I. Overview
In patients with advanced breast cancer, the incidence of bone metastases is 65%-75%, and the first bone metastases account for 27%-50%. Bone related events (SREs) such as bone pain and bone injury are common complications of breast cancer metastases and seriously affect patients’ quality of life.
SREs are defined in clinical studies as increased bone pain or new bone pain, pathologic fractures (vertebral fractures, non-vertebral fractures), vertebral compression or deformation, spinal cord compression, post-radiotherapy symptoms (due to bone pain or prevention of pathologic fractures or spinal cord compression) and hypercalcemia. These are the main factors that affect the patient’s ability of autonomous activity and quality of life.
II. Diagnostic methods of bone metastasis
Bone radionuclide scan (ECT) is the most commonly used method for initial screening of bone metastases. It has the advantages of high sensitivity, early detection of abnormal bone metabolic foci and whole-body imaging. However, it also has the disadvantages of low specificity, cannot indicate osteogenic or osteolytic lesions, and cannot show the extent of bone destruction.
Bone ECT is recommended for routine screening of breast cancer with bone pain, pathological fracture, elevated alkaline phosphatase or hypercalcemia, and for routine examination of patients with locally advanced breast cancer (T3N1M0 or higher) and recurrent metastatic breast cancer.
Bone X-ray, CT scan and magnetic resonance imaging (MRI) are the main diagnostic imaging methods for bone metastases. For patients with abnormal bone ECT scans, X-ray, CT, and MRI should be performed for suspected bone metastases to determine whether there is bone destruction and to understand bone stability.
X-ray plain film is the basic method for bone metastasis diagnosis, which has the advantages of visualization and high diagnostic specificity, but also has the disadvantage of low sensitivity. Bone CT scan is the most important imaging method for the diagnosis of bone metastases, which is more sensitive for the diagnosis of bone cortical destruction, with high sensitivity and specificity, and can distinguish osteolytic or osteogenic changes. x-ray and CT can be used to evaluate the efficacy of treatment of bone metastases.
MRI scans are highly sensitive for the diagnosis of bone metastases and are accurate in indicating the extent of lesion invasion, but are less specific than CT. However, the special imaging principle of MRI makes it possible to diagnose false positives, so MRI abnormalities alone cannot diagnose bone metastases.
Positron emission computed tomography (PET/CT) can detect the abnormal signal of bone metastasis at the early clinical stage with high sensitivity and specificity. However, the panel believes that the value of PET/CT in the diagnosis of bone metastases needs further study and is not routinely recommended in clinical practice.
Bone biopsy is the gold standard for the diagnosis of bone metastases from breast cancer. For clinically suspicious bone metastases, especially those single bone lesions without soft tissue metastases or visceral metastases, puncture biopsy should be pursued for definite pathological diagnosis.
Biochemical indicators of bone metabolism may suggest the diagnosis as well as for dynamic testing of the treatment process, but they are not yet recommended as a method of bone metastasis diagnosis and clinical routine.
In conclusion, for the clinical diagnosis of bone metastasis of breast cancer, ECT can be used as a primary screening test, X-ray and CT can clarify the presence of bone destruction, MRI can help to understand the impact of bone metastasis on surrounding tissues, especially the stability of the spine, and the value of PET/CT needs further study.
Clinical manifestations of breast cancer bone metastasis
In some patients, the repair of osteolytic lesions after treatment can be misdiagnosed as osteogenic changes due to excessive calcification in the imaging.
The characteristics of breast cancer bone metastasis: bone metastasis with pain seriously affects patients’ quality of life, but bone metastasis itself does not directly threaten patients’ lives; there are many effective treatments, and patients without combined visceral metastasis have a relatively long survival.
IV. Treatment of bone metastases
(I) Treatment goals
The main goals of comprehensive treatment of breast cancer bone metastases are
(1) Prevention and treatment of SREs;
(2) To relieve pain;
(3) To restore function and improve quality of life;
(4) control tumor progression and prolong survival.
