Zoledronic Acid Administration Research Articles

Effects of Zoledronic Acid on Orthodontic Tooth Movement in Rats.

The purpose of this study was to assess the effects of the administration of zoledronic acid (ZA) during orthodontic movement in rats. A hundred and twenty male Wistar rats were applied force of 30 cN with spring closed nickel-titanium to move the upper right first molar to mesial. In the Control Movement group (CM), only tooth movement was performed; the Control Acid Zoledronic group (CAZ) received a single dose (0.1 mg/kg) of ZA; the Experimental Acid Zoledronic group (EAZ) received a single dose (0.1 mg/kg) one week prior to the start of tooth movement; and the Control Without movement group (CWM) that received no drug and without application of tooth movement. The animals were euthanized after 3, 7 and 14 days. Tooth movement was measured using a caliper, the number of osteoclasts using TRAP staining, the expression of mature and immature collagen using picrosirius staining, and the presence of hyaline areas and root resorption using HE. The data were compared using two-way ANOVA, Tukey HSD, Games-Howell and chi-squared test, at the 5% significance level. It was observed a smaller number of osteoclasts and greater percentage of hyaline area in the EAZ group. There was no difference among the groups regarding bone remodeling, root resorption and tooth movement for all observed times.

Severe Hypocalcemia After the Administration of Zoledronic Acid for Osteoporotic Fracture

Zoledronic acid is a potent intravenous bisphosphonate used in the treatment of osteoporosis and malignancy-induced hypercalcemia or bone metastasis. Although zoledronic acid generally seems to be safe and well-tolerated, rare but life-threatening nephrotoxicity or hypocalcemia may occur. The majority of cases of hypocalcemia with zoledronic acid have been seen in patients with underlying malignancy and are asymptomatic or mild. Vitamin D deficiency, renal failure, hypoparathyroidism, and hypomagnesemia have been reported as risk factors for hypocalcemia. Here, the author reports a case of severe symptomatic hypocalcemia following the administration of zoledronic acid for the treatment of osteoporotic fracture. This patient also had underlying but unrecognized vitamin D deficiency and chronic kidney disease. Following the administration of calcium and vitamin D, her symptoms improved and calcium levels returned to normal within several days. To avoid serious hypocalcemia with zoledronic acid, calcium and vitamin D status and renal function should be assessed and corrected if appropriate. J Med Cases. 2016;7(10):441-444 doi: http://dx.doi.org/10.14740/jmc2646w

Efficacy and safety of once-yearly zoledronic acid in Japanese patients with primary osteoporosis: two-year results from a randomized placebo-controlled double-blind study (ZOledroNate treatment in Efficacy to osteoporosis; ZONE study)

SummaryIn a 2-year randomized, placebo-controlled study of 665 Japanese patients with primary osteoporosis, once-yearly administration of zoledronic acid (5 mg) reduced the risk of new morphometric vertebral fractures.IntroductionThe purpose of this study was to determine the efficacy and safety of once-yearly intravenous infusion of ZOL in Japanese patients with primary osteoporosis.MethodsThis was a two-year multicenter, randomized, placebo-controlled, double-blind, parallel-group comparative study (ZONE Study). Subjects were 665 Japanese patients between the ages of 65 and 89 years who had prevalent vertebral fracture. Subjects were randomly assigned to receive once-yearly intravenous infusion of 5 mg of ZOL or placebo at baseline and 12 months.ResultsThe 2-year incidence of new morphometric vertebral fracture was 3.0 % (10/330 subjects) in the ZOL group and 8.9 % (29/327) in the placebo group (p = 0.0016). The 24-month cumulative incidence of new morphometric vertebral fracture was 3.3 % in the ZOL group versus 9.7 % in the placebo group (log-rank test: p = 0.0029; hazard ratio: 0.35; 95 % confidence interval: 0.17–0.72). The cumulative incidence of any clinical fracture, clinical vertebral fracture, and non-vertebral fracture was significantly reduced in the ZOL group by 54, 70, and 45 %, respectively, compared to the placebo group. At 24 months, ZOL administration increased bone mineral density in the lumbar spine, femoral neck, and total hip (t test: p < 0.0001). No new adverse events or osteonecrosis of the jaw were observed in this study.ConclusionsOnce-yearly administration of ZOL 5 mg to Japanese patients with primary osteoporosis reduced the risk of new morphometric vertebral fractures and was found to be safe.

Systemic and local zoledronic acid treatment with hydroxyapatite bone graft: A histological and histomorphometric experimental study.

