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Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder leading to progressive heterotopic ossifications (HO) of muscles, tendons, and ligaments, which can be induced by trauma or by surgery. Despite strong medical advice to the contrary, an FOP patient insisted on surgery to alleviate her complete trismus, which caused an unbearable impact on her quality of life (QOL). The entire trismus history of this FOP patient is presented. [18F]‐NaF position emission tomography/computed tomography (PET/CT) scans were introduced as an imaging method for heterotopic bone formation activity. To place our findings into context, a systematic review on jaw surgery in FOP was performed. After falling down the stairs, a 9‐year‐old patient developed mobility impairment of her left‐sided jaw. During the following 13 years bone scintigraphy showed persistent activity of the disease leading to progressive left‐sided zygomatico‐mandibular fusion by HO, resulting in complete trismus. Within 1 month after HO removal on the left side and a matching right coronoidectomy, [18F]‐NaF PET/CT demonstrated a substantial flare‐up activity followed by new HO in both masseter and temporalis muscles. Despite recurrent HO and trismus her QOL increased due to a stable increased interincisal opening of 5.5 mm. Although systematic review reveals a 100% risk of HO recurrence after jaw surgery, information on improved QOL is scarce. In conclusion, surgery in FOP may be beneficial for QOL despite new HO formation. Assessment of disease activity using [18F]‐NaF PET/CT is possible before HO is evident on CT and may serve as a new and quantitative marker of the disease. © 2017 The Authors. JBMR Plus Published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

Low body mass index (BMI) is a well-established risk factor for fracture in postmenopausal women. Height and obesity have also been associated with increased fracture risk at some sites. We investigated the relationships of weight, BMI, and height with incident clinical fracture in a practice-based cohort of postmenopausal women participating in the Global Longitudinal study of Osteoporosis in Women (GLOW). Data were collected at baseline and at 1, 2, and 3 years. For hip, spine, wrist, pelvis, rib, upper arm/shoulder, clavicle, ankle, lower leg, and upper leg fractures, we modeled the time to incident self-reported fracture over a 3-year period using the Cox proportional hazards model and fitted the best linear or nonlinear models containing height, weight, and BMI. Of 52,939 women, 3628 (6.9%) reported an incident clinical fracture during the 3-year follow-up period. Linear BMI showed a significant inverse association with hip, clinical spine, and wrist fractures: adjusted hazard ratios (HRs) (95% confidence intervals [CIs]) per increase of 5 kg/m(2) were 0.80 (0.71-0.90), 0.83 (0.76-0.92), and 0.88 (0.83-0.94), respectively (all p

Antiosteoporosis medication (AOM) does not abolish fracture risk, and some individuals experience multiple fractures while on treatment. Therefore, criteria for treatment failure have recently been defined. Using data from the Global Longitudinal Study of Osteoporosis in Women (GLOW), we analyzed risk factors for treatment failure, defined as sustaining two or more fractures while on AOM. GLOW is a prospective, observational cohort study of women aged ≥55 years sampled from primary care practices in 10 countries. Self-administered questionnaires collected data on patient characteristics, fracture risk factors, previous fractures, AOM use, and health status. Data were analyzed from women who used the same class of AOM continuously over 3 survey years and had data available on fracture occurrence. Multivariable logistic regression was used to identify independent predictors of treatment failure. Data from 26,918 women were available, of whom 5550 were on AOM. During follow-up, 73 of 5550 women in the AOM group (1.3%) and 123 of 21,368 in the non-AOM group (0.6%) reported occurrence of two or more fractures. The following variables were associated with treatment failure: lower Short Form 36 Health Survey (SF-36) score (physical function and vitality) at baseline, higher Fracture Risk Assessment Tool (FRAX) score, falls in the past 12 months, selected comorbid conditions, prior fracture, current use of glucocorticoids, need of arms to assist to standing, and unexplained weight loss ≥10 lb (≥4.5 kg). Three variables remained predictive of treatment failure after multivariable analysis: worse SF-36 vitality score (odds ratio [OR] per 10-point increase, 0.85; 95% confidence interval [CI], 0.76-0.95; p = 0.004); two or more falls in the past year (OR, 2.40; 95% CI, 1.34-4.29; p = 0.011), and prior fracture (OR, 2.93; 95% CI, 1.81-4.75; p

Previous fractures of the hip, spine, or wrist are well-recognized predictors of future fracture, but the role of other fracture sites is less clear. We sought to assess the relationship between prior fracture at 10 skeletal locations and incident fracture. The Global Longitudinal Study of Osteoporosis in Women (GLOW) is an observational cohort study being conducted in 17 physician practices in 10 countries. Women aged ≥55 years answered questionnaires at baseline and at 1 and/or 2 years (fractures in previous year). Of 60,393 women enrolled, follow-up data were available for 51,762. Of these, 17.6%, 4.0%, and 1.6% had suffered 1, 2, or ≥3 fractures, respectively, since age 45 years. During the first 2 years of follow-up, 3149 women suffered 3683 incident fractures. Compared with women with no previous fractures, women with 1, 2, or ≥3 prior fractures were 1.8-, 3.0-, and 4.8-fold more likely to have any incident fracture; those with ≥3 prior fractures were 9.1-fold more likely to sustain a new vertebral fracture. Nine of 10 prior fracture locations were associated with an incident fracture. The strongest predictors of incident spine and hip fractures were prior spine fracture (hazard ratio [HR] = 7.3) and hip (HR = 3.5). Prior rib fractures were associated with a 2.3-fold risk of subsequent vertebral fracture, and previous upper leg fracture predicted a 2.2-fold increased risk of hip fracture. Women with a history of ankle fracture were at 1.8-fold risk of future fracture of a weight-bearing bone. Our findings suggest that a broad range of prior fracture sites are associated with an increased risk of incident fractures, with important implications for clinical assessments and risk model development.

