The role of selective estrogen receptor modulators in the prevention and treatment of osteoporosis.

Osteoporosis can affect almost everyone in the population, and although clinical outcome of fracture is manifested in late life, the disease process begins in the early postmenopausal years in women. The pharmacologic agents currently available for osteoporosis prevention and treatment act by inhibiting bone resorption, and include estrogen or hormone replacement therapy (estrogen with progestin), bisphosphonates, salmon calcitonin nasal spray, and selective estrogen receptor modulators (SERMs). Raloxifene is a benzothiophene SERM that has estrogen against effects in bone and on serum lipid metabolism and estrogen antagonist effects on breast and uterine tissue. This article summarizes the effects of these antiresorptive agents, as measured by changes in bone mineral density, biochemical markers of bone turnover, and incident fractures in postmenopausal osteoporosis.

Raloxifene hydrochloride, a selective estrogen receptor modulator: safety assessment of effects on cognitive function and mood in postmenopausal women.

Raloxifene hydrochloride (HCl) is a selective estrogen receptor modulator with estrogen agonist effects on bone and lipid metabolism and estrogen antagonist effects on reproductive tissues. Animal studies suggest that raloxifene may affect brain function as well, although the effects of raloxifene on the human brain remain to be established. This paper presents an early safety assessment of raloxifene effects on cognition and mood in postmenopausal women participating in a randomized, double-blind osteoporosis treatment trial. Psychometric test batteries were administered to postmenopausal women at baseline and 1, 6, and 12 months after initiating treatment with raloxifene (60 and 120 mg/day). The Memory Assessment Clinics (MAC) battery and Walter Reed Performance Assessment Battery (PAB) were used to assess multiple and independent aspects of cognitive function, while mood was assessed with the Geriatric Depression Scale (GDS). After 12 months of treatment, there were no significant differences between the raloxifene groups and placebo on performance in either the MAC battery or the PAB. The only significant difference observed was a slight increase in performance favoring the raloxifene 120 mg/day group in an assessment of verbal memory on the MAC battery after 1 month of treatment. Scores on the GDS and the self-reported incidence of mood-related events were not different between treatment groups at any of the assessment periods. These data do not suggest that raloxifene impairs cognition or affects mood in postmenopausal women treated for 1 year. Studies to further assess the safety and potential efficacy of raloxifene with respect to cognitive function are ongoing.

Treatment of established postmenopausal osteoporosis with raloxifene: a randomized trial.

Raloxifene is a selective estrogen receptor modulator that in experimental animals acts as an estrogen receptor antagonist in breast and endometrium but as an estrogen receptor agonist in the skeletal and cardiovascular systems. We conducted a 1-year prospective, randomized, double-blind trial in 143 postmenopausal osteoporotic women (mean +/- SD age, 68.4+/-5.0 years) with at least one prevalent vertebral fractures and low bone mineral density (BMD), comparing groups receiving raloxifene at 60 mg/day (RLX60) or 120 mg/day (RLX120) and a control group receiving supplements of 750 mg/day of calcium and 400 IU/day of vitamin D. There were no differences among groups in the occurrence of uterine bleeding, thrombophlebitis, breast abnormalities, or increased endometrial thickness (assessed by ultrasonography). As compared with controls, the changes in values over 1 year for RLX60 and RLX120, respectively, were significant for serum bone alkaline phosphatase (-14.9%, -8.87%), serum osteocalcin (-20.7%, -17.0%), and urinary C-telopeptide fragment of type I collagen/creatinine (-24.9%, -30.8%), markers of bone turnover; for serum total cholesterol (-7.0% for RLX60) and low density lipoprotein cholesterol (LDL) (-11.4% for RLX60) and for the LDL/HDL cholesterol ratio (-13.2%, -8.3%). BMD increased significantly in the total hip (1.66% for RLX60) and ultradistal radius (2.92%, 2.50%). There were nonsignificant trends toward increases over controls in BMD for lumbar spine, total body, and total hip (for RLX120). Using a >15% cutoff definition, raloxifene had no effect on incident fractures, but using a >30% cutoff, there was a dose-related reduction (p = 0.047). We conclude that raloxifene therapy is well tolerated, reduces serum lipids, and does not stimulate the uterus or breasts. It has beneficial effects on bone, although, under the conditions of this study, these appear to be of a smaller magnitude than have been reported with estrogen therapy.

Postmenopausal estrogen therapy, 1995.

