Zoledronic Acid Treatment Research Articles

Combination Therapy with Zoledronic Acid and Parathyroid Hormone Improves Bone Architecture and Strength following a Clinically-Relevant Dose of Stereotactic Radiation Therapy for the Local Treatment of Canine Osteosarcoma in Athymic Rats.

Clinical studies using definitive-intent stereotactic radiation therapy (SRT) for the local treatment of canine osteosarcoma (OSA) have shown canine patients achieving similar median survival times as the current standard of care (amputation and adjuvant chemotherapy). Despite this, there remains an unacceptable high risk of pathologic fracture following radiation treatment. Zoledronic acid (ZA) and parathyroid hormone (PTH) are therapeutic candidates for decreasing this fracture risk post-irradiation. Due to differing mechanisms, we hypothesized that the combined treatment with ZA and PTH would significantly improve bone healing more than ZA or PTH treatment alone. Using an orthotopic model of canine osteosarcoma in athymic rats, we evaluated bone healing following clinically-relevant doses of radiation therapy (12 Gy x 3 fractions, 36 Gy total). Groups included 36 Gy SRT only, 36 Gy SRT plus ZA, 36 Gy SRT plus ZA and PTH, 36 Gy SRT plus PTH, and 36 Gy SRT plus localized PTH treatment. Our study showed significant increases in bone volume and increased polar moments of inertia (in the distal femoral metaphysis) 8 weeks after radiation in the combined (ZA/PTH) treatment group as compared to radiation treatment alone. Histomorphometric analysis revealed evidence of active mineralization at the study endpoint as well as successful tumor-cell kill across all treatment groups. This work provides further evidence for the expanding potential indications for ZA and PTH therapy, including post-irradiated bone disease due to osteosarcoma.

Osteonecrosis of the jaws (ONJ) in mice after extraction of teeth with periradicular disease

Osteonecrosis of the jaws (ONJ) is a complication of antiresorptive medications, such as denosumab or bisphosphonates, prescribed to patients with bone malignancy or osteoporosis. The most common instigating local factor in ONJ pathogenesis is tooth extraction. However, in adults the great majority of teeth are extracted due to dental disease. Here, we have investigated alveolar bone healing after extraction of healthy teeth or teeth with naturally occurring periradicular disease in mice treated with high dose zoledronic acid (ZA), a potent bisphosphonate, or OPG-Fc, a RANKL inhibitor. C57BL/6 mice were treated for eight weeks and in vivo micro-CT was performed to identify spontaneously occurring periradicular lesions around the roots of maxillary molars. Then, extractions of molars with and without dental disease were performed in all groups. Four weeks later, animals were euthanized and maxillae were dissected and analyzed. Clinically, all vehicle animals with extraction of healthy or diseased teeth, and most OPG-Fc or ZA animals with extraction of healthy teeth showed normal mucosal healing. On the contrary, most animals with OPG-Fc or ZA treatment and extraction of diseased teeth demonstrated impaired healing with visible mucosal defects. Radiographically, bone socket healing was significantly compromised in OPG-Fc and ZA-treated mice with periradicular disease in comparison to other groups. Histologically, all vehicle animals showed normal mucosal healing and socket remodeling. OPG-Fc and ZA animals with extraction of healthy teeth showed normal mucosal healing, woven bone formation in the socket, and decreased remodeling of the original socket confines. OPG-Fc and ZA animals with extraction of diseased teeth showed mucosal defects, persistent prominent inflammatory infiltrate, bone exposure and areas of osteonecrosis. These findings support that dental disease is critical in the pathogenesis of ONJ, not only as the instigating cause for tooth extraction, but also as a compounding factor in ONJ development and pathophysiology.

