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Determinants of trabecular bone score (TBS) and vertebral fractures assessed semiquantitatively (SQ1-SQ3) were studied in 496 women with fragility fractures. TBS was associated with age, parental hip fracture, alcohol intake and BMD, not SQ1-SQ3 fractures. SQ1-SQ3 fractures were associated with age, prior fractures, and lumbar spine BMD, but not TBS., Introduction: Trabecular bone score (TBS) and vertebral fractures assessed by semiquantitative method (SQ1-SQ3) seem to reflect different aspects of bone strength. We therefore sought to explore the determinants of and the associations between TBS and SQ1-SQ3 fractures., Methods: This cross-sectional sub-study of the Norwegian Capture the Fracture Initiative included 496 women aged ≥ 50 years with fragility fractures. All responded to a questionnaire about risk factors for fracture, had bone mineral density (BMD) of femoral neck and/or lumbar spine assessed, TBS calculated, and 423 had SQ1-SQ3 fracture assessed., Results: Mean (SD) age was 65.6 years (8.6), mean TBS 1.27 (0.10), and 33.3% exhibited SQ1-SQ3 fractures. In multiple variable analysis, higher age (β per SD = - 0.26, 95% CI: - 0.36,- 0.15), parental hip fracture (β = - 0.29, 95% CI: - 0.54,- 0.05), and daily alcohol intake (β = - 0.43, 95% CI - 0.79, - 0.08) were associated with lower TBS. Higher BMD of femoral neck (β per SD = 0.34, 95% CI 0.25-0.43) and lumbar spine (β per SD = 0.40, 95% CI 0.31-0.48) were associated with higher TBS. In multivariable logistic regression analyses, age (OR per SD = 1.94, 95% CI 1.51-2.46) and prior fragility fractures (OR = 1.71, 95% CI 1.09-2.71) were positively associated with SQ1-SQ3 fractures, while lumbar spine BMD (OR per SD = 0.75 95% CI 0.60-0.95) was negatively associated with SQ1-SQ3 fractures. No association between TBS and SQ1-SQ3 fractures was found., Conclusion: Since TBS and SQ1-SQ3 fractures were not associated, they may act as independent risk factors, justifying the use of both in post-fracture risk assessment.

Serum parathyroid hormone (PTH) was associated with increased bone turnover markers and cortical porosity of the inner transitional zone at the proximal femur. These results suggest that PTH through increased intracortical bone turnover leads to trabecularisation of inner cortical bone in postmenopausal women., Introduction: Vitamin D deficiency leads to secondary hyperparathyroidism and increased risk for fractures, whereas its association with cortical porosity is less clear. We tested (i) whether serum 25-hydroxyvitamin D (25(OH)D) and PTH were associated with cortical porosity and (ii) whether the associations of 25(OH)D) and PTH with fracture risk are dependent on cortical porosity., Methods: This case-control study included 211 postmenopausal women, 54-94 years old, with prevalent fractures and 232 controls from the Tromsø Study. Serum 25(OH)D, PTH, and bone turnover markers (procollagen type I N-terminal propeptide [PINP] and C-terminal cross-linking telopeptide of type I collagen [CTX]) were measured. Femoral subtrochanteric cortical and trabecular parameters were quantified using computed tomography, and femoral neck areal bone mineral density (FN aBMD) was quantified using dual-energy X-ray absorptiometry., Results: Compared with controls, fracture cases exhibited reduced serum 25(OH)D and increased PTH, PINP, and CTX, increased femoral subtrochanteric cortical porosity, and reduced cortical thickness and FN aBMD (all, p < 0.05). Serum 25(OH)D was not associated with cortical parameters (all, p > 0.10). PTH was associated with increased PINP, CTX, and cortical porosity of the inner transitional zone and reduced trabecular bone volume/tissue volume and FN aBMD (p ranging from 0.003 to 0.054). Decreasing 25(OH)D and increasing PTH were associated with increased odds for fractures, independent of age, height, weight, calcium supplementation, serum calcium, cortical porosity, and thickness., Conclusions: These data suggest that serum PTH, not 25(OH)D, is associated with increased intracortical bone turnover resulting in trabecularisation of the inner cortical bone; nevertheless, decreasing 25(OH)D) and increasing PTH are associated with fracture risk, independent of cortical porosity and thickness.

