Non-antiosteoporotic effects of bisphosphonates: latest studies and prospects

After their initial synthesis in 1865, bisphosphonates were largely used for industrial purposes to prevent calcium carbonate precipitation in the textile, agricultural, and oil sectors. More than 100 years later, bisphosphonates were shown to inhibit bone resorption in animal models. Since then, the role of bisphosphonates in the treatment of hypercalcemia, Paget’s disease, and osteoporosis, as well as in the reduction of morbidity associated with bone metastases from breast, prostate, and plasma cell malignancies, has been established. The American Society of Clinical Oncology recommends “the extensive and early use of bisphosphonates” to prevent skeletal complications, such as pathologic fractures, surgery for fracture or impending fracture, radiation, spinal cord compression, and hypercalcemia, in women with metastatic bone disease from breast cancer. A more recent international panel of experts concluded that bisphosphonates reduce the frequency and severity of skeletal complications in patients with bone metastases from a variety of different cancers. In the setting of cancer treatment–induced bone loss, the panel advised considering the use of bisphosphonates in patients presenting with risk factors for fractures but did not endorse the use of bisphosphonates in the adjuvant setting. Clinical trials with bisphosphonates in patients with metastatic breast cancer have failed to demonstrate an overall survival (OS) benefit. However, bisphosphonates might have an impact on longterm survival if used in earlier stages of disease. The dissemination of breast cancer cells to bone marrow instigates a vicious self-sustaining cycle of destruction, whereby individual tumor cells release growth factors that stimulate stromal cells and osteoblasts to produce the receptor activator for nuclear factor B ligand (RANKL), leading to the activation of osteoclasts. These activated osteoclasts resorb bone matrix–liberating potent growth factors that promote tumor cell colonization, inhibit apoptosis, and drive proliferation. Bisphosphonates are potent inhibitors of osteoclasts, thereby interrupting this self-perpetuating cycle. Three clinical trials with the non–nitrogen-containing oral bisphosphonate clodronate in early breast cancer produced mixed results. A single-center German study involving 302 women with early breast cancer and detectable bone marrow metastases demonstrated a striking reduction in bone and visceral metastases and improvement in disease-free survival (DFS) and OS with two years of adjuvant clodronate therapy. With longer follow-up, the gain in OS persisted, although differences in DFS and bone metastasis–free and visceral metastasis–free survival were no longer apparent. A larger placebo-controlled multicenter study found that a similar schedule of oral clodronate for 2 years in conjunction with standard therapy for stage I to III breast cancer reduced the incidence of bone metastasis and improved OS with no observed difference in nonosseous metastasis. However, a small Finnish trial reported that three years of adjuvant clodronate did not improve overall survival and had no effect on bone recurrences and a negative impact on nonskeletal recurrences, particularly in women with estrogen receptor–negative disease. There are concerns that these results were skewed by imbalances between the clodronate and observation groups. On the basis of the data, which remained unconvincing when pooled in a meta-analysis, the US Food and Drug Administration announced that it would not consider approving clodronate in adjuvant breast cancer therapy until the results from the NSABP (National Surgical Adjuvant Breast and Bowel Project) B-34 study—in which 3,323 women with stage I to II disease have been randomly selected to receive three years of clodronate or placebo—were available. There is reason to believe that newer generation bisphosphonates may deliver greater efficacy. Non–nitrogen-containing bisphosphonates, such as clodronate, can be metabolized to an adenosine triphosphate analog that is toxic for macrophages and osteoclasts. Nitrogen-containing bisphosphonates, including zoledronic acid and ibandronate, have a very different mechanism of action and are much more potent inhibitors of osteoclast-mediated bone resorption. They inhibit the mevalonate pathway that leads to the prenylation of key intracellular signaling proteins. Many of these proteins are guanosine triphosphate–binding peptides essential for signal transduction, including Rho and Ras, that regulate key osteoclast functions, including attachment and survival. Inhibition of prenylation alters cell membrane integrity and induces osteoclast apoptosis. Nitrogen-containing bisphosphonates have also been shown to directly induce tumor cell apoptosis, inhibit angiogenesis, and prevent JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 27 NUMBER 25 SEPTEMBER 1 2009

