Risk factors for multi-joint disease in patients with glucocorticoid-induced osteonecrosis.

This study investigated risk factors for osteonecrosis involving multiple joints (MJON) among glucocorticoid-treated patients. The best predictor of MJON was cumulative oral glucocorticoid dose. Risk of MJON was 12-fold higher in patients who had a second risk factor for osteonecrosis. Further research is needed into strategies for prevention of MJON. INTRODUCTION: Osteonecrosis (ON) is a debilitating musculoskeletal condition in which bone cell death can lead to mechanical failure. When multiple joints are affected, pain and disability are compounded. Glucocorticoid treatment is one of the most common predisposing factors for ON. This study investigated risk factors for ON involving multiple joints (MJON) among glucocorticoid-treated patients. METHODS: Fifty-five adults with glucocorticoid-induced ON were prospectively enrolled. MJON was defined as ON in ≥ three joints. Route, dose, duration, and timing of glucocorticoid treatment were assessed. RESULTS: Mean age of enrolled subjects was 44 years, 58% were women. Half had underlying conditions associated with increased ON risk: systemic lupus erythematosus (29%), acute lymphoblastic leukemia (11%), HIV (9%), and alcohol use (4%). Mean daily oral dose of glucocorticoids was 29 mg. Average cumulative oral dose was 30 g over 5 years. The best predictor of MJON was cumulative oral glucocorticoid dose. For each increase of 1,000 mg, risk of MJON increased by 3.2% (95% CI 1.03, 1.67). Glucocorticoid exposure in the first 6 months of therapy, peak dose (oral or IV), and mean daily dose did not independently increase risk of MJON. The risk of MJON was 12-fold in patients who had a second risk factor (95% CI 3.2, 44.4). CONCLUSIONS: Among patients with glucocorticoid-induced ON, cumulative oral dose was the best predictor of multi-joint disease; initial doses of IV and oral glucocorticoids did not independently increase risk. Further research is needed to better define optimal strategies for prevention and treatment of MJON.

Low volumetric bone density is a risk factor for early complications after spine fusion surgery.

This study aims to investigate lumbar spine (LS) volumetric bone density (vBMD) as a risk factor for complications (pseudoarthrosis, instrumentation failure, adjacent fractures), re-operation, and time to complication after fusion. INTRODUCTION: Lumbar spine (LS) fusion surgery is increasingly performed worldwide. Complications after fusion result in significant morbidity and healthcare costs. Multiple factors, including osteoporosis, have been suggested to contribute to risk of complications and re-operation. However, most studies have used DXA, which is subject to artifact in patients with spine pathology, and none have investigated the relationship between BMD and timing of post-operative complications. This study aims to investigate LS volumetric bone density (vBMD) as a risk factor for complications (pseudoarthrosis, instrumentation failure, adjacent fractures), re-operation, and time to complication after fusion. METHODS: We evaluated a cohort of 359 patients who had initial LS fusion surgery at our institution, had pre-operative LS CTs and post-operative imaging available for review. Demographic factors, smoking status, vBMD, and details of surgical procedure were related to likelihood and timing of post-operative complications. RESULTS: Mean age was 60 ± 14 years, vBMD 122 ± 37 g/cm3. Median follow-up was 11 months. Skeletal complications occurred in 47 patients (13%); 34 patients (10%) required re-operation. Low vBMD (directly measured and estimated using HU) and smoking were associated with increased risk of skeletal complications. Each increase in baseline vBMD of 10 g/cm3 decreased the complication hazard and increased the complication-free duration in time-to-event analysis (hazard ratio 0.91, 95% CI 0.83-0.98, p < 0.02). CONCLUSIONS: Low vBMD was a significant risk factor for early post-operative complications in patients undergoing LS fusion. Prospective studies are needed to confirm these findings and to elucidate the optimal timing for follow-up and strategies for prevention of post-operative complications in this population.

The 25(OH)D level needed to maintain a favorable bisphosphonate response is ≥33 ng/ml.

