Paget's disease: complications and controversies.
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Animals↗
Biomedical subjects
J G Haddad
Publications and source records attributed to J G Haddad.
Paget's disease of bone.
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Bone Resorption↗
Bone disease in burn patients.
Burn patients are at risk for bone disease due to aluminum (Al) exposure from use of antacids and albumin, partial immobilization, and increased production of endogenous glucocorticoids. Moreover, severely burned children are growth impaired up to 3 years after the burn. To determine the extent of bone disease, we studied nine men and three women, ages 18-41 years, with greater than 50% body surface area burn. Seven patients underwent iliac crest bone biopsy following double tetracycline labeling, one additional patient expired after a single label, and three others had postmortem specimens obtained for quantitative Al only. Serial serum and urine samples were obtained weekly until biopsy or death. All biopsied patients had reduced bone formation and osteoid area, surface, and width, with mineral apposition rate, osteoblast surface, and osteoclast number with normal eroded surfaces compared to age- and sex-matched normal ambulatory volunteers. Burn patients also had reduced bone formation, mineral apposition rate, osteoid area, and surface compared to age-matched volunteers at short-term bed rest. Serum levels of osteocalcin were low. Most patients had mild hypercalcemia but only a third had hypercalciuria. All patients had elevated Al in blood or urine; urine Al correlated inversely with serum osteocalcin. In 60% significant bone Al was detectable by stain or quantitation. Our data are compatible with burn patients having markedly reduced bone turnover. Al loading, partial immobilization, endogenous corticosteroids, and cytokine production may be among the etiologic factors.
Adolescent↗
Human plasma transport of vitamin D after its endogenous synthesis.
Transport of vitamin D3 from its sites of cutaneous synthesis into the circulation has been assumed to be via the plasma vitamin D binding protein (DBP). We studied vitamin D transport from the skin in seven healthy volunteers who received whole body irradiation with 27 mJ/cm2 dosage of ultraviolet B light (290-320 nm). Samples of venous blood were collected serially in EDTA and immediately chilled. In KBr, plasma samples were ultracentrifuged to provide a rapid separation of proteins of density < and > 1.3 g/ml. Upper and lower phases and serial fractions were analyzed for vitamin D3 (extraction, HPLC), cholesterol (enzyme assay), and human DBP (hDBP) (radial immunodiffusion). Total plasma vitamin D (basal level < 1 ng/ml) increased by 10 h and peaked at 24 h (9 +/- 1 ng/ml). 98% of the D3 remained at the density > 1.3 layers for up to 7 d, whereas cholesterol (> 85%) was detected at density < 1.3 and all of the hDBP was at density > 1.3. In three volunteers who each ingested 1.25 mg of vitamin D2, the total plasma D2 increased to 90 +/- 32 ng/ml by 4 h, and the D2 was evenly distributed between the upper and lower layers at 4, 8, and 24 h after the dose, indicating a continuing association of the vitamin with chylomicrons and lipoproteins, as well as with hDBP. Actin affinity chromatography removed D3 from plasma of irradiated subjects, indicating the association of the D3 with DBP. These findings indicate that endogenously synthesized vitamin D3 travels in plasma almost exclusively on DBP, providing for a slower hepatic delivery of the vitamin D and the more sustained increase in plasma 25-hydroxycholecalciferol observed after depot, parenteral administration of vitamin D. In contrast, the association of orally administered vitamin D with chylomicrons and lipoproteins allows for receptor-mediated, rapid hepatic delivery of vitamin D, and the reported rapid but less-sustained increases in plasma 25-hydroxycholecalciferol.
Adult↗
The cluster phenomenon in patients who have multiple vertebral compression fractures.