(II) Treatment options
Breast cancer bone metastasis is already a systemic disease, and the treatment options available include.
(1) chemotherapy and targeted therapy;
(2) Bisphosphonate therapy;
(3) surgical treatment;
(4) Radiation therapy;
(5) Analgesia and other supportive treatments such as endocrine therapy. Physicians should develop an individualized and comprehensive treatment plan according to the patient’s specific condition.
(C) Treatment principles
Breast cancer bone metastasis as recurrent metastatic disease should be treated mainly by systemic therapy, and chemotherapy, endocrine therapy and molecular targeted therapy should be selected according to the principle of classification therapy. Bone modifying drugs, including bisphosphonates, have become the basic treatment to prevent and treat SREs. reasonable local treatment can better control the symptoms of bone metastases, among which surgery is an active means to treat single bone metastases and radiation therapy is an effective local treatment.
The choice of systemic therapy for recurrent metastatic breast cancer is based on the hormone receptor status [estrogen receptor/progesterone receptor (ER/PR)], human epidermal growth factor receptor 2 (HER-2) results, age, menstrual status, and the rate of disease progression of the patient’s tumor tissue. In principle, endocrine therapy is preferred for patients with hormone-responsive breast cancer with slow disease progression, chemotherapy is preferred for patients with recurrent metastases with rapid disease progression, and anti-HER-2 agents such as trastuzumab and lapatinib should be considered for patients with HER-2 overexpression.
Characteristics of recurrent metastatic breast cancer with slow progression.
(1) ER-positive and/or PR-positive tumor tissue at the primary and/or recurrent metastases.
(2) Patients with recurrent metastases who have a long postoperative disease-free survival (e.g., recurrent metastases after 2 years postoperatively).
(3) Visceral metastases with soft tissue and bone metastases only or without obvious symptoms (e.g. non-diffuse pulmonary and liver metastases, other visceral metastases with modest tumor load that are not life-threatening).
For hormone-responsive breast cancer, patients should be defined as suitable for endocrine therapy based on the patient’s potential benefit from endocrine therapy, and patients who meet one or more of the following criteria are considered likely to benefit from endocrine therapy: positive ER and/or PR at the primary site and/or recurrent metastases; elderly patients; long disease-free postoperative interval; and previous benefit from endocrine therapy.
(IV) Endocrine therapy and chemotherapy
1. Endocrine therapy: Since bone metastases of breast cancer do not pose a direct threat to life and patients without combined visceral metastases have a relatively long survival, unnecessary combination chemotherapy should be avoided as much as possible. For patients with advanced breast cancer, if the disease remains stable for a long time after treatment, it should be considered as a clinical benefit, because the survival of patients with stable disease for more than 6 months is the same as that of patients in clinical remission (CR +PR). As endocrine therapy is more suitable for long-term use, the duration of treatment can be maximized in order to prolong disease control.
For postmenopausal recurrent metastatic breast cancer, the first choice of first-line endocrine therapy for failure of triamcinolone acetonide (TAM) therapy is third-generation aromatase inhibitors (AI), including anastrozole, letrozole, exemestane, and AI is preferred for failure of TAM adjuvant therapy, while patients who fail AI adjuvant therapy can be treated with fulvestrant, and failure of non-steroidal AI therapy can be replaced by steroidal AI, or steroidal AI combined with everolimus.
Premenopausal patients can choose chemotherapy, but for patients who are suitable for endocrine therapy, the strategy of choosing endocrine therapy is preferred. Compared with the choice of chemotherapy, patients who benefit from endocrine therapy once the disease remission time is long and patients have better quality of life. Premenopausal patients can adopt the strategy of postmenopausal patients based on ovarian function suppression, and ovarian function suppression combined with AI is preferred.
