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Osteonecrosis of the jaws in patients on chronic bisphosphonate therapy has been reported in small series since 2003. We present two patients with multiple myeloma who developed osteonecrosis of the jaws on intravenous treatment with zolendronic acid and pamidronate, respectively. The patients were treated with debridement of the involved bone and long-term antibiotic therapy.
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Geranyl diphosphate synthase catalyzes the condensation of dimethylallyl diphosphate (C(5)) with isopentenyl diphosphate (C(5)) to produce geranyl diphosphate (C(10)), the essential precursor of monoterpenes. The enzyme from peppermint and spearmint (Menthaxpiperita and Mentha spicata, respectively) functions as a heterodimer or heterotetramer consisting of a 40kDa subunit and 33kDa subunit. The DNAs encoding each subunit were joined with different sized linkers and in both possible orders, and expressed in Escherichia coli to yield the corresponding fused protein. The properties of the recombinant fused version, in which the small subunit was followed by the large subunit with a 10 amino acid linker, resembled those of the native heteromeric enzyme in kinetics, product chain-length specificity, and architecture, and this form thus provided a suitable single gene transcript for biotechnological purposes. Bisphosphonate substrate analogs of the type that inhibit farnesyl diphosphate synthase (C(15)) and geranylgeranyl diphosphate synthase (C(20)) also inhibited the fused geranyl diphosphate synthase, apparently by interacting at both the allylic and homoallylic co-substrate binding sites. The results of inhibition studies, along with the previously established role of the small subunit and related mutagenesis experiments, suggest that geranyl diphosphate synthase employs a different mechanism for chain-length determination than do other short-chain prenyltransferases.
BACKGROUND: The most frequent site of metastases from prostate cancer is bone. Bisphosphonates reduce excessive bone turnover while preserving bone structure and mineralization in patients with other tumor types. We conducted a double-blind, placebo-controlled, randomized trial to determine whether the first-generation bisphosphonate sodium clodronate could improve bone progression-free survival (BPFS) times among men with bone metastases from prostate cancer. METHODS: Between June 1994 and July 1998, 311 men who were starting or responding to first-line hormone therapy for bone metastases were randomly assigned to receive oral sodium clodronate (2080 mg/day) or placebo for a maximum of 3 years. The primary endpoint of the trial was symptomatic BPFS. Secondary endpoints included overall survival, treatment toxicity, and change in World Health Organization (WHO) performance status. Time-to-event data were analyzed using the log-rank chi-square test and Kaplan-Meier curves. All statistical tests were two-sided. RESULTS: Baseline characteristics were balanced across the two groups. After a median follow-up of 59 months, the sodium clodronate group showed statistically nonsignificant better symptomatic BPFS (hazard ratio [HR] = 0.79, 95% confidence interval [CI] = 0.61 to 1.02; P =.066) and overall survival (HR = 0.80, 95% CI = 0.62 to 1.03; P =.082) than the control group. Patients in the clodronate group were less likely to have a worsened WHO performance status (HR = 0.71, 95% CI = 0.56 to 0.92; P =.008). However, the clodronate group reported more gastrointestinal problems and increased lactate dehydrogenase levels and required more frequent modification of the trial drug dose (HR for any adverse event = 1.71, 95% CI = 1.21 to 2.41; P =.002). Results of subgroup analyses suggested that clodronate might be more effective the sooner after diagnosis of metastatic bone disease it is started. CONCLUSION: These results suggest that further studies of the effect of newer generation bisphosphonates on BPFS in men with metastatic prostate cancer are warranted.
The major clinical manifestations of multiple myeloma are related to the loss of bone. This bone loss often leads to pathologic fractures, spinal cord compression, hypercalcemia, and bone pain. This article reviews the cytokine network involved in myeloma bone disease; describes the signaling cascade involved in osteoclastogenesis and mechanisms of action of novel therapeutic options for myeloma bone disease such as osteoprotegerin, RANK human immunoglobulin fusion protein, the proteasome inhibitor PS-341, and bisphosphonates; and summarizes the latest clinical trial results using oral and intravenous bisphosphonates for bone disease in multiple myeloma.
A 33-year-old woman with T(4c)N(3) breast cancer with metastases in the skeleton (M(1)) received five cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC regimen) before conception and during the first trimester. Salvage radiotherapy (28 Gy) was delivered during the 17th week. Tamoxifen and zolendronic acid were also administered throughout the second and third trimesters. The patient was not aware of her pregnancy until the 28th week. A female phenotypically normal infant was delivered in the 35th week of gestation by cesarean section. The child is functioning normally 12 months after delivery. The literature of anthracycline treatment during conception and the first trimester is reviewed. The effects of tamoxifen and biphosphonate therapy on the fetus during pregnancy are also discussed.