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Ischemia as a potential etiologic factor in idiopathic unilateral sudden sensorineural hearing loss: Analysis of posterior circulation arteries

Bone is one of the most common sites of distant metastasis of malignant tumors, whose is second only to those of lung metastasis and liver metastasis. Malignant tumors with high incidence of bone metastasis include prostate cancer, breast cancer, and lung cancer, and nearly 70% of patients with advanced breast or prostate cancers have bone metastasis. Bone metastasis often causes pain, fracture, and hypercalcemia, which can seriously affect the quality of life. No standard treatment exists for tumor bone metastasis, and combining multiple therapies is often necessary. Bisphosphonates and radionuclides are extensively used individually to treat multiple bone metastases, but the concurrent use of both drugs is rarely researched. In this paper, recent studies on the concurrent use of radionuclides and bisphosphonates were reviewed. Key words: Neoplasm metastasis; Radiopharmaceuticals; Combined modality therapy; Bisphosphonates

Bone metastases and multiple myeloma cause debilitating clinical symptoms including intractable bone pain, disabling multiple fractures and hypercalcemia. Adjuvant endocrine therapies with aromatase inhibitors or androgen deprivation further accelerate bone loss and increase in fracture risk (cancer treatment-induced bone loss) . Bisphosphonates appear to be a current mainstay for the treatment and prevention of the skeletal-related morbidity in cancers. However, osteonecrosis of the jaw emerges as a major concern associated with long-term bisphosphonate use. It is important to clarify the clinical impact of long-term bisphosphonate use and make beneficial use of this agent by eliminating underlying risk of its adverse effects.

Bisphosphonates are commonly used for the treatment of osteoporosis and bone metastases caused by breast cancer and were recently reported to be associated with a reduced risk of breast cancer, possibly acting through the mevalonate pathway, but their association with risk of other cancers is unknown. The Molecular Epidemiology of Colorectal Cancer study is a population-based, case-control study in northern Israel of patients with colorectal cancer and age-, sex-, clinic-, and ethnic group-matched controls. Long-term use of bisphosphonates before diagnosis was assessed in a subset of 933 pairs of postmenopausal female patients and controls, enrolled in Clalit Health Services, using computerized pharmacy records. The use of bisphosphonates for more than 1 year before diagnosis, but not for less than 1 year, was associated with a significantly reduced relative risk (RR) of colorectal cancer (RR, 0.50; 95% CI, 0.35 to 0.71). This association remained statistically significant after adjustment in a model for vegetable consumption, sports activity, family history of colorectal cancer, body mass index, and use of low-dose aspirin, statins, vitamin D, and postmenopausal hormones (RR, 0.41; 95% CI, 0.25 to 0.67). Concomitant use of bisphosphonates and statins did not further reduce the risk. The use of oral bisphosphonates for more than 1 year was associated with a 59% relative reduction in the risk of colorectal cancer, similar to the recently reported association of this drug class with reduction in breast cancer risk.

This study aimed to correlate probable predisposing factors for sensorineural hearing loss in elderly by investigating the audiologic characteristics and frequency of mutations in genes considered responsible for non-syndromic hearing loss. Sixty elderly patients were separated into two groups: the Case Group, composed of 30 individuals, 21 females and nine males, all 60 years old or older and presenting diagnoses of sensorineural hearing loss, and the Control Group, composed of 30 elderly individuals matched to the experimental group by age and gender, presenting normal hearing. The patients underwent anamnesis and pure tone audiometry in frequencies of 250, 500, 1000, 2000, 3000, 4000 and 6000 Hz. Blood samples were collected from each patient for analysis of mutations in nuclear and mitochondrial genes related to non-syndromic sensorineural hearing loss. It was observed a greater tendency to noise exposure and consumption of alcohol in the Case Group. The statistically significant symptoms between the groups were tinnitus and hearing difficulty in several situations as: silent environment, telephone, television, sound location and in church. All the individuals of Case Group presented sensorineural and bilateral hearing loss. The symmetry and progression of the hearing impairment were also statistically significant between the groups. No genetic mutations were identified. The most reported symptoms were communication difficulties and tinnitus. The predominant auditory characteristics included sensorineural, bilateral, progressive and symmetrical hearing loss. It was not evidenced a relationship between sensorineural hearing loss in elderly and genes considered responsible for non-syndromic hearing loss as no genetic mutation was found in this study.

