Strategies of treatment of Paget's disease with bisphosphonates.
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Alkaline Phosphatase↗
Biomedical subjects
S E Papapoulos
Publications and source records attributed to S E Papapoulos.
Malignancy-associated hypercalcaemia: resolution of controversies over vitamin D metabolism by a pathophysiological approach to the syndrome.
OBJECTIVE: Parathyroid hormone-related protein (PTHrP) is recognized as a major pathogenetic factor of humoral hypercalcaemia of malignancy but its action on vitamin D metabolism is controversial. Our aim was to study the relation between serum 1,25-dihydroxyvitamin D and humoral activity in malignancy-associated hypercalcaemia. DESIGN: Prospective, cross-sectional, single-centre study of patients with documented solid malignancies, hypercalcaemia and suppressed plasma PTH concentrations. PATIENTS AND METHODS: Vitamin D metabolites, PTH, nephrogenous cyclic AMP (N-cAMP), PTHrP and biochemical parameters of calcium and bone metabolism were measured in 39 patients with solid malignancies and hypercalcaemia and bone scans were performed. RESULTS: In 27 patients plasma PTHrP levels were elevated (69%) and in 9 patients (23%) serum 1,25-(OH)2D concentrations were not appropriately suppressed (> 92 pmol/l). Patients with plasma PTHrP levels below the upper limit of normal (< 1.6 pmol/l) had lower serum 1,25-(OH)2D concentrations than those with elevated levels (> 1.6 pmol/l) (47 +/- 6 vs 70 +/- 7 pmol/l, respectively; P < 0.04). Serum 1,25-(OH)2D concentrations were higher in patients with negative bone scans than in those with metastatic bone disease (80 +/- 9 vs 50 +/- 5 pmol/l; P < 0.01) and similar levels of plasma PTHrP. In the patients with negative bone scans there was a significant relation between plasma PTHrP and serum 1,25-(OH)2D (r = 0.51; P < 0.03) whereas there was no such correlation in those with a positive scan. CONCLUSION: Contrary to current belief, serum 1,25-(OH)2D concentrations are not generally suppressed in humoral hypercalcaemia of malignancy and PTHrP is a determinant of these levels in the absence of demonstrable bone metastases. These findings provide further insights into the pathophysiology of malignancy-associated hypercalcaemia and may help in the clinical management of these patients.
Aged↗
Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Effects of mutant gene dosage on phenotype.
Neonatal severe hyperparathyroidism is a rare life-threatening disorder characterized by very high serum calcium concentrations (> 15 mg/dl). Many cases have occurred in families with familial hypocalciuric hypercalcemia, a benign condition transmitted as a dominant trait. Among several hypothesized relationships between the two syndromes is the suggestion that neonatal severe hyperparathyroidism is the homozygous form of familial hypocalciuric hypercalcemia. To test this hypothesis, we refined the map location of the gene responsible for familial hypocalciuric hypercalcemia on chromosome 3q. Analyses in 11 families defined marker loci closely linked to the gene responsible for familial hypocalciuric hypercalcemia. These loci were then analyzed in four families with parental consanguinity and offspring with neonatal severe hyperparathyroidism. Each individual who was homozygous for loci that are closely linked to the gene responsible for familial hypocalciuric hypercalcemia had neonatal severe hyperparathyroidism. The calculated odds of linkage between these disorders of > 350,000:1 (lod score = 5.56). We conclude that dosage of the gene defect accounts for these widely disparate clinical phenotypes; a single defective allele causes familial hypocalciuric hypercalcemia, while two defective alleles causes neonatal severe hyperparathyroidism.
Chromosome Mapping↗
Inducible production of nitric oxide in osteoblast-like cells and in fetal mouse bone explants is associated with suppression of osteoclastic bone resorption.
