Osteoclast abnormalities in fractured bone during bisphosphonate treatment for osteoporosis: a case report.

Bisphosphonates have been widely used in the treatment of an array of bone disorders. Recent complications have included unusual femoral fractures in patients who have received long term bisphosphonate treatment for osteoporosis. Although it has been shown that bisphosphonates are effective by blunting osteoclast resorption, there has been little morphologic description of the local tissue activity at the site of these unusual fractures. To evaluate for local changes to bone morphology at the fracture site in patients presenting with a bisphosphonate-related femur fracture, a sample of cortical bone was obtained at the site of a bisphosphonate fracture and was processed in a nondecalcified manner. The specimen was evaluated for potential cellular changes consistent with bisphosphonate treatment. Significant osteoclast abnormalities at the fracture site were found in a 69-year-old woman treated for 2 years with Fosamax substantiating that bone remodeling at this site is distinctly abnormal. Addressing the osteoclast dysfunction should be a focus of future therapeutic attention and intervention.

Eosinophilic Metallosis: A Newly Described Entity in Failed Metal-on-Metal Arthroplasty.

In recent years, metal-on-metal (MoM) orthopaedic implants have been associated with significant adverse tissue reactions, prompting revision surgeries and recalls by manufacturers. Adverse tissue reactions consist of a wide range of pathologic findings but are generally characterized by a histiocytic reaction to metal debris, with or without an inflammatory response. Inflammation is generally that of a lymphocytic infiltration that prompts concern of an immune reaction. Only occasionally have eosinophils been documented-never as a marked infiltrate. In this article, we present the first histologic description of a dominant eosinophilic infiltrate associated with MoM arthroplasty. In our case report, the patient is a 53-year-old woman who presented with recurrent fluid collections surrounding the hip after a MoM total hip arthroplasty. At the time of surgical revision, tissue samples were taken and found to consist of lymphocytes and a prominent infiltrating eosinophilia. To our knowledge, no factors predictive of this type of tissue response have been identified, and its significance remains unclear despite ongoing research about the nature of the immune response to metal. Future work may help to elucidate whether the type and significance of this response can be predicted preoperatively and modulated, if necessary, postoperatively.

Acidosis-induced osteomalacia: metabolic studies and skeletal histomorphometry.

The pathogenesis of osteomalacia was investigated in three patients with chronic metabolic acidosis. Serum levels of parathyroid hormone and vitamin D metabolites were measured, and bone biopsy specimens were analyzed after double tetracycline labeling. Parathyroid hormone concentrations were normal in patients 1 and 3 and slightly elevated in patient 2. Vitamin D metabolism was undisturbed. Static indicators of bone remodeling substantiated the diagnosis of osteomalacia in each case. In patient 1 fluorescent microscopy revealed no evidence of tetracycline uptake. In patients 2 and 3 active mineralization was evident at all osteoid seams, but because double labels were rare, the mineral apposition rate appears to have been substantially reduced in most bone-forming units. Our results indicate that acidosis-induced osteomalacia, unlike that due to vitamin D deficiency, may be associated with mineral deposition at every possible site. Nevertheless, like other causes of osteomalacia, metabolic acidosis prevents mineral apposition at a normal rate even if mineral deposition is ubiquitous. We suggest that titration of newly deposited phosphate causes the observed impairment of mineral apposition and ultimately leads to osteomalacia.

Histochemical demonstration of iron but not aluminum in a case of dialysis-associated osteomalacia.

A patient undergoing hemodialysis is described in whom osteomalacia developed despite protracted treatment with calcitriol. Appropriately stained biopsy sections exhibited iron at all marrow-osteoid interfaces and a small fraction of trabecular mineralization fronts. Aluminum, the metal usually associated with osteomalacia in patients undergoing hemodialysis, was not histochemically demonstrable, even though spectrophotometrically measured bone aluminum content was substantial. These observations suggest two interpretations: iron may have caused osteomalacia through effects on bone cells and at mineralization fronts; alternatively, aluminum may have caused osteomalacia while remaining histochemically undetectable. It is possible that both metals exerted toxic effects simultaneously.

