Christopher White

Prevalent vertebral deformities: Relationship to bone mineral density and spinal osteophytosis in elderly men and women

The aims of this study were to ascertain vertebral deformity prevalence in elderly men and women and to describe the association between bone mineral density (BMD) at the lumbar spine and femoral neck, severity of spinal degenerative disease and vertebral deformity prevalence. We performed standardized spinal radiographs in a random sample of 300 elderly men and women participating in the Dubbo Osteoporosis Epidemiology Study, a population-based study of fracture risk factors. Radiographs were read independently by masked observers for the prevalence of vertebral deformity and severity of osteophytosis. BMD was measured by dual-energy X-ray absorptiometry. The prevalence of vertebral deformities was critically dependent on the criterion used. The less strict criteria seemed to overestimate deformities at either end of the spine region analysed. However, irrespective of the criterion used, prevalence of deformity was higher in men than in women (25% vs 20% for the 3 SD criterion, 17% vs 12% for the 4 SD criterion and 27% vs 25% for the 25% criterion). Femoral neck BMD was more strongly associated with vertebral deformities than spinal BMD for the 25% criterion (OR/SD change in BMD 1.39 (p=0.02) vs 1.20 (p=0.19)), 3 SD criterion (OR/SD change in BMD 1.45 (p=0.01) vs 1.10 (p=0.34)) and 4 SD criterion (OR/SD change in BMD 1.98 (p=0.0002) vs 1.68 (p=0.008)). BMD was also more strongly associated with biconcave deformities than either wedge or crush deformities and more so in men than in women. Severity of spinal osteophytosis was not associated with vertebral deformity. In conclusion, femoral neck BMD is at least equivalent to the lumbar spine BMD in strength of association with prevalent vertebral fractures. Spinal osteophytosis falsely elevates BMD without a concomitant decrease in fracture risk, indicating that any interpretation of spinal BMD needs to be adjusted for osteophytosis. These findings support the use of femoral neck bone densitometry in older men and women. Moreover, these data indicate that current criteria for radiological assessment of vertebral deformity are sufficiently loose to include a substantial proportion of non-fractures in the elderly, with important implications for the design of clinical trials. However, irrespective of the criterion used, vertebral deformities in men are at least as common, if not more so, than in women, suggesting that vertebral osteoporotic fractures are overlooked in men.

Increased formation and decreased resorption of bone in mice with elevated vitamin D receptor in mature cells of the osteoblastic lineage

The microarchitecture of bone is regulated by complex interactions between the bone‐forming and resorbing cells, and several compounds regulate both actions. For example, vitamin D, which is required for bone mineralization, also stimulates bone resorption. Transgenic mice overexpressing the vitamin D receptor solely in mature cells of the osteoblastic bone‐forming lineage were generated to test the potential therapeutic value of shifting the balance of vitamin D activity in favor of bone formation. Cortical bone was 5% wider and 15% stronger in these mice due to a doubling of periosteal mineral apposition rate without altered body weight or calcium homeostatic hormone levels. A 20% increase in trabecular bone volume in transgenic vertebrae was also observed, unexpectedly associated with a 30% reduction in resorption surface rather than greater bone formation. These findings indicate anabolic vitamin D activity in bone and identify a previously unknown pathway from mature osteoblastic cells to inhibit osteoclastic bone resorption, counterbalancing the known stimulatory action through immature osteoblastic cells. A therapeutic approach that both stimulates cortical anabolic and inhibits trabecular resorptive pathways would be ideal for treatment of osteoporosis and other osteopenic disorders.—Gardiner, E. M., Baldock, P. A., Thomas, G. P., Sims, N. A., Henderson, N. K., Hollis, B., White, C. P., Sunn, K. L., Morrison, N. A., Walsh, W. R., Eisman, J. A. Increased formation and decreased resorption of bone in mice with elevated vitamin D receptor in mature cells of the osteoblastic lineage. FASEB J. 14, 1908–1916 (2000)

Allelic variation in the vitamin D receptor, lifestyle factors and lumbar spinal degenerative disease

