calcitonin and Osteitis-Deformans

Salmon calcitonin, available as a therapeutic agent for more than 30 years, demonstrates clinical utility in the treatment of such metabolic bone diseases as osteoporosis and Paget's disease, and potentially in the treatment of osteoarthritis. This review considers the physiology and pharmacology of salmon calcitonin, the evidence based research demonstrating efficacy and safety of this medication in postmenopausal osteoporosis with potentially an effect on bone quality to explain its abilities to reduce the risk of spine fracture, the development of an oral salmon calcitonin preparation, and the therapeutic rationale for this preparation's chondroprotective effect in osteoarthritis.

Topics: Adult; Aged; Bone Density; Bone Density Conservation Agents; Bone Resorption; Calcitonin; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Middle Aged; Osteitis Deformans; Osteoporosis, Postmenopausal; Parathyroid Hormone; Spinal Fractures; Treatment Outcome

Topics: Aged; Bone Density Conservation Agents; Calcitonin; Diphosphonates; Humans; Male; Osteitis Deformans

Calcitonin (CT) inhibits osteoclast-mediated bone resorption and is being used to treat Paget's disease of bone, hypercalcemia of malignancy and postmenopausal osteoporosis. The formation of antibodies against heterologuous calcitonins like salmon calcitonin (sCT) is common and occurs in 40-70% of the patients treated for more than 4 months. Not all of these patients, however, develop a secondary resistance to sCT, therefore the clinical significance of sCT antibodies is discussed controversially. In vivo and in vitro approaches demonstrate a neutralizing effect in 35 to 60% of the patient sera with antibodies against sCT. These neutralizing antibodies appear to explain most cases of clinically relevant secondary resistance to sCT treatment, which occurs in 25-45% of the patients after treatment periods of 6 months and longer. A positive treatment response to human CT after development of secondary resistance to sCT proves the diagnosis of antibody related resistance. Few cases develop secondary resistance in the absence of sCT binding antibodies, the mechanism of this phenomenon is unclear. Antibody related resistance is a significant problem in long term treatment with sCT. Especially in conditions like postmenopausal osteoporosis, where no readily accessable marker of treatment response is available, the development of sCT antibodies and their possible neutralizing effect has to be considered.

Topics: Animals; Antibodies; Calcitonin; Drug Resistance; Female; Humans; Hypercalcemia; Neoplasms; Osteitis Deformans; Osteoporosis, Postmenopausal

Many papers were published on both Paget's disease and fibrous dysplasia during the past year. In Paget's disease, evidence for a generalized, probably viral disorder of the skeleton has been adduced, although focal radiologic features dominate the clinical picture. Unusual clinical manifestations were highlighted in several clinical reports. A search for biochemical abnormalities other than increased serum alkaline phosphatase and urinary hydroxyproline levels yielded evidence for secondary hyperparathyroidism in many cases, and also, a confusing array of abnormalities in vitamin D metabolite levels. The application of newer imaging techniques such as computed tomography, MR imaging, bone marrow scintigraphy, and thermography was reported. The year's reports particularly highlighted new forms of effective therapy, including intranasal calcitonin, second- and third-generation bisphosphonates, and gallium nitrate. Finally, the feasibility of joint replacement in arthritic joints secondary to Paget's disease was again documented. Fibrous dysplasia continued to be an enigmatic disorder with no new insights as to etiology. Reports of unusual clinical features, imaging characteristics, bony distribution, and an array of endocrine linkages were prominent. A highlight of the year's reports was the discovery of an increased female sex steroid receptor number of dysplastic cells, and the possibility that sex steroids linked to their receptors may be responsible for the bony overgrowth. Concern was again expressed as to the possibility of malignant transformation of dysplastic lesions and the possible contribution of radiotherapy treatment to sarcoma development.

Topics: Calcitonin; Endocrine System Diseases; Fibrous Dysplasia of Bone; Humans; Osteitis Deformans; Vitamin D

Clinical interest in salmon calcitonin began in 1972 when this peptide was shown to be effective in the treatment of Paget's disease. Salmon calcitonin is more potent than porcine calcitonin, with human calcitonin intermediate in potency. Salmon calcitonin is a highly effective therapeutic agent in the treatment of Paget's disease. During chronic treatment with salmon calcitonin, alkaline phosphatase activity and urinary hydroxyproline excretion decrease on an average of 50% in patients with Paget's disease. Patients may experience a variety of clinical benefits during chronic treatment, including relief of bone pain, a reversal of neurological deficits, stabilization or improvement of hearing loss, and improvement of vascularity of bone. Radiologic healing of osteolytic lesions in particularly striking with calcitonin treatment. Paget's disease patients prefer treatment with salmon calcitonin administered by means of a nasal spray. Salmon calcitonin has an excellent safety profile and produces mild side effects in a small percentage of patients. The most common side effects associated with salmon calcitonin administration are nausea and facial flushing. It is unusual to observe severe side effects. In about 20% of patients, production of antibodies may neutralize the effects of the exogenously administered calcitonin; these patients respond to human calcitonin. At this time salmon calcitonin should still be considered a valuable therapeutic agent in the treatment of Paget's disease, particularly in patients with osteolytic lesions.

