Center for Bone Disease

Marshfield, WI, United States

Center for Bone Disease

Marshfield, WI, United States
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Majewski J.,McGill University | Schwartzentruber J.A.,McGill University | Marcadier J.,Childrens Hospital of Eastern Ontario | Fryns J.-P.,University Hospitals Leuven | And 6 more authors.
Human Mutation | Year: 2011

Hajdu-Cheney syndrome (HCS) is a rare genetic disorder whose hallmark is acro-osteolysis, shortening of terminal phalanges, and generalized osteoporosis. We assembled a cohort of seven families with the condition and performed whole exome resequencing on a selected set of affected patients. One protein-coding gene, NOTCH2, carried heterozygous truncating variants in all patients and their affected family members. Our results replicate recently published studies of HCS and further support this as the causal gene for the disorder. In total, we identified five novel and one previously reported mutation, all clustered near the carboxyl terminus of the gene, suggesting an allele specific genotype-phenotype effect since other mutations in NOTCH2 have been reported to cause a form of Alagille syndrome. Notch-mediated signaling is known to play a role in bone metabolism. Our results support a potential therapeutic role for Notch pathways in treatment of osteoporosis. © 2011 Wiley-Liss, Inc.

McKiernan F.E.,Center for Bone Disease | Shrestha L.K.,The University of Oklahoma Health Sciences Center | Berg R.L.,Biomedical Informatics Research Center | Fuehrer J.,Biomedical Informatics Research Center
Osteoporosis International | Year: 2014

Summary: The temporal evolution of a low serum alkaline phosphatase value may relate to its cause. Precipitous lowering of serum alkaline phosphatase below the lower range of normal is uncommon and may indicate severe physiologic stress and increased short-term mortality. Introduction: The differential diagnosis of a low serum alkaline phosphatase (ALP) value (hypophosphatasemia) is wide ranging, anecdotal, and unfamiliar. The temporal evolution of hypophosphatasemia may relate to its cause. The purpose of this study is to report conditions and circumstances associated with precipitous lowering of serum ALP below the lower range of normal. Methods: Marshfield Clinic IRB approved use of their electronic medical record to search for subjects with at least two serum ALP values ≤40 U/L (normal 40-125 U/L). When the temporal evolution of the qualifying ALP values indicated a precipitous lowering from usually normal serum ALP values, the subject was deemed to have acute hypophosphatasemia. Thirty years of laboratory data and 10 years of clinical narrative were analyzed. Associated diagnoses, clinical circumstances, and short-term mortality were recorded. Results: A total of 458,767 subjects had 2,584,051 serum ALP values, and 5,190 (1.1%) subjects had at least two serum values ≤40 U/L. A detailed review of 1,276 subjects selected on the basis of their lowest ALP value and age identified 190 subjects with acute hypophosphatasemia. Acute hypophosphatasemia was recorded during periods of major trauma/surgery, multisystem failure, acute anemia, blood product transfusions (often massive), apheresis, hypo-magnesemia, and acute caloric restriction. Twenty-eight subjects (15%) died within 35 days of their nadir serum ALP. Conclusion: Acute hypophosphatasemia is associated with profound illness or physiologic stress and followed by increased short-term mortality. The temporal evolution of hypophosphatasemia may relate to its cause. © International Osteoporosis Foundation and National Osteoporosis Foundation 2013.

Epperla N.,Marshfield Clinic | McKiernan F.E.,Center for Bone Disease
Skeletal Radiology | Year: 2014

Hepatitis C-associated osteosclerosis (HCAO) is a rare sclerosing bone condition characterized by debilitating, predominantly lower extremity bone pain, accelerated bone turnover, and a generalized increase in histologically normal trabecular and cortical bone tissue. Herein we report the clinical presentation and imaging results of the 19th case of HCAO. Clinicians, particularly those caring for a population at risk for HCV infection, should be aware of this uncommon condition. The etio-pathogenesis of HCAO remains obscure but may bear important lessons in bone biology that could lead to new treatment options for osteoporosis. © 2014 ISS.

