Citations

Abstract Although median levels of bone turnover are increased in postmenopausal women, it is unclear whether the low circulating levels of endogenous estrogen exert a regulatory role on these levels. This issue was evaluated by assessing the effect of a blockade of estrogen synthesis on bone turnover markers in 42 normal women (mean age ± SD, 69 ± 5 years) randomly assigned to groups receiving the potent aromatase inhibitor letrozole or placebo for 6 months. Letrozole treatment reduced serum estrone (E1) and estradiol (E2) to near undetectable levels (p < 0.0001). This treatment did not affect bone formation markers but, as compared with the placebo group, increased bone resorption markers (urine 24-h pyridinoline [PYD] by 13.3% [p < 0.05] and 24-h urine deoxypyridinoline [DPD] by 14.2% [p < 0.05]) and decreased serum parathyroid hormone (PTH) by 22% (p = 0.002). These data indicate that in late postmenopausal women even the low serum estrogen levels present exert a restraining effect on bone turnover and support the concept that variations in these low levels may contribute to differences in their rate of bone loss.

Abstract Localized disruption of bone architecture leads to an increased risk of pathological fractures in patients with Paget's disease, but the impact of the disease on overall fracture risk is unknown. We addressed this issue among 236 Olmsted County, Minnesota residents (107 women and 129 men) first diagnosed with Paget's disease from 1950 through 1994. These subjects (mean ± SD age at diagnosis, 69.6 ± 12.2 years) were followed subsequently for 2798 person-years. During this period of observation, 33 pathological fractures were attributed to Paget's disease (1 skull, 11 vertebra, 1 shaft/distal humerus, 1 pelvis, 6 proximal femur, 2 shaft/distal femur, and 11 tibia/fibula). Excluding the fractures through pagetic bone, there was no increase in overall fracture risk in this cohort (standardized incidence ratio [SIR], 1.2; 95% CI, 0.9-1.4). However, there was a statistically significant increase in the risk of subsequent vertebra (SIR, 3.0; 95% CI, 2.2-4.1) and rib fractures (SIR, 1.7; 95% CI, 1.1-2.4) but not fractures of the proximal femur (SIR, 0.6; 95% CI, 0.3-1.1) or distal forearm (SIR, 1.4; 95% CI, 0.7-2.5). Thus, unselected patients with Paget's disease in the community, who mostly have mild disease, have a significantly increased risk of vertebral fractures, although this may relate partly to increased surveillance. Additional work is needed to clarify the relationship between Paget's disease and vertebral fractures and to identify individuals at increased risk for more aggressive therapy.

Abstract An age-stratified sample of 304 women from Rochester, Minnesota, aged 30–94 years (median 60 years) at baseline underwent measurement of femoral neck bone mineral density (BMD) over a follow-up period extending to 16 years. The average rate of change in femoral neck BMD was −1.0% per year (range −10.0% to +13.4%) and did not vary significantly with age. Because there was no marked increase in the rate of loss around the time of menopause, nor convincing evidence of there being a subset of fast losers, there was fairly good tracking of individual values over time; the correlation of baseline with femoral neck BMD values 16 years later was 0.83. Although a large number of potential determinants was assessed, the only consistent predictor of femoral neck bone loss in women of different ages was baseline femoral neck BMD (r = −0.15; p = 0.023). Otherwise, different sets of risk factors were identified for premenopausal women, women within 20 years of menopause, and women 20 years or more postmenopausal, but the predictive power of these different multivariate models was modest. Nonetheless, these data indicate that femoral neck BMD is quite predictable for extended periods of time. This is reassuring with respect to the use of statistical models that incorporate such data to estimate future fracture risk.

