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PubMed2003

Zoledronic acid: an advance in tumour bone disease therapy and a new hope for osteoporosis.

The two main therapeutic applications of bisphosphonates are tumour bone disease and osteoporosis. They constitute the standard treatment for cancer hypercalcaemia, and placebo-controlled trials have shown that the prolonged administration of bisphosphonates, such as pamidronate or clodronate, can reduce the frequency of complications from tumour bone disease due to metastatic breast cancer or myeloma by a quarter to one-half. The results obtained with the intravenous route appear to be more impressive and more rapidly obtained than with oral compounds. Both agents can reduce the risk of vertebral, wrist and hip fractures by 30 - 50%, whereas other antiresorptive agents, such as raloxifene (Eli Lilly & Co.) or calcitonin (Unigene Laboratories Inc.), have only been demonstrated to reduce the incidence of vertebral fractures. The short infusion time (4 mg over 15 min) offers a convenient therapy and constitutes the most evident advantage of zoledronic acid, which will improve patients' quality of life. Zoledronic acid has the potential to change the treatment of osteoporosis dramatically.

Animals↗

PubMed2003

Fever after zoledronic acid administration is due to increase in TNF-alpha and IL-6.

The most common adverse event typically associated with bisphosphonate therapy is transient fever. The aim of this study was to define the role of the main cytokines of the acute-phase reaction interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) involved in the pathogenesis of zoledronic acid-induced fever. Eighteen consecutive cancer patients with bone metastases were treated, for the first time, with a single dose of 4 mg zoledronic acid infusion. They were prospectively evaluated for circulating TNF-alpha, interferon-gamma (IFN-gamma), and IL-6 levels at different times, just before and 1, 2, 7, and 21 days after diphosphonate infusion. Clinical and standard laboratory parameters were recorded at the same time points. TNF-alpha circulating levels increased significantly 1 and 2 days after zoledronic acid infusion (respectively, p = 0.002 and p < 0.001) and then decreased to levels similar to the basal levels. IL-6 levels increased significantly 1 day after the infusion (p = 0.007), returning to values similar to the median basal values 2 days after zoledronic acid administration. Moreover, in patients who experienced fever, the TNF-alpha and IL-6 increases were higher than in patients without fever. No statistically significant differences in IFN-gamma were identified at different time points in patients with and without fever. Our results show that zoledronic acid induces transient TNF-alpha and IL-6 increases and that these increases are higher in patients who have developed fever, suggesting that these cytokines could be responsible for fever pathogenesis. The sharp reduction in serum calcium levels observed in patients with fever may be related to zoledronic acid pharmacokinetic modifications.

Acute-Phase Reaction↗

PubMed2004

Short-term safety assessment in the use of intravenous zoledronic acid in children.

The clinical side effects of the potent new bisphosphonate zoledronic acid in children are unknown. In this study of 34 children with various bone disorders, the frequency of postinfusion flu-like illness, hypocalcemia, and hypophosphatemia was 85%, 74%, and 82%, respectively. No renal side effects were detected after up to 3 consecutive infusions.

Adolescent↗

PubMed2005

Cost-effectiveness of oral ibandronate versus IV zoledronic acid or IV pamidronate for bone metastases in patients receiving oral hormonal therapy for breast cancer in the United Kingdom.

