1. The document discusses bone metabolism and prostate cancer, describing how factors like RANK ligand and osteoprotegerin regulate the balance between bone formation and resorption.
2. It summarizes a clinical trial comparing denosumab, a RANK ligand inhibitor, to zoledronic acid for treating bone metastases in prostate cancer patients. Denosumab delayed time to first skeletal-related event compared to zoledronic acid and reduced risk of multiple events.
3. Rates of adverse events were generally similar between the treatments, though denosumab resulted in fewer acute phase reactions and more cases of osteonecrosis of the jaw compared to zoledronic acid.
Dr. Sehdev explains bone health as it relates to cancer, including bone metastases, treatment options, the impact of cancer treatment on bone health, and what you can do to keep your bones strong.
This document discusses glucocorticoid induced osteoporosis. It begins with an epidemiology section noting that glucocorticoids are the most common cause of secondary osteoporosis. Treatment options discussed include adequate calcium and vitamin D, exercise therapy, optimal treatment of underlying disease, smoking cessation, and drug therapies. Drug therapies shown to increase bone mineral density and reduce fractures include alendronate, risedronate, zoledronic acid, teriparatide, and denosumab. Head-to-head trials found that teriparatide was more effective at reducing fractures than alendronate. The EuroGIOPS study similarly found teriparatide more effective at improving bone mineral density and
Radium-223 is an alpha-emitting radionuclide used to treat advanced prostate cancer that has metastasized to the bone. It localizes rapidly in areas of new bone formation due to its similarity to calcium. Phase 3 trials showed Radium-223 improved overall survival by 3.6 months and delayed time to first skeletal-related event compared to placebo. Radium-223 also reduced bone pain symptoms with fewer side effects than beta-emitting radionuclides due to its short range in tissue.
Breast cancer a focus on bone health integrityMohamed Abdulla
This document summarizes information about bone health and integrity in the context of breast cancer. It discusses how breast cancer commonly spreads to bone, causing skeletal-related events like fractures. It notes that bone-targeted therapies like bisphosphonates and denosumab can help prevent these events by inhibiting bone resorption. Clinical trials show these drugs reduce the risk of skeletal complications when used adjuvantly or for metastatic breast cancer in bone. The document thus emphasizes the importance of bone health for breast cancer patients and the role of anti-resorptive therapies.
- Bone metastases affect up to 70% of breast cancer patients and are a major source of morbidity. They develop through a 'vicious cycle' where tumor cells stimulate bone resorption.
- Bisphosphonates like zoledronic acid and denosumab inhibit bone resorption by targeting RANK ligand, breaking this cycle. They significantly reduce skeletal complications in metastatic breast cancer.
- A large trial found denosumab reduced the risk of first skeletal-related event compared to zoledronic acid and time to first on-study bone metastasis. It provides an effective alternative to bisphosphonates for preventing bone complications.
Prof. Jon Tobias's presentation from Osteoporosis 2016: What are the properties of the perfect therapy?
Find out more at: https://nos.org.uk/conference
Dr. Sehdev explains bone health as it relates to cancer, including bone metastases, treatment options, the impact of cancer treatment on bone health, and what you can do to keep your bones strong.
This document discusses glucocorticoid induced osteoporosis. It begins with an epidemiology section noting that glucocorticoids are the most common cause of secondary osteoporosis. Treatment options discussed include adequate calcium and vitamin D, exercise therapy, optimal treatment of underlying disease, smoking cessation, and drug therapies. Drug therapies shown to increase bone mineral density and reduce fractures include alendronate, risedronate, zoledronic acid, teriparatide, and denosumab. Head-to-head trials found that teriparatide was more effective at reducing fractures than alendronate. The EuroGIOPS study similarly found teriparatide more effective at improving bone mineral density and
Radium-223 is an alpha-emitting radionuclide used to treat advanced prostate cancer that has metastasized to the bone. It localizes rapidly in areas of new bone formation due to its similarity to calcium. Phase 3 trials showed Radium-223 improved overall survival by 3.6 months and delayed time to first skeletal-related event compared to placebo. Radium-223 also reduced bone pain symptoms with fewer side effects than beta-emitting radionuclides due to its short range in tissue.
Breast cancer a focus on bone health integrityMohamed Abdulla
This document summarizes information about bone health and integrity in the context of breast cancer. It discusses how breast cancer commonly spreads to bone, causing skeletal-related events like fractures. It notes that bone-targeted therapies like bisphosphonates and denosumab can help prevent these events by inhibiting bone resorption. Clinical trials show these drugs reduce the risk of skeletal complications when used adjuvantly or for metastatic breast cancer in bone. The document thus emphasizes the importance of bone health for breast cancer patients and the role of anti-resorptive therapies.
- Bone metastases affect up to 70% of breast cancer patients and are a major source of morbidity. They develop through a 'vicious cycle' where tumor cells stimulate bone resorption.
- Bisphosphonates like zoledronic acid and denosumab inhibit bone resorption by targeting RANK ligand, breaking this cycle. They significantly reduce skeletal complications in metastatic breast cancer.
- A large trial found denosumab reduced the risk of first skeletal-related event compared to zoledronic acid and time to first on-study bone metastasis. It provides an effective alternative to bisphosphonates for preventing bone complications.
Prof. Jon Tobias's presentation from Osteoporosis 2016: What are the properties of the perfect therapy?
Find out more at: https://nos.org.uk/conference
Pathophysiology of Metastatic Bone Disease and the Role of Bisphosphonatesshabeel pn
This document summarizes metastatic bone disease and the role of bisphosphonates. It discusses how bisphosphonates like pamidronate and zoledronic acid inhibit osteoclast activity to prevent skeletal complications from bone metastases. Clinical trials showed bisphosphonates reduced skeletal complications, bone pain, and hypercalcemia compared to placebo in cancers like breast cancer and multiple myeloma. Zoledronic acid was found to be more potent than pamidronate in suppressing bone turnover based on markers and time to first skeletal event.
We report the 11-year follow-up of a premenopausal woman with osteogenesisimperfecta (OI) who
was treated with alendronate. A 41-year-old Japanese premenopausal woman with OI type I who had
frequently experienced painful fragility fractures consulted our clinic because of chronic back pain associated
with spinal osteoporosis. She had undergone heart surgery (aortic valve replacement) because of aortic
regurgitation 5 years before her first consultation with our clinic. After surgery, she began taking warfarin (3
mg/day), and this treatment was continued during our follow-up period. She was treated with alendronate (5
mg/day or 35 mg/week) for 11 years. The patient’s urinary cross-linked N-terminal telopeptides of type I
collagen and serum alkaline phosphatase levels decreased, while the bone mineral density of her lumbar
spine (L2–L4) increased, as measured using dual energy X-ray absorptiometry. The serum calcium and
phosphorus levels stayed within the normal ranges. Three non-vertebral fractures occurred at the hip, ankle,
and ring finger during the 11-year treatment period, but no adverse effects were observed. Thus, the present
case report showed the long-term outcome and safety of alendronate treatment in a premenopausal woman
with OI type I.
This document summarizes current and newer therapies for osteoporosis. It describes the FDA-approved pharmacologic options including bisphosphonates, estrogens, raloxifene, calcitonin, parathyroid hormone, and denosumab. It then discusses the efficacy of these current treatments in reducing vertebral and non-vertebral fractures. The document notes the need for newer agents due to safety concerns with long-term bisphosphonate use. It introduces several promising new therapies in development including denosumab, anti-sclerostin antibodies, and cathepsin K inhibitors which have shown increases in bone mineral density and reductions in fracture risk in clinical trials.
Prof. Richard Keen's presentation from Osteoporosis 2016: Teaching old dogs new tricks? Combination therapy in osteoporosis.
Find out more at: https://nos.org.uk/conference
Bone is a dynamic tissue that is continuously renewed through the process of bone remodeling. This process is carried out by basic multicellular units containing osteoclasts, which resorb bone, and osteoblasts, which form new bone. A normal bone remodeling cycle maintains bone mass and quality through a balanced relationship between bone resorption and formation. Dysfunctions in osteoclasts or osteoblasts can disrupt this balance and lead to metabolic bone diseases characterized by either high or low bone turnover.
Musculoskeletal Complications of Cancer and its TreatmentsInsideScientific
Cancer frequently associates with the occurrence of cachexia, a debilitating syndrome responsible for reduced tolerance to anticancer therapies, as well as increased morbidity and mortality. Dr. Bonetto's group reported that animals bearing cancers not only show reduced skeletal muscle mass and strength, but also dramatic bone loss, despite the absence of bone metastases. Their latest findings revealed that muscle and bone depletion may also occur as a direct consequence of anticancer treatments (i.e., chemotherapy). There is now substantial agreement on the fact that abnormalities of the so-called ‘muscle-bone crosstalk’ may contribute to the onset of cachexia secondary to cancer or chemotherapy. Clinical and experimental observations also suggest that pharmacological bone preservation may concurrently benefit muscle mass in animal models, burn patients and osteoporotic women.
In this webinar Dr. Bonetto will present evidence that bone preservation directly impacts muscle size and function in cachexia, thus also contributing to unraveling novel pathogenetic mechanisms and opening new avenues for treatment.
This presentation discusses preventing osteoporotic fractures in men receiving androgen deprivation therapy (ADT) for prostate cancer. ADT is associated with rapid bone loss and increased fracture risk. Effective therapies for preventing bone loss and fractures include bisphosphonates like alendronate and zoledronic acid, which increase bone mineral density, as well as denosumab, which increases BMD and reduces vertebral fractures. Not all men on ADT require drug therapy; screening can help identify those at highest risk due to factors like older age, low body weight, steroid use, or preexisting osteopenia/osteoporosis.
1) Teriparatide (PTH 1-34), when administered intermittently as a daily injection, increases bone formation and improves bone microarchitecture by stimulating osteoblast number and function more than osteoclast activity.
2) A histomorphometric study found that patients treated with teriparatide for 6-18 months showed significantly higher bone formation in cancellous and endocortical bone compared to those treated with alendronate.
3) Teriparatide treatment for 12-24 months resulted in increased trabecular bone volume and reduced marrow space without any abnormal bone architecture effects according to paired-biopsy studies.
Denosumab vs bisfosfonato en metástasis óseasMauricio Lema
This document summarizes key findings from three head-to-head clinical trials comparing denosumab to zoledronic acid for the treatment of bone metastases in solid tumors. The main points are:
1) A prespecified integrated analysis of the three trials found that denosumab was superior to zoledronic acid, reducing the risk of first skeletal-related events by 17%.
2) Denosumab provided benefits across multiple solid tumor types, reducing the risk of first skeletal-related events in breast cancer, prostate cancer, and other solid tumors compared to zoledronic acid.