The bone biopsy protocol for evaluating osteoporosis and osteomalacia.

Although this paper has dealt with well-established diagnostic procedures, I have attempted to present a practical summary based on experience with over 400 cases. A complete and modern approach to the evaluation of the bone biopsy for metabolic bone disease may be summarized as follows: Preoperative double labeling with tetracycline (two 3-day courses of tetracycline separated by 12 days); Full-thickness iliac bone biopsy yielding a 5- to 6-mm diameter specimen; Undecalcified sectioning (5-10 mu) processed in glycol or methyl methacrylate; Histomorphometric analysis with light microscope and planimeter; Tetracycline analysis with fluorescent microscope.

Microscopic bone pathology in two cases of surgically treated secondary hyperparathyroidism. Report of a distinct skeletal lesion.

We report bone biopsy findings in two hemodialysis patients with a history of secondary hyperparathyroidism treated by parathyroidectomy. Discrete, punched-out lesions in trabecular bone, which show little evidence of resorption or osteoblast activity, probably correspond to previous zones of osteoclastic tunneling resorption. Because we have seen these lesions in no other clinical setting, we suggest that they are residua of healed secondary hyperparathyroidism in dialysis patients. Their persistence may be due in part to aluminum intoxication.

Sampling error in diagnosing hyperparathyroid changes in bone in small needle biopsies.

Sampling error in diagnosing the effects of hyperparathyroidism on bone was studied retrospectively by subdividing large-core bone biopsy samples and evaluating them histologically. We used intratrabecular osteoclastic tunneling resorption as the diagnostic feature of secondary hyperparathyroidism in 10 hemodialysis patients. All biopsies were taken with a large-core bone biopsy instrument, resulting in a mean biopsy width of 5 mm. The processed tissue slides were divided into halves (mean width 2.5 mm) and subsequently into thirds (mean width 1.6 mm), mimicking smaller bone biopsy instruments such as the Jamshidi needle. In 30% of the cases the diagnosis of secondary hyperparathyroidism would have been missed if taken by a Jamshidi-type needle, and 60% if taken by a needle with a core diameter of 1.6 mm. Our findings emphasize the necessity of utilizing large-core bone biopsies in diagnosing certain metabolic bone diseases.

Intracortical osteosarcoma.

A case of osteosarcoma arising in the tibia of a 15-year-old boy is reported. Of particular interest was the benign roentgenographic appearance and the confinement of the tumor within the cortex of the bone, an extremely rare phenomenon consistent with origin within the primitive mesenchyme of the Haversian canals.

Absence of correlation between coronary arterial atherosclerosis and severity or duration of diabetes mellitus of adult onset.

The relation between the severity and duration of diabetes mellitus and the severity of ischemic heart disease is uncertain. The clinical findings and the findings at autopsy were studied in 185 patients with diabetes mellitus of adult onset who ranged in age from 37 to 91 years and had a clinical diagnosis of diabetes established for a few days to 50 years before death. No statistically significant association was demonstrated either by simple correlation or by multivariate regression analysis between the clinically diagnosed severity or duration of diabetes and either the overall coronary disease, the number of diseased vessels or the number of myocardial infarctions. The presence of other expected correlations in the multivariate analysis suggested that the results of this study were not spurious. However, comparison with 185 age- and sex-matched control patients revealed that on the average, diabetic patients have more overall coronary disease (p < 0.002), more diffuseness of coronary disease (p < 0.005), more coronary collateralization (p < 0.001), more vessels involved by atherosclerosis (p < 0.001) and more myocardial infarcts (p < 0.001). The results suggest that although diabetes mellitus of adult onset is a condition in which the larger coronary arteries are subject to more atherosclerosis than are those in nondiabetic subjects, the progression of the atherosclerotic disease is unrelated to the duration or severity of the diabetes mellitus.

