RANKL as a target for the treatment of osteoporosis.

Osteoporosis is characterized by compromised bone strength, predisposing to an increased risk of fracture. Because bone is constantly remodeled, and bone mass and structure are determined by the balance between bone resorption and bone formation, it is important to maintain normal bone turnover. Therefore, therapies that reduce bone resorption have been the mainstream of osteoporosis treatment. Receptor activator of nuclear factor-kappa B ligand (RANKL)-RANK signaling was found to play a pivotal role in the regulation of osteoclastic bone resorption, and inhibition of RANKL-RANK system has become an important therapeutic target for the treatment of osteoporosis. Denosumab, a fully human monoclonal anti-RANKL neutralizing antibody, is developed as a drug for the treatment of osteoporosis. This review summarized pharmacokinetic and pharmacodynamic properties of denosumab, clinical studies including phase 2 dose-ranging and its extension study, phase 3 fracture prevention study (FREEDOM) with extension up to 10 years, studies on male osteoporosis (ADAMO study), and on glucocorticoid-induced osteoporosis, along with relevant clinical studies in Japan. In addition, mechanism of denosumab action that can explain its long-term sustained effects, combination and sequential treatment as well as the problems in discontinuation of denosumab, and finally safety of denosumab therapy is discussed.

Antiresorptive agents' bone-protective and adjuvant effects in postmenopausal women with early breast cancer.

Potent antiresorptive drugs (bisphosphonate and denosumab) are often used to protect bone health in postmenopausal breast cancer patients. In addition, clinical trials have shown that these drugs increase disease-free survival, though the mechanism of adjuvant benefit is largely unknown. Here we review the bone health and adjuvant data for both classes of antiresorptive drugs and highlight differences in their pharmacology. Inhibition of bone resorption is vitally important to protect against osteoporotic fractures, and may also contribute to adjuvant survival benefits by making the bone microenvironment less amenable to breast cancer metastasis. After a course of therapy, stoppage of bisphosphonates yields a persistent antiresorptive effect, whereas discontinuation of denosumab causes a rebound increase in bone resorption markers and a loss of bone mineral density to baseline levels. Whether the potential adjuvant benefits of denosumab are also rapidly lost after drug discontinuation deserves further investigation.

An open-label study in healthy men to evaluate the risk of seminal fluid transmission of denosumab to pregnant partners.

AIMS: Denosumab is a fully human monoclonal immunoglobulin G2 antibody that inhibits bone resorption and increases bone mass and strength. The present clinical study assessed serum and seminal fluid pharmacokinetics following a single denosumab dose in healthy men, and evaluated whether denosumab in seminal fluid poses any risk to a fetus in the event of unprotected sexual intercourse with a pregnant partner. METHODS: An open-label, single-dose study in 12 healthy men was conducted over a 106-day period. Subjects received a single subcutaneous dose of 60-mg denosumab on day 1. Serum and seminal fluid samples were collected at specified time points to assess denosumab pharmacokinetics. Adverse events were recorded. RESULTS: Denosumab was measurable at low concentrations in seminal fluid (~2% of serum concentrations). The mean [standard deviation (SD)] maximum observed drug concentration (Cmax ) was 6170 (2070) ng ml(-1) (serum) and 100 (81.9) ng ml(-1) (seminal fluid). The median time to Cmax (tmax ) was 8 days (serum) and 21 days (seminal fluid). The mean (SD) area under the plasma concentration-time curve (AUC) from time zero to the time of the last quantifiable concentration (AUClast ) was 333 000 (122 000) day•ng ml(-1) (serum) and 5220 (4880) day•ng ml(-1) (seminal fluid). The mean (SD) Cmax and AUC ratios between seminal fluid and serum were 0.0217 (0.0154) and 0.0170 (0.0148), respectively. Using conservative assumptions for ejaculate volume (6 ml), vaginal absorption (100%) and placental transfer (100%), the measured mean denosumab seminal fluid Cmax would result in fetal exposure that was more than 110 times below the preclinically derived 'no effect level' for denosumab. CONCLUSIONS: These results indicate a negligible risk to a fetus exposed to denosumab via seminal fluid transfer to a pregnant partner.

