Appendicular Tissue at Diagnosis and at Follow Up in Women Over 50y With Coeliac Disease.

Coeliac disease (CD) affects lean, fat and bone composition in the limbs. Many studies compare CD patients with controls who are inappropriate in relation to weight, sex, and age. Thus, although CD patients may have deficiency of appendicular lean and bone, whether this applies when these variables are controlled is uncertain. Following diagnosis, it also remains uncertain whether lean and bone increase or decline. Forty-four female CD patients aged 50-79 yr at diagnosis were age and weight matched with 44 healthy controls. Fifteen CD patients were followed up after 7.5 ± 2.7 yr. Body composition and spine and hip Bone Mineral Content (BMC) were measured using DXA. Changes after 7.5 yr were compared with initial data and with data corrected for expected losses of lean and bone. At diagnosis BMC was low in both upper and lower limbs (p < 0.0001), lean was low in the upper limb (p < 0.03) and fat content was similar. BMC z scores were lower in the lower limbs than in axial sites (p< 0.02). At follow up lean when corrected for expected loss had not declined; only fat increased. BMC was unchanged but all patients had received bone active agents. If the expected decline in BMC were accounted for, BMC was greater than expected in both upper and lower limbs (p < 0.004). Appendicular Lean mass is not low in CD and does not change on treatment. BMC at diagnosis is lowest at the lower limb and may be worth measuring in women of this age to alert to the possibility of CD. BMC does not decline after treatment. If allowance is made for expected bone loss BMC increases slightly, but it would take about 15 yr to achieve the age related mean.

Lower Limb Metaphyseal Bone Is Lost in Men with Coeliac Disease and Does Not Relate to Parathyroid Status.

Aims. To investigate regional lower limb bone density and associations with weight, PTH, and bone breakdown in coeliac men. Methods. From whole body DXA scans bone mineral density (BMD) was measured in 28 coeliac men, in the lower limb (subdivided into 6 regions, 3 being metaphyseal (mainly trabecular) and 2 diaphyseal (mainly cortical)). BMD at femoral neck (FN) and lumbar spine L2-4, body weight, height, serum calcium, alkaline phosphatase, parathyroid hormone (PTH), and urinary calcium and NTx/Cr, a measure of bone breakdown, were also measured. Age matched healthy men provided values for BMD calculation of z and T scores and for biochemical measurements. Results. Low BMD z scores were found at metaphyseal regions in the leg (p < 0.001) and in the FN (p < 0.05). The distal metaphyseal region BMD in the leg was lower than spine or FN (p < 0.05). PTH, urinary calcium/creatinine, and urinary NTx/Cr were similar to controls. Both metaphyseal and diaphyseal BMD z scores were associated with body weight (p < 0.02), but not with either PTH or urinary NTx/Cr. Conclusions. Low BMD lower limb regions comprising mostly trabecular bone occur early in CD and in the absence of elevated PTH or increased bone resorption. Low BMD is associated with low body weight.

Health-related quality of life in women referred for bone density assessment: relationships with bone mineral density, fracture and co-morbidity.

PURPOSE: To identify variables that might influence health-related quality of life (HRQoL) in patients with and without a history of fracture, attending bone mineral density (BMD) assessment prior to diagnosis of osteoporosis. METHODS: This cross-sectional study included 312 newly referred postmenopausal women attending for a DXA scan, without a diagnosis of osteoporosis. Data were obtained from the medical history and the General Practitioner's letter. HRQoL, using SF36 was scored using published algorithms with reference to an age-related population from England. Regression analyses were used to determine relationships between HRQoL and BMD, age, fracture status and co-morbidities. RESULTS: For all patients, the age-related physical component summary (PCS) and mental component summary (MCS) scores were 46 ± 10 and 47 ± 10, respectively. Controlling for confounding variables, low BMD at the femoral neck was associated with worse PCS scores (p = 0.010) and MCS scores (p = 0.034) in patients without fracture. In patients with a history of fracture, this relationship was less evident, and younger age (p < 0.00), increasing BMI (p = 0.016) and number of co-morbidities (p = 0.042) were associated with reductions in PCS scores. CONCLUSIONS: Patients referred for BMD assessment before a diagnosis of osteoporosis had reduced PCS scores. In patients without fracture, low BMD contributed to this reduction in health-related quality of life. Low PCS scores in patients with fracture were seen only in younger subjects with osteoporosis.

