Dose Of Zoledronate Research Articles

Liposome encapsulated zoledronate favours M1-like behaviour in murine macrophages cultured with soluble factors from breast cancer cells.

BackgroundTumour stromal macrophages differentiate to tumour-associated macrophages (TAMs) with characteristics of immunosuppressive M2-type macrophages, having a central role in promoting tumour vascularisation, cancer cell dissemination and in suppressing anti-cancer immune responses. Bisphosphonates (BPs) are a group of drugs commonly used as anti-resorptive agents. Further, nitrogen containing BPs like Zoledronate (ZOL), are known to cause unspecific inflammatory reactions hence the hypothesis that its use could modulate TAMs polarization toward a more inflammatory phenotype.MethodsWe studied the in vitro polarization of J774 murine macrophages upon culture in 4T1 breast cancer cell-conditioned medium (4T1CM) and stimulation with LPS and free and liposome-encapsulated bisphosphonates.ResultsIn this system, breast cancer soluble factors reduced the pro-inflammatory activation of macrophages but increased the secretion of matrix metalloproteinases (MMPs). In the presence of 4T1CM, a non-cytotoxic dose of liposome-encapsulated ZOL (ZOL-LIP) enhanced the expression of iNOS and TNF-α, markers of M1 activation, but did not diminish the expression of M2-type markers. In contrast, clodronate treatment either as a free drug (CLO) or liposome-encapsulated (CLO-LIP) decreased the expression of the M1-type markers and was highly cytotoxic to the macrophages.ConclusionsBreast cancer cells soluble factors modulate macrophages toward M2 activation state. Bisphosphonates may be applied to counteract this modulation. We propose that ZOL-LIP may be suitable for favouring cytotoxic immune responses by TAMs in breast cancer, whereas CLO-LIP may be appropriate for TAM depletion.

Biomarkers of bone remodeling in multiple myeloma patients to tailor bisphosphonate therapy.

Patients with multiple myeloma may be susceptible to osteonecrosis of the jaw (ONJ) and stress fractures due to long-term aminobisphosphonate (aBP) therapy. However, it is unknown whether urinary N-telopeptide (NTX) or other bone biomarkers are predictive of skeletal-related events (SRE) or the impact of cessation of aBP therapy on bone remodeling. We studied markers of bone turnover over a 6-month period after a single dose of zoledronic acid in 29 patients with multiple myeloma in remission who previously received 8 to 12 doses of pamidronate or zoledronate (NCT00577642). Our primary objective was to determine the duration of time urinary NTX levels remain suppressed after a single dose of zoledronate. A secondary objective was to identify and correlate other markers of bone remodeling with NTX changes. Thirty cytokines, based on their possible role in bone remodeling, were tested using cytokine arrays. Candidates were confirmed by ELISA. All patients had continued suppression of NTX levels, except 1 patient who had an increase in NTX levels associated with an SRE. GDF-15 and decorin were found to decrease, whereas bone-specific alkaline phosphatase (BSALP) increased. Although not significant in aggregate, osteopontin and osteoprotegerin levels increased in at least half of the patients. Our data show that NTX levels continue to be suppressed after aBP therapy, and suggest that suppressed NTX levels may be predictive of freedom from SRE in this patient population. Furthermore, osteoblast suppression by aBP may be reversible in myeloma. These data provide the basis for less frequent dosing of aBPs.

Early, middle, or late administration of zoledronate alleviates spontaneous nociceptive behavior and restores functional outcomes in a mouse model of CFA-induced arthritis.

