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Background Microscopic colitis is a common cause of chronic watery diarrhea of unknown origin. Some patients develop diarrhea after cholecystectomy, and some patients with microscopic colitis have evidence of bile acid malabsorption. However, the association between cholecystectomy and microscopic colitis has not been studied. A protective effect of appendectomy on the development of ulcerative colitis also has been reported, but its relationship with microscopic colitis has not been studied. The aim of this study was to assess cholecystectomy and appendectomy as potential risk factors for the development of microscopic colitis in a nested case-control study. Materials and methods Using the Rochester Epidemiology Project, we identified all Olmsted County (Minnesota) residents with an initial diagnosis of microscopic colitis between January 1, 1985, and December 31, 2001. Rates of antecedent cholecystectomy or appendectomy in patients with microscopic colitis were compared with age-, gender-, and calendar year-matched community controls through conditional logistic regression. Results Microscopic colitis was identified in 130 cases. Cholecystectomy preceded the diagnosis of microscopic colitis in 12 cases (9%) compared with 17 (13%) in the control group (odds ratio [OR] 0.7; 95% CI 0.3-1.5). Appendectomy preceded the diagnosis of microscopic colitis in 39 subjects (30%) compared with 28 (22%) in the control group (OR 1.6; 95% CI 0.9-2.7). Similar results were obtained when the analysis was restricted to microscopic colitis subtype (lymphocytic colitis or collagenous colitis). Conclusions In this population-based nested case-control study, no significant association was seen between cholecystectomy or appendectomy and the development of microscopic colitis or its subtypes.

Background and aims The risk, fate, and ideal management of colorectal dysplasia in inflammatory bowel disease (IBD) remain debated. We estimated the incidence, long-term outcome, and risk factors for progression of colorectal dysplasia (adenomas [adenoma-associated lesions or masses (ALMs)], flat dysplasia, and dysplasia-associated lesions or masses [DALMs]) in a population-based IBD cohort from Olmsted County, Minnesota. Materials and methods The Rochester Epidemiology Project was used to identify cohort patients with colorectal dysplasia. Medical records were reviewed for demographic and clinical characteristics. Histology slides were reviewed by a pathologist blinded to previous pathology reports. The cumulative incidence of dysplasia was estimated, and the association between patient characteristics and recurrence/progression of dysplasia was assessed using proportional hazards regression. Results Twenty-nine (4%) IBD patients developed flat dysplasia (n = 8), DALMs (n = 1), ALMs in areas of IBD (n = 18), or ALMs outside areas of IBD (n = 2). Among 6 patients with flat low-grade dysplasia (fLGD) who did not undergo colectomy, none progressed during a median of 17.8 (range 6-21) years of observation with a median of 3 (range 0-12) surveillance colonoscopies. Four (22%) patients with ALMs in areas of IBD who did not undergo surgery developed LGD or DALMs. Primary sclerosing cholangitis and dysplasia located proximal to the splenic flexure were significantly associated with risk for recurrence/progression of dysplasia. Conclusions This population-based cohort study from Olmsted County, Minnesota did not confirm an increased risk of cancer related to fLGD, whereas 22% of patients with ALMs in areas of IBD developed fLGD or DALMs.

We used QCT scans obtained in 687 men and women, 21–97 years of age, to estimate the factor of risk for vertebral fracture, Φvert, defined as the ratio of spinal loading to vertebral strength. With age, vertebral strength declined and Φvert increased significantly more in women than men. Age- and sex-specific differences in Φvert closely resembled previously reported vertebral fracture incidence. Introduction: Despite the high prevalence of vertebral fractures, little is known about the interaction between spinal loading and vertebral fragility. Materials and Methods: We assessed the ratio of spinal loading to vertebral strength (i.e., the factor of risk, Φvert) in an age- and sex-stratified population-based sample of 700 women and men 21–97 years of age. We measured volumetric BMD (vBMD, mg/cm3) and cross-sectional area (CSA, cm2) of the midvertebral bodies of L1–L3 using QCT and computed vertebral compressive strength from these data using engineering beam theory. A biomechanical model of the trunk was used to estimate compressive forces applied to the L3 vertebral body during standing, bending forward, and bending forward while lifting 10 kg. The factor of risk for fracture, Φvert, was computed as the ratio of spinal compressive force to vertebral strength for each activity. Results: Men had a higher vertebral strength at all ages, largely because of their greater CSA. Whereas both sexes exhibited a marked decline in vertebral compressive strength with age (p < 0.001), the decline was greater in women than men (−43% versus −31%, p = 0.008). Compressive forces on L3 were greater in men than women, because of their greater body weight and height. For both sexes, forces during bending and lifting were 8-fold higher than those experienced during upright standing. For all activities, Φvert increased with age, but significantly more so in women than men (p < 0.001). For bending and lifting, Φvert-bending exceeded 1.0 in 30% of women and 12% of men ≥50 years of age, values that are similar to the reported frequency of vertebral fracture. Conclusion: These findings illustrate potential mechanisms underlying vertebral fractures and provide strong rationale for further evaluation of this QCT-based biomechanical approach for assessment of fracture risk.

BACKGROUND The prevalence of monoclonal gammopathy of undetermined significance (MGUS), a premalignant plasma-cell disorder, among persons 50 years of age or older has not been accurately determined. We used sensitive laboratory techniques to ascertain the prevalence of MGUS in a large population in a well-defined geographic area. METHODS We identified all living residents of Olmsted County, Minnesota, as of January 1, 1995. We obtained serum that remained after the performance of routine clinical tests at Mayo Clinic or asked subjects for whom such serum was unavailable to provide a sample. Agarose-gel electrophoresis was performed on all serum samples, and any serum sample with a discrete band of monoclonal protein or thought to have a localized band was subjected to immunofixation. RESULTS Serum samples were obtained from 21,463 of the 28,038 enumerated residents 50 years of age or older (76.6 percent). MGUS was identified in 694 (3.2 percent) of these persons. Age-adjusted rates were higher in men than in women (4.0 percent vs. 2.7 percent, P

Background In the Rome II criteria, patients with both constipation and abdominal pain (AP) (i.e., "painful constipation" (PC)), who do not satisfy criteria for irritable bowel syndrome (IBS) are included in the same functional constipation (FC) category as patients with constipation without AP (i.e., "painless constipation" (PLC)). What differences, if any, exist between FC without (i.e., PLC) and with AP (i.e., PC) are unclear. Methods To compare clinical features among PLC, PC, constipation-predominant IBS (C-IBS), and non-C-IBS, a validated questionnaire was mailed (with telephone follow-up of nonresponders) to an age-stratified random sample of 5,200 adult women in Olmsted County, Minnesota. Results Altogether, 2,800 women (53%) responded. The age-adjusted prevalence of PLC (7.1 per 100; 95% confidence interval (95% CI), 6.2-8.0) was higher compared to PC (0.9 per 100; 95% CI, 0.6-1.2). Compared to PLC, patients with PC reported worse general health (i.e., excellent or very good = 37.5% vs 51.2%), more somatic symptoms (mean score = 1.3 vs 0.9), and urinary urgency (% often = 58% vs 32%), and had a higher prevalence of hysterectomy. Bowel symptoms significantly impacted > or =1 domain of quality of life (QOL) in 18% of PC versus 9% of PLC. In a logistic discriminant model, age, general health, impact of bowel symptoms on QOL, somatic symptoms, and urinary urgency independently discriminated between bowel subtypes. Conclusions Patients with PC more closely resemble those with C-IBS than PLC. Consideration should be given to separating PC from PLC in the Rome criteria and in therapeutic trials.

To evaluate the proportion and characteristics of patients with chronic pain who do not seek treatment and assess whether these patients have unmet pain care needs.We performed a cross-sectional survey of residents of Olmsted County, Minnesota, from March through June 2004, with additional visit and diagnosis data from the Rochester Epidemiology Project database. Study participants were a random, population-based sample of eligible adult (30 years) residents of Olmsted County with at least 1 visit to a local health care facility in the past 3 years.Of the 5897 eligible participants, 3575 people (60.6%) responded. Of the respondents who reported pain of more than 3 months' duration, 497 (22.4%) of the 2211 patients stated that they had not informed their physician about their pain. Of these silent sufferers, 70.6% (351/497) reported having moderate or severe pain, 49.2% (243/497) reported having frequent pain (8 days per month), and 40.6% (202/497) met both criteria. Silent sufferers also reported that pain interfered with their general activity and sleep to a level only slightly less than the chronic pain sufferers who reported discussing their pain with a physician. Silent sufferers made an average of 5.2 ambulatory physician visits per year, which was less than those who sought physician help for their pain (8.6 ambulatory visits per year; P.001). Men and younger participants were more likely to be silent about their pain (P.001).More than 1 in 5 people with chronic pain did not seek physician care for their pain. This group is unknown to physicians and therefore represents an unreported patient group with an unmet need for pain care.

