Tim Cundy

Publications of Tim Cundy

• Should measurement of vitamin D and treatment of vitamin D insufficiency be routine in New Zealand?

  Authors: Mark J Bolland, Andrew Grey, James S Davidson, Tim Cundy, Ian R Reid

  The New Zealand medical journal. 01/2012; 125(1349):83-91.

  Epidemiological studies have reported associations between lower vitamin D levels and a great variety of diseases, prompting calls for widespread treatment of individuals with low vitamin D levels.Epidemiological studies have reported associations between lower vitamin D levels and a great variety of diseases, prompting calls for widespread treatment of individuals with low vitamin D levels. Most of New Zealand's population have vitamin D levels for at least part of the year that are considered insufficient (25-hydroxyvitamin D <50-80 nmol/L). However, evidence for benefits of vitamin D supplementation in such populations is controversial and there is some evidence of harmful effects. Until adequately powered, randomised, controlled trials of vitamin D supplementation demonstrate safe improvements in health, clinicians should not focus on detecting/treating individuals with vitamin D insufficiency, instead treating those at high risk of vitamin D deficiency (25-hydroxyvitamin D <25 nmol/L), such as the frail elderly, and those with specific clinical indications. Treatment for such individuals does not require vitamin D measurements. Requests for vitamin D measurements in Auckland have nearly quadrupled in the past decade, from 8500 in the year 2000 to 32,800 in 2010, with substantial increases in cost. Vitamin D measurement is often inaccurate and imprecise, and the vast majority of tests performed currently do not reveal vitamin D deficiency. Therefore, a move away from routine vitamin D measurements seems sensible, though they are still indicated when investigating suspected metabolic bone disease or hypocalcaemia.

• Paget's disease of bone.

  Authors: Tim Cundy, Ian R Reid

  Clinical biochemistry. 01/2012; 45(1-2):43-8.

  To review recent advance in understanding the causation and management of Paget's disease. We review recent publications concerning the aetiology of the disease and the use of biochemical markers ofTo review recent advance in understanding the causation and management of Paget's disease. We review recent publications concerning the aetiology of the disease and the use of biochemical markers of bone turnover in diagnosis and treatment. Epidemiologic studies suggest that Paget's disease is decreasing in prevalence and severity (implying that environmental factors are important) but there is also strong evidence of a genetic predisposition particularly through the SQSTM1 gene. Genome-wide association studies have identified polymorphisms at several other loci that are associated with the disease. Plasma alkaline phosphatase activity (ALP) is widely used, but less helpful in patients with disease of limited extent. Of the newer markers, plasma procollagen-1 N-peptide (PINP) performs best. Treatment with potent bisphosphonates usually produces long-term remission. Both genetic and environmental factors appear to be important in the aetiology of Paget's disease. Effective long-term disease suppression can be achieved with bisphosphonate treatment.

• Paget's disease in patients of Asian descent in New Zealand.

  Authors: Shyam Sankaran, Dorit Naot, Andrew Grey, Tim Cundy

  Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 09/2011;

  Paget's disease is considered to be uncommon in Asian people, but we have noted a recent increase in the number of Asian patients referred to our clinic, on a background of an apparently decreasingPaget's disease is considered to be uncommon in Asian people, but we have noted a recent increase in the number of Asian patients referred to our clinic, on a background of an apparently decreasing prevalence in the population of European descent. In this paper we report clinical and epidemiological features of patients of Asian descent with Paget's disease, referred between 1973 and 2010 to the Auckland Paget's disease clinic. No Asian patients were referred before 1993, but 14 have presented between 1993 and 2010, with a median of eight years between arrival into New Zealand and time of diagnosis. The patients were predominantly of south Asian origin. None of the eight patients tested carried a mutation in exon 8 of the SQSTM1 gene. The number of new Paget's disease referrals expressed as a proportion of the potentially at-risk Asian population in the Auckland region (derived from census data) was 1/10(4) in 2006-2011. Amongst Europeans, the corresponding value decreased from 10/10(4) in 1986-1991 to 2/10(4) in 2006-2010. The increased number of people of Asian descent diagnosed with Paget's disease in the Auckland region has paralleled the increasing size of the local Asian population. The continuing decline of Paget's disease in the European population, in conjunction with the emergence of the disease in the Asian population, supports the view that an environmental determinant to the disease exists and that Asians are not genetically protected. It also implies that the apparent reduction in Paget's disease prevalence in western cities is unlikely to be explicable by the rising Asian population of these cities. © 2011 American Society for Bone and Mineral Research.