Topics: Calcitonin; Humans; Osteitis Deformans

In most countries, calcitonin is available in the form of injections, and less frequently as an intranasal spray. An oral route of administration should improve compliance. In a preliminary feasibility study, we have compared the acute biological action of injectable salmon calcitonin (50 IU), with the injectable calcitonin analogue ASC 710 (0.2 mg) and oral ASC 710 (20 mg) in 6 patients suffering from active Paget's disease of bone. The intensity and duration of the biological response were not significantly different in the 3 modes of therapy. In conclusion, the oral calcitonin analogue ASC 710 possesses an antiresorbing activity in Paget's disease comparable to that of an injection of salmon calcitonin which demonstrates that it can cross the intestinal barrier.

Topics: Administration, Intranasal; Administration, Oral; Aged; Bone Resorption; Calcitonin; Chromatography, High Pressure Liquid; Feasibility Studies; Female; Humans; Injections, Subcutaneous; Male; Middle Aged; Osteitis Deformans

The purpose of this study was to establish the smallest dose of nasally administered salmon calcitonin (SCT) which, if given in conjunction with a previously published calcium/thiazide treatment, would be as effective as parenteral SCT in the treatment of Paget's disease of bone. Forty patients suffering from symptomatic Paget's disease were treated with 0.5 g calcium three times daily, 10 mg/day clopamide, and 400 IU nasally administered salmon calcitonin given once or twice weekly. This regimen was given for 5 months, after which all treatment was ceased for 4 months. Parenteral SCT (100 IU) was then given three times weekly for 5 months to 25 of the patients. With the oral/nasal treatment, the plasma alkaline phosphatase level (AP) decreased by 30 +/- 15 (SD)% when the SCT was given once weekly and by 39 +/- 11% (P less than 0.05) when the SCT was given twice weekly. There were similar decreases in the fasting urinary hydroxyproline:creatinine ratios. The parenteral SCT reduced the AP by 33 +/- 23%. Though reduction in bone pain was similar with both treatments, most patients preferred the oral/nasal treatment. It is concluded that the oral/nasal treatment, when the SCT is given twice weekly, has similar efficacy to parenteral SCT, and is a well tolerated, effective initial treatment for Paget's disease of bone.

Topics: Administration, Intranasal; Administration, Oral; Adult; Aged; Aged, 80 and over; Alkaline Phosphatase; Benzothiadiazines; Calcitonin; Calcium; Creatine; Diuretics; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Hydroxyproline; Male; Middle Aged; Osteitis Deformans; Sodium Chloride Symporter Inhibitors

The effects of multivalent metal ions (Cu(2+)/Zn(2+)/Al(3+)) on the aggregation of salmon calcitonin (sCT)--a therapeutic peptide used worldwide in the treatment of osteoporosis and Paget's disease--have been studied in vitro using NMR (both solution state and solid state), TEM, ThT-fluorescence, and FT-IR spectroscopy. Overall, the various results indicated that the metal-ions-induced conformational transitions in the peptide--mostly toward the β-sheet--facilitate the aggregation of sCT in solution. First, the solution NMR has been used to check the interaction between the peptide and the metal ions. Following this, the formation and characterization of calcitonin aggregates has been performed using TEM, solid state NMR, and FT-IR spectroscopy. The TEM and ThT-fluorescence results revealed that the sCT peptide incubated with Cu(2+) and Zn(2+) metal ions (in aqueous environment) forms globular aggregates, while that with Al(3+) ions forms fibrils. The solid state NMR and FT-IR studies revealed the presence of a substantial amount of β-sheet content in sCT aggregates (formed in the presence of these metal ions) compared to the monomeric sCT, indicating that the metal binding is concomitant with conformational changes. The present study becomes crucial while prescribing this drug peptide under physio-pathological conditions associated with an abnormal accumulation of metal ions (Cu(2+)/Zn(2+)/Al(3+)) in the body (i.e., abnormal metal ion homeostasis).

