RESUMO
The objective of this article was to estimate the prevalence of Paget's disease of bone in the United States from a statistically derived sample of the general population. Pelvic radiographs obtained in the First National Health and Nutrition Examination Survey (NHANES-I) were reviewed for the presence of Paget's disease. Age, sex, and geographic distribution of Paget's disease of the pelvic region were determined. The overall prevalence of Paget's disease in the United States was estimated. Pelvic Paget's disease is estimated to be present in 0.71 + 0.18% of the radiographs of the general population. The disease was higher in frequency in people who were in the older decades of life with the highest prevalence of 2.32 + 0.54% in the 65- to 74-year-old people. There is a slight male predominance in the 45- to 74-year age group. The regional distribution suggests the highest prevalence in the Northeast (1.48 + 0.52%) with the lowest prevalence in the South (0.26+0.25%). The prevalence was equal in white people and black people. An estimate of the overall prevalence of Paget's disease in the United States was at least 1% and perhaps as much as 2 % of the general population with near equal sex distribution and the highest prevalence in the northeastern United States.
Assuntos
Osteíte Deformante/epidemiologia , Ossos Pélvicos/patologia , Adulto , Distribuição por Idade , Idoso , Feminino , Inquéritos Epidemiológicos , Humanos , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/patologia , Masculino , Pessoa de Meia-Idade , Osteíte Deformante/diagnóstico por imagem , Osteíte Deformante/patologia , Ossos Pélvicos/diagnóstico por imagem , Prevalência , Radiografia , Estudos de Amostragem , Distribuição por Sexo , Estados Unidos/epidemiologiaRESUMO
The Buschke-Ollendorff syndrome is an association of cutaneous lesions, dermatofibrosis lenticularis disseminata, with osteopoikilosis. This condition is inherited in an autosomal dominant pattern. In order to clarify the biochemical nature of the skin lesions, we have examined 12 patients with the Buschke-Ollendorf syndrome, representing 2 unrelated kindreds. Histologically, the lesions were characterized by excessive amounts of unusually broad, interlacing elastic fibers in the dermis. Digestion of skin secretions with pancreatic elastase completely removed these fibers. Electron microscopy of the dermis further revealed markedly branched elastic fibers without fragmentation. The accumulation of elastin in the skin was also demonstrated by measurements of desmosine employing a radioimmunoassay. The desmosine content of the skin lesions increased 3- to 7-fold when compared to the skin either from healthy controls or from uninvolved skin adjacent to a lesion. The results indicate that the skin lesions of the Buschke-Ollendorff syndrome are connective tissue nevi of the elastin type. Cell cultures from these patients may provide a convenient model to study the control mechanisms involved in elastin metabolism.
Assuntos
Elastina/metabolismo , Fibroma/ultraestrutura , Osteosclerose/patologia , Neoplasias Cutâneas/ultraestrutura , Pele/ultraestrutura , Desmosina/análise , Tecido Elástico/ultraestrutura , Fibroma/metabolismo , Humanos , Osteopecilose/genética , Osteopecilose/metabolismo , Osteosclerose/metabolismo , Pele/metabolismo , Neoplasias Cutâneas/metabolismo , SíndromeRESUMO
Aromatic position 4 somatostatin (SS) analogs were synthesized by solid phase methodology and assayed in vivo for their effects on pentobarbital-stimulated GH levels in fed rats and insulin and glucagon levels in fasted rats. [F5-Phe4]SS was approximately 3 times more active than somatostatin in inhibiting all three hormones. [Phe4,D-Trp8]SS inhibited GH about 4 times more effectively than somatostatin and was only twice as active as somatostatin in the pancreas. [rho-NH2-Phe4]SS exhibited strong selectivity toward inhibition of GH, being 4 times more potent than somatostatin in the pituitary while only about 40% as active in the pancreas. [rho-NH2-Phe4,D-Trp8]SS maintained this same degree of selectivity toward GH inhibition and exhibited a striking 15-fold increase in activity in the pituitary compared to somatostatin. All four analogs inhibited GH for a longer period of time than somatostatin when administered sc at a dose of 10 microgram/100 g BW. [rho-NH2-Phe4,D-Trp8]SS was the longest acting of these analogs, with approximately a 2-h duration of inhibition of GH. [Phe4]SS, administered iv at a dose of 50 microgram/100 g BW, also inhibited GH for approximately 2 h. These data further support the feasibility of developing long-acting somatostatin analogs with selectivity toward a given hormone.