2. Chemotherapy: Patients with bone metastases from breast cancer, such as those with negative ER and PR, short disease-free postoperative interval, rapid disease progression, combined with visceral metastases, and those who do not respond to endocrine therapy should consider chemotherapy. The recommended drugs for chemotherapy of metastatic breast cancer include: anthracyclines, paclitaxel, cabergoline, vincristine and gemcitabine.
The following chemotherapy regimens are available: anthracycline combined with cyclophosphamide (AC), anthracycline combined with paclitaxel (AT), cabitabine combined with docetaxel (XT), and gemcitabine combined with paclitaxel (GT). Patients treated with adjuvant therapy with endocrine therapy only and no chemotherapy can choose the AC regimen. Patients who have not been treated with anthracycline and paclitaxel chemotherapy for adjuvant therapy may choose the AT regimen, such as patients who have failed CMF adjuvant chemotherapy.
Patients who have failed adjuvant anthracycline therapy. The options are XT and GT regimens. Patients who have failed paclitaxel therapy, for whom there is no standard regimen recommendation, may consider agents such as cabitabine, vincristine, gemcitabine and platinum, either as single agents or in combination with chemotherapy. Patients who benefit from combination chemotherapy can be considered for maintenance therapy. However, patients with bone metastases alone should try not to use combination chemotherapy.
(E) Radiation therapy
Radiation therapy is an effective method for palliative treatment of breast cancer bone metastases. The goal of radiation therapy for patients with bone metastases is to prevent or alleviate symptoms or functional impairment brought about by bone metastatic lesions within the survival time of tumor patients. Bone pain is a common symptom of bone metastases and one of the main reasons affecting patients’ quality of life and mobility. The risk of pathologic fractures in weight-bearing areas such as the spine and femur is about 30%. Pathological fracture will significantly affect the quality and duration of survival of patients.
The main role of radiotherapy in the treatment of breast cancer bone metastases is to relieve bone pain and reduce the risk of pathological fracture, and the combination with antitumor therapies including bisphosphonates and molecularly typed drugs can effectively increase the effectiveness of treatment.
External irradiation using high-energy radiation to target localized lesions of bone metastases is a common and effective method of palliative treatment of bone metastases. Effective external irradiation can achieve symptomatic remission in 50-80% of patients with bone metastases, and complete remission in nearly one-third of patients, and can be maintained for varying time periods. The main indications for external irradiation are: symptomatic bone metastases for pain relief and restoration of function; and selective prophylactic radiotherapy for weight-bearing bone metastases, such as spinal or femoral metastases.
The commonly used doses and fractionation methods for external irradiation are: 40Gy/20F/4w, 30Gy/10F/2w, 20Gy/4F/2w, 23Gy/4F/3w, 8Gy/F, etc. Based on the extensive literature finding similar symptom relief rates with the above split-dose regimens, long courses of more than 2 weeks are not recommended in principle as palliative radiotherapy for bone metastases, unless the metastatic site is adjacent to a vital organ and a relatively low split dose is desired to mitigate the late response of normal tissue.
Single 8Gy radiotherapy regimens are significantly less expensive to treat than fractionated irradiation, but recurrent symptoms require reirradiation, and the incidence of radiotherapy and pathologic fractures is higher than fractionated radiotherapy, and is generally appropriate for advanced patients with difficulty in mobility and lifting.
Special highly conformal radiotherapy techniques such as stereotactic radiotherapy have the advantage over conventional radiotherapy in that they can provide rapid dose drop distribution and achieve better protection of critical organs adjacent to metastases. Therefore, the main indications are spinal metastases, and it is more advantageous in patients who need retreatment due to recurrent symptoms. The application of precise irradiation technique requires higher stability of body fixation and rationalization of target area outlining, so it must be implemented carefully under strict quality control.
Surgical treatment of bone metastases, especially kyphoplasty and vertebroplasty for spinal metastases can rapidly increase spinal stability in the short term and is not a contraindication to palliative radiotherapy, but there is a lack of sufficient clinical data on the timing of both to form a consensus.