Nitric oxide (NO) has been suggested to be involved in the regulation of osteoclast activity. Since osteoblasts, through the release of various factors, are the main regulators of osteoclastic resorption, first we have investigated whether osteoblast-like cells and fetal mouse long bone explants are able to produce NO. Second, we have assessed the effect of NO on osteoclastic resorption in whole bone cultures. In this study we show that primary rat osteoblast-like cells as well as the clonal rat osteoblast-like cell line UMR-106, stimulated with IFN-gamma together with TNF-alpha and LPS, produce NO, measured as nitrite production. IL-1 alpha enhanced while TGF-beta 2 inhibited TNF-alpha + IFN-gamma + LPS-stimulated NO production in UMR-106 cells dose dependently. Both the cytokines, however, had no effect when given alone. The competitive inhibitor of NO production, NG-monomethyl-arginine (L-NMMA), and cycloheximide abolished the increase in nitrite production induced by TNF-alpha + IFN-gamma + LPS, while hydrocortisone had no effect, as previously reported for chondrocytes. Calciotropic hormones had either no effect [1,25(OH)2D3] or had a small inhibitory effect (parathyroid hormone) on stimulated NO production. Furthermore, we found that in cultured fetal mouse long bone explants the combination of TNF-alpha + IFN-gamma + LPS as well as the NO donor sodium nitroprusside could inhibit osteoclastic resorption, measured as 45Ca release. The inhibition of resorption was prevented by concurrent administration of L-NMMA. Histological evaluation revealed that the TNF-alpha + IFN-gamma + LPS-induced inhibition of 45Ca release was associated with a decrease in the number of tartrate-resistant acid phosphatase-positive osteoclasts. We propose that the NO production by osteogenic cells (osteoblasts and chondrocytes) may represent an important regulatory mechanism of osteoclastic activity especially under pathological conditions characterized by release of bone-resorbing inflammatory cytokines.
Animals↗
Clinical and biochemical response to single infusion of pamidronate in patients with active rheumatoid arthritis: a double blind placebo controlled study.
OBJECTIVE: To assess the effects of 3-amino-1-hydroxypropylidine-1,1-bisphosphonate (pamidronate) in rheumatoid arthritis (RA). METHODS: Thirty patients with active RA were randomly allocated to receive a single intravenous infusion of placebo, 20 mg pamidronate, or 40 mg pamidronate. RESULTS: Pamidronate treatment resulted in a rapid and sustained reduction in urinary calcium and hydroxyproline excretions. A sustained reduction in serum corrected calcium was only noted in the group treated with 40 mg pamidronate. In both groups treated with pamidronate a temporary increase in serum parathyroid hormone was noted. Compared to the placebo group clinical variables of disease activity improved significantly in both groups treated with aminohydroxypropylidine bisphosphonate. The erythrocyte sedimentation rate and serum C-reactive protein levels improved significantly in patients treated with 40 mg pamidronate. No serious side effects were documented. CONCLUSION: A single infusion of pamidronate in patients with RA is safe, suppresses bone resorption, and reduces disease activity. It is suggested that the effect on disease activity is dose dependent.
Adult↗
Aminohydroxy propylidene bisphosphonate (APD) treatment improves the clinical skeletal manifestations of Gaucher's disease.
OBJECTIVE: To evaluate the long-term effects and safety of aminohydroxy propylidene bisphosphonate (APD) treatment on the frequency and severity of the clinical skeletal manifestations of Gaucher's disease. METHODOLOGY: Five adolescents who suffered from recurrent bone crisis episodes and atraumatic bone fractures due to Gaucher's disease were treated with APD for 14 to 83 months. RESULTS: During the 6 years before treatment, the patients suffered from 6 to 17 bone crisis episodes, or 1 to 2.8 episodes per patient per year. Three patients were free from bone crisis episodes during 14 to 32 months of ADP treatment, while two patients had two such episodes during 60 and 83 months of APD treatment (these represent a decrease in bone crisis episodes from 1 and 2.8 per year to 0.4 and 0.3 per year, respectively). Although four patients suffered from 1 to 3 atraumatic bone fractures during the 6 years preceding treatment (a total of 10 fractures), only one patient sustained a fracture on APD treatment (total of 219 months of treatment). Using APD was not associated with clinical side effects, biochemical aberrations, significant changes in liver and kidney function, or changes in serum levels of the hormones regulating mineral metabolism. In all patients, a band-like metaphyseal sclerosis appeared on radiography of the long bone. However, APD did not interfere with bone growth. CONCLUSIONS: The marked clinical improvement in the clinical skeletal manifestations of Gaucher's disease and the absence of toxic side effects in adolescent patients treated with APD support previous findings in three adult patients on the efficacy of APD and indicate possibilities for its use in inducing prolonged remissions in affected patients.
