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The RANK (receptor activator of nuclear factor κB)/RANKL (RANK ligand)/OPG (osteoprotegerin) axis is activated after myocardial infarction (MI), but its pathophysiological role is not well understood. Here, we investigated how global and cell compartment-selective inhibition of RANKL affects cardiac function and remodeling after MI in mice. Global RANKL inhibition was achieved by treatment of human RANKL knock-in (huRANKL-KI) mice with the monoclonal antibody AMG161. huRANKL-KI mice express a chimeric RANKL protein wherein part of the RANKL molecule is humanized. AMG161 inhibits human and chimeric but not murine RANKL. To dissect the pathophysiological role of RANKL derived from hematopoietic and mesenchymal cells, we selectively exchanged the hematopoietic cell compartment by lethal irradiation and across-genotype bone marrow transplantation between wild-type and huRANKL-KI mice, exploiting the specificity of AMG161. After permanent coronary artery ligation, mice were injected with AMG161 or an isotype control antibody over 4 weeks post-MI. MI increased RANKL expression mainly in cardiomyocytes and scar-infiltrating cells 4 weeks after MI. Only inhibition of RANKL derived from hematopoietic cellular sources, but not global or mesenchymal RANKL inhibition, improved post-infarct survival and cardiac function. Mechanistically, hematopoietic RANKL inhibition reduced expression of the pro-inflammatory cytokine IL-1ß in the cardiac cellular infiltrate. In conclusion, inhibition of RANKL derived from hematopoietic cellular sources is beneficial to maintain post-ischemic cardiac function by reduction of pro-inflammatory cytokine production. KEY MESSAGES: Experimental myocardial infarction (MI) augments cardiac RANKL expression in mice. RANKL expression is increased in cardiomyocytes and scar-infiltrating cells after MI. Global or mesenchymal cell RANKL inhibition has no influence on cardiac function after MI. Inhibition of RANKL derived from hematopoietic cells improves heart function post-MI. Hematopoietic RANKL inhibition reduces pro-inflammatory cytokines in scar-infiltrating cells.

Unlabelled: IL-35 is a novel anti-inflammatory cytokine, but the exact role of IL-35 in the progression of RA remains unclear, especially associated with osteoporosis and bone erosion. The present research has not been reported. Our purpose is to study how IL-35 affects RA bone destruction., Introduction: This study investigated the effect of interleukin-35 (IL-35) on OPG and RANKL expression in collagen-induced arthritis (CIA) in rats and in cultured fibroblast-like synoviocytes (FLS)., Methods: Thirty DBA/1J mice were randomly assigned to three groups (n = 10 per group): the control group, the CIA group, and the CIA + IL-35 group. Collagen-induced arthritis was induced by immunization with collagen. IL-35 was intraperitoneally injected daily for 10 days, starting from the 24(th) day after immunization. FLS cells were isolated and cultured from CIA. The expression of IL-17, RANKL, and OPG was determined by RT-PCR and Western blot. Each experiment was repeated three times., Results: CIA mice exhibited arthritis symptoms on day 24, followed by a rapid progression of arthritis. The expression of IL-17 and RANKL was increased and the expression of OPG was decreased in CIA mice compared with control mice. IL-35 treatment inhibited the development of arthritis in CIA mice, accompanied by a decrease in the expression of IL-17 and RANKL and an increase in the expression of OPG. Furthermore, IL-35 dose-dependently inhibited the expression of RANKL and increased the expression of OPG in cultured FLS cells., Conclusion: IL-35 inhibits RANKL expression and increases OPG expression in CIA mice. IL-35 may be used for treating rheumatoid arthritis.