Abstract We report a 4-year randomized, double-blind, placebo-controlled clinical trial in 236 normal postmenopausal women (mean age ± SE, 66.3 ± 0.2 years) who were randomized to a calcium (1600 mg/day as the citrate) or placebo group. The women were seen every 6 months; 177 completed the trial. Net percentage changes in each group are given relative to baseline. The differences in net percentage changes (calcium group minus placebo group) in medians were: for lumbar spine bone density, 2.0% (p < 0.001) at year 1 and 0.3% (not significant) at year 4; for proximal femur bone density, 1.3% (p = 0.003) at year 1 and 1.3% (p = 0.015) at year 4; and for total body bone mineral, 0.4% (p = 0.002) at year 1 and 0.9% (p = 0.017) at year 4. Similar differences at year 4 were: −18.9% (p = 0.002) for parathyroid hormone (PTH), −11.9% (p = 0.026) for serum osteocalcin, and −32.2% (p = 0.003) for urine free pyridinoline. We conclude that long-term administration of calcium supplements to elderly women partially reverses age-related increases in serum PTH level and bone resorption and decreases bone loss. However, the effects on bone loss were weaker than those reported for estrogen, bisphosphonates, or calcitonin therapy, indicating that calcium supplements alone cannot substitute for these in treating established osteoporosis. Nonetheless, because of their safety, high tolerance, and low expense, calcium supplements may be a useful preventive measure for elderly postmenopausal women whose bone mineral density values are normal for their age.

Abstract Bone mass is purportedly reduced by an endogenous or exogenous excess of thyroid hormone or, perhaps, by calcitonin deficiency. Patients who have undergone thyroidectomy could be subject to all of these effects, yet their practical implications in terms of fracture risk are poorly defined. Interpretation is further hampered by the focus on women, where results may be influenced by involutional osteoporosis. Consequently, we assessed the potential for fractures among the 136 Rochester, Minnesota men who underwent thyroidectomy between 1935 and 1979, relative to a group of age-matched control men from the community. With 2194 person-years of follow-up in each group, survival free of any fracture of vertebra, proximal humerus, distal forearm, pelvis, or proximal femur was similar in the two groups (p = 0.23), and the relative risk of any of these fractures for thyroidectomized patients versus their controls was increased only 1.5-fold (95% CI, 0.7–3.2). The difference was entirely accounted for by a statistically significant excess of proximal femur fractures in the men with thyroidectomy. Risk factors for fractures among men with thyroidectomy included greater age at surgery, greater extent of surgery, and the presence of risk factors for secondary osteoporosis. Thus, thyroidectomy, performed mainly for adenoma or goiter, seems to have little overall influence on the risk of age-related fractures in men. However, the association with hip fractures requires further evaluation.

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 We evaluated different definitions of osteoporosis in a population-based sample of 348 men (age 22–90 years) compared with 351 women (age 21–93 years). Thirty-six men (10%) and 46 women (13%) had a history of osteoporotic fracture (hip, spine, or distal forearm due to moderate trauma at ≥ age 35). In logistic regression analysis, osteoporotic fracture risk was associated with bone mineral density (BMD) at all sites (neck, trochanter, total hip, lumbar spine, and total wrist) in both genders (p < 0.001) except spinal BMD in men. After adjusting for age, total hip BMD was the strongest predictor of fracture risk in women (odds ratio [OR] per 1 SD decline, 2.4; 95% confidence interval [CI], 1.6–3.7), while wrist BMD was best in men (OR, 1.5; 95% CI, 1.1–2.0). Among men but not women, bone mineral apparent density (BMAD) was a better predictor of fracture than BMD (wrist BMAD OR, 1.7; 95% CI, 1.3–2.3). Hip BMD/BMAD decreased linearly from age 20 years onward in both genders, while spinal BMD/BMAD declined after age 40 in women but not in men. In both genders, total wrist BMD/BMAD decreased after age 50. By World Health Organization criteria, the age-adjusted prevalence of osteoporosis at the hip, spine, or wrist was 35% among women ≥50 years of age. A similar approach (BMD > 2.5 SD below the young male mean) produced an osteoporosis prevalence rate in men ≥50 years of age of 19%. Thus, bone density predicts fracture risk in men as it does in women, and the prevalence of osteoporosis in men, using sex-specific normal values, is substantial. These observations indicate a need for better prevention and treatment strategies for men.