Assuntos
Hormônio do Crescimento/metabolismo , Insulina/metabolismo , Somatostatina/análogos & derivados , Aminoácidos/análise , Animais , Insulina/sangue , Secreção de Insulina , Cinética , Masculino , Pentobarbital/farmacologia , Fragmentos de Peptídeos/síntese química , Ratos , Somatostatina/síntese química , Somatostatina/farmacologia , Relação Estrutura-AtividadeRESUMO
An improved rat anterior pituitary primary cell culture technique for studying GH-releasing activity of human pancreatic GH-releasing factor (hpGRF) and its analogs is described. Male pituitaries, dispersed by a combination of trypsin digestion and mechanical agitation, were plated at a density of 200,000 cells per well and cultured for 4 days. The attached cells were then stimulated with synthetic hpGRF which was comprised of the first 29 residues of the larger, originally isolated forms and which was amidated at the C-terminal (hpGRF-29). Analogs of hpGRF-29 which were modified in positions 1, 2, 3, or 7, and other secretagogues were similarly tested. Medium was collected after 3 h, and secreted hormone was measured by RIA. The cells were extremely sensitive to hpGRF-29 stimulation, and this effect was specific. The minimal effective dose of hpGRF-29 was an unprecedented 0.4 X 10(-15)M. No stimulation of LH, FSH, or PRL by hpGRF-29 was observed. Bombesin and vasoactive intestinal peptide were ineffective in stimulating GH release. [D-Trp6]LHRH (a potent LHRH agonist), also did not release GH but did stimulate secretion of LH and FSH at doses ranging from 0.4 X 10(-10)M to 1.0 X 10(-9)M. Responses of the cells to hpGRF-29 analogs were characterized by distinct heterologous dose-response curves. [D-Ala2]hpGRF-29 was 50 times more active than its parent 29-amino-acid peptide. [D-Thr7]hpGRF-29, another analog that differed from hpGRF-29 by the insertion of a D-isomer for the naturally occurring L-residue, was about 10,000 times less effective in stimulating GH secretion than was hpGRF-29 itself. Potencies of these and other analogs with respect to GH release in vitro were similar to those estimated in vivo. Thus, this primary cell culture provides an extremely sensitive, selective, and reproducible system for studying hpGRF structure-activity relationships. Further, such tremendous sensitivity to hpGRF can provide a system to study changes in pituitary sensitivity to hpGRF during different physiological states.
Assuntos
Hormônio Liberador de Hormônio do Crescimento/análogos & derivados , Hormônio do Crescimento/metabolismo , Adeno-Hipófise/metabolismo , Sequência de Aminoácidos , Animais , Bombesina/farmacologia , Células Cultivadas , Relação Dose-Resposta a Droga , Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/farmacologia , Hormônio Liberador de Hormônio do Crescimento/farmacologia , Masculino , Fragmentos de Peptídeos/farmacologia , Adeno-Hipófise/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Sermorelina , Relação Estrutura-Atividade , Pamoato de Triptorrelina , Peptídeo Intestinal Vasoativo/farmacologiaRESUMO
Peripherally injected bombesin inhibits GH secretion in conscious, freely moving rats and in sodium pentobarbital-anesthetized rats. This inhibition of GH secretion is unusually prolonged, lasting up to 90 min after a single ip injection. The duration of inhibition of GH secretion by bombesin is greater than that observed for somatostatin (SRIF) in the same bioassay. The inhibition of GH release occurs concomitantly with stimulation of gastrin release and is independent of stimulatory effects of bombesin on plasma glucose. The structurally related mammalian gastrin-releasing peptide also inhibits GH secretion in the pentobarbital-anesthetized rat after peripheral injection. Peripherally administered bombesin blocks GH-releasing factor stimulation of GH secretion. Prior treatment of pentobarbital-anesthetized rats with SRIF-specific anti-serum blocks the inhibitory effect of bombesin on GH secretion. No effect of bombesin on GH secretion was observed in primary cultures of rat anterior pituitary cells. These data suggest that peripherally administered bombesin stimulates SRIF secretion, most probably of hypothalamic origin, which, in turn, inhibits pituitary secretion of GH. This sensitivity of the hypothalamus to a peripherally rather than centrally administered peptide has important mechanistic and therapeutic implications.
Assuntos
Bombesina/farmacologia , Hormônio do Crescimento/metabolismo , Peptídeos/farmacologia , Somatostatina/metabolismo , Animais , Relação Dose-Resposta a Droga , Interações Medicamentosas , Soros Imunes , Masculino , Ratos , Ratos Endogâmicos , Somatostatina/imunologia , Fatores de TempoRESUMO
Clinical delineation of the warfarin embryopathy and the recent discovery of osteocalcin (a vitamin K-dependent bone protein) suggest that coumadin therapy could adversely affect the skeleton. Using bone densitometry and metacarpal cortical width measurement, we found normal cortical bone mass in 17 adults receiving long term coumadin therapy.