Topics: Aluminum; Amino Acid Sequence; Bone Density Conservation Agents; Calcitonin; Cations; Copper; Humans; Molecular Sequence Data; Nuclear Magnetic Resonance, Biomolecular; Osteitis Deformans; Osteoporosis; Protein Structure, Secondary; Spectroscopy, Fourier Transform Infrared; Zinc

Topics: Amifostine; Anti-Inflammatory Agents; Calcitonin; Calcium; Diphosphonates; Disease Progression; Drug Resistance; Humans; Osteitis Deformans; Steroids; Treatment Outcome

Calcitonin is used to reduce high serum calcium levels in patients with malignancy, and as therapy for osteoporosis and Paget's disease. Receptors for the peptide have been identified in some human cancer cells including those of lung, breast, bone, prostate, and medullary carcinoma of the thyroid, suggesting that an imaging agent for the receptors might be useful in nuclear oncology. A modified chloramine-T method was used to label a pharmaceutical form of salmon calcitonin (SCT) with iodine-123. Labelling can be performed within 5 min including purification, resulting in >95% radiochemical purity and 70% yield. Digestion analysis shows labelling with two iodine atoms on the tyrosine residue. A Chinese hamster ovary cell-based assay showed that the receptor binding and activation were not impaired by the labelling. Biodistribution in mice was similar to that of commercially available mono-iodinated 125I-labelled SCT, kidney being the principal target organ. Evaluation in three patients previously diagnosed as having Paget's disease (injected with 37 MBq [123I]diiodotyrosyl22-SCT, containing less than 4 IU hormone, imaged dynamically up to 0.5 h and at intervals up to 24 h) shows early uptake in liver, kidney and sites of known Paget's disease but not in normal bone, and later uptake in thyroid and stomach. Blood clearance was fitted to a biexponential with half-lives of 3.4-7.4 min and 3-34 h. Radiation dosimetry was estimated using MIRDOSE 3. The highest doses (mean mGy/MBq) were to thyroid (6.8x10(-1)) and kidney (6.0x10(-2)), with a whole-body dose 3.0x10(-2). High performance liquid chromatography analysis revealed that urinary radioactivity was mostly in the form of iodide and diiodotyrosine within minutes of injection, indicating rapid in vivo breakdown. In summary, [123I]diiodotyrosyl22-SCT binds to calcitonin receptors and can image sites of Paget's disease but its imaging potential is not optimal because of rapid breakdown and clearance from target tissues, and an alternative radiolabelling approach is required.

Topics: Aged; Animals; Calcitonin; CHO Cells; Cricetinae; Diiodotyrosine; Diphosphonates; Female; Humans; Injections, Intravenous; Iodine Radioisotopes; Isotope Labeling; Male; Mice; Middle Aged; Organotechnetium Compounds; Osteitis Deformans; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Calcitonin; Tissue Distribution

3 patients with prolonged, diffuse, bone pain due to Paget's disease were treated with intranasal salmon calcitonin, 200-400 U/d for 12 months. Within the first 3 months, in all 3 bone turnover decreased 31-35% (as assessed by serum alkaline phosphatase activity and urinary hydroxyproline/creatinine ratio). After 1 year of nasal calcitonin the reduction in serum alkaline phosphatase was 24%, and in urinary hydroxyproline 10%. In addition, pain and functional impairment markedly improved during the year. It is concluded that daily nasal calcitonin spray is well tolerated and effective initial treatment for Paget's disease of the bone.

Topics: Administration, Intranasal; Adult; Aerosols; Aged; Alkaline Phosphatase; Analgesics; Calcitonin; Female; Humans; Hydroxyproline; Male; Middle Aged; Osteitis Deformans

Topics: Aged; Analgesics; Calcitonin; Early Ambulation; Femoral Neck Fractures; Fractures, Spontaneous; Hip Prosthesis; Humans; Male; Osteitis Deformans; Osteolysis; Postoperative Complications; Radiography

The use of calcitonin (CT) is established as a treatment of Paget's disease of bone and postmenopausal osteoporosis (PMO). Salmon calcitonin (sCT), which differs in 14 of the 32 amino acids from human calcitonin, has found a wider distribution world wide, although antibody formation against sCT has been reported in more than 70% of the patients on continuous sCT treatment. The clinical significance of these antibodies has been discussed controversially, because the occurrence of antibodies is not always associated with the development of secondary resistance. Using an in vitro bioassay, based on the CT-mediated increase of the cyclic AMP (cAMP) production of the human breast cancer cell line T 47 D we could identify a neutralizing activity against sCT in the serum of a subset of patients with formation of antibodies against sCT which was related to the development of secondary resistance. Antibody formation against human calcitonin (hCT) has been reported only once before. Binding and neutralizing antibodies were now observed in 1 of 33 patients with PMO treated with hCT. Due to a low neutralizing activity, clinical sequelae were not to be expected in this patient. The formation of neutralizing antibodies against calcitonin is common after treatment with salmon but a rare phenomenon after treatment with human calcitonin. We recommend monitoring of patients with postmenopausal osteoporosis and Paget's disease of bone on long term treatment with sCT or hCT for neutralizing antibody formation in order to evaluate the therapeutic effect of treatment.

