Commonality and individuality of bisphosphonates
Principle of action
Bisphosphonates are stable analogs of pyrophosphonate molecules. Osteoclasts accumulate in the mineralized bone matrix and lead to bone resorption through enzymatic hydrolysis, while bisphosphonates inhibit osteoclast-mediated bone resorption. Bisphosphonates inhibit osteoclast maturation, inhibit the function of mature osteoclasts, inhibit the aggregation of osteoclasts at the site of bone resorption, and inhibit the spread, infiltration, and adhesion of tumor cells to the bone matrix.
Indications
1.Hypercalcemia;
2.Bone pain;
3.Treatment and prevention of bone-related events (SREs). Bone related events (SREs) have a critical impact on the quality of life of patients with bone metastases from breast cancer, including pathological fractures, spinal cord compression, radiotherapy to relieve bone pain or prevent and treat pathological fractures or spinal cord compression, skeletal surgery, changes in anti-cancer regimen to treat bone pain, and hypercalcemia due to malignancy. The current use of bisphosphonates in breast cancer bone metastases is aimed precisely at reducing the incidence of SREs.
Clinical studies have confirmed the effectiveness of bisphosphonates in the treatment of bone metastases from breast cancer. As recommended by the UK National Institute for Clinical Recommendations for Treatment Options (NICE), these drugs are now being widely used to treat bone complications of advanced breast cancer. And subsequent clinical studies have demonstrated that bisphosphonates can prevent bone-related events (SREs) in patients with bone metastases from breast cancer. Therefore, breast cancer bone metastases with expected survival ≥ 3 months and creatinine less than 3.0 mg/dL should be promptly treated with bisphosphonates along with the chemotherapy and hormonal therapy required to treat the disease.
The clinical activity and efficacy of bisphosphonates vary depending on the side chain attached to the central carbon atom in the chemical structure of bisphosphonates.
The first generation of bisphosphonates is represented by clodronate, which entered clinical use 30 years ago.
Dosage and Administration: clodronate disodium, oral 1600 mg/day for 3C4 weeks; clodronate disodium is primarily cleared by the kidneys; therefore, it is important to maintain adequate water intake during clodronate disodium therapy clodronate disodium capsules should be swallowed whole. A single daily dose of 1600 mg is recommended; if the daily dose is higher than 1600 mg, the excess is recommended to be administered as a second dose in divided doses. Under no circumstances should clodronate be taken with milk, food or medication containing calcium or other divalent cations as they will reduce the absorption of clodronate.
The second generation are nitrogen-containing bisphosphonates, including disodium pamidronate and alendronate, which have a stronger effect on inhibiting bone resorption than the first generation drugs.
Dosage and administration: pamidronate 60-90 mg iv >2h 1/3C4 weeks;
The third generation is zoledronic acid, a nitrogen-containing bisphosphonate with a heterocyclic structure, and ibandronate, which does not contain a cyclic structure containing nitrogen, which has further improved in terms of strength of action and efficacy than the second generation.
Dosage and Administration.
Zoledronic acid 4 mg iv>15 min for 1 / 3-4 weeks.
Ibandronate 6mg iv>15 minutes for 1 / 3-4 weeks.
1. Ibandronic acid for metastatic bone disease.
Conventional dose: 6mg IV every 3-4 weeks, each IV not shorter than 15 minutes, 1 / 3-4 weeks.
2.Ibandronic acid loading dose (Loading Dose): loading dose of ibandronic acid can provide rapid relief to patients with metastatic bone pain with severe pain, usage: 6mg/day for 3 consecutive days, then 6mg/time every 3-4 weeks.
Ibandronic acid is currently available in two formulations, intravenous and oral. 6mg of Ibandronic acid administered intravenously and 50mg of Ibandronic acid administered orally are comparable in efficacy, and the oral formulation of bisphosphonates is convenient for home use and for use in combination with oral chemotherapy and endocrine drugs.
5.2 Indications and timing of bisphosphonate use.
Expert opinion
Recommend the use of bisphosphonates
The use of bisphosphonates is not recommended
Hypercalcemia due to bone metastases
Bone pain due to bone metastases
Abnormal ECT, X-ray (or CT, or MRI) confirmed bone metastases
Abnormal ECT with normal X-rays, but CT or MRI showing bone destruction
Imaging diagnosis of bone destruction, even without bone pain symptoms
Abnormal ECT with normal X-rays and no bone destruction on CT or MRI
Patients at risk of bone metastasis (high lactate dehydrogenase or elevated alkaline phosphatase)
5.3 The use of bisphosphonates and precautions.
1, before using bisphosphonates, patients should be tested for serum electrolyte levels, focusing on blood creatinine, serum calcium, phosphate, magnesium and other indicators.
