Comparison of the effects of intravenous pamidronate and oral clodronate on symptoms and bone resorption in patients with metastatic bone disease

Bisphosphonate drugs are a group of pyrophosphate analogues which bind avidly to hydroxyapatite bone mineral surfaces and their major action is to inhibit osteoclast activity and thus bone resorption. In oncology, their role in metastatic bone disease is well established, but there is increasing interest in their potential role in preventing and treating cancer-induced bone loss and their possible anti-tumour effects. Metastatic bone disease is associated with a variety of skeletal complications, including pathologic fractures, bone pain, impaired mobility, spinal cord compression and hypercalcaemia. Intravenous bisphosphonates, particularly zoledronic acid, in conjunction with rehydration, are now established as the treatment of choice for hypercalcaemia. For treatment of bone pain, it has also been shown that bisphosphonates can be an effective supplementary approach to radiotherapy. In breast cancer and myeloma, bisphosphonates have now become part of standard therapy to treat and prevent skeletal-related events (SRE) and, until recently, treatment was largely with intravenous pamidronate or oral clodronate. However, large, randomised, multicentre trials using intravenous administration of the highly potent bisphosphonate zoledronic acid every 3-4 weeks have recently demonstrated a reduction of 20% in the risk of developing an SRE compared with pamidronate for patients with breast cancer. Moreover, these trials have demonstrated, for the first time, that a bisphosphonate significantly reduces the occurrence of skeletal events in hormone-refractory prostate cancer and in non-small cell lung cancer and a range of other solid tumours. Investigations into the potential of the relatively low potency bisphosphonate, clodronate, for the prevention of bone metastases in breast cancer have produced conflicting data. Further large, randomised studies with clodronate and zoledronic acid are planned and until the results are available it is not possible to identify a definite adjuvant role for bisphosphonates. Evidence is accumulating in vitro that bisphosphonates are also able to directly affect tumour cells, in addition to their effects on osteoclasts, with zoledronic acid being particularly potent. Over recent decades there has been a significant improvement in cure rates and survival times in certain cancers and the use of chemotherapy and hormone therapy has expanded greatly, leading to increasing numbers of long-term survivors who have received these treatments. Management of treatment-induced bone loss is therefore assuming a greater importance and bisphosphonates represent an attractive treatment option in such patients. Several placebo-controlled trials using oral clodronate, oral risedronate, intravenous pamidronate and intravenous zoledronic acid have all now demonstrated benefits in reducing the loss in bone mineral density.

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The Use of Bone Markers in a 6-Week Study to Assess the Efficacy of Oral Clodronate in Patients with Metastatic Bone Disease

Calcified Tissue International ◽

10.1007/s00223-007-9061-x ◽

2007 ◽

Vol 81 (5) ◽

pp. 341-351 ◽

Cited By ~ 17

Author(s):

J. E. Brown ◽

E. V. McCloskey ◽

J. A. Dewar ◽

J. J. Body ◽

D. A. Cameron ◽

...

Keyword(s):

Bone Disease ◽

Bone Markers ◽

Metastatic Bone Disease ◽

Oral Clodronate

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Interleukin-8 stimulation of osteoclastogenesis and bone resorption is a mechanism for the increased osteolysis of metastatic bone disease

Bone ◽

10.1016/s8756-3282(03)00086-3 ◽

2003 ◽

Vol 33 (1) ◽

pp. 28-37 ◽

Cited By ~ 272

Author(s):

Manali S Bendre ◽

Donna C Montague ◽

Terry Peery ◽

Nisreen S Akel ◽

Dana Gaddy ◽

...

