Reduce Bone Pain Research Articles

Continuous Improvement of Bone Mineral Density Two Years Post Zoledronic Acid Discontinuation in Patients with Thalassemia-Induced Osteoporosis: Long-Term Follow-Up of a Randomized, Placebo-Controlled Trial.

Zoledronic acid is a third generation aminobisphosphonate with proven efficacy in patients with thalassemia major (TM) and osteoporosis. We report here the results of the long-term follow-up (36 months) of our TM patients with osteoporosis who participated in a randomized, placebo-controlled, trial with zoledronic acid. Sixty-six patients with TM-induced osteoporosis (21M/45F; median age 35.5 years) were studied. The majority of patients had pathological fractures and/or bone pain due to osteoporosis. Patients were blindly randomized to receive zoledronic acid at a dose of 4 mg, iv, in 15 min infusion, every 6 months (group A, n=23) or every 3 months (group B, n=21), or to receive placebo every 3 months (group C, n=22) for a period of one year. There was no difference in terms of gonadal dysfunction between the three studied groups. All patients were under oral calcium (500 mg) administration during study period, while hypogonadic patients were allowed to continue their hormonal replacement therapy. After the first 12 months of therapy, patients of groups A and B discontinued zoledronic acid treatment, while patients of group C were allowed to receive zoledronic acid at a dose of 4 mg, every 3 months, for 12 months and then to stop zoledronic acid therapy. Effects were monitored by measuring BMD of the lumbar spine, femoral neck and forearm using DEXA, at baseline, and then after 12 and 36 months post zoledronic acid administration. Patients were also asked to quantify their degree of bone pain on Huskisson's visual analogue scale and the McGill-Melzack scoring system at baseline, and then every 6 months for 36 months. Patients of groups A and C showed no differences in terms of BMD of all three evaluated sites after 12 months of therapy, while patients of group B achieved a significant increase in their lumbar spine BMD (p=0.028), and a borderline increase in their femoral neck BMD. Zoledronic acid reduced bone pain in groups A+B, while there was no bone pain relief in placebo group after 12 months of therapy. Interestingly, after 36 months, patients of both groups A and B showed a dramatic increase in BMD of all studied sites compared with baseline values (p=0.001, p=0.001, and <0.001 for BMD of lumbar spine, femoral neck, and forearm, respectively). Patients of group C who received zoledronic acid for 12 months after the placebo period showed also a dramatic increase in BMD of all studied sites at 36 month (p=0.008, p=0.018, and <0.001 for BMD of lumbar spine, femoral neck, and forearm, respectively), while they also reduced significantly bone pain scores (p<0.001). At 36 month, there was no difference in terms of BMD of lumbar spine and forearm between patients of groups A and B, while BMD of the femoral neck continued to be higher in group B (either as a T-score absolute value or as a T-score percentage change; p=0.01). No skeletal related events were observed during the study period. This study suggests that zoledronic acid is an effective treatment in increasing BMD in TM-induced osteoporosis. Its effect seems to be continued even 24 months after the discontinuation of the drug. Studies with larger number of patients are required to clarify the best dose and treatment duration of zoledronic acid for the management of TM-induced osteoporosis.

Zoledronic Acid Increases Bone Mineral Density in Patients with Thalassemia Intermedia-Induced Osteoporosis Regardless of the Incessant Bone Marrow Expansion.