[Pharmacokinetics of anti-RANKL antibody drugs:Denosumab.]

Antibody drug is a kind of glycoprotein which molecular weight is over one hundred thousand. The number of pharmaceutical approval of antibody drug has been increasing in recent years. In terms of a working mechanism and pharmacokinetics, antibody drug is markedly different from existing low molecular weight drugs. In prospect, about body kinetics is the same. This paper describes general features of antibody drug mainly about internal kinetics in the first half. In the last half, body kinetics of human anti-RANKL monoclonal antibody called Denosumab and body kinetics changes in special population are outlined.

Using early biomarker data to predict long-term bone mineral density: application of semi-mechanistic bone cycle model on denosumab data.

Osteoporosis is a chronic skeletal disease characterized by low bone strength resulting in increased fracture risk. New treatments for osteoporosis are still an unmet medical need because current available treatments have various limitations. Bone mineral density (BMD) is an important endpoint for evaluating new osteoporosis treatments; however, the BMD response is often slower and less profound than that of bone turnover markers (BTMs). If the relationship between BTMs and BMD can be quantified, the BMD response can be predicted by the changes in BTM after a single dose; therefore, a decision based on BMD changes can be informed early. We have applied a bone cycle model to a phase 2 denosumab dose-ranging study in osteopenic women to quantitatively link serum denosumab pharmacokinetics, BTMs, and lumbar spine (LS) BMD. The data from two phase 3 denosumab studies in patients with low bone mass, FREEDOM and DEFEND, were used for external validation. Both internal and external visual predictive checks demonstrated that the model was capable of predicting LS BMD at the denosumab regimen of 60 mg every 6 months. It has been demonstrated that the model, in combination with the changes in BTMs observed from a single-dose study in men, is capable of predicting long-term BMD outcomes (e.g., LS BMD response in men after 1 year of treatment) in different populations. We propose that this model can be used to inform drug development decisions for osteoporosis treatment early via evaluating LS BMD response when BTM data become available in early trials.

Pharmacokinetics, pharmacodynamics, safety and immunogenicity of recombinant, fully human anti-RANKL monoclonal antibody (MW031) versus denosumab in Chinese healthy subjects: a single-center, randomized, double-blind, single-dose, parallel-controlled trial.

BACKGROUND: MW031 is a biosimilar candidate of denosumab (Prolia®). This study aimed to compare the pharmacokinetics, pharmacodynamics, safety and immunogenicity of MW031 to denosumab in healthy Chinese participants. RESEARCH DESIGN AND METHODS: In this single-center, randomized, double-blind, parallel-controlled, single-dose trial, participants were given 60 mg MW031 (N = 58) or denosumab (N = 61) by subcutaneous injection and observed for 140 days. The primary endpoint was the bioequivalence of PK parameters (Cmax, AUC0-∞), and secondary endpoints including PD parameter, safety, and immunogenicity. RESULTS: A comparison of main PK parameters showed that the geometric mean ratios (GMR) (90% confidence intervals [CIs]) of AUC0-∞ and Cmax for MW031 over denosumab were 105.48% (98.96%, 112.43%) and 98.58% (92.78%, 104.75%), respectively. The inter-CV values of AUC0-∞ and Cmax for MW031 ranged from 19.9% to 23.1%. PD parameter (sCTX) in the MW031 and denosumab groups were similar, and the positivity rates of immunogenicity were 0% in both groups. This study also showed similar safety profiles in both groups, and there were no drug-related, high-incidence and previously unreported adverse reactions. CONCLUSION: This trial confirmed similar pharmacokinetic profiles of MW031 and denosumab in healthy male participants, and pharmacodynamic profile, immunogenicity and safety were comparable for both drugs. TRIAL REGISTRATION: NCT04798313; CTR20201149.