Zoledronic acid in vivo increases in vitro proliferation of rat mesenchymal stromal cells

Background and purpose — Bisphosphonates are widely used in the treatment of bone loss, but they might also have positive effects on osteoblastic cells and bone formation. We evaluated the effect of in vivo zoledronic acid (ZA) treatment and possible concomitant effects of ZA and fracture on the ex vivo osteogenic capacity of rat mesenchymal stromal cells (MSCs).Methods — A closed femoral fracture model was used in adult female rats and ZA was administered as a single bolus or as weekly doses up to 8 weeks. Bone marrow MSCs were isolated and cultured for in vitro analyses. Fracture healing was evaluated by radiography, micro-computed tomography (μCT), and histology.Results — Both bolus and weekly ZA increased fracture-site bone mineral content and volume. MSCs from weekly ZA-treated animals showed increased ex vivo proliferative capacity, while no substantial effect on osteoblastic differentiation was observed. Fracture itself did not have any substantial effect on cell proliferation or differentiation at 8 weeks. Serum biochemical markers showed higher levels of bone formation in animals with fracture than in intact animals, while no difference in bone resorption was observed. Interestingly, ex vivo osteoblastic differentiation of MSCs was found to correlate with in vivo serum bone markers.Interpretation — Our data show that in vivo zoledronic acid treatment can influence ex vivo proliferation of MSCs, indicating that bisphosphonates can have sustainable effects on cells of the osteoblastic lineage. Further research is needed to investigate the mechanisms.

Doses effects of zoledronic acid on mineral apatite and collagen quality of newly-formed bone in the rat's calvaria defect

Due to their inhibitory effects on resorption, bisphosphonates are widely used in the treatment of diseases associated to an extensive bone loss. Yet, little is known about bisphosphonates effects on newly-formed bone quality. In the present study, adult male Sprague-Dawley rats (n=80) with a bone defect calvaria area were used and short-term effects of zoledronic acid (ZA) were studied on the healing bone area. Three ZA treatments were tested by using either: 1°) a low single dose (120μgZA/kg, n=10; equivalent to human osteoporosis treatment), 2°) a low fractionated doses (20μgZA/kg daily for 6days either a total of 120μg/kg, n=15), and 3°) a high fractionated doses, (100μgZA/kg weekly for 6weeks, n=15; equivalent to 6months of human bone metastasis treatment). For each treatment, a control “vehicle” treatment was performed (with an identical number of rats). After ZA administration, the intrinsic bone material properties were evaluated by quantitative backscattered electron imaging (qBEI) and Raman microspectroscopy. Neither single nor fractionated low ZA doses modify the intrinsic bone material properties of the newly-formed bone compared to their respective control animals. On the opposite, the high ZA treatment resulted in a significant decrease of the crystallinity (−25%, P< 0.05) and of the hydroxyproline-to-proline ratio (−30%, P<0.05) in newly-formed bones. Moreover, with the high ZA treatment, the crystallinity was positively correlated with the hydroxyproline-to-proline ratio (ρ=0.78, P<0.0001). The present data highlight new properties for ZA on bone formation in a craniofacial defect model. As such, ZA at high doses disrupted the apatite crystal organization. In addition, we report here for the first time that high ZA doses decreased the hydroxyproline-to-proline ratio suggesting that ZA may affect the early collagen organization during the bone healing.

Zoledronic Acid Effect on Chondrocyte Apoptosis in Degenerative Osteoarthritis Model

Apoptosis refers to cell death without inflammatory process, and is related to degenerative changes in joints. We hypothesized that zoledronic acid (ZA) would have a positive effect on chondrocyte viability and decreases in chondrocyte loss, which are important for the progression of degeneration. This study aimed to reveal the difference in time-dependent apoptotic changes in cartilage tissue in the anterior cruciate ligament (ACL) transection model of osteoarthritis (OA) in rat knees after treatment with zoledronic acid. We randomly divided 48 male Wistar albino rats into 6 groups. The knees of all rats except those in the control group underwent the operation for ACL transection. ZA for half of the rats and saline solution for the others was injected weekly into knees. Animals were killed at 0, 3, and 6 weeks after surgery. Apoptosis of chondrocytes were analyzed using the terminal deoxynucleotidyl transferase dUTP nick end labeling method. Comparison of groups was performed using Kruskal Wallis analysis and the Mann Whitney U test. Significant differences were observed between the groups treated with ZA and saline. ZA treatment significantly decreased the number of apoptotic cells in chondral tissue. ZA prevents time-dependent degenerative changes in chondral tissue by decreasing chondrocyte death. Intra-articular ZA may have the potential to treat and conserve chondral viability. ZA prevents chondrocyte loss and may play a therapeutic role in OA and conserving joint health. Further studies are needed to evaluate the potential of intra-articular ZA for the prevention or treatment of age-related degenerative changes.

