Anti-tumour activity of bisphosphonates in human myeloma cells

Multiple myeloma is a haematological malignancy characterized by an expansion of malignant plasma cells within the bone marrow and is frequently associated with bone disease involving the development of osteolytic bone lesions, pathological fractures, osteoporosis and hypercalcaemia. A class of anti-resorptive drugs known as bisphosphonates have been in use to treat osteoclast-mediated bone diseases for the past 3 decades, and are currently proving effective in the treatment of the bone disease associated with multiple myeloma. Recent studies have suggested that bisphosphonate treatment may also result in an improvement in survival in some patients with multiple myeloma. These effects on survival may reflect an indirect effect of the bisphosphonates on tumour growth, via inhibition of osteoclast activity and hence a reduction in the release of tumour growth factors. However, it is also possible that bisphosphonates may have a direct effect on myeloma cells. In support of this we have demonstrated that bisphosphonates can decrease cell proliferation and induce apoptosis in human myeloma cells in vitro, and this review discusses the possibility that bisphosphonates may have not only an anti-resorptive action, but may also have a direct anti-tumour activity.     

Bisphosphonates--mechanisms of action in multiple myeloma

Bisphosphonates are a class of anti-resorptive drugs, which are effective in the treatment of osteoclast-mediated bone disease, including the osteolytic bone disease, which is a major clinical feature of patients with multiple myeloma. Recently, increases in survival following treatment with pamidronate have been observed in some patients with multiple myeloma, raising the possibility that bisphosphonates may also have an anti-tumour effect. We have demonstrated that bisphosphonates can have an anti-tumour effect in human myeloma cell in vitro, and that these anti-tumour effects induced by potent nitrogen-containing bisphosphonates are a result of inhibition of enzymes of the mevalonate pathway. However, we and others have been unable to demonstrate an anti-tumour effect of the potent bisphosphonate ibandronate in vivo, using murine models of multiple myeloma. It is therefore likely that only by studying patients receiving bisphosphonates will we be able to determine whether these compounds have a clinically important anti-tumour effect.     

The role of bisphosphonates in the management of advanced cancer with a focus on non-small-cell lung cancer. Part 1: Mechanisms of action, role of biomarkers and preclinical applications

With recent advances in cancer management, patients with metastatic bone disease are likely to have a prolonged clinical course, with skeletal-related events such as pain, hypercalcemia, pathologic fractures, spinal cord and nerve compression. Bisphosphonate use has resulted in the reduction of skeletal-related complications for a number of tumors including breast, prostate and myeloma, and improvements in the quality of life for patients. There is now evidence that newer, highly potent, nitrogen-containing bisphosphonates reduce skeletal complications in patients with bone metastases from other solid tumors (including lung cancer). The early identification of patients at high risk for developing bone metastases may help curtail a complex and costly clinical problem--skeletal-related events. In this article, we review the different mechanisms of bisphosphonates and the potential role of newer-generation bisphosphonates, such as zoledronic acid, in the management of advanced, metastatic bone disease. We include a review of mechanistic studies and preclinical data. Additionally, the utility of evolving concepts such as bone markers and imaging of bone metastases are discussed.     

The antineoplastic role of bisphosphonates: from basic research to clinical evidence.

Bisphosphonates are now well established as successful agents for the prevention and treatment of postmenopausal osteoporosis, corticosteroid-induced bone loss and Paget's disease. Bisphosphonates have also recently become important in the management of cancer-induced bone disease, and they now have a widely recognized role for patients with multiple myeloma and bone metastases secondary to breast cancer and prostate cancer. Recent studies suggest that, besides the strong antiosteoclastic activity, the efficacy of such compounds in the oncological setting could also be due also to direct antitumor effect, exerted at different levels. Here, after a brief analysis of the chemical structure, we will review the antineoplastic and biological properties of bisphosphonates. We will start from well estabilished mechanisms of action and go on to discuss the latest evidence and hypotheses. In particular, we will review the antiresorptive properties in malignant osteolysis and the recent evidence of a direct antitumor effect. Furthermore, this review will analyze the influence of bisphosphonates on cancer growth factor release, their effect on cancer cell adhesion, invasion and viability, the proapoptotic potential on cancer cells, the antiangiogenic effect, and, finally, the immunomodulating properties of bisphosphonates on the gammadelta T cell population.     