UNLABELLED: Why only some osteoporotic patients maintain response to prolonged bisphosphonate therapy is unknown. We examined bisphosphonate response and its association with serum 25 hydroxy vitamin D (25(OH)D) level in a "real world" setting. Serum 25(OH)D level was strongly associated with maintaining bisphosphonate response arguing that vitamin D may be involved in optimizing prolonged bisphosphonate therapy. INTRODUCTION: This study examined the maintenance of bisphosphonate response in the "real world" setting and the association between 25(OH)D and bisphosphonate response using an established composite definition of response. METHODS: Postmenopausal women with low bone mineral density (BMD) treated with bisphosphonates were identified from two New York City practices. Patients were excluded for a history of chronic steroid use, metabolic bone disease, or bisphosphonate non-adherence. Patients were categorized as bisphosphonate non-responders if they had a T-score < -3 that persisted between dual-energy X-ray absorptiometry (DEXA) scans, a >3% decrease in BMD, or an incident fracture on bisphosphonate therapy, criteria based on the EUROFORS trial. Demographic and clinical data including mean 25(OH)D levels between DEXA scans were obtained. Mean 25(OH)D levels were compared between responders and non-responders and multiple logistic regression analysis was performed to identify factors associated with non-response. RESULTS: A total of 210 patients were studied. A favorable response to bisphosphonate therapy was seen in 47% (N = 99/210). Patients with a mean 25(OH)D ≥33 ng/ml had a ~4.5-fold greater odds of a favorable response (P < 0.0001). 25(OH)D level was significantly associated with response - a 1 ng/ml decrease in 25(OH)D was associated with ~5% decrease in odds of responding (odds ratio = 0.95; 95% confidence interval, 0.92-0.98; P = 0.0006). CONCLUSIONS: Patients with a mean 25(OH)D ≥33 ng/ml had a substantially greater likelihood of maintaining bisphosphonate response. This threshold level of 25(OH)D is higher than that considered adequate by the Institute of Medicine, arguing that higher levels may be required for specific therapeutic outcomes.

Lymphokine-mediated bone resorption requires endogenous prostaglandin synthesis.

Enhanced synthesis of prostaglandin (PG) E by explanted fetal rat bones was initiated by lymphocyte-conditioned media but not by physiological levels of parathyroid hormone. Rapid release of PGE from bone occurred only when the lymphokine was present. Synthesis of PGE preceded and was necessary for the bone resorption caused by the lymphokine preparation. Local production of prostaglandins in response to inflammatory cell or tumor-derived factors may in part be responsible for the localized bone loss that occurs in certain pathological states.

Limitation of excessive myelopoiesis by the intrinsic modulation of macrophage-derived prostaglandin E.

The clonal proliferation of the committed granulocyte-macrophage stem cell is controlled by a balance between mutually opposing factors, colony stimulating factor and prostaglandin E, both of monocyte-macrophage derivation. Increases beyond a critical concentration of colony stimulating factor within the local milieu of the mononuclear phagocyte induces the coincident elaboration of prostaglandin E, a self-regulated response which serves to limit the unopposed humoral stimulation of myelopoiesis.

Stage-dependent reduction in T colony formation in Hodgkin's disease. Coincidence with monocyte synthesis of prostaglandins.