To identify potentially preventable risk factors for sensorineural hearing loss (SNHL) in extremely premature infants. A case control study of survivors with gestational age (GA) < 28 weeks or birthweight (BW) < 1000 g using data collected prospectively in our Neonatal Intensive Care Unit database. Each subject with bilateral SNHL > 40 dB was matched according to GA, BW and sex with two controls who had neither sensorineural nor conductive hearing loss. Infants with SNHL had increased mean (+/- s.d.) days ventilated (53 +/- 21 vs 37 +/- 23 days, P = 0.006) and in oxygen (107 +/- 44 vs 69 +/- 28 days, P = 0.02) compared with controls. The risk for SNHL was increased for infants who spent > 90 days in oxygen (OR 4.0 [95% CI 1.1-15.6]), had maximum FiO2 > 0.90 (5.6 [1.2-26.9]), minimum plasma Na < 125 mmol/L (5.6 [1.1-27.8] or maximum pH > 7.60 (5.6 [1.1-89.0]). Neither maximum serum bilirubin nor exposure to ototoxic drugs was associated with SNHL. Avoidance of severe hyponatraemia and extreme alkalosis, as well as use of surfactant to minimize the severity of hyaline membrane disease, may result in a decreased incidence of SNHL in extremely premature infants.

Objective To compare the histopathologic and immunohistochemical differences between primary renal cell carcinomas and paired bone metastases in order to discuss the significance in the selection of standard targeted therapies.Methods The clinical data of 19 patients who underwent nephrectomy and resection of bone metastases successively from January 2003 to September 2013 were analysed retrospectively.The paraffin-embedded surgical samples of all the patients were obtained for histopathologic and immunohistochemical analysis.The differences of Fuhrman grades,expression of Ki-67,CD34,vascular endothelial growth factor receptor 2 (VEGFR2),epidermal growth factor receptor (EGFR) and CXC subfamily receptor 4 (CXCR4) were compared between primary renal cell carcinomas and their paired bone metastases.Microvessel density (MVD) was evaluated by the CD34 immunostaining.Results The Fuhrman grades of samples from bone metastases were higher than that of primary tumors (36.8％,7/19) (P=0.008).The Ki-67 label index was (4.00±3.96)％ in primary tumors and (7.90±7.38)％ in bone metastases (P=0.033).The microvessel density (MVD) was 58.13±22.90 in primary tumors and 46.71±25.40 in the bone metastases (P=0.026).The immunohistochemistry scores of VEGFR2 were 4.68±1.20 in primary tumors and 4.05±1.58 in bone metastases (P=0.014).The immunohistochemistry scores of EGFR were 5.89±1.05 in primary tumors and 5.47± 1.12 in bone metastases (P=0.134).The immunohistochemistryscores of CXCR4 in cytomembrane and cytoplasm were 1.74±1.97 in primary tumors and 2.16± 1.64 in bone metastases (P=0.414).The inununohistochemistry scores of CXCR4 in cell nucleus were 2.52±2.09 in primary tumors and 3.42±1.95 in bone metastases (P=0.009).Conclusions The Fuhrman grades and the expression of Ki-67 and CXCR4 in cell nucleus were higher in bone metastases than that in the primary renal cell carcinomas.The MVD and the expression of VEGFR2 were lower in bone metastases than that in the primary tumors.The above alternations may contribute to the poor prognosis of bone metastasis and the poor result of angiosuppressive therapy. Key words: Carcinoma, renal cell; Immunohistochemistry; Neoplasm metastasis; Molecular targeted therapy