Adherence to oral bisphosphonates is low. A screening strategy is proposed based on the response of biochemical markers of bone turnover after 3 months of therapy. If no change is observed, the clinician should reassess the adherence to the treatment and also other potential issues with the drug., Introduction: Low adherence to oral bisphosphonates is a common problem that jeopardizes the efficacy of treatment of osteoporosis. No clear screening strategy for the assessment of compliance is widely accepted in these patients., Methods: The International Osteoporosis Foundation and the European Calcified Tissue Society have convened a working group to propose a screening strategy to detect a lack of adherence to these drugs. The question to answer was whether the bone turnover markers (BTMs) PINP and CTX can be used to identify low adherence in patients with postmenopausal osteoporosis initiating oral bisphosphonates for osteoporosis. The findings of the TRIO study specifically address this question and were used as the basis for testing the hypothesis., Results: Based on the findings of the TRIO study, specifically addressing this question, the working group recommends measuring PINP and CTX at baseline and 3 months after starting therapy to check for a decrease above the least significant change (decrease of more than 38% for PINP and 56% for CTX). Detection rate for the measurement of PINP is 84%, for CTX 87% and, if variation in at least one is considered when measuring both, the level of detection is 94.5%., Conclusions: If a significant decrease is observed, the treatment can continue, but if no decrease occurs, the clinician should reassess to identify problems with the treatment, mainly low adherence., Competing Interests: A Diez-Perez is speaker or advisor for Amgen, Lilly, Merck, UCB and Active Life Sci. Bo Abrahamsen reports current institutional research grants and contracts with Novartis and UCB, past institutional research contracts with Amgen and NPS Pharmaceuticals. D. Agnusdei has a consultancy contract with Eli Lilly. Erik F Eriksen is a speaker and advisor for Amgen, Lilly, Merck, IDS and Shire. Núria Guañabens is speaker or advisor for Amgen, Lilly and Alexion Pharmaceuticals. Robert Josse is medical advisory board member and speaker honoraria and research grant: Merck,Amgen,Lilly. Daniel Prieto-Alhambra’s research group has received unrestricted grants from AMGEN S.A. Jean-Yves Reginster has consulting fees or paid advisory boards in Servier, Novartis, Negma, Lilly, Wyeth, Amgen, GlaxoSmithKline, Roche, Merckle, Nycomed-Takeda, NPS, IBSA-Genevrier, Theramex, UCB, Asahi Kasei, Endocyte, Radius Health also has lecture fees when speaking at the invitation of the commercial sponsors: Merck Sharp and Dohme, Lilly, Rottapharm, IBSA, Genevrier, Novartis, Servier, Roche, GlaxoSmithKline, Merckle, Teijin, Teva, Analis, Theramex, Nycomed, NovoNordisk, Ebewee Pharma, Zodiac, Danone, Will Pharma, Amgen, PharmEvo. He has grant support from industry: Bristol Myers Squibb, Merck Sharp & Dohme, Rottapharm, Teva, Roche, Amgen, Lilly, Novartis, GlaxoSmithKline, Servier, Pfizer, Theramex, Danone, Organon, Therabel, Boehringer, Chiltern, Galapagos. M. Carola Zillikens has received fee for speaking and advice from Amgen, Eli Lilly and MSD. R. Eastell has consulting fees from Amgen, AstraZeneca, Chronos, GSK, Immunodiagnostic Systems, Fonterra Brands, Ono Pharma, Lilly, Bayer, Janssen Research, Alere, CL Biosystems, Teijin Pharm, D-Star, Roche Diagnostics, Inverness Medical; grant support from Amgen, Alexion, Immunodiagnostic Systems, Roche, AstraZeneca. Kim E Naylor, Maria Luisa Brandi, Cyrus Cooper, Elaine Dennison, Deborah Gold, Peyman Hadji, Mickael Hiligsmann, Robert Horne, John A Kanis, Barbara Obermayer-Pietsch, René Rizzoli, and Stuart Silverman have no conflict of interest.

