Angelo A. Licata

Intermittent cyclical etidronate treatment of postmenopausal osteoporosis

Abstract Background. To determine the effects of etidronate (a bisphosphonate that inhibits osteoclast-mediated bone resorption) in the treatment of postmenopausal osteoporosis, we conducted a prospective, two-year, double-blind, placebo-controlled, multicenter study in 429 women who had one to four vertebral compression fractures plus radiographic evidence of osteopenia. Methods. The patients were randomly assigned to treatment with phosphate (1.0 g) or placebo twice daily on days 1 through 3, etidronate (400 mg) or placebo daily on days 4 through 17, and supplemental calcium (500 mg) daily on days 18 through 91 (group 1, placebo and placebo; group 2, phosphate and placebo; group 3, placebo and etidronate; and group 4, phosphate and etidronate). The treatment cycles were repeated eight times. The bone density of the spine was measured by dual-photon absorptiometry, and the rates of new vertebral fractures were determined from sequential radiographs. Results. After two years, the patients receiving etidro...

Four-year study of intermittent cyclic etidronate treatment of postmenopausal osteoporosis: Three years of blinded therapy followed by one year of open therapy

Abstract purpose: To determine the effect of long-term intermittent cyclic etidronate treatment on spinal bone density and vertebral fracture rates. patients and methods: Postmenopausal osteoporotic women (n = 423) were randomized initially into a 2-year, double-blind, multicenter study; it was extended to a third year of blinded treatment followed by open-label treatment: 357 patients continued treatment in Year 3 (305 receiving blinded therapy and 52 receiving calcium supplementation) and 277 in Year 4. During Years 1 through 3, patients received doubleblind treatment with phosphate (1.0 g) or placebo twice daily for 3 days, etidronate (400 mg) or placebo daily for 14 days, and calcium (500 mg) daily for the remainder of each 91-day treatment cycle. During Year 4, open-label intermittent cyclic etidronate therapy (without preceding phosphate) was administered to all patients. Spinal bone density and vertebral fracture rates were the main outcome measures. results: During Year 3, etidronate therapy maintained the significant increases in spinal bone mineral density of the first 2 years. Over the 3-year period, proximal femur bone density increased in etidronate-treated patients. Etidronate therapy for 3 years significantly decreased the vertebral fracture rate in patients at higher risk for fracture (low spinal bone density and three or more vertebral fractures at study entry), as compared with nonetidronate treatment (228 versus 412 fractures per 1,000 patient-years, respectively; p conclusions: Three years of intermittent cyclic etidronate therapy produced significant increases in spinal and hip bone density, with a significant reduction in vertebral fracture rates in patients at higher fracture risk. Maintenance of bone mass and low fracture rate were observed when etidronate was continued for an additional year.