Osteoporosis represents an important cause of morbidity in adult patients with thalassemia. Its pathogenesis is multifactorial, and includes mainly bone marrow expansion, endocrine dysfunction and iron overload. Patients with thalassaemia intermedia (TI) seem to have a more expanded bone marrow with pressure on cortical bone, which causes pain and bone loss in several cases. The measurement of soluble transferrin receptor (sTfR) and erythropoietin (Epo) in the serum is considered as accurate marker of erythropoietic activity in thalassemia. Bisphosphonates are potent inhibitors of osteoclast activity and have been used for the management of thalassemia-induced osteoporosis. The aim of this study was to evaluate the effect of zoledronic acid, the most potent aminobisphosphonate, on bone mineral density (BMD) of patients with TI and explore possible correlations with bone marrow expansion and erythropoietic activity. Thirty-five patients with TI and osteopenia or osteoporosis (13M/22F, median age 45 years) were evaluated. Twenty-three were randomized to receive zoledronic acid, 4 mg, IV, every 3 months (n=12) or every 6 months (n=11) for one year, while 12 patients received placebo every 3 months. There was no difference in terms of the presence of gonadal dysfunction between the three studied groups. BMD of the lumbar spine (L), femoral neck and forearm was determined in all patients, using DEXA, before and 12 months after treatment. Bone marrow expansion was assessed by the measurement of sTfR and Epo serum levels, using an ELISA methodology (R&D Systems, Minneapolis, MN, USA), before and 12 months post zoledronic acid or placebo administration. In all patients markers of bone remodelling, such as C-telopeptide of collagen type-I (CTX) and bone specific alkaline phosphatase (bALP) were also measured by ELISA (Nordic Bioscience Diagnostics, Herlev, Denmark, and Quidel, San Diego, CA, USA, respectively). Patients were asked to quantify their degree of bone pain on Huskisson's visual analogue scale and the McGill-Melzack scoring system before and 12 months post-therapy. All patients had increased values of sTfR, Epo, CTX, and bALP compared with 40 controls of similar age and gender (p<0.001). Patients who received zoledronic acid showed a significant increase in their L-BMD (p=0.01), which was accompanied by a dramatic reduction in CTX and bALP values ((p<0.001). There was no difference in terms of L-BMD changes between zoledronic acid groups. Placebo group showed an aggravation of L-BMD (p=0.041) and markers of bone remodelling at 12 months. No other changes were observed in the BMD of other sites. Zoledronic acid reduced bone pain, which remained stable in placebo group during the study period. There was only weak correlation between baseline sTfR levels and L-BMD, while there was no correlation between Epo or hemolytic parameters (indirect bilirubin, reticulocytes counts, and LDH) with BMD of all studied sites. Serum sTfR and Epo values showed a significant elevation after 12 months of therapy in all studied groups (p<0.01, p<0.02, and p<0.01, respectively); this elevation was irrespective of the L-BMD changes. This study suggests that the increase of BMD produced by zoledronic acid in TI is irrespective of the continuous increase of bone marrow expansion, which is considered a major cause of bone loss in this hemoglobinopathy.

Effect of Miglustat on Bone Disease in Adults with Type 1 Gaucher Disease: A Pooled Analysis of Three Multinational, Open-Label Studies

Background: Bone manifestations are a source of disability among patients with Gaucher disease (GD) and a focus of disease management. The effect of enzyme replacement therapy (ERT) on GD bone disease can be limited and may take up to 8 years to become manifest. Miglustat, a glucosylceramide synthase inhibitor, may have a positive influence on GD bone disease. Objectives: The aim of this analysis was to evaluate the effects of miglustat on bone manifestations and bone mineral density (BMD) in patients with type 1 GD. Methods: This was a pooled analysis of data collected prospectively over an observation period of 2 years from patients who participated in 3 multinational, open-label clinical trials evaluating the efficacy and tolerability of miglustat 100 mg TID (the currently approved therapeutic dose). Bone manifestations were assessed qualitatively and in relation to treatment and spleen status. The effects of miglustat on BMD were assessed by dual-energy x-ray absorptiometry at the lumbar spine and/or femoral neck. Bone response was defined as a positive change in BMD, based on the change in BMD Z-score from baseline to months 6, 12, and 24. Changes in BMD were also analyzed according to spleen status and baseline severity of osteopenia. Results: The analysis involved 72 patients, including 41 (57%) who had received previous ERT and 20 (28%) who had undergone splenectomy. Patients' mean (SD) age was 41.2 (13.1) years. The most frequent bone-related manifestations at study entry were osteoporosis (43/63 [68%] patients) and bone pain (41/65 [63%] patients). At 2 years, 54/65 (83%) patients reported no bone pain. The reductions in bone pain were comparable among all subgroups, including high-risk patients (ie, splenectomized). No new cases of bone crisis, avascular necrosis, or pathologic fractures were reported. BMD Z-scores were improved from baseline at both the lumbar spine and femoral neck at each time point (months 6, 12, and 24) ( P < 0.001). As early as 6 months after the initiation of miglustat monotherapy, significant increases from baseline in the BMD Z-score were observed at both the lumbar spine (mean, 0.15; P = 0.022) and femoral neck (0.23; P < 0.001); the increases remained significant at 12 months (0.19 [ P = 0.012] and 0.21 [ P = 0.017], respectively) and 24 months (0.21 [ P = 0.015] and 0.18 [ P = 0.039]). Significant increases in BMD Z-scores were observed at the femoral neck in splenectomized patients ( P < 0.001) and at both sites in osteoporotic patients (lumbar spine: P < 0.001; femoral neck: P = 0.006). Conclusion: This pooled analysis of 3 open-label studies of miglustat 100 mg TID suggests that miglustat monotherapy may reduce the incidence of bone pain and improve BMD in patients with type 1 GD, including those with a history of splenectomy and/or osteoporosis.

