Phosphaturic Mesenchymal Tumor.

Phosphaturic mesenchymal tumors (PMTs) are neoplasms associated with tumor-induced osteomalacia. Patients typically present with pathologic fractures in the setting of chronic hypophosphatemic hyperphosphaturic osteomalacia, as well as gradual muscle weakness, bone pain, and difficulty walking. Because of their rarity and nonspecific symptomatology, phosphaturic mesenchymal tumors often go undiagnosed for years. Even when discovered on imaging, the tumors can be diagnostically challenging for radiologists. Phosphaturic mesenchymal tumors often tend to be small and can be located nearly anywhere in the body, and, therefore, can mimic many other tumors. This case highlights the imaging and pathologic markers of a phosphaturic mesenchymal tumor, often found in a patient with tumor-induced osteomalacia.

Etidronate for osteoporosis in primary biliary cirrhosis: a randomized trial.

BACKGROUND/AIM: Osteoporosis is a common complication of primary biliary cirrhosis but there is no accepted therapy for the osteoporosis. In this randomized controlled trial, we compared the effects of etidronate to placebo on the treatment of osteoporosis associated with primary biliary cirrhosis. METHODS: Sixty-seven patients with primary biliary cirrhosis and osteopenia, defined by bone mineral density criteria (T-score < -2.0) were enrolled. Measurements of the lumbar spine and proximal femur, as well as x-rays of the lumbar spine, were obtained. Patients received cyclical etidronate 400 mg/day for 14 days every 3 months for at least 1 year. Supplemental calcium was administered on the days patients did not receive etidronate. RESULTS: Of the 67 patients entered, 60 completed at least 1 year of therapy. There was no significant difference in changes in bone density at either the lumbar spine or femur in patients receiving etidronate when compared to placebo. Fractures occurred in eight patients, four receiving etidronate. Etidronate therapy was associated with a significant reduction in markers of bone turnover compared to placebo. These changes did not correlate with changes in bone density. CONCLUSIONS: Cyclical etidronate administered with supplemental calcium did not significantly improve bone density in patients with primary biliary cirrhosis.

Fracture risk among patients with Paget's disease: a population-based cohort study.

Localized disruption of bone architecture leads to an increased risk of pathological fractures in patients with Paget's disease, but the impact of the disease on overall fracture risk is unknown. We addressed this issue among 236 Olmsted County, Minnesota residents (107 women and 129 men) first diagnosed with Paget's disease from 1950 through 1994. These subjects (mean +/- SD age at diagnosis, 69.6+/-12.2 years) were followed subsequently for 2798 person-years. During this period of observation, 33 pathological fractures were attributed to Paget's disease (1 skull, 11 vertebra, 1 shaft/distal humerus, 1 pelvis, 6 proximal femur, 2 shaft/distal femur, and 11 tibia/fibula). Excluding the fractures through pagetic bone, there was no increase in overall fracture risk in this cohort (standardized incidence ratio [SIR], 1.2; 95% CI, 0.9-1.4). However, there was a statistically significant increase in the risk of subsequent vertebra (SIR, 3.0; 95% CI, 2.2-4.1) and rib fractures (SIR, 1.7; 95% CI, 1.1-2.4) but not fractures of the proximal femur (SIR, 0.6; 95% CI, 0.3-1.1) or distal forearm (SIR, 1.4; 95% CI, 0.7-2.5). Thus, unselected patients with Paget's disease in the community, who mostly have mild disease, have a significantly increased risk of vertebral fractures, although this may relate partly to increased surveillance. Additional work is needed to clarify the relationship between Paget's disease and vertebral fractures and to identify individuals at increased risk for more aggressive therapy.

Long-term trends in the incidence of Paget's disease of bone.