This study was performed to evaluate whether early, middle, or late treatment of zoledronate, an approved bisphosphonate that blocks bone resorption, can reduce nociceptive behaviors in a mouse arthritis model. Arthritis was produced by repeated intra-articular knee injections of complete Freund's adjuvant (CFA). A dose-response curve with zoledronate (3, 30, 100, and 300 μg/kg, i.p., day 4 to day 25, twice weekly for 3 weeks) was performed, and the most effective dose of zoledronate (100 μg/kg, i.p.) was initially administered at different times of disease progression: day 4 (early), day 15 (middle), or day 21 (late) and continued until day 25 after the first CFA injection. Flinching of the injected extremity (spontaneous nociceptive behavior), vertical rearings and horizontal activity (functional outcomes), and knee edema were assessed. Zoledronate improved both functional outcomes and reduced flinching behavior. At day 25, the effect of zoledronate on flinching behavior and vertical rearings was greater in magnitude when it was given early or middle rather than late in the treatment regimen. Chronic zoledronate did not reduce knee edema in CFA-injected mice nor functional outcomes in naïve mice by itself. These results suggest that zoledronate may have a positive effect on arthritis-induced nociception and functional disabilities.

Local application of zoledronate enhances miniscrew implant stability in dogs

The primary purposes of this study were to evaluate how locally delivered zoledronate affects the longitudinal stability of miniscrew implants (MSIs) and the healing of bone around MSIs. Using a randomized split-mouth design, 60 unloaded MSIs (5×1.6mm) were placed in skeletally mature male foxhound-mixed breed dogs. The MSIs were randomly assigned to bilateral pairs of pilot holes (1.1mm) that had been injected with either bisphosphonate zoledronate (n=30, experimental group) or buffered saline solution (n=30, control group). MSI stability was evaluated weekly for 8weeks using resonance frequency analyses (Osstell Mentor; Integration Diagnostics, Göteborg, Sweden). Microcomputed tomography (6-μm voxel size) was used to determine the bone volume fractions of 3 layers of bone (6-24, 24-42, and 42-60μm) surrounding the MSIs. Resonance frequency analysis showed that the control MSIs were significantly (P<0.05) less stable than the experimental MSIs. Although there was little or no change in stability over time for the MSIs treated with zoledronate, the stability of the control MSIs decreased during the first 4weeks, increased through week 6, and then decreased again. The 6- to 24-μm layer closest to the MSIs, on both the experimental and the control sides, showed significantly (P<0.05) less bone than did the 24- to 42-μm and the 42- to 60-μm layers. After 8weeks, there was significantly more cortical bone surrounding the control than the experimental MSIs. In contrast, there was significantly more trabecular bone surrounding the experimental than the control MSIs. One small locally delivered dose of zoledronate maintained the stability of MSIs over time, primarily because of greater amounts of trabecular bone surrounding the MSIs. Even though zoledronate enhanced the stability of MSIs in dogs, it should not be used clinically until further studies confirm its safe use in patients.

Cortical bone loss at the tibia in postmenopausal women with osteoporosis is associated with incident non-vertebral fractures: Results of a randomized controlled ancillary study of HORIZON

BackgroundIn postmenopausal women, yearly intravenous zoledronate (ZOL) compared to placebo (PLB) significantly increased bone mineral density (BMD) at lumbar spine (LS), femoral neck (FN), and total hip (TH) and decreased fracture risk. The effects of ZOL on BMD at the tibial epiphysis (T-EPI) and diaphysis (T-DIA) are unknown. MethodsA randomized controlled ancillary study of the HORIZON trial was conducted at the Department of Osteoporosis of the University Hospital of Berne, Switzerland. Women with ≥1 follow-up DXA measurement who had received ≥1 dose of either ZOL (n=55) or PLB (n=55) were included. BMD was measured at LS, FN, TH, T-EPI, and T-DIA at baseline, 6, 12, 24, and 36 months. Morphometric vertebral fractures were assessed. Incident clinical fractures were recorded as adverse events. ResultsBaseline characteristics were comparable with those in HORIZON and between groups. After 36 months, BMD was significantly higher in women treated with ZOL vs. PLB at LS, FN, TH, and T-EPI (+7.6%, +3.7%, +5.6%, and +5.5%, respectively, p<0.01 for all) but not T-DIA (+1.1%). The number of patients with ≥1 incident non-vertebral or morphometric fracture did not differ between groups (9 ZOL/11 PLB). Mean changes in BMD did not differ between groups with and without incident fracture, except that women with an incident non-vertebral fracture had significantly higher bone loss at predominantly cortical T-DIA (p=0.005). ConclusionZOL was significantly superior to PLB at T-EPI but not at T-DIA. Women with an incident non-vertebral fracture experienced bone loss at T-DIA.

