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Lewiecki E.M.,New Mexico Clinical Research and Osteoporosis Center
Journal of Clinical Densitometry | Year: 2010

Asymptomatic primary hyperparathyroidism (PHPT) may cause adverse skeletal effects that include high bone remodeling, reduced bone mineral density (BMD), and increased fracture risk. Parathyroid surgery, the definitive treatment for PHPT, has been shown to increase BMD and appears to reduce fracture risk. Current guidelines recommend parathyroid surgery for patients with symptomatic PHPT or asymptomatic PHPT with serum calcium >1. mg/dL above the upper limit of normal, calculated creatinine clearance <60. mL/min, osteoporosis, previous fracture, or age <50. yr. The type of operation performed (parathyroid exploration or minimally invasive procedure) and localizing studies to identify the abnormal parathyroid glands preoperatively should be individualized according to the skills of the surgeon and the resources of the institution. In patients who choose not to be treated surgically or who have contraindications for surgery, medical therapy should include a daily calcium intake of at least 1200. mg and maintenance of serum 25-hydroxyvitamin D levels of at least 20. ng/mL (50. nmol/L). Bisphosphonates and estrogens have been shown to provide skeletal benefits that appear to be similar to parathyroid surgery. Cinacalcet reduces serum calcium in PHPT patients with intractable hypercalcemia but has not been shown to improve BMD. It is not known whether any medical intervention reduces fracture risk in patients with PHPT. There are insufficient data on the natural history and treatment of normocalcemic PHPT to make recommendations for management of this disorder. © 2010 The International Society for Clinical Densitometry.


Lewiecki E.M.,New Mexico Clinical Research and Osteoporosis Center
Expert Opinion on Biological Therapy | Year: 2010

Importance of the field: Osteoporosis is a common skeletal disease that is associated with an imbalance in bone remodeling. Denosumab is an investigational fully human monoclonal antibody to receptor activator of NF-κB ligand (RANKL), a cytokine member of the TNF family that is the principal mediator of osteoclastic bone resorption. Areas covered in this review: The efficacy and safety of denosumab in the management of postmenopausal osteoporosis is evaluated by reviewing the published literature and presentations at scientific meetings through 2009. What the reader will gain: This review focuses on the data on fracture risk reduction and safety endpoints of denosumab in the treatment of postmenopausal osteoporosis. Take home message: In postmenopausal women with osteoporosis, denosumab (60 mg by subcutaneous injection every 6 months) increased bone mineral density, reduced bone turnover markers, and reduced the risk of vertebral, hip and non-vertebral fractures. Denosumab was well tolerated with a safety profile generally similar to placebo. It is a promising emerging drug for the prevention and treatment of postmenopausal osteoporosis. © 2010 Informa UK Ltd.


Lewiecki E.M.,New Mexico Clinical Research and Osteoporosis Center
Nature Reviews Rheumatology | Year: 2011

Postmenopausal osteoporosis is a disease of high bone remodeling, with an imbalance of bone resorption over bone formation, resulting in decreased bone mineral density and disruption of bone microarchitecture. With our improved understanding of the molecular and cellular regulators and mediators of bone remodeling, new targets for therapeutic intervention have been identified. Receptor activator of nuclear factor κB ligand (RANKL) is the principal regulator of osteoclast differentiation, activity, and survival; denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and is approved for the treatment of women with postmenopausal osteoporosis at high risk of fractures. Cathepsin K is a protease produced by activated osteoclasts that degrades the protein matrix of bone. An inhibitor of cathepsin K, odanacatib, is in phase III clinical trials for the treatment of postmenopausal osteoporosis; it decreases bone resorption while seeming to suppress bone formation less than other antiresorptive agents. Sclerostin is a cytokine produced by osteocytes that inhibits osteoblastic bone formation; investigational monoclonal antibodies to sclerostin, such as AMG 785, have osteoanabolic properties with the potential to improve clinical outcomes in patients with osteoporosis. These and other novel interventions that target newly recognized regulators of bone remodeling are promising agents for the treatment of osteoporosis. © 2011 Macmillan Publishers Limited. All rights reserved.