Assuntos
Osso e Ossos/efeitos dos fármacos , Varfarina/farmacologia , Adulto , Idoso , Osso e Ossos/anatomia & histologia , Densitometria , Feminino , Humanos , Masculino , Metacarpo/anatomia & histologia , Pessoa de Meia-Idade , Vitamina K/antagonistas & inibidores , Varfarina/uso terapêuticoRESUMO
Human adrenomedullin, a novel hypotensive peptide, contains a six-member ring structure similar to that found in calcitonin gene-related peptide and pancreatic amylin. Unlike the full-sequence peptide, human adrenomedullin-(15-22) [hADM-(15-22)], which contains the ring structure, increases systemic arterial pressure in the rat but not the cat. We undertook the present study to investigate the mechanism by which hADM-(15-22) increases systemic arterial pressure in the rat. Injection of hADM-(15-22) in doses of 10 to 300 nmol/kg i.v. increased systemic arterial pressure in a dose-dependent manner and was threefold less potent than norepinephrine when doses were compared on a nanomole basis. However, the ring structures of human calcitonin gene-related peptide and human amylin, human calcitonin gene-related peptide-(1-8) and human amylin-(1-8), respectively, had no significant effect on systemic arterial pressure in the rat. Pressor responses to hADM-(15-22) were reduced significantly after administration of phentolamine or reserpine. Responses to hADM-(15-22) were not altered by the angiotensin type 1 blocking agent DuP 753 or the endothelin-A/endothelin-B receptor blocking agent bosentan, and responses to hADM-(15-22) and the nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium (DMPP) were reduced after bilateral adrenalectomy. Pressor responses to DMPP were reduced by hexamethonium, whereas the nicotinic blocking agent had no effect on the pressor response to hADM-(15-22). These data suggest that increases in systemic arterial pressure in response to hADM-(15-22) in the rat are mediated by the activation of alpha-adrenergic receptors by catecholamines released from the adrenal medulla. The present data suggest that hADM-(15-22) releases catecholamines from the adrenal medulla by a noncholinergic mechanism.
Assuntos
Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Catecolaminas/fisiologia , Fragmentos de Peptídeos/farmacologia , Peptídeos/farmacologia , Pressorreceptores/efeitos dos fármacos , Adrenalectomia , Adrenomedulina , Animais , Gatos , Relação Dose-Resposta a Droga , Feminino , Humanos , Injeções Intravenosas , Masculino , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Proadrenomedullin N-terminal 20 peptide (PAMP) is a 20-amino acid hypotensive peptide expressed in the adrenal medulla. We investigated the localization and function of PAMP receptors in the human adrenal gland. Autoradiography showed the presence of [125I]PAMP-binding sites in both zona glomerulosa and adrenal medulla that were displaced by cold PAMP and PAMP(12-20) but not by other preproadrenomedullin-derived peptides. PAMP, but not PAMP(12-20), counteracted, in a concentration dependent manner, both aldosterone response of zona glomerulosa cells and catecholamine response of adrenal medulla cells to BAYK-8644, the selective agonist of voltage-activated Ca2+ channels, as well as to K+ and angiotensin II. PAMP(12-20) partially reversed this antisecretagogue effect of PAMP. Collectively, these findings suggest (1) that PAMP inhibits Ca2+-dependent, agonist-stimulated aldosterone and catecholamine secretion, acting via specific receptors and through a mechanism involving the impairment of Ca2+ influx; and (2) that PAMP(12-20) acts as a weak antagonist of PAMP receptors, thereby suggesting that both C- and N-terminal sequences of the PAMP molecule are required for this peptide to exert its antisecretagogue action on the human adrenal gland.
