Yair Liel

Awareness of Osteoporosis and Compliance with Management Guidelines in Patients with Newly Diagnosed Low-Impact Fractures

Abstract: A pre-existing fracture is a strong predictor of additional osteoporotic fractures. Consequently, current guidelines emphasize the need for treating patients with existing osteoporotic fractures. The present study aimed to assess the implementation of osteoporosis guidelines in routine practice. To this end, we reviewed the hospital charts of women and men aged 50 years and older with new fractures due to low or moderate impact treated in the emergency room, orthopedic surgery and rehabilitation departments. Notation of osteoporosis as a contributing cause for the fracture, performance of screening laboratory tests for possible secondary causes and treatment recommendations were abstracted from the record. In addition, we utilized the centralized pharmacy and laboratory computerized databases of the largest health maintenance organization in the area to follow dispensation of osteoporosis drugs and performance of screening laboratory tests in the community following fracture incidents. During the corresponding periods of January and February 1998 and 1999, 183 patients aged 50 years and older with low-impact fractures were treated in the emergency room only and 113 were hospitalized. Osteoporosis was rarely mentioned in the medical documentation. During the 6 month period after the fracture incident at least 70% of the emergency room patients and 62% of the hospitalized patients received no osteoporosis drugs. However, an encouraging significant trend toward increasing use of osteoporosis drugs, both prior to and after a fracture incident, was noted between the two survey periods among the emergency room fracture patients, but not among the hospitalized patients. Calcium supplements were the most commonly used osteoporosis drug. Bisphosphonates, hormone replacement therapy, raloxifene and calcitonin were rarely prescribed. Men were less likely than women to receive treatment for osteoporosis. Systematic laboratory evaluations for secondary causes of osteoporosis were not performed. We conclude that despite extensive attempts at increasing awareness among health professionals and the public at large, osteoporosis is still rarely singled out as a problem in patients with newly diagnosed low-impact fractures, and the majority of them are not managed according to guidelines. Further studies should address specific problems in physicians’ and patients’ attitude that may account for the present situation.

Nonspecific Intestinal Adsorption of Levothyroxine by Aluminum Hydroxide

PURPOSE To evaluate the adverse effect of aluminum hydroxide on levothyroxine pharmacokinetics in hypothyroid patients and study the mechanism of this effect. DESIGN An in vivo open study supplemented by in vitro experiments. SETTING A university hospital-based outpatient service. INTERVENTION Administration for 2 to 4 weeks of an aluminum hydroxide-containing preparation to patients balanced on replacement thyroxine therapy. MEASUREMENTS Serum thyrotropin (TSH). RESULTS A significant increase in serum TSH was observed during seven periods of aluminum hydroxide administration (7.19 +/- 1.3 versus 2.62 +/- 0.8 mU/L; P = 0.012). In vitro studies indicated a considerable nonspecific adsorptive capacity of aluminum hydroxide for thyroxine. CONCLUSIONS The results indicate an adverse effect of aluminum hydroxide on levothyroxine bioavailability through a mechanism involving nonspecific adsorption, or complexing, of levothyroxine to aluminum hydroxide. We recommend close monitoring of serum TSH levels in patients receiving oral thyroid hormone replacement therapy who concurrently take aluminum hydroxide-containing medications. Adjustment of the levothyroxine dose, or cessation of the antacid, may be necessary.

Preparation for radioactive iodine administration in differentiated thyroid cancer patients.

objective Because in recent years the practice of TSH suppression has changed, and thyroxine doses have been reduced significantly in the treatment of patients with low‐risk differentiated thyroid cancer, the goal of this study was to determine the time needed to attain a target TSH level (of 30 mIU/l) following levothyroxine withdrawal in patients treated with thyroxine according to current guidelines, in anticipation of radioactive iodine (RAI) administration.

A quantitative assessment of a methodology for collaborative specification and evaluation of clinical guidelines

We introduce a three-phase, nine-step methodology for specification of clinical guidelines (GLs) by expert physicians, clinical editors, and knowledge engineers and for quantitative evaluation of the specifications quality. We applied this methodology to a particular framework for incremental GL structuring (mark-up) and to GLs in three clinical domains. A gold-standard mark-up was created, including 196 plans and subplans, and 326 instances of ontological knowledge roles (KRs). A completeness measure of the acquired knowledge revealed that 97% of the plans and 91% of the KR instances of the GLs were recreated by the clinical editors. A correctness measure often revealed high variability within clinical editor pairs structuring each GL, but for all GLs and clinical editors the specification quality was significantly higher than random (p<0.01). Procedural KRs were more difficult to mark-up than declarative KRs. We conclude that given an ontology-specific consensus, clinical editors with mark-up training can structure GL knowledge with high completeness, whereas the main demand for correct structuring is training in the ontologys semantics.