3) Denosumab demonstrated efficacy in reducing both the time to first skeletal-related event and the risk of subsequent skeletal
This document discusses osteoporosis treatment in patients with chronic kidney disease (CKD). It notes that while CKD patients have a high risk of fracture similar to postmenopausal osteoporosis, CKD-mineral and bone disorder (CKD-MBD) is more complex. Evaluating fracture risk in CKD patients is challenging as laboratory tests, bone turnover markers, and imaging modalities all have limitations. Bone biopsy remains the gold standard but has limitations for use in clinical practice. Treatment should be based on the underlying pathophysiology and more research is needed on fracture outcomes in CKD-MBD patients.
This document discusses osteoporosis and its treatment. It defines osteoporosis as a bone mineral density (BMD) at least 2.5 standard deviations below the young adult mean. It lists common risk factors for osteoporotic fractures such as female sex, smoking, family history, and low calcium/vitamin D intake. It discusses screening tools like FRAX score and recommendations for BMD testing and lifestyle changes. It provides guidelines for initiating drug therapy and lists common osteoporosis treatments like bisphosphonates, denosumab, calcium/vitamin D, and raloxifene.
Teriparatide (brand name Forteo) is a form of parathyroid hormone that stimulates new bone formation. It is the only osteoporosis drug approved to build new bone.
The document discusses how teriparatide works by activating osteoblasts through intermittent exposure to parathyroid hormone. This leads to increased bone mineral density, especially in the spine and hip. Clinical trials showed teriparatide reduced the risk of vertebral fractures by 65% and nonvertebral fractures by 53% compared to placebo.
Teriparatide is recommended for patients with severe osteoporosis who have failed or cannot tolerate bisphosphonate therapy. It may also be used off-label to
Metastatic bone disease: An old dogma and a new insightMohamed Abdulla
Metastatic bone disease is a challenging condition that places a heavy burden on patients. New insights into the cellular and molecular mechanisms have led to improved treatments. Cancer cells interact with the bone microenvironment through factors like RANKL, RANK, and osteoprotegerin, inducing a "vicious cycle" of bone destruction. Emerging therapies target these interactions by inhibiting RANKL with drugs like denosumab. Radiopharmaceuticals like radium-223 also show promise by targeting areas of new bone growth in metastases. While radiation remains important for pain relief, combination therapies offer the potential for improved outcomes in metastatic bone disease.
Louis Stodieck, BioServe Space Technologies, University of Colorado at Boulder: "AMGEN Countermeasures for Bone and Muscle Loss in Space and on Earth." Presented at the 2013 International Space Station Research and Development Conference, http://www.astronautical.org/issrdc/2013.
Recent advances in osteoporosis new copyDr Sourya M
Osteoporosis is characterized by low bone mass and deterioration of bone structure, making bones fragile and prone to fractures. Key drugs used to treat osteoporosis include calcium, vitamin D, bisphosphonates, SERMs, calcitonin, PTH and teriparatide, and denosumab. Newer drugs under development include romosozumab, a sclerostin inhibitor that strongly increases bone mineral density, abaloparatide, and integrin antagonists. Non-drug approaches also show promise such as biomaterials and gut serotonin inhibitors.
This document summarizes key findings from the ASBMR 2015 conference related to diabetes and bone health. It describes several studies presented at the conference that investigated the relationship between type 1 and type 2 diabetes and fracture risk. One study found that elderly men with type 2 diabetes did not have an increased risk of vertebral fractures compared to non-diabetic men. Another study found that measures of bone microarchitecture and glycemic control, rather than bone mineral density, were predictors of fractures in individuals with type 1 diabetes. A third study found evidence of altered trabecular microarchitecture in the tibia of youth with type 1 diabetes compared to controls.
This document discusses the pharmacotherapy of osteoporosis. It begins by defining osteoporosis and describing the problem it presents. It then covers the types of osteoporosis and risk factors. Diagnostic methods like DEXA scans and laboratory tests are outlined. Current treatment options are explained, including bisphosphonates, selective estrogen receptor modulators, calcitonin, vitamin D, and teriparatide. Specific drugs like alendronate, pamidronate, ibandronate, and raloxifene are described in detail. Non-pharmacological treatment and recent advances like neridronate and denosumab are also summarized.
This document discusses treatments for bone metastases from prostate cancer. It focuses on using external beam radiotherapy, systemic radiopharmaceuticals like strontium-89 and radium-223, and bisphosphonates to treat bone metastases and provide relief from pain. It describes how these treatments work, their effectiveness, and options for preventing bone metastases rather than just treating symptoms once they occur.
This document summarizes guidelines for palliative radiotherapy for bone metastases. It finds that single fraction or short fractionated regimens of 8 Gy, 20 Gy in 4 fractions, 24 Gy in 6 fractions or 30 Gy in 10 fractions provide effective pain relief with minimal side effects. Bisphosphonates or surgery do not obviate the need for radiotherapy but may be used in combination. Stereotactic body radiotherapy and radiopharmaceuticals may benefit select patients but require further study.
1) A study observed increased OPG levels in the feces and biopsy cultures of children with inflammatory bowel disease compared to non-IBD controls. Immunostaining of biopsies showed OPG signal in goblet cells of IBD patients.
2) Experiments with intestinal epithelial cell lines found nuclear OPG expression and secretion increased with TNF-α and IL-1β treatment. Knockdown of OPG via siRNA decreased OPG secretion but did not affect IL-8 levels.
3) Future studies aim to investigate the role of OPG in intestinal epithelial cell-bacteria interactions and overexpression of OPG-GFP in intestinal epithelial cells.
Osteoporosis is a disease characterized by low bone mass and deterioration of bone tissue, leading to fragile bones and increased risk of fractures. It is defined by the World Health Organization as a bone mineral density score of -2.5 or below. Those at highest risk include older adults, especially post-menopausal women, and those with low calcium/vitamin D intake or other risk factors such as smoking. Symptoms may include back pain or loss of height from vertebral fractures. Treatment focuses on calcium and vitamin D supplementation, as well as bisphosphonate medications to decrease bone resorption and reduce fracture risk. Prevention emphasizes building strong bones through diet, exercise and lifestyle habits during childhood and adolescence.
Pathophysiology of Metastatic Bone Disease and the Role of Bisphosphonatesshabeel pn
This document summarizes metastatic bone disease and the role of bisphosphonates. It discusses how bisphosphonates like pamidronate and zoledronic acid inhibit osteoclast activity to prevent skeletal complications from bone metastases. Clinical trials showed bisphosphonates reduced skeletal complications, bone pain, and hypercalcemia compared to placebo in cancers like breast cancer and multiple myeloma. Zoledronic acid was found to be more potent than pamidronate in suppressing bone turnover based on markers and time to first skeletal event.
We report the 11-year follow-up of a premenopausal woman with osteogenesisimperfecta (OI) who
was treated with alendronate. A 41-year-old Japanese premenopausal woman with OI type I who had
frequently experienced painful fragility fractures consulted our clinic because of chronic back pain associated
with spinal osteoporosis. She had undergone heart surgery (aortic valve replacement) because of aortic
regurgitation 5 years before her first consultation with our clinic. After surgery, she began taking warfarin (3
mg/day), and this treatment was continued during our follow-up period. She was treated with alendronate (5
mg/day or 35 mg/week) for 11 years. The patient’s urinary cross-linked N-terminal telopeptides of type I
collagen and serum alkaline phosphatase levels decreased, while the bone mineral density of her lumbar
spine (L2–L4) increased, as measured using dual energy X-ray absorptiometry. The serum calcium and
phosphorus levels stayed within the normal ranges. Three non-vertebral fractures occurred at the hip, ankle,
and ring finger during the 11-year treatment period, but no adverse effects were observed. Thus, the present
case report showed the long-term outcome and safety of alendronate treatment in a premenopausal woman
with OI type I.
This document summarizes current and newer therapies for osteoporosis. It describes the FDA-approved pharmacologic options including bisphosphonates, estrogens, raloxifene, calcitonin, parathyroid hormone, and denosumab. It then discusses the efficacy of these current treatments in reducing vertebral and non-vertebral fractures. The document notes the need for newer agents due to safety concerns with long-term bisphosphonate use. It introduces several promising new therapies in development including denosumab, anti-sclerostin antibodies, and cathepsin K inhibitors which have shown increases in bone mineral density and reductions in fracture risk in clinical trials.
Prof. Richard Keen's presentation from Osteoporosis 2016: Teaching old dogs new tricks? Combination therapy in osteoporosis.
Find out more at: https://nos.org.uk/conference
Bone is a dynamic tissue that is continuously renewed through the process of bone remodeling. This process is carried out by basic multicellular units containing osteoclasts, which resorb bone, and osteoblasts, which form new bone. A normal bone remodeling cycle maintains bone mass and quality through a balanced relationship between bone resorption and formation. Dysfunctions in osteoclasts or osteoblasts can disrupt this balance and lead to metabolic bone diseases characterized by either high or low bone turnover.
Musculoskeletal Complications of Cancer and its TreatmentsInsideScientific
Cancer frequently associates with the occurrence of cachexia, a debilitating syndrome responsible for reduced tolerance to anticancer therapies, as well as increased morbidity and mortality. Dr. Bonetto's group reported that animals bearing cancers not only show reduced skeletal muscle mass and strength, but also dramatic bone loss, despite the absence of bone metastases. Their latest findings revealed that muscle and bone depletion may also occur as a direct consequence of anticancer treatments (i.e., chemotherapy). There is now substantial agreement on the fact that abnormalities of the so-called ‘muscle-bone crosstalk’ may contribute to the onset of cachexia secondary to cancer or chemotherapy. Clinical and experimental observations also suggest that pharmacological bone preservation may concurrently benefit muscle mass in animal models, burn patients and osteoporotic women.
In this webinar Dr. Bonetto will present evidence that bone preservation directly impacts muscle size and function in cachexia, thus also contributing to unraveling novel pathogenetic mechanisms and opening new avenues for treatment.
This presentation discusses preventing osteoporotic fractures in men receiving androgen deprivation therapy (ADT) for prostate cancer. ADT is associated with rapid bone loss and increased fracture risk. Effective therapies for preventing bone loss and fractures include bisphosphonates like alendronate and zoledronic acid, which increase bone mineral density, as well as denosumab, which increases BMD and reduces vertebral fractures. Not all men on ADT require drug therapy; screening can help identify those at highest risk due to factors like older age, low body weight, steroid use, or preexisting osteopenia/osteoporosis.
1) Teriparatide (PTH 1-34), when administered intermittently as a daily injection, increases bone formation and improves bone microarchitecture by stimulating osteoblast number and function more than osteoclast activity.
2) A histomorphometric study found that patients treated with teriparatide for 6-18 months showed significantly higher bone formation in cancellous and endocortical bone compared to those treated with alendronate.
3) Teriparatide treatment for 12-24 months resulted in increased trabecular bone volume and reduced marrow space without any abnormal bone architecture effects according to paired-biopsy studies.
