Skeletal Events In Patients Research Articles

Multistate Analysis of Skeletal Events in Patients with Bone Metastases

Cancer patients with bone metastases are at increased risk of experiencing skeletal events associated with severe morbidity. Clinical trials of palliative therapies must perform rigorous and robust evaluation of new treatments on the basis of meaningful summaries of the course of skeletal events over time, while dealing with potentially high mortality rates during observation. The purpose of this article is to present a multistate model that can be easily used to reflect possible courses of the disease process, indicate how simple methods of analysis can be used to estimate clinically relevant features of the process, and contrast this approach with some of the alternative methods. The relation between the multistate approach and previously used methods is highlighted.

Zoledronic acid is effective in preventing and delaying skeletal events in patients with bone metastases secondary to genitourinary cancers

Zoledronic acid is effective in preventing and delaying skeletal events in patients with bone metastases secondary to genitourinary cancers

Bisphosphonates for malignancy-related bone disease: current status, future developments

This review relates to the efficacy and safety of bisphosphonates in metastatic bone disease. It discusses practical recommendations and possible future indications for bisphosphonate therapy. The current aims of bisphosphonates for metastatic bone disease are to prevent skeletal-related events (SREs), reduce bone pain and improve quality of life. Phase III clinical trials of clodronate and pamidronate have established their efficacy against bone complications in patients with breast cancer and multiple myeloma, while randomized trials have shown SRE reductions with zoledronic acid in patients with breast cancer and multiple myeloma, prostate cancer, and lung and other solid tumors. These bisphosphonates also have some effect on metastatic bone pain. Ibandronate is a new aminobisphosphonate, available in more than 40 countries outside of the US as intravenous and oral formulations for the prevention of skeletal events in patients with breast cancer and bone metastases. Phase III studies have shown that both intravenously and orally administered ibandronate have efficacy for the prevention of skeletal events and for the reduction of metastatic bone pain. In addition to efficacy, the long-term tolerability of bisphosphonates in metastatic bone disease influences drug selection. Besides their use in patients with established bone metastases, recent and ongoing research suggests that bisphosphonates also have clinical benefit in the adjuvant setting, and for the treatment of cancer-treatment-induced bone loss. Such interesting new developments may underpin a new era of bisphosphonate use sometime in the near future.

Zoledronic acid is effective in preventing and delaying skeletal events in patients with bone metastases secondary to genitourinary cancers

Patients with metastatic bone disease often have severe bone pain and debilitating skeletal complications. Zoledronic acid is the only bisphosphonate shown to be safe and effective in reducing skeletal-related events (SREs), including pathological fractures, spinal cord compression, and radiation or surgery to bone in patients with bone metastases from advanced prostate cancer or renal cell carcinoma (RCC). In both tumour types, zoledronic acid significantly decreased the overall risk of developing an SRE, delayed their onset and significantly reduced the incidence of SREs compared with placebo. In patients with RCC, zoledronic acid also significantly delayed the time to progression of bone lesions by 5 months compared with placebo. Zoledronic acid is safe and well tolerated with long-term use.

Ibandronate is effective in preventing skeletal events in patients with bone metastases secondary to colorectal carcinoma

3639 Background: Patients with metastatic colorectal carcinoma (CRC) often develop metastases to bone with a high risk of complications. Methods: A randomized, placebo-controlled trial was conducted to evaluate the efficacy and safety of ibandronate in patients with bone metastases from CRC. The primary efficacy endpoint was proportion of patients with skeletal related events (defined as pathologic fracture, spinal cord compression, radiation therapy to bone, change in antineoplastic therapy and surgery to bone). Secondary endpoints included time to first skeletal event, skeletal morbidity rate (events/year) and time to progression of bone lesions. Results: In 30 patients with CRC, treatment with intravenous ibandronate 6mg over a15-minute infusion significantly reduced the proportion of patients with skeletal events (39% versus 78% with placebo; p=0.019) and prolonged the time to first event by at least 6 months (median >279 versus 93 days with placebo; p=0.009). Ibandronate also significantly reduced the skeletal morbidity rate (mean 2.36 versus 3.14 with placebo; p=0.018) and prolonged time to progression of bone lesions (214 days versus 81 days with placebo; p=0.018). Ibandronate was well tolerated with very rare grade 3 or 4 toxicity. The incidence of renal adverse events was comparable to placebo and there were no clinically-relevant changes of serum creatinine. Conclusion: Ibandronate provided significant clinical benefit in patients with bone metastases secondary to CRC. This small pilot study suggests a role for ibandronate in metastatic bone disease from colorectal carcinoma. Larger confirmatory studies are required. No significant financial relationships to disclose.