Context: A middle-aged woman with recent-onset painful swollen fingers and widespread periostitis, elevated serum alkaline phosphatase (ALP) activity and erythrocyte sedimentation rate, and accelerated skeletal turnover was found not to have mutations in the gene sequences for exon 1 of receptor activator of nuclear factor-κB (RANK), osteoprotegerin (OPG), or sequestosome-1. Introduction: Hyperphosphatasia refers to disorders that feature elevated serum ALP activity (hyperphosphatasemia) usually from excesses of the bone isoform of ALP. Such conditions include familial expansile osteolysis, expansile skeletal hyperphosphatasia, and a familial form of early-onset Paget's disease of bone (PDB2), all from constitutive activation of RANK, and juvenile Paget's disease from OPG deficiency. Patient and Methods: A 38-yr-old woman developed painful swollen fingers and achy bones after an episode of unexplained pericarditis and restrictive lung disease. Sequence analysis of exon 1 of TNFRSF11A encoding RANK, TNFRSF11B encoding OPG, and SQSTM1 encoding sequestosome-1 searched for mutations responsible for familial expansile osteolysis, expansile skeletal hyperphosphatasia, or PDB2, juvenile Paget's disease, or Paget's disease of bone (PDB), respectively. Results: Serum ALP and osteocalcin and urinary hydroxyproline were increased. Radiographs showed widespread, symmetric hyperostosis in the limbs where bone scintigraphy demonstrated enhanced radionuclide uptake. Iliac crest histology revealed accelerated skeletal turnover. No mutations were detected in the three genes examined. Three years of therapy with 70 mg alendronate orally once weekly improved symptoms, radiographic abnormalities, and biochemical markers. Conclusions: Our patient manifested a unique, sporadic hyperphosphatasia syndrome. Unexplained, transient inflammation seemed to cause her pericarditis, restrictive lung disease, and periostitis with accelerated skeletal turnover that responded well to antiinflammatory drugs and alendronate therapy.

Objective: Our purpose was to investigate the long-term effects of raloxifene, compared with opposed and unopposed estrogen replacement therapy, on echocardiographic parameters of left ventricular systolic function in healthy postmenopausal women. A total of 157 women were studied in 2 randomized, double-blind, placebo-controlled, 2-year studies. Study design: In study I, 60 postmenopausal women who had undergone hysterectomy received daily raloxifene, 60 mg (n = 15); raloxifene, 150 mg (n = 15); conjugated equine estrogens (CEE), 0.625 mg (n = 15); or placebo (n = 15). In study II, 97 postmenopausal women who had not undergone hysterectomy received daily raloxifene, 60 mg (n = 24); raloxifene, 150 mg (n = 24); CEE, 0.625 mg, plus medroxyprogesterone acetate (MPA), 2.5 mg (n = 24); or placebo (n = 25). M-mode, quantitative 2-dimensional and Doppler echocardiographic measurements were performed at baseline and after 1 and 2 years. Results: Neither after 1 year nor after 2 years of treatment were echocardiographic parameters found to differ from baseline in both raloxifene groups, as well as in the unopposed CEE and the CEE/MPA groups, compared with the placebo group. Conclusion: Within 2 years of raloxifene treatment, no effect on echocardiographic parameters of left ventricular systolic function was found. Unopposed CEE or CEE/MPA also showed no effect. (Am J Obstet Gynecol 2002;186:729-36.)

Antiosteoporosis medication (AOM) does not abolish fracture risk, and some individuals experience multiple fractures while on treatment. Therefore, criteria for treatment failure have recently been defined. Using data from the Global Longitudinal Study of Osteoporosis in Women (GLOW), we analyzed risk factors for treatment failure, defined as sustaining two or more fractures while on AOM. GLOW is a prospective, observational cohort study of women aged ≥55 years sampled from primary care practices in 10 countries. Self-administered questionnaires collected data on patient characteristics, fracture risk factors, previous fractures, AOM use, and health status. Data were analyzed from women who used the same class of AOM continuously over 3 survey years and had data available on fracture occurrence. Multivariable logistic regression was used to identify independent predictors of treatment failure. Data from 26,918 women were available, of whom 5550 were on AOM. During follow-up, 73 of 5550 women in the AOM group (1.3%) and 123 of 21,368 in the non-AOM group (0.6%) reported occurrence of two or more fractures. The following variables were associated with treatment failure: lower Short Form 36 Health Survey (SF-36) score (physical function and vitality) at baseline, higher Fracture Risk Assessment Tool (FRAX) score, falls in the past 12 months, selected comorbid conditions, prior fracture, current use of glucocorticoids, need of arms to assist to standing, and unexplained weight loss ≥10 lb (≥4.5 kg). Three variables remained predictive of treatment failure after multivariable analysis: worse SF-36 vitality score (odds ratio [OR] per 10-point increase, 0.85; 95% confidence interval [CI], 0.76-0.95; p = 0.004); two or more falls in the past year (OR, 2.40; 95% CI, 1.34-4.29; p = 0.011), and prior fracture (OR, 2.93; 95% CI, 1.81-4.75; p

