Bone metastasis is an advanced stage of malignant tumor disease progression, especially common in breast cancer, prostate cancer, lung cancer, colorectal cancer and other tumors, and its incidence is as high as 15% to 70%, among which the incidence of pathological fracture in patients with bone metastasis within 1 year is 22% to 52%%. The pain, fracture, functional impairment and psychological disorder associated with bone metastasis seriously affect the quality of life of patients with rib tumor. In this paper, we will discuss the occurrence, classification, treatment, rehabilitation and clinical value of bone markers of malignant tumor bone metastases in order to standardize the clinical treatment of bone metastases. I. Occurrence and types of bone metastasis Tumor bone metastasis is a complex multi-step process. After the tumor cells reach the bone marrow with blood flow, they destroy bone tissue through the interaction with osteoblasts, osteoclasts and bone stromal cells, and release a variety of growth factors stored in bone tissue, so that the tumor cells keep proliferating to form metastatic foci. Bone metastases can be divided into three types: osteolytic, osteogenic and mixed. Generally speaking, osteolytic metastasis is the main type of metastasis in breast cancer and lung cancer, while osteogenic metastasis is the main type of metastasis in prostate cancer. Diagnosis and efficacy of bone metastases At present, the clinical diagnosis of bone metastases mainly includes the following means, including ECT bone imaging, X-ray, CT, MRI, etc. ECT bone imaging is to show the abnormality of bone metastasis lesions by combining 99mTc-labeled phosphate compounds with crystal surface and organic matter (osteoid) and depositing them in the bone, and then detecting the intensity of gamma rays emitted by 99mTc through ECT machine. This technique is a functional, metabolic imaging that is particularly sensitive to active osteoblastic lesions and allows early detection of bone metastatic lesions before anatomical or morphological changes occur. In addition, ECT bone imaging can reveal the skeletal situation of the whole body in a single examination, and can detect some lesions that are beyond the scope of X-ray, CT, MRI, etc. or not easily observable. It is safe, easy, non-invasive, painless and has no absolute contraindications, and is now widely used for early screening of bone metastases. However, ECT bone imaging also has the problem of low specificity. ECT bone imaging cannot be used for the evaluation of the efficacy of bone metastases. Magnetic resonance imaging (MRI) is also a means of early diagnosis of bone metastases, which can show structural abnormalities inside the bone without deformation of the overall bone structure. PET (positron emission computed tomography) is an emerging nuclide imaging technique in recent years, which can show the location of tumor by the high glucose uptake of tumor cells. However, due to the high price, it is still difficult to promote the application. X-rays and CT scans are the confirmatory imaging methods for bone metastases. For patients with bone abnormalities detected by ECT scan, MRI or PET, X-ray and CT scan should be performed to confirm the diagnosis of bone metastases and to understand the severity of bone destruction. Treatment of bone metastasis A comprehensive treatment strategy should be adopted for bone metastasis of malignant tumors, which means to reasonably apply various existing treatments to control tumor progression, relieve bone metastasis pain, prevent and treat bone-related events, so as to improve patients’ quality of life and prolong their survival. Specific integrated treatment tools include systemic antitumor therapy to target the cause, pharmacological analgesic therapy to relieve painful symptoms, bisphosphonate therapy to prevent and reduce bone-related events, radiation therapy to relieve compressive neuralgia or reduce the risk of fracture of weight-bearing bones, and surgical bone replacement therapy to restore the function of the body if necessary. Antitumor therapy Bone metastasis is an advanced stage in the development of malignant tumor disease and is mostly a local manifestation of systemic tumor metastasis, for which systemic therapy for tumors should be the main choice for treatment and control of tumors. For different tumors, the systemic treatment means are different. However, the evaluation of the efficacy of systemic treatment for bone metastasis of any tumor must be based on the results of radiographs and CT scans, following the idea of excluding the previous ineffective programs and preferring the unused programs, and following the principle of “no change in the formula if it is effective and no change if it is ineffective”. Breast cancer: Breast cancer bone metastasis can be treated with chemotherapy, endocrine therapy, molecular targeted therapy and other treatment options. Commonly used chemotherapeutic drugs include paclitaxel, anthracycline, Noviben, Kinzel, Siroda, platinum and so on. As patients with bone and soft tissue metastases