admission. This proportion could already be greater in some parts of the country and may increase if referrals of cases of self-poisoning increase faster than the facilities for their assessment and management. The provision of social work and psychiatric expertise in casualty departments may be one means of preventing unnecessary medical admissions without risk to the patients. Dr Blake's and Dr Bramble's figures do not demonstrate, however, that any advantage would attach to medical teams taking over assessment from psychiatrists except that, by implication, assessments would be completed sooner by staff working on the ward full time. What the figures actually suggest is that if assessment of overdoses were left to house doctors there would be an increase in admissions to psychiatric units (by 19°U), outpatients (by 5O°'), and referrals to social services (by 140o). So for house doctors to assess overdoses would provide no economy for the psychiatric or social services. The study does not tell us what the consequences would have been for the six patients who the psychiatrists would have admitted but to whom the house doctors would have offered outpatient appointments. E J SALTER

Vitamin D deficiency.

Medical genetics was revolutionized during the 1980s by the application of genetic mapping to locate the genes responsible for simple Mendelian diseases. Most diseases and traits, however, do not follow simple inheritance patterns. Genetics have thus begun taking up the even greater challenge of the genetic dissection of complex traits. Four major approaches have been developed: linkage analysis, allele-sharing methods, association studies, and polygenic analysis of experimental crosses. This article synthesizes the current state of the genetic dissection of complex traits--describing the methods, limitations, and recent applications to biological problems.

https://focus.psychiatryonline.org/doi/pdf/10.1176/foc.4.3.442

Genetic dissection of complex traits

Bone density achieved in early adulthood is the major determinant of risk of osteoporotic fracture. Up to 60% of women suffer osteoporotic fractures as a result of low bone density, which is under strong genetic control acting through effects on bone turnover. Here we show that common allelic variants in the gene encoding the vitamin D receptor can be used to predict differences in bone density, accounting for up to 75% of the total genetic effect on bone density in healthy individuals. The genotype associated with lower bone density was overrepresented in postmenopausal women with bone densities more than 2 standard deviations below values in young normal women. The molecular mechanisms by which bone density is regulated by the vitamin D receptor gene are not certain, although allelic differences in the 3' untranslated region may alter messenger RNA levels. These findings could open new avenues to the development and targeting of prophylactic interventions. It follows that other pathophysiological processes considered to be subject to complex multifactorial genetic regulation may also be modulated by a single gene with pleiotropic transcriptional actions.

Prediction of Bone-Density from Vitamin-D Receptor Alleles

Medical genetics was revolutionized during the 1980s by the application of genetic mapping to locate the genes responsible for simple Mendelian diseases. Most diseases and traits, however, do not follow simple inheritance patterns. Geneticists have thus begun taking up the even greater challenge of the genetic dissection of complex traits. Four major approaches have been developed: linkage analysis, allele-sharing methods, association studies, and polygenic analysis of experimental crosses. This article synthesizes the current state of the genetic dissection of complex traits—describing the methods, limitations, and recent applications to biological problems.

Genetic Dissection of Complex Traits

This review describes normal bone anatomy and physiology as an introduction to the subsequent articles in this section that discuss clinical applications of iliac crest bone biopsy. The normal anatomy and functions of the skeleton are reviewed first, followed by a general description of the processes of bone modeling and remodeling. The bone remodeling process regulates the gain and loss of bone mineral density in the adult skeleton and directly influences bone strength. Thorough understanding of the bone remodeling process is critical to appreciation of the value of and interpretation of the results of iliac crest bone histomorphometry. Osteoclast recruitment, activation, and bone resorption is discussed in some detail, followed by a review of osteoblast recruitment and the process of new bone formation. Next, the collagenous and noncollagenous protein components and function of bone extracellular matrix are summarized, followed by a description of the process of mineralization of newly formed bone matrix. The actions of biomechanical forces on bone are sensed by the osteocyte syncytium within bone via the canalicular network and intercellular gap junctions. Finally, concepts regarding bone remodeling, osteoclast and osteoblast function, extracellular matrix, matrix mineralization, and osteocyte function are synthesized in a summary of the currently understood functional determinants of bone strength. This information lays the groundwork for understanding the utility and clinical applications of iliac crest bone biopsy.

