osteoprotegerin and Pain

Cancer-induced bone diseases are common and can have a devastating impact at the end of life. One of the most difficult sequelae of cancer is metastases to the skeleton, an event that results in bone destruction and bone cancer pain. Bone cancer pain is usually progressive as the disease advances, and is particularly difficult to treat. Recently, experimental models of bone cancer pain have been developed and have provided seminal insight in understanding the pathophysiology of bone cancer pain. Animal models of bone cancer provided the finding that bone destruction (osteolysis) is associated with pain, and it has been determined that cancer-induced osteolysis is mediated by osteoclasts. Having established that RANK ligand contributed to cancer-induced osteoclastogenesis, it was determined that disruption of the RANKL-RANK axis with OPG inhibited tumor-induced osteoclastogenesis and decreased bone cancer pain.

Topics: Bone Neoplasms; Carrier Proteins; Glycoproteins; Humans; Membrane Glycoproteins; Osteoprotegerin; Pain; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

An etiological treatment is currently lacking for Langerhans Cell Histiocytosis (LCH). Receptor activator of nuclear factor κB ligand (RANKL) appears to play a central role in the lesional immunological process inducing compensatory osteoprotegerin (OPG) activation. In a preliminary study we aimed to evaluate for the first time the use of denosumab, a RANKL inhibitor, as a targeted treatment strategy in LCH in order to support and enhance endogenous OPG action in order to control or alter the lesional immunological process.. Two adult female patients with painful osteolytic bone lesions and concomitant pulmonary involvement received bimonthly denosumab 120mg in a total of 4 doses.. Both patients reported an immediate pain relief within the first two weeks following the 1st dose of denosumab. One month following the last dose an almost full remission of the initial osteolytic and lung lesions was observed, although an apparent new bone lesion was detected in one patient that was treated with a single intralesional steroid injection. No adverse events were recorded throughout the treatment period. Both patients have no active disease 6months following the last denosumab dose.. Denosumab could be considered an effective treatment option in adults with multisystem LCH also exerting a significant analgesic effect in bone lesions, warranting further investigation.

Topics: Adult; Bone Density Conservation Agents; Bone Diseases; Denosumab; Female; Histiocytosis, Langerhans-Cell; Humans; Lung Diseases; Magnetic Resonance Imaging; Osteoprotegerin; Pain; Positron-Emission Tomography; RANK Ligand; Treatment Outcome

The aim of the study was evaluate tooth movement, receptor activator of nuclear factor KB ligand (RANKL), osteoprotegerin (OPG), and RANKL/OPG ratio in gingival crevicular fluid (GCF) in compression side and pain level during initial orthodontic tooth treatment to determine the efficacy of low-level laser therapy (LLLT). Ten volunteers who required fixed appliance positioned from the upper first premolars to upper first molars were selected. For each patient, the upper first premolar of the quadrant 1 was chosen to be irradiated with a laser diode at 670 nm, 200 mW, and 6.37 W/cm(2), applied on the distal, buccal, and lingual sides during 9 min on days 0, 1, 2, 3, 4, and 7. The same procedure was applied in the first premolar of the contralateral quadrant inserting the tip but without laser emission. Samples of GCF from the compression side of the upper first premolars to distalize were collected at baseline and after 2, 7, 30, and 45 days posttreatment for determination of RANKL and OPG by enzyme-linked immunosorbent assay. In addition, tooth movement was assessed by scanning models and pain intensity was assessed using a visual analog scale. There was improvement in the parameters studied (pain, tooth movement, levels of RANKL in GCF, and RANKL/OPG ratio) in the laser group when compared to the control group, although differences were not statistically significant. The accumulated retraction of the upper premolar at 30 days was higher in the laser group, and this difference was statistically significant between groups. LLLT delivered in repeated doses (six times in the initial 2 weeks) leads in some extent to a slight orthodontical improvement.