Bisphosphonates have traditionally been indicated for treatment and control of osteoporosis because they inhibit osteoclastmediated bone resorption and reduce the release of calcium into the blood stream (1). They are currently being used by millions of people (mostly women) worldwide (2). Accumulating evidence over the past 10 years has demonstrated that the use of third-generation nitrogen-containing bisphosphonates can effectively treat bone metastases in women with breast cancer (3). It has been hypothesized that bisphosphonates can also prevent bone metastases altogether and could therefore be implemented in an adjuvant setup in women with breast cancer (4,5). A recent randomized controlled study failed to demonstrate such an effect using third-generation bisphosphonate (6). If bisphosphonate use is associated with a generalized reduced risk of malignancy, one would expect to see reduced risk of developing breast cancer or other cancers in regular users of secondgeneration bisphosphonates, such as osteoporotic women. One would also expect to see reduced risks of developing contralateral breast cancer in women with breast cancer who were further treated with bisphosphonates. Three descriptive studies have thus far shown a strong and similar negative association between the use of common second-generation oral bisphosphonates and the risk of breast cancer (7–9). These findings raised the possibility of con founding by indication. Bisphosphonates are used by osteoporotic women, and osteoporosis is the result of reduced circulating estrogen levels. Estrogen is strongly associated with risk of breast cancer, and women with low estrogen levels are expected to have lower breast cancer rates. Thus, the negative association with bisphosphonate use could actually reflect a negative association with low estrogen levels in the body. However, evidence that the degree of breast cancer risk reduction among bisphosphonate users was not correlated with the degree of bone density loss (7), that risk reduction was seen only after a year of treatment (8), and that postmenopausal bisphosphonates users also demonstrated a reduced risk of colorectal cancer (10,11), all suggest that the association between bisphosphonate use and reduced risk of cancer is real. Mechanistically, nitrogen-containing bisphosphonates inhibit protein prenylation by blocking the mevalonate pathway. Selective inhibition of farensyl pyrophosphate synthase by bisphosphonates can lead to diminished posttranslational prenylation of small GTPase proteins (including signaling molecules such as proteins of the Ras and Rho families) that promote tumorigenesis and metastases (12). In a mouse model, use of bisphosphonates was associated with the suppression of Rho and Ras pathways (13). Further support for a possible role of bisphosphonates in primary prevention of cancer comes from numerous previous reports on the negative association between the use of statins and the risk of cancer in various organs [eg, (14–20)]. Statins, which use the same mevalonate pathway as do bisphosphonates (acting upstream of the farensylation–geranylation step), have been shown to be associated with cancer risk reduction and with possibly improved survival of patients with cancers in multiple sites (21).

The use of both bisphosphonates and palliative radiotherapy for the prevention and treatment of skeletal complications in women with bone metastases from breast cancer is well established. We undertook an evaluation of palliative radiotherapy utilization rates in breast cancer patients who received bisphosphonates for the treatment of bone metastases in a major Canadian cancer center. Charts and electronic files of breast cancer patients with bone metastases who had received either clodronate or pamidronate at any time between January 2000 and December 2001 at our center were retrospectively reviewed. The utilization rates of palliative radiotherapy in these patients were examined. The percentage of patients receiving bisphosphonates for the treatment of bone metastases who also received palliative radiotherapy to bone remained relatively constant over our study period in the range of 70%. In patients commenced on bisphosphonates before 1998, 42.9% received palliative radiotherapy as initial therapy for bone metastases, whereas in 2001 only 27.8% of patients received palliative radiotherapy before commencing bisphosphonate therapy. There has been a marked improvement in the time between the diagnosis of bone metastases and the commencement of bisphosphonates from a median of 446 days before 1998 to 21 days in 2001. At the same time, there was also an improvement in time between diagnosis of bone metastases and initiation of palliative radiotherapy from a median of 265 days before 1998 to 49 days in 2001. Use of bisphosphonates has not reduced the utilization rates of palliative radiotherapy in breast cancer patients with bone metastases. There is a trend of initiating bisphosphonates before delivery of palliative radiotherapy. The latter was also delivered earlier in the course of bone metastases.