Denosumab vs bisfosfonato en metástasis óseasMauricio Lema
This document summarizes key findings from three head-to-head clinical trials comparing denosumab to zoledronic acid for the treatment of bone metastases in solid tumors. The main points are:
1) A prespecified integrated analysis of the three trials found that denosumab was superior to zoledronic acid, reducing the risk of first skeletal-related events by 17%.
2) Denosumab provided benefits across multiple solid tumor types, reducing the risk of first skeletal-related events in breast cancer, prostate cancer, and other solid tumors compared to zoledronic acid.
3) Denosumab demonstrated efficacy in reducing both the time to first skeletal-related event and the risk of subsequent skeletal
This document discusses osteoporosis treatment in patients with chronic kidney disease (CKD). It notes that while CKD patients have a high risk of fracture similar to postmenopausal osteoporosis, CKD-mineral and bone disorder (CKD-MBD) is more complex. Evaluating fracture risk in CKD patients is challenging as laboratory tests, bone turnover markers, and imaging modalities all have limitations. Bone biopsy remains the gold standard but has limitations for use in clinical practice. Treatment should be based on the underlying pathophysiology and more research is needed on fracture outcomes in CKD-MBD patients.
This document discusses osteoporosis and its treatment. It defines osteoporosis as a bone mineral density (BMD) at least 2.5 standard deviations below the young adult mean. It lists common risk factors for osteoporotic fractures such as female sex, smoking, family history, and low calcium/vitamin D intake. It discusses screening tools like FRAX score and recommendations for BMD testing and lifestyle changes. It provides guidelines for initiating drug therapy and lists common osteoporosis treatments like bisphosphonates, denosumab, calcium/vitamin D, and raloxifene.
Teriparatide (brand name Forteo) is a form of parathyroid hormone that stimulates new bone formation. It is the only osteoporosis drug approved to build new bone.
The document discusses how teriparatide works by activating osteoblasts through intermittent exposure to parathyroid hormone. This leads to increased bone mineral density, especially in the spine and hip. Clinical trials showed teriparatide reduced the risk of vertebral fractures by 65% and nonvertebral fractures by 53% compared to placebo.
Teriparatide is recommended for patients with severe osteoporosis who have failed or cannot tolerate bisphosphonate therapy. It may also be used off-label to
Metastatic bone disease: An old dogma and a new insightMohamed Abdulla
Metastatic bone disease is a challenging condition that places a heavy burden on patients. New insights into the cellular and molecular mechanisms have led to improved treatments. Cancer cells interact with the bone microenvironment through factors like RANKL, RANK, and osteoprotegerin, inducing a "vicious cycle" of bone destruction. Emerging therapies target these interactions by inhibiting RANKL with drugs like denosumab. Radiopharmaceuticals like radium-223 also show promise by targeting areas of new bone growth in metastases. While radiation remains important for pain relief, combination therapies offer the potential for improved outcomes in metastatic bone disease.
Louis Stodieck, BioServe Space Technologies, University of Colorado at Boulder: "AMGEN Countermeasures for Bone and Muscle Loss in Space and on Earth." Presented at the 2013 International Space Station Research and Development Conference, http://www.astronautical.org/issrdc/2013.
Recent advances in osteoporosis new copyDr Sourya M
Osteoporosis is characterized by low bone mass and deterioration of bone structure, making bones fragile and prone to fractures. Key drugs used to treat osteoporosis include calcium, vitamin D, bisphosphonates, SERMs, calcitonin, PTH and teriparatide, and denosumab. Newer drugs under development include romosozumab, a sclerostin inhibitor that strongly increases bone mineral density, abaloparatide, and integrin antagonists. Non-drug approaches also show promise such as biomaterials and gut serotonin inhibitors.
This document summarizes key findings from the ASBMR 2015 conference related to diabetes and bone health. It describes several studies presented at the conference that investigated the relationship between type 1 and type 2 diabetes and fracture risk. One study found that elderly men with type 2 diabetes did not have an increased risk of vertebral fractures compared to non-diabetic men. Another study found that measures of bone microarchitecture and glycemic control, rather than bone mineral density, were predictors of fractures in individuals with type 1 diabetes. A third study found evidence of altered trabecular microarchitecture in the tibia of youth with type 1 diabetes compared to controls.
This document discusses the pharmacotherapy of osteoporosis. It begins by defining osteoporosis and describing the problem it presents. It then covers the types of osteoporosis and risk factors. Diagnostic methods like DEXA scans and laboratory tests are outlined. Current treatment options are explained, including bisphosphonates, selective estrogen receptor modulators, calcitonin, vitamin D, and teriparatide. Specific drugs like alendronate, pamidronate, ibandronate, and raloxifene are described in detail. Non-pharmacological treatment and recent advances like neridronate and denosumab are also summarized.
This document discusses treatments for bone metastases from prostate cancer. It focuses on using external beam radiotherapy, systemic radiopharmaceuticals like strontium-89 and radium-223, and bisphosphonates to treat bone metastases and provide relief from pain. It describes how these treatments work, their effectiveness, and options for preventing bone metastases rather than just treating symptoms once they occur.
This document summarizes guidelines for palliative radiotherapy for bone metastases. It finds that single fraction or short fractionated regimens of 8 Gy, 20 Gy in 4 fractions, 24 Gy in 6 fractions or 30 Gy in 10 fractions provide effective pain relief with minimal side effects. Bisphosphonates or surgery do not obviate the need for radiotherapy but may be used in combination. Stereotactic body radiotherapy and radiopharmaceuticals may benefit select patients but require further study.
1) A study observed increased OPG levels in the feces and biopsy cultures of children with inflammatory bowel disease compared to non-IBD controls. Immunostaining of biopsies showed OPG signal in goblet cells of IBD patients.
2) Experiments with intestinal epithelial cell lines found nuclear OPG expression and secretion increased with TNF-α and IL-1β treatment. Knockdown of OPG via siRNA decreased OPG secretion but did not affect IL-8 levels.
3) Future studies aim to investigate the role of OPG in intestinal epithelial cell-bacteria interactions and overexpression of OPG-GFP in intestinal epithelial cells.
Osteoporosis is a disease characterized by low bone mass and deterioration of bone tissue, leading to fragile bones and increased risk of fractures. It is defined by the World Health Organization as a bone mineral density score of -2.5 or below. Those at highest risk include older adults, especially post-menopausal women, and those with low calcium/vitamin D intake or other risk factors such as smoking. Symptoms may include back pain or loss of height from vertebral fractures. Treatment focuses on calcium and vitamin D supplementation, as well as bisphosphonate medications to decrease bone resorption and reduce fracture risk. Prevention emphasizes building strong bones through diet, exercise and lifestyle habits during childhood and adolescence.
This document provides information about osteoporosis. It begins by defining osteoporosis as a disease where bone density and quality are reduced, making bones more porous and fragile and greatly increasing the risk of fractures. It notes that bone loss occurs silently and progressively, with no symptoms until the first fracture. The document then discusses bone structure, the cells involved in bone formation and resorption, risk factors for osteoporosis, its prevalence in India, and common fracture sites. It outlines the assessment and diagnosis of osteoporosis as well as lifestyle and medical treatments to prevent fractures.
1) The document discusses osteoporosis, including the challenges it presents, its prevalence, risk factors, diagnosis, complications, management principles, and treatment goals.
2) Key points include that osteoporosis is a disease characterized by low bone mass and deterioration of bone tissue, leading to fragility and increased risk of fractures. It affects millions worldwide, with over 50% of women and 20% of men experiencing fractures due to osteoporosis in their lifetimes.
3) Diagnosis involves bone mineral density tests to measure bone density and predict fracture risk. Treatment aims to prevent further bone loss and fractures, relieve pain and deformities, and improve quality of life.
This document discusses various types of secondary osteoporosis, including those caused by chronic liver diseases, Cushing syndrome, Gaucher disease, cystic fibrosis, and diabetes. It provides details on the pathophysiology and mechanisms by which these conditions can lead to osteoporosis, such as through imbalances in the OPG/RANK/RANKL pathway, deficiencies in IGF-1 or vitamin K, elevated inflammatory cytokines, and effects on osteoblast and osteoclast activity. The document also covers topics like bone remodeling and epidemiology of osteoporosis.
This document summarizes guidelines for evaluating and managing patients with fragility fractures. It defines fragility fractures as fractures caused by low-impact falls from standing height or less. Fragility fractures are common in older adults and have severe consequences, including disability, reduced quality of life, and increased mortality. The document outlines best practices for assessing fragility fracture patients, including obtaining a detailed medical history, physical exam, lab tests, bone mineral density testing, and imaging to evaluate for additional fractures. The goal is to diagnose any underlying osteoporosis and implement secondary prevention strategies to reduce future fracture risk.
Everything you need to know about moa of bone targeted agents amgen 2017Mohamed Abdulla
This document summarizes key information about giant cell tumor of bone (GCTB) and a phase II study of the RANK ligand inhibitor denosumab for treatment of GCTB. The study showed that nearly all GCTB patients treated with denosumab had stable disease or an objective response, with few experiencing disease progression. Histological analysis found that denosumab significantly reduced or eliminated RANK-positive tumor giant cells in GCTB tissue specimens. These results suggest that denosumab is an effective treatment that stabilizes disease in the majority of GCTB patients.
This document summarizes current dilemmas in early management of castration-resistant prostate cancer (CRPC). It discusses definitions of CRPC and its natural history progression. Factors contributing to inevitable disease progression despite androgen deprivation therapy include alternate androgen biosynthesis, androgen receptor abnormalities, proliferation cascades, and changes in histology. Genetic alterations in prostate cancer like BRCA mutations are also reviewed. Recent positive clinical trial results establishing new standards of care for both chemo-naïve and post-docetaxel CRPC are highlighted. Optimal sequencing of available therapies remains an area of ongoing research due to heterogeneity in patient populations and lack of head-to-head trials.
The document discusses the use of bortezomib, a proteasome inhibitor, for the treatment of mantle cell lymphoma (MCL). It summarizes several clinical trials that have shown bortezomib to be effective against MCL both as a single agent and in combination with chemotherapy regimens like R-CHOP. Ongoing studies are further exploring bortezomib combinations and schedules to improve outcomes for MCL patients.
The document summarizes results from a phase 3 clinical trial of the drug odanacatib for treating osteoporosis in postmenopausal women. Key findings include:
- Odanacatib significantly reduced the risk of morphometric vertebral fractures by 54%, hip fractures by 47%, and nonvertebral fractures by 23% compared to placebo.
- Bone mineral density increased substantially with odanacatib therapy over 5 years.
- Safety analyses found low rates of adverse events with odanacatib, though some rare skin conditions were more common compared to placebo and require further investigation.
The document discusses several novel treatments for osteoporosis, including denosumab, anti-sclerostin monoclonal antibodies, and lasofoxifene. Denosumab is an antibody to RANK ligand that inhibits bone resorption and reduces fracture risk. Blocking sclerostin may allow unlimited bone formation and a potential cure for osteoporosis. Lasofoxifene reduces fracture risk and also reduces risks of breast cancer and heart disease, with no increased risk of uterine cancer.