Radionuclide therapy, commonly referred to as “internal radiation”, involves the intravenous injection of highly osteophilic isotope drugs to exert a certain anti-tumor effect in the bone metastases through the bioabsorbable dose of the decaying isotope drugs.
Nuclear therapy can generally play a certain role in relieving osteolytic lesions, and it is most suitable for patients whose bone metastases are too widely distributed, so that external irradiation is difficult to achieve one by one on the symptomatic parts. , and should be used with clinical caution.
Although radiotherapy is an important local treatment to relieve symptomatic bone metastases, it cannot replace bisphosphonate therapy because it can show symptom relief only when it exerts anti-tumor effects and achieves a certain degree of bone repair through radiation. In patients who do not achieve clear symptomatic relief or whose pain cannot be completely controlled by treatment, pain medication is also still required according to the three-step principle.
(vi) Surgical treatment
The purpose of surgical treatment of bone metastases is to improve patients’ quality of life. Advances in bone surgery technology can maximize the solution to the problems of bone strength loss, pathological fracture and tumor compression of nerves in patients with cancer bone metastases, and can reduce pain and restore limb function, thus improving patients’ quality of life.
Patients with bone metastases should be closely followed up and observed to detect bone metastases at an early stage, make appropriate judgment on whether long bones with potential pathological fractures need surgery, and strive for effective surgical treatment before fracture and paraplegia to effectively improve patients’ quality of life.
Surgical treatment of bone metastases from breast cancer includes: simple internal fixation, lesion removal plus internal fixation, lesion removal plus artificial joint replacement, decompression after spinal cord compression and reconstruction of spinal stability.
Fixation therapy may be considered selectively for the treatment of patients with bone metastases from breast cancer with pathological fractures or decompression due to spinal cord compression with an expected survival time of >3 months. Prophylactic fixation may be considered electively for patients with bone metastases from breast cancer with femoral metastases >2.5 cm in diameter, or femoral neck metastases, or bone cortical destruction >50%, with an expected survival time >3 months. The panel recommends timely involvement of an orthopedic surgeon in deciding the timing of surgery.
Factors considered in the development of the surgical treatment plan: predicted sensitivity of radiotherapy and hormonal therapy, time to onset of action; tumor type and staging of chemotherapy; risk of pathologic fracture, spinal cord compression or compression; spinal instability, intractable pain; patient expected to survive more than 3 months; systemic condition to tolerate surgery and anesthesia (Karnofsky or Burchenal score); good local surgical conditions (soft tissue and bone); isolated bone metastases/absence of visceral metastases; metastases and time to metastases; better quality of life before surgery.
(vii) Analgesic drug therapy
Pain medication is the main method to relieve the pain of breast cancer bone metastases. The pain medication for bone metastasis pain should follow WHO cancer three step pain relief guideline: preferred oral and non-invasive route of administration; administered by step; administered on time; individualized administration; and attention to specific details.
Analgesic drugs include NSAIDs, opioid analgesics, and adjuvant drugs.
Commonly used NSAIDs include: acetaminophen, ibuprofen, diclofenac sodium, indomethacin, naproxen, celecoxib, cronoxicam, etc.
Commonly used opioid analgesics include: morphine extended-release tablets, fentanyl transdermal patches, oxycodone controlled-release tablets, morphine immediate release tablets, codeine, methadone, etc. Pethidine should not be used for cancer pain treatment.
Adjuvant drugs include tricyclic antidepressants, anticonvulsants, neuroleptics, glucocorticoids, etc.
Non-steroidal anti-inflammatory drugs are the basic drugs for pain management of bone metastasis pain. When the pain relief effect is not good or moderate to severe pain occurs, the combination of opioid analgesics is recommended. The choice of opioid extended-release agents for on-time dosing facilitates sustained bone pain relief. However, approximately 63% of patients with painful bone metastases have sudden onset (flare-up) pain in conjunction with ongoing chronic pain.