Effects of Amiodarone on Thyroid Function

Amiodarone was approved by the Food and Drug Administration in 1985 for the treatment of serious ventricular arrhythmia. It is also efficacious in the treatment of paroxysmal supraventricular tachycardia and atrial fibrillation and flutter [1]. In addition, use of amiodarone after myocardial infarction may reduce complex ventricular ectopy and cardiac-related mortality [2, 3]. Use of amiodarone may improve survival rates in patients with heart failure [4-6]. However, in view of the results of recent studies, the efficacy of amiodarone in improving survival after myocardial infarction and in patients with heart failure has been questioned ([7, 8]; Camm JA, for the European Myocardial Infarction Amiodarone Trial, paper presented at the American College of Cardiology 1996 Meeting, Orlando, Florida). Side effects of amiodarone are often related to daily or cumulative dose and duration of treatment and include corneal microdeposits, photosensitivity, cutaneous hyperpigmentation, pulmonary toxicity, hepatotoxicity, peripheral neuropathy, drug interactions, hyperthyroidism, and hypothyroidism [9-23]. Smaller doses of amiodarone, such as those used for supraventricular arrhythmias [1], may be associated with fewer side effects. Using a MEDLINE search of articles published from 1975 to 1995, we identified and reviewed English-language articles on the effects of amiodarone on thyroid physiology and the recognition and management of amiodarone-induced thyrotoxicosis and hypothyroidism. Effects of Amiodarone on Thyroid Physiology Amiodarone is an iodine-rich benzofuran derivative (Figure 1). Approximately 37% of amiodarone (by weight) is organic iodine; 10% of the latter is deiodinated to yield free iodine. A maintenance dose of 200 to 600 mg/d results in a daily intake of organic iodide of 75 to 225 mg, at least 10% of which is deiodinated. Because the normal dietary requirement of iodine is only 0.2 to 0.8 mg/d [24], the increased amount of iodine intake associated with amiodarone causes a massive expansion of the iodide pool [25]. In patients treated with amiodarone, urinary and plasma levels of inorganic iodide increase 40-fold, whereas thyroid iodide uptake and clearance decrease significantly [25]. Therefore, thyroid hormone dynamics change in almost all patients receiving amiodarone [26]. Figure 1. Chemical structures of thyroxine, triiodothyronine, and amiodarone. Amiodarone has many effects on thyroid physiology. It decreases the peripheral deiodination of thyroxine to triiodothyronine by inhibiting type I iodothyronine 5-deiodinase [27-30], resulting in an increase of serum levels of thyroxine and reverse triiodothyronine and a decrease of serum levels of triiodothyronine (by 20% to 25%), as seen in the euthyroid sick syndrome [31, 32]. Amiodarone also inhibits entry of thyroxine and triiodothyronine into peripheral tissue. Serum thyroxine levels increase by an average of 40% above pretreatment levels after 1 to 4 months of treatment with amiodarone; in 40% of all patients, the serum thyroxine levels (and free thyroxine index) may increase to levels above the normal range. This is an expected finding and in itself does not constitute evidence of hyperthyroidism [23]. In addition, an increase in thyroid-stimulating hormone levels secondary to inhibition of thyroxine-triiodothyronine deiodination in the pituitary is seen during the early phase of treatment (from 1 to 3 months) [33]. This inhibition is a crucial step in the feedback regulation of secretion of thyroid-stimulating hormone [34]. By themselves, elevated serum levels of thyroid-stimulating hormone are not an indication for thyroxine replacement therapy in these patients. With long-term administration of amiodarone (>3 months), serum levels of thyroid-stimulating hormone often return to normal, and the response of thyroid-stimulating hormone to thyrotropin-releasing hormone may be reduced [33, 35-38]. Changes in thyroid function test results, which occur in euthyroid patients receiving amiodarone, are summarized in Figure 2. Figure 2. Changes in thyroid hormone physiology and thyroid function test results in euthyroid patients who received amiodarone. Abnormal results of thyroid function tests (without overt dysfunction of the thyroid gland) occur more often as the duration of treatment increases and doses accumulate. Serum levels of amiodarone or desethylamiodarone generally do not predict these abnormal test results [39]. One exception is the increase in reverse triiodothyronine levels in the first 2 weeks after commencement of amiodarone therapy; this shows a direct correlation with serum amiodarone levels [40]. In addition, in the absence of factors that may independently affect reverse triiodothyronine metabolism (such as hyperthyroidism, hypothyroidism, surgery, fasting, systemic illnesses, and concomitant use of corticosteroids or -blockers), the efficacy and toxicity of amiodarone can be monitored by serial measurements of