Little is known about the natural history of patients who have multiple compression fractures. During an eight-year period, eight patients who suffered relentless nonmechanical back pain after an initial compression fracture were evaluated. Radiographs and radionuclide bone scans were obtained in all eight patients and showed the temporal clustering of at least five spontaneous thoracic or lumbar vertebral compression fractures within a period of eight months. The patient database during this eight-year period included 21 patients with a similar number of fractures but without the phenomenon of temporal clustering. Age and gender distribution, premorbid activity levels, presence of secondary causes of osteopenia, dietary history, and vertebral bone density measurements were similar in both groups. Five of the eight patients with cluster fractures were on chronic glucocorticoid therapy for treatment of an underlying illness. All five patients experienced an exacerbation of their chronic illness that required an increase in the dose of their steroid medication within three months preceding the onset of the cluster fractures. No patient in the noncluster fracture control group experienced a similar exacerbation of an underlying illness or required a similar boost in their steroid medication. The temporal clustering of numerous fractures (cluster phenomenon) is a cause of transient severe disability in patients who have profound osteopenia, and may be precipitated by exacerbation of an intercurrent illness or by an associated obligate increase in glucocorticoid medication in a patient with preexisting severe osteopenia.
Aged↗
Bone densitometry observations of osteopetrosis in response to bone marrow transplantation.
Spinal bone density was measured in eight patients with osteopetrosis to assess the natural history of the disease and to monitor the response to therapy. Quantitative computed tomographic scans of the lumbar vertebra were obtained in seven patients, and dual photon absorptiometric scans were obtained when the technique became available. Six children were afflicted with the infantile malignant recessive condition and two with the less severe dominant condition. In all cases, bone densitometry values ranged from four to five times higher than the mean for normal age and gender-matched controls. In four children with recessive osteopetrosis, quantitative computed tomographic and dual photon absorptiometric scans showed an excellent correlation (R = 0.93) between the methods. Quantitative computed tomographic values ranged from 597 to 730 mg/cm3 (mean = 655 mg/cm3) in children with osteopetrorickets and from 901 to 1000 mg/cm3 (mean = 980 mg/cm3) in the same children when the rickets was cured. In two children treated with bone marrow transplantation, bone densitometry values returned to normal within three years. Bone densitometry provides a safe and noninvasive method for observing the natural history and therapeutic response of the osteopetrotic syndromes.
Absorptiometry, Photon↗
Osteopetrorickets. The paradox of plenty. Pathophysiology and treatment.
Rickets is a common and paradoxical feature of infantile malignant osteopetrosis and results from the inability of osteoclasts to maintain a normal calcium-phosphorus balance in the extracellular fluid. Despite a markedly positive total body calcium balance, rickets arises when the serum calcium x phosphorus product is insufficient to mineralize newly formed chondroid and osteoid. In five children with malignant infantile osteopetrosis, there were clinical, radiographic, biochemical, and histologic findings of rickets. Characteristic biochemical abnormalities included hypocalcemia, hypophosphatemia, and elevated levels of serum acid phosphatase, alkaline phosphatase, c-terminal parathyroid hormone, and 1,25-dihydroxyvitamin D. The urinary calcium/creatinine ratio was markedly depressed. The serum calcium x phosphorus product was below 30 in all children at the time the rickets was diagnosed, and above 40 by the time the rickets had resolved. Baseline bone density measurements were markedly elevated in all children (> 5 standard deviation above normal) and showed even significant increases (> 7 SD) when the rickets was treated with vitamin D and calcium. The children showed marked clinical improvement, decreased lethargy, increase in mobility and activity, and stimulation of appetite, without any additional adverse hematologic or neurologic effects. The rickets was reversible in all children: in one by HLA-identical sibling bone marrow transplantation and in four by physiologic doses of vitamin D and calcium. The parathyroid and renal responses to hypocalcemia were appropriate, but glucocorticoids, used in treating the hematologic complications of the disease, may have blunted the intestinal response to maximal vitamin D stimulation. This latter blockade can be overcome by increasing dietary calcium. By liberalizing rather than by restricting calcium and phosphorus intake, hypocalcemia can be minimized, phosphorus metabolism can be improved, and rickets can be cured.
Bone Marrow Transplantation↗
Identification of the sterol- and actin-binding domains of plasma vitamin D binding protein (Gc-globulin).
