Paget's disease of bone: exploring the questions.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
F S Kaplan
Publications and source records attributed to F S Kaplan.
The role of morphogens in endochondral ossification.
The formation of bone occurs normally by one of two developmental processes: intramembranous or endochondral ossification. Endochondral ossification occurs in the morphogenesis of the limb buds and growth plates, and in the regeneration of bone following injury (fracture callus). Two classes of diffusible morphogen-like molecules (MLMs) involved in limb development are the bone morphogenetic proteins (BMPs) and retinoic acid (RA). These MLMs are associated, respectively, with the apical ectodermal ridge (AER) and the zone of polarizing activity (ZPA) of the primitive limb bud. They function as potent regulators of pattern formation and are involved in tissue proliferation and differentiation. The presence of endochondral ossification in fracture callus suggests a role for MLMs in that process as well. To date, virtually nothing is known about the role of morphogens in the regeneration of bone (fracture healing). In this article, we review the current knowledge of MLMs in bone formation and propose a theory on their role in fracture healing. We hypothesize that MLMs involved in fracture healing may also express spatial and temporal information. A more complete understanding of the role of morphogens in both limb development and fracture healing is of major importance to practicing orthopedists and their patients.
Animals↗
A bone morphogenetic protein subfamily: chromosomal localization of human genes for BMP5, BMP6, and BMP7.
Bone morphogenetic proteins (BMPs) were originally identified by the ability of a demineralized bone extract to induce endochondral osteogenesis in vivo. Seven BMP cDNAs (BMP1 through BMP7) have been recovered through molecular cloning. Recombinant protein products from six of these clones (BMP2 through BMP7) are members of the transforming growth factor beta (TGF-beta) superfamily of regulatory molecules. Based upon a high degree of amino acid sequence homology, BMP5, BMP6, and BMP7 constitute a subfamily within the BMPs. Using human-rodent somatic cell hybrid lines and cDNA probes, we mapped the three members of this subfamily of genes to the human chromosomes. BMP5 and BMP6 are syntenic on human chromosome 6, while BMP7 is syntenic with previously localized BMP2 on human chromosome 20. This analysis reveals that BMP6 maps to a conserved region between the mouse and human genomes. Sequence analysis suggests that the Drosophila 60A gene is the dipteran homolog of this BMP subfamily and may provide clues to the physiologic functions of the products of these genes in human biology.
Animals↗
Osteon morphometry in females with femoral neck fractures.
The authors measured osteon dimensions and number in specimens of cortical bone obtained from the medial femoral neck (calcar) from nine female patients treated with hemiarthroplasty for femoral neck fractures, and from 12 (seven women, five men) age-matched cadavers without fractures. Specimens from the same location in 14 (seven women, seven men) younger patients treated with total hip arthroplasty (THA) for osteoarthrosis were also studied. There were fewer osteons per unit area and the osteons and their Haversian canals were bigger in the fracture group than in the nonfracture or osteoarthritic groups. Patients with femoral neck fractures also exhibited a decreased Singh index and an increased intracortical porosity compared with age-matched normal controls. By contrast, the osteoarthritic group showed no difference in osteon or Haversian dimensions, osteon number per unit area, Singh index, or in porosity compared with the nonfracture group. These morphometric differences found in the cortical bone of the medial femoral neck may play a role in the incidence of fractures.
Aged↗
The articular manifestations of Paget's disease of bone. A case report.
Disorders of joints are commonly associated with Paget's disease of bone but are often disregarded or attributed to the underlying Pagetic condition. The authors evaluated a 69-year-old man with extensive Paget's disease of bone, degenerative arthritis, calcific periarthritis, and gout. The degenerative arthritis and calcific periarthritis of the shoulders was originally mistaken for Paget's disease of the proximal humerus. The wrist arthritis was attributed to Paget's disease until evaluation of surgical pathology specimens showed intraarticular gouty granulomas. In evaluating and treating a patient with Paget's disease of bone, the orthopedic surgeon should be aware that the successful treatment of associated articular disorders may require therapeutic measures in addition to those used in treating the Paget's disease.
Aged↗
A longitudinal study of metacarpal bone morphometry in anorexia nervosa.