The similarity of pharmacokinetics, pharmacodynamics, safety, and immunogenicity between recombinant fully human anti-RANKL monoclonal antibody injection (MW032) and denosumab (Xgeva®) in healthy Chinese subjects: A single-center, randomized, double-blind, single-dose, parallel-controlled clinical study.

OBJECTIVE: To compare the pharmacokinetics (PK), pharmacodynamics (PD), safety and immunogenicity between MW032 (denosumab biosimilar) and Xgeva® (denosumab) in healthy Chinese subjects. STUDY DESIGN: In this single-center, randomized, double-blind, single-dose, parallel-controlled design study, 120 healthy male subjects were randomized 1:1 to receive a single dose subcutaneous injection of 120 mg MW032 or Xgeva®, with an observation period of 161 days. The primary endpoint was the bioequivalence of PK parameters (Cmax, AUC0-t), and secondary endpoints including PD parameters, safety, and immunogenicity. RESULTS: One hundred and twelve subjects completed the study, including 56 subjects in each group. The geometric mean ratio and 90% CI for AUC0-t and Cmax were 1.117 (1.034, 1.205) and 1.060 (0.984, 1.142), respectively, which were both within the equivalence interval (0.8, 1.25). The inter-subject variation ranged from 21.37% to 27.37%. The PD parameters between MW032 and Xgeva® were similar. There was no statistically significant difference in the positive incidence of anti-drug antibody test between the two groups. Both MW032 and Xgeva® appeared to be well-tolerated and no Grade 3 or above serious adverse reactions occurred. The adverse reactions observed in the study were reported for denosumab generally. Moreover, there were no high-incidence or previously unreported adverse reactions. CONCLUSION: This study evidenced that the PK profiles of MW032, a denosumab biosimilar, and Xgeva® were bioequivalent. We also found that the PDs, safety, and immunogenicity were similar between the two drugs. Therefore, our results supported the next confirmatory studies for the development of MW032.

Safety and pharmacokinetics of a biosimilar of denosumab (KN012): Phase 1 and bioequivalence study in healthy Chinese subjects.

BACKGROUND: KN012 is a proposed biosimilar candidate for the reference drug denosumab, with the brand name Prolia®. This study explored the tolerance, variability, and pharmacokinetics (PK) of denosumab and its biosimilar in healthy Chinese subjects. RESEARCH DESIGN AND METHODS: A randomized, double-blind, parallel, two-arm study was performed to analyze the bioequivalence of denosumab biosimilar (60 mg) compared with denosumab. RESULTS: The PK properties of denosumab biosimilar were similar to those of denosumab. When denosumab biosimilar was compared to denosumab, the geometric mean ratios (GMRs) of Cmax, AUC0-t, and AUC0-∞ were 98.74%, 102.54%, and 102.18%, respectively, and the 90% confidence interval was observed to be within 80-125%. The inter-subject variability ranged from 31.4% to 34.6%. Five subjects in the denosumab biosimilar group and one subject in the denosumab group were positive for anti-drug antibodies (ADAs) and negative for neutralizing antibodies (NAbs). Adverse reactions were observed in 100% (52 subjects) and 94.0% (47 subjects) of the subjects in the denosumab biosimilar and denosumab groups, respectively. Reductions in the blood calcium and phosphate levels were the most common adverse reactions. CONCLUSION: The PK characteristics were comparable for the denosumab biosimilar and denosumab groups. Their safety profiles were also similar. TRIAL REGISTRATION: : The trial is registered at the Chinese Clinical Trial website (http://www.chinadrugtrials.org.cn/index.html #CTR20181231).

Denosumab biosimilar in postmenopausal osteoporotic women: A randomized, assessor-blind, active-controlled clinical trial.