Prostaglandin synthesis and T lymphocyte colony formation have been examined in previously untreated patients with Hodgkin's disease. Mononuclear cells have been isolated from peripheral blood and spleens of these patients. Significant augmentation in prostaglandin E levels were noted in the mononuclear cell cutures from Hodgkin's disease patients compared with controls (1.64 +/- 0.29 vs. 0.39 +/- 0.09 ng/10(6) cells, P < 0.005). Measured prostaglandin E levels increased with advancing stage of disease. Virtually all of the prostaglandins were synthesized by the adherent monocyte cell population. Prostaglandin E was the major product. Clonal expansion of a T lymphocyte precursor cell, which gives rise to colonies > 50 cells, was determined by a layered soft agar method. T colony formation was significantly reduced in patients with stage II, III, and IV disease. There were progressively reduced colony numbers seen with advancing stage of disease (609 +/- 209, 416 +/- 158, 207 +/- 58 compared with normals 2,274 +/- 360 colonies/10(6) cells plated; P < 0.005). The addition of inhibitors of endogenous prostaglandin synthesis resulted in significant augmentation of T colony number. However, a consistent relative decrease in T colony number was seen even when endogenous prostaglandin E synthesis was blocked. It would appear that both the prostaglandin-dependent and independent T colony precursor cells are lost with progressive stage of disease. A causative role of augmented prostaglandin synthesis in this stage-dependent reduction of T colony formation could not be established.

Prostaglandin E inhibition of T-lymphocyte colony formation: a possible mechanism of monocyte modulation of clonal expansion.

Prostaglandin and monocyte modulation of a T-lymphocyte cell capable of undergoing clonal expansion was studied. Circulating human mononuclear cells were isolated by density centrifugation. After 24 h in culture with phytohemagglutinin present, the cells were mixed with 0.3% agar and overlayed onto a 0.5% agar layer that contained media and phytohemagglutinin. At day 6, colonies that contained greater than 50 cells were counted. These colonies represented clonal prolifertion of a phytohemagglutinin-responsive T-lymphocyte precursor. This responder cell accounted for less than 0.3% of the starting cell population. Colonies were comprised of cells which, when isolated, formed E rosettes. These colony cells could be shown to have helper or suppressor function as measured by their ability to promote or inhibit immunoglobulin synthesis. By these latter criteria the colony cells were considered to be mature T lymphocytes. The addition of prostaglandin E to the cultures demonstrated a linear, r = 0.82, dose-dependent inhibition of colony formation with a 50% point of inhibition (I50) = 0.18 muM. Low numbers of normal monocytes when added to the cultures mimicked the effect of synthetic prostaglandin E2. A highly significant correlation could be shown for endogenous prostaglandin E levels and colony counts. It appears that monocytes through their synthesis of prostaglandin E2 can restrict the clonal expansion of a circulating T-lymphocyte precursor.

Gallium nitrate inhibits calcium resorption from bone and is effective treatment for cancer-related hypercalcemia.

Approximately two-thirds of patients who receive the anticancer drug gallium nitrate develop mild hypocalcemia. To evaluate the mechanism of drug-induced hypocalcemia, we tested the effects of gallium nitrate upon in vitro release of 45Ca++ from explanted fetal rat bones. The drug significantly inhibited 45Ca++ release in response to stimulation with both parathyroid hormone and a lymphokine preparation with osteoclast activating factor activity. The inhibitory effects on bone resorption were both time- and dose-dependent. Later, in a pilot study, we treated 10 patients who had cancer-related hypercalcemia with gallium nitrate administered by continuous infusion. All patients responded by a reduction of total serum calcium to normal or subnormal concentrations (13.8 +/- 1.05 mg/dl, mean +/- SD pretreatment, to 8.03 +/- 1.03 mg/dl, mean posttreatment nadir). Our results indicate that gallium nitrate effectively treats cancer-related hypercalcemia and that it probably acts by inhibiting calcium release from bone.

Gallium nitrate for acute treatment of cancer-related hypercalcemia: clinicopharmacological and dose response analysis.

