Potential role of pancreatic and enteric hormones in regulating bone turnover.
Explore the source record for details and available documents.
Amyloid↗
Biomedical subjects
Sundeep Khosla
Publications and source records attributed to Sundeep Khosla.
Circulating osteoblast-lineage cells in humans.
BACKGROUND: Although current evidence suggests that only a minuscule number of osteoblast-lineage cells are present in peripheral blood, we hypothesized that such cells circulate but that their concentration has been vastly underestimated owing to the use of assays that required adherence to plastic. We further reasoned that the concentration of these cells is elevated during times of increased bone formation, such as during pubertal growth. METHODS: We used flow cytometry with antibodies to bone-specific proteins to identify circulating osteoblast-lineage cells in 11 adolescent males and 11 adult males (mean [+/-SD] age, 14.5+/-0.7 vs. 37.7+/-7.6 years). Gene expression and in vitro and in vivo bone-forming assays were used to establish the osteoblastic lineage of sorted cells. RESULTS: Cells positive for osteocalcin and cells positive for bone-specific alkaline phosphatase were detected in the peripheral blood of adult subjects (1 to 2 percent of mononuclear cells). There were more than five times as many cells positive for osteocalcin in the circulation of adolescent boys (whose markers of bone formation were clearly increased as a result of pubertal growth) as compared with adult subjects (P<0.001). The percentage of cells positive for osteocalcin correlated with markers of bone formation. Sorted osteocalcin-positive cells expressed osteoblastic genes, formed mineralized nodules in vitro, and formed bone in an in vivo transplantation assay. Increased values were also found in three adults with recent fractures. CONCLUSIONS: Osteoblast-lineage cells circulate in physiologically significant numbers, correlate with markers of bone formation, and are markedly higher during pubertal growth; therefore, they may represent a previously unrecognized circulatory component to the process of bone formation.
Adolescent↗
Osteoporosis assessment by whole body region vs. site-specific DXA.
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.
Absorptiometry, Photon↗
Estrogen receptor alpha and beta heterodimers exert unique effects on estrogen- and tamoxifen-dependent gene expression in human U2OS osteosarcoma cells.
The 17beta-estradiol (E2) receptor isoforms [estrogen receptor (ER) alpha and ERbeta] bind E2 and selective ER modulators (SERMs) as homodimers (alpha/alpha or beta/beta) or heterodimers (alpha/beta) to regulate gene expression. Although recent studies have shown that ER homodimers regulate unique sets of E2-responsive genes, little information exists regarding the transcriptional actions of the ERalpha/beta heterodimer. This paper describes the development of a U2OS human osteosarcoma (osteoblast) cell line stably expressing both ERalpha and ERbeta isoforms at a ratio of 1:4, a ratio reported to exist in normal, mature osteoblast cells derived from cancellous bone. The regulation of endogenous genes by E2 and 4-hydroxy-tamoxifen were measured in these cells using gene microarrays and real-time RT-PCR. Both E2 and 4-hydroxy-tamoxifen were shown to regulate unique sets of endogenous genes in the U2OS-ERalpha/beta heterodimer cell line (20% and 27% of total, respectively), compared with all the genes regulated in U2OS-ER homodimer cell lines. Furthermore, two novel E2-regulated genes, retinoblastoma binding protein 1 and 7-dehydrocholesterol reductase, were found to contain estrogen response element-like sequences that directly bind the ERalpha/beta heterodimer. These results suggest that the expression of both ER isoforms, forming functional ERalpha/beta heterodimers, result in unique patterns of gene regulation, many of which are distinct from the genes regulated by the ER homodimers.
Blotting, Western↗
Mechanisms of sex steroid effects on bone.
Sex steroids play a major role in the regulation of bone turnover. Thus, gonadectomy in either sex is associated with an increase in bone remodeling, increased bone resorption, and a relative deficit in bone formation, resulting in accelerated bone loss. Recent physiological studies have established an important role for estrogen in regulating bone turnover not only in females, but also in males. Studies in mice with knock out of the estrogen receptor, aromatase, or androgen receptor have provided important insights into the in vivo mechanisms of sex steroid action on bone. The cellular and molecular mediators of sex steroid effects on the bone-forming osteoblasts and bone-resorbing osteoclasts are also being increasingly better defined. Estrogen inhibits bone remodeling by concurrently suppressing osteoblastogenesis and osteoclastogenesis from marrow precursors. Both estrogen and androgens inhibit bone resorption via effects on the receptor activator of NF-kappaB ligand (RANKL)/RANK/osteoprotegerin system, as well as by reducing the production of a number of pro-resorptive cytokines, along with direct effects on osteoclast activity and lifespan. Sex steroid effects on bone formation are also likely mediated by multiple mechanisms, including a prolongation of osteoblast lifespan via non-genotropic mechanisms, as well as effects on osteoblast differentiation and function. These pleiotropic actions of sex steroids on virtually all aspects of bone metabolism belie the importance of the skeleton not only in providing structural support for the body and in locomotion, but also as a dynamic tissue responsive, among other things, to the reproductive needs of the organism for calcium.
