Brown JP, Compston J, International Task Force on Osteonecrosis of the Jaw: Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res 2015, 30:3-23. 56. Shane E, Burr D, Abrahamsen B, Adler RA, Brown TD, Cheung AM, Cosman F, Curtis JR, Dell R, Dempster DW, Ebeling PR, Einhorn TA, Genant HK, Geusens P, Klaushofer K, Lane JM, McKiernan F, McKinney R, Ng A, Nieves J, O’Keefe R, Papapoulos S, Howe TS, van der Meulen MC, Weinstein RS, Whyte MP: Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2014, 29:1-23. 57. Pazianas M, Cooper C, Ebetino FH, Russell RG: Long-term treatment with bisphosphonates and their safety in postmenopausal osteoporosis. Ther Clin Risk Manag 2010, 6:325-343. Current Opinion in Pharmacology 2015, 22:115–130

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58. Reid IR, Black DM, Eastell R, Bucci-Rechtweg C, Su G, Hue TF, Mesenbrink P, Lyles KW, Boonen S, HORIZON Pivotal Fracture Trial and HORIZON Recurrent Fracture Trial Steering Committees: Reduction in the risk of clinical fractures after a single dose of zoledronic Acid 5 milligrams. J Clin Endocrinol Metab 2013, 98:557-563. 59. Grey A, Bolland MJ, Horne A, Wattie D, House M, Gamble G,  Reid IR: Five years of anti-resorptive activity after a single dose of zoledronate — results from a randomized double-blind placebo-controlled trial. Bone 2012, 50:1389-1393. This paper describes the remarkably long duration of response to a single infused dose of zoledronate. 60. Grey A, Bolland M, Mihov B, Wong S, Horne A, Gamble G, Reid IR: Duration of antiresorptive effects of low-dose zoledronate in osteopenic postmenopausal women: a randomized, placebocontrolled trial. J Bone Miner Res 2014, 29:166-172. 61. Pazianas M, Abrahamsen B, Ferrari S, Russell RG: Eliminating the need for fasting with oral administration of bisphosphonates. Therap Clin Risk Manage 2013, 9:395-402. 62. Lyles KW, Colo´n-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, Hyldstrup L, Recknor C, Nordsletten L, Moore KA, Lavecchia C, Zhang J, Mesenbrink P, Hodgson PK, Abrams K, Orloff JJ, Horowitz Z, Eriksen EF, Boonen S, for the HORIZON Recurrent Fracture Trial: Zoledronic acid in reducing clinical fracture and mortality after hip fracture. N Engl J Med 2007, 357:1799-1809. 63. Colo´n-Emeric CS, Mesenbrink P, Lyles KW, Pieper CF, Boonen S, Delmas P, Eriksen EF, Magaziner J: Potential mediators of the mortality reduction with zoledronic acid after hip fracture. J Bone Miner Res 2010, 25:91-97. 64. Beaupre LA, Morrish DW, Hanley DA, Maksymowych WP, Bell NR, Juby AG, Majumdar SR: Oral bisphosphonates are associated with reduced mortality after hip fracture. Osteoporos Int 2011, 22:983-991. 65. Wolfe F, Bolster MB, O’Connor CM, Michaud K, Lyles KW, Colo´n Emeric CS: Bisphosphonate use is associated with reduced risk of myocardial infarction in patients with rheumatoid arthritis. J Bone Miner Res 2013, 28:984-991. A registry study suggesting that bisphosphonate therapy may reduce myocardial infarctions in patients with rheumatoid arthritis. 66. Pazianas M, Abrahamsen B, Eiken PA, Eastell R, Russell RG: Reduced colon cancer incidence and mortality in postmenopausal women treated with an oral bisphosphonate — Danish National Register Based Cohort Study. Osteoporos Int 2012, 23:2693-2701. 67. Gronich N, Rennert G: Beyond aspirin — cancer prevention with statins, metformin and bisphosphonates. Nat Rev Clin Oncol 2013, 10:625-642. 68. Crosara Teixeira M, Braghiroli MI, Sabbaga J, Hoff PM: Primary prevention of colorectal cancer: myth or reality? World J Gastroenterol 2014, 20:15060-15069. 69. Varela I, Pereira S, Ugalde AP, Navarro CL, Suarez MF, Cau P et al.: Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging. Nat Med 2008, 14:767-772. 70. Gordon LB, Massaro J, D’Agostino RB, Campbell SE, Brazier J, Brown WT, Kleinman ME, Kieran MW: Impact of farnesylation inhibitors on survival in Hutchinson–Gilford progeria syndrome. Circulation 2014, 130:27-34. 71. Lo´pez-Otı´n C, Blasco MA, Partridge L, Serrano M, Kroemer G: The hallmarks of aging. Cell 2013, 153:1194-1217. 72. Jiang K: Drug development for progeria yields insights into normal aging. Nat Med 2013, 19:515. 73. Misra J, Mohanty ST, Madan S, Fernandes JA, Ebetino FH, Roehl H, Russell RG, Bellantuono I: Can bisphosphonates extend life span? Effects on stem cell survival, DNA repair and tissue regeneration. J Bone Miner Res 2013, 28 Supplement Abstract 0415 Annual Meeting of the American Society for Bone and Mineral Research. Baltimore, MD October 4–7, 2013. Current Opinion in Pharmacology 2015, 22:115–130