Adolescent↗
Dual photon absorptiometry for bone mineral measurements using a gamma camera.
A gamma camera was equipped with a special collimator and arm assembly for bone mineral measurements with dual photon absorptiometry (DPA). The system was evaluated in vitro and in vivo and compared both with a rectilinear DPA and a dual energy X-ray (DEXA) system. All 3 systems showed a linear response in measurements of 4 vials, containing different amounts of hydroxyapatite. Phantom measurements with the gamma camera system showed a precision of 1.6% to 2.8%. Results obtained in 8 healthy volunteers with rectilinear and gamma camera systems were well correlated (R2 = 0.78). With the photon beam directed from posterior to anterior, the separation of vertebrae was easy with the gamma camera system. We conclude that bone mineral measurements can be made with a gamma camera for assessment of fracture risk and in the decision process whether a patient needs treatment or not. For follow-up, the precision of DPA with a gamma camera is inadequate.
Absorptiometry, Photon↗
Bisphosphonates: pharmacology and effects on the growing skeleton.
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Bone Density↗
The role of bisphosphonates in the prevention and treatment of osteoporosis.
Bisphosphonates are synthetic compounds that are taken up preferentially by the skeleton and suppress osteoclast-mediated bone resorption. There are structural differences among the various bisphosphonates that account for considerable differences in antiresorptive potencies and in activity/toxicity ratios. Bisphosphonates are given to patients with established vertebral osteoporosis, either intermittently or continuously, but controlled, long-term data are only available for intermittent regimens. They decrease the rate of bone loss, increase spinal bone mineral density (BMD), and stabilize BMD for at least 4 years of treatment without any significant side effects. This increase in bone mass is not due to redistribution of calcium in the skeleton, as at sites with predominantly cortical bone, BMD values either do not change or increase with treatment. Bisphosphonates also appear to decrease the frequency of new vertebral fractures in some patients with established osteoporosis, but this effect needs to be verified. Other issues that need to be addressed include the optimal mode and dose of administration and hence the choice of bisphosphonate, the duration of treatment, the changes in bone metabolism following treatment arrest, and finally the efficacy of bisphosphonates in the prevention of hip fractures.
Bone Density↗
Improved treatment of Paget's disease with dimethylaminohydroxypropylidene bisphosphonate.
A group of 89 patients with Paget's disease of bone were treated with different intravenous or oral doses of the nitrogen-containing bisphosphonate dimethylaminohydroxypropylidene bisphosphonate (dimethyl-APD). Biochemical remission was obtained in 82% of treatments, and in the rest a clear response was found. Oral dimethyl-APD was well tolerated, and a dose of 200 mg/day for 10 days was sufficient to induce remission in the majority of patients. The remission probability was 3 months for 50% of patients, and the recurrence-free period was 27 months. The remission probability as well as the recurrence-free period did not differ among oral and intravenous treatments or among patients who had never been treated with nitrogen-containing bisphosphonates and those who had received pamidronate in the past and were treated for a recurrence of the disease. Dimethyl-APD is a very effective bisphosphonate devoid of side effects, which given for a short period can induce long-lasting remissions in patients with Paget's disease of bone.
Administration, Oral↗
Quantification of adherent and nonadherent cells cultured in 96-well plates using the supravital stain neutral red.
