Biomedical subjects
L V Avioli
Publications and source records attributed to L V Avioli.
Effect of estrogen and calcitonin on vertebral bone density and vertebral height in osteoporotic women.
Estrogen and calcitonin increase bone density of osteoporotic women, particularly on the axial skeleton. To verify whether the effect of these drugs might in part be biased by spurious increases in bone density due to radiologically irrelevant microfractures, and consequent subtle decreases in vertebral height, we followed the changes in vertebral bone density (VBD), assessed by quantitative computed tomography, in relation to vertebral height (VH) in 60 osteoporotic women. VH was measured as the sum of anterior, central and posterior heights of L1-L3 vertebral bodies on lateral radiographs. Patients received either salmon calcitonin (sCT: 50 IU subcutaneously three times per week, n = 18), hormonal replacement therapy (HRT: conjugated estrogen 0.625 mg/day, days 1-25, plus medroxyprogesterone acetate 10 mg/day, days 16-25 of each month; n = 21) or calcium alone (Ca: 1000 mg/day, n = 21). After 1 year, VBD increased in the HRT group (+5.0 +/- 1.9%, p = 0.010), did not change significantly in the sCT group (+3.3 +/- 2.3%, p = 0.167), and decreased by 6.1 +/- 1.0% (p less than 0.001) in the Ca group. By analysis of variance, the changes induced by HRT and sCT were significantly different from those observed in the Ca group (F = 7.982, p less than 0.001). VH decreased slightly in all three subsets of patients (-0.9 +/- 0.5% in sCT, -1.5 +/- 0.3% in HRT, -0.1 +/- 0.5% in Ca), but these changes were not significantly different between groups (F = 2.545, p = 0.081).(ABSTRACT TRUNCATED AT 250 WORDS)
Calcitonin therapy in osteoporotic syndromes.
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Estrogen status and heredity are major determinants of premenopausal bone mass.
To analyze their relative effects on premenopausal bone mass, we have studied the impact of lifelong estrogen exposure, assessed by an estrogen score (ES; computed on age at menarche, average length of menstrual cycles since menarche, and use of birth control pills), heredity, and some environmental factors on vertebral bone density (VBD), of 63 premenopausal women (age, 19-40 yr). Compared with women with normal bone density (Z score > -1), subjects with low VBD (Z score < -1) had significantly lower ES (15.1 +/- 3.9 vs. 18.7 +/- 2.4, P = 0.001), higher age at menarche (13.8 +/- 1.7 vs. 12.6 +/- 1.4 yr, P = 0.005), and lower serum estradiol (46.9 +/- 37 vs. 86.6 +/- 57 pg/ml, P = 0.023) and estrone levels (107.4 +/- 60 vs. 178.8 +/- 9.0 pg/ml, P = 0.05). Likewise, women in the lowest quartile for VBD had significantly lower ES (15.3 +/- 4.5 vs. 18.1 +/- 2.7, P = 0.006) and higher age at menarche (13.9 +/- 1.9 vs. 12.8 +/- .4, P = 0.02) than those in the upper three quartiles. A higher proportion of subjects with irregular menses (52 vs. 23%, P = 0.03) and a positive family history of osteoporosis (86 vs. 61%, P = 0.04) was found in the low VBD group compared with subjects with normal VBD. VBD correlated positively with ES (r = 0.44, P = < 0.001) and negatively with age at menarche (r = -0.30, P = 0.03) by simple linear regression, whereas no correlation was found between VBD and age, body mass index, parity, lactation, physical activity, sunlight exposure, and dietary calcium and vitamin D intakes. The correlation between VBD and ES improved after correcting for the effect of all the other variables by partial correlation analysis (Pearson partial r = 0.57, P = < 0.01), which also disclosed a significant contribution of dietary calcium to VBD. However, ES was the only significant independent determinant of VBD, by stepwise multiple regression analysis (R2 = 0.24). Therefore, premenopausal estrogen exposure, and possibly genetic predisposition, rather than environmental factors, are the major determinants for the development of peak bone mass before menopause.
Structure-function relationship of parathyroid hormone: activation of phospholipase-C, protein kinase-A and -C in osteosarcoma cells.