• Familial Paget disease and SQSTM1 mutations in New Zealand.

  Authors: Tim Cundy, Dorit Naot, Usha Bava, David Musson, Pak Cheung Tong, Mark Bolland

  Calcified tissue international. 09/2011; 89(3):258-64.

  Genetic factors play an important role in the pathogenesis of Paget disease of bone (PDB). SQSTM1 is the most important disease-associated gene identified to date. We investigated the relationship ofGenetic factors play an important role in the pathogenesis of Paget disease of bone (PDB). SQSTM1 is the most important disease-associated gene identified to date. We investigated the relationship of family history, phenotype, and SQSTM1 mutation status in New Zealand (a country with a high prevalence of PDB) in patients with a family history and/or a severe phenotype. We studied 61 unrelated subjects with familial PDB. Family history was subclassified into three groups according to the closeness of the relationship. We also studied a fourth group of 19 unrelated patients defined by early onset and/or severe disease but no family history. The PDB phenotype was defined according to age, alkaline phosphatase activity, and disease extent on scintiscan at the time of diagnosis. Mutations in exon 8 of SQSTM1 were detected by screening of genomic DNA. Four different mutations were identified; the ubiquitous P392L mutation and the truncating mutation E396X accounted for 89% of cases. Overall 26% of patients with familial PBD in New Zealand had disease-associated mutations in the SQSTM1 gene. Mutations were most prevalent (60%) in those with a parent or sibling and at least one other relative affected (P < 0.002). The severity of the phenotype was significantly related to SQSTM1 mutation status but not the strength of the family history (P < 0.005). SQSTM1 mutations were found in 10.5% of patients with early onset and/or severe disease but no family history.

• Proposed new diagnostic criteria for gestational diabetes--a pause for thought?

  Authors: T Cundy

  Diabetic medicine : a journal of the British Diabetic Association. 08/2011; 29(2):176-80.

  New criteria for the diagnosis of gestational diabetes promulgated by the International Association of Diabetes and Pregnancy Study Groups (IADSPG) have been adopted by a number of groups, includingNew criteria for the diagnosis of gestational diabetes promulgated by the International Association of Diabetes and Pregnancy Study Groups (IADSPG) have been adopted by a number of groups, including the American Diabetes Association. These criteria will increase two- to three-fold the number of women diagnosed with gestational diabetes and have enormous resource implications. The recommendations are derived from observations made in the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study, which demonstrated continuous relationships between maternal glucose tolerance and two clinically relevant outcomes of pregnancy (caesarean section rate and neonatal hypoglycaemia) and two surrogate measures (birth weight and cord C-peptide). The recent randomized intervention studies in mild gestational diabetes indicate that the major effects of detecting and treating mild gestational diabetes are a reduction in mean birthweight of 100-140 g, and a reduction in the incidence of shoulder dystocia. However, the women included in these studies were identified using different diagnostic criteria, and it cannot be assumed that women diagnosed by the less stringent IADSPG criteria will have the same benefit. Moreover, as the majority of cases of macrosomia and shoulder dystocia occur in women with normal glucose tolerance, the real impact of diagnosing many more 'cases' of gestational diabetes is likely to be minimal. The concentration on mild degrees of hyperglycaemia may well be misplaced, as most of the outcomes usually attributed to gestational diabetes are more strongly associated with maternal obesity and weight gain in pregnancy. The new testing procedure (with diagnosis based on a single blood glucose measurement) will inevitably be imprecise. Given the many reservations about the new criteria an urgent but dispassionate debate is required on the risks, costs and benefits of their introduction.

