Melton, L. Joseph

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is associated with a long-term risk of progression to multiple myeloma (MM) or related malignancy. To prevent serious myeloma-related complications, lifelong annual follow-up has been recommended, but its value is unknown. We reviewed all patients from southeastern Minnesota seen at Mayo Clinic between 1973 and 2004 with MGUS who subsequently progressed to MM. Of 116 patients, 69% had optimal follow-up of MGUS. Among these, abnormalities on serial follow-up laboratory testing led to the diagnosis of MM in 16%, whereas MM was diagnosed only after serious MM-related complications in 45%. In the remaining, workup of less serious symptoms (25%), incidental finding during workup of unrelated medical conditions (11%), and unknown (3%) were the mechanisms leading to MM diagnosis. High-risk MGUS patients (≥ 1.5 g/dL and/or non-IgG MGUS) were more likely to be optimally followed (81% vs 64%), and be diagnosed with MM secondary to serial follow-up testing (21% vs 7%). This retrospective study suggests that routine annual follow-up of MGUS may not be required in low-risk MGUS. Future studies are needed to replicate and expand our findings and to determine the optimal frequency of monitoring in higher-risk MGUS patients.

Abstract It has been suggested recently that, although fluoride therapy may decrease the occurrence of vertebral fractures, it could increase the risk of hip fractures. To evaluate this possibility, we combined retrospective data from five medical centers that have had a large experience with this therapeutic regimen. In 416 osteoporotic patients who were followed for more than 1,000 patient-years of fluoride treatment, there were 17 nontraumatic hip fractures. This incidence of 1.6% per year is similar to the incidence, 1.9% per year, for 120 of the patients in this series who had been followed prospectively for 3 years prior to initiation of fluoride therapy. The expected incidence for women of the same age in the general community is 0.5% per year. Thus, untreated osteoporotic women are at increased risk for hip fracture, but treatment with fluoride seems neither to decrease nor to increase the incidence of hip fracture substantially.

Abstract To determine whether Colles' fracture, generally considered a manifestation of postmenopausal osteoporosis, is associated with a decrease in bone density at the site of fracture, we measured bone mineral density of the ultradistal radius (UDR-BMD) by single-photon absorptiometry with computer-assisted image processing. In 119 normal women (ages 22–92 years), UDR-BMD decreased by 17% between ages 30 and 75 years. From UDR-BMD measurements in these normal women and in 40 women (ages 53–80 years) with Colles' fracture alone, a population-based analysis was made to estimate fracture risk at different values of UDR-BMD. Colles' fracture was uncommon at UDR-BMD > 0.40 g/cm2 (the “fracture threshold”). As bone density decreased below this level, fractures became more frequent (a “gradient of risk”).

AbstractAlthough age-related variations in areal bone mineral density (aBMD) and the prevalence of osteoporosis have been well characterized, there is a paucity of data on femoral strength in the population. Addressing this issue, we used finite-element analysis of quantitative computed tomographic scans to assess femoral strength in an age-stratified cohort of 362 women and 317 men, aged 21 to 89 years, randomly sampled from the population of Rochester, MN, and compared femoral strength with femoral neck aBMD. Percent reductions over adulthood were much greater for femoral strength (55% in women, 39% in men) than for femoral neck aBMD (26% in women, 21% in men), an effect that was accentuated in women. Notable declines in strength started in the mid-40s for women and one decade later for men. At advanced age, most of the strength deficit for women compared with men was a result of this decade-earlier onset of strength loss for women, this factor being more important than sex-related differences in peak bone strength and annual rates of bone loss. For both sexes, the prevalence of “low femoral strength” (<3000 N) was much higher than the prevalence of osteoporosis (femoral neck aBMD T-score of −2.5 or less). We conclude that age-related declines in femoral strength are much greater than suggested by age-related declines in femoral neck aBMD. Further, far more of the elderly may be at high risk of hip fracture because of low femoral strength than previously assumed based on the traditional classification of osteoporosis. © 2010 American Society for Bone and Mineral Research

Abstract Venous stasis syndrome may complicate deep vein thrombosis (DVT; i.e. post-phlebitic syndrome), but, in most cases, venous stasis syndrome is not post-phlebitic. The objective of this study was to determine the risk factors (including prior DVT) for venous stasis syndrome, and to assess venous outflow obstruction and venous valvular incompetence as possible mechanisms for venous stasis syndrome. This was a case–control study nested within a population-based inception cohort. The study population consisted of 232 Olmsted County, MN residents with a first lifetime venous thromboembolism (VTE) and 133 residents without VTE. Measurements included a questionnaire and physical examination for venous stasis syndrome; strain gauge outflow plethysmography, venous continuous wave Doppler ultrasonography and passive venous drainage and refill testing for venous outflow obstruction and venous valvular incompetence. Altogether, 161 (44%), 43 (12%), and 136 (38%) subjects respectively, had venous stasis syndrome, venous outflow obstruction and venous valvular incompetence. Independent risk factors for venous stasis syndrome included increasing patient age and body mass index (BMI), prior DVT, longer time interval since DVT, and varicose veins. Both venous outflow obstruction ( p = 0.003) and venous valvular incompetence ( p < 0.0001) were strongly associated with venous stasis syndrome. Increasing age and prior DVT were significantly associated with venous outflow obstruction, while prior DVT, varicose veins and venous stasis syndrome diagnosed prior to the incident DVT were significantly associated with venous valvular incompetence. The risks of venous outflow obstruction, venous valvular incompetence and venous stasis syndrome were higher with left leg DVT. In conclusion, increasing patient age and BMI, prior DVT (particularly left leg DVT), longer time interval since DVT and varicose veins are independent risk factors for venous stasis syndrome. Venous stasis syndrome related to DVT is due to venous outflow obstruction and venous valvular incompetence, while venous stasis syndrome related to older age and to varicose veins is due to venous outflow obstruction and to venous valvular incompetence, respectively.