Osteoporosis is a known complication of anorexia nervosa. Although calorie and mineral malnutrition may contribute to changes in bone mass and morphometry, hypoestrogenism is thought to be the most important etiologic factor. In a seven-year longitudinal study of six women aged 19 to 35 years with adolescent-onset anorexia nervosa, the objective was to correlate menstruation and bone morphometry. At the onset of the study, five women were amenorrheic and had abnormal metacarpal bone morphometry. After seven years, three women remained amenorrheic and below 85% of ideal body weight. Anteroposterior roentgenographs of the nondominant second metacarpal taken at the beginning and end of the study revealed an increase in medullary canal diameter (p less than 0.03) and medullary area (p less than 0.04) and a decrease in combined cortical thickness (p less than 0.04) and percent cortical area (p less than 0.02). These findings suggest progressive endosteal resorption in the absence of compensatory periosteal apposition. Such bone remodeling characteristics are distinctly abnormal in this age group. The three women who regained menses showed up to one third less endosteal resorption and less cortical thinning than did the three women who remained amenorrheic. Resumption of menses may be an important milestone in preventing further cortical bone loss in anorexia nervosa.
Adult↗
Estrogen receptors in fracture healing.
Estrogen has profound effects on the regulation of bone metabolism, but its role in fracture healing is unknown. Several recent reports have documented the presence of estrogen receptors in vitro and in diseased tissue. The authors investigated estrogen receptors in nonneoplastic skeletal tissues by immunohistochemical and radioligand binding techniques. Using a fibular osteotomy model of fracture healing in New Zealand rabbits, radioligand binding detected specific, high affinity, saturable estradiol binding sites at low levels throughout fracture healing, with a trend towards a bimodal distribution. Peaks occurred three and 16 days after osteotomy. No estrogen receptor was found by either method in later fracture callus, growth plate, or periosteum. These findings suggest a possible role for estrogen in the early inductive phase and later phase of endochondral ossification in fracture healing.
Animals↗
Bone morphogenetic protein: chromosomal localization of human genes for BMP1, BMP2A, and BMP3.
Bone morphogenetic protein (BMP) induces endochondral bone formation in vivo. The human genes have been cloned for a group of proteins containing BMP activity (BMP1, BMP2A, and BMP3). Two of the proteins are members of the transforming growth factor-beta supergene family (BMP2A and BMP3), while BMP1 is a novel regulatory protein. Using somatic cell hybrid lines, cDNA probes were used to map BMP1 to chromosome 8, BMP2A to chromosome 20, and BMP3 to the p14-q21 region of chromosome 4. This analysis reveals that the BMP2A and BMP3 genes map to conserved regions between mouse and human, while the BMP1 gene does not. The locations of the BMP genes were found to overlap with the loci for several disorders of cartilage and bone formation.
Bone Diseases↗
Transient infantile osteopetrosis.
Explore the source record for details and available documents.
Biopsy↗
Trabecular structure: preliminary application of MR interferometry.
A new approach to probe the structure of trabecular bone in the vertebral bodies in humans was evaluated, and preliminary data are presented. The proposed method is based on the hypothesis that the presence of two physical phases--bone and bone marrow--causes a magnetic field distribution across the imaging voxel. The resulting spread in resonance frequency produces line broadening, which is measured as the decay rate of the region of interest signal intensity that has the properties of an interferogram. The interferogram is the result of two principal chemically shifted components of bone marrow--fat and water--getting in and out of phase with one another while being attenuated by T2* processes from the magnetic field distribution within the measuring volume. The time constant for the decay (T2*) can then be obtained by means of curve-fitting techniques. T2* in healthy persons is found to increase slightly with age. However, patients with osteoporosis (low bone mineral density and/or spine compression fractures) have significantly prolonged T2* values, which are interpreted as arising from an increase in the intertrabecular space.
Adolescent↗
Hurler syndrome with special reference to histologic abnormalities of the growth plate.
Hurler syndrome is a mucopolysaccharide disorder resulting from an heritable deficiency in alpha-L-iduronidase, an enzyme required in the catabolism of heparan sulfate and dermatan sulfate glycosaminoglycan (GAGs). The resultant intracellular accumulation of GAG leads to disruption of the intracellular and extracellular environment and dysfunction of multiple organ systems. Among the most noted manifestations of this disease is disproportionate short trunk dwarfism, which develops during the first years of life. Histochemical and electron-microscopic observations on a 30-month-old child with Hurler syndrome showed marked irregularities in chondrocyte orientation within the growth plate, along with disruption of the normal columnar architecture. Vacuolization with enlargement of the cellular border was the characteristic ultrastructural finding. An heritable abnormality in the enzymatic degradation of structural glycosaminoglycans leads to profound disruption of the normal mechanisms of growth and development.