• Genome-wide association identifies three new susceptibility loci for Paget's disease of bone.

  Authors: Omar M E Albagha, Sachin E Wani, Micaela R Visconti, Nerea Alonso, Kirsteen Goodman, Maria Luisa Brandi, Tim Cundy, Pui Yan Jenny Chung, Rosemary Dargie, Jean-Pierre Devogelaer [......] Socrates Papapoulos, Javier del Pino Montes, Thomas Ratajczak, Sarah L Rea, Domenico Rendina, Rogelio Gonzalez-Sarmiento, Marco Di Stefano, Lynley C Ward, John P Walsh, Stuart H Ralston

  Nature genetics. 05/2011; 43(7):685-9.

  Paget's disease of bone (PDB) is a common disorder characterized by focal abnormalities of bone remodeling. We previously identified variants at the CSF1, OPTN and TNFRSF11A loci as risk factors forPaget's disease of bone (PDB) is a common disorder characterized by focal abnormalities of bone remodeling. We previously identified variants at the CSF1, OPTN and TNFRSF11A loci as risk factors for PDB by genome-wide association study. Here we extended this study, identified three new loci and confirmed their association with PDB in 2,215 affected individuals (cases) and 4,370 controls from seven independent populations. The new associations were with rs5742915 within PML on 15q24 (odds ratio (OR) = 1.34, P = 1.6 × 10(-14)), rs10498635 within RIN3 on 14q32 (OR = 1.44, P = 2.55 × 10(-11)) and rs4294134 within NUP205 on 7q33 (OR = 1.45, P = 8.45 × 10(-10)). Our data also confirmed the association of TM7SF4 (rs2458413, OR = 1.40, P = 7.38 × 10(-17)) with PDB. These seven loci explained ∼13% of the familial risk of PDB. These studies provide new insights into the genetic architecture and pathophysiology of PDB.

• Proton pump inhibitors and severe hypomagnesaemia.

  Authors: Tim Cundy, Jonathan Mackay

  Current opinion in gastroenterology. 03/2011; 27(2):180-5.

  Hypomagnesaemia has recently been recognized as a rare, but severe, complication of proton pump inhibitor (PPI) use. We reviewed all the cases published to date in peer-reviewed journals to summarizeHypomagnesaemia has recently been recognized as a rare, but severe, complication of proton pump inhibitor (PPI) use. We reviewed all the cases published to date in peer-reviewed journals to summarize what is known of the epidemiology, risk factors, cause and treatment. Hypomagnesaemia has been described with all substituted pyridylmethylsulphonyl benzimidazadole derivatives and is a class effect, recurring with substitution of one PPI for another. A long duration of use and high rates of adherence are probably risk factors, but the prevalence is unknown. The diagnosis is often missed, despite the severe symptomatology. Renal magnesium handling is normal, so implicating impairment of net intestinal absorption as the proximate cause. It is not known whether this is the consequence of defective absorption of magnesium through the active or passive transport processes, or increased losses. PPI-associated hypomagnesaemia is a rare, but potentially life-threatening, side-effect that has emerged only in the era of mass use of these agents. The cause of hypomagnesaemia remains poorly understood, but it responds rapidly to withdrawal of the PPI.

• Response to publication of PRISM trial.

  Authors: Ian R Reid, Tim Cundy, Mark J Bolland, Andrew Grey

  Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 06/2010; 25(6):1463-4; author reply 1465-6.

• Genome-wide association study identifies variants at CSF1, OPTN and TNFRSF11A as genetic risk factors for Paget's disease of bone.

  Authors: Omar M E Albagha, Micaela R Visconti, Nerea Alonso, Anne L Langston, Tim Cundy, Rosemary Dargie, Malcolm G Dunlop, William D Fraser, Michael J Hooper, Gianluca Isaia, Geoff C Nicholson, Javier del Pino Montes, Rogelio Gonzalez-Sarmiento, Marco di Stefano, Albert Tenesa, John P Walsh, Stuart H Ralston

  Nature genetics. 06/2010; 42(6):520-4.