Keyword(s):

Bone Resorption ◽

Bone Disease ◽

Metastatic Bone Disease ◽

Interleukin 8 ◽

Stimulation Of

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The dual specific Src/Abl kinase inhibitor AZD0530 inhibits the formation and activity of human osteoclasts

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.3602 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 3602-3602 ◽

Cited By ~ 1

Author(s):

J. Klein-Nulend ◽

M. A. van Duin ◽

T. P. Green ◽

V. Everts ◽

T. J. de Vries

Keyword(s):

Bone Resorption ◽

Tumor Cell ◽

Bone Disease ◽

Culture System ◽

Kinase Inhibitor ◽

Osteoclast Formation ◽

Metastatic Bone Disease ◽

Osteoclastic Bone Resorption ◽

Abl Kinase ◽

Actin Rings

3602 Background: Gene knockout studies have demonstrated the critical importance of the non-receptor TK Src to osteoclast bone resorptive function. Deregulated Src TK activity is also reported as a hallmark of the invasive cancer cell. Bone metastatic cancer cells interact with and activate osteoclasts in a destructive cycle of bone degradation and stimulation of tumor cell growth. Therefore targeting Src activity would appear to be a rational therapeutic approach in treating metastatic bone disease. We have reported previously (AACR 2005) on the activity of the dual Src/Abl kinase inhibitor AZD0530 in inhibiting the bone resorptive activity of mature rabbit osteoclasts in a bone slice model. Here we tested the effect of AZD0530 in a human co-culture system, examining its activity on i) osteoclast formation by peripheral blood mononuclear cells (PBMCs) co-cultured with osteoblasts, and ii) osteoclastic bone resorption. Methods and Results: PBMC adhesion to osteoblasts and osteoblast morphology was not affected by AZD0530 (0.1–10 μM). However, AZD0530 inhibited the formation of multinucleated osteoclast-like cells dose dependently. PBMC-osteoblast co-cultures were then exposed to 1 μM AZD0530 for different time intervals. AZD0530 was most effective in inhibiting the formation of osteoclast-like cells when added at the onset of osteoclastogenesis, suggesting that Src activity is important during the initial induction of osteoclast formation. Formation of actin rings, to which c-Src co-localizes, is a prerequisite for osteoclastic bone resorption. The effect of AZD0530 on formation of actin rings was analyzed using the co-culture system on cortical bone slices. AZD0530 prevented migration of osteoclast precursors to the bone surface, and the subsequent formation of actin rings. On withdrawal of the drug, this process was reversible. Conclusions: Our data suggest that Src activity is pivotal for the formation, migration and activity of osteoclasts. Data reported elsewhere suggest AZD0530 will also impact on tumor cells directly. AZD0530 is a promising new anti-cancer drug with potential to additionally treat metastatic bone disease through its inhibition of both osteoclast activity and tumor cell invasion into and within the bone micro-environment. No significant financial relationships to disclose.

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A phase II, randomized, open-label, pilot study to evaluate the safety and the effects on bone resorption of saracatinib (AZD0530) in patients with prostate cancer or breast cancer with metastatic bone disease

Bone ◽

10.1016/j.bone.2010.10.044 ◽

2011 ◽

Vol 48 (1) ◽

pp. S17 ◽

Cited By ~ 1

Author(s):

M. Aklilu* ◽

A. Hussain ◽

C.P. Evans ◽

R.A. Hannon ◽

A. Lipton ◽

...

Keyword(s):

Breast Cancer ◽

Prostate Cancer ◽

Pilot Study ◽

Bone Resorption ◽

Phase Ii ◽

Bone Disease ◽

Metastatic Bone Disease ◽

Open Label

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Zoledronic Acid (ZOL) Markedly Improves Bone Mineral Density (BMD) for Patients (Pts) with Monoclonal Gammopathy of Undetermined Significance (MGUS) and Bone Loss.

Blood ◽

10.1182/blood.v110.11.3606.3606 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3606-3606

Author(s):

James R. Berenson ◽

Ori Yellin ◽

Ralph V. Boccia ◽

Marshall S. Flam ◽

Siu-Fun Wong ◽

...