Data in support of the bone analysis of NOD-SCID mice treated with zoledronic acid and prednisolone.

This paper reports data on the bone, specifically the tibia and mandible, of nonobese diabetic mice with severe combined immunodeficiency disease (NOD–SCID mice) treated with zoledronic acid (ZA) and prednisolone (PSL). The data described here are related to the research article titled “Zoledronic acid basically increases circulating soluble RANKL level in mice, and in glucocorticoid-administrated mice, more increases lymphocytes derived sRANKL by bacterial endotoxic stimuli” [1]. The present data and the NOD–SCID mice experiments described contain insights into the role of bone-remodeling factors induced by ZA treatment.

Efficacy of proximal femoral nail antirotation fixation combined with zoledronic acid in treatment of osteoporotic intertrochanteric fracture

Objective To compare the clinical outcomes between proximal femoral nail antirotation (PFNA) combined with zoledronic acid and PFNA only in the treatment of osteoporotic intertrochanteric fracture in the elderly patients. Methods A retrospective analysis was made on 72 patients that completed the follow-up after PFNA for osteoporotic intertrochanteric fracture from November 2011 to May 2014. According to the application of zoledronic acid (5 mg, once a year) after PFNA, the patients were divided into study group (n=30) and control group(n=42). Bone healing and subsequent refracture were assessed with X-ray postoperatively. Harris hip score was recorded. Bone mineral density before operation and one year after operation were compared between the two groups. Adverse effect of zoledronic acid was recorded during hospitalization. Results Mean period of follow-up was 15 months (range, 12-26 months). One year after operation, Harris score, new fracture incidence, mean fracture union time were (82.65±6.24)points, 3%(1/30) and (14.26±2.24)weeks in study group, while (81.85±5.38)points, 14%(6/42) and (15.26±3.05)weeks in control group. There were no statistical differences between the two groups (P>0.05), but the subsequent fracture was higher in control group. One year after operation, lumbar and contralateral non-injury hip bone marrow density were (0.78±0.16)g/cm2 and (0.71±0.14)g/cm2 in study group , higher than (0.75±0.13)g/cm2 and (0.69±0.13)g/cm2 in control group (P<0.05). But there were no significant differences between the two groups before operation. All fractures were healed at postoperative 1 year. No intolerable adverse events occurred in study group. Conclusions PFNA is effective in the treatment of osteoporotic intertrochanteric fracture. In the meantime, the combination with zoledronic acid has no influence on bone healing while increasing bone mineral density, and may decrease the occurrence of subsequent fragile fractures. Key words: Diphosphonates; Osteoporotic fractures; Hip fractures; Treatment outcome

Osteocytic connexin hemichannels suppress breast cancer growth and bone metastasis.