How can bone turnover markers be best utilized for prediction of skeletal events in patients with solid tumors?

How can bone turnover markers be best utilized for prediction of skeletal events in patients with solid tumors?

Osteonecrosis of the Jaw in Myeloma Patients Receiving Pamidronate or Zoledronate.

Background: Pamidronate (P) and zoledronate (Z) are bisphosphonates (BPs) that reduce the risk of skeletal events in patients with multiple myeloma (MM). Although published comparative data and the drug label are confined to patients with bone lesions, the drugs are widely used in patients without bone lesions and often in those with smoldering myeloma. Systematic safety data are available only for short-term administration (up to 2 years) but the drugs are commonly administered for prolonged periods of time. Recently, reports of osteonecrosis (ON) of the jaw (mandible and/or maxilla) have appeared with the chronic use of BPs predominantly P and Z. ON has been identified in association with BP therapy in patients with MM, other malignancies, and non-cancerous conditions.Methods: We reviewed the medical and dental records of MM patients with confirmed, clinically obvious ON seen at our MM program between March 2001 and June 2004. Several clinical and pathological characteristics were evaluated.Results: Seven patients with ON of the jaw were identified amongst approximately 600 MM patients seen at our institution during this time period. An additional case, identified very recently on clinical grounds, is being investigated. There were 6 men and 1 woman, with a median age of 60 years (range, 56–64). All 7 patients were on P or Z at the time of diagnosis, and the median duration of prior BP therapy was 43 months (range, 4–75). All had received corticosteroids previously, and 3 had received thalidomide. Two had received local radiation to the jaw previously, and 2 had a history of dental extraction more than 3 years prior to this diagnosis. ON involved the mandible in 5, the maxilla in 1, and both in 1. Symptoms included local pain and discomfort. Therapy was variable, and the multiple approaches used included systemic analgesics (n=7), surgical debridement (n=6; repeatedly in 3), gingivoplasty (n=1), teeth extraction (n=2), prolonged antibiotic therapy (n=2), and hyperbaric oxygen therapy (n=2). Some symptom control was achieved in all patients, but all continued to have persistent problems at the time of last contact (n=6) or death from progressive myeloma (n=1). The limited data suggested that surgical intervention controlled symptoms for a short while but was invariably followed by worse symptoms.Conclusions: We conclude that jaw ON is a newly identified serious complication of pamidronate and zoledronate therapy that is difficult to manage. Possible contribution of other agents such as corticosteroids and thalidomide to its causation remains to be determined. The prevalence rate of 1.5% in our patient population is very likely an underestimate because only symptomatic patients have been identified. A multi-pronged approach is necessary to identify the extent of this problem in MM patients, and broaden our understanding of it. Amongst the steps to be taken are: (1) careful assessment of the need for continued P or Z therapy in patients who have received the drugs for 2 years, (2) jaw imaging in patients with any local symptoms, (3) discontinuation of BP therapy in patients developing ON, (4) reporting details of cases with ON to FDAs MedWatch Program, and (5) avoidance of P/Z in patients with plasma cell dyscrasias where the utility of these drugs has not been established (e.g. smoldering myeloma). An additional step that may be useful as a prospective clinical investigation would be to perform detailed imaging studies of the jaw in all MM patients who have received P and/or Z for 3 years or more.