Investigating the synergistic efficacy of BMP-7 and zoledronate on bone allografts using an open rat osteotomy model

Bone grafts are well-established in the treatment of fracture non-unions but union is still not always achieved. Harvesting autograft is associated with donor site morbidity and the available amount of bone is limited. Allograft is more easily obtained and available in greater quantities but lacks the osteoinductive characteristics of autograft. We have previously shown a synergistic effect of bone morphogenetic protein (BMP-7), systemic bisphosphonates and autograft. In the present study we hypothesized that the combination of allograft+BMP-7+systemic ZA is more effective than autograft alone, which is currently the most frequently used aid in augmenting fracture and non-union healing.Femoral osteotomies were performed on 82 male Sprague Dawley rats and fixed with intramedullary K-wires. The rats were randomized into 7 groups: i. saline, ii. autograft, iii. allograft, iv. allograft+BMP-7, v. autograft+zoledronate (ZA), vi. allograft+ZA and vii. allograft+BMP-7+ZA. Autografts were harvested from the contralateral tibia. Allografts were obtained from donor rats and frozen. BMP-7 was administered locally in the form of a putty placed circumferentially around the osteotomy. At 2weeks, the rats were injected with a single dose of either saline or ZA. The rats were sacrificed at 6weeks and the femurs were evaluated using radiography, histology, μCT and three-point bending tests.Complete radiological healing was seen in all rats in the BMP-7 groups. The callus volume was larger and the calluses were denser with allograft+BMP-7+ZA than in all other groups (μCT, p<0.001). Mechanical testing yielded a substantially higher peak force with the allograft+BMP-7+ZA combination than all other groups (p<0.01, p<0.001). This was further reinforced in the 59% increase in the peak force observed in the osteotomized femurs of the allograft+BMP-7+ZA group compared to the control femurs (p<0.01), whereas significant decreases of 22–27% were observed in the saline or bone-graft alone groups (p<0.01, p<0.05). Thus our results suggest that allograft combined with the anabolic effect of BMP-7 and the anti-catabolic effect of zoledronate is more efficient than autograft alone.

Duration of Antiresorptive Effects of Low-Dose Zoledronate in Osteopenic Postmenopausal Women: A Randomized, Placebo-Controlled Trial

Annual intravenous administration of 5 mg zoledronate decreases fracture risk, but the optimal dosing regimen for zoledronate has not been determined. We set out to evaluate the antiresorptive effects of a single administration of lower doses of zoledronate. A total of 180 postmenopausal women with osteopenia enrolled in a double-blind, randomized, placebo-controlled trial over 2 years at an academic research center. Participants were randomized to a single baseline administration of intravenous zoledronate in doses of 1 mg, 2.5 mg, or 5 mg, or placebo. The primary endpoint was change in bone mineral density(BMD) at the lumbar spine. Secondary endpoints were change in BMD at the proximal femur and total body, and changes in biochemical markers of bone turnover. After 2 years, the change in spine BMD was greater in each of the zoledronate groups than in the placebo group; values are mean (95% confidence interval [CI]) difference versus placebo: zoledronate 1 mg 4.4% [2.7% to 6.1%]; 2.5 mg 5.5% [3.9% to 7.2%]; 5 mg 5.3% [3.8% to 6.7%], p < 0.001 for each dose). Change in BMD at the total hip was greater in each of the zoledronate groups than the placebo group (mean [95% CI] difference versus placebo: zoledronate 1 mg 2.6% [1.5% to 3.7%]; 2.5 mg 4.4% [3.5% to 5.3%]; 5 mg 4.7% [3.7% to 5.7%], p < 0.001 for each dose). Each of the bone turnover markers, β-C-terminal telopeptide of type I collagen (β-CTX) and procollagen type-I N-terminal propeptide (P1NP), was lower in each of the 2.5-mg and 5-mg zoledronate groups than the placebo group throughout the trial (p < 0.001 versus placebo for each marker for each dose at each time point). For each endpoint, changes were similar in the 2.5-mg and 5-mg zoledronate groups, whereas those in the 1-mg group were smaller than those in the other zoledronate groups. These data demonstrate that single administrations of zoledronate 1 mg or 2.5 mg produce antiresorptive effects that persist for at least 2 years. Trials assessing the antifracture efficacy of intermittent low doses of zoledronate, in particular the 2.5-mg dose, are justified.