Assuntos
Glândulas Suprarrenais/metabolismo , Cálcio/metabolismo , Fragmentos de Peptídeos/fisiologia , Peptídeos/fisiologia , Proteínas/fisiologia , Receptores de Superfície Celular/fisiologia , Glândulas Suprarrenais/efeitos dos fármacos , Adulto , Aldosterona/análise , Aldosterona/metabolismo , Análise de Variância , Autorradiografia , Sítios de Ligação , Canais de Cálcio/metabolismo , Cromatografia Líquida de Alta Pressão , Epinefrina/análise , Epinefrina/metabolismo , Humanos , Técnicas In Vitro , Pessoa de Meia-Idade , Norepinefrina/análise , Norepinefrina/metabolismo , Fragmentos de Peptídeos/metabolismo , Peptídeos/metabolismo , Potássio/metabolismo , Proteínas/metabolismo , Radioimunoensaio , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/metabolismoRESUMO
Alendronate, an aminobisphosphonate, is much more potent than etidronate, an older bisphosphonate, in inhibiting osteoclast-mediated bone resorption, and unlike etidronate, therapeutic doses of alendronate are not associated with abnormal mineralization. In the present study, we compared the effectiveness, safety, and tolerability of 6 months of daily oral administration of alendronate (40 mg) with those of etidronate (400 mg) in 89 patients with clinically active Paget's disease. The primary efficacy end point was the percent change in serum alkaline phosphatase. Other end points included changes in urinary deoxypyridinoline excretion, pain, functional impairment scores, and radiological osteolysis. Tetracycline-labeled bone biopsies were obtained for histomorphometric analysis from a subset of 43 patients at the 6-month visit. The alendronate-treated group had significantly greater decreases in both serum alkaline phosphatase (79% vs. 44%) and urinary deoxypyridinoline (75% vs. 51%) than the etidronate-treated group (P < 0.001 in both cases). Normalization of serum alkaline phosphatase was much more frequent in alendronate-treated patients (63.4% vs. 17.0%; P < 0.001). Alendronate was well tolerated and had a safety profile similar to that of etidronate. Histomorphometry revealed decreased bone turnover and no qualitative abnormalities, including no direct negative effects on bone mineralization, with alendronate treatment. One patient receiving etidronate developed frank osteomalacia. Alendronate appears to be a highly effective treatment for Paget's disease of bone that offers an important therapeutic advance over etidronate.
Assuntos
Alendronato/uso terapêutico , Ácido Etidrônico/uso terapêutico , Osteíte Deformante/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Alendronato/efeitos adversos , Fosfatase Alcalina/sangue , Aminoácidos/urina , Biópsia , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Cálcio/sangue , Ácido Etidrônico/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteíte Deformante/patologia , Osteíte Deformante/fisiopatologia , Dor , Fosfatos/sangue , RadiografiaRESUMO
Investigation of the kindred of a 58-year-old woman with all of the features of "adult" hypophosphatasia revealed 12 individuals in 3 generations with subnormal circulating total alkaline phosphatase (AP) activity. The pattern of inheritance suggested autosomal dominant transmission, with incomplete penetrance of the trait particularly in the young males. Hypophosphatasic individuals other than the proposita were clinically well but had loss of permanent teeth, showing that dental abnormalities could be the only clinical manifestation of the disorder. Radiographic investigation of the proposita revealed that completion of stress fractures was necessary for healing; maturation of incomplete fractures resulted in stable Looser zones. Skeletal survey and radionuclide bone imaging were unremarkable in hypophosphatasic individuals without fracture. Subclinical osteopenia was found in several affected women by metacarpal cortical width and bone densitometric measurements. Laboratory studies showed increased plasma and urinary phosphoethanolamine levels in affected individuals. Phosphoethanolamine and phosphoserine appeared to be natural subtrates for AP since a negative correlation existed between each substrate and circulating total AP activity. Phosphoethanolamine and phosphoserine levels were greatest in the clinically affected proposita; furthermore, only she showed absence of leukocyte AP activity. Heat fractionation of her total circulating AP activity suggested severe reduction in the bone isoenzyme. Hypophosphatasic children had higher levels of total circulating AP than affected adults; the increase was apparently secondary to increased bone isoenzyme. Iliac crest bone biopsies showed greater abnormality in affected women. Osteoidosis was particularly pronounced in the proposita's younger affected sister and hypophosphatasic daughter. Histomorphometric analyses of the biopsies revealed a paucity of osteoblasts despite increased quantities of unmineralized matrix. The finding that hypophosphatasic children in this kindred had higher circulating total AP activity than adults and were able to model their skeleton normally, together with observations that the bone biopsy in adults had a paucity of osteoblasts, suggests that some factor(s) during growth is able to induce both AP activity and osteoblast function, or, that this disorder is an "abiotrophy" with deficient osteoblastic formation and/or accelerated destruction in adult life.
