|
1
|
Veronesi F, Salamanna F, Borsari V, Ruffilli A, Faldini C, Giavaresi G. Unlocking diagnosis of sarcopenia: The role of circulating biomarkers - A clinical systematic review. Mech Ageing Dev 2024; 222:112005. [PMID: 39521148 DOI: 10.1016/j.mad.2024.112005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 10/24/2024] [Accepted: 11/06/2024] [Indexed: 11/16/2024]
Abstract
Sarcopenia, the gradual loss of muscle mass, strength, and function with age, poses a significant risk to older adults, making early diagnosis crucial for preventing disability and enhancing quality of life. Biomarkers are vital for the early detection, monitoring progression, and assessing the efficacy of treatments for sarcopenia, offering a detailed evaluation of muscle health. This systematic review examined the clinical potential of circulating biomarkers in sarcopenia by analyzing studies up to May 2024 from PubMed, Scopus, Web of Science. A total of 45 studies involving 641,730 patients were reviewed, revealing notable biomarker differences between sarcopenic and non-sarcopenic individuals. Sarcopenic patients exhibited lower levels of certain microRNAs, hemoglobin, albumin, and anti-inflammatory factors, alongside higher levels of red and white blood cells, pro-inflammatory factors, growth factors, matrix proteins, free thyroxine, cortisol, and adiponectin. Additionally, they had lower levels of irisin, free triiodothyronine, and insulin, with reduced phosphatidylcholines and elevated spermidine. The studies were generally of fair to good quality, but due to heterogeneity, a meta-analysis was not feasible. The review underscores the need for standardized biomarkers and diagnostic criteria and suggests that improving outcomes for sarcopenic patients may involve addressing inflammation, metabolic, and hormonal issues through nutrition, medication, and exercise.
Collapse
Affiliation(s)
- F Veronesi
- Surgical Sciences and Technologies, IRCCS Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, Bologna 40136, Italy
| | - F Salamanna
- Surgical Sciences and Technologies, IRCCS Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, Bologna 40136, Italy.
| | - V Borsari
- Surgical Sciences and Technologies, IRCCS Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, Bologna 40136, Italy
| | - A Ruffilli
- 1st Orthopaedic and Traumatologic Clinic, IRCCS Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, Bologna 40136, Italy; Department of Biomedical and Neuromotor Science - DIBINEM, University of Bologna, Bologna, Italy
| | - C Faldini
- 1st Orthopaedic and Traumatologic Clinic, IRCCS Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, Bologna 40136, Italy; Department of Biomedical and Neuromotor Science - DIBINEM, University of Bologna, Bologna, Italy
| | - G Giavaresi
- Surgical Sciences and Technologies, IRCCS Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, Bologna 40136, Italy
| |
Collapse
|
|
2
|
Samakkarnthai P, Sfeir JG, Atkinson EJ, Achenbach SJ, Wennberg PW, Dyck PJ, Tweed AJ, Volkman TL, Amin S, Farr JN, Vella A, Drake MT, Khosla S. Determinants of Bone Material Strength and Cortical Porosity in Patients with Type 2 Diabetes Mellitus. J Clin Endocrinol Metab 2020; 105:dgaa388. [PMID: 32556277 PMCID: PMC7458544 DOI: 10.1210/clinem/dgaa388] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 06/12/2020] [Indexed: 12/13/2022]
Abstract
CONTEXT Reduced bone material strength index (BMSi) and increased cortical porosity (CtPo) have emerged as potentially contributing to fracture risk in type 2 diabetes mellitus (T2DM) patients. OBJECTIVE To determine whether BMSi or CtPo are related to other diabetic complications. DESIGN Cross-sectional observational study. SETTING Subjects recruited from a random sample of southeast Minnesota residents. PARTICIPANTS A total of 171 T2DM patients (mean age, 68.8 years) and 108 age-matched nondiabetic controls (mean age, 67.3 years). MAIN MEASURES Bone material strength index was measured using microindentation, skin advanced glycation end-products (AGEs) measured using autofluorescence, high-resolution peripheral quantitative computed tomography at the distal radius and tibia, assessment of diabetic microvascular complications including urine microalbuminuria, retinopathy, neuropathy, and vascular disease (ankle brachial index and transcutaneous oxygen tension [TcPO2]). All analyses were adjusted for age, sex, and body mass index. RESULTS Skin AGEs were negatively correlated with the BMSi in both T2DM (r = -0.30, P < 0.001) and control (r = -0.23, P = 0.020) subjects. In relating diabetic complications to CtPo, we found that T2DM patients with clinically significant peripheral vascular disease (TcPO2 ≤ 40 mm Hg) had higher (+21.0%, P = 0.031) CtPo at the distal tibia as compared to controls; in these subjects, CtPo was negatively correlated with TcPO2 at both the distal tibia (r = -0.39, P = 0.041) and radius (r = -0.41, P = 0.029). CONCLUSIONS Our findings demonstrate that bone material properties are related to AGE accumulation regardless of diabetes status, while CtPo in T2DM patients is linked to TcPO2, a measure of microvascular blood flow.
Collapse
Affiliation(s)
- Parinya Samakkarnthai
- Robert and Arlene Kogod Center on Aging and Division of Endocrinology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
- Division of Endocrinology, Phramongkutklao Hospital and College of Medicine, Bangkok, Thailand
| | - Jad G Sfeir
- Robert and Arlene Kogod Center on Aging and Division of Endocrinology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | | | - Sara J Achenbach
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Paul W Wennberg
- Department of Cardiovascular Diseases and Gonda Vascular Center, Mayo Clinic, Rochester, Minnesota
| | - Peter J Dyck
- Department of Neurology, Mayo Clinic, Rochester, Minnesota
| | - Amanda J Tweed
- Robert and Arlene Kogod Center on Aging and Division of Endocrinology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Tammie L Volkman
- Robert and Arlene Kogod Center on Aging and Division of Endocrinology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Shreyasee Amin
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
- Division of Rheumatology, Mayo Clinic, Rochester, Minnesota
| | - Joshua N Farr
- Robert and Arlene Kogod Center on Aging and Division of Endocrinology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Adrian Vella
- Robert and Arlene Kogod Center on Aging and Division of Endocrinology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Matthew T Drake
- Robert and Arlene Kogod Center on Aging and Division of Endocrinology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Sundeep Khosla
- Robert and Arlene Kogod Center on Aging and Division of Endocrinology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| |
Collapse
|
|
3
|
Trabecular bone mineral density correlations using QCT: Central and peripheral human skeleton. J Mech Behav Biomed Mater 2020; 112:104076. [PMID: 32911222 DOI: 10.1016/j.jmbbm.2020.104076] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 07/30/2020] [Accepted: 08/28/2020] [Indexed: 11/24/2022]
Abstract
Musculoskeletal injuries to the lower leg and foot-ankle joint are associated with external mechanical loads resulting from motor vehicle crashes, under body blasts, falls from height, or sports. As an intrinsic material property, the bone mineral density (BMD) is related to bone strength. The clinically recognized biological sites for BMD evaluation are the hip and spine. The focus of this study was to define the correlation between BMD from standard clinical sites (hip and lumbar spine) compared to BMD from non-standard sites (foot-ankle-distal tibia bones). Twenty-one post-mortem human subjects (PMHS) with mean age, height, and mass of 63 ± 11 years, 179 ± 7 cm, and 86 ± 13 kg, respectively were used for analysis. Clinical BMD software (Mindways Software, Inc.) was used for trabecular BMD quantification using quantitative computed tomography (QCT). In quantification of BMD of the foot-ankle-distal tibia (hind foot), the trabecular BMD of the talus (316 ± 86mg/cc) was highest followed by the distal tibia (238 ± 72 mg/cc) and then calcaneus (147 ± 51 mg/cc). To correlate BMD values from foot bone regions with the central skeleton BMD values within the same PMHS, there were 18 lumbar spine and 12 hip BMDs available. The BMD of the distal tibia correlated best with the hip intertrochanter BMD (R2 of 0.72). Calcaneus BMD best correlated with the hip femoral neck BMD (R2 = 0.64). In summary, the hind foot bone BMD values correlated better with the hip as compared to the lumbar spine BMD from the same PMHS. These findings indicate that, in the absence of a direct measure of foot-bone BMD, hip BMD might be a better predictor of injury risk to hind foot rather than lumbar spine BMD, or alternatively, calcaneal trabecular BMD can be used to predict the risk of injury to hip. Further, these relationships between central and peripheral regions can also be implemented in finite element models for improved failure predictions.