Localization of osteoid osteomas--use of radionuclide scanning and autoimaging in identifying the nidus.

Surgical excision of osteoid osteomas is curative, but intraoperative localization and pathologic identification in submitted fragments may be difficult. We used preoperative technetium-99m methylene diphosphonate injection and intraoperative probing to localize the nidus of three clinically suspected cases of osteoid osteoma. Then in the pathology department, fine grain specimen x-rays and specimen autoimaging on undeveloped film were utilized. In all cases, technetium radioactivity localized within the lesion. Although the nidus was identified by fine grain specimen x-rays in only one case, the subsequent histologically proved osteoid osteoma corresponded in all cases to the fragment with the most intense autoimaging. We conclude that isotope scanning is effective in localizing osteoid osteomas at surgery, and autoimaging is effective in identifying the nidus itself by the pathologist.

Intramembranous localization of bacteria in beta-hemolytic group B streptococcal chorioamnionitis.

An unusual pathologic finding consisting of large colonies of bacteria, localized immediately beneath the epithelial layer of the amnion, has been observed in association with an example of group B beta-hemolytic streptococcal chorioamnionitis. Postpartum endometritis as well as neonatal sepsis and meningitis occurred. Histologic examination of the umbilical cord and placenta revealed routine features of intraamniotic inflammation, but the membranes were characterized by the presence of unusual darkly staining deposits of material immediately beneath the amniotic epithelium. Subsequent special stains revealed these to be colonies of gram-positive cocci. We have been unable to find a previous description of this observation in association with streptococcal or with other types of chorioamnionitis.

Squamous-cell carcinoma of Stensen's duct.

A case of epidermoid carcinoma of Stensen's duct, the major duct of the parotid gland, is reported, The literature on this rare tumor is reviewed including four previously reported cases. In the current case, both the gross appearance of the tumor confined to the duct and the lack of histologic involvement of adjacent parotid tissue establish that the carcinoma arose from the duct itself, presumably following development of squamous metaplasia. The patient was alive without evidence of disease 12 months following surgery.

Localization of technetium-99m methylene diphosphonate in bone using microautoradiography.

Technetium-99m methylene diphosphonate ([99mTc]MDP) is the most widely used bone-scanning agent today. In order to determine the precise bone locus of 99mTc corresponding to the delayed bone scan image, and to test the potential clinical use of this agent in enhancing the information obtained by bone scan, we employed [99mTc]MDP in this microautoradiographic study of normal bone and bone reparative tissue. Four white rabbits underwent operations in which two 1.5-mm drill holes were created in the subtrochanteric regions of both of their femora. An additional four white rabbits underwent sham operations of their femora, in which neither drilling nor periosteal injury occurred. Two rabbits were controls and did not undergo operation. After 7 days, the first two groups of rabbits were injected with [99mTc]MDP and bone scanned 2 h later. After the scans were completed, all three groups of animals were killed and their femora histologically processed for microautoradiography and routine histopathology. In the two groups that were injected with [99mTc]MDP, all bones showed the isotope to be clearly localized along mineralization fronts. The isotope was occasionally found in the substance of the osteoid, but was absent from the cytoplasm and nuclei of osteoblasts and osteocytes. Osteocytic lacunae showed the presence of isotope at their borders, but no identifiable pattern of isotope uptake was noted. Neither osteoclasts nor Howships lacunae showed isotope uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of propranolol on bone metabolism in the rat.

Propranolol, a nonspecific beta-blocker has many physiologic effects. Its effects on bone in vivo are unknown, although beta receptor sites have been found on osteoblasts. In this study, the hypothesis tested was that low doses of propranolol could alter bone properties and enhance orthotopic endochondral bone formation. In a group of nonsurgical rats, propranolol treatment increased femoral torsional strength on biomechanical testing. In the rat surgical model used, right femora were fixed to a polyethylene plate and then defects were created mid-diaphysis and subsequently filled with demineralized bone matrix. These rats (defect rats) were randomly divided into groups that were given propranolol or a saline carrier for 19 consecutive days. In the defect rats, increased trabecular femoral metaphyseal mineral apposition rates were observed in propranolol-treated groups. Densitometry and roentgenographic scoring of callus formation after 12 weeks in propranolol-treated rats revealed increased callus and bone union. The results of this study indicate that propranolol treatment can significantly affect bone properties.