Assuntos
Hipofosfatasia/genética , Adolescente , Adulto , Fatores Etários , Idoso , Fosfatase Alcalina/sangue , Biópsia , Criança , Pré-Escolar , Feminino , Frequência do Gene , Humanos , Hipofosfatasia/diagnóstico , Hipofosfatasia/patologia , Ílio/patologia , Masculino , Pessoa de Meia-Idade , Osteogênese , Osteólise/diagnóstico , Osteólise/genética , Osteólise/patologia , Linhagem , Fenótipo , Fatores SexuaisRESUMO
Research and management of XLH have concentrated on the disease in childhood, and the natural history and morbidity of XLH in adult life are thus poorly understood. We have studied 22 adults (6 men) with XLH to clarify these aspects of this most common inherited form of rickets and osteomalacia. Most study participants had presented with rickets in early childhood and had undergone tibial osteotomies on at least 1 occasion. Seventeen individuals had genu varum, 1 had genu valgum, and 4 had straight legs, attributable to successful osteotomies in 2. Five subjects reported increasing lower limb deformity in the late teens or subsequently. Eight subjects complained of bone pain, 6 of whom had radiologic evidence of pseudofractures; pseudofractures were found in 4 additional asymptomatic individuals. None of 16 subjects who underwent transiliac bone biopsy had normal double tetracycline labeling; accordingly, all were considered to have osteomalacia. Bone pain was associated with a relative osteoid volume in excess of 25%. Relative osteoid volume was inversely related to serum 1,25(OH)2D concentration (r = -0.74, p less than 0.02), but unrelated to serum concentrations of calcium and phosphate or their product. Eighteen participants complained of joint pain, predominantly in the knees and ankles. The severity of joint pain correlated with the degree of lower limb deformity (p = 0.011) which, in turn, was related to fasting serum phosphate concentration (r = -0.56, p less than 0.025) and TmP/GFR (r = -0.70, p less than 0.005). Enthesopathy affected 33% of those younger than 30 years, and all those above this age. Nineteen individuals had experienced significant dental problems, most commonly abscess formation. Eight had required complete dental clearance. Twelve women from the group had a total of 22 live births. Fifteen of these were by cesarean section, although radiologic evidence of pelvic narrowing was not found in any subject. Serum ALP was elevated in all but 3 of the 18 untreated subjects. Levels correlated with those of other indices of bone turnover (BGP r = 0.82, p less than 0.005; urine total HP r = 0.60, p less than 0.025; urine free HPr = 0.78, p less than 0.005), but were not related to the degree of osteomalacia found on bone biopsy. Serum levels of iPTH, 25(OH)D, 1,25(OH)2D, and thyroid hormones were generally normal in the untreated patients. We conclude that adults with untreated XLH have osteomalacia that is frequently symptomatic. Even greater morbidity is caused by degenerative joint disease arising from lower limb deformities.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Hipofosfatemia Familiar/genética , Cromossomo X , Adulto , Idoso , Osso e Ossos/patologia , Feminino , Ligação Genética , Humanos , Hipofosfatemia Familiar/metabolismo , Hipofosfatemia Familiar/patologia , Masculino , Pessoa de Meia-Idade , Doenças Musculares/patologia , Osteoartrite/patologia , Osteomalacia/patologia , Dor , Fosfatos/sangue , Estudos ProspectivosRESUMO
Three sisters, each with chondrocalcinosis/arthropathy, are described who have the clinical, laboratory and pathologic findings characteristic of the adult form of hypophosphatasia. Premature loss of adult teeth, arthralgias and pain from bilateral femoral pseudo-fractures were associated with subnormal circulating alkaline phosphatase levels, phosphoethanolaminuria and osteomalacia diagnosed by iliac crest biopsy. Assay of alkaline phosphatase activity in the blood of kindred members revealed hypophosphatasemia in one of two younger brothers. Several subjects in subsequent generations also had suspiciously low alkaline phosphatase activity, but did not have histories of significant dental, bone or joint disease. Review of the medical records of the sisters' parents, aunts and uncles revealed normal alkaline phosphatase levels in their father and five of his siblings, but consistently low levels in their mother and two of her siblings. Despite hypophosphatasemia, the sisters' mother and her siblings lived to old age without clinical or radiographic evidence of bone disease. Our findings suggest that although adult hypophosphatasia can be transmitted as a dominant trait in some kindreds, there is considerable variation in the clinical expression of the biochemical defect. One person, generation or family may manifest clinical bone disease and arthropathy whereas the biochemical defect may be present but remain asymptomatic in others. Furthermore, in some cases, the adult form of hypophosphatasia may represent a developmental disorder with hypophosphatasemia appearing during adulthood.
