Incidence of bisphosphonate‐associated osteonecrosis of the jaws in breast cancer patients

BACKGROUND:

Bisphosphonate‐associated osteonecrosis of the jaws (BP‐ONJ) is a relatively new disease. The aim of this study was to evaluate the prevalence of BP‐ONJ in breast cancer patients with osseous metastasis and bisphosphonate therapy.

METHODS:

A retrospective study was conducted in a EUSOMA accredited breast unit in Germany. All patients treated from January of 2000 to March of 2006 with metastatic breast cancer and bisphosphonate therapy were reviewed. All patients were contacted, and missing data were completed through structured interviews with their dentists and physicians (n = 75). Primary outcome was the development of BP‐ONJ and the detection of possible additional trigger factors for the development of BP‐ONJ.

RESULTS:

A total of 117 patients with breast cancer fulfilled the inclusion criteria, and data for 75 still living patients were included. Of these 75, 4 patients developed a BP‐ONJ, resulting in a prevalence of 5.3%: 3 patients received zoledronate only; 1 patient had first pamidronate followed by zoledronate and ibandronate. A tooth extraction could be identified as an additional trigger factor for 2 patients.

CONCLUSIONS:

With a prevalence of 5.3%, BP‐ONJ in breast cancer patients has become a relevant disease that should be discussed with patients for whom bisphosphonates have been recommended. Appropriate dental care before bisphosphonate therapy commences has been advised to reduce the occurrence of BP‐ONJ. Cancer 2009. © 2009 American Cancer Society.     

Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors.

PURPOSE: Osteonecrosis of the jaw (ONJ) has been associated recently with the use of pamidronate and zoledronic acid. We studied the incidence, characteristics, and risk factors for the development of ONJ among patients treated with bisphosphonates for bone metastases. PATIENTS AND METHODS: ONJ was assessed prospectively since July 2003. The first bisphosphonate treatment among patients with ONJ was administered in 1997. Two hundred fifty-two patients who received bisphosphonates since January 1997 were included in this analysis. RESULTS: Seventeen patients (6.7%) developed ONJ: 11 of 111 (9.9%) with multiple myeloma, two of 70 (2.9%) with breast cancer, three of 46 (6.5%) with prostate cancer, and one of 25 (4%) with other neoplasms (P = .289). The median number of treatment cycles and time of exposure to bisphosphonates were 35 infusions and 39.3 months for patients with ONJ compared with 15 infusions (P < .001) and 19 months (P = .001), respectively, for patients with no ONJ. The incidence of ONJ increased with time to exposure from 1.5% among patients treated for 4 to 12 months to 7.7% for treatment of 37 to 48 months. The cumulative hazard was significantly higher with zoledronic acid compared with pamidronate alone or pamidronate and zoledronic acid sequentially (P < .001). All but two patients with ONJ had a history of dental procedures within the last year or use of dentures. CONCLUSION: The use of bisphosphonates seems to be associated with the development of ONJ. Length of exposure seems to be the most important risk factor for this complication. The type of bisphosphonate may play a role and previous dental procedures may be a precipitating factor.     

Osteonecrosis of the jaw in prostate cancer patients with bone metastases treated with zoledronate: a retrospective analysis

Osteonecrosis of the jaw (ONJ) has recently been reported as a potentially serious complication of prolonged treatment with intravenous bisphosphonates. We studied its frequency in prostate cancer patients receiving intravenous zoledronate. The medical and dental records of 52 consecutive patients with prostate cancer and bone metastases treated at our institute between January 2002 and October 2005 were reviewed. All patients received intravenous zoledronate 4 mg every 3 or 4 weeks and concomitant conventional prostate cancer treatments. We analysed the association of ONJ with the number of administrations of zoledronate and exposure to chemotherapy. At a median follow-up of 7 months (range 1-41) after the initiation of zoledronate, ONJ occurred in six patients (12%, 95% C.I. 5.4-23.0%). All six ONJ cases occurred after the 9^th administration of zoledronate. The median number of zoledronate administrations was 17 (range 9-24) and 8 (range 1-32) for patient developing and not developing ONJ, respectively (p =0.02). Chemotherapy with docetaxel was also associated with a strong, but not statistically significant, trend towards increased risk of ONJ (OR 3.8, 95% C.I. 0.4-35.6, p =0.24). The length of exposure to zoledronate was associated with an increased frequency of ONJ in prostate cancer patients. A possible role of chemotherapy with docetaxel as a cofactor for ONJ merits further evaluation.     