BACKGROUND: Oral ibandronate is a single-nitrogen bisphosphonate whose efficacy is similar to that of IV ibandronate for the treatment of bone metastases. OBJECTIVE: The aim of this study was to compare the cost-effectiveness of oral ibandronate with zoledronic acid and generic pamidronate (both administered by IV) for the treatment of bone metastases in patients with breast cancer receiving oral hormonal therapy in the United Kingdom. METHODS: A global economic model was adapted to the UK National Health Service. Patients were assumed to receive oral hormonal therapy for 50% of their projected 14.3-month survival. The primary outcome was incremental cost per quality-adjusted life-year (QALY). Bisphosphonate efficacy data for relative risk reduction of skeletal-related events (SREs) were obtained from clinical trials. Resource use data and costs associated with IV bisphosphonate infusions were derived from published studies and a unit cost database; monthly drug acquisition costs were obtained from the British National Formulary. Utility scores were applied to time with or without an SRE to adjust survival for quality of life. Therefore, differences in QALYs were driven by utility weights rather than survival time. Model design and inputs were validated through expert UK clinician review. The absence of comparative efficacy and safety data from clinical trials for the different bisphosphonates was a model limitation that we addressed by supporting our assumptions with UK expert clinician opinion and with expert clinician opinion outside of the United Kingdom, and by conducting sensitivity analyses. RESULTS: The projected total cost per patient was pound307 less with oral ibandronate compared with zoledronic acid, and pound158 less compared with the use of generic pamidronate (due to a reduction in staff time for infusions, avoidance of renal safety monitoring visits, and, in the case of IV generic pamidronate, a reduction in the number of SREs). Oral ibandronate was estimated to lead to a gain of 0.02 QALY, making it the economically dominant treatment option. CONCLUSIONS: In this study, we found that oral ibandronate was cost-effective for the management of bone metastases from breast cancer among patients receiving oral hormonal therapy in the United Kingdom. Oral ibandronate provided effective SRE and bone-pain management while avoiding resource use and costs associated with regular IV bisphosphonate infusions. Due to uncertainty surrounding the model assumptions, it would be valuable to repeat the analyses using data from comparative bisphosphonate trials, once they become available.

Administration, Oral↗

PubMed2006

Zoledronic acid treatment impairs protein geranyl-geranylation for biological effects in prostatic cells.

BACKGROUND: Nitrogen-containing bisphosphonates (N-BPs) have been designed to inhibit osteoclast-mediated bone resorption. However, it is now accepted that part of their anti-tumor activities is related to interference with the mevalonate pathway. METHODS: We investigated the effects of zoledronic acid (ZOL), on cell proliferation and protein isoprenylation in two tumoral (LnCAP, PC-3,), and one normal established (PNT1-A) prostatic cell line. To assess if inhibition of geranyl-geranylation by ZOL impairs the biological activity of RhoA GTPase, we studied the LPA-induced formation of stress fibers. The inhibitory effect of ZOL on geranyl geranyl transferase I was checked biochemically. Activity of ZOL on cholesterol biosynthesis was determined by measuring the incorporation of 14C mevalonate in cholesterol. RESULTS: ZOL induced dose-dependent inhibition of proliferation of all the three cell lines although it appeared more efficient on the untransformed PNT1A. Whatever the cell line, 20 microM ZOL-induced inhibition was reversed by geranyl-geraniol (GGOH) but neither by farnesol nor mevalonate. After 48 hours treatment of cells with 20 microM ZOL, geranyl-geranylation of Rap1A was abolished whereas farnesylation of HDJ-2 was unaffected. Inhibition of Rap1A geranyl-geranylation by ZOL was rescued by GGOH and not by FOH. Indeed, as observed with treatment by a geranyl-geranyl transferase inhibitor, treatment of PNT1-A cells with 20 microM ZOL prevented the LPA-induced formation of stress fibers. We checked that in vitro ZOL did not inhibit geranyl-geranyl-transferase I. ZOL strongly inhibited cholesterol biosynthesis up to 24 hours but at 48 hours 90% of this biosynthesis was rescued. CONCLUSION: Although zoledronic acid is currently the most efficient bisphosphonate in metastatic prostate cancer management, its mechanism of action in prostatic cells remains unclear. We suggest in this work that although in first intention ZOL inhibits FPPsynthase its main biological actitivity is directed against protein Geranylgeranylation.

Alkyl and Aryl Transferases↗

PubMed2006

Scleritis complicating zoledronic acid infusion.

We present a case of severe unilateral posterior scleritis associated with zoledronic acid administration that was recognized and treated in a timely manner. Subsequent use of pamidronate was associated with milder inflammation in the same eye that eventually resolved with continued monthly infusions, indicating the possibility of immunologic tolerance. Physicians prescribing these drugs should be aware of this side effect, which, if not recognized and treated appropriately, is potentially devastating. We review the published data as well as the current treatment recommendations.

Aged↗

PubMed2003

New insights into the actions of bisphosphonate zoledronic acid in breast cancer cells by dual RhoA-dependent and -independent effects.

Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate and its use in reducing osteoporosis and cancer-induced osteolysis is increasing. Recent findings indicated that ZOL has a direct effect on cancer cells. In this study, the effect of ZOL was examined on the aggressive MDA-MB-231 breast cancer cell line. ZOL induces an important inhibition of cell invasion at low concentrations (1 microM). This is not explained by modifications of proteases involved in cell invasiveness (matrix metalloproteinases and urokinase-type plasminogen activator), but by a disorganisation of actin cytoskeleton due to RhoA inhibition related to its defective prenylation as it was reversed by geranylgeraniol (GGOH) and mimicked by the Rho selective inhibitor C3 exoenzyme. In addition, ZOL inhibits the chemotactic effect induced by stromal cell-derived factor 1(SDF-1), a chemokine greatly involved in cancer metastasis to bone. This effect is related to both reduction of cell motility induced by RhoA inhibition and to a decreased expression of CXCR-4, the SDF-1 receptor. Finally, ZOL reduces Cox-2 expression and, consequently, the secretion of prostaglandins E2 (PGE2) in a RhoA-independent manner. This inhibition could contribute to bone protection in breast cancers because PGE2 stimulates osteoclast-mediated bone resorption. In summary, new insights in the mechanism of ZOL action on aggressive breast cancer cells are demonstrated and could explain its beneficial action in both the reduction of osteolysis and prevention of metastasis.

Bone Resorption↗

PubMed2002

Broad clinical activity of zoledronic acid in osteolytic to osteoblastic bone lesions in patients with a broad range of solid tumors.

Bone metastases are a common feature of a variety of solid tumors and are associated with substantial skeletal morbidity, including severe bone pain and pathologic fractures. Treatment with bisphosphonates, primarily pamidronate, is the current standard of care for patients with breast cancer and multiple myeloma who have predominantly osteolytic lesions. However, until recently no bisphosphonate had demonstrated efficacy in patients with osteoblastic lesions, which are common during the progression of prostate cancer and other solid tumors. Zoledronic acid, a potent, new-generation, nitrogen-containing bisphosphonate, has demonstrated significant benefits for patients with bone metastases resulting from a broad range of primary tumors, including multiple myeloma and breast, lung, kidney, and prostate cancers, and other solid tumors. Benefits include a decreased incidence of pathologic fractures and longer time to the first skeletal complication. Zoledronic acid is the first and only bisphosphonate to be proved effective in patients with all types of bone lesions, from osteolytic to osteoblastic, and therefore represents an important therapeutic advancement in the treatment of bone metastases.

Bone Neoplasms↗

PubMed2002

Efficacy and safety of zoledronic acid in the treatment of bone metastases associated with lung cancer and other solid tumors.

Advanced solid tumors are often aggressive and recurrent, and overall survival remains relatively poor despite contemporary therapeutic interventions. Bone metastases are common in these patients, and skeletal-related events, including bone pain, pathologic fractures, and potentially life-threatening hypercalcemia of malignancy, undermine the quality of patient survival. Bisphosphonates are widely used in the treatment of bone metastases associated with breast cancer and multiple myeloma, but have not been extensively investigated in the treatment of patients with solid tumors other than breast or prostate cancer. However, a new-generation nitrogen-containing bisphosphonate, zoledronic acid, has shown significant clinical benefits in indications in which other bisphosphonates have failed. In a phase III clinical trial in patients with bone metastases from solid tumors other than breast or prostate cancer, treatment with zoledronic acid (4 mg via 15-minute infusion) was well tolerated and significantly decreased the incidence of skeletal-related events and increased the time to first skeletal-related event compared with placebo-treated patients. This was the first demonstration of palliative efficacy for bisphosphonate therapy in patients with bone metastases from a wide variety of solid tumors.

Bone Neoplasms↗

PubMed2004

The effect of intravenous zoledronic acid on glucocorticoid-induced multiple vertebral fractures in juvenile systemic lupus erythematosus.

Glucocorticoids are widely used in the treatment of lupus patients, and adverse effects, which include osteoporosis and associated fractures, are frequent. Treatment of osteoporosis of young patients should be effective and not harmful to bone growth and remodeling. Bisphosphonates are drugs that decrease the incidence of bone fractures, but their use in juvenile patients is still controversial because of their possible side effects on the growing skeleton. However, recently published studies showed that linear growth continued normally after treatment with these drugs, and there was no excessive suppression of bone remodeling or mineralization defects. Zoledronic acid is a new intravenous bisphosphonate that has been approved by the US FDA for use with hypercalcemia of malignancies and might be an effective treatment for postmenopausal osteoporosis. The authors report a case of a young girl with systemic lupus who developed multiple vertebral collapses due to glucocorticoid therapy, and zoledronic acid was used producing significant clinical and densitometric improvement.