74. Hadji P, Coleman R, Gnant M: Bone effects of mammalian target of rapamycin (mTOR) inhibition with everolimus. Crit Rev Oncol Hematol 2013, 87:101-111. 75. Tchetina EV, Maslova KA, Krylov MY, Myakotkin VA: Association of bone loss with the upregulation of survival-related genes and concomitant downregulation of mammalian target of rapamycin and osteoblast differentiation-related genes in the peripheral blood of late postmenopausal osteoporotic women. J Osteoporos 2015 http://dx.doi.org/10.1155/2015/ 802694. 76. Yuen T, Stachnik A, Iqbal J, Sgobba M, Gupta Y, Lu P, Colaianni G, Ji Y, Zhu LL, Kim SM, Li J, Liu P, Izadmehr S, Sangodkar J, Bailey J, Latif Y, Mujtaba S, Epstein S, Davies TF, Bian Z, Zallone A, Aggarwal AK, Haider S, New MI, Sun L, Narla G, Zaidi M: Bisphosphonates inactivate human EGFRs to exert antitumor actions. Proc Natl Acad Sci U S A 2014, 111:17989-17994. 77. Stachnik A, Yuen T, Iqbal J, Sgobba M, Gupta Y, Lu P, Colaianni G,  Ji Y, Zhu LL, Kim SM, Li J, Liu P, Izadmehr S, Sangodkar J, Scherer T, Mujtaba S, Galsky M, Gomez J, Epstein S, Buettner C, Bian Z, Zallone A, Aggarwal AK, Haider S, New MI, Sun L, Narla G, Zaidi M: Repurposing of bisphosphonates for the prevention and therapy of nonsmall cell lung and breast cancer. Proc Natl Acad Sci U S A 2014, 111:17995-18000. Bisphosphonates may prevent cancer by interactions with EGFR. 78. Coxon FP, Joachimiak L, Najumudeen AK, Breen G, Gmach J, Oetken-Lindholm C, Way R, Dunford JE, Abankwa D, Błaz˙ewska KM: Synthesis and characterization of novel phosphonocarboxylate inhibitors of RGGT. Eur J Med Chem 2014, 84:77-89. 79. Berndt N, Hamilton AD, Sebti SM: Targeting protein prenylation for cancer therapy. Nat Rev Cancer 2011, 11:775-791. 80. Black WC: Peptidomimetic inhibitors of cathepsin K. Curr Top Med Chem 2010, 10:745-751. 81. Wijkmans J, Gossen J: Inhibitors of cathepsin K: a patent review (2004–2010). Expert Opin Ther Pat 2011, 21:1611-1629. 82. Kometani M, Nonomura K, Tomoo T, Niwa S: Hurdles in the drug discovery of cathepsin K inhibitors. Curr Top Med Chem 2010, 10:733-744. 83. Kumar S, Dare L, Vasko-Moser JA, James IE, Blake SM, Rickard DJ, Hwang SM, Tomaszek T, Yamashita DS, Marquis RW, Oh H, Jeong JU, Veber DF, Gowen M, Lark MW, Stroup G: A highly potent inhibitor of cathepsin K (relacatib) reduces biomarkers of bone resorption both in vitro and in an acute model of elevated bone turnover in vivo in monkeys. Bone 2007, 40:122-131. 84. Ochi Y, Yamada H, Mori H, Nakanishi Y, Nishikawa S, Kayasuga R, Kawada N, Kunishige A, Hashimoto Y, Tanaka M, Sugitani M, Kawabata K: Effects of ONO-5334, a novel orally-active inhibitor of cathepsin K, on bone metabolism. Bone 2011, 49:1351-1356. 85. Eastell R, Nagase S, Ohyama M, Small M, Sawyer J, Boonen S, Spector T, Kuwayama T, Deacon S: Safety and efficacy of the cathepsin K inhibitor ONO-5334 in postmenopausal osteoporosis: the OCEAN study. J Bone Miner Res 2011, 26:1303-1312. 86. Langdahl B, Binkley N, Bone H, Gilchrist N, Resch H, Rodriguez Portales J, Denker A, Lombardi A, Le Bailly De Tilleghem C, Dasilva C, Rosenberg E, Leung A: Odanacatib in the treatment of postmenopausal women with low bone mineral density: five years of continued therapy in a phase 2 study. J Bone Miner Res 2012, 27:2251-2258. 87. Gauthier JY, Chauret N, Cromlish W, Desmarais S, Duong le T, Falgueyret JP, Kimmel DB, Lamontagne S, Le´ger S, LeRiche T, Li CS, Masse´ F, McKay DJ, Nicoll-Griffith DA, Oballa RM, Palmer JT, Percival MD, Riendeau D, Robichaud J, Rodan GA, Rodan SB, Seto C, The´rien M, Truong VL, Venuti MC, Wesolowski G, Young RN, Zamboni R, Black WC: The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg Med Chem Lett 2008, 18:923-928. 88. http://www.mercknewsroom.com/news-release/research-and development-news/merck-announces-data-pivotal-phase3-fracture-outcomes-st. Press release announcing outcome of LOFT trial with odanacatib. www.sciencedirect.com