In this study, the aim was to compare the relative efficacy of systemic and local zoledronic acid (ZA) on a hydroxyapatite (HA) bone graft in a rat critical-size calvarial bone defect. In total, 84 female rats were divided into four groups: Empty control (EC) group with no treatment applied; HA group, in which only HA bone graft material was used in the calvarium; and HA plus local ZA (HA+LZA) and HA plus systemic ZA (HA+SZA) groups, in which animals received ZA locally or systemically, respectively, with HA bone graft material in the calvarium. A 5-mm standardised critical-size calvarial bone defect was created with a standard trephine drill and the respective treatment was applied. Rats were sacrificed 7, 14 and 28 days later. The numbers of osteoclasts and osteoblasts, and degree of bone formation were evaluated histopathologically and histomorphometrically. Statistically significant differences were detected between the HA, HA+LZA and HA+SZA groups and the EC group for new bone formation (P<0.05). Osteoblast numbers in the HA+LZA and HA+SZA groups were significantly higher compared with those in the EC and HA groups (P<0.05). No statistically significant difference was detected between the HA+LZA and HA+SZA groups in new bone formation or osteoblast number (P>0.05). Bone formation was significantly higher in the HA group than in the EC group (P<0.05). The numbers of osteoclasts in the HA+LZA and HA+SZA groups were significantly higher than those in the groups EC and HA (P<0.05); however, there was no significant difference between groups HA+LZA and HA+SZA (P>0.05). Within the limitations of this study, systemic or local administration of ZA enhanced new bone formation with a HA bone graft in a rat critical-size calvarial defect model.

Should the cardiac rhythm be monitored following administration of zoledronic acid in elderly osteoporotic women?

Should the cardiac rhythm be monitored following administration of zoledronic acid in elderly osteoporotic women?

Improvement of renal function by changing the bone-modifying agent from zoledronic acid to denosumab.

BackgroundIn order to help in selecting the optimum bone-modifying agent (BMA; zoledronic acid or denosumab), we investigated the impact of the BMA on the renal function of patients with bone metastases.Materials and methodsThe present study consisted of 118 patients who were treated with denosumab for bone metastases secondary to prostate cancer, renal cell cancer, and urothelial cancer at our hospital between 2012 and 2015. The clinical course of the renal function of these patients, treated with zoledronic acid or denosumab, was retrospectively evaluated.ResultsOf the 118 patients who were treated with denosumab during the study period, 57 (48 %) had previously been administered zoledronic acid and 61 (52 %) had received denosumab as the first-line BMA. The reasons for changing from zoledronic acid to denosumab were increased creatinine serum level (26 patients, 46 %), patient preference (16 patients, 28 %), difficulty with venous infusion (10 patients, 17 %), and other reasons (5 patients, 9 %). The median level of creatinine clearance in the patients who changed from zoledronic acid to denosumab due to increased serum creatinine level was 59.9 ml/min before administration of zoledronic acid, 40.9 ml/min at the beginning of denosumab treatment, 47.5 ml/min at 3 months after administration of denosumab, and 52.0 ml/min at the last follow-up. There were significant differences.ConclusionsFor the first time, we demonstrated that the renal function of some patients, which had deteriorated following zoledronic acid administration, successfully improved after changing to denosumab.

The role of vitamin E in the prevention of zoledronic acid-induced nephrotoxicity in rats: a light and electron microscopy study.

IntroductionBisphosphonates are widely used in metastatic cancer such as prostate and breast cancer, and their nephrotoxic effects have been established previously. In this study we aimed to evaluate both the nephrotoxic effects of zoledronic acid (ZA) and the protective effects of vitamin E (Vit-E) on this process under light and electron microscopy.Material and methodsA total of 30 male Sprague-Dawley rats were divided into 3 groups. The first group constituted the control group. The second group was given i.v. ZA of 3 mg/kg once every 3 weeks for 12 weeks from the tail vein. The third group received the same dosage of ZA with an additional i.m. injection of 15 mg Vit-E every week for 12 weeks. Tissues were taken 4 days after the last dose of ZA for histopathological and ultrastructural evaluation. Paller score, tubular epithelial thickness and basal membrane thickness were calculated for each group.ResultsFor group 2, the p-values are all < 0.001 for Paller score, epitelial thickness, and basal membrane thickness. For group 3 (ZA + Vit. E), the p-values are < 0.001 for Paller score, 0.996 for epitelial thickness, and < 0.001 basal membrane thickness. Significant differences were also observed in ultrastructural changes for group 2. However, adding Vit-E to ZA administration reversed all the histopathological changes to some degree, with statistical significance.ConclusionsAdministration of ZA had nephrotoxic effects on rat kidney observed under both light and electron microscopy. Concomitant administration of Vit-E significantly reduces toxic histopathological effects of ZA.

