Melton, Lee J.

Abstract Background: Monoclonal gammopathy of undetermined significance (MGUS) is defined by a monoclonal protein concentration in serum of 3 g/dL or less and a proportion of plasma cells in the bone marrow of 10% or less, absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency related to the proliferation of the monoclonal plasma cells. Two major questions remain unanswered: What proportion of patients with MGUS in the population is unrecognized clinically? What is the likely duration of MGUS at the time of its discovery? Methods: We examined the serum of 21,463 (77%) of the 28,038 enumerated residents of Olmsted County, Minnesota, in a population-based screening study and found that MGUS was present in 1.3% of persons 50 years of age and 3.8% of those 70 years of age. The risk of progression of MGUS to multiple myeloma (MM), primary amyloidosis (AL), Waldenstrom’s macroglobulinemia (WM), or related plasma cell disorders was 1% per year. Results: By age 70, only 21% of Olmsted County residents with MGUS, as determined by the prevalence study, had been recognized by routine clinical practice (Fig. 1). This is probably higher in Olmsted County than elsewhere because serum protein electrophoresis is frequently ordered on Mayo Clinic patients. The incidence of MGUS, estimated from the prevalence data, indicates onset of the condition long before clinical recognition. The duration of MGUS prior to detection at age 70 is shown in Fig. 2. Thus, 30% of patients recognized to have MGUS at age 70 probably had MGUS onset before age 50 and 55% had a prior (unrecognized) MGUS already by age 60. The median duration of MGUS prior to its recognition on the basis of clinical practice is 11 years (median). Linear extrapolation of the incidence curve implies a first appearance of MGUS around 30 years of age. Figure 1 Figure 1 Figure 2 Figure 2

Abstract Background: Hematological cancer patients are at an increased risk for VTE (RR range = 12–32). However, whether VTE risk among such patients can be further stratified is uncertain. Objective: To test hematological cancer type, stage, stage progression and chemotherapy as potential risk factors for VTE among active hematological cancer patients after controlling for other previously-identified VTE risk factors. Methods: Using the resources of the Rochester Epidemiology Project, Mayo Clinic Master Diagnostic Index and Mayo Clinic Tumor Registry, we identified all Olmsted County, MN residents with active hematological cancer over the 28-year period, 1973–2000. From this prevalence cohort, we identified 86 patients with no prior VTE (controls) who were matched on age and date of hematological cancer diagnosis to 86 hematological cancer patients with incident VTE over the same time frame (cases). For all cases and controls, we reviewed the complete medical records in the community for baseline and hematological cancer-related characteristics. Hematological cancers were re-staged at the dates of the cancer and VTE diagnosis. We tested these characteristics as potential risk factors for VTE in active hematological cancer using conditional logistic regression. Results: In an initial multivariate analysis that included body mass index (BMI), hospitalization, and any infection or central venous catheter placement within 90 days prior to the VTE event, VTE was significantly associated with hospitalization (OR=6.70; p<0.001), and marginally associated with any infection (OR=2.18; p=0.09). After adjusting for the above variables, chemotherapy administered within the preceding 90 days was significantly associated with VTE (OR=4.25; p=0.02), while stage progression was marginally associated (OR=4.79; p=0.10). Compared to all other hematological cancer types, acute leukemia (OR=5.95; p=0.01) and non-Hodgkin’s lymphoma (OR=2.61; p=0.01) were associated with VTE. However, after adjusting for BMI, hospitalization, any infection and central venous catheter, only non-Hodgkin’s lymphoma was independently associated with VTE (OR=3.79, p=0.009), while acute leukemia was not (OR=2.66, p=0.35). Conclusions: Hematological cancer type (in particular, non-Hodgkin’s lymphoma and possibly acute leukemia), recent hospitalization, recent chemotherapy, and possibly stage progression and recent infection, are risk factors for VTE among patients with active hematological cancer.

Abstract To determine the accuracy of self-reported risk factors for osteoporosis, an age-stratified random sample of Rochester, MN, women was studied. Results from a structured face-to-face interview were compared with information documented in contemporary inpatient and outpatient health care records in the community. Using the × statistic to evaluate concordance of these two data sources, we found substantial agreement for a history of proximal femoral and distal forearm fractures, peptic ulcer disease, estrogen replacement therapy and oral contraceptive use, and cigarette and alcohol exposure. Moderate agreement was seen for histories of other age-related fractures, hysterectomy or oophorectomy, thyroidectomy, and use of thyroid supplements. Poor agreement was found for prior thyroid disease, gastrectomy, and corticosteroid or anticonvulsant use. This study demonstrates a need for greater attention to the quality of self-reported risk factor data in studies of bone loss and fractures.

Abstract The impact of primary hyperparathyroidism (HPT) on the population has not been well documented, and even less information is available for asymptomatic HPT. Only 57 deaths were attributed to the condition in the United States in 1986, for a reported HPT death rate of 0.24 per million per year. Many more patients were affected, however, and the incidence of hospitalization for HPT was 6.6 per 100,000 in 1986, counting all listed diagnoses, and 2.9 per 100,000 counting only first-listed diagnoses. Surgery was performed on approximately 10,000 hospitalized patients in the United States in 1986, for a parathyroidectomy rate of about 4.2 per 100,000 per year. When nonhospitalized cases are included, the rates are even higher. The estimated annual incidence of HPT was 42.1 per 100,000 in Rochester, Minnesota in 1974–1976; the prevalence of HPT was 4.3 per 1000 in a population survey in Sweden. By any of these measures, HPT is more common in women than men and increases with aging in both sexes. The potential cost of HPT could be as high as $420 million/year in the United States, but no formal estimates have been made. Disability related to HPT or its treatment has not been quantified; randomized clinical trials to determine the utility of parathyroidectomy have not been performed; and no assessment of cost benefit or cost effectiveness of any therapeutic modality has been carried out. Until patient management and cost issues are resolved, it is premature to consider an aggressive program to screen the general population for HPT.

