Colin R. Paterson

Osteogenesis imperfecta after the menopause

: We studied the fracture rate as a function of age in 45 women and 20 men with osteogenesis imperfecta. In each variant of the disorder, the fracture rate in women peaked in childhood, declined in adolescence, and rose again after the menopause. In contrast, the fracture rate in men remained low after adolescence. After the menopause women were vulnerable to crush fractures of the spine as well as fractures of the long bones. We conclude that the increased fracture rate after the menopause in women with osteogenesis imperfecta reflects the superimposition of the effects of age-related bone loss on those of the defective collagen structure of osteogenesis imperfecta, and that hormone-replacement therapy may be specifically indicated in this group of patients from the time of the menopause. We also suggest that osteogenesis imperfecta should be included in the differential diagnosis of women presenting with crush fractures of the spine.

Variations in the serum concentration and urine excretion ofα 2HS-glycoprotein, a bone-related protein, in normal individuals and in patients with osteogenesis imperfecta

SummaryThe concentration ofα2HS-glycoprotein was measured in the serum and urine of normal individuals and of patients with osteogenesis imperfecta. The serum concentration ofα2HS-glycoprotein was higher in normal children than in adults. In women values showed a progressive agerelated decrease, from 632 mg/l at 21–30 years to 573 mg/l at 51–60 years. In men there was no such age-related variation, and values were higher than in women of comparable age; the mean value for men aged 20–60 years was 648 mg/l. Of 48 patients with osteogenesis imperfecta, 11 had an abnormally high concentration ofα2HS-glycoprotein in serum; the cause of this is not clear. In urine of 24 normal individuals the mean value of the ratio albumin:α2HS-glycoprotein was 20±3; in serum the corresponding ratio was 70. Urine excretion ofα2HS-glycoprotein was lowest in female children (132±29 µg/24 h) and highest in male adults (592±91 µg/24 h); values in patients with osteogenesis imperfecta did not differ from normal.

Classical osteogenesis imperfecta and allegations of nonaccidental injury.

We report 12 patients with osteogenesis imperfecta initially diagnosed with nonaccidental injuries. As a result, formal hearings, care proceedings, and criminal proceedings ensued and seven of the children were removed from their parents. The features suggestive of osteogenesis imperfecta at the time of the initial investigation included a positive family history in six patients, scleral discoloration in nine, abnormally large anterior fontanels in four, excessive numbers of wormian bones in four, abnormal bone texture in two, and abnormal biochemical findings in three. There were discrepancies between the fractures and other clinical evidence of inflicted trauma. The seven patients removed from their homes eventually were returned. Five patients remained at home. Information was available on the subsequent history of the patients for an average of 4.8 years. Although seven patients have had additional fractures, there have been no additional allegations of nonaccidental injury. When investigating children with unexplained fractures, it is important to review carefully their clinical history, family history, physical examination findings, and radiographic findings. Misdiagnosing patients with nonaccidental injuries causes substantial harm to the family and particularly to the child. Level of evidence: Level IV (case series). See the Guidelines for Authors for a complete description of levels of evidence.

Psychiatric morbidity in primary hyperparathyroidism.

Psychiatric symptoms are well recognized as a feature of patients with primary hyperparathyroidism. We have applied a standardized psychiatric interview to 15 patients before and after surgery. Thirteen had a lower psychiatric score (less psychiatric morbidity) after surgery and improvements were particularly seen in symptoms of fatigue, depression, irritability, sleep disturbance and lack of concentration. The levels of intellectual impairment and of anxiety were unchanged after surgery. The psychiatric scores in an additional group of 21 hyperparathyroid patients, in whom a decision to treat conservatively had been made independently, were similar to those in the surgically treated patients after surgery. Among all the untreated patients no relationship was found between overall psychiatric score and serum levels of calcium or parathyrin.