Zoledronic Acid Use and Risk of Cognitive Decline among Elderly Women and Men with Osteoporosis.

Bisphosphonates are the first line treatment options in the prevention and treatment of osteoporosis among elderly women or men. Age associated cognitive decline may increase due to adverse effects of medications. The aim of the present study was to observe the course of cognitive skills in elderly subjects treated with a bisphosphonate. This prospective study enrolled 120 community-dwelling, non-demented women and men with osteoporosis aged 65 and older who were treated with first-ever zoledronic acid. Mini mental state examination (MMSE) was measured along with geriatric depression scale (GDS) measurement, clock drawing test (CDT), and other clinical and laboratory evaluations that could affect cognition at baseline and 12 months. The primary outcome was at least one point decrease in the final MMSE score at one year. Scores of MMSE (28.29±2.17 and 28.23±2.37, p=0.681), GDS (3.24±2.88 and 2.96±2.88, p=0.062) and CDT (3.69±0.68 and 3.75±0.60, p=0.268) did not change after zoledronic acid infusion at one year. Education in years and presence of newly started medicines with anticholinergic properties was independently associated with at least one point reduction in MMSE score [odds ratio: 3.07 (%95 confidence interval: 1.00-9.44)]. Among elderly woman and men with osteoporosis, cognitive functions remained stable 12 months after the administration of first-ever zoledronic acid.

Zoledronic acid impairs stromal reactivity by inhibiting M2-macrophages polarization and prostate cancer-associated fibroblasts

Zoledronic acid (ZA) is a biphosphonate used for osteoporosis treatment and also proved to be effective to reduce the pain induced by bone metastases when used as adjuvant therapy in solid cancers. However, it has been recently proposed that ZA could have direct anti-tumour effects, although the molecular mechanism is unknown. We herein unravel a novel anti-tumour activity of ZA in prostate cancer (PCa), by targeting the pro-tumorigenic properties of both stromal and immune cells. Particularly, we demonstrate that ZA impairs PCa-induced M2-macrophages polarization, reducing their pro-invasive effect on tumour cells and their pro-angiogenic features. Crucially, ZA administration reverts cancer associated fibroblasts (CAFs) activation by targeting the mevalonate pathway and RhoA geranyl-geranylation, thereby impairing smooth muscle actin-α fibers organization, a prerequisite of fibroblast activation. Moreover, ZA prevents the M2 macrophages-mediated activation of normal fibroblast, highlighting the broad efficacy of this drug on tumour microenvironment. These results are confirmed in a metastatic xenograft PCa mouse model in which ZA-induced stromal normalization impairs cancer-stromal cells crosstalk, resulting in a significant reduction of primary tumour growth and metastases. Overall these findings reinforce the efficacy of ZA as a potential therapeutic approach to reduce cancer aggressiveness, by abrogating the supportive role of tumour microenvironment.

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.

Acute kidney injury after a single intravenous zoledronic acid administration in patients with osteoporosis

Acute kidney injury after a single intravenous zoledronic acid administration in patients with osteoporosis

Acute kidney injury after a single intravenous zoledronic acid administration in patients with osteoporosis

Acute kidney injury after a single intravenous zoledronic acid administration in patients with osteoporosis

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.

An intrapleural administration of zoledronic acid for inoperable malignant mesothelioma patients: a phase I clinical study protocol.

BackgroundThe third generation of bisphosphonates is clinically in use for patients of osteoporosis or malignancy-linked hypercalcemia. The agents can also produce anti-tumor effects on bone metastasis of several types of tumors. We recently found that one of the agents achieved cytotoxicity to mesothelioma in vitro and in an orthotopic animal model. Mesothelioma is resistant to a number of chemotherapeutic agents, and suppression of local tumor growth is beneficial to the patients since metastasis to extra-thoracic organs is relatively infrequent until a late stage.Methods/designWe demonstrated in an orthotopic mouse model that an intrapleural but not intravenous injection of zoledronic acid, one of the third generation bisphosphonates, at a clinically equivalent dose suppressed the tumor growth. Nevertheless, a high concentration of zoledronic acid administrated in the pleural cavity produced pleural adhesion. We also showed that zoledronic acid produced synergistic cytotoxic effects with cisplatin, the first-line chemotherapeutic agent for mesothelioma. We then planned to conduct a phase I clinical study to investigate any adverse effects and a possible clinical benefits produced by an intrapleural administration of zoledronic acid to mesothelioma patients who became resistant to the first-line chemotherapeutic agents. The clinical trial is a dose escalation study starting with 0.4, 1, 4, 8 and 16 mg per person since safety of administration of zoledronic acid into the pleural cavity remains unknown. Each dose group consists of three persons and the protocol allows to repeat administration of the same dose into the pleural cavity at a 4-weeks interval.DiscussionWe will conduct a possible combinatory study of intrapleural administration of zoledronic acid and systemic administration of the first-line agent to a chemotherapy-naïve patient based on the maximum tolerance dose of zoledronic acid determined by the present clinical trial. We propose that administration of bisphosphonates in a closed cavity is a treatment strategy for tumors developed in the cavity probably through the direct cytotoxic activity.Trial registration: UMIN clinical trials registry, Japan. Register ID: UMIN8093.