The mammalian plasma vitamin D binding protein (DBP), or Gc-globulin, is recognized to have at least two functional properties: sterol binding and G-actin sequestration. Affinity labeling of the sterol binding site with the radioactive electrophilic ligand, 3 beta-(bromoacetoxy)-25-hydroxycholecalciferol, followed by limited proteolysis, permitted the isolation and identification of three overlapping peptides in the amino terminus of the molecule. When G-actin affinity chromatography was applied to other proteolytic fragments, two fragments from the carboxy terminus of the molecule were isolated and identified. Another, large, tryptic fragment displayed both sterol- and actin-binding properties. The amino-terminal assignment of the sterol-binding domain was confirmed by demonstrating sterol-specific binding by an in vitro transcribed and translated product of a mutated rat DBP cDNA encoding a protein truncated in its carboxy terminus. The sterol-binding domain was localized to the region between the first-amino-terminal disulfide bond, and the actin-binding domain was found between residues 350 and 403. A high degree of sequence conservation in these regions was found among human, rat, and mouse DBP's. These functional domain assignments confirm the apparent independence of these two binding activities and help to explain the observed triprotein complex of DBP-actin-DNase I and the competition between DBP and profilin for G-actin binding. Our findings should facilitate more precise delineation of the binding domains by site-directed mutagenesis experiments.
Actins↗
Vitamin D--solar rays, the Milky Way, or both?
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Aged↗
Elevation of blood vitamin D2 levels does not impede the release of vitamin D3 from the skin.
The mechanism for the transfer of fat-soluble vitamin D3 from the avascular basal cellular layers of the epidermis to dermal capillaries and peripheral circulation is unknown, although vitamin D-binding protein (DBP) is thought to mediate this process. To evaluate the effect of increased occupancy of vitamin D carrier(s) on vitamin D3 removal from the skin, serial serum vitamin D2 and D3 concentrations were determined in three groups of six healthy volunteers given combinations of an oral dose of vitamin D2 (50,000 IU) and a fixed dose of UVB radiation (27 mJ/cm2). Serum vitamin D3 levels increased significantly following UVB (time effect, P < .01 by ANOVA), but the response remained unchanged after pretreatment with vitamin D2, increasing from 3 +/- 1 to 14 +/- 5 ng/mL (mean +/- SEM), versus UVB alone, 5 +/- 1 to 16 +/- 5 ng/mL. Elevation of serum vitamin D2 levels was also similar in the groups given vitamin D2 alone (< 1 to 64 +/- 8 ng/mL) and vitamin D2 + UVB (< 1 to 45 +/- 8 ng/mL). There was no time or treatment effect for changes in serum levels of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, or (DBP) levels (P > .1). We conclude that vitamin D3 egress from the skin is not affected by elevated circulating vitamin D concentrations; thus, the cutaneous release of vitamin D is probably mediated by a protein such as DBP with a high carrying capacity for the vitamin.
Administration, Oral↗
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↗
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↗
Vitamin D3 binding protein required for in vitro activation of macrophages after alkylglycerol treatment of mouse peritoneal cells.
In vitro treatment of peritoneal cells with dodecylglycerol (DDG) in 10% foetal calf serum (FCS) supplemented medium RPMI-1640 results in a greatly enhanced Fc receptor-mediated phagocytic activity of macrophages. This macrophage activation process requires a serum factor in the alpha 2-globulin fraction. When mouse peritoneal cells were treated with 50 ng DDG/ml in a serum-free 0.1% egg albumin-supplemented medium RPMI-1640 (EA medium) for 30 min and cultured in EA medium containing electrophoretically fractionated alpha 2-globulin for 3 hr, a markedly enhanced activation of macrophages was observed. To improve fractionation of alpha 2-globulin, FCS was first precipitated with 50% saturated ammonium sulphate and then the supernatant electrophoretically fractionated. The resultant alpha 2-globulin fraction was unable to support activation of macrophages. Vitamin D3 binding protein (DBP) of the alpha 2-globulin fraction is known to be precipitable by 50% saturated ammonium sulphate. When human alpha 2-globulin was treated with antiserum against human DBP and used in a medium for cultivation of DDG-treated peritoneal cells, no significant activation of macrophages was observed. Cultivation of DDG-treated peritoneal cells in a medium containing a low concentration of purified human DBP (group specific component, Gc) produced a greatly enhanced ingestion activity of macrophages. Purified human Gc protein, when used in an EA medium for step-wise cultivation of DDG-treated B and untreated T cells, was efficiently converted to a macrophage-activating factor.
Animals↗
Racial pigmentation and the cutaneous synthesis of vitamin D.