serum reverse triiodothyronine levels [41]. Serum levels of reverse triiodothyronine that are threefold to fivefold greater than baseline levels are associated with adequate antiarrhythmic response; levels that are more than five times the baseline values are associated with a greater chance for drug toxicity. Effects of Amiodarone on Cardiac Tissue Receptors Independent of its effects on thyroid hormone physiology, amiodarone has some electrophysiologic effects on cardiac muscle cells that simulate those of hypothyroidism [42]. The effects seen with long-term administration may be mediated by amiodarone itself, its active metabolite desethylamiodarone, or both. In the hearts of pigs treated with amiodarone, the maximum binding capacity of -receptors and calcium channels is reduced [43]. The maximum binding capacity for triiodothyronine is unchanged, suggesting that no functional reduction in the number of triiodothyronine receptors occurs. However, desethylamiodarone competitively inhibits the binding of triiodothyronine to its nuclear receptors and may be responsible for the local hypothyroid-like effects [43]. In a comparison of rats with normal thyroid function and those that had had thyroidectomy [44], amiodarone reduced cardiac -receptor density and heart rate in the former but not the latter group. This finding implies that a minimum serum thyroid hormone level is necessary for the drug to produce some of its cardiac effects. These changes occur independently of alterations in thyroid secretion and serum triiodothyronine levels. Exogenous triiodothyronine-mediated increase in -receptor density and heart rate is also partly inhibited by amiodarone [45]. These observations suggest that the lowering of -receptor density by amiodarone is related to triiodothyronine antagonism at the cardiac cellular level. Incidence of Clinical Thyroid Dysfunction in Patients Receiving Amiodarone In various studies [10, 35, 46-50], the incidence of amiodarone-induced thyrotoxicosis has been reported to be 1% to 23% and that of hypothyroidism has been reported to be 1% to 32%. As many as 49% of patients in a study in which phenytoin was used as a supplementary antiarrhythmic agent [26] developed thyroid dysfunction within 60 months of follow-up. However, the overall incidence of amiodarone-induced thyroid dysfunction is more reasonably estimated to be 2% to 24% [26]. Amiodarone-induced thyrotoxicosis prevails in areas with low iodine intake, and hypothyroidism is prevalent in areas with high iodine intake. Thus, thyrotoxicosis is more common in Italian than American patients (10% compared with 2%), but hypothyroidism is less common (2% compared with 22%) [35]. This difference is generally similar to the difference in the incidence of iodide-induced thyrotoxicosis, which is more common in iodide-deficient areas than in iodide-replete areas [51]. However, this geographic predilection is not substantiated by all studies [52, 53]. Although amiodarone crosses the placental barrier, its use in nine pregnant women was not associated with clinical thyroid dysfunction in their neonates [54]. Thyroid function test results were normal in all neonates except one who had clearly abnormal serum levels of thyroxine and thyroid-stimulating hormone. In another series of five neonates born to women receiving amiodarone [55], one was found to have hypothyroidism requiring treatment with triiodothyronine for a few weeks. In a review of adverse effects associated with amiodarone therapy in 34 pregnant women [56], hypothyroidism was reported in three neonates (9%) and hyperthyroidism was reported in none. Amiodarone-Induced Thyrotoxicosis The factors leading to the development of thyrotoxicosis in some patients treated with amiodarone are not completely understood. Amiodarone-induced thyrotoxicosis occurs in patients with underlying goiter and those with no apparent thyroid disorder [57]. A predominance among men is sometimes reported [26, 58]. Lack of response of thyroid-stimulating hormone to stimulation of thyrotropin-reducing hormone may predict development of amiodarone-induced thyrotoxicosis [59], but this is not uniformly accepted [26, 60]. Pathogenesis Amiodarone-induced thyrotoxicosis is often caused by excessive synthesis of thyroid hormone induced by iodine, especially in patients with underlying thyroid disease. However, various other mechanisms have been proposed. Disturbance of Thyroid Iodine Autoregulation Intrinsic autoregulatory mechanisms in the thyroid modulate the glands iodine handling according to its iodine content [61]. Alterations in these mechanisms may cause thyroid dysfunction in the presence of excess iodine [62, 63]. A disturbance of these mechanisms is suggested by the high iodine content of the thyroid in patients with amiodarone-induced thyrotoxicosis (compared with those who have normal thyroid function) while they are receiving amiodarone [64] and by return of iodine content to normal during resolution of thyrotoxicosis [38]. T