Assuntos
Condrocalcinose/genética , Hipofosfatasia/genética , Artropatias/genética , Adolescente , Adulto , Idoso , Fosfatase Alcalina/sangue , Criança , Pré-Escolar , Condrocalcinose/etiologia , Feminino , Genes Dominantes , Humanos , Hipofosfatasia/complicações , Hipofosfatasia/diagnóstico , Hipofosfatasia/enzimologia , Artropatias/etiologia , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
Paget's bone disease is rare in young adults. Severe osteolytic Paget's bone disease in a 28-year-old man was found to respond, clinically, biochemically, and radiographically, within one month to daily subcutaneous injections of 0.5 mg of synthetic human calcitonin. After two years of therapy, he remains asymptomatic and has no biochemical evidence of Paget's bone disease while receiving injections three times a week. Despite aggressive disease, young patients may rapidly demonstrate the same beneficial response to synthetic human calcitonin therapy as has been observed in middle-aged or elderly patients with Paget's bone disease.
Assuntos
Calcitonina/uso terapêutico , Osteíte Deformante/tratamento farmacológico , Adulto , Osso e Ossos/diagnóstico por imagem , Humanos , Masculino , Osteíte Deformante/diagnóstico por imagem , Osteíte Deformante/metabolismo , RadiografiaRESUMO
Axial osteomalacia--a rare osteosclerotic bone disorder characterized by axial skeleton pain, coarsening of the trabecular bone pattern on radiographs of the axial but not appendicular skeleton, and osteomalacia on biopsy of a rib or iliac crest--has been reported in 10 apparently sporadic cases, all of which were in middle-aged or elderly Caucasian men. The etiology is unknown but has been postulated to be a bone cell defect. We describe the clinical, laboratory, pathologic and family study of a black mother and son with axial osteomalacia associated with polycystic liver and kidney disease. Investigation of the son suggested that radiographic osteosclerosis can be detected in early adulthood. Limited skeletal survey of his three children revealed no abnormalities. Examination of undecalcified iliac crest bone after in vivo tetracycline labeling revealed severe osteomalacia in the son despite normal circulating calcium, inorganic phosphate and vitamin D metabolite levels and persistently elevated alkaline phosphatase activity. Although osteoblasts appeared flat and inactive, histochemical studies showed intense alkaline phosphatase activity in the osteoblasts along most trabecular bone surfaces. Electron microscopy revealed intact matrix vesicles within unmineralized osteoid. The presence also of unexplained myopathy in the son--characterized by proximal muscle weakness, persistently elevated circulating creatine phosphokinase levels and pathogenic changes of myopathy on biopsy of quadriceps muscle--together with impaired bone mineralization, suggests that a disorder of vitamin D action may be involved in the pathogenesis of this unusual condition. Axial osteomalacia affects blacks as well as Caucasians, women as well as men, may be familial, and may perhaps be a developmental abnormality inherited in association with polycystic kidney and liver disease.
Assuntos
Osteomalacia/genética , Adolescente , Adulto , Idoso , Biópsia , Criança , Cistos/genética , Feminino , Humanos , Ílio/patologia , Hepatopatias/genética , Masculino , Pessoa de Meia-Idade , Osteomalacia/diagnóstico , Osteomalacia/patologia , Doenças Renais Policísticas/genéticaRESUMO
PURPOSE: We identify a new syndrome of acquired painful diffuse osteosclerosis associated with past intravenous drug abuse in two adults. METHODS: A 28-year-old white woman and a 38-year-old black man with a history of non-A, non-B chronic active hepatitis were referred to us for increasing bone pain that was especially severe in their lower extremities. They were studied at our clinical research center. RESULTS: Skeletal radiographs documented progressive generalized osteosclerosis. Increased bone mass was confirmed by dual-energy radiography, and bone scintigraphy showed diffusely increased radionuclide accumulation. Serum biochemical studies revealed elevated alkaline phosphatase activity and osteocalcin levels, mild to moderately increased 1,25-dihydroxyvitamin D concentrations, and normal parathyroid hormone levels. In urine, hydroxyproline excretion was elevated, whereas calcium levels were reduced. Iliac crest histomorphometry showed increased rates of bone formation. Hematology, renal function, serum protein electrophoresis, and screening for fluorosis as well as vitamin A and heavy metal poisoning were all normal. Family histories were negative. Both patients were seropositive for antibody against hepatitis C virus as well as against Epstein-Barr virus (antiviral capsid antigen IgG but not IgM). Each subject was seronegative for cytomegalovirus, human immunodeficiency virus (HIV) 1 and 2, and human T-cell lymphotropic virus (HTLV) 1 and 2. Assay for reverse transcriptase in lymphocyte co-culture fluid and polymerase chain reaction studies using HIV-1 primers on peripheral monocyte DNA were negative. Treatment with synthetic salmon calcitonin in both individuals rapidly led to decreased bone pain and to a decline in biochemical parameters of accelerated bone turnover. CONCLUSION: Painful diffuse osteosclerosis can follow intravenous drug abuse and is possibly caused by parenteral transmission of a virus that in some way stimulates bone formation.