Adolescent↗

PubMed2006

The effect of zoledronic acid on serum osteoprotegerin in early stage multiple myeloma.

We evaluated the effect of zoledronic acid (ZA) on serum levels of osteoprotegerin (OPG) and the ligand for receptor activator of nuclear factor kappaB (RANKL) in patients with smoldering myeloma. In treated subjects we found an increase of OPG accounting for an effect of ZA on osteoblast and/or bone marrow stromal cells together with the direct effect on osteoclasts.

Diphosphonates↗

PubMed2002

Highly potent geminal bisphosphonates. From pamidronate disodium (Aredia) to zoledronic acid (Zometa).

Bisphosphonates (BPs) are pyrophosphate analogues in which the oxygen in P-O-P has been replaced by a carbon, resulting in a metabolically stable P-C-P structure. Pamidronate (1b, Novartis), a second-generation BP, was the starting point for extensive SAR studies. Small changes of the structure of pamidronate lead to marked improvements of the inhibition of osteoclastic resorption potency. Alendronate (1c, MSD), with an extra methylene group in the N-alkyl chain, and olpadronate (1h, Gador), the N,N-dimethyl analogue, are about 10 times more potent than pamidronate. Extending one of the N-methyl groups of olpadronate to a pentyl substituent leads to ibandronate (1k, Roche, Boehringer-Mannheim), which is the most potent close analogue of pamidronate. Even slightly better antiresorptive potency is achieved with derivatives having a phenyl group linked via a short aliphatic tether of three to four atoms to nitrogen, the second substituent being preferentially a methyl group (e.g., 4g, 4j, 5d, or 5r). The most potent BPs are found in the series containing a heteroaromatic moiety (with at least one nitrogen atom), which is linked via a single methylene group to the geminal bisphosphonate unit. Zoledronic acid (6i), the most potent derivative, has an ED(50) of 0.07 mg/kg in the TPTX in vivo assay after sc administration. It not only shows by far the highest therapeutic ratio when comparing resorption inhibition with undesired inhibition of bone mineralization but also exhibits superior renal tolerability. Zoledronic acid (6i) has thus been selected for clinical development under the registered trade name Zometa. The results of the clinical trials indicate that low doses are both efficacious and safe for the treatment of tumor-induced hypercalcemia, Paget's disease of bone, osteolytic metastases, and postmenopausal osteoporosis.

Animals↗

PubMed2006

First-line therapy with thalidomide, dexamethasone and zoledronic acid decreases bone resorption markers in patients with multiple myeloma.

BACKGROUND: Bone involvement is frequently observed in multiple myeloma (MM) patients both at diagnosis and during the course of the disease. The evaluation of biochemical markers of bone turnover could allow a dynamic evaluation of the effects of a given therapy on bone metabolism. METHODS: In the present study, markers of bone resorption [urinary free pyridinoline (PYD), deoxypyridinoline (DPYD), N-terminal telopeptide of collagen I (NTX) and C-terminal telopeptide (serum crosslaps)] and of bone formation [bone alkaline phosphatase (BAP) and osteocalcin] were evaluated at diagnosis and after induction therapy in 40 patients (23M, 17F, median age = 53.5 yr) enrolled in the 'Bologna 2002' clinical trial. By study design, all patients received 4 months of combined thalidomide (100 mg/d for 2 wk then 200 mg/d), dexamethasone (40 mg/d on days 1-4, 9-12, 17-20/28 on odd cycles and on days 1-4 on even cycles) and zoledronic acid (4 mg/28 d). RESULTS: At diagnosis, although bone resorption markers were increased in more than 40% of the patients, only NTX (P = 0.029) and crosslaps (P = 0.000) were significantly related to the extent of skeletal lesions, as assessed by X-ray. After 4 months of therapy, a significant decrease in mean (+/-SE) urinary NTX (52.7 +/-6.9 nmol/mmol creatinine +/-6.9 vs. 14 +/- 1.42 nmol/mmol creatinine, P = 0.000) and serum crosslaps (6242.4 +/-945 pmol/L vs. 1414.9 +/- 173.8 pmol/L, P = 0.000) was observed in patients obtaining > or =partial response, at variance to what has been detected in patients showing <partial response. CONCLUSIONS: Among all bone resorption markers, urinary NTX and serum crosslaps seem to be strictly related to the extent of bone involvement in MM. Combined thalidomide + dexamethasone and zoledronic acid seem to be highly effective in reducing bone resorption in sensitive patients, although the relative contribution of each drug cannot yet be determined.

