Elizabeth J. Atkinson

Population‐Based Study of Age and Sex Differences in Bone Volumetric Density, Size, Geometry, and Structure at Different Skeletal Sites

In a population‐based, cross‐sectional study, we assessed age‐ and sex‐specific changes in bone structure by QCT. Over life, the cross‐sectional area of the vertebrae and proximal femur increased by ∼15% in both sexes, whereas vBMD at these sites decreased by 39–55% and 34–46%, respectively, with greater decreases in women than in men.

Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men

Young adult males who cannot produce or respond to estrogen (E) are osteopenic, suggesting that E may regulate bone turnover in men, as well as in women. Both bioavailable E and testosterone (T) decrease substantially in aging men, but it is unclear which deficiency is the more important factor contributing to the increased bone resorption and impaired bone formation that leads to their bone loss. Thus, we addressed this issue directly by eliminating endogenous T and E production in 59 elderly men (mean age 68 years), studying them first under conditions of physiologic T and E replacement and then assessing the impact on bone turnover of withdrawing both T and E, withdrawing only T, or only E, or continuing both. Bone resorption markers increased significantly in the absence of both hormones and were unchanged in men receiving both hormones. By two-factor ANOVA, E played the major role in preventing the increase in the bone resorption markers, whereas T had no significant effect. By contrast, serum osteocalcin, a bone formation marker, decreased in the absence of both hormones, and both E and T maintained osteocalcin levels. We conclude that in aging men, E is the dominant sex steroid regulating bone resorption, whereas both E and T are important in maintaining bone formation.

Bone density and fracture risk in men

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

Effects of Sex and Age on Bone Microstructure at the Ultradistal Radius: A Population-Based Noninvasive In Vivo Assessment

In a population‐based cross‐sectional study, we examined effects of sex and age on bone microstructure at the wrist using high‐resolution 3‐D pQCT. Compared with women, men had thicker trabeculae in young adulthood and had less microstructural damage with aging. These findings may contribute to the virtual immunity of men to age‐related increases in wrist fractures.

Vertebral fractures predict subsequent fractures.

Abstract:This population-based study documents an increase in most types of fractures following the occurrence of a clinically recognized vertebral fracture among 820 Rochester, Minnesota, residents. During 4349 person-years of follow-up, 896 new fractures were observed. Relative to incidence rates in the community, there was a 2.8-fold increase in the risk of any fracture, which was greater in men (standardized incidence ratio (SIR), 4.2; 95% CI, 3.2–5.3) than women (SIR, 2.7; 95% CI, 2.4–3.0). The estimated cumulative incidence of any fracture after 10 years was 70%. The greatest increase in risk was for subsequent fractures of the axial skeleton, in particular a 12.6-fold increase (95% CI, 11–14) in additional vertebral fractures. There was a lesser increase in most limb fractures, including a 2.3-fold increase (95% CI, 1.8–2.9) in hip fractures and a 1.6-fold increase (95% CI, 1.01–2.4) in distal forearm fractures. There was a slightly greater association with distal forearm fractures among those whose first vertebral fracture occurred before age 70 years but a similar relationship with hip fractures, including cervical and intertrochanteric hip fractures separately, regardless of age at the initial vertebral fracture. There was also an equivalent increase in subsequent fracture risk whether the initial vertebral fracture was attributed to severe or moderate trauma. These data show that vertebral fractures represent an important risk factor for fractures in general, not just those of the spine and hip.

A Population-Based Assessment of Rates of Bone Loss at Multiple Skeletal Sites : Evidence for Substantial Trabecular Bone Loss in Young Adult Women and Men

Using QCT, we made a longitudinal, population‐based assessment of rates of bone loss over life at the distal radius, distal tibia, and lumbar spine. Cortical bone loss began in perimenopause in women and later in life in men. In contrast, trabecular bone loss began in young adulthood in both sexes.

Relationship of bone turnover to bone density and fractures.