Unlabelled: We tested whether cortical porosity of the proximal femur measured using StrAx1.0 software provides additional information to areal bone mineral density (aBMD) or Fracture Risk Assessment Tool (FRAX) in differentiating women with and without fracture. Porosity was associated with fracture independent of aBMD and FRAX and identified additional women with fractures than by osteoporosis or FRAX thresholds., Introduction: Neither aBMD nor the FRAX captures cortical porosity, a major determinant of bone strength. We therefore tested whether combining porosity with aBMD or FRAX improves identification of women with fractures., Methods: We quantified femoral neck (FN) aBMD using dual-energy X-ray absorptiometry, FRAX score, and femoral subtrochanteric cortical porosity using StrAx1.0 software in 211 postmenopausal women aged 54-94 years with nonvertebral fractures and 232 controls in Tromsø, Norway. Odds ratios (ORs) were calculated using logistic regression analysis., Results: Women with fractures had lower FN aBMD, higher FRAX score, and higher cortical porosity than controls (all p < 0.001). Each standard deviation higher porosity was associated with fracture independent of FN aBMD (OR 1.39; 95% confidence interval 1.11-1.74) and FRAX score (OR 1.58; 1.27-1.97) in all women combined. Porosity was also associated with fracture independent of FRAX score in subgroups with normal FN aBMD (OR 1.88; 1.21-2.94), osteopenia (OR 1.40; 1.06-1.85), but not significantly in those with osteoporosis (OR 1.48; 0.68-3.23). Of the 211 fracture cases, only 18 women (9%) were identified using FN aBMD T-score < -2.5, 45 women (21%) using FRAX threshold >20%, whereas porosity >80th percentile identified 61 women (29%). Porosity identified 26% additional women with fractures than identified by the osteoporosis threshold and 21% additional women with fractures than by this FRAX threshold., Conclusions: Cortical porosity is a risk factor for fracture independent of aBMD and FRAX and improves identification of women with fracture.

Background: Transient postoperative hypocalcemia is one of the most common complications after thyroidectomy. Permanent hypocalcemia, however, is rare, but usually requires life-long treatment and follow-up. The risk of permanent hypocalcemia has been shown to be significantly higher in patients with Graves' disease. In the present study we evaluated short-term and long-term changes in serum calcium, phosphate, magnesium, and parathyroid hormone (PTH) levels in order to characterize subjects at risk of postoperative hypoparathyroidism., Methods: Forty patients who underwent total thyroidectomy for Graves' disease were included in the study. Calcium, phosphate, magnesium, and PTH were measured before surgery and regularly during the year that followed., Results: Postoperative hypocalcemia was seen in 21/40 (53 %) patients. Undetectable PTH (<0.6 pmol/L) was registered in 11/40 (27 %) patients. All patients with measurable PTH 6-48 h after operation regained normal calcium. Of those with undetectable PTH after 6-48 h, four developed permanent hypocalcemia. We found a significantly lower serum calcium level before operation in patients who developed permanent hypocalcemia compared to those who did not (p < 0.001). We also found a significant correlation between the decrease in serum magnesium from time 0 to 48 h after operation and permanent hypocalcemia (p = 0.015)., Conclusions: Serum calcium prior to operation, serum PTH, and degree of decrease in magnesium levels in serum 48 h after operation may predict development of permanent hypocalcemia. Magnesium plays an important role in calcium homeostasis via stimulation of PTH secretion and modulation of PTH receptor sensitivity. Both mechanisms may have played a role for the findings reported in this article.

