Malignant Bone Disease Research Articles

Bone turnover markers: a key tool for understanding osteoporosis

A search of the Web of Science database (http://apps. isiknowledge.com) for publications by Pierre Delmas indicates that he has 30 original publications concerning bone turnover markers out of the 67 publications with citation counts over 100. It is clear that his contribution to the field of bone turnover markers is great and bone turnover marker research has been a large fraction of his contribution to research into metabolic bone diseases. Dr. Delmas has contributed to many aspects of research into bone turnovermarkers. In a seminal paper, he was the first to use a specific HPLC assay to measure the 24-h excretion of pyridinoline and deoxypyridinoline in normal adults of both sexes, in patients with primary hyperparathyroidism, and in patients with Paget’s disease before and after intravenous pamidronate therapy. He concluded these assays were the first sensitive and specific bone resorption markers [1]. He sought to identify the sources of variation in these and other markers, such as the effects of age, menopause, gender, growth, exercise, season, and renal function, such that we could make better use of these markers. He validated these markers in studies of bone histomorphometry in osteoporosis and other metabolic bone diseases, as well as endocrine diseases and malignant bone disease. He examined their clinical utility in each of these disorders. He based his work not just on his very productive research INSERM unit in Lyon, but also on collaborations with scientists from around the world and with industry. The area to which he made the greatest contribution was to postmenopausal osteoporosis. He was able to demonstrate that high bone resorption that was a consequence of estrogen deficiency of menopause was associated with high rates of bone loss and increased risk of fracture; the contribution of these results to our ability to predict fracture is covered in the article in this issue by Dr. Melton. The detailed study of bone turnover markers in postmenopausal woman allowed Dr. Delmas to contribute to two major concepts that today we all take for granted. The first of these was that bone turnover markers remain elevated long after the menopause, a report from the OFELY study [1]. This was a population-based study of 693 women including 432 women who were 1 to 40 years past menopause. This was a comprehensive study of three bone formation markers (osteocalcin, bone alkaline phosphatase, and procollagen type I C-propeptide) and two bone resorption markers (Nand C-telopeptides of type I collagen). Dr. Delmas showed that bone turnover markers increased by 37% to 97% at the time of menopause and that the increase was associated with the onset of irregular menstruation and elevation in follicle-stimulating hormone. Bone formation markers remained elevated for up to 40 years after menopause. He adjusted the urinary excretion of bone resorption markers for total body bone mineral and reported that these too remained elevated for up to 40 years after menopause. He examined the relationship between bone turnover markers and bone mineral density and found only a weak association in premenopausal women, but a stronger relationship in postmenopausal women, especially those women who were 30 or more years after menopause, in whommarkers accounted for 52% of bone mineral density variance. This concept of high bone turnover and increased Osteoporos Int (2009) 20 (Suppl 3):S237–S238 DOI 10.1007/s00198-008-0695-y

Platelet is a major contributor to circulating levels of Dickkopf‐1: clinical implications in patients with multiple myeloma

Platelet is a major contributor to circulating levels of Dickkopf‐1: clinical implications in patients with multiple myeloma

Preserving Functional Independence in Elderly Patients with Cancer-Associated Bone Disease: The Role of Zoledronic Acid

Increases in life expectancy in the developed world will inevitably lead to larger numbers of elderly patients with cancer-associated (malignant) bone disease. Most elderly patients with metastatic cancer also suffer from numerous comorbidities. The management of bone health in this setting requires special consideration. This article centers on malignant bone disease in the elderly and the role of bisphosphonates in geriatric oncology. The challenges involved in the treatment of older patients with bone metastases are described, and the potential utility of bisphosphonates, such as zoledronic acid, is discussed. Moreover, recent data from several large clinical trials suggest that zoledronic acid provides additional benefits, including antitumor effects that may extend beyond the preservation of bone health and prevention of skeletal-related events.