Existing data on the epidemiology of Paget's disease of bone are limited by the lack of directly determined secular trends in clinically diagnosed Paget's disease. In the current study, we examine trends in Paget's disease incidence in Olmsted County, MN, using data from the Rochester Epidemiology Project medical records linkage system. During the period 1950 through 1994, 236 Olmsted County, MN residents were diagnosed for the first time with Paget's disease of bone at a mean age of 69.6 years. Overall, there were 129 (54.7%) men and 107 women, and the age-adjusted incidence of Paget's disease was 12.7 per 100,000 person-years (95% CI 10.4-14.9) among the men compared with 7.0 per 100,000 person-years (95% CI 5.6-8.3) among Olmsted County women (male/female ratio of 1.8:1). The higher incidence in males compared with females and the increase in incidence with older age were statistically significant. The incidence of Paget's disease in Olmsted County seems to have increased over the first part of the study period and then declined. This may have resulted from ascertainment bias: the introduction of a 12-test automated serum chemistry panel in 1974 might have led to a sudden increase in the apparent incidence of Paget's disease followed by a compensatory decrease. In addition, there was a decrease in the proportion of patients who were symptomatic at diagnosis, from 36% in 1950-1959 to 27% in 1980-1994. This finding also suggests that routine measurement of alkaline phosphatase may have led to more diagnosis of asymptomatic individuals. The subsequent fall in the incidence of Paget's disease is consistent with previous reports, although this apparent decline could be artifactual to the extent that the reservoir of undiagnosed cases in the population was exhausted by earlier testing.

Insulin-like growth factor system abnormalities in hepatitis C-associated osteosclerosis. Potential insights into increasing bone mass in adults.

Hepatitis C-associated osteosclerosis (HCAO) is a rare disorder characterized by a marked increase in bone mass during adult life. Despite the rarity of HCAO, understanding the mediator(s) of the skeletal disease is of great interest. The IGFs-I and -II have potent anabolic effects on bone, and alterations in the IGFs and/or IGF-binding proteins (IGFBPs) could be responsible for the increase in bone formation in this disorder. Thus, we assayed sera from seven cases of HCAO for IGF-I, IGF-II, IGF-IIE (an IGF-II precursor), and IGFBPs. The distribution of the serum IGFs and IGFBPs between their ternary ( approximately 150 kD) and binary (approximately 50 kD) complexes was also determined to assess IGF bioavailability. HCAO patients had normal serum levels of IGF-I and -II, but had markedly elevated levels of IGF-IIE. Of the IGFBPs, an increase in IGFBP-2 was unique to these patients and was not found in control hepatitis C or hepatitis B patients. IGF-I and -II in sera from patients with HCAO were carried, as in the case of sera from control subjects, bound to IGFBP-3 in the approximately 150-kD complex, which is retained in the circulation. However, IGF-IIE was predominantly in the approximately 50-kD complex in association with IGFBP-2; this complex can cross the capillary barrier and access target tissues. In vitro, we found that IGF-II enhanced by over threefold IGFBP-2 binding to extracellular matrix produced by human osteoblasts and that in an extracellular matrix-rich environment, the IGF-II/IGFBP-2 complex was as effective as IGF-II alone in stimulating human osteoblast proliferation. Thus, IGFBP-2 may facilitate the targeting of IGFs, and in particular IGF-IIE, to skeletal tissue in HCAO patients, with a subsequent stimulation by IGFs of osteoblast function. Our findings in HCAO suggest a possible means to increase bone mass in patients with osteoporosis.

Paget's disease of bone: indications for treatment and goals of therapy.

Paget's disease of bone is a common disorder of unknown etiology characterized by increased bone remodeling and abnormal bone architecture. The pathologic process is initiated by an increase in osteoclast-mediated bone resorption, accompanied by a compensatory increase in bone formation. The increased bone remodeling results in a disorganized mosaic of woven and lamellar bone. This bone is highly vascular and gradually becomes enlarged and structurally weakened. Paget's disease is generally diagnosed in patients older than 40 years of age, usually as an incidental finding. The disease may be monostotic or polyostotic. The pelvis, femur, spine, tibia, skull, and humerus are most commonly involved. Most patients with Paget's disease are asymptomatic. Pain is the most common presenting symptom. Complications of the disease include bowing deformity of the long bones, fracture, and a variety of nerve compression syndromes. Malignant degeneration of Paget's disease is a rare complication. As safer, more effective therapies have become available, the indications for treatment and goals of therapy have changed. The difficult issue that clinicians are currently facing is whether to treat patients with asymptomatic disease. The progressive nature of the disease, the severity of its complications, its potential negative impact on quality of life, and the availability of therapy capable of controlling its activity have led many experts in the field to recommend treatment of asymptomatic patients who have active disease at sites where complications are likely to develop. There are, however, no data to prove that complications can be prevented by decreasing the rate of bone remodeling in Paget's disease, nor any data to define who is at risk for complications. Until more information is available, the management of patients with Paget's disease will continue to be based on clinical observation and theoretical considerations. This review examines the present understanding of Paget's disease, the rationale for the proposed indications for treatment and the goals of therapy.