Estrogen therapy offers women important benefits, including the potential prolongation of life by prevention of coronary heart disease (CHD) and osteoporotic fractures, and improvement of life by prevention of menopausal symptoms. Not all women can accept the potential side effects and risks, however, which include uterine bleeding, cystic mastitis, fluid retention, and increased risk of uterine cancer and breast cancer. Thus, the benefits and risks must be patiently weighed for each individual, and the alternatives of no treatment or other treatment should be clear. We review here the pertinent information that now makes these decisions quite sound.

Pamidronate: an unrecognized problem in gastrointestinal tolerability.

Pamidronate (aminohydroxypropylidine bisphosphonate, APD) is an effective agent for treatment of Paget's disease of bone, and it has also been thought to be effective for treatment of osteoporosis. We desired to study a newer, time-release preparation of pamidronate, and carried out a placebo-controlled, double-masked study of postmenopausal osteoporosis. The original formulation was in a rapidly dissolving gelatin capsule. We encountered four episodes of esophagitis in 49 enrolled patients. We therefore discontinued treatment with this preparation and later began the study again using a standard tablet preparation. We encountered an additional case of erosive esophagitis in 1 patient of 40 receiving this tablet preparation. No patient was receiving concomitant medication which could cause esophagitis. Two of the patients gave a past history of hiatal hernia and 1 gave a history of gastric ulcer 27 years previously. The diagnosis of esophagitis was confirmed in all cases by endoscopy. Healing of the esophagitis promptly ensued after discontinuation of the pamidronate and the use of antacid medication.

Epidemiology and clinical features of osteoporosis in young individuals.

Due to the lack of epidemiologic data on osteoporosis in the young, we identified all 22 Olmsted County, MN, residents aged 20-44 years when first diagnosed with established osteoporosis in 1976-1990. The overall age- and sex-adjusted incidence rate was 4.1 per 100,000 person-years (95% CI 2.4-5.9) with a female to male ratio of age-adjusted rates of 1.2:1. The majority represented secondary osteoporosis (12 steroid-induced, 3 postmenopausal, 2 delayed puberty, 2 anticonvulsant-induced, 2 gastrointestinal disease, 2 alcoholism, 1 anorexia nervosa, and 7 other etiologies; some individuals had more than one factor present) but two had idiopathic osteoporosis (incidence 0.4 per 100,000 person-years, 95% CI 0-0.9). To further characterize the patients with idiopathic osteoporosis, we also reviewed the entire Mayo Clinic experience with such patients from 1976 to 1990, regardless of residency. A total of 56 patients (30 female/26 male) were identified with a median age at diagnosis of 34 years. Only 8% were hypercalciuric at presentation. There was a preponderance of cancellous bone fractures (vertebral 81%, rib 37%, wrist 13%), although 13% did have hip fractures. Transiliac bone biopsies were available in 18 patients. As compared to age- and sex-matched controls, the osteoporotic subjects had a significant reduction in trabecular bone volume, cortical thickness, and mean wall thickness, the latter suggesting an abnormality in osteoblast function in these individuals.(ABSTRACT TRUNCATED AT 250 WORDS)

Relative value of transdermal and oral estrogen therapy in various clinical situations.

OBJECTIVE: In this study, we reviewed the comparative effectiveness of transdermal and oral estrogen therapy in various groups of women. DESIGN: On the basis of published data and personal clinical experience, we compiled recommendations for use of the various modes of estrogen replacement therapy. MATERIAL AND METHODS: The use of injectable estrogen or implantable estrogen pellets can no longer be recommended because of their expense, inconvenience, and unphysiologic pattern of serum estrogen response. The two main estrogen preparations currently used in the United States--orally administered conjugated estrogens and transdermally administered estradiol--undergo different metabolism, and these processes are reflected in differing levels of circulating hormones and hepatic by-products, including blood clotting factors, binding proteins, renin substrate, and apolipoproteins, and in varied composition of the bile. RESULTS: At least theoretically, transdermal estrogen therapy might be more beneficial than oral estrogen therapy for women who smoke cigarettes or who have migraine headaches, hypertriglyceridemia, hepatobiliary disorders, fibrocystic breast disease, or a history of thromboembolism. In contrast, women with hypercholesterolemia might respond better to oral than to transdermal estrogen therapy. CONCLUSION: Additional properly designed clinical studies are necessary before these recommendations for estrogen replacement therapy can be validated or refuted.