Application of sub-regional analysis to bone mineral density of the lower limb from whole body DXA scans.

Bone mineral density at spine and hip is widely used to diagnose osteoporosis. Certain conditions cause changes in bone density at other sites, particularly in the lower limb, with fractures occurring in non-classical locations. Bone density changes at these sites would be of interest for diagnosis and treatment. We describe an application, based on an existing software option for Hologic scanners, which allows reproducible measurement of bone density at six lower limb sites (upper femur, mid-femur, lower femur; upper leg, mid-leg, lower leg). In 30 unselected subjects, referred for bone density, precision (CV%) measured on 2 occasions, separated by repositioning, ranged from 1.7% (mid-femur) to 4.5% at the lowest leg site. Intra-operator precision, measured by three operators on ten subjects on three occasions, was between 1.0% and 2.9%, whilst inter-operator precision was between 1.0% and 3.6%, according to region. These values compare well with those at the spine and upper femur, and in the literature. There was no evidence that this operator agreement improved between occasions 1 and 3. This technique promises to be useful for assessing bone changes at vulnerable sites in the lower limb, in diverse pathological states and in assessing response to treatment.

Matched-cohort study of body composition, physical function, and quality of life in men with idiopathic vertebral fracture.

OBJECTIVE: To determine the effect of 6 years of routine management on body composition, physical functioning, and quality of life, and their interrelationships, in men with idiopathic vertebral fracture. METHODS: Twenty men with idiopathic vertebral fracture (patients: mean ± SD age 58 ± 6 years) were age and height matched to 28 healthy controls with no known disease. The primary outcome was skeletal muscle mass (appendicular lean mass by dual x-ray absorptiometry) assessed at 2 visits (0 and 6 years). Physical functioning and quality of life domains were assessed by the Senior Fitness Test and Short Form 36 (SF-36) questionnaire at visit 2 only. Data were analyzed by repeated-measures analysis of variance, independent t-tests, and correlation. RESULTS: At visit 1, appendicular lean mass was 9% lower in patients than controls. Although patients better maintained appendicular lean mass between visits (interaction P = 0.016), at visit 2 appendicular lean mass remained 5% lower in patients than controls. Furthermore, patients' appendicular lean mass change was correlated with femoral neck bone density change (r = 0.507, P = 0.023). Physical function tests were 13-27% lower in patients compared with controls (P = 0.056 to 0.003), as were SF-36 quality of life physical domains (13-26% lower; P = 0.028 to <0.001). CONCLUSION: Despite an association between changes in muscle mass and bone density, routine management of men with idiopathic vertebral fracture does not address muscle loss. Combined with the observation of reduced physical functioning and quality of life, this study identifies novel targets for intervention in men with idiopathic vertebral fracture.

Does anastrozole affect bone resorption similarly in early and late postmenopausal women?

The aim of this study was to determine whether the bone-resorption response to anastrozole differed according to initial patient age in postmenopausal women with breast cancer in a cross-sectional study. Second-morning void urines were collected for measurement of urinary cross-linked N-telopeptide of type I collagen (uNTx, corrected for creatinine and log-transformed) from postmenopausal women, 99 with breast cancer on anastrozole (ABC), 88 with newly diagnosed breast cancer (NDBC), and 137 community-dwelling healthy control (HC) women. Bone mineral density (BMD) was also measured at the lumbar spine (LS, L2-L4) and the femoral neck (FN) in the ABC group. uNTx (nanomole bone collagen equivalents/millimole creatinine) levels increased with age in HC subjects. In patients <70 years, anastrozole treatment led to a significant increase in uNTx compared with age-related HC subjects (1.74 vs. 1.55, P < 0.005). Patients >70 years showed no such increase compared to HC (1.72 vs. 1.69, nonsignificant); however, NDBC women >70 years had uNTx levels significantly lower than HC women (1.59 vs. 1.69, P < 0.05). There was no difference in uNTx levels above and below the age of 70 years in NDBC women (1.56 vs. 1.59, nonsignificant). ABC women were more likely to have a positive LS BMD z score than age-matched controls. Anastrozole treatment increases bone turnover more in younger postmenopausal women with breast cancer than in older women compared to healthy controls. Higher LS BMD in ABC patients may help protect against fracture.