Collapse
|
|
4
|
Kapuš O, Gába A, Lehnert M. Relationships between bone mineral density, body composition, and isokinetic strength in postmenopausal women. Bone Rep 2020; 12:100255. [PMID: 32181269 PMCID: PMC7063090 DOI: 10.1016/j.bonr.2020.100255] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Revised: 02/24/2020] [Accepted: 03/02/2020] [Indexed: 11/25/2022] Open
Abstract
Objectives The increase in body fat mass (BFM) and the loss of lean body mass (LBM) or muscle strength with age affects bone mineral (BMD). These factors increase the prevalence and incidence of obesity and sarcopenia, which have unclear effects on bone mineral density. The purpose of this study was to determine how the above selected factors affect BMD. Methods A cross-sectional study was conducted involving 58 women (aged 62.1 ± 4.8 years). Total body, left proximal femur, lumbar spine BMD, and body composition parameters were measured with dual-energy x-ray absorptiometry. Isokinetic flexion and extension strength of the dominant leg were measured at 60 deg./s. Grip strength was measured with the dominant upper extremity. To determine the volume of physical activity (PA), the PA level was monitored for seven consecutive days using an ActiGraph model GT1M accelerometer. Results BFM was positively associated with BMD of the proximal femur (β = 0.31; P < 0.05), whereas LBM or appendicular lean mass (ALM) did not relate to BMD at any sites. Dominant isokinetic strength also did not relate to BMD at any site. A/G (android/gynoid) fat ratio shows positive association with lumbar spine BMD after adjusting for YSM (years since menopause), height, smoking status, and steps per day. Conclusion We observed a positive association between proximal femur BMD and BFM, but not between LBM, ALM or isokinetic strength. A/G ratio and BMI showed a positive association with lumbar spine BMD or proximal femur BMD, respectively.
Collapse
Affiliation(s)
- Ondřej Kapuš
- Faculty of Science, Palacký University, Olomouc, Czech Republic
| | - Aleš Gába
- Faculty of Physical Culture, Palacký University, Olomouc, Czech Republic
| | - Michal Lehnert
- Faculty of Physical Culture, Palacký University, Olomouc, Czech Republic
| |
Collapse
|
|
5
|
Gandolfini I, Regolisti G, Bazzocchi A, Maggiore U, Palmisano A, Piotti G, Fiaccadori E, Sabatino A. Frailty and Sarcopenia in Older Patients Receiving Kidney Transplantation. Front Nutr 2019; 6:169. [PMID: 31781571 PMCID: PMC6861371 DOI: 10.3389/fnut.2019.00169] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 10/23/2019] [Indexed: 12/14/2022] Open
Abstract
Kidney transplantation is the treatment of choice for most of the patients with end-stage renal disease (ESRD). It improves quality of life, life expectancy, and has a lower financial burden to the healthcare system in comparison to dialysis. Every year more and more older patients are included in the kidney transplant waitlist. Within this patient population, transplanted subjects have better survival and quality of life as compared to those on dialysis. It is therefore crucial to select older patients who may benefit from renal transplantation, as well as those particularly at risk for post-transplant complications. Sarcopenia and frailty are frequently neglected in the evaluation of kidney transplant candidates. Both conditions are interrelated complex geriatric syndromes that are linked to disability, aging, comorbidities, increased mortality, and graft failure post-transplantation. Chronic kidney disease (CKD) and more importantly ESRD are characterized by multiple metabolic complications that contribute for the development of sarcopenia and frailty. In particular, anorexia, metabolic acidosis and chronic low-grade inflammation are the main contributors to the development of sarcopenia, a key component in frail transplant candidates and recipients. Both frailty and sarcopenia are considered to be reversible. Frail patients respond well to multiprofessional interventions that focus on the patients' positive frailty criteria, while physical rehabilitation and oral supplementation may improve sarcopenia. Prospective studies are still needed to evaluate the utility of formally measuring frailty and sarcopenia in the older candidates to renal transplantation as part of the transplant evaluation process.
Collapse
Affiliation(s)
- Ilaria Gandolfini
- UO Nefrologia, Azienda Ospedaliero-Universitaria di Parma & Dipartimento di Medicina e Chirurgia, Università di Parma, Parma, Italy
- Dipartimento di Medicina e Chirurgia, Università di Parma, Parma, Italy
| | - Giuseppe Regolisti
- UO Nefrologia, Azienda Ospedaliero-Universitaria di Parma & Dipartimento di Medicina e Chirurgia, Università di Parma, Parma, Italy
- Dipartimento di Medicina e Chirurgia, Università di Parma, Parma, Italy
| | - Alberto Bazzocchi
- Diagnostic and Interventional Radiology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Umberto Maggiore
- UO Nefrologia, Azienda Ospedaliero-Universitaria di Parma & Dipartimento di Medicina e Chirurgia, Università di Parma, Parma, Italy
- Dipartimento di Medicina e Chirurgia, Università di Parma, Parma, Italy
| | - Alessandra Palmisano
- UO Nefrologia, Azienda Ospedaliero-Universitaria di Parma & Dipartimento di Medicina e Chirurgia, Università di Parma, Parma, Italy
| | - Giovanni Piotti
- UO Nefrologia, Azienda Ospedaliero-Universitaria di Parma & Dipartimento di Medicina e Chirurgia, Università di Parma, Parma, Italy
| | - Enrico Fiaccadori
- UO Nefrologia, Azienda Ospedaliero-Universitaria di Parma & Dipartimento di Medicina e Chirurgia, Università di Parma, Parma, Italy
- Dipartimento di Medicina e Chirurgia, Università di Parma, Parma, Italy
| | - Alice Sabatino
- Dipartimento di Medicina e Chirurgia, Università di Parma, Parma, Italy
| |
Collapse
|
|
6
|
Leonard MB, Wehrli FW, Ziolkowski SL, Billig E, Long J, Nickolas TL, Magland JF, Nihtianova S, Zemel BS, Herskovitz R, Rajapakse CS. A multi-imaging modality study of bone density, bone structure and the muscle - bone unit in end-stage renal disease. Bone 2019; 127:271-279. [PMID: 31158505 DOI: 10.1016/j.bone.2019.05.022] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Revised: 05/16/2019] [Accepted: 05/16/2019] [Indexed: 01/10/2023]
Abstract
End stage renal disease (ESRD) is associated with sarcopenia and skeletal fragility. The objectives of this cross-sectional study were to (1) characterize body composition, bone mineral density (BMD) and bone structure in hemodialysis patients compared with controls, (2) assess whether DXA areal BMD (aBMD) correlates with peripheral quantitative CT (pQCT) measures of volumetric BMD (vBMD), cortical dimensions and MRI measures of trabecular microarchitecture, and (3) determine the magnitude of bone deficits in ESRD after adjustment for muscle mass. Thirty ESRD participants, ages 25 to 64 years, were compared with 403 controls for DXA and pQCT outcomes and 104 controls for MRI outcomes; results were expressed as race- and sex- specific Z-scores relative to age. DXA appendicular lean mass index (ALMI kg/m2) and total hip, femoral neck, ultradistal and 1/3rd radius aBMD were significantly lower in ESRD, vs. controls (all p < 0.01). pQCT trabecular vBMD (p < 0.01), cortical vBMD (p < 0.001) and cortical thickness (due to a greater endosteal circumference, p < 0.02) and MRI measures of trabecular number, trabecular thickness, and whole bone stiffness were lower (all p < 0.01) in ESRD, vs. controls. ALMI was positively associated with total hip, femoral neck, ultradistal radius and 1/3rd radius aBMD and with tibia cortical thickness (R = 0.46 to 0.64). Adjustment for ALMI significantly attenuated bone deficits at these sites: e.g. mean femoral neck aBMD was 0.79 SD lower in ESRD, compared with controls and this was attenuated to 0.33 with adjustment for ALMI. In multivariate models within the dialysis participants, pQCT trabecular vBMD and cortical area Z-scores were significant and independently (all p < 0.02) associated with DXA femoral neck, total hip, and ultradistal radius aBMD Z-scores. Cortical vBMD (p = 0.01) and cortical area (p < 0.001) Z-scores were significantly and independently associated with 1/3rd radius areal aBMD Z-scores (R2 = 0.62). These data demonstrate that DXA aBMD captures deficits in trabecular and cortical vBMD and cortical area. The strong associations with ALMI, as an index of skeletal muscle, highlight the importance of considering the role of sarcopenia in skeletal fragility in patients with ESRD.