My Prostate Cancer Story by Paul SchellhammerTony Crispino
With permission of Dr. Schellhammer this slide deck should be interesting to any PCa patient. Dr. Schellhammer is a former president of the American Urological Association and a leading authority on prostate cancer. He has fought i long battle. He and his colleague, Paul Lange operated on each other and had vastly different results.
Alpharadin<sup>®</sup> (Xofigo<sup>®</sup>) in the treatment of skeletal meta...Michael
Xofigo is a new radiopharmaceutical for treating metastatic bone cancer from prostate cancer. It delivers targeted alpha radiation directly to bone metastases through a mechanism similar to calcium uptake in bone. Clinical trials found Xofigo improved overall survival, decreased markers of disease progression, and reduced pain compared to placebo with fewer side effects than chemotherapy. Xofigo's short-range alpha emissions allow it to specifically target tumor cells in bone while sparing surrounding healthy tissue.
Renal Cell Carcinoma A New Standard Of Carefondas vakalis
This document summarizes the current standard of care for renal cell carcinoma (RCC), focusing on targeted therapies such as anti-angiogenesis agents. It reviews the biology and risk factors for RCC, the clinical efficacy and safety profiles of drugs like sorafenib and sunitinib, and phase III trial results demonstrating improved progression-free and overall survival compared to interferon-alpha. It concludes that anti-angiogenic therapies such as sorafenib, sunitinib, and temsirolimus have become the new standard first-line treatment for metastatic RCC based on superior clinical outcomes over existing immunotherapy options.
Metastatic castration-resistant prostate cancer (mCRPC) is an advanced form of prostate cancer that has spread to other organs and continues to progress despite hormone therapy. Current treatments aim to reduce testosterone levels, disrupt microtubules during cell division, activate the immune system, or use radiopharmaceuticals, but all have limitations like toxicity or development of resistance. Researchers are exploring new targets and combinations of drugs to block cancer progression and prolong survival for men with mCRPC, which remains largely incurable.
2020 OA Vision: Emerging Therapeutics on the OA landscapeOARSI
Philip Conaghan MBBS PhD FRACP FRCP
Director, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds
Deputy Director, NIHR Leeds Biomedical Research Centre
1) Castrate-resistant prostate cancer (CRPC) has become increasingly treatable over the past decade with the approval of several new drugs including docetaxel, sipuleucel-T, cabazitaxel, denosumab, and abiraterone.
2) Clinical trials have shown that docetaxel improves survival when used to treat metastatic CRPC and cabazitaxel improves survival in CRPC progressing after docetaxel.
3) Denosumab has been shown to delay skeletal-related events in men with bone metastases from prostate cancer compared to zoledronic acid. Abiraterone has also improved survival in CRPC progressing after chemotherapy.
The document discusses various strategies for overcoming resistance to endocrine therapy in advanced breast cancer, including targeting downstream signaling pathways like PI3K/Akt/mTOR that are often aberrantly activated in endocrine resistant disease. It reviews clinical trials demonstrating improved progression-free survival when adding drugs like everolimus or CDK4/6 inhibitors to hormonal therapy. The goal is to inhibit compensatory survival pathways that become relied upon by cancer cells to drive continued growth in the face of endocrine therapy.
Osteoporosis, How to diagnose and treat _ Oral and Infusion Treatment.pptxparyanti2
The VERT study found that daily treatment with risedronate significantly reduced the risk of new vertebral fractures by 41% and new morphometric vertebral fractures by 49% compared to placebo in postmenopausal women with osteoporosis over 3 years. Risedronate also reduced the risk of hip fractures by 39% and other nonvertebral fractures by 25%, although the results for nonvertebral fractures were not statistically significant. The study demonstrated that risedronate is a safe and effective treatment for reducing fracture risk in postmenopausal osteoporosis.
The document summarizes key points from the 18th International Conference on Co-morbidities and Adverse Drug Reactions in HIV. It discusses findings related to bone health, cardiovascular health, and physical activity levels in people living with HIV. Regarding bone health, studies showed bone mineral density loss with tenofovir-containing antiretroviral therapy and PrEP. Loss was also seen with glucocorticoid use. For cardiovascular health, studies suggested lower risk of atherosclerotic events with NNRTI-based initial ART and possible lower risk with atazanavir. Physical activity levels were associated with comorbidity risk, with higher risk at lower activity levels.
This document discusses the management of bone metastases. It begins by explaining how tumor cells interact with bone cells, disrupting normal bone metabolism and increasing osteoclast activity. This leads to skeletal complications over several years for cancers like myeloma, breast, and prostate. Common sites of bone metastases are then outlined. Treatment options discussed include systemic therapies like bisphosphonates and denosumab which target osteoclasts and RANKL, as well as local therapies like surgery, radiation, vertebroplasty, and kyphoplasty. Denosumab is positioned as an alternative to zoledronic acid, with potential advantages of subcutaneous dosing and reduced risks of osteonecrosis of the jaw and renal toxicity. Guidelines recommend
This study evaluated the long-term clinical and radiological outcomes of 126 patients with 239 osteoporotic vertebral fractures treated with balloon kyphoplasty compared to a conservatively treated control group. Patients undergoing kyphoplasty had significantly reduced pain scores and improved disability scores that were maintained at the 2-year follow-up, while the control group showed no significant changes. Kyphoplasty also significantly restored vertebral height and alignment, while conservative treatment did not significantly impact radiographic measures. This study demonstrates the long-term benefits of balloon kyphoplasty over conservative care for osteoporotic vertebral fractures.
The document summarizes key information about prostate cancer including incidence, mortality rates, clinical stages, risk groups for localized prostate cancer, treatment options for advanced disease including hormone therapy and chemotherapy, and results from clinical trials of chemotherapy agents like docetaxel and cabazitaxel.
1) Anti-angiogenic therapy targets tumor angiogenesis and has become an established treatment for metastatic colorectal cancer (mCRC).
2) Bevacizumab, a monoclonal antibody targeting VEGF, has shown efficacy in multiple phase III trials in combination with chemotherapy as first-line and maintenance therapy for mCRC.
3) Additional anti-angiogenic agents approved for mCRC include aflibercept, ramucirumab, and regorafinib, which have demonstrated benefits in later lines of therapy.
Asco 2006 Update Genitourinary Cancer Selected Abstractsfondas vakalis
The document summarizes several studies on targeted therapies for kidney cancer presented at the 2006 ASCO conference. Key findings include:
- Sunitinib and temsirolimus were shown to be superior to interferon for metastatic kidney cancer in phase 3 trials, with longer progression-free and overall survival.
- The TARGET trial found sorafenib increased progression-free survival compared to placebo in advanced RCC and improved overall survival after patients on placebo crossed over.
- A global phase 3 trial found temsirolimus alone or with interferon improved overall survival over interferon in poor-risk metastatic RCC patients.
Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor used as an immunosuppressant in transplant patients. Several studies showed that using sirolimus with reduced or eliminated calcineurin inhibitor doses improved renal function and reduced toxicity compared to standard calcineurin inhibitor regimens. However, sirolimus use was also associated with higher rates of delayed graft function. Overall, these studies demonstrated that sirolimus can allow for reduction or elimination of nephrotoxic calcineurin inhibitors while maintaining efficacy.
Similar to ECCLU 2011 - N. Clarke - Bone targeted agents (20)
1) The study examines how and why certain breast cancer cells metastasize to bone through a "seed pre-selection" process.
2) It finds that high Src activity (denoted by a "Src activity signature" or SRS) in primary tumors associates with bone metastasis.
3) In ER-/ERBB2- breast cancers, cytokines CXCL12 and IGF1 in the tumor microenvironment activate Src which promotes cell survival and bone metastasis. Long term exposure to these cytokines in vitro selects for breast cancer cells with higher Src activity and bone metastatic ability.
The document discusses renal cancer (kidney cancer) and advances in its treatment. It describes several targeted drugs that have improved outcomes for metastatic renal cell carcinoma (mRCC) compared to previous immunotherapy options. Drugs include tyrosine kinase inhibitors like sunitinib, sorafenib, pazopanib and axitinib as well as the mTOR inhibitor temsirolimus. Clinical trials have established these as standard first and second line options depending on a patient's risk level and prior treatment history. Ongoing research focuses on optimizing treatment sequencing and identifying biomarkers to guide more personalized therapy selection.
The document summarizes highlights from the 11-ICML Lugano conference in 2011, including:
1) Studies showing the impact of the tumor microenvironment in lymphoma prognosis and the predictive value of increased macrophages in Hodgkin's lymphoma biopsies.
2) High response rates to antiviral treatment in patients with indolent B-cell lymphoma associated with HCV infection.
3) A PET-based approach can effectively guide treatment for limited-stage diffuse large B-cell lymphoma.
4) R-CHOP induction followed by rituximab maintenance improves survival over R-FC induction for elderly patients with mantle cell lymphoma.
This document summarizes the management of urinary bladder cancer. It discusses staging, histopathologic types, and treatment options for non-muscle invasive and muscle invasive bladder cancer as well as metastatic disease. Standard first-line chemotherapy for metastatic bladder cancer includes gemcitabine and cisplatin or MVAC. Newer chemotherapy regimens and agents are also discussed.
The document discusses new drugs for the treatment of lymphomas. It outlines several monoclonal antibodies that target antigens on B-cells, including CD20, CD19, CD22 and CD37. Ofatumumab and GA-101 are new anti-CD20 monoclonal antibodies that exhibit enhanced binding and cell-killing properties compared to Rituximab. Inotuzumab Ozogamicin is an antibody-drug conjugate targeting CD22 that is internalized and releases a cytotoxic drug, showing promising activity in early clinical trials.
This document discusses treatment of diffuse large B-cell lymphoma (DLBCL). It notes that DLBCL is a heterogeneous disease with genetic subgroups that have different prognoses and responses to treatment. The addition of the antibody rituximab to chemotherapy improves outcomes for DLBCL compared to chemotherapy alone. Strategies discussed to improve outcomes include increasing chemotherapy dose intensity and the potential role of the drug bortezomib for the activated B-cell subtype.
This document discusses treatment of diffuse large B-cell lymphoma (DLBCL). It notes that DLBCL is a heterogeneous disease with genetic subgroups that have different prognoses and responses to treatment. The addition of the antibody rituximab to chemotherapy like CHOP has improved outcomes for DLBCL compared to chemotherapy alone in the post-rituximab era. Strategies to further improve outcomes include targeting specific genetic subgroups like the activated B-cell subtype using drugs like bortezomib that inhibit pathways like NF-kB.