The mineral and mechanical properties of bone in chronic experimental diabetes.

The long-term effects of experimentally induced diabetes on bone were studied in eight male Lewis rats, intravenously (i.v.) injected with 65 mg/kg of streptozocin (STZ) and maintained for 12 months. Eight untreated age-matched rats served as controls. In the STZ-treated rats, experimentally induced diabetes was documented by the presence of hyperglycemia at 24 h and at 3 and 12 months. Significantly less weight was gained and less growth occurred in the STZ-treated rats despite careful attention to feeding and hydration. Mineral alterations were detected in the bones of the animals with experimental diabetes. Decreased hydroxyapatite crystal perfection, decreased Ca/P of the ash, and decreased ash content in the tibial metaphyses with increased ash content in the tibial diaphyses, was noted relative to controls. Bone osteocalcin content was increased in the metaphyses of the STZ-treated rats. While absolute measures of stiffness, torsional strength and energy absorption were decreased in the bones of the STZ-treated animals, when torsional strength and stiffness were normalized for differences in both growth and geometry, the normalized stiffness values for the diabetic bones were increased. The results suggest that in experimental diabetes certain aspects of bone mineralization are adversely affected and lead to reduced strength-related properties. However, a compensatory increase in stiffness occurs. The reason for this increase, although not known, may be related to changes in bone crystal structure.

Pigmented villonodular synovitis (giant-cell tumor of the tendon sheath and synovial membrane). A review of eighty-one cases.

We reviewed the cases of eighty-one patients with pigmented villonodular synovitis and giant-cell tumor of the tendon sheath. The average duration of symptoms prior to consulting a physician was twenty-seven months. The lesion was slow-growing, was located in one joint or tendon sheath, and usually was asymptomatic in a finger or thumb but painful in a knee or toe. Twenty-nine per cent of the finger or thumb lesions and 21 per cent of the knee lesions that were followed recurred. Approximately 70 per cent of the radiographs showed abnormalities that ranged from soft-tissue swelling to bone erosion. Six lesions were incidental findings during arthrotomy for some other lesion. The histological characteristics of the solitary nodular, multiple nodular, and diffuse lesions suggested that they have a common histogenesis that is characterized by proliferation of fibroblastic or histiocytic mesenchymal cells, or both, beneath the synovial or tenosynovial lining cells, and by collagen production. Foam cells and iron deposits appear to be secondary changes and are usually seen in the periphery of the expanding nodules. The centrifugal growth pattern and the distinct differences between the lesional tissue and the adjacent hyperplastic synovial tissue suggest that pigmented villonodular synovitis is a true neoplastic process.

The coexistence and characteristics of osteoarthritis and osteoporosis.

We defined the clinical features and radiographic coexistence of osteoarthritis and osteoporosis in fifty women with primary coxarthrosis and fifty age-matched women (average age, 69 +/- 5 years) with idiopathic osteoporosis. The patients with osteoarthritis had undergone total hip replacement. The diagnosis of primary osteoarthritis was established by clinical, radiographic, and histological criteria, and the diagnosis of osteoporosis was confirmed by histomorphometric analysis of specimens taken at iliac-bone biopsy. In the arthritic patients, spinal osteoporosis was identified by radiographic evidence of compression fractures, kyphosis, and scoliosis. Femoral osteoporosis was demonstrated by the index of Singh et al. and the femoral canal-shaft ratio. In the osteoporotic patients coxarthrosis was measured radiographically by the scale of Kellgren and Lawrence. On the average, the osteoporotic patients were twelve kilograms lighter than the osteoarthritic patients. Fifty-eight per cent of the osteoporotic and 18 per cent of the osteoarthritic patients had a scoliotic curve of at least 10 degrees. The prevalence of osteoarthritis of the hip in the osteoporotic women was 4 per cent, and the prevalence of compression fractures in the arthritic women was 6 per cent, which was approximately one-quarter of the expected incidence. These results show that: (1) osteoporosis does not protect against the development of coxarthrosis, (2) coxarthrosis is a negative risk factor for osteoporotic compression fractures, and (3) scoliosis and an ectomorphic habitus are clinical markers that identify a risk for osteoporosis.(ABSTRACT TRUNCATED AT 250 WORDS)