In an inception cohort of 196 Olmsted County, Minnesota, residents with Parkinson's disease (PD) first recognized in 1976 to 1995, we tested whether the increased risk of bone fractures is associated with concomitant dementia. Using the data resources of the Rochester Epidemiology Project, information about PD, dementia, other clinical risk factors for fracture and fracture events was obtained from review of complete inpatient and outpatient medical records spanning each subject's residence in the community. Compared to an equal number of age- and sex-matched non-PD referent subjects from the community, PD patients were at a 2.2-fold increased risk of fractures generally and a 3.2-fold greater risk of hip fractures specifically. Adjusting for age, the independent predictors of overall fracture risk in the PD subjects included female sex (hazard ratio [HR] 1.6; 95% confidence interval [CI], 1.1-2.3), dementia (HR, 1.6; 95% CI, 1.1-2.4) and chronic depression, which was associated with a reduced risk (HR, 0.4; 95% CI, 0.2-0.8). Hip fractures were predicted by dementia (HR, 2.2; 95% CI, 1.2-4.1). The increased fracture risk in patients with PD is not entirely explained by concomitant dementia, and additional study is needed to determine the relative contributions to fracture risk of falls versus bone loss in these patients.

Because little information is currently available on the epidemiology of shoulder arthroplasty, this study was designed to evaluate the characteristics of patients undergoing this procedure and changes in practice patterns. Residents of Olmsted County, Minnesota, who underwent shoulder arthroplasty between 1976 and 2000 were identified (98 residents, 112 procedures). A relatively lower initial rate of shoulder arthroplasty was followed by a statistically significant steady increase (P.0001), with an age- and sex-adjusted annual operative incidence rate of 1.4 per 100,000 person-years (1976-1980) to 10.1 per 100,000 person-years (1996-2000). Increased utilization of shoulder arthroplasty during the last decade was mainly a result of its application in osteoarthritis. A significant need exists for examination of utilization patterns for shoulder arthroplasty. An aging population and an increased demand and awareness by the public regarding interventions to improve quality of life will shape the future of arthroplasty, reinforcing the need for future studies of this nature.

Summary Background Bence Jones proteinuria is a disorder that is defined by the excretion of monoclonal light-chain protein. About 15–20% of patients with multiple myeloma secrete monoclonal light chains only, without expression of the normal immunoglobulin heavy chain, which constitutes light-chain multiple myeloma. The definition, prevalence, and progression of these premalignant phases of light-chain multiple myeloma have not been fully characterised. We aimed to identify a subset of patients with idiopathic Bence Jones proteinuria who had a high risk of progression to light-chain multiple myeloma analogous to that seen in patients with smouldering multiple myeloma. Methods In this retrospective cohort study, we studied all patients seen at the Mayo Clinic (Rochester, MN, USA) within 30 days of diagnosis of idiopathic Bence Jones proteinuria between Jan 1, 1960, and June 30, 2004. Inclusion criteria were monoclonal light chain in the urine (≥0·2 g/24 h), absence of intact monoclonal immunoglobulin (M protein) in the serum, and no evidence of multiple myeloma, light-chain amyloidosis, or other related plasma-cell proliferative disorders. The primary endpoint was progression to symptomatic multiple myeloma or light-chain amyloidosis. We examined the cumulative probability of progression and the association of potential risk factors on progression rates to identify patients with a high risk of progression to multiple myeloma or light-chain amyloidosis. Findings We identified 101 patients with idiopathic Bence Jones proteinuria. During 901 total person-years of follow-up, 27 (27%) patients developed multiple myeloma and seven (7%) developed light-chain amyloidosis. The major risk factors for progression were amount of urinary excretion of M protein per 24 h, proportion of bone marrow plasma cells, presence of a markedly abnormal free-light-chain ratio ( 100), and reduction of all three uninvolved immunoglobulins. Based on the risk of progression, monoclonal light-chain excretion of 0·5 g/24 h or greater or at least 10% bone marrow plasma cells, or both, in the absence of end-organ damage was used to define light-chain smouldering multiple myeloma. The cumulative probability of progression to active multiple myeloma or light-chain amyloidosis in patients with light-chain smouldering multiple myeloma was 27·8% (95% CI 14·2–39·2) at 5 years, 44·6% (27·9–57·4) at 10 years, and 56·5% (36·3–70·2) at 15 years. Interpretation Light-chain smouldering multiple myeloma as defined in this study is associated with a high risk of progression to symptomatic light-chain multiple myeloma, and this subset of patients needs careful observation and could benefit from clinical trials of early intervention. Funding Jabbs Foundation (Birmingham, UK), US National Cancer Institute, and Henry J Predolin Foundation (Madison, WI, USA).

Objectives: To investigate the cost-effectiveness of universal bone densitometry in women aged 65 and older combined with alendronate treatment for those diagnosed with osteoporosis (femoral neck T-score ≤−2.5). Design: A Markov model with a lifetime time horizon and eight health states (no fracture, distal forearm fracture, radiographic (but clinically inapparent) vertebral fracture, clinical vertebral fracture, hip fracture, hip and vertebral fracture, and other fractures), using the societal perspective. Setting: Women living independently and those in nursing homes. Participants: Caucasian women aged 65, 75, 85, or 95. Intervention: Bone densitometry of the hip, with 5 years of alendronate therapy for those found to have osteoporosis versus no intervention (densitometry or drug therapy). Measurements: Lifetime accumulated quality adjusted life years (QALYs), costs, and incremental cost-effectiveness ratios. Results: The cost per QALY gained for the screen-and-treat strategy was $43,000 per QALY gained for 65-year-old women and $5,600 per QALY gained for 75-year-old women. For 85- and 95-year-old women, the screen-and-treat strategy was cost saving. Sensitivity analyses showed that the screen-and-treat strategy was cost-effective even under assumptions of reduced adherence to drug therapy, reduced fracture reduction benefit from alendronate therapy, or reduced QALYs saved by preventing fracture. Conclusion: Universal bone densitometry combined with alendronate therapy for those found to have osteoporosis is highly cost-effective for women aged 65 and older and may be cost saving for ambulatory women aged 85 and older (whether independently living or residing in nursing homes).

We updated the incidence of primary hyperparathyroidism in Rochester, Minnesota. The lower rates previously noted persisted, whereas parathyroidectomies at our institution remained high. These data suggest an etiologic factor may be responsible for the peak incidence in the 1970s. Introduction: Automated serum calcium measurements were associated with a dramatic rise in primary hyperparathyroidism in the early 1970s, but a progressive decline in the incidence thereafter was unexpected and suggested a fundamental change in the epidemiology of the disease. Our objective was to evaluate trends in the incidence of primary hyperparathyroidism since 1992. Materials and Methods: In this population-based descriptive study, Rochester, MN, residents who met defined diagnostic criteria for primary hyperparathyroidism from January 1993 through December 2001 were identified through the medical record linkage system of the Rochester Epidemiology Project and the Mayo Clinic Laboratory Information System. Changes in incidence were evaluated by Poisson regression. Results: Altogether, 136 Rochester residents (94 women and 42 men) were newly identified with primary hyperparathyroidism in 1993–2001. Their mean age was 56 years, and 93% had definite disease. The overall age- and sex-adjusted (to 2000 U.S. whites) rate during this period was 21.6 per 100,000 person-years, which was less than the annual rate of 29.1 per 100,000 observed in 1983–1992 and 82.5 per 100,000 in July 1974–1982. Although community incidence declined, the number of parathyroidectomies performed at our institution increased during the same period. Serum calcium was deleted from the automated chemistry panel in June 1996, but most subjects remained asymptomatic at diagnosis (95%) with mild hypercalcemia. The majority of subjects were observed without parathyroid surgery (75%), and there was minimal impact on patient management from the 1990 NIH consensus conference on asymptomatic primary hyperparathyroidism. Conclusions: The lower incidence of primary hyperparathyroidism noted through 1992 has persisted in our community through 2001, whereas parathyroidectomies at our institution remained high. These data suggest that some underlying etiologic factor, in addition to the introduction of automated serum calcium testing, may have been responsible for the peak incidence in the 1970s.