Recent evidence indicates that after PTh interaction with its receptor, both protein kinase-A (PKA) and protein kinase-C (PKC) are activated. To investigate the relationship between PTH structure and protein kinase stimulation, we have analyzed the effects of synthetic PTH fragments on PKA and PKC in the rat osteogenic sarcoma cells, UMR 106-01. Activation of PKA by 10(-7) M bovine (b) PTH-(1-34) was maximal (2.7-fold of control) at 5 min and remained elevated 15 min after hormone exposure. bPTH-(2-34), at equimolar doses, also stimulated PKA, but with a lower potency (1.4-fold of control), whereas propionyl bPTH-(2-34) [pbPTH-(2-34)], bPTH-(3-34), [Tyr34]bPTH-(7-34) amide [bPTH-(7-34)], and bPTH-(30-34) were ineffective. On the other hand, translocation of PKC activity from the cytosol to the membrane after exposure to bPTH-(1-34) was transient, with a peak at 1 min (1.9-fold of control), and returned to basal levels after 5 min. Other fragments, bPTH-(2-34), pbPTH-(2-34), bPTH-(3-34), and bPTH-(7-34), were also active on PKC, with relative potencies of 81%, 67%, 62%, and 51% of bPTH-(1-34), respectively, whereas bPTH-(30-34) was inactive. bPTH-(1-34), bPTH-(2-34), pbPTH-(2-34), and bPTH-(3-34) also induced inositol 1,4,5-trisphosphate production, with a potency order of 1.6-, 1.6-, 1.5-, and 1.6-fold over the control value, respectively, thus indicating activation of phospholipase-C. Neither bPTH-(7-34) nor bPTH-(30-34) caused a statistically significant increase in inositol 1,4,5-trisphosphate production. These results demonstrate that PTH signal transduction through the two different pathways can be dissociated; while activation of the cAMP/PKA system requires amino acids 1 and 2, the phospholipase-C/PKC system is coupled to a longer domain of the hormone's N-terminus.
Heterogeneous intracellular free calcium responses to parathyroid hormone correlate with morphology and receptor distribution in osteogenic sarcoma cells.
The osteogenic sarcoma cell line UMR 106-01 exhibits heterogeneous morphology and hormone response in subconfluent monolayer cultures. In these studies we have explored the correlation between morphological profiles and patterns of cytosolic calcium [Ca2+]i response to PTH and other agonists in single UMR 106-01 cells loaded with the Ca(2+)-sensitive fluorescent indicator, fura-2. Realtime recording of [Ca2+]i revealed that PTH (10(-7) M) produced a transient [Ca2+]i rise in 19% of the cells studied. [Ca2+]i transients were also induced by prostaglandins E2 and F2 alpha, and fetal bovine serum, but with different response frequencies (20%, 12%, and 58%, respectively). Spatial resolution of changes in [Ca2+]i by video image analysis revealed that the response to PTH was more frequent in large polygonal cells with long cytoplasmic processes and less common in smaller cells growing in clusters, whereas there was no clear subtype specificity for the effects of epidermal growth factor and fetal bovine serum on [Ca2+]i. Autoradiographic analysis of cell monolayers demonstrated a higher density of PTH-binding sites on cells with cytoplasmic extensions, whereas epidermal growth factor-binding sites were largely on colony-forming cells. Thus, the [Ca2+]i response to hormonal stimulation is heterogeneous within UMR 106-01 cell populations and within single cells, and it correlates with receptor density. This suggests that osteoblastic cells respond to PTH by activation of changes in [Ca2+]i only at certain specific steps during osteoblast development or stages of the cell cycle.
Evaluating health care services from the perspective of the elderly.
The increasingly important over-50 age group continues to grow, presenting a unique segment for health care marketers. The present study examines the elderly's expectations and perceptions of service quality, exploring the relationship between service quality and age. In addition, the study investigates the relationship between the image of an out-patient clinic and the perceived level of service quality. The findings suggest that the elderly expect more information and more personalized attention from the multiple health care providers associated with each service encounter. Implications for exceeding the elderly's expectation of service quality and future research directions are also presented.
Parathyroid hormone positively regulates its own cAMP response in cultured human osteoblasts.
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Significance of osteoporosis: a growing national health care problem.
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Osteoporosis syndromes: patient selection for calcitonin therapy.
Synthetic calcitonin-salmon is a treatment option for older patients with postmenopausal osteoporotic syndromes. Some clinical trials reveal a simple suppression of annual bone-loss rates with calcitonin therapy, whereas others show significant dose-related increases in vertebral and long-bone mass. Response is greater in patients with high-turnover (type I) osteoporosis than in those with the low/normal (type II) form. Candidates for calcitonin-salmon therapy include older women with established vertebral fractures, those who are osteopenic by bone mass analysis, and those in need of preventive therapy because of an accumulation of risk factors.
Bone maturation and resorption by peritoneal macrophages in noninsulin-dependent streptozocin-induced diabetes in the rat.
The existence of osteopenia in noninsulin-dependent diabetes mellitus (NIDDM) is controversial. In this regard rats with a diabetic condition that simulates NIDDM have normal bone mineral content. However, normal total mineral content in bones does not preclude abnormalities in more delicate functions in bones of rats with NIDDM (specifically, bone maturation and response of bone matrix to resorptive activity). To evaluate these functions, bone maturation was studied in tibias from 14-week old male and female rats with streptozocin-induced NIDDM and controls. The ability of macrophages to resorb bone was studied in bone particles that were obtained from femors of male rats with NIDDM and controls. The diabetic rats had the overt NIDDM condition for 8 weeks at the time of the study. We found that bone maturation/mineralization remained intact in the diabetic rats and that response of the bone particles that were obtained from their femors to the resorptive activity of macrophages was similar to that of the bone particles that were obtained from controls. These data suggest that in the rat, a diabetic condition that simulates NIDDM does not alter the physiologic functions of the bone matrix.