OBJECTIVE To describe the relation between spinal degenerative disease, allelic variation in the vitamin D receptor gene, and lifestyle factors in a population-based association study. METHODS Random population-based sample of 110 men and 172 women over 60 years of age participating in the Dubbo Osteoporosis Epidemiology Study who had spinal radiographs (performed according to a standardised approach), assessment of lifestyle factors, bone densitometry as well as blood taken for genotyping. RESULTS Spinal degenerative disease of varying severity was common in this sample. Multivariate analysis of genetic and lifestyle factors simultaneously strengthened the statistical significance of each indicating the presence of additive gene environment interaction. Allelic variation in the vitamin D receptor gene was associated with severity of osteophytosis (adjusted OR “TT” v “tt” 0.41, 95% CI 0.17, 0.97), presence of disc narrowing (adjusted OR “TT” v “tt” 0.45, 95% CI 0.20, 0.99) and weakly with presence of osteophytosis (adjusted OR “TT” v “tt” 0.47, 95% CI 0.19, 1.16) but not with severity of disc narrowing (OR “TT” v “tt” 1.05, 95% CI 0.40, 2.72) or apophyseal arthritis (OR “TT” v“tt” 0.63, 95% CI 0.24, 1.59). Adjustment for femoral neck bone density did not change these findings suggesting that the association is not mediated through bone density. Presence and severity of spinal degenerative disease increased with age at all sites. Current smoking increased both the presence (adjusted OR 9.70, 95% CI 2.08, 45.1) and severity (adjusted OR 2.91, 95% CI 1.16, 9.03) of spinal osteophytosis with intermediate values for past smokers. Severity of osteophytosis was also independently associated with body mass index and quadriceps strength consistent with a contributory effect of physical loading. CONCLUSIONS In this elderly sample, both genetic and lifestyle factors were associated with the presence and severity of spinal degenerative disease. There were site specific differences in associations at the spine, which may be because of misclassification of disease status or may indicate possible environmental and genetic differences in the pathophysiology of spinal degenerative disease. Further studies are required to confirm these findings in different population samples and to further explore potential aetiological mechanisms particularly gene environment interaction.

THE ROLES OF EXERCISE AND FALL RISK REDUCTION IN THE PREVENTION OF OSTEOPOROSIS

In summary, the optimal model for the prevention of osteoporotic fractures includes maximization and maintenance of bone strength and minimization of trauma. Numerous determinants of each have been identified, but further work to develop preventative strategies based on these determinants remains to be undertaken. Physical activity is a determinant of peak BMD. There also is evidence that activity during growth modulates the external geometry and trabecular architecture, potentially enhancing skeletal strength, while during the adult years activity may reduce age-related bone loss. The magnitude of the effect of a 7% to 8% increase in peak BMD, if maintained through the adult years, could translate to a 1.5-fold reduction in fracture risk. Moreover, in the older population, appropriate forms of exercise could reduce the risk of falling and, thus, further reduce fracture risk. These data must be considered as preliminary in view of the paucity of long-term fracture outcome data from randomized clinical trials. However, current information suggests that the optimal form of exercise to achieve these objectives may vary through life. Vigorous physical activity (including weight-bearing, resistance, and impact components) during childhood may maximize peak BMD. This type of activity seems optimal through the young adult years, but as inevitable age-related degeneration occurs, activity modification to limit the impact component of exercise may become necessary. In the elderly, progressive strength training has been demonstrated to be a safe and effective form of exercise that reduces risk factors for falling and may also enhance BMD. In the frail elderly, activity to improve balance and confidence also may be valuable. Group activities such as Tai Chi may be cost-effective. Precise prescriptions must await the outcome of well-designed, controlled longitudinal studies that include fracture as an outcome. However, increased physical activity seems to be a sensible component of strategies to reduce osteoporotic fracture.