Although the skeleton is one of predominant sites for breast cancer metastasis, why breast cancer cells often become dormant after homing to bone is not well understood. Here, we reported an intrinsic self-defense mechanism of bone cells against breast cancer cells: a critical role of connexin (Cx) 43 hemichannels in osteocytes in the suppression of breast cancer bone metastasis. Cx43 hemichannels allow passage of small molecules between the intracellular and extracellular environments. The treatment of bisphosphonate drugs, either alendronate (ALN) or zoledronic acid (ZOL), opened Cx43 hemichannels in osteocytes. Conditioned media (CM) collected from MLO-Y4 osteocyte cells treated with bisphosphonates inhibited the anchorage-independent growth, migration and invasion of MDA-MB-231 human breast cancer cells and Py8119 mouse mammary carcinoma cells and this inhibitory effect was attenuated with Cx43(E2), a specific hemichannel blocking antibody. The opening of osteocytic Cx43 hemichannels by mechanical stimulation had similar inhibitory effects on breast cancer cells and this inhibition was attenuated by Cx43(E2) antibody as well. These inhibitory effects on cancer cells were mediated by ATP released from osteocyte Cx43 hemichannels. Furthermore, both Cx43 osteocyte-specific knockout mice and osteocyte-specific Δ130–136 transgenic mice with impaired Cx43 gap junctions and hemichannels showed significantly increased tumor growth and attenuated the inhibitory effect of ZOL. However, R76W transgenic mice with functional hemichannels but not gap junctions in osteocytes did not display a significant difference. Together, our studies establish the specific inhibitory role of osteocytic Cx43 hemichannels, and exploiting the activity of this channel could serve as a de novo therapeutic strategy.

Histological and biomechanical effects of zoledronate on fracture healing in an osteoporotic rat tibia model.

This study aims to investigate the effects of zoledronate therapy on histological and biomechanical properties of bone healing via a fracture model generated on osteoporotic rat tibiae. Ovariectomized 40 Wistar-Dawley female rats weighing 300 g to 350 g were used in the study. After one week, 2 IU/g heparin injection was started subcutaneously. After four weeks of daily injections, osteoporosis was ensued proven with bone mineral density measurements. Osteoporotic rats were separated into four equal groups randomly as group A (control), group B (calcium and vitamin D), group C (0.1 mg/kg subcutaneous zoledronic acid), and group D (calcium and vitamin D / 0.1 mg/kg subcutaneous zoledronic acid). Six weeks later, all rats were sacrificed, their tibiae were resected, and histopathologic and biomechanical studies were performed. Group C (30.2±1 Nm) and group D (33.3±3 Nm) had significantly higher peak torque values than group A (21.6±6 Nm) and group B (23.6±4 Nm) (p=0.007 and p=0.005, respectively). Group C (1.8) and group D (2.0) had higher stiffness values than group A (1.4) and group B (1.7); however, the difference was not statistically significant (p>0.05 for all). According to histopathological and biomechanical test results, single dose zoledronic acid treatment improves fracture healing in an osteoporotic rat fracture model. Orally administered daily calcium and vitamin D treatment had no effect on fracture healing. There was no additional improvement in fracture healing when calcium and vitamin D treatment was added to zoledronic acid treatment. Positive effects of zoledronic acid treatment on osteoporotic fracture healing and callus quality should be shown by future clinical studies.

Analysis of acute phase side-effects of diphosphonate treatment in elderly patients with primary osteoporosis

Objective To investigate the acute phase adverse effects and influencing factors of adverse effects of diphosphonate treatment in the elderly patients with primary osteoporosis. Methods A total of 208 patients[male 25 patients, female 183 patients, age 60~93 with a average of (75.51±7.73)years]with primary osteoporosis were selected from 1 Jan 2012 to 30 Nov 2015, admitted to Department of Geriatrics. According to the serious condition of osteoporosis and willingness of patients, 208 patients were divided into zoledronic acid treatment group, alendronate treatment group, and pamidronic acid group, and received corresponding diphosphonate treatment. All kinds of adverse reactions of diphosphonate in each treatment group were closely to be observed after administration of diphosphonate in 3 days and 7 days. Results The incidence rate of adverse reactions in the zoledronic acid treatment group (59/134, 44.03%; 60/134, 44.78%) was obviously higher than that in the alendronate treatment group (1/57, 1.75%; 1/57, 1.75%), and the pamidronic acid group (3/17, 17.65%; 3/17, 17.65%) after treatment of diphosphonate in three and seven days (P 0.05). There were three patients suffering from severe acute kidney injure (AKI) and three patients suffering from hypokalemia in the 134 patients treatment with zoledronic acid. Conclusions There are obvious differences in the incidence rate of acute phase adverse reactions in the osteoporosis patients who received different treatment policy (P<0.05). The safety issues in the kidney function and electrolyte abnormality (such as hypokalemia) should be paid much enough attention in the primary osteoporosis patients who receive zoledronic acid treatment. Key words: Osteoporosis/DT; Diphosphonates/AE

