The inhibition of RANKL causes greater suppression of bone resorption and hypercalcemia compared with bisphosphonates in two models of humoral hypercalcemia of malignancy.

Morony, Sean; Warmington, Kelly; Adamu, Stephen; Asuncion, Frank; Geng, Zhaopo; Grisanti, Mario; Tan, Hong Lin; Capparelli, Casey; Starnes, Charlie; Weimann, Bernadette; Dunstan, Colin R.; Kostenuik, Paul J.

doi:10.1210/en.2004-1583

Cited by 97Bone Metabolism and DiseasesBone health and treatmentsBone health and osteoporosis research

The inhibition of RANKL causes greater suppression of bone resorption and hypercalcemia compared with bisphosphonates in two models of humoral hypercalcemia of malignancy.

Morony, Sean, Warmington, Kelly, Adamu, Stephen, Asuncion, Frank, Geng, Zhaopo, Grisanti, Mario, Tan, Hong Lin, Capparelli, Casey +4 more·2005·Endocrinology

DOI 10.1210/en.2004-1583

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Abstract

Humoral hypercalcemia of malignancy (HHM) is mediated primarily by skeletal and renal responses to tumor-derived PTHrP. PTHrP mobilizes calcium from bone by inducing the expression of receptor activator for nuclear factor-κB ligand (RANKL), a protein that is essential for osteoclast formation, activation, and survival. RANKL does not influence renal calcium reabsorption, so RANKL inhibition is a rational approach to selectively block, and thereby reveal, the relative contribution of bone calcium to HHM. We used the RANKL inhibitor osteoprotegerin (OPG) to evaluate the role of osteoclast-mediated hypercalcemia in two murine models of HHM. Hypercalcemia was induced either by sc inoculation of syngeneic colon (C-26) adenocarcinoma cells or by sc injection of high-dose recombinant PTHrP (0.5 mg/kg, sc, twice per day). In both models, OPG (0.2–5 mg/kg) caused rapid reversal of established hypercalcemia, and the speed and duration of hypercalcemia suppression were significantly greater with OPG (5 mg/kg) than with high-dose bisphosphonates (pamidronate or zoledronic acid, 5 mg/kg). OPG also caused greater reductions in osteoclast surface and biochemical markers of bone resorption compared with either bisphosphonate. In both models, hypercalcemia gradually returned despite clear evidence of ongoing suppression of bone resorption by OPG. These data demonstrate that osteoclasts and RANKL are important mediators of HHM, particularly in the early stages of the condition. Aggressive antiresorptive therapy with a RANKL inhibitor therefore might be a rational approach to controlling HHM.

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“In contrast, bisphosphonates have a different mechanism of action that can be associated with normal or even increased osteoclast numbers despite clear antiresorptive effects (129 -138).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [137]