Peroxidase Activity in Mammary Tumors--Effect of Tamoxifen

Abstract Dimethylbenz(a)anthracen (DMBA)-induced tumors in rats were studied for changes in size, cytosolic estrogen (ER) and progesterone (PgR) receptors, and for peroxidase activity before treatment, after 15 days of treatment with the anti-estrogen tamoxifen, and 15 days following cessation of the treatment. Mean size of the tumors decreased significantly during the treatment period to 1/3 the original size and ER and PgR decreased significantly to 1/5 their original levels. Peroxidase activity increased 30 -fold. All the changes reversed significantly 15 days after cessation of tamoxifen treatment. These results are consistent with a previous study in which regression of the tumors was induced by castration and recovery was brought about by treatment with estradiol. In DMBA-induced mammary tumors in rats, peroxidase activity in regressing and growing tumors is in inverse relation to changes in tumor size, ER and PgR, which are accepted indicators of estrogenic activity.

Association between Bone Mineral Density and Incidence of Breast Cancer

Introduction Previous studies have suggested an inverse relationship between bone mineral density (BMD) and breast cancer incidence. The primary objective of this study was to assess whether BMD is associated with risk of subsequent breast cancer occurrence in the female population of southern Israel. Methods The electronic medical charts of women who underwent BMD at the Soroka Medical Center (SMC) between February 2003 and March 2011 were screened for subsequent breast cancer diagnoses. Women were divided by tertiles of BMD at 3 skeletal sites: lumbar spine (LS, L1–4), total hip (TH) and femoral neck (FN). The incidence of breast cancer was calculated. Results Of 15268 women who underwent BMD testing, 86 were subsequently diagnosed with breast cancer. Most women in the study were older than 50 years (94.2% and 92.7%, respectively; p = 0.597). Women who subsequently developed breast cancer had a higher mean body-mass index (BMI) (30.9±5.5 vs. 29.1±5.7 p = 0.004) and the mean BMD Z-score was significantly higher than in those without breast cancer for all 3 skeletal sites (LS: 0.36±1.58 vs. −0.12±1.42, p = 0.002; TH: 0.37±1.08 vs. 0.03±1.02, p = 0.002; FN: 0.04±0.99 vs. −0.18±0.94; p = 0.026). Women in the highest Z-score tertiles at the FN and TH had a higher chance of developing breast cancer compared to the lowest tertile; odds ratio of 2.15, 2.02, respectively (P = 0.004 and 0.01 respectively). No association was found between the BMD Z-score and the stage, histology, grade or survival from breast cancer. Conclusions This study provides additional support for an inverse association between BMD and the risk of breast cancer.

Differential Effect of TPA on PGE2 and Cicaprost-Induced cAMP Synthesis in UMR-106 cells

PGE2 and prostacyclin each enhance cAMP synthesis in the osteoblast-like cell line UMR-106. The amount of cAMP induced by PGE2 was 5-7-fold greater than the amount induced by cicaprost or iloprost, stable prostacyclin analogues. Both PGE2 and the two prostacyclin analogues enhanced cAMP synthesis with similar time dependence. The EC50 values of PGE2 and cicaprost were 3 X 10(-6) and 5 x 10(-8) M, respectively. Short-term incubation of the cells with 12-o-tetradecanoylphorbol 13-acetate (TPA) markedly reduced the PGE2-induced cAMP synthesis. In contrast, cells that were incubated with the same concentrations of TPA in the presence of cicaprost or iloprost showed a 1.6-fold increase in cAMP formation. The marked disparity between the cAMP response to cicaprost and PGE2 in the presence of TPA suggests that the two prostanoids induce cAMP synthesis in the UMR-106 cells by interaction with different receptors. These observations support the idea that the osteoblastic UMR-106 cells may express specific prostacyclin receptors and suggest that prostacyclin may have a unique role in osteoblasts.

