Melton, L. Joseph

Abstract We propose here a new unitary model for the pathophysiology of involutional osteoporosis that identifies estrogen (E) deficiency as the cause of both the early, accelerated and the late, slow phases of bone loss in postmenopausal women and as a contributing cause of the continuous phase of bone loss in aging men. The accelerated phase in women is most apparent during the first decade after menopause, involves disproportionate loss of cancellous bone, and is mediated mainly by loss of the direct restraining effects of E on bone cell function. The ensuing slow phase continues throughout life in women, involves proportionate losses of cancellous and cortical bone, and is associated with progressive secondary hyperparathyroidism. This phase is mediated mainly by loss of E action on extraskeletal calcium homeostasis which results in net calcium wasting and increases in the level of dietary calcium intake required to maintain bone balance. Because elderly men have low circulating levels of both bioavailable E and bioavailable testosterone (T) and because recent data suggest that E is at least as important as T in determining bone mass in aging men, E deficiency may also contribute substantially to the continuous bone loss of aging men. In both genders, E deficiency increases bone resorption and may also impair a compensatory increase in bone formation. For the most part, this unitary model is well supported by observational and experimental data and provides plausible explanations to traditional objections to a unitary hypothesis.

Abstract To assess the influence of bone turnover on bone density and fracture risk, we measured serum levels of osteocalcin (OC), bone alkaline phosphatase (BAP), and carboxy-terminal propeptide of type I procollagen (PICP), as well as 24-h urine levels of cross-linked N-telopeptides of type I collagen (NTx) and the free pyridinium cross-links, pyridinoline (Pyd) and deoxypyridinoline (Dpd), among 351 subjects recruited from an age-stratified random sample of Rochester, Minnesota women. PICP, NTx, and Dpd were negatively associated with age among the 138 premenopausal women. All of the biochemical markers were positively associated with age among the 213 postmenopausal women, and the prevalence of elevated turnover (>1 standard deviation [SD] above the premenopausal mean) varied from 9% (PICP) to 42% (Pyd). After adjusting for age, most of the markers were negatively correlated with bone mineral density (BMD) of the hip, spine, or forearm as measured by dual-energy X-ray absorptiometry, and women with osteoporosis were more likely to have high bone turnover. A history of osteoporotic fractures of the hip, spine, or distal forearm was associated with reduced hip BMD and with elevated Pyd. After adjusting for lower BMD and increased bone resorption, reduced bone formation as assessed by OC was also associated with prior osteoporotic fractures. These data indicate that a substantial subset of elderly women has elevated bone turnover, which appears to adversely influence BMD and fracture risk. Combined biochemical and BMD screening may provide better prediction of future fracture risk than BMD alone.

Abstract To meet expectations for the participation of minority populations in research, we committed to enroll 140 minority subjects in addition to a random sample of Olmsted County, Minnesota residents (90% white) for a study of risk factors for age-related bone loss and fractures. We successfully enrolled 597 additional minority subjects but encountered specific problems with respect to identification of potential subjects, recruitment, obtaining informed consent, transportation to the study site, and collecting study data. These problems were resolved by observing the tenets of outreach to a diverse study population, namely (1) understand the target population; (2) establish explicit recruitment goals; (3) agree on research plans between study staff and minority communities; (4) continuously evaluate the recruitment process; and (5) maintain lines of communication. Success depended especially on the recruitment of cultural advisors from the different ethnic groups. These special efforts increased the recruitment cost substantially; the total expense of $122,000 for recruiting 550 Asian, Hispanic, and Somali subjects was almost 5-fold higher than the $26,000 required to recruit 699 mostly white study subjects from the population who were contacted by mail. Although it is not impossible to recruit minority subjects, investigators (and grant reviewers) should recognize that significant resources are required to gain access to ethnic communities for research. These results should contribute to more realistic budgets for recruiting minority subjects into clinical research studies.