Animals↗
Contributions of bone density and structure to fracture risk assessment in men and women.
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 men > or =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.
Absorptiometry, Photon↗
Pathophysiology of age-related bone loss and osteoporosis.
Explore the source record for details and available documents.
Aged↗
The role of the immune system in the pathophysiology of osteoporosis.
The role of the immune system in the development of senile osteoporosis, which arises primarily through the effects of estrogen deficiency and secondary hyperparathyroidism, is slowly being unraveled. This review focuses on our current understanding of how the components of this complex-interlinked system are regulated and how these fit with previous models of senile and postmenopausal osteoporosis. There is certainly substantial evidence that bone remodeling is a tightly regulated, finely balanced process influenced by subtle changes in proinflammatory and inhibitory cytokines as well as hormones and cellular components that act primarily but not exclusively through the receptor activator of nuclear factor-kappaB (RANK)/RANK ligand/osteoprotegerin system. In addition, an acute or chronic imbalance in the system due to infection or inflammation could contribute to systemic (or local) bone loss and increase the risk of fracture. Although significant progress has been made, there remains much to be done in unraveling this complex interaction between the immune system and bone.
Aging↗
Magic bullets to kill nasty osteoclasts.
Explore the source record for details and available documents.
Animals↗
A randomized placebo-controlled trial of short-term graded transdermal estradiol in healthy gonadotropin-releasing hormone agonist-suppressed pre- and postmenopausal women: effects on serum markers of bone turnover, insulin-like growth factor-I, and osteoclastogenic mediators.
The acute effects of estradiol on procollagen type 1 formation in pre- and postmenopausal women are controversial. Twenty-three premenopausal women and 13 postmenopausal women received two consecutive im injections of 3.75 mg leuprolide acetate 3 wk apart to block endogenous ovarian steroidogenesis. Transdermal estradiol therapy commenced on the night of the second leuprolide injection in all subjects, except five pre- and two postmenopausal women who were randomized to receive placebo patches. Estradiol therapy was applied incrementally, with each dose of 0.05, 0.10, 0.15, and 0.20 mg/d administered for 4 consecutive days, to mimic the estradiol changes typifying the follicular phase of the menstrual cycle. Blood aminoterminal propeptide of type I procollagen (PINP), intact osteocalcin (OC), carboxyterminal telopeptide of type I collagen (CTx), IGF-I, and estradiol were measured before and at the end of each estradiol increment. Potential mediators such as osteoprotegerin and receptor activator of nuclear factor-kappaB ligand (RANKL) were also measured. Despite comparable increases in serum estradiol, PINP increased more in postmenopausal compared with premenopausal women (between-group P = 0.03) and occurred at a time when CTx and OC did not change. CTx and IGF-I changed minimally and inconsistently, whereas OC, RANKL, and osteoprotegerin were stable. Repeated measures linear regression disclosed a significant negative association between increases in estradiol and PINP in premenopausal women (P = 0.0006) only. This suggests that lower dose estradiol should greatly increase PINP. Analogous regressions also showed significant negative relationships between changes in estradiol and RANKL in both pre- (P = 0.04) and postmenopausal (P = 0.002) women. Changes in serum markers of bone formation (PINP or OC) did not correlate with those of IGF-I. We conclude that lower dose estradiol rapidly increases osteoblastic collagen synthesis in women at a time when collagen degradation is stable and that this response differs between pre- and postmenopausal women. The effect of estradiol on bone formation does not appear to be mediated by IGF-I. In contrast, RANKL is likely to mediate the effect of estradiol on osteoclastogenesis.
Administration, Cutaneous↗
Relationship of volumetric BMD and structural parameters at different skeletal sites to sex steroid levels in men.