Zoledronate Effects on Systemic and Jaw Osteopenias in Ovariectomized Periostin-Deficient Mice

Osteoporosis and periodontal disease (PD) are frequently associated in the elderly, both concurring to the loss of jaw alveolar bone and finally of teeth. Bisphosphonates improve alveolar bone loss but have also been associated with osteonecrosis of the jaw (ONJ), particularly using oncological doses of zoledronate. The effects and therapeutic margin of zoledronate on jaw bone therefore remain uncertain. We reappraised the efficacy and safety of Zoledronate (Zol) in ovariectomized (OVX) periostin (Postn)-deficient mice, a unique genetic model of systemic and jaw osteopenia. Compared to vehicle, Zol 1M (100 µg/kg/month) and Zol 1W (100 µg/kg/week) for 3 months both significantly improved femur BMD, trabecular bone volume on tissue volume (BV/TV) and cortical bone volume in both OVX Postn+/+ and Postn−/− (all p<0.01). Zol 1M and Zol 1W also improved jaw alveolar and basal BV/TV, although the highest dose (Zol 1W) was less efficient, particularly in Postn−/−. Zol decreased osteoclast number and bone formation indices, i.e. MAR, MPm/BPm and BFR, independently in Postn−/− and Postn+/+, both in the long bones and in deep jaw alveolar bone, without differences between Zol doses. Zol 1M and Zol 1W did not reactivate inflammation nor increase fibrous tissue in the bone marrow of the jaw, whereas the distance between the root and the enamel of the incisor (DRI) remained high in Postn−/− vs Postn+/+ confirming latent inflammation and lack of crestal alveolar bone. Zol 1W and Zol 1M decreased osteocyte numbers in Postn−/− and Postn+/+ mandible, and Zol 1W increased the number of empty lacunae in Postn−/−, however no areas of necrotic bone were observed. These results demonstrate that zoledronate improves jaw osteopenia and suggest that in Postn−/− mice, zoledronate is not sufficient to induce bone necrosis.

Local application of zoledronate for maximum anchorage during space closure

Orthodontists have used various compliance-dependent physical means such as headgears and intraoral appliances to prevent anchorage loss. The aim of this study was to determine whether 1 local application of the bisphosphonate zoledronate could be used to prevent anchorage loss during extraction space closure in rats. Thirty rats had their maxillary left first molars extracted and their maxillary left second molars protracted into the extraction space with a 10-g nickel-titanium closing coil for 21 days. Fifteen control rats received a local injection of phosphate-buffered saline solution, and 15 experimental rats received 16 μg of the bisphosphonate zoledronate. Bisphosphonate was also delivered directly into the extraction site and left undisturbed for 5 minutes. Cephalograms and incremental thickness gauges were used to measure tooth movements. Tissues were analyzed by microcomputed tomography and histology. The control group demonstrated significant (P <0.05) tooth movements throughout the 21-day period. They showed significantly greater tooth movements than the experimental group beginning in the second week. The experimental group showed no significant tooth movement after the first week. The microcomputed tomography and histologic observations showed significant bone loss in the extraction sites and around the second molars of the controls. In contrast, the experimental group had bone preservation and bone fill. There was no evidence of bisphosphonate-associated osteonecrosis in any sample. A single small, locally applied dose of zoledronate provided maximum anchorage and prevented significant bone loss.

