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Byline: S. Khosla (1), H. M. Arrighi (3), L. J. Melton, III (2), E. J. Atkinson (2), W. M. O'Fallon (2), C. Dunstan (3), B. L. Riggs (1) Keywords: Key words:BMD -- Bone turnover -- OPG -- RANK-L -- Sex steroids Abstract: Osteoprotegerin (OPG) is a potent antiresorptive molecule that binds the final effector for osteoclastogenesis, receptor activator of NF-kB ligand (RANK-L). OPG production is regulated by a number of cytokines and hormones, including sex steroids, but there are few data on age and gender effects on circulating serum OPG levels, as well as possible relationships between OPG levels and bone turnover markers or bone mineral density (BMD). Thus, we measured serum OPG levels in an age-stratified, random sample of men (n= 346 age range, 23--90 years) and women (n= 304 age range 21--93 years) and related them to sex steroid levels, bone turnover markers and BMD. Serum OPG levels increased with age in both men (R= 0.39, p&lt 0.001) and women (R= 0.18, p&lt 0.01). Premenopausal women had higher OPG levels than men under age 50 years (171 +- 6 pg/ml vs 134 +- 6 pg/ml, respectively, p&lt 0.001), whereas serum OPG levels were no different in postmenopausal women compared with men = 50 years (195 +- 7 pg/ml vs 188 +- 7 pg/ml, respectively, p= 0.179). OPG levels correlated inversely with serum bioavailable testosterone levels in men = 50 years (R=--0.27, p&lt 0.001), but no associations were present with either estrogen or testosterone levels in the women. In the men, there was a trend for OPG levels to be associated positively with bone resorption markers and inversely with BMD. Collectively, the gender difference in OPG levels suggests that sex steroids may regulate OPG production in vivo, as has been found in vitro. Moreover, OPG production may also rise with increases in bone turnover, probably as a homeostatic mechanism to limit bone loss. Further studies directly testing these hypotheses should provide additional insights into the potential role of OPG in bone loss related to aging and sex steroid deficiency. Author Affiliation: (1) Endocrine Research Unit, Division of Endocrinology, Metabolism, and Nutrition, Department of Internal Medicine, US (2) Department of Health Sciences Research, Mayo Clinic and Foundation, Rochester, MN , US (3) Amgen Inc., Thousand Oaks, CA, USA, US Article note: Received: 14 August 2001 / Accepted: 20 November 2001

Byline: A. N. A. Tosteson (1), S. E. Gabriel (3), M. R. Grove (2), M. M. Moncur (2), T. S. Kneeland (2), L. J. Melton III (3) Keywords: Key words:Cost-effectiveness -- Fracture -- Osteoporosis -- Postmenopausal women -- Quality-adjusted life years -- Utility Abstract: The objective of the study was to estimate the impact of hip and vertebral fractures on quality of life in postmenopausal women using a preference-based health measure that is appropriate for economic evaluations and to investigate correlates of health outcome. Interviews to assess health-related quality of life, which also documented other health conditions and characteristics, were undertaken in women age 50 years and older without osteoporotic fractures compared with women with hip and/or vertebral fracture(s). Health status was characterized by self-reported physical limitations and the mental and physical component summary scores of the SF-36. Quality-adjusted life years (QALYs), which reflect each individual's assessment of her overall health utility, were estimated with time tradeoff values. Regression methods were used to examine QALY correlates (e.g. time since fracture) for each fracture group and to estimate differences in QALYs between fracture and non-fracture subjects after accounting for other patient characteristics. Among 382 women ages 50--96 years, fracture subjects were significantly older, less likely to use hormone replacement therapy and more likely to report physical limitations than non-fracture subjects. On the QALY scale, where 1 represents perfect health and 0 represents death, mean QALY values were 0.82 (95% CI: 0.76, 0.87) among 114 women with one or more vertebral fractures and 0.63 (95% CI: 0.52, 0.74) among 67 with hip fracture compared with 0.91 (95% CI: 0.88, 0.94) among 201 women without fracture. No significant correlates of QALYs were identified among women with vertebral fracture alone. Among hip fracture subjects, time since hip fracture and presence of a vertebral fracture were significant correlates of QALYs. In multiple regression analyses, estimated QALY differences (fracture minus non-fracture subjects) ranged from --0.05 to --0.55 and were equivalent to losses of 20--58 days, 23--65 days and 115--202 days per year for vertebral fracture (p= 0.001), hip fracture (p= 0.009) and hip plus vertebral fracture (p&lt 0.001) subjects, respectively, depending on age. Thus to adequately assess the cost-effectiveness of osteoporosis treatment, the negative impact of vertebral fractures on QALYs, even among women who have survived a hip fracture, must be considered. Author Affiliation: (1) Department of Medicine and the (2) Center for the Evaluative Clinical Sciences, Department of Community and Family Medicine, Dartmouth Medical School, Hanover, New Hampshire , US (3) Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA, US Article note: Received: 2 February 2001 / Accepted: 23 July 2001