A review of corrective osteotomies for deformity in Paget's disease.

Corrective diaphyseal osteotomies for pagetic deformities may require a long time for union. However, metaphyseal osteotomies healed uneventfully. The use of plate fixation was associated with a lower rate of complications in diaphyseal osteotomies in Paget's disease. External fixation was associated with the highest rate of complications. Medical treatment did not seem to minimize blood loss or expedite union rate or time to union.

Medullary thyroid carcinoma: clinicopathologic features and long-term follow-up of 65 patients treated during 1946 through 1970.

We retrospectively reviewed the medical records of 65 consecutive patients with medullary thyroid carcinoma, who had had their primary surgical treatment at the Mayo Clinic during the years 1946 through 1970. Of these patients, 58 had sporadic and 7 had familial medullary thyroid carcinoma. Thyroid nodules were the most common initial manifestation. Near-total thyroidectomy was the most frequent initial operation. Survival was affected by the following factors: male sex, familial inheritance, size of the tumor, stage of the tumor (American Joint Committee on Cancer), and completeness of initial resection of the tumor. The mean duration of follow-up was 23.5 years, and the maximal follow-up was 36 years. Among 52 patients without initial distant metastatic involvement and with complete resection of the tumor, 20-year survival free of distant metastatic lesions was 81%. Overall 10- and 20-year survival rates were 63% and 44%, respectively. Because of the substantial morbidity and mortality associated with medullary thyroid carcinoma, early diagnosis and thorough initial resection of the tumor are important.

Effects of altered calcium intake on diurnal and calcium-stimulated plasma calcitonin in normal women.

We sought to determine if any protective effect of dietary calcium (Ca) or Ca supplements on bone could be at least partially mediated by increased calcitonin (CT) secretion. First we studied 10 healthy premenopausal women (median age, 35.5 years) who were randomized to high or low dietary Ca intake (1752 versus 391 mg elemental Ca per day) for 2 weeks and then crossed over. At the end of each dietary period, blood was drawn on 1 day at 0800, 1200, 1700, and 2000 h to assess diurnal variation of plasma CT levels. CT secretory reserve was assessed on the next day by Ca infusion (2 mg Ca per kg body weight over 5 minutes). Next, we studied 10 healthy premenopausal women who took a low-Ca diet (approximately 400 mg Ca per day) for a 2 week control period. The women were then randomized to high- or low-Ca intake [400 mg dietary Ca +/- 1500 mg Ca per day (as supplemental CaCO3)] and then crossed over. At the end of each study period, the diurnal variation in CT was tested on day 1; the CT secretory reserve was assessed on day 3 by an oral Ca load (500 mg as CaCO3)] and on day 5 by Ca infusion. Plasma immunoreactive CT was measured in whole plasma (iCT) and after silica extraction (exCT), predominantly monomeric CT. Neither increased dietary Ca nor Ca supplements affected the diurnal levels of iCT or exCT or augmented plasma CT responses to an oral Ca load.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of oral contraceptive and estrogen administration on plasma calcitonin in pre- and postmenopausal women.

Estrogen (E) therapy and administration of oral contraceptives (OC) reportedly increase plasma calcitonin (CT) concentrations in women, effects said to mediate in part the beneficial actions of E on bone. To further examine this theory, we tested the effects of three cycles of OC therapy in 12 young women, comparing them to 10 healthy women before and after three normal menstrual cycles. We also determined the effects of 3 months of E therapy (ethinyl estradiol, 20 micrograms/day, 25 of 30 days) in 14 healthy postmenopausal women, using a crossover design (studied after 3 months with and 3 months without E). We determined CT by radioimmunoassay (antiserum G-1701) in whole plasma (iCT) and silica cartridge extracts of plasma (exCT) after overnight fasting, after calcium (Ca) infusion (2 mg Ca/kg over 5 minutes), and during a normal day at 0800, 1200, 1700, and 2000 h. In no control study was there a significant diurnal change in iCT or exCT, and neither OC nor E therapy altered this. Similarly, OC administration did not affect basal CT levels or the normal iCT and exCT responses to Ca infusion. E therapy induced expected changes in serum Ca, phosphorus, and alkaline phosphatase and urinary Ca and cAMP excretion; basal and diurnal plasma exCT levels were decreased significantly, consonant with the decrement in serum Ca. E did not alter normal iCT and exCT responses to Ca infusion. Thus, administration of either OC or E has no stimulatory effect on CT secretion, which suggests that the beneficial actions of E on bone are not mediated through CT-induced inhibition of bone resorption.(ABSTRACT TRUNCATED AT 250 WORDS)

Cosecretion of calcitonin gene products: studies with a C18 cartridge extraction method for human plasma PDN-21 (katacalcin).

