Michael D. Fallon

Estrogen receptors in bone in a patient with polyostotic fibrous dysplasia (McCune-Albright syndrome).

MOST investigators think that estrogen acts indirectly on bone,1 since direct skeletal action would require the presence of hormone-specific receptors in bone cells.2 , 3 However, recent advances i...

Sclerosteosis Nemogenetic and pathophysiologic analysis of an American kinship

We studied an American kinship with sclerosteosis, an autosomal-recessive disorder of bone remodeling and bone overgrowth of the calvaria, skull base, and tubular bones. Unlike osteopetrosis, which is attributed to abnormal immune and osteoclast function as well as bone resorption, sclcrosteosis appears to be primarily a disorder of osteoblast (bone formation) hyperactivity. Related to cranial vascular and neural foramina1 narrowing and reduced intracranial volume, affected patients with sclerosteosis demonstrate frequent seventh nerve palsy, progressive optic and cranial neuropathics, mixed hearing loss, brainstem compression, intracranial hypertension with increased elastance, and sudden, premature death. Management should involve early childhood identification of homozygotes, monitoring and aggressive treatment of intracranial hypertension, and extensive bone removal from skull, posterior fossa, and cervical spine.

Enzyme replacement therapy for infantile hypophosphatasia attempted by intravenous infusions of alkaline phosphatase-rich Paget plasma: Results in three additional patients

After biochemical and radiographic studies, enzyme replacement therapy in three patients with the infantile form of hypophosphatasia was attempted by weekly intravenous infusions of bone alkaline phosphatase-rich (BAP) plasma from patients with Paget bone disease. Subsequently, circulating BAP activity was substantially increased in each patient, and in one was maintained in the normal range for nearly 2 months. Despite partial or complete correction of the deficiency of circulating BAP activity, we observed no radiographic evidence for arrest of progressive osteopenia or improvement in rachitic defects in any of the patients. Failure of infants with hypophosphatasia to show significant healing of rickets on correction of circulating BAP activity supports the hypothesis that this isoenzyme functions in situ during normal skeletal mineralization.

Mast-cell proliferation in postmenopausal osteoporosis

SummaryBecause mast cell proliferation has been reported in disorders of abnormal bone remodeling, we quantitated the number of mast cells in undecalcified section of iliac crest bone from 16 untreated women with postmenopausal osteoporosis and contrasted the findings to values from 10 normal women and 12 normal men. The mean number of marrow mast cells was greater in normal women than men (1.17 vs 0.40 cells per mm2,P<0.05). Compared to the normal women, osteoporotic women had a greater number of mast cells in the marrow (3.38 vs 1.17 cells per mm2,P<0.01). However, there was no statistically significant correlation between the number of marrow mast cells and either the patients age or the severity of the bone lesions, as assessed by histomorphometry. Our findings confirm the association between increased numbers of mast cells and postmenopausal osteoporosis.

Infantile hypophosphatasia: Normalization of circulating bone alkaline phosphatase activity followed by skeletal remineralization: Evidence for an intact structural gene for tissue nonspecific alkaline phosphatase

After a 3-month course of weekly intravenous infusions of pooled normal plasma in an attempt at enzyme replacement therapy, we observed gradual and prolonged normalization of circulating alkaline phosphatase (AP) activity in a boy with infantile hypophosphatasia. During this 4-month period, when hypophosphatasemia had been corrected, electrophoretic and heat denaturation studies suggested that the AP in serum was skeletal in origin. Serial radiographic and histologic studies of bone demonstrated skeletal remineralization and the appearance of AP activity in osteoblasts and chondrocytes after the infusions. Considerable clinical improvement coincided with the skeletal remineralization. Our observations indicate that in one patient with infantile hypophosphatasia the structural gene for the tissue-nonspecific (bone/liver/kidney) AP isoenzyme was intact and could be expressed with marked physiologic effect. Infantile hypophosphatasia may result from absence or inactivation of a circulating factor(s) that regulates the expression of the gene for tissue nonspecific AP.

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.

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.

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.

Osteoporosis and hip fracture in a young woman with anorexia nervosa

A 35-year-old woman with a 17-year history of anorexia nervosa (AN) sustained a pathologic fracture of the hip. Osteoporosis was confirmed by quantitative computed tomography of the lumbar spine and transiliac bone biopsy. Severe bone disease may exist in the anorexia nervosa syndrome and may to some extent be reversible on treatment of the underlying condition. AN could have profound effects on the peak bone mass achieved in the lifetime of the individual. Asymptomatic and symptomatic osteoporosis in young women may be based upon AN. Patients should be informed that osteoporosis can cause pathologic fractures as a sequela of self-imposed chronic malnutrition.

Osteomalacia and osteitis fibrosa in a man ingesting aluminum hydroxide antacid

A 53-year-old man with a history of long-term aluminum hydroxide antacid ingestion reported diffuse bone pain and multiple stress fractures over a two-year period. An undecalcified transiliac bone biopsy specimen revealed osteomalacia with osteitis fibrosa; plasma parathyroid hormone and cyclic AMP levels were normal. Following withdrawal of antacids and treatment with calcium and phosphorus, an initially elevated plasma, 1,25-dihydroxyvitamin D level fell to within the normal range, accompanied by decreased bone pain, healed stress fractures, and increased axial bone mineral content as determined by computed tomography of lumbar trabecular bone. Phosphate deprivation and 1,25-dihydroxyvitamin D excess may contribute to the poor mineralization and exaggerated resorption of bone observed in this syndrome. The clinical, biochemical, radiologic, and histologic features of previously reported cases are reviewed. Early recognition of this syndrome is important, since appropriate therapy promotes skeletal remineralization and prevents morbidity.