Assessment of Circulating Dickkopf-1 with a New Two-Site Immunoassay in Healthy Subjects and Women with Breast Cancer and Bone Metastases

The aim of our study was to investigate the sex- and age-related changes of serum Dickkopf-1 (Dkk-1), a soluble inhibitor of the Wnt signaling pathway, in healthy individuals and in patients with breast cancer (BC) and bone metastases (BM) using a new ELISA. Association of serum Dkk-1 with markers of bone turnover was also investigated. Serum Dkk-1 measurements were performed using a commercial sandwich ELISA in 150 healthy men, 175 healthy pre- and postmenopausal women (20-65 years), 22 women with BC and BM (mean age 63 years), and 16 women with BC and metastases at sites other than bone (mean age 53 years). Intra- and interassay coefficients of variation were below 7% and 12%, respectively. The detection limit was determined to be 0.018 microg/L. In healthy women and men, Dkk-1 did not change with age. Serum Dkk-1 modestly correlated with serum bone alkaline phosphatase (r = 0.19, P = 0.013) and serum C-terminal cross-linking telopeptide of type I collagen (r = 0.19, P = 0.014) in women but not in men. Dkk-1 levels were higher in women with BC and BM (5.57 +/- 5.50 microg/L) than in healthy age-matched controls (3.47 +/- 1.47 microg/L, P < 0.0001) and women with metastases at sites other than bone (3.57 +/- 1.66 microg/L, P = 0.0003). In conclusion, serum Dkk-1 is stable with age in healthy women and men and increases in patients with BC and BM. Measurements of circulating Dkk-1 with this new ELISA may be useful for the clinical investigation of patients with malignant bone diseases.

Osteonecrosis of the Jaw and the Role of Bisphosphonates: A Critical Review

Osteonecrosis of the jaw (ONJ), a condition characterized by necrotic exposed bone in the maxillofacial region, has been reported in patients with cancer receiving bisphosphonate therapy, and rarely in patients with postmenopausal osteoporosis or Paget disease of bone receiving such therapy. In the absence of a uniform definition, the American Academy of Oral and Maxillofacial Surgeons (AAOMS), the American Society for Bone and Mineral Research (ASBMR), and other groups have established similar diagnostic criteria for bisphosphonate-related ONJ, which is more commonly reported in patients with advanced malignancies with skeletal metastases who receive higher doses, and is more rarely reported in patients with osteoporosis and Paget disease who receive lower doses. However, a critical review of the literature reveals that the etiology of ONJ remains unknown, and to date no direct causal link to bisphosphonates has been established. Despite an increased awareness of ONJ and recent improvements in preventive strategies, patients and physicians alike continue to express concern about the potential risks of bisphosphonate treatment in both oncologic and nononcologic settings. Although much remains to be learned about this condition, including its true incidence in various patient populations, its pathophysiology, and optimal clinical management, evidence to date suggests that the positive benefits of bisphosphonates in patients with malignant bone disease, osteoporosis, or Paget disease outweigh the relatively small risk of ONJ.

Incidence and risk factors of bisphosphonate‐associated osteonecrosis of the jaws

Intravenous bisphosphonate therapy has been used for treatment of benign and malignant bone diseases and has been linked to osteonecrosis of the jaws. Records of 638 patients treated with intravenous bisphosphonates were reviewed. Drug used, number of infusions, dosing interval, dosage, duration, and occasion of osteonecrosis, diagnosed by history and physical examination, were analyzed. The overall incidence of osteonecrosis was 0.94% (6/638). No significant relationship was observed between the incidence of osteonecrosis and demographic parameters, primary tumor, cumulative drug dose, or dosing interval. However, patients who developed osteonecrosis had a significantly greater mean number of infusions (p = .016) and significantly greater mean hours of infusion time (p = .0036). The findings suggest positive correlation between the development of osteonecrosis and drug exposure as measured by number of infusions and total infusion hours. However, the relatively low incidence of osteonecrosis precluded definition of a direct dose-response relationship.

Impact of skeletal complications on patients’ quality of life, mobility, and functional independence

Skeletal-related events (SREs) from malignant bone disease cause considerable morbidity and can dramatically reduce patients' quality of life. Pathologic fractures often require surgical intervention and palliative radiotherapy. Thus, patients suffer impaired mobility, loss of functional independence, and diminished health-related quality of life (HRQOL). Bisphosphonates can delay the onset and reduce the incidence of SREs and have become the standard of care for the treatment of malignant bone disease; however, minimal information on the effects of bisphosphonate treatment on HRQOL is available. Targeted HRQOL assessments for patients with malignant bone disease are currently under development and are discussed herein.

Regular dosing of zoledronic acid maintains continuous suppression of osteolysis in patients with malignant bone disease

Regular dosing of zoledronic acid maintains continuous suppression of osteolysis in patients with malignant bone disease

Ostéonécrose maxillaire sous bisphosphonates et implants dentaires

Bisphosphosnates are reference products used to treat osteoporosis, malignant bone disease, Paget's disease, and hypercalcemia. However these drugs seem to induce osteonecrosis of the jaws. This osteonecrosis is frequently observed and must be evoked in patients presenting with oral ulceration under bisphosphonate therapy. We report the case of a long-term fully dental implanted patient treated by bisphosphonates who presented a maxillar ostenecrosis with no previous radiotherapy. The risk factors and mechanism of this induced osteonecrosis are described. But could long term osseo-integrated dental implants be a triggering factor?