PDN-21, the carboxyl-terminal flanking peptide encoded by the calcitonin (CT) gene, has been found in plasma of patients with medullary thyroid carcinoma and reportedly is cosecreted with CT. To test whether PDN-21 and CT are cosecreted in normal subjects, we developed a RIA for PDN-21 and measured immunoreactive CT and PDN-21 in whole plasma and silica or C18 cartridge extracts of plasma (exCT, exPDN-21) before and after calcium (Ca) infusion (2 mg Ca/kg over 5 min) in nine normal men and nine normal women. Plasma CT and immunoreactive PDN-21 levels were often below the assay detection limits. In contrast, basal exCT and exPDN-21 were detectable in all plasma samples, and the concentrations of both were significantly higher in men than in women [basal exCT (mean +/- SE): men, 4.8 +/- 0.3 ng/L; women, 2.4 +/- 0.3 (P less than 0.001); basal exPDN-21: men, 4.7 +/- 0.3 ng/L; women, 3.3 +/- 0.3 (P less than 0.01)]. Ca infusion sharply increased CT and PDN-21 concentrations in both sexes, but the increments were greatest in men [mean (+/-SE) increment of exCT: men, 37.2 +/- 3.9 ng/L; women, 15.7 +/- 4.3 (P less than 0.002); mean increment of exPDN-21: men, 29.7 +/- 4.7 ng/L; women, 11.0 +/- 3.1 (P less than 0.005)]. The molar concentrations of exCT and exPDN-21 were closely correlated (r = 0.97; P less than 0.001). With our antiserum, the extraction-concentration technique for measurement of PDN-21 had increased sensitivity and decreased nonspecific interference compared to the whole plasma assay. We conclude that CT and PDN-21 are cosecreted from normal thyroid C-cells under the control of extracellular fluid Ca, and that men have greater secretory capacity for both peptides than women. Plasma PDN-21 may serve alternatively to CT as a marker for C-cell activity.

Axial and appendicular bone mineral density in patients with long-term deficiency or excess of calcitonin.

Whether calcitonin deficiency causes and calcitonin excess prevents bone loss is controversial. We therefore measured plasma calcitonin levels and bone mineral density at the radius (by single photon absorptiometry) and lumbar spine (dual photon absorptiometry) in patients with an excess or deficiency of calcitonin. We studied 21 patients who had undergone subtotal thyroidectomy 6.8 to 29 years previously and had no calcitonin secretory reserve, and 11 patients who had received a diagnosis of medullary thyroid carcinoma 6.8 to 23 years previously and had chronic hypercalcitoninemia. Bone-density values, expressed as Z-scores (i.e., as the number of standard deviations above or below the normal means adjusted for age and sex), were indistinguishable from normal in the patients who had undergone thyroidectomy (means +/- SE: radius, 0.36 +/- 0.15; spine, 0.27 +/- 0.17). In the patients with medullary thyroid cancer, radial bone-density values were normal (-0.26 +/- 0.39), but spinal density was significantly reduced (-0.75 +/- 0.17, P less than 0.01). There were no significant correlations between the duration of calcitonin excess or deficiency and the bone density at either site. Bone mineral density was not affected by whether or not thyroxine replacement therapy was given. We conclude that skeletal mass is not affected by endogenous plasma calcitonin in adults.

Plasma calcitonin in primary hyperparathyroidism: failure of C-cell response to sustained hypercalcemia.