Peripatetic intravenous service for metabolic bone disease: case study in patient centred-care for new NHS.

OBJECTIVE: To develop a 'close to patient' peripatetic intravenous service (PIVS) for delivery of specialist osteoporosis care in a community setting without increasing cost and with a reduced carbon footprint. RESEARCH DESIGN AND METHODS: Cost and feasibility of a PIVS for intravenous (i.v.) bisphosphonate treatment were modelled using UK National Health Service costings and then tested in the field for 1 year. Average patient mileage to peripatetic sites was compared with mileage travelled if treated at the base hospital (current practice). The method of travel to hospital (current practice) or peripatetic sites (new study) was ascertained together with patients' preference for the new or the current system. Peripatetic sites were researched and those with suitable facilities selected. Data for fuel consumption were based on a usage of 1 litre per 14.5 km. MAIN OUTCOME MEASURES: The main outcome measure was cost comparison between hospital and peripatetic services. Others included patient satisfaction, miles saved, method of travel to the clinic and changes in CO(2) emissions. RESULTS: Cost per patient, including drugs, lies between pound557 and pound622 annually for 1000 and 500 patients, respectively which is cost-neutral compared with hospital attendance. PIVS was rated more convenient by 98% of patients. Hospital transport was significantly reduced and the total monthly saving of 2000 miles has reduced CO(2) emission by 6072 kg p.a. No medical emergency occurred in 410 infusions. CONCLUSIONS: PIVS is cost neutral compared with a conventional service, leads to a better patient experience, a significant cutback in hospital transport costs and a reduction of the NHS carbon footprint. However not all drugs may be suitable for this service: the area served was rural with large distances and poor public transport and mileage savings may not accrue in urban areas. Insurance was not included in the calculation of costs.

Circulating and tissue-derived isoforms of bone alkaline phosphatase in Paget's disease of bone.

BACKGROUND: Alkaline phosphatase (ALP) is routinely used in the assessment of Paget's disease of bone (PDB); however, the individual bone ALP isoforms (B/I, B1, and B2) have not been investigated in this disorder. METHODS: Subjects comprised 37 patients (mean age 74 years) with symptomatic PDB confirmed by radiograph and stratified into high and low total ALP activity groups and 66 healthy individuals (mean age 64 years). Extracts of human cancellous and cortical bone tissues were also investigated. The bone ALP isoforms, measured by HPLC, were compared with two bone ALP immunoassays (Metra and Ostase), and the bone formation marker intact amino-terminal procollagen type I propeptide (iPINP). RESULTS: All bone ALP isoforms were increased in high ALP activity PDB compared with the low ALP activity and control groups (p < 0.0001). The B2 isoform had the greater relative activity representing 36%, 50%, and 71%, of the total ALP activity in the control, low and high ALP activity groups, respectively. Compared with controls, B2 was increased in the low ALP activity PDB group (p < 0.05). ROC analysis showed a validity of approximately 80% for B2 to discriminate patients with PDB. CONCLUSION: All bone ALP isoforms were increased in patients with high ALP activity PDB and the B2 isoform was even elevated in the low ALP activity PDB group. The bone ALP isoform B2 may be of use in the management of PDB but that has to be further elucidated in subsequent studies.

Increased circulating Dickkopf-1 in Paget's disease of bone.