Topics: Antibodies; Antibody Formation; Breast Neoplasms; Calcitonin; Cyclic AMP; Drug Resistance; Female; Humans; Iodine Radioisotopes; Osteitis Deformans; Osteoporosis, Postmenopausal; Receptors, Calcitonin; Tumor Cells, Cultured

In 15 patients suffering from Paget's disease, the serum levels of alkaline phosphatase (ALP), 25-hydroxycholecalciferol (25OHD3), 24,25-dihydroxycholecalciferol (24,25 [OH] 2D3), 1,25-dihydroxycholecalciferol (1,25 [OH] 2D3), and parathormone (PTH) as well as urinary excretion of hydroxyproline (HP) have been determined before and after three-month calcitonin therapy. Before therapy, high concentrations of serum ALP and urinary HP excretion had been observed, whereas serum levels of 24,25 (OH) 2D3 were below the lower limit of the normal range. Calcitonin therapy caused a 31% reduction in ALP and a 50% reduction in HP, as well as a significant increase in serum levels of 24,25 (OH) 2D3; the levels of 25OHD3, 1,25 (OH) 2D3, and PTH remained unchanged after treatment. The significant negative correlation between 24,25 (OH) 2D3 and ALP and HP before and after calcitonin therapy suggests that in Paget's disease there is an uncompensated increased bone usage of 24,25 (OH) 2D3.

Topics: 24,25-Dihydroxyvitamin D 3; Adult; Aged; Alkaline Phosphatase; Calcifediol; Calcitonin; Calcitriol; Female; Humans; Hydroxyproline; Male; Middle Aged; Osteitis Deformans; Parathyroid Hormone; Time Factors; Vitamin D

Topics: Bone Diseases; Calcitonin; Clinical Trials as Topic; History, 20th Century; Humans; North America; Osteitis Deformans; Osteoporosis

Topics: Bone Diseases; Calcitonin; Calcium; Female; Humans; Hypercalcemia; Male; Osteitis Deformans; Osteoporosis, Postmenopausal

Nineteen patients with postmenopausal osteoporosis were treated with 200 u (15 nmol) synthetic salmon calcitonin (sCT) intranasally per day for 15 months. Six months after the start of the nasal administration of sCT, antibodies were recognized in 7, and after 15 months in 10 of the 19 patients studied. The half-maximal dilution of serum binding to 60 pmol/l [125I]sCT (dilution-50) ranged from 2 to 490, and half-maximal inhibition of [125I]sCT binding (60 pmol/l) from 91 to 221 pmol/l sCT. In a cultured breast cancer cell line (T47D) cAMP production was stimulated by sCT (EC50 70 pmol/l). Stimulated cAMP production by sCT (50 pmol/l) was reduced to between 4% and 23% in the presence of serum from patients with antibody dilution-50 of [125I]sCT binding exceeding 32. In patients with lower titer antibodies cAMP production was only marginally suppressed. The values of patients with postmenopausal osteoporosis were in the range of those of earlier studied patients with Paget's disease and clinical resistance to sCT. There was a linear relation between the antibody dilution-50 and the serum dilution required for half-maximal inhibition of cAMP production (P less than 0.01). In conclusion, neutralizing antibodies to sCT may contribute to the decreased responsiveness of bone mineral loss during prolonged treatment with sCT.

Topics: Administration, Intranasal; Aged; Antibody Formation; Calcitonin; Female; Humans; Middle Aged; Neutralization Tests; Osteitis Deformans; Osteoporosis, Postmenopausal

Topics: Administration, Intranasal; Adult; Aged; Alkaline Phosphatase; Animals; Antibodies; Antibody Specificity; Calcitonin; Creatine; Female; Humans; Hydroxyproline; Immunoglobulin G; Male; Middle Aged; Osteitis Deformans