  Paget's disease of bone (PDB) is a common disorder with a strong genetic component characterized by focal increases in bone turnover, which in some cases is caused by mutations in SQSTM1. To identifyPaget's disease of bone (PDB) is a common disorder with a strong genetic component characterized by focal increases in bone turnover, which in some cases is caused by mutations in SQSTM1. To identify additional susceptibility genes, we performed a genome-wide association study in 750 individuals with PDB (cases) without SQSTM1 mutations and 1,002 controls and identified three candidate disease loci, which were then replicated in an independent set of 500 cases and 535 controls. The strongest signal was with rs484959 on 1p13 near the CSF1 gene (P = 5.38 x 10(-24)). Significant associations were also observed with rs1561570 on 10p13 within the OPTN gene (P = 6.09 x 10(-13)) and with rs3018362 on 18q21 near the TNFRSF11A gene (P = 5.27 x 10(-13)). These studies provide new insights into the pathogenesis of PDB and identify OPTN, CSF1 and TNFRSF11A as candidate genes for disease susceptibility.

• Ocular manifestations of juvenile Paget disease.

  Authors: Nathan M Kerr, Hamilton R Cassinelli, Linda A DiMeglio, Cristina Tau, Beyhan Tüysüz, Tim Cundy, Andrea L Vincent

  Archives of ophthalmology. 06/2010; 128(6):698-703.

  To determine the prevalence and spectrum of retinal changes in juvenile Paget disease. Observational case series and literature review with analysis. Patients with clinical and molecular evidence ofTo determine the prevalence and spectrum of retinal changes in juvenile Paget disease. Observational case series and literature review with analysis. Patients with clinical and molecular evidence of juvenile Paget disease were recruited by members of the International Hyperphosphatasia Collaborative Group. Participants underwent ophthalmic examinations consisting of at least best-corrected Snellen visual acuity and dilated fundal examination or color fundus photography. A MEDLINE literature search was performed, and all identified case reports were reviewed for information regarding ocular phenotype. Fourteen eyes from 7 patients were examined. The mean (SD) patient age was 22 (8) years, and 4 patients were female. Retinal abnormalities were evident in 12 of 14 eyes and were reported among an additional 12 patients in the literature. Retinal abnormalities included mottling of the retinal pigment epithelium, peripapillary atrophy, angioid streaks, and choroidal neovascularization. Cumulative number of retinal abnormalities was strongly associated with increasing age. Juvenile Paget disease is associated with progressive retinopathy characterized by the development of angioid streaks, which may be complicated by choroidal neovascularization, the predominant cause of visual loss. Osteoprotegerin or its signaling pathway may have a role in calcification of Bruch membrane and in the pathogenesis of angioid streaks. Retinopathy in patients with juvenile Paget disease may be a sign of a more generalized vascular disorder.

• Paget's disease of bone--becoming a rarity?

  Authors: Sonja Bastin, Helen Bird, Gregory Gamble, Tim Cundy

  Rheumatology (Oxford, England). 07/2009;