Collapse
Affiliation(s)
- Mary B Leonard
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States of America; Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States of America.
| | - Felix W Wehrli
- Department of Radiology, University of Pennsylvania, Philadelphia, PA, United States of America
| | - Susan L Ziolkowski
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States of America
| | - Erica Billig
- Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, United States of America
| | - Jin Long
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States of America
| | - Thomas L Nickolas
- Department of Medicine, Columbia University, New York, NY, United States of America
| | - Jeremy F Magland
- Department of Radiology, University of Pennsylvania, Philadelphia, PA, United States of America
| | - Snejana Nihtianova
- Susanne M. Glasscock School of Continuing Studies, Rice University, Houston, TX, United States of America
| | - Babette S Zemel
- Department of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, United States of America
| | - Rita Herskovitz
- Department of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, United States of America
| | - Chamith S Rajapakse
- Department of Radiology, University of Pennsylvania, Philadelphia, PA, United States of America; Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, United States of America
| |
Collapse
|
|
7
|
Curcio F, Ferro G, Basile C, Liguori I, Parrella P, Pirozzi F, Della-Morte D, Gargiulo G, Testa G, Tocchetti CG, Bonaduce D, Abete P. Biomarkers in sarcopenia: A multifactorial approach. Exp Gerontol 2016; 85:1-8. [DOI: 10.1016/j.exger.2016.09.007] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 09/05/2016] [Accepted: 09/08/2016] [Indexed: 12/11/2022]
|
|
8
|
HART NICOLASH, NIMPHIUS SOPHIA, WEBER JASON, SPITERI TANIA, RANTALAINEN TIMO, DOBBIN MICHAEL, NEWTON ROBERTU. Musculoskeletal Asymmetry in Football Athletes. Med Sci Sports Exerc 2016; 48:1379-87. [DOI: 10.1249/mss.0000000000000897] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
|
|
9
|
Huo K, Hashim SI, Yong KLY, Su H, Qu QM. Impact and risk factors of post-stroke bone fracture. World J Exp Med 2016; 6:1-8. [PMID: 26929915 PMCID: PMC4759351 DOI: 10.5493/wjem.v6.i1.1] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Revised: 11/27/2015] [Accepted: 01/22/2016] [Indexed: 02/06/2023] Open
Abstract
Bone fracture occurs in stroke patients at different times during the recovery phase, prolonging recovery time and increasing medical costs. In this review, we discuss the potential risk factors for post-stroke bone fracture and preventive methods. Most post-stroke bone fractures occur in the lower extremities, indicating fragile bones are a risk factor. Motor changes, including posture, mobility, and balance post-stroke contribute to bone loss and thus increase risk of bone fracture. Bone mineral density is a useful indicator for bone resorption, useful to identify patients at risk of post-stroke bone fracture. Calcium supplementation was previously regarded as a useful treatment during physical rehabilitation. However, recent data suggests calcium supplementation has a negative impact on atherosclerotic conditions. Vitamin D intake may prevent osteoporosis and fractures in patients with stroke. Although drugs such as teriparatide show some benefits in preventing osteoporosis, additional clinical trials are needed to determine the most effective conditions for post-stroke applications.
Collapse
|
|
10
|
Fonseca H, Moreira-Gonçalves D, Amado F, Esteves JL, Duarte JA. Skeletal deterioration following ovarian failure: can some features be a direct consequence of estrogen loss while others are more related to physical inactivity? J Bone Miner Metab 2015; 33:605-14. [PMID: 25298329 DOI: 10.1007/s00774-014-0626-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Accepted: 08/05/2014] [Indexed: 11/26/2022]
Abstract
Findings on experimental animals show that ovarian failure is accompanied by a decrease in motor activity. As mechanical loading has a vital role in the maintenance of skeletal health, our aim was to determine to what extent this decrease in motor activity contributes to ovariectomy-induced bone loss. Thirty-two female Wistar rats were ovariectomized or sham-operated and housed in standard cages or with access to running wheels for 36 weeks with their running distance monitored. Markers of bone turnover were assayed in the serum, and bone geometry, trabecular and cortical bone microarchitecture, mineralization degree, and biomechanical properties were assessed in the femur. Differences between groups were determined by one-way ANOVA. Although reduced motor activity and sex steroid deficiency both resulted in decreases in trabecular bone volume, trabecular number decreases were mostly associated with sex steroid deficiency, whereas trabecular thickness decreases were mostly associated with sedentary behavior. Cortical bone appeared to be more sensitive to variations in motor activity, whereas bone turnover rate and bone tissue mineralization degree seemed to be primarily affected by sex steroid deficiency, even though they were further aggravated by sedentary behavior. Increases in femur length were mostly a consequence of sex steroid deficiency, whereas femoral neck length was also influenced by sedentary behavior. Differences in mechanical properties resulted mostly from differences in physical activity. Both the direct effect of sex steroid deficiency and the indirect effect of motor activity changes are implicated in bone loss following ovariectomy.
Collapse
Affiliation(s)
- Hélder Fonseca
- CIAFEL, Faculty of Sport, University of Porto, Rua Dr. Plácido Costa 91, 4200-450, Porto, Portugal.
| | - Daniel Moreira-Gonçalves
- CIAFEL, Faculty of Sport, University of Porto, Rua Dr. Plácido Costa 91, 4200-450, Porto, Portugal
| | - Francisco Amado
- Escola Superior de Saude, Universidade de Aveiro, Aveiro, Portugal
| | - José L Esteves
- INEGI, Faculty of Engineering, University of Porto, Porto, Portugal
| | - José Alberto Duarte
- CIAFEL, Faculty of Sport, University of Porto, Rua Dr. Plácido Costa 91, 4200-450, Porto, Portugal
| |
Collapse
|
|
11
|
Bergen HR, Farr JN, Vanderboom PM, Atkinson EJ, White TA, Singh RJ, Khosla S, LeBrasseur NK. Myostatin as a mediator of sarcopenia versus homeostatic regulator of muscle mass: insights using a new mass spectrometry-based assay. Skelet Muscle 2015; 5:21. [PMID: 26180626 PMCID: PMC4502935 DOI: 10.1186/s13395-015-0047-5] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Accepted: 05/29/2015] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Myostatin is a protein synthesized and secreted by skeletal muscle that negatively regulates muscle mass. The extent to which circulating myostatin levels change in the context of aging is controversial, largely due to methodological barriers. METHODS We developed a specific and sensitive liquid chromatography with tandem mass spectrometry (LC-MS/MS) assay to measure concentrations of myostatin and two of its key inhibitors, follistatin-related gene (FLRG) protein and growth and serum protein-1 (GASP-1) in 80 younger (<40 years), 80 older (>65 years), and 80 sarcopenic older women and men. RESULTS Older women had 34 % higher circulating concentrations of myostatin than younger women. Per unit of lean mass, both older and sarcopenic older women had >23 % higher myostatin levels than younger women. By contrast, younger men had higher myostatin concentrations than older men with and without sarcopenia. Younger men had approximately twofold higher concentrations of myostatin than younger women; however, older women and sarcopenic older women had significantly higher relative myostatin levels than the corresponding groups of men. In both sexes, sarcopenic older subjects had the highest concentrations of FLRG. Circulating concentrations of myostatin exhibited positive, but not robust, correlations with relative muscle mass in both sexes. CONCLUSIONS Our data suggest that myostatin may contribute to the higher prevalence of sarcopenia in women but acts as a homeostatic regulator of muscle mass in men. Moreover, this new LC-MS/MS-based approach offers a means to determine the extent to which myostatin serves as a biomarker of muscle health in diverse conditions of muscle loss and deterioration.