To assess the influence of bone turnover on bone density and fracture risk, we measured serum levels of osteocalcin (OC), bone alkaline phosphatase (BAP), and carboxy‐terminal propeptide of type I procollagen (PICP), as well as 24‐h urine levels of cross‐linked N‐telopeptides of type I collagen (NTx) and the free pyridinium cross‐links, pyridinoline (Pyd) and deoxypyridinoline (Dpd), among 351 subjects recruited from an age‐stratified random sample of Rochester, Minnesota women. PICP, NTx, and Dpd were negatively associated with age among the 138 premenopausal women. All of the biochemical markers were positively associated with age among the 213 postmenopausal women, and the prevalence of elevated turnover (>1 standard deviation [SD] above the premenopausal mean) varied from 9% (PICP) to 42% (Pyd). After adjusting for age, most of the markers were negatively correlated with bone mineral density (BMD) of the hip, spine, or forearm as measured by dual‐energy X‐ray absorptiometry, and women with osteoporosis were more likely to have high bone turnover. A history of osteoporotic fractures of the hip, spine, or distal forearm was associated with reduced hip BMD and with elevated Pyd. After adjusting for lower BMD and increased bone resorption, reduced bone formation as assessed by OC was also associated with prior osteoporotic fractures. These data indicate that a substantial subset of elderly women has elevated bone turnover, which appears to adversely influence BMD and fracture risk. Combined biochemical and BMD screening may provide better prediction of future fracture risk than BMD alone.

Role of serum leptin, insulin, and estrogen levels as potential mediators of the relationship between fat mass and bone mineral density in men versus women.

Although fat mass is related to bone mineral density (BMD), the potential mechanism(s) of this effect remain to be defined. Thus, we assessed the role of the candidate hormones, leptin, insulin, and estrogen in mediating fat mass effects on the skeleton. Specifically, we related these hormones and fat mass to BMD at the total hip, mid-lateral spine, and mid-distal radius in a sample of 137 premenopausal women (age range 21-54 years), 165 postmenopausal women (34-93 years), and 343 men (23-90 years) recruited from the general population. Fat mass and BMD were significantly related in pre- and postmenopausal women at multiple sites, whereas this relationship was only weakly present in men at the total hip. Serum leptin levels were also significantly related to BMD in the women, but not in the men. Insulin was associated with hip BMD in the women, and bioavailable estradiol (E2) was correlated with BMD at all sites in men and in postmenopausal women. In the women, adjusting for leptin reduced the strength of the association between fat mass and BMD, with further adjustments for insulin or bioavailable E2 having no additional effects. Adjusting for leptin in the men had no consistent effect on the relationship between fat mass and BMD. Collectively, these data suggest that there is a sexual dimorphism in the relationship of fat mass and leptin to BMD, with both being positively associated with BMD in women but not in men. In women, leptin may also mediate at least part of the protective effect of fat mass on the skeleton.

Incidence of primary hyperparathyroidism in Rochester, Minnesota, 1993-2001: An update on the changing epidemiology of the disease

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.

Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss

DNA methyltransferase 1 (DNMT1) is crucial for maintenance of methylation, gene regulation and chromatin stability. DNA mismatch repair, cell cycle regulation in post-mitotic neurons and neurogenesis are influenced by DNA methylation. Here we show that mutations in DNMT1 cause both central and peripheral neurodegeneration in one form of hereditary sensory and autonomic neuropathy with dementia and hearing loss. Exome sequencing led to the identification of DNMT1 mutation c.1484A>G (p.Tyr495Cys) in two American kindreds and one Japanese kindred and a triple nucleotide change, c.1470–1472TCC>ATA (p.Asp490Glu–Pro491Tyr), in one European kindred. All mutations are within the targeting-sequence domain of DNMT1. These mutations cause premature degradation of mutant proteins, reduced methyltransferase activity and impaired heterochromatin binding during the G2 cell cycle phase leading to global hypomethylation and site-specific hypermethylation. Our study shows that DNMT1 mutations cause the aberrant methylation implicated in complex pathogenesis. The discovered DNMT1 mutations provide a new framework for the study of neurodegenerative diseases.