Purpose: The aim of this study was to assess patients' preferences for efficacy, safety, and mode of administration in relation to available bone-targeted agents (BTA) for the prevention of skeletal-related events (SREs) associated with bone metastases in Europe., Methods: Adults in France (n = 159), Germany (n = 166), and the United Kingdom (UK; n = 159) with a self-reported physician diagnosis of bone metastases secondary to a solid tumour completed an online discrete- choice experiment survey of ten questions, choosing between pairs of hypothetical BTA profiles. Profiles were defined by five treatment attributes: delay of first SRE, delay of worsening of pain, annual risk of osteonecrosis of the jaw (ONJ), annual risk of renal impairment, and mode of administration. Profiles were generated using an experimental design with known statistical properties. A main-effects random parameters logit (RPL) model was applied to relate participants' choices to the characteristics of the BTA profiles., Results: The most important treatment attributes for patients across all three countries were time until first SRE, annual risk of renal complications and time until pain worsening. For these attributes, better levels of outcomes were significantly preferred to worse levels (p < 0.05). A 120-minutes infusion every 4 weeks was the least preferred mode of administration. Risk of ONJ was judged by patients in the UK and Germany to be the least important attribute., Conclusions: Patients consider delaying SREs, avoiding renal impairment and delaying pain worsening as the most important goals to consider when selecting treatment to prevent the bone complications commonly associated with bone metastases.

Purpose: Three bone-targeted agents (BTAs) are approved in the USA for prevention of bone complications among solid tumor patients with bone metastases: two intravenous bisphosphonates (IV BP) (pamidronate and zoledronic acid), and one subcutaneous receptor activator of nuclear factor-kappaB (RANK) ligand inhibitor (denosumab). Using electronic medical record data from outpatient community and hospital-affiliated oncology clinics, we examined the characteristics of patients who initiated treatment with a BTA in 2011 and followed them for a maximum of 12 months., Methods: Adult patients with bone metastasis secondary to solid tumors newly treated with a BTA during 2011 were identified from the Oncology Services Comprehensive Electronic Records (OSCER) database. We examined patient characteristics at BTA initiation, treatment patterns, and compliance during a 12-month period. Sensitivity analyses were performed in a subgroup of patients who had confirmed 12 months of follow-up data., Results: Denosumab patients (N = 1,594) were older (65 % ≥65 years vs. 60 % ≥65 years), further along in their disease progression (time since bone metastasis diagnosis: 16 % ≥2 years vs. 10 % ≥2 years), less likely to switch BTA (overall: 6 vs. 14 %; subgroup: 8 vs. 19 %), and more compliant with treatment (overall: median doses of 7 vs. 4; subgroup: 11 vs. 8) compared to IV BP patients (N = 1,975). Findings were consistent across gender, age, tumor type, naïve, and transition strata., Conclusions: Patients receiving denosumab and IV BPs may differ. Despite higher age and more advanced disease, patients treated with denosumab are more likely to stay on treatment and have better compliance.

We report the case of a 48-year-old man with acquired Fanconi syndrome due to IgG-kappa monoclonal gammopathy, who received a single dose of denosumab 60 mg for secondary prevention of skeletal fractures, in conjunction with oral calcium and vitamin D supplementation. The treatment was complicated with a severe, symptomatic hypocalcemia occurring 1 month after the injection and necessitating 4 weeks of intravenous calcium gluconate therapy. Similarly to bisphosphonates, inhibitors of the receptor activator of nuclear factor kappa-B ligand may not be appropriate for the treatment of acquired Fanconi syndrome and other forms of osteomalacia regardless of the degree of renal insufficiency and vitamin D levels. Clinicians should carefully interpret the radiographic and bone densitometry results in light of diverse mechanisms of bone demineralization and potential dependence of calcium homeostasis on high bone turnover.

Giant cell tumor of bone (GCTB) is a rare primary bone tumor that primarily affects young adults, but can be seen in children. The primary modality of treatment is surgical resection; however, this is not always possible given the location and extent of the neoplasm. Recent developments in the understanding of the underlying molecular pathogenesis of disease have pointed to interactions between the stromal component producing receptor activator of nuclear factor-kappaB (RANK) and RANK-ligand (RANKL) causing the formation of osteoclast-like giant cells that drive bone destruction. The development of a monoclonal humanized antibody to RANKL, denosumab, has been shown to reduce skeletal-related events from osteoporosis and from bony metastases from solid tumors. Recent phase II clinical trials with denosumab in skeletally mature adolescents over age 12 years and adults with GCTB, have shown both safety and efficacy, leading to its accelerated US FDA approval on 13 June 2013. In children who are skeletally immature, safety and efficacy has not been established, and there has been only published anecdotal use.