Abstract The role of the IGFs and IGFBPs on age-related changes in BMD in adult men and women is not well understood. Studying an age-stratified community based sample of 344 men and 276 women, we found higher IGFBP-2 levels to be associated with lower BMD. IGFBP-2, which increases with age in both men and women, was the strongest, most consistent predictor of BMD among the IGF/IGFBPs studied. Introduction: Insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are important regulators of tissue growth and metabolism, but their association with BMD in adult men and women is controversial. Materials and Methods: In an age-stratified, random sample of the community population, we examined the role of serum levels of IGF-I, IGF-II, and IGFBP-1, −2, and −3 on BMD of the proximal femur (total hip), lateral spine, midshaft, and ultradistal radius as measured by DXA. We explored the association before and after adjustment for potential confounders, including age, bioavailable estradiol and testosterone, sex hormone binding globulin (SHBG), and measures of total fat and skeletal muscle mass. Results: We studied 344 men (age, 23-90 years) and 276 women (age, 21-93 years; 166 postmenopausal) not on hormone replacement or oral contraceptives. In both men and women, IGF-I and IGFBP-3 levels fell with advancing age, whereas IGFBP-2 levels tended to rise with age. There was an inverse association of IGFBP-2 with BMD at most skeletal sites in men and both premenopausal and postmenopausal women, whereas lower IGF-I and IGFBP-3 were associated with lower BMD in men and postmenopausal women only. Lower IGF-II was associated with lower BMD in men only. There were no associations between IGFBP-1 and BMD in either sex. After adjustment for age, in most cases, we found no further associations between IGF-I, IGF-II, or IGFBP-3 and BMD. In contrast, after age adjustment, higher IGFBP-2 remained a predictor of lower BMD in men and postmenopausal women at all sites except for the lateral spine (for men: r = −0.21, −0.20, and −0.19, all p < 0.001; and for postmenopausal women: r = −0.34, −0.24, and −0.25, all p < 0.01, for the total hip, midshaft, and ultradistal radius, respectively). IGFBP-2 remained an independent negative predictor of BMD in men, postmenopausal women, and all women combined after additional adjustment for bioavailable sex steroids, but not at all sites after adjustment for SHBG and muscle mass. In premenopausal women, IGFBP-2 had similar associations as seen in postmenopausal women, but they were weaker and not statistically robust. Conclusions: Among the IGF/IGFBPs in our study, IGFBP-2 was a key negative predictor of BMD among men and women, particularly postmenopausal women. Our findings suggest a potential role of the IGF/IGFBP system in regulating bone loss in aging men and women and identify a previously under-recognized, potentially deleterious role for IGFBP-2, a known inhibitor of IGF action that increases with age in both sexes. Whether the action of the IGF/IGFBP system on bone metabolism is mediated partly through its effects on muscle mass or SHBG deserves further study.

Abstract In a population-based cross-sectional study, we examined effects of sex and age on bone microstructure at the wrist using high-resolution 3-D pQCT. Compared with women, men had thicker trabeculae in young adulthood and had less microstructural damage with aging. These findings may contribute to the virtual immunity of men to age-related increases in wrist fractures. Introduction: Although changes in bone microstructure contribute to fracture risk independently of BMD, it has not heretofore been possible to assess this noninvasively in population-based studies. Materials and Methods: We used high-resolution 3-D pQCT imaging (voxel size, 89 μm) to define, in a random sample of women (n = 324) and men (n = 278) 21–97 years of age, sex and age effects on bone microstructure at the wrist. Results: Relative to young women (age, 20–29 years), young men had greater trabecular bone volume/tissue volume (BV/TV; by 26%, p = 0.001) and trabecular thickness (TbTh; by 28%, p < 0.001) but similar values for trabecular number (TbN) and trabecular separation (TbSp). Between ages 20 and 90 years, cross-sectional decreases in BV/TV were similar in women (−27%) and in men (−26%), but whereas women had significant decreases in TbN (−13%) and increases in TbSp (+24%), these parameters had little net change over life in men (+7% and −2% for TbN and TbSp, respectively; p < 0.001 versus women). However, TbTh decreased to a greater extent in men (−24%) than in women (−18%; p = 0.010 versus men). Conclusions: Whereas decreases with age in trabecular BV/TV are similar in men and women, the structural basis for the decrease in trabecular volume is quite different between the sexes. Thus, over life, women undergo loss of trabeculae with an increase in TbSp, whereas men begin young adult life with thicker trabeculae and primarily sustain trabecular thinning with no net change in TbN or TbSp. Because decreases in TbN have been shown to have a much greater impact on bone strength compared with decreases in TbTh, these findings may help explain the lower life-long risk of fractures in men, and specifically, their virtual immunity to age-related increases in distal forearm fractures.