Effect of 1-year intravenous ibandronate treatment on time to serum creatinine increase in patients with skeletal metastases from breast cancer

733 Background: In a 2-year, phase III clinical trial, intravenous ibandronate, a newly-approved aminobisphosphonate for the prevention of skeletal events in patients with breast cancer and bone metastases, was shown to have a renal adverse event profile comparable to placebo (Body JJ, et al. Ann Oncol 2003;14:1399–405). This abstract reports the results of an analysis of time to renal function deterioration from this trial, over the first year of treatment. Methods: Women with a confirmed diagnosis of metastatic breast cancer were included in this multicenter, randomized, double-blind study, and received placebo or 6mg ibandronate infused over 1–2 hours every 3–4 weeks. A post-hoc Kaplan-Meier analysis assessed time to serum creatinine increase, defined by an increase of 0.5mg/dL from baseline (if <1.4mg/dL); 1.0mg/dL from baseline (if ≥1.4mg/dL), or twice the baseline value. Results: 309 patients were randomized to treatment and included in this safety analysis (placebo n=157, ibandronate 6mg n=152). The Kaplan-Meier estimate of the time to first deterioration of renal function over 1 year of treatment was comparable between the placebo and ibandronate groups. The proportion of patients without defined serum creatinine increases after 48 weeks was 96% with placebo and 98% with ibandronate 6mg (ns, p>0.05 versus placebo). Conclusions: There was no clinically-relevant increase in serum creatinine levels with intravenous ibandronate over 1 year of treatment. Considered alongside previously-reported 2-year renal adverse event data from the same trial, these results demonstrate that a 6mg dose infused every 3–4 weeks does not affect renal functioning. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Pharmaceuticals Roche Pharmaceuticals Roche Pharmaceuticals Roche Pharmaceuticals F. Hoffmann-La Roche

Effect of 1-year intravenous ibandronate treatment on time to serum creatinine increase in patients with skeletal metastases from breast cancer

733 Background: In a 2-year, phase III clinical trial, intravenous ibandronate, a newly-approved aminobisphosphonate for the prevention of skeletal events in patients with breast cancer and bone metastases, was shown to have a renal adverse event profile comparable to placebo (Body JJ, et al. Ann Oncol 2003;14:1399–405). This abstract reports the results of an analysis of time to renal function deterioration from this trial, over the first year of treatment. Methods: Women with a confirmed diagnosis of metastatic breast cancer were included in this multicenter, randomized, double-blind study, and received placebo or 6mg ibandronate infused over 1–2 hours every 3–4 weeks. A post-hoc Kaplan-Meier analysis assessed time to serum creatinine increase, defined by an increase of 0.5mg/dL from baseline (if <1.4mg/dL); 1.0mg/dL from baseline (if ≥1.4mg/dL), or twice the baseline value. Results: 309 patients were randomized to treatment and included in this safety analysis (placebo n=157, ibandronate 6mg n=152). The Kaplan-Meier estimate of the time to first deterioration of renal function over 1 year of treatment was comparable between the placebo and ibandronate groups. The proportion of patients without defined serum creatinine increases after 48 weeks was 96% with placebo and 98% with ibandronate 6mg (ns, p>0.05 versus placebo). Conclusions: There was no clinically-relevant increase in serum creatinine levels with intravenous ibandronate over 1 year of treatment. Considered alongside previously-reported 2-year renal adverse event data from the same trial, these results demonstrate that a 6mg dose infused every 3–4 weeks does not affect renal functioning. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Pharmaceuticals Roche Pharmaceuticals Roche Pharmaceuticals Roche Pharmaceuticals F. Hoffmann-La Roche

Oral ibandronate for the treatment of metastatic bone disease in breast cancer: efficacy and safety results from a randomized, double-blind, placebo-controlled trial