UNLABELLED: 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 E(2)) 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 E(2) 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 E(2) (-9%, p = 0.038) levels, and these decreases were even greater in the elderly men (age > or = 60 years, -60% and -38% for bio T and bio E(2), 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 E(2) levels were associated consistently with vBMD and variably with bone geometric parameters in the elderly men; middle-aged men showed associations with bio E(2) and bio T at some sites. At all cortical sites, vBMD was associated with bio E(2) at low (<30 pM, R = 0.27-0.41, p < 0.05-0.001) but not high (> or =30 pM, R = -0.003 to 0.12, p = not significant) levels; no such differences were evident at trabecular sites. CONCLUSIONS: In men, bio E(2) is the most consistent predictor of vBMD and some bone geometric variables as assessed by QCT. We also extend our previous findings on a possible "threshold" for skeletal estrogen deficiency by showing that this is most evident for cortical sites.
Adult↗
Evaluation of a prediction model for long-term fracture risk.
UNLABELLED: 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.
Absorptiometry, Photon↗
Population-based study of age and sex differences in bone volumetric density, size, geometry, and structure at different skeletal sites.
UNLABELLED: 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 approximately 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. INTRODUCTION: The changes in bone structure and density with aging that lead to fragility fractures are still unclear. MATERIALS AND METHODS: In an age- and sex-stratified population sample of 373 women and 323 men (age, 20-97 years), we assessed bone geometry and volumetric BMD (vBMD) by QCT at the lumbar spine, femoral neck, distal radius, and distal tibia. RESULTS: In young adulthood, men had 35-42% larger bone areas than women (p < 0.001), consistent with their larger body size. Bone area increased equally over life in both sexes by approximately 15% (p < 0.001) at central sites and by approximately 16% and slightly more in men at peripheral sites. Decreases in trabecular vBMD began before midlife and continued throughout life (p < 0.001), whereas cortical vBMD decreases began in midlife. Average decreases in trabecular vBMD were greater in women (-55%) than in men (-46%, p < 0.001) at central sites, but were similar (-24% and -26%, respectively) at peripheral sites. With aging, cortical area decreased slightly, and the cortex was displaced outwardly by periosteal and endocortical bone remodeling. Cortical vBMD decreased over life more in women ( approximately 25%) than in men (approximately 18%, p < 0.001), consistent with menopausal-induced increases in bone turnover and bone porosity. CONCLUSIONS: Age-related changes in bone are complex. Some are beneficial to bone strength, such as periosteal apposition with outward cortical displacement. Others are deleterious, such as increased subendocortical resorption, increased cortical porosity, and, especially, large decreases in trabecular vBMD that may be the most important cause of increased skeletal fragility in the elderly. Our findings further suggest that the greater age-related decreases in trabecular and cortical vBMD and perhaps also their smaller bone size may explain, in large part, why fragility fractures are more common in elderly women than in elderly men.
Adult↗
A potentially deleterious role of IGFBP-2 on bone density in aging men and women.
UNLABELLED: 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.
Adult↗
Native osteoprotegerin gene transfer inhibits the development of murine osteolytic bone disease induced by tumor xenografts.
OBJECTIVE: Multiple myeloma is a plasma cell malignancy characterized by the development of osteolytic lesions leading to bone pain, pathologic fractures, and hypercalcemia. Osteoprotegerin (OPG) is a potent inhibitor of osteoclast differentiation and activation, but is limited as a therapeutic agent due to its short circulating half-life. In order to overcome these limitations, the therapeutic effects of native OPG gene transfer are examined. MATERIALS AND METHODS: We used replication-incompetent lentiviral vectors to transfer the unmodified, native human OPG gene ex vivo into human ARH-77 cells injected into severe combined immunodeficient (SCID) mice, to determine gene transfer efficiency as well as the impact on disease progression in this in vivo model. RESULTS: We can efficiently transfer and express either the LacZ marker gene or the native human OPG gene into human ARH-77 cells. Moreover, transfer of the OPG gene into ARH-77 cells reduces the development of osteolytic bony lesions when these cells are injected into SCID mice, compared to mice injected with either unmodified ARH-77 cells or ARH-77 cells transduced with the OPG gene in the antisense orientation. This therapeutic effect was manifested as a reduction in vertebral compression deformities and in the number and size of long-bone osteolytic lesions on skeletal radiographs, as well as a decrease in osteoclast surface on histologic analysis. CONCLUSIONS: A lentiviral vector can efficiently transfer the native human OPG gene to myeloma cells ex vivo and inhibit myeloma-induced bone destruction, thereby suggesting a therapeutic potential for unmodified, native OPG gene transfer for osteoclast-dependent skeletal disorders.