The Effect on Implant Fixation of Soaking Tricalcium Phosphate Granules in Bisphosphonate

The use of bone grafting is a well-established way to enhance initial implant fixation in situations with reduced bone stock. Ceramic bone substitutes are inferior alternatives to autogenous or allogeneic bone graft. Improvement of bone graft substitutes is needed. We investigated whether biomechanical implant fixation and osseointegration of experimental implant grafted with β-TCP granules (Conduit) could be improved by soaking the β-TCP granules in bisphosphonate (zoledronate). In 10 dogs, a pair of titanium coated implants surrounded by a 2.5 mm gap was inserted into the proximal part of each tibia. The gap was grafted with β-TCP granules either soaked with zoledronate or saline. At 12 weeks, the implants were evaluated with biomechanical push-out test and histomorphometrical analysis. We found that bisphosphonate increased one of the three biomechanical parameters, but found no difference in the amount of new bone or β-TCP granules between the two treatment groups. This study indicates that local treatment of β-TCP granules with zoledronate not only has the potential to increase implant fixation but also calls for further experimental research in order to optimize the dose of zoledronate.

The 5-year impact of a single dose of zoledronate

The 5-year impact of a single dose of zoledronate

Low-Dose Zoledronate in Osteopenic Postmenopausal Women

Context: Annual iv administration of 5 mg zoledronate decreases fracture risk. The skeletal effects of annual treatment with doses of zoledronate under 4 mg have not been assessed. Objective: Our objective was to determine the skeletal effects of single doses of zoledronate of 5 mg or less. Design, Setting, and Participants: This was a double-blind, randomized, placebo-controlled trial over 1 yr at an academic research center in 180 postmenopausal women with osteopenia. Intervention: Intervention was a single baseline administration of iv zoledronate in doses of 1, 2.5, or 5 mg, or placebo. Main Outcome Measures: The primary endpoint was change in bone mineral density (BMD) at the lumbar spine. Secondary endpoints were change in BMD at the proximal femur and total body and changes in biochemical markers of bone turnover. Results: After 12 months, change in spine BMD was greater in each of the zoledronate groups than in the placebo group [mean (95% confidence interval) difference vs. placebo was 3.5% (2.2–...

Effect of low level laser therapy and zoledronate on the viability and ALP activity of Saos-2 cells

A limited number of clinical studies indicate the supportive role of low level laser therapy (LLLT) on medical and/or surgical approaches carried out in treatment modalities for bisphosphonate related necrosis of jaws (BRONJ), the most common side effect of bisphosphonates used to inhibit bone resorption. The purpose of this study was to investigate the effects of LLLT on cell proliferation and alkaline phosphatase (ALP) activity of human osteoblast-like cells (Saos-2) treated with different doses of zoledronate, the most potent bisphosphonate. Saos-2 cells were treated with different concentrations of zoledronate and were irradiated with diode laser (wavelength 808nm, 10s, 0.25 or 0.50W). Cell numbers and ALP activity of the cells were determined. LLLT mildly increased the proliferation rate or ALP activity, while zoledronate reduced both. When applied together, LLLT lessened the detrimental effects of zoledronate and improved cell function and/or proliferation. Based on the results of this study, it was concluded that LLLT has biostimulative effects on Saos-2 cells, even after treatment with zoledronate. LLLT may serve as a useful supportive method for BRONJ treatment through enhancement of healing by osteoblasts.

Five years of anti-resorptive effects after 1 or 2 doses of zoledronate — Data from 2 randomized controlled trials

Five years of anti-resorptive effects after 1 or 2 doses of zoledronate — Data from 2 randomized controlled trials

Zoledronic dose adjustment in cancer patients

BackgroundZoledronic acid (ZA) is used in the prevention of skeletal related events in patients with advanced malignancies involving bone as well as in the treatment of tumour-induced hypercalcaemia. Due to...

