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PubMed1997

Zoledronate (CGP 42'446), a bisphosphonate, protects against metaphyseal intracortical defects in experimental inflammatory arthritis.

This study investigated zoledronate (CGP 42'446), a bisphosphonate, as a potential prophylactic and therapeutic agent against intracortical defects in metaphyseal bone in an experimental model of inflammatory arthritis. Inflammatory arthritis was induced in the right tibiofemoral joint of rabbits by the repeated injection of carrageenan. Three groups of animals were treated with the bisphosphonate daily, beginning at different points after the induction of arthritis. Cross sections of the right distal femoral metaphysis were prepared, and intracortical defects were examined by computerized image analysis. The percentage of total bone area with defects (the ratio of void area to total bone area) was greatly increased in the arthritic group compared with that in the normal group (p < 0.001). In all groups treated with the bisphosphonate, there was a significantly lower percentage of total bone area with defects compared with that in the arthritic group (p < 0.001). Treatment was likewise effective in reducing the zonal (anterior and posterior) predilection for the formation of defects observed in arthritis. Although inflammatory arthritis has a substantial effect in producing intracortical defects in metaphyseal bone, a bisphosphonate, zoledronate, was considerably effective in preventing these changes from occurring.

Animals↗
PubMed2000

Changes in cross-sectional geometry of the distal femoral metaphysis associated with inflammatory arthritis are reduced by a bisphosphonate (zoledronate).

An increased risk of fracture is a feature of rheumatoid arthritis and of animal models of inflammatory arthritis. We examined geometrical changes in the metaphyseal cortex of the distal femur in an animal model of inflammatory arthritis. Additionally, we examined the effect of a bisphosphonate in preventing these changes. Five groups of rabbits were studied: normal controls, those with inflammatory arthritis, and three groups with arthritis treated with bisphosphonate. To determine geometrical properties, image analysis was performed on digitized cross sections of the femoral metaphyseal cortices. The results demonstrated that the posterior cortical wall was significantly less thick in rabbits with arthritis than in normal rabbits and in the rabbits in the three bisphosphonate treatment groups (p < 0.05). Moment of inertia about the lateral-medial axis was reduced in rabbits with arthritis compared with normal rabbits (p < 0.05). Cross-sectional area was not significantly different between groups. The changes suggest a mechanism of weakening of bone in arthritis; when the results are coupled with results of previous porosity studies, severe directional weakness is apparent. Bisphosphonate was effective in preserving bone integrity in inflammatory arthritis.

Animals↗
PubMed2002

Adaptive dose finding for phase I clinical trials of drugs used for chemotherapy of cancer.

Phase I clinical trials of cancer chemotherapy drugs are intended to determine the maximum tolerable dose (MTD). Thestandard method employed is a rule-based dose-escalation scheme in which escalation depends on the number of patients at a dose level that have dose-limiting toxicity (DLT). The MTD is thus defined in terms of the rules and a series of dose levels selected for sampling. For some trials it is desirable to have a more precise definition of the MTD, and to determine the MTD more accurately than possible with the rule-based schemes. Continuous reassessment methods (CRMs) define the MTD to be the dose at which a fixed fraction of patients experience DLT, and thus appear suited to these trials. It is shown, however, that these methods can have failure modes that in fact make them unattractive. An alternative data-driven dose-finding method is described that combines the robustness of the rule-based methods and with features of CRMs. The method has two stages. In the first stage, doses are escalated by a factor of 1.5. In the second stage, which begins at the first instance of DLT, a two-parameter logistic dose-response model estimates the MTD from the DLT experience of all patients. The model is initialized by setting the dose (d10) at which 10 per cent of patients would experience DLT to half the dose at which the first DLT was observed, and the dose (d90) at which 90 per cent would experience DLT to ten times d10. Weights are assigned such that the information at d10 and d90 is equivalent to that of one patient at each of the two doses. Cohorts of three patients are treated in both stages, and the dose for a new cohort in the second stage is the estimated MTD. The only prior information required to specify the design completely is the dose which will be given to the first cohort. Two stopping rules are investigated; among the requirements for these are that at least three (or four) DLTs be observed and at least nine patients be treated in the second stage. Simulations show that a coefficient of variation of approximately 0.4 on a target DLT probability of 0.3 is obtained over a wide variation in dose-response characteristics of the study drug. The performance of the new method is compared to that of rule-based methods.

Algorithms↗
PubMed2005

Primary hyperparathyroidism and neuropsychiatric alterations in a nonagenarian woman.