For patients with frequent episodes of sudden pain, relief can be achieved by increasing the dose of pain medication on schedule. In a minority of patients, the pain cannot be controlled by increasing the dose of pain medication on schedule, or even by increasing the dose of pain medication on schedule because of intolerable adverse drug reactions. The primary method of controlling sudden onset pain is to use a single dose of a rapid-acting or short-acting analgesic at 5% to 10% of the daily dose.
For patients with refractory sudden onset pain, patient-controlled drug pumping may be considered. In case of neuropathic pain, adjuvant medication should be selected according to the condition. For example, if burning pain or cramping pain is present, tricyclic antidepressants such as amitriptyline, nortriptyline or doxepin may be combined; if electric shock-like pain or shooting pain is present, anticonvulsants such as gabapentin or carbamazepine may be combined. Analgesics can be combined with bisphosphonates, radiotherapy and other methods.
V. Expert consensus on the clinical application of bone modification drugs for breast cancer
(I) Commonality and individuality of bisphosphonates
1. Principle of action.
Bisphosphonates are stable analogues of pyrophosphonate molecules. Osteoclasts gather in mineralized bone matrix and lead to bone resorption through enzymatic hydrolysis, while bisphosphonates can inhibit osteoclast-mediated bone resorption, 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.
2.Indications.
(1) Hypercalcemia;
(2) Bone pain;
(3) Treatment and prevention of SREs.
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 to prevent and treat pathological fractures or spinal cord compression, skeletal surgery, changes in anti-cancer regimens to treat bone pain, and hypercalcemia due to malignancy. The current use of bone-modifying drugs in breast cancer bone metastases is primarily aimed at treating and preventing SREs, reducing antitumor therapy-induced bone loss (CTIBL), and increasing bone mineral density (BMD).
Clinical studies have confirmed that bisphosphonates are effective 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 in advanced breast cancer. And subsequent clinical studies have demonstrated that bisphosphonates can prevent the development of SREs in patients with bone metastases from breast cancer.
Therefore, if the expected survival of breast cancer bone metastasis is ≥3 months and creatinine is less than 3.0 mg/dl, bisphosphonates should be given promptly along with chemotherapy and hormonal therapy required for the treatment of the disease.
3, clinical use and use: the side chains connected with the central carbon atom in the chemical structure of bisphosphonates are different, and the clinical activity and efficacy of bisphosphonates are also different.
The first generation of bisphosphonates is represented by disodium clodronate, and these drugs entered clinical use 30 years ago. Dosage and Administration: Disodium clodronate is currently available in two formulations: intravenous and oral. The oral bisphosphonate formulation is convenient for home use and for use in combination with oral chemotherapy and endocrine drugs.
Clinically, clodronate disodium 400 mg/d intravenously for 3 days, followed by clodronate disodium 1600 mg/d orally for 3-4 weeks as one cycle. Disodium clodronate is primarily cleared by the kidneys; therefore, it is important to maintain adequate water intake during disodium clodronate therapy. Disodium clodronate capsules should be swallowed whole. Under no circumstances should clodronate be taken with milk, food or medications containing calcium or other divalent cations, as they will reduce the absorption of clodronate.
The second generation are nitrogen-containing bisphosphonates. These include disodium pamidronate and alendronate, which have stronger in vitro activity than the first generation drugs in inhibiting bone resorption. Dosage and administration: Pamidronate is administered intravenously at 60-90 mg per dose for no less than 2h every 3-4 weeks.
The third-generation drugs are zoledronic acid, a nitrogen-containing bisphosphonate with a heterocyclic structure, and ibandronate, a nitrogen-containing drug without a cyclic structure, which have further improved their strength and efficacy compared with the second-generation drugs. Dosage and administration: Zoledronic acid 4 mg, intravenous infusion >15 min. every 3-4 weeks. Ibandronate 6 mg intravenously for >15 min. every 3-4 weeks.
(1) Ibandronic acid for metastatic bone disease: regular dose of 6 mg every 3-4 weeks by intravenous infusion for not less than 15 min.