Ibandronate reduces radiotherapy-resistant metastatic bone pain in patients with solid tumors: A comparison of i.v. and oral formulations

19517 Background: Bisphosphonates are used to treat metastatic bone disease (MBD). However, some bisphosphonates are associated with renal toxicity. Ibandronate (IA) is a single-nitrogen, noncyclic bisphosphonate with a renal safety profile similar to placebo in phase III trials. This study compares the effects of i.v. IA 6mg and oral IA 50mg on bone pain, analgesic intake and renal safety. Methods: Recruited patients fulfilled the following criteria: age ≥18, solid tumors with at least one bone lesion, normal renal (serum creatinine ≤1.5mg/dL) and hepatic function, WHO performance status 0, I or II, life expectancy ≥6 months, normal serum calcium or asymptomatic hypercalcemia. Patients were excluded if they were pregnant or lactating, taking nephrotoxic drugs or osteoclast activity modulators. Eligible patients (n=52) were recruited for a two-arm study, with 26 patients per group treated over 6 months. Groups were matched for age, gender, weight, height, blood pressure, site of primary tumor, site and number of bone metastases and number of irradiated sites. Intravenous IA 6mg was administered over 15 minutes every 4 weeks. Oral IA 50mg was administered as a single, daily tablet before breakfast. Studies were ceased on occurrence of new bone events. Primary endpoint was reduction in bone pain and reduced analgesic use. Results: There were no significant differences in patient demographics between the two treatment arms. The percentage of patients receiving i.v. IA that achieved stable or progressive disease was 15.4%; those receiving oral IA attained 11.5% stable or progressive disease. Pain (Brief Pain Inventory questionnaire) and analgesic intake were assessed at baseline, 3 and 6 months. Both i.v. and oral IA caused a significant and sustainable decrease in each of the pain indices (p&lt;0.0005) with no significant difference between i.v. and oral groups. Both i.v. and oral IA treatment led to a trend in decrease of analgesic use. Conclusions: Oral and i.v. ibandronate have comparable efficacy for palliation of bone pain in MBD patients. No significant financial relationships to disclose.

Quantitative bone ultrasonography at phalanges in patients with high-risk monoclonal gammopathy of unknown significance (MGUS) and myeloma treated with zoledronic acid

8115 Background: Bisphosphonates are commonly used for metastatic bone disease in order to prevent skeletal-related events, to reduce bone pain and to improve quality of life. Zoledronic acid is commonly used in myeloma patients (pts), but additional studies are needed to determine the optimal timing, schedule and duration of treatment. Aim of the present study is to assess bone mineral density (BMD) in patients with high-risk MGUS and myeloma receiving zoledronic acid, using quantitative ultrasound analysis in transmission through phalanges. Methods: DBM Sonic Bone Profiler is the only ultrasound device that applies the method of signal analysis in transmission through phalanges. This technique has proven to be particularly effective in the diagnosis and treatment monitoring of post-menopausal osteoporosis. Measurements of BMD were performed by ultrasonography at distal metaphysis of the first phalanx of the II, III, IV and V hand finger, at baseline and at 1, 3, 6, 9, 12, 15 and 18 months. Results: 12 pts with high-risk MGUS (8 IgG k, 4 IgG lambda) and 4 pts with myeloma IIIA (3 IgG k, 1 IgA lambda), 6 males/ 10 females, median age 69 years, received zoledronic acid 4 mg intravenously every 4 weeks for at least 12 courses. All subjects took daily oral supplements containing elemental calcium (1 g) and vitamin D (400 IU). Myeloma patients also received chemotherapy. 4/6 males (66%) and 5/10 females (50%) improved amplitude-dependent speed of sound (AD-SoS) over the least significant change after 6 months. Mean difference from baseline value of AD-SoS shows a trend after 4 months of treatment, and became significant after 16 months (p&lt;0.005). Conclusions: Densitometric-structural evaluation of bone tissue at phalanges is safe and useful to evaluate bone quality changes during treatment with zoledronic acid, that determines a significant and sustained increase in ultrasonographic parameters of bone density and structure. No significant financial relationships to disclose.