Safety Profile of Intravenous Bisphosphonates

Because of their proven efficacy, intravenous bisphosphonates play an important role in reducing the risk of skeletal-related events including pathologic fractures, spinal cord compression, and palliative radiotherapy to bone in patients with malignant bone lesions. Overall, intravenous bisphosphonates have an acceptable safety profile and are commonly associated with transient and manageable flu-like symptoms after initial infusions. In addition, bisphosphonates have dose- and infusion rate-dependent effects on renal function that can be proactively managed in patients with reduced creatinine clearance rates by following recommended dosing guidelines. Recently, there have been reports of osteonecrosis of the jaw (ONJ) in patients with advanced cancer receiving complex chemotherapeutic treatment regimens and supportive care with bisphosphonates. ONJ prevention and management recommendations have been developed that may reduce the risk of ONJ and the impact of ONJ on quality of life. Moreover, bisphosphonate therapy has resulted in considerable clinical benefits in patients with malignant bone disease; therefore, the potential for adverse events such as ONJ must be placed into context with these meaningful benefits.

Management of Bisphosphonate Treatment in Clinical Practice

Bisphosphonates have become important tools for the treatment of bone lesions from various solid tumors or from multiple myeloma. Management of bone health in patients with malignant bone disease from breast cancer, prostate cancer, lung cancer, and multiple myeloma was discussed in clinical case workshops held during the ZENITH meeting (April 2007, Prague, Czech Republic). Physicians in attendance were generally in agreement that bisphosphonate therapy is recommended for treatment of bone metastases and that treatment should be sustained over the duration of disease progression. Consensus is still evolving regarding the optimal duration of therapy and the emerging role of bisphosphonates in the management of bone loss in the adjuvant setting. Bisphosphonates have proven efficacy in reducing and delaying skeletal-related events in patients with bone metastases, and play a key role in preserving patient functional independence and quality of life. Furthermore, bisphosphonate therapy is a cost-effective strategy in the care of patients with bone metastases compared with the cost of treatment for fractures and other skeletal complications. Finally, communication with patients is critical to increase awareness of the benefits of bisphosphonate therapy. Increased patient involvement with treatment decisions will likely encourage patient compliance and thereby maximize clinical benefit from bisphosphonate therapy.

Bisphosphonates: from preclinical evidence to survival data in the oncologic setting

Bisphosphonate therapy has become a standard of therapy for patients with malignant bone disease. In vivo pre-clinical data suggest that bisphosphonates may exert an antitumor effect and preliminary clinical data show promising activity on metastatic disease in cancer patients. This review will describe the pre-clinical evidence of action of bisphosphonates on osteoclasts and tumor cells, in both in vitro and animal models. In addition, the effects of principal bisphosphonates on skeletal disease progression in patients with cancers in different sites, including breast cancer, prostate cancer and non-small cell lung cancer will be reported. The preliminary clinical data from retrospective trials on the effect of bisphosphonates on survival will be described and the ongoing adjuvant phase III trial will be analyzed. This review will describe the preliminary clinical evidences from prospective studies on the effect of zoledronic acid treatment on the prevention of bone metastases.

Bisphosphonates: Reducing the risk of skeletal complications from bone metastasis

Women with advanced breast cancer often develop bone metastases that are associated with skeletal-related events (SREs), which reduce quality of life and increase the risk of death. Because patients who experience one SRE are more likely to experience subsequent events, the goal of therapy is to preserve quality of life by delaying the onset of the first SRE and reducing the incidence of subsequent SREs. Bisphosphonates are used for clinical management of malignant bone disease, and data suggest that early treatment (e.g., before bone pain) may confer additional clinical benefit. Furthermore, data from subsets of zoledronic acid trials suggest that long-term bisphosphonate therapy may provide sustained clinical benefit throughout the disease course. Bisphosphonates are generally safe and well tolerated; adverse events are more often mild and transient. Zoledronic acid has proven efficacy for reducing risk of SREs, and ongoing studies are under way to evaluate customized treatment schedules.