Five years of anti-resorptive activity after a single dose of zoledronate — Results from a randomized double-blind placebo-controlled trial

Intravenous zoledronate 5mg, administered annually, prevents fractures in people with osteoporosis, but the optimal dosing schedule is not known. Previously, we reported that a single dose of 5mg zoledronate stably decreased bone turnover and increased bone mineral density (BMD) for 3years in a randomized controlled trial in 50 postmenopausal women with osteopenia. We have now completed a 2-year double-blind extension of this trial, during which no additional treatment was administered. The primary endpoint was change in the bone turnover markers procollagen type-I N-terminal propeptide (P1NP) and β-C-terminal telopeptide of type I collagen (β-CTX); the secondary endpoint was change in BMD at lumbar spine, total hip and total body. Mean levels of the each of the bone turnover markers were lower in the zoledronate group throughout the study (P<0.0001 for each marker). After 5years, mean (95% CI) levels of β-CTX and P1NP were 277ng/L (150, 404) and 28μg/L (16, 40) lower in the zoledronate group, corresponding to reductions of 48% and 45%, respectively. BMD was higher in the zoledronate group during the study (P<0.0001 for each site). After 5years, BMD in the zoledronate group was higher by 4.2% (1.1, 7.2) at the lumbar spine, by 5.3% (2.7, 7.9) at the total hip, and by 2.7% (1.1, 4.2) at the total body. These findings suggest that the anti-resorptive effects of a single 5mg dose of zoledronate persist for at least 5years in postmenopausal women. Trials assessing the anti-fracture efficacy of dosing intervals of zoledronate of up to 5years are justified.

Effects of Intravenous Zoledronate on Bone Turnover and Bone Density Persist for at Least Five Years in HIV-Infected Men

In HIV-infected men, the antiresorptive effects of zoledronate persist for at least 2 yr after the second annual dose. Our objective was to determine the duration of action of zoledronate in men. This was 4-yr extension of a 2-yr, double-blind, randomized, placebo-controlled trial at an academic research center. Participants included 43 HIV-infected men with bone mineral density (BMD) T score below -0.5, 35 of whom entered the extension study. Intervention was annual administration of 4 mg iv zoledronate or placebo at baseline and 1 yr and no intervention subsequently. We evaluated changes in the bone turnover markers, serum osteocalcin and serum C-telopeptide (CTx), and changes in BMD at the lumbar spine, total hip, and total body. There was no time × treatment interaction between 1 and 5 yr after the second zoledronate dose for osteocalcin or CTx (P > 0.4) or any BMD site (P > 0.7). Between 1 and 5 yr after the second dose, on average, osteocalcin was 41% lower (95% confidence interval = 19-62%; P < 0.001), CTx 52% lower (33-71%; P < 0.001), lumbar spine BMD 3.7% greater (0.3-7.0%; P = 0.03), total hip BMD 2.3% greater (0.3-4.3%; P = 0.02), and total body BMD 2.5% greater (0.8-4.1%; P = 0.004) in the zoledronate group than the placebo group. Five years after the second dose, the between-groups differences were 38% (13-62%) for osteocalcin, 49% (20-77%) for CTx, 3.5% (0.7-6.7%) for lumbar spine BMD, 3.4% (1.4-5.4%) for total hip BMD, and 1.6% (0.2-3.1%) for total body BMD. The effects of two annual 4-mg doses of zoledronate in men persist for at least 5 yr after the second dose. Larger trials assessing the antifracture efficacy of less frequent dosing of zoledronate are justified.

Pharmacotherapy of Paget's disease of bone

Introduction: Paget's disease of the bone is a common condition in some populations, affecting almost 10% of older adults in western Europe. Though frequently asymptomatic, it can sometimes result in severe disabilities. Timely intervention is now able to arrest disease progression in the majority of patients.Areas covered: Studies describing the pharmacotherapy of Paget's disease are described in this review, based on a weekly Current Contents search for the term ‘Paget’ from 1995, and from personal knowledge and published references from earlier literature.Expert opinion: Potent bisphosphonates are the cornerstone of current therapy and have been shown to produce biochemical remission, radiographic healing, pain relief and an improved quality of life. A single intravenous dose of zoledronate has produced the highest response rates and the most sustained remissions of any medication studied so far. It is not clear whether Paget's disease is cured in these patients, or whether they merely undergo a prolonged remission. As a result of this approach, we seldom need to retreat patients and our clinical experience is entirely consonant with the long-term follow-up results from the zoledronate trials, indicating that this treatment results in better clinical outcomes and greater quality of life for patients with Paget's disease.