Abstract In an age- and sex-stratified population sample (n = 700), we estimated fall-related loads and bone strength indices at the UDR and FN. These load/strength ratios more closely simulated patterns of wrist and hip fractures occurring in the same population than did measurement of vBMD. Introduction: Areal BMD measurements, although associated with fracture risk, incompletely explain patterns of fragility fractures. Moreover, population-based assessments relating applied loads and whole bone strength to fracture patterns have not been made. Materials and Methods: Using QCT, we assessed volumetric BMD (vBMD), cross-sectional geometry, and axial (EA) and flexural (EI) rigidities (indices of bone's resistance to compressive and bending loads, respectively) at the ultradistal radius (UDR) and femoral neck (FN) and estimated the loads applied to the wrist and hip during a fall. We used fall load (FL)/bone strength ratios to estimate fracture risk. Results: vBMD in young adults was similar between sexes. Decreases in vBMD over life were also similar (30% and 28%) at UDR but were somewhat greater (46% and 34%) at FN in women versus men, respectively. In young adults, FL/strength ratios at UDR were 32–51% lower (better) in men than in women and increased (worsened) over life less in men (+4% to +22%) than in women (+20% to +33%). In young adults, FL/strength ratios at FN were only marginally better in men than in women but worsened less over life in men (+22% to +36%) than in women (+40% to +62%). Conclusions: The 6:1 female preponderance and the virtual immunity of men for age-related increases in wrist fractures are largely explained by the more favorable FL/strength ratios at UDR in young adult men (because of larger bone size and more favorable geometry) versus women and to maintaining this advantage over life. The 2-fold lower incidence of hip fractures in men versus women is largely explained by age-related increases (worsening) of FL/bone strength ratios that are only one-half of the increases in women. The moderate increases in these ratios with aging are insufficient to explain the >4-fold increase in hip fracture incidence after age 75 in both sexes, suggesting contributions of other factors, especially the well-documented increased frequency of injurious falls among the elderly.

AbstractAmong 454 operations done for peptic ulcer between 1956 and 1985 on residents of Rochester, Minnesota, U.S.A. in whom ulcer size could be determined accurately, 50 operations (11% of the total) were performed for giant ulcers and 404 (89%) for nongiant ulcers. The annual operation rate per 100,000 residents for giant ulcer did not clearly decline during the 30‐year period in contrast to the dramatic fall in operation rates for nongiant ulcers. Nonetheless, the ratio of operation rates for giant ulcer compared to nongiant ulcer changed relatively little. Giant ulcers required emergency operation for massive bleeding more often than nongiant ulcers. Also, giant ulcers presented with unusual and severe complications such as gastrocolic fistula. Survival after surgery for giant ulcer was poorer than survival after an operation for nongiant ulcer. We conclude that giant ulcers are operated on somewhat less often today than in the past, while operations for nongiant ulcers are much less frequent. The giant ulcers that are operated on, however, are more prone to massive bleeding and are associated with poorer postoperative survival than their nongiant counterparts.