  Objectives. Paget's disease is a chronic bone disorder of unknown cause. Recent studies have reported an unexplained reduction in both prevalence and disease severity. We undertook a radiographicObjectives. Paget's disease is a chronic bone disorder of unknown cause. Recent studies have reported an unexplained reduction in both prevalence and disease severity. We undertook a radiographic survey to determine the current prevalence of Paget's disease in New Zealand (previously recognized as a high prevalence area). Methods. A total of 3350 plain abdominal radiographs taken in 2005-06 in subjects of European descent >54 years old were examined for Paget's disease. The results were compared with those of a similar survey from 1996-98. The medical record of affected subjects was examined to determine when the disease had been first recognized and the plasma ALP at that time. Results. Paget's disease was detected in 87 radiographs (2.6%). In 55 cases (63%), it was already known to have been present, for a mean 14 years beforehand. The newly recognized or 'incident' cases were significantly older (mean age 86 vs 67 years, P < 0.0001) and had milder disease (ALP 139 vs 239 u/l, P < 0.0001) than the known cases. Compared with the 1996-98 survey, the age distribution of affected patients was shifted to the right, with a significantly lower proportion in the youngest age group (55-69 years, P < 0.004). Conclusions. These results confirm the secular trend of Paget's disease presenting later in life and in milder form, suggesting that there are important environmental determinants. The relatively few 'incident' cases are mostly in the very elderly. Given the secular trend and limitations to life expectancy, it is predicted that Paget's disease will become increasingly rare.

• Osteonecrosis of the jaw.

  Authors: Ian R Reid, Tim Cundy

  Skeletal radiology. 02/2009; 38(1):107.

• Osteonecrosis of the jaw.

  Authors: Ian R Reid, Tim Cundy

  Skeletal radiology. 01/2009; 38(1):5-9.

  Osteonecrosis of the jaw (ONJ) was first reported in the dental literature in 2003. The term was coined to describe a spectrum of dental problems seen in cancer patients treated with high doses ofOsteonecrosis of the jaw (ONJ) was first reported in the dental literature in 2003. The term was coined to describe a spectrum of dental problems seen in cancer patients treated with high doses of intravenous bisphosphonates for the prevention of skeletal-related events. By consensus, the syndrome is now defined by the presence of exposed bone in the mouth which fails to heal after appropriate intervention over a period of 6 or 8 weeks. It is most common in patients with breast or prostate cancers, or multiple myeloma treated with bisphosphonates, of whom about 5% develop the condition. In patients receiving the much lower drug doses used in osteoporosis, the incidence appears to be approximately 1/100,000 patient-years, probably comparable to that in the general population. It is likely that ONJ results from direct drug toxicity to cells of bone and soft tissue. The bone in ONJ lesions does not appear to be 'frozen' but rather there is very active bone resorption taking place, which is likely to be responsible for the local release at high concentrations of bisphosphonates. Infection probably plays a pivotal role in driving this resorption, so its active management is critical. Obvious abnormalities are apparent with a variety of radiologic modalities, and it is not clear that radiographs are inferior to other approaches. Most authors favor a conservative approach to surgical debridement of the lesions.

• ABSENCE OF SOMATIC SQSTM1 MUTATIONS IN PAGET'S DISEASE OF BONE.

  Authors: Brya G Matthews, Dorit Naot, Usha Bava, Karen E Callon, Rocco P Pitto, Stuart A McCowan, Diana Wattie, Tim Cundy, Jill Cornish, Ian R Reid

  The Journal of clinical endocrinology and metabolism. 12/2008;

  Background: Paget's disease is a common focal bone disorder that appears to be caused by a combination of genetic and environmental factors. Mutations in the SQSTM1 gene are found in around a thirdBackground: Paget's disease is a common focal bone disorder that appears to be caused by a combination of genetic and environmental factors. Mutations in the SQSTM1 gene are found in around a third of families with Paget's disease, and 8% of sporadic cases. Other potential loci linked to the disease have also been identified, and a number of environmental factors have been suggested to be involved in the disease. However, the focal nature of Paget's is still unexplained. Therefore, we examined the possibility that somatic mutations in the SQSTM1 gene are present in the local lesions, using RNA collected from primary osteoblast and bone marrow cell cultures of patients with this condition. Methods: SQSTM1 was sequenced, and allelic discrimination for the common P392L mutation was performed in cDNA samples from 14 osteoblast cultures and from 14 cultures of bone marrow cells. Results: In these 28 samples drawn from 23 patients, the wild-type sequence of SQSTM1 was found in all but one marrow sample, which was heterozygous for the P392L mutation. DNA from peripheral blood in this subject had an identical sequence of SQSTM1, indicating that this was a germ-line mutation. Conclusion: We conclude that somatic mutations for SQSTM1 are not commonly present in Paget's disease.