To elucidate the biologic relevance of circulating sCT antibodies, an in vitro bioassay system for the detection of neutralizing antibodies was developed utilizing the human breast carcinoma cell line T47D. We reasoned that the inhibition of the dose-dependent cAMP response to sCT in the T47D assay system by anti-sCT antibodies could be used to determine the in vivo relevance of these antibodies. In this report the clinical course of nine patients with Paget's disease of bone treated with intranasal sCT was correlated with the presence of 125I-sCT binding and neutralizing antibodies. Of these seven patients, four were found to have neutralizing antibodies; the appearance of the antibodies coincided with the development of resistance. One of these patients was subsequently treated with human calcitonin and revealed a good response to the treatment. There was no clinical resistance observed in the three patients with 125I-sCT binding antibodies but no neutralizing antibodies; no resistance was observed in two patients without 125I-sCT binding or neutralizing antibodies. We conclude that this new technique to determine the biologic relevance of circulating anti-sCT antibodies may be an useful adjunct for determining the cause of resistance in patients treated with sCT.

Topics: Administration, Intranasal; Alkaline Phosphatase; Antibodies; Biological Assay; Calcitonin; Drug Resistance; Humans; Neutralization Tests; Osteitis Deformans; Tumor Cells, Cultured

A cause for the resistance to intranasal salmon calcitonin (sCT) therapy in patients with Paget's disease is the occurrence of neutralizing antibodies to sCT. As a result, a new formulation of intranasal human calcitonin (hCT) was developed, and the efficacy investigated in patients treated earlier with sCT.. Twelve patients with Paget's disease were treated twice daily for 6 months with 1 mg synthetic hCT administered intranasally. Five patients demonstrated low-titer antibodies to sCT, and four of the patients did not respond previously to 1-year therapy with intranasal sCT. The hypocalcemic effect of 3 mg hCT was compared to that of 0.1 mg sCT before and after the intranasal hCT therapy. Serum alkaline phosphatase and the ratio between the urinary excretion of hydroxyproline and creatinine were measured before and during intranasal hCT treatment.. The hypocalcemic response to 3 mg intranasal hCT (-6.60 +/- 0.67%, mean +/- standard error) was similar before and at the end of intranasal hCT therapy (-5.92 +/- 0.80%, p greater than 0.1). Intranasal sCT (0.1 mg) lowered serum calcium less effectively (-2.86 +/- 0.76%) than 3 mg intranasal hCT (p less than 0.05). The presence of low-titer antibodies to sCT did not affect the hypocalcemic response to sCT or hCT. As a result of the 6-month intranasal hCT regimen, serum alkaline phosphatase and urinary hydroxyproline/creatinine ratio were reduced to 62 +/- 5% (p less than 0.001) and 80 +/- 7% (p less than 0.05) respectively, of pretreatment levels. In four patients previously resistant to intranasal sCT therapy because of neutralizing antibodies to sCT, serum alkaline phosphatase was similarly lowered by intranasal hCT to 66 +/- 6% of pretreatment levels (p less than 0.05).. A new formulation of intranasal hCT effectively lowered serum calcium levels, alkaline phosphatase concentrations, and urinary hydroxyproline excretion in patients with Paget's disease, some of whom were previously resistant to intranasal sCT because of neutralizing antibodies.

Topics: Administration, Intranasal; Adult; Aged; Aged, 80 and over; Alkaline Phosphatase; Antibodies; Calcitonin; Calcium; Drug Resistance; Female; Humans; Hydroxyproline; Male; Middle Aged; Osteitis Deformans

Salmon calcitonin (sCT) is biologically effective when intranasally (i.n.) administered. CT is the treatment of choice for Paget's disease; however, the chronic nature of the disease makes parenteral administration uncomfortable due to the high incidence of adverse reactions occurring after CT injection. The aim of our study was to investigate the efficacy, safety and tolerability of a sCT i.n. spray in the long-term treatment of Paget's disease. Ten pts (4M,6F; age between 58-74 years) with radiological lesions characteristic of Paget's disease, serum alkaline phosphatase (sALP) levels at least 50% above the normal range and never treated for their disease before, were given 200 IU/day of sCT nasal spray for 6 months. sALP levels were measured at month 3 and 6 of therapy; clinical data were recorded every month. sALP levels significantly dropped after 3 months of treatment (72 +/- 6% of basal level, p less than 0.01). After 6 months of therapy sALP levels were similar to the 3 month levels. Pain and functional impairment self-evaluated by the patients decreased after 6 months of therapy: pain index from 5.5 +/- 2.2 to 2.1 +/- 1.1, p less than 0.01; functional impairment index from 2.2 +/- 0.5 to 0.7 +/- 0.5, p less than 0.01. Side-effects were not observed during the entire period of the study. In conclusion, the 200 IU daily regimen of the i.n. spray of sCT without absorption enhancer was, for our patients, effective, safe, and well tolerated in the long-term therapy of Paget's disease.