UNLABELLED: Dickkopf-1 (Dkk-1) is a secreted inhibitor of Wnt signaling which in adults regulates bone turnover. Dkk-1 over-production is implicated in osteolytic disease where it inhibits bone formation and stimulates bone breakdown. Recently it was reported that osteoblastic cells from Paget's disease of bone (PDB) over-expressed Dkk-1. OBJECTIVE: To see if increased Dkk-1 was detected in serum from patients with PDB. RESULTS: Dkk-1 and total serum alkaline phosphatase activity (tsAP) were significantly elevated in sera from PDB patients. Patients with polyostotic PDB had significantly higher levels of tsAP but not Dkk-1, than monostotic patients. TsAP but not Dkk-1, was significantly lower in sera from bisphosphonate treated versus untreated PDB patients. Dkk-1 and tsAP were not significantly correlated. CONCLUSIONS: Dkk-1 may be a useful biomarker of PDB and we speculate that Dkk-1 may play a central role in the etiology of PDB.

Bone resorption in stroke and institutionalized subjects.

Stroke increases the risk of hip fracture on the affected side. Although bone is lost by 1 year, rapidity of onset and relationship with immobility are uncertain. Using the bone resorption marker urinary cross-linked N telopeptide of type I collagen (uNTx), we examined bone resorption in the first 4 weeks after stroke, relating uNTx with bone density and mobility in subjects over 60 years. Two separate control groups acted as comparators, healthy (HC) and institutionalized (IC) controls, the latter to control for the effects of institutionalization. uNTx, urinary calcium (both related to creatinine and log-transformed), heel bone mineral density (BMD), Tinetti scores, and Barthel scores for prestroke function were measured. Log uNTx/Cr was lower in males compared with females, but this difference was not evident in stroke or IC subjects. Log uNTx/Cr was inversely related with BMD in females from both control groups and in male stroke subjects. Tinetti scores were divided into tertiles and were lower in stroke than IC subjects (P < 0.01). Log uNTx/Cr was similar in stroke and IC subjects in the lowest Tinetti tertile. Log uNTx/Cr was higher in stroke subjects of both sexes in the lowest tertile compared with the higher two tertiles combined (P < 0.05) and higher in all tertiles compared with HC subjects (P < 0.05). Subjects with a prestroke Barthel index of < or = 17 had higher log uNTx/Cr compared with HCs. Log uCa/Cr was higher only in male stroke patients. Bone resorption in stroke starts early, and measures to reduce this are merited.

Platelet-derived growth factor stimulates osteoprotegerin production in osteoblastic cells.

Osteoprotegerin (OPG) is a major regulator of osteoclastogenesis, bone resorption and vascular calcification. OPG is produced by various cell types including mesenchymally derived cells, in particular, osteoblastic cells. Here we show OPG production by osteoblastic cells was stimulated by platelet-derived growth factor (PDGF) in two human osteosarcoma cell lines (MG63, Saos-2), a mouse pre-osteoblastic cell line (MC3T3-E1) and human bone marrow stromal cells (hMSC) by 152%, 197%, 113% and 45% respectively over 24 h. OPG was measured in the cell culture medium by immunoassay. PDGF isoforms AA, BB and AB show similar stimulation of OPG production. Message for OPG was also increased similarly to the increased secretion into the culture medium. Using specific inhibitors of cell signalling we demonstrate that PDGF acts through the PDGF receptor, PKC, PI3K, ERK and P38 and not via NF-kB or JNK. The importance of PDGF in fracture healing suggests a role for OPG production in countering bone resorption during the early phase of this process.

Bone loss after stroke over 52 weeks at os calcis: influence of sex, mobility and relation to bone density at other sites.

BACKGROUND: As life expectancy increases after stroke, skeletal consequences become increasingly important, and patients at risk of fracture require identification. We have investigated peripheral bone mineral density (BMD) measurement at the heel as a possible surrogate for hip dual energy X-ray absorptiometry measurement and we have related bone loss over 52 weeks to balance and mobility. METHODS: BMD at the heel (PIXI), proximal femur and whole body (QDR4500A), Tinetti (a measure of mobility and balance) and Barthel (a measure of activities of daily living) scores were measured in 52 patients (27 males and 25 females) within 8 weeks of stroke and repeated in 27 (15 males and 12 females) after 52 weeks. RESULTS: BMD was not initially low at the femoral neck (FN). A significant fall occurred on the stroke side (SS) over 52 weeks at the heel, FN and total hip (TH), in both sexes, but was greater in women. On the non-SS, women lost bone at the TH and heel. Patients who were in the lowest Tinetti score tertile initially, showed significant loss of bone in the FN (14.5%) and at the heel (12.2%) on the SS. BMD at the SS heel correlated with the FN at 8 weeks (r = 0.64, P<0.01) and at 52 weeks (r = 0.60, P<0.01) after stroke. Women lost more bone than men on SS but also lost bone on the non-SS at the same sites, suggesting that SS bone loss may result from factors additional to stroke. CONCLUSION: Heel BMD was a useful surrogate for hip BMD. Low initial Tinetti scores were an indicator of bone loss and, together with initial BMD measurements, provide a useful indication for those needing early prophylaxis against bone loss.