Current treatment of cancer-related hypercalcemia is limited by agents of limited effectiveness or excessive toxicity. Gallium nitrate is a new drug which both inhibits bone resorption and increases calcium content of bone. We have now treated 39 episodes of hypercalcemia with gallium nitrate administered as a continuous i.v. infusion for 5-7 days at 3 daily dose levels (100 and 200 mg/m2, and 50 mg/m2 by brief infusion followed by 150 mg/m2). Nadir calcium values were significantly lower (9.2 +/- 1.5 mg/dl) for patients who received the highest dose relative to patients who received the lowest dose (10.5 +/- 1.6 mg/dl, P less than 0.001). While the actual percentage of patients who achieved normocalcemia was higher at the highest dose relative to the lowest dose (86 versus 60%), this difference was not statistically significant. Mean serum concentration of inorganic phosphorous declined significantly for all patients from 2.9 +/- 0.86 mg/dl at base line to 1.8 +/- 0.66 mg/dl (P less than 0.001). Pharmacokinetic studies suggested that a threshold plasma gallium concentration of approximately 1 microgram/ml must be attained to achieve acute normalization of elevated serum calcium levels. Steady-state plasma gallium levels were attained after 48 h; there was no evidence of drug accumulation in plasma after 2 days. Effects on serum creatinine concentration were negligible, and there were no other toxic reactions. These data confirm preclinical experiments which suggested that inhibition of bone resorption by gallium nitrate is dependent upon the dose and duration of drug exposure. We conclude that gallium nitrate is effective treatment for cancer-related hypercalcemia. The drug is now being evaluated against standard treatment in a randomized, double-blind trial.

In vivo and in vitro biological activities of two human cell lines derived from anaplastic lung cancers.

Cell lines Lu-65 and SK-Luci-6 were established from two patients with anaplastic (non-oat cell) lung cancers. These cell lines showed in vivo and in vitro functional activities that could explain the paraneoplastic syndromes which were clinically manifested. In both patients, elevated white blood cell counts occurred in the absence of any evidence of sepsis. Tumor fragments taken directly from one patient and transplanted to nude mice produced a progressive leukocytosis in the mice. Tissue culture-derived cells from both cell lines enhanced white blood cell numbers following heterotransplantation to nude mice. Cell-free extracts from both cell lines were found to enhance granulocyte-macrophage colony formation in soft agar. Greater colony formation was consistently found with the cell line (SK-Luci-6) that was derived from the patient manifesting the more marked leukocytosis. These data suggest that the tumor cells release colony-stimulating activities. Coincidently, one cell line (Lu-65) synthesized and released large amounts of prostaglandin E2 with little or no other prostaglandin product; the other cell line produced no prostaglandins. When the tumor cell lines were cocultured with explanted fetal rat bones, enhanced bone resorption with excessive calcium release occurred. Bone-resorbing activity correlated with tumor prostaglandin synthesis for the cell line releasing prostaglandin E2. An osteolytic factor that was neither prostaglandin nor parathyroid hormone was released by the SK-Luci-6 cell line. Hypercalcemia was a persistent feature only in the patient from whom the latter tumor line was derived.

Tumor necrosis factor-alpha stimulates phosphatidylinositol breakdown by phospholipase C to coordinately increase the levels of diacylglycerol, free arachidonic acid and prostaglandins in an osteoblast (MC3T3-E1) cell line.

The effects of (human recombinant) tumor necrosis factor-alpha on phosphatidylinositol breakdown, release of 1,2-diacylglycerols, mobilization of arachidonate from diacylglycerol and prostaglandin synthesis were examined in a model osteoblast cell line (MC3T3-E1). Tumor necrosis factor-alpha (10 nM) caused a specific (30%) decrease in the mass of phosphatidylinositol (and no other phospholipids) within 30 min of exposure. Tumor necrosis factor-alpha doubled the rate of incorporation of [32P]orthophosphoric acid into phosphatidylinositol, indicating that the turnover of inositol phosphate was enhanced, and increased the content of diacylglycerol in parallel with phosphatidylinositol breakdown. The cytokine (10-50 nM; 4 h) also promoted a specific release of 24-34% of the [3H]arachidonate from prelabeled phosphatidylinositol, a release of 80% of the 3H-fatty acid from the diacylglycerol pool, and a 30-fold increase in the synthesis of prostaglandin E2. The tumor necrosis factor-alpha induced liberation of [3H]arachidonate from diacylglycerol, cellular arachidonate release and the synthesis of prostaglandin E2 were each blocked by an inhibitor of diacylglycerol lipase, the compound RHC 80267 (30 microM). Therefore, we conclude that, in the MC3T3-E1 cell line, tumor necrosis factor-alpha activates a phosphatidylinositol-specific phospholipase C (phosphatidylinositol inositolphosphohydrolase; EC 3.1.4.3) to release diacylglycerol, and increases the metabolism of diacylglycerol to liberate arachidonate for prostaglandin synthesis.