The document discusses the current state of cancer vaccines, focusing on HPV vaccines. It outlines the types of vaccines as prophylactic, preventive, or therapeutic. HPV vaccines have proven highly effective as prophylactic vaccines in preventing cervical cancer. Clinical trials demonstrated up to 100% efficacy of the HPV vaccines Gardasil and Cervarix in preventing precancerous lesions. However, challenges remain regarding cross-protection against other HPV types, long-term duration of protection, and reducing production costs to increase global access.
- Ovarian cancer is the ninth most common cancer in women and the fifth leading cause of cancer death in women. Risk factors include age over 60, obesity, talcum powder use, fertility drugs, genetic predispositions like BRCA mutations.
- Surgical staging is essential for determining prognosis and appropriate treatment. For early stage disease adjuvant chemotherapy is recommended. Advanced stage disease is treated with cytoreductive surgery followed by platinum/taxane chemotherapy.
- Prognosis depends on stage and completeness of cytoreduction. Median survival is 39 months for optimal vs 17 months for suboptimal cytoreduction. Secondary surgery and chemotherapy may provide benefit for recurrence in some patients.
This document summarizes key information about ovarian cancer, including epidemiology, staging, treatment milestones, prognostic factors, and recent clinical trials. It notes that the median age of diagnosis is 63 years and discusses improvements in 5-year survival over time. New developments discussed include the role of surgery, chemotherapy regimens, targeted therapies like bevacizumab, and trials in recurrent settings.
Nearly 500,000 new cases of cervical cancer occur worldwide each year, with the majority in developing countries. Infection with HPV is responsible for virtually all cervical cancer cases. Screening includes Pap smears and HPV testing, while vaccination may prevent up to 70% of cases but is not widely available due to cost. Diagnosis is through biopsy and histopathological examination, while staging uses the FIGO system based on tumor size and spread. Treatment depends on stage but commonly includes surgery such as hysterectomy with or without radiation or chemotherapy.
- Cervical cancer is a major cause of cancer deaths worldwide, with over 500,000 new cases and 260,000 deaths estimated annually. Most deaths occur in developing countries where screening and prevention programs are lacking.
- Early detection through screening programs can make cervical cancer highly curable, but the majority of cases in developing nations are diagnosed at late stages when survival rates are low. Vaccination and screening can help prevent a large percentage of cervical cancer cases.
- Risk factors for cervical cancer include human papillomavirus infection and lack of access to healthcare. While HPV infection is necessary, most infections clear without causing cancer. Other factors like multiple pregnancies, smoking, and HIV infection can increase the risk.
The document summarizes the current state of metastatic breast cancer treatment. It discusses how survival rates have improved over time and metastatic breast cancer is now considered a chronic, treatable disease rather than an immediately terminal condition. Treatment involves systemic therapies like chemotherapy, endocrine therapy, targeted therapies, as well as radiation, surgery, and supportive care. Selection of optimal first-line systemic treatment depends on disease characteristics and patient factors. Ongoing research focuses on tailoring and sequencing treatments to overcome resistance and further extend patient survival and quality of life.
1) Breast cancer is heterogeneous with different subtypes defined by receptor status and gene expression profiles. The subtypes have different biological behaviors and clinical outcomes.
2) Accurate diagnosis requires biopsy (FNA or core) followed by receptor testing before treatment decisions. Surgery options include breast conserving therapy or mastectomy with/without reconstruction.
3) For early breast cancer, sentinel lymph node biopsy guides the need for further axillary lymph node dissection. Omission of further dissection may be adequate for sentinel node positive patients.
- The document discusses liver and hepatobiliary cancers, focusing on hepatocellular carcinoma (HCC). It covers the epidemiology, risk factors, screening and diagnosis of HCC as well as staging systems and treatment options.
- Risk factors for HCC include hepatitis B and C infection, alcohol consumption, and aflatoxin intake. Screening ultrasound and AFP tests are used for early diagnosis in high-risk patients. The BCLC staging system guides treatment which includes resection, transplantation, ablation, and embolization.
- For intermediate stage HCC, transarterial chemoembolization provides the best outcomes, with 70-80% of patients surviving 1 year and 50% surviving 3 years. However
The document discusses guidelines for screening, diagnosis, staging, adjuvant therapy, advanced disease treatment, and follow-up for colorectal cancer from both the ESMO and NCCN perspectives. It provides recommendations for screening the general and high-risk populations. It also outlines the diagnostic and staging workup, including endoscopy, biopsy, imaging, and surgical staging. Guidelines are presented for adjuvant therapy based on cancer stage. Recommendations are provided for managing both synchronous and metachronous metastatic disease, as well as rectal cancer treatment.
1) A trial found that adding bevacizumab to chemotherapy for stage III colon cancer extended disease-free survival compared to chemotherapy alone, delaying cancer relapse but not preventing it completely.
2) There was no overall survival benefit observed from adding bevacizumab, suggesting it delays but does not alter the underlying biology of the disease.
3) The interpretation is that relapses were delayed by bevacizumab treatment but then occurred at a steady rate later on, similar to the chemotherapy alone group.
This document provides an overview of squamous cell carcinoma of the head and neck (SCCHN), including its anatomical sites, incidence and mortality rates, risk factors, staging guidelines, and treatment approaches. It discusses the roles of surgery, radiation therapy, chemotherapy, concurrent chemoradiation, and targeted therapies like cetuximab in managing localized and advanced SCCHN. Concurrent chemoradiation is now standard for improving local control and organ preservation compared to radiation alone. The addition of cetuximab to radiation was shown to improve locoregional control and overall survival.
This document summarizes the state of the art in head and neck cancer treatment. It discusses epidemiology, risk factors, staging, treatment modalities including surgery, radiotherapy, chemotherapy, targeted therapy. It highlights recent findings like the role of HPV and molecular targeted agents. It also discusses the benefits of concurrent chemoradiation compared to radiotherapy alone as well as induction chemotherapy followed by chemoradiation for locally advanced disease.
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
Osteoporosis - Definition , Evaluation and Management .pdfJim Jacob Roy
Osteoporosis is an increasing cause of morbidity among the elderly.
In this document , a brief outline of osteoporosis is given , including the risk factors of osteoporosis fractures , the indications for testing bone mineral density and the management of osteoporosis
- Video recording of this lecture in English language: https://youtu.be/kqbnxVAZs-0
- Video recording of this lecture in Arabic language: https://youtu.be/SINlygW1Mpc
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
These lecture slides, by Dr Sidra Arshad, offer a quick overview of the physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar lead (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
6. Describe the flow of current around the heart during the cardiac cycle
7. Discuss the placement and polarity of the leads of electrocardiograph
8. Describe the normal electrocardiograms recorded from the limb leads and explain the physiological basis of the different records that are obtained
9. Define mean electrical vector (axis) of the heart and give the normal range
10. Define the mean QRS vector
11. Describe the axes of leads (hexagonal reference system)
12. Comprehend the vectorial analysis of the normal ECG
13. Determine the mean electrical axis of the ventricular QRS and appreciate the mean axis deviation
14. Explain the concepts of current of injury, J point, and their significance
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. Chapter 3, Cardiology Explained, https://www.ncbi.nlm.nih.gov/books/NBK2214/
7. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
ABDOMINAL TRAUMA in pediatrics part one.drhasanrajab
Abdominal trauma in pediatrics refers to injuries or damage to the abdominal organs in children. It can occur due to various causes such as falls, motor vehicle accidents, sports-related injuries, and physical abuse. Children are more vulnerable to abdominal trauma due to their unique anatomical and physiological characteristics. Signs and symptoms include abdominal pain, tenderness, distension, vomiting, and signs of shock. Diagnosis involves physical examination, imaging studies, and laboratory tests. Management depends on the severity and may involve conservative treatment or surgical intervention. Prevention is crucial in reducing the incidence of abdominal trauma in children.
Basavarajeeyam is a Sreshta Sangraha grantha (Compiled book ), written by Neelkanta kotturu Basavaraja Virachita. It contains 25 Prakaranas, First 24 Chapters related to Rogas& 25th to Rasadravyas.
Histololgy of Female Reproductive System.pptxAyeshaZaid1
Dive into an in-depth exploration of the histological structure of female reproductive system with this comprehensive lecture. Presented by Dr. Ayesha Irfan, Assistant Professor of Anatomy, this presentation covers the Gross anatomy and functional histology of the female reproductive organs. Ideal for students, educators, and anyone interested in medical science, this lecture provides clear explanations, detailed diagrams, and valuable insights into female reproductive system. Enhance your knowledge and understanding of this essential aspect of human biology.
Muktapishti is a traditional Ayurvedic preparation made from Shoditha Mukta (Purified Pearl), is believed to help regulate thyroid function and reduce symptoms of hyperthyroidism due to its cooling and balancing properties. Clinical evidence on its efficacy remains limited, necessitating further research to validate its therapeutic benefits.
Promoting Wellbeing - Applied Social Psychology - Psychology SuperNotesPsychoTech Services
A proprietary approach developed by bringing together the best of learning theories from Psychology, design principles from the world of visualization, and pedagogical methods from over a decade of training experience, that enables you to: Learn better, faster!