BackgroundWe report the first results of a randomized trial assessing a new oral aminobisphosphonate, ibandronate, in patients with bone metastases from breast cancer. Patients and methodsPatients (n = 435) received placebo, or oral ibandronate 20 mg or 50 mg once-daily for 96 weeks. The primary efficacy measure was the number of 12-week periods with new bone complications [skeletal morbidity period rate (SMPR)]. Multivariate Poisson regression analysis assessed the relative risk reduction of skeletal-related events. Secondary efficacy analyses included bone pain and analgesic use. Adverse events were monitored. ResultsSMPR was significantly reduced with oral ibandronate [placebo 1.2, 20 mg group 0.97 (P = 0.024),50 mg group 0.98 (P = 0.037)]. Ibandronate 50 mg significantly reduced the need for radiotherapy (P = 0.005 versus placebo). The relative risk of skeletal events was reduced by 38% (20 mg dose) and 39% (50 mg dose) versus placebo (P = 0.009 and P = 0.005). The tolerability profile of ibandronate was similar to placebo. ConclusionsOral ibandronate is an effective and well-tolerated treatment for metastatic bone disease. The 50 mg dose is being further evaluated in clinical trials, and this dose was recently approved in the European Union for the prevention of skeletal events in patients with breast cancer and bone metastases.

The Role of Adjuvant Therapy with Bisphosphonates in Cancer

An understanding of the pathophysiology of bone metastases requires a knowledge of normal and abnormal bone remodeling. This knowledge is helpful in understanding mechanisms of action of bone active agents such as bisphosphonates. When malignant cells infiltrate bone spaces, the balance of bone formation and bone resorption is disrupted: bone remodeling and turnover become abnormal. The consequent ‘vicious cycle’ plays a central role in the progressive destruction of bone and the progression of bone metastases. This cycle in breast cancer is beginning to be understood and involves the secretion by malignant cells of substances such as parathyroid hormone related protein (PTHrP) which leads to an increase in focal and generalized bone resorption resulting in the release of breakdown products such as transforming growth factor beta which in turn stimulates the further growth of malignant cells. Study of the intricacies of this ‘vicious cycle’ has thrown some light on potential opportunities for the therapy of bone metastases. However, physiological mechanisms resulting in bone pain are poorly understood. Clinical aspects of bone metastases in breast cancer, prostate cancer, and myeloma, together with what is known about their individual pathophysiology are discussed in this review. Biochemical markers of bone resorption and formation are now available for study and early research suggests that skeletal events in patients with malignant bone disease as well as the treatment of these events may correlate with levels of serum and urine markers of bone turnover.

Ulcerative esophagitis caused by etidronate

Bisphosphonates are emerging as an important component in the treatment of established osteoporosis. Other possible clinical uses of bisphosphonates are currently being explored, such as prevention of perimenopausal bone loss, treatment of corticosteroid-induced osteopenia, and treatment of skeletal manifestations of malignancy. 1 Meunier PJ Confravreux E Tuninon I Hardouin C. Cyclic alendronate therapy prevents bone loss in the early postmenopausal period. J Bone Miner Res. 1995; 10 ([abstract]): S357 Google Scholar , 2 Mulder H Struys A. Intermittent cyclical etidronate in the prevention of corticosteroid-induced bone loss. Br J Rheumatol. 1994; 33: 348-350 Crossref PubMed Scopus (155) Google Scholar , 3 Berenson J Lichtenstein A Porter L. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. New Engl J Med. 1996; 334: 488-493 Crossref PubMed Scopus (992) Google Scholar Among the bisphosphonates, etidronate has been the most extensively studied in the treatment of metabolic bone diseases and is currently the most widely available of all bisphosphonates for the treatment of postmenopausal osteoporosis. The efficacy, clinical tolerance, and safety of etidronate have been well established in many controlled clinical trials. 4 Harris ST Watts NB Jackson RD. Four-year study of intermittent cyclic etidronate treatment of postmenopausal osteoporosis: three years of blinded therapy followed by one year of open therapy. Am J Med. 1993; 95: 557-567 Abstract Full Text PDF PubMed Scopus (382) Google Scholar , 5 Silberstein EB Schnur W. Cyclic oral phosphate and etidronate increase femoral and lumbar bone mineral density and reduce lumbar spine fracture rate over three years. J Nucl Med. 1992; 33: 1-5 PubMed Google Scholar

