Bench to bedside: elucidation of the OPG–RANK–RANKL pathway and the development of denosumab

Lacey, David L.; Boyle, William J.; Simonet, W S; Kostenuik, Paul J.; Dougall, William C.; Sullivan, John K.; Martín, Javier San; Dansey, Roger

doi:10.1038/nrd3705

Cited by 570 publications

(477 citation statements)

References 143 publications

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“…These cells secret parathyroid hormone related peptide (PTHrp) which stimulates the stromal cells and osteoblasts to synthesize and release more RANKL. RANKL promotes osteoclastogenesis and promotes synthesis of molecules like tumor growth factor-β (TGF-β), insulin like growth factors (IGFs) and fibroblast growth factors (FGF) by the osteoclasts which, in turn, exert trophic effect on the tumor cells; hence the vicious cycle [1,4].…”

Section: Discussionmentioning

confidence: 99%

Severe Refractory Hypocalcemia in a Patient with Metastatic Prostate Carcinoma Following Denosumab Injection

Ali¹,

Farhat²,

Imran³

et al. 2016

J Clin Case Rep

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An 86-year-old male with a history of metastatic castrate sensitive prostate cancer received a single dose of Denosumab for his bony metastases. Two weeks later, he presented to the hospital due to left foot cellulitis and was incidentally found to have profound hypocalcemia whereas his serum calcium was normal at the time of Denosumab injection. A thorough workup was undertaken which showed severe Vitamin D deficiency. He was diagnosed with Denosumab induced hypocalcemia with underlying Vitamin D deficiency which was refractory to supplemental calcium and Vitamin D. This case demonstrates the potential of Denosumab to cause profound hypocalcemia which can be resistant to therapy. Bone metastasis is a common clinical encounter and Denosumab is an effective therapy to prevent skeletal related events (SRE). Therefore, given its widespread use, it is extremely important to identify and treat risk factors that may aggravate hypocalcemia when treated with Denosumab.

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Section: Discussionmentioning

confidence: 99%

Severe Refractory Hypocalcemia in a Patient with Metastatic Prostate Carcinoma Following Denosumab Injection

Ali¹,

Farhat²,

Imran³

et al. 2016

J Clin Case Rep

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“…Within this group are the bisphosphonates, which inhibit protein prenylation in the mature osteoclast, reducing osteoclast capacity to resorb bone, (1) and denosumab, a monoclonal antibody to RANK ligand that inhibits osteoclast formation, function, and survival. (2) Although several new anabolic agents are in development, (3)(4)(5) teriparatide is currently the only available anabolic therapy for osteoporosis in the United States, with the addition of only PTH in the EU (referred to as PTH). Teriparatide (TPTD) and PTH act by direct stimulation of osteoblast activity and recruitment (both remodeling and modeling-based formation) as well as stimulation of remodeling, favoring bone formation (remodeling-based formation).…”

Section: Introductionmentioning

confidence: 99%

Treatment Sequence Matters: Anabolic and Antiresorptive Therapy for Osteoporosis

Cosman

Nieves

Dempster

2016

Journal of Bone and Mineral Research

201

129

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The effects of anabolic medications (teriparatide [TPTD] and parathyroid hormone [PTH]) differ in patients who have received recent treatment with potent antiresorptives. This perspective reviews studies evaluating bone density (BMD) and histomorphometric effects of treatment sequences beginning with TPTD/PTH followed by potent antiresorptives and those beginning with potent antiresorptives followed by switching to or adding TPTD. Effect of treatment sequence on spine BMD outcome is minor, with modest quantitative differences. However, when individuals established on potent bisphosphonates are switched to TPTD, hip BMD declines below baseline for at least the first 12 months after the switch to TPTD. This transient hip BMD loss is more prominent when the antiresorptive is denosumab; in this setting, hip BMD remains below baseline for almost a full 24 months. In a controlled comparison of those who switched from alendronate to TPTD versus those who added TPTD to ongoing alendronate, the effect on hip BMD was improved with combination therapy. Furthermore, hip strength improved with the addition of TPTD to ongoing alendronate, whereas it was neutral after switching from alendronate to TPTD, primarily due to the effect on cortical bone. Bone biopsy studies indicate that TPTD stimulates bone formation in patients who have not been treated previously as well as in patients on prior and ongoing bisphosphonates. Histomorphometric evidence suggests that use of alendronate with TPTD blocks the TPTD-induced increase in cortical porosity. When possible, we suggest anabolic therapy first, followed by potent antiresorptive therapy. The common practice of switching to TPTD only after patients have an inadequate response to antiresorptives (intercurrent fracture or inadequate BMD effect) is not the optimal utilization of anabolic treatment. In fact, this may result in transient loss of hip BMD and strength. In this setting, continuing a potent antiresorptive while starting TPTD might improve hip outcomes.

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“…It differs from bisphosphonates that inhibit bone resorption by inducing apoptosis in mature osteoclasts. Denosumab inhibits not only bone resorption by mature osteoclasts but also osteoclast formation from hematopoetic precursors [110][111][112]. Denosumab was effective in controlling serum calcium levels in patients with HHM and was approved by the FDA for the treatment of skeletal metastases in malignancy, HHM and postmenopausal osteoporosis based on the trials delivered [113,114].…”

Section: Pthrp/pth1r Antogonists and Agonistsmentioning

confidence: 99%

Untitled

2017

EMIJ

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In this mini-review the role of parathyroid hormone-related peptide (PTHrP) in physiology and pathophysiology is discussed. Evolving from an unknown humoral factor in the HHM (Hypercalcemia of malignancy) syndrome its role as a "masterregulator" in the PTH family following identification is reviewed. PTHrP has more paracrine and autocrine functions in virtually all tissues than classical endocrine functions and is essential in embryonic, fetal and post-natal life. The physiological functions are near endless. The development of PTH/PTHrP receptor antagonist and agonists has been difficult and disappointing. Its role as a possible cytokine itself and as a regulatory thermogenesis factor in brown adipose tissue in cancer cachexia is discussed. PTHrP assays must be improved for PTHrP to be a reliable biomarker in oncology and to resolve the function of local proteolytic PTHrP fragments which are largely a mystery until now.

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Bench to bedside: elucidation of the OPG–RANK–RANKL pathway and the development of denosumab

Cited by 570 publications

References 143 publications

Severe Refractory Hypocalcemia in a Patient with Metastatic Prostate Carcinoma Following Denosumab Injection

Severe Refractory Hypocalcemia in a Patient with Metastatic Prostate Carcinoma Following Denosumab Injection

Treatment Sequence Matters: Anabolic and Antiresorptive Therapy for Osteoporosis

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