Top 10 Best Ayurvedic Kidney Stone Syrups in India
ECCLU 2011 - N. Clarke - Bone targeted agents
1. Bone Targeted Agents in Prostate Cancer NW Clarke Professor of Urological Oncology Manchester UK
2. Normal Physiology: The Balance Between Bone Resorption and Formation Activation Adapted from Baron, R. General Principles of Bone Biology. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 5th ed. 2003;1-8. Osteoblasts Formation Osteoid Tissue Resting Osteoblasts Mesencymal cells and Preosteoblasts Resorption Osteoclasts Reversal Apoptotic Osteoclasts Preosteoblasts
7. Bone Formation and Destruction in Prostate Cancer Clarke NW et al BJU 1991 / 1992 Eur Urol 1992
8. Bone Metabolism and Prostate Cancer Osteoblast Activated Osteoclast Pre-fusion Osteoclast CFU-M Multinucleated Osteoclast Adapted from: Boyle WJ, et al. Nature . 2003;423:337-342. Clines et al. Mol Endocrinol. 2007 February; 21(2):486-498 Hofbauer LC, et al. JAMA . 2004;292:490-495. RANKL RANK
9. Bone Metabolism and Prostate Cancer Osteoblast Activated Osteoclast TNF- PTH IL-1 PTHrP Glucocorticoids Vitamin D PGE 2 IL-11 IL-6 Pre-fusion Osteoclast CFU-M Multinucleated Osteoclast CFU-M = colony-forming unit-macrophage; PTH = parathyroid hormone; PGE 2 = prostaglandin E 2 ; IL = interleukin; PTHrP = PTH-related peptide; RANKL = receptor activator of nuclear factor kappa B ligand. ET-1 = endothelin ET-1 RANKL RANK
10. Bone Metabolism and Prostate Cancer Adapted from Roodman D. N Engl J Med . 2004;350:1655. PTHrP, BMP, TGF-β, IGF, FGF, VEGF, ET1, WNT Osteoblasts Activated Osteoclast PDGF, BMPs TGF-β, IGFs FGFs Tumor Cell CA +2 RANKL RANK OPG
12. Bone Markers in Osteolytic and Osteoblastic Metastatic Bone Disease Coleman RE, et al. JCO. 2005;23(22):1-11. U/L (median) Baseline BAP n = 744 n = 611 n = 263 n = 247 n = 318 nmol/mmol Creatinine (median) Baseline NTx n = 762 n = 626 n = 366 n = 379 n = 319 202 155 162 134 268 0 50 100 150 200 250 300 BC PC NSCLC Other ST MM 76 68 68 57 89 0 20 40 60 80 100 BC PC NSCLC Other ST MM
13. Increased Bone Resorption in Metastatic Bone Disease NTx excretion (nmol/mmol creatinine) % Coleman et al. J Clin Oncol 2005;23:4925-4935 . Normal Markedly elevated Modestly elevated
14. Influence of Accelerated Bone Resorption on Outcome in CRPC Relative Risk* P value 95% C.I. Brown J et al JNCI 2005 NTX > 100 v < 100 nmol/mmol creatinine Placebo treated patients n = 200 All SREs 2.36 1.30 - 4.29 .021 First SRE 2.56 1.44 - 4.55 .001 Prog Disease 2.17 1.17 - 4.05 .014 Death 5.09 2.90 - 8.91 <.001
15. Can Bone Directed Therapies Help? Osteoblast Activated Osteoclast TNF- PTH IL-1 PTHrP Glucocorticoids Vitamin D PGE 2 IL-11 IL-6 Pre-fusion Osteoclast CFU-M Multinucleated Osteoclast CFU-M = colony-forming unit-macrophage; PTH = parathyroid hormone; PGE 2 = prostaglandin E 2 ; IL = interleukin; PTHrP = PTH-related peptide; RANKL = receptor activator of nuclear factor kappa B ligand. ET-1 = endothelin ET-1 RANKL RANK
16. Can Bone Directed Therapies Help? Osteoblast Activated Osteoclast Pre-fusion Osteoclast CFU-M Multinucleated Osteoclast Endothelin-1 Blockade Bisphosphonates RANK Ligand Blockade
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19. Skeletal Related Events Saad et al. JNCI 2004; 96:879
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22. Bone Resorption is Dependent on RANK Ligand An Essential Mediator of Osteoclast Activity Bone Osteoblast Lineage Inactive Osteoclast CFU-M Pre-Fusion Osteoclast Multinucleated Osteoclast CFU-M = colony forming unit macrophage Growth Factors Hormones Cytokines RANK RANKL RANK Ligand is Essential for Osteoclast Formation, Function, and Survival Adapted from Boyle WJ, et al. Nature. 2003;423:337-342.
23. Osteoprotegerin (OPG) Neutralises the Effects of RANK Ligand Bone Osteoblast Lineage Inactive Osteoclast CFU-M Pre-Fusion Osteoclast Multinucleated Osteoclast CFU-M = colony forming unit macrophage Growth Factors Hormones Cytokines RANK RANKL Osteoclast Formation, Function, and Survival Inhibited by OPG OPG Adapted from Boyle WJ, et al. Nature. 2003;423:337-342.
24. Denosumab Binds RANK Ligand and Inhibits Osteoclast Formation, Function and Survival Adapted from Roodman D. N Engl J Med . 2004;350:1655. PTHrP, BMP, TGF-β, IGF, FGF, VEGF, ET1, WNT Osteoblasts Inactivate Osteoclast PDGF, BMPs TGF-β, IGFs FGFs Tumor Cell CA +2 Bone Resorption Inhibited RANKL RANK Denosumab
25. RANK Ligand Inhibition with Denusomab in Cancer Patients with Bone Metastases Adapted from Suarez T, et al. J Clin Oncol. 2006;24(18S):6S. Abstract 8562 and poster. Median Percent Change in uNTx -120 -100 -80 -60 -40 -20 0 20 40 60 Visit Week 0 1 2 5 9 13 17 21 25 33 IV Bisphosphonate 180 mg Q4W 180 mg Q12W Total Denosumab
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37. Inhibiting the Endothelin Axis ET A Antagonists and Prostate Cancer ET A R ET B R ET-1 ET-1 Metastasis Disease progression Angiogenesis Osteoblast stimulation Vasodilatation Apoptosis ZD4054 specifically blocks ET A R, with no detectable activity at ET B R Morris CD et al. Br J Cancer 2005;92:2148–2152 Atrasentan ZD4054
38. ZD4054 VS Placebo: Overall Survival ZD4054 15 mg versus placebo: HR 0.62; 80%CI 0.38, 0.99; P = 0.19 ZD4054 10 mg versus placebo: HR 0.38; 80%CI 0.22, 0.64; P = 0.019 Proportion of patients alive Time to death (days) 0 0.2 0.4 0.6 0.8 1.0 0 50 100 150 200 250 300 350 500 450 400 James ND et al Eur Urol Epub 2008 ZD4054 15 mg Placebo ZD4054 10 mg
39. ZD4054 Phase III Programme ENTHUSE M0 (15) ZD4054 vs placebo Metastatic (M1) No symptoms No Metastases (M0) No Symptoms Metastatic (M1) Symptomatic ENTHUSE M1 (14) ZD4054 vs placebo ENTHUSE M1C (33) docetaxel +/- ZD4054
52. Radium-223 vs Placebo in CRPC Time to first SRE Overall survival Nilsson et al Lancet Oncol 2007: 8: 587-94
53. Induction chemotherapy Clinical response R A N D O M I Z E Consolidation therapy + Sr-89 Consolidation therapy Tu S-M Lancet 2001 Chemotherapy + Radio-Pharmaceuticals Randomised phase II Studies
54. Combination Therapies Ketoconazole + Chemotherapy + 89 Sr Shi-Ming Tu et al The Lancet 2001
55. Combination Bone Targeted Therapies: The NCRI Trapeze Study docetaxel + prednisolone zoledronic acid + Sr-89 + D RANDOMISE docetaxel + prednisolone A docetaxel + prednisolone zoledronic acid + B docetaxel + prednisolone strontium - 89 + C docetaxel + prednisolone (cycles 7-10) docetaxel + prednisolone (cycles 7-10) docetaxel + prednisolone (cycles 7-10) docetaxel + prednisolone (cycles 7-10) + 28 Days * + 28 Days *
56. Surgery and Metastatic Spinal Cord Compression BD White et al BMJ 2008: 337 Metastatic spinal cord compression
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59. White, B D et al. BMJ 2008;337:a2538 Management of patients with suspected metastatic spinal cord compression
Bone remodeling is the process by which old bone is replaced by new bone and consists of phases: resting, resorption, reversal, and formation. 1-4 Activation : Resting bone surface is converted to a remodeling surface during activation of the bone remodeling process. 1-4 Recruitment of osteoclast precursors to the bone and their differentiation into mature, active osteoclasts occurs. 1-4 Resorption phase : Osteoclasts remove both mineral and organic components of bone matrix by generating an acidic microenvironment between the cell and bone surface. 1-4 The resorbing surface has a scalloped, eroded appearance known as Howship’s or resorption lacuna. 2 Reversal phase : Reversal begins once the osteoclasts have resorbed most of the mineral and organic matrix. Apoptosis of osteoclasts occurs in this phase and osteoblasts are recruited to the bone surface. 1-4 Formation phase : The removal of old bone by osteoclasts is followed by replacement with new, healthy osteoid (unmineralized collagen matrix) by osteoblasts. The collagen matrix provides the basic bone structure for mineral (predominantly hydroxyapatite) deposition. During the mineralization phase, these deposits gradually harden into the newly formed matrix, resulting in good quality bone. 1-4 Goldring S. Osteoporosis and Rheumatic Disease. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 5 th ed. Washington, D.C: American Society for Bone and Mineral Research;2003;379-382. Holick MF, et al. Introduction to Bone and Mineral Metabolism. In: Harrison’s Online. Accessed 10/20/2004. Lindsay R, et al. Pathophysiology of bone loss. In: Lobo RA, ed. Treatment of the Postmenopausal Woman: Basic and Clinical Aspects. 2 nd ed. New York, NY:Lippincott Williams & Wilkins 1999:305-314. Baron, R. General Principles of Bone Biology. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 5th ed. Washington, D.C: American Society for Bone and Mineral Research;2003:1-8.
Many different factors can affect osteoclast activity, but RANK ligand is required to mediate or permit their effects on bone resorption. Several factors (eg, parathyroid hormone [PTH], TNF, interleukin [IL]-1) stimulate the expression of RANK ligand by cells of the osteoblast lineage and other cells (eg, activated T cells), resulting in increased bone loss. 1-3 Evidence from gene deletion and other studies indicates that RANK ligand is an essential mediator of osteoclast activity. 1,2 RANK ligand is a key factor regulating osteoclastogenesis and bone resorption. 1,2 Consistent with this are the following observations: Within bone, most receptors for hormones, growth factors, and cytokines are present on osteoblasts rather than osteoclasts, regardless of whether the predominant action of these factors is bone formation or bone resorption. 2 Most osteotropic growth factors, hormones, and cytokines upregulate RANK ligand mRNA expression in osteoblast cell lines and primary cell cultures. 1,2 The anti-osteoclast effects of OPG, the natural endogenous inhibitor of RANK ligand, occur in normal animals and are consistent across various disease models. 2 This reproducibility supports the idea that most osteoclast activating factors act indirectly via RANK ligand. 2 Boyle WJ, et al. Nature. 2003;423:337-342. Kostenuik PJ, et al. C urr Pharm Des. 2001;7:613-635. Hofbauer LC, et al. JAMA . 2004;292:490-495.
Many different factors can affect osteoclast activity, but RANK ligand is required to mediate or permit their effects on bone resorption. Several factors (eg, parathyroid hormone [PTH], TNF, interleukin [IL]-1) stimulate the expression of RANK ligand by cells of the osteoblast lineage and other cells (eg, activated T cells), resulting in increased bone loss. 1-3 Evidence from gene deletion and other studies indicates that RANK ligand is an essential mediator of osteoclast activity. 1,2 RANK ligand is a key factor regulating osteoclastogenesis and bone resorption. 1,2 Consistent with this are the following observations: Within bone, most receptors for hormones, growth factors, and cytokines are present on osteoblasts rather than osteoclasts, regardless of whether the predominant action of these factors is bone formation or bone resorption. 2 Most osteotropic growth factors, hormones, and cytokines upregulate RANK ligand mRNA expression in osteoblast cell lines and primary cell cultures. 1,2 The anti-osteoclast effects of OPG, the natural endogenous inhibitor of RANK ligand, occur in normal animals and are consistent across various disease models. 2 This reproducibility supports the idea that most osteoclast activating factors act indirectly via RANK ligand. 2 Boyle WJ, et al. Nature. 2003;423:337-342. Kostenuik PJ, et al. C urr Pharm Des. 2001;7:613-635. Hofbauer LC, et al. JAMA . 2004;292:490-495.