The varying epidermal melanin content that produces racial pigmentation determines the number of photons that reach the lower (malpighian) cellular layers, where vitamin D3 synthesis takes place. We investigated the effect of racial pigmentation on vitamin D3 formation, stimulating the process with a fixed dose of UVB radiation (wavelengths, 290 to 320 nm). Vitamin D nutritional status was further assessed measuring serum 25-hydroxyvitamin D and the most active serum metabolite, 1,25-dihydroxyvitamin D. Experimental subjects were young (third decade of life) and healthy, representing the white, Oriental (East Asian), Indian (South Asian), and black races. Basal serum vitamin D3 levels were similar among groups, ranging from 2.3 +/- 0.6 nmol/L (mean +/- SEM) for blacks to 3.4 +/- 1.0 nmol/L for Indians. Following whole-body exposure to 27 mJ/cm2 of UVB, there was a significant racial group effect on serum vitamin D3 levels. Post-UVB levels were significantly higher in whites (31.4 +/- 4.4 nmol/L) than in Indians or blacks (12.8 +/- 2.9 and 9.1 +/- 2.1 nmol/L, respectively), while the levels in Orientals (27.8 +/- 4.4 nmol/L) differed significantly from those in blacks and Indians but not in whites. Race had only a marginal effect on serum 25-hydroxyvitamin D, with higher levels in whites than in blacks (69.9 +/- 12.7 vs 29.7 +/- 6.2 nmol/L). Serum 1,25-dihydroxyvitamin D and vitamin D binding protein levels were similar in all groups. We conclude that while racial pigmentation has a photoprotective effect, it does not prevent the generation of normal levels of active vitamin D metabolites.
Adult↗
Cutaneous formation of vitamin D in psoriasis.
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Adult↗
Skin types and epidermal photosynthesis of vitamin D3.
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Cholecalciferol↗
Disruption of microfilament organization in living nonmuscle cells by microinjection of plasma vitamin D-binding protein or DNase I.
Plasma vitamin D-binding protein (DBP), which binds to monomeric actin, causes the breakdown of stress fibers when it is microinjected into nonmuscle cells. Disruption of the stress fiber network is also accompanied by shape changes in the cell that resemble those seen after cytochalasin treatment. When DBP was coinjected with fluorescently labeled alpha-actinin, no fluorescent stress fibers or attachment plaques were visible 30 min after injection. Twelve hours later the cells regained their flattened shape and their stress fibers. Fluorescently labeled DBP causes the same reversible changes in cell shape as the unlabeled protein. Upon injection, the labeled DBP diffuses throughout the cytoplasm, becoming localized by 12 hr in a punctate pattern, presumably due to lysozomal sequestration. Similar injections of DBP into skeletal myotubes and cardiac myocytes did not lead to shape changes or breakdown of nascent and/or fully formed myofibrils, even though DBP has a 2-fold higher binding affinity for muscle actin over that of the nonmuscle isoactins. Similar differential effects in nonmuscle cells were also observed after the microinjection of DNase I, another protein capable of binding monomer actin. The effects of these microinjected monomer actin-binding proteins imply that an accessible pool of monomer actin is needed to maintain stress fiber integrity in nonmuscle cells but not the integrity of the nascent or fully formed myofibrils in muscle cells.
Actin Cytoskeleton↗
Angiopathic consequences of saturating the plasma scavenger system for actin.
Two plasma proteins, vitamin D-binding protein (actin monomer sequestrant) and gelsolin (actin polymer severing), have been found in association with actin in plasma from ill humans and during experimental injury. In vitro, these are the only plasma proteins that display a high affinity for actin. We infused increasing amounts of globular actin intravenously to rats to evaluate its disposition in plasma and tissues. Intravascular filament formation, microthrombi, and endothelial injury were observed, especially in the pulmonary circulation. These pathological changes were not observed when the globular actin in the infusate had been preincubated with the vitamin D-binding protein in vitro. Complexes of actin with both proteins were found in the plasma, suggesting a saturable, plasma actin-binding system in vivo. Our findings suggest that in vivo saturation of these proteins' actin-binding capacities may serve as a paradigm for pulmonary vascular disorders seen during widespread tissue trauma and cell lysis.
Actins↗