We report on the clinical and biochemical outcomes in two adult patients with active polyostotic fibrous dysplasia (FD) treated with the RANK-L inhibitor, denosumab, following unsatisfactory responses to prior long-term bisphosphonate therapy. A 44-year-old female (case 1) who had received a cumulative dose of 20 mg zoledronic acid over 2.5 years and a 48-year-old male (case 2) who had received a cumulative dose of 45 mg zoledronic acid over 8 years both experienced minimal reductions in pain scores and markers of bone turnover. Following initiation of denosumab 60 mg sc, changes in bone pain, bone turnover [assessed by serum amino-terminal propeptide of type I collagen (PINP) and urinary deoxypyridinoline] were monitored over a period of 20 and 8 months, respectively. Following administration of denosumab, both patients demonstrated a rapid and pronounced biochemical response: Within 4-7 weeks, bone turnover markers fell to levels within the respective reference range, and one patient reported a reduction in pain. Treatment with denosumab was well tolerated. However, transient asymptomatic hypocalcaemia and/or hypophosphatemia associated with a transient two to threefold increase in serum PTH levels was observed in both patients. Dosing intervals for denosumab varied significantly between the two patients, depending on disease activity at baseline. Denosumab appears to be effective in reducing bone turnover in adult patients with active FD. However, caution should be exercised, and patients should be monitored carefully as significant fluctuations in biochemical and hormonal indices can occur.

Osteonecrosis of the jaw (ONJ) is a clinical condition associated with long-term exposure to inhibitors of bone resorption, mainly bisphosphonates. Denosumab (DMab) is a human monoclonal antibody of the receptor activator of nuclear factor kappa-B ligand. It prevents osteoclast-mediated bone resorption and is widely prescribed for the management of postmenopausal osteoporosis. Whereas ONJ has already been reported in women treated with DMab, we report for the first time the development of ONJ, following tooth extraction, in a male patient treated for idiopathic osteoporosis with DMab. Due to the constant increase in DMab prescription, for the management of osteoporosis, in both genders, physicians should be made aware of this potential risk.

Unlabelled: Dextromethorphan (DXM), a commonly used antitussive, is a dextrorotatory morphinan. Here, we report that DXM inhibits the receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastogenesis and bone resorption by abrogating the activation of NF-κB signalling in vitro. Oral administration of DXM ameliorates ovariectomy (OVX)-induced osteoporosis in vivo., Introduction: DXM was reported to possess anti-inflammatory properties through inhibition of the release of pro-inflammatory factors. However, the potential role and action mechanism of DXM on osteoclasts and osteoblasts remain unclear. In this study, in vitro and in vivo studies were performed to investigate the potential effects of DXM on osteoclastogenesis and OVX-induced bone loss., Methods: Osteoclastogenesis was examined by the TRAP staining, pit resorption, TNF-α release, and CCR2 and CALCR gene expression. Osteoblast differentiation was analyzed by calcium deposition. Osteogenic and adipogenic genes were measured by real-time PCR. Signaling pathways were explored using Western blot. ICR mice were used in an OVX-induced osteoporosis model. Tibiae were measured by µCT and serum markers were examined with ELISA kits., Results: DXM inhibited RANKL-induced osteoclastogenesis. DXM mainly inhibited osteoclastogenesis via abrogation of IKK-IκBα-NF-κB pathways. However, a higher dosage of DXM antagonized the differentiation of osteoblasts via the inhibition of osteogenic signals and increase of adipogenic signals. Oral administration of DXM (20 mg/kg/day) partially reduced trabecular bone loss in ovariectomized mice., Conclusion: DXM inhibits osteoclast differentiation and activity by affecting NF-κB signaling. Therefore, DXM at suitable doses may have new therapeutic applications for the treatment of diseases associated with excessive osteoclastic activity.