Many different factors can affect osteoclast activity, but RANK ligand is required to mediate or permit their effects on bone resorption. Several factors (eg, parathyroid hormone [PTH], TNF, interleukin [IL]-1) stimulate the expression of RANK ligand by cells of the osteoblast lineage and other cells (eg, activated T cells), resulting in increased bone loss. 1-3 Evidence from gene deletion and other studies indicates that RANK ligand is an essential mediator of osteoclast activity. 1,2 RANK ligand is a key factor regulating osteoclastogenesis and bone resorption. 1,2 Consistent with this are the following observations: Within bone, most receptors for hormones, growth factors, and cytokines are present on osteoblasts rather than osteoclasts, regardless of whether the predominant action of these factors is bone formation or bone resorption. 2 Most osteotropic growth factors, hormones, and cytokines upregulate RANK ligand mRNA expression in osteoblast cell lines and primary cell cultures. 1,2 The anti-osteoclast effects of OPG, the natural endogenous inhibitor of RANK ligand, occur in normal animals and are consistent across various disease models. 2 This reproducibility supports the idea that most osteoclast activating factors act indirectly via RANK ligand. 2 Boyle WJ, et al. Nature. 2003;423:337-342. Kostenuik PJ, et al. C urr Pharm Des. 2001;7:613-635. Hofbauer LC, et al. JAMA . 2004;292:490-495.
The “vicious cycle” hypothesizes that tumor cells interact with the bone marrow microenvironment to drive bone destruction and tumor growth in a symbiotic relationship. Tumor cells secrete parathyroid-hormone-related peptide (PTHrP), which is the primary stimulator of osteoblast production of RANK Ligand 1 PTHrP induces both the production of RANK Ligand and down-regulates OPG production by osteoblasts, thereby stimulating osteoclastogenesis 2 Other factors produced and secreted by tumor cells (endothelin-1(ET-1), IL-6, prostaglandin E 2 , TNF, and macrophage colony-stimulating factor) also increase the expression of RANK Ligand 1,4 The increased expression of RANK Ligand in the tumor environment leads to increased formation, activation and survival of osteoclasts, and resulting osteolytic lesions 3 Osteolysis (process of bone resorption) then leads to the release of growth factors derived from bone, including: 1,2 transforming growth factor- β (TGF- β ) insulin-like growth factors (IGFs) fibroblast growth factors (FGFs) platelet-derived growth factor (PDGF) bone morphogenetic proteins (BMPs) These factors increase the production of PTHrP or promote tumor growth directly 1 Specifically, the growth factors bind to receptors on the surface of the tumor cells activating autophosphorylation and signaling through pathways involving SMAD (cytoplasmic mediators of most TGF- β signals) and mitogen-activated protein kinase (MAPK) 2 Bone destruction increases local extracellular calcium (Ca 2+ ) concentrations, which have also been shown to promote tumor growth and the production of PTHrP 2 Thus, tumor-cell proliferation and production of PTHrP through the signaling of these pathways is promoted and the cycle continues Roodman GD, N Engl J Med. 2004;350:1655-64. Mundy GR, et al. Nature Reviews Cancer. 2002;2:584-93. Kitazawa S, et al. J Pathol. 2002;198:228–36. Guise TA, et al. Endocrin Rev . 1998;19:18-54.
Many different factors can affect osteoclast activity, but RANK ligand is required to mediate or permit their effects on bone resorption. Several factors (eg, parathyroid hormone [PTH], TNF, interleukin [IL]-1) stimulate the expression of RANK ligand by cells of the osteoblast lineage and other cells (eg, activated T cells), resulting in increased bone loss. 1-3 Evidence from gene deletion and other studies indicates that RANK ligand is an essential mediator of osteoclast activity. 1,2 RANK ligand is a key factor regulating osteoclastogenesis and bone resorption. 1,2 Consistent with this are the following observations: Within bone, most receptors for hormones, growth factors, and cytokines are present on osteoblasts rather than osteoclasts, regardless of whether the predominant action of these factors is bone formation or bone resorption. 2 Most osteotropic growth factors, hormones, and cytokines upregulate RANK ligand mRNA expression in osteoblast cell lines and primary cell cultures. 1,2 The anti-osteoclast effects of OPG, the natural endogenous inhibitor of RANK ligand, occur in normal animals and are consistent across various disease models. 2 This reproducibility supports the idea that most osteoclast activating factors act indirectly via RANK ligand. 2 Boyle WJ, et al. Nature. 2003;423:337-342. Kostenuik PJ, et al. C urr Pharm Des. 2001;7:613-635. Hofbauer LC, et al. JAMA . 2004;292:490-495.
Many different factors can affect osteoclast activity, but RANK ligand is required to mediate or permit their effects on bone resorption. Several factors (eg, parathyroid hormone [PTH], TNF, interleukin [IL]-1) stimulate the expression of RANK ligand by cells of the osteoblast lineage and other cells (eg, activated T cells), resulting in increased bone loss. 1-3 Evidence from gene deletion and other studies indicates that RANK ligand is an essential mediator of osteoclast activity. 1,2 RANK ligand is a key factor regulating osteoclastogenesis and bone resorption. 1,2 Consistent with this are the following observations: Within bone, most receptors for hormones, growth factors, and cytokines are present on osteoblasts rather than osteoclasts, regardless of whether the predominant action of these factors is bone formation or bone resorption. 2 Most osteotropic growth factors, hormones, and cytokines upregulate RANK ligand mRNA expression in osteoblast cell lines and primary cell cultures. 1,2 The anti-osteoclast effects of OPG, the natural endogenous inhibitor of RANK ligand, occur in normal animals and are consistent across various disease models. 2 This reproducibility supports the idea that most osteoclast activating factors act indirectly via RANK ligand. 2 Boyle WJ, et al. Nature. 2003;423:337-342. Kostenuik PJ, et al. C urr Pharm Des. 2001;7:613-635. Hofbauer LC, et al. JAMA . 2004;292:490-495.
This was a phase III, multicenter, international, double-blind, placebo-controlled study in 643 men with prostate cancer and metastatic bone disease Patients were stratified on entry into the study according to the presence or absence of distant metastases at the time of the initial diagnosis of prostate cancer Patients were randomly assigned to receive either 4 or 8 mg ZOMETA or placebo via 5-minute infusion every 3 weeks The 8-mg dose was associated with a rise in serum creatine levels in some patients. Protocol amendments therefore increased the infusion time to 15 minutes and the infusate volume to 100 mL, and reduced the 8-mg dose to 4 mg; the group was thereafter referred to as the 8/4 mg group. No efficacy conclusions were drawn from the 8/4 mg group; however, this group was included in safety analyses Patients were also given supplemental calcium (500 mg) and vitamin D (400 International Units) open-label and instructed to take one dose each day with food to prevent hypocalcemia Core analysis of the study results was at 15 months. Patients who completed the core phase were given the option of continuing to receive study medication for another 9 months and 186 patients elected to continue. Of these, 122 patients completed 24 months of treatment. Final analyses were performed at 24 months
In the presence of low levels of macrophage colony-stimulating factor (M-CSF), Receptor Activator of Nuclear Factor-kappa B (RANK) Ligand is essential for osteoclast formation, function, and survival. 1-4 Osteoclasts are the cells responsible for resorbing bone. Many different factors (e.g., PTH, TNF, IL-1) can lead to bone loss, but they all stimulate the expression of RANK Ligand by cells of the osteoblast lineage and other cells (e.g., activated T cells). 2,5 Maturation of pre-fusion osteoclasts to multinucleated osteoclasts and finally to activated osteoclasts is initiated when RANK Ligand binds to RANK on the preosteoclast and mature osteoclast. 5 In addition to being expressed on osteoclasts and osteoclast progenitors, RANK has been observed on cartilage cells (chondrocytes), mammary gland epithelial cells, and trophoblast cells. 6,7 The RANK Ligand polypeptide is a type II transmembrane protein found on the surface of expressing cells as well as in a proteolytically released (cleaved) soluble form. 3 1. Yasuda H, et al. Proc Natl Acad Sci USA. 1998;95:3597–3602. 2. Fuller K, et al. J Exp Med. 1998;188:997–1001. 3. Lacey DL, et al. Cell . 1998;93:165–176. 4. Lacey DL, et al. Am J Pathol. 2000;157:435-448. 5. Boyle WJ, et al. Nature. 2003;423:337-342. 6. Fata JE, et al. Cell. 2000:103:41-50. 7. Hsu H, et al. Proc Natl Acad Sci USA. 1999:96:3540-3545.
RANK Ligand is expressed (both in a transmembrane and soluble form) from the osteoblast lineage cells. 1 RANK Ligand subsequently binds to RANK on immature and mature osteoclasts. 2 Maturation of pre-fusion osteoclasts to multinucleated osteoclasts and finally to activated osteoclasts is initiated when RANK Ligand binds to its receptor, RANK. The right side of the graphic depicts inhibition of RANK Ligand by naturally occurring osteoprotegerin (OPG). OPG, a member of the tumor necrosis factor (TNF) receptor family, binds to and neutralizes the effects of RANK Ligand, thereby inhibiting bone resorption. OPG is an important inhibitor of the terminal differentiation and function of osteoclasts. OPG acts as a decoy receptor by binding with RANK Ligand, thereby inhibiting osteoclastogenesis and the survival of pre-existing osteoclasts. 1-5 When RANK Ligand is bound and neutralized by OPG, osteoclasts cannot form 5,6 , function 6 or survive 7 . 1. Lacey DL, et al. Cell. 1998;93:165–176 2. Boyle WJ, et al. Nature. 2003;423:337-342. 3. Simonet WS, et al. Cell . 1997;89:309–319. 4. Bekker PJ, et al. J Bone Min Res. 2001;16:348-360. 5. Yasuda H, et al. Proc Natl Acad Sci USA . 1998;95:3597-3602. 6. Fuller K, et al. J Exp Med. 1998;188:997-1001. 7. Lacey DL, et al. Am J Pathol. 2000;157:435-448.