Bisphosphonates in the prevention and treatment of bone metastases

Bisphosphonates have an established role in treating tumor-induced hypercalcemia and decreasing the incidence of skeletal-related events. Recent data suggest that these agents may also prevent skeletal metastases. This review explains how cancer metastasizes to bone and how bisphosphonates may block this process, with a summary of clinical trials supporting the use of bisphosphonates to treat and prevent bone metastases. For skeletal metastases in patients with breast cancer, multiple myeloma, or other solid tumors, bisphosphonates are important adjuncts to systemic therapy. Despite promising results in metastatic prostate cancer, additional trials are needed before bisphosphonates become part of standard treatment in this setting. Ongoing trials are evaluating the preventive role of the third-generation bisphosphonates in breast cancer patients. Until the results of these trials are presented, bisphosphonates should only become a component of adjuvant treatment in the context of a clinical trial. Bone loss, a common consequence of cancer treatment, should be treated with the usual measures indicated for the management of osteoporosis, including bisphosphonates.     

The use of bisphosphonates in cancer patients

Skeletal-related events resulting from bone metastases or osteoporosis can significantly contribute to morbidity and mortality in cancer patients. Expert opinion on the effectiveness of bisphosphonates in this setting is evolving. Here we review current evidence on the risks and benefits of bisphosphonate therapy for a wide variety of cancers, as well as clinical management of its adverse effects. A MEDLINE search of English-language literature (1966 through May 2006) was conducted using the terms bisphosphonate, cancer, multiple myeloma, malignancy, and randomized controlled clinical studies. Studies were selected based on clinical pertinence, with an emphasis on phase III clinical trials. We reviewed bibliographies for other relevant articles. Accumulating evidence reveals that bisphosphonate therapy has a significant effect in preventing skeletal complications in multiple myeloma, breast cancers, and prostate cancer, and in reducing skeletal complications in other metastatic bone malignancies. Emerging data indicate that bisphosphonates are useful for preventing bone loss resulting from cancer or its therapy. The efficacy of bisphosphonates for early-stage breast cancers remains controversial. Significant risks of bisphosphonate therapy include nephrotoxicity, electrolyte abnormalities, and osteonecrosis of the jaw. Bisphosphonate therapy has a clear role in the management of skeletal metastases associated with a variety of cancers. However, significant side effects require ongoing monitoring and treatment.     

Management of Metastatic Bone Disease and Hypercalcemia of Malignancy

Thirty years of research have established bisphosphonates as the most effective agents for the inhibition of osteoclast-mediated bone resorption, and they play an important role in the management of malignant bone disease. Bisphosphonates have been systematically improved through chemical engineering, and the newest nitrogen-containing compounds, including zoledronic acid and ibandronate, are 1000-fold more potent than first-generation compounds. Consequently, they can be administered at low molar doses via short intravenous infusions without compromising renal safety. Bisphosphonates have a variety of metabolic effects on osteoclasts. Nitrogen-containing bisphosphonates inhibit protein prenylation via the mevalonate pathway, thereby inhibiting osteoclast activation and inducing apoptosis. Preclinical studies suggest that bisphosphonates also have direct and indirect antitumor activity. In animal models, bisphosphonates reduced skeletal tumor burden and bone metastases. Currently, intravenous bisphosphonates are the standard therapy for hypercalcemia of malignancy, and they have become an integral part of the treatment of bone metastases in conjunction with standard antineoplastic agents. Intravenous bisphosphonates quickly normalize serum calcium, reduce skeletal complications, and palliate bone pain in patients with bone metastases. Intravenous pamidronate (90mg via 2-hour infusion every 3–4 weeks) has, until recently, been the international standard for the treatment of osteolytic bone lesions from breast cancer or multiple myeloma. However, 4mg zoledronic acid (via 15-minute infusion) is quickly becoming the new standard based on evidence that it is as safe and effective as 90mg pamidronate in patients with breast cancer and multiple myeloma and significantly more effective for hypercalcemia of malignancy. Consequently, the American Society of Clinical Oncology guidelines for breast cancer and multiple myeloma recommend pamidronate or zoledronic acid for patients with radiographic evidence of osteolytic bone destruction. Moreover, 4mg zoledronic acid is the only bisphosphonate that has demonstrated significant clinical benefit in patients with other solid tumors, including lung cancer, and prostate cancer patients with primarily osteoblastic bone metastases. Bisphosphonates also may have activity in the adjuvant setting to prevent or delay the development of bone metastases. Studies with oral clodronate in early breast cancer have provided clinical evidence that bone metastases can be inhibited, and the studies are ongoing with more potent bisphosphonates. Bisphosphonates have also been shown to prevent cancer treatment-induced bone loss. These and other studies continue to redefine the role of bisphosphonates in the treatment of malignant bone disease and the management of bone health in cancer patients.     