Characterization of prostaglandin endoperoxide synthase from a human cell line.

Prostaglandin endoperoxide synthase has been purified from the recently established human lung tumor cell line, Lu-65. By gel filtration, the purified enzyme migrated with a relative molecular weight of 115,000, unlike the ovine enzyme, which migrated at 155,000. Two protein bands of 45,000 and 68,000 were seen when the purified Lu-65 enzyme was fractionated under reducing conditions by SDS-polyacrylamide gel electrophoresis; in contrast, purified ovine prostaglandin endoperoxide synthase showed the Mr 68,000 band under the same conditions. The purified Lu-65 enzyme showed both cyclooxygenase and hydroperoxidase activities, and metabolized [3H]arachidonic acid to 3H-labeled products that, when separated by reverse-phase HPLC, co-eluted with authentic prostaglandin D2 and prostaglandin E2. An apparent Km for arachidonic acid of 3 mM was measured for the purified enzyme, and the crude membrane-bound enzyme showed an apparent Km of 1.6 mM. Under the same conditions, an apparent Km of 17 microM was measured for the purified ovine enzyme.

Gallium nitrate inhibits accelerated bone turnover in patients with bone metastases.

Bone metastases are a major source of morbidity in patients with cancer. Previously, we found that gallium nitrate was a highly effective treatment for cancer-related hypercalcemia. Laboratory studies have shown that this drug inhibits bone resorption in vitro and that short-term treatment in vivo increases the calcium content of bone. We evaluated the clinical effects of gallium nitrate on biochemical parameters of increased bone turnover in 22 patients with bone metastases. Treatment with gallium nitrate for five to seven days caused a median reduction in 24-hour urinary calcium excretion of 66% relative to baseline measurements (P less than .01). Hydroxyproline (OHP) excretion was also significantly reduced (P less than .01). The greatest reduction in hydroxyprolinuria occurred in patients with high baseline excretion. Ionized serum calcium and serum phosphorous declined significantly after treatment (P less than .01 for each). Serum immunoreactive parathyroid hormone (PTH) increased significantly (P less than .01), as did serum levels of 1,25 (OH)2-vitamin D3 (P less than .05). Urinary phosphorous excretion and serum levels of 25-OH-vitamin D3 were not significantly changed. No major toxic reactions occurred as a result of this treatment. These results indicate that gallium nitrate significantly reduces biochemical parameters associated with accelerated bone turnover and that this agent may be useful for preventing pathologic conditions associated with bone metastases.

Maintenance etidronate in the prevention of malignancy-associated hypercalcemia.

Normocalcemic patients with cancer who had been successfully treated for an episode of hypercalcemia were enrolled in a randomized, multisite, double-blind, placebo-controlled trial designed to determine the efficacy of maintenance oral etidronate in preventing the recurrence of moderate to severe hypercalcemia (serum calcium level, greater than 11.5 mg/dL [greater than 2.87 mmol/L]). Ten (40%) of 25 etidronate-treated patients and 17 (46%) of 37 placebo-treated patients had recurrence of hypercalcemia within 150 days. Although patients taking etidronate had a longer time to the development of hypercalcemia (median, 55 days vs 28 days), this was not significantly different from the control group. The high attrition rate in this trial from hypercalcemia and other malignancy-related causes represents a major difficulty in conducting studies with agents that may require prolonged administration before producing a therapeutic effect.