Lewiecki E.M.,New Mexico Clinical Research and Osteoporosis Center
Current Osteoporosis Reports | Year: 2010

Measurement of bone mineral density (BMD) is used to diagnose osteoporosis, assess fracture risk, and monitor response to therapy. Of the different methods for measuring BMD, dual-energy X-ray absorptiometry (DXA) is the only technology for classifying BMD according to criteria established by the World Health Organization (WHO) and the only technology that is validated for BMD input with the WHO fracture risk assessment algorithm, FRAX. Vertebral fracture assessment (VFA) by DXA provides an image of the thoracic and lumbar spine for the purpose of detecting vertebral fracture deformities. Identification of a previously unrecognized vertebral fracture may change diagnostic classification, assessment of fracture risk, and treatment decisions. In comparison with standard radiographs of the spine, the correlation for detecting moderate and severe vertebral fractures is good, with a smaller dose of ionizing irradiation, greater patient convenience, and lower cost. Optimal performance of DXA and VFA requires training and adherence to quality standards. © 2010 Springer Science+Business Media, LLC.


Lewiecki E.M.,New Mexico Clinical Research and Osteoporosis Center
Maturitas | Year: 2010

Osteoporosis is a common skeletal disease associated with an imbalance in bone remodeling resulting in a reduction in bone strength and increased fracture risk. The principal regulator of osteoclastic bone resorption is receptor activator of nuclear factor-κB ligand (RANKL), a cytokine member of the tumor necrosis factor family. The binding of RANKL to its receptor on the cell surface of osteoclasts and pre-osteoclasts increases the formation, activity, and survival of osteoclasts. Denosumab is an investigational fully human monoclonal antibody to RANKL. By binding to RANKL, denosumab prevents RANKL from binding to its receptor, resulting in a decrease in bone resorption due to reduction in the formation, activity, and survival of osteoclasts. In postmenopausal women with osteoporosis, denosumab 60 mg by subcutaneous injection every 6 months increased bone mineral density (BMD), reduced bone turnover markers, and reduced the risk of vertebral, hip, and non-vertebral fractures. In postmenopausal women with low BMD, denosumab increased BMD and reduced bone turnover markers. It was well tolerated with a safety profile generally similar to placebo. Denosumab is a promising emerging drug for the prevention and treatment of postmenopausal osteoporosis. It may be particularly useful in clinical practice for the treatment of patients with gastrointestinal contraindications or side effects with oral bisphosphonates and for patients with malabsorption. © 2010 Elsevier Ireland Ltd. All rights reserved.


Lewiecki E.M.,New Mexico Clinical Research and Osteoporosis Center
Reviews in Endocrine and Metabolic Disorders | Year: 2010

Osteoporosis is a common disease characterized by low bone strength that increases the risk of fractures. The consequences of fractures include increases in morbidity, mortality, and healthcare costs. Randomized clinical trials have shown that pharmacological therapy can reduce the risk of fractures. In clinical practice, however, failure to achieve optimal therapeutic benefit is common for reasons that include taking medication incorrectly, stopping it prematurely, malabsorption, and the presence of unrecognized diseases or conditions with adverse skeletal effects. Monitoring for anti-fracture effectiveness in individual patients is limited by the absence of clinical tools to directly measure bone strength. It is therefore necessary to monitor therapy with biomarkers such as bone mineral density and bone turnover markers. This is a review of the utility of these tools in the care of individual patients. © Springer Science+Business Media, LLC 2010.


Lewiecki E.M.,New Mexico Clinical Research and Osteoporosis Center
Expert Opinion on Biological Therapy | Year: 2013

Osteoporosis is a systemic skeletal disorder that weakens bones and increases the risk of fractures. It is caused by perturbations of bone remodeling, the coupled process whereby bone is continually resorbed and formed in small discrete units. Despite the availability of cost-effective pharmacological agents that reduce fracture risk, many patients who could benefit from treatment are not receiving it. Advances in the understanding of the molecular regulators of bone remodeling have led to the identification of new targets for therapeutic intervention. Monoclonal antibodies directed to these targets have recently been developed, providing new ways of modulating bone remodeling that may provide additional benefits beyond previously available therapy. Areas covered: An approved fully human monoclonal antibody to receptor activator of nuclear factor-κB ligand, the principal regulator of osteoclastic bone resorption, reduces the risk of fractures in postmenopausal women with osteoporosis. Monoclonal antibodies in development include inhibitors of sclerostin and Dickhopf1, with osteoanabolic activity that may be beneficial in the treatment of osteoporosis. Expert opinion: Monoclonal antibodies to molecular regulators of bone remodeling represent a new class of compounds for the management of osteoporosis and other skeletal disorders associated with an imbalance of bone resorption and formation. © 2013 Informa UK, Ltd.