Unlabelled: Kinsenoside is able to improve bone turnover rate in ovariectomized (OVX) mice. In vitro analysis shows that kinsenoside antagonizes osteoclast development and bone resorption., Introduction: Kinsenoside, the main active compound of the traditional Taiwanese herb Anoectochilus formosanus, has an antiinflammatory effect. This study investigates whether kinsenoside inhibits osteoporosis and osteoclastogenesis., Methods: OVX mice were used to examine the antiosteoporotic activity of kinsenoside. The trabecular bone microarchitecture was assessed by microcomputed tomography. In vitro experiments were performed to determine the mechanisms of the antiosteoporotic effects of kinsenoside., Results: Microcomputed tomography scanning showed that kinsenoside suppresses bone loss in OVX mice. Kinsenoside decreases plasma CTx concentration. Reverse transcription polymerase chain reaction (RT-PCR) analysis also showed that kinsenoside reduces the femoral mRNA expression of tartrate-resistant acid phosphatase (TRAP) and matrix metalloproteinase-9 (MMP-9). Kinsenoside inhibits osteoclast formation in bone marrow cells (BMs) and RAW 264.7 cells. Western blot was used to analyze osteoclast-associated signaling pathways in RAW 264.7 cells. Results show that kinsenoside does not inhibit IKK phosphorylation but suppresses the phosphorylation of IκBα and p65. Kinsenoside significantly inhibits the RANKL induction of IKK activity. Kinsenoside inhibits the RANKL-triggered nuclear translocations of NF-κB and nuclear factor of activated T cells c1 (NFATc1). RT-PCR was used to analyze osteoclast precursor fusion and resorption-associated gene expression in BMs. Kinsenoside inhibits the expression of cathepsin K (CAK), dendritic cell-specific transmembrane protein, MMP-9, and TRAP., Conclusions: Kinsenoside inhibits osteoclastogenesis from macrophages by attenuating RANKL-induced NF-κB and NFATc1 activities, which in turn, prevents bone loss from OVX mice.

Unlabelled: The objective was to undertake a health economic analysis of denosumab for the treatment of osteoporosis in women from the UK, using the FRAX® tool. Denosumab was cost-effective in women with a risk of major osteoporotic fracture meeting or exceeding approximately 20% who are unable to take, comply with or tolerate generic alendronate., Introduction: Denosumab is a novel biologic agent developed for the treatment of osteoporosis, which has been shown to reduce the risk of fractures in a phase-III trial. The objective of the present study was to undertake a health economic analysis of denosumab in women from the UK. Ten-year probabilities of a major osteoporotic fracture at which denosumab is a cost-effective alternative to no treatment, generic alendronate, risedronate and strontium ranelate were estimated., Methods: A previously published Markov model was adapted to incorporate fracture and mortality risk assessments based on absolute fracture probability, as estimated by FRAX®. The model included treatment persistence and residual effect after discontinuation., Results: At a willingness-to-pay (WTP) of £30,000 per quality-adjusted life year and a 10-year fracture probability equivalent to a woman with a prior fragility fracture, denosumab was cost-effective compared to no treatment from the age of 70 years. At the same WTP, denosumab was-irrespective of age-cost-effective compared to no treatment at a major osteoporotic fracture probability of approximately 20%. Denosumab was estimated to cost-effectively replace strontium, risedronate and generic alendronate at 10-year probabilities exceeding 11, 19 and 32%, respectively., Conclusion: FRAX® facilitates the estimation of cost-effectiveness-based intervention thresholds applicable to patients with different combinations of clinical risk factors, which more closely matches the situation in clinical practice. Denosumab is cost-effective in patients with major osteoporotic fracture probabilities meeting or exceeding approximately 20% who are unable to take, comply with or tolerate generic alendronate.

Unlabelled: In the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) study, women with incident clinical fractures reported significant declines in health-related quality of life (HRQoL). The largest declines were observed when the assessment was <3 months post fracture. The largest impact of incident clinical fractures was on physical function, and that of incident clinical vertebral fractures was on back pain., Introduction: In the FREEDOM trial, denosumab significantly reduced the risk of new vertebral, hip, and nonvertebral fractures. We evaluated the effect of denosumab on HRQoL and the association between incident clinical fractures and HRQoL., Methods: The FREEDOM trial enrolled 7,868 women aged 60-90 years with a total hip and/or lumbar spine BMD T-score <-2.5 and not <-4.0 at either site. Women were randomized to receive denosumab 60 mg or placebo every 6 months, in addition to daily calcium and vitamin D. HRQoL was assessed with the Osteoporosis Assessment Questionnaire-Short Version (OPAQ-SV) at baseline and every 6 months for 36 months. The OPAQ-SV assesses physical function, emotional status, and back pain. Higher scores indicate better health status., Results: No statistically significant differences in mean change in HRQoL from baseline to end of study were found when comparing treatment groups. Compared with women without any incident fractures during the study, women with incident clinical fractures reported significant declines in physical function (-4.0 vs. -0.5) and emotional status (-5.0 vs. -0.8) at month 36 (P < 0.001 for both). Importantly, time-dependent covariate analyses demonstrated that the largest declines were observed when the assessment was <3 months post fracture. The largest impact of incident clinical fractures was on physical function, and that of incident clinical vertebral fractures was on back pain., Conclusions: These findings not only demonstrate that incident clinical fractures impact HRQoL but also contribute new information regarding the impact of these fracture events on HRQoL over time.