Palliative Treatment of Bone Metastases in Hormone-Refractory Prostate Cancer: Effects of Pamidronate on the Carboxyterminal Telopeptide of Type-I Collagen Level in Patients with Increasing Prostate-Specific Antigen Levels

Purpose: Bisphosphonates have been reported to be effective in reducing bone pain and skeletal-related events associated with bone metastases in hormone-refractory prostate cancer (HRPC). However, whether bone resorption is reduced primarily by these particular drugs is difficult to evaluate because patients with HRPC are usually treated with secondary or tertiary hormonal manipulations including second-line antiandrogens, high-dose diethylstilbestrol, or low-dose dexamethasone therapies, some of which may also be effective. Thus, we assessed changes in the level of the carboxyterminal telopeptide of type-I collagen (ICTP), a bone resorption marker, before and after pamidronate administration in HRPC patients with increasing prostate-specific antigen (PSA) levels. Patients and Methods: Twenty-one HRPC patients with bone metastases and increasing PSA levels were intravenously treated with pamidronate at a dose of 30 mg either every 2 or every 4 weeks. Pamidronate administration was started immediately after confirmation of three consecutive increases in the PSA level. Results: In 14 patients (67%), the ICTP levels decreased after the administration of pamidronate, despite increasing PSA levels. In 7 of these cases, the ICTP levels were lower than those recorded for 6 months or longer before the start of pamidronate administration. The characteristics of the responders were compared with those of the non-responders. Conclusion: In 67% of the HRPC patients with increasing PSA levels, pamidronate reduced the accelerated turnover of bone metabolism caused by metastases of prostate cancer.

Acidic microenvironment created by osteoclasts causes bone pain associated with tumor colonization

Bone pain is one of the most common complications in cancer patients with bone metastases. Previous findings that inhibitors of osteoclastic bone resorption such as bisphosphonates (BPs) reduce bone pain suggest a critical role of osteoclasts. Osteoclasts destroy bone by secreting protons, thereby making adjacent microenvironment acidic. Because acidosis is a well-known cause of pain, it is plausible that an osteoclasts-created acidic microenvironment may cause bone pain associated with cancer colonization in bone. To test this notion, we studied an animal model in which inoculation of MRMT-1 rat breast cancer cells into the tibiae in female rats induced hyperalgesia. Radiographic and histological analyses demonstrated that MRMT-1 cells caused aggressive bone destruction with an increased number of osteoclasts. Behavioral analyses showed that rats exhibited hyperalgesia in the tumor-inoculated legs. The BP zoledronic acid (ZOL) significantly reduced the hyperalgesia. In addition, immunohistochemical examinations revealed that c-Fos expression in the ipsilateral spinal cord neurons was increased. ZOL decreased these c-Fos-positive neurons. To investigate the role of acidosis, mRNA expression of acid-sensing receptors including acid-sensing channels (ASICs) and transient receptor potential channel-vanilloid subfamily member 1 (TRPV1) in the dorsal root ganglions (DRGs) was determined. The expression of ASIC1a and ASIC1b was increased in the ipsilateral DRGs, whereas the ASIC3 and TRPV1 expression was not changed. Of note, ZOL reduced the expression of ASIC1a and ASIC1b. In conclusion, our data suggest that an acidic microenvironment created by osteoclasts, at least in part, contributes to the induction of hyperalgesia through upregulating ASICs expression.