Early Changes in Biochemical Markers of Bone Formation Predict BMD Response to Teriparatide in Postmenopausal Women With Osteoporosis

The relationship between early changes in biochemical markers of bone turnover and the subsequent BMD response to daily teriparatide therapy in women with postmenopausal osteoporosis was studied. Changes in five biochemical markers, obtained from a subset of women enrolled in the Fracture Prevention Trial, were examined. Early increases in the PICP and the PINP were the best predictors of BMD response to teriparatide in this analysis.

Gorham's syndrome: A case report and review of the literature

Gorhams syndrome is a rare disorder involving a proliferation of vascular channels associated with extensive loss of bony matrix. A case report is presented with a review of the 97 previously reported cases. The age of patients at presentation has ranged from less than one to 75 years (mean: 27 years). Sixty-four percent have been men. Fifty-seven percent have had a history of prior trauma. Laboratory values for systemic measures have usually been normal. The disease usually arrests spontaneously, but this is unpredictable. Sixteen patients (16 percent) have died of the disorder, with 10 deaths due to chest wall involvement, three to spinal cord transection, two to sepsis, and one to asphyxia and aspiration. Although the mechanism of bone loss is unknown, osteoclasts were focally increased in the case described herein. Further information and investigation are needed to better understand this unusual disorder.

Cyclical Etidronate in the Treatment of Postmenopausal Osteoporosis: Efficacy and Safety After Seven Years of Treatment

PURPOSE To determine the efficacy and safety of cyclical etidronate for up to 7 years in the treatment of postmenopausal osteoporosis and to examine the effects of discontinuing treatment after 2 or 5 years of therapy. PATIENTS AND METHODS Patients were randomized at entry into the original study in 1986 to blinded treatment for 2 years with either a calcium (placebo) or an intermittent cyclical etidronate regimen, which most patients continued for a third year. Following this phase of the study, patients were enrolled into an open-label, follow-up study (years 4 and 5), during which all patients received cyclical etidronate treatment. In the present double-blind study (years 6 and 7), patients were rerandomized to receive intermittent cyclical therapy with either etidronate or placebo; all patients received calcium. The treatment regimen consisted of 400 mg/day etidronate or placebo for 14 days, followed by 76 days of elemental calcium (500 mg/day); this cycle was repeated approximately 4 times in each year. Of the 193 patients who continued in years 6 and 7 of the study, 93 were randomized to receive cyclical etidronate and 100 were randomized to receive calcium only. For purposes of efficacy analyses, patients were categorized by their total years of cumulative etidronate treatment (7, 5, 4, or 2 years). There were 51, 46, 42, and 54 patients in the 7-, 5-, 4-, and 2-year groups, respectively. Annual assessments included lumbar spine bone mineral density (BMD), as measured by densitometry, and vertebral radiographs. RESULTS The groups receiving cyclical etidronate during this 2-year study period (7- and 4-year groups) had statistically significant mean percent increases in spinal BMD of 1.8% and 2.2%, respectively (P < 0.05) at the week 104 observation time. The 5- and 2-year groups, which did not receive etidronate during this period, had mean values of 1.4% and 0.2%, respectively (not significant) at week 104. In the 7-, 5-, 4-, and 2-year groups, the increases in spinal BMD at the end of 7 years were 7.6%, 8.6%, 8.1%, and 3.9%, respectively; these values were statistically significant for all groups compared with original baseline (year 0) (P < 0.05). BMD of the femur and wrist was maintained throughout the 7-year period. The incidence and rate of vertebral fractures were lowest in patients with the longest exposure to etidronate. Etidronate was well tolerated during the study, with low incidences of gastrointestinal side effects and nonvertebral fractures. CONCLUSIONS Long-term cyclical etidronate is a safe, effective, and well-tolerated treatment for postmenopausal osteoporosis. Bone mass is maintained for at least 2 years after treatment with etidronate is stopped; however, further gains in spinal bone mass are seen in patients who continue therapy.

Bone density vs bone quality: what's a clinician to do?

Studies of the epidemiology of osteoporosis and of drug treatments for it have challenged the concept that denser bone means stronger bone. Bone strength or resistance to fracture is not easily measured by routine densitometry, being a function of both density and quality. Denser bone is not necessarily stronger. The concept of bone strength has moved beyond density alone and now includes a number of characteristics collectively referred to as bone quality.