Collapse
Affiliation(s)
- H Robert Bergen
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905 USA.,Medical Genome Facility-Proteomics Core, Mayo Clinic College of Medicine, Rochester, MN 55905 USA
| | - Joshua N Farr
- Division of Endocrinology, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905 USA.,Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, MN 55905 USA
| | - Patrick M Vanderboom
- Medical Genome Facility-Proteomics Core, Mayo Clinic College of Medicine, Rochester, MN 55905 USA
| | - Elizabeth J Atkinson
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN 55905 USA
| | - Thomas A White
- Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, MN 55905 USA
| | - Ravinder J Singh
- Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905 USA
| | - Sundeep Khosla
- Division of Endocrinology, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905 USA.,Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, MN 55905 USA
| | - Nathan K LeBrasseur
- Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, MN 55905 USA.,Department of Physical Medicine and Rehabilitation, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905 USA
| |
Collapse
|
|
12
|
Kalinkovich A, Livshits G. Sarcopenia--The search for emerging biomarkers. Ageing Res Rev 2015; 22:58-71. [PMID: 25962896 DOI: 10.1016/j.arr.2015.05.001] [Citation(s) in RCA: 128] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2015] [Revised: 05/06/2015] [Accepted: 05/06/2015] [Indexed: 12/12/2022]
Abstract
Sarcopenia, an age-related decline in skeletal muscle mass and function, dramatically affects the life quality of elder people. In view of increasing life expectancy, sarcopenia renders a heavy burden on the health care system. However, although there is a consensus that sarcopenia is a multifactorial syndrome, its etiology, underlying mechanisms, and even definition remain poorly delineated, thus, preventing development of a precise treatment strategy. The main aim of our review is to critically analyze potential sarcopenia biomarkers in light of the molecular mechanisms of their involvement in sarcopenia pathogenesis. Normal muscle mass and function maintenance are proposed to be dependent on the dynamic balance between the positive regulators of muscle growth such as bone morphogenetic proteins (BMPs), brain-derived neurotrophic factor (BDNF), follistatin (FST) and irisin, and negative regulators including TGFβ, myostatin, activins A and B, and growth and differentiation factor-15 (GDF-15). We hypothesize that the shift in this balance to muscle growth inhibitors, along with increased expression of the C- terminal agrin fragment (CAF) associated with age-dependent neuromuscular junction (NMJ) dysfunction, as well as skeletal muscle-specific troponin T (sTnT), a key component of contractile machinery, is a main mechanism underlying sarcopenia pathogenesis. Thus, this review proposes and emphasizes that these molecules are the emerging sarcopenia biomarkers.
Collapse
|
|
13
|
Abstract
Aging-induced declines in muscle size and quality are thought to contribute to catabolic alterations in bone, but changes in bone with age also profoundly alter its response to muscle-derived stimuli. This review provides an overview of some of the alterations that occur in muscle and bone with aging, and discusses the cellular and molecular mechanisms that may impact these age-associated changes.
Collapse
Affiliation(s)
- Susan A Novotny
- Orthopedic Research Department, Gillette Children's Specialty Healthcare, Saint Paul, Minnesota;
| | - Gordon L Warren
- Department of Physical Therapy, Georgia State University, Atlanta, Georgia; and
| | - Mark W Hamrick
- Cellular Biology & Anatomy, Georgia Regents University, Augusta, Georgia
| |
Collapse
|
|
14
|
Willie BM, Birkhold AI, Razi H, Thiele T, Aido M, Kruck B, Schill A, Checa S, Main RP, Duda GN. Diminished response to in vivo mechanical loading in trabecular and not cortical bone in adulthood of female C57Bl/6 mice coincides with a reduction in deformation to load. Bone 2013; 55:335-46. [PMID: 23643681 DOI: 10.1016/j.bone.2013.04.023] [Citation(s) in RCA: 113] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2012] [Revised: 04/03/2013] [Accepted: 04/26/2013] [Indexed: 11/19/2022]
Abstract
Bone loss occurs during adulthood in both women and men and affects trabecular bone more than cortical bone. The mechanism responsible for trabecular bone loss during adulthood remains unexplained, but may be due at least in part to a reduced mechanoresponsiveness. We hypothesized that trabecular and cortical bone would respond anabolically to loading and that the bone response to mechanical loading would be reduced and the onset delayed in adult compared to postpubescent mice. We evaluated the longitudinal adaptive response of trabecular and cortical bone in postpubescent, young (10 week old) and adult (26 week old) female C57Bl/6J mice to axial tibial compression using in vivo microCT (days 0, 5, 10, and 15) and dynamic histomorphometry (day 15). Loading elicited an anabolic response in both trabecular and cortical bone in young and adult mice. As hypothesized, trabecular bone in adult mice exhibited a reduced and delayed response to loading compared to the young mice, apparent in trabecular bone volume fraction and architecture after 10 days. No difference in mechanoresponsiveness of the cortical bone was observed between young and adult mice. Finite element analysis showed that load-induced strain was reduced with age. Our results suggest that trabecular bone loss that occurs in adulthood may in part be due to a reduced mechanoresponsiveness in this tissue and/or a reduction in the induced tissue deformation which occurs during habitual loading. Therapeutic approaches that address the mechanoresponsiveness of the bone tissue may be a promising and alternate strategy to maintain trabecular bone mass during aging.
Collapse
Affiliation(s)
- Bettina M Willie
- Julius Wolff Institut, Charité-Universitätsmedizin Berlin, Germany.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
15
|
Sapir-Koren R, Livshits G. Is interaction between age-dependent decline in mechanical stimulation and osteocyte-estrogen receptor levels the culprit for postmenopausal-impaired bone formation? Osteoporos Int 2013; 24:1771-89. [PMID: 23229466 DOI: 10.1007/s00198-012-2208-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2012] [Accepted: 10/02/2012] [Indexed: 12/19/2022]
Abstract
Declining estrogen levels during menopause are widely considered to be a major cause of age-dependent bone loss, which is primarily manifested by increased bone resorption by osteoclasts. We present accumulating evidence supporting another aspect of metabolic bone loss, suggesting that the combined interaction between age-dependent factors, namely, estrogen deficiency and reduced day-by-day activity/mechanical stimulation, directly leads to a reduction in anabolic processes. Such decreased bone formation results in diminished bone strength and failure to maintain the load-bearing competence of a healthy skeleton and to postmenopausal osteoporosis disorder. Estrogen receptors (ERs), as mediators of estrogenic actions, are essential components of bone osteocyte and osteoblast mechano-adaptive responses. ER expression appears to be upregulated by adequate circulating estrogen levels. ERα signaling pathways participate in the mechanotransduction response through obligatory "non-genomic" actions that occur independently of estrogen binding to ER and by a potentially "genomic", estrogen-dependent mode. The experimental data indicate that cross talk between the ERα-"non-genomic" and Wnt/β-catenin signaling pathways constitutes the major regulatory mechanism. This interaction uses mechanically and ER-induced prostaglandin E2 as a mediator for the downregulation of osteocyte production of sclerostin. Sclerostin suppression, in turn, is a central prerequisite for load-induced formation and mineralization of the bone matrix. It is therefore plausible that future strategies for preventing and treating postmenopausal osteoporosis may use estrogenic compounds (such as selective estrogen receptor modulators or phytoestrogens) with physical activity, to complement antiresorptive therapy, aimed at stopping further bone loss and possibly even reversing it by stimulation of bone gain.