Objective: We sought to investigate the long-term effect of raloxifene and continuous combined hormone replacement therapy (ccHRT) on impedance to flow within the uterine artery in postmenopausal women. Study Design: A prospective, randomized, double-blind, placebo-controlled 2-year study was performed in 95 postmenopausal women. They received either 60 mg of raloxifene daily (raloxifene 60 group), 150 mg of raloxifene daily (raloxifene 150 group), ccHRT, or placebo. At baseline and thereafter every 6 months, color Doppler ultrasonography was used to measure the pulsatility index (PI) of the uterine artery. Results: After 24 months of treatment, compared with placebo, significant decreases were found in the PI in the raloxifene 150 group ( P =.021) and in the ccHRT group ( P =.007). In the raloxifene 150 group compared with the placebo group, after 6 and 24 months, decreases were observed in median PI of –5% and –15%, respectively, and in the ccHRT group decreases of –2% and –19%, respectively, were found. Conclusion: Long-term use of 150 mg of raloxifene daily or ccHRT reduces impedance to flow within the uterine artery. This indicates that high-dose raloxifene may exert cardiovascular protection. (Am J Obstet Gynecol 2001;185:557-62.)

Objectives: there is considerable uncertainty about the underlying cause of decreased intestinal calcium absorption that occurs in postmenopausal women. In a previous study, estrogen treatment did not result in an increased intestinal calcium absorption using strontium as a marker. A possible explanation could be that the calcium/strontium load given to the women was too high (∼600 mg Ca), which might result in an insensitive test with respect to the possible stimulation of active strontium transport by estrogen. Therefore, the purpose of this study was to reinvestigate the effect of estrogen on active intestinal strontium absorption using a load of 2.5 mmol of strontium only. Methods: the effect of estrogen on intestinal strontium absorption was measured in eight normal postmenopausal women. The study included two baseline strontium absorption tests, which were performed with an interval of 10 days for calculating the within subject variation (SER). Thereafter the effect of 2 months of estrogen treatment on intestinal strontium absorption was assessed. Fractional absorption (FC240) and the area under the concentration time curve (AUC) 4 h after an oral strontium load of 2.5 mmol were calculated. Results: the within subject SER of FC240 and AUC0-240 were 2.3±0.76 and 1.2±0.41, respectively. FC240 and AUC0-240 of strontium were unchanged after treatment with estrogen. Conclusions: in normal postmenopausal women, we did not find a modulating effect of short-term treatment with a (supra) physiological dose of estrogen on intestinal calcium absorption as measured by the strontium absorption test.

Objective To exclude pre-existing endometrial pathology in asymptomatic early post-menopausal women before starting hormone replacement therapy by transvaginal ultrasound (TVS) and saline infusion sonohysterography (SIS). Methods In a cross-sectional study, 148 healthy women (mean age, 51.1 years; range, 46–59 years) underwent ultrasound evaluation of the endometrium before participation in a clinical trial. TVS was used to measure double-layer endometrial thickness. SIS was performed at the same visit to measure anterior and posterior single-layer endometrial thickness, and to identify endometrial abnormalities when present. Ultrasound results were defined as informative if the endometrium could be adequately visualized. Findings on TVSs were defined as abnormal if a double-layer endometrial measurement >5.0 mm was obtained. Findings on SIS were defined as abnormal if one or both single layers of the endometrium measured >2.5 mm, or if focal endometrial thickening or a polyp was present. Results Of the 148 eligible women, informative TVS results were obtained from 134 women, SIS results from 133 women and both procedures combined from 119 women. TVS scans gave abnormal results in 8.2% of women (11 of 134) and SIS gave abnormal results in 36.8% of women (49 of 133). Of the 14 women with a non-informative TVS, eight had abnormal SIS results. Of the 15 women with a non-informative SIS, three had abnormal TVS results. In the 119 women with both informative TVS and SIS, abnormal TVS scans were found in 6.7% of women (eight of 119) and abnormal SIS in 34.5% of women (41 of 119). All eight women with abnormal TVS had an abnormal SIS, whereas 29.7% (33 of 111) of the women with a normal TVS had an abnormal SIS. Conclusions Ultrasound evaluation demonstrated endometrial abnormalities in 34.5% (41 of 119) of asymptomatic post-menopausal women. SIS is more accurate than TVS in the detection of endometrial abnormalities. Copyright © 2000 International Society of Ultrasound in Obstetrics and Gynecology

Background: Intestinal strontium absorption is becoming accepted as a clinical and diagnostic tool for assessing intestinal calcium absorption in humans. However, little is known about whether intestinal strontium absorption, like that of calcium, is stimulated by calcitriol in healthy humans.Methods: The effect of calcitriol on intestinal strontium absorption was measured in eight healthy men, ages 20–60 years. Before administration of calcitriol, two tests were performed with an interval of 10 days for calculating the within-subject variation (SER). Before the third test, 0.5 μg of calcitriol was given twice daily for 3 days. In each test, the fractional strontium absorption (Fc240) and the area under the concentration-time curve (AUC0–240) 4 h after an oral strontium load of 2.5 mmol were calculated.Results: The within-subject SER of Fc240 and AUC0–240 was 1.7 ± 0.7 and 0.83 ± 0.1, respectively. The stimulatory effect of calcitriol on Fc240 and AUC0–240 was 35% (21.8 ± 2.0 to 28.8 ± 2.4; P = 0.003) and 61% (8.97 ± 0.97 to 14.4 ± 1.3 mmol · L−1 · min; P = 0.001), respectively.Conclusions: Although the reproducibility of AUC0–240 and its sensitivity to calcitriol were better than those of Fc240, the Fc240 of strontium is preferred for a clinical test because of its simplicity, requiring only two instead of five blood samples.