Bisphosphonate-associated osteonecrosis of the jaw: a review of 35 cases and an evaluation of its frequency in multiple myeloma patients

Over a period of 28 months, we observed five cases of osteonecrosis of the jaw (ONJ) in cancer patients treated with bisphosphonates (BP) at our institution. This prompted us to undertake a retrospective, multicenter study to analyse the characteristics of patients who exhibited ONJ and to define the frequency of ONJ in multiple myeloma (MM). We identified 35 cases in Gruppo Italiano Studio Linfomi centers during the period 2002 - 05. The median time from cancer diagnosis to the clinical onset of ONJ was 70 months. In these 35 cases of ONJ, 24 appeared 20 - 60 months after starting BP treatment. The time for the onset of ONJ was significantly shorter for patients treated with zoledronic acid alone than for those treated with pamidronate followed by zoledronic acid. The frequency of ONJ in the MM group during the study period was 1.9%, although the nature of the present study may have resulted in an underestimation of ONJ cases. Our analysis strongly suggested an association between the use of BP and the occurrence of ONJ, although we were unable to identify any definite risk factors with a retrospective study. The most frequently ONJ-associated clinical characteristics were chemotherapy treatment, steroid treatment, advanced age, female sex, anemia, parodonthopaties/dental procedures and thalidomide (in the case of MM patients).     

Adverse effects of bisphosphonates: current issues

Four bisphosphonates are used for the treatment of metastatic bone disease: clodronate, which is available outside the United States in both intravenous and oral formulations; intravenous pamidronate; intravenous zoledronic acid; and ibandronate, which is also available in intravenous and oral forms. Since the use of bisphosphonates in patients with cancer is palliative, their impact on patients' quality of life and their adverse-effect profiles are essential considerations for effective patient management. The most common adverse effects associated with bisphosphonates are renal toxicity, acute-phase reactions, gastrointestinal (GI) toxicity, and osteonecrosis of the jaw (ONJ). The incidence of these adverse events varies significantly between bisphosphonates. Renal toxicity is a potentially life-threatening event reported in studies of zoledronic acid and, to a lesser extent, pamidronate. In contrast, the renal safety profile of intravenous ibandronate and oral bisphosphonates is similar to that of placebo. Acute-phase reactions occur only with intravenous aminobisphosphonates and may be more common with zoledronic acid. Gastrointestinal effects occur only with oral agents (clodronate and ibandronate) and may be avoided by adhering to dosing instructions. More recently, ONJ has recently emerged as a complication of bisphosphonate use. However, its true incidence is not yet known. The potential adverse effects of bisphosphonates should be considered in the context of the individual patient's characteristics and preferences when selecting a bisphosphonate for metastatic bone disease.     

A different schedule of zoledronic acid can reduce the risk of the osteonecrosis of the jaw in patients with multiple myeloma.

Osteonecrosis of the jaw (ONJ) is a reported complication of bisphosphonate use. The incidence ranges between 6 and 13% and seems to be higher in people treated with zoledronic acid (ZA) than with pamidronate. We retrospectively evaluated the incidences of ONJ and skeletal-related events (SRE) in 106 patients with multiple myeloma divided in two groups according to the schedule of administration of bisphosphonates: 51 received monthly administrations until tolerated (group A, standard schedule), 55 were treated monthly during the first year and then every 3 months (group B, reduced schedule). The incidence of SRE was similar (15.1 per 100 person years in group A and 17.7 in group B). ONJ occurred in seven patients, six in group A and one in group B (P=0.049). The risk of ONJ was eight-fold lower with the reduced schedule than with the standard schedule. The only significant risk factor for ONJ was the type of bisphosphonate (P=0.006). The incidence of ONJ was significantly higher with ZA than with pamidronate + ZA (9.1 vs 1.6 per 100 person-years). No ONJ was observed in patients treated only with pamidronate. A reduced schedule of ZA may be safer than the standard schedule while maintaining anti-resorptive efficacy.     