Collapse
Affiliation(s)
- R Sapir-Koren
- Human Population Biology Research Unit, Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel
| | | |
Collapse
|
|
16
|
Giambini H, Khosla S, Nassr A, Zhao C, An KN. Longitudinal changes in lumbar bone mineral density distribution may increase the risk of wedge fractures. Clin Biomech (Bristol, Avon) 2013; 28:10-4. [PMID: 23142501 PMCID: PMC3551990 DOI: 10.1016/j.clinbiomech.2012.10.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2012] [Revised: 10/11/2012] [Accepted: 10/16/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND Trabecular bone strength diminishes as a result of osteoporosis and altered biomechanical loading at the vertebral and spinal levels. The spine consists of the anterior, middle and posterior columns and the load supported by the anterior and middle columns will differ across different regions of the spine. Stress shielding of the anterior column can contribute to bone loss and increase the risk of wedge fracture. There is a lack of quantitative data related to regional spinal bone mineral density distribution over time. We hypothesize that there is an increase in the posterior-to-anterior vertebral body bone mineral density ratio and a decrease in whole-body bone mineral density over time. METHODS Bone mineral density was measured in 33 subjects using quantitative computed tomography scans for L1-L3 vertebrae, region (anterior and posterior vertebral body), and time (baseline and 6 years after). FINDINGS Lumbar bone mineral density decreased significantly (Δ: ~15%) from baseline to the 6th year visit. Individual vertebra differences over time (L1: ~14%, L2: ~14%, L3: ~17%) showed statistical significance. Anterior bone mineral density change was significantly greater than in the posterior vertebral body region (Δ anterior: ~18%; Δ posterior: ~13%). Posterior-to-anterior bone mineral density ratio was significantly greater in the 6th year compared to baseline values (mean (SD), 1.33 (0.2) vs. 1.23 (0.1)). INTERPRETATION This study provides longitudinal quantitative measurement of bone mineral density in vertebrae as well as regional changes in the anterior and posterior regions. Understanding bone mineral density distribution over time may help to decrease the risk of wedge fractures if interventions can be developed to bring spine loading to its normal state.
Collapse
Affiliation(s)
- Hugo Giambini
- Biomechanics Laboratory, Division of Orthopedic Research, Mayo Clinic, Rochester, Minnesota USA
| | - Sundeep Khosla
- Division of Endocrinology, Metabolism and Nutrition, Department of Internal Medicine, College of Medicine Mayo Clinic, Rochester, Minnesota USA
| | - Ahmad Nassr
- Biomechanics Laboratory, Division of Orthopedic Research, Mayo Clinic, Rochester, Minnesota USA,Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota USA
| | - Chunfeng Zhao
- Biomechanics Laboratory, Division of Orthopedic Research, Mayo Clinic, Rochester, Minnesota USA
| | - Kai-Nan An
- Biomechanics Laboratory, Division of Orthopedic Research, Mayo Clinic, Rochester, Minnesota USA
| |
Collapse
|
|
17
|
de Pablo P, Cooper MS, Buckley CD. Association between bone mineral density and C-reactive protein in a large population-based sample. ACTA ACUST UNITED AC 2012; 64:2624-31. [PMID: 22487938 DOI: 10.1002/art.34474] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
OBJECTIVE Several studies suggest that bone mineral density (BMD) is reduced in chronic inflammatory diseases. Higher serum levels of C-reactive protein (CRP) have been associated with lower BMD in women and older adults. However, it is not clear whether this association holds in a representative sample of the general population. The purpose of this study was to examine the relationship between BMD and CRP level in a large representative US population-based sample from the National Health and Nutrition Examination Survey (NHANES). METHODS We included participants age ≥20 years with BMD (total and subregions) measured by dual x-ray absorptiometry scans and complete information on covariates from NHANES. The association between CRP level and BMD was evaluated using multivariate linear regression models, adjusting for potential confounders and further adjusting for comorbid diseases, medications, and serum vitamin D levels. RESULTS The study sample included 10,475 participants (53% Caucasian, 22% Mexican American, 18% African American, and 7% other races). Men had higher BMD and lower CRP concentrations than women. BMD (total body BMD as well as subtotal BMD and BMD of the extremities, ribs, and trunk subregions) was inversely associated with quintiles of CRP concentration both in men and in women in a dose-dependent manner (for total BMD, P for trend < 0.0001 for men, P for trend = 0.0005 for women). The associations were independent of medications, comorbidities, and other potential confounders. The results remained largely unchanged with further adjustment for serum vitamin D levels. CONCLUSION Among men and women in a large representative population-based sample, the CRP level was inversely and independently associated with total BMD in a dose-dependent manner.
Collapse
Affiliation(s)
- Paola de Pablo
- University of Birmingham College of Medical and Dental Sciences, City Hospital, Sandwell and West Birmingham Hospitals NHS Trust, and Queen Elizabeth Hospital, University Hospital Birmingham NHS Trust, Birmingham, UK.
| | | | | |
Collapse
|
|
18
|
LeBrasseur NK, Achenbach SJ, Melton LJ, Amin S, Khosla S. Skeletal muscle mass is associated with bone geometry and microstructure and serum insulin-like growth factor binding protein-2 levels in adult women and men. J Bone Miner Res 2012; 27:2159-69. [PMID: 22623219 PMCID: PMC3645866 DOI: 10.1002/jbmr.1666] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Skeletal muscle and bone form highly-integrated systems that undergo significant age-related changes, but the relationships between muscle mass and trabecular versus cortical bone or trabecular microarchitecture have not been systematically investigated. Thus, we examined the association between appendicular skeletal muscle mass (ASM) relative to height squared (relative ASM) and bone parameters at several sites assessed by conventional as well as high-resolution peripheral QCT in a cohort of 272 women and 317 men aged 20 to 97 years. In women, relative ASM was associated with cortical thickness (CtTh) at the femoral neck, lumbar spine, radius, and tibia (age-and physical activity adjusted r = 0.19-0.32; all p < 0.01). Relative ASM was also associated with trabecular volumetric bone mineral density (vBMD) at the femoral neck and spine (all p < 0.05), and trabecular bone volume to tissue volume (BV/TV), number (TbN), thickness (TbTh), and separation (TbSp) at the radius (all p ≤ 0.05). In all men, relative ASM was associated with CtTh at all sites (age- and physical activity-adjusted r = 0.17-0.28; all p < 0.01). Associations between relative ASM and trabecular vBMD at the spine in men were lost after adjusting for age; however, relative ASM was associated with trabecular vBMD at the femoral neck and TbN and TbSp at the radius (all p < 0.01). We also investigated circulating factors associated with bone health that may be indicative of relative ASM and found that serum insulin-like growth factor (IGF) binding protein-2 (IGFBP-2) levels were the most robust negative predictors of relative ASM in both sexes. Collectively, these data add to the growing body of evidence supporting the highly-integrated nature of skeletal muscle and bone, and provide new insights into potential biomarkers that reflect the health of the musculoskeletal system.
Collapse
|
|
19
|
Johannesdottir F, Aspelund T, Siggeirsdottir K, Jonsson BY, Mogensen B, Sigurdsson S, Harris TB, Gudnason VG, Lang TF, Sigurdsson G. Mid-thigh cortical bone structural parameters, muscle mass and strength, and association with lower limb fractures in older men and women (AGES-Reykjavik Study). Calcif Tissue Int 2012; 90:354-64. [PMID: 22451219 PMCID: PMC5111551 DOI: 10.1007/s00223-012-9585-6] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2011] [Accepted: 03/04/2012] [Indexed: 10/28/2022]
Abstract
In a cross-sectional study we investigated the relationship between muscle and bone parameters in the mid-thigh in older people using data from a single axial computed tomographic section through the mid-thigh. Additionally, we studied the association of these variables with incident low-trauma lower limb fractures. A total of 3,762 older individuals (1,838 men and 1,924 women), aged 66-96 years, participants in the AGES-Reykjavik study, were studied. The total cross-sectional muscular area and knee extensor strength declined with age similarly in both sexes. Muscle parameters correlated most strongly with cortical area and total shaft area (adjusted for age, height, and weight) but explained <10 % of variability in those bone parameters. The increment in medullary area (MA) and buckling ratio (BR) with age was almost fourfold greater in women than men. The association between MA and muscle parameters was nonsignificant. During a median follow-up of 5.3 years, 113 women and 66 men sustained incident lower limb fractures. Small muscular area, low knee extensor strength, large MA, low cortical thickness, and high BR were significantly associated with fractures in both sexes. Our results show that bone and muscle loss proceed at different rates and with different gender patterns.