The “vicious cycle” hypothesizes that tumor cells interact with the bone marrow microenvironment to drive bone destruction and tumor growth in a symbiotic relationship. Tumor cells secrete parathyroid-hormone-related peptide (PTHrP), which is the primary stimulator of osteoblast production of RANK Ligand 1 PTHrP induces both the production of RANK Ligand and down-regulates OPG production by osteoblasts, thereby stimulating osteoclastogenesis 2 Other factors produced and secreted by tumor cells (endothelin-1(ET-1), IL-6, prostaglandin E 2 , TNF, and macrophage colony-stimulating factor) also increase the expression of RANK Ligand 1,4 The increased expression of RANK Ligand in the tumor environment leads to increased formation, activation and survival of osteoclasts, and resulting osteolytic lesions 3 Osteolysis (process of bone resorption) then leads to the release of growth factors derived from bone, including: 1,2 transforming growth factor- β (TGF- β ) insulin-like growth factors (IGFs) fibroblast growth factors (FGFs) platelet-derived growth factor (PDGF) bone morphogenetic proteins (BMPs) These factors increase the production of PTHrP or promote tumor growth directly 1 Specifically, the growth factors bind to receptors on the surface of the tumor cells activating autophosphorylation and signaling through pathways involving SMAD (cytoplasmic mediators of most TGF- β signals) and mitogen-activated protein kinase (MAPK) 2 Bone destruction increases local extracellular calcium (Ca 2+ ) concentrations, which have also been shown to promote tumor growth and the production of PTHrP 2 Thus, tumor-cell proliferation and production of PTHrP through the signaling of these pathways is promoted and the cycle continues Roodman GD, N Engl J Med. 2004;350:1655-64. Mundy GR, et al. Nature Reviews Cancer. 2002;2:584-93. Kitazawa S, et al. J Pathol. 2002;198:228–36. Guise TA, et al. Endocrin Rev . 1998;19:18-54.
Forty subjects had responded (uNTx below 50 nM BCE/mM creatinine) up to the time of data cut off. For responders, the duration of response was defined as the time from the first occurrence of uNTx reducing below 50 to the first occurrence of uNTx rising above 50 nM BCE/mM creatinine. For responders who remained below 50 nM BCE/mM creatinine, the duration of response was censored at the time of last evaluation of uNTx. 1 Because more than 50% of responding subjects maintained below 50 in each of the 3 treatment arms, the median cannot be estimated. At the time of data cut off, 30%, 29% and 32% of subjects had uNTx rising above 50 nM BCE/mM creatinine in IV BP, denosumab Q4W, and denosumab Q12W, respectively. 1,2 Suarez T, et al. J Clin Oncol. 2006;24(18S):6S (abstract #8562). Amgen, data on file.
Key Points This was an international, randomized, double-blind, active-controlled trial comparing denosumab with zoledronic acid for the treatment of bone metastases in patients with castration-resistant prostate cancer The primary endpoint was time to first on-study SRE comparing denosumab with zoledronic acid for noninferiority Secondary efficacy endpoints, evaluated only if noninferiority was demonstrated, were superiority tests comparing denosumab and zoledronic acid for time to first on-study SRE and time to first and subsequent SRE(s) (multiple-event analysis) Background Eligible patients were men 18 years old with histologically confirmed prostate cancer and current or prior radiographic evidence of at least one bone metastasis and documented failure of at least 1 hormonal therapy Patients were randomized 1:1 to receive either SC injections of denosumab 120 mg and an IV placebo Q4W, or an IV infusion (lasting no less than 15 minutes) of zoledronic acid 4 mg and an SC injection of placebo Q4W Daily supplementation with calcium and vitamin D was strongly recommended Key exclusion criteria included current or prior IV bisphosphonate or oral bisphosphonate administration to treat bone metastasis References XGEVA™ (denosumab) prescribing information, Amgen. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet . 2011;377:813-822. XGEVA™ PI 2010: 9,14 Fizazi K, et al. Lancet 2011;377: 815,Table 1 Fizazi K, et al. Lancet 2011;377: 815,A,2 XGEVA™ PI 2010: 2,2.1 Fizazi K, et al. Lancet 2011;377: 815,A,1 Fizazi K, et al. Lancet 2011;377: 814,B,1-2 XGEVA™ PI 2010: 9,14 Fizazi K, et al. Lancet 2011;377: 813,Methods Fizazi K, et al. Lancet 2011;377: 815,A,2 XGEVA™ PI 2010: 9,14 Fizazi K, et al. Lancet 2011;377: 814,A,2;B,1 XGEVA™ PI 2010: 2,2.1 Fizazi K, et al. Lancet 2011;377: 815,A,1 Fizazi K, et al. Lancet 2011;377: 814,B,5; 815,A,1 XGEVA™ PI 2010: 3,6.1 Fizazi K, et al. Lancet 2011;377: 814,B,1-2
Key Points A total of 1901 patients were randomized to receive denosumab (n = 950) or zoledronic acid (n = 951) Baseline age, race, and ECOG performance status variables were balanced between groups Background Randomization was stratified by previous SRE, PSA level ( 10 g/L vs 10 g/L), and chemotherapy for prostate cancer within 6 weeks before randomization Patients in the zoledronic acid arm had a slightly longer median time from bone metastases diagnosis to study randomization (denosumab, 3.94 months; zoledronic acid, 5.19 months) although the quartiles were similar Reference Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet . 2011;377:813-822. Fizazi K, et al. Lancet 2011;377: 815,Table 1 Fizazi K, et al. Lancet 2011;377: 815,Table 1
Key Points Protocol-mandated dose adjustments of IV zoledronic acid for baseline creatinine clearance occurred in 213 (22%) patients per the Zometa prescribing information. One hundred forty-three (15%) patients required zoledronic acid doses to be withheld on study for serum creatinine increases per the Zometa prescribing information Reference Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet . 2011;377:813-822. Fizazi K, et al. Lancet 2011;377: 817,B,1; 818,B,1 Fizazi K, et al. Lancet 2011;377: 817,B,1; 818,B,1
Key Points Denosumab significantly delayed the time to first on-study SRE by 18% compared with zoledronic acid (HR = 0.82; 95% CI, 0.71–0.95; P .001 for noninferiority and P = .008 for superiority) 1 The median (95% CI) time to first on-study SRE was 20.7 months in the denosumab group and 17.1 months in the zoledronic acid group, a difference of 3.6 months 1 Between-group divergence is evident beginning at 3 months after initiation of treatment 2 References XGEVA™ (denosumab) prescribing information, Amgen. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet . 2011;377:813-822. XGEVA™ PI, 2010: 11,Table 2 XGEVA™ PI, 2010: 11,Table 2 Fizazi K, et al. Lancet 2011;377: 816,Figure 2 Fizazi K, et al. Lancet 2011;377: 816,Figure 2
Key Points Denosumab significantly delayed the time to first and subsequent on-study SREs (rate ratio = 0.82; 95% CI, 0.71–0.94; adjusted P = .009) 1 A total of 1078 events occurred, 494 in the denosumab treatment group, and 584 in the zoledronic acid treatment group 2 References XGEVA™ (denosumab) prescribing information, Amgen. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet . 2011;377:813-822. XGEVA™ PI, 2010: 11,Table 2 Fizazi K, et al. Lancet 2011;377: 816,Figure 3 Fizazi K, et al. Lancet 2011;377: 816,Figure 3 XGEVA™ PI, 2010: 11,Table 2
Key Point Overall disease progression (HR = 1.06; 95% CI, 0.95–1.18; P = .30) was similar between study groups Reference Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet . 2011;377:813-822. Fizazi K, et al. Lancet 2011;377: 817,Figure 4,B Fizazi K, et al. Lancet 2011;377: 817,Figure 4,B
Key Points Overall survival (HR = 1.03; 95% CI, 0.91–1.17; P = .65) was similar between study groups 1 Overall survival and progression-free survival were similar between arms in all three trials 1 Mortality was higher with denosumab in a subgroup analysis of patients with multiple myeloma (HR = 2.26; 95% CI, 1.13–4.50; n = 180) 2 References Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet . 2011;377:813-822. XGEVA™ (denosumab) prescribing information, Amgen. Fizazi K, et al. Lancet 2011;377: 817,Figure 4,A Fizazi K, et al. Lancet 2011;377: 817,Figure 4,A XGEVA™ PI, 2010: 10-14
Key Points Overall rates of AEs and serious AEs were similar between the two study groups (97% in the denosumab and zoledronic acid groups) The most common AEs were anemia, back pain, decreased appetite, nausea, and fatigue Reference Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet . 2011;377:813-822. Fizazi K, et al. Lancet 2011;377: 818,Table 4 Fizazi K, et al. Lancet 2011;377: 818,Table 4
Key Point The incidence of AEs of interest was similar between the two study treatment groups Background During the first 3 days of treatment, AEs potentially associated with acute phase reactions occurred in 8% of denosumab and 18% of zoledronic acid patients AEs potentially associated with renal impairment occurred in 15% of the denosumab group and 16% of the zoledronic acid group Positively adjudicated ONJ occurred in 22 (2%) patients in the denosumab group and 12 (1%) patients in the zoledronic acid group ( P = .09) AEs of hypocalcemia were reported in 121 (13%) patients in the denosumab group and 55 (6%) patients in the zoledronic acid group New primary malignancies were identified in 18 (2%) patients in the denosumab group and 10 (1%) patients in the zoledronic acid group Reference Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet . 2011;377:813-822. Fizazi K, et al. Lancet 2011;377: 818,Table 4 Fizazi K, et al. Lancet 2011;377: 819,A,3 Fizazi K, et al. Lancet 2011;377: 818,Table 4 Fizazi K, et al. Lancet 2011;377: 819,A,3 Fizazi K, et al. Lancet 2011;377: 818,Table 4
Key Point ONJ occurred infrequently in both treatment groups, and was usually associated with risk factors Background Positively adjudicated ONJ occurred in 22 (2%) patients in the denosumab group and 12 (1%) patients in the zoledronic acid group ( P = .09) A history of tooth extraction, poor oral hygiene, and/or dental appliance utilization was present in 17 (77%) of the patients with ONJ in the denosumab group and 10 (83%) of the patients with ONJ in the zoledronic acid group On-study chemotherapy use was reported by 14 (64%) of patients with ONJ in the denosumab group and nine (75%) of the patients with ONJ in the zoledronic acid group As of April 2010, 10 (45%) patients with ONJ in the denosumab group had undergone limited surgeries and two (9%) had bone resections compared with three (25%) patients in the zoledronic acid group who received limited surgical treatment and one (8%) who underwent bone resection Reference Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet . 2011;377:813-822. Fizazi K, et al. Lancet 2011;377: 818,Table 4 Fizazi K, et al. Lancet 2011;377: 818,B,5 Fizazi K, et al. Lancet 2011;377: 818,B,5; 819,A,1 Fizazi K, et al. Lancet 2011;377: 818,Table 4 Fizazi K, et al. Lancet 2011;377: 818,B,5 Fizazi K, et al. Lancet 2011;377: 818,B,5; 819,A,1
Key Points The results of this study demonstrated that denosumab was superior to zoledronic acid in delaying time to first and subsequent SRE(s) in advanced prostate cancer patients with bone metastases Denosumab had several potentially beneficial characteristics
ZD4054 is a specific endothelin A receptor antagonist with no effect on the B receptor. This means that the beneficial effects of endothelin receptor B mediated apoptosis are unaffected while the endothelin receptor A mediated stimulation of progression, angiogenesis and osteoblasts are blocked.
Although based on only 40 deaths in total, a marked improvement in overall survival was seen.