Zoledronic acid increases the circulating soluble RANKL level in mice, with a further increase in lymphocyte-derived soluble RANKL in zoledronic acid- and glucocorticoid-treated mice stimulated with bacterial lipopolysaccharide

The nitrogen-containing bisphosphonate (BP) zoledronic acid (ZA) is a potent antiresorptive drug used in conjunction with standard cancer therapy to treat osteolysis or hypercalcemia due to malignancy. However, it is unclear how ZA influences the circulating levels of bone remodeling factors. The aim of this study was to evaluate the effects of ZA on the serum levels of soluble receptor activator of NF-kB ligand (sRANKL) and osteoprotegerin (OPG). The following four groups of C57BL/6 mice were used (five mice per group): (1) the placebo+phosphate-buffered saline (PBS) group, in which placebo-treated mice were injected once weekly with PBS for 4weeks; (2) the placebo+ZA group, in which placebo-treated mice were injected once weekly with ZA for 4weeks; (3) the prednisolone (PSL)+PBS group, in which PSL-treated mice were injected once weekly with PBS for 4weeks; and (4) the PSL+ZA group, in which PSL-treated mice were injected once weekly with ZA for 4weeks. At the 3-week time point, all mice were subjected to oral inflammatory stimulation with bacterial lipopolysaccharide (LPS). The sera of these mice were obtained every week and the levels of sRANKL and OPG were measured using enzyme-linked immunosorbent assay. At the time of sacrifice, femurs were prepared for micro-computed tomography (micro-CT), histological, and histomorphometric analyses. Our data indicated that ZA administration remarkably reduced bone turnover and significantly increased the basal level of sRANKL. Interestingly, the PSL+ZA group showed a dramatically elevated sRANKL level after LPS stimulation. In contrast, the PSL+ZA group in nonobese diabetic mice with severe combined immunodeficiency disease (NOD-SCID mice), which are characterized by the absence of functional T- and B-lymphocytes, showed no increase in the sRANKL level. Our data suggest that, particularly with combination treatment of ZA and glucocorticoids, surviving lymphocytes might be the source of inflammation-induced sRANKL. Thus, circulating sRANKL levels might be modulated by ZA.

Rheumatoid Arthritis Exacerbates the Severity of Osteonecrosis of the Jaws (ONJ) in Mice. A Randomized, Prospective, Controlled Animal Study.

Rheumatoid arthritis (RA), an autoimmune inflammatory disorder, results in persistent synovitis with severe bone and cartilage destruction. Bisphosphonates (BPs) are often utilized in RA patients to reduce bone destruction and manage osteoporosis. However, BPs, especially at high doses, are associated with osteonecrosis of the jaw (ONJ). Here, utilizing previously published ONJ animal models, we are exploring interactions between RA and ONJ incidence and severity. DBA1/J mice were divided into four groups: control, zoledronic acid (ZA), collagen-induced arthritis (CIA), and CIA-ZA. Animals were pretreated with vehicle or ZA. Bovine collagen II emulsified in Freund's adjuvant was injected to induce arthritis (CIA) and the mandibular molar crowns were drilled to induce periapical disease. Vehicle or ZA treatment continued for 8 weeks. ONJ indices were measured by micro-CT (µCT) and histological examination of maxillae and mandibles. Arthritis development was assessed by visual scoring of paw swelling, and by µCT and histology of interphalangeal and knee joints. Maxillae and mandibles of control and CIA mice showed bone loss, periodontal ligament (PDL) space widening, lamina dura loss, and cortex thinning. ZA prevented these changes in both ZA and CIA-ZA groups. Epithelial to alveolar crest distance was increased in the control and CIA mice. This distance was preserved in ZA and CIA-ZA animals. Empty osteocytic lacunae and areas of osteonecrosis were present in ZA and CIA-ZA but more extensively in CIA-ZA animals, indicating more severe ONJ. CIA and CIA-ZA groups developed severe arthritis in the paws and knees. Interphalangeal and knee joints of CIA mice showed advanced bone destruction with cortical erosions and trabecular bone loss, and ZA treatment reduced these effects. Importantly, no osteonecrosis was noted adjacent to areas of articular inflammation in CIA-ZA mice. Our data suggest that ONJ burden was more pronounced in ZA treated CIA mice and that RA could be a risk factor for ONJ development. © 2016 American Society for Bone and Mineral Research.