Depression in temporal lobe epilepsy surgery patients: an FDG-PET study.

PURPOSE: Depression is common in temporal lobe epilepsy (TLE) and after temporal lobectomy, and its etiology is obscure. In nonepileptic depression (including depression associated with other neurologic disorders), a consistent PET imaging finding is frontal lobe hypometabolism. Many TLE patients have hypometabolism involving frontal regions. Thus in data available from routine clinical assessments in an epilepsy surgery unit, we tested the hypothesis that the pattern of hypometabolism, particularly in the frontal lobe, may be associated with the depression seen in patients with TLE and TLE surgery. METHODS: We studied 23 medically refractory TLE patients who underwent anterior temporal lobectomy and who had preoperative FDG-PET scanning. All patients had pre- and postoperative psychiatric assessment. By using statistical parametric mapping (SPM-99), patterns of hypometabolism were compared between patients who had a preoperative history of depression (n=9) versus those who did not (n=14) and between those in whom postoperative depression developed (n=13) versus those in whom it did not (n=10). A significant region of hypometabolism was set at p<0.001 for a cluster of >or=20 contiguous voxels. RESULTS: Patients with a history of depression at any time preoperatively showed focal hypometabolism in ipsilateral orbitofrontal cortex compared with those who did not (t=4.64; p<0.001). Patients in whom depression developed postoperatively also showed hypometabolism in the ipsilateral orbitofrontal region (t=5.10; p<0.001). CONCLUSIONS: Although this study is methodologically limited, and other explanations merit consideration, orbitofrontal cortex dysfunction, already implicated in the pathophysiology of nonepileptic depression, may also be relevant to the depression of TLE and temporal lobectomy.

Excess non-spine fractures in women over 50 years with celiac disease: a cross-sectional, questionnaire-based study.

The association of celiac disease with fracture is controversial. Recent studies may have underestimated the impact by studying patients with low fracture risk. Since postmenopausal women are at greatest risk of fracture, we have investigated non-spine fracture occurrence in women > or =50 years with celiac disease. Patients were recruited from hospital and general practice as well as from volunteers, controls from general practice. All completed a questionnaire detailing fracture occurrence. Three hundred and eighty-three female celiac patients and 445 female controls aged > or =50 years at time of study were compared. Mean age was 61.4+/-7.8 years in celiac patients and 62.7+/-9.9 years in controls. Celiac patients were lighter but not shorter. Celiac patients displayed greater "all fracture" prevalence (odds ratio [OR], 1.51; confidence interval [CI], 1.13:2.02) and fracture after 50 years (OR, 2.20; CI, 1.49:3.25). Wrist fracture was more frequent (OR, 1.65; CI, 1.12:2.41), but significance was lost once height and weight were taken into account. Celiac patients had more multiple fractures (OR, 2.96; CI, 1.81:4.83). To investigate the association of fracture with time from diagnosis, 324 celiac patients were paired with a control by age. No excess fracture risk was found more than 10 years before diagnosis amongst celiac patients diagnosed after age 50 years, but risk increased in the period from 10 years before diagnosis to 5 years after and remained high more than 5 years after diagnosis ( p<0.05). Wrist fracture only increased in the period more than 5 years after diagnosis ( p<0.05). In women diagnosed before 50 years, no excess fracture risk existed. Fracture risk in female celiac patients >50 years is increased overall but is related largely to the peri-diagnostic period. Wrist fracture risk is partly accounted for by height and weight, but is more common more than 5 years after diagnosis. Celiac testing may be indicated in thin women over 50 years with multiple fractures, and after diagnosis adequate calcium and vitamin D intake should be ensured.