OBJECTIVE: The study assessed the efficacy, safety, pharmacokinetic (PK), and immunogenicity profiles of denosumab-biosimilar and denosumab-reference in postmenopausal osteoporotic women from India. MATERIALS AND METHODS: In this randomized, assessor-blind, active-control, multicenter trial, 114 patients were randomly allocated to receive denosumab-biosimilar (n = 58) or denosumab-reference (n = 56) at a subcutaneous dose of 60 mg every 6 months, for a year. Vitamin D and oral calcium were given daily. Lumbar spine bone mineral density (BMD) change was the primary end point. RESULTS: Of 114 randomized patients, 111 (denosumab-biosimilar, n = 56; denosumab-reference, n = 55) completed the study. All 114 patients were part of safety and immunogenicity analyses, 110 (denosumab-biosimilar, n = 56; denosumab-reference, n = 54) were part of efficacy analysis, and 20 (denosumab-biosimilar, n = 10; denosumab-reference, n = 10) were part of PK analysis. The bone mineral density (BMD) (lumbar spine) percent change at 1 year with denosumab-biosimilar and denosumab-reference (7.22 vs. 7.62; difference:-0.40; 95% confidence interval: -5.92, 5.12) showed no statistically relevant difference. Likewise, alkaline phosphatase (bone-specific) and PK parameters also did not show statistically relevant differences. Adverse events were reported in 44.83% of patients on denosumab-biosimilar versus 33.93% of patients on denosumab-reference; most events were mild or moderate and not related to the study drugs. No patients showed anti-denosumab antibody positivity. CONCLUSIONS: Denosumab-biosimilar and denosumab-reference showed biosimilarity in osteoporotic postmenopausal women. Availability of denosumab-biosimilar provides a treatment alternative for patients.

Current Treatments and New Developments in the Management of Glucocorticoid-induced Osteoporosis.

Glucocorticoids (GCs) are often used for improvement of quality of life, particularly in the elderly, but long-term GC use may cause harm; bone loss and fractures are among the most devastating side effects. Fracture risk is particularly high in patients with a severe underlying disease with an urgent need for treatment with high-dose GCs. Moreover, it is important to realize that these patients suffer from an augmented background fracture risk as these patients have a high presence of traditional risk factors for osteoporosis, such as high age, low body mass index (BMI), smoking and relatives with osteoporosis or hip fractures. It is thus crucial for prevention of osteoporotic fractures to use the lowest dose of GC for a short period of time to prevent fractures. Another important task is optimal treatment of the underlying disease; for instance, fracture risk is higher in patients with active rheumatoid arthritis than in patients in whom rheumatoid arthritis is in remission. Thus, fracture risk is generally highest in the early phase, when GC dosage and the disease activity of the underlying disease are high. Finally, some of the traditional risk factors can be modulated, e.g., smoking and low BMI. Life-style measures, such as adequate amounts of calcium and vitamin D and exercise therapy are also crucial. In some patients, anti-osteoporotic drugs are also indicated. In general, oral bisphosphonates (BPs) are the first choice, because of their efficacy and safety combined with the low cost of the drug. However, for those patients who do not tolerate oral BPs, alternatives ("second-line therapies") are available: BP intravenously (zoledronic acid), denosumab (Dmab), and teriparatide. Both zoledronic acid and Dmab have been proven to be superior to oral bisphosphonates like risedronate in improvement of bone mineral density. For teriparatide, vertebral fracture reduction has been shown in comparison with alendronate. Thus, to reduce the global burden of GC use and fracture risk, fracture risk management in GC users should involve at least involve life-style measures and the use of the lowest possible dose of GC. In high-risk patients, anti-osteoporotic drugs should be initiated. First choice drugs are oral BPs; however, in those with contraindications and those who do not tolerate oral BPs, second-line therapies should be started. Although this is a reasonable treatment algorithm, an unmet need is that the most pivotal (second-line) drugs are not used in daily clinical practice at the initial phase, usually characterized by high-dose GC and active underlying disease, when they are most needed. In some patients second-line drugs are started later in the disease course, with lower GC dosages and higher disease activity. As this is a paradox, we think it is a challenge for physicians and expert committees to develop an algorithm with clear indications in which specific patient groups second-line anti-osteoporotic drugs should or could be initiated as first-choice treatment.

Pharmacokinetics, pharmacodynamics, safety, and tolerability of single-dose denosumab in healthy Chinese volunteers: A randomized, single-blind, placebo-controlled study.