(2) Loading dose of ibandronate: loading dose of ibandronate can provide rapid relief to patients with metastatic bone pain with severe pain.
Ibandronic acid is available in two kinds of formulations: intravenous 6 mg and oral 50 mg, while the oral formulation can be used at home or in combination with oral chemotherapy and endocrine drugs.
(B) Indications for the use of bone modifying drugs and timing of drug administration
A single randomized clinical study suggests that denosumab (denosumab) 120 mg administered subcutaneously every 4 weeks can also be considered for those who need bisphosphonate therapy for breast cancer bone metastases. Because of the convenience of subcutaneous injection and the absence of routine monitoring of renal function during treatment, denosumab offers a new treatment option for patients with bone metastases. Clinical studies are currently underway in mainland China.
Each bone-modifying drug cannot be used in combination with other types of bone-modifying drugs.
(C) The use of bone modifying drugs and precautions
1.Before using bisphosphonates, patients’ serum electrolyte levels should be tested, focusing on blood creatinine, serum calcium, phosphate, magnesium and other indicators.
Clinical studies have shown that the first-generation clodronate, second-generation pamidronate and third-generation zoledronic acid and ibandronate are all useful in the treatment of bone metastases from breast cancer and can be used to treat hypercalcemia, bone pain, prevention and treatment of SREs. 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 and 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 in combination therapy should be supplemented with calcium and vitamin D daily at a dose of calcium 1200-1500 mg/d and vitamin D3 400-800 IU.
6.In patients with mild to moderate renal insufficiency (creatinine clearance > 30 ml/min), no dose adjustment is required, but in patients with severe renal insufficiency (creatinine clearance ≤ 30 ml/min), the dose should be adjusted or the infusion time should be extended according to the instructions of different products. Patients with creatinine clearance < 30 ml/min or on dialysis should be closely monitored while receiving denosumab to prevent the occurrence of hypocalcemia.
7. In view of the risk of osteonecrosis of the jaw in a few patients after long-term use of bisphosphonates as reported in the literature, oral examination should be performed before the use of bisphosphonates, appropriate prophylactic treatment should be carried out, daily oral cleaning should be paid attention to during the use of the drug, and oral surgery, including tooth extraction, should be avoided as much as possible. If maxillofacial bone exposure and failure to heal occur during medication without causation or after oral surgery, contact a specialist for treatment as soon as possible.
(IV) Medication timing and discontinuation indications
1.Duration of medication.
Studies have shown that bisphosphonates have been used in metastatic breast cancer for more than 2 years, so the recommended duration of drug use in clinical practice can be 2 years or even longer, but a reasonable duration of drug use should be adopted according to patient safety and clinical benefit.
The recommended duration of bisphosphonate use varies depending on the purpose of treatment for bone metastases and bone loss: 2 years is recommended for breast cancer patients with bone metastases, with dosing once every 3-4 weeks, but continued use should be encouraged in clinical practice when safe and effective. For the prevention of bone loss due to CTIBL in breast cancer patients, the recommended duration is 5 years with 2 doses per year.
Bisphosphonates may sometimes be the only systemic drug retained after discontinuation of chemotherapy in patients with bone metastases, and the interval between doses may be extended during maintenance therapy.
2. Indications for discontinuation.
(1) Adverse reactions monitored during use and clearly related to bisphosphonates.
(2) Tumor deterioration, metastasis to other organs and life-threatening during the course of treatment.
(3) When deemed necessary by the clinician.
(4) It should be noted that the remission of bone pain after other treatments is not an indication for drug discontinuation.
(E) The role of bone biochemical markers
Bone biochemical markers can reflect the rate of bone resorption and formation during bone metastasis and indicate the extent of bone destruction and repair. Studies have shown that the levels of bone markers at baseline and on treatment [e.g., levels of the bone resorption marker type I collagen N-terminal peptide (NTX), and the osteogenic marker bone specific alkaline phosphatase (BAP)] correlate with the prognosis of patients with bone metastases.