Abstract Although it is a cardinal feature of involutional osteoporosis, there is often disagreement on what constitutes a vertebral fracture. We measured vertebrae T4-L5 in 52 healthy women to develop a normal range (mean ± 3 SD) for vertebral shape and used these data to assess the prevalence of vertebral fractures. We classified vertebral fractures by type of deformity (wedge, biconcavity, or compression) and further by the degree of deformity (grades 1 and 2). In 195 postmenopausal women who were an age-stratified random sample of the Rochester population (ages 47–94), 40 (21%) had vertebral fractures (mean, 2 per person). There was a similar number of compression and wedge fractures, and grade 2 fractures were as common as grade 1. In a referral sample of 74 women with suspected osteoporosis, 62 (84%) had vertebral fractures (mean, 3.3 per person). Wedge fractures were most common, and grade 2 fractures were more common than grade 1. The distribution of type and grade of fractures differed between the two patient groups (P < 0.01). Bone mineral density of the lumbar spine was related to mean fracture grade (r = −0.33, P < 0.05) and to fracture number (r = −0.57, P < 0.001) but not to fracture type. We conclude that a comprehensive approach is required in describing vertebral fractures. Using this approach we found distortion in the fracture characteristics of women referred to an osteoporosis clinic compared to women in the community.

Abstract 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.

AbstractIn a series of postmenopausal women previously studied by our group, pernicious anemia was associated with reduced bone mineral density of the spine and with vertebral fractures. To determine whether osteoporotic fractures represent an important clinical problem for such patients, we conducted a population-based retrospective cohort study of all Rochester, Minnesota residents newly diagnosed with pernicious anemia from 1950 through 1979. These 131 individuals were followed through the inpatient and outpatient records of all medical care providers in the community for 1550 person-years. In comparison with fracture rates from the general community, patients with pernicious anemia had a 1.9-fold increase in proximal femur fractures, a 1.8-fold increase in vertebral fractures, and a 2.9-fold increase in distal forearm fractures (all p < 0.05). Increases in the risk of proximal humerus and pelvis fractures were not statistically significant. Clinicians should be aware that pernicious anemia is associated with an increased risk of osteoporotic fractures, but the mechanism is unknown.

Abstract High caffeine consumption has been proposed as a risk factor for osteoporotic fracture, but the evidence associating high caffeine intake with low bone density is inconsistent. We therefore examined the influence of caffeine consumption on bone mineral at six skeletal sites in an age-stratified random sample of white women residing in Rochester, Minnesota. After age adjustment, there was no association between overall caffeine consumption and bone mineral at five of the six sites. In the femoral shaft, however, there was a statistically significant interaction between age and caffeine consumption so that high caffeine intake was associated with slight reductions in bone mineral among elderly subjects but with modestly increased bone mineral at younger ages. When caffeine intake was categorized by source, no consistent influence of coffee, tea, or other caffeinated beverage consumption could be detected on bone mineral. Caffeine intake was, however, positively associated with cigarette smoking and alcohol consumption. After adjusting for age, caffeine consumption was not correlated with biochemical indices of bone turnover, circulating concentrations of estradiol and estrone, or other dietary and musculoskeletal variables. These data suggest that caffeine intake in the range consumed by a representative sample of white women is not an important risk factor for osteoporosis. Among elderly women, however, in whom calcium balance performance is impaired, high caffeine intake may predispose to cortical bone loss from the proximal femur.

AbstractIn a population-based retrospective cohort study, Rochester women aged 35–69 years who were first diagnosed with one or more vertebral fractures in 1950–1979 were followed for the development of a subsequent hip fracture. The 336 women with no history of hip fracture at the time of their vertebral fracture experienced 52 proximal femur fractures in 4788 person-years of follow-up. The standardized morbidity ratio (SMR) of observed to expected hip fractures was 1.8 (95% CI, 1.3–2.4) and was higher for intertrochanteric than cervical femoral fractures (SMR, 2.3 versus 1.3; P = 0.07). Hip fracture risk among women with symptomatic vertebral fractures was slightly less than in those with asymptomatic vertebral fractures (SMR, 1.8 versus 2.3; not significant), and younger women had no higher risk of a subsequent hip fracture than women who were ≥60 years of age at the time of their vertebral fracture (SMR, 1.4 versus 1.8; not significant). Alternative explanations are possible, but these data are consistent with heterogeneity in the pathogenesis of different osteoporotic fractures.

Abstract Bone mineral density (BMD) was measured at the lumbar spine and cervical and intertrochanteric regions of the proximal femur by dual-photon absorptiometry and bone mineral content was assessed at the distal and midradius by single-photon absorptiometry in an age-stratified random sample of 304 Rochester, Minnesota women aged 30–94 years. Over follow-up extending to 10 years (median 8.3 years), 93 women experienced 163 new fractures. After adjusting for age, these bone mineral measurements predicted the likelihood of any incident fracture due to moderate trauma, with relative hazards varying from 1.4 to 1.6 per SD decrease in baseline bone mineral. A 1 SD decrease in lumbar spine BMD increased the risk of a new vertebral fracture comparably to a 17 year increase in age; a 1 SD decrease in femoral BMD was comparable to a 13–14 year increase in age on the risk of a hip fracture. We conclude that bone mineral measurements made at a variety of skeletal sites can predict the occurrence for at least 8–10 years of moderate trauma fractures of the sort that might be related to osteoporosis.