Topics: Adolescent; Child; Female; Gingival Crevicular Fluid; Humans; Lasers, Semiconductor; Low-Level Light Therapy; Male; Orthodontics; Osteoprotegerin; Pain; Pain Measurement; RANK Ligand; Time Factors; Tooth Movement Techniques

Whilst not strictly a neuropathic injury, cancer-induced bone pain (CIBP) is a unique state with features of neuropathy and inflammation. Recent work has demonstrated that osteoclasts damage peripheral nerves (peptidergic C fibres and SNS) within trabeculated bone leading to deafferentation. In addition, glia cell activation and neuronal hyperexcitability within the dorsal horn, are all similar to a neuropathy. Gabapentin and carbamazepine (both anti-convulsants that modulate neuropathy) are effective at attenuating dorsal horn neuronal excitability and normalizing pain-like behaviours in a rat model of CIBP. However alterations in neuroreceptors in the dorsal horn do not mimic neuropathy, rather only dynorphin is upregulated, glia cells are active and hypertrophic and c-fos expression is increased post-noxious behavioural stimulus. CIBP perhaps illustrates best the complexity of cancer pains. Rarely are they purely neuropathic, inflammatory, ischaemic or visceral but rather a combination. Management is multimodal with radiotherapy, analgesics (opioids, NSAIDs), bisphosphonates, radioisotopes and tumouricidal therapies. The difficulty with opioids relates to efficacy on spontaneous pain at rest and movement-related pain. Potential adjuvants to standard analgesic therapies for CIBP are being explored in clinical trials and include inhibitors of glutamate release.

Topics: Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Bone Density Conservation Agents; Bone Diseases; Bone Neoplasms; Diphosphonates; Drug Administration Routes; Endothelin-1; Humans; Lidocaine; N-Methylaspartate; Osteoprotegerin; Pain; Receptors, Vitronectin

A middle-aged woman with recent-onset painful swollen fingers and widespread periostitis, elevated serum alkaline phosphatase (ALP) activity and erythrocyte sedimentation rate, and accelerated skeletal turnover was found not to have mutations in the gene sequences for exon 1 of receptor activator of nuclear factor-kappaB (RANK), osteoprotegerin (OPG), or sequestosome-1.. Hyperphosphatasia refers to disorders that feature elevated serum ALP activity (hyperphosphatasemia) usually from excesses of the bone isoform of ALP. Such conditions include familial expansile osteolysis, expansile skeletal hyperphosphatasia, and a familial form of early-onset Paget's disease of bone (PDB2), all from constitutive activation of RANK, and juvenile Paget's disease from OPG deficiency.. A 38-yr-old woman developed painful swollen fingers and achy bones after an episode of unexplained pericarditis and restrictive lung disease. Sequence analysis of exon 1 of TNFRSF11A encoding RANK, TNFRSF11B encoding OPG, and SQSTM1 encoding sequestosome-1 searched for mutations responsible for familial expansile osteolysis, expansile skeletal hyperphosphatasia, or PDB2, juvenile Paget's disease, or Paget's disease of bone (PDB), respectively.. Serum ALP and osteocalcin and urinary hydroxyproline were increased. Radiographs showed widespread, symmetric hyperostosis in the limbs where bone scintigraphy demonstrated enhanced radionuclide uptake. Iliac crest histology revealed accelerated skeletal turnover. No mutations were detected in the three genes examined. Three years of therapy with 70 mg alendronate orally once weekly improved symptoms, radiographic abnormalities, and biochemical markers.. Our patient manifested a unique, sporadic hyperphosphatasia syndrome. Unexplained, transient inflammation seemed to cause her pericarditis, restrictive lung disease, and periostitis with accelerated skeletal turnover that responded well to antiinflammatory drugs and alendronate therapy.

Topics: Adaptor Proteins, Signal Transducing; Adult; Alkaline Phosphatase; Biomarkers; Bone and Bones; Bone Density Conservation Agents; Female; Fingers; Humans; Inflammation; Osteoprotegerin; Pain; Periostitis; Radiography; Radionuclide Imaging; Receptor Activator of Nuclear Factor-kappa B; Sequestosome-1 Protein; Syndrome