Synergistic activity of the histone deacetylase inhibitor suberoylanilide hydroxamic acid and the bisphosphonate zoledronic acid against prostate cancer cells in vitro

Bisphosphonates are widely used agents for the treatment of malignant bone disease. They inhibit osteoclast-mediated bone resorption and can have direct effects on cancer cells. In this study, we investigated whether the anticancer activity of the third-generation bisphosphonate zoledronic acid (ZOL) could be enhanced by combination with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). We found that ZOL and SAHA cooperated to induce cell death in the prostate cancer cell lines LNCaP and PC-3. The effect was synergistic, as evidenced by combination index isobologram analysis. ZOL and SAHA synergized to induce dissipation of the mitochondrial transmembrane potential, to activate caspase-3, and to trigger DNA fragmentation, showing that the combination of ZOL and SAHA resulted in the initiation of apoptosis. Because ZOL acts by inhibiting the mevalonate pathway, thereby preventing protein prenylation, we explored whether the mevalonate pathway was also the target of the cooperative action of ZOL and SAHA. We found that geranylgeraniol, but not farnesol, significantly reduced ZOL/SAHA-induced cell death, indicating that the synergistic action of the agents was due to the inhibition of geranylgeranylation. Consistently, a direct inhibitor of geranylgeranylation, GGTI-298, synergized with SAHA to induce cell death, whereas an inhibitor of farnesylation, FTI-277, had no effect. In addition, SAHA synergized with mevastatin, an inhibitor of the proximal enzyme in the mevalonate pathway. These in vitro findings provide a rationale for an in vivo exploration into the potential of combining SAHA and ZOL, or other inhibitors of the mevalonate pathway, as an effective strategy for anticancer therapy.

Pathologic fractures correlate with reduced survival in patients with malignant bone disease

Data from randomized, controlled trials of zoledronic acid were retrospectively analyzed to assess the effect of pathologic fractures on survival in patients with malignant bone disease. A Cox regression model was used to estimate the effect of fractures (time-dependent variable) on survival in patients with stage III multiple myeloma or bone metastases from solid tumors enrolled in 3 large trials. Patients were randomized to receive zoledronic acid, pamidronate, or placebo every 3-4 weeks for up to 24 months (prostate cancer, breast cancer, and multiple myeloma) or up to 21 months (lung and other solid tumors). A total of 3049 patients with multiple myeloma (n = 513), breast (n = 1130), prostate (n = 640), or lung cancer or other solid tumors (n = 766) were included in this analysis. Patients with multiple myeloma had the highest fracture incidence (43%), followed by breast (35%), prostate (19%), and lung cancer (17%). In all tumor types except lung, pathologic fracture was associated with a significant increase in risk of death, and breast cancer patients had the greatest increased risk. After adjustment for baseline characteristics, including performance status and prior skeletal complications, breast cancer patients who developed a pathologic fracture on study had a significant 32% increased risk of death relative to patients without a fracture (hazard ratio = 1.32; P < .01); patients with multiple myeloma or prostate cancer had a >20% increased risk of death. These results suggest that fractures are associated with increased risk of death in patients with malignant bone disease. Therefore, preventing fractures is an important goal of therapy.

MP-08.23: Zoledronic acid produces benefits in patients with early malignant bone disease from hormone-refractory prostate cancer

The majority of patients with advanced prostate cancer (PC) develop bone metastases that can result in skeletal-related events (SREs) including pathologic fracture, spinal cord compression, hypercalcemia of malignancy, and radiotherapy or surgery to bone. Zoledronic acid has demonstrated efficacy in reducing and delaying SREs in patients with hormone-refractory prostate cancer (HRPC). Bone metastases in patients with recurrent PC are now often diagnosed earlier in the course of disease progression, often before the onset of SREs or bone pain.

Bisphosphonates in cancer therapy

Bisphosphonates are the standard of care in the treatment of malignant bone diseases, because of their ability to inhibit osteoclast-mediated bone destruction. We review here preclinical evidence that bisphosphonates also exert direct antitumour effects and antiangiogenic properties. Furthermore, we describe new insights on how bisphosphonates may act synergistically in combination with antineoplastic drugs or γδ T cells to exhibit antitumour activity. These findings reveal new exciting possibilities to fully exploit the antitumour potential of bisphosphonates in the clinical practice.

