[Inhibition of receptor activator of nuclear kappa-B ligand: pathophysiology and preclinical data]


OCTOBER 20, 2011

LAM KID - 2011;1(02)

[Bone remodeling is a lifelong process, in which the balanced functions of osteoclasts and osteoblasts have a key role. In certain conditions, for example during the dramatical hormonal changes in the postmenopausal period, the upset of this balance leads to a pathologically increased bone loss. Such conditions lead to an increased bone loss, which results in an increased risk of fractures. Bone resorption is primarily regulated by a member of the tumor necrosis factor family, receptor activator of nuclear factor κB ligand, which plays a central role in the development, function and survival of osteoclasts. Catabolic effects of this ligand is inhibited by another member of the tumor necrosis factor family, osteoprotegerin, which binds to the ligand and prevents its interaction with its receptor, the receptor activator of nuclear factor κB. Osteoclast activity is at least partly dependent on the relative balance of the ligand and osteoprotegerin. It has been shown in a number of animal models that inhibition of the ligand markedly decreases bone resorption and increases cortical and cancellous bone volume, density and strength, without having any significant effect on other organs. On the basis of these findings, inhibition of receptor activator of nuclear κB ligand is a promising therapy of conditions characterised by increased bone loss. In phase 3 clinical trials, denosumab therapy significantly increased bone mineral density at various regions of the skeleton and significantly decreased the levels of bone turnover markers compared with placebo and alendronate therapy, and significantly decreased the incidence of new vertebral, total hip and nonvertebral fractures compared with placebo. On the basis of these findings, denosumab therapy offers a novel, revolutionary solution for the treatment of postmenopausal osteoporosis.]



Further articles in this publication


[Pain relief in metastatic bone disease]

BOÉR Katalin

[Metastatic bone disease is a hallmark of distant relapse of a number of solid tumours. The treatment of bone metastases is palliative, the main goal is to relieve pain, whereas it’s also important to reduce the risk of bone fractures, prolong survival and maintain the physical activity of patients. Pain is one of the most common symptoms of bone metastases, and state-of-the-art pain relief has an important role in maintaining the patients’ quality of life. Therapies to control pain include drug therapy, radiotherapy, surgery, systemic oncotherapy, such as chemotherapy and/or hormone therapy, multibone radioisotope therapy and administration of bisphosphonates. Regarding the relief of pain caused by malignant tumours, the guidelines developed by the World Health Organization should be followed. The algorithm of pain relief starts with assessment of the pain’s intensity and includes both pharmacological and nonpharmacological interventions. Analgesics used for pain relief include nonopioids, opioids and adjuvant agents. The pain can be efficiently relieved with the combined use of modern analgesics in the great majority of patients.]


[Pain relief in the neurologist’s view]


[Pain, on the basis of its anatomical origin, can be nociceptive (somatic, visceral) or neuropathic, that is, occuring as a direct consequence of a lesion or disease affecting the somatosensory system. The past few years’ epidemiological studies showed that chronic neuropathic pain affects 7-8% of the general population. Diagnosis of neuropathic pain can be established without instrumental examinations, with the help of validated tests that can be used by any physician. Neuropathic pain greatly deteriorates the patients’ quality of life, and the effect of traditional analgesics is insufficient for its treatment. Thus, it is important to know those treatment procedures and drugs that have been proved to be efficient for relieving neuropathic pain.]


[Pain management in rheumatology]

NAGY Katalin

[Pain is the most common symptom in rheumatology, which can be of mechanical or inflammatory origin, acute and chronic, nociceptive, neuropathic and psychogenic. Pain can be relieved by analgesics, nonsteroidal anti-inflammatory drugs, opioids, adjuvants and special drugs depending on the etiology, for example a gout attack can be stopped by colchicine. For pain relief, we use therapeutic guidelines of the World Health Organization (WHO), which recommends the use of analgesics, NSAIDs and adjuvants as the first step, weaker opioids as the second, and strong opioids as the third step. In rheumatology, the first step's drugs are generally used. If possible, NSAIDs should be administered briefly, potentially combined with analgesics and muscle relaxants. If pain management is insufficient, tramadol should be given. Pain relief in rheumatology also include the use of local and intraarticular injections, physiotherapy, TENS and balneotherapy. Complex therapies that combine the above mentioned methods is often more effective than the use of medications only.]


[Osteoid osteoma]



[Connections of bone turnover and energy homeostasis in women]


[BACKGROUND - A new discovery of the past decade has been the previously unknown relationship between the bone metabolic unit and energy homeostasis. On the basis of data from previous animal and clinical studies, osteocalcin has been considered the major mediator of this relationship. Cathepsin K is a cysteine protease type osteolytic enzyme, which has a role in bone resorption, and which is a pharmaceutical target in the treatment of osteoporosis and bone metastasis. According to data from animal studies, its deficiency or selective inhibition decreases the differentiation of preadipocytes, body weight and serum levels of insulin and glucose in obese mice. The aim of our study was to elucidate the role of cathepsin K in the human bone - metabolic axis in women (n=66). PATIENTS AND METHODS - 21 healthy and 45 glucose intolerant women were examined. OGTT, IVGTT and hyperinsulinaemic euglycaemic clamp were performed to assess carbohydrate homeostasis, insulin secretion, whole-body and muscle glucose utilization (M-1 and M-3). Circulating levels of bone markers and adipokines were measured, and DEXA was used to measure BMD, fat and muscle mass. RESULTS - Cathepsin K levels showed a significant (p<0.05), negative correlation with BMI, body fat percent and OGTT glucose and insulin area under the curve (AUC), and a positive correlation with M values. No correlation was found between cathepsin K levels and IVGTT measurements. CONCLUSION - Cathepsin K - in women - is not only a participant of the bone metabolism - energy homeostasis axis. Its role in human glucose homeostasis differs from what could be expected on the basis of animal experiments, because increasing cathepsin K levels indicate, paradoxically, improving metabolic state in women. Our data suggest that insulin regulation of cathepsin K is mediated by the incretin system.]