An acute increase in serum calcium stimulates calcitonin (CT) secretion, but the effects of chronic hypercalcemia are controversial. Histopathological studies have shown C-cell hyperplasia in primary hyperparathyroidism (1 degree HPT), although circulating levels of CT have been variously reported to be normal, elevated, or depressed. We reexamined this relationship using CT RIA in conjunction with a silica extraction technique that conveys improved sensitivity and specificity for monomeric CT. Nine men and seven women with surgically documented 1 degree HPT were studied preoperatively before and after a short calcium infusion (2 mg Ca/kg, for 5 min), as were 72 normal men and 76 normal women. Basal whole plasma immunoreactive CT and silica-extractable CT concentrations in 1 degree HPT were indistinguishable from normal, regardless of sex. In addition, the whole plasma and silica-extractable CT responses to calcium stimulation were normal or blunted in patients with 1 degree HPT. We conclude that hypercalcemia resulting from 1 degree HPT is not associated with augmented CT secretion in response to an iv calcium infusion.

Secretion and metabolism of monomeric human calcitonin: effects of age, sex, and thyroid damage.

Some data suggest that human calcitonin (CT) secretion is lower in women than in men, decreases with age and the menopause, and is absent in thyroidectomized persons. To further explore CT secretory physiology, we have studied basal and calcium-stimulated plasma immunoreactive CT (iCT) and silica-extractable monomeric CT concentrations in 148 healthy volunteers and 33 patients with a history of thyroid damage (total or subtotal thyroidectomy, radioiodine treatment for thyrotoxicosis). Both whole-plasma iCT and extractable CT levels were lower basally and after calcium infusion in women than in men, basal levels being reduced about 50% and calcium-stimulated values about 75% from those of male subjects. There were no significant changes in basal iCT or extractable CT concentrations with age, and CT secretory capacity (CT response to calcium infusion) likewise did not change with age. Infusion of monomeric CT to constant concentration in 27 persons permitted estimates of CT metabolic clearance rates (MCRs) and secretion rates (SRs). Calculated MCRs of about 9 ml/min.kg-1 (persons aged 21-30 yr) and 6 ml/min.kg-1 (persons aged 54-70 yr) were in good agreement with published data, and did not differ between the sexes. SRs were dependent upon the assay method used to estimate basal plasma CT concentrations, being highest when whole-plasma iCT values were used. Based on estimates of plasma monomeric CT from the silica extraction procedure, the SR of CT was 59 +/- 6 (SE) ng/d.kg-1 in men, and 22 +/- 3 ng/d.kg-1 in women. Thyroid damage reduced, but did not abolish, apparent CT immunoreactivity, even in silica extracts of plasma. However, all subsets of thyroid-damaged patients had absent-to-markedly-impaired CT secretion in response to calcium infusion. We conclude that CT secretion is substantially lower both basally and after stimulation in women than in men, and that this difference in CT immunoreactivity probably reflects differences in circulating CT bioactivity. The sex difference in plasma CT concentrations probably results from lower rates of CT secretion in women, not increased MCR. There is no age-related decrease of plasma CT concentrations (or CT secretory reserve), calling into question the concept that a progressive deficiency of CT is partly responsible for age-related ("senile") osteoporosis. Surgical or radiation damage to the thyroid gland commonly abolishes C-cell response to calcium; such CT-deficient patients form a population suitable for determining whether or not reduced CT secretion can impair skeletal homeostasis.

Calcitonin secretion in postmenopausal osteoporosis.

Calcitonin deficiency has been implicated in the pathogenesis of accelerated bone loss, especially in postmenopausal osteoporosis. To investigate this issue, we studied 25 patients with untreated postmenopausal osteoporosis, 14 age-matched and sex-matched healthy controls (spinal bone mineral density greater than or equal to age-specific and sex-specific mean), and 5 women who had undergone total thyroidectomy. Each subject received an intravenous infusion of 2 mg of elemental calcium per kilogram of body weight over 5 minutes, to test the C-cell secretory reserve. We measured calcitonin by radioimmunoassay in whole plasma and in silica-cartridge extracts of plasma, the latter method providing greatly improved sensitivity and specificity for monomeric calcitonin. Basal immunoreactive calcitonin concentrations, whether measured in whole plasma or in extracts, were significantly higher in the subjects with osteoporosis (P less than 0.01) than in the healthy controls. The calcitonin secretory reserve, as assessed by calcium stimulation, was normal in the osteoporotic group but virtually absent in the thyroidectomy group. We conclude that postmenopausal osteoporosis is not associated with and does not result from calcitonin deficiency. On the contrary, excessive skeletal calcium release may stimulate calcitonin secretion in patients with the disorder.