Collapse
Affiliation(s)
| | - Thor Aspelund
- University of Iceland, Reykjavik, Iceland
- Icelandic Heart Association, Kopavogur, Iceland
| | | | | | - Brynjolfur Mogensen
- University of Iceland, Reykjavik, Iceland
- Landspitali-Univerisity Hospital, Reykjavik, Iceland
| | | | | | - Vilmundur G. Gudnason
- University of Iceland, Reykjavik, Iceland
- Icelandic Heart Association, Kopavogur, Iceland
| | | | - Gunnar Sigurdsson
- University of Iceland, Reykjavik, Iceland
- Icelandic Heart Association, Kopavogur, Iceland
- Landspitali-Univerisity Hospital, Reykjavik, Iceland
| |
Collapse
|
|
20
|
Adams MA, Dolan P. Biomechanics of vertebral compression fractures and clinical application. Arch Orthop Trauma Surg 2011; 131:1703-10. [PMID: 21805360 DOI: 10.1007/s00402-011-1355-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2011] [Indexed: 12/27/2022]
Abstract
Local biomechanical factors in the etiology of vertebral compression fractures are reviewed. The vertebral body is particularly vulnerable to compression fracture when its bone mineral density (BMD) falls with age. However, the risk of fracture, and the type of fracture produced, does not depend simply on BMD. Equally important is the state of degeneration of the adjacent intervertebral discs, which largely determines how compressive forces are distributed over the vertebral body. Disc height also influences load-sharing between the vertebral body and neural arch, and hence by Wolff's Law can influence regional variations in trabecular density within the vertebral body. Vertebral deformity is not entirely attributable to trauma: it can result from the gradual accumulation of fatigue damage, and can progress by a quasi-continuous process of "creep". Cement injection techniques such as vertebroplasty and kyphoplasty are valuable in the treatment of these fractures. Both techniques can stiffen a fractured vertebral body, and kyphoplasty may contribute towards restoring its height. The presence of cement can limit endplate deformation, and thereby partially reverse the adverse changes in load-sharing which follow vertebral fracture. Cement also reduces time-dependent "creep" deformation of damaged vertebrae.
Collapse
Affiliation(s)
- Michael A Adams
- Centre for Comparative and Clinical Anatomy, University of Bristol, Southwell Street, Bristol BS2 8EJ, UK.
| | | |
Collapse
|
|
21
|
Abstract
Osteoporosis, a condition associated with significant morbidity and mortality, is prevalent in the growing elderly population. Aging is associated with characteristic changes in the complex pathways of bone remodeling and in patterns of food intake. Whereas the traditional focus of nutritional supplementation for protection of bone health has centered around calcium and vitamin D, a multitude of nutrients have been identified with effects on bone, both individually and in combination. An integrative physiology approach can assist in formulating a deeper understanding of the complex interactions of nutrition and aging with bone, with the goal of identifying modifiable risk factors for the prevention of bone loss.
Collapse
Affiliation(s)
- Rifka C Schulman
- Division of Endocrinology, Diabetes, and Bone Disease, Mount Sinai School of Medicine, New York, NY 10128, USA
| | | | | |
Collapse
|
|
22
|
Melton LJ, Riggs BL, Müller R, Achenbach SJ, Christen D, Atkinson EJ, Amin S, Khosla S. Determinants of forearm strength in postmenopausal women. Osteoporos Int 2011; 22:3047-54. [PMID: 21308363 PMCID: PMC3150635 DOI: 10.1007/s00198-011-1540-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2010] [Accepted: 12/20/2010] [Indexed: 12/31/2022]
Abstract
UNLABELLED Bone strength at the ultradistal radius, quantified by micro-finite element modeling, can be predicted by variables obtained from high-resolution peripheral quantitative computed tomography scans. The specific formula for this bone strength surrogate (-555.2 + 8.1 × [trabecular vBMD] + 19.6 × [cortical area] + 4.2 × [total cross-sectional area]) should be validated and tested in fracture risk assessment. INTRODUCTION The purpose of this study was to identify key determinants of ultradistal radius (UDR) strength and evaluate their relationships with age, sex steroid levels, and measures of habitual skeletal loading. METHODS UDR failure load (~strength) was assessed by micro-finite element (μFE) modeling in 105 postmenopausal controls from an earlier forearm fracture case-control study. Predictors of bone strength obtained by high-resolution peripheral quantitative computed tomography (HRpQCT) in this group were then evaluated in a population-based cohort of 214 postmenopausal women. Sex steroids were measured by mass spectrometry. RESULTS A surrogate variable (-555.2 + 8.1 × [trabecular vBMD] + 19.6 × [cortical area] + 4.2 × [total cross-sectional area]) predicted UDR strength modeled by μFE (R(2) = 0.81), and all parameters except total cross-sectional area declined with age. Evaluated cross-sectionally, the 21% fall in predicted bone strength between ages 40-49 years and 80+ years more resembled the change in trabecular volumetric bone mineral density (vBMD) (-15%) than that in cortical area (-41%). In multivariable analyses, measures of body composition and physical activity were stronger predictors of UDR trabecular vBMD, cortical area, total cross-sectional area, and predicted bone strength than were sex steroid levels, but bio-available estradiol and testosterone were correlated with body mass. CONCLUSIONS Bone strength at the UDR, as quantified by μFE, can be predicted from variables obtained by HRpQCT. Predicted bone strength declines with age with changes in UDR trabecular vBMD and cortical area, related in turn to reduced skeletal loading and sex steroid levels. The predicted bone strength formula should be validated and tested in fracture risk assessment.
Collapse
Affiliation(s)
- L J Melton
- Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA.
| | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Allen MD, Johnstone J, Rice CL, Marsh GD. Differences in leg bone geometry in young, old and very old women. Eur J Appl Physiol 2011; 111:2865-71. [DOI: 10.1007/s00421-011-1902-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2010] [Accepted: 03/01/2011] [Indexed: 10/18/2022]
|
|
24
|
Rantalainen T, Hoffrén M, Linnamo V, Heinonen A, Komi PV, Avela J, Nindl BC. Three-month bilateral hopping intervention is ineffective in initiating bone biomarker response in healthy elderly men. Eur J Appl Physiol 2011; 111:2155-62. [DOI: 10.1007/s00421-011-1849-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2010] [Accepted: 01/20/2011] [Indexed: 11/29/2022]
|
|
25
|
Abstract
In recent decades the population of both elderly men and women has grown substantially worldwide. Aging is associated with a number of pathologies involving various organs including the skeleton. Age-related bone loss and resultant osteoporosis put the elderly population at an increased risk for fractures and morbidity. Fortunately, in parallel our understanding of this malady has also grown substantially in recent years. A number of clinical as well as translational studies have been pivotal in providing us with an understanding of the pathophysiology of this condition. This article discusses the current concepts of age-related modulation of the skeleton involving intrinsic factors such as genetics, hormonal changes, levels of oxidative stress, and changes in telomere length, as well as extrinsic factors such as nutritional and lifestyle choices. It also briefly outlines recent studies on the relationship between bone and fat in the marrow as well as the periphery.
Collapse
Affiliation(s)
- Farhan A Syed
- Abbott Bioresearch Center, Worcester, MA 01545, USA.
| | | |
Collapse
|
|
26
|
Abstract
The physiology of bone loss in aging women and men is largely explained by the effects of gonadal sex steroid deficiency on the skeleton. In women, estrogen deficiency is the main cause of early rapid postmenopausal bone loss, whereas hyperparathyroidism and vitamin D deficiency are thought to explain age-related bone loss later in life. Surprisingly, estrogen deficiency also plays a dominant role in the physiology of bone loss in aging men. Many other factors contribute to bone loss in aging women and men, including defective bone formation by aging osteoblasts, impairment of the growth hormone/insulin-like growth factor axis, reduced peak bone mass, age-associated sarcopenia, leptin secreted by adipocytes, serotonin secreted by the intestine, and a long list of sporadic secondary causes. Further elucidation of the relative importance of each of these factors will lead to improved preventive and therapeutic approaches for osteoporosis.
