Faculty Bibliography

We recently demonstrated that insulin growth factor-I (IGF-I) cosegregates with bone mineral density (BMD) in progenitor crosses of two inbred strains of mice. Additionally, we reported that men with idiopathic osteoporosis (IOM) have low serum IGF-I levels, which can be related to BMD and bone turnover. In this study, we considered the possibility that serum IGF-I levels are influenced by molecular genetic variation in the IGF-I structural gene, and that a polymorphic microsatellite (CA repeat) in this locus can be used as a genetic marker for such comparisons. We studied 171 men and women, classified according to the trial in which they were participating. First, in 25 Caucasian men with IOM we noted a very high frequency (64%) of homozygosity for the most common allele (192 bp) in a dinucleotide repeat 1 kb upstream from the transcription start site of the IGF-I gene. This compared with a frequency of only 32% in healthy populations (both men and women) (P < 0.004). Next, we determined that for 116 healthy Caucasian men and women the 192/192 genotype was associated with lower serum IGF-I levels than all other genotypes (192/192: 129 +/- 7 ng/mL vs. others: 154 +/- 7 ng/mL, P = 0.03). We also noted that subjects possessing one 194-bp allele exhibited serum IGF-I levels 25% higher than those homozygous for 192 bp (192/192), (P < 0.005) even after correction for age and sex. Similarly, for men with the 192/192 genotype, serum IGF-I concentrations were lower than any other genotype (145 +/- 10 ng/mL vs. 183 +/- 9 ng/ml P < 0.02). In conclusion, low serum IGF-I levels found in men with IOM are associated with homozygosity for a specific allele of the IGF-I microsatellite (192/192), and individual variation in serum IGF-I levels is influenced by genetic factors and may be specifically influenced by variation at the IGF-I structural locus. Further family and pedigree studies are needed to characterize the relationship of bone mass acquisition to the IGF-I genotype.

Aging is associated with a marked decline in bone mineral density (BMD), an increased likelihood of falling and a much greater propensity for fracture. Several factors contribute to aging-related bone loss, including reduced bone formation, increased bone resorption, recent bodyweight loss, poor nutritional status and the coexistence of other, often rheumatological, conditions. Any of these factors can lead to an uncoupling of the bone remodelling unit. In addition, the frequent use of glucocorticoids to treat a vast array of conditions has contributed to an ever-expanding group of elderly individuals who are at extremely high risk for spine and hip fractures. Owing to the surprisingly high morbidity and mortality associated with these fractures in the elderly, an understanding of the pathogenesis and epidemiology of glucocorticoid-induced osteoporosis is paramount. The factors that contribute to bone loss in older individuals treated with glucocorticoids include reduced muscle mass, poor nutrition, hypogonadism, vitamin D deficiency and secondary hyperparathyroidism. Recent studies suggest that a prophylactic approach to this problem could have a huge impact on the medical, social and economic costs of osteoporosis.

Although peripheral bone mass measurements have been available for more than a quarter of a century to predict osteoporotic fractures, these studies fell out of favor in the late 1980s and early 1990s as axial measurements replaced appendicular determinations for risk assessment and therapeutic responsiveness. Within the last half decade there has been a resurgence in utilization of peripheral measurements, primarily because of improved technology, enhanced precision, and greater accessibility. There are now nearly 11,000 peripheral densitometers in use around the world with quantitative ultrasound (QUS) of the calcaneus and peripheral densitometry (pDXA) of the wrist or calcaneus the most popular. Three recent prospective studies involving more than 20,000 postmenopausal women have demonstrated that QUS of the calcaneus can predict future fractures as accurately as central measurements of the spine or femur. This has raised the possibility that widespread screening with QUS or pDXA will soon become a reality. In this articles we hypothesize that global utilization of peripheral technology by primary care physicians is an absolutely necessity for the successful identification and treatment of all osteoporotic patients. But despite improvements in the accuracy and precision of these machines, several critical questions remain. In particular the issues which demand further study include: 1. The rate of false negative tests by peripheral instruments; 2. The utilization of appendicular sites to measure therapeutic efficacy of various antiosteoporotic drugs; 3. The timing of follow-up measurements to assess responsiveness; 4. The relationship between fracture risk education and incremental changes in bone mass; 5. The interrelationship between bone density and bone architecture and 6. cost effectiveness of peripheral vs central measurements. Notwithstanding these issues, peripheral scanning by one of several techniques is likely to be at the forefront of screening for osteoporosis risk, not only in specialized clinics but at the "point of care" in primary care offices.

Epidermal growth factor (EGF) is a polypeptide present in mammalian salivary glands which has been shown to have mitogenic and gastric acid inhibitory properties in vivo. The mechanisms of action of EGF at the level of the parietal cell are not clear. In the present study, we have examined the effects of EGF on both acid and macromolecular (intrinsic factor, IF) secretion stimulated by the cyclic AMP-mediated agonist histamine using the rabbit isolated gastric gland model. Acid secretion was assessed by the accumulation of [14C]aminopyrine (AP) in glands and IF in the supernatants by the binding of [57Co]cyanocobalamin. Histamine (10(-6) to 5 x 10(-5) M) resulted in a 4-6 fold increase in [14C]AP and IF (P less than 0.05). EGF alone (10(-8) M, 10(-7) M) had no significant effect on basal [14C]AP accumulation or IF secretion (P less than 0.05). EGF (10(-7) M) significantly inhibited the histamine dose-response curve for [14C]AP and IF, but a relatively greater inhibition was observed at higher histamine concentration. These data demonstrate that EGF inhibits both acid and IF secretion in vitro at concentrations consistent with those observed in vivo. The observations further support the hypothesis that EGF may play a role in the regulation of parietal cell secretion.

In order to determine whether the proteinuria observed in some renal donors was glomerular or tubular in origin, and to determine whether creatinine clearance was an accurate index of glomerular filtration rate (GFR) in subjects with reduced nephron mass, 29 donors were evaluated 9-18 years after uninephrectomy. Results were compared with those in 31 age-, sex-, and race-matched controls evaluated at the same time. Mean creatinine clearance (Ccreat) in donor was 78% that of controls, which was similar to the 85% ratio of inulin clearance (Cin) in donors compared with that of controls. Furthermore, the ratio of Ccreat/Cin was similar in both donors and controls. One third of the renal donors had an elevated albumin excretion compared with controls (microalbuminuria [12-220 mg/24 hr] in seven patients; 301 and 1084 mg/24 hr in two patients). There was no correlation between albuminuria and blood pressure, nor was there a demonstrable clinical cause for the albuminuria in most patients. In contrast to these results, excretion of beta-2 microglobulin, an index of tubular proteinuria, was normal in all but one patient. The prevalence of hypertension was higher in donors compared with the expected prevalence adjusted for age, sex, and race. These results verify that creatinine clearance is a reliable measure of GFR in long-term renal donors. They also demonstrate an increased frequency of glomerular proteinuria and hypertension in renal donors. Despite these mild abnormalities, GFR is well preserved for up to 18 years postuninephrectomy.