CLC028 POSTER Rapid reduction in bone pain following loading-dose ibandronate in lung cancer patients with bone metastases

CLC028 POSTER Rapid reduction in bone pain following loading-dose ibandronate in lung cancer patients with bone metastases

Medical Therapy in Adults With Fibrous Dysplasia of Bone

In open studies, bisphosphonate therapy (pamidronate, alendronate) reduced bone pain associated with fibrous dysplasia of bone and was associated to some radiological improvement. Calcium, vitamin D, and phosphorus supplements may be useful in patients with deficiency. We are awaiting results from controlled trials testing bisphosphonates. Fibrous dysplasia of bone (FD), a rare disease caused by osteoblastic lineage differentiation defects, is associated with bone pain, fracture, and bone deformity, but few therapeutic options are available. We reviewed published data on the treatment of FD with bisphosphonates (pamidronate, alendronate), calcium, vitamin D, and phosphorus. We also present new results on FD therapy with a more potent bisphosphonate, zoledronic acid, given intravenously at the dose of 4 mg every 6 months. Pamidronate therapy, given intravenously every 6 months at a dose of 180 mg in adults, relieved bone pain, decreased bone resorption, and improved the radiological aspect (filling of lytic lesions and/or thickening of cortices) in approximately 50% of patients. BMD in affected sites was also significantly increased after pamidronate treatment. Those results have been obtained only in open studies, without controls, by several research groups. In a series of nine patients on long-term pamidronate treatment, but resisting to this medication and switched to intravenous zoledronic acid, no substantial improvement was observed. There is some biological rationale supporting the use of calcium and vitamin D in patients with deficiency to improve FD lesions by limiting secondary hyperparathyroidism. Phosphorus supplementation may prevent mineralization defects in those patients who have both FD and renal phosphate wasting. However, we are lacking clinical evidence for the efficacy of such supplements. Bisphosphonate treatment reduces increased osteoclastic activity in FD and probably improves bone pain, but their use should be better studied in randomized controlled trials.

Impact of zoledronic acid (Z) on pain in prostate cancer patients with bone metastases in a randomised placebo-control trial

4638 Background: Bone metastases occur in up to 80% of advanced prostate cancer patients and can results in painful Skeletal-Related Events (SREs). Z is the only biphosphonate approved for metastatic prostate cancer that decreases the occurrence of SREs which include pathologic fractures, severe bone pain requiring radiation therapy, spinal cord compression, surgery to bone and hypercalcemia of malignancy which may lead to daily activity limitations. We performed retrospective analyses on data from a placebo-controlled study of Z to investigate which items of the Brief Pain Inventory (BPI) were most sensitive to changes in patient’s pain due to treatment. Methods: Prostate cancer patients with bone metastases received Zoledronate 4 mg (n = 201) or placebo (n = 201). The BPI was administered at baseline (visit 2), and visits 3 (weeks 3–4), 4 (weeks 6–8), and then every second visit (every 6 weeks) until study end. Changes in BPI individual item scores and the Pain Severity and Pain Interference scale scores were compared between Z and placebo groups. Post-baseline missing data was replaced by Last Observation Carried Forward (LOCF). Results: Z was statistically significantly better than placebo for changes in BPI items ‘pain at its worst’, ‘pain at its least’, ‘pain on average’, and the BPI pain severity scale (p &lt; 0.05) at visit 4 (weeks 6–8), and visit 6 (week 12). For ‘pain right now’ there were statistically significant differences at visit 4, but not visit 6. Z was also superior to placebo for ‘pain right now’ and the Pain Severity and Interference scales at visit 12 (week 30–32) (p &lt; 0.05). Finally Z was superior to placebo for ‘interference with general activities’ at visits 12 (week 30–32), 16 (weeks 42–44), and LOCF (p &lt; 0.05). Conclusion: Our findings suggest that Z significantly reduces bone pain and general activity limitations in prostate cancer patients with bone metastases. Several items in the BPI are more sensitive to Z treatment including ‘pain at its worst’, ‘pain at its least’, ‘pain on average’, and the BPI Pain Severity scale. [Table: see text]