Incidence and risk factors of bisphosphonate associated osteonecrosis of the jaws

9074 Background: Intravenous bisphosphonate therapy has been used for treatment of various benign and malignant bone diseases, including bony metastasis. Recent single case reports have described osteonecrosis (ON) of the mandible or maxilla as a previously unknown complication of this therapy. Methods: Records of 638 patients treated with intravenous pamidronate or zoledronic acid were reviewed to determine the incidence of jaw ON. Number of infusions, dosing interval, dosage administered, and duration of treatment were analyzed to determine risk factors for the development of this complication. Results: Mean age of the study group was 67 years and 61% were female. The most common primary malignancies included prostate, lung, breast, and multiple myeloma. The overall incidence of osteonecrosis was 6/638 (0.94%). Patients treated with pamidronate (n=336), zoledronic acid (n=169), and both agents (n=133) had an incidence of ON of 1.2%, 0%, and 1.5% respectively (p=NS). No significant relationship was observed between the incidence of ON and demographic parameters, primary tumor, cumulative drug dose, or dosing interval. However, patients who developed ON had a significantly greater mean number of infusions (20.7 versus 10.7, p=0.016) and significantly greater mean hours of infusion time (42.7 versus 17.7, p=0.0036) than those who did not develop the complication. Underlying dental disease appears to be associated with ON. Conclusions: This review represents the largest single series to date of patients treated with IV bisphosphonate therapy. The findings suggest positive correlation between the development of ON and drug exposure as measured by number of infusions and total infusion hours. However, this data must be interpreted with caution as the overall incidence of the complication was low (&lt;1%), precluding rigorous statistical analysis. Dental comorbidity should be addressed prior to initiation of bisphosphonate therapy. No significant financial relationships to disclose.

Measurement of DKK1 and FRP in breast and prostate cancer patients with bone metastases: Impact of zoledronic acid (ZA)

19659 Background: Bone metastases produce an imbalance in osteoblast and osteoclast activity. While metastases from prostate cancer are osteoblastic, metastases from breast cancer may be osteolytic, osteoblastic or mixed. The wnt/frizzled pathway is involved in maturation of osteoblasts and in adult bone homeostasis. We explored the wnt antagonists dickkopf (DKK1) and frizzled related protein (FRP) as potential biomarkers in bone metastasis after ZA treatment. Methods: This is a pilot cohort study in bisphosphonate naive breast and prostate cancer patients with bone metastases. Cancer therapy was not specified. Patients received 2 monthly doses of ZA 4 mg IV. Pre- and post-treatment (day 60) sera were collected for measurement of FRP and DKK1, along with IL-6, calcium, creatinine and bone-specific alkaline phosphatase (BAP, a marker of osteoblast activity). Primary endpoint: mean change in FRP and DKK1; Secondary endpoints: correlation of biomarkers with each other and comparison of breast vs. prostate cancer patients. Biomarkers were measured using standard ELISA assays. Statistics: comparison of means = student t-test, correlation coefficients = Pearson. Results: Mature data from 14 patients are reported here, 9 with breast and 5 with prostate cancer. Mean age = 61 years (range 42–89). Two breast cancer patients were premenopausal. One prostate and 3 breast cancer patients received chemotherapy; all others were treated hormonally. After ZA, calcium decreased in all patients (p = 0.09). BAP decreased in all but 1 breast and 1 prostate cancer patient (mean decrease 20.0, p = 0.16). IL-6 was undetectable in most patients. FRP decreased in all but 4 patients (mean decrease 6.2, p = 0.13). There was no discernable pattern for DKK1. Pre-treatment DKK1 correlated with FRP (p = 0.01, r2 = 0.39), but there was no correlation post-treatment. Post-treatment DKK1 correlated with both serum calcium (p = 0.04, r2 = 0.49) and BAP (p = 0.005, r2 = 0.65). There was no difference between breast and prostate cancer patients. Conclusions: It is feasible to measure DKK1 and FRP in patients with malignant bone disease. Treatment with ZA has measurable effects upon these and other serum markers. Further studies with more patients are needed to evaluate their potential as biomarkers. No significant financial relationships to disclose.

New developments of aminobisphosphonates: the double face of Janus

BackgroundBisphosphonate (BP) therapy has become a standard of therapy for patients with malignant bone disease. In vivo preclinical and preliminary clinical data indicate that BPs may prevent cancer treatment-induced bone loss and the onset of malignant bone disease in patients with early-stage cancer. DesignThis review will describe the preclinical evidences of action of BPs on osteoclasts and tumor cells. In addition, the effects of principal BPs on skeletal disease progression in patients with breast cancer, prostate cancer, non-small-cell lung cancer and other cancers will be reported. The preliminary clinical data from retrospective trials on the effect of zoledronic acid (ZA) on survival will be described and the ongoing adjuvant phase III trial will be analyzed. ConclusionsThis review will describe the preliminary clinical evidences from prospective studies on the effect of ZA treatment on the prevention of bone metastasis.