Metastatic Bone Disease & Role of Zoledronic Acid
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Metastatic Bone Disease & Role of Zoledronic Acid

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Metastatic Bone Disease is Cancer that begins in an organ, such as the lungs, breast, or prostate, and then spreads to bone. ...

Metastatic Bone Disease is Cancer that begins in an organ, such as the lungs, breast, or prostate, and then spreads to bone.
More than 1.2 million new cancer cases are diagnosed each year. Approximately 50% of these tumours can spread (metastasize) to the skeleton.
With improved medical treatment of many cancers — especially breast, lung, and prostate — patients are living longer. However, the primary cancers in more of these patients are spreading to bone. The tumours that result are called bone metastases.
Here the role of Zoledronic Acid have been fall in place in treatment.

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Metastatic Bone Disease & Role of Zoledronic Acid Metastatic Bone Disease & Role of Zoledronic Acid Presentation Transcript

  • Metastatic Bone Diseases(MBD) Pathophysiology, Treatment Options & Role of Bisphosphonate(Zoledronic Acid) Market InformationsPresenter: Mrinmoy Roy, Medico- Marketing AIC, Philippines
  • Metastatic Bone Diseases(MBD)  Cancer that begins in an organ, such as the lungs, breast, or prostate, and then spreads to bone is called metastatic bone disease (MBD).  More than 1.2 million new cancer cases are diagnosed each year. Approximately 50% of these tumours can spread (metastasize) to the skeleton.  With improved medical treatment of many cancers — especially breast, lung, and prostate — patients are living longer. However, the primary cancers in more of these patients are spreading to bone. The tumours that result are called bone metastases.
  • Organs involved in MBD  The most common cancers that arise from organs and spread to bone include:  Breast  Lung  Thyroid  Kidney  Prostate
  • Pathophysiology of MBD  MBD causes pain in the area of spread, damages and weakens bone, and puts the patient at a greater risk for broken bones. It can make it hard to participate in daily activities.  The biggest concern for patients with MBD is the general loss in quality of life.  How much of an effect MBD has on a patient will vary and is associated with how much the cancer has spread, which bones are affected, and how severe the bone damage is.  There are a range of treatment options, however, that can help patients manage pain and maintain their independence and activity levels.
  • Pathophysiology of MBD cont...  After the lung and the liver, the skeleton is the most common site of spread of cancers that begin in organs. Metastases to the lung and liver are often not detected until late in the course of disease because patients experience no symptoms. In contrast, bone metastases are generally painful when they occur.  Cancer most commonly spreads to these sites in the skeleton:  Spine  Pelvis  Ribs  Skull  Upper arm  Long bones of the leg
  • Bone Damage  Sometimes, the tumour can completely destroy the bone in a particular area. This type of process is termed osteolytic bone destruction. This type of damage is most common in cancers that have spread to bone from the lung, thyroid, kidney, and colon.  Alternatively, new bone can form in response to the cancer spread. This new bone, called osteoblastic, grows abnormally and causes the bone to be weak and deformed. It is more frequently seen in spread of prostate, bladder, and stomach cancer.  Breast cancer often behaves in a mixed osteolytic and osteoblastic manner. Osteolytic and osteoblastic metastatic bone disease occurs because the different cancer cells secrete factors that interact
  • Normal Osteoclastic Functions
  •  Because MBD weakens the affected bones, people with the disease are prone to fractures. Broken bones caused by MBD are termed "pathological fractures."  Sometimes the bone has not yet broken but is so weak that a break is imminent. Such scenarios are termed "impending pathologic fractures." Patients with impending or actual fractures may be forced to remain on bed-rest for long periods of time, which can lead to possible chemical imbalances in the blood such as increased calcium levels (hyper- calcemia).  Patients with cancer that has spread to the spinal bones may develop nerve damage that can lead to paralysis or loss of the use of the legs and/or arms. Effects
  • Symptoms  Pain. The most common symptom of MBD is pain. Patients may have pain in the spine, pelvis, or extremities because the bone has been weakened by the tumour.  Fractures. Weakened bones break more easily. A fracture from a minor injury is another possible sign of MBD.  Anaemia. The most common sites of spread — spine, pelvis, ribs, skull, upper arm, and long bones of the leg — correspond to areas of bone marrow that produce high levels of red blood cells, the cells responsible for carrying oxygen to tissues in the body. Anaemia (decreased red blood cell production) is a common blood abnormality in patients with MBD.  A cancer patient who experiences any pain, especially in the back, legs, and arms, should notify his or her doctor immediately. Pain that occurs without activity (i.e., walking or lifting an object) is particularly concerning.
  • Diagnosis  Medical History and Physical Examination  Doctor will ask questions about the nature of any pain ,current health, and past medical conditions.  Imaging Tests  X-rays.  The x-ray examination can tell an oncologist a great deal of information about whether and how much of the bone is involved.  Other imaging tests: Bone scan is helpful in determining if other bones, in addition to the one in question, are involved with metastatic bone disease. In select cases, a computerized tomography (CT) scan and/or magnetic resonance image (MRI) may be ordered, especially in cases where This x-ray of the upper arm shows a pathological fracture in the humerus (arrow). A technetium bone scan demonstrates extensive bony metastasis throughout the skeleton (arrows).