Management of bone lesions in multiple myeloma

Bone destruction is a key feature of multiple myeloma, which causes significant impairment of patients' activity. Some of the mechanisms regulating bone destruction have recently been clarified, and the management of bone diseases in myeloma patients has made considerable progress. Moreover,imaging techniques for screening bone lesions have been developed, such as PET scan or (99m)Tc scan, other than regular X-ray analysis. We describe here strategies for the management of bone disease in myeloma, e.g., ( I ) effective chemotherapy against myeloma cells, (II) decrease of osteoclasts by bisphosphonates, (III) surgical treatment of damaged bone, (IV) irradiation to lytic bone lesion and (V) other forms of supportive care. All of these approaches should be effectively integrated to improve the quality of life of myeloma patients.     

Bone complications in multiple myeloma

Multiple myeloma is the malignant proliferation of plasma cells involving more than 10% of the bone marrow. The bone complications associated with multiple myeloma include bone pain, pathologic fractures, hypercalcemia of malignancy and cord compressions. The principal pathophysiology of bone disease in multiple myeloma is a shift in the balance of bone remodeling toward bone resorption. In recent years, bisphosphonates have become an important treatment for the bone complications of multiple myeloma. Potent inhibitors of osteoclast activity, bisphosphonates interfere with biochemical pathways and induce osteoclast apoptosis. Bisphosphonates also antagonize osteoclastogenesis and promote differentiation of osteoblasts, as well as inhibiting other aspects of osteoclast homeostasis and metabolism. Several studies have evaluated treatment with bisphosphonates in patients with multiple myeloma, and have demonstrated the efficacy of clodronate (Bonefos; Anthra Pharmaceuticals; Princeton, NJ; www.bonefos.com), pamidronate (Aredia; Novartis Pharmaceuticals Corp; East Hanover, NJ; www.pamidronate.com) and zoledronic acid (Zometa; Novartis Pharmaceuticals Corp; East Hanover, NJ; www.us.zometa.com) in reduction of pain, reduction of SREs and survival. Moreover, recent data suggest direct and indirect antimyeloma activity of pamidronate and zoledronic acid.     

Myeloma bone disease: pathophysiology and management.

Bone disease is a major feature of multiple myeloma. Myeloma-induced bone destruction is the result of an increased activity of osteoclasts, which is not accompanied by a comparable increase of osteoblast function. Recent studies have revealed that new molecules such as the receptor activator of nuclear factor-kappa B (RANK), its ligand (RANKL), osteoprotegerin (OPG), and macrophage inflammatory protein-1alpha are implicated in osteoclast activation and differentiation, while proteins such as dickkopf-1 inhibit osteoblastic bone formation. These new molecules seem to interfere not only with the biology of myeloma bone destruction but also with tumour growth and survival, creating novel targets for the development of new antimyeloma treatment. Currently, bisphosphonates play a major role in the management of myeloma bone disease. Clodronate, pamidronate and zoledronic acid are the most effective bisphosphonates in symptomatic myeloma patients. Biochemical markers of bone remodeling have been used in an attempt to identify patients more likely to benefit from early treatment with bisphosphonates. Furthermore, using microarray techniques, myeloma patients may be subdivided into molecular subgroups with certain clinical characteristics, such as propensity for lytic lesions that may need early prophylactic treatment. Recent phase I studies with recombinant OPG and monoclonal antibodies to RANKL appear promising.     