To investigate the clinical features and prognosis of bone metastases in colorectal cancer patients. The clinical data of 104 cases of colorectal cancer with bone metastasis were collected and retrospectively analyzed. Among all the 104 patients included, 45 (43.3%) patients had multiple bone metastases, and 59 (56.7%) patients had single bone metastasis. Pelvis (46.1%) was the most common site, followed by thoracic vertebrae (41.3%), lumbar vertebrae (40.4%), sacral vertebrae (29.8%) and ribs (29.8%). One hundred and two patients (98.1%) were complicated with other organ metastases. The median time from colorectal cancer diagnosis to bone metastasis was 16 months, and the median time from bone metastasis to first skeletal-related events (SREs) was 1 month. The most common skeletal-related events (SREs) were the need for radiotherapy (44.2%), severe bone pain (15.4%) and pathologic fracture (9.6%). The median survival time of patients with bone metastases was 10.0 months, and 8.5 months for patients with SREs. ECOG score, systemic chemotherapy and bisphosphonate therapy were prognostic factors by univariate analysis (all P < 0.05). ECOG score and systemic chemotherapy were independent prognostic factors by Cox multivariate analysis. Bone metastasis in colorectal cancer patients has a poor prognosis and the use of chemotherapy and bisphosphonates may have a benefit for their survival.

The molecular mechanism and clinical significance of bone metastases in malignant tumors were discussed by literature review. In recent years, studies on bone metastasis of malignant tumors at home and abroad have revealed the dependence between tumor cells and bone microenvironment. Bone microenvironment maintains bone homeostasis by balancing the functions of osteoblasts and osteoclasts. The destruction of this balance can transform the normal ecological niche into a transfer niche. In this paper, the predisposing sites of bone metastases are discussed from the physical structure and physiological function of bone, and the research progress of bone metastasis regulation is analyzed from the aspects of colonization, dormancy and reactivation. It is concluded that the disseminated tumor cells in bone can remain dormant for many years until they enter the large metastases. Key words: Tumor; Bone metastasis; Microenvironment; Bone homeostasis; Dormancy

Objective To investigate the assessment and treatment strategy of patients with renal cell carcinoma. Methods The clinical data of 43 patients with renal cell carcinoma and bone metastases admitted to the First Affiliated Hospital of Nanjing Medical University from January 2006 to December 2018 were retrospectively analyzed. The follow-up time was 6 years, with an average age of 55.4 years (21-87 years). There were 29 males, 14 females, 22 cases of limb bone metastasis, 12 cases of spinal metastasis, 9 cases of multiple bone metastasis, 21 cases of Fuhrman grade 1 and 2, 19 cases of T1, and 20 cases of N0. All patients were confirmed by postoperative pathological examination or imaging data suggesting that bone metastasis are from renal cell carcinoma. Forty-three patients underwent primary renal surgery, and molecular targeted therapy was used after the operation. The treatment process was smooth, no obvious discomfort, and postoperative pathology showed clear cell carcinoma.22 patients with limb bones metastasis and 12 patients with spinal metastasis included in the study all met the indications for secondary surgery after the disease assessment. After communicating with the patient, 13 patients with limbs metastasis and 6 patients with spinal metastasis received local treatment, including complete resection of the extremities and spinal fixation, the remaining 15 patients and 9 patients with multiple bone metastasis were treated conservatively. There were 19 patients in the local treatment group, 13 patients with limbs bone metastasis, 6 patients with spinal bone metastasis, the average age was 54.9 years, the average diameter of the primary tumor was 4.7 cm. There were 24 patients in the conservative treatment group, 9 patients with limbs metastasis, 6 patients with spinal metastases and 9 cases with multiple bone metastasis, with an average age of 56 years and a primary tumor diameter of 5.6 cm. Limb metastatic lesions were evaluated according to the patient's general condition, bone pain, fracture risk, and bone metastasis. Spinal lesions were evaluated according to Tokuhashi score, Harrington score, Tomita score, vertebral stability assessment, and molecular targeted therapy. Aminokinase inhibitors, conservative treatment with local radiotherapy and bisphosphonate treatment. Results During the follow-up period, the 1-year overall survival rate of the local treatment group was 100.0%, the 2-year overall survival rate was 89.4%, and the 5-year overall survival rate was 73.7%. The 1-year overall survival rate of the conservative treatment group was 87.5%, and the 2-year overall survival rate was 62.5%. The 5-year overall survival rate was 16.7%. The 2-year and 5-year survival rates of the local treatment group were statistically different (P=0.044, P=0.000) compared with the conservative treatment group. For patients with limb bone metastasis, the 5-year survival rate was significantly higher in patients receiving topical treatment than in the conservative treatment group (P=0.011). For spinal metastasis, spinal pain in the local treatment group was alleviated to varying degrees. No spinal instability and spasticity were observed after follow-up. In the spine patients who received conservative treatment, 3 patients developed paraplegia, which was statistically different from local treatment (P=0.046). Another 9 patients with multiple bone metastases did not undergo local surgery, and all died after multiple organ failure. Conclusions At the same time of molecular targeted therapy, according to the evaluation results, selective treatment of bone metastases with secondary surgical indications, including complete resection of the extremities and spinal fixation, can significantly improve the survival and quality of life of those patients. Key words: Carcinoma, renal cell; Bone metastasis; Condition evaluation; Treatment strategy; Complete resection; Spine fixation