Prevalent vertebral deformities are predictive of future clinical fractures independent of bone density. We used a Markov model with eight health states to estimate from the societal perspective the cost-effectiveness of using spine radiographs to identify postmenopausal women age 60 or older with one or more vertebral deformities and then treat them with anti-resorptive drug therapy to prevent fractures. We compared three strategies: 5 years of amino-bisphosphonate (alendronate) therapy for all, 5 years of alendronate therapy for only those with prevalent a radiographic vertebral deformity or no initial alendronate treatment. Lifetime direct medical and indirect costs, quality adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) were tracked. For women with one or more prevalent vertebral deformities, the costs per QALY gained ranged from 5,084 dollars (for an 80 year old with a T-score of -2.4) to 61,192 dollars (for a 60 year old with a T-score of -1.0). For women without prevalent vertebral deformity, the costs per QALY gained ranged from 41,897 dollars (for a 60 year old with a T-score of -2.4) to 166,219 dollars (for an 80 year old with a T-score of -1.0). These results were modestly sensitive to reasonable changes in fracture rates, disutility, discount rates and assumptions about the accuracy of spinal radiographs for detecting vertebral deformity. Assuming a societal willingness to pay per QALY gained of 50,000 dollars, the strategy of performing spine radiographs in post-menopausal osteopenic women with T-scores at or below -1.5 and treating those with 1 or more prevalent vertebral deformities is likely to be cost-effective. However, further research on the accuracy of vertebral deformity ascertainment from routine clinical radiographs and on the efficacy of amino-bisphosphonate drugs for reducing the risk of non-vertebral fractures in osteopenic women is needed to define more precisely the subset of osteopenic post-menopausal women in whom use of spinal radiographs is most cost-effective.

Background & Aims: The incidence of hepatocellular carcinoma (HCC) has been increasing in the United States. Although resource-intensive treatment modalities have been increasingly applied, these patients still have poor survival. We examined 2 nationally representative databases, the Multiple Cause of Death file and the Nationwide Inpatient Sample database, to examine trends in mortality and hospital service utilization related to HCC. Methods: In both databases, a priori criteria were used to identify cases of HCC. All other available diagnostic fields were examined to characterize coexistent liver disease. Age-, sex-, and race-specific mortality from HCC was calculated, and temporal changes in mortality rates were evaluated using the multivariable Poisson model. Hospital service utilization was estimated based on length of stay, total hospitalization charges, and principal procedures. Results: The age-, sex-, and race-specific mortality from HCC increased from 1.54 to 2.58 per 100,000 per year between 1980 and 1998. Male sex, African and Asian race, and increasing age were also associated with higher mortality. The estimated total charge for HCC hospitalizations nationwide increased from $241 million in 1988 to $509 million in 2000 after inflation adjustment. Commonly employed procedures in 2000 included angiography/embolization, resection, local ablative therapy, and liver transplantation. Conclusions: In the recent past, mortality and hospital service utilization related to HCC increased substantially. Closer epidemiologic surveillance to understand causation of HCC at the population level and to help implement primary and secondary prevention is urgently warranted.

We hypothesized that the presence of monoclonal free kappa or lambda immunoglobulin light chains in monoclonal gammopathy of undetermined significance (MGUS), as detected by the serum free light chain (FLC) assay increases the risk of progression to malignancy. Of 1384 patients with MGUS from Southeastern Minnesota seen at the Mayo Clinic from 1960 to 1994, baseline serum samples obtained within 30 days of diagnosis were available in 1148. At a median follow-up of 15 years, malignant progression had occurred in 87 (7.6%) patients. An abnormal FLC ratio (kappa-lambda ratio < 0.26 or > 1.65) was detected in 379 (33%) patients. The risk of progression in patients with an abnormal FLC ratio was significantly higher compared with patients with a normal ratio (hazard ratio, 3.5; 95% confidence interval [CI], 2.3-5.5; P < .001) and was independent of the size and type of the serum monoclonal (M) protein. Patients with an abnormal serum FLC ratio, non–immunoglobulin G (non-IgG) MGUS, and a high serum M protein level (≥ 15 g/L) had a risk of progression at 20 years of 58% (high-risk MGUS) versus 37% with any 2 of these risk factors (high-intermediate risk), 21% with one risk factor (low-intermediate risk), and 5% when none of the risk factors were present (low risk).

Epidemiological studies have confirmed that gastroesophageal symptoms are highly prevalent. However, studies linking epidemiology with clinical or chart data are scarce. We aimed to determine the frequency of endoscopy and endoscopic findings, as well as predictors of health-care utilization, among people with reflux symptoms in the community.A previous survey of 2,118 Olmsted County, MN, residents in 1993 identified 242 subjects with frequent reflux symptoms (at least weekly) who received care at a medical center in the county. Data were abstracted from Mayo Clinic records between 1988 and 1998.Overall, 130 of the 242 (54%, 95% CI 47-60%) had sought care for reflux. Twenty-five patients (10%) had visited a gastroenterologist; 47 (19%) had an upper endoscopy (EGD), 64 (26%) had an upper GI X-ray, and one had an ambulatory 24-h esophageal pH study. Long segment Barrett's esophagus was detected in 4 (9%) of those having an EGD and adenocarcinoma was found in one patient with Barrett's. Three patients had surgery for gastroesophageal reflux disease. Thirteen patients (5%) died, but no deaths were due to esophageal reflux or adenocarcinoma. Age, higher education, frequent heartburn, and dysphagia were all significant, independent predictors of consulting.Although many people in the community have frequent reflux symptoms, few have investigations, and deaths were unrelated to reflux disease or its complications. Data from referral clinic or endoscopy series should not be extrapolated to the large numbers of people in the community with symptoms of reflux.

Background & Aims: The epidemiology of fecal incontinence (FI) is incompletely understood. We report the prevalence, clinical spectrum, health care-seeking behavior, and quality of life (QOL) in community women with FI. Methods: A questionnaire was mailed to an age-stratified random sample of 5300 Olmsted County, Minnesota, women identified by the Rochester Epidemiology Project. Symptom severity was assessed by a validated scale, and impact on QOL was evaluated for subjects who had any FI during the past year. The prevalence of FI was calculated with direct age adjustment to the 2000 US white female population. Results: Altogether, 2800 of 5300 women (53%) responded to the survey. The overall age-adjusted prevalence of FI in the past year was 12.1 per 100 (95% confidence interval, 11.0–13.1). The prevalence increased with age from 7 (third decade) to 22 (sixth decade) per 100 and was steady thereafter. Symptoms were mild (45%), moderate (50%), or severe (5%), and symptom severity was related to the impact of FI on QOL and physician-consulting behavior. Moderate to severe impact on ≥1 domain of QOL was reported by 6% with mild, 35% with moderate, and 82% with severe symptoms, whereas 5% with mild, 10% with moderate, and 48% with severe FI had consulted a physician for FI in the past year. Conclusions: More than 1 of 10 adult women in the population have FI; almost 1 of 15 have moderate to severe FI. FI significantly impacts QOL and prompts health care utilization predominantly in women with moderate to severe symptoms.

OBJECTIVE To determine whether there was a significant increase in the incidence of thyroid carcinoma in Olmsted County, Minnesota, that may be attributed to the widespread use of therapeutic head and neck irradiation between 1920 and the 1950s or to exposure to atomic fallout at the Nevada Test Site in the 1960s. METHODS Rochester Epidemiology Project resources were used to identify potential cases of thyroid carcinoma among residents of Olmsted County between 1935 and 1984. We extended this earlier study through 1999. RESULTS During the study period, thyroid carcinoma was newly diagnosed in 263 residents. In women, the age-adjusted incidence increased from 2.7 per 100,000 person-years (p-y) in 1935-1949 to 9.2 per 100,000 p-y in 1990-1999 ( P =.001); in men, the rate increased from 0.8 to 5.0 per 100,000 p-y ( P =.007). However, most of the increase occurred before 1965 and remained relatively stable thereafter. Similar trends were observed for papillary carcinoma alone. CONCLUSION Although the incidence of thyroid carcinoma increased significantly between 1935 and 1964, no significant increases have been seen since 1965, suggesting that neither atmospheric atomic fallout from the Nevada Test Site nor use of ionizing radiation to treat conditions of the head and neck significantly affected the incidence of thyroid carcinoma in Olmsted County.

