Age-specific effects of estrogen receptors' polymorphisms on the bone traits in healthy fertile women: the BONTURNO study

<p>Abstract</p> <p>Background</p> <p>Skeletal characteristics such as height (Ht), bone mineral density (BMD) or bone turnover markers are strongly inherited. Common variants in the genes encoding for estrogen receptor alpha (ESR1) and beta (ESR2) are proposed as candidates for influencing bone phenotypes at the population level.</p> <p>Methods</p> <p>We studied 641 healthy premenopausal women aged 20–50 years (yrs) participating into the BONTURNO study. Exclusion criteria were irregular cyclic menses, low trauma fracture, metabolic bone or chronic diseases. Serum C-telopeptide of type I collagen (CTX), osteocalcin (OC), and N-terminal propeptide of type I procollagen (P1NP) were measured in all enrolled subjects, who underwent to lumbar spine (LS), total hip (TH) and femoral neck (FN) BMD evaluation by DXA. Five hundred seventy Caucasian women were genotyped for ESR1 rs2234693 and rs9340799 and ESR2 rs4986938 polymorphisms.</p> <p>Results</p> <p>Although no genotype differences were found in body parameters, subjects with combined ESR1 CCGG plus ESR2 AA-AG genotype were taller than those with opposite genotype (P = 0.044). Moreover, ESR1 rs2234693 genotypes correlated with family history of osteoporosis (FHO) and hip fracture (FHF) (P < 0.01), while ESR2 AA-AC genotypes were strongly associated with FHF (OR 2.387, 95% CI 1.432–3.977; P < 0.001).</p> <p>When clustered by age, 20–30 yrs old subjects, having at least one ESR1 rs2234693 C allele presented lower LS- (P = 0.008) and TH-BMD (P = 0.047) than TT genotypes. In 41–50 yrs age, lower FN-BMD was associated with ESR2 AA (P = 0.0180) subjects than in those with the opposite genotype. ESR1 rs2234693 and rs9340799 and ESR2 rs4986938 polymorphisms did not correlate with age-adjusted values of OC, CTX and P1NP.</p> <p>Conclusion</p> <p>These findings support the presence of age-specific effects of ESR1 and ESR2 polymorphisms on various skeletal traits in healthy fertile women.</p

Statins, fracture risk, and bone remodeling

Statins inhibit HMG-CoA reductase and reduce the intracellular formation of mevalonate. They are chemical compounds able to reduce total cholesterol by 15-40% and LDL cholesterol by 20-60%, and to increase HDL cholesterol by 5-15%. They also reduce triglycerides by 10- 30%. Statins, blocking the mevalonate pathway, inhibit the prenylation of proteins, which is essential to perform their biological function. A great deal of research has documented the positive effect of statins on bone formation and the importance of bone morphogenetic protein-2 (BMP-2) in mediating this effect. Statins are also able to decrease osteoblast apoptosis. The positive effect of statins on bone formation is accompanied by an inhibition of osteoclast activity, which gives statins the ability to uncouple the bone remodeling processes. Patients taking statins have a higher femoral bone density than those who do not. The lipophilic statins seem to be more effective than the hydrophilic statins in protecting bone. In several clinical trials, but not in all, the use of statins had been associated with a reduction in the fracture risk. In conclusion, statins have a positive effect on bone in vitro, but such an efficacy in humans has yet to be clearly demonstrated. Randomized, controlled trials are needed to provide a satisfactory answer on this issue

Relationship between Bone Specific Alkaline Phosphatase, Osteocalcin and Age in Osteoporotic Women

Background: Osteoporosis is a serious disabiliting disease and a leading cause of fractures, especially in postmenopausal women. Several serum markers of bone metabolism have been investigated, but their pattern over age and gender in the general population is unclear. The objective of this study was to examine the relationship between bone formation markers osteocalcin (OC), bone specific alkaline phosphatase (bALP) and age in postmenopausal women with osteoporosis. Patients and Methods: The study population was obtained from a cohort of 236 postmenopausal women who underwent osteodensitometry using dual energy X-ray absorptiometry with measurement of bone mineral density (BMD). Forty-eight (20.3%) patients (median age 62, range 49-76 years) with osteoporosis (Tscore < -2.5 SD) were enrolled in the study. There were 17 (35%) patients aged 49-59 years (Group A), and 31 (65%) patients aged over 59 years (Group B). Results: PTH (76.0\ub113.1 vs. 81.9\ub113.9 ng/L), calcium (2.23\ub10.41 vs. 2.32\ub10.56 mmol/L), and creatinine (68.1\ub115.2 vs. 71.0\ub126.1 \u3bcmol/L) serum levels did not differ significantly (p=NS) between Groups (A vs. B). In Group B patients, both OC (28.5\ub117.8 vs. 46.2\ub119.3 ng/mL; p=0.003), and bALP (57.3\ub112.4 vs. 66.4\ub18.7 U/ L; p=0.005) were higher, while the serum concentration of estradiol (78.1\ub118.6 vs. 66.7\ub117.8 pmol/L; p=0.001) was lower. Moreover, a significant relationship between age and both OC (r=0.39, p=0.008) and bALP (r=0.31, p=0.009) was found only in Group B patients, but there was no relationship (p=NS) with BMD. Conclusion: In postmenopausal women the increase of bone formation markers later in life may be an expression of increased bone turnover, which is partially the cause of osteoporosis, while the role of estrogen is still unclear

Bone organic matrix components: their roles in skeletal physiology

Bone matrix is composed mainly of inorganic materials, while the bone organic compartment is a minor and complex structural entity, surrounding and supporting cells. Three major classes of biomolecules are involved in this organic part: structural proteins, specialized proteins, and proteoglycans. This review will briefly summarize our knowledge about the role and regulation of these specific bone components

Primary hyperparathyroidism in the nineties. How has it changed ?