Objective To summarize the clinical features of neuroblastoma (NB) with bone metastasis, and preliminarily to analyze the relationship between clinical features, treatment effects and prognosis of NB with bone metastasis and further studying why children with NB would have bone metastasis happened.As such, this paper was seek for more effective therapy to improve patients′survival rates. Methods The retrospective research was carried out to analyze the medical records of 130 patients with bone metastasis of NB from March 2007 to July 2013 who were diagnosed and systematically treated in Beijing Children′s Hospital(BCH) Affiliated to Capital Medical University accor-ding to BCH-NB-2007 protocol.The data were reviewed for the medical history, clinical features and laboratory examination results before treatment.The research evaluated the treatment outcome and overall survival rate of the 88 cases treated and followed up all along at BCH.The deadline for follow-up was December 31, 2014. Results One hundred and thirty children of NB with bone metastasis were included in the research.There were 87 boys and 43 girls; the age was between 8-147 months, the median age was 41 months, 94(72.3%) children′s age was less than 5 years old.The main primary site was retroperitoneal and adrenal region(106 cases, 81.5%) and mediastinum(17 cases, 13.1%). The main clinical symptoms were fever(81 cases, 62.3%), bone pain(51 cases, 39.2%), abdominal pain(29 cases, 22.3%), and abdominal mass(14 cases, 10.8%). A total of 88 cases got systemic treatment and follow-up at BCH.Only 1 infant with NB, at 8 months old with a retroperitoneal mass, with bone marrow and bone metastasis, but no MYCN gene amplification, was given carboplatin plus etoposide and cyclophosvnamide, vincristine and doxorubicin according to European neuroblastoma risk grouping for alternating 8 times, he received tumor resection after 4 courses of chemotherapy and was followed up for 20 months, and the condition was now in stable.The remaining 87 patients as high risk(HR)-NB, were treated regularly by BCH-NB-2007 protocol, with the median follow-up time of 23 months, 52 cases(59.1%) turned out to have tumor progression or relapse.Forty cases died of tumor related diseases and 1 case died of measles infection.The expected overall survival rates were 49.5% in 3 years and 41.3% in 5 years. Conclusions NB with bone metastasis was very common in children over 18 months, and their common clinical symptoms are fever, bone pain and anemia.More than 80% of primary tumor was located in retroperitoneal and adrenal gland area, most of the patients with bone marrow metastasis.Since the overall prognosis is poor in these children, continuous clinical and further study is needed to investigate the causes of bone metastasis in children with NB, and to provide a basis for more effective treatment. Key words: Neuroblastoma; Bone metastasis; Clinical features; Prognosis