Bisphosphonates: biological response modifiers in breast cancer

Bone recurrence constitutes one third of initial sites of relapse and one half of distant sites of relapse at 10 years from diagnosis of breast cancer. Bone pain, fracture (including vertebral fracture resulting from increased bone resorption following chemotherapy-induced menopause), and hypercalcemia are components of skeletal morbidity. The pathophysiology of malignant osteopathy occurs because of the secretion of substances (such as parathyroid hormone-related peptide), by the malignant cell, which stimulate osteoclast function; this in turn feeds further growth, which causes a vicious cycle. Interruption of this cycle by bisphosphonates may inhibit the growth of malignant cells. Bisphosphonates are drugs that inhibit bone turnover by decreasing bone resorption. Side effects of bisphosphonates include upper gastrointestinal symptoms (in oral nitrogen-containing bisphosphonates) and diarrhea (in oral non-nitrogen-containing bisphosphonates) and an acute phase-like reaction with intravenous (I.V.) pamidronate. Bisphosphonates have different molecular mechanisms of action: Nitrogen-containing bisphosphonates (eg, pamidronate and alendronate) inhibit the mevalonate-signaling pathway while the non-nitrogen-containing drugs (eg, clodronate) incorporate into adenosine triphosphate analogues. There is in vitro evidence that these drugs also possess anticancer properties. In hypercalcemia patients, treatment with pamidronate and zoledronate produce prompt and efficient normocalcemia. Intravenous pamidronate and zoledronate, oral clodronate, and ibandronate reduce skeletal complications in patients with bone metastases; I.V. pamidronate and clodronate are useful for bone pain relief. Three adjuvant bisphosphonate trials are discussed herein: 2 small open-label studies giving conflicting results and a large placebo-controlled trial of oral clodronate. This latter trial shows a reduction in the incidence of skeletal metastases (while the patients are on therapy) and an improved survival at 5 years.     

Systematic Literature Review and Network Meta‐Analysis Comparing Bone‐Targeted Agents for the Prevention of Skeletal‐Related Events in Cancer Patients With Bone Metastasis

Background.

Complications from skeletal-related events (SREs) constitute a challenge in the care of cancer patients with bone metastasis (BM).

Objectives.

This study evaluated the comparative effectiveness of pamidronate, ibandronate, zoledronate, and denosumab in reducing the morbidity of SREs in cancer patients with BM.

Methods.

Medline (1948 to January 2014), Embase (1980 to January 2014), the Cochrane Library (2014 issue 1), and Web of Science with Conference Proceedings (1970 to January 2014) were searched. Only randomized controlled trials assessing denosumab, bisphosphonates, or placebo in cancer patients with BM were included. The primary outcomes were SREs and SREs by type. The network meta-analysis (NMA) was performed with a random-effects Bayesian model.

Results.

The NMA included 14 trials with 10,192 patients. Denosumab was superior to placebo in reducing the risk of SREs (odds ratio [OR]: 0.49; 95% confidence interval [CI]: 0.31–0.75), followed by zoledronate (OR: 0.57; 95% CI: 0.41–0.77) and pamidronate (OR: 0.55; 95% CI: 0.41–0.72). Ibandronate compared with placebo could not reduce the risk of SREs. Denosumab was superior to placebo in reducing the risk of pathologic fractures (OR: 0.50; 95% CI: 0.32–0.79), followed by zoledronate (OR: 0.61; 95% CI: 0.43–0.86). Denosumab was superior to placebo in reducing the risk of radiation (OR: 0.51; 95% CI: 0.35–0.75), followed by pamidronate (OR: 0.67; 95% CI: 0.52–0.86) and zoledronate (OR: 0.70; 95% CI: 0.52–0.96).