Bisphosphonates and breast carcinoma

BACKGROUND. Bisphosphonates are analogues of endogenous pyrophosphates in which a carbon atom replaces the central atom of oxygen. Bisphosphonates are potent inhibitors of osteoclastic bone resorption and are effective in decreasing the incidence of skeletal complications in breast carcinoma patients with osteolytic bone metastases. METHODS. Zoledronate is a new, potent third-generation bisphosphonate that is 500-1000 times more potent than pamidronate. A Phase II clinical trial of 0.4, 2.0, or 4.0 mg of zoledronate as a 5-minute infusion or 90 mg of pamidronate as a 2-hour infusion recently was completed. In addition, osteoprotegerin (OPG) recently has been identified as a novel, naturally occurring protein that inhibits osteoclast formation. RESULTS. A 5-minute infusion of 2.0 or 4.0 mg of zoledronate is at least as effective as 90 mg of pamidronate in preventing skeletal complications. OPG currently is entering Phase I clinical trials. Finally, tumor cells staining strongly for matrix metalloproteinases are observed in osteolytic pathologic bone fractures secondary to metastatic carcinoma. In many of these lesions frequent tumor cells are observed and osteoclasts are rare. CONCLUSIONS. Bisphosphonate treatment can decrease skeletal events in patients with breast carcinoma that is metastatic to bone. Current trials to improve results further are employing more potent bisphosphonates such as zoledronate and nonbisphosphate inhibitors of osteoclasts such as OPG. An osteoclast-independent phase of bone destruction also deserves further consideration.

Bisphosphonates and breast carcinoma: present and future.

Bisphosphonates are analogues of endogenous pyrophosphates in which a carbon atom replaces the central atom of oxygen. Bisphosphonates are potent inhibitors of osteoclastic bone resorption and are effective in decreasing the incidence of skeletal complications in breast carcinoma patients with osteolytic bone metastases. Zoledronate is a new, potent third-generation bisphosphonate that is 500-1000 times more potent than pamidronate. A Phase II clinical trial of 0.4, 2.0, or 4.0 mg of zoledronate as a 5-minute infusion or 90 mg of pamidronate as a 2-hour infusion recently was completed. In addition, osteoprotegerin (OPG) recently has been identified as a novel, naturally occurring protein that inhibits osteoclast formation. A 5-minute infusion of 2.0 or 4.0 mg of zoledronate is at least as effective as 90 mg of pamidronate in preventing skeletal complications. OPG currently is entering Phase I clinical trials. Finally, tumor cells staining strongly for matrix metalloproteinases are observed in osteolytic pathologic bone fractures secondary to metastatic carcinoma. In many of these lesions frequent tumor cells are observed and osteoclasts are rare. Bisphosphonate treatment can decrease skeletal events in patients with breast carcinoma that is metastatic to bone. Current trials to improve results further are employing more potent bisphosphonates such as zoledronate and nonbisphosphate inhibitors of osteoclasts such as OPG. An osteoclast-independent phase of bone destruction also deserves further consideration.

Advances in the biology and treatment of multiple myeloma.

Advances in the understanding of the cellular and molecular derangements involved in the initiation and progression of multiple myeloma are beginning to be translated into novel therapeutic approaches. The myeloma stem cell has been under intense scrutiny regarding its normal B-cell counterpart. Oncogenes, tumor-suppressor genes, and cell-survival genes have all been found to be dysregulated in some myeloma patients. Growth factors, especially interleukin-6, appear to be critical for disease progression, and interruption of autocrine and paracrine loops has been achieved with resultant inhibition of myeloma cell growth. Mechanisms of drug resistance and the implications of the multidrug resistance phenotype are just beginning to be understood. High-dose therapeutic regimens with autologous peripheral blood stem cell or allogeneic bone marrow rescue are rigorously being studied with an emphasis on exploiting the graft-versus-myeloma effect. Pamidronate, a second-generation bisphosponate, has been shown to be effective at decreasing adverse skeletal events in patients with advanced myeloma. The topoisomerase 1 inhibitor, topotecan, has shown activity in an initial study.

Clinical research update: zoledronate.