Unlabelled: Once-yearly administration of intravenous zoledronic acid for 3 years in humans affects the kinetics of matrix filling in by mineral, independent of bone turnover., Introduction: Yearly 5-mg infusions of zoledronic acid (ZOL) for 3 years have shown pronounced antifracture efficacy. The purpose of the present study was to test whether ZOL affects the kinetics of forming bone material properties maturation., Methods: Iliac crest biopsies from the HORIZON-PFT clinical trial were analyzed by Raman microspectroscopy in actively bone-forming surfaces as a function of tissue age in trabecular and osteonal bone, to determine ZOL's effect on bone material quality indices maturation kinetics., Results: Mineral/matrix ratio increased in both groups as a function of tissue age, at both osteonal- and trabecular-forming surfaces; ZOL exhibiting the greatest increase in the trabecular surfaces only. The proteoglycan content showed a dependency on tissue age in both trabecular and osteonal surfaces, with ZOL exhibiting lower values in the tissue age 8-22 days in the trabecular surfaces. Mineral crystallinity (crystallite length and thickness) showed a dependence on tissue age, with ZOL exhibiting lower crystallite length compared with placebo only in the 8- to 22-day-old tissue at trabecular surfaces, while crystal thickness was lower in the 1- to 5-day-old tissue at both osteonal and trabecular surfaces., Conclusions: The results of the present study suggest that once-yearly administration of intravenous ZOL for 3 years in humans does not exert any adverse effects on the evolution of bone material properties at actively forming osteonal and trabecular surfaces, while it may have a beneficial effect on the progression of the mineral-to-matrix ratio and mineral maturity bone quality indices.

Unlabelled: Guidelines concerning the definition of failure of therapies used to reduce the risk of fracture are provided., Introduction: This study aims to provide guidelines concerning the definition of failure of therapies used to reduce the risk of fracture., Methods: A working group of the Committee of Scientific Advisors of the International Osteoporosis Foundation was convened to define outcome variables that may assist clinicians in decision making., Results: In the face of limited evidence, failure of treatment may be inferred when two or more incident fractures have occurred during treatment, when serial measurements of bone remodelling markers are not suppressed by anti-resorptive therapy and where bone mineral density continues to decrease., Conclusion: The provision of pragmatic criteria to define failure to respond to treatment provides an unmet clinical need and may stimulate research into an important issue.

The ever increasing use of magnetic resonance imaging in clinical practice has led to the recognition of a new entity, bone marrow lesions (BMLs). These lesions are characterized by excessive water signals in the marrow space and have emerged as a central component of many different diseases affecting the musculoskeletal system. BMLs have in particular been associated with a wide variety of inflammatory and non-inflammatory rheumatologic conditions and are not only considered significant sources of pain, but also linked to the worsening of patient prognosis in many disease states. In this review, we summarize the current knowledge on BMLs with an emphasis on the clinical and histological features of this entity in inflammatory and non-inflammatory disease and provide a unifying hypothesis based on the appearance with various imaging technologies. We also try to pair this hypothesis with the apparent beneficial effects of various treatment regimens, mainly within the group of bone antiresorptive drugs (calcitonin, bisphosphonates) on symptoms associated with BMLs.