Conclusion.

This NMA showed that denosumab, zoledronate, and pamidronate were generally effective in preventing SREs in cancer patients with BM. Denosumab and zoledronate were also associated with reductions in the risk of pathologic fractures and radiation compared with placebo. Denosumab was shown to be the most effective of the bone-targeted agents.     

Osteonecrosis of the jaw in patients with bone metastases treated with bisphosphonates: a retrospective study

OBJECTIVE: Bone metastases are a major cause of morbidity in cancer patients. Treatment includes bisphosphonates, which are also associated with avascular osteonecrosis of the jaw (ONJ). Our aim was to evaluate the correlation between bisphosphonates and ONJ. PATIENTS AND METHODS: Of the 539 patients with bone metastases treated in our department from June 2002 to December 2006 with i.v. bisphosphonates, eight (1.5%) developed ONJ. RESULTS: The eight patients with ONJ had all been given zoledronic acid, and two had also been treated with pamidronic acid. In four of the patients, ONJ was diagnosed during treatment, while in the remaining four it was diagnosed several months after therapy with bisphosphonates had ended. Six of these patients received local noninvasive treatment, of whom five progressed. Two showed apparent autolimitation of the disease. The remaining two patients underwent surgical resection and currently show no signs of relapse. All eight ONJ patients presented with various concomitant risk factors such as paradontopathy, dental extraction, or spontaneous avulsion. CONCLUSIONS: Our results show that ONJ can appear months after interruption of treatment and that a surgical approach can be used in suitable cases. Closer cooperation is needed among specialists to define guidelines for the prevention of ONJ in patients with bone metastases.     

Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: definition and management of the risk related to zoledronic acid

PurposeBisphosphonates (BPs) are currently used to treat bone lesions in patients with multiple myeloma (MM). Osteonecrosis of the jaw (ONJ) has been reported as an adverse event of such treatment, especially after treatment with zoledronic acid (ZA). The aim of this study was to evaluate incidence, risk factors, management, and prevention strategies of ONJ in order to optimize the current standard use of BPs in MM.Patients and MethodsWe reviewed the medical records of 105 patients with MM treated in 2 hematology departments with monthly pamidronate 90 mg and/or ZA 4 mg and evaluated for ≥ 12 months. Because they are risk factors for ONJ development, we analyzed patient and disease features, previous MM treatments, type and number of BP infusions, and previous history of dental procedures.ResultsSeventeen patients (16%) with MM treated with BPs developed ONJ after a median number of 43 BP infusions (vs. 28 in patients without ONJ; P = .035). In 11 of 17 patients, ONJ arose after a tooth extraction. Among risk factors, the administered doses of ZA were significantly associated with ONJ, and 12 consecutive doses of ZA proved to double the risk of developing this complication. Regular hard- and soft-tissue oral assessment was of benefit in the prevention of further ONJ occurrence.ConclusionThe most important risk factor for ONJ is represented by the number of ZA infusions. Tooth extractions and invasive procedures should be avoided. A multidisciplinary approach including oncohematologists and dental teams proved critical to better identify, prevent, and manage ONJ.     