Assuntos
Osteosclerose/etiologia , Abuso de Substâncias por Via Intravenosa/complicações , Adulto , Anticorpos Antivirais/sangue , Remodelação Óssea/fisiologia , Calcitonina/uso terapêutico , Feminino , Hepacivirus/imunologia , Herpesvirus Humano 4/imunologia , Humanos , Imunoglobulina G/sangue , Masculino , Osteosclerose/diagnóstico por imagem , Osteosclerose/microbiologia , Dor/tratamento farmacológico , Dor/etiologia , RadiografiaRESUMO
Twenty-six women with untreated postmenopausal osteoporosis underwent iliac crest biopsy following tetracycline-labeling and mineral metabolism studies. Histomorphometric assessment of their bone remodeling rates, including formation determined by the tetracycline-labeling technique, revealed considerable variation. Eight women had no evidence of active bone formation (inactive remodeling osteoporosis), whereas the others showed a spectrum of bone formation rates (active remodeling osteoporosis). Clinical and biochemical studies failed to predict the histomorphometric findings. Postmenopausal osteoporosis is a histologically heterogeneous disorder with morphologic expression in bone that cannot be predicted by single or combined routine clinical and laboratory parameters. Bone biopsy, necessary to identify the histologic lesion and assess skeletal dynamics, may prove to be important for optimal therapy of osteoporosis, as a variety of agents--with different effects on bone remodeling--are available.
Assuntos
Calcificação Fisiológica , Menopausa , Osteoporose/patologia , Idoso , Desenvolvimento Ósseo , Reabsorção Óssea , Feminino , Humanos , Ílio/metabolismo , Ílio/patologia , Pessoa de Meia-Idade , Osteoporose/metabolismo , Hormônio Paratireóideo/sangue , TetraciclinaRESUMO
PURPOSE AND PATIENTS AND METHODS: X-linked hypophosphatemia (XLH) is the most common inherited form of rickets, yet its influence on skeletal mass in adulthood is controversial and incompletely characterized. Accordingly, we measured bone mass at several skeletal sites using histomorphometric and radiographic techniques in 19 adults (four men) with XLH (age range 20 to 66 years). Most subjects had not received medical therapy for XLH since puberty. RESULTS: Eight of 14 subjects who underwent transiliac bone biopsy had an elevated cancellous bone volume (osteoid and calcified bone), and the group's mean value was supranormal (p less than 0.01). Mineralized bone volume, however, was above normal in only three subjects (NS). Another measure of trabecular bone density, vertebral mineral density by computed tomography, was elevated in three of 13 subjects, and the mean value of the group was increased (p = 0.05). Integral spine bone mineral density (BMD) assessed by dual photon absorptiometry (DPA) was elevated in six of 16 subjects, and the mean was also above normal (p less than 0.01). However, total body calcium, total body BMD (both by DPA), and forearm bone mineral content assessed by single photon absorptiometry (predominantly cortical bone) were normal in almost all subjects, as were the group means for these parameters. Mean regional BMD (by DPA) was below normal in the upper and lower limbs (p less than 0.001) and above normal in the spine (p less than 0.005) and ribs (p less than 0.01). There was no relationship between these indices of bone mass and either biochemical or clinical parameters of disease severity, although men tended to have higher z-scores for axial bone density than premenopausal women whose values, in turn, tended to be higher than those in postmenopausal women (NS). CONCLUSION: We conclude that axial bone mass tends to be increased in adults with XLH, sometimes dramatically so, and this is only partially attributable to hyperosteoidosis. Peripheral bone mass, however, tends to be diminished. Despite these group trends, most adults with untreated XLH have normal indices of bone mass as assessed by a variety of techniques at the commonly used measurement sites. These findings suggest that "osteoporotic" fractures are unlikely to develop as a late complication of XLH in adults.
