William A. Murphy

Postmenopausal osteoporosis: A heterogeneous disorder as assessed by histomorphometric analysis of iliac crest bone from untreated patients

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.

Significant developmental elevation in serum parathyroid hormone levels in a large kindred with familial benign (hypocalciuric) hypercalcemia

Abstract 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.

Painful diffuse osteosclerosis after intravenous drug abuse

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.

Mixed-sclerosing-bone-dystrophy: Report of a case and review of the literature

We present clinical, laboratory, radiologic, genetic, and pathologic findings in a 49-year-old man with mixed-sclerosing-bone-dystrophy (MSBD), review the six cases previously reported as “MSBD”, and examine the nosology of this rare bone dysplasia. Our asymptomatic patient showed radiographic changes consistent with osteopoikilosis, osteopathia striata, and melorheostosis and had widespread osteosclerosis of the axial skeleton. Several previous reports of combined osteosclerotic disorders suggest the latter finding represents osteopetrosis, however, histologic examination of our patients iliac crest excluded that diagnosis. Limited radiographic surveys of his eight children were unremarkable except for isolated bone islands in two sons. Literature review revealed that “MSBD” has actually been used generically to describe the association of a variety of osteosclerotic bone dysplasias when they occur together in a single patient.

Axial osteomalacia: Clinical, laboratory and genetic investigation of an affected mother and son☆☆☆

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.

Osteosclerosis, osteomalacia, and bone marrow aplasia: A combined late complication of thorotrast administration

A 37-year-old female with thrombocytopenia since childhood developed diffuse osteosclerosis followed by bone marrow aplasia 23 years after Thorotrast administration. Tissue deposition of Thorotrast was documented by radiospectroscopy (liver, bone) and autoradiography (bone). Bone marrow failure in this patient was clinically ascribed to diffuse myelofibrosis, but at autopsy marrow fibrosis was only focal. An unsuspected bone mineralization defect was manifested by thick osteoid seams. It is suggested that osteosclerosis, osteomalacia, and bone marrow aplasia represent a combined experession of Thorotrast cytotoxicity.

Fluoroscopic evaluation of skeletal problems

Fluoroscopically positioned spot films are widely used in gastrointestinal and chest roentgenography. Little or no mention is made of the diagnostic use of fluoroscopic spot filming for skeletal roentgenography in major texts or recent literature, and a rough survey of practicing radiologists showed us that such procedure was frequently underutilized or not utilized. While skeletal pathology is usually depicted quite accurately by plain radiographs there are times when a problem may be rapidly and simply clarified by fluoroscopically positioned spot films. In an attempt to assess the value of fluoroscopy for evaluation of musculoskeletal problems, we reviewed 46 cases in which fluoroscopically positioned spot films were obtained.