Decreased occurrence of osteonecrosis of the jaw after implementation of dental preventive measures in solid tumour patients with bone metastases treated with bisphosphonates. The experience of the National Cancer Institute of Milan

Background: Screening of the oral cavity and dental care wassuggested as mandatory preventive measures of osteonecrosisof the jaw (ONJ) in patients receiving bisphosphonates (BPs).We investigated the occurrence of ONJ before and after implementationof dental preventive measures when starting BP therapy. Patients and methods: Since April 2005, 154 consecutive patientstreated with BPs (POST-Group) have undergone a baseline mouthassessment (dental visit ± orthopantomography of thejaws) to detect potential dental conditions and dental careif required. A retrospective review was also conducted of allconsecutive cancer patients with bone metastases (PRE-Group)and treated for the first time with BPs from January 1999 toApril 2005 in our clinic without receiving any preventive measure.Incidence proportion and incidence rate (IR) were used to estimatethe incidence of ONJ. Results: Among the study population (966 patients; male/female= 179/787), 73% had breast cancer. 25% of patients were givenzoledronic acid (ZOL), 62% pamidronate (PAM), 8% PAM followedby ZOL and 5% clodronate. ONJ was observed in 28 patients (2.9%);we observed a reduction in the incidence of ONJ from 3.2% to1.3%, when comparing—pre and post-implementation of preventivemeasures programme. Considering the patients exposed to ZOL,the performance of a dental examination and the applicationof preventive measures led to a sustained reduction in ONJ IR(7.8% in the PRE-Group versus 1.7% in the POST-Group; P = 0.016),with an IR ratio of 0.30 (95% confidence interval 0.03–1.26). Conclusions: ONJ is a manageable and preventable condition.Our data confirm that the application of preventive measurescan significantly reduce the incidence of ONJ in cancer patientsreceiving BPs therapy. Dental exams combined to the identificationof patients at risk in cooperation with the Dental Team canimprove outcomes and increase the number of ONJ-free patients. Key words: bisphosphonates, bone metastases, dental preventive measures, dental team, ONJ, osteonecrosis of the jaw, osteoporosis Received for publication February 15, 2008. Revision received June 17, 2008. Accepted for publication June 23, 2008.     

Propriétés antitumorales du bisphosphonate zolédronate et implications thérapeutiques potentielles en clinique

Zoledronate, just as other bisphosphonates, inhibit osteoclast mediated bone resorption. This is the reason why they are used in the treatment of bone metastasis, in order to block osteolysis. Zoledronate and some other bisphosphonates (clodronate, pamidronate, ibandronate, alendronate, risédronate, minodronate) also exhibit antitumor properties in vitro. They act directly on tumor cells by blocking tumor cell adhesion, invasion and proliferation, and by inducing tumor cell apoptosis. However, their high bone mineral affinity decreases their bioavailability to a significant extent and, thus, should weaken their in vivo antitumor potential. Despite of this, several studies (most of them being performed with zoledronate) show that bisphosphonates have an in vivo antitumor activity. This review focuses on zoledronate and on results obtained in several experimental models showing that this bisphosphonate interferes with the growth of tumors and metastases which are thriving in tissues others than the skeletal tissue. The significance of these findings is discussed in the light of several ongoing clinical trials which examine the benefits of using zoledronate and other bisphosphonates in the adjuvant treatment of cancers at an early stage of the disease.     

Osteonecrosis of the maxilla and mandible in patients with advanced cancer treated with bisphosphonate therapy

Cases of osteonecrosis of the jaw (ONJ) have been reported with an increasing frequency over the past 5 years. ONJ is most often identified in patients with cancer who are receiving intravenous bisphosphonate (IVBP) therapy, but it has also been diagnosed in patients receiving oral bisphosphonates for nonmalignant conditions. To further categorize risk factors associated with ONJ and potential clinical outcomes of this condition, we performed a retrospective study of patients with metastatic bone disease treated with intravenous bisphosphonates who have been evaluated by the Memorial Sloan-Kettering Cancer Center Dental Service between January 1, 1996 and January 31, 2006. We identified 310 patients who met these criteria. Twenty-eight patients were identified as having ONJ at presentation to the Dental Service and an additional 7 patients were subsequently diagnosed with ONJ. Statistically significant factors associated with increased likelihood of ONJ included type of cancer, duration of bisphosphonate therapy, sequential IVBP treatment with pamidronate followed by zoledronic acid, comorbid osteoarthritis or rheumatoid arthritis, and benign hematologic conditions. Our data do not support corticosteroid use or oral health as a predictor of risk for ONJ. Clinical outcomes of patients with ONJ were variable with 11 patients demonstrating improvement or healing with conservative management. Our ONJ experience is presented here.     