  •  The diagnosis of metastatic bone disease should not be assumed unless a patient has a known primary cancer that has previously spread to bone.  In adults older than 45 years of age who have no personal history of cancer and who have a bone growth detected in an x-ray, a specialist consultation should be obtained with an orthopaedic surgeon who has formal advanced training in cancer surgery (orthopaedic oncologist).  The orthopaedic oncologist will determine whether this bone tumour is a metastasis from an unknown primary carcinoma or a primary bone cancer (sarcoma).  For example, if an area of bone has been destroyed, the possible diagnoses include metastatic bone disease or a primary bone cancer, such as myeloma or lymphoma. Cancers that begin in bone are much less common in adults older than 45 years. Other diseases, such as Paget's sarcoma, post-radiation sarcoma, hyperparathyroidism, and fractures due to osteoporosis, are also possibilities. Additional tests will likely be needed to determine the exact diagnosis.  A biopsy may be necessary. This involves taking a piece of tissue MBD vs. Primary Bone Cancer
  • Ongoing Tests  Early identification of metastatic bone disease is very important in order for treatment options to be most effective in maintaining quality of life.  Cancer patients should routinely be evaluated with certain blood tests, including a complete blood count, because loss of red blood cells (anaemia) is a frequent finding in metastatic bone disease or multiple myeloma.  Blood chemistries (i.e., electrolytes, calcium, and alkaline phosphatase) may be abnormal in patients with widespread disease. An analysis of the urine (urinalysis) can detect blood, which may be present in patients with renal cell carcinoma. Thyroid function tests, CEA, CA125, and prostate specific antigen (PSA) may be abnormal in patients with specific tumours. Serum and urine protein electrophoresis
  • Final Diagnosis  After the history, physical examination, x-ray and laboratory tests are completed, your doctor will determine whether you have metastatic bone disease.  It is important to point out that many cancer patients have bone pain from certain types of chemotherapy, and that just because you have bone or joint pain, it does not mean that you have MBD. Nevertheless, careful follow up is very important if you are having pain.
  • Treatment Options  Non surgical Treatment a. Radiation I. Local Field Radiation II. Hemibody Radiation III. Radio-isotop Therapy b. Medication Treatment I. Chemotherapy II. Endocrine Therapy III. Bisphosphonates  Surgical Removal of the tumour
  • Bisphosphonates  These drugs help prevent bone damage caused by tumours.They work by interfering with osteoclasts, the cells that are involved in the breakdown of bone.  Bisphosphonates are also used to treat bone pain and elevated calcium levels in the blood (which can cause a variety of uncomfortable and dangerous health problems).
  • Zoledronic Acid  Class of drugs: Bisphosphonate  High affinity for calcium  Binds to bone surfaces  Nitrogen: increased affinity, potency  Prevent bone resorption and remodeling  IV formulations tx for bone resorption 2° metastatic tumors, osteolytic lesions
  • Zoledronic Acid: Common Uses  Prevention and treatment of osteoporosis in postmenopausal women  Increase bone mass in men with osteoporosis  Tx of glucocorticoid-induced osteoporosis  Tx of Paget’s disease of bone  Hypercalcemia of malignancy  Bone metastases of solid tumors  breast and prostate carcinoma; other solid tumors  Osteolytic lesions of multiple myeloma
  • Biologic Actions of Zoledronic Acid  Osteoclastic toxicity  Apoptosis  Inhibited release of bone induction proteins  BMP, ILG1, ILG2  Reduced bone turnover, resorption  Reduced serum calcium*  Hypermineralization*  “sclerotic” changes in lamina dura of alveolar bone * = goal of medicinal use
  • Medical Indication for IV BP  Bone metastasis, hypercalcemia  RANKL-mediated osteoclastic resorption  Multiple myeloma, breast CA, prostate CA  Paracrine-like effect  PTH-like peptide osteoclastic resorption  Small cell carcinoma, oropharyngeal cancers  Endocrine-like effect
  • Pharmacokinetics  Circulating half-life: 0.5-2 hrs  Rapid uptake into bone matrix  30-70% of IV/ dose accumulates in bone  Remainder excreted in urine  Repeated doses accumulate in bone  Removed only by osteoclast- mediated resorption  “Biologic Catch 22”
  • Side effects  Fatigue, anaemia, muscle aches, fever, and/or swelling in the feet or legs.  Flu-like symptoms are commonly experienced after the first zoledronate infusion, although not subsequent infusions, and are thought to occur because of its potential to activate human γδ T cells (gamma/delta T cells).  Risk of severe renal impairment. Appropriate hydration is important prior to administration & adequate calcium and vitamin D intake prior to Zoledronate therapy in patients with pre-existing hypocalcaemia.  Monitor for other mineral metabolism disorders; avoid invasive dental procedures for those who develop osteonecrosis of the jaw.