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Bone Disease ◽

Metastatic Bone Disease ◽

Lymphocytic Leukemia ◽

High Risk Population ◽

Mineral Density ◽

T Score ◽

Increased Risk ◽

Prior Use

Abstract MGUS occurs in 5% of individuals over 70 yrs of age and these pts have been found to have increased rates of bone resorption. Osteoporosis associated with MGUS have higher bone resorption compared to sex and aged-matched pts with osteoporosis but without evidence of MGUS. Not only do pts with MGUS have a higher prevalence of osteopenia/osteoporosis than the normal population but they also have an increased risk of fractures (fx). ZOL has been shown to increase BMD in the treatment of gonadotropin agonist-induced osteoporosis in men with prostate cancer without metastatic bone disease when administered every 3 mos at 4 mg. The rationale for the use of ZOL for pts with osteopenia/osteoporosis in the setting of MGUS is based on these studies coupled with the knowledge that pts with this disorder have a higher prevalence of bone loss and fx risk. To date, no agents have been formally studied in the treatment of osteopenia/osteoporosis associated with MGUS. A schedule of 4 mg every 6 mos has been shown to be safe and effective in increasing BMD for other cancer pts without metastatic bone disease but with significant bone loss. This open-label study was designed to evaluate the efficacy and safety of this dose and schedule of ZOL for MGUS pts with significant loss of bone. Pts had to have osteopenia/osteoporosis (T-score worse than -1) as verified by a DEXA scan and a diagnosis of MGUS. Pts with prior use of oral bisphosphonates (BIS) or fluorides for more than three mos within the last two yrs or prior use of intravenous (IV) BIS within the last two yrs were excluded. ZOL at 4 mg was administered IV at 0, 6, and 12 mos. To assess the efficacy of ZOL therapy, DEXA scans and skeletal surveys were conducted at screening and one mo after the final ZOL infusion (13 mos). Fifty-four pts were enrolled on this trial with an average age of 68 (range, 50 to 91 yrs). The starting L-spine T-scores ranged from −3.97 to −1.10 (mean = −2.16). After one year of ZOL therapy, T-scores improved by a mean of +0.55 (range, −0.40 to +3.90; P = 0.0042). This corresponded to a mean increase in BMD of +25.5% (range, −19.0% to +134%). Similar evaluation in the hip showed baseline T-scores of −3.50 to −1.00 (mean = −1.88). The mean change in T-score was +0.27 (range, −0.60 to +2.00; P = 0.0046) corresponding to a mean increase of +14.4% (range, −54.5% to +163%). One pt developed chronic lymphocytic leukemia while on study whereas no other pt showed progression to myeloma or a related B-cell disorder. No pt developed osteonecrosis of the jaw or a significant adverse renal event. During the study, no pt developed a new fx. This trial suggests that ZOL administered at 4 mg every 6 mos significantly improves BMD in MGUS pts with bone loss (osteopenia/osteoporosis); and, thus, suggests that this is a safe and effective treatment to prevent the development of new fxs in this high risk population.

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Role of Pamidronate Disodium in the Treatment of Metastatic Bone Disease

Tumori Journal ◽

10.1177/030089169808400403 ◽

1998 ◽

Vol 84 (4) ◽

pp. 442-455 ◽

Cited By ~ 10

Author(s):

Carla Ripamonti ◽

Fabio Fulfaro ◽

Chiara Ticozzi ◽

Alessandra Casuccio ◽

Franco De Conno

Keyword(s):