Abstract While severe primary hyperparathyroidism (HPT) is clearly associated with osteitis fibrosa cystica, it remains uncertain whether mild, asymptomatic primary HPT adversely affects the skeleton. Thus, we assessed the incidence of age-related fractures in a large, population-based inception cohort of 407 cases of primary HPT (93 men and 314 women) recognized during the 28-year period, 1965–1992. Fracture risk was assessed by comparing new fractures at each site to the number expected from gender- and age-specific fracture incidence rates for the general population (standardized incidence ratios, SIRs). These community patients with primary HPT mostly had mild disease (mean ± SD serum calcium, 10.9 ± 0.6 mg/dl). Altogether, 471 fractures occurred during 5766 person-years of follow-up. Overall fracture risk was significantly increased in these patients (SIR 1.3, 95% confidence interval [CI] 1.1–1.5). Primary HPT was associated with an increased risk of vertebral (SIR 3.2, 95% CI 2.5–4.0), distal forearm (SIR 2.2, 95% CI 1.6–2.9), rib (SIR 2.7, 95% CI 2.1–3.5), and pelvic fractures (SIR 2.1, 95% CI 1.1–3.5). The risk of proximal femur fractures was only marginally increased (SIR 1.4, 95% CI 1.0–2.0). By univariate analysis, increasing age and female gender were significant predictors of fracture risk, although higher serum calcium levels were also associated with increased fracture risk, and parathyroid surgery may have had a protective effect. By multivariate analysis, however, only age (relative hazard [RH] per 10-year increase, 1.6, 95% CI 1.4–1.9) and female gender (RH 2.3, 95% CI 1.2–4.1) remained significant independent predictors of fracture risk. Thus, primary HPT among unselected patients in the community is associated with a significant increase in the risk of vertebral, Colles', rib, and pelvic fractures. These data have important implications for the current trend to recommend nonsurgical management for patients with mild primary HPT.

Background and Purpose— Following publication of concerns about the results of the National Institute of Neurological Disorders and Stroke (NINDS) intravenous tissue plasminogen activator (t-PA) in acute stroke treatment trial, NINDS commissioned an independent committee “to address whether there is concern that eligible stroke patients may not benefit from t-PA given according to the protocol used in the trials and, whether the subgroup imbalance (in baseline stroke severity) invalidates the entire trial.” Methods— The original NINDS trial data were reanalyzed to assess the t-PA treatment effect, the effect of the baseline imbalance in stroke severity between the treatment groups on the t-PA treatment effect, and whether subgroups of patients did not benefit from receiving t-PA. Results— A clinically important and statistically significant benefit of t-PA therapy was identified despite subgroup imbalances in baseline stroke severity and an increased incidence of symptomatic intracerebral hemorrhage in t-PA treated patients. The adjusted t-PA to placebo odds ratio (OR) of a favorable outcome was 2.1 (95% CI, 1.5 to 2.9). Although these exploratory analyses found no statistical evidence that the t-PA treatment effect differed among patient subgroups, the study was not powered to detect subgroup treatment differences. Conclusions— These findings support the use of t-PA to treat patients with acute ischemic stroke within 3 hours of onset under the NINDS t-PA trial protocol. Health professionals should work collaboratively to develop guidelines to ensure appropriate use of t-PA in acute ischemic stroke patients.

Abstract OBJECTIVE To report presenting clinical symptoms, previous medical history, and survival rates for people with saccular intracranial aneurysms (IAs), in a defined population. METHODS The medical records of all residents of Olmsted County, Minnesota, with possible IAs were reviewed. Clinical manifestations at the time of diagnosis, previous medical history, demographic factors, and survival rates after diagnosis were determined. RESULTS Of 270 people with IAs detected between 1965 and 1995, 188 exhibited symptoms at the time of diagnosis, including 74% of women and 63% of men (P = 0.054). Intracranial hemorrhage (ICH) was the most common presenting symptom (60% of all patients and 86% of patients who exhibited symptoms), followed by cranial nerve palsy, transient ischemic attacks, and seizures. Survival rates after detection (with the exclusion of cases that were first detected during autopsies) were dependent on the occurrence of ICH; 23% of patients who presented with ICH died by 1 day after diagnosis, compared with 5% of those who did not exhibit symptoms or exhibited symptoms but without ICH at presentation. At 5 years, 44.7% of patients with hemorrhage had died, compared with 29.4% of patients with symptoms other than hemorrhage. After the first 24 hours after detection, survival rates did not differ significantly for those presenting with or without hemorrhage. Predictors of better survival rates also included lower age and later calendar year of presentation. CONCLUSION This study provides the first data on aneurysm characteristics, clinical symptoms, and survival rates among people with IAs in a defined population. During the study period, most aneurysms were detected in the context of an aneurysm-related symptom (particularly among women), with a large proportion of patients presenting with ICH. After the acute phase of hemorrhage, long-term survival rates among people with IAs were similar for those presenting with or without ICH.