Animals↗
Relationship of estrogen receptor genotypes to bone mineral density and to rates of bone loss in men.
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 (P < 0.001 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 P < 0.001 and P < 0.009 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 (P < 0.001 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.
Adult↗
Fracture risk in monoclonal gammopathy of undetermined significance.
UNLABELLED: To assess fractures in monoclonal gammopathy of undetermined significance (MGUS), the precursor of multiple myeloma, we followed 488 Olmsted County, MN, residents with MGUS in a retrospective cohort study. There was a 2.7-fold increase in the risk of axial fractures but no increase in limb fractures. The pathophysiologic basis for the increased axial fractures should be determined. INTRODUCTION: Multiple myeloma is often preceded by monoclonal gammopathy of undetermined significance (MGUS). Fractures are common in myeloma as a result of lytic bone lesions, generalized bone loss, and elevated bone turnover from excessive cytokine production. Whether fractures are also increased in MGUS is unknown. MATERIALS AND METHODS: In a population-based retrospective cohort study, 488 Olmsted County, MN, residents with MGUS first diagnosed in 1960-1994 (52% men; mean age, 71.4 +/- 12.8 years) were followed for 3901 person-years; follow-up was censored at progression to myeloma. The relative risk of fractures was assessed by standardized incidence ratios (SIRs), and risk factors were evaluated in proportional hazards models. RESULTS AND CONCLUSIONS: Altogether, 200 patients experienced 385 fractures. Compared with expected rates in the community, statistically significant increases were seen for fractures at most axial sites, for example, vertebrae (SIR, 6.3; 95% CI, 5.2-7.5). There was a slight increase in hip (SIR, 1.6; 95% CI, 1.2-2.2) but not distal forearm fractures (SIR, 0.8; 95% CI, 0.4-1.5). The relative risk (SIR) of any axial fracture was 2.7 (95% CI, 2.3-3.1) compared with only 1.1 (95% CI, 0.9-1.4) for all limb fractures combined. In a multivariate analysis, the independent predictors of any subsequent fracture were age (hazard ratio [HR] per 10-year increase, 1.4; 95% CI, 1.2-1.6) and corticosteroid use (HR, 1.8; 95% CI, 1.2-2.6); greater weight at diagnosis (HR per 10 kg, 0.8; 95% CI, 0.8-0.9), and IgG monoclonal protein (HR, 0.7; 95% CI, 0.5-0.97) were protective. Baseline monoclonal protein level, a determinant of myeloma progression, did not predict fracture risk. Thus, the risk of axial, but not peripheral, fractures is increased among MGUS patients even before progression to myeloma. The pathophysiologic basis for this should be determined because elevated bone turnover, for example, might be treatable.
Accidental Falls↗
Dose-response of estrogen on bone versus the uterus in ovariectomized mice.
BACKGROUND: Estrogen is known to have important effects on both reproductive and non-reproductive tissues. Moreover, there is increasing interest in developing compounds that may have selective effects on bone versus reproductive tissues. METHODS: Since mouse models are often used in these studies, we administrated increasing doses of estradiol (E2) (0 to 500 microg/kg/day) by slow release pellets to ovariectomized 6-month-old C57BL/6 mice and assessed skeletal and uterine responses following 2 months of treatment. RESULTS: The mice lost bone at multiple sites following ovariectomy (OVX); however, while the lowest E2 dose of 5 microg/kg/day completely prevented loss of cancellous bone (at the lumbar spine and tibial metaphysis), it had no stimulatory effects on the uterus. Higher doses of E2 resulted in further increases in bone mineral density, with eventual stimulation of the uterus at a dose of 40 microg/kg/day. By contrast, when 3-month-old C57BL/6 mice were administered the same doses of E2 and studied after 1 month, the 5 microg/kg/day dose resulted in uterine hypertropy, but was not able to prevent loss of cancellous bone. CONCLUSIONS: Thus these results (i) provide data on the dose-response for the effects of E2 on mouse bone and (ii) indicate that the relative effects of E2 on bone versus the uterus are highly dependent on the particular experimental conditions used. This issue needs to be considered in evaluating agents with potential 'selective' effects on bone versus reproductive tissues.
Animals↗