• Paget disease of bone.

  Authors: Tim Cundy, Mark Bolland

  Trends in endocrinology and metabolism: TEM. 10/2008; 19(7):246-53.

  Despite significant advances in management, Paget disease remains an enigmatic disorder. There are no animal models, and while its end result - a focal disorder of accelerated bone turnover - isDespite significant advances in management, Paget disease remains an enigmatic disorder. There are no animal models, and while its end result - a focal disorder of accelerated bone turnover - is easily recognized, the causes and evolution of the disorder remain uncertain. Recent evidence strongly implicates both genetic and environmental factors in its etiology. The authors consider some of the unresolved questions surrounding Paget disease, including the attenuating prevalence and severity of the disease; how these observations might be reconciled with an apparently highly penetrant genetic susceptibility; what the putative environmental triggers of Paget disease might be; and what relapse after treatment tells us. Most observations seem to fit best with the idea that Paget disease behaves as a multifocal benign neoplasm.

• Failure to detect measles virus ribonucleic acid in bone cells from patients with Paget's disease.

  Authors: Brya G Matthews, Muhammad A Afzal, Philip D Minor, Usha Bava, Karen E Callon, Rocco P Pitto, Tim Cundy, Jill Cornish, Ian R Reid, Dorit Naot

  The Journal of clinical endocrinology and metabolism. 05/2008; 93(4):1398-401.

  BACKGROUND: Paget's disease is a condition of focal accelerated bone turnover. Electron-microscopy investigations of osteoclasts from pagetic lesions have identified nuclear inclusion bodies thatBACKGROUND: Paget's disease is a condition of focal accelerated bone turnover. Electron-microscopy investigations of osteoclasts from pagetic lesions have identified nuclear inclusion bodies that have a similar appearance to viral nucleocapsid particles. Subsequently, RNA from several paramyxoviruses has been detected in pagetic tissue, and it was suggested that these viruses, in particular measles, might play a role in the etiology of Paget's disease. We have tested for measles virus sequences in osteoblasts and bone marrow cells collected from pagetic lesions and healthy bone. METHODS: Bone and bone marrow samples were taken from Paget's patients and control subjects, and cells were cultured from each of these tissues. RNA was extracted from 13 osteoblast cultures and 13 cultures of bone marrow cells derived from pagetic lesions, and from 26 and 23 control osteoblast and bone marrow cultures, respectively. These samples were sourced from 22 patients with Paget's disease and 31 controls. RT-PCR-nested PCR amplification was used for the detection of the genes for the measles nucleocapsid and matrix proteins. RESULTS: Measles virus sequences were not detected in any of the pagetic or control samples. However, measles virus sequences were identified in samples of a measles virus culture isolate included as a positive control, and in a brain sample from a patient with subacute sclerosing panencephalitis, a condition associated with chronic measles infection. CONCLUSION: The results of the study do not support the hypothesis that measles virus plays a role in the pathogenesis of Paget's disease.

• Identification of a major locus for Paget's disease on chromosome 10p13 in families of British descent.

  Authors: Gavin Ja Lucas, Phillip L Riches, Lynne J Hocking, Tim Cundy, Geoff C Nicholson, John P Walsh, Stuart H Ralston

  Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 02/2008; 23(1):58-63.