Osteoporosis is widely viewed as a major public health concern, but the exact magnitude of the problem is uncertain and likely to depend on how the condition is defined. Noninvasive bone mineral measurements can be used to define a state of heightened fracture risk (osteopenia), or the ultimate clinical manifestation of fracture can be assessed (established osteoporosis). If bone mineral measurements more than 2 standard deviations below the mean of young normal women represent osteopenia, then 45% of white women aged 50 years and over have the condition at one or more sites in the hip, spine, or forearm on the basis of population-based data from Rochester, Minnesota. A smaller proportion is affected at each specific skeletal site: 32% have bone mineral values this low in the lumbar spine, 29% in either of two regions in the proximal femur, and 26% in the midradius. Although this overall estimate is substantial, some other serious chronic diseases are almost as common. More importantly, low bone mass is associated with adverse health outcomes, especially fractures. The lifetime risk of any fracture of the hip, spine, or distal forearm is almost 40% in white women and 13% in white men from age 50 years onward. If the enormous costs associated with these fractures are to be reduced, increased attention must be given to the design and implementation of control programs directed at this major health problem.

The ability of regional data from whole body scans to provide an accurate assessment of site-specific BMD, osteoporosis prevalence and fracture risk has not been fully explored. To address these issues, we measured total body (TBBD) and site-specific BMD in an age-stratified population sample of 351 women (21-93 years) and 348 men (22-90 years). We found an excellent correlation between AP lumbar spine and total body lumbar spine subregion BMD (r2=0.92), but weaker ones for total hip compared to pelvis region (r2=0.72) or between total wrist and left arm subregion from the whole body scan (r2=0.83). The error in estimating site-specific BMD from total body regions ranged from 4.3% (lumbar spine) to 11.2% (femoral neck) in women and from 4.9 to 11.1%, respectively, in men. Site-specific versus regional measurements at the lumbar spine and total hip/pelvis provided comparable overall estimates of osteoporosis prevalence, but disagreed on the status of individuals; measurements at whole body regions underestimated osteoporosis as assessed at the femoral neck or total wrist. All measurements were associated with a history of various fractures [age adjusted odds ratios (OR), 1.3 to 2.1 in women and 1.2 to 1.5 in men] and were generally interchangeable, but femoral neck BMD provided the best estimate of osteoporotic fracture risk in women (OR, 2.9; 95% CI, 1.7-5.0). Although there are strong correlations between BMD from dedicated scans of the hip, spine and distal forearm and corresponding regions on the whole body scan, the measurements provide somewhat different estimates of osteoporosis prevalence and fracture risk.

Although bone mineral density (BMD) is a strong predictor of fractures, it is only a surrogate for bone strength. Bone structural parameters can now be measured on BMD scans, but it is unclear whether they would be more useful for risk assessment. We measured structural parameters using the Hip Structural Analysis Program and evaluated their association, compared with standard hip BMD, with fracture risk in a population-based sample of 213 postmenopausal women and 200 menor =50 years of age. Altogether, 38% of the women and 27% of the men had experienced a fracture due to moderate trauma (half involved hip, spine or distal forearm), while 23% and 36%, respectively, had a previous fracture due to severe trauma. In logistic regression analyses adjusted for age, the hip BMD and structural parameters were all associated with moderate trauma fractures generally, and osteoporotic fractures specifically, in women, but the best predictor in a multivariate model was femoral neck BMD (odds ratio [OR], 2.8; 95% confidence interval [CI], 1.9-4.0). BMD and the structural parameters were strongly correlated, however, and could be interchanged with little reduction in predictive power. These variables were less predictive of moderate trauma fractures in men. The best model included age (OR per 10 years, 1.5; 95% CI, 1.1-2.1), femoral neck section modulus (OR, 1.6; 95% CI, 1.1-2.5) and intertrochanteric buckling ratio (OR, 1.6; 95% CI, 1.3-2.0). Correction for body size did not alter these relationships. Fractures due to severe trauma were best predicted by structural parameters: in women, femoral neck buckling ratio (OR, 1.2; 95% CI, 1.04-1.5) and, in men, intertrochanteric buckling ratio (OR, 1.4; 95% CI, 1.2-1.6). These data suggest that selected structural variables as assessed by dual-energy X-ray absorptiometry would be as good as standard BMD measurements for predicting fracture risk. Because of the strong correlations, however, some judgment can be used in selecting the variables easiest to measure.

Colorectal cancer (CRC) screening has been advocated increasingly during the past 2 decades, but there is little direct evidence that it has affected cancer incidence or presentation at the population level. This study assessed concurrent trends in CRC incidence, presentation, survival, mortality, and polypectomies in Olmsted County, Minnesota.Longitudinal observational study was conducted of all Olmsted County residents with colorectal adenocarcinoma first diagnosed in 1980-1999.Altogether, 889 invasive CRCs were diagnosed among Olmsted County residents from 1980 through 1999. Annual age- and sex-adjusted CRC incidence rates decreased significantly during this period (P = .02) with a 23% decline from 60 per 100,000 in 1980-1984 to 46 per 100,000 in 1995-1999. This was primarily accounted for by a 40% reduction in left-sided CRC (P.001). The incidence of right-sided CRC remained unchanged, but the proportion of right-sided CRC increased from 46% to 58%. Cancer stage shifted downward, and survival improved over time. The overall proportion of screen-detected CRC rose from 8% to 17%. Annual adjusted adenomatous polypectomy rates increased dramatically from 86 to 320 per 100,000 (P.001).The incidence of CRC in Olmsted County has declined in recent years. An impact of screening is suggested by the observed upward trend in screen-detected cases, a favorable stage shift, and a concurrent rise in polypectomy rates. However, the incidence of right-sided cancer remains unaltered and might be less affected by historically used screening interventions. Most CRCs still present symptomatically, and more effective population screening is needed.

Background. Several studies have documented the substantial health and economic burdens associated with sarcopenia among the elderly, but there has been no systematic study among Asians. A cross-sectional survey of elderly community-dwelling Chinese volunteers (262 men and 265 women), aged 70 years and older, was undertaken in Hong Kong. The purposes of this study were to evaluate the prevalence of and risk factors for sarcopenia in elderly Chinese, and to compare these observations with those in white persons. Methods. Muscle mass was estimated by dual-energy X-ray absorptiometry. In this study, sarcopenia was defined as a total adjusted skeletal muscle mass two standard deviations or more below the normal mean for young Asian men and women in this study. The relationship between risk factors (alcohol consumption, cigarette smoking, regular exercise, body mass index, medical conditions) and sarcopenia was studied by multiple logistic regression. Results. The prevalence of sarcopenia was 12.3% in Chinese men and 7.6% in Chinese women aged 70 years and older, which was slightly lower than figures observed in white persons. Being underweight was a significant risk factor in both men (odds ratio, 39,1; 95% confidence interval, 11.3 to 134.6) and women (odds ratio, 9.7; 95% confidence interval, 2.8 to 33.8). No other risk factors were found in Chinese men or women. Conclusions. Sarcopenia exists among elderly Chinese men and women, albeit at a lower rate than in white persons. This may be due to the lower muscle mass among young men and women or to an attenuated rate of loss in muscle mass with aging in the Chinese elderly. Being underweight is a major risk factor for sarcopenia in both sexes.

Simulations play an increasingly important role in the evaluation of osteoporosis interventions. Existing evaluations have been based on "reduced-form" cohort simulations that do not reflect the complexity and heterogeneity of osteoporosis and its outcomes. Such simplified models offer parsimony and ease of use, but they also are limited in their ability to explain and extrapolate outcomes in a way that is most useful for both clinical and health policy decision makers. Alternatively, evaluations could be based on "structural" microsimulations, which explicitly model the underlying biology of osteoporosis at the individual level. The structural approach presents technical challenges, including the need to obtain more-detailed data and the requirement that underlying biological models be validated. However, evaluations based on structural microsimulation may ultimately provide substantially more useful information, resulting in improved decision making.