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Expression of RANKL/RANK/OPG in primary and metastatic human prostate cancer as markers of disease stage and functional regulation
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Denosumab for Treatment of Hypercalcemia of Malignancy
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Multiple myeloma/hypercalcemia
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RANKL Inhibition: A Novel Strategy to Decrease Femoral Head Deformity After Ischemic Osteonecrosis
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Key roles of the OPG–RANK–RANKL system in bone oncology
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Bone Disease in Multiple Myeloma: Biologic and Clinical Implications
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One Year of Abaloparatide, a Selective Activator of the PTH1 Receptor, Increased Bone Formation and Bone Mass in Osteopenic Ovariectomized Rats Without Increasing Bone Resorption
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Denosumab: A New Agent in the Management of Hypercalcemia of Malignancy
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OPG-Fc inhibits ovariectomy-induced growth of disseminated breast cancer cells in bone
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Inhibition of tooth movement by osteoprotegerin vs. pamidronate under conditions of constant orthodontic force
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Biglycan: an emerging small leucine-rich proteoglycan (SLRP) marker and its clinicopathological significance
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Differential effects of biologic versus bisphosphonate inhibition of wear debris‐induced osteolysis assessed by longitudinal micro‐CT
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The RANKL inhibitor OPG-Fc increases cortical and trabecular bone mass in young gonad-intact cynomolgus monkeys
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Targeting RANKL in breast cancer: bone metastasis and beyond
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Caffeine may enhance orthodontic tooth movement through increasing osteoclastogenesis induced by periodontal ligament cells under compression
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Receptor Activator of NF-κB Ligand Inhibition Suppresses Bone Resorption and Hypercalcemia but Does Not Affect Host Immune Responses to Influenza Infection
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One Year of Transgenic Overexpression of Osteoprotegerin in Rats Suppressed Bone Resorption and Increased Vertebral Bone Volume, Density, and Strength
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Denosumab for bone diseases: translating bone biology into targeted therapy
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Inhibition of bone resorption and growth of breast cancer in the bone microenvironment
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Plant polyphenols in the treatment of age‐associated diseases: Revealing the pleiotropic effects of icariin by network analysis
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Bone metastasis in breast cancer: The story of RANK-Ligand
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RANKL inhibition: Clinical implications for the management of patients with multiple myeloma and solid tumors with bone metastases
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Osteoprotegerin Abrogated Cortical Porosity and Bone Marrow Fibrosis in a Mouse Model of Constitutive Activation of the PTH/PTHrP Receptor
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Temporal patterns of osteoclast formation and activity following withdrawal of RANKL inhibition
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RANK promotes colorectal cancer migration and invasion by activating the Ca2+-calcineurin/NFATC1-ACP5 axis
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Effects of abaloparatide and teriparatide on bone resorption and bone formation in female mice
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Systemic Osteoprotegerin Gene Therapy Restores Tumor-induced Bone Loss in a Therapeutic Model of Breast Cancer Bone Metastasis
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Oncological Emergencies from Pathophysiology and Diagnosis to Treatment: A Narrative Review
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Electrolyte Disturbances in Critically Ill Cancer Patients: An Endocrine Perspective
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Metabolic Bone Disease in Children
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Hypocalcaemia following denosumab in prostate cancer: A clinical review
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Role of RANK ligand in normal and pathologic bone remodeling and the therapeutic potential of novel inhibitory molecules in musculoskeletal diseases
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Animal Models of Cancer-Associated Hypercalcemia
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Evaluating the potential of Vitamin D and curcumin to alleviate inflammation and mitigate the progression of osteoarthritis through their effects on human chondrocytes: A proof-of-concept investigation
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Denosumab and the current status of bone-modifying drugs in breast cancer
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Endocrine and metabolic disorders in HTLV-1 infected patients
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Electrolyte Complications of Malignancy
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Association of periodontitis with rheumatoid arthritis and atherosclerosis: Novel paradigms in etiopathogeneses and management?
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Targeting of HIF2-driven cachexia in kidney cancer
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Overcoming Irinotecan Resistance by Targeting Its Downstream Signaling Pathways in Colon Cancer
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Analysis on Survival and Prognostic Factors for Cancer Patients with Malignancy-associated Hypercalcemia
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Treatment of immobilization-related hypercalcaemia with denosumab
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On the Evolution and Contemporary Roles of Bone Remodeling
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Denosumab is Effective for Controlling Serum Calcium Levels in Patients with Humoral Hypercalcemia of Malignancy Syndrome: A Case Report on Parathyroid Hormone-related Protein-producing Cholangiocarcinoma
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The many roles of RANKL-RANK signaling in bone, breast and cancer
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Electrolyte Complications of Malignancy
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Involvement of molecular mimicry between human T‐cell leukemia virus type 1 gp46 and osteoprotegerin in induction of hypercalcemia
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Prolonged Hypocalcemia Following a Single Dose of Denosumab for Diffuse Bone Metastasis of Gastric Cancer after Total Gastrectomy
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Serum calcium concentration is maintained when bone resorption is suppressed by osteoprotegerin in young growing male rats
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RANK pathway in cancer: underlying resistance and therapeutic approaches
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Rib Fractures and Death from Deletion of Osteoblast βcatenin in Adult Mice Is Rescued by Corticosteroids
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Investigation on Controlling Therapy of Bone Skeletal and Marrow Cancer: A Biophysical Chemistry and Molecular Dynamic Study of Bisphosphonates Interaction with Bone Structures
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Magic Bullets to Kill Nasty Osteoclasts
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Malignancy-Associated Hypercalcemia and Medical Management
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Humoral Hypercalcemia in a Patient with Cholangiocellular Carcinoma – Effective Therapy with Denosumab
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Safety of In-hospital Parenteral Antiosteoporosis Therapy Following a Hip Fracture: A Retrospective Cohort
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Calcifications in oral carcinomas: Depicts diversity of calcium in cancer biology!
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On the evolution and contemporary roles of bone remodeling
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Humanizing a Mouse Gene for Human Therapeutics: Lessons From Denosumab
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Paraneoplastic Hypercalcaemia as a Cause of Unexplained Renal Impairment in a Patient With Seminoma: A Case Report
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Mechanistic Role of RANKL in Cancer-induced Bone Diseases and Development of a Targeted Therapy to Inhibit this Pathway
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Pharmacoepidemiologic Investigation of the Risk Factors Associated with Hypocalcemia Induced by Denosumab
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Severe hypercalcemia in a patient with chronic lymphocytic leukemia and non-small cell lung carcinoma
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RANKL: Targeting bone and cancer to treat skeletal complications of malignancy
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Calcium Disorders
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Hypercalcaemia
Marcocci, C., Saponaro, F., & Cetani, F. (2022) · doi:10.1093/med/9780198870197.003.0082
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Gropp, K. E. (2022) · Toxicologic Pathology · doi:10.1177/01926233221123778
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The RANKL Inhibitor Osteoprotegerin (OPG) Causes Greater Suppression of Bone Resorption and Hypercalcemia Compared to Bisphosphonates in Two Models of Humoral Hypercalcemia of Malignancy
Morony, S., Warmington, K. S., Adamu, S., Asuncion, F., Geng, Z., Grisanti, M. S., Tan, H. L. E., Capparelli, C., Starnes, C. O., Dunstan, C. R., et al. (2005) · Cited by 13 · see citing works
Self-citation
Osteoprotegerin prevents and reverses hypercalcemia in a murine model of humoral hypercalcemia of malignancy.
Capparelli, C., Kostenuik, P. J., Morony, S., Starnes, C. O., Weimann, B., Van, G. Y., Scully, S. A., Qi, M., Lacey, D. L., & Dunstan, C. R. (2000) · PubMed · Cited by 147 · see citing works
Self-citation
Therapeutic efficacy of a soluble receptor activator of nuclear factor kappaB-IgG Fc fusion protein in suppressing bone resorption and hypercalcemia in a model of humoral hypercalcemia of malignancy.
Oyajobi, B. O., Anderson, D. M., Traianedes, K., Williams, P. J., Yoneda, T., & Mundy, G. R. (2001) · PubMed · Cited by 119 · see citing works
Malignancy-related hypercalcemia
Lumachi, F., & Basso, S. M. M. (2014) · Padua Research Archive (University of Padova)
Increased Renal Calcium Reabsorption by Parathyroid Hormone–Related Protein Is a Causative Factor in the Development of Humoral Hypercalcemia of Malignancy Refractory to Osteoclastic Bone Resorption Inhibitors
Onuma, E., Azuma, Y., Saito, H., Tsunenari, T., Watanabe, T., Hirabayashi, M., Sato, K., Yamada‐Okabe, H., & Ogata, E. (2005) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-04-2531 · Cited by 34 · see citing works