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89. Bone HG, Dempster DW, Eisman JA, Greenspan SL, McClung MR,  Nakamura T, Papapoulos S, Shih WJ, Rybak-Feiglin A, Santora AC, Verbruggen N, Leung AT, Lombardi A: Odanacatib for the treatment of postmenopausal osteoporosis: development history and design and participant characteristics of LOFT, the Long-Term Odanacatib Fracture Trial. Osteoporos Int 2015, 26:699-712. Paper describing the LOFT trial with odanacatib. 90. Costa AG, Cusano NE, Silva BC, Cremers S, Bilezikian JP, Cathepsin K: its skeletal actions and role as a therapeutic target in osteoporosis. Nat Rev Rheumatol 2011, 7:447-456. 91. Pennypacker BL, Chen CM, Zheng H, Shih MS, Belfast M, Samadfam R, Duong le T: Inhibition of cathepsin K increases modeling-based bone formation, and improves cortical dimension and strength in adult ovariectomized monkeys. J Bone Miner Res 2014, 29:1847-1858. 92. Gerbaix M, Vico L, Ferrari SL, Bonnet N: Periostin expression contributes to cortical bone loss during unloading. Bone 2015, 71:94-100. 93. Cle´ment-Demange L, Clezardin P: Emerging therapies in bone metastasis. Curr Opin Pharmacol 2015. (this volume). 94. Napoli N: Questions on therapy with DPP-4 inhibitors and bone homeostasis. Diabetes Metab Res Rev 2014, 30:201203. 95. Gilbert MP, Pratley RE: The impact of diabetes treatments on bone health in patients with type 2 diabetes mellitus. Endocr  Rev 2015, 4:er20121042 (Epub ahead of print). A detailed review of the bone changes that occur in diabetes and the effects of various treatments.