Objective— Although diabetes mellitus is reported as a risk factor for venous thromboembolism (VTE), persons with diabetes are frequently hospitalized for medical illness or surgery, or confined to a nursing home, all major VTE risk factors. Consequently, we tested diabetes for an independent association with incident VTE. Methods and Results— Using Rochester Epidemiology Project resources, we identified all Olmsted County, Minn residents who met objective criteria for incident VTE over the 25-year period, 1976 to 2000 (n=1922), and 1 to 2 resident controls per case, matched on age, gender, and length of medical history (n=2115). Complete medical histories in the community were reviewed for previously identified independent VTE risk factors and diabetes-related variables. We tested diabetes and diabetes complications (retinopathy, nephropathy or neuropathy, and ketoacidosis) as potential VTE risk factors, both alone and after adjusting for VTE risk factors. Univariately, diabetes by clinical diagnosis or by stricter criteria (fasting ambulatory blood glucose ≥140 mg/dL or antidiabetic drug therapy), and diabetes complications, were associated with overall incident VTE. However, after controlling for hospitalization for major surgery or medical illness and nursing home confinement, diabetes was no longer associated with VTE. Conclusion— Diabetes mellitus and diabetes complications are not independent risk factors for incident VTE.

Abstract The incidence of distal forearm fractures peaks during the adolescent growth spurt, but the structural basis for this is unclear. Thus, we studied healthy 6- to 21-yr-old girls (n = 66) and boys (n = 61) using high-resolution pQCT (voxel size, 82 μm) at the distal radius. Subjects were classified into five groups by bone-age: group I (prepuberty, 6–8 yr), group II (early puberty, 9–11 yr), group III (midpuberty, 12–14 yr), group IV (late puberty, 15–17 yr), and group V (postpuberty, 18–21 yr). Compared with group I, trabecular parameters (bone volume fraction, trabecular number, and thickness) did not change in girls but increased in boys from late puberty onward. Cortical thickness and density decreased from pre- to midpuberty in girls but were unchanged in boys, before rising to higher levels at the end of puberty in both sexes. Total bone strength, assessed using microfinite element models, increased linearly across bone age groups in both sexes, with boys showing greater bone strength than girls after midpuberty. The proportion of load borne by cortical bone, and the ratio of cortical to trabecular bone volume, decreased transiently during mid- to late puberty in both sexes, with apparent cortical porosity peaking during this time. This mirrors the incidence of distal forearm fractures in prior studies. We conclude that regional deficits in cortical bone may underlie the adolescent peak in forearm fractures. Whether these deficits are more severe in children who sustain forearm fractures or persist into later life warrants further study.

We hypothesized that increased monoclonal free kappa or lambda immunoglobulin light chains in smoldering multiple myeloma (SMM), as detected by the serum free light chain (FLC) assay, indicates an increased risk of progression to active myeloma. Baseline serum samples obtained within 30 days of diagnosis were available in 273 patients with SMM seen from 1970 to 1995. At a median follow-up of surviving patients of 12.4 years, transformation to active disease has occurred in 59%. The best breakpoint for predicting risk of progression was an FLC ratio of 0.125 or less, or 8 or more (hazard ratio, 2.3; 95% CI, 1.6-3.2). The extent of abnormality of FLC ratio was independent of SMM risk categories defined by number of bone marrow plasma cells (BMPCs) and size of serum M proteins (BMPC ≥ 10% and serum M protein ≥ 3 g/dL; BMPC ≥ 10% but serum M protein < 3 g/dL; and serum M protein≥ 3 g/dL but BMPC < 10%). Incorporating the FLC ratio into the risk model, the 5-year progression rates in high-, intermediate-, and low-risk groups were 76%, 51%, and 25%, respectively. The serum immunoglobulin FLC ratio is an important additional determinant of clinical outcome in patients with SMM.

Clinical peripheral vascular disease (PVD) was studied in an incidence cohort of 1073 residents of Rochester, Minnesota, who were found to have diabetes mellitus in the period 1945–69. About 8%; of patients already had clinical evidence of PVD at the time of diagnosis of diabetes. The proportion increased with the age at which diabetes was discovered. Among those unaffected initially, the incidence of subsequent PVD was slightly greater for men, 21.3 per 1000 person-years, than for women, 17.6 per 1000, and it increased both with age and duration of diabetes. The cumulative incidence of subsequent PVD was estimated to be 15%; at 10 yr and 45% at 20 yr after the diagnosis of diabetes. The age-adjusted prevalence of residents with diabetes and a history of PVD was 3.3 per 1000 population 30 yr of age or over on 1 January 1970.