Optimizing clinical benefits of bisphosphonates in cancer patients with bone metastases

Bisphosphonates are important treatments for bone metastases. Considerations for optimizing the clinical benefits of bisphosphonates include efficacy, compliance, and safety. Several bisphosphonates are approved for clinical use; however, few have demonstrated broad efficacy in the oncology setting and been compared directly in clinical trials. Among patients with bone metastases from breast cancer, the efficacy of approved bisphosphonates was evaluated in a Cochrane review, showing a reduction in the risk of skeletal-related events (SREs) ranging from 8% to 41% compared with placebo. Between-trial comparisons are confounded by inconsistencies in trial design, SRE definition, and endpoint selection. Zoledronic acid has demonstrated clinical benefits beyond those of pamidronate in a head-to-head trial that included patients with breast cancer or multiple myeloma. Compliance and adherence also have effects on treatment efficacy. In a comparison study, the adherence rates with oral bisphosphonates were found to be significantly lower compared with those of intravenous bisphosphonates. The safety profiles of oral and intravenous bisphosphonates differ. Oral bisphosphonates are associated with gastrointestinal side effects, whereas intravenous bisphosphonates have dose- and infusion rate-dependent effects on renal function. Osteonecrosis of the jaw is an uncommon but serious event in patients receiving monthly intravenous bisphosphonates or denosumab. The incidence of this event can be reduced with careful oral hygiene. A positive benefit-risk ratio for bisphosphonates has been established, and ongoing clinical trials will determine whether individualized therapy is possible.     

Prevention and Treatment of Myeloma Bone Disease

Osteolytic bone disease is the most common complication of multiple myeloma, resulting in skeletal-related events (SREs) that cause significant morbidity. Bone destruction in myeloma is due to an increased activity of osteoclasts coupled with suppressed bone formation by osteoblasts. Currently, bisphosphonates are the mainstay of the treatment of myeloma bone disease. Zoledronic acid and pamidronate have shown similar efficacy in reducing SREs in a randomized study in the conventional chemotherapy era. However, in a recent study (the Myeloma-IX trial of the UK Medical Research Council, MRC), zoledronic acid was found to be superior to clodronate in reducing SREs, but also it produced a survival advantage of approximately 10?months in patients with bone disease at baseline. During recent years, novel agents targeting bone have been used in myeloma. This review focuses on the established therapy of myeloma bone disease and also on recent advances in treatment that take advantage of the better understanding of the pathophysiology of bone disease.     

多发性骨髓瘤骨病临床诊疗专家共识（2021）

多发性骨髓瘤骨病(MBD)是多发性骨髓瘤(MM)患者的常见并发症,严重影响其生活质量和生存期,因此强调规范化的诊断和治疗。此次中国临床肿瘤学会(CSCO)指南工作委员会组织专家组,在2014版MBD专家共识的基础上进行了更新补充,推荐对于初治的MM患者,无论是否存在骨病的影像学证据,均应使用双膦酸盐和/或地舒单抗积极预防MBD及骨相关事件。在双膦酸盐使用期间,应该密切监测肾功能及颌骨改变,对于肾功能不全的患者需要减量甚至禁用,同时这类患者宜优先选用地舒单抗。希望本共识作为学术性指导意见,能够提供恰当的临床诊疗参考,以便使患者获得最佳的治疗,具体实施时应该根据患者的个体情况而定。     

The role of bisphosphonates in the management of advanced cancer with a focus on non-small-cell lung cancer. Part 2: Clinical studies and economic analyses

Newer-generation intravenous bisphosphonates have resulted in the reduction of skeletal-related complications, i.e. skeletal-related events (SREs) such as pain, hypercalcemia, pathologic fractures and spinal cord and nerve compression, as well as improvements in the quality of life in patients with metastatic bone disease who are likely to have a prolonged clinical course. Highly potent, nitrogen-containing bisphosphonates such as zoledronic acid reduce SREs in patients with bone metastases from other solid tumors (including lung cancer). Part one of our review discussed the mechanisms of action by bisphosphonates as well as potential roles for bone markers and imaging in lung cancer. In this article, part two of our review, we examine the economic and clinical impact of bisphosphonates in lung cancer, with a focus on the potential role of newer-generation bisphosphonates in the management of advanced, metastatic bone disease of lung cancer.     