Osteoclasts play a part in pain due to the inflammation adjacent to bone

Bone disorders with increased osteoclastic bone resorption are frequently associated with bone pain and inhibitors of osteoclasts reduce bone pain. Osteoclasts degrade bone minerals by secreting protons through the vacuolar H+-ATPase, creating acidic microenvironments. Because acidosis is a well-known cause of pain, we reasoned that osteoclasts cause pain through proton secretion. We explored this using an animal model in which a single subcutaneous injection of the complete Freund's adjuvant (CFA) in the hind-paw caused inflammatory hyperalgesia (hyper-responsiveness to noxious stimuli). Osteoclastic bone resorption was increased in the metatarsal bones in the CFA-injected hind-paws. CFA-induced hyperalgesia was significantly suppressed by the bisphosphonates, zoledronic acid (ZOL) and alendronate and osteoprotegerin. c-src-deficient mice in which osteoclasts are inherently dysfunctional exhibited reduced CFA-induced hyperalgesia. Repeated subcutaneous injections of parathyroid hormone-related protein into the hind-paw also induced hyperalgesia with increased osteoclastic bone resorption. The hyperalgesia was associated with increased mRNA expression of acid-sensing ion channel (ASIC) 1a, 1b and 3 in the ipsi-lateral dorsal root ganglions (DRGs) by RT-PCR and c-Fos in the ipsi-lateral spinal dorsal horn by immunohistochemistry. Of note, ZOL decreased the ASIC1a mRNA expression and c-Fos. Treatment of the DRG cell line F-11 with acid (pH5.5) increased ASIC1a, 1b and 3 mRNA expression and nuclear c-Fos expression. The ASIC blocker amiloride inhibited acid-induced c-Fos expression in F-11 cells. Moreover, F-11 cells transfected with the transient receptor potential channel vanilloid subfamily member 1 (TRPV1) showed increased acid-induced nuclear c-Fos expression compared with parental F-11 cells. Finally, bafilomycin A1, an inhibitor of the vacuolar H+-ATPase, reversed the hyperalgesia and down-regulated ASIC1a mRNA expression in the DRGs. These results led us to propose that osteoclasts play a part in CFA-induced inflammatory pain through an activation of the acid-sensing receptors including ASICs and TRPV1 by creating acidosis.

Reduced bone pain by intensive bisphosphonate-therapy of new diagnosed bone metastases

Reduced bone pain by intensive bisphosphonate-therapy of new diagnosed bone metastases

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.

A Case of Hepatitis C-Associated Osteosclerosis in an Elderly Japanese Man

Hepatitis C-Associated Osteosclerosis (HCAO) is characterized by a marked increase in bone mass with deep bone pain. Since 1992, eleven cases of HCAO have been reported. This report describes an elderly Japanese man with HCAO, whose clinical course we followed for 3 years. A 68-year-old man developed pain in both pretibial regions in June 2000, and he had frequent episodic loss of muscular strength in his hands. He had recieved blood transfusion for a bleeding ulcer 43 years before and was seropositive for hepatitis C virus. His serum alkaline phosphatase (ALP) level was markedly increased, while his serum calcium was slightly decreased and serum phosphate was normal. Skeletal radiographs of the lower extremities showed a progressive increase in skeletal density, but did not show any apparent deformity. Administration of nonsteroidal anti-inflammatory drugs led to a reduction in bone pain. Treatment with vitamin D3 and calcium decreased the number of episodes of sudden muscular weakness and maintained serum calcium within the normal range. Three years after the onset of the disease, bone mineral density of his lumbar vertebrae and left hip rose from 0.963 g/cm2 to 1.096 g/cm2, and from 0.938 g/cm2 to 1.383 g/cm2, respectively. His serum ALP level decreased from 2889 to 277 IU/L (normal range: 104-338) and serum calcium normalized. These findings were accompanied by a decrease in bone pain. This case and previous reports suggest that the skeletal tissue of this disease appears to be of good quality.