  Mutations of SQSTM1 are an important cause of PDB, but other genes remain to be discovered. A major susceptibility locus for PDB was identified on chromosome 10p13 by a genome-wide linkage scan inMutations of SQSTM1 are an important cause of PDB, but other genes remain to be discovered. A major susceptibility locus for PDB was identified on chromosome 10p13 by a genome-wide linkage scan in families of British descent, which accounted for the vast majority of cases not caused by SQSTM1 mutations. INTRODUCTION: Paget's disease of bone (PDB) has a strong genetic component, and several susceptibility loci have been identified by genome-wide linkage scans. We previously identified three susceptibility loci for PDB using this approach on chromosomes 5q35, 2q36, and 10p13 in 62 families of mainly British descent, but subsequently, mutations in the SQSTM1 gene were found to be the cause of PDB in 23 families from this cohort. Here we reanalyzed the results of our genome-wide search in families from this cohort who did not have SQSTM1 mutations. MATERIALS AND METHODS: The study population consisted of 210 individuals from 39 families of predominantly British descent with autosomal dominant inheritance of PDB in whom SQSTM1 mutations had been excluded by mutation screening. The average family size was 5.44 +/- 3.98 (SD) individuals (range, 2-24 individuals). Genotyping was performed using standard techniques with 382 microsatellite markers spaced at an average distance of 9.06 cM throughout the autosomes. Multipoint linkage analysis was performed using the GENEHUNTER program under models of homogeneity and heterogeneity. RESULTS: Multipoint parametric linkage analysis under a model of homogeneity and nonparametric linkage analysis under a model of heterogeneity both showed strong evidence of linkage to a single locus on chromosome 10p13 (LOD score, +4.08) close to the marker D10S1653 at 41.43cM. No evidence of linkage was detected at the chromosome 2q36 locus previously identified in this population, and linkage to other candidate loci previously implicated in the pathogenesis of PDB was excluded. CONCLUSIONS: We conclude that there is an important susceptibility gene for PDB on chromosome 10p13 in families of British descent and find no evidence to support the existence of a susceptibility locus on chromosome 2q36 or other previously identified candidate loci for PDB in this population. The gene that lies within the 10p13 locus seems to account for the development of PDB in the vast majority of families of British descent who do not carry SQSTM1 mutations.

• Differing causes of pregnancy loss in type 1 and type 2 diabetes.

  Authors: Tim Cundy, Greg Gamble, Leonie Neale, Rose Elder, Paul McPherson, Patrick Henley, Janet Rowan

  Diabetes care. 11/2007; 30(10):2603-7.

  OBJECTIVE: Women with type 2 and type 1 diabetes have differing risk factors for pregnancy loss. We compared the rates and causes of pregnancy loss in women with type 1 and type 2 diabetes. RESEARCHOBJECTIVE: Women with type 2 and type 1 diabetes have differing risk factors for pregnancy loss. We compared the rates and causes of pregnancy loss in women with type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: We utilized prospectively collected data on all pregnancies in a 20-year period (1986-2005) from a single center with a high prevalence of type 2 diabetes. Pregnancy losses included terminations for medical reasons and deaths up to 1 month postpartum but not spontaneous pregnancy losses <20 weeks' gestation. RESULTS: There were 870 pregnancies in women with known diabetes (330 with type 1 and 540 with type 2 diabetes) and 325 in women with diabetes diagnosed in pregnancy but persisting postpartum (97% type 2 diabetes). The rate of pregnancy loss was similar in type 1 and type 2 diabetes (2.6 vs. 3.7%, P = 0.39), but the causes of pregnancy loss differed. In type 1 diabetes >75% were attributable to major congenital anomalies or prematurity; in type 2 diabetes >75% were attributable to stillbirth or chorioamnionitis (P = 0.017). Women with type 2 and type 1 diabetes had similar A1C at presentation and near term, but the former were older (P < 0.001) and more obese (P < 0.0001). CONCLUSIONS: There are significant differences in the main causes of pregnancy loss in women with type 1 and type 2 diabetes. The higher rates of stillbirth in women with type 2 diabetes, suggest that other features, such as obesity, contribute significantly to pregnancy losses.

• Addition of monofluorophosphate to estrogen therapy in postmenopausal osteoporosis: a randomized controlled trial.

  Authors: Ian R Reid, Tim Cundy, Andrew B Grey, Anne Horne, Judith Clearwater, Ruth Ames, Brandon J Orr-Walker, Fiona Wu, Margaret C Evans, Gregory D Gamble, Alan King

  The Journal of clinical endocrinology and metabolism. 07/2007; 92(7):2446-52.