双膦酸盐类药物治疗骨髓瘤骨病的临床研究

 目的 总结双膦酸盐类药物对我国多发性骨髓瘤患者骨病的疗效及其意义。方法 采用历史同期对照研究分析1995年2月至2007年12月205例多发性骨髓瘤患者,比较应用双膦酸盐类药物组（简称用药组）和未用双膦酸盐类药物组（简称未用药组）患者骨骼事件的发生率,骨病改善的程度,并分析此类药物的应用对预后的影响。结果 骨骼事件发生率用药组低于未用药组[38.9%(35/90)比54.8%(63/115)]（P＜0.01）,用药组发生第一次骨事件时间及发生第一次病理性骨折的时间均明显长于未用药组[（34.7±3.2）个月比（27.5±3.2）个月,（47.2±3.6）个月比（42.7±5.0）个月]（均P＜0.05）。分层分析上述时间,MP/M2及VAD/DVD为主的方案组中用药组发生第一次骨骼事件的时间均明显长于未用药组[（59.4±5.6）个月比（30.1±4.0）个月,（29.0±4.0）个月比（22.4±4.7）个月]（P=0.024,P=0.043）。治疗6周期后不同治疗组评价骨髓瘤骨病（MBD）的治疗反应,用药组有效+显效者比例明显高于未用药组[80.0%（64/80）比48.7%（37/76）]（P<0.001）;高钙血症治疗的有效率分别为100%（70/70）、98.3%（59/60）,二者差异无统计学意义（P=0.278）。治疗6周期后用药组骨痛缓解有效+显效者的比例及ECOG评分≤2分者比例均显著高于未用药组[83.9%（73/87）比63.2%（55/87）（P=0.001）;80.0%（68/85）比53.5%（46/86）]（P=0.001;P＜0.001）。治疗6周期后,用药组骨髓浆细胞比例明显低于未用药组[（10.5±6.5）%比（19.2±3.5）%]（P=0.025）,而其他反映肿瘤负荷的指标差异无明显统计学（均P 0.05）。90例用药组中双膦酸盐类药物不良反应轻微,常见不良反应包括胃肠道反应3例（3.3%）、发热1例（1.1%）、皮疹2例（2.2%）。应用双膦酸盐不影响总体生存时间[（39.4±4.2）个月比（36.2±2.9）个月]（P=0.580）。结论 双膦酸盐可有效降低骨骼事件的发生率,延长第一次骨骼事件及病理性骨折的发生时间。双膦酸盐可明显改善MBD治疗反应、ECOG评分,缓解骨骼疼痛,从而提高生存质量。双膦酸盐的应用不能延长患者的总体生存时间。     

The role of bisphosphonates in multiple myeloma: mechanisms, side effects, and the future

Zoledronic acid and pamidronate are two potent anticatabolic nitrogen-containing bisphosphonates (BPs) used extensively in diseases with high bone turnover such as multiple myeloma (MM). In this review we focus on their biology and their current and future use in MM, and highlight some of the most common and emerging side effects. Although the primary target cells for BPs are osteoclasts, new insights suggest other cell types of the bone microenvironment as possible targets, including osteoblasts, endothelial cells, immune cells, and cancer cells. Here, we focus on the current guidelines for the use of BPs in MM and address side effects such as renal toxicity, osteonecrosis of the jaw, and low-energy fractures. Finally, we approach the future of BP use in MM in the context of other bone-targeted agents, evaluating ongoing clinical trials addressing alternate dosing and schedules of BP administration in MM patients.     