A retrospective analysis of 2-year survival data from breast cancer patients treated with zoledronic acid showed that patients with high NTX normalization at baseline after 3 months of zoledronic acid treatment had a lower risk of death than those who failed to normalize, suggesting that NTX normalization with zoledronic acid treatment may improve patient survival. However, this result has yet to be confirmed by further prospective, randomized clinical trials. Bone markers are currently used as reference indicators in bisphosphonate therapy for breast cancer, and the panel does not recommend their routine clinical use.
(vi) The question of whether to change drugs after the occurrence of SREs to prevent the reoccurrence of SREs
If some specific SREs (hypercalcemia, bone surgery, radiotherapy) occur during the application of phosphonates, the use of such drugs will be discontinued as an observational endpoint in clinical studies, but they should not be discontinued in clinical practice and should be continued.
If SREs occur during bisphosphonate therapy, a switch to another bisphosphonate may be considered. In a phase II trial, patients with bone metastases from breast cancer (n=31) who experienced SREs or progression of bone metastases during treatment with first- and second-generation bisphosphonates (clodronate, pamidronate) and switched to zoledronic acid showed a significant reduction in pain at week 8 (P<0.001) and a trend toward lower urinary NTX levels (P=0.008). However, it is believed that the benefit of switching is yet to be confirmed by more clinical study data.
(vii) Antitumor therapy-induced bone loss (CTIBL)
CTIBL is a problem that should receive clinical attention. It can occur in patients of different ages after chemotherapy, hormonal therapy especially ovarian function suppression and aromatase inhibitor therapy. The American Society of Clinical Oncology (ASCO) guidelines for bone health in women with breast cancer recommend that all women with breast cancer should be evaluated for osteoporosis risk.
Patients at high risk include those over 65 years of age, 60-64 years of age but with one of the following risk factors: family history of osteoporosis, weight <70 kg, previous non-traumatic fracture or other risk factors for pathological fracture due to osteoporosis, postmenopausal women being treated with aromatase inhibitors, premenopausal women being treated with treatments that may lead to early menopause (chemotherapy, ovarian denervation).
During adjuvant treatment for breast cancer, bisphosphonate therapy should be initiated when the BMD score (T-Score) is below -2.5; bisphosphonates should be considered when the T-Score is between -2.5 – -1.0; bisphosphonates are not recommended when the T-Score is above -1.0. The use of bisphosphonates for osteoporosis is not the same as for bone metastases, but can be used every 3-6 months and adjusted according to changes in BMD scores after treatment.
Three large clinical studies-Z-FAST, ZO-FAST and E_ZO_FAST-looked at the role of zoledronic acid in preventing bone loss caused by endocrine therapy for breast cancer. The results showed that early application of zoledronic acid in patients receiving adjuvant letrozole therapy significantly increased lumbar spine and hip BMD compared to delayed therapy, suggesting that zoledronic acid 4 mg every 6 months administered concurrently with aromatase inhibitor therapy in breast cancer patients is effective in preventing CTIBL.
The ABCSG-12 study in premenopausal women with breast cancer, treated with pharmacologic ovarian denervation in combination with triamcinolone or anastrozole, treated with zoledronic acid (4 mg/6 months), showed that zoledronic acid was effective in preventing treatment-related bone loss at 5-year follow-up. The expert panel opinion may consider zoledronic acid to prevent bone loss caused by endocrine therapy for breast cancer.
(H) The role of bisphosphonates in preventing bone metastases
In vitro studies have shown that bisphosphonates have antitumor effects, and studies ZO-FAST and ABCSG-12 have suggested that the use of zoledronic acid may significantly reduce the risk of bone metastases and may also have a potential role in preventing visceral metastases. However, clinical studies on bisphosphonates for the prevention of bone metastases from breast cancer are still ongoing and they are not currently recommended clinically for the prevention of bone metastases.