Monoclonal gammopathy of undetermined significance of the immunoglobulin M class was diagnosed in 213 patients at the Mayo Clinic, 29 (14%) of whom developed lymphoma, Waldenstrom macroglobulinemia, or a related disorder over 1567 person-years of follow-up. The cumulative probability of progression was 10% at 5 years, 18% at 10 years, and 24% at 15 years, or approximately 1.5% per year. The concentration of serum monoclonal protein at diagnosis and the initial serum albumin value were the only independent predictors of progression with multivariate analysis. By contrast, during 285 person-years of follow-up, 34 (71%) of 48 patients with smoldering Waldenstrom macroglobulinemia (SWM) progressed to Waldenstrom macroglobulinemia (WM), which required therapy, along with amyloid light chain (AL) amyloidosis (1) and lymphoma (1). The cumulative probability of progression was 6% at 1 year, 39% at 3 years, 59% at 5 years, and 65% at 10 years. The percentage of lymphoplasmacytic cells in the bone marrow, size of the serum monoclonal (M) spike, and hemoglobin value were significant independent risk factors for progression.

In a population-based, cross-sectional study, we related age-associated changes in vBMD and in bone structural parameters to circulating bioavailable estradiol and testosterone levels in men. Associations between these bone mass/structural parameters and sex steroid levels were progressively stronger with age. Our previously postulated “threshold” for skeletal estrogen deficiency was most evident at cortical sites. Introduction: Serum sex steroids, particularly estrogen levels, are associated with bone mass in men, and previous work has suggested that there may be a “threshold” bioavailable estradiol (bio E2) level below which the male skeleton becomes estrogen deficient. However, previous studies addressing this issue have exclusively used DXA, which cannot separate trabecular from cortical bone or provide information on bone geometry or structure. Materials and Methods: In an age-stratified population sample of 314 men (age, 22-91 years), we assessed volumetric BMD (vBMD) and bone geometry by QCT at the lumbar spine, femoral neck, distal radius, and distal tibia and related these to circulating bio E2 and bio testosterone (T) levels. Results: Compared with young men (age, 20-39 years), middle-aged men (age, 40-59 years) had significantly lower bio T (−26%, p < 0.001) and bio E2 (−9%, p = 0.038) levels, and these decreases were even greater in the elderly men (age ≥ 60 years, −60% and −38% for bio T and bio E2, respectively, p < 0.001 for both). Reflecting their intact gonadal status, vBMD/structural parameters were not related to sex steroid levels in young men, whereas bio E2 levels were associated consistently with vBMD and variably with bone geometric parameters in the elderly men; middle-aged men showed associations with bio E2 and bio T at some sites. At all cortical sites, vBMD was associated with bio E2 at low (

The NOF cost-effectiveness model, based on clinical risk factors and femoral neck aBMD, predicted overall fracture risk in a cohort of postmenopausal women followed for up to 22 years. Introduction: To assess the ability of a statistical model to predict long-term fracture risk for a population of postmenopausal women, we compared observed fractures to those predicted by the National Osteoporosis Foundation's (NOF) cost-effectiveness model. Materials and Methods: In this population-based study, 393 postmenopausal Rochester, MN, women had baseline measurements of femoral neck areal BMD (aBMD) and assessment of the clinical risk factors (personal fracture history, family history of osteoporotic fracture, low body weight, and smoking status) that were included in the NOF model. They were then followed prospectively for up to 22 years. Fractures were ascertained by periodic interview and review of community medical records. Standardized incidence ratios (SIRs) compared observed fractures to predicted numbers. Results: During 4782 person-years of follow-up, 212 women experienced 503 fractures, two-thirds of which were caused by moderate trauma. When undiagnosed (incidentally noted) vertebral and rib fractures were excluded, there was general concordance between observed and predicted fractures of the hip (SIR, 0.78; 95% CI, 0.56-1.01), distal forearm (SIR, 1.22; 95% CI, 0.86-1.68), spine (SIR, 0.76; 95% CI, 0.50-1.11), and all other sites combined (SIR, 1.18; 95% CI, 0.97-1.42). Fracture prediction by the NOF model was about as good after 10 years as it was earlier during follow-up. Conclusions: This study validates the ability of a statistical model based on femoral neck aBMD and common clinical risk factors to predict the actual occurrence of fractures in a cohort of postmenopausal white women.

Pathologic fractures, especially of the axial skeleton, are extremely common in patients with multiple myeloma and cluster around the time of diagnosis. Osteoporotic fractures seem to be less of a problem in these patients. Introduction: It is generally believed that fractures are common in patients with multiple myeloma as a result of lytic bone lesions, generalized bone loss, and/or elevated bone turnover from excessive cytokine production, but the actual risk of pathologic versus osteoporotic fractures has not been quantified. Materials and Methods: In a population-based retrospective cohort study, 165 Olmsted County, MN, residents with myeloma diagnosed from 1945 to 2001 (55% men; mean age, 70.7 ± 11.1 years) were followed for 537 person-years. The relative risk of fractures was assessed by standardized incidence ratios (SIRs), and risk factors were evaluated in proportional hazards models. Results: Altogether, 134 patients experienced 463 fractures. In the year before diagnosis, 16 times more fractures were observed than expected, mostly pathologic fractures of the vertebrae and ribs. Subsequently, there was a 9-fold increase in fracture risk. However, 69% of these fractures were pathologic, and another 11% were found incidentally on myeloma monitoring. With the latter two groups excluded, subsequent fracture risk was elevated 3-fold, with a 2-fold increase in the risk of an osteoporotic fracture. In multivariate analyses, the predictors of overall fracture risk were oral corticosteroid use and elevated serum calcium levels, whereas pathologic fractures were additionally predicted by use of chemotherapy. Conclusion: There is a dramatic increase in fractures around the time of diagnosis of myeloma, most of which are pathologic fractures. The most important predictor of overall fracture risk is oral corticosteroid use.

Perception of sensations arising from the gastrointestinal tract may be diminished in obese subjects and thus facilitate overeating. Alternatively, excess food intake may cause gastrointestinal (GI) symptoms in obese patients. We evaluated the relationship between body mass index (BMI) and specific GI symptoms in the community.Residents of Olmsted County, MN were selected at random to receive by mail one of two validated questionnaires. The association of reported GI symptoms with BMI (kg/m(2)) was assessed using a logistic regression analysis adjusting for age, gender, psychosomatic symptom score, and alcohol and tobacco use.Response rate was 74% (1,963 of 2,660). The prevalence of obesity (BMIor = 30 kg/m(2)) was 23%. There was a positive relationship between BMI and frequent vomiting (p= 0.02), upper abdominal pain (p= 0.03), bloating (p= 0.002), and diarrhea (p= 0.01). The prevalence of frequent lower abdominal pain, nausea, and constipation was increased among obese (BMIor = 30 kg/m(2)) compared to normal weight participants, however, no significant association was found between BMI and these symptoms.In the community, increasing BMI is associated with increased upper GI symptoms, bloating, and diarrhea. Clarification of the cause-and-effect relationships and the mechanisms of these associations require further investigation.

OBJECTIVE To determine the long-term outcome of patients with monoclonal gammopathy of undetermined significance (MGUS). PATIENTS AND METHODS We reviewed the medical records of 241 patients with MGUS who were examined at the Mayo Clinic in Rochester, Minn, between January 1, 1956, and December 31, 1970. RESULTS Follow-up was 3579 person-years (median, 13.7 years; range, 0-39 years). Only 14 patients (6%) were alive and had no substantial increase of M protein at last follow-up; 138 patients (57%) died without evidence of multiple myeloma or a related disorder; a malignant lymphoplasma cell proliferative disorder developed in 64 patients (27%). The interval from diagnosis of MGUS to diagnosis of multiple myeloma or related disorder ranged from 1 to 32 years (median, 10.4 years). CONCLUSIONS The median survival rate of study patients with MGUS was only slightly shorter than that of a comparable US population. Risk of progression of MGUS to lymphoplasma cell malignancy is indefinite and persists even after more than 30 years of follow-up, with no reliable predictors of malignant evolution.