Implications of bone metastases and the benefits of bone-targeted therapy

Several cancers, including those originating in the breast, prostate, and lung, exhibit a propensity to metastasize to bone, resulting in debilitating skeletal complications. These sequelae, such as intractable pain, pathologic fractures, spinal compression, and hypercalcemia, greatly erode the patients' quality of life. Bisphosphonates, a class of antiresorptive drugs, are now the mainstay of the treatment of skeletal-related events in myeloma bone disease and many solid cancers with bone metastases. Current evidence indicates that newer-generation nitrogen-containing bisphosphonates, particularly zoledronic acid, are potent inhibitors of bone resorption. In addition, increased understanding of the pathogenesis of bone metastasis has resulted in the development of several bone-targeted therapies including a monoclonal antibody targeting the receptor activator of nuclear factor (NF)-κB ligand (RANKL). In this review, clinical evidence regarding the efficacy and safety of currently available bone-targeted therapies including bisphosphonates and anti-RANKL monoclonal antibody in the treatment of bone metastasis due to breast cancer, prostate cancer, lung cancer, and multiple myeloma bone disease will be summarized.     

Jaw complications associated with bisphosphonate use in patients with plasma cell dyscrasias

Osteonecrosis of the jaw has been linked with bisphosphonate use in breast cancer and multiple myeloma patients. We report 17 cases of patients with plasma cell dyscrasia being treated with bisphosphonate who developed osteonecrosis/osteomyelitis of the jaw. Seventeen patients evaluated at our institution between 1998 and 2005 are reported. All were being treated with bisphosphonates for a median of 5 mo proor to the onset of jaw symptoms. Sixteen of the 17 patients are 54 yr or older. None of the patients had been irradiated in the jaw nor had obvious osseous manifestation of multiple myeloma in the jaw. Thirteen patients were receiving zoledronic acid and four patients were receiving pamidronate at the onset of jaw symptoms. Six of the 17 did receive both agents at some time and all of these individuals were receiving zoledronic acid at diagnosis. Microorganisms were isolated in 7/17 patients with the most common organism being actinomycosis. We have initiated the following guidelines in an effort to ameliorate the incidence of this complication. Patients should have a full dental examination at the time of diagnosis of the plasma cell dyscrasia especially if bisphosphonates are to be considered as part of the therapy. In addition, bisphosphonates are held for a period of 3 mo prior to invasive dental procedures to allow for the osteoclastic recovery, therefore enhanced debris removal and lessening the chance of creating a fertile bacterial medium. Following the dental procedure we would re-introduce bisphosphonates only after the healing process is complete. Finally, multiple myeloma patients diagnosed with jaw osteonecrosis probably have a concurrent infection and should be aggressively treated with antibiotics.     

Antitumor effects and anticancer applications of bisphosphonates

Bisphosphonates are firmly entrenched in the treatment of metastatic bone disease secondary to several tumor types, including breast cancer, prostate cancer, and myeloma. More recently, an emerging body of preclinical and clinical evidence indicates that bisphosphonates might also exhibit antitumor activity. This expanded role for bisphosphonates in the adjuvant setting might have profound clinical implications in many cancer types, particularly in the context of prevention of bone metastasis. Increased understanding of the mechanistic basis of the antitumor effects indicates that these might occur via direct mechanisms such as induction of apoptosis and inhibition of tumor cell adhesion and invasion, as well as indirect mechanisms such as inhibition of angiogenesis. There is also considerable evidence to suggest that nitrogen-containing bisphosphonates might exert additive or synergistic interactions with standard cytotoxic agents. However, mature clinical data with bisphosphonates are limited and, thus far, provide conflicting evidence regarding the antitumor role of bisphosphonates, but have mostly been conducted with first-generation bisphosphonates such as clodronate that are not as effective as next-generation bisphosphonates. Several large randomized clinical trials are ongoing with the next-generation bisphosphonate zoledronic acid to prospectively confirm an antitumor role for bisphosphonates in various tumor types. This review assesses the current body of preclinical and clinical evidence in favor of an antitumor effect of bisphosphonates in different cancer types.