In this study we present a rapid, simple, sensitive, inexpensive, and environment-friendly assay for determination of the number of adherent or nonadherent cells cultured in 96-well plates using the supravital stain neutral red. We describe a validation of the method and demonstrate its application to study the effects of hormones (i.e., parathyroid hormone) and cytokines (i.e., tumor necrosis factor-alpha) on the growth of primary cultures of adherent osteoblast-like cells. In addition we show that this method can also be applied to conveniently determine proliferation of cells which grow in suspension, like the CTLL-2 and B-9 cells, which are widely used to measure IL-2 and IL-6 bioactivity, respectively. In these bioassays the changes in optical density induced by IL-2 and IL-6 measured with the neutral red assay are directly comparable with the relative changes measured with the [3H]thymidine incorporation assay. For all types of cells tested, the optical density at 550 nm was directly proportional to the number of cells. The assay, which can be used for different purposes, is an excellent alternative to already existing methods. It is not only easy to perform but also very reproducible, making it ideal for screening of large numbers of samples. Therefore this assay offers a reliable and flexible tool to determine both stimulatory and inhibitory effects of hormones, cytokines, and drugs on cell growth or to study the effects on cell viability.
Animals↗
Bisphosphonates in osteoporosis?
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Animals↗
Physicochemical considerations in the development and prevention of calcium oxalate urolithiasis.
Calcium oxalate urolithiasis is very common in western societies. In recent years significant progress has been made in identifying and quantitating physico-chemical processes involved in calcium oxalate urinary stone formation. The ability of urine to inhibit the agglomeration of calcium oxalate crystals is an important protective mechanism against stone formation. The process of crystal agglomeration is modulated to a large extent by citrate and it is disturbed in patients with hypocitraturia. Dietary factors, in particular high animal protein intake appear to affect adversely the ability of urine to inhibit calcium oxalate crystal agglomeration. Effective prevention of calcium oxalate urolithiasis should aim at restoring the urine's ability to inhibit the agglomeration of crystals and more emphasis should be given to dietary measures.
Calcium Oxalate↗
Urinary collagen crosslink excretion: a better index of bone resorption than hydroxyproline in Paget's disease of bone?
The 24 h urinary excretion of the collagen degradation products pyridinoline (Pyr) and deoxypyridinoline (Dpyr) have been proposed as specific and quantitative indices of bone resorption. We compared the value of the urinary excretion of Pyr and Dpyr to that of hydroxyproline (OHP) in 11 patients with Paget's disease of bone before and during treatment with inhibitors of bone resorption, during admission to a metabolic ward and maintenance on a gelatin-free diet. Pyr and Dpyr excretion rates were significantly correlated with those of OHP (r = 0.81 and 0.77, respectively, P < 0.001; n = 106). The rate and degree of suppression of bone resorption were monitored in 6 of the patients similarly treated with intravenous dimethyl-APD at a dose of 4 mg/day for 10 days, by daily measurements of the 24 h urinary excretion of Pyr, Dpyr and OHP. Treatment with dimethyl-APD resulted in a decrease in the three indices of bone resorption. The percentage change from baseline values was similar for the three indices, although changes in Dpyr appeared to follow more closely those of OHP. Our findings suggest that Pyr and Dpyr are useful and specific indices of bone resorption in Paget's disease of bone. They appear to confer no advantage, however, over the traditional determination of the urinary excretion of OHP, in the monitoring of response to treatment of such patients with inhibitors of bone resorption. Further studies are required to establish the value of these new biochemical indices of bone resorption, possibly in more subtle disorders of bone metabolism such as osteoporosis.
Amino Acids↗
Bone metabolism in rheumatoid arthritis; relation to disease activity.
Biochemical parameters of bone metabolism were investigated in 105 ambulant, non-steroid treated patients with RA and compared with parameters of disease activity. Urinary calcium (Ca) and hydroxyproline (OHP) excretions, as parameters of bone resorption and serum alkaline phosphatase (AP), as a parameter of bone formation, were positively related to parameters of disease activity. Serum osteocalcin, another parameter of bone formation, was not related to parameters of disease activity. Patients with active disease (ESR > or = 28 mm and Ritchie articular index > or = 8) had a significant higher urinary Ca and OHP excretion (62 and 42% higher, respectively) than patients with inactive disease. Serum AP and OC were slightly higher (19 and 16%, respectively) in patients with active disease. These results suggest that in RA patients bone metabolism is related to disease activity. In active disease bone resorption seems to be increased more than bone formation, suggesting that prolonged disease activity may contribute to generalized and/or localized osteopenia.
Adult↗
Palliative pamidronate treatment in patients with bone metastases from breast cancer.
