Leland Graves

Clinical and Basic Aspects of Glucocorticoid Action in Bone

Publisher Summary The chapter describes the effects of glucocortieoids in bones. Cortisol, the glucocorticoid secreted by the adrenal gland, is essential in physiologic doses for the differentiation and function of osteoblasts and osteoclasts, and modulates the effects of other hormones and mediators of cell function, whereas supraphysiologic doses inhibit bone formation. These direct effects on bone, combined with effects on other systems that indirectly regulate bone metabolism, cause rapid bone loss in patients treated with glucocorticoids. The most commonly prescribed compounds are prednisone, prednisolone, methylprednisolone, betamethasone, dexamethasone, and triamcinolone. Glucocorticoids are widely used in the treatment of asthma, collagen-vascular disease, inflammatory bowel disease, granulomatous, and skin diseases. The skeletal response to glucocorticoids is not disease specific, and accelerated bone loss has been described in patients with each of these diseases when they are treated with steroids. The usual risk factors for involutional osteoporosis do not apply to the same extent to glucocorticoid-induced bone loss. The overall effect of glucocorticoids is catabolic. Inhibition of pituitary secretion of growth hormone and alterations in IGF-binding proteins lead to a fall in the biologic activity of growth factors with loss of their anabolic effect on bone and other tissues. Gonadotrophin secretion is inhibited and, along with direct inhibitory effects of glucocorticoids on gonadal secretion of estrogen/testosterone, leads to a fall in circulating gonadal hormone concentrations. Deficiency in gonadal hormones causes an increase in bone resorption. Membrane transport systems are also altered by glucocorticoids, resulting in inhibition of gastrointestinal absorption of calcium and decreased renal tubular absorption of calcium and phosphorus.

Effect of hospitalist consultation on treatment of osteoporosis in hip fracture patients

The objective of this study was to determine if hospitalist consultation during admission for hip fracture results in improved treatment for osteoporosis. This was a retrospective chart review, carried out in a university-based academic hospital. Administrative discharge data was used to identify patients discharged between 1 September 1999 and 1 September 2001, discharged with the diagnosis of hip fracture. Eighty-two patient charts were reviewed after exclusion for traumatic and pathologic fractures. Treatment for osteoporosis consisted of medications recommended by the National Osteoporosis Foundation (NOF), including calcium (±vitamin D), estrogen, raloxifene, calcitonin, alendronate and risedronate. Osteoporosis treatment improvement was defined as the addition of a medication for osteoporosis that strengthened treatment. Twenty-nine percent of patients in our study received treatment for osteoporosis at the time of discharge from the hospitalization for hip fracture. While 20% received calcium, only 7% received a bisphosphonate. Twelve percent received improvement in osteoporosis treatment from admission to discharge. Those that received hospitalist consultation did not have a significant improvement in osteoporosis treatment (P=0.314), but had significantly more co-morbid illnesses and were significantly older than those receiving no consultation (P<0.05). Identification of osteoporosis as a medical problem was significantly associated with osteoporosis treatment (P<0.05). Potential barriers to hospitalist consultations effect on osteoporosis treatment included patient age and co-morbidities. Further research is needed to identify and overcome barriers to effective osteoporosis treatment in patients with fractures.

Prophylactic use of zoledronic acid to prevent early bone loss is safe and feasible in patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation

Ganguly S, Divine CL, Aljitawi OS, Abhyankar S, McGuirk JP, Graves L. Prophylactic use of zoledronic acid to prevent early bone loss is safe and feasible in patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation. 
Clin Transplant 2011 DOI: 10.1111/j.1399‐0012.2011.01527.x. 
© 2011 John Wiley & Sons A/S.

Effect of exendin (exenatide)—GLP 1 receptor agonist on the thyroid and parathyroid gland in a rat model☆

Exenatide or Exendin-4 is a 39-amino acid agonist of the glucagon like peptide (GLP-1) receptor approved for the adjunctive treatment for type 2 diabetes. Recent reports suggest that GLP-1 agonists may also have distant effects including C-cell thyroid hyperplasia. The aim of this study was to evaluate the effect of exendin-4 on the thyroid and parathyroid cells in a rat model. Rat thyroids were stained for calcitonin, H&E and for carcinoembryonic antigen (CEA). Thyroid C-cell hyperplasia was graded on H&E stained slides using cell size and secretory granule numbers, morphological features of the parathyroid glands and the serum calcium concentrations of the rats were also evaluated. Counts of stained cells/high power field and intensity of staining were recorded by two pathologists. Data were analyzed by ANOVA/post-tests. C cell hypertrophy was elevated in exenatide-treated vs. untreated animals (22.5 ± 8.7 vs. 10.5 ± 2.7 cells/HPF). CEA staining failed to show effects by exendin. Calcitonin staining was significantly elevated in exenatide treated controls (P<0.001). Parathyroid glands were histologically normal in both groups, and serum calcium levels were within normal range in all animals. In summary, exenatide was associated with C cell hyperplasia and increased calcitonin staining of thyroids, but was unrelated to CEA levels. These data raise important concerns about the effects of exenatide which, given its wide clinical use, should be clarified with urgency.

Glucocorticoid-Induced Osteoporosis: A Clinician's Perspective

Glucocorticoid-induced osteoporosis is the leading cause of medication-induced osteoporosis. The fracture incidence after 1 yr of glucocorticoid therapy has been found to be 17% and observational studies suggest that fractures eventually occurin 30 to 50% of chronic glucocorticoid-treated patients. An increased risk of fracture develops within as quickly as 3 mo, and with doses of prednisone as low as 2.5 mg daily. Despite effective methods of prevention and treatment, only 50% of chronic glucocoriticoid-treated patients undergo any evaluation for osteoporosis and less than one in four receives treatment. This article addresses the various issues the clinician faces in managing patients receiving chronic glucocorticoids. It begins and ends with a case perspective. Evidence-based information is used to outline the current best strategy for the prevention and treatment of glucocorticoid-induced osteoporosis.