Estrogen is now known to play an important role in bone metabolism in men. Thus, we examined possible relationships between polymorphisms of the estrogen receptor (ER)-alpha and -beta genes, bone mineral density (BMD), and rates of bone loss in an age-stratified random sample of 283 Rochester, Minnesota, men aged 22-90 yr. DNA was analyzed for the XbaI and PvuII ER-alpha and AluI ER-beta polymorphisms. The X/P and x/p alleles of the ER-alpha gene were in strong linkage disequilibrium. BMD at multiple sites did not differ as a function of either the ER-alpha or -beta genotype. However, the ER-alpha (but not ER-beta) genotypes did modulate the previously described relationships between BMD or rates of bone loss and bioavailable estradiol (E(2)) levels in these men. At the femoral neck, BMD was associated with bioavailable E(2) levels in men with the XX (R = 0.66) or PP (R = 0.51) genotypes (P0.001 for both) but not in men with the xx (R = 0.15; P = 0.188) or pp (R = 0.12; P = 0.356) genotypes. The interactions between bioavailable E(2) levels and the XbaI and PvuII genotypes were significant at the P0.001 and P0.009 levels, respectively. Moreover, rates of bone loss at the midradius in men aged 60-90 yr were modestly correlated with serum bioavailable E(2) levels in subjects with the X (R = 0.47) or P (R = 0.42) alleles (P0.001 for both) but not in those with the xx (R = 0.15; P = 0.430) or pp (R = 0.21; P = 0.372) genotypes. The overall effect of genotype on midradius rate of bone loss was clearly significant for the XbaI polymorphism (P = 0.009) when bioavailable E(2) levels were low (40 pmol/liter) but not for the PvuII polymorphism. These data thus indicate that the ER-alpha genotype may modulate the relationship between BMD or rates of bone loss and estrogen levels in men and that bone mass in men with the X or P alleles may be more susceptible to the consequences of estrogen deficiency (and conversely, benefit most from estrogen sufficiency) than in men with the xx or pp genotypes.

Objective To determine whether undiagnosed celiac disease is associated with irritable bowel syndrome (IBS) or dyspepsia in the community. Subjects and Methods A self-report bowel disease questionnaire was mailed to a random sample of Olmsted County, Minnesota, residents aged 20 to 50 years. All respondents who reported symptoms of dyspepsia or IBS (cases) and all respondents without notable gastrointestinal symptoms (controls) were invited to participate (260 eligible subjects; 150 [58%] were studied). Each respondent was examined by a physician, and the medical records of each were reviewed (3 subjects did not meet the criteria for dyspepsia or IBS at the time of the physician interview). Serum was obtained to measure antiendomysial antibodies and tissue transglutaminase (TTg) IgA antibodies using validated assays. Results A total of 34 subjects had dyspepsia (20 had ulcerlike dyspepsia), 50 had IBS (19 had diarrhea-predominant IBS), and 15 met criteria for both dyspepsia and IBS; 78 were asymptomatic healthy controls. The overall prevalence of positive TTg serology was 4% (95% confidence interval [CI], 1.5%-8.5%). The number of subjects who were seropositive for TTg was 2 of 34 (5.9%) with dyspepsia (95% CI, 0.7%-19.7%), 2 of 50 (4.0%) with IBS (95% CI, 0.5%-13.7%), and 2 of 78 (2.6%) of asymptomatic controls (95% CI, 0.3%-9.0%) ( P =.64 IBS vs controls; P =.58 dyspepsia vs controls). No subjects had positive antiendomysial antibodies. Conclusion In this community, celiac disease did not explain the presence of either IBS or dyspepsia.

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.

Global aging superimposed on existing infectious diseases and trauma will aggravate competition for health care resources to diagnose and treat osteoporosis. Efforts to implement public health measures are needed, but the targeted approach to assessment and treatment of high-risk individuals must also be refined. Increases in the elderly population worldwide will cause a dramatic rise in osteoporotic fractures, but other age-related diseases will increase as well. Changes will be superimposed on existing public health problems (e.g., malaria, alcoholism), and these acute health care needs will take priority in some areas. Societies in most parts of the world may have to limit osteoporosis control to broad public health measures, and such efforts (e.g., calcium and vitamin D supplementation) should be supported. In these regions, clinical decision-making will generally be limited to treating patients with fractures (who presumably have already failed any public health measures in place), or in a few wealthy countries, to patients with low bone density identified by case-finding. Case-finding approaches will vary with the resources available, although unselective (mass) screening by bone densitometry is largely ineffective and unaffordable anywhere. The key to clinical decision-making on behalf of individuals will be an assessment of absolute fracture risk, and the tools needed to predict the risk of an osteoporotic fracture over the next 10 years are now being developed. These include bone density measures, but also incorporate other risk factors (e.g., fracture history, corticosteroid use), which may allow extension of fracture risk prediction to nonwhite populations and to men. Even with a universal risk prediction tool, cost-effective treatment thresholds will vary by country based on the level of fracture risk in the region and on the resources available for health care. To better compete for these resources, efforts should be made to lower the cost of osteoporosis interventions. Additionally, evidence is needed that these interventions are really effective in reducing fractures in the community.

It is widely accepted based on volunteer studies that levels of psychological distress are similar in those with functional gastrointestinal (GI) disorders and health in the community, while increased psychological distress in outpatients is largely explained by health-care seeking.To determine if psychological distress, life event stress, or social support is associated with functional GI disorders in a population-based study.A nested case-control study was performed by first mailing a self-report bowel disease questionnaire to a random sample of Olmsted County, Minnesota, aged 20-50 yr. All persons who reported symptoms of nonulcer dyspepsia (NUD) or irritable bowel syndrome (IBS) (cases), or an absence of GI symptoms (controls), were invited to complete a series of validated questionnaires designed to measure psychological distress, life event stress, social support, current symptoms, and physician visits.103 subjects with functional GI disorders and 119 controls participated (85% of eligible). Functional GI disorders were more likely to be reported by those with higher scores on each of the nine SCL-90-R scales used to measure psychological distress (except phobic anxiety), and those with more negative and total life event stress. In a multiple logistic regression model (including age and gender), somatization, interpersonal sensitivity, and total life event stress were independently associated with functional GI disorders. Findings were similar when subjects with the IBS and NUD were analyzed separately compared to controls.Contrary to current dogma, psychosocial factors were significantly associated with functional GI disorders in this community sample. This suggests that these factors may be involved in the etiopathogenesis rather than just driving health-care utilization.

BACKGROUND Benign breast disease is an important risk factor for breast cancer. We studied a large group of women with benign breast disease to obtain reliable estimates of this risk. METHODS We identified all women who received a diagnosis of benign breast disease at the Mayo Clinic between 1967 and 1991. Breast-cancer events were obtained from medical records and questionnaires. To estimate relative risks, we compared the number of observed breast cancers with the number expected on the basis of the rates of breast cancer in the Iowa Surveillance, Epidemiology, and End Results registry. RESULTS We followed 9087 women for a median of 15 years. The histologic findings were nonproliferative lesions in 67 percent of women, proliferative lesions without atypia in 30 percent, and atypical hyperplasia in 4 percent. To date, 707 breast cancers have developed. The relative risk of breast cancer for the cohort was 1.56 (95 percent confidence interval, 1.45 to 1.68), and this increased risk persisted for at least 25 years after biopsy. The relative risk associated with atypia was 4.24 (95 percent confidence interval, 3.26 to 5.41), as compared with a relative risk of 1.88 (95 percent confidence interval, 1.66 to 2.12) for proliferative changes without atypia and of 1.27 (95 percent confidence interval, 1.15 to 1.41) for nonproliferative lesions. The strength of the family history of breast cancer, available for 4808 women, was a risk factor that was independent of histologic findings. No increased risk was found among women with no family history and nonproliferative findings. In the first 10 years after the initial biopsy, an excess of cancers occurred in the same breast, especially in women with atypia. CONCLUSIONS Risk factors for breast cancer after the diagnosis of benign breast disease include the histologic classification of a benign breast lesion and a family history of breast cancer.