Structural simulation of adenosine phosphate via plumbagin and zoledronic acid competitively targets JNK/Erk to synergistically attenuate osteoclastogenesis in a breast cancer model.

The treatment of breast cancer-induced osteolysis remains a challenge in clinical settings. Here, we explored the effect and mechanism of combined treatment with zoledronic acid (ZA) and plumbagin (PL), a widely investigated component derived from Plumbago zeylanica, against breast cancer-induced osteoclastogenesis. We found that the combined treatment with PL and ZA suppressed cell viability of precursor osteoclasts and synergistically inhibited MDA-MB-231-induced osteoclast formation (combination index=0.28) with the abrogation of recombinant mouse receptor activator of nuclear factor-κB ligand (RANKL)-induced activation of NF-κB/MAPK (nuclear factor-κB/mitogen-activated protein kinase) pathways. Molecular docking suggested a putative binding area within c-Jun N-terminal kinase/extracellular signal-regulated kinase (JNK/Erk) protease active sites through the structural mimicking of adenosine phosphate (ANP) by the spatial combination of PL with ZA. A homogeneous time-resolved fluorescence assay further illustrated the direct competitiveness of the dual drugs against ANP docking to phosphorylated JNK/Erk, contributing to the inhibited downstream expression of c-Jun/c-Fos/NFATc-1 (nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1). Then, in vivo testing demonstrated that the combined administration of PL and ZA attenuated breast cancer growth in the bone microenvironment. Additionally, these molecules prevented the destruction of proximal tibia, with significant reduction of tartrate-resistant acid phosphatase (TRAcP)-positive osteoclast cells and potentiation of apoptotic cancer cells, to a greater extent when combined than when the drugs were applied independently. Altogether, the combination treatment with PL and ZA could significantly and synergistically suppress osteoclastogenesis and inhibit tumorigenesis both in vitro and in vivo by simulating the spatial structure of ANP to inhibit competitively phosphorylation of c-Jun N-terminal kinase/extracellular signal-regulated kinase (JNK/Erk).

Pharmacokinetics of Zoledronic acid[once-yearly bisphosphonate(intravenous infusion)].

Zoledronic acid hydrate(zoledronic acid)is an osteoporosis therapeutic agent which shows the fracture suppression effect with once-yearly intravenous infusion. Although zoledronic acid is quickly disappeared from the blood after intravenous infusion, it is taken into the bone immediately and incorporated into the bone tissue. In addition, zoledronic acid shows the potent suppression effect on bone resorption by inhibiting farnesyl diphosphate synthase of the mevalonate pathway(FPPS)strongly. In vivo study, the single intravenous administration of zoledronic acid to the mature ovariectomized(OVX)rats demonstrated to suppress the decreasing bone strength dose-dependently in 32 weeks, corresponding to more than one year in human. Changes in bone resorption markers in the study of Japanese osteoporosis patients(ZONE Study)indicated that bone resorption inhibition action was maintained also over one year. The fracture suppression and increase of bone density with once-yealy administration was demonstrated in clinical trials in the osteoporosis patients in Japan and other countries, and zoledronic acid was currently approved for osteoporosis in September 2016 in Japan. Zoledronic acid is expected to contribute to the treatment of osteoporosis as a new bisphosphonate with once-yearly administration.