The prolonged administration of bisphosphonates can reduce the frequency of morbid skeletal events in patients with metastatic breast carcinoma or multiple myeloma. The development of more potent bisphosphonates will simplify current therapeutic schemes and could improve the therapeutic effectiveness of bisphosphonate therapy. Zoledronate (CGP-42446) is the most potent of the clinically tested compounds. It is a cyclic third-generation bisphosphonate that is 100-850 times more active than pamidronate in several in vivo and in vitro pharmacological test systems. The first therapeutic trial with zoledronate has been performed in patients with tumor-induced hypercalcemia (corrected calcium [Ca] > 2.75 mmol/L after rehydration). In a Phase I multicenter trial, it was shown that a single infusion was already effective at dose levels of 0.02 and 0.04 mg of zoledronate/kg bodyweight, thus 1.2 and 2.4 mg total dose for an average 60-kg individual. Five of 5 patients became normocalcemic after a dose of 0.02 mg/kg, and 14 of 15 (93%) after a dose of 0.04 mg/kg. The median time to normalization of serum Ca was 2 days and the median duration of action was 33 days, suggesting that zoledronate has a faster onset and a longer duration of action than other clinically tested bisphosphonates. Zoledronate was well tolerated; the only side effect was an increase in body temperature in 30% of the cases, which was probably not drug-related in many patients. A Phase I trial also has been initiated in patients with lytic bone metastases. Zoledronate was given as monthly short infusions (5-30 minutes) at doses between 0.1-8.0 mg. There was an analgesic effect and even at low doses (2 mg and above), the effects on the biochemical markers of bone resorption appeared to be greater than after 90-mg pamidronate infusions. These initial human data suggest that zoledronate can be administered as convenient short intravenous infusions and lead to a more marked and a more prolonged inhibition of bone resorption than is currently possible with available compounds. Future trials will have to determine whether prolonged treatment with this extremely potent bisphosphonate also can have a greater effect on the morbidity of bone metastases.
To study the anti-resorptive effects of zoledronate and pamidronate on growing long bones we have performed a histomorphometric analysis of the three regions of the proximal tibial cancellous bone of bone formed before, during, and after drug treatment. Male rats (190-220 g) were treated subcutaneously for 10 days with zoledronate (0.028-2.8 microg/kg) or pamidronate (3.7-370 microg/kg) and sacrificed 5 days later. To delineate the three regions of cancellous bone, and for dynamic bone histomorphometry, calcein and demeclocycline were injected at various times. Both bisphosphonates caused a dose-dependent suppression of cancellous bone turnover and resorption to produce an increase in cancellous bone, but zoledronate was 100 times more potent than pamidronate. The increase in the bone amount and connectivity was more pronounced in the bone formed during treatment where transient bone resorption and normal bone formation led to a positive bone balance. In the bone formed before treatment, inhibition of bone resorption associated with reduced bone formation produced a net gain in amount of bone. Although both bone regions showed a positive bone balance, more bone accumulated in the bone formed during treatment probably because its trabecular bone surface was three times greater. In the primary spongiosa formed after treatment, a moderate increase in the bone amount and connectivity was observed only at the highest dose of both bisphosphonates. The bone formed before, during, and after treatment with bisphosphonates responds differently due to differences in bone architecture, rates of modeling and remodeling, and period of drug exposure.
OBJECTIVE: We have previously shown that the woven pagetic bone in patients with Paget's disease is characterized by an impaired degree of beta-isomerization of C-telopeptides of type I collagen molecules, which results in a preferential urinary excretion of nonisomerized type I collagen C-telopeptide breakdown products (CTX). The aim of this study was to measure the urinary excretion of nonisomerized (alpha) and beta-isomerized (beta) CTX in patients with Paget's disease treated with a bisphosphonate. METHODS: We studied 28 patients with active Paget's disease of bone who were a part of a randomized, double-blind, placebo-controlled study comparing the effects of several doses of a single injection of zoledronate, a new potent bisphosphonate. Serum bone alkaline phosphatase (BAP) and type I collagen C-terminal extension propeptide (PICP) and urinary excretion of free deoxypyridinoline (free D-Pyr), N-telopeptide breakdown products (NTX), alphaCTX, and betaCTX were measured at baseline and 5, 10, 30, and 60 days after injection. RESULTS: At baseline, all markers were significantly increased in the patients compared with a group of 97 sex- and age-matched controls, with a greater increase in BAP (12-fold), NTX (19-fold), and alphaCTX (10-fold) compared with PICP (2.2-fold), free D-Pyr (2.5-fold), and betaCTX (3-fold). The ratio of alphaCTX to betaCTX was about 3-fold higher than in controls (2.1 versus 0.76; P < 0.001). After a single intravenous injection of zoledronate (200 or 400 microg), all markers decreased within 5 days, except for BAP and free D-Pyr, which decreased on day 10. The maximum decrease was greater and occurred faster for NTX, alphaCTX (-55% after 10 days), and betaCTX (-42% after 10 days) than for free D-Pyr (-25% after 30 days). After the initial decrease, the urinary excretion of betaCTX increased between days 10 and 30 and returned to pretreatment levels after 2 months, in contrast to the sustained decrease in alphaCTX and NTX that was maintained up to 60 days. The urinary ratio of alphaCTX to betaCTX decreased significantly between days 10 and 60, and returned to within the normal range in most patients after 2 months of treatment, probably reflecting the progressive replacement of woven bone by a lamellar bone with a higher and normal degree of beta-isomerization of type I collagen, as previously documented by histology. CONCLUSION: The determination of the urinary ratio of alphaCTX to betaCTX could be useful for monitoring the effect of bisphosphonate treatment in restoring bone quality in patients with Paget's disease.