Authors: Morony, S., Warmington, K., Adamu, S., Asuncion, F., Geng, Z., Grisanti, M., Tan, H. L., Capparelli, C., Starnes, C., Weimann, B., Dunstan, C. R., & Kostenuik, P. J.
Affiliations: Amgen (United States) (US)
Corresponding author: Kostenuik, Paul J.
ORCID: Asuncion, Frank
Grisanti, Mario
Tan, Hong Lin
Dunstan, Colin R.
Kostenuik, Paul J.
Venue: Endocrinology
Publisher: The Endocrine Society
Published: 2005-08-01
Volume: 146
Issue: 8
Pages: 3235-3243
ISSN: 0013-7227 (ISSN-L)
1945-7170
DOI: 10.1210/en.2004-1583
OpenAlex: W1989046476
Cited by: 97
References: 64
Citations by year: 2025: 1 · 2024: 3 · 2023: 4 · 2022: 5 · 2021: 3 · 2020: 5 · 2019: 2 · 2018: 1 · 2017: 3 · 2016: 3 · 2015: 6 · 2014: 2 · 2013: 6 · 2012: 5
FWCI: 2.99
Type: journal article
Language: en
Open access: closed
Locations: Endocrinology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
Health Sciences › Medicine › Oncology › Bone health and treatments
Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
Keywords: humoral hypercalcemia of malignancy, RANKL inhibition, osteoprotegerin, bisphosphonates, pamidronate, zoledronic acid, bone resorption, osteoclasts, parathyroid hormone-related protein, colon adenocarcinoma, antiresorptive therapy, hypercalcemia
MeSH terms: Pamidronate, Adenocarcinoma, Animals, Antineoplastic Agents, Bone Resorption, Calcium, Carrier Proteins, Colonic Neoplasms, Diphosphonates, Disease Models, Animal, Glycoproteins, Humans, Hypercalcemia, Ligands, Membrane Glycoproteins, NF-kappa B, Receptors, Tumor Necrosis Factor, Receptors, Cytoplasmic and Nuclear, Parathyroid Hormone-Related Protein, Cell Line, Tumor, Mice, Osteoprotegerin, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B

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The inhibition of RANKL causes greater suppression of bone resorption and hypercalcemia compared with bisphosphonates in two models of humoral hypercalcemia of malignancy.

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