  • Contraindications  Poor renal function (e.g. CrCl<30 mL/min)  Hypocalcaemia  Pregnancy  Paralysis
  • Complications A rare complication that has been recently observed in cancer patients being treated with bisphosphonates is osteonecrosis of the jaw. This has mainly been seen in patients with multiple myeloma treated with zoledronate who have had dental extractions.
  • Dosage & Administration  Only available in IV preparation  Approved for tx of hypercalcemia of malignancy  4mg IV over no less than 15 mins
  • Evidence Zoledronic Acid in Metastatic Bone Diseases  Effective in the prevention of complications of bone metastases in breast cancer and multiple myeloma  Zoledronate is effective in prostate cancer, Zoledronate was tested and showed efficacy in other tumour types such as lung, renal, colorectal, and bladder cancer  Benefit-risk profile is well established, with known, manageable renal adverse events  Recommended in ASCO guidelines for the management of multiple myeloma and metastatic breast cancer patients with bone lesions*, † Hillner, et al. J Clin Oncol. 2003;21:4042-4057. † Berenson, et al. J Clin Oncol. 2002;20:3719-3736.
  • Efficacy of Zoledronic Acid vs Placebo in Advanced Prostate Cancer
  • A American Society of Clinical Oncology
  • Research  Zoledronic acid has been found to have a direct antitumour effect and to synergistically augment the effects of other antitumor agents in osteosarcoma cells.  With hormone therapy for breast cancer  An increase in Disease-Free Survival (DFS) was found in the ABCSG-12 trial, in which 1,803 premenopausal women with endocrine-responsive early breast cancer received anastrozole with zoledronic acid. A retrospective analysis of the AZURE trial data revealed a DFS survival advantage, particularly where estrogen had been reduced.
  • Hormone Therapy for Breast Cancer: ABSCG-12
  • AZURE: Direct Antitumour effect of Zoledronic Acid
  • Meta-Analysis  In a meta-analysis of trials where upfront zoledronic acid was given to prevent aromatase inhibitor- associated bone loss, active cancer recurrence appeared to be reduced.  The results of clinical studies of adjuvant treatment on early-stage hormone-receptor-positive breast- cancer patients under hormonal treatment - especially with the bisphosphonate zoledronic acid - caused excitement because they demonstrated an additive effect on decreasing disease relapses at bone or other sites.
  • Clinical Trials  A number of clinical and in vitro and in vivo preclinical studies, which are either ongoing or have just ended, are investigating the mechanisms and antitumoral activity of bisphosphonates.  Ongoing large trials testing bisphosphonates as adjuvant treatment of breast cancer include NSABP B-34, the NATAN trial,and SWOG-S0307.  A 2010 review concluded that "adding zoledronic acid 4 mg intravenously every 6 months to endocrine therapy in premenopausal women with hormone receptor-positive early breast cancer ... is cost- effective from a US health care system perspective."
  • Zoledronic acid & Endocrine therapy in premenopausal women with hormone receptor-positive early breast cancer
  • MBD Incidence in Philippines  Cancer is the 3rd leading cause of morbidity and mortality in the Philippines.  Leading cancer sites/types are lung, breast, cervix, liver, colon and rectum, prostate, stomach, oral cavity, ovary and leukaemia.  1 out of 13 Filipino women will develop breast cancer in her lifetime. The province of Pampanga has the highest incidence rate in the entire country.  The Philippines has the highest incidence rate of breast cancer in Asia and registered the highest increase of 589% among 187 countries over a 30 year period from 1980 to 2010.  There is high-incidence of thyroid cancer in the country. With an estimated 2500 new cases diagnosed every year, thyroid cancer ranks seventh as the leading type of cancer among Filipinos. It is five times more prevalent among women than in men and more predominantPhilippine Society of Nuclear
  • Philippines Generic Name Brand Name Company Indication Dosage Price Zoledroni c Acid Zometa Novertis Healthcare (Zuellig) Pathological Fractures, Spinal Compression, Radiation or Surgery to Bone or Tumour induced Hypercalcemia, Advanced Malignancies involving Bone 4 mg IV Infusion every 3-4 weeks Pwd for Inj (vial) 4mgx1’s (P17,618.75 ) Infusion conc (vial) 4mg/5mlx1’ s (P15,731.03 ) Zoledroni c Acid Zoletali s Pan-Ject Pharma (Vitalis) Pathological Fractures, Spinal Compression, Radiation or Surgery to Bone or Tumour induced Hypercalcemia, Infusion(vial ) 4mg/5mlx1’ s NA
  • Anti MBD Market in Philippines SL No Generic Name Brand Name Compan y YTD 2010 YTD 2011 YTD 2012 1 Zoledronic Acid Zometa Novartis (Zuellig) 93,678,23 4 php 94,354,718 php 97,076,186 php 2 Denosum ab XGEVA GSK (Zuellig) NA NA 3,457,800 php