OBJECTIVE Women have higher leptin levels than men at a certain degree of adiposity. The role of oestrogens in the regulation of serum leptin levels remains inconclusive. The aim of the present study was to investigate the effect of unopposed oestrogen replacement therapy, during two months, on serum leptin levels in postmenopausal women. DESIGN A double-blind, placebo-controlled, randomized study. SUBJECTS Twenty-five healthy postmenopausal women were studied (mean (± SD) age: 52.9 ± 2.7 years, range of age: 48.7–57.4 years; mean body mass index (BMI): 26.4 ± 4.2 kg/m2, range of BMI: 21.0–39.0 kg/m2). Twelve of these women were treated with 2 mg 17β-oestradiol daily, and 13 postmenopausal women received placebo. MEASUREMENTS Before and at the end of a 2-month study period, anthropometric and bio-electrical impedance measurements were performed, and fasting blood samples were taken, to determine serum levels of sex hormones and leptin. RESULTS During the 2-month study period, body weight had increased significantly in the placebo group compared with the treatment group, but no significant changes were observed in percentage of body fat or the amount of body fat in kg between the groups. Following administration of 17β-estradiol, the median leptin level increased from 17.6 μg/l to 24.1 μg/l after 2 months (P = 0.008 compared with baseline). This increase was significantly different from the placebo group (P = 0.019), which showed no change in circulating leptin levels. CONCLUSION This study demonstrates that unopposed oestrogen replacement therapy during 2 months in postmenopausal women slightly, but significantly, increases total serum leptin levels. This observation suggests a role for oestrogens in the regulation of leptin.

Summary OBJECTIVE Impaired intestinal calcium absorption in postmenopausal women is often indirectly linked to decreased serum 1,25(OH)2D or to intestinal resistance to its action rather than directly to low circulating oestrogen levels following the menopause. The purpose of this clinical study was to investigate the short-term effect of oral 17b-oestradiol on intestinal calcium absorption, with strontium as a marker. DESIGN AND PATIENTS Twenty-five healthy postmenopausal women participated in this randomised double blind placebo controlled clinical trial. Twelve women received oestradiol therapy (2 mg/day) and thirteen placebo for 2 months. Fractional strontium absorption (Fc240) was assessed at baseline and after 2 months of oestradiol/placebo therapy. RESULTS Intestinal strontium absorption (Fc240) was unchanged after treatment with 17b-oestradiol (10·1 6 5·0 vs. 10·2 6 3·8 (%)). Serum total calcitriol (1,25(OH)2 D) was unchanged after treatment with placebo (88 6 22 vs .7 96 21 (pmol/l)) but increased after treatment with oestradiol (88 6 30 vs .1 166 33 (pmol/l); P< 0·005). Serum vitamin D binding protein (DBP) increased after oestradiol but not after placebo treatment. The free serum 1,25(OH)2D index was calculated. This index did not change after oestrogen therapy (1·6 6 0·5 vs. 1·8 6 0·5). CONCLUSION In healthy postmenopausal women, short-term suppletion with exogenous oral oestrogen did not influence intestinal calcium absorption as measured by the strontium absorption test.

In this study we examined whether the effect of continuously combined hormone replacement therapy (HRT) on bone metabolism is influenced by dydrogesterone dose, smoking and initial degree of bone turnover. In a double-blind randomized study, 123 healthy postmenopausal women (mean age 51.7 years; range 30-61 years) received 17 beta-estradiol, 2 mg orally per day, continuously combined with either 2.5, 5, 10 or 15 mg of dydrogesterone daily. At baseline and at 3 and 6 months of therapy, bone formation was assessed by determining total alkaline phosphatase (TAP), bone-derived alkaline phosphatase (BAP), and the carboxy-terminal propeptide of collagen type I (PICP) in serum; bone resorption was assessed by the calcium/creatinine (Ca/Creat) and hydroxyproline/creatinine (Hp/Creat) ratio in 2-h fasting urine, and the serum carboxy-terminal pyridinolyne cross-linked telopeptide of collagen type I (ICTP). Dydrogesterone dose did not influence the effect of HRT on any of the bone markers. Combining the data of the four treatment groups, the decrease in each marker, compared to baseline values, was significant. However, in non-smokers, compared to smokers, after 6 months of therapy the decline in BAP and TAP was significantly more pronounced and the plasma estradiol level was significantly higher. For each bonemarker at baseline, women in the highest quartile, compared to women in the lowest quartile, showed a significantly stronger decrease in this marker in response to HRT. We conclude that dydrogesterone dose does not modify the effectiveness of replacement therapy. However, smoking and a low bone turnover at baseline may diminish its beneficial effect on bone.

Fractures may be associated with higher morbidity in obese postmenopausal women than in nonobese women. We compared health-care utilization, functional status, and health-related quality of life (HRQL) in obese, nonobese, and underweight women with fractures. Information from the GLOW study, started in 2006, was collected at baseline and at 1, 2, and 3 years. In this subanalysis, self-reported incident clinical fractures, health-care utilization, HRQL, and functional status were recorded and examined. Women in GLOW (n = 60,393) were aged ≥55 years, from 723 physician practices at 17 sites in 10 countries. Complete data for fracture and body mass index were available for 90 underweight, 3,270 nonobese, and 941 obese women with one or more incident clinical fractures during the 3-year follow-up. The median hospital length of stay, adjusted for age, comorbidities, and fracture type, was significantly greater in obese than nonobese women (6 vs. 5 days, p = 0.017). Physical function and vitality score were significantly worse in obese than in nonobese women, both before and after fracture; but changes after fracture were similar across groups. Use of antiosteoporosis medication was significantly lower in obese than in nonobese or underweight women. In conclusion, obese women with fracture undergo a longer period of hospitalization for treatment and have poorer functional status and HRQL than nonobese women. Whether these differences translate into higher economic costs and adverse effects on longer-term outcomes remains to be established.