Osteogenesis imperfecta and other heritable disorders of bone

This chapter summarizes the many recent advances in our understanding of the principal heritable disorders of bone. In the course of little more than a decade many diseases that were recognizable only by their clinical and radiological features have become explicable in molecular terms. Large numbers of mutations of the genes coding for collagen, for alkaline phosphatase, for the cell surface receptors for parathyroid hormone and for calcium, and for a number of other proteins, are recognized. The chapter covers the many variants of osteogenesis imperfecta, the most common heritable cause of fractures. It also covers osteopetrosis, hypophosphatasia, pseudohypoparathyroidism (with Albrights hereditary osteodystrophy), familial benign hypercalcaemia, autosomal dominant hypocalcaemia and the molecular causes of some chondrodysplasias.

Skin content of 7-dehydrocholesterol in patients with malabsorption

The mechanism for the development of vitamin D deficiency in patients with malabsorption remains unclear. We wished to examine the hypothesis that one factor was a reduced skin content of 7-dehydrocholesterol, the precursor for the formation of vitamin D in the presence of ultraviolet radiation. We measured 7-dehydrocholesterol in skin samples from 9 patients who had previously had vitamin D deficiency due to malabsorption (6 with Crohns disease, 2 with primary biliary cirrhosis, and 1 with idiopathic pseudo-obstruction). We found no evidence of reduced levels of 7-dehydrocholesterol in the skin in these patients. Lack of 7-dehydrocholesterol does not contribute to vitamin D deficiency in malabsorption.

Determination of 7-dehydrocholesterol in human skin by high-performance liquid chromatography.

A two-stage chromatographic procedure has been devised for the measurement of 7-dehydrocholesterol in human skin. Extracts containing ergosterol as internal standard underwent preparative chromatography on a Spherisorb S5W column using hexane-1% isopropanol as solvent, and an eluted fraction was analysed with an Ultrasphere 5-microns ODS column with methanol-tetrahydrofuran-17.5 mM KH2PO4 (95:1:4, v/v) as solvent and using an amperometric detector at 1.7 V. 7-Dehydrocholesterol could be reliably assayed in human skin samples as small as 5 mm in diameter. In hospital patients skin 7-dehydrocholesterol concentrations ranged from 12 to 81 micrograms/g dry weight.

Osteogenesis Imperfecta after the Menopause

We studied the fracture rate as a function of age in 45 women and 20 men with osteogenesis imperfecta. In each variant of the disorder, the fracture rate in women peaked in childhood, declined in adolescence, and rose again after the menopause. In contrast, the fracture rate in men remained low after adolescence. After the menopause women were vulnerable to crush fractures of the spine as well as fractures of the long bones. We conclude that the increased fracture rate after the menopause in women with osteogenesis imperfecta reflects the superimposition of the effects of age-related bone loss on those of the defective collagen structure of osteogenesis imperfecta, and that hormone-replacement therapy may be specifically indicated in this group of patients from the time of the menopause. We also suggest that osteogenesis imperfecta should be included in the differential diagnosis of women presenting with crush fractures of the spine.

The value of serum 25-hydroxyvitamin D measurements in hypoparathyroid and pseudohypoparathyroid patients treated with calciferol.

In 23 patients with hypoparathyroidism or pseudohypoparathyroidism treated with vitamin D, and in whom the dosage was adjusted downward or upward in response to hypercalcemia or hypocalcemia respectively, assays of serum 25-hydroxyvitamin D (25-OHD) were carried out in addition to the usual serum calcium assays. In 120 assays there was a significant correlation between serum 25-OHD levels and serum calcium levels (corrected for serum albumin). There was, however, no clear distinction between the 25-OHD levels of patients who were hypocalcemic, normocalcemic or hypercalcemic. The highest serum 25-OHD level found in a hypocalcemic patient was 1193 nmol/L and the lowest serum 25-OHD level found in a hypercalcemic patient was 605 nmol/L. It was not possible to predict subsequent episodes of hypocalcemia or hypercalcemia from the serum 25-OHD levels. The 25-OHD assay was found to be useful only in checking compliance. We conclude that the assay of serum 25-OHD is of no more value than serum calcium alone in the management of compliant patients.