Testicular dysfunction in men with primary hypothyroidism; reversal of hypogonadotrophic hypogonadism with replacement thyroxine

Primary hypothyroidism can cause disturbances in normal gonadal function. The aim of this study was to investigate the relationship in men between hypogonadism and primary hypothyroidism and the extent to which free and total testosterone levels rose after introduction of replacement thyroxine.

Insulin expressing hepatocytes not destroyed in transgenic NOD mice.

BackgroundThe liver has been suggested as a suitable target organ for gene therapy of Type 1 diabetes. However, the fundamental issue whether insulin-secreting hepatocytes in vivo will be destroyed by the autoimmune processes that kill pancreatic β cells has not been fully addressed. It is possible that the insulin secreting liver cells will be destroyed by the immune system because hepatocytes express major histocompatibility complex (MHC) class I molecules and exhibit constitutive Fas expression; moreover the liver has antigen presenting activity. Together with previous reports that proinsulin is a possible autoantigen in the development of Type 1 diabetes, the autoimmune destruction of insulin producing liver cells is a distinct possibility.MethodsTo address this question, transgenic Non-Obese Diabetic (NOD) mice which express insulin in the liver were made using the Phosphoenolpyruvate Carboxykinase (PEPCK) promoter to drive the mouse insulin I gene (Ins).ResultsThe liver cells were found to possess preproinsulin mRNA, translate (pro)insulin in vivo and release it when exposed to 100 nmol/l glucagon in vitro. The amount of insulin produced was however significantly lower than that produced by the pancreas. The transgenic PEPCK-Ins NOD mice became diabetic at 20–25 weeks of age, with blood glucose levels of 24.1 ± 1.7 mmol/l. Haematoxylin and eosin staining of liver sections from these transgenic NOD PEPCK-Ins mice revealed the absence of an infiltrate of immune cells, a feature that characterised the pancreatic islets of these mice.ConclusionsThese data show that hepatocytes induced to produce (pro)insulin in NOD mice are not destroyed by an ongoing autoimmune response; furthermore the expression of (pro)insulin in hepatocytes is insufficient to prevent development of diabetes in NOD mice. These results support the use of liver cells as a potential therapy for type 1 diabetes. However it is possible that a certain threshold level of (pro)insulin production might have to be reached to trigger the autoimmune response.

Tissue specific and vitamin D responsive gene expression in bone

Studies of gene expression in bone have adopted a number of molecular approaches that seek to determine those cis and trans-acting factors responsible for the development and physiological regulation of this unique tissue. The majority of studies have been performed in vitro, focussing on the expression of genes such as osteocalcin, bone sialoprotein and type I collagen which demonstrate restricted or altered expression patterns in osteoblasts. These studies have demonstrated a large number of cis and trans acting factors that modulate the tissue specific and vitamin D responsive expression of these genes. These include the response elements and regions mediating basal and vitamin D dependent transcription of these genes as well as some of the transcription factors that bind to these regions and the nucleosomal organisation of these genes within a nuclear framework. In vivo studies, including the introduction of transgenes into transgenic mice, extend these in vitro observations within a physiological context. However, in part due to limitations in each approach, these in vitro and in vivo studies are yet to accurately define all the necessary cis and trans-acting factors required for tissue specific and vitamin D responsive gene expression. Advances have been made in identifying many cis-acting regions within the flanking regions of these genes that are responsible for their restricted expression patterns, but a vector incorporating all the necessary cis-acting regions capable of directing gene expression independent of integration site has not yet been described. Similarly, trans-acting factors that determine the developmental destiny of osteoblast progenitors and the restricted expression of these genes remain elusive and, despite advances in the understanding of protein-DNA interactions at vitamin D response elements contained within these genes, further intermediary factors that interact with the transcriptional machinery to modulate vitamin D responsiveness need to be identified.

Bone turnover is suppressed in insulin resistance, independent of adiposity.