Unlabelled: We report a direct comparison of receptor activator of nuclear factor kappa B ligand (RANKL) inhibition (RANK-Fc) with bisphosphonate treatment (alendronate, ALN) from infancy through early adulthood in a mouse model of osteogenesis imperfecta. Both ALN and RANK-Fc decreased fracture incidence to the same degree with increases in metaphyseal bone volume via increased number of thinner trabeculae., Introduction: The potential therapeutic benefit of RANKL inhibitors in osteogenesis imperfecta (OI) is under investigation. We report a direct comparison of RANKL inhibition (RANK-Fc) with bisphosphonate treatment (ALN) from infancy through early adulthood in a model of OI, the oim/oim mouse., Methods: Two-week-old oim/oim, oim/+, and wildtype (+/+) mice were treated with RANK-Fc 1.5 mg/kg twice per week, ALN 0.21 mg/kg/week or saline (n = 12-20 per group) for 12 weeks., Results: ALN and RANK-Fc both decreased fracture incidence (9.0 ± 3.0 saline 4.4 ± 2.7 ALN, 4.3 ± 3.0 RANK-Fc fractures per mouse). Serum TRACP-5b activity decreased to 65% after 1 month in all treated mice, but increased sacrifice with RANK-Fc to 130-200% at sacrifice. Metaphyseal density was significantly increased with ALN in +/+ and oim/oim mice (p < 0.05) and tended to increase with RANK-Fc in +/+ mice. No changes in oim/oim femur biomechanical parameters occurred with treatment. Both ALN and RANK-Fc significantly increased trabecular number (3.73 ± 0.77 1/mm for oim/oim saline vs 7.93 ± 0.67 ALN and 7.34 ± 1.38 RANK-Fc) and decreased trabecular thickness (0.045 mm ± 0.003 for oim/oim saline vs 0.034 ± 0.003 ALN and 0.032 ± 0.002 RANK-Fc) and separation in all genotypes (0.28 ± 0.08 mm for oim/oim saline vs 0.12 ± 0.010 ALN and 13 ± 0.03 RANK-Fc)., with significant increase in bone volume fraction (BVF) with ALN, and a trend towards increased BVF in RANK-Fc., Conclusion: Treatment of oim/oim mice with either a bisphosphonate or a RANK-Fc causes similar decreases in fracture incidence with increases in metaphyseal bone volume via increased number of thinner trabeculae.

Unlabelled: Serious adverse events of infections that occurred in subjects receiving denosumab or placebo in the Fracture Reduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) study were examined in detail. Serious adverse events of infections in denosumab subjects had heterogeneous etiology, with no clear clinical pattern to suggest a relationship to time or duration of exposure to denosumab., Introduction: Denosumab reduces the risk for new vertebral, hip, and nonvertebral fractures compared with placebo. In the pivotal phase 3 fracture trial (FREEDOM), the overall safety profile and incidence of adverse events including adverse events of infections were similar between groups. Serious adverse events of erysipelas and cellulitis were more frequent in denosumab-treated subjects. In this report, we further evaluate the details of infectious events in FREEDOM to better understand if RANKL inhibition with denosumab influences infection risk., Methods: FREEDOM was an international multicenter, randomized, double-blind, placebo-controlled study in postmenopausal women with osteoporosis randomly assigned to receive placebo (n = 3,906) or denosumab 60 mg every 6 months (n = 3,902). The incidence of adverse events and serious adverse events categorized within the Medical Dictionary for Regulatory Activities system organ class, "Infections and Infestations," was compared between the placebo and denosumab groups by body systems and preferred terms. The temporal relationship between occurrence of serious adverse events of infections of interest and administration of denosumab was explored., Results: Serious adverse events of infections involving the gastrointestinal system, renal and urinary system, ear, and endocarditis were numerically higher in the denosumab group compared with placebo, but the number of events was small. No relationship was observed between serious adverse events of infections and timing of administration or duration of exposure to denosumab., Conclusions: Serious adverse events of infections that occurred with denosumab treatment had heterogeneous etiology, with no clear clinical pattern to suggest a relationship to time or duration of exposure to denosumab.