Topics: Administration, Inhalation; Aerosols; Aged; Alkaline Phosphatase; Calcitonin; Drug Evaluation; Female; Humans; Male; Middle Aged; Osteitis Deformans

Topics: Administration, Intranasal; Antibodies; Calcitonin; Female; Humans; Hypocalcemia; Male; Osteitis Deformans

Subcutaneous daily or bidaily administration of synthetic salmon calcitonin is an effective form of therapy for Paget's disease, but the requirement for parenteral injection deters geriatric patients from using the drug. This study compares a new intranasal preparation of salmon calcitonin to subcutaneous drug in 18 patients with Paget's disease using two different protocols. In the first protocol, 15 patients not previously treated with salmon calcitonin were given the agent for 3 months by either the intranasal or subcutaneous route. Seven patients treated with intranasal calcitonin had a mean fall in the serum alkaline phosphatase of 33% over a 3-month period compared to a fall of 40% in the subcutaneously treated group; the difference between the two treatment groups was not statistically significant. In the second protocol, three patients previously stabilized on subcutaneous calcitonin were switched to the nasal spray with no subsequent change in alkaline phosphatase values during 6 months of treatment. These results demonstrate that intranasal salmon calcitonin is effective in lowering the serum alkaline phosphatase in Paget's disease. Ease of administration and patient acceptance make intranasal calcitonin a reasonable alternative for geriatric patients.

Topics: Administration, Intranasal; Aged; Alkaline Phosphatase; Calcitonin; Dose-Response Relationship, Drug; Female; Humans; Injections, Subcutaneous; Male; Middle Aged; Osteitis Deformans; Radiography

To ascertain whether salmon calcitonin, usually given parenterally, could control active Paget's disease when given by nasal insufflation, intranasal salmon calcitonin (INSC) was given to nine men with Paget's disease whose serum alkaline phosphatase (SAP) levels were elevated twofold or more. Treatment with 100, 200, and 400 IU/day for three to nine months was well tolerated. SAP fell 31%-51% in three patients and more than 20% in two others. Three of four men who had previously received salmon calcitonin (SC) by injection had no response of SAP but had a rise in antibodies to SC. INSC is mildly effective and more convenient than parenteral SC, but dose response and efficacy relative to parenteral SC have not been established, thereby raising questions of cost-effectiveness.

Topics: Administration, Intranasal; Aged; Alkaline Phosphatase; Calcitonin; Drug Evaluation; Humans; Male; Middle Aged; Osteitis Deformans; Random Allocation

On 7 patients with mild-to-moderately active Paget's disease, 200 IU of salmon calcitonin (SCT) nasal spray (NS), induced a significant decrease of the total urinary hydroxyproline excretion (THP) during the 8-16 hour and the 0-24 hour (P less than 0.05) periods after treatment as compared to control day. However, the administration of 100 IU of SCT intramuscularly (i.m.) caused a significantly greater effect than 200 IU-NS during the second 8 hour period after its administration (P less than 0.01) and on the over-all 24 hour effect (P less than 0.05). On 3 patients with severe Paget's disease, SCT-NS was essentially ineffective whereas the injection of SCT induced a marked diminution of the THP excretion.

Topics: Administration, Intranasal; Aged; Aged, 80 and over; Calcitonin; Drug Administration Schedule; Female; Humans; Hydroxyproline; Injections, Intramuscular; Male; Middle Aged; Osteitis Deformans

Twenty-one women with primary osteoporosis received an intramuscular injection of 100 IU of salmon calcitonin at 8 AM. Blood samples IU of salmon calcitonin at 8 AM. Blood samples were collected up to 5 h postcalcitonin and urine was collected for 24 h in three periods of 8 h each. A significant fall of the total hydroxyproline excretion (THP) was observed in every period but the maximum effect took place 8-16 h postcalcitonin. The effect was more pronounced in those patients with a greater basal excretion of THP and in those with a more significant diminution of their bone mass. A significant diminution of the urinary excretion of calcium was found 8-24 h postcalcitonin, while phosphate excretion increased throughout the three 8 h periods. The effect of calcitonin in osteoporotic women was compared with the results obtained in 9 patients with Paget's disease. In absolute in 9 patients with Paget's disease. In absolute values the fall of THP excretion was significantly greater in the pagetic patients but the percentage diminution was not significantly different in osteoporotic women and in pagetic patients. Salmon calcitonin induced a significant acute diminution of bone turnover in patients with osteoporosis, as defined by decreases in total urinary hydroxyproline. The calcitonin-induced hypocalcemia does not seem to be an accurate index of the hormone action in osteoporosis.