Lewiecki E.M.,New Mexico Clinical Research and Osteoporosis Center
Discovery medicine | Year: 2011

Bone remodeling is the process by which the adult skeleton is continually renewed through the highly coordinated activity of three types of cells - osteoclasts, osteoblasts, and osteocytes. Disruptions in signaling among these cells and alterations in their activity have been associated with skeletal diseases. In a rare accident of nature, some families have been found to have dense and strong bones due to a recessive loss of function mutation in the SOST gene that encodes for sclerostin, a protein expressed by osteocytes that downregulates osteoblastic bone formation. Individuals who are homozygous for this mutation have sclerosteosis, a disease with no detectable circulating sclerostin, resulting in generalized osteosclerosis with skeletal deformities, cranial nerve compression, and increased intracranial pressure due to boney overgrowth in the skull, and premature death. However, family members who are heterozygous carriers for the mutation have normal phenotype and normal lifespan, with dense bones and low risk of fracture. This observation has led to the concept that compounds that reduce sclerostin levels might mimic the heterozygous carrier state and be effective in the treatment of osteoporosis. To this end, monoclonal antibodies to sclerostin have been developed. Preclinical and early clinical studies of sclerostin inhibitors have shown robust stimulation of osteoblastic bone formation. The investigational compound that has advanced the furthest in development is AMG 785 (CDP7851), a humanized monoclonal antibody to sclerostin. Monoclonal antibodies to sclerostin represent a class of compounds with potential benefit in the treatment of osteoporosis and other skeletal disorders.


Lewiecki E.M.,New Mexico Clinical Research and Osteoporosis Center
Journal of Clinical Densitometry | Year: 2010

Health maintenance and disease management require vigilance in assessing risk, communicating risk, and balancing the expected benefits of therapeutic interventions with potential harms. The evaluation of skeletal health includes identification of clinical risk factors for fracture, bone density testing in appropriate patients, and the use of validated algorithms for estimating the probability of fracture. To reduce the burden of osteoporotic fractures, patients at risk for fracture must be identified and treated with effective agents that are taken regularly, correctly, and for a sufficient length of time to achieve the desired benefit. These goals may be enhanced by shared decision making, a process by which the clinician and the patient share all applicable information and negotiate a plan of treatment that is acceptable to both. As an educator and a partner in making treatment decisions, the clinician must be familiar with the medical evidence and able to discuss complex medical information in a manner that is understood by the patient, with appropriate consideration of the patient's expectations, beliefs, and concerns. After treatment is started, risk communication, patient education, and shared decision making should be continued in an effort to maintain good compliance and persistence with therapy. Further study is needed to identify and validate optimal risk communication tools for the care of patients with osteoporosis. Challenges to shared decision making include competition from other health care priorities for limited patient encounter time during office visits, poor reimbursement, insufficient knowledge of the medical evidence, inadequate communication skills, and cognitive/affective disorders limiting patient participation in making treatment decisions. © 2010 The International Society for Clinical Densitometry.


Lewiecki E.M.,New Mexico Clinical Research and Osteoporosis Center
Current Osteoporosis Reports | Year: 2010

Medications are approved by regulatory agencies for treating osteoporosis when at least one randomized placebo-controlled clinical trial shows a reduction in vertebral fracture risk and the benefit-risk ratio is determined to be acceptable. Subjects who participate in registration trials are a generally homogeneous group carefully screened with strict entry criteria. Individual patients who are treated for osteoporosis in clinical practice commonly differ from subjects enrolled in these clinical trials according to confounding factors that include age, sex, comorbidities, compliance, and persistence. Because the goal of therapy is reduction of fracture risk, and this cannot be directly assessed in an individual patient, biomarkers are commonly used as surrogate end points for effectiveness. This article reviews the clinical use and abuse of the two biomarkers most commonly used to assess the effectiveness of therapy in clinical practice: bone mineral density testing and measurement of markers of bone turnover. © Springer Science+Business Media, LLC 2010.

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