Context The contribution of insulin resistance vs adiposity to bone mineral density (BMD), bone turnover, and fractures in humans remains unclear. Objective To evaluate BMD and bone turnover markers (BTMs) in lean (n = 18) and overweight/obese individuals with (n = 17) and without (n = 34, insulin-sensitive [Obsensitive, n=15] or insulin-resistant [Obresistant, n=19] by homeostasis model assessment insulin resistance) diabetes mellitus. Design Observational study. Outcome measures Insulin sensitivity was assessed using the hyperinsulinemic-euglycemic clamp; whole body BMD and fat mass (FM) using dual energy X-ray absorptiometry; and by measurement of BTMs [osteocalcin (OC), procollagen type 1 N-terminal propeptide (P1NP), and collagen type 1 cross-linked C-terminal telopeptide (CTx)], with the patient fasting and during clamp hyperinsulinemia. Results Fasting BTMs correlated with glucose infusion rate/fat-free mass (GIR/FFM) and adiponectin and, inversely, with fasting insulin and visceral fat (P ≤ 0.04 for all). Obsensitive, Obresistant, and diabetic individuals were matched by their FM percentage. Clamp GIR/FFM was similar in the lean and Obsensitive subjects (P = 1) and approximately twofold greater (P < 0.001) than in the Obresistant and diabetic subjects. BMD was greater in Obresistant than in Obsensitive (P = 0.04) and lean (P = 0.001) subjects. At baseline, compared with Obsensitive and lean subjects, Obresistant and diabetic individuals had lower OC, P1NP, and CTx levels. This reached statistical significance for Obresistant vs lean and Obresistant vs Obsensitive for both OC and CTx and for diabetic vs lean for CTx (P ≤ 0.04 for all). During hyperinsulinemia, lean individuals suppressed CTx more than did diabetic individuals (P = 0.03). On multiple regression analysis, visceral adiposity explained 16.7% and 19.3% of the baseline OC and CTx variability, respectively. Conclusions Increased visceral adiposity and higher fasting insulin in insulin-resistant states are associated with lower fasting OC and CTx and failure to further suppress with more insulin.

Sex steroid hormone stability in serum tubes with and without separator gels

Abstract Background: A pilot study showing a decrease in androstenedione concentration in serum collected into gel-containing serum tubes (STs) triggered an investigation of the effect of serum collection tube on steroid hormone stability. Methods: In the main study, two tube types were examined: BD Vacutainer® SST™II Advance and BD Vacutainer® Serum Tube. Forty-seven serum samples from apparently healthy volunteers were collected and analysed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) for testosterone, androstenedione, 17-hydroxyprogesterone (17-OHP) (n=20); and oestradiol (n=27). Primary specimens were centrifuged once, maintained at room temperature and extracted within 2 h for day zero (d0) results. To assess stability following refrigeration (2–8 °C), aliquots were taken from the primary tube on day one (d1) and day five (d5) and analysed immediately. Differences in measurand concentration between tubes at d0 and following storage (d1 and d5) were evaluated for statistical significance. Results: There was a progressive and statistically significant decrease in androstenedione concentration from d0 to d5 (p<0.001) in the SST™II tubes. In addition, there was a statistically significant reduction in testosterone, 17-OHP and oestradiol concentrations at d5 (p<0.01). Interestingly, oestradiol and testosterone concentrations increased with time in plain STs (p<0.01). The only change likely to have a clinical impact was that of androstenedione in serum gel tubes. Conclusions: To optimise conditions and to reduce pre-analytical error we recommend the use of plain serum collection tubes for androstenedione and rapid separation of serum from cells when oestradiol and testosterone are requested.

Calcium metabolism in pregnancy and lactation

Homeostatic adaptation to maternal calcium metabolism is a prerequisite for optimal delivery of sufficient calcium to the fetus and neonate during pregnancy and lactation, respectively. This article outlines the major adaptations known to occur and the physiological regulators likely to be principally involved. Importantly, different adaptive responses are used in pregnancy and lactation. The rarity of calcium disorders in pregnancy underscores the successful implementation of these adaptations in most women. For those few women with either pre-existing or pregnancy-acquired disorders of calcium metabolism, a knowledge of normal physiology is essential to understand the implications for managing these disorders in pregnant women.