Bisphosphonates in Oncology

Pamidronate (pamidronic acid) is an aminobisphosphonate that interferes with the mevalonate pathway inducing osteoclast-apoptotic cell death. A 90mg dose of pamidronate administered in a 2- to 24-hour infusion achieves normocalcemia in >90% of unselected patients. Zoledronate (zoledronic acid) is more effective than pamidronate in normalising calcium levels in patients with tumor-induced hypercalcemia, at least in patients without bone metastases; however, zoledronate should be used with caution in patients with renal insufficiency. Pamidronate can be safely administered in hypercalcemic patients with renal insufficiency. Clinically meaningful bone pain relief occurs in about half of patients treated with pamidronate. Pamidronate also achieved significantly better pain control than placebo in patients with breast cancer (bone metastases) or myeloma, in 2-year placebo-controlled trials. Pamidronate 90mg administered over 2 hours every 3–4 weeks for 2 years has been shown to reduce the frequency of skeletal-related events in patients with bone metastases from breast cancer by up to 40% and in patients with multiple myeloma by nearly 50%. In the largest randomized double-blind trial that compared zoledronate 4 or 8mg with pamidronate 90mg every 3–4 weeks in patients with breast cancer or myeloma, the primary efficacy endpoint (proportion of patients experiencing at least one skeletal-related event) was similar in all three treatment groups. The 8mg dose of zoledronate had to be lowered to 4mg during the trial because of renal toxicity. Indeed, concern about the renal toxicity of zoledronate has led authorities to recommend controlling serum creatinine levels before each infusion. When the data were analyzed by a complex multiple-event analysis, the hazard ratio for developing a bone complication was reduced by about 16% in patients treated with zoledronate compared with pamidronate after 2 years of therapy. This superiority of zoledronate was observed in the breast cancer subgroup but not in myeloma patients. However, multiple-event analyses rely on assumptions that are not unanimously accepted. The short duration of zoledronate infusion (15 minutes compared with 1.5–2 hours for pamidronate) is its most evident advantage, but cost savings have not been confirmed so far in limited micro-costing analyses. Positive effects of pamidronate therapy on bone mass have been shown in patients with prostate cancer who are undergoing androgen-blockade therapy; antineoplastic therapy-induced bone loss was prevented. Studies with bisphosphonates are ongoing in breast cancer patients receiving aromatase inhibitors for the prevention of cancer treatment-induced bone loss. Zoledronate appears to be more potent than pamidronate for the prevention of endocrine therapy-induced bone loss.     

Osteonecrosis of the jaw: dental outcomes in metastatic breast cancer patients treated with bisphosphonates with/without bevacizumab

The etiology, optimal management, and outcome of osteonecrosis of the jaw (ONJ) are not well understood. Because healing after mucosal trauma requires revascularization, theoretically, the combination of bevacizumab (bev) and a bisphosphonate (BP) could affect the time to development of ONJ and/or the response to dental therapy. We reviewed all cases of ONJ in metastatic breast cancer patients treated at our institution with bev+BPs and BPs alone between October 2002 and April 2010. We identified 27 ONJ patients with a median age of 57 years (range, 40 to 68 years). Seven patients received bev+BPs; 20 patients received BPs alone. Patients received intravenous zolendronate (95%), pamidronate (20%), or both (15%). Patients were treated with antibiotics (93%), alveoplasty/debridement (67%), and chlorhexidine scrub (81%). There was no difference in dental treatment between the groups or by the year of diagnosis (before 2007 versus 2007-2010). Complete resolution (CR) was achieved in 24% of all patients; 33% treated with bev+BPs, and 21% treated with BPs alone. Rates of CR improved from 15% to 33% after 2007. The median time to response was 5.6 months (range, 1.3 to 67.5 months). The addition of bev to BPs did not appear to alter the time to development of ONJ (32.6 months versus 34.6 months, respectively). The number of BP treatments administered before the diagnosis of ONJ between bev+BPs and BPs (32 doses versus 36.5 doses) was similar. However, our sample size was too small to characterize the difference statistically. Because dental management of ONJ has not changed over time at our institute, early recognition and screening may account for the improvement in dental outcomes.     