Unlabelled: The final analysis of this 2-year, randomized, crossover study showed that postmenopausal women with osteoporosis were more adherent, compliant, and persistent with subcutaneous denosumab injections every 6 months than with once-weekly alendronate tablets. After receiving both treatments, women reported greater satisfaction with injectable denosumab and preferred it over oral alendronate., Introduction: Osteoporosis patients who are non-compliant or non-persistent with therapy may have suboptimal clinical outcomes. This 2-year, randomized, open-label, crossover study compared treatment adherence between subcutaneous denosumab, 60 mg every 6 months, and oral alendronate, 70 mg once weekly., Methods: Postmenopausal women at 25 centers in the USA and Canada with bone mineral density T-scores -4.0 to -2.0 and no prior bisphosphonate use received alendronate then denosumab, or denosumab then alendronate, over successive 12-month periods. Adherence required both compliance (denosumab injections 6 months apart or ≥ 80% of alendronate tablets) and persistence (both denosumab injections or ≥ 2 alendronate doses in the last month and completion of the treatment period)., Results: Of the 250 women enrolled (124 alendronate, 126 denosumab), 221 entered the second year (106 denosumab, 115 alendronate). Denosumab was associated with less non-adherence than alendronate (first year, 11.9% vs 23.4%; second year, 7.5% vs 36.5%). Risk ratios for non-adherence, non-compliance, and non-persistence favored denosumab in both years (p < 0.05). Of 198 subjects expressing treatment preference, 183 (92.4%) preferred the injections over the oral therapy. BMD improved further when subjects received denosumab after alendronate and remained stable when they received alendronate after denosumab., Conclusion: Based on the final results of this crossover study after women had received each treatment for up to 1 year, postmenopausal women with osteoporosis were more adherent, compliant, and persistent with subcutaneous denosumab injections every 6 months than with once-weekly alendronate tablets and reported increased treatment preference and satisfaction with injectable denosumab over oral alendronate.

Purpose: The purpose of this study was to assess the necessity of post-marketing safety monitoring focused on osteonecrosis of the jaw (ONJ) in patients with bone metastatic cancer treated with denosumab (AMG162)., Methods: The ONJ safety data from three randomized phase III trials were pooled, and risk ratios and power were computed using traditional methods and simulation., Results: A total of 89 ONJ cases (1.57%; 95% CI, 1.26-1.92) were reported with 52 (1.83%; 95% CI, 1.37-2.39) occurring in the denosumab group (n = 2,841) and 37 (1.30%; 95% CI, 0.92-1.79) in the zoledronic acid group (n = 2,836). Overall, the pooled risk ratio (RR) for ONJ was 1.40 (95% CI, 0.92-2.13; p = 0.11). In the trials reporting superior therapeutic efficacy of denosumab, the RR for ONJ was 1.61 (95% CI, 0.99-2.62; p = 0.052). However, neither separately nor pooled had any trial adequate power (>80%) to detect excess relative risks of ONJ of up to 76%, assuming fixed ONJ rates in the control arms. The joint power of the trials to detect the observed excess relative risk of 40% was only 36%. The rate of mucosal healing in patients with ONJ appeared similar in both groups (RR, 1.28; 95% CI, 0.66-2.45; p = 0.5)., Conclusions: Although the overall frequency of ONJ was low, post-marketing risk-benefit studies with this novel compound appear warranted focusing specifically on this rare toxicity, which can potentially have a high impact on quality of life.