Whether elderly patients with asymptomatic or minimally symptomatic primary hyperparathyroidism (PHPT) should be treated or not is still under debate. Several literature reports have shown improvements in terms of bone density and physical and mental well-being after surgical resolution of PHPT. Here, we present the case of a 93-year-old hypertensive woman, who had suffered for one year from cognitive impairment, accompanied during the last month by behavioral alterations (and polyuria and polydipsia), which resulted in sopor leading to hospitalization. A CT brain scan evidenced cortical atrophy and cerebrovascular disease, and biochemical analyses were remarkable for hypercalcemia (11.4-12.6 mg/dL, corrected for albumin levels) associated with increased parathormone levels (95.4-100.6 pg/mL). A diagnosis of PHPT was established. Densitometry evaluation of radius showed osteopenia. Withdrawal of psycho-therapy drugs and thiazidic, together with i.v. saline hydration and loop diuretics, significantly improved the patient's mental state and resolved behavioral alterations. As the patient and her relatives refused the surgical option, and the clinical situation improved after medical normalization of calcium levels, PHPT was managed conservatively, and calcium levels were maintained within the normal range through i.v. administration of zoledronate at 8-week intervals. Our case highlights the importance of considering hypercalcemia as the cause of onset of behavioral alterations and worsening of mental condition in elderly patients with cognitive decline. Therapy with bisphosphonates in patients with PHPT who are unfit for or refuse surgery seems advisable, but needs further study.

Aged↗
PubMed2004

Bisphosphonates induce apoptosis of stromal tumor cells in giant cell tumor of bone.

Giant cell tumour of bone (GCT) is an aggressive primary neoplasm that results in the production of osteolytic lesions. Stromal cells, which form the main neoplastic component of this tumor, regulate the formation of osleoclast-like giant cells that are ultimately responsible for bone destruction. Bisphosphonates prevent bone resorption by inhibiting osteoclast activity and promoting osteoclast apoptosis, and they have been known to induce apoptosis of primary neoplastic cells such as those in breast and prostate cancers. We hypothesized that in bisphosphonates may induce apoptosis not only in osteoclast-like giant cells but also in neoplastic stromal cells of GCT both in vitro and in vivo. Twelve patients with GCT were treated with weekly injections of pamidronate for a period of 6 weeks prior to surgery. GCT specimens were collected at the time of biopsy and during definitive surgery. TUNEL assay was used to evaluate apoptotic DNA fragmentation in cells. In addition, twelve GCT primary cultures from these patients were treated with zoledronate, pamidronate, or alendronate for 48 hours at different doses (3, 30, or 150 microM) and subjected to apoptosis assay by flow cytometry following fluorescent Annexin-V labeling. The results showed that pamidronate significantly induced apoptosis in both osteoclast-like giant cells and stromal tumor cells, in vivo. All three bisphosphonates caused substantial apoptosis of stromal tumor cells in cultures. Zoledronate was the most potent reagent, resulting in an average cell death of 27.41% at 150 microM, followed by pamidronate (22.23%) and alendronate (15.3%). Our observations suggest that these drugs may be considered as potential adjuvants in the treatment of GCT.

Alendronate↗
PubMed2005

Effect of zoledronate on bone quality in the treatment of aseptic loosening of hip arthroplasty in the dog.

Periprosthetic bone loss, which is a direct cause of aseptic loosening in total hip arthroplasty (THA), can be suppressed by bisphosphonates. It is unknown how the quality of this bone is affected in the presence of both wear debris (from implant) and bisphosphonates. The objective of this study was to evaluate the effect of zoledronate (ZLN) on bone quality in the presence of wear debris [polyethylene (PE) particles] in a canine model of uncemented THA. Thirty dogs underwent THA, and aseptic loosening was induced via implantation of PE particles packed into the femoral component. For 26 weeks until sacrifice, two groups (each n = 10) received weekly injections of ZLN (low dose 2 mug/kg, high dose 10 mug/kg) and the third group (control) received saline. Histological and radiographic examinations were performed to evaluate the degree of implant reaction. Histomorphometry (static/dynamic) was performed to evaluate bone turnover. Back-scattered electron imaging was used to quantify the newly formed bone and to evaluate the mineralization distribution. Density fractionation and X-ray diffraction were used to evaluate mineral properties, while four-point bending was used to determine mechanical properties. A dose-dependent presence of newly formed subperiosteal bone was found, which appeared to be less mineralized than the adjacent cortical bone. The high-dose ZLN group showed decreased cortical porosity and turnover and increased mineralization profile, failure strength, and modulus. We conclude that ZLN affects some of the material properties of cortical bone and allows the newly formed subperiosteal bone to remain and therefore affect the overall quality of the bone.

Animals↗
PubMed1997

Antiresorptive effect of a single infusion of microgram quantities of zoledronate in Paget's disease of bone.