PURPOSE: An open, randomized study was performed to assess the effects of supportive pamidronate treatment on morbidity from bone metastases in breast cancer patients. PATIENTS AND METHODS: Eighty-one pamidronate patients and 80 control patients were monitored for a median of 18 and 21 months, respectively, for events of skeletal morbidity and the radiologic course of metastatic bone disease. The oral pamidronate dose was 600 mg/d (high dose [HD]) during the earliest study years, then changed to 300 mg/d (low dose [LD]) because of gastrointestinal toxicity. Twenty-nine of 81 pamidronate (HD/LD) patients first received 600 mg/d and were then changed to 300 mg/d; 52 of 81 pamidronate LD patients received 300 mg/d throughout the study. Tumor treatment was unrestricted. RESULTS: An overall intent-to-treat analysis was performed. In the pamidronate group, the occurrence of hypercalcemia, severe bone pain, and symptomatic impending fractures decreased by 65%, 30%, and 50%, respectively; event-rates of systemic treatment and radiotherapy decreased by 35% (P < or = .02). The event-free period (EFP), radiologic course of disease, and survival did not improve. Subgroup analyses suggested a dose-dependent treatment effect. Compared with their controls, in pamidronate HD/LD patients, events occurred 60% to 90% less frequently (P < or = .03) and the EFP was prolonged (P = .002). In pamidronate LD patients, event-rates decreased by 15% to 45% (P < or = .04). Gastrointestinal toxicity of pamidronate caused a 23% drop-out rate, but other cancer-associated factors seemed to contribute to this toxicity. CONCLUSION: Pamidronate treatment of breast cancer patients efficaciously reduced skeletal morbidity. The effect appeared to be dose-dependent. Further research on dose and mode of treatment is mandatory.
Bone Neoplasms↗
The effect of tissue type plasminogen activator (tPA) on osteoclastic resorption in embryonic mouse long bone explants: a possible role for the growth factor domain of tPA.
Osteoblasts produce proteolytic enzymes and their production is regulated by osteotropic agents. It has been suggested that these proteases play a role in bone resorption by removing the superficial collagenous layer from the bone matrix and indirectly inducing migration of osteoclast precursors towards the bone matrix. We examined the effect of the plasminogen activator tPA on osteoclastic resorption using 17-day-old mouse embryonic long bone explants representing different stages of osteoclast development, that is, radii containing already mature osteoclasts and metacarpals containing no mature osteoclasts but only osteoclast precursors/progenitors which are still confined to the periosteum. Tissue type PA stimulated osteoclastic resorption (measured as 45Ca-release) in 17-day-old fetal metacarpals but not in radii of the same animal. Blocking the enzymatic activity of tPA did not inhibit its effect on osteoclastic resorption. Plasmin, the direct product of PA enzymatic activity, did not induce osteoclastic resorption. However, a tPA-mutant missing the growth-factor-like domain of the molecule, failed to stimulate 45Ca-release from the metacarpals. In addition, in both systems tPA and transforming growth factor alpha had similar effects on osteoclastic resorption. The finding that tPA stimulated 45Ca-release only in the metacarpals suggests that tPA has an effect on osteoclast formation rather than on the activity of already mature osteoclasts. Under the experimental conditions used this effect seems to be mediated by the growth factor domain of tPA rather than by the enzymatic activity of the molecule.
Amino Acid Chloromethyl Ketones↗
Modulation of tumour-induced bone resorption by bisphosphonates.
Tumour cells produce systemic or local factors which can stimulate osteoclast development and activity leading to increased bone resorption. The clinical consequences are bone pain, fractures and hypercalcaemia. Inhibitors of osteoclast-mediated bone resorption, such as the bisphosphonates, are now the treatment of choice for tumour-induced hypercalcaemia. Recent evidence indicates that these compounds, especially the newer ones, reduce skeletal morbidity in patients with metastatic bone disease and improve their quality of life. Better understanding of the mechanisms underlying tumour-induced bone resorption and development of more potent and less toxic bisphosphonates will lead to improved management of patients with malignant diseases involving the skeleton.
Bone Resorption↗