Primary hyperparathyroidism is the most common cause of hypercalcemia and 80-85% of the patients have parathyroid tumors. The purpose of this retrospective review was to analyse whether differences exist between patients with parathyroid tumors treated in the 1980s and 1990s. Between 1980-1997, 253 patients underwent initial surgical neck exploration for hyperfunctioning parathyroid tumors. Renal (polyuria, nocturia, renal colic due to lithiasis), rheumatologic (bone and joint pain), neurological (fatigue, memory loss, depression) and gastrointestinal (dyspepsia, anorexia, nausea) symptoms were recorded and main biochemical parameters were measured. In all patients one or more preoperative localization procedures were carried out prior to successful parathyroidectomy, and the confirmation of imaging findings was obtained after surgery. The patients were divided in two groups. Group A: 121 patients undergoing surgery from 1980-1989; Group B: 132 patients in whom parathyroidectomy was performed from 1990-1997. There were no differences (p=NS) between the two groups in average age, preoperative serum creatinine and intact-PTH levels. Symptoms were most common in Group A, and pre-operative serum calcium levels were significantly lower in Group B. Ultrasonography (n=191) sensitivity did not improve significantly (82.8% vs 82.9%), but positive predictive value (PPV) was higher (89.8% vs 96.0%). CT-scan (n=73) sensitivity was 79.2% and 82.6%, and PPV was 95.0% and 100% in Groups A and B, respectively. 201Tl/99mTc subtraction scintigraphy (n=111, Group A) was 84.6% sensitive (PPV=92.6%) whereas 99mTc-sestamibi scanning (n=90, Group B) was 85.1% sensitive (PPV=96.1%). In conclusion, the clinical features of parathyroid tumors has changed in the nineties and increasing asymptomatic pHPT rate has been found. Although sensitivity and PPV of preoperative localization procedures has improved moderately, at present noninvasive techniques may offer excellent results and should be used in all patients with suspected parathyroid tumors

Femoral and lumbar spine BMD changes in patients with primary hyperparathyroidism. Different improvement following successful parathyroidectomy in male and female patients

Introduction. The aim of this study was to analyze the femoral neck and lumbar spine BMD changes in patients with PHPT following successful PTx, and to correlate the results with the age and sex of the patients. Patients and Methods. Thirty-nine patients (median age 57 years, range 23-76) with confirmed PHPT underwent both femoral neck and lumbar (L2-L4 region) spine osteodensitometry using a dual-energy X-ray absorptiometry. Patients were divided into three groups: Group A (12 premenopausal women, mean age 44.1 +/- 9.0 years), Group B (16 postmenopausal women, mean age 64.2 +/- 6.9 years; p=0.00), and Group C (11 men, mean age 54.1 +/- 14.8 years; p=NS in respect of women\u2019s age). None of the Group B patients had received estrogen replacement therapy at any time, and no Group A patient had used oral contraceptives. Preoperative s-alkaline phosphatase (ALP), s-bone-ALP, s-osteocalcin, and s-PTH 1-88 levels did not differ significantly (p=NS) among the three groups. In Group A patients s-creatinine levels were lower (p=0.016), whereas s-calcium levels (A=2.94 +/- 0.24, B=2.80 +/- 0.17, C=2.92 +/- 0.25 mmol/L; p=0.012), L2-L4 BMD values (A=0.8588 +/- 0.0781, B=0.7301 +/- 0.1363, C=0.8002 +/- 0.1465 g/cm2; p=0.007), and trochanteric BMD values (A=0.5871 +/- 0.0964, B=0.5213 +/- 0.2117, C=0.6865 +/- 0.9703 g/cm2; p=0.023) were higher. Results. At short-term (mean 13 months, range 9-15 months) follow-up following successful PTx all biochemical parameters were normal with significant (p<0.05) differences in respect of the preoperative values. Overall postoperative BMD values improved between 4.77% and 11.48% (median 6.37%). Significant differences were found only in Group A (L2-L4=0.8588 +/- 0.0781 vs 0.9575 +/- 0.1063, p=0.016; femoral neck=0.6056 +/- 0.1217 vs 0.722 +/- 0.1382, p=0.039; total hip: 0.7415 +/- 0.1424 vs 0.8890 +/- 0.1267, p=0-013) and in Group C patients (0.8002 +/- 0.1465 vs 0.9411 +/- 0.137, p=0.023). Conclusions: In patients with PHPT, at long-term follow-up, BMD of the lumbar spine significantly improves after PTx in premenopausal women, suggesting a higher bone sensitivity to serum PTH normalization