Introduction: Greater awareness of the relationship between co-morbidities and fracture risk may improve fracture-prediction algorithms such as FRAX. Materials and methods: We used a large, multinational cohort study (GLOW) to investigate the effect of co-morbidities on fracture risk. Women completed a baseline questionnaire detailing past medical history, including co-morbidity history and fracture. They were re-contacted annually to determine incident clinical fractures. A co-morbidity index, defined as number of baseline co-morbidities, was derived. The effect of adding the co-morbidity index to FRAX risk factors on fracture prevention was examined using chi-squared tests, the May-Hosmer test, c index and comparison of predicted versus observed fracture rates. Results: Of 52,960 women with follow-up data, enrolled between October 2006 and February 2008, 3224 (6.1%) sustained an incident fracture over 2. years. All recorded co-morbidities were significantly associated with fracture, except for high cholesterol, hypertension, celiac disease, and cancer. The strongest association was seen with Parkinson's disease (age-adjusted hazard ratio [HR]: 2.2; 95% CI: 1.6-3.1; P< 0.001). Co-morbidities that contributed most to fracture prediction in a Cox regression model with FRAX risk factors as additional predictors were: Parkinson's disease, multiple sclerosis, chronic obstructive pulmonary disease, osteoarthritis, and heart disease. Conclusion: Co-morbidities, as captured in a co-morbidity index, contributed significantly to fracture risk in this study population. Parkinson's disease carried a particularly high risk of fracture; and increasing co-morbidity index was associated with increasing fracture risk. Addition of co-morbidity index to FRAX risk factors improved fracture prediction. © 2012 Elsevier Inc.

Osteoporosis is a common and costly problem. Approximately half of women aged 50 and older will sustain a fragility fracture, and the greatest morbidity occurs in those aged 65 and older.1 Mortality can reach 20% for a hip or vertebral fracture within the first year and continues to rise for up to 10 years.2–4 Medications are available to reduce the risk of fractures.5–8 Oral, intravenous, inhaled, and subcutaneous medications reduce the risk of vertebral fractures 50% or more,5,6 and some medications also substantially reduce the risk of nonvertebral and hip fractures.5,6 Despite the availability of a variety of medications, few recent data are available on factors that determine whether individuals with new fragility fractures are treated. Previous studies suggest that fewer than 5% of individuals admitted to hospital with hip fracture leave the hospital with a diagnosis of osteoporosis and that fewer than 1% are treated.9 Similar studies have documented poor treatment rates in individuals with vertebral fractures. Data from the National Health and Nutrition Examination Survey (NHANES) suggest that fewer than 14% of women with a diagnosis of osteoporosis are treated with an antiresorptive medication and that the number of risk factors for fracture does not alter rates of medication use.10 Previous studies have focused on a single community or country, often under the umbrella of a national or insurance-based health care environment. Such local or national health environments may limit or support osteoporosis medication use. Global data are needed to better identify barriers to treatment across a range of practices, regions, and healthcare systems. Such data with differing healthcare costs, guidelines, reimbursements, and access to care may clarify obstacles to treatment after a fracture. The Global Longitudinal Study of Osteoporosis in Women (GLOW) is a multinational, observational, prospective study designed to provide information on patterns of management of fracture and fracture risk in women aged 55 and older, with an oversampling of elderly women over a 5-year period on an international basis. The goals of the present study were to determine the proportion of women not receiving therapy at baseline who suffered an incident fracture and were receiving treatment at 1-year follow-up and to understand the factors that predict treatment. To examine this, GLOW participants who had sustained a fragility fracture during their first year of follow-up were surveyed.

The consequences of bone disease in primary hyperparathyroidism (PHPT) are still a matter of discussion. We studied transiliac bone biopsies of 24 patients (9 men and 15 women) with mild to moderate PHPT, proven by surgery. Histomorphometric data were compared with control values obtained from autopsy bone samples. The biopsies of the PHPT patients were characterized by increased trabecular bone volume (P < 0.01) and surface (P < 0.02), increased osteoid volume and increased osteoid and resorption surfaces (P < 0.001). Cortical porosity showed a non-significant increase in the PHPT patients. In the patients the fasting serum concentrations of parathyroid hormone (PTH(l–84)) correlated positively with cortical porosity (r = 0.50, P = 0.02), osteoid volume (r = 0.40, P = 0.05), osteoid surface (r = 0.50, P = 0.01), and eroded surface (r = 0.59, P < 0.01). It is concluded that moderate PHPT is associated with preservation of trabecular bone, whereas cortical bone may be lost in these patients. Cortical porosity and the parameters of bone turnover correlate well with the fasting serum PTH(l–84) concentration.