Unlabelled: This study evaluated the benefits of ZOL versus placebo on health-related quality of life (HRQoL) among patients from HORIZON-RFT. At month 24 and end of the study visit, ZOL significantly improved patients' overall health state compared to placebo as assessed by the EQ-5D VAS., Introduction: To evaluate the benefits of zoledronic acid (ZOL) versus placebo on health-related quality of life (HRQoL) among patients from The Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Recurrent Fracture Trial (HORIZON-RFT)., Methods: In this randomized, double-blind, placebo-controlled trial, 2,127 patients were randomized to receive annual infusion of ZOL 5 mg (n = 1,065) or placebo (n = 1,062) within 90 days after surgical repair of low-trauma hip fracture. HRQoL was measured using EQ-5D Visual Analogue Scale (VAS) and utility scores (EuroQol instrument) at months 6, 12, 24, 36, and end of the study visit. Analysis of covariance model included baseline EQ-5D value, region, and treatment as explanatory variables., Results: At baseline, patients (mean age 75 years; 24% men and 76% women) were well matched between treatment groups with mean EQ-5D VAS of 65.82 in ZOL and 65.70 in placebo group. At the end of the study, mean change from baseline in EQ-5D VAS was greater for ZOL vs. placebo in all patients (7.67 ± 0.56 vs. 5.42 ± 0.56), and in subgroups of patients experiencing clinical vertebral fractures (8.86 ± 4.91 vs. -1.69 ± 3.42), non-vertebral fractures (5.03 ± 2.48 vs. -1.07 ± 2.16), and clinical fractures (5.19 ± 2.25 vs. -0.72 ± 1.82) with treatment difference significantly in favor of ZOL. EQ-5D utility scores were comparable for ZOL and placebo groups, but more patients on placebo consistently had extreme difficulty in mobility (1.74% for ZOL vs. 2.13% for placebo; p = 0.6238), self-care (4.92% vs. 6.69%; p = 0.1013), and usual activities (10.28% vs. 12.91%; p = 0.0775)., Conclusion: ZOL significantly improves HRQoL in patients with low-trauma hip fracture.

Unlabelled: Changes in bone mineral density and bone strength following treatment with zoledronic acid (ZOL) were measured by quantitative computed analysis (QCT) or dual-energy X-ray absorptiometry (DXA). ZOL treatment increased spine and hip BMD vs placebo, assessed by QCT and DXA. Changes in trabecular bone resulted in increased bone strength., Introduction: To investigate bone mineral density (BMD) changes in trabecular and cortical bone, estimated by quantitative computed analysis (QCT) or dual-energy X-ray absorptiometry (DXA), and whether zoledronic acid 5 mg (ZOL) affects bone strength., Methods: In 233 women from a randomized, controlled trial of once-yearly ZOL, lumbar spine, total hip, femoral neck, and trochanter were assessed by DXA and QCT (baseline, Month 36). Mean percentage changes from baseline and between-treatment differences (ZOL vs placebo, t-test) were evaluated., Results: Mean between-treatment differences for lumbar spine BMD were significant by DXA (7.0%, p < 0.01) and QCT (5.7%, p < 0.0001). Between-treatment differences were significant for trabecular spine (p = 0.0017) [non-parametric test], trabecular trochanter (10.7%, p < 0.0001), total hip (10.8%, p < 0.0001), and compressive strength indices at femoral neck (8.6%, p = 0.0001), and trochanter (14.1%, p < 0.0001)., Conclusions: Once-yearly ZOL increased hip and spine BMD vs placebo, assessed by QCT vs DXA. Changes in trabecular bone resulted in increased indices of compressive strength., Competing Interests: Dr. Eastell serves as a consultant, has received honoraria for speaking, and has received grant funding from Novartis, Amgen, Sanofi-Aventis, Lilly, Organon, Pfizer, and Procter & Gamble Pharmaceuticals. Dr. Lang serves as a consultant for Merck and has received grant funding from Novartis. Dr. Boonen serves as a consultant, has received honoraria for speaking, and has received grant funding from Novartis. Dr. Cummings reports no conflict of interest. Dr. Cauley has received research grants from Merck, Eli Lilly, Pfizer, Novartis and Procter & Gamble, and has received honoraria from Novartis. Dr. Horowitz was an employee of Novartis until 2003. He has no other conflict of interest. Dr. Kerzberg has no conflict of interest. Dr. Bianchi has received consulting fees from Novartis. Dr. Kendler serves on advisory boards or as a consultant for Novartis, Servier, Eli Lilly, Amgen, Wyeth and Nycomed. Dr. Leung has no conflict of interest. Dr. Man has received honoraria for speaking from Sanofi-Aventis, Roche, Merck and Novartis. Dr. Mesenbrink is an employee of Novartis Pharmaceuticals Corporation who funded the study and owns stock in the company. Dr. Eriksen serves as a consultant and has received honoraria for speaking from Novartis. Dr. Black serves as a consultant for Nycomed and Zosano, and has research contracts with Novartis and Roche.