Breast Cancer ◽

Quality Of Life ◽

Multiple Myeloma ◽

Bone Resorption ◽

Bone Metastases ◽

Bone Disease ◽

Metastatic Bone Disease ◽

Pamidronate Disodium ◽

Phase Ii And Iii

Aims and Background Bone metastases are a common feature of advanced neoplastic disease and are considered to be among the most frequent causes of pain and complications in oncologic patients. The main objective of the treatment of such patients is to control their symptoms and improve their quality of life. Pamidronate disodium is a second-generation bisphosphonate capable of inhibiting bone resorption (particularly osteoclast activity) without affecting bone reminerali-zation. After a brief introduction concerning the pathophysiology of bone metastases and neoplastic bone pain, we herein present data on the clinical pharmacology and toxicity of bisphosphonates in general, and pamidronate in particular. We conclude by reviewing the literature on the use of pamidronate in phase II and III trials involving patients with metastatic bone disease. Methods The paper is based on a review of articles published between 1984 and 1997 selected from the Cancerline and Medline databases. Results In the considered phase II and III studies involving patients with bone metastases (breast cancer and multiple myeloma in particular), pamidronate proved to be efficacious in reducing the incidence of pain and skeletal complications, decreasing the excretion of metabolic markers of bone resorption and improving the quality of life. Intravenous infusions of 60-90 mg over a period of 2 hr every 3-4 weeks did not cause any significant toxic effects and was easily managed. Conclusions Pamidronate is a bisphosphonate that is efficacious in the treatment of symptomatic bone metastases and can be considered an important therapeutic option in association with systemic treatments, radiotherapy and normal supportive care, especially in patients with breast cancer and multiple myeloma. Further randomized studies are necessary to confirm the positive preliminary results in other neoplasms, analyze the cost/benefit ratio of the treatment, and verify the possibility that, in addition to being used for palliative purposes, pamidronate may also prevent or delay the appearance of bone metastases.

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Histomorphometric analysis of osteoclastic bone resorption in metastatic bone disease from various primary malignomas

Virchows Archiv A Pathological Anatomy and Histopathology ◽

10.1007/bf00710766 ◽

1986 ◽

Vol 409 (6) ◽

pp. 817-828 ◽

Cited By ~ 14

Author(s):

H. -Albrecht Kulenkampff ◽

Thomas Dreyer ◽

Wilhelm Kersjes ◽

G�nter Delling

Keyword(s):

Bone Resorption ◽

Bone Disease ◽

Metastatic Bone Disease ◽

Osteoclastic Bone Resorption ◽

Histomorphometric Analysis

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Biochemical markers of bone turnover in patients with metastatic bone disease

Clinical Chemistry ◽

10.1093/clinchem/41.10.1489 ◽

1995 ◽

Vol 41 (10) ◽

pp. 1489-1494 ◽

Cited By ~ 91

Author(s):

L M Demers ◽

L Costa ◽

V M Chinchilli ◽

L Gaydos ◽

E Curley ◽

...

Keyword(s):

Bone Resorption ◽

Bone Turnover ◽

Bone Metastases ◽

Cancer Patients ◽

Bone Disease ◽

Biochemical Markers ◽

Clinical Evidence ◽

Metastatic Bone Disease ◽

Z Score ◽

Markers Of Bone Turnover

Abstract Several biochemical markers of bone formation and bone resorption have recently been developed. These markers have been evaluated for clinical utility in patients with metabolic bone disease, including Paget disease and osteoporosis, and for their potential use in cancer patients whose disease has metastasized to bone. We have evaluated seven markers of bone turnover in the plasma and urine of 94 patients with newly diagnosed or progressive malignancy with and without clinical evidence of bone metastases. As determined by a positive bone scan and (or) bone survey, 30 patients had metastases to bone; 51 patients had metastatic cancer without overt bony involvement; and 13 patients had local disease without bone metastases. To evaluate the predictive value of these markers in the metastatic population, we utilized a "Z-score" and logistic regression analysis to distinguish patients with documented bone metastatic disease from those patients without clinical evidence of bone metastases. The higher the Z-score, the better the marker predicts the presence of bone metastases. With this statistical approach, urine N-telopeptide measurements had the highest Z-score and the most significant association with the probability of bone metastases. Urine deoxypyridinoline was the second most predictive marker of bone metastases. Thus, biochemical markers of bone resorption might be of use to predict the presence of bone metastases in cancer patients and to monitor the efficacy of antiresorptive therapy in patients treated for metastatic bone disease.

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