Assessment of urinary bone markers for monitoring treatment of osteoporosis.

BACKGROUND: The usefulness of urinary markers of bone turnover in monitoring therapy depends on their within-person variability compared with their responses to therapy. The aim of this study was to assess the performance of two such markers on this basis. METHODS: We measured variation, during a whole year, of cross-linked N-terminal telopeptide of collagen I (NTx) and urinary deoxypyridinoline (DPD) as ratios to creatinine concentration and after log-transformation of the ratios in untreated women stratified into three bone density classes, of which the lowest was osteoporotic. We also measured changes in bone mineral density at the lumbar spine (LSBMD) and hip (FNBMD) in untreated women with normal bones and in those with moderate osteopenia and calculated the reference change value (RCV; or least significant change) at P <0.05 for all of these measures. We made the same measurements on women treated with bisphosphonates, estrogen replacement (HRT), or calcium and examined their individual responses to treatment compared with RCV. RESULTS: After 12 months on bisphosphonates, LSBMD changed more than RCV (2.55%) in 47% of women compared with 44% of those on HRT and 13% of those on calcium. Response of FNBMD was less. Log NTx (RCV= -28%) responded to bisphosphonates in 78%, regardless of BMD, but less often to HRT (67%). Log DPD (RCV= -30%) responded to bisphosphonates less frequently (31% at 12 months). CONCLUSIONS: NTx has advantages over DPD in monitoring therapy for osteoporosis when mailed urine samples are used.

Knee angles and rickets in nigerian children.

Knee angles of 2,036 normal Nigerian children up to 12 years old were measured directly or from photographs. The knees were bowed (varus) in the first 6 months. At 21 to 23 months, the distribution of angles became strongly bimodal: about half were varus and half were valgus (knock-kneed), with few in between. After this they were all valgus, with few exceptions. Hence, the change from varus to valgus in individual infants must be sudden (a few weeks), although the changeover of the whole population appears smooth and gradual. They became maximally and uniformly knock-kneed (-7.1 degrees +/- 1.4 degrees) between 3 and 3.5 years, with little change thereafter. On the other hand, 120 patients with rickets discovered during screening had large knee angles, in either sense, with a bimodal distribution and frequency maxima at +10 degrees (varus) and -12 degrees (valgus). Varus knee is uncommon after 2 years. Large knee angles between 2 and 5 years suggest rickets.

Therapeutic equivalence of alendronate 35 milligrams once weekly and 5 milligrams daily in the prevention of postmenopausal osteoporosis.

OBJECTIVE: To evaluate the efficacy and safety of alendronate 35 mg once weekly compared with alendronate 5 mg daily in the prevention of osteoporosis. METHODS: We compared the efficacy and safety of treatment with alendronate 35 mg once weekly (n = 362) and alendronate 5 mg daily (n = 361) in a 1-year, double-blind, multicenter study of postmenopausal women (6 months or greater), aged 40-70 years, with lumbar spine and femoral neck bone mineral density T-scores between -2.5 and 1. The primary efficacy end point was the comparability of lumbar spine bone mineral density increases, defined by strict prespecified criteria. RESULTS: Mean increases in lumbar spine bone mineral density at 12 months were equivalent (difference between the alendronate 35-mg once-weekly group and the alendronate 5-mg daily group [90% confidence interval] at month 12 was -0.3% [-0.6, 0.1], well within the prespecified bounds of +/-1.0%). Bone mineral density increases at other skeletal sites and effects on bone turnover were also virtually identical for the two dosing regimens. Both treatment regimens were well tolerated, and the larger weekly unit dose was not associated with an increased frequency of upper gastrointestinal events. CONCLUSION: Alendronate 35 mg once weekly is therapeutically equivalent to alendronate 5 mg daily and provides patients with greater dosing convenience, in addition to the proven efficacy of alendronate and good tolerability.