Bone disorders with increased osteoclastic bone resorption are frequently associated with bone pain and inhibitors of osteoclasts reduce bone pain. Osteoclasts degrade bone minerals by secreting protons through the vacuolar H+-ATPase, creating acidic microenvironments. Because acidosis is a well-known cause of pain, we reasoned that osteoclasts cause pain through proton secretion. We explored this using an animal model in which a single subcutaneous injection of the complete Freund's adjuvant (CFA) in the hind-paw caused inflammatory hyperalgesia (hyper-responsiveness to noxious stimuli). Osteoclastic bone resorption was increased in the metatarsal bones in the CFA-injected hind-paws. CFA-induced hyperalgesia was significantly suppressed by the bisphosphonates, zoledronic acid (ZOL) and alendronate and osteoprotegerin. c-src-deficient mice in which osteoclasts are inherently dysfunctional exhibited reduced CFA-induced hyperalgesia. Repeated subcutaneous injections of parathyroid hormone-related protein into the hind-paw also induced hyperalgesia with increased osteoclastic bone resorption. The hyperalgesia was associated with increased mRNA expression of acid-sensing ion channel (ASIC) 1a, 1b and 3 in the ipsi-lateral dorsal root ganglions (DRGs) by RT-PCR and c-Fos in the ipsi-lateral spinal dorsal horn by immunohistochemistry. Of note, ZOL decreased the ASIC1a mRNA expression and c-Fos. Treatment of the DRG cell line F-11 with acid (pH5.5) increased ASIC1a, 1b and 3 mRNA expression and nuclear c-Fos expression. The ASIC blocker amiloride inhibited acid-induced c-Fos expression in F-11 cells. Moreover, F-11 cells transfected with the transient receptor potential channel vanilloid subfamily member 1 (TRPV1) showed increased acid-induced nuclear c-Fos expression compared with parental F-11 cells. Finally, bafilomycin A1, an inhibitor of the vacuolar H+-ATPase, reversed the hyperalgesia and down-regulated ASIC1a mRNA expression in the DRGs. These results led us to propose that osteoclasts play a part in CFA-induced inflammatory pain through an activation of the acid-sensing receptors including ASICs and TRPV1 by creating acidosis.

Topics: Acid Sensing Ion Channels; Animals; Bone and Bones; Bone Resorption; Cell Line; Diphosphonates; Freund's Adjuvant; Genes, src; Hyperalgesia; Inflammation; Injections, Intravenous; Injections, Spinal; Injections, Subcutaneous; Macrolides; Male; Membrane Proteins; Mice; Mice, Mutant Strains; Nerve Tissue Proteins; Osteoclasts; Osteoprotegerin; Pain; Parathyroid Hormone; Posterior Horn Cells; Reverse Transcriptase Polymerase Chain Reaction; Sodium Channels; TRPV Cation Channels; Vacuolar Proton-Translocating ATPases

This study investigated the effects of the receptor activator for nuclear factor kappaB ligand (RANKL) inhibitor, osteoprotegerin (OPG), on tumor-induced allodynia, osteolysis, and bone histology in the mammary tumor (MRMT-1) rat model for bone cancer pain.. Rats (n = 8/group) were inoculated with MRMT-1 or culture medium in the proximal right tibia, injected with OPG or vehicle subcutaneously 2-3 times weekly, evaluated for mechanical allodynia with von Frey paw stimulation, and euthanized on Day 20 for necropsy. Three groups were evaluated starting on Day 5 and received the following interventions beginning on Day 1: tumor and OPG, tumor and vehicle, or culture medium and vehicle. Three additional groups received the same interventions but were evaluated starting on Day 3. A seventh group started OPG on Day 8 after tumor inoculation.. Starting OPG on Day 1 reduced allodynia significantly compared with vehicle injections; pain relief was observed within 5-6 days after tumor inoculation and lasted throughout follow-up. Starting OPG on Day 8 did not reverse allodynia significantly compared with the tumor control group. Regardless of treatment start time, OPG treatment reduced osteoclast number and tartrate-resistant acid phosphatase levels, increased bone mineral density, preserved normal bone volume and integrity on micro-computed tomography, reduced relative tumor volume in the bone, and reduced staining for glial fibrillary acidic protein in the spinal cord.. RANKL inhibition with OPG reduced bone resorption and bone pain in rats with malignant bone disease; further study is warranted to determine if RANKL inhibition has similar benefits in humans.