The prolonged administration of bisphosphonates can reduce the frequency of morbid skeletal events in patients with metastatic breast carcinoma or multiple myeloma. The development of more potent bisphosphonates will simplify current therapeutic schemes and could improve the therapeutic effectiveness of bisphosphonate therapy. Zoledronate (CGP-42446) is the most potent of the clinically tested compounds. It is a cyclic third-generation bisphosphonate that is 100-850 times more active than pamidronate in several in vivo and in vitro pharmacological test systems. The first therapeutic trial with zoledronate has been performed in patients with tumor-induced hypercalcemia (corrected calcium [Ca] > 2.75 mmol/L after rehydration). In a Phase I multicenter trial, it was shown that a single infusion was already effective at dose levels of 0.02 and 0.04 mg of zoledronate/kg bodyweight, thus 1.2 and 2.4 mg total dose for an average 60-kg individual. Five of 5 patients became normocalcemic after a dose of 0.02 mg/kg, and 14 of 15 (93%) after a dose of 0.04 mg/kg. The median time to normalization of serum Ca was 2 days and the median duration of action was 33 days, suggesting that zoledronate has a faster onset and a longer duration of action than other clinically tested bisphosphonates. Zoledronate was well tolerated; the only side effect was an increase in body temperature in 30% of the cases, which was probably not drug-related in many patients. A Phase I trial also has been initiated in patients with lytic bone metastases. Zoledronate was given as monthly short infusions (5-30 minutes) at doses between 0.1-8.0 mg. There was an analgesic effect and even at low doses (2 mg and above), the effects on the biochemical markers of bone resorption appeared to be greater than after 90-mg pamidronate infusions. These initial human data suggest that zoledronate can be administered as convenient short intravenous infusions and lead to a more marked and a more prolonged inhibition of bone resorption than is currently possible with available compounds. Future trials will have to determine whether prolonged treatment with this extremely potent bisphosphonate also can have a greater effect on the morbidity of bone metastases.

Clinical research update

The prolonged administration of bisphosphonates can reduce the frequency of morbid skeletal events in patients with metastatic breast carcinoma or multiple myeloma. The development of more potent bisphosphonates will simplify current therapeutic schemes and could improve the therapeutic effectiveness of bisphosphonate therapy. Zoledronate (CGP-42446) is the most potent of the clinically tested compounds. It is a cyclic third-generation bisphosphonate that is 100-850 times more active than pamidronate in several in vivo and in vitro pharmacological test systems. The first therapeutic trial with zoledronate has been performed in patients with tumor-induced hypercalcemia (corrected calcium [Ca] > 2.75 mmol/L after rehydration). In a Phase I multicenter trial, it was shown that a single infusion was already effective at dose levels of 0.02 and 0.04 mg of zoledronate/kg bodyweight, thus 1.2 and 2.4 mg total dose for an average 60-kg individual. Five of 5 patients became normocalcemic after a dose of 0.02 mg/kg, and 14 of 15 (93%) after a dose of 0.04 mg/kg. The median time to normalization of serum Ca was 2 days and the median duration of action was 33 days, suggesting that zoledronate has a faster onset and a longer duration of action than other clinically tested bisphosphonates. Zoledronate was well tolerated; the only side effect was an increase in body temperature in 30% of the cases, which was probably not drug-related in many patients. A Phase I trial also has been initiated in patients with lytic bone metastases. Zoledronate was given as monthly short infusions (5-30 minutes) at doses between 0.1-8.0 mg. There was an analgesic effect and even at low doses (2 mg and above), the effects on the biochemical markers of bone resorption appeared to be greater than after 90-mg pamidronate infusions. These initial human data suggest that zoledronate can be administered as convenient short intravenous infusions and lead to a more marked and a more prolonged inhibition of bone resorption than is currently possible with available compounds. Future trials will have to determine whether prolonged treatment with this extremely potent bisphosphonate also can have a greater effect on the morbidity of bone metastases. Cancer 1997; 80:1699-701.© 1997 American Cancer Society.

Efficacy of Pamidronate in Reducing Skeletal Events in Patients with Advanced Multiple Myeloma

Efficacy of Pamidronate in Reducing Skeletal Events in Patients with Advanced Multiple Myeloma