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BACKGROUND: Preclinical and clinical data have suggested that high-dose calcitriol (1,25-dihydroxycholecalciferol) has activity against prostate carcinoma. Pulse-dosed calcitriol and dexamethasone may maximize tolerability and efficacy. The authors examined the toxicity of pulse-dosed calcitriol with zoledronate and with the addition of dexamethasone at the time of disease progression. METHODS: Patients with progressive prostate carcinoma were eligible for the current study. In cohorts of 3-6 patients, calcitriol was administered for 3 consecutive days per week, starting at a dose of 4 microg per day. Doses were escalated to 30 microg per day. Intravenous zoledronate (4 mg) was administered monthly. Dexamethasone could be added to the regimen at disease progression. Toxicities, markers of bone turnover, plasma calcitriol levels, and clinical outcomes were recorded. RESULTS: Thirty-one patients were treated in cohorts that were defined by the calcitriol dose administered (4, 6, 8, 10, 14, 20, 24, or 30 microg). Seven patients received dexamethasone. Three patients had their doses reduced due to calcium-related laboratory findings. Patients tolerated therapy well, even in the 30 microg cohort; therefore, a maximum tolerated dose was not defined. Peak plasma levels observed in the 24 microg and 30 microg cohorts ranged from 391 to 968 pg/mL. Minimal antitumor effects were observed. CONCLUSIONS: Calcitriol was well tolerated at doses up to and including 30 microg 3 times per week in combination with intravenous zoledronate 4 mg monthly, with or without dexamethasone, in patients with progressive prostate carcinoma. Peak plasma levels in the 24 microg and 30 microg cohorts were greater than the levels associated with antitumor effects preclinically. Due to the cumbersome dosing schedule and the lack of significant activity observed, Phase II trials of this regimen are not planned.
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BACKGROUND: The purpose of the study was to evaluate the efficacy and safety of a bone-targeted regimen consisting of zoledronate, thalidomide, and interferon-gamma in patients with renal cell carcinoma and bone metastases. METHODS: Eligible patients had radiographic evidence of bone metastasis. Impending pathologic fractures or spinal cord compressions must have been controlled by surgery or radiation therapy before enrollment. Zoledronate (4 mg) was given intravenously every 4 weeks, thalidomide (300 mg) was given orally once a day, and interferon-gamma (100 microg) was given subcutaneously once a week. Patients were evaluated for time to skeletal-related events, the appearance of calcification in osteolytic metastases, and levels of the bone formation/resorption markers. RESULTS.: Fifteen patients were treated between November 2002 and November 2003; 12 had previously undergone surgery, radiation, or embolization for their bone metastases; 11 had more than 3 sites of bone involvement; and 9 also had nonosseous metastases in the lung, liver, lymph node, pancreas, or adrenal gland. The median time to progression was 8.3 weeks (range, 2.1-48 weeks). The median time to a skeletal-related event was 12.0 weeks (range, 3.9-46.4 weeks). Two patients discontinued treatment because of adverse drug reactions (1 deep venous thrombosis and 1 myocardial infarction). Two patients experienced pain improvement and developed calcification in osseous metastases; these patients also showed favorable changes in bone marker levels. CONCLUSIONS: In this pilot study a bone-targeted regimen combining zoledronate, thalidomide, and interferon-gamma was well tolerated and might provide clinical benefit for a small subset of patients with renal cell carcinoma and bone metastases.