Bevacizumab and osteonecrosis of the jaw: incidence and association with bisphosphonate therapy in three large prospective trials in advanced breast cancer

Long-term bisphosphonate therapy is associated with increased risk of osteonecrosis of the jaw (ONJ). In a retrospective analysis, a 16% ONJ incidence was reported in patients receiving bisphosphonates with anti-angiogenic therapy (bevacizumab or sunitinib) for bone metastases from breast, colon, or renal cell cancers. To assess ONJ incidence with bevacizumab, we analysed data from 3,560 patients receiving bevacizumab-containing therapy for locally recurrent or metastatic breast cancer (LR/MBC) in two double-blind, randomised trials (AVADO and RIBBON-1) and a large, non-randomised safety study (ATHENA). The overall incidence of ONJ with bevacizumab was 0.3% in the blinded phase of the two randomised trials and 0.4% in the single-arm study. There was a trend towards increased ONJ incidence in patients who received bisphosphonate therapy versus those with no bisphosphonate exposure (0.9 vs. 0.2%, respectively, in the pooled analysis of the randomised trials; 2.4 vs. 0%, respectively, in ATHENA). In conclusion, this is the largest analysis of ONJ in patients receiving bevacizumab for LR/MBC. The 0.3–0.4% incidence is considerably lower than previously suggested with anti-angiogenic therapy in a small retrospective analysis. The risk of ONJ appeared to be increased in patients exposed to bisphosphonates, a pattern consistent with observations before the introduction of anti-angiogenic therapy to breast cancer management. The 0.9–2.4% incidence seen in bisphosphonate-exposed patients receiving bevacizumab is within the 1–6% range reported for bisphosphonates alone. Good oral hygiene, dental examination, and avoidance of invasive dental procedures remain important in patients receiving bisphosphonates, irrespective of bevacizumab administration.     

Neurotoxicity of bortezomib therapy in multiple myeloma: a single-center experience and review of the literature

BACKGROUND: Bortezomib is active in heavily pretreated multiple myeloma patients; the dose-limiting toxicity is peripheral neuropathy (PN). METHODS: The authors retrospectively reviewed the incidence, severity, and risk factors for PN in 78 patients who received bortezomib. The median age was 57 years (range, 33-80 years), 62% of patients were men, and 37% of patients were African Americans. Seventeen patients (22%) had diabetes mellitus (DM), and 66 patients (85%) had received thalidomide. Before bortezomib treatment, 37% of the patients reported subjective, grade 1 or 2 PN. Patients received bortezomib alone (n = 10 patients) plus dexamethasone (n = 36 patients) and thalidomide (n = 20 patients) or chemotherapy (n = 12 patients). PN affected 52% of patients, including grade 3 and 4 PN in 15% and 7%, respectively. RESULTS: Twelve patients stopped bortezomib because of side effects that included PN (n = 9 patients), diarrhea (n = 2 patients) and cytomegalovirus pneumonia (n = 1 patient); 11 patients had dose reductions because of PN. Grade 4 PN affected 6 patients (sensory, n = 4 patients; motor/sensory, n = 2 patients). The onset of grade 4 PN was sudden rather than cumulative. Factors that were predictive of PN grade were baseline PN (P = .002), prior thalidomide use (P = .03), and the presence of DM (P = .03). Multiple myeloma responses included complete, near complete, and partial responses in 5% of patients, 10% of patients, and 27% of patients, respectively. Responses were independent of PN and of whether bortezomib was combined with chemotherapy or thalidomide. Patients remained on therapy longer for a median of 5 cycles (range, 2-36 cycles) when they received bortezomib plus thalidomide versus 3 cycles (range, 1-19 cycles) for the other combinations. PN therapy was mostly supportive. It was noteworthy that 6 of 9 patients with PN who received lenalidomide as salvage therapy after bortezomib had significant improvement in their symptoms. CONCLUSIONS: The risk of bortezomib-related PN was greater in patients who had PN and DM at baseline. The authors concluded that an unexpected, symptomatic improvement of PN on lenalidomide is worth further investigation.     