Zoledronate (CGP 42446) is a third generation imidazole ring containing bisphosphonate that has been found in animal studies to be up to 850 times more potent than pamidronate. In this first study reporting the effects of this drug in humans, 16 patients with active Paget's disease of bone [baseline serum alkaline phosphatase activity (SAP) at least twice the upper limit of normal] were treated in a fixed ascending dose-ranging protocol with a single 1-hour infusion of either 24, 72, 216, or 400 microg of zoledronate (four patients per dose). SAP and two markers of bone resorption, 24-hour urinary hydroxyproline/creatinine excretion (OHP) and 24-hour urinary calcium/creatinine excretion, were measured at baseline, 24 hours postinfusion (day 1) and on postinfusion days 3, 7, 10, and 14. Safety parameters including vital signs, hemogram, and chemistries were measured at the same time points. At the 24- and 72-microg doses there were no consistent or meaningful changes in the bone resorption markers. However, with the 216 microg dose, urinary OHP decreased from baseline by a mean of 16-19% on days 3, 7, 10, and 14; with the 400 microg dose, OHP decreased by a mean of 33-48% at days 1, 7, and 10 and by 16% at day 14. Urinary calcium/creatinine decreased from baseline with the 216 microg dose by a mean of 15-40% on days 1, 3, 7, 10, and 14 and with the 400 microg dose by a mean of 55-71% on days 3, 7, 10, and 14. As expected, there was no reduction in SAP during the 14-day postinfusion period. There was no evidence of an acute phase reaction (pyrexia, myalgia, or arthralgia), leukopenia, or renal or hepatic toxicity. We conclude that single infusions of microgram amounts of zoledronate were capable of inhibiting bone resorption in patients with active Paget's disease during a 2-week study interval. This anti-bone resorbing effect was not associated with any clinically or biochemically observed toxicity. This potent new bisphosphonate appears to be a promising compound for the management of skeletal disorders characterized by increased bone resorption.

Adult↗
PubMed2005

[Osteonecrosis of the jaws as a possible adverse effect of the use of bisphosphonates].

BACKGROUND: Bisphosphonates are widely used in the treatment of cancer patients with hypercalcemia and bone metastases or in osteoporosis therapy. Current reports have focused on therapy-resistant osteonecrosis of the jaws as a possible side effect of bisphosphonates. Official German drug committees have recently warned about the possibility of these side effects in the publication organs Deutsches Arzteblatt and Deutsche Apotheker Zeitung. CASE REPORTS: So far we have had experience with seven patients showing therapy-resistant osteonecrosis of the mandible under bisphosphonate medication. The presentation of these cases is intended to call attention to this clinically important side effect of bisphosphonate medication.

Aged↗
PubMed2006

[Bisphosphonate-associated osteonecrosis of the jaw].

BACKGROUND: Bisphosphonates (BP) are widely used in patients with osteoporosis or malignant tumors with bony metastases such as breast cancer and plasmocytoma because of their potency to affect osteoclasts and bone resorption. Osteonecrosis of the jaw (ONJ) has been described as a potential side effect since 2003. After a review of the literature we present results of a questionnaire, which was sent to departments of oral and maxillofacial surgery (OMFS) in German-speaking countries. MATERIAL AND METHODS: We present 349 patients from the literature, 54 patients from the departments of OMFS and 19 cases from our own department. These patients ware analyzed depending on their disease, their medication, localization of the affected area, histological signs and therapeutic outcome. RESULTS: Of 73 patients, 68 (93%) were treated with pamidronate or zoledronate; 69 (94%) patients suffered from malignant diseases, 3 (5%) had osteoporosis, and 1 (1%) had Paget's disease. In 57 (78%) patients the ONJ affected the mandible, in 12 (16%) the maxilla and in 4 (5%) both jaws. A previous tooth extraction was reported in 38 (52%) patients, and in 35 (48%) ONJ occurred spontaneously. Histological findings were similar to osteomyelitis with a high number of actinomyces colonies. Nine (12%) patients received non-surgical treatment only, 52 (71%) patients underwent minor surgical procedures (e. g. decortication) and 19 (26%) patients underwent marginal or segmental resection of the jaw. Considering all treatment modalities, healing was achieved in 55; the most effective was marginal and segmental resection (88%). DISCUSSION: Though millions of patients receive BP treatment only a few suffer from ONJ. The incidence in cancer patients with pamidronate and zoledronate therapy is 4%-10%. Because of the similarity to "phossy jaw", seen in patients dealing with white phosphorus in the nineteenth century, some authors call the new entity "bis-phossy jaw". As the pathogenesis of ONJ is not clear we recommend that the descriptive term bisphosphonate-associated osteonecrosis should be used. Bone resection and safe soft tissue closure is the treatment of choice. We recommend systematic dental care for patients receiving BP medication. Information exchange between oncologists, oral and maxillofacial surgeons and dentists is important.

Aged↗
PubMed2006

Digeranyl bisphosphonate inhibits geranylgeranyl pyrophosphate synthase.