from breast cancer have slower tumor progression, single agent chemotherapy is generally chosen so that patients can tolerate it better, but it is necessary to emphasize the adequate dosage of drugs. Endocrine therapy for breast cancer is an important treatment option for patients with hormone receptor-positive bone metastases. These include the anti-estrogen drug triamcinolone, progestin analogs, third-generation aromatase inhibitors, and the estrogen receptor modulator fulvestrant. Endocrine therapy is particularly suitable for elderly and frail patients who are receptor positive and cannot tolerate chemotherapy because of its lesser toxicity and efficacy compared to chemotherapy. Molecular targeted drug therapy for breast cancer is also an important option for breast cancer with bone metastases. For patients with HER-2 overexpression, Herceptin, a monoclonal antibody drug targeting HER-2, is an option. In recent years Lapatinib, Eressa and Bevacizumab have also shown outstanding efficacy in advanced breast cancer. 2.Lung cancer: The medical treatment of bone metastases from lung cancer can be divided into two parts: small cell lung cancer and non-small cell lung cancer. The systemic treatment of small cell lung cancer is mainly based on chemotherapy, and the drugs of choice include platinum, VP-16, CPT-1, paclitaxel, doxorubicin, Jianze, isocyclophosphamide, topotecan, irinotecan, norviben, etc., among which platinum combined with VP-16 is the first-line regimen. Systemic therapy for non-small cell lung cancer includes chemotherapy and molecular targeted therapy. The main chemotherapeutic drugs include platinum, Kinzel, Tysol, Noviben, Siroda, Irinotecan and other drugs, among which platinum combined with other drugs is the common two-drug combination regimen. The main molecular targeting drug is Irisa, which has outstanding efficacy for Asian non-smoking lung adenocarcinoma patients. 3.Prostate cancer: The medical treatment of prostate cancer mainly includes drug depot tumor, estrogenic drug tumor, and anti-androgenic drug tumor. The main drugs are gonadotropin-releasing hormone analogs, such as inhibition of the Nadir; . Estrogenic drugs include estradiol, polyphosphate estradiol, ethinyl estradiol, trimethoprim; anti-androgenic drugs include progesterone drugs and non-steroidal anti-androgenic drugs, the latter including flutamide, ketoconazole. Analgesic treatment of bone pain in bone metastases Most bone metastases are accompanied by pain of different degrees, and analgesic treatment of bone metastases should be the basic treatment for this group of patients. The control of cancer pain should follow the new WHO three-step analgesic principles, which are as follows: the first step includes non-steroidal anti-inflammatory analgesics ± adjuvant drugs, mainly for mild pain; the second step includes opioid analgesics ± non-steroidal ± adjuvant drugs, mainly for mild to moderate pain; the third step includes opioid analgesics ± non-steroidal ± adjuvant drugs, mainly for moderate to severe pain. . The basic principle of its application is that when pain is not controlled in the previous ladder, the next analgesic drug selection ladder should be entered. In general, as the application of drug ladder increases, drug-related toxic side effects also increase, so attention should be paid to the symptomatic management of drug toxic side effects. Commonly used nonsteroidal anti-inflammatory analgesics include acetaminophen, ibuprofen, diclofenac sodium, indomethacin, naproxen, celecoxib, cronoxicam, etc. Opioid analgesics include morphine extended-release tablets, fentanyl transdermal patches, oxycodone controlled-release tablets, morphine immediate-release tablets, codeine, methadone, etc. Adjunctive medications include tricyclic antidepressants, anticonvulsants, neuroleptics, glucocorticoids, etc. Bisphosphonate therapy Hypercalcemia, bone pain, and bone-related events are common complications in patients with bone metastases. These complications will seriously affect patients’ quality of life, aggravate their psychological stress, and shorten their survival time. Bisphosphonates are an important drug of choice for patients with bone metastases. By inhibiting the differentiation and maturation of osteoclasts, interfering with osteoclast-mediated bone resorption, preventing the aggregation of osteoclasts at the site of bone resorption, and inhibiting the spread, infiltration and adhesion of tumor cells to the bone matrix, this class of drugs reduces the occurrence of bone-related complications such as fracture, and is increasingly becoming the basic treatment for patients with bone metastases. There are three generations of bisphosphonates, the first generation is represented by clodronate; the second generation is nitrogen-containing bisphosphonates, including pamidronate disodium, whose effect of inhibiting bone resorption is stronger than that of the first generation; the third generation is nitrogen-containing bisphosphonate zoledronic acid with heterocyclic structure, and ibandronate without cyclic structure containing