Effect of surgical menopause and estrogen replacement on cytokine release from human blood mononuclear cells.
To determine whether mononuclear cell secretory products contribute to the changes in bone turnover that characterize the development of postmenopausal osteoporosis, we evaluated the effects of oophorectomy and subsequent estrogen replacement on the spontaneous secretion of interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-alpha) and on the phytohemagglutinin A-induced secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) from peripheral blood mononuclear cells. In 15 healthy premenopausal women who underwent oophorectomy, increases in GM-CSF activity were observed as early as 1 week after surgery, whereas elevations in IL-1 and TNF-alpha and in hydroxyproline/creatinine and calcium/creatinine ratios, two urinary indices of bone resorption, were detectable 2 weeks after the surgical procedure. Six of the oophorectomized women received no estrogen therapy after surgery and in these subjects hydroxyproline/creatinine and calcium/creatinine ratios plateaued 6 weeks postoperatively, and all three cytokines reached the highest levels 8 weeks after oophorectomy, when the study ended. In the remaining 9 women, who were started on estrogen replacement therapy 4 weeks after oophorectomy, decreases in the indices of bone resorption paralleled decreases in the secretion of the cytokines, with lower levels detected after 2 weeks of therapy. In the women who did not receive estrogen therapy, circulating osteocalcin, a marker of bone formation, increased beyond preoperative levels 8 weeks after oophorectomy, whereas in the estrogen-treated subjects osteocalcin remained unchanged in the entire study period. In 9 female controls who underwent simple hysterectomy, cytokine release and biochemical indices of bone turnover did not change after surgery. These data indicate that changes in estrogen status in vivo are associated with the secretion of mononuclear cell immune factors in vitro and suggest that alterations in the local production of bone-acting cytokines may underlie changes in bone turnover caused by surgically induced menopause and estrogen replacement.
Hyperparathyroidism, estrogens, and osteoporosis.
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Significance of osteoporosis: a growing international health care problem.
The international incidences of osteoporosis and the hip fracture syndrome are increasing at alarming rates. The estimated increases in rates of fracture over the next decade may also prove to be conservative, because of progressive increases in numbers of elderly people who will fall because of muscular degeneration, failing vision, postural hypotension, and loss of cognitive function resulting from the ever-increasing abuse of mixtures of drugs. Changing patterns of hip fracture care, including extended use of hospital beds and of rehabilitation and nursing-home beds could lead to substantial and escalating annual costs in national health care budgets. Such a budget currently approximates 10 billion dollars in the United States alone.
Heterogeneity of osteoporotic syndromes and the response to calcitonin therapy.
In the past, the osteoporotic syndrome has been variably classified as "senile," "postmenopausal," "involutional," "Type I," and "Type II," primarily on the basis of age, fracture incidence patterns, and/or fracture sites. Histological analyses of bone biopsy specimens from osteoporotic individuals also reveal a wide spectrum of cellular activity and rates of bone formation and resorption. These range from those that show an abundance of osteoblasts and osteoclasts with increments in both bone formation and bone turnover (i.e., "active" or "high-turnover" osteoporosis) to others demonstrating minimal cellular activity and relatively little active bone formation or resorption ("inactive" or "low-turnover" osteoporosis). The varied states of bone activity are reflected in associated changes in noninvasive biochemical markers of bone turnover such as circulating bone-gla-protein (BGP) or the urinary hydroxyproline/creatinine ratio (OH-Pr/Cr). Both BGP and OH-Pr/Cr are elevated in patients with high-turnover osteoporotic syndromes. The significance of this mode of categorizing osteoporotic patients is exemplified by the response to remedial therapy such as salmon calcitonin. Recent studies demonstrate a striking sensitivity of patients with high-turnover osteoporosis to calcitonin, with as much as 22% increments in vertebral bone mass recorded during a 12-month therapeutic interval. These promising results should also be compared with other forms of therapy in which an increase in vertebral bone mass of only 7-8% was sufficient to cause a significant decrease in the incidence of vertebral fracture rates.
Is there an effective treatment for glucocorticoid-induced osteoporosis?
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Regulation of skeletal remodeling by parathyroid hormone.
PTH is responsible for the maintenance of calcium homeostasis and normocalcemia. Secretion of PTH is stimulated or suppressed by perturbations in the serum calcium level. The calciotropic effects of PTH are mediated primarily by bone, where PTH-stimulated remodeling may release calcium to the extracellular fluid, and by the kidneys, where calcium reabsorption and phosphate excretion are increased. The effects of PTH in bone are bipolar: including regulation of multiple cell types, especially, both osteoblasts and osteoclasts, and stimulating both bone formation (anabolic effects) and bone resorption (catabolic) effects. The purpose of this review is to discuss the available data regarding PTH-regulated bone remodeling, the role of second messengers produced by polyphosphoinositide hydrolysis, the possible role of G proteins in regulating this reaction, and the biologic effects of activating this system. Greater insight into the complexities of parathyroid hormone-regulated bone remodeling are still required.