Collapse
Affiliation(s)
- Bart L Clarke
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic College of Medicine, 200 1st Street Southwest, Rochester, MN 55905, USA.
| | | |
Collapse
|
|
27
|
Female reproductive system and bone. Arch Biochem Biophys 2010; 503:118-28. [PMID: 20637179 DOI: 10.1016/j.abb.2010.07.006] [Citation(s) in RCA: 99] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2010] [Revised: 07/03/2010] [Accepted: 07/09/2010] [Indexed: 12/20/2022]
Abstract
The female reproductive system plays a major role in regulating the acquisition and loss of bone by the skeleton from menarche through senescence. Onset of gonadal sex steroid secretion at puberty is the major factor responsible for skeletal longitudinal and radial growth, as well as significant gain in bone density, until peak bone density is achieved in third decade of life. Gonadal sex steroids then help maintain peak bone density until menopause, including during the transient changes in skeletal mineral content associated with pregnancy and lactation. At menopause, decreased gonadal sex steroid production normally leads to rapid bone loss. The most rapid bone loss associated with decreased estrogen levels occurs in the first 8-10 years after menopause, with slower age-related bone loss occurring during later life. Age-related bone loss in women after the early menopausal phase of bone loss is caused by ongoing gonadal sex steroid deficiency, vitamin D deficiency, and secondary hyperparathyroidism. Other factors also contribute to age-related bone loss, including intrinsic defects in osteoblast function, impairment of the GH/IGF axis, reduced peak bone mass, age-associated sarcopenia, and various sporadic secondary causes. Further understanding of the relative contributions of the female reproductive system and each of the other factors to development and maintenance of the female skeleton, bone loss, and fracture risk will lead to improved approaches for prevention and treatment of osteoporosis.
Collapse
|
|
28
|
Rantalainen T, Nikander R, Heinonen A, Multanen J, Häkkinen A, Jämsä T, Kiviranta I, Linnamo V, Komi PV, Sievänen H. Neuromuscular performance and body mass as indices of bone loading in premenopausal and postmenopausal women. Bone 2010; 46:964-9. [PMID: 20064632 DOI: 10.1016/j.bone.2010.01.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2009] [Revised: 12/22/2009] [Accepted: 01/05/2010] [Indexed: 12/31/2022]
Abstract
The strong association between body mass and skeletal robusticity has been attributed to increasing skeletal loading with increasing mass. However, it is unclear whether body mass is merely a coarse substitute for bone loading rather than a true independent predictor of bone strength. As indices of neuromuscular performance, impulse and peak power were determined from vertical ground reaction force during a maximal counter movement jump test in 221 premenopausal and 82 postmenopausal women. Bone compressive (BSI(d) g(2)/cm(4)) and bending (SSImax(mid) mm(3)) strength indices were measured with peripheral quantitative computed tomography (pQCT) at the distal ((d)) and midshaft ((mid)) sites of the tibia. A two-step forced regression model for predicting bone strength indices was constructed. Age, height and body mass were entered first, followed by impulse as an indicator of skeletal loading. The basic model explained 14% (P<0.001) of the variance in BSI(d) in the premenopausal group and 16% (P=0.004) in the postmenopausal group, and 32% (P<0.001) and 25% (P<0.001) of the variance in SSImax(nud) respectively. Entering impulse into the model increased the explanatory power by 9% (P<0.001) and 7% (P<0.001) for BSI(d) and by 8% (P<0.001) and 12% (P<0.001) for SSImax(mid). Furthermore, impulse replaced body mass as an independent significant factor explaining the variance in bone strength. These results indicate that neuromuscular performance should be measured and preferred over body mass in models predicting skeletal robusticity.
Collapse
Affiliation(s)
- Timo Rantalainen
- Department of Biology of Physical Activity, University of Jyväskylä, Finland.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Rantalainen T, Sievänen H, Linnamo V, Hoffrén M, Ishikawa M, Kyröläinen H, Avela J, Selänne H, Komi PV, Heinonen A. Bone rigidity to neuromuscular performance ratio in young and elderly men. Bone 2009; 45:956-63. [PMID: 19631780 DOI: 10.1016/j.bone.2009.07.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2009] [Revised: 06/23/2009] [Accepted: 07/15/2009] [Indexed: 11/15/2022]
Abstract
Given the adaptation of bone to prevalent loading, bone loss should follow, but lag behind, the decline in physical performance during aging. Furthermore, bone responsiveness to load-induced strains is believed to decrease with aging. However, the relationship between bone and lean body ( approximately muscle) mass appears to remain rather constant throughout adulthood. The purpose of this study was to examine the association between age and bone to neuromuscular performance ratio. Young (N=20, age 24 SD+/-2 years, body mass 77+/-11 kg, height 178+/-6 cm) and elderly (N=25, 72+/-4 years, 75+/-9 kg, 172+/-5 cm) men served as subjects. Bone structural traits were measured at the right distal tibia and tibial mid-shaft with peripheral quantitative computed tomography (pQCT). Maximal section modulus (Z(max50)), total area (ToA(d)), cortical area (CoA(50)), total density (ToD(d)) and cortical density (CoD(50)) were determined from the pQCT images. Neuromuscular performance was measured by recording vertical ground reaction force (GRF) in maximal bilateral hopping. Load-induced strains were estimated by calculating appropriate indices for compressive and tensile loading that took into account both the bone structure and apparent biomechanics of the given bone site. Young subjects had significantly higher maximal GRF compared to older men (4260+/-800 N vs. 3080+/-600 N, P<0.001). They also had smaller ToA(d) (1100+/-170 mm(2) vs. 1200+/-100 mm(2), P=0.028) while their ToD(d) was higher (370+/-46 g/cm(3) vs. 330+/-22 g/cm(3), P=0.002). The Z(max50) did not differ significantly between young (1660+/-320 mm(3)) and elderly men (1750+/-320 mm(3)) (P=0.224). Compressive (0.484+/-0.102 vs. 0.399+/-0.078, P=0.016) and tensile (0.107+/-0.016 vs. 0.071+/-0.018, P<0.001) strain indices were significantly higher in the younger group. In conclusion, the difference in bone to loading ratio at the tibial mid-shaft is bigger than expected from the delay in bone adaptation alone. Potential candidates to explain this phenomenon include a decrease in mechanosensitivity with aging, inability of maximal physical performance to adequately represent the bone loading environment, or the need to maintain constant safety factors to functional strains.
Collapse
Affiliation(s)
- T Rantalainen
- Neuromuscular Research Centre, Department of Biology of Physical Activity, University of Jyväskylä, Finland.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
30
|
BECK BELINDAR. Muscle Forces or Gravity-What Predominates Mechanical Loading on Bone? Med Sci Sports Exerc 2009; 41:2033-6. [DOI: 10.1249/mss.0b013e3181a8c4b6] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
|
|
31
|
McNeil CJ, Raymer GH, Doherty TJ, Marsh GD, Rice CL. Geometry of a weight-bearing and non-weight-bearing bone in the legs of young, old, and very old men. Calcif Tissue Int 2009; 85:22-30. [PMID: 19533013 DOI: 10.1007/s00223-009-9261-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2008] [Accepted: 05/13/2009] [Indexed: 01/17/2023]
Abstract
Bone geometry is an important determinant of bone strength and is influenced by muscle pull and weight-bearing. Muscle mass and exposure to weight-bearing decrease with age and thus the purpose of the study was to compare bone geometry of the weight-bearing (tibia) and non-weight-bearing (fibula) bones of the leg in different age groups. Magnetic resonance images of the right leg were acquired in 13 young (26 yr), 13 old (66 yr), and 13 very old men (83 yr). Cortical, medullary and total cross-sectional areas (CSA) of the bones were measured at approximately one-third and two-thirds the length of the leg. Muscle CSA of the anterior, lateral and posterior compartments was measured at the proximal site. Cortical CSA was approximately 14 to 22% smaller in the elderly in the tibia but similar across age in the fibula. Medullary CSA was larger with age (approximately 5 to 65%) in both bones but approximately 15 to 440% greater in the tibia than fibula. Total CSA was similar across age in both bones. Muscle mass was similar between young and old but approximately 25% less in the very old and as a consequence, the magnitude of differences in bone geometry at proximal and distal sites varied in the two elderly groups. These findings indicate that there is a complex age-dependent interaction between muscle pull and weight-bearing. The greater age-related differences in bone geometry in the tibia suggest the weight-bearing role of the tibia makes it more susceptible than the fibula to the reduced activity typically associated with aging.