Effectiveness and Safety of Zoledronic Acid in the Treatment of Osteoporosis.

The effectiveness of current treatments for osteoporosis is limited by poor patient compliance. However, a favorable dosing regimen of zoledronic acid (ZA) has the potential to improve patient compliance and thus clinical outcomes. The author conducted a retrospective analysis to examine adherence to and the antiosteoporotic effects of a once-yearly infusion of 5 mg of ZA in Taiwanese patients with osteoporosis for up to 48 months. Five men and 149 postmenopausal women (mean age, 77.1 years) were included. Prior to ZA treatment, 66.2% of patients had fractures; most patients discontinued previous treatments due to compliance or convenience issues. Approximately 85% of patients received at least 2 infusions of ZA. Following ZA treatment, bone mineral density improved from baseline at 12 months (11% from baseline; P=.01) and 48 months (20.7% from baseline; P=.009). In addition there was a significant reduction in mean beta-C-telopeptide at all time points from 12 (P<.001) to 36 months (P=.010). New clinical fractures occurred in 16 (10.4%) patients, of which 12 patients experienced a single fracture. Zoledronic acid had an acceptable safety profile; no adverse events were considered to be drug related. Treatment with ZA improved bone health by enhancing bone mineral density and reducing bone turnover, even in high-risk patients. Low fracture rates and high adherence further elucidate the benefits of ZA in the treatment of osteoporosis.

Zoledronic Acid Treatment After Acute Spinal Cord Injury: Results of a Randomized, Placebo-Controlled Pilot Trial

ObjectiveTo determine the effect of intravenous zoledronic acid 5 mg on the extent and course of bone loss after spinal cord injury (SCI). DesignDouble-blind, randomized, placebo-controlled parallel-group trial. SettingAcute in-patient, tertiary-care rehabilitation hospital. ParticipantsConvenience sample of 17 in-patients with SCI <12 weeks before randomization; American Spinal Injury Association Impairment scale A, B, or C and medically stable. Twelve patients were evaluated at the primary endpoint at 6 months. MethodsPatients meeting study criteria were randomly assigned to zoledronic acid 5 mg or matching placebo. Dual x-ray absorptiometry scan and serum for bone markers (type 1 procollagen amino-terminal propeptide, bone-specific alkaline phosphatase, collagen type 1 cross-linked C-telopeptide) were obtained at baseline and after 3 months, 6 months, and the every 6 months for up to 2 years. Main Outcome MeasuresThe primary endpoint was change in bone mineral density (BMD) at the total hip after 6 months; secondary endpoints were changes in BMD at other skeletal sites and changes in levels of serum bone markers. ResultsThe group treated with zoledronic acid had a smaller decrease in BMD at 6 months at the total hip than the placebo group (right: −2.2 ± 3.4% versus −8.6 ± 3.5%, respectively, P = .03; left: −3.7 ± 1.0% versus −12.3 ± 6.9%, P = .03). Differences in BMD at the femoral neck were similar (right: −5.1 ± 6.5% versus −20.0 ± 6.4%, P = .01; left: −1.1 ± 3.5% versus −11.1 ± 7.4%, P = .02) with larger bone loss and smaller between group differences at the knee. Zoledronic acid resulted in a decrease in serum levels of both formation and resorption markers. ConclusionsZoledronic acid is effective at mitigating bone loss after SCI. Duration of efficacy and activity at different skeletal sites may differ from that observed in able-bodied individuals and needs further study.