Rechallenge of patients who had discontinued alendronate therapy because of upper gastrointestinal symptoms

BACKGROUND There have been reports from physicians in clinical practice that up to 30% of patients taking bisphosphonate therapy develop upper gastrointestinal (UGI) symptoms, many or most of which they assume to be related to the drug. However, in several large placebo-controlled clinical trials of bisphosphonates, the incidence of UGI symptoms has been > or =30%, even among patients receiving placebo, perhaps reflecting a high background incidence of UGI events in osteoporotic patients. OBJECTIVE To assess the relationship between alendronate treatment and UGI complaints in patients who had discontinued treatment with alendronate in clinical practice because of UGI symptoms, we compared the incidence of such events on rechallenge with alendronate or placebo. METHODS This was a multicenter, double-blind trial in which postmenopausal women with osteoporosis who had previously discontinued alendronate therapy because of a UGI adverse experience were randomized to daily treatment with either alendronate 10 mg or matching placebo (1:1 ratio) for 8 weeks. The primary end point was the cumulative incidence of discontinuations due to any UGI adverse experience. Secondary end points were the incidence of any clinical adverse experiences and the percentage change from baseline in urinary N-telopeptide adjusted for urinary creatinine at week 8. RESULTS A total of 172 women were included in the study. They were a mean of 20.9 years past menopause, ranging in age from 41 to 90 years (mean, 67.0 years); 90.7% were white. On rechallenge, 14.8% (13/88) of patients in the alendronate group and 16.7% (14/84) in the placebo group discontinued treatment because of UGI adverse experiences. CONCLUSION The results of this study suggest that many UGI adverse experiences reported during therapy with alendronate may reflect a high background incidence of UGI complaints and an increased sensitivity to detection of such complaints, rather than a causal relationship to therapy.

Clinical practice guidelines for healthy eating for the prevention and treatment of metabolic and endocrine diseases in adults: cosponsored by the American Association of Clinical Endocrinologists/the American College of Endocrinology and the Obesity Society: executive summary.

J. Michael Gonzalez-Campoy, MD, PhD, FACE1; Sachiko T. St. Jeor, PhD, RD2; Kristin Castorino, DO3; Ayesha Ebrahim, MD, FACE4; Dan Hurley, MD, FACE5; Lois Jovanovic, MD, MACE6; Jeffrey I. Mechanick, MD, FACP, FACN, FACE, ECNU7; Steven M. Petak, MD, JD, MACE, FCLM8; Yi-Hao Yu, MD, PhD, FACE9; Kristina A. Harris10; Penny Kris-Etherton, PhD, RD11; Robert Kushner, MD12; Maureen Molini-Blandford, MPH, RD13; Quang T. Nguyen, DO14; Raymond Plodkowski, MD15; David B. Sarwer, PhD16; Karmella T. Thomas, RD17

Taking vitamin D with the largest meal improves absorption and results in higher serum levels of 25‐hydroxyvitamin D

Many patients treated for vitamin D deficiency fail to achieve an adequate serum level of 25‐hydroxyvitamin D [25(OH)D] despite high doses of ergo‐ or cholecalciferol. The objective of this study was to determine whether administration of vitamin D supplement with the largest meal of the day would improve absorption and increase serum levels of 25(OH)D. This was a prospective cohort study in an ambulatory tertiary‐care referral center. Patients seen at the Cleveland Clinic Foundation Bone Clinic for the treatment of vitamin D deficiency who were not responding to treatment make up the stugy group. Subjects were instructed to take their usual vitamin D supplement with the largest meal of the day. The main outcome measure was the serum 259(OH)D level after 2 to 3 months. Seventeen patients were analyzed. The mean age (±SD) and sex (F/M) ratio were 64.5 ± 11.0 years and 13 females and 4 males, respectively. The dose of 25(OH)D ranged from 1000 to 50,000 IU daily. The mean baseline serum 25(OH)D level (±SD) was 30.5 ± 4.7 ng/mL (range 21.6 to 38.8 ng/mL). The mean serum 25(OH)D level after diet modification (±SD) was 47.2 ± 10.9 ng/mL (range 34.7 to 74.0 ng/mL, p < .01). Overall, the average serum 25(OH)D level increased by 56.7% ± 36.7%. A subgroup analysis based on the weekly dose of vitamin D was performed, and a similar trend was observed.