OBJECTIVE To examine several dimensions of health-related quality of life (HRQL) in postmenopausal women who report previous fractures, and to provide perspective by comparing these findings with those in other chronic conditions (diabetes, arthritis, lung disease). PATIENTS AND METHODS Fractures are a major cause of morbidity among older women. Few studies have examined HRQL in women who have had prior fractures and the effect of prior fracture location on HRQL. In this observational study of 57,141 postmenopausal women aged 55 years and older (enrollment from December 2007 to March 2009) from 17 study sites in 10 countries, HRQL was measured using the European Quality of Life 5 Dimensions Index (EQ-5D) and the health status, physical function, and vitality questions of the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). RESULTS Reductions in EQ-5D health-utility scores and SF-36–measured health status, physical function, and vitality were seen in association with 9 of 10 fracture locations. Spine, hip, and upper leg fractures resulted in the greatest reductions in quality of life (EQ-5D scores, 0.62, 0.64, and 0.61, respectively, vs 0.79 without prior fracture). Women with fractures at any of these 3 locations, as well as women with a history of multiple fractures (EQ-5D scores, 0.74 for 1 prior fracture, 0.68 for 2, and 0.58 for ≥3), had reductions in HRQL that were similar to or worse than those in women with other chronic diseases (0.67 for diabetes, 0.69 for arthritis, and 0.71 for lung disease). CONCLUSION Previous fractures at a variety of bone locations, particularly spine, hip, and upper leg, or involving more than 1 location are associated with significant reductions in quality of life.

To study the effect of calcium supplementation on perimenopausal bone loss, 295 women were randomized into a control group and 2 supplementation groups receiving, respectively, 1000 and 2000 mg elemental calcium/day for a period of 2 yr. We observed a significant decrease in lumbar bone loss in relation to the calcium supplementation (mean loss after 2 yr of 3.5% in the control group vs. 1.3% and 0.7% in the 1000 and 2000 mg groups, respectively), a significant increase in urinary calcium excretion, and a significant decrease in the urinary hydroxyproline/creatinine ratio, serum alkaline phosphatase, osteocalcin, and 1, 25-dihydroxyvitamin D. The effect of calcium supplementation on lumbar bone loss was significant in the first year of supplementation, but not in the second. However, the urinary hydroxyproline/creatinine ratio and the serum alkaline phosphatase level remained significantly decreased in the treatment groups at the end of the study; this was not the case for serum osteocalcin. Calcium supplementation did not have a significant effect on metacarpal cortical bone loss. The difference in biochemical parameters between the 2 supplementation groups was small. No significant interaction was observed between the menopausal status of the subjects and the effect of calcium supplementation. We conclude that calcium supplementation retards lumbar bone loss in the first year of calcium supplementation by reducing bone turnover. However, the effect on lumbar bone loss over a longer time span is still uncertain. © 1991 by The Endocrine Society.

Summary. objective Because of an overlap between serum PTH values In healthy controls and hyperparathyroid patients we sought to evaluate a short stimulation and suppression test for differentiating the two groups. subjects Subjects were 34 patients with primary hyperparathyroidlsm (PHPT) and 25 healthy controls. design After stimulation with Intravenous EDTA (10 mg/kg body weight In 5 minutes) blood samples were obtained for up to 15 minutes. After an oral calcium dose of 1 g, blood samples were obtained at 1 and 2 hours. After an Intravenous calcium dose (2.5 mg/kg body weight in 30 seconds), blood samples were obtained serially for 20 minutes. measurement Serum PTH(1–84) was measured by a double antibody technique. results The intravenous EDTA test resulted in an average 2-6-fold Increase of serum PTH(1–84) In hyperparathyroid patients, whereas it increased 10.5-fold in controls. A response was absent in three of 23 patients. There was an overlap in results between patients with mild hyperparathyroldism and controls. The oral calcium dose decreased serum PTH(1–84) In patients to 0.73 and in controls to 0.55 of the basal value, but six of 15 patients and two of 12 controls did not respond. The intravenous calcium test resulted in a drop of serum PTH(1–84) In hyperparathyrold patients to 0.51 and in control subjects to 0.40 of the basal value, and non-responders were not observed. There was a strong correlation between the responses to the EDTA and the calcium Infusion tests In the patients (r=0.97, P < 0.1). Fasting serum calcium and serum PTH(1–84) showed a positive correlation in PHPT patients (r= 0.75, P< 0.001) and a negative correlation in control subjects (r= -0.41, P

Estrogens may affect the essential n-6 and n-3 fatty acids arachidonic acid (AA; C20:4n-6) and docosahexaenoic acid (DHA; C22:6n-3). Therefore, we investigated the long-term effects of hormone replacement therapy and raloxifene, a selective estrogen-receptor modulator, in two randomized, double-blind, placebo-controlled studies. In study I, 95 healthy, non-hysterectomized, early postmenopausal women (age range 47-59 years) received one of the following treatments: daily raloxifene 60 mg (n=24), daily raloxifene 150 mg (n=23), 0.625 mg conjugated equine estrogens (CEE) plus 2.5 mg medroxyprogesterone acetate (MPA; n=24), or placebo (n=24). In study II, 30 men (age range 60-69 years) received daily 120 mg raloxifene (n=15) or placebo (n=15). In study I, plasma cholesteryl ester fatty acids were measured at baseline and after 6, 12, and 24 months in 83 (drop out rate 13%), 73 (23%), and 70 (25%) women respectively. In study II, fatty acids were measured at baseline and after 3 months in 29 men (drop out rate 3%). In postmenopausal women, administration of 150 mg raloxifene increased AA by a mean of +6.1% (P=0.055, not significant). Administration of CEE plus MPA increased AA by +14.1% (P