Cartilage↗
Fibrodysplasia ossificans progressiva: a clue from the fly?
Fibrodysplasia (myositis) ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by symmetrical congenital malformations of the blastemal anlage of the hands and feet and by progressive heterotopic chondrogenesis and ossification of the soft connective tissues. There is neither an established pathogenesis nor an effective treatment for this disabling disorder. We reevaluated the published data on the natural history of FOP and discovered an array of developmental gradients (characteristic patterns of disease expression) similar to developmental anomalies induced by pleiotropic mutations of the decapentaplegic (dpp) locus in Drosophila melanogaster. The protein encoded by the dpp locus is a member of the transforming growth factor-beta (TGF-beta) family of molecules. It shares 75% sequence homology with the c-terminal region of two recently cloned human bone morphogenetic proteins (BMP-2A, BMP-2B), also members of the TGF-beta family. The striking sequence identity across so large an evolutionary distance suggests that the BMP-2 genes in man and the dpp gene in the fly may be derived from a common ancestral gene. BMP is the only molecule discovered thus far that is capable of inducing endochondral ossification in vivo. Expression of endochondral bone formation is the basis for limb formation in embryogenesis, longitudinal bone growth in postnatal life, and local bone regeneration (fracture healing) following injury. We believe that FOP is a genetic disorder characterized by a disturbed developmental expression of this endochondral program and may represent a mutation resulting in a dominant gain of function. The developmental similarities between decapentaplegic in the fly and FOP in man suggest a useful model for the study of FOP. The use of such a model might be especially fruitful in suggesting a molecular basis for FOP.
Animals↗
Alkaline phosphatase production by periosteal cells at various oxygen tensions in vitro.
A mammalian periosteal cell culture system was developed to investigate the metabolic response of fresh calf bone periosteal cells to various oxygen tensions in vitro. Two predominant cell phenotypes were seen in the culture system. A rapidly proliferating mat of alkaline phosphatase-negative cells supported the growth of overlying clusters of alkaline phosphatase-positive cells. The appearance and subsequent population growth of the alkaline phosphatase-positive cells correlated directly with increases in enzyme activity on biochemical assay. Alkaline phosphatase production was optimal at lower oxygen tensions (5%, 9%), which approximated capillary pO2. In addition, the preconfluence oxygen environment was more critical to the final expression of the enzyme activity than the postconfluence environment. The mechanism of the environmental regulation of alkaline phosphatase gene expression at various oxygen tensions is not known. Periosteal cells were highly sensitive to oxygen tension and expressed alkaline phosphatase enzyme activity at oxygen levels approximating capillary rather than atmospheric pO2.
Alkaline Phosphatase↗
Regional migratory osteoporosis. A case report and review of the literature.
Regional migratory osteoporosis (RMO) is an idiopathic disorder characterized by bouts of severe periarticular lower limb pain associated with rapidly developing localized osteoporosis. Symptoms often reverse spontaneously after six to nine months. Recurrence of symptoms in an adjacent joint is a distinguishing feature. Routine laboratory tests are uninformative. Diagnosis is made after exclusion of more common entities. Knowledge of RMO can prevent unnecessary invasive procedures. Vertebral osteoporosis has recently been associated with RMO. A 50-year-old physician developed the symptoms and signs of RMO superimposed upon well-documented idiopathic vertebral osteoporosis. This association should be recognized when evaluating lower limb pain.
Humans↗
Calcium homeostasis.