Gallium nitrate regulates rat osteoblast expression of osteocalcin protein and mRNA levels.

Gallium nitrate, a group IIIa metal salt, has been found to be clinically effective for the treatment of accelerated bone resorption in cancer-related hypercalcemia and Paget's disease. Here we report the effects of gallium nitrate on osteocalcin mRNA and protein levels on the rat osteoblast-like cell line ROS 17/2.8. Gallium nitrate reduced both constitutive and vitamin D3-stimulated osteocalcin protein levels in culture medium by one-half and osteocalcin mRNA levels to one-third to one-tenth of control. Gallium nitrate also inhibited vitamin D3 stimulation of osteocalcin and osteopontin mRNA levels but did not affect constitutive osteopontin mRNA levels. Among several different metals examined, gallium was unique in its ability to reduce osteocalcin mRNA levels without decreasing levels of other mRNAs synthesized by ROS 17/2.8 cells. The effects of gallium nitrate on osteocalcin mRNA and protein synthesis mimic those seen when ROS 17/2.8 cells are exposed to transforming growth factor beta 1 (TGF beta 1); however, TGF-beta 1 was not detected in gallium nitrate-treated ROS 17/2.8 cell media. Use of the RNA polymerase II inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole demonstrated that gallium nitrate did not alter the stability of osteocalcin mRNA. Transient transfection assays using the rat osteocalcin promoter linked to the bacterial reporter gene chloramphenicol acetyltransferase indicated that gallium nitrate blocked reporter gene expression stimulated by the osteocalcin promoter. This is the first reported effect of gallium nitrate on isolated osteoblast cells.

Role of protein kinase A in collagenase-1 gene regulation by prostaglandin E1: studies in a rabbit synoviocyte cell line, HIG-82.

Gene expression of the matrix-degrading enzyme collagenase-1 in rabbit synoviocytes and human fibroblasts is down-regulated by prostaglandin E1 (PGE1) through a cyclic adenosine monophosphate (cAMP)-dependent pathway. In the current study, we examined the role of protein kinase A (PKA) in the PGE1-mediated effect on collagenase-1 gene expression. Collagenase-1 gene expression was rapidly induced several-fold above control both by a phorbol ester, 12-o-tetradecanoyl phorbol 13 acetate, and interleukin-1 beta (IL-1 beta) in HIG-82 synoviocytes. Treatment with PGE1 and forskolin increased PKA activity in the HIG-82 cells within 15 minutes of adding the stimulating agents. Two inhibitors of PKA, the isoquinoline-sulfonamide derivative, H-89 and a cAMP analog, RpcAMP, blocked the ability of PGE1 to down-regulate collagenase-1 gene expression. However, if PGE1 was added from 6 h to 30 minutes before the PKA inhibitor H-89, collagenase-1 gene expression was inhibited. Constitutive PKA activity was increased in HIG-82 synoviocytes stably transfected with an expression vector pCMV.C alpha that caused the HIG-82 cells to overexpress an active catalytic subunit of PKA. Cells stably transfected with an inactive, mutated C-alpha-variant showed no change in PKA activity. Collagenase-1 mRNA levels in TPA-stimulated cells were reduced to baseline levels in the pCMV.C alpha but not in the mutated C-alpha-transfected cells. These data show the importance of PKA in regulating collagenase-1 gene expression in a synoviocyte cell line.

Bone strength and related traits in HcB/Dem recombinant congenic mice.