Topics: Animals; Bone Density; Bone Neoplasms; Bone Resorption; Female; Mammary Neoplasms, Experimental; Neoplasm Transplantation; Osteoprotegerin; Pain; RANK Ligand; Rats; Rats, Sprague-Dawley; Time Factors

Topics: Acidosis; Analgesics; Animals; Antineoplastic Agents; Atrasentan; Bone Neoplasms; Diphosphonates; Disease Models, Animal; Glycoproteins; Humans; Ion Channels; Neoplasms; Osteoprotegerin; Pain; Pyrrolidines; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

Bone cancer pain most commonly occurs when tumors originating in breast, prostate, or lung metastasize to long bones, spinal vertebrae, and/or pelvis. Primary and metastatic cancers involving bone account for approximately 400,000 new cancer cases per year in the United States alone, and >70% of patients with advanced breast or prostate cancer have skeletal metastases. Whereas pain resulting from bone cancer can dramatically impact an individual's quality of life, very little is known about the mechanisms that generate and maintain this pain. To begin to define the mechanisms that give rise to advanced bone cancer pain, osteolytic 2472 sarcoma cells or media were injected into the intramedullary space of the femur of C3H/HeJ mice, and the injection hole was sealed using dental amalgam, confining the tumor cells to the bone. Twelve days after injection of 2472 tumor cells, animals showed advanced tumor-induced bone destruction of the injected femur, bone cancer pain, and a stereotypic set of neurochemical changes in the spinal cord dorsal horn that receives sensory inputs from the affected femur. Administration of osteoprotegerin, a naturally secreted decoy receptor that inhibits osteoclast maturation and activity and induces osteoclast apoptosis, or vehicle was begun at 12 days, when significant bone destruction had already occurred, and administration was continued daily until day 21. Ongoing pain behaviors, movement-evoked pain behaviors, and bone destruction were assessed on days 10, 12, 14, 17, and 21. The neurochemistry of the spinal cord was evaluated at days 12 and 21. Results indicated that osteoprotegerin treatment halted further bone destruction, reduced ongoing and movement-evoked pain, and reversed several aspects of the neurochemical reorganization of the spinal cord. Thus, even in advanced stages of bone cancer, ongoing osteoclast activity appears to be involved in the generation and maintenance of ongoing and movement-evoked pain. Blockade of ongoing osteoclast activity appears to have the potential to reduce bone cancer pain in patients with advanced tumor-induced bone destruction.

Topics: Animals; Bone Neoplasms; Disease Models, Animal; Glycoproteins; Male; Mice; Mice, Inbred C3H; Neurons, Afferent; Osteoclasts; Osteolysis; Osteoprotegerin; Pain; Proto-Oncogene Proteins c-fos; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Sarcoma, Experimental; Spinal Cord

Topics: Bone Neoplasms; Chronic Disease; Glycoproteins; Models, Biological; Neural Conduction; Osteoclasts; Osteolysis; Osteoprotegerin; Pain; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Spinal Cord; Synaptic Transmission

Bone cancer pain is common among cancer patients and can have a devastating effect on their quality of life. A chief problem in designing new therapies for bone cancer pain is that it is unclear what mechanisms drive this distinct pain condition. Here we show that osteoprotegerin, a secreted 'decoy' receptor that inhibits osteoclast activity, also blocks behaviors indicative of pain in mice with bone cancer. A substantial part of the actions of osteoprotegerin seems to result from inhibition of tumor-induced bone destruction that in turn inhibits the neurochemical changes in the spinal cord that are thought to be involved in the generation and maintenance of cancer pain. These results demonstrate that excessive tumor-induced bone destruction is involved in the generation of bone cancer pain and that osteoprotegerin may provide an effective treatment for this common human condition.

Topics: Animals; Astrocytes; Behavior, Animal; Bone Demineralization, Pathologic; Glycoproteins; Hindlimb; Male; Mice; Mice, Inbred C3H; Osteoclasts; Osteoprotegerin; Osteosarcoma; Pain; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Sarcoma, Experimental; Spinal Cord

Topics: Animals; Bone Neoplasms; Bone Resorption; Carrier Proteins; Glycoproteins; Membrane Glycoproteins; Mice; Osteoclasts; Osteolysis; Osteoprotegerin; Osteosarcoma; Pain; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor