Introduction
Breast cancer is one of the most common cancers in women. However, the prognosis of breast cancer is good if treated early. In the United States, 90 percent of patients with breast cancer survive. Adjuvant chemotherapy and systemic therapy treat early breast cancer. However, systemic therapy has some toxicities, such as osteoporosis, loss of bone density, the fragility of bone, and susceptibility of bone to fracture. The long-term toxicities need to be prevented, and thus the introduction of osteoclastic inhibitors came into clinical practice. Osteoclastic inhibitors are agents that inhibit the process of osteoclast (bone-eating cells) cells. Bisphosphonates and Denosumab are potent inhibitors that delay the process of the osteoclasts. Therefore, bisphosphonates are effective drugs given intravenously or orally to patients to delay bone morbidity in cancer.
What Is Breast Cancer?
Breast cancer is a type of cancer that develops in the breast tissue. It occurs when the cells in the breast begin to grow uncontrollably, forming a lump or mass known as a tumor. Breast cancer can occur in both men and women, although it is much more common in women.
There are several different types of breast cancer:
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Ductal carcinoma in situ (DCIS) - DCIS is a non-invasive form of breast cancer where the abnormal cells are contained within the milk ducts and have not spread outside of the ducts.
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Invasive ductal carcinoma - Invasive ductal carcinoma and invasive lobular carcinoma are more serious types of breast cancer where the abnormal cells have spread outside of the ducts or lobules and into nearby breast tissue.
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Invasive lobular carcinoma - Invasive lobular carcinoma are also more serious types of breast cancer.
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Inflammatory breast cancer - Inflammatory breast cancer is a rare and aggressive form of breast cancer that causes the breast to become red, swollen, and tender.
Breast cancer is typically diagnosed through a combination of methods, including mammography, ultrasound, and biopsy. Treatment options for breast cancer may include surgery, radiation therapy, chemotherapy, hormone therapy, targeted therapy, or a combination of these approaches, depending on the stage and type of cancer, as well as the patient's overall health and other factors. Early detection and treatment of breast cancer can improve the chances of successful treatment and survival.
What Are Osteoclast Inhibitors?
Metastatic breast cancer in women can cause related skeletal problems such as bone pain, osteoporosis, hypercalcemia, bone fracture, bone weakening, and spinal cord compression. Metastatic breast cancer is a type of cancer that can invade other body parts. Osteoclastic inhibitors are bone-modifying agents used to prevent skeletal-related problems in metastatic breast cancer. Bisphosphonates and Denosumab are osteoclast inhibitors that prevent bone resorption along with an anti-tumor response.
Bisphosphonates are a class of drugs that protect bone. Bisphosphonate is used for the treatment of osteoporosis. Osteoporosis is a condition in which bone becomes weak and fragile, susceptible to fracture. Bisphosphonates prevent bone loss in anti-estrogen therapy that causes skeletal problems. Several studies show the role of bisphosphonate anti-tumor activities. These drugs are used in the management of early breast cancer to prevent cancer-related bone morbidity.
What Is the Mechanism of Osteoclast Inhibitors?
Tumor (a group of abnormally growing cells) cells release cytokines, stimulating osteoclastic activities and causing bone resorption in bony metastasis. Osteoclastic inhibitor inhibits this osteoclastic event. Bisphosphonates prevent skeletal-related events such as bone pain, bone fracture, spinal cord compression, and hypercalcemia (a condition in which calcium levels increase in the blood). Bisphosphonates are pyrophosphate analog that binds to hydroxyapatite mineral present in the bone. Hydroxyapatite is the mineral present in the bone that makes bone rigid and strong.
During Osteoclastic activity, bisphosphonate is released by the cell. The presence of free bisphosphonate in the cell induces internal change that promotes apoptosis (programmed cell death) of osteoclasts. Bisphosphonates block the mevalonate pathway in the cell, which inhibits the signaling process and promotes the inhibition of osteoclastic activities. The exact mechanism of an antitumor role of bisphosphonate is still unclear, but several studies show bisphosphonates inhibit cell migration, invasion, and metastasis. Bisphosphonates are basically of two types:
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Nitrogen-Containing Bisphosphonates - Alendronate, Risedronate, Pamidronate, and Zoledronate.
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Non-nitrogen Containing Bisphosphonates - Clodronate and Etidronate.
What Is the Role of Bisphosphonates in Breast Cancer?
Clodronate administrated orally in patients with breast cancer was found to have a beneficial effect on reducing skeletal reducing events. Another study evaluated the efficacy of Pamidronate in preventing skeletal-reducing events in breast cancer patients who are on hormonal therapy that causes osteolytic events. Studies show that both oral and intravenous Ibandronate at a 6 mg intravenous dose decreases the burden of bone-related problems in metastatic cancer. As a result, bisphosphonates have been shown to improve skeletal-related morbidity in patients with breast cancer. However, Zoledronate is used in the adjuvant role to manage breast cancer. The use of Zoledronate helps in the reduction of disease progression. Several studies concluded that the administration of bisphosphonate therapy reduced the risk of breast cancer recurrence by 34 percent and breast cancer death by 17 percent in post-menopausal (a condition in which the menstrual cycle in women stops permanently) women.
Bisphosphonate prevents bony events in post-menopausal women and treats hypercalcemia induced by systemic therapy of breast cancer. Bisphosphonate gives beneficial oncological results and is considered a primary treatment in early breast cancer.
The use of bisphosphonates in preventing therapy-induced bone loss has been investigated, and studies show the efficacy of Risedronate on patients with breast cancer who had chemotherapy-induced menopause. Risedronate prevented bone loss and increased bone mineral density in patients with breast cancer. The optimum dose for Zoledronate is 4 milligrams intravenously every six months for three years. Studies have concluded that oral and intravenous bisphosphonate therapy has been efficacious in preventing bone loss in patients treated with hormone therapy in breast cancer.
What Are the Adverse Effects of Bisphosphonates?
The long-term treatment for bisphosphonates results in complications. Osteonecrosis of the jaw is the major side effect of bisphosphonates. The tooth extraction process or damage to jaw bone are considered risk factors for jaw osteonecrosis. The withdrawal of potent bisphosphonates is recommended in this case.
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Fever.
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Fatigue.
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Arthralgia (joint pain).
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Gastrointestinal disorders.
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Impaired renal functions.
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Osteonecrosis of the Jaw - Osteonecrosis is a condition characterized by premature tissue death. It is a rare complication seen in 1 percent of patients when administered with high doses of Zoledronate.
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Hypocalcemia- The risk of hypocalcemia is associated with a high dose of bisphosphonate. Hypocalcemia is a condition characterized by a low level of calcium present in the blood. The patient should be monitored regularly for early diagnosis of hypocalcemia. Vitamin D and calcium supplements are suggested for these patients.
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Femur Fracture - Although it is an atypical risk in cancer. But femur fractures are seen in patients who are dependent on bisphosphonate for the long term.
Conclusion
Bisphosphonates are effective in treating skeletal-related morbidity in cancer. In addition, bisphosphonates also act as an antitumor effect in cancer. The risk of recurrence is low in patients treated with bisphosphonates. The benefit of bisphosphonate is more than the adverse effect of it. Proper monitoring of patients on long-term bisphosphonate in breast cancer is recommended for early diagnosis of renal dysfunction. The use of bisphosphonates in breast cancer reduces bone morbidity and enhances disease-survival life for patients.