Assuntos
Densidade Óssea , Hipofosfatemia Familiar/fisiopatologia , Absorciometria de Fóton , Adulto , Idoso , Biópsia , Feminino , Humanos , Hipofosfatemia Familiar/diagnóstico por imagem , Hipofosfatemia Familiar/patologia , Ílio/patologia , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X , Cromossomo XRESUMO
PURPOSE: A large kindred with familial benign hypercalcemia (FBH) is described because of the new observation of developmental increases in serum immunoreactive parathyroid hormone (iPTH) levels in affected individuals that lead to significantly elevated values in adults. PATIENTS AND METHODS: After identification of the proposita, 46 kindred members spanning 5 generations, ages 1.5 to 91 years, were surveyed biochemically and/or studied by chart review. Two hypercalcemic adults underwent biopsy of the iliac crest following tetracycline labeling for histomorphometric study. RESULTS: Of the 46 individuals studied, 19 were found to be affected. Serum iPTH levels, determined in three separate immunoassays, became supranormal by about age 30 years in the group of 15 hypercalcemic subjects examined biochemically and appeared to increase further thereafter. Serum alkaline phosphatase activity and creatinine levels were normal in these individuals, but inorganic phosphate levels were lower than in unaffected kindred members. Three of five affected adults older than age 40 years who were studied radiographically had changes suggestive of osteomalacia. Biopsy of the iliac crest of one of the subjects, a 51-year-old woman, confirmed the presence of defective skeletal mineralization. CONCLUSIONS: In this kindred, FBH in adults can be especially difficult to distinguish from primary hyperparathyroidism because serum iPTH levels may be elevated. Furthermore, the disorder may not be totally benign. Osteomalacia, perhaps due to mild hypophosphatemia, can develop during adulthood. Review of data from other kindreds for evidence of developmental elevations in serum iPTH levels with careful search for skeletal disease in late adult life will help to clarify if we have observed an unusual variant of FBH.
Assuntos
Hipercalcemia/sangue , Hipercalcemia/genética , Hormônio Paratireóideo/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/sangue , Criança , Pré-Escolar , Feminino , Humanos , Hipercalcemia/complicações , Hipercalcemia/diagnóstico , Hipofosfatemia Familiar/complicações , Lactente , Masculino , Pessoa de Meia-Idade , Osteomalacia/diagnóstico por imagem , Osteomalacia/etiologia , Linhagem , Radiografia , Análise de RegressãoRESUMO
Three adult sisters with osteopetrosis in infancy had spontaneous resolution of bone modeling defects and osteosclerosis. During adolescence, basal ganglia calcification developed in two. Renal tubular acidosis (type I) was diagnosed in each during early adulthood. The disorder was transmitted apparently as a recessive trait--the same mode of inheritance as for the "malignant" form of osteopetrosis which is usually fatal during childhood. Electron microscopy of bone suggested that osteoclasts failed to form "ruffled membranes" characteristic of active bone resorbing cells. Chronic systemic acidosis may have ameliorated the skeletal manifestations of this new syndrome.
Assuntos
Acidose Tubular Renal/genética , Doenças dos Gânglios da Base/genética , Osteopetrose/genética , Acidose Tubular Renal/patologia , Adulto , Doenças dos Gânglios da Base/patologia , Biópsia , Osso e Ossos/patologia , Calcinose/genética , Feminino , Genes Recessivos , Humanos , Testes de Função Renal , Microscopia Eletrônica , Osteopetrose/patologia , Linhagem , SíndromeRESUMO
PURPOSE: The potent bisphosphonates offer great promise in the management of Paget's disease of bone, but are currently available only as parenteral preparations in most countries. There is a need for a well-tolerated, oral therapy. Furthermore, none of the currently available therapies have been rigorously demonstrated to heal the lytic bone lesions characteristic of this condition. Alendronate is a potent new oral aminobisphosphonate that has shown promising effects on Paget's disease in preliminary studies. METHODS: We report a double-blind, randomized comparison of oral alendronate 40 mg/day and placebo over 6 months in 55 patients with Paget's disease. Efficacy was determined from measurements of biochemical indices of bone turnover (serum alkaline phosphatase and urine N-telopeptide) and blinded radiologic assessment of lytic bone lesions. RESULTS: N-telopeptide excretion declined by 86% and serum alkaline phosphatase by 73% in patients receiving alendronate, but remained stable in patients receiving placebo (P < 0.001 between groups for both indices). Responses were similar whether or not patients had previously received bisphosphonate treatment. Alendronate treatment normalized alkaline phosphatase in 48% of patients. Forty-eight percent of alendronate-treated patients showed radiologic improvement in osteolysis whereas in the placebo group only 4% improved (P = 0.02 for between-groups comparison). No patient in either group showed worsening of osteolysis. Bone histomorphometry indicated that alendronate tended to normalize turnover indices. There was no evidence of abnormal mineralization in bone biopsies taken from 12 alendronate-treated subjects. The treatment was well tolerated. CONCLUSION: Oral alendronate appears to be a safe and effective therapy for Paget's disease and results in healing of lytic bone lesions.