Abnormal bone metabolism is a recognized complication of end-stage renal disease, but fracture risk following renal transplantation has not been well quantified. We followed the 86 Olmsted County, Minnesota, residents who underwent initial renal transplantation in 1965-1995 for 911 person-years (median, 10.6 years per subject) in a retrospective cohort study. Fractures, and possible risk factors, were assessed through review of each subject's complete community medical records. Altogether, 117 fractures were observed during follow-up extending to 33 years. The cumulative incidence of any fracture at 15 years was 60% versus 20% expected ( P0.001). There was a significantly increased risk of fractures generally [standardized incidence ratio (SIR), 4.8; 95% CI, 3.6-6.4] and vertebral (SIR, 23.1; 95% CI, 12.3-39.6) and foot fractures (SIR, 8.4; 95% CI, 5.1-12.9) especially. Age at first transplantation, renal failure due to diabetes, pancreas transplantation, peripheral neuropathy, peripheral vascular disease and blindness were all associated with overall fracture risk. In a multivariate analysis, however, only age and diabetic nephropathy were independent predictors of fracture risk generally, while higher activity status was protective. Diabetes was the only independent predictor of lower limb fractures, whereas age and osteoporosis history predicted vertebral fractures. Cumulative corticosteroid dosage was not associated with increased fracture risk in this analysis. Despite the fact that our patients had few risk factors for preexisting bone disease attendant to postmenopausal osteoporosis, prior corticosteroid use or renal osteodystrophy, these data indicate that renal transplantation is associated with a significant increase in fracture risk among unselected patients in the community. Diabetic patients, particularly, experience excess lower limb fractures. Patients and their care providers should be aware of this elevated fracture risk, which continues long-term.

Little effort has been made to quantitate adverse outcomes of monoclonal gammopathy of undetermined significance (MGUS) of the immunoglobulin M (IgM) class, which progresses to lymphoma or Waldenström macroglobulinemia, whereas IgA and IgG MGUS progress to multiple myeloma, primary amyloidosis (AL), or a related plasma cell disorder. From 1960 to 1994, IgM MGUS was diagnosed in 213 patients in southeastern Minnesota. The end point was progression to lymphoma or a related disorder, as assessed with the Kaplan-Meier method. The 213 patients were followed up for 1567 person-years (median, 6.3 years per patient). Lymphoma developed in 17 patients (relative risk [RR], 14.8), Waldenström macroglobulinemia in 6 (RR, 262), primary amyloidosis in 3 (RR, 16.3), and chronic lymphocytic leukemia in 3 (RR, 5.7). The relative risk of progression was 16-fold higher in the patients with IgM MGUS than in the white population of the Iowa Surveillance, Epidemiology, and End Results Program. Cumulative incidence of progression was 10% at 5 years, 18% at 10 years, and 24% at 15 years. On multivariate analysis, the serum monoclonal protein and serum albumin concentrations at diagnosis were the only risk factors for progression to lymphoma or a related disorder. Risk for progression to lymphoma or a related disorder at 10 years after the diagnosis of MGUS was 14% with an initial monoclonal protein concentration of 0.5 g/dL or less, 26% with 1.5 g/dL, 34% for 2.0 g/dL, and 41% for more than 2.5 g/dL. (Blood. 2003;102:3759-3764)

Background & Aims: The epidemiology of primary sclerosing cholangitis (PSC) in the United States is unknown. We report the incidence, clinical spectrum, and outcomes of PSC in Olmsted County, Minnesota. Methods: Using the Rochester Epidemiology Project, a medical records linkage system in Olmsted County, Minnesota, we identified county residents with PSC, and the diagnosis was confirmed according to clinical, biochemical, radiographic, and histologic criteria. Results: Twenty-two patients met diagnostic criteria for PSC in 1976–2000. The age-adjusted (to 2000 U.S. whites) incidence of PSC in men was 1.25 per 100,000 person-years (95% CI, 0.70 to 2.06) compared with 0.54 per 100,000 person-years (95% CI, 0.22 to 1.12) in women. The prevalence of PSC in 2000 was 20.9 per 100,000 men (95% CI, 9.5 to 32.4) and only 6.3 per 100,000 women (95% CI, 0.1 to 12.5). Seventy-three percent of cases had inflammatory bowel disease, the majority with ulcerative colitis. Survival among PSC patients was significantly less than expected for the Minnesota white population of similar age and gender ( P Conclusions: These data represent the first population-based estimates of the incidence and prevalence of PSC in the United States. The incidence and prevalence of PSC were approximately one third of those previously described for primary biliary cirrhosis in the same population. Our data suggest that the prevalence of PSC in the United States, with its attendant medical burdens, is significantly greater than previously estimated.

Background & Aims: Osteopenia is common in patients with ulcerative colitis (UC), but less is known about fracture risk. Previously we were unable to demonstrate increased fractures in a population-based cohort with Crohn’s disease. Methods: Medical records of 273 Olmsted County, Minnesota residents initially diagnosed with UC in 1940–1993 were reviewed for evidence of subsequent fractures, as were records of a control cohort of county residents matched on age and gender. Cumulative fracture incidence after diagnosis was estimated by using the Kaplan-Meier method. The hazard ratio of fracture in cases relative to control subjects was estimated by Cox proportional hazards regression, which was also used to evaluate potential risk factors for fracture. Results: Median follow-up was 13 years (range, 1 day–53 years). The cumulative incidence of any fracture from time of diagnosis was 40% at 25 years versus 42% in control subjects (P = 0.615). The hazard ratio in cases compared to control subjects was 1.1 (95% confidence interval, 0.8–1.6) for any fracture and 1.3 (95% confidence interval, 0.6–2.8) for any osteoporotic fracture (hip, spine, or wrist as a result of moderate trauma). Other causes of secondary osteoporosis were associated with increased fracture risk, whereas estrogen use was protective. One hundred three cases received any corticosteroids (38%), and 34 (12%) had taken corticosteroids for 6 months or longer. Corticosteroids and bowel resection were not associated with fracture risk. Conclusions: In this population-based cohort of patients with UC, fracture risk was not elevated relative to matched community control subjects. Use of corticosteroids did not appear to significantly influence the risk of fracture.

This guide is a summary reference on the rehabilitation principles that should be applied in the treatment and prevention of osteoporosis. As this guide addresses primarily rehabilitation issues required by osteoporotic fracture or low bone mass, the health professional is directed to the National Osteoporosis Foundation’s companion piece, Physician’s Guide to Prevention and Treatment of Osteoporosis (‘Physician’s Guide’), for other treatment approaches. Rehabilitation and exercise are often viewed as a means to improve function, such as activities of daily living (ADL) for patients. Psychosocial factors also impact strongly on functional ability and the general health of the osteoporotic patient. The information in this guide is based on scientific evidence from basic research, consensus from an expert panel convened by the National Osteoporosis Foundation (NOF), clinical studies, and randomized controlled clinical trials. The small number of randomized trials points to the need for more of them in the future. The majority of the studies on rehabilitation approaches and exercise recommendations related to osteoporosis are based on studies among white perimenopausal women. Clearly, osteoporosis affects men and non-white women as well. It can also affect younger as well as older individuals with certain chronic conditions and medication use. Until we have additional data, recommendations for these other populations should be on an individual basis. The committee believes that the guidelines have universal application in terms of recommending life-long, safe activities and exercises for all people. This guide’s recommendations are not intended as rigid standards of practice, but must be tailored for use by physicians in consultation with their patients. Executive Summary

Bone loss has been reported in patients with prostate cancer treated with androgen deprivation therapy. We assess fracture risk following bilateral orchiectomy.Through the Rochester Epidemiology Project we identified 429 Olmsted County, Minnesota men who underwent bilateral orchiectomy in 1956 to 2000, almost all for prostate cancer. Fractures were ascertained from comprehensive medical records and compared with expected numbers based on local incidence rates (standardized incidence ratio, SIR). Potential risk factors were assessed with proportional hazards models.During 1961 person-years of followup 161 men experienced 267 fractures, for a cumulative incidence after 15 years of 40% compared to 19% expected (p0.001). However, 42 were pathological fractures and 82 were found incidentally on radiological surveys for metastasis. Overall fracture risk was increased (SIR 3.42, 95% CI 2.91-3.99) but was reduced by excluding the pathological and incidental fractures (SIR 2.04, 95% CI 1.66-2.47). The increase was largely accounted for by the moderate trauma fractures of the hip, spine and distal forearm traditionally linked with osteoporosis (SIR 3.50, 95% CI 2.71-4.43). In multivariate analyses risk factors for fractures generally included patient age, inactivity, prior radiological diagnosis of osteoporosis, chemotherapy and use of nonsteroidal antiandrogens, while independent risk factors for the traditional osteoporotic fractures included age, inactivity and diagnosis of osteoporosis.Fractures are common in men with prostate cancer due to advanced age, occurrence of pathological fractures and enhanced skeletal surveillance but there remains a significant increase in osteoporotic fracture risk following bilateral orchiectomy.