The effects of zoledronic acid treatment on depression and quality of life in women with postmenopausal osteoporosis: A clinical trial study

Background:Osteoporosis affects quality of life (QoL) and may lead to depression in women. The purpose of this study was to evaluate the effects of zoledronic acid (ZA) treatment on depression and QoL in women with postmenopausal osteoporosis (PO).Materials and Methods:A total of 88 newly diagnosed women with PO were included in this study. All patients were treated with once-yearly ZA (5 mg). A QoL questionnaire from the European Foundation for Osteoporosis and Beck Depression Inventory were given to patients at baseline and at 12 months. The results for baseline and post - 12th month were compared, and bone mineral density (BMD) levels were compared.Results:The consumption of once-yearly ZA (5 mg) treatment increases BMD at levels of lumbers 1–4 (P = 0.026), total Hip T score's P value is same as femoral neck (P: 0,033). ZA 5 mg treatment also improved QoL (P = 0.001) and reduced depression (P = 0.001).Conclusion:ZA treatment increases BMD levels and QoL while reducing depression. Once-yearly ZA (5 mg) may be considered for postmenopausal women as a first-line treatment.

Effects of Preventive Long-Term Treatment with Strontium Ranelate and Zoledronic Acid on Bone Quality in Ovariectomized Rats

The aim of this work was to study the effects on bone quality produced by long-range treatment with zoledronic acid (ZA) or strontium ranelate (SrR) in ovariectomized rats. Sixty 6-month-old female Wistar rats were divided: SHAM (n=15), simulated intervention; OVX (n=15), ovariectomized; OVX+ZA (n=15), ovariectomized treated with ZA (0.083 mg/kg i. v. at the beginning of the study); and OVX+SrR (n=15), ovariectomized treated with SrR (0.033 g/kg/day by oral gavage). Rats were sacrificed 8 months later. Femoral (F) and lumbar (L) bone mineral density (BMD), trabecular and cortical microstructure, biomechanical testing and Raman spectrometry were performed. FBMD and LBMD decreased in OVX rats with no changes with SrR. ZA treatment prevented changes to BMD. Ovariectomy produced a reduction in micro-CT parameters, while SrR treatment did not avoid these changes. ZA treatment increased micro-CT parameters with respect to the SHAM group. The microstructural parameters of the cortical region were not modified in any of the groups. Ovariectomy produced a decrease in biomechanical parameters that was maintained with SrR. ZA treatment produced an increase in these parameters being higher than those of the SHAM group. Ovariectomy and treatments did not produce differences in crystallinity or substitution index. Mineralization index (MI) decreased in the OVX group. SrR did not revert this effect though ZA avoided it. According to our results preventive treatment with SrR did not revert the alterations in bone quality due to ovariectomy in rats. Treatment with ZA not only reverted the effects of ovariectomy, but also improved bone quality with respect to control rats.

Osteoporosis treatment with zoledronic acid in pediatric population at a university hospital in Western Saudi Arabia. A 13-year experience.

Objectives:To highlight the clinical benefit, efficacy, and safety of zoledronic acid (ZA) therapy in children and adolescents with primary and secondary osteoporosis.Methods:This is a retrospective observational study of 131 children and adolescents visiting the Pediatric Endocrine Clinic at King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia, between January 2002 and January 2015. Clinical and laboratory data were collected for each patient and adverse events were evaluated.Results:The mean patient age was 11.43 years. There was a significant decrease in the number of fractures after ZA treatment for primary osteoporosis (p=0.000) and in secondary osteoporosis (p=0.005). There was a significant decrease in both osteocalcin (p=0.001) and C-terminal telopeptide (p=0.003) in patients with primary osteoporosis, as well as osteocalcin (p=0.003) and C-terminal telopeptide (p=0.008) in patients with secondary osteoporosis after treatment.Conclusion:The use of ZA in children and adolescent appears to have favorable effects on fracture rate and quality of life, including pain and mobility in symptomatic individuals. Intravenous ZA is comparable to other bisphosphonate agents in its efficacy and safety and features a more convenient infusion protocol with no documented long-term complications, thus, we advise its use in pediatric population.