Can Physicians Structure Clinical Guidelines? Experiments with a Mark-Up-Process Methodology

We have previously developed an architecture and a set of tools called the Digital electronic Guideline Library (DeGeL), which includes a web-based tool for structuring (marking-up) free-text clinical guidelines (GLs), namely, the URUZ Mark-up tool. In this study, we developed and evaluated a methodology and a tool for a mark-up-based specification and assessment of the quality of that specification, of procedural and declarative knowledge in clinical GLs. The methodology includes all necessary activities before, during and after the mark-up process, and supports specification and conversion of the GLs free-text representation through semi-structured and semi-formal representations into a machine comprehensible representation. For the evaluation of this methodology, three GLs from different medical disciplines were selected. For each GL, as an indispensable step, an ontology-specific consensus was created, determined by a group of expert physicians and knowledge engineers, based on GL source. For each GL, two mark-ups in a chosen GL ontology (Asbru) were created by a distinct clinical editor; each of the clinical editors created a semi-formal mark-up of the GL using the URUZ tool. To evaluate each mark-up, a gold standard mark-up was created by collaboration of physician and knowledge engineer, and a specialized mark-up-evaluation tool was developed, which enables assessment of completeness, as well as of syntactic and semantic correctness of the mark-up. Subjective and objective measures were defined for qualitative and quantitative evaluation of the correctness (soundness) and completeness of the marked-up knowledge, with encouraging results.

Interaction Between Estrogen and Vitamin D–Endocrine System: A Potential Addition to the Unitary Model of Osteoporosis

In a recent article, Riggs et al. presented an intriguing hypothesis, which focuses on estrogen deficiency as the primary factor responsible for early and late postmenopausal osteoporosis in women, as well as for involutional osteoporosis in men. As indicated by Dr. Bilizikian, in an accompanying editorial, the apparent weaknesses of this theory involves incomplete data on the extraskeletal actions of estrogen, such as its alleged direct actions on the kidney and intestinal absorption of calcium. Our group is involved in a series of ongoing studies on the interactions between estrogen and the vitamin D–endocrine system. Our initial observation indicated that estrogen up-regulates vitamin D receptors (VDR) in osteoblastlike cells (ROS 17/2.8) and increases the response of the cells to any given concentration of 1,25-dihydroxyvitamin D. Additional observations indicate that estrogen is directly involved in up-regulation of VDR in the intestine (Liel Y, Shany S, Smirnoff P, Schwartz B, unpublished data). As in osteoblasts, our results indicate that exposure to estrogen increases intestinal mucosa response to vitamin D. Results in osteoblastic cell lines and in rat intestinal mucosa (and unpublished observations from our laboratory on duodenal mucosa) indicate that the effect of estrogen on VDR is associated with increased amounts of VDR mRNA in the respective tissues, suggesting that the increase in VDR protein expression is likely induced by increased VDR gene transcription, or increased stability of the message. In conclusion, the observations that estrogen activity involves up-regulation of VDR in osteoblasts and the intestine supports the notion that estrogen deficiency has a central role in the pathogenesis of postmenopausal osteoporosis, both in skeletal and extraskeletal sites, and provides a missing link to the set of evidence presented by Riggs et al. The reversible resistance of target tissues to vitamin D, produced by estrogen deficiency, may be of particular importance for the pathogenesis of involutional osteoporosis. REFERENCES

Acute adrenal crisis complicating hypertensive congenital adrenal hyperplasia due to 11β-hydroxylase deficiency

In its classical form, congenital adrenal hyperplasia due to 11 β‐hydroxylase deficiency is characterized by hypertension and abnormal sexual development. Suppression of ACTH secretion by means of administering glucocorticoids fulfills the therapeutic goal of reducing blood pressure and decreasing androgen production. The present report describes the case of a patient suffering from congenital adrenal hyperplasia due to 11β‐hydroxylase deficiency who developed an acute adrenal crisis, unprovoked by stress, following interruption of glucocorticoid replacement therapy. It is suggested that patients on a suppressive dose of glucocorticoids for adrenal hyperplasia are at increased risk for acute adrenal insufficiency if therapy is interrupted, and that deoxycorticosterone (DOC) in the absence of a glucocorticoid is insufficient to prevent manifestations of adrenal crisis.