BACKGROUND: Denosumab is a fully human monoclonal antibody against receptor activator of nuclear factor kappa-B ligand, a cytokine essential for the formation, function and survival of osteoclasts. This study assessed the pharmacokinetics, pharmacodynamics, safety and tolerability of single-dose denosumab (60 and 120 mg) in healthy Chinese volunteers. METHODS: This randomized (3:3:2), single-blind, placebo-controlled study enrolled healthy Chinese volunteers to receive single subcutaneous injection of denosumab 60 mg, 120 mg, or placebo. Study consisted of screening period (up to 21 days), treatment and assessment period (19 weeks), and an end-of-study visit (at week 26). Denosumab pharmacokinetics and pharmacodynamics parameters were estimated using non-compartmental analysis. Safety and tolerability were assessed throughout the study. RESULTS: A total of 63 volunteers received the study treatment and 62 (98.4%) completed the study. Denosumab serum concentrations peaked at around Day 10 with dose-proportional increase from 60 mg to 120 mg. The mean terminal half-life of denosumab 60 mg and 120 mg was 15 days and 26 days, respectively. The serum C-terminal cross-linking telopeptide of type I collagen concentration-time profiles were similar (>80% decrease within 5 days) between denosumab 60 mg and 120 mg groups. The most commonly reported adverse event (AE) was decreased blood calcium levels (denosumab 60 mg, n = 13; denosumab 120 mg, n = 13; placebo, n = 1); however only one volunteer had calcium level below the abnormality value of potential clinical importance and none of the volunteers developed symptoms of hypocalcemia. The majority of AEs were of mild to moderate intensity. There were no deaths, serious AEs, or withdrawal from study due to AEs. No clinically significant findings in vital signs or electrocardiogram were observed. CONCLUSIONS: Both denosumab 60 mg and 120 mg were well tolerated with no new safety concerns identified in healthy Chinese volunteers with similar pharmacokinetics and pharmacodynamics profiles to that of Caucasians. TRIAL REGISTRATION: ClinicalTrial.gov NCT02135640.

Denosumab: A Review in Postmenopausal Osteoporosis.

Denosumab (Prolia®; Pralia®) is a human monoclonal antibody targeting the key bone resorption mediator RANKL. The drug is administered via subcutaneous injection once every 6 months and is approved for various indications, including the treatment of postmenopausal (PM) women with osteoporosis at increased/high risk of fracture or failure/intolerance of other osteoporosis therapies (indications featured in this review). Denosumab showed benefit in several phase 3 or 4 studies in PM women with osteoporosis or low bone mineral density (BMD), including the pivotal 3-year double-blind FREEDOM trial and its 7-year open-label extension. Denosumab reduced the risk of vertebral, nonvertebral and hip fractures and increased BMD across skeletal sites versus placebo in FREEDOM, with these benefits maintained over up to 10 years' therapy in the extension. The drug was also more effective in improving BMD than bisphosphonates, including in women switched from a bisphosphonate regimen, in 1-year trials; however, whether these differences translate into differences in anti-fracture efficacy is unclear. Denosumab was generally well tolerated over up to 10 years' treatment, although an increased risk of multiple vertebral fractures was observed after discontinuation of the drug. Thus, denosumab is a key treatment option for PM women with osteoporosis who have an increased/high risk of fracture or failure/intolerance of other osteoporosis therapies, although the potential for multiple vertebral fractures to occur after discontinuation of the drug requires consideration of subsequent management options.

Novel strategy using tryptic peptide immunoaffinity-based LC-MS/MS to quantify denosumab in monkey serum.

AIM: Denosumab is a recombinant fully human IgG2 that has a high affinity and specificity for human RANKL. Commercially available RANKL labeled with an Fc fragment cannot be used to establish an indirect ELISA. To characterize denosumab pharmacokinetic a robust and accuracy method should be developed urgently. RESULTS: In this study, an immunoaffinity enrichment method coupled with LC-MS/MS was established. The LC-MS/MS method acquired a linear range from 0.1 to 30 µg/ml. The intra- and inter-run precision (CV%) was within 11.5 and 10.5%, respectively. More importantly, the LC-MS/MS pharmacokinetic data were consistent with ELISA. CONCLUSION: This approach accelerated the quantification, reduced the costs and provided an alternative in case of lacking the special antigen to denosumab or a RANKL-biotinylated reagent.