Calcium affects on vascular endpoints

Calcium is one of the most abundant minerals in the body and its metabolism is one of the basic biologic processes in humans. Although historically linked primarily to bone structural development and maintenance, calcium is now recognized as a key component of many physiologic pathways necessary for optimum health including cardiovascular, neurological, endocrine, renal, and gastrointestinal systems. A recent meta-analysis published in August 2011 showed a potential increase in cardiovascular events related to calcium supplementation. The possible mechanism of action of this correlation has not been well elucidated. This topic has generated intense interest due to the widespread use of calcium supplements, particularly among the middle aged and elderly who are at the most risk from cardiac events. Prior studies did not control for potential confounding factors such as the use of statins, aspirin or other medications. These controversial results warrant additional well-designed studies to investigate the relationship between calcium supplementation and cardiovascular outcomes. The purpose of this review is to highlight the current literature in regards to calcium supplementation and cardiovascular health; and to identify areas of future research.

Transient osteoporosis of the hip: review of the literature

Transient osteoporosis of the hip (TOH) is a temporary clinical condition of unknown etiology which usually resolves with conservative therapy though may be complicated by fracture or progression to avascular necrosis (AVN). TOH may be slightly more prevalent in men but when it occurs in women, it is most often seen in the latter part of pregnancy. Though fracture is a rare complication of TOH when it occurs, it is most often associated with TOH occurring in pregnancy. Magnetic resonance imaging (MRI) is the best method to diagnosis TOH. Low signal intensity on T1-weighted images, high signal intensity on T2-weighted images, and homogenous pattern of edema (the femoral head and/or neck) with normal subchondral area are in favor of TOH. A shortened course to recovery is reported by use of bisphosphonates, calcitonin, or teriparatide. Based on reported cases, core decompression is not superior to medical therapy. Transient osteoporosis of the hip, which often has no known etiology, usually resolves with conservative therapy but may predispose the patient to fracture or avascular necrosis. Diagnostic method of choice is magnetic resonance imaging. Bisphosphonates, calcitonin, or teriparatide are reported as a useful approach to reduce duration of recovery.

Ral signaling pathway in health and cancer

The Ral (Ras‐Like) signaling pathway plays an important role in the biology of cells. A plethora of effects is regulated by this signaling pathway and its prooncogenic effectors. Our team has demonstrated the overactivation of the RalA signaling pathway in a number of human malignancies including cancers of the liver, ovary, lung, brain, and malignant peripheral nerve sheath tumors. Additionally, we have shown that the activation of RalA in cancer stem cells is higher in comparison with differentiated cancer cells. In this article, we review the role of Ral signaling in health and disease with a focus on the role of this multifunctional protein in the generation of therapies for cancer. An improved understanding of this pathway can lead to development of a novel class of anticancer therapies that functions on the basis of intervention with RalA or its downstream effectors.

Don't Forget the Thyroid: Graves' Disease

PRESENTATION An atypical presentation can confound the diagnosis, and that is what happened when a 33-year-old African-American woman presented to another hospital with a 3-month history of worsening abdominal pain. She had been in good health until she started experiencing persistent abdominal pain and distension associated with nausea, vomiting, loose stools, decreased appetite, and weight loss. Her past medical history was significant for an episode of deep venous thrombosis during pregnancy and an unevaluated thyroid nodule. She had no history of heavy alcohol or intravenous drug use, and her family history was unremarkable. Unemployed, she was taking classes at the local community college. Her clinical picture at the outside hospital was consistent with liver disease. The patient’s initial physical examination showed jaundice, abdominal distension and tenderness, and a positive

Osteoporosis management in older patients who experienced a fracture

Background Fractures in older patients are common, morbid, and associated with increased risk of subsequent fractures. Inpatient and outpatient management and treatment of fractures can be costly. With more emphasis placed on quality care for Medicare beneficiaries, we studied if patients were receiving proper screening for osteoporosis and treatment after diagnosis of fracture. This study aims to determine if adequate screening and treatment for osteoporosis occurs in the postfracture period. Methods A retrospective analysis of Medicare beneficiaries aged 67 years or older was gathered from a single institution in both inpatient and outpatient visits. Based on International Classification of Diseases ninth revision codes, primary diagnosis of fractures of neck and trunk, upper limb, and lower limb were obtained in addition to current procedural terminology codes for fracture procedures. We studied patients who had been screened for osteoporosis with a bone mineral study or received osteoporosis treatment after their fracture. Results Medicare beneficiaries totaling 1,375 patients were determined to have an inclusion fracture between June 1, 2013 and November 30, 2014. At the time of our analysis on December 1, 2014, 1,219 patients were living and included in the analysis. Of these patients, 256 (21.0%) either received osteoporosis testing with bone mineral density or received treatment for osteoporosis. On sex breakdown, 208/820 (25.4%) females received proper evaluation or treatment of osteoporosis in comparison to 48/399 (12.0%) males. This is in comparison to the Centers for Medicare and Medicaid Services’ national average of 19.1% for osteoporosis management in females. Conclusion A minority of studied patients received evaluation or treatment for osteoporosis after their fracture. Postfracture investigation and treatment for osteoporosis in Medicare beneficiaries is inadequate. If improved, Medicare costs could be reduced by prevention of future fractures. Future studies could determine how best to ensure this intervention occurs.