/pdf/normal-bone-anatomy-and-physiology-1lgrfttlz8.pdf

Normal Bone Anatomy and Physiology

The relative importance of genetic factors in determining bone mass in different parts of the skeleton is poorly understood. Lumbar spine and proximal femur bone mineral density and forearm bone mineral content were measured by photon absorptiometry in 38 monozygotic and 27 dizygotic twin pairs. Bone mineral density was significantly more highly correlated in monozygotic than in dizygotic twins for the spine and proximal femur and in the forearm of premenopausal twin pairs, which is consistent with significant genetic contributions to bone mass at all these sites. The lesser genetic contribution to proximal femur and distal forearm bone mass compared with the spine suggests that environmental factors are of greater importance in the aetiology of osteopenia of the hip and wrist. This is the first demonstration of a genetic contribution to bone mass of the spine and proximal femur in adults and confirms similar findings of the forearm. Furthermore, bivariate analysis suggested that a single gene or set of genes determines bone mass at all sites.

/pdf/genetic-determinants-of-bone-mass-in-adults-a-twin-study-21jo4nayb2.pdf

Genetic determinants of bone mass in adults. A twin study.

Background Prolonged corticosteroid therapy increases the risk of osteoporosis and fracture. We studied whether corticosteroid-induced osteoporosis could be prevented by treatment with calcium, calcitriol (1,25-dihydroxyvitamin D3), and calcitonin. Methods One hundred three patients starting long-term corticosteroid therapy were randomly assigned to receive 1000 mg of calcium per day orally and either calcitriol (0.5 to 1.0 μg per day orally) plus salmon calcitonin (400 IU per day intranasally), calcitriol plus a placebo nasal spray, or double placebo for one year. Data on treatment efficacy were available for 92 of these patients. Bone density was measured every four months for two years by photon absorptiometry. There were no significant differences between groups with respect to age, underlying disease, initial bone density, or corticosteroid dose during the first year. Results Calcitriol (mean dose, 0.6 μg per day), with or without calcitonin, prevented more bone loss from the lumbar spine (mean rates...

https://www.nejm.org/doi/pdf/10.1056/NEJM199306173282404

Prevention of corticosteroid osteoporosis. A comparison of calcium, calcitriol, and calcitonin.

Hip fractures are the most serious complication of osteoporosis. Although low proximal femoral bone mineral density (BMD) does not cause hip fractures directly, it is clearly a prerequisite for the increased risk associated with aging. To investigate the mechanism of the age-related decline in proximal femoral bone mineral density, we have examined the relative importance of muscle strength, physical fitness, and body mass index (BMI) in addition to age in the determination of proximal femoral BMD in 73 healthy female volunteers age 20-75 years. Muscle strength was an independent predictor of BMD at all three sites in the proximal femur as well as in the lumbar spine and forearm; proximal femur BMD was also predicted by physical fitness. BMI was a positive predictor of bone mass at all sites. In the proximal femur, age was not an independent predictor of BMD at any site. In postmenopausal women muscle strength was a significant predictor of bone mass in the femur and forearm, but not in the spine. However, BMI remained predictive of bone mineral at all sites. Muscle strength, physical fitness, and weight appear to exert independent effects upon bone mass. Age effects may be mediated indirectly through associated changes in these factors. The integrated physical load on the skeleton may be a final common pathway.

Muscle strength, physical fitness, and weight but not age predict femoral neck bone mass.

Bone mass and its mineral content are under genetic control. The vitamin D receptor (VDR) gene has been shown to be a major locus for genetic effects on bone mineral density (BMD), and polymorphisms in this gene accounted for a large proportion of genetic variance in BMD in an Australian population. In this study, we investigated whether similar associations are present in a North American population. We studied 139 normal healthy women (age 53.2 +/- 14.5, mean +/- SD) and 43 severely osteoporotic postmenopausal women (age 65.8 +/- 5.9). In the 127 of them with complete genetic studies, the distribution of genotypes, determined by polymerase chain reaction on leukocyte DNA samples, agreed closely with that in the Australian population. BMD was strongly related to age and weight, and, thus was adjusted for these parameters prior to genetic analysis. We found that age modulated the effect of VDR genotypes on femoral neck BMD (FN-BMD) (TaqI, p = 0.036; BsmI, p = 0.118; ApaI, p = 0.041) such that the effect of genotype was greatest among younger (premenopausal) women and declined with age so that there was no discernible difference by age 70. Among the younger women, a high FN-BMD was associated with the TT (or aa or bb) genotype while low FN-BMD was associated with the tt (or AA or BB) genotype.(ABSTRACT TRUNCATED AT 250 WORDS)

Philip N. Sambrook

Papers

Prediction of Bone-Density from Vitamin-D Receptor Alleles

Genetic determinants of bone mass in adults. A twin study.

Prevention of corticosteroid osteoporosis. A comparison of calcium, calcitriol, and calcitonin.

Muscle strength, physical fitness, and weight but not age predict femoral neck bone mass.

The contribution of vitamin D receptor gene alleles to the determination of bone mineral density in normal and osteoporotic women