nitrogen, whose effect strength and efficacy have been further improved than the second generation. Clinical studies have shown that bisphosphonates are effective in reducing the incidence of bone-related events in patients with bone metastases by 41% for zoledronic acid, 23% for disodium pamidophosphate, 18% for ibandronate, and 8% to 31% for clodronate. Zoledronic acid significantly reduced the risk of bone-related events in most tumors, including 41% in breast cancer, 36% in prostate cancer, 32% in lung cancer, 58% in kidney cancer, and 31% in other solid tumors. A recently completed study comparing the third-generation bisphosphonate drug zoledronic acid with the second-generation drug pamiphosphate disodium showed that zoledronic acid and pamiphosphate disodium were superior to patients in reducing the risk of bone-related events by 37% and 22%, respectively. Zolay phosphate was also superior to disodium pamiphosphate in controlling bone metastasis pain. In addition, during the application of bisphosphonates, it is important to pay attention to the toxic side effects of this class of drugs, especially the problem of osteomyelitis of the mandibular mandible. A new comprehensive analysis of the data showed that the application of bisphosphonates increased the incidence of osteomyelitis of the maxillofacial mandible by a factor of 3. In patients with long-term bisphosphonate application, the incidence of mandibular osteomyelitis was as high as 5.48%. Other treatments Fracture is a serious concomitant event in bone metastases. The incidence of pathological fracture within one year in the blank control group was found to be 52% for breast cancer, 25% for prostate cancer, 37% for multiple myeloma, and 22% for other solid tumors in the blank control group, with the risk of pathological fracture complicating bone metastases in weight-bearing parts such as the spine and femur being about 30%. Once patients with bone metastases develop pathological fracture radiation, the quality of life and mobility of patients will be seriously affected. Therefore, radiation therapy is usually an important treatment option for patients with weight-bearing bone metastases in the spine, femur, and humerus, which can rapidly relieve bone pain and reduce the risk of pathological fracture. The main indications for radiation therapy are symptomatic bone metastases and bone metastases in weight-bearing areas. Extracorporeal irradiation regimens for bone metastases include 40GY/20F, 30Gy/10F, 20Gy/5F, and 800cGy/single dose. There was no significant difference in the efficacy and tolerability of these irradiation regimens for the relief of bone pain. In addition, advances in orthopedic surgical techniques have provided more treatment options for patients with bone metastases. Surgical procedures include fixation of the bone injury site, diseased bone replacement, and release of the compressed nerve. Fixation therapy may be considered elective for patients with pathologic fractures or spinal cord compression who have breast cancer metastases with an expected survival time of >4 weeks. Prophylactic fixation treatment can be considered electively for patients with femoral metastases >2.5 cm in diameter, or femoral neck bone metastases, or bone cortical destruction >50%, and expected survival time >4 weeks. Clinical value evaluation of bone markers In recent years, the application of bone markers for clinical efficacy and prognosis evaluation of bone metastases has attracted widespread attention in the industry. The markers from urine include calcium (Ca/Cr), hydroxyproline, amino-terminal peptide (NTX/Cr), carboxy-terminal peptide (Ctx/Cr), pyridinoline (PYD/Cr), and deoxypyridinoline (DPD/Cr); the markers from serum representing bone resorption are amino-terminal peptide (S-NTX), carboxy-terminal peptide (S-Ctx), and RANKL/OPG. Serum markers representing bone formation are bone alkaline phosphatase (BALP), osteocalcin, C-terminal type 1 procollagen (PICP), and N-terminal type 1 procollagen (PINP). It has been found that urinary NTX concentration and bone BALP are significantly elevated in patients with bone metastases, that patients with high levels of NTX and bone BALP are at significantly increased risk of SRE, and that elevated levels of NTX are associated with shorter survival. It has also been shown that in patients with high levels of NTX and BALP, the application of zolay phosphate can rapidly reduce the levels of these markers and may prolong the survival time of patients. Studies have suggested that bone markers such as NTX and BALP can be used for the diagnosis of bone metastases, prognosis, and prediction of the risk of SRE. In the treatment of bone metastases with bisphosphonates, changes in bone markers can also be used as important reference indicators for patient outcome evaluation, but there are some differences between different tumors. In addition, since there is a correlation between bone marker levels and bone density status, the detection of bone markers has some reference value for the problem of treatment-related bone loss.