Treatment of postmenopausal osteoporosis with transdermal estrogen.

OBJECTIVE: To evaluate the tolerance and effectiveness of transdermal estrogen for women with established postmenopausal osteoporosis and vertebral fractures. DESIGN: Double-blind, randomized, placebo-controlled clinical trial lasting 1 year. SETTING: Referral-based outpatient clinic. PATIENTS: Seventy-five postmenopausal women, 47 to 75 years of age, with one or more vertebral fractures due to osteoporosis. INTERVENTIONS: Thirty-nine women received dermal patches delivering 0.1 mg of 17 beta-estradiol for days 1 to 21 and oral medroxyprogesterone acetate for days 11 to 21 of a 28-day cycle. Another 39 women received placebo. MEASUREMENTS: Bone turnover assessed by biochemical markers and iliac bone histomorphometry; bone loss assessed by serial measurement of bone density; and vertebral fracture rate. RESULTS: Compared with the placebo group, the median annual percentage change in bone mineral density in the estrogen group reflected increased or steady-state bone mineral density at the lumbar spine (5.3 compared with 0.2; P = 0.007), femoral trochanter (7.6 compared with 2.1; P = 0.03), and midradius (1.0 compared with -2.6, P less than 0.001) but showed no significant difference at the femoral neck (2.6 compared with 1.4; P = 0.17). Estrogen treatment uniformly decreased bone turnover as assessed by several methods including serum osteocalcin concentration (median change, -0.35 compared with 0.02 nmol/L; P less than 0.001). Histomorphometric evaluation of iliac biopsy samples confirmed the effect of estrogen on bone formation rate per bone volume (median change, -12.9 compared with -6.2% per year; P = 0.004). Also, 8 new fractures occurred in 7 women in the estrogen group, whereas 20 occurred in 12 women in the placebo group, yielding a lower vertebral fracture rate in the estrogen group (relative risk, 0.39; 95% CI, 0.16 to 0.95). CONCLUSIONS: Transdermal estradiol treatment is effective in postmenopausal women with established osteoporosis.

Estrogen replacement therapy for the prevention of osteoporosis.

Estrogen replacement therapy is the most effective single means of preventing and treating osteoporosis. The most common objection by patients, the resumption of menses if the uterus is present, may be eliminated by providing estrogen and progestin continuously. An additional concern, endometrial carcinoma, appears to be largely alleviated by coadministration of progestin. Evidence indicates that concomitant progestin administration actually reduces the incidence of endometrial carcinoma to less than that in untreated women. An incidental but potentially more important benefit is protection against coronary artery disease. Optimal management includes initiation of estrogen therapy shortly after menopause, long-term continuation and calcium supplementation.

Estrogen replacement therapy: current recommendations.

Estrogen replacement therapy is effective for the prevention and treatment of postmenopausal osteoporosis and should be offered to all women at high risk for osteoporosis. Such therapy is particularly beneficial for prevention of spinal compression fractures; in addition, it alleviates menopausal symptoms (hot flushes, genitourinary symptoms, and changes in mood). In each patient, these benefits must be weighted against the potential risks of endometrial hyperplasia and carcinoma, breast tenderness, hypertension, vascular headaches, and the inconvenience of menstrual bleeding if the uterus is intact. The risk of endometrial cancer associated with estrogen replacement therapy can be considerably reduced by the addition of a progestin, and other side effects can be diminished or eliminated by use of the new transdermal estrogen preparations. Thus, estrogen replacement therapy should be considered in all women who have experienced natural or surgically induced menopause, and it is advisable in women who have osteoporosis or an increased risk for this disorder and no contra-indications to its use. Estrogen replacement therapy should be instituted as soon after menopause as possible and seems to be well tolerated until at least 75 years of age.

Influence of phlebotomy treatment on abnormal hypothalamic-pituitary function in genetic hemochromatosis.