108. Aspenberg P: Special review: accelerating fracture repair in humans: a reading of old experiments and recent clinical trials. Bonekey Rep 2013, 2:244. 109. Einhorn TA, Gerstenfeld LC: Fracture healing: mechanisms and interventions. Nat Rev Rheumatol 2014. 110. Molvik H, Khan W: Bisphosphonates and their influence on fracture healing: a systematic review. Osteoporos Int 2015, 26:1251-1260. 111. Goldhahn J, Fe´ron JM, Kanis J, Papapoulos S, Reginster JY, Rizzoli R, Dere W, Mitlak B, Tsouderos Y, Boonen S: Implications for fracture healing of current and new osteoporosis treatments: an ESCEO consensus paper. Calcif Tissue Int 2012, 90:343-353. 112. Rao SK, Rao AP: A literature review and case series of accelerating fracture healing in postmenopausal osteoporotic working women. J Orthop 2014, 11:150-152. 113. Little DG, McDonald M, Bransford R et al.: Manipulation of the anabolic and catabolic responses with OP-1 and zoledronic acid in a rat critical defect model. J Bone Miner Res 2005, 20:2044-2052. 114. Wilkinson JM, Little DG: Bisphosphonates in orthopedic applications. Bone 2011, 49:95-102. 115. Wilkinson JM, Eagleton AC, Stockley I et al.: Effect of pamidronate on bone turnover and implant migration after total hip arthroplasty: a randomized trial. J Orthop Res 2005, 23:1-8. 116. Aspenberg P: Bisphosphonates and implants: an overview. Acta Orthop 2009, 80:119-123.

96. Jamal SA, Reid LS, Hamilton CJ: The effects of organic nitrates on osteoporosis: a systematic review. Osteoporos Int 2013, 24:763-770.

117. Lai KA, Shen WJ, Yang CY et al.: The use of alendronate to prevent early collapse of the femoral head in patients with nontraumatic osteonecrosis. A randomized clinical study. J Bone Joint Surg Am 2005, 87:2155-2159.

97. Kleyer A, Schett G: Arthritis and bone loss: a hen and egg story. Curr Opin Rheumatol 2014, 26:80-84.

118. Mobasheri A: The future of osteoarthritis therapeutics: emerging biological therapy. Curr Rheumatol Rep 2013, 15:385.

98. Payne JB, Golub LM, Thiele GM, Mikuls TR: The link between periodontitis and rheumatoid arthritis: a periodontist’s perspective. Curr Oral Health Rep 2015, 2:20-29 PMID: 25657894.

119. Karsdal MA, Bay-Jensen AC, Lories RJ, Abramson S, Spector T,  Pastoureau P, Christiansen C, Attur M, Henriksen K, Goldring SR, Kraus V: The coupling of bone and cartilage turnover in osteoarthritis: opportunities for bone antiresorptives and anabolics as potential treatments? Ann Rheum Dis 2014, 73:336-348. An excellent review of the potential use of bone active therapies in osteoarthritis.

99. Hao L, Chen J, Zhu Z, Reddy MS, Mountz JD, Chen W, Li YP, Odanacatib, Cathepsin K: Specific inhibitor, inhibits inflammation and bone loss caused by periodontal diseases. J Periodontol 2015, 16:1-18. 100. Guerrini MM, Takayanagi H: The immune system, bone and RANKL. Arch Biochem Biophys 2014, 561:118-123. 101. Takayanagi H: New developments in osteoimmunology. Nat Rev Rheumatol 2012, 8:684-689. 102. Geusens P: The role of RANK ligand/osteoprotegerin in rheumatoid arthritis. Ther Adv Musculoskelet Dis 2012, 4:225-233. 103. Vis M, Gu¨ler-Yu¨ksel M, Lems WF: Can bone loss in rheumatoid arthritis be prevented? Osteoporos Int 2013, 24:2541-2553. 104. Eastell R, Walsh JS: Is it time to combine osteoporosis  therapies? Lancet 2013, 382:5-7. A good review of how osteoporosis therapies might be combined effectively. 105. Seeman E, Martin T: Co-administration of antiresorptive and  anabolic agents: a missed opportunity. J Bone Miner Res 2015 http://dx.doi.org/10.1002/jbmr.2496. Another good review of how osteoporosis therapies might be combined effectively. 106. Tella SH, Gallagher JC: Prevention and treatment of  postmenopausal osteoporosis. J Steroid Biochem Mol Biol 2014, 142:155-170. An excellent review of the current and future treatments. 107. Cosman F: Anabolic and antiresorptive therapy for osteoporosis: combination and sequential approaches. Curr Osteoporos Rep 2014, 12:385-395. www.sciencedirect.com