Fracture susceptibility depends jointly on bone mineral content (BMC), gross bone anatomy, and bone microarchitecture and quality. Overall, it has been estimated that 50-70% of bone strength is determined genetically. Because of the difficulty of performing studies of the genetics of bone strength in humans, we have used the HcB/Dem series of recombinant congenic (RC) mice to investigate this phenotype. We performed a comprehensive phenotypic analysis of the HcB/Dem strains including morphological analysis of long bones, measurement of ash percentage, and biomechanical testing. Body mass, ash percentage, and moment of inertia each correlated moderately but imperfectly with biomechanical performance. Several chromosome regions, on chromosomes 1, 2, 8, 10, 11, and 12, show sufficient evidence of linkage to warrant closer examination in further crosses. These studies support the view that mineral content, diaphyseal diameter, and additional nonmineral material properties contributing to overall bone strength are controlled by distinct sets of genes. Moreover, the mapping data are consistent with the existence of pleiotropic loci for bone strength-related phenotypes. These findings show the importance of factors other than mineral content in determining skeletal performance and that these factors can be dissected genetically.

Prostaglandin E1 inhibits collagenase gene expression in rabbit synoviocytes and human fibroblasts.

Cartilage breakdown, as seen in inflammatory and degenerative joint diseases, can be mediated by proteolytic enzymes, such as the metalloproteinase collagenase, the only enzyme able to digest collagen at neutral pH. In vitro collagenase gene expression can be stimulated by the phorbol ester tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate. We have investigated the effect of prostaglandin E1 (PGE1) on 12-O-tetradecanoyl-phorbol-13-acetate-stimulated collagenase mRNA levels in the rabbit synoviocyte cell line HIG-82. PGE1, but not PGE2 or PGF2 alpha, was able to selectively reduce collagenase mRNA levels in a dose-dependent fashion. PGE1 markedly increased intracellular levels of cAMP, while PGE2 and PGF2 alpha had little or no effect on cAMP production in the HIG-82 synoviocytes. Agents known to increase intracellular cAMP levels, such as the adenyl cyclase activator forskolin and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), mimicked the effect of PGE1, on collagenase mRNA levels. PGE1, forskolin, and IBMX also decreased collagenase mRNA levels in human skin fibroblasts, demonstrating that this observation was not unique to the HIG-82 cell line. Transient transfection experiments carried out in HIG-82 cells using a 1.2-kilobase portion of the 5'-flanking region of the human collagenase gene linked to the reporter gene luciferase demonstrated that PGE1, forskolin, and IBMX exert their inhibitory effect on the promoter region of the collagenase gene.

A multicenter trial of low dose gallium nitrate in patients with advanced Paget's disease of bone.

Gallium nitrate is a potent antiresorptive drug that has been extensively tested in patients with accelerated bone turnover. We have evaluated the effects of this new agent in a pilot multicenter trial of 49 patients with advanced Paget's disease of bone. Patients were randomized to receive 0.05, 0.25, or 0.5 mg/kg.day gallium nitrate administered by sc injection in two 14-day cycles. Serum alkaline phosphatase, fasting 2-h urinary hydroxyproline and N- telopeptide collagen cross-links excretion, and quality of life were assessed every 2 weeks for 12 weeks. The group mean alkaline phosphatase activity at baseline was 854 +/- 100 (+/- SEM) IU/L. The mean changes from baseline to week 12 in serum alkaline phosphatase were +0.5%, -24%, and -31%, respectively, for the three doses tested. The differences for each of the higher dose levels (0.25 and 0.5 mg/kg.day) was statistically significant (P < or = 0.05), and nearly half of the patients treated with the 0.5 mg/kg.day dose achieved a 50% or more reduction in enzyme activity. The nadir value in hydroxyproline excretion occurred at 10 weeks, with mean changes of +9%, -10%, and -17% for the 0.05, 0.25, and 0.5 mg/kg.day doses, respectively; the difference was significant only at the 0.5 mg/kg.day level (P < 0.01). Urinary collagen cross-link excretion showed a significant decrease at the 0.25 and 0.5 mg/kg.day doses. We also observed a definite, but nonsignificant, trend for improved quality of life in patients treated at the highest drug dose. Minor discomfort at the injection site was frequently reported, but did not lead to interruption of therapy. Our results in these patients who had received moderate to extensive prior therapies with other drugs show that cyclical, low dose, sc administration of gallium nitrate is safe and effective for treating patients with advanced Paget's disease of bone.