Byline: L. J. Melton III (1), R. D. Brown Jr (2), S. J. Achenbach (1), W. M. O'Fallon (1), J. P. Whisnant (1), J. P. Whisnant (2) Keywords: Key words:Epidemiology -- Hip fracture -- Osteoporosis -- Stroke Abstract: The overall risk of fracture following stroke has not been well quantified. We addressed this issue in a population-based retrospective cohort study among the 387 Rochester, Minnesota residents who survived for 90 days following their first cerebral infarction during the 10-year period, 1960--69. Cases were matched by age and sex to controls from the general population of Rochester, and subsequent fractures were assessed through review of each subject's complete (inpatient and outpatient) medical records in the community. With comparable follow-up, the 128 fractures observed among cases were little more than the 118 seen among controls, and the cumulative incidence of any fracture after 25 years was not significantly different (71% versus 66% p=0.464). Using stratified Cox analysis, there was no increase in the risk of fractures generally (hazard ratio (HR), 1.1 95% CI, 0.8--1.6) or hip fractures specifically (HR, 1.1 95% CI, 0.6--2.1) compared with controls. Among the stroke patients with hemiparesis or hemiplegia, the majority of fractures occurred on the impaired side. In a multivariate analysis, fracture risk increased with age (HR per 10 years, 1.6 95% CI, 1.4--2.0), with hospitalization at onset of stroke (HR, 2.0 95% CI, 1.3--3.2) and with moderate functional impairment (HR, 1.6 95% CI, 1.02--2.5) but not severe disability (HR, 0.8 95% CI, 0.4--1.6). No other characteristic of the stroke or its treatment was an independent predictor of overall fracture risk. Patients and their caretakers need to be aware of the risk of fracture from falls, particularly when moderate impairment permits the patient to be independently mobile. Author Affiliation: (1) Department of Health Sciences Research, US (2) Department of Neurology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA, US Article note: Received: 29 September 2000 / Accepted: 26 April 2001

Byline: L.J. Melton, III (1), T.M. Therneau (1), D.R. Larson (1) Keywords: Key words: Epidemiology Incidence Osteoporosis Proximal femur (hip) fracture Secular trends Abstract: In this population-based descriptive study covering the 65-year period, 1928--92, there was a 5-fold increase in hip fracture prevalence among Rochester, Minnesota residents between 1928--42 and 1973--82, from 135.8 to 675.8 per 100 000. This change was dictated almost entirely by an increase in the incidence of first hip fractures due to moderate trauma (n = 2058) that was observed among Rochester women through 1950, and among men through 1980, that affected all age groups. Declining incidence rates thereafter led to a 9% fall in hip fracture prevalence from 1973--82 due to 1983--92 to a rate of 612.7 per 100 000. A 13.7-year increase in age at first hip fracture over the study period was accounted for by aging of the underlying population, and a comparable 13.9-year increase in the age at death following hip fracture appeared to result from improved survival in the population generally. Thus, trends in hip fractures prevalence were mainly determined by changes in incidence rather than relative changes in age at onset and death following hip fracture. Author Affiliation: (1) Department of Health Sciences Research, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA, US