Management of Osteoporosis in Chronic Kidney Disease.

Chronic kidney disease (CKD) patients with coexisting osteoporosis are becoming common. Many of the therapeutic agents used to treat osteoporosis are known to be affected by the renal function. It is generally thought that osteoporosis in G1 to G3 CKD patients can be treated as in non-CKD patients with osteoporosis. In stage 4 or more advanced CKD patients and CKD patients on dialysis with osteoporosis, however, bisphosphonates must be used with caution, bearing in mind the potential development of such disorders as adynamic bone disease. The use of vitamin D preparations in low doses is relatively safe. In postmenopausal women, raloxifene must be administered with caution. When using denosumab, the serum calcium concentrations should be monitored carefully to prevent the development of hypocalcemia, and active vitamin D preparations should be administered concomitantly. The present article provides an overview of the management of osteoporosis in CKD patients.

[Effect of drugs for osteoporosis on cardiovascular diseases and effect of cardio vascular drugs on osteoporosis]. / Effet des médicaments de l'ostéoporose sur les maladies cardiovasculaires et effet des médicaments à visée cardiovasculaire sur l'ostéoporose.

Osteoporosis and cardiovascular diseases are epidemiologically associated. Calcification phenomena of atherosclerotic plaque involve cytokines and growth factors also involved in bone remodeling. Drugs given for either of these two conditions could act on these mechanisms. Can osteoporosis drugs have an influence on the occurrence of cardiovascular events? Conversely, can the treatment of hypertension alter the course of osteoporosis? It is possible that administration of high doses of calcium (1g/day) in patients who already have important dietary intake can increase the risk of myocardial infarction. Epidemiological studies show links between low serum vitamin D levels and cardiovascular disease but interventional studies show that vitamin D administration in moderately deficient subjects vitamin D does not prevent the occurrence of cardiovascular events. Cohort studies show a beneficial effect of beta-blockers and thiazides administered to hypertensive patients: they reduce by 20% risk of fracture of the proximal femur. Should we focus on these anti-hypertensive treatments for our patients with osteoporosis?

Prediction of denosumab effects on bone remodeling: A combined pharmacokinetics and finite element modeling.

Denosumab is a fully human monoclonal antibody that inhibits receptor activator of nuclearfactor-kappa B ligand (RANKL). This key mediator of osteoclast activities has been shown to inhibit osteoclast differentiation and hence, to increase bone mineral density (BMD) in treated patients. In the current study, we develop a computer model to simulate the effects of denosumab treatments (dose and duration) on the proximal femur bone remodeling process quantified by the variation in proximal femur BMD. The simulation model is based on a coupled pharmacokinetics model of denosumab with a pharmacodynamics model consisting of a mechanobiological finite element remodeling model which describes the activities of osteoclasts and osteoblasts. The mechanical behavior of bone is described by taking into account the bone material fatigue damage accumulation and mineralization. A coupled strain-damage stimulus function is proposed which controls the level of bone cell autocrine and paracrine factors. The cellular behavior is based on Komarova et al.׳s (2003) dynamic law which describes the autocrine and paracrine interactions between osteoblasts and osteoclasts and computes cell population dynamics and changes in bone mass at a discrete site of bone remodeling. Therefore, when an external mechanical stress is applied, bone formation and resorption is governed by cell dynamics rather than by adaptive elasticity approaches. The proposed finite element model was implemented in the finite element code Abaqus (UMAT routine). In order to perform a preliminary validation, in vivo human proximal femurs were selected and scanned at two different time intervals (at baseline and at a 36-month interval). Then, a 3D FE model was generated and the denosumab-remodeling algorithm was applied to the scans at t0 simulating daily walking activities for a duration of 36 months. The predicted results (density variation) were compared to existing published ones performed on a human cohort (FREEDOM).