Nitrogen containing-bisphosphonates (N-BPs), widely used to treat bone diseases, have direct antitumor effects via the inactivation of Ras proteins. In addition to the direct antitumor activities, N-BPs expand gammadeltaT cells, which exhibit major histocompatibility complex-unrestricted lytic activity. BPs accumulate intermediate metabolites which may be tumor antigens in target cells. The purpose of our study was to clarify the cytotoxicity of gammadelta T cells expanded ex vivo by the most potent N-BP, zoledronate (ZOL). Especially, we focused on the importance of pretreatment against target cells also with ZOL; 1 microM ZOL plus IL-2 increased the absolute number of gammadeltaT cells 298-768 fold for 14 days incubation. The small cell lung cancer and fibrosarcoma cell lines pretreated with 5 microM ZOL showed a marked increase in sensitivity to lysis by gammadeltaT cells. While, untreated cell lines were much less sensitive to lysis by gdT cells. Video microscopy clearly demonstrated that gammadeltaT cells killed target cells pre-treated with ZOL within 3 hr. Pretreatment with 80 microg/kg ZOL also significantly enhanced the antitumor activity of gammadeltaT cells in mice xenografted with SBC-5 cells. These findings show that ZOL significantly stimulated the proliferation of gammadeltaT cells and that gammadeltaT cells required pre-treatment with ZOL for cytotoxic activity against target cells.
Patients with osteoporosis and joint disabilities represent a constant growing and challenging population to be treated in the musculoskeletal clinical field. Especially in the case of total hip arthroplasty, new solutions should be developed to compensate for the double negative factors, peri-implant osteolysis, and osteoporotic bone loss, affecting the quality of implant outcome. The goal of this study was then to establish a proof of concept for orthopedic implant used as Zoledronate delivery in osteoporotic rats, and in particular, to verify if this approach could increase the initial implant stability. Twenty-five female 6-month-old Wistar rats were ovariectomized 6 weeks before the implantation to induce osteoporosis. The animals were randomly separated in five groups representing the different Zoledronate concentrations in the HA coating: 0, 0.2, 2.1, 8.5, and 16 microg/implant. Histomorphometric measures and peri-implant bone volume fraction were assessed and mechanical stability tests were performed. Bone volume fraction and biomechanical results clearly illustrate the positive effect of Zoledronate coated implants in the osteoporotic rats. A remarkable result was to show the existence of a window of Zoledronate content (0.2 to 8.5 microg/implant) in which the mechanical fixation of the implant increased. We were able to establish the proof of concept for orthopedic implants used as a drug delivery system in osteoporotic rats. The local bisphosphonate delivery from a calcium phosphate coating allowed increase of the mechanical fixation of an orthopedic implant. This study shows that orthopedic implants containing bisphosphonates could be beneficial for osteoporotic patients in need of a total joint replacement.
We have investigated the pharmacologic effects of a new bisphosphonate compound, CGP 42'446 [2-(imidazol-1-yl)-1-hydroxyethylidene-1,1-bisphosphonate], on bone metabolism. The compound exhibited potent inhibitory activity on the bone resorption induced by 1,25-dihydroxyvitamin D3 both in vivo in the thyroparathyroidectomized rat (ED50 0.072 microgram/kg SC) and in vitro in mouse calvarial cultures (IC50 0.002 microM). A comparison of the in vivo and in vitro inhibitory potencies of a total of nine bisphosphonates revealed an excellent correlation between the two assays (r = 0.97). CGP 42'446 also potently inhibited calvarial bone resorption induced by parathyroid hormone (1-34), parathyroid hormone-related protein (1-34), and recombinant human interleukin-1 beat. Short-term treatment of growing rats with CGP 42'H446 dose-dependently increased the radiographic density of the tibial proximal metaphysis (ED50 1.7 micrograms/kg SC) as well as increasing the calcium and hydroxyproline content of femoral trabeculae (ED50 values 0.17 and 1.1 micrograms/kg SC, respectively), but there was no detectable effect on cortical bone. On a molar basis in this range of in vivo screening assays, CGP 42'H446 was between 940-fold (thyroparathyroidectomized rat) and 87-fold (rat femoral trabecular calcium content) more potent than pamidronate. It is concluded that CGP 42'446 is a promising new, highly potent bisphosphonate for the suppression of the increased bone resorption associated with various diseases.
The increased generation and up-regulated activity of bone resorbing cells (osteoclasts) play a part in the impairment of bone remodeling in many bone diseases. Numerous drugs (bisphosphonates, calcitonin, selective estrogen receptor modulators) have been proposed to inhibit this increased osteoclastic activity. In this report, we describe a pit resorption assay quantified by scanning electron microscopy coupled with image analysis. Total rabbit bone cells with large numbers of osteoclasts were cultured on dentin slices. The whole surface of the dentin slice was scanned and both the number of resorption pits and the total resorbed surface area were measured. Resorption pits appeared at 48 h and increased gradually up to 96 h. Despite the observation of a strong correlation between the total resorption area and the number of pits, we suggest that area measurement is the most relevant marker for osteoclastic activity. Osteotropic factors stimulating or inhibiting osteoclastic activity were used to test the variations in resorption activity as measured with our method. This reproducible and sensitive quantitative method is a valuable tool for screening for osteoclastic inhibitors and, more generally, for investigating bone modulators.