To test the hypothesis that deficiencies in hypothalamic-pituitary function in genetic hemochromatosis result from cellular injury by iron deposits, we conducted provocative tests in 11 men with genetic hemochromatosis before and after iron depletion by serial phlebotomy and in 10 control subjects. We gave combination intravenous injections of insulin (0.15 U/kg), luteinizing hormone releasing hormone (LHRH, 100 micrograms), and thyrotropin releasing hormone (400 micrograms) and then measured plasma glucose, growth hormone, corticosteroids, follicle-stimulating hormone, luteinizing hormone, prolactin, and thyroid-stimulating hormone at 30-minute intervals for 90 minutes. Phlebotomy caused a substantial decrease in median values for serum ferritin, deferoxamine-chelatable iron, and hepatic iron concentration. Before phlebotomy, stimulation by hypoglycemia and thyrotropin releasing hormone caused significantly less secretion of growth hormone (P = 0.004) and prolactin (P = 0.03) in patients than in control subjects. No significant improvement was noted, however, in growth hormone or prolactin secretion after phlebotomy. Of the 11 patients, 7 had secondary hypogonadism, and phlebotomy did not improve the serum testosterone, follicle-stimulating hormone, luteinizing hormone, or responses to LHRH in any case. Chlorpromazine injections failed to elevate serum prolactin in all patients, and administration of levodopa caused a partial reduction in serum prolactin; thus, the hypothalamus may be an important locus of endocrine malfunction in these patients. We conclude that abnormal hypothalamic-pituitary function in genetic hemochromatosis is not substantially improved by iron-depletion therapy.

Outpatient percutaneous biopsy of the iliac crest: methods, morbidity, and patient acceptance.

Bone histology and histomorphometry have become important in the diagnosis and management of metabolic bone disease, but the invasive nature of the biopsy procedure has limited its use. We describe an outpatient technique for obtaining one or more transiliac bone biopsy specimens. Thirty-eight women with osteoporosis, each of whom had sustained one or more spinal compression fractures, underwent two separate bone biopsies during which two 7.5-mm transiliac cores of bone were removed. No morbidity (such as infection or hemorrhage) was encountered. Subjective responses to the level of pain were surveyed by questionnaire. At the time of biopsy, 46% of the study subjects experienced no or only mild discomfort, and 24% judged their pain to be severe. At 16 hours after biopsy, 64% had no or mild pain and 8% experienced severe pain. At 7 days after biopsy, 79% experienced no or mild pain but 9% judged their pain to be severe. In four patients, temporary ambulatory disability occurred but resolved spontaneously in 7 to 10 days. We conclude that the described outpatient bone biopsy procedure is safe, efficient, and generally acceptable to patients.

Serum angiotensin-converting enzyme activity. Its use in the evaluation and management of hypercalcemia associated with sarcoidosis.

Serum angiotensin-converting enzyme (SACE) was measured in 14 patients (eight women and six men) with sarcoidosis and hypercalcemia. Thirteen patients were treated with prednisone, and 12 achieved normal or nearly normal serum calcium values. Two patients had coexistent hyperparathyroidism. Seven of eight patients with serial SACE measurements exhibited parallel falls in SACE and serum calcium levels. Eleven patients were successfully treated with alternate-day prednisone regimens. The data suggest that serial SACE measurements are useful in the evaluation and management of sarcoidosis with hypercalcemia. In patients with sarcoidosis, the reduction of SACE levels during glucocorticoid treatment may be due to a suppression of granuloma formation. Concomitant falls in serum calcium level suggest an important role of the granuloma or its cellular precursors in vitamin D metabolism.

An analysis of diabetic pregnancies at Mayo Clinic, 1950-79.

We reviewed the records of pregnant diabetic women attended at Mayo Clinic during the years 1950-79 and matched each nonaborted diabetic pregnancy with two control pregnancies. Abortions occurred in 49 of 277 diabetic pregnancies (17.7%). The relative risk of other adverse outcomes of pregnancy (+/- 95% confidence interval) in comparison with controls was as follows: perinatal mortality, 7.0 (3.6-13.8); major congenital birth defects, 6.3 (2.8-14.2); and respiratory distress, 9.0 (4.5-17.9). Diabetic ketoacidosis resulted in fetal death in 5 of 18 cases. Patients with mean fasting blood glucose levels of less than or equal to 140 mg/dl had a perinatal mortality of 81 per 1000 births and an incidence of respiratory distress and congenital birth defects of 18.9% and 9.9%, respectively. Patients with mean blood glucose levels greater than 140 mg/dl had corresponding rates of 306 per 1000, 20.4%, and 11.2%, respectively. Hydramnios occurred almost exclusively in diabetic women, and its presence was associated with a twofold increase in the frequency of perinatal death. Analysis of diabetic pregnancy outcome by decade showed no appreciable decrease in the occurrence of perinatal mortality, congenital birth defects, or respiratory distress over the 30-yr period.