120. Walsh DA, Chapman V: Bisphosphonates for osteoarthritis. Arthritis Res Ther 2011, 13:128. 121. Reginster JY, Badurski J, Bellamy N, Bensen W, Chapurlat R,  Chevalier X, Christiansen C, Genant H, Navarro F, Nasonov E, Sambrook PN, Spector TD, Cooper C: Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial. Ann Rheum Dis 2013, 72:179-186. The results of a trial using strontium therapy in osteoarthritis. 122. Eriksen EF, Ringe JD: Bone marrow lesions: a universal bone  response to injury? Rheumatol Int 2012, 32:575-584. A comprehensive review of bone marrow lesions and their response to anti-resorptive drugs. 123. Mantyh PW: The neurobiology of skeletal pain. Eur J Neurosci  2014, 39:508-519. A masterly review of the biology and management of skeletal pain. 124. Bolland MJ, Grey A, Reid IR: Calcium supplements and cardiovascular risk: 5 years on. Ther Adv Drug Saf 2013, 4:199-210. 125. Shin CS, Kim KM: The risks and benefits of calcium supplementation. Endocrinol Metab (Seoul) 2015, 30:27-34. 126. Marini F, Brandi ML: Pharmacogenetics of osteoporosis. Best  Pract Res Clin Endocrinol Metab 2014, 28:783-793. An interesting review of the potential use of pharmacogenetics in osteoporosis. 127. Eriksen EF, Dı´ez-Pe´rez A, Boonen S: Update on long-term treatment with bisphosphonates for postmenopausal Current Opinion in Pharmacology 2015, 22:115–130

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osteoporosis: a systematic review. Bone 2014, 58: 126-135. 128. Reginster JY1, Neuprez A, Beaudart C, Lecart MP, Sarlet N, Bernard D, Disteche S, Bruyere O: Antiresorptive drugs beyond bisphosphonates and selective oestrogen receptor modulators for the management of postmenopausal osteoporosis. Drugs Aging 2014, 31:413-424. 129. Costa AG, Bilezikian JP: Sclerostin: therapeutic horizons based upon its actions. Curr Osteoporos Rep 2012, 10:64-72.

The first report of the clinical effects of the anti-sclerostin antibody romosozumab on bone density and turnover. 133. Tella SH, Gallagher JC: Biological agents in management of osteoporosis. Eur J Clin Pharmacol 2014, 70:1291-1301. 134. Glover SJ, Eastell R, McCloskey EV, Rogers A, Garnero P, Lowery J, Belleli R, Wright TM, John MR: Rapid and robust response of biochemical markers of bone formation to teriparatide therapy. Bone 2009, 45:1053-1058.

131. Kahn M: Can we safely target the WNT pathway? Nat Rev Drug  Discov 2014, 13:513-532. An excellent review of the Wnt pathway.

135. Leder BZ1, O’Dea LS, Zanchetta JR, Kumar P, Banks K, McKay K, Lyttle CR, Hattersley G: Effects of abaloparatide, a human parathyroid hormone-related peptide analog, on bone mineral density in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 2015, 100:697-706. These studies of abaloparatide, a human parathyroid hormone-related peptide analogue show promise as a potential new drug for osteoporosis.

132. McClung MR, Grauer A, Boonen S, Bolognese MA, Brown JP,  Diez-Perez A, Langdahl BL, Reginster JY, Zanchetta JR, Wasserman SM, Katz L, Maddox J, Yang YC, Libanati C, Bone HG: Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med 2014, 370:412-420.

136. Reid IR: Short-term and long-term effects of osteoporosis  therapies. Nat Rev Endocrinol 2015 http://dx.doi.org/10.1038/ nrendo.71. A comprehensive and excellent review of current therapies for osteoporosis.

130. Ke HZ, Richards WG, Li X, Ominsky MS: Sclerostin and Dickkopf-1 as therapeutic targets in bone diseases. Endocr Rev 2012, 33:747-783.

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