Low-Dose Zoledronate in Osteopenic Postmenopausal Women: A Randomized Controlled Trial

Annual iv administration of 5 mg zoledronate decreases fracture risk. The skeletal effects of annual treatment with doses of zoledronate under 4 mg have not been assessed. Our objective was to determine the skeletal effects of single doses of zoledronate of 5 mg or less. This was a double-blind, randomized, placebo-controlled trial over 1 yr at an academic research center in 180 postmenopausal women with osteopenia. Intervention was a single baseline administration of iv zoledronate in doses of 1, 2.5, or 5 mg, or placebo. The primary endpoint was change in bone mineral density (BMD) at the lumbar spine. Secondary endpoints were change in BMD at the proximal femur and total body and changes in biochemical markers of bone turnover. After 12 months, change in spine BMD was greater in each of the zoledronate groups than in the placebo group [mean (95% confidence interval) difference vs. placebo was 3.5% (2.2-4.8%) for 1 mg, 4.0% (2.7-5.3%) for 2.5 mg, and 3.6% (2.3-4.9%) for 5 mg zoledronate, P < 0.001 for each dose]. Change in BMD at the total hip was greater in each of the zoledronate groups than the placebo group [mean (95% confidence interval) difference vs. placebo was 2.7% (1.9-3.5%) for 1 mg, 3.6% (2.8-4.4%) for 2.5 mg, and 3.6% (2.8-4.4%) for 5 mg zoledronate, P < 0.001 for each dose]. Each of the bone turnover markers, β-C-terminal telopeptide of type I collagen and procollagen type I N-terminal propeptide, was lower by at least 40% in each of the zoledronate groups than the placebo group throughout the trial (P < 0.001 vs. placebo for each marker for each dose). There was evidence for a dose-dependent effect of zoledronate on each of the markers (P for trend <0.001). Annual administration of doses of iv zoledronate lower than 5 mg produces substantial antiresorptive effects. Trials assessing the antifracture efficacy of low doses of zoledronate are justified.

Inhibition of osteoclasts prevents cartilage loss and pain in a rat model of degenerative joint disease

To investigate the relationship between efficacy of a bisphosphonate, pain and extent of joint damage in the monosodium iodoacetate (MIA) model of painful degenerative joint disease. Zoledronate treatment was initiated prior to and at various times following model induction, including late time points representing advanced disease. Radiographic and histological structural parameters were correlated with pain as measured by weight bearing. Intraarticular (IA) MIA resulted in a progressive loss of bone mineral density (BMD) and chondrocytes, thinning of cartilage, loss of proteoglycan, resorption of calcified cartilage and subchondral bone, as well as pain. This was completely prevented by pre-emptive chronic zoledronate treatment with joint sections being histologically indistinguishable from saline-injected controls. When initiation of treatment was delayed efficacy was reduced. In animals with advanced joint degeneration, treatment partially restored BMD and had a significant, but limited, effect on pain. We confirmed these radiographic and behavioral findings in the medial meniscal tear model. To understand the mechanism-of-action of zoledronate we investigated an early time point 4 days post-model induction when chondrocytes were histologically viable, with minor loss of proteoglycan and generalized synovitis. Osteoclast-mediated resorption of the calcified cartilage was observed and was prevented by two doses of zoledronate. Subchondral bone remodeling plays an important role in nociception and the pathobiology of the MIA model with osteoclasts being implicated in both bone and cartilage resorption. Inhibition of osteoclastic activity when initiated early leads to improved efficacy.