Precise maintenance of the physiologic levels of both extracellular and intracellular ionized calcium is essential to life. Calcium and phosphate homeostasis is complex, yet three important hormones are responsible for modulating most of the extracellular control of these minerals. Parathyroid hormone acts directly on bone and kidney and indirectly on the intestine to maintain or restore the serum calcium level. The signal for increased PTH synthesis and secretion is a decrease in the serum ionized calcium concentration and a decrease in serum levels of 1,25(OH)2-D. Calcitonin is produced in parafollicular cells of the thyroid and inhibits bone resorption in pharmacologic doses. These cells recognize the calcium signal in a different way. A diminution in serum calcium decreases calcitonin production and release. The role of calcitonin in normal human physiology, however, remains in dispute. Finally, the biologically potent metabolite of vitamin D, 1,25(OH)2-D, stimulates intestinal absorption of calcium and phosphate. It also probably plays a role in the orderly mineralization and resorption of bone and has some influence on renal resorption of filtered calcium and phosphorus. A major stimulus to its production by proximal renal tubule cells is elevated PTH and decreased serum levels of calcium and phosphate. The absence of PTH as well as high serum calcium and phosphate levels can reduce its synthesis and secretion. These three hormones along with other mediators and messengers work in concert to maintain the normal calcium homeostasis. A disturbance at any level in this intricate regulatory network will result in a host of compensatory changes that may lead to clinical disease. A complete understanding of these normal mechanisms is a prerequisite to investigating the etiology and treatment of the various pathologic responses seen with many of the metabolic bone disorders.
Calcitonin↗
Quantitative computed tomography reflects vertebral fracture morbidity in osteopenic patients.
We studied the relationship between spontaneous vertebral compression fractures and lumbar vertebral trabecular bone density in 69 consecutive patients with suspected osteopenia. Seven had biopsy-confirmed osteomalacia. The remaining 62 were divided into three groups: group 1--asymptomatic patients suspected of having osteopenia on plain films, but with no vertebral compression fractures (N = 24); group II--those with one to five vertebral compression fractures (N = 16); and group III--those with six or more vertebral compression fractures (N = 22). A quantitative computed tomographic (QCT) scan of the lumbar spine was performed on all patients. Patients in group I had QCT values of 94 +/- 23 mg/cm3 (mean +/- SE); those in group II had QCT values of 66 +/- 28 mg/cm3; and those in group III had values of 34 +/- 28 mg/cm3. There were significant differences among all groups (P less than .001), although there was considerable overlap of individuals among the groups. There was no significant difference between the mean QCT value of patients with one compression fracture and the value of those with between two and five compression fractures. Patients with biopsy-proven osteomalacia had higher vertebral trabecular bone density than patients with osteoporosis and compression fractures. Our study provides evidence suggesting a strong inverse relationship between QCT-measured vertebral bone density and the presence of vertebral compression fractures in a group of osteopenic patients.
Absorptiometry, Photon↗
Proximal femoral focal deficiency. Evidence for a defect in proliferation and maturation of chondrocytes.
Proximal femoral focal deficiency is a rare congenital malformation, characterized by a failure of normal development of the proximal part of the femur. To our knowledge, there have been no reports on the histology of fetal growth plates that are affected by this disorder. To characterize this focal developmental anomaly further, we studied the histopathology of the growth plates and epiphyses from a twenty-one-week fetus with unilateral proximal femoral focal deficiency. Although the shape of the cartilaginous anlage of the fetus appeared normal, the growth plate of the proximal part of the involved femur was markedly abnormal. The major findings were: (1) striking failure of the proximal growth plate to migrate proximally, away from the central part of the diaphysis, and failure of formation of a normal growth plate; (2) failure of organization of proliferative and hypertrophic chondrocytes into longitudinal columns; (3) truncation of an immature hypertrophic zone that had abnormal septal architecture; and (4) disorganized vascular invasion with a honeycomb rather than a columnar pattern of primary trabeculae. In contrast, the histological characteristics of the growth plates from the distal part of the femur and from all other long bones were normal.
Cartilage↗
Treatment of castration-induced osteoporosis by a capacitively coupled electrical signal in rat vertebrae.
Castrated male Sprague Dawley rats were subjected to various capacitively coupled electrical fields for six and eight weeks at two and 4.5 months after castration, respectively, with pairs of electrodes that were located paraspinally on the surface of the skin dorsally at the eleventh thoracic and fourth lumbar levels. When the animals were killed, dry and ash weights per unit of volume (apparent density), elastic modulus, ultimate stress, work to failure, trabecular area fraction, and mean trabecular width were determined for selected vertebrae. The results indicated that a sixty-kilohertz, 100-microampere signal (a calculated current density of five microamperes root-mean-square per square centimeter and a field of twelve millivolts root-mean-square per centimeter) significantly reversed the castration-induced osteoporosis in the lumbar vertebrae and restored bone mass per unit of volume in rats that had been stimulated for eight weeks after castration.
Animals↗