Setting up a homecare service for zoledronic acid treatment of osteoporosis

Increasingly, patients are able to receive parenteral medicines at home rather than in the hospital setting. We describe our approach to setting up a new intravenous zoledronic acid homecare service...

Zoledronic Acid in Non-Ambulatory Children and Young Adults with Fragility Fractures and Low Bone Mass Associated with Spastic Quadriplegic Cerebral Palsy and Other Neuromuscular Disorders

Non-ambulatory patients with neurological disorders such as spastic quadriplegic cerebral palsy often have low bone mineral density (BMD) and fragility fractures from disuse osteoporosis. Limited data exists on zoledronic acid (a third generation bisphosphonate) treatment in the pediatric population. We report a case series of 10 patients with spastic quadriplegic cerebral palsy (n=6), spinal muscular atrophy (n=2), and myelomeningocele (n=2) treated with zoledronic acid for fragility fractures and/or low BMD associated with the underlying conditions. The clinical and BMD outcomes were retrospectively studied and compared with a historical cohort of 32 patients treated with intravenous pamidronate. Mean lumbar BMD increased significantly ( P < 0.01) by 28% at1 yearin zoledronic acid group, and by 19% in pamidronate group. Mean lumbar BMD weight-adjusted Z-scores improved from -4.31 at baseline to -2.55( P =0.003) at 1 year in zoledronic group, and from -3.66 to -2.30 in pamidronate group ( P =0.001). Total number of fractures in the zoledronic group was 18 before treatment and reduced to zero after treatment with an average follow-up of 3.9 years. All patients tolerated zoledronic acid infusion with fever in 3 patients (30%) during the initial infusion and nohypocal cemianoted during the treatment cycles. Treatment with zoledronic acid is safe, significantly improves bone density and reduces fractures in children and young adults with fragility fractures and low bone mass secondary to neuromuscular disorders. Further follow up studies are needed to confirm safety and efficacy in long-term fracture prevention.

Zoledronic acid in children with osteogenesis imperfecta and Bruck syndrome: a 2-year prospective observational study.

Treatment with zoledronic acid (ZA) over 2 years, among 33 children with osteogenesis imperfecta (OI) and five Bruck syndrome cases, showed reduction in fracture rates, pain, and improvement in bone mineral density (BMD) and motor milestones of development. This is the first study reporting the use of bisphosphonates in patients with Bruck syndrome (BS). OI and BS are genetic disorders that result in bone fragility and reduced BMD. There is little literature describing the efficacy and safety of ZA in this population. In this study, we assess the response to treatment with ZA at six monthly intervals in Egyptian children with OI and BS for a period of 2 years. Thirty-three patients with OI and five patients with BS were treated with 0.1 mg/kg ZA intravenously every 6 months for 2 years during which they were followed up using different parameters. A clinical severity score (CSS) was applied to the patients before and 2 years after the start of therapy. Comparison of disease severity and response to ZA treatment between autosomal-dominant (AD) and autosomal-recessive (AR) OI patients was also done. After 6 months of treatment, OI and BS patients showed a significant increase in BMD Z-scores (P < 0.003 in the spine and P < 0.004 in the hip), together with a significant drop in fracture rate (P < 0.001), relief of pain (P < 0.001), and improvement in ambulation (P < 0.001). CSS was significantly reduced after 2 years of treatment in both OI and BS patients. AR-OI patients were more severely affected than AD-OI patients and showed more significant improvement. Zoledronic acid proved to be safe and effective in the treatment of OI and BS. The biannual infusion protocol was convenient to patients. There was a positive correlation between disease severity and benefits of the treatment. The use of the CSS proved to be of value in the assessment of the degree of severity in OI, and with some modifications, it was a valuable tool for the assessment of response to treatment.