A comprehensive review of denosumab for bone metastasis in patients with solid tumors.

BACKGROUND: Denosumab is fully human monoclonal antibody that specifically binds and inactivates receptor activator of NF-kB ligand (RANKL), an important ligand that regulates bone remodeling. In this review, we aimed to show the clinical data about denosumab treatment and discuss its advantages for the management of patients with solid tumors and bone metastasis. SCOPE: Denosumab showed positive results in clinical studies of solid tumors with bone metastasis. PubMed database and ASCO Symposium Meeting abstracts were searched until August 2015 by using the terms 'denosumab', 'RANKL inhibitor' and 'bone metastasis'. The last search was on 21 August 2015. All resulting studies were retrieved and were also checked for related publications. Clinical trials in this review fulfilled the following criterion: inclusion of sufficient data to allow estimation of the efficacy and safety of denosumab. FINDINGS: The effects of denosumab on skeletal-related events (SREs) were investigated in three large randomized trials: one in patients with breast cancer, one in patients with prostate cancer, and one in patients with multiple myeloma or solid tumors other than breast or prostate cancer. In the breast cancer and prostate cancer studies denosumab was non-inferior and also superior to zoledronic acid in terms of the primary outcome time to first on-study SRE. In the third study denosumab was non-inferior to zoledronic acid but was not superior to zoledronic acid in solid tumors excluding breast and prostate cancer with bone metastases. In the three studies median overall survival and disease progression rates were similar between zoledronic acid and denosumab. Denosumab has also been studied in bone loss associated with hormonal therapy in both breast and prostate cancer. Adjuvant denosumab significantly reduced the risk of clinical fracture risk by 50% in breast cancer patients and by 62% in non-metastatic prostate cancer patients treated with adjuvant aromatase inhibitors or androgen deprivation therapy. In addition, biochemical markers of bone turnover and fractures were significantly reduced in patients under denosumab treatment. CONCLUSION: The promising outcomes in the initial trials with denosumab have shown clinical activity and a favorable safety profile in patients with solid tumors and bone metastasis. Denosumab significantly reduced treatment-related osteoporosis associated with breast and prostate cancer and was superior to zoledronic acid in prevention or delaying of SRE.

[The use of drugs in chronic renal insufficiency: primum non nocere! (First do not harm!). The paradigmatic cases of azathioprine, metformin and denosumab]. / Uso dei farmaci nell'insufficienza renale: primum non nocere! I casi esemplificativi di azatioprina, metformina e denosumab.

Renal function reduction rises difficulties in dealing with many drugs. These problems are mainly due to the need of decreasing progressively the doses of the drugs that are cleared by the kidneys, in parallel with the progressive reduction in renal function. The degree of renal impairment should be better measured as the estimated glomerular filtration rate, avoiding to simply rely on plasma creatinine. Physicians should also be aware of the important potential side effects of some very effective and safe drugs, when they are used in patients with relevant reduction in renal function, independently of their possible plasma accumulation. As paradigmatic, we will discuss here the case of azathioprine, metformin and denosumab use, when renal function is heavily decreased.

Denosumab-related osteonecrosis of the jaw: a case report and management based on pharmacokinetics.

Denosumab, a monoclonal antibody against the receptor activator for nuclear factor-kappa B ligand (RANKL), is a recently approved antiresorptive drug that suppresses osteoclast formation by targeting preosteclasts, in contrast to the traditional antiresorptive bisphosphonates that target mature osteoclasts. Osteonecrosis of the jaw (ONJ) is a well-known, if rare, side effect of bisphosphonate therapy; however, cases of ONJ have also been reported since 2010 in patients taking denosumab. We describe here a patient who developed ONJ while receiving denosumab; the pharmacokinetics of denosumab and bisphosphonates are discussed in the context of ONJ management.

Mejoría clínica e inmunológica de miastenia grave tras tratamiento con denosumab / Clinical and immunological improvement of myasthenia gravis following treatment with denosumab

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