  INTRODUCTION: Treatment of osteoporosis with high-dose fluoride alone does not reduce fracture risk. We hypothesized that the antifracture efficacy of fluoride could be optimized by its use in lowINTRODUCTION: Treatment of osteoporosis with high-dose fluoride alone does not reduce fracture risk. We hypothesized that the antifracture efficacy of fluoride could be optimized by its use in low doses combined with an antiresorptive agent. EXPERIMENTAL SUBJECTS: Subjects included 80 women with postmenopausal osteoporosis who had been taking estrogen for at least 1 yr. METHODS: Subjects were randomized to receive monofluorophosphate (MFP) (fluoride content of 20 mg/d) or placebo over 4 yr in a double-blind trial. RESULTS AND DISCUSSION: There were progressive increases in lumbar spine bone density over the duration of the study (MFP, 22%; placebo, 6%; P < 0.0001). In the trabecular bone of L3, these increases were even greater (MFP, 49%; placebo, 2.5%; P < 0.0001). In the proximal femur, there were smaller but significant treatment effects (P = 0.015). Total body scans and their subregions also showed significantly greater increases in the MFP group. Bone formation markers increased significantly in the MFP group at yr 1. Hyperosteoidosis was present in biopsies from five of seven MFP subjects, with osteomalacia in two of seven. The hazards ratio for vertebral fractures was 0.20 (95% confidence interval, 0.05-1.30), and the incidence rate ratio was 0.12 (95% confidence interval, 0.06-0.23; P < 0.01). The hazards ratio for nonvertebral fractures was 3.3 (95% confidence interval, 0.8-12.0). CONCLUSIONS: We conclude that fluoride at 20 mg/d produces substantial increases in bone mineral density but still interferes with bone mineralization. This indicates that most previous studies with this ion have used toxic doses and that much lower doses should be assessed to find a safe dose window for the use of this powerful anabolic agent.

• Bone formation markers in adults with mild osteogenesis imperfecta.

  Authors: Tim Cundy, Anne Horne, Mark Bolland, Greg Gamble, James Davidson

  Clinical chemistry. 06/2007; 53(6):1109-14.

  BACKGROUND: Plasma concentrations of procollagen peptides are decreased in osteogenesis imperfecta (OI), whereas other bone formation markers may be increased. We examined the utility of combiningBACKGROUND: Plasma concentrations of procollagen peptides are decreased in osteogenesis imperfecta (OI), whereas other bone formation markers may be increased. We examined the utility of combining these markers in the diagnosis of OI in adults. METHODS: We measured plasma concentrations of procollagen-1 N-peptide (P1NP), osteocalcin, and bone alkaline phosphatase in 24 patients with nondeforming OI, 25 patients with low bone mass due to other causes, and 38 age- and sex-matched controls. The discriminant ability of various test combinations was assessed by the construction of ROC curves. RESULTS: The median (range) ratio of osteocalcin to P1NP was significantly greater in patients with type I OI [1.75 (0.80-3.86)] than in controls [0.59 (0.34-0.90)] and patients with other causes of low bone mass [0.48 (0.05-1.38); P <0.0001]. This ratio allowed nearly complete differentiation between healthy controls and patients with type I OI, but not patients with type IV OI. With a cutoff of 0.97 for osteocalcin:P1NP, the sensitivity and specificity were maximized at 95% (95% CI 76%-100%) and 88% (69%-97%), respectively, for patients with other causes of low bone mass vs those with type I OI only. For patients with other causes of low bone mass vs all OI patients, sensitivity and specificity were 83% (63%-95%) and 88% (69%-97%), respectively. The addition of bone alkaline phosphatase data did not improve the discriminant ability of the osteocalcin:P1NP ratio. CONCLUSIONS: The osteocalcin:P1NP ratio is a sensitive and specific test for type I OI in adults, but it has less utility in the diagnosis of other types of nondeforming OI.