Bone Metastases in Breast Cancer

Patients with advanced breast cancer who develop bone metastases suffer from longterm skeletal morbidity. Complications of bone metastases include pain, pathologic fractures, and spinal cord compression, which have a significant impact on the quality of life of patients. Treatment options for patients with bone metastases include surgery, radiation, and analgesics to reduce bone pain and to prevent or repair fractures. Intravenous bisphosphonates can delay the onset of bone metastasis and reduce the percentage of patients who experience skeletal complications of bone metastasis, thus reducing skeletal morbidity. For the past 6 years, pamidronate disodium (90 mg administered by 2-hour intravenous infusion) has been the treatment of choice for the prevention of skeletal complications of bone metastases in patients with breast cancer. However, a more potent bisphosphonate, zoledronic acid (4 mg administered by 15-minute intravenous infusion), was approved for use and has improved efficacy in patients with bone metastases. Because of the increased efficacy and more convenient infusion time, zoledronic acid may become the new standard of care for the treatment and prevention of skeletal complications secondary to bone metastases in patients with breast cancer. Phase III clinical trials have shown that patients with an existing skeletal complication are more likely to develop subsequent complications compared with patients who have not experienced a complication. Therefore, zoledronic acid therapy should be initiated when the patient is diagnosed with bone metastasis.

Effectiveness of Palliative Radiotherapy in the Treatment of Bone Metastases Employing the Brief Pain Inventory

Background: Many randomized trials in the treatment of bone metastases have reported that radiotherapy reduces bone pain and decreases analgesic consumption. However, reporting of other pain-related functional outcomes has been sparse. The primary objective of this study was to prospectively determine changes in pain intensity and its functional interference following palliative radiotherapy for painful bone metastases.Materials and Methods: Patients with symptomatic bone metastases treated with palliative radiotherapy from May 2003 to June 2005 were followed with the Brief Pain Inventory (BPI) at baseline, 1, 2, and 3 months after the delivery of radiotherapy. Radiotherapy outcome was assessed using the International Bone Metastases Consensus response definitions.Results: One hundred and ninety-nine patients were treated with palliative radiotherapy. All three pain scores and seven functional interference items at two months showed a significant improvement compared to the baseline. Complete, partial and overall response rates of the 101 patients who completed the BPI assessment at two months were 21%, 45% and 66%, respectively.Conclusions: External beam radiation therapy was found to be effective in palliating pain from bone metastases and reducing pain-related functional interference. Incorporating functional interference outcomes in future clinical trials may improve the assessment of meaningful treatment effect.

Zoledronic Acid Is an Effective Treatment for Osteoporosis in Patients with Thalassemia Major: Results of a Randomized, Placebo-Controlled, Trial.

Osteoporosis in thalassemia major (TM) is due to several factors, including bone marrow expansion, iron overload, hormonal deficiency, and increased osteoclast activity. Potent inhibitors of osteoclast function, such as bisphosphonates, have been recently used in the management of TM-induced osteoporosis. The aim of this trial was to determine the efficacy and safety of a third-generation aminobisphosphonate, zoledronic acid, on osteoporosis and bone remodeling in patients with TM. Sixty-six patients with TM-induced osteoporosis (21M/45F; median age 35.5 years) have been enrolled in this study. The majority of patients had pathological fractures and/or bone pain due to osteoporosis at baseline. Patients were randomized to receive zoledronic acid at a dose of 4 mg, iv, in 15 min infusion, every 6 months (23 patients; group A) or every 3 months (21 patients; group B), or to receive placebo every 3 months (22 patients; group C), for a period of one year. All patients were under oral calcium (500 mg) administration during the treatment period. Effects were monitored by measuring bone mineral density (BMD) in comparison with a series of serum bone remodeling indices: i) bone resorption markers [C-telopeptide of type-I collagen (CTX), tartrate-resistant acid phosphatase isoform-5b (TRACP-5b)], ii) bone formation markers [bone-alkaline phosphatase (bALP), osteocalcin (OC), and C-terminal propeptide of collagen type-I (CICP)], and iii) osteoclast stimulating factors [receptor activator of nuclear factor-κB ligand (RANKL), and osteoprotegerin (OPG)]. BMD of the lumbar spine, femoral neck and forearm was determined using DEXA, before and 12 months after treatment. The above biochemical parameters were measured at baseline and before the administration of zoledronic acid or placebo in each cycle. We also evaluated these markers in 30 healthy, age and gender-matched, controls. All patients had increased values of CTX, TRACP-5b, bALP, CICP, sRANKL, OPG, and sRANKL/OPG ratio, compared with controls (p<0.02). Patients of group A showed no differences in terms of BMD of all three evaluated sites after 12 months of treatment, while they showed a reduction in serum levels of CTX (p=0.02), bALP (p=0.02) and OC (p=0.01). Conversely patients of group B achieved a significant increase in their lumbar spine BMD after 12 months of therapy (p=0.007), which was accompanied by a dramatic decrease in serum CTX (p=0.004), bALP (p<0.0001), CICP (p<0.0001), and OC (p=0.005). Patients of group C showed an aggravation of BMD of the lumbar spine (p=0.041) at 12 months, while there was no alteration in BMD of other sites as well as in markers of bone remodeling. There was no effect of zoledronic acid on sRANKL and OPG in all patients. Zoledronic acid reduced bone pain in patients of groups A and B, while there was no bone pain relief in placebo group. No severe side-effects were observed in this study. We conclude that zoledronic acid, at a dose of 4 mg, iv, every 3 months is an effective treatment in increasing BMD and reducing osteoclast activity and bone resorption in TM-induced osteoporosis. Longer follow-up studies are required to clarify the exact role of zoledronic acid in the management of these patients.