Bone metastases can be associated with a significant worsening of patient morbidity and mortality. Bisphosphonates have been extensively researched and shown to delay the onset and reduce the incidence of complications from bone metastases. The most commonly used bisphosphonates are intravenous pamidronate, intravenous ibandronate, intravenous zoledronic acid and oral/intravenous clodronate. Several bone-targeted agents with innovative mechanisms of action are currently being developed. These include receptor activator of nuclear factor-kB ligand (RANKL) inhibitors, CCR1 inhibitors, Src inhibitors, DKK1-neutralising antibodies, activin antagonists and endothelin-1 inhibitors. In an era of individualised medicine, oncologists are being faced with an increasing number of questions when dealing with bone-targeted agents. These questions not only include the choice of which drug to use (i.e. bisphosphonates or RANKL inhibitor) but also the best treatment strategy to use. This review will provide medical oncologists with a practical guide to the use of bone-targeted agents.

Unlabelled: We examined RANKL expression and OCL formation in cultured bone marrow cells from eight postmenopausal women in response to E(2). E(2) treatment inhibited the ability of hematopoietic cells to form OCLs in response to RANKL, and decreased RANKL production. These changes are likely involved in the ability of E(2) to influence the development of osteoporosis., Introduction: Estrogen (E(2)) deficiency at menopause increases osteoclast (OCL) formation and bone resorption, predisposing women to osteoporosis. We examined receptor activator of NF-kappa B-ligand (RANKL) expression and in vitro OCL formation in cultured bone marrow cells from eight postmenopausal women before and after 3 weeks of E(2) therapy and three untreated premenopausal women., Methods: TRAP staining and resorption pit assay determined OCL number and function. Flow cytometry measured the distribution of marrow cell types and expression of RANKL in the macrophage-enriched fraction (R1) and a lymphocyte-enriched fraction (R2)., Results: RANKL (3-100 ng/ml) produced a dose-dependent increase in in vitro OC formation and E(2) therapy significantly (p < 0.01) inhibited OCL formation by 33 to 50%. A small proportion of marrow cells bound anti- RANKL Ab (0.2-4.3%). There was no effect of E(2) on the percentage of cells binding the anti-RANKL Ab in the R1 fraction. In the R2 fraction E(2) treatment decreased the percentage of cells binding anti-RANKL Ab by 68 +/- 9% (p < 0.01)., Conclusion: Three weeks of E(2) treatment had a dual action. It inhibited the ability of hematopoietic cells to form OCLs in response to RANKL, and decreased the production of RANKL in cells of the bone marrow. The observed changes in the osteoclastic potential of bone marrow cells are likely involved in the ability of E(2) to regulate bone mass and influence the development of osteoporosis.

Unlabelled: Weekly treatment of gonad-intact cynomolgus monkeys (for up to 6 months) with the RANKL inhibitor OPG-Fc reduced bone turnover markers and increased volumetric cortical and trabecular BMD and BMC at radial and tibial metaphyses. OPG-Fc was well tolerated in this study without evidence of change in measured toxicologic parameters vs. control., Introduction: RANKL is the primary mediator of osteoclast formation, function, and survival. The catabolic effects of RANKL are inhibited by OPG, a soluble decoy receptor for RANKL. We investigated the safety and pharmacology of OPG-Fc in gonad-intact cynomolgus monkeys., Methods: Males and females were treated weekly with vehicle (n = 5/sex) or OPG-Fc (15 mg/kg) by s.c. (n = 5/sex) or i.v. (n = 3/sex) injection for 6 months., Results: Routine toxicologic investigations, hematologic parameters, body and organ weights, and ophthalmologic and electrocardiographic findings were not affected by OPG-Fc treatment. Because s.c. and i.v. dosing of OPG-Fc caused similar effects, these groups were combined for analyses. The following endpoints were significantly different in males and/or females treated with OPG-Fc relative to sex-matched vehicle controls after 6 months (p < 0.05). Biochemical markers of bone turnover (urine N-telopeptide and serum osteocalcin) were significantly decreased with OPG-Fc treatment. Cortical and trabecular volumetric BMD and BMC, cortical thickness, and cross-sectional moment of inertia were significantly increased by OPG-Fc treatment at the proximal tibia and distal radius metaphyses. Increases in cortical thickness were associated with significantly greater periosteal circumference., Conclusions: OPG-Fc increased cortical and trabecular BMD and BMC in young gonad-intact cynomolgus monkeys.