The healing of segmental bone defects induced by demineralized bone matrix. A radiographic and biomechanical study.

UNLABELLED: We studied the effect of demineralized bone matrix on the repair of large femoral diaphyseal defects in a rat model by clinical, radiographic, and biomechanical methods. A standard procedure was first developed to create segmental defects that did not heal and in which non-union developed consistently. The effect of demineralized bone matrix on repair was then assessed by physical examination, serial radiographs, and biomechanical studies to determine deformation to failure, stiffness, torsional strength, and energy absorption. By twelve weeks, the defects that had been treated with demineralized bone matrix showed satisfactory repair and remodeling in most animals based on clinical and radiographic evaluation. The biomechanical studies demonstrated that the bone induced by demineralized bone matrix had an energy-absorption capacity and stiffness equal to those of intact rat femoral bone. The bone induced by demineralized bone matrix achieved 35 per cent of the torsional strength of normal bone and an increased capacity to deform under load. These biomechanical properties are similar to those observed in the early stages of normal fracture repair. CLINICAL RELEVANCE: An effective, readily available alternative to autologous bone-graft material would have a variety of clinical uses in orthopaedic surgery, such as augmenting fusions, aiding in the repair of high-risk fractures, and filling or bridging bone defects. Demineralized bone matrix may provide an important tool for these purposes by inducing bone that has the mechanical properties of fracture callus. This would reduce the morbidity associated with harvesting autologous bone and have an advantage over allografts or synthetic biomaterials that require incorporation by the host before they can support mechanical loads.

The osteogenic response to distant skeletal injury.

We tested the hypothesis that when one bone of the skeleton is injured, others experience an osteogenic response. Although similar or related phenomena have been observed previously, the purposes of the study were to determine if this response was reproducible, to characterize it in terms of its magnitude and duration, and to show how it is related to the type of injury sustained. To obtain this information, a model was used in which an intramedullary nail was implanted in the femur and a standard closed fracture was subsequently produced. The osteogenic response was measured by histomorphometry. Eight-four nine-week-old male Sprague-Dawley rats were divided into seven groups of twelve animals each. Groups I and II consisted of control animals in which no injury was produced. In Group-III rats, cortical drilling of the intercondylar notch and piriformis fossa of the right femur was performed, without intramedullary nailing. In Groups IV through VII, half of each group received intramedullary nails only, and in the other half intramedullary nailing was done and a closed transverse diaphyseal fracture was produced. With two different fluorochrome labels, rates of mineral apposition were measured in the left and right tibiae of all animals. The labeling periods differed in each group and were designed to determine when the peak response occurred, how long it lasted, and whether aging during the course of the experiment affected the response.(ABSTRACT TRUNCATED AT 250 WORDS)

Arthrogryposis multiplex congenita in an infant with posterior agenesis of the corpus callosum.

A term male infant with arthrogryposis multiplex congenita and agenesis of the corpus callosum is described. Physical examination revealed multiplex dysmorphic features and fixed joints. A muscle biopsy showed type II fibers to be more than 12% smaller than type I fibers, consistent with the diagnosis of fiber type disproportion. The CT scan disclosed absence of the posterior corpus callosum and moderate atrophy of the cerebellar hemispheres. The pathogenetic mechanism for the muscle (and thus joint) abnormalities of this infant is discussed with respect to a central etiology.