Broskey N.T.,University of Lausanne | Greggio C.,University of Lausanne | Boss A.,University of Bern | Boutant M.,Nestlé | And 10 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Context: Sarcopenia is thought to be associated with mitochondrial (Mito) loss. It is unclear whether the decrease in Mito content is consequent to aging per se or to decreased physical activity. Objectives: The objective of the study was to examine the influence of fitness on Mito content and function and to assess whether exercise could improve Mito function in older adults. Design and subjects: Three distinct studies were conducted: 1) a cross-sectional observation comparing Mito content and fitness in a large heterogeneous cohort of older adults; 2) a case-control study comparing chronically endurance-trained older adultsandsedentary (S) subjects matched for age and gender; and 3) a 4-month exercise intervention in S. Setting: The study was conducted at a university-based clinical research center. Outcomes: Mito volume density (MitoVd) was assessed by electron microscopy from vastus lateralis biopsies, electron transport chain proteins by Western blotting, mRNAs for transcription factors involved in M biogenesis by quantitative RT-PCR, and in vivo oxidative capacity (ATPmax) by 31Pmagnetice resonance spectroscopy. Peak oxygen uptake was measured by graded exercise test. Results: Peak oxygen uptake was strongly correlated with MitoVd in 80 60- to 80-year-old adults. Comparison of chronically endurance-trained older adults vs S revealed differences in MitoVd, ATPmax, and some electron transport chain protein complexes. Finally, exercise intervention confirmed that S subjects are able to recover MitoVd, ATPmax, and specific transcription factors. Conclusions: These data suggest the following: 1) aging per se is not the primary culprit leading to Mito dysfunction; 2) an aerobic exercise program, even at an older age, can ameliorate the loss in skeletal muscle Mito content and may prevent aging muscle comorbidities; and 3) the improvement of Mito function is all about content. © 2014 by the Endocrine Society.

McKiernan F.E.,Center for Bone Disease | Berg R.L.,Biomedical Informatics Research Center | Fuehrer J.,Biomedical Informatics Research Center
Journal of Bone and Mineral Research | Year: 2014

A serum alkaline phosphatase value below the age-adjusted lower limits of normal (hypophosphatasemia) is uncommonly encountered in clinical practice. The electronic and paper medical records of 885,165 patients treated between 2002 and 2012 at a large, rural, multispecialty health clinic were interrogated to estimate the prevalence and characterize the clinical and radiographic findings of adults whose serum alkaline phosphatase was almost always low (persistent hypophosphatasemia). We hypothesized that some of these patients might harbor previously unrecognized hypophosphatasia, a rare, inherited condition of impaired mineralization of bones and teeth. Persistent hypophosphatasemia (serum alkaline phosphatase ≤30 IU/L) was found in 1 of 1544 adult patients. These adult patients had more crystalline arthritis, orthopedic surgery, chondrocalcinosis, calcific periarthritis, enthesopathy, and diffuse idiopathic skeletal hyperostosis than a general adult patient population. A gender effect was observed. The clinical and radiographic findings of adult patients with persistent hypophosphatasemia resemble those of the adult form of hypophosphatasia. Clinicians should take notice of persistent hypophosphatasemia, consider the diagnosis of hypophosphatasia, and be cautious when considering potent anti-remodeling therapy in these adults. This population warrants further evaluation. © 2014 American Society for Bone and Mineral Research.

McKiernan F.E.,Center for Bone Disease
Journal of Clinical Densitometry | Year: 2016

Had Violet's abdominal MR not been performed, or its findings not appreciated, the cause of her clinical event might never have been known because our current concept of osteoporotic vertebral fracture (VF) is substantially predicated on a change in either vertebral height or shape on lateral or sagittal spine imaging. The intention of this commentary is to stimulate a multidisciplinary conversation of osteoporotic VFs from an integrated clinical, physiological, and imaging perspective. For research and epidemiological purposes, osteoporotic VFs have been defined as a reduction in anterior, middle, or posterior vertebral height although the required minimum height reduction (e.g., 15% or 20%) varies among definition schemes. We further classify osteoporotic VFs to be "clinical" when they are accompanied by back pain and "morphometric" when they are not, and we have generally accepted the assertion that most of the osteoporotic VFs are painless, that is, morphometric. This dichotomous VF definition scheme has been the foundation of osteoporosis epidemiology and the primary endpoint in most pivotal osteoporosis pharmaceutical trials. Although, having served the osteoporosis community well, our clinical experience, refined by recent insights into vertebral anatomy and spinal biomechanics, advances in vertebral imaging, and 2 decades of vertebral augmentation suggest that the spectrum of osteoporotic VFs is more complicated than this scheme suggests. © 2016 The International Society for Clinical Densitometry.