2. Clinical studies have shown that the first generation of clodronate, the second generation of pamidronate and the third generation of zoledronic acid and ibandronate, all have the effect of treating bone metastases from breast cancer. All can be used to treat hypercalcemia, bone pain, prevention and treatment of bone metastasis related events. The results of clinical studies have shown that the third-generation bisphosphonates zoledronic acid and ibandronate have the advantages of better efficacy, lower toxicity and more convenient use.
3. The choice of drug therapy should take into account the general condition of the patient and the overall condition of the disease, as well as the concurrent treatment received. Intravenous use of zoledronic acid and ibandronic acid has the advantage of shorter infusion time.
4, Bisphosphonates can be used in combination with radiotherapy, chemotherapy, endocrine therapy and painkillers.
5, long-term use of bisphosphonates should pay attention to the daily supplementation of calcium 500mg and vitamin D.
6.In patients with mild to moderate renal insufficiency (creatinine clearance >30ml/min), no dose adjustment is required, but in patients with severe renal insufficiency (creatinine clearance >30ml/min), dose adjustment should be reduced or infusion time should be extended according to the instructions of different products.
7. In view of the risk of osteonecrosis of the jaw in a few patients after long-term use of bisphosphonates, attention should be paid to oral examination and daily oral cleaning before using bisphosphonates, and oral surgery, including tooth extraction, should be avoided as far as possible during the drug administration.
5.4 Dosing time and discontinuation indications.
1.Duration of medication: It is proved that the median time of bone-related events is 6-18 months when bisphosphonates are used in breast cancer, so the duration of medication should be at least 6 months.
2.Discontinuation indication.
Adverse reactions monitored during use and clearly related to bisphosphonates;
Tumor deterioration during treatment, metastasis to other organs and life-threatening;
When the clinician considers it necessary ;
However, after relief of bone pain with other treatments is not an indication for discontinuation.
5.5 Biochemical markers.
There are some biochemical markers that may help physicians understand the patient’s response to treatment with bisphosphonates – but they are currently limited to the scientific field and are not recommended for clinical use.
5.6 Clinical data and expert opinion.
1. The role of bisphosphonates in preventing bone metastases
Although studies have suggested that bisphosphonates may have a role in preventing bone metastases and may potentially have a role in preventing visceral metastases, clinical studies of bisphosphonates for the prevention of bone metastases are still ongoing. Therefore, but for patients without imaging evidence of bone metastasis, as well as patients with extraosseous metastasis but no evidence of bone metastasis, bisphosphonates are not recommended at present.
2.Biphosphonates as adjuvant therapy after breast cancer surgery
In vitro studies have shown that bisphosphonates have antitumor effects, but clinical studies are still in progress. Although some small sample studies have proved that after standard radiotherapy, chemotherapy and endocrine therapy, the risk of bone metastasis or even visceral metastasis can be reduced by adding bisphosphonates after breast cancer surgery, but large-scale studies have not yet been completed, so bisphosphonates are not recommended as adjuvant therapy after breast cancer surgery at present.
3.Bone loss due to antitumor therapy in breast cancer patients (CTIBL)
Cancer Treatment-induced Bone Loss (CTIBL) is a clinical problem that should be taken seriously and can occur in elderly patients, after chemotherapy, after hormone therapy, especially ovarian suppression and aromatase inhibitor therapy, and according to ASCO bone health guidelines, bone mineral density (BMD) should be measured and The ASCO guidelines recommend routine BMD testing for all patients older than 65 years; or age 60-64 years, but with one of the following risk factors: family history of osteoporosis, weight <70 Kg, previous non-traumatic fracture, or other risk factors. The ASCO guidelines also recommend BMD testing for postmenopausal women regardless of age, as long as they are receiving BMD should be routinely checked in postmenopausal women, regardless of age, who are receiving AI therapy, in premenopausal women, and in patients undergoing treatment that may lead to premature menopause (chemotherapy, ovarian denervation). above -1.0 is not recommended. The use of bisphosphonates for osteoporosis is not the same as for bone metastases, which can be used every 3-6 months, and the dosing should be adjusted according to the change in BMD score after treatment. While breast cancer patients are at risk of osteoporosis due to their age and treatment, physicians should routinely assess the bone health of these women and do not currently recommend the use of bisphosphonates for the prevention of osteoporosis.
4. The question of whether to change medication after a bone-related event to prevent another bone-related event
After some specific bone-related events (high calcium, bone surgery, radiotherapy), the use of bisphosphonates will be stopped as an observation endpoint in clinical studies, but they should not be stopped in clinical practice, but should continue to be used, but after the first bone metastasis aggravated by SRE during the use of a certain type of bisphosphonates, it can be considered to switch to another type of bisphosphonates, and some experts believe that whether the benefit of switching is pending more clinical study data Some experts believe that the benefit of switching needs to be supported by more clinical study data.