Reduction of pain as the primary determinant of improved quality of life of cancer patients receiving zoledronic acid (Zol) for bone involvement

8022 Background: Bone metastases/lesions from breast cancer (BC), prostate cancer (PC), and multiple myeloma (MM) cause clinically significant skeletal morbidity and severe bone pain that diminish quality of life (QOL). We conducted an open-label, multicenter study to investigate the effect of Zol on pain and QOL. Methods: Pts with ≥ 1 bone lesion of BC, PC, or MM received Zol (4 mg) every 3–4 wk for up to 6 infusions. Worst pain during the preceding 7 days was assessed at baseline, before each infusion, and 4 wk after last infusion using a 100-mm visual analogue scale (VAS). QOL was assessed at baseline and before infusions 2 and 6 using the Functional Assessment of Cancer Therapy-General (FACT-G) Scale that evaluates physical, social, emotional, and functional well-being. Results: 260 pts with BC (n = 80), PC (n = 104), or MM (n = 76) were treated at 33 centers. At baseline, mean VAS pain score was 44.5 and mean total FACT-G score was 1.5 (on a scale of 0 to 4). Zol consistently reduced pain scores throughout the study, with significant reductions observed beginning at infusion 2. At final visit, mean pain scores were significantly reduced from baseline in all pts (-20.9 ± 2.1 SEM; P < .001), and in each tumor type (BC: -21.5 ± 3.3; PC: -20.9 ± 4.0; MM: -20.6 ± 3.8; all P < .001). Zol also significantly improved mean total FACT-G scores (-0.14 ± 0.04 SEM; P < .001) and physical (-0.34 ± 0.05; P < .001) and emotional (-0.17 ± 0.05; P < .002) well-being compared with baseline in all pts. FACT-G scores at infusion 6 by tumor type showed that, compared with baseline, Zol significantly improved mean total scores in pts with BC (-0.15 ± 0.08; P < .05) or MM (-0.21 ± 0.06; P < .001), emotional well-being in pts with BC (-0.16 ± 0.07; P < .02 [infusion 2]) or PC (-0.16 ± 0.08; P < .05), and physical well-being in all pts (BC: -0.35 ± 0.11; PC: -0.21 ± 0.09; MM: -0.45 ± 0.08; P < .001). Among the parameters of emotional well-being, reduction in pain was most significant and was the primary factor affecting the overall score. Conclusions: These results suggest that Zol significantly reduces bone pain and improves QOL in pts with bone lesions from advanced cancer, and they provide a rationale for further investigating the effect of Zol on bone pain. No significant financial relationships to disclose.

567Zoledronic acid provides long-term reduction of bone pain in patients with bone metastases secondary to prostate cancer

567Zoledronic acid provides long-term reduction of bone pain in patients with bone metastases secondary to prostate cancer

572Long-term reduction of bone pain and skeletal morbidity with zoledronic acid in patients with prostate cancer and bone metastases

572Long-term reduction of bone pain and skeletal morbidity with zoledronic acid in patients with prostate cancer and bone metastases