Adult↗

PubMed2004

Targeting osteoclasts with zoledronic acid prevents bone destruction in collagen-induced arthritis.

OBJECTIVE: To study the effect of zoledronic acid (ZA) on synovial inflammation, structural joint damage, and bone metabolism in rats during the effector phase of collagen-induced arthritis (CIA). METHODS: CIA was induced in female dark agouti rats. At the clinical onset of CIA, rats were assigned to treatment with vehicle or single subcutaneous doses of ZA (1.0, 10, 50, or 100 microg/kg). Clinical signs in all 4 paws were scored on a daily basis. After 2 weeks, the joints in the hind paws were assessed using plain radiographs, microfocal computed tomography (micro-CT), histologic scoring, and histomorphometry, and the serum levels of type I collagen crosslinks were measured by enzyme-linked immunosorbent assay. RESULTS: Although ZA mildly exacerbated synovitis, it effectively suppressed structural joint damage. At doses of >/=10 microg/kg, ZA significantly reduced radiographic bone erosions, Larsen scores, and juxtaarticular trabecular bone loss as quantified by micro-CT. ZA prevented increased type I collagen (bone) breakdown in CIA and diminished histologic scores of focal bone erosion by up to 80%. Increases in the percentage of eroded surface, osteoclast surface, and osteoclast numbers associated with CIA were prevented by ZA, even though synovitis scores were unchanged. CONCLUSION: Single doses (>/=10 microg/kg) of ZA strikingly reduced focal bone erosions and juxtaarticular trabecular bone loss, although synovitis was mildly exacerbated. Targeting osteoclasts with ZA may therefore be an effective strategy for preventing structural joint damage in rheumatoid arthritis.

Animals↗

PubMed2003

Long-term zoledronic acid treatment increases bone structure and mechanical strength of long bones of ovariectomized adult rats.

Zoledronic acid (ZOL) is a highly potent heterocyclic bisphosphonate which has been shown to inhibit bone resorption in short-term experiments in young growing animals. In this investigation we have evaluated the effects of a 1-year administration to mature, ovariectomized (OVX) rats as a model for postmenopausal osteoporosis in order to elucidate (1) the temporal changes in urinary biochemical markers of bone turnover and femoral bone mineral density (BMD), (2) to measure changes of static and dynamic histomorphometric parameters and mechanical strength, and (3) to assess the preventive effects of chronic treatment with ZOL on these parameters. In urine, deoxypyridinoline increased after OVX and was significantly reduced by ZOL administration, indicative of a reduced bone collagen turnover. These changes were accompanied by alterations of tibial cancellous bone: trabecular bone volume and parameters of bone architecture were significantly augmented by ZOL and bone formation rates fell as a consequence of suppressed bone turnover, but were still measurable. No signs of "frozen bone" or osteomalacia could be detected. BMD of the whole femurs rose in sham-operated control animals (SHAM) during the entire experimental period, whereas in OVX animals, BMD plateaued after 32 weeks at a lower level. ZOL at a low dose (0.3 mg/kg/week s.c.) did not alter whole femur BMD, but at higher doses (1.5 and 7.5 mg/kg/week s.c.) BMD increased to the level of the SHAM group. A distinct pattern was noted for the distal quarter of the femur, a region rich in cancellous bone: BMD initially increased in all treatment groups except the OVX group, and at a later stage fell again at a comparable rate irrespective of treatment. Mechanical stability, as assessed by a 3-point bending test, was significantly increased by all doses of ZOL and exceeded OVX and sham-operated controls. The effects on mechanical properties were observed at a low dose which did not measurably increase femoral BMD after 1-year treatment. Multiregression analysis revealed a significant positive correlation between maximum load and BMD, and a significant negative correlation of maximum load with labeled perimeter, a marker of bone formation and turnover. No significant correlation was found with urinary deoxypyridinoline, a marker of bone resorption. The data show that mechanical testing detects improvements of functional bone quality following low dose bisphosphonate treatment which are not identified by standard DXA measurements of BMD.

Animals↗

PubMed2026

Bone progression in multiple myeloma: Benefit of zoledronic acid for patients achieving at least Very Good Partial Response and prognostic value of bone turnover markers.