Unlabelled: In a 5-year study involving 119 postmenopausal women, zoledronic acid 4 mg given once-yearly for 2, 3 or 5 years was well tolerated with no evidence of excessive bone turnover reduction or any safety signals. BMD increased significantly. Bone turnover markers decreased from baseline and were maintained within premenopausal reference ranges., Introduction: After completion of the core study, two consecutive, 2-year, open-label extensions investigated the efficacy and safety of zoledronic acid 4 mg over 5 years in postmenopausal osteoporosis., Methods: In the core study, patients received 1 to 4 mg zoledronic acid or placebo. In the first extension, most patients received 4 mg per year and then patients entered the second extension and received 4 mg per year or calcium only. Patients were divided into three subgroups according to years of active treatment received (2, 3 or 5 years). Changes in BMD and bone turnover markers (bone ALP and CTX-I) were assessed., Results: All subgroups showed substantial increases in BMD and decreases in bone markers. By the end of the core study, 37.5% of patients revealed a suboptimal reduction (< 30%) of bone ALP levels. After subsequent study drug administration during the extensions, there was no evidence of progressive reduction of bone turnover markers. Furthermore, increased marker levels after treatment discontinuation demonstrates preservation of bone remodelling capacity., Conclusions: This study showed that zoledronic acid 4 mg once-yearly was well tolerated and effective in reducing biomarkers over 5 years. Detailed analysis of bone marker changes, however, suggests that this drug regimen causes insufficient reduction of remodelling activity in one third of patients.

Introduction: Bone microarchitecture, a component of bone strength, is generally measured on transiliac bone biopsy samples. The objective of this study was to determine whether assessment of four grades of vertebral fracture severity could serve as a noninvasive surrogate marker for trabecular bone volume and microarchitecture., Methods: Baseline vertebral fracture severity was determined by semiquantitative assessment of spine radiographs from 190 postmenopausal women with osteoporosis. Bone-structure indices were obtained by 2D histomorphometry and 3D microcomputed tomography (CT) analyses. Significance of differences was determined after adjusting for age, height, and lumbar spine bone mineral density., Results: There were significant (P < 0.05) trends in decreasing bone volume, trabecular number, and connectivity, and increasing trabecular separation with greater vertebral fracture severity. Histomorphometric bone volume was 25 and 36% lower (P < 0.05) in women with moderate and severe fractures than in women with no fractures, respectively. Compared with women without fractures, women with mild, moderate, and severe fractures had lower (P < 0.05) microCT bone volume (23, 30, and 51%, respectively)., Conclusions: Microarchitectural deterioration was progressively worse in women with increasing severity of vertebral fractures. We conclude that assessment of vertebral fracture severity is an important clinical tool to evaluate the severity of postmenopausal osteoporosis.

Estrogen deficiency has recently been implicated in the pathogenesis of male osteoporosis. We therefore investigated estrogen and androgen status in 63 men admitted to our clinic with the diagnosis of osteoporosis over a period of 2 years. The diagnosis was based on the presence of either low-energy fractures of the spine or a BMD T-score <-- 2.5 in the spine or hip. Thirty-six patients had one or more low-energy fractures of the spine, 47 displayed a lumbar BMD T-score <-- 2.5 and 39 a hip BMD T-score <-- 2.5. Based on the history, clinical examination and extensive biochemical testing, 42 of the 63 were classified as having primary osteoporosis. Of these 42 patients, 14 (33%) exhibited serum estradiol levels below the normal range (p<0.001). Two of the patients (3%) displayed male hypogonadism with serum testosterone below the normal range. In 37 of the 63 patients a complete estrogen status was available. In this group 26 were classified as having primary osteoporosis. Of these, no single case of male hypogonadism was demonstrable, while 10 (38%) exhibited undetectable serum estradiol levels (<48 pM). Thus, estrogen deficiency is much more prevalent than androgen deficiency in primary male osteoporosis. Future screening tests for osteoporosis in men should therefore include assessment of serum estradiol.