Ayub A.,Jacksonville University | Kenney C.V.,Marshfield Clinic | McKiernan F.E.,Center for Bone Disease
Journal of Clinical Rheumatology | Year: 2011

We report a case of painful, nodular periostitis in a lung transplant recipient on long-term voriconazole therapy. Symptoms, signs, and laboratory abnormalities resolved quickly after drug withdrawal. The presentation more closely resembles periostitis deformans than hypertrophic osteoarthropathy, suggesting that the fluoride moiety of voriconazole may be pathogenic for this condition. Clinicians should be aware of this association. Copyright © 2011 by Lippincott Williams &Wilkins.

McKiernan F.E.,Center for Bone Disease | Berg R.L.,Biomedical Informatics Research Center | Linneman J.G.,Biomedical Informatics Research Center
Osteoporosis International | Year: 2011

Summary: This very large dual X-ray absorptiometry (DXA) cohort confirmed a significant, inverse relationship between bone mineral density (BMD) Z-scores and the presence of secondary causes of osteoporosis but receiver operating characteristic (ROC) curves indicate that Z-score diagnostic thresholds (such as -2.0) discriminate poorly between the presence and absence of secondary causes of osteoporosis. Introduction: BMD Z-score diagnostic thresholds have been proposed to detect secondary causes of osteoporosis. To determine the sensitivity and diagnostic utility of such thresholds, we analyzed comprehensive BMD and personal health information data from a large, multispecialty group practice. Methods: Adult subjects were assigned their lowest axial BMD Z-score and ICD-9 diagnosis codes for secondary causes of osteoporosis when cited at least twice in their electronic medical record. Multiple logistic regression was used to model the prevalence of matching ICD-9 codes as a function of Z-score. ROC curves were used to investigate various Z-score cut points for sensitivity and specificity. Results: Eighteen thousand six hundred seventy-four subjects were analyzed. Secondary causes of osteoporosis were identified in 31% of men and 16% of women. The frequency of secondary causes varied with age and between genders and varied inversely with Z-score. No inflection point was observed in this relationship to suggest a useful clinical decision threshold. The difference in mean Z-score of those with and without a secondary cause of osteoporosis was biologically slight (±0.3). Low Z-score diagnostic thresholds were insensitive to the presence of secondary causes of osteoporosis and provided relatively poor predictive value. Conclusions: This DXA cohort confirmed a significant inverse relationship between Z-score and the presence of secondary causes of osteoporosis but diagnostic Z-score thresholds discriminate poorly between the presence and absence of secondary causes of osteoporosis. If only patients with very low Z-scores are evaluated for secondary causes of osteoporosis the diagnostic specificity may be high but most cases will be missed. © 2010 International Osteoporosis Foundation and National Osteoporosis Foundation.

McKiernan F.E.,Center for Bone Disease | Hocking J.,Center for Bone Disease | Cournoyer S.,Center for Bone Disease | Berg R.L.,Center for Bone Disease | Linneman J.,Center for Bone Disease
Journal of Clinical Densitometry | Year: 2011

A longer dual-energy X-ray absorptiometry (DXA) femur scan field might be useful for the detection of atypical, subtrochanteric femur fractures (ASFF). Thirty adult subjects underwent triplicate measures of femoral neck (FN) and total hip (TH) bone mineral density (BMD) by DXA using a conventional (i.e., short) and a longer femur scan field. Differences in measured BMD between the 2 scan field lengths were small and less than the precision error inherent in DXA testing. A longer proximal femur scan field does not substantially alter BMD measurements made at the FN and TH and may be useful for the detection of ASFF in clinical practice. © 2011 The International Society for Clinical Densitometry.

Mckenna M.J.,St Vincents University Hospital | Mckenna M.J.,University College Dublin | Heffernan E.,University College Dublin | Heffernan E.,St Vincents University Hospital | And 3 more authors.
QJM | Year: 2014

Stress fractures are repetitive strain injuries that occur in normal bones and in abnormal bones. Stress fractures share many features in common but differences depend on the status of the underlying bone. This review article for clinicians addresses aspects about stress fractures with particular respect to fatigue fractures, Looser zones of osteomalacia, atypical Looser zones, atypical femoral fractures associated with bisphosphonate therapy and stress fractures in Paget's disease of bone. © The Author 2013. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved.

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