Topics: Aged; Calcitonin; Calcium; Female; Humans; Hydroxyproline; Middle Aged; Osteitis Deformans; Osteoclasts; Osteoporosis; Phosphates

Progressive hearing loss is a potential complication of Paget's disease, a metabolic disorder of accelerated bone formation and resorption. Calcitonin (Calcimar) is a recently introduced synthetic hormone used as a systemic treatment. Some studies have shown it to halt the progression of hearing loss. This is the first study of the effects of calcitonin on hearing loss to use a large number of patients with continuous use of the drug and long-term follow-up. It confirms that the drug is effective. We conducted chart reviews to compare the degree of hearing loss over time in 45 patients. Twenty-six patients have been taking salmon calcitonin for five to eight years to date and nineteen have received no treatment. Hearing loss was recorded at the initial examination (trial 1), one to four years later (trial 2), and then one to five years after the second evaluation (trial 3). Statistical analyses show a strong relationship between treatment and rate of hearing loss. The average hearing loss in the control group progressed from 47 dB in the first trial to 59 dB in the second trial to 75 dB in the third trial. Average hearing loss in the treated group remained at 47 dB over time. The difference in hearing loss over time between the two groups was less than 1 dB for the treated group and more than 28 dB for the control group. Results thus clearly show that calcitonin is effective in halting the progression of hearing loss in Paget's disease.

Topics: Aged; Calcitonin; Follow-Up Studies; Hearing Loss, Sensorineural; Humans; Middle Aged; Osteitis Deformans; Time Factors

Topics: Administration, Intranasal; Aged; Calcitonin; Hormones; Humans; Osteitis Deformans

The effectiveness of Synthetic Salmon Calcitonin (SSCT) administered as a nasal spray was assessed via clinical, biological, and radiological variables in 5 Pagetic patients during a 6 months course therapy, the results show that intranasal administration does not decrease the activity of SSCT in Paget's disease of bone.

Topics: Administration, Intranasal; Aged; Alkaline Phosphatase; Calcitonin; Creatinine; Female; Follow-Up Studies; Humans; Hydroxyproline; Male; Middle Aged; Osteitis Deformans; Radiography

Patients with Paget's disease of bone were found to have elevated serum levels of type I procollagen carboxyterminal peptide (pColl-I-C) which correlated with other measurements of disease activity. The elevated levels of pColl-I-C decreased within hours after the injection of salmon calcitonin and within weeks after oral dichloromethylene diphosphonate treatment. The decrease in serum pColl-I-C after a single injection of salmon calcitonin was associated with a decrease in urinary hydroxyproline excretion, both of which rose toward pretreatment values within 7 h. The pColl-I-C levels remained normal for months after dichloromethylene diphosphonate therapy was discontinued. Using a RIA for the type III procollagen amino-terminal peptide (pColl-III-N), it was found that serum levels were also elevated in patients with Paget's disease. The levels of pColl-III-N also decreased after the injection of salmon calcitonin, but not to the same extent as those of pColl-I-C. After chronic therapy with dichloromethylene diphosphonate, serum levels of pColl-III-N decreased, but not into the normal range. We postulate that whereas pColl-I-C is derived from synthesis of mineralized bone collagen, pColl-III-N is derived from the loose fibrous stroma replacing marrow in areas closely associated with active Pagetic bone disease.

Topics: Antibody Specificity; Calcitonin; Clodronic Acid; Humans; Hydroxyproline; Osteitis Deformans; Peptide Fragments; Procollagen; Radioimmunoassay; Time Factors

The hypocalcemia following administration of calcitonin may be an index to disease activity in Paget's disease of bone. Therefore, we assessed the effect of a single injection of 100 MRC units of salmon calcitonin (SCT) on plasma calcium in 28 patients with active Paget's disease before and after 6 months of treatment with dichloromethylene diphosphonate (Cl2MDP) at a dose of 400 mg/day (3 patients), 800 mg/day (8 patients), 1.600 mg/day (9 patients) or 2.600 mg/day (8 patients). The mean SCT-induced hypocalcemia was reduced by Cl2MDP and there was a significant positive correlation between the decrease of serum calcium induced by SCT and bone resorption evaluated by the number of osteoclasts on bone biopsy taken in pagetic iliac crest. After Cl2MCP treatment, 5 patients manifested a paradoxical hypercalcemic response to SCT injection ranging from +0.3 mg/dl to +0.5 mg/dl, which was sustained over the 9 hours following injection. As these patients had a dramatic inhibition of bone resorption induced by Cl2 MDP, it is suggested that the hypercalcemic response to SCT might reflect persistence or exaggeration of the early hypercalcemic effect of CT which reportedly precedes the hypocalcemic response to SCT.