Objective To investigate the effects of 1 mg 17beta-estradiol continuously combined with 2.5, 5, 10, or 20 mg dydrogesterone on the serum lipid profile of postmenopausal women. Design Serum lipid profile was measured in two 1-year studies performed in healthy, nonhysterectomized, postmenopausal women. One study (n = 182) had an open design and investigated oral 17beta-estradiol 1 mg daily continuously combined with dydrogesterone 2.5 mg daily; the other study (n = 326) had a double-blind, randomized design and investigated oral 17beta-estradiol 1 mg daily continuously combined with dydrogesterone at doses of 5, 10, or 20 mg daily. Results With all four dosages of dydrogesterone, serum total and low-density lipoprotein cholesterol were significantly reduced (-4.6% to -7.6% and -6.3% to -11.6%, respectively), whereas high-density lipoprotein cholesterol was significantly increased (+4.3% to +7.4%). Serum apolipoprotein A1 and B also improved significantly, reflecting the favorable changes in high-density lipoprotein and low-density lipoprotein cholesterol, as did lipoprotein(a). Conclusion Oral 17beta-estradiol 1 mg daily continuously combined with dydrogesterone 2.5 to 20 mg daily has beneficial effects on serum lipid profile in postmenopausal women.

Objectives: Lipoprotein(a) (Lp(a)) and homocysteine (Hcy) are independent cardiovascular risk factors, which have been shown to be lowered by hormone replacement therapy (HRT). In this 2-year study, the long-term effects of raloxifene (Rlx) in two doses, on Lp(a) and Hcy, were studied and compared with the effects of continuously combined hormone replacement therapy (ccHRT). Methods: In a prospective, randomized, double-blind, placebo-controlled 2-year study, 95 healthy, non-hysterectomized, early postmenopausal women, received daily either oral Rlx 60 mg ( N =24) or 150 mg ( N =23), ccHRT (conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg; N =24) or placebo ( N =24). Fasting serum Lp(a) and plasma Hcy concentrations were measured at baseline and at 6, 12 and 24 months. Results: The mean individual changes compared to baseline after 24 months were for Lp(a): Rlx 60: −5%, Rlx 150: −7%, ccHRT: −34%, placebo: +1% and for Hcy: Rlx 60: −3%, Rlx 150: −4%, ccHRT: −4%, placebo: +6%. ANCOVA was significant for Lp(a) under ccHRT versus placebo ( P =0.001) and for Lp(a) under ccHRT versus each of the two Rlx groups ( P Conclusions: Long-term treatment with Rlx was not as effective as ccHRT in lowering Lp(a). Although not significant and without an obvious dose-related response, the Hcy values showed the same trend for each treatment arm, which is in line with data reported earlier.

Recent brain imaging studies have shown that estrogens alter brain activation patterns upon working memory tasks in postmenopausal women. Estrogens, however, have many systemic side effects. We investigated the effect of the Selective estrogen receptor modulator (SERM) raloxifene on brain activation patterns during a memory task in postmenopausal women with functional magnetic resonance imaging (fMRI). Twenty postmenopausal and right handed women (mean age 65.7 years; SD 3.0) were included in this double blind, placebo controlled and randomized study. Whole brain fMRI was performed before and after three months of daily treatment with raloxifene 60 mg or placebo. Each scanning session consisted of a visual encoding task, a recognition test and a simple photic stimulation test. Data analyses was performed with SPM99b software. Specific regions of interest for the tasks were defined based on previous experiments. Visual encoding activated the ventral route, posterior medial temporal lobe and frontal cortex in both groups. Treatment interactions for raloxifene compared to placebo were a decrease in activation in the left parahippocampal gyrus and left lingual gyrus, and an increase in activation in the right superior frontal gyrus. The mean recognition test and the simple photic stimulation test showed no treatment interactions. Our results show that raloxifene affects brain activation patterns upon visual encoding in postmenopausal women.

There is considerable evidence that the extracellular fluid volume (ECV) may change in disease states or during longitudinal Intervention studies. Therefore, the measurement of ECV is Important for studying body composition in patients and laboratory animals. We present a modified plasma bromide (Br-, non-radioactive) assay using anion-exchange chromatography, in which a small blood sample of 200 microL (100 microL of plasma) appeared to be enough to reproducibly measure ECV. The inter- and intra-assay accuracy of the Br- analysis ranged from -1.6% to 0.9% and from -0.5% to 0%, respectively. The inter- and intra-assay precision ranged from 1.3% to 1.7% and from 0.6% to 1.2%, respectively. This modified precise and accurate Br- analysis in a small blood sample was applied to investigate whether the ECV changed in rats after ovariectomy. Ovariectomy significantly (P.05) reduced the ECV as compared with results in SHAM rats. This observation indicates that a change in clinical condition may change ECV, which has consequences for the determination of, for example, the fractional absorption and the relative bioavailability of compounds principally distributed through the ECV.

Studies were carried out to examine the mechanism of action of estrogen on intestinal calcium absorption in the rat. Three-month-old Wistar rats were sham-operated or ovariectomized (OVX). They were fed a diet containing 0.4% Ca, 0.4% P, and 2000 IU vitamin D3/kg. Eight weeks after operation, both OVX and sham-operated rats were randomly assigned to eight treatment groups. Five groups received per 100 g of body weight 12.5 ng calcitriol (1, 25-dihydroxyvitamin D3); 7.5 microg of estradiol-benzoate; 7.5 microg of estradiol-benzoate and 0.1 mg of ICI 182780; 12.5 ng of calcitriol and 0.1 mg of ICI 182780; and 0.1 mg of ICI 182780, respectively. Three groups received the various vehicles used. Intestinal calcium absorption was measured in vivo using single pass perfusion of the duodenum. OVX did not change intestinal calcium absorption. A pharmacological dose of estradiol-benzoate caused a significant increase in intestinal absorption of calcium, which was comparable to that of a pharmacological dose of calcitriol in both OVX and sham-operated rats. Estrogen-induced rise in intestinal calcium absorption was completely blocked to basal level by the pure estrogen receptor (ER) antagonist ICI 182780. In contrast, ICI 182780 did not antagonize calcitriol-enhanced intestinal calcium absorption. Our findings suggest that estrogen stimulates intestinal calcium absorption via an ER.