The proliferative capacity and cellular and biochemical characteristics of human trabecular bone osteoblasts were analysed throughout their replicative lifespan in vitro. Like several other cell types, human osteoblasts demonstrated a typical Hayflick phenomenon of cellular aging comprising a period of rapid proliferation until cumulative population doubling level (CPDL) 22 to 24, followed by a phase of slow growth and the final cessation of cell division at CPDL 32 to 34. Comparing young cells (less than 20% lifespan completed) and old cells (more than 90% lifespan completed) revealed a progressive increase in population doubling (PD) time, a decrease in attachment frequency, a decrease in the number of S-phase positive cells, a decrease in the rates of DNA, RNA and protein synthesis, an increase in the protein content per cell and an increased proportion of senescence-specific beta-galactosidase positive cells. While osteoblastic production of collagen type I decreased progressively during aging, alkaline phosphatase activity dropped rapidly after the first few passages and then remained constant during the rest of the proliferative lifespan, Significant morphological changes from thin and spindle-shaped early passage young cells to large, flattened and irregularly shaped late passage old cells full of intracellular debris were observed. In comparison, osteoblasts established from an osteoporotic bone sample showed a maximum CPDL of less than 5, had a longer PD time and exhibited abnormal senescent morphology. Thus, we have demonstrated for the first time that human osteoblasts, like several other diploid cell types, have a limited proliferative capacity in vitro and undergo aging and senescence as measured by various cellular and biochemical markers. In addition, preliminary studies show that cells from osteoporotic bone have a severely reduced proliferative capacity. This model of bone cell aging facilitates study of the molecular mechanisms of osteoblast senescence as well as factors related to osteoblast dysfunction in patients with osteoporosis.

To define the role of parathyroid gland function in the pathophysiology of bone loss in type I (postmenopausal) osteoporosis, we measured serum intact parathyroid hormone (PTH) concentration by immunoradiometric assay (IRMA) and by multisite immunochemiluminometric assay (ICMA) in 63 postmenopausal osteoporotic women (PMOp) with vertebral compression fractures and in 75 age-comparable postmenopausal normal women (PMNl). Also, tetracycline-based histomorphometric indices in cancellous bone were assessed in iliac biopsy samples from 61 PMOp and 28 PMNl women. Serum PTH concentrations by IRMA were similar in PMOp and PMNl (medians, 3.92 and 3.77 pmol/l; NS) but were significantly lower in PMOp by the more sensitive ICMA (medians, 2.82 and 3.14 pmol/l; P less than 0.01). By multiple linear regression analysis, serum PTH was directly related (P less than 0.001) to activation frequency, bone resorption rate, bone formation rate, and the calculated rate of bone loss. For each unit (pmol/l) increase in serum PTH by ICMA, activation frequency increased by 1.3%/year more (P = 0.01), bone resorption rate increased by 3.9%/year more (P = 0.003), and the rate of cancellous bone loss was 2.8% greater (P = 0.0003) in the PMOp women compared with the PMNl women. Concentrations of serum estradiol, but not serum estrone, had a weak opposing effect to PTH, especially for bone formation rate. These data suggest that in PMOp the bone has increased sensitivity to the biologic effects of PTH. This may represent one of the fundamental pathophysiologic defects in PMOp and, in the setting of estrogen deficiency, may explain, in part, their greater rate of bone loss.