Osteoporosis is a global problem that will increase in significance with the growing elderly population. The condition affects both sexes and all races, albeit to different degrees. This article reviews the epidemiology of osteoporosis as it relates to age, sex, ethnicity, and other risk factors and makes projections for the future as populations continue to age worldwide.

This population-based, retrospective cohort study examined the association of tobacco use and diagnosis of a depressive disorder (DD) and suicide attempts (SA) before and after discharge from an inpatient addiction program (IAP). All 813 Olmsted County, Minnesota residents (537 males, 276 females) admitted for the first time to the IAP for treatment of alcoholism during the period 1972-1983 were studied. Tobacco use status at admission was classified as ever (current or former use) (85.5%), never (8.6%), or missing (5.9%). Subjects were followed through 1994. Current or former use of tobacco was markedly lower among those with a prior diagnosis of DD than those without this diagnosis (73.6% vs. 89.3%, p

Background— The outcome of mitral valve prolapse (MVP) is controversial, with marked discrepancies in reported complication rates. Methods and Results— We conducted a community study of all Olmsted County, Minn, residents first diagnosed with asymptomatic MVP between 1989 and 1998 (N=833). Diagnosis, motivated by auscultatory findings (n=557) or incidental (n=276), was always confirmed by echocardiography with the use of current criteria. End points analyzed during 4581 person-years of follow-up were mortality (n=96, 19±2% at 10 years), cardiovascular morbidity (n=171), and MVP-related events (n=109, 20±2% at 10 years). The most frequent primary risk factors for cardiovascular mortality were mitral regurgitation from moderate to severe ( P =0.002, n=131) and, less frequently, ejection fraction P =0.003, n=31). Secondary risk factors independently predictive of cardiovascular morbidity were slight mitral regurgitation, left atrium ≥40 mm, flail leaflet, atrial fibrillation, and age ≥50 years (all P P =0.17 versus expected), cardiovascular morbidity of 0.5%/y, and MVP-related events of 0.2%/y. Patients with ≥2 secondary risk factors (n=250) had mortality similar to expected ( P =0.20) but high cardiovascular morbidity (6.2%/y, P P P =0.01 versus expected), high morbidity (18.5%/y, P P Conclusions— Natural history of asymptomatic MVP in the community is widely heterogeneous and may be severe. Clinical and echocardiographic characteristics allow separation of the majority of patients with excellent prognosis from subsets of patients displaying, during follow-up, high morbidity or even excess mortality as direct a consequence of MVP.

Here we review and extend a new unitary model for the pathophysiology of involutional osteoporosis that identifies estrogen (E) as the key hormone for maintaining bone mass and E deficiency as the major cause of age-related bone loss in both sexes. Also, both E and testosterone (T) are key regulators of skeletal growth and maturation, and E, together with GH and IGF-I, initiate a 3- to 4-yr pubertal growth spurt that doubles skeletal mass. Although E is required for the attainment of maximal peak bone mass in both sexes, the additional action of T on stimulating periosteal apposition accounts for the larger size and thicker cortices of the adult male skeleton. Aging women undergo two phases of bone loss, whereas aging men undergo only one. In women, the menopause initiates an accelerated phase of predominantly cancellous bone loss that declines rapidly over 4–8 yr to become asymptotic with a subsequent slow phase that continues indefinitely. The accelerated phase results from the loss of the direct restraining effects of E on bone turnover, an action mediated by E receptors in both osteoblasts and osteoclasts. In the ensuing slow phase, the rate of cancellous bone loss is reduced, but the rate of cortical bone loss is unchanged or increased. This phase is mediated largely by secondary hyperparathyroidism that results from the loss of E actions on extraskeletal calcium metabolism. The resultant external calcium losses increase the level of dietary calcium intake that is required to maintain bone balance. Impaired osteoblast function due to E deficiency, aging, or both also contributes to the slow phase of bone loss. Although both serum bioavailable (Bio) E and Bio T decline in aging men, Bio E is the major predictor of their bone loss. Thus, both sex steroids are important for developing peak bone mass, but E deficiency is the major determinant of age-related bone loss in both sexes.

The authors previously reported an increase in the incidence of diabetes mellitus among Rochester, Minnesota, residents during the period 1970-1989. This study provides updated rates from data collected through 1994. Trends in diabetes surveillance, i.e., the proportion of residents who had a blood glucose measurement in each year between 1987 and 1994, are also provided. The authors reviewed medical records to identify residents aged 30 years or more who first met National Diabetes Data Group criteria for diabetes between January 1, 1970, and December 31, 1994. Age- and sex-adjusted incidence rates were calculated for successive quinquennia (5-year periods), and Poisson regression was used to test for an effect of calendar year; calendar period (1970-1989 vs. 1990-1994) was added to assess whether the association with calendar year varied in the most recent quinquennium. Altogether, 1,992 Rochester residents first met National Diabetes Data Group criteria for diabetes between 1970 and 1994. The age-adjusted incidence per 100,000 person-years increased 67% for males (267.0 vs. 444.8) and 42% for females (225.4 vs. 319.1) between 1970-1974 and 1990-1994. Calendar year (p < 0.001) and calendar period (p = 0.026) were significant, suggesting that rates accelerated during 1990-1994. The proportion of residents with at least one blood glucose measurement per year was unchanged (p = 0.181) from 1987 to 1994, while the incidence of diabetes increased (p = 0.033). Thus, the authors conclude that the increase in diabetes incidence accelerated over the last quinquennium and was not due to increased surveillance.

Because estrogen (E) and T are the major sex steroids in women and men, respectively, the traditional view had been that E primarily regulated bone turnover in women and T played the analogous role in men. The description of ER- deficient and aromatase-deficient males, however, initiated a major shift in our thinking on the relative roles of T and E in regulating the male skeleton, because these individuals all had unfused epiphyses, high bone turnover, and osteopenia. Similar, albeit less striking, findings were noted in mouse models with knock-out of either the ER-α or the aromatase genes. Although these human experiments of nature and mouse knock-out models clearly demonstrated an important role for E in the growth and maturation of the male skeleton, they did not define the role of E vs. T in regulating the adult male skeleton. The past several years have witnessed an accumulation of evidence from observational as well as direct interventional studies that now clearly indicates that E plays a major, a...

Background A monoclonal gammopathy of undetermined significance (MGUS) occurs in up to 2 percent of persons 50 years of age or older. Reliable predictors of progression have not been identified, and information on prognosis is limited. Methods We identified 1384 patients residing in southeastern Minnesota in whom MGUS was diagnosed at the Mayo Clinic from 1960 through 1994. The primary end point was progression to multiple myeloma or another plasma-cell cancer. Results During 11,009 person-years of follow-up, MGUS progressed in 115 of the 1384 patients to multiple myeloma, IgM lymphoma, primary amyloidosis, macroglobulinemia, chronic lymphocytic leukemia, or plasmacytoma (relative risk of progression, 25.0, 2.4, 8.4, 46.0, 0.9, and 8.5, respectively). The overall relative risk of progression was 7.3 in these patients as compared with the white population of the Iowa Surveillance, Epidemiology, and End Results program. In 32 additional patients, the monoclonal protein concentration increased to more than 3...

The summum bonum of osteoporosis treatment is the prevention of new fractures. In vitro studies have shown that 60 ‐ 80% of the compressive strength of bone is caused by its mineral content. (1) Correspondingly, observational studies show that baseline bone mineral density (BMD) measurements at multiple skeletal sites can predict various types of osteoporotic fractures in postmenopausal women. (2) In general, a decrease in BMD of 1.0 SD increases the risk of future fractures by ;2.0-fold. The observational data from epidemiological studies have been confirmed by results of randomized clinical trials (RCTs) showing that antiresorptive agents both increase BMD and decrease vertebral frac