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Clinical Oncology

[Bone metastases - Current treatment strategy]

BOÉR Katalin, NÉMETH Zsuzsanna

[Bone is the most common site of metastatic disease in many solid tumours, mainly in breast, prostate and lung cancer. Patients with bone metastases are at risk for skeletal-related events such as bone pain, pathological fractures requiring surgery and/or radiation to bone lesions, hypercalcemia, and spinal cord compression. Skeletal-related events are major source of morbidity for cancer patients and may be associated with negative impact on quality of life and survival. Bisphosphonates inhibit osteoclast function and are widely used in the treatment of malignant bone disease, as preventive therapy against skeletal-related events. Recently, the NF-κappa B-ligand (RANKL)-mediated osteoclast activity and this pathway in bone metabolism became a prime target for the treatment of bone metastases. The fi rst drug targeting the RANK-RANKL pathway is denosumab, a fully monoclonal human antibody which binds to RANKL and inhibits osteoclast activity. Nowadays optimal treatment of bone metastases requires multidisciplinary management of patients including the administration of bone-modifying agents such bisphosphonates or denosumab. The use of bone-targeted agents is a valuable additional treatment in the fi ght against bone metastases and multiple, randomised trials have demonstrated the effectivity of these drugs in reducing skeletal morbidity caused by advanced cancer.]


[New approaches to the treatment of osteoporosis]


[Osteoporosis is a significant health care problem, and its treatment is of major interest. Despite of the wide spectrum of therapeutical modalities, the effective cure for all forms of this condition has not yet been developed. For this reason, the focus is on the development of new pharmacological approaches. The RANK/RANKL/OPG system discovered one and a half decades ago provides a tool for the neutralization of the osteoclast-stimulating RANKL by the use of monoclonal antibodies. Catepsin-K inhibitors offer another pathway for the inhibition of bone degradation. Anti-sclerostin and anti-Dkk-1 antibodies may stimulate bone formation by the release of Wnt signal transduction system. Other administration methods for PTH analogs, new generations of selective estrogen receptor modulators and antibodies against vitronectin receptors as well as potential new drug targets will enable us to fight bone loss more efficiently.]


[The efficacy of ibandronate and the importance of adherence - Results of the BOUNCE study]

DONÁTH Judit, POÓR Gyula

[Bisphosphonates play a substantial role inthe treatment of postmenopausal osteo-porosis. Ibandronate is the first bisphos-phonate that can be used both orally andintravenously. A number of studies haveproved that ibandronate reduces boneturnover, increases bone mineral densityand reduces the risk of vertebral fractures.It is a well-known fact that the patients’adherence to oral medications is very poorthroughout the world. So far, very fewinternational studies have been performedon the patients’ compliance in medicinetaking. The BOUNCE study, carried out inseveral countries including Hungary tostudy the adherence of patients in the oralintake of ibandronate, aims to fill this gap.]


[Denosumab - pharmacokinetic and clinical evidences]


[Denosumab is a fully human monoclonal antibody to RANKL modifying bone resorption in a rapid, sustained and reversible way. In postmenopausal women with low bone mineral density, denosumab 60 mg every 6 months increased mineral density, and reduced bone turnover. In postmenopausal women, it reduced the risk of vertebral, hip, and non-vertebral fractures. Increase in body mass index and reduction in bone turnover was more pronounced with denosumab than with alendronate. In patients who were switched from alendronate to denosumab, positive effects on bone were more pronounced than in those continuing alendronate. Denosumab was safe and well tolerated, and it holds the promise of becoming an efficacious therapy for postmenopausal osteoporosis.]


[The pathogenic and clinical significance of the RANK-RANKL-osteoprotegerin system in rheumatoid arthritis]


[Rheumatoid arthritis (RA) is characterised by increased local and generalised bone resorption, which manifests in the develoment of marginal erosions and generalised osteoporosis, respectively. An increasing number of data suggest that lymphocytes, proinflammatory cytokines and other mediators involved in inflammation contribute to arthritic bone resorption. Therefore, the term ‘osteoimmunology’ has also become widely used. In RA, Receptor Activator of Nuclear Factor kappa B (RANK) and its ligand (RANKL) play a crucial role in bone resorption. These proteins, which belong to the tumor necrosis factor a (TNF-a) receptor and TNF ligand superfamilies, respectively, activate osteoclasts while interacting with T cells, synovial fibroblasts and other cytokines (e.g. IL-1, IL-17), which results in bone resorption. Osteoprotegerin (OPG) is a decoy receptor that also belongs to the TNF receptor family and inhibits RANK-RANKL interactions. There is increased RANKL production and decreased OPG production in RA. The interaction of RANKL with IL-17 is particularly important. Regarding therapy, sulfasalazine, methotrexate and biological agents, especially TNF inhibitors suppress RANKL-mediated bone resorption and thus the development of joint erosions. RANKL-RANK interaction can be directly inhibited by recombinant OPG or anti-RANKL antibody (denosumab). Among these agents, denosumab gave promising results in experiments performed in animal models of arthritis. These were followed by a phase II human RA trial, which proved that denosumab decreased MRI erosion scores in RA.]