Bisphosphonates directly regulate cell proliferation, differentiation, and gene expression in human osteoblasts

Bisphosphonates are widely used clinically to treat bone diseases in which bone resorption is in excess. However, the mechanism of bisphosphonate action on bone is not fully understood. Studies of direct action of bisphosphonates on bone have been limited mainly to their effects on bone-resorbing osteoclast cells, with implications that some activity may be mediated indirectly through paracrine factors produced by the bone-forming osteoblast cells. Little is known about the direct effects of bisphosphonates on osteoblasts. In this report, the direct actions of several bisphosphonates on cell proliferation, gene expression, and bone formation by cultured human fetal osteoblasts were examined. Osteoblast cell proliferation was decreased, and cytodifferentiation was increased in a dose-dependent manner in cultures treated with the bisphosphonate pamidronate. In addition, pamidronate treatment increased total cellular protein, alkaline phosphatase activity, and type I collagen secretion in osteoblasts. Consistent with the above-mentioned findings, the rate of bone formation was also increased in osteoblasts cultured with pamidronate. The actions of two other bisphosphonates, the weak-acting etidronate and the potent new analogue zoledronate, were also compared with the action of pamidronate on proliferation of immortalized human fetal osteoblast (hFOB) cells and rate of bone formation. Pamidronate and zoledronate decreased hFOB cell proliferation with equal potency, whereas etidronate decreased proliferation only at much higher concentrations. Studies comparing EDTA and etidronate indicate that etidronate may act indirectly on the hFOB cells by reducing free divalent ion concentrations, whereas pamidronate and zoledronate appear to act on the hFOB cells by a direct action. Both pamidronate and zoledronate increase hFOB cell bone formation, whereas no increase is observed with etidronate and EDTA. Taken together, these observations strongly suggest that treatment with pamidronate or zoledronate enhances the differentiation and bone-forming activities of osteoblasts.     

双膦酸盐治疗乳腺癌骨转移患者的临床病理特征及预后分析*

目的:探讨乳腺癌骨转移患者的临床、病理、治疗及预后因素。方法:收集2005年1 月至2013年4 月天津医科大学肿瘤医院收治的183 例至少接受6 个月双膦酸盐治疗的乳腺癌骨转移患者的临床资料,根据双膦酸盐类型分为帕米膦酸二钠组、唑来膦酸组及帕米膦酸二钠序贯唑来膦酸组,探讨骨转移的特点、骨相关事件（skeletal-related events,SREs）、治疗及预后特征。结果:胸椎和肋骨为骨转移的常见转移部位,骨转移至发生首次SREs的中位时间为4.2 个月,51.9%（95/ 183）患者发生SREs,累计SREs事件数达167 次,其中110 次（65.9%）发生在骨转移后1 年内,SREs类型以骨放疗为主。患者在不同双膦酸盐药物组的SREs发生率差异无统计学意义（P > 0.05）。 183 例患者骨转移后的中位生存期为43.1 个月,激素受体状态、无病生存期、是否合并内脏转移及脊柱转移与否是乳腺癌骨转移患者的独立预后因素（P < 0.05）。 结论:胸椎和肋骨是乳腺癌骨转移的常见转移部位,SREs主要发生在骨转移后1 年内并以骨放疗为主。激素受体阴性、无病生存期短、合并内脏及脊柱转移是影响乳腺癌患者骨转移不良预后的独立因素。