Robert D. Tiegs

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.

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

Existing data on the epidemiology of Pagets disease of bone are limited by the lack of directly determined secular trends in clinically diagnosed Pagets disease. In the current study, we examine trends in Pagets 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 Pagets 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 Pagets 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 Pagets 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 Pagets 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 Pagets 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.

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.

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.

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.

Morbidity and Mortality Associated With Paget’s Disease of Bone: A Population-Based Study

Introduction: Limited information is available about the clinical features of Pagets disease of bone among unselected patients in the community. We examined morbidity and mortality associated with this condition in a large inception cohort of Olmsted County, MN, residents with a new diagnosis of Pagets disease from 1950 through 1994.

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 Pagets 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 Pagets 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 Pagets 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 Pagets 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 Pagets disease and vertebral fractures and to identify individuals at increased risk for more aggressive therapy.

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

Pagets 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. Pagets 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 Pagets 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 Pagets 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 Pagets disease, nor any data to define who is at risk for complications. Until more information is available, the management of patients with Pagets disease will continue to be based on clinical observation and theoretical considerations. This review examines the present understanding of Pagets disease, the rationale for the proposed indications for treatment and the goals of therapy.

Identification and Molecular Characterization of a Novel Splice-Site Mutation (G1205C) in the SQSTM1 Gene Causing Paget’s Disease of Bone in an Extended American Family

Paget’s disease of bone (PDB) is a common late-onset bone disorder characterized by focal areas of abnormal bone remodeling. Positional cloning efforts resulted in the identification of seven genetic loci (PDB1-7) with putative involvement in the pathogenesis of PDB. Meanwhile, the PDB-causing gene from the PDB3 region on chromosome 5q35 has been identified as the SQSTM1 gene. All mutations identified in this gene so far are located in or close to the ubiquitin-associated (UBA) domain of the protein. In 2001, we reported genotyping results of genetic markers located in the PDB3 region in an extended American family, indicating the involvement of the PDB3 locus. Here, we report the identification of a novel mutation (G1205C) in the SQSTM1 gene in this family. The G1205C mutation is located in the splice donor site of intron 7 and reverse-transcription polymerase chain reaction experiments showed that the presence of the C allele results in the production of two abnormal mRNA transcripts. Translation of the first transcript would result in a protein that lacks amino acids 351-388, including 26 amino acids of the second PEST domain in addition to two amino acids of the UBA domain. The second mutant mRNA transcript could result in a truncated protein (390X) that lacks almost the complete UBA domain. PDB mutations that disrupt the function of the PEST domain of SQSTM1 have not been reported before, so probably the pathogenic effect of both transcripts resides in the disruption of the ubiquitin-binding properties of the protein.

F-18 fluorodeoxyglocose positron emission tomography/computed tomography in the diagnosis of chronic myopathic sarcoidosis

Muscle involvement is a frequent histopathological feature of sarcoidosis, occurring in 50% to 80% of patients, but it is rarely symptomatic, and often, underreported. Although computed tomography and magnetic resonance imaging findings of muscular sarcoidosis have been described, the fluorodeoxyglucose positron emission tomography imaging characteristics have only recently been reported in a case of localized uptake in the lower extremities. We present a case of diffuse uptake within the most common clinical variant of symptomatic muscular sarcoidosis, chronic myopathy, showing significant uptake of F-18 fluorodeoxyglocose on a positron emission tomography/computed tomography fusion examination.