Collapse
Affiliation(s)
- Chris J McNeil
- Canadian Centre for Activity and Aging, School of Kinesiology, The University of Western Ontario, Arthur and Sonia Labatt Health Sciences Building, London, ON N6A 5B9, Canada
| | | | | | | | | |
Collapse
|
|
32
|
|
|
33
|
Sherk VD, Palmer IJ, Bemben MG, Bemben DA. Relationships between body composition, muscular strength, and bone mineral density in estrogen-deficient postmenopausal women. J Clin Densitom 2009; 12:292-8. [PMID: 19155180 DOI: 10.1016/j.jocd.2008.12.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2008] [Revised: 12/07/2008] [Accepted: 12/07/2008] [Indexed: 11/20/2022]
Abstract
The purpose of this study was to examine relationships between muscular strength, body composition, and bone mineral density (BMD) in untrained postmenopausal women who are not on hormone replacement therapy (HRT). Fifty-five women (age: 63.3+/-0.6yr) completed menstrual history, physical activity, and calcium intake questionnaires. Total and regional body composition and total body, anteroposterior lumbar spine, nondominant forearm, and right proximal femur BMD were measured using dual-energy X-ray absorptiometry (DXA) (GE Lunar Prodigy, Prodigy enCORE software version 10.50.086, Madison, WI). Participants performed strength tests for 3 upper body and 5 lower body resistance exercises. Women with a relative skeletal muscle mass index (RSMI) value less than 5.45 kg/m(2) were defined as a sarcopenia group (SAR). SAR had significantly (p < 0.05) lower total body and forearm BMD compared with those who were not sarcopenic. BMD sites were significantly correlated with upper body strength (UBS) and lower body strength (LBS) (r = 0.28-0.50, p < 0.01), with the strength of relationship being site specific. Strength and fat mass (FM) significantly predicted total body BMD (R(2) = 0.232-0.241, p < 0.05), FM variables predicted spine BMD (R(2) = 0.109-0.140, p < 0.05), and LBS and RSMI predicted hip BMD sites (R(2) = 0.073-0.237, p < 0.05). Body composition variables failed to significantly predict LBS. In conclusion, the contribution of body composition and strength variables to BMD varied by site as FM was more important for total body, forearm and spine BMD, and LBS exerted greater influence on the hip sites.
Collapse
Affiliation(s)
- Vanessa D Sherk
- Department of Health and Exercise Science, University of Oklahoma, 1401 Asp Avenue, Norman, OK 73019, USA
| | | | | | | |
Collapse
|
|
34
|
Looker AC, Melton LJ, Harris T, Borrud L, Shepherd J, McGowan J. Age, gender, and race/ethnic differences in total body and subregional bone density. Osteoporos Int 2009; 20:1141-9. [PMID: 19048179 PMCID: PMC3057045 DOI: 10.1007/s00198-008-0809-6] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2008] [Accepted: 10/01/2008] [Indexed: 10/21/2022]
Abstract
SUMMARY Total body bone density of adults from National Health and Nutrition Examination Survey (NHANES) 1999-2004 differed as expected for some groups (men>women and blacks>whites) but not others (whites>Mexican Americans). Cross-sectional age patterns in bone mineral density (BMD) of older adults differed at skeletal sites that varied by degree of weight-bearing. INTRODUCTION Total body dual-energy X-ray absorptiometry (DXA) data offer the opportunity to compare bone density of demographic groups across the entire skeleton. METHODS The present study uses total body DXA data (Hologic QDR 4500A, Hologic, Bedford MA, USA) from the NHANES 1999-2004 to examine BMD of the total body and selected skeletal subregions in a wide age range of adult men and women from three race/ethnic groups. Total body, lumbar spine, pelvis, right leg, and left arm BMD and lean mass from 13,091 adults aged 20 years and older were used. The subregions were chosen to represent sites with different degrees of weight-bearing. RESULTS Mean BMD varied in expected ways for some demographic characteristics (men>women and non-Hispanic blacks>non-Hispanic whites) but not others (non-Hispanic whites>Mexican Americans). Differences in age patterns in BMD also emerged for some characteristics (sex) but not others (race/ethnicity). Differences in cross-sectional age patterns in BMD and lean mass by degree of weight-bearing in older adults were observed for the pelvis, leg, and arm. CONCLUSION This information may be useful for generating hypotheses about age, race, and sex differences in fracture risk in the population.
Collapse
Affiliation(s)
- A C Looker
- National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, MD 20782, USA.
| | | | | | | | | | | |
Collapse
|
|
35
|
Abstract
To better define the relationship between vascular calcification and bone mass/structure, we assessed abdominal aortic calcification (AAC), BMD, and bone microstructure in an age-stratified, random sample of 693 Rochester, MN, residents. Participants underwent QCT of the spine and hip and high-resolution pQCT (HRpQCT) of the radius to define volumetric BMD (vBMD) and microstructural parameters. AAC was quantified with the Agatston scoring method. In men, AAC correlated with lower vertebral trabecular and femoral neck vBMD (p < 0.001), but not after age or multivariable (age, body mass index, smoking status) adjustment. Separation into <50 and >or=50 yr showed this pattern only in the older men. BV/TV and Tb.Th inversely correlated with AAC in all men (p < 0.001), and Tb.Th remained significantly correlated after age adjustment (p < 0.05). Tb.N positively correlated with AAC in younger men (p < 0.001) but negatively correlated in older men (p < 0.001). The opposite was true with Tb.Sp (p = 0.01 and p < 0.001, respectively). Lower Tb.N and higher Tb.Sp correlated with AAC in older men even after multivariable adjustment. Among all women and postmenopausal women, AAC correlated with lower vertebral and femoral neck vBMD (p < 0.001) but not after adjustment. Lower BV/TV and Tb.Th correlated with AAC (p = 0.03 and p = 0.04, respectively) in women, but not after adjustment. Our findings support an age-dependent association between AAC and vBMD. We also found that AAC correlates with specific bone microstructural parameters in older men, suggesting a possible common pathogenesis for vascular calcification and deterioration in bone structure. However, sex-specific differences exist.
Collapse
|
|
36
|
Abstract
The risk of osteoporotic fracture can be viewed as a function of loading conditions and the ability of the bone to withstand the load. Skeletal loads are dominated by muscle action. Recently, it has become clear that bone and muscle share genetic determinants. Involution of the musculoskeletal system manifests as bone loss (osteoporosis) and muscle wasting (sarcopenia). Therefore, the consideration of pleiotropy is an important aspect in the study of the genetics of osteoporosis and sarcopenia. This Perspective will provide the evidence for a shared genetic influence on bone and muscle. We will start with an overview of accumulating evidence that physical exercise produces effects on the adult skeleton, seeking to unravel some of the contradictory findings published thus far. We will provide indications that there are pleiotropic relationships between bone structure/mass and muscle mass/function. Finally, we will offer some insights and practical recommendations as to the value of studying shared genetic factors and will explore possible directions for future research. We consider several related questions that together comprise the general paradigm of bone responses to mechanical loading and the relationship between muscle strength and bone parameters, including the genetic factors that modulate these responses. We believe that further progress in understanding the common genetic etiology of osteoporosis and sarcopenia will provide valuable insight into important biological underpinnings for both conditions and may translate into new approaches to reduce the burdens of both conditions through improved diagnosis, prevention, and early targeted treatment.
Collapse
|
|
37
|
Engelke K, Adams JE, Armbrecht G, Augat P, Bogado CE, Bouxsein ML, Felsenberg D, Ito M, Prevrhal S, Hans DB, Lewiecki EM. Clinical Use of Quantitative Computed Tomography and Peripheral Quantitative Computed Tomography in the Management of Osteoporosis in Adults: The 2007 ISCD Official Positions. J Clin Densitom 2008; 11:123-62. [PMID: 18442757 DOI: 10.1016/j.jocd.2007.12.010] [Citation(s) in RCA: 374] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2007] [Accepted: 12/05/2007] [Indexed: 10/22/2022]
|