Immobilization may lead to severe bone loss. Physical activity decreases with age and lower mobility might influence bone loss. We have evaluated the degree of mobility and parameters of bone turnover in 70 residents of a nursing home (mean age +/- SD 81 +/- 9 years) and 68 residents of an old people's home (mean age +/- SD 84 +/- 6 years). The mobility was assessed with a standing and walking score from 1 (severely disabled) to 5 (standing/walking without help). When the subjects were arranged according to increasing walking score from 1 to 5, fasting urinary hydroxyproline/creatinine ratio gradually decreased from 31 +/- 19 to 14 +/- 5 mumol/mmol (P less than 0.001). There was also a significant linear decrease of fasting urinary calcium/creatinine ratio, and serum calcium concentration and a significant increase of serum albumin and 1,25-dihydroxyvitamin D concentrations with increasing walking score. These data indicate that lower mobility in the elderly leads to higher bone resorption, which may suppress the formation of 1,25-dihydroxyvitamin D.

We describe a clinical study comparing the value of measurements of intact human PTH [hPTH(1-84)] and total PTH immunoreactivity [hPTH-(1-84) plus fragments]. A two-step immunochemical method was used to separate plasma hPTH-(1-84) from all circulating PTH fragments. The first step involved extraction and concentration of plasma PTH using solid phase antiamino-terminal PTH antibodies. After elution, the PTH immunoextract was analyzed using a sensitive mid- and C-region immunoassay. Complete separation in the immunoextraction step was proven by Sephadex G-75 gel filtration. hPTH-(1-84) values in fasting patients showed a clear distinction between those with primary hyperparathyroidism and those with nonparathyroid hypercalcemia, in contrast with small overlap in total immunoreactive PTH values. The hPTH-(1-84) values increased faster and more substantially in response to long EDTA and calcium infusion tests, compared with total PTH immunoreactivity, in normal subjects. Infusion of EDTA (10 mg/kg BW) in 5 min) elicited a readily measurable response of hPTH-(1-84) between 5 and 10 min after starting the infusion. Ingestion of 1000 mg calcium caused a decrease in hPTH-(1-84) in 1 h or less. More than 50% of patients with terminal renal failure had normal hPTH-(1-84) values despite elevated total immunoreactive PTH concentrations. We conclude that the two-step hPTH-(1-84) assay is more specific and sensitive than most regional PTH assays. Measurements of hPTH-(1-84) levels may identify disorders of parathyroid function at an early stage and provide a useful tool for the study of parathyroid physiology.

Bone mineral density (BMD) of the lumbar spine was measured in 286 women (46-55 years of age) using dual photon absorptiometry. The women were classified in three categories: premenopausal, perimenopausal and postmenopausal. The postmenopausal group was subdivided according to the number of years since the last uterine bleeding. With multiple linear regression analysis of lumbar BMD on age and menopausal status, an acceleration of bone loss was observed during the perimenopausal period and the following first two postmenopausal years. No significant bone loss was detected in relation to age or during the later postmenopausal years. Applying both an additive and a multiplicative model of bone loss, the mean perimenopausal bone loss was 0.061 gram-equivalents hydroxyapatite (geqHA)/cm2 and 6.4%, respectively. In the first 2 postmenopausal years the mean bone loss was 0.044 geqHA/cm2 and 5.1% per year. These results suggest a substantial menopause related acceleration of lumbar bone loss in a relatively short time span with its onset in the perimenopausal period.

• Serum vitamin D metabolites were measured in 160 normocalcemic urinary calcium stone formers and in 217 control subjects. No difference in concentrations of 25-hydroxyvitamin D (25[OH]D), 24,25-dihydroxyvitamin D (24,25[OH] 2 D), and 1,25-dihydroxyvitamin D (1,25[OH] 2 D) was found between stone formers and control subjects. Values for 25(OH)D and 24,25(OH) 2 D were higher in hypercalciuric stone formers than in normocalciuric stone formers independent of seasonal fluctuation. No difference in concentration of serum 1,25(OH) 2 D was found between hypercalciuric and normocalciuric stone formers. No correlations were present between the serum concentrations of the measured vitamin D metabolites and of measures of calcium and phosphate metabolism. These findings suggest no major pathophysiologic role of the main vitamin D metabolites in urinary calcium stone formation. ( Arch Intern Med 1985;145:681-684)

To the Editor. —In the February 1980 issue of theArchives(140:205-207), Rao et al report a series of patients with hyperparathyroidism (HPT) after head and neck irradiation with x-ray therapy. In the discussion, they mention the absence of reports on HPT after radioactive iodine (131I) therapy. Tisell et al,1however, in 1976, described a patient who experienced HPT nine years after131I therapy for hyperthyroidism. Our series of 77 patients with HPT contains two patients who received sodium iodide I 131 therapy 11 and 20 years before diagnosis of HPT because of toxic nodular goiter. In these same series, there are ten other patients with HPT and foregoing x-ray irradiation for benign diseases in childhood or adolescence. Report of Cases. —Case 1.—An 80-year-old woman was treated 11 years previously with 8 mCi of sodium iodide I 131 because of toxic nodular goiter. She was admitted to