Topics: Alkaline Phosphatase; Bone and Bones; Calcitonin; Calcium; Clodronic Acid; Diphosphonates; Humans; Hydroxyproline; Osteitis Deformans

In order to evaluate whether or not the action of salmon calcitonin (sCT) at the kidney level could be mediated through specific receptors for the hormone, we have studied the effects of sCT infusions on urinary excretion of cyclic nucleotides in humans. Parallel in vitro studies have been conducted by evaluating the effects of sCT on cyclic nucleotide levels in primary cultures of cortical and medullary human kidney cells. In vivo experiments showed that sCT induced an increase in cGMP in human urine, which was rapid and short-lasting, being superimposable on the increase of urinary excretion of calcium and magnesium. The increase of inorganic phosphate urinary excretion was delayed and appeared to parallel that of urinary cAMP. On the other hand, our in vitro experiments showed that sCT stimulated the guanylate cyclase-cGMP system of human kidney cortical cells at nanomolar concentrations, while higher concentrations of the hormone were required to activate the adenylate cyclase-cAMP system. In addition, sCT was not able to significantly modify the cellular levels of either nucleotide in human kidney medullary cells. Present data demonstrated a direct effect of sCT on human kidney cortical cGMP production, while the efficacy of sCT on the kidney cortex adenylate cyclase-cAMP system appears to be delayed and/or reduced.

Topics: Aged; Calcitonin; Calcium; Cells, Cultured; Creatinine; Cyclic AMP; Cyclic GMP; Dose-Response Relationship, Drug; Female; Humans; Kidney; Magnesium; Male; Middle Aged; Osteitis Deformans; Parathyroid Hormone; Phosphates

One hundred and four patients with Paget's disease of bone received treatment with a calcium/thiazide regimen, salmon calcitonin, or ethane-1-hydroxy-1, 1-diphosphonate (EHDP). Most patients commenced therapy with the calcium/thiazide regimen; in 67% of these, the disease was satisfactorily controlled for some years. When the response was unsatisfactory, calcitonin was given. This was frequently effective, but produced troublesome nausea in 28% of patients. When these side effects were unacceptable, or the response was not adequate, EHDP was given, unless the patient appeared to be at risk of fracture. It is suggested that the calcium/thiazide regimen has a place in the management of Paget's disease; that calcitonin is more frequently effective, but has a high incidence of unpleasant, though not serious, side effects; and that EHDP is a useful agent in the treatment of Paget's disease, but must be administered with care, and does carry a small risk of pathological fracture.

Topics: Aged; Alkaline Phosphatase; Calcitonin; Calcium; Chlorthalidone; Dose-Response Relationship, Drug; Etidronic Acid; Female; Fractures, Bone; Humans; Kinetics; Male; Middle Aged; Nausea; Osteitis Deformans; Risk

Bone Gla protein (BGP) was measured in the plasma by radioimmunoassay (RIA) during treatment of 59 patients with bone diseases including Paget's disease (N = 9), primary hyperparathyroidism (N = 25), chronic renal failure (N = 20), and cancer involving bone (N = 5). Plasma BGP was increased above normal in all patients. BGP decreased in the patients with Paget's disease following the acute and chronic administration of salmon calcitonin. Plasma BGP was higher in women then in men with primary hyperparathyroidism. Following parathyroidectomy, BGP decreased in both sexes but the decrease was significant in women only. Plasma BGP was increased in patients with renal osteodystrophy and did not change after hemodialysis. In the patients with bone cancer, plasma BGP decreased during treatment of the attendant hypercalcemia with salmon calcitonin. Although plasma BGP and serum alkaline phosphatase (AP) levels were generally correlated in these studies, there were examples of dissociation between the two. The measurement of plasma BGP appears to provide a specific index of bone metabolism that may in some circumstances be more sensitive than serum alkaline phosphatase measurement. However, further studies are necessary to establish the clinical value of plasma BGP measurement by RIA in the management of patients with bone diseases.

Topics: Alkaline Phosphatase; Bone and Bones; Bone Diseases; Bone Neoplasms; Calcitonin; Calcium-Binding Proteins; Chronic Kidney Disease-Mineral and Bone Disorder; Female; Humans; Hyperparathyroidism; Male; Osteitis Deformans; Osteocalcin; Parathyroid Glands; Radioimmunoassay; Renal Dialysis; Vitamin K

Topics: Aged; Calcitonin; Etidronic Acid; Humans; Male; Osteitis Deformans; Phenytoin; Seizures