Bacterial profile and bone healing in rats receiving cancer therapeutic doses of bisphosphonates and corticosteroids: a pilot study

The microbial aetiology of bisphosphonate-related osteonecrosis of the jaw (BRONJ) remains undefined. This study investigated the oral microbiota and socket healing after zoledronic acid (ZA) and dexamethasone (DX) administration. Fourteen rats assigned randomly to experimental (n=8) and control (n=6) groups were injected with ZA+DX or saline, respectively, for 3 weeks prior to and 9 weeks after the extraction of left first upper and lower molars. Whole genomic DNA probes of 38 bacterial species and five Candida species were hybridized to DNA extracted from biofilm samples on exposed bone and adjacent teeth. Only experimental rats exhibited exposed bone at euthanasia. All BRONJ-like lesions were colonized by Staphylococcus pasteuri, Streptococcus parasanguinis, and Streptococcus mitis. A significant correlation was observed between the mean proportions of species colonizing BRONJ-like lesions and the teeth of experimental rats (r=0.818, P<0.001). Significant differences were seen in several species colonizing the teeth of control rats compared to experimental rats (P<0.05). Micro-computed tomography analyses revealed higher residual bone in mandibular (P=0.001) and maxillary (P=0.108) tooth sockets of experimental rats. BRONJ-like lesions were colonized mainly by non-pathogenic bacteria. ZA+DX administered to rats at doses equivalent to those given to cancer patients resulted in changes to the oral biofilm and impaired bone healing following tooth extraction.

A Case of Severe, Prolonged, Refractory Hypophosphatemia After Zoledronic Acid Administration

Zoledronic acid (ZA) administration has been associated with electrolyte abnormalities, including hypocalcemia, hypomagnesemia, hypokalemia, and hypophosphatemia. We describe a case of severe, refractory hypophosphatemia in a patient who received ZA for hypercalcemia of malignancy (HCM). Little data are available that describe the incidence or degree of severity of hypophosphatemia that can occur following ZA administration. In addition, no formal recommendations exist to guide monitoring for or management of electrolyte derangements in the setting of bisphosphonate use. Our patient required daily, high-dose phosphorus replacement beginning day 4 following ZA administration. The average daily dose of phosphorus, including both intravenous and enteral administration, was highest in the first 2 weeks after ZA, averaging 77 mmol/d days 4 through 15, and does not include sources of phosphorus from the patient’s nutrition support. Despite this high amount of supplementation, which was well beyond what meets normal daily requirements and the amount expected to treat “usual” hypophosphatemia, the patient did not achieve sustained normal serum phosphorus levels for over 30 days after ZA. ZA is a favorable option for treating HCM because of its longer duration of action, potent serum calcium-lowering effects, and favorable safety profile. The risk of hypophosphatemia with ZA use is reviewed.

Local administration of enriched mononuclear cells, platelets and zoledronic acid for preventing collapse of the femoral head in the early stage of osteonecrosis: study protocol for a prospective randomized parallel-controlled clinical trial

Background: Although there are many treatments for osteonecrosis of the femoral head, conservative treatment is often ineffective. Once collapse of the femoral head occurs, the damage is irreversible. Our previous animal studies have shown that local administration of zoledronic acid prevents collapse of the osteonecrotic femoral head. Additionally, bone marrow mononuclear cell therapy has a good short-term clinical effect on osteonecrosis of the femoral head. Currently, it is unclear whether a combination of bone marrow mononuclear cells and platelet-rich plasma may have efficacy in preventing early-stage collapse of the osteonecrotic femoral head. Methods/Design: A prospective, randomized, parallel-controlled, single-center clinical trial will be completed at the Chinese PLA General Hospital, China. One hundred patients with Ficat I-II osteonecrosis of the femoral head will be recruited and equally randomized into treatment and control groups. The treatment group will be given injection of enriched autologous mononuclear cells and zoledronic acid into the necrotic area following core decompression by drilling. In the control group, core decompression by drilling will be done, but no treatment will be given. Patients will be followed up at 3, 6, 12 and 18 months. Dynamic perfusion MR imaging, three-dimensional CT reconstruction, and anteroposterior and lateral X-ray observations of the hip joint will be performed to observe blood supply, bone formation and femoral appearance in the necrotic area. Harris score of the hip joint and a numeric rating scale score will be used to evaluate hip function and pain. These indicators will be used as primary outcome measures. Scores from the 36-Item Short-Form Health Survey and activity of daily living scale will be used as secondary outcome measures. Discussion: The outcomes of this trial will provide quantitative data and related information for evaluating the efficacy of local administration of enriched bone marrow mononuclear cells, platelets and zoledronic acid for the clinical prevention of collapse of the early-stage osteonecrotic femoral head. Trial registration: ClinicalTrial.gov identifier: NCT02721940. Written approval for this protocol was obtained from the ethics committee of the Chinese PLA General Hospital in China (approval No. S2015-082-01).

Severe Hypocalcemia After the Administration of Zoledronic Acid for Osteoporotic Fracture

Severe Hypocalcemia After the Administration of Zoledronic Acid for Osteoporotic Fracture