The Magnolia study demonstrated that continuation of zoledronic acid (ZOL) beyond 2 years reduces the risk of progressive bone disease (PBD) in patients with multiple myeloma (MM). This follow-up study investigated the effects of ZOL in patients achieving very good partial response (VGPR) compared to patients who did not and whether bone turnover markers could identify patients at an increased risk of PBD following treatment cessation. Two Magnolia trial subgroups were analysed: patients with VGPR or better after 2 years of ZOL, randomized to either continued treatment or observation, and patients randomized to observation in whom serial bone markers (C-terminal cross-linked telopeptide of type I collagen [CTX], procollagen type I N-terminal propeptide [P1NP], bone-specific alkaline phosphatase [BAP], tartrate-resistant acid phosphatase isoform 5b [TRAcP]) were measured for up to 4 years. Continued monthly ZOL beyond 2 years significantly reduced the risk of PBD (hazard ratio 0.40; 95% confidence interval [CI] 0.16-0.92) in patients with VGPR or better (subgroup 1). After ZOL discontinuation, bone markers increased gradually. Elevated CTX (≥0.30 μg/L) and TRAcP (≥4 U/L) levels were associated with increased 6-month PBD risk (29% and 15% respectively) (subgroup 2). Continuation of ZOL beyond 2 years seems to reduce skeletal progression risk in patients achieving VGPR or better. Elevated CTX or TRAcP levels may help identify patients who could benefit from re-initiating ZOL.

Humans↗

PubMed2005

[Clinical study of zoledronic acid in the treatment of cancer-induced hypercalcemia].

OBJECTIVE: To investigate the effect and safety of zoledronic acid (Zoledex) in patients with cancer-induced hypercalcemia. METHODS: Seventeen patients with cancer-induced hypercalcemia (corrected blood calcium > 2.70 mmol/L) were treated intravenously by 4 mg zoledex within 15 minutes on the first day. The corrected blood calcium was observed every 4 days in the following 28 days. RESULTS: The response rate was 94.1% (16/17). The mean corrected blood calcium became normal after the first dose of zoledex (P < 0.01). The lowest value was found on the fourteenth day after treatment. The main side effects consisted of fever (29.4%, 5/17), hypocalcemic tetany (11.8%, 2/17) and arythmia (5.9%, 1/17). CONCLUSION: Zoledex is effective and safe in the treatment of patient with cancer-induced hypercalcemia.

Adult↗

PubMedDate not supplied

Effects of zoledronic acid on proteinase plasma levels in patients with bone metastases.

BACKGROUND: The effects of the bisphosphonate derivative zoledronic acid (ZA) on the circulating levels of matrix metalloproteinase-2 (MMP-2), matrix metallo-proteinases-9 (MMP-9), cathepsin B (Cath B) and urokinase-type plasminogen activator (uPA) in patients with bone metastasis (BMTS) and the possible correlation with the symptomatic response induced by this drug in these patients were evaluated. PATIENTS AND METHODS: Proteinase levels were determined by enzyme-linked immunosorbent assay (ELISA) in the plasma of 30 patients with painful bone metastases from breast or prostate cancer undergoing multiple treatment with ZA (4 mg i.v., every 4 weeks). Healthy subjects (HS) of both genders (12 female and 30 male) served as the control group. The symptomatic response to ZA was assessed by the visual analog scale score (VAS). RESULTS: The median MMP-2 and MMP-9 pretreatment levels were more elevated in BMTS as compared to HS (p < or = 0.0001). Conversely, uPA levels were lower in BMTS p = 0.0033; no significant difference was observed for Cath B. ZA administration was associated with a symptomatic response (VAS score < or =4) in 25/30patients (83.3%) (p < 0.0001). This phenomenon paralleled a decrease of Cath B and MMP-2 plasma concentrations from baseline values on week 12 (p = 0.05). A similar trend, although not statistically significant, was also noted for MMP-9 and uPA. However, no direct relationship was observed between the analgesic effect induced by ZA and changes in the circulating levels of these enzymes. CONCLUSION: These data show that ZA administration may provide relief from bone pain in patients with diffuse skeletal metastases and confirm a possible implication of cysteine proteinases and matrix metalloproteinases in bone metastasis formation, but not in the pathogenesis of metastatic bone pain.

Aged↗