A primary cellular target of the clinical nitrogenous bisphosphonates is the isoprenoid biosynthetic pathway. Specifically these drugs inhibit the enzyme farnesyl pyrophosphate synthase and deplete cells of larger isoprenoids. Inhibition of this enzyme results in impaired processing of both farnesylated and geranylgeranylated proteins. We recently showed that isoprenoid-containing bisphosphonates such as digeranyl bisphosphonate inhibit protein geranylgeranylation and not farnesylation. Here, we show that this impairment results from potent and specific inhibition of geranylgeranyl pyrophosphate synthase, which leads to enhanced depletion of intracellular geranylgeranyl pyrophosphate relative to the nitrogenous bisphosphonate zoledronate.

Apoptosis↗
PubMed2005

Novel biomaterials for bisphosphonate delivery.

One type of gem-bisphosphonate (Zoledronate) has been chemically associated onto calcium phosphate (CaP) compounds of various compositions. For that purpose, CaP powders of controlled granulometry have been suspended in aqueous Zoledronate solutions of variable concentrations. Using mainly (31)P NMR spectroscopy, two different association modes have been observed, according to the nature of the CaP support and/or the initial concentration of the Zoledronate solution. beta-tricalcium phosphate (beta-TCP) and mixtures of hydroxyapatite and beta-TCP (BCPs) appear to promote Zoledronate-containing crystals formation. On the other hand, at concentrations <0.05 mol l(-1) CDAs (calcium deficients apatites) seem to undergo chemisorption of the drug through a surface adsorption process, due to PO(3) for PO(4) exchange, that is well described by Freundlich equations. At concentrations >0.05 mol l(-1), crystalline needles of a Zoledronate complex form onto the CDAs surface. The ability of such materials to release Zoledronate, resulting in the inhibition of osteoclastic activity, was shown using a specific in vitro bone resorption model.

Animals↗
PubMed2004

Calcium phosphate drug delivery system: influence of local zoledronate release on bone implant osteointegration.

Despite total hip replacement (THR) gives generally satisfactory results, the quality of outcome in young patients is markedly decreased compared to the average THR outcome. For this population, pharmacological treatment with bisphosphonate would be beneficial to decrease the peri-implant osteolysis. However, as this population does not necessarily suffer from osteoporosis, a nonsystemic treatment would be preferable. Zoledronate was then grafted to hydroxyapatite (HA) coating of titanium implants. The implants were inserted in rat condyles with various zoledronate concentrations. A positive concentration-dependent effect was observed on the peri-implant bone density and on different histomorphometric parameters. Importantly for the outcome of the implants, the mechanical fixation was increased by the local presence of zoledronate. The obtained results open the way of an easy transformation of currently existing HA-coated implants by grafting bisphosphonate onto the coating in order to increase their service life in the patients.

Animals↗
PubMed2005

Neuropathy-induced osteopenia in rats is not due to a reduction in weight born on the affected limb.

Changes in bone mineral density (BMD) are associated with clinical neuropathies. Following nerve injury in the rat, there is a loss of BMD, which may be related to nerve injury or reduced mechanical loading. The purpose of this study was to investigate if altered mechanical loading is solely responsible for the observed loss of BMD in neuropathic pain models. In addition, we sought to study the action of chronic bisphosphonate treatment on both neuropathy-induced osteopenia and pain. We therefore had two hypotheses: firstly, that nerve injuries can have variable effects on hind limb bone loss in rats which are not attributable to differences in the extent of hind limb disuse and, secondly, that bisphosphonate treatment can reverse bone loss in a rat mononeuropathy model, and this is not attributable to bisphosphonate effects on nociception or hind paw unweighting. Male Sprague-Dawley rats were subject to chronic constriction injury (CCI), partial sciatic nerve ligation (PSN) or L5 + L6 spinal nerve ligation (SNL). Loss of BMD, defined as a numerically lower BMD as compared to control animals, was extreme following CCI (maximum ipsilateral/contralateral difference of 0.023 +/- 0.011); BMD loss following either PSN or SNL in the rat was subtle (0.010 +/- 0.002 and 0.013 +/- 0.012 g/cm2, respectively), significant only at early time points and had resolved by 7 weeks post-surgery. Chronic bisphosphonate treatment significantly inhibited CCI-induced osteopenia in the rat without inhibiting the reduction in weight-bearing tactile allodynia or mechanical hyperalgesia. Loss of BMD is observed in rats in a variety of neuropathic pain models. Lack of correlation between neuropathy-induced bone loss and weight bearing demonstrates that the bone loss is not simply a function of reduced mechanical loading and suggests that altered bone-nerve signaling is involved. Furthermore, chronic bisphosphonate treatment inhibits neuropathy-induced osteopenia without affecting behavioral measurements of neuropathic pain. This indicates that osteopenia is not directly related to neuropathic pain behaviors.

Alendronate↗