Spironolactone, but not flutamide, administration prevents bone loss in hyperandrogenic women treated with gonadotropin-releasing hormone agonist.

GnRH agonists (GnRHa) have recently been proposed for the treatment of hirsutism in women with the polycystic ovary syndrome (PCOS). As most of these subjects have increased androgen secretion from both ovaries and adrenal glands, the association of GnRHa with antiandrogen drugs might enhance the clinical response to treatment. On the other hand, this association might also potentiate the adverse effects of GnRHa on bone metabolism, generating a potentially harmful situation at the skeletal level. In this study we investigated in 41 PCOS patients the skeletal effects of a 6-month course of GnRHa (tryptorelin, 3.75 mg, i.m., monthly), either alone (n = 12) or associated with the antiandrogen drugs spironolactone (100 mg, orally, once daily; n = 14) or flutamide (250 mg, once daily; n = 15). In all subjects bone mineral density was measured before and after treatment by dual energy x-ray absorptiometry at the lumbar spine (L2-L4) and at the femoral neck and Ward's triangle. In addition, at baseline and after 6 months of therapy, bone metabolism markers (serum and urinary calcium, serum phosphorus and alkaline phosphatase, plasma osteocalcin, and urinary hydroxyproline) and endocrine parameters (serum gonadotropins, estradiol, and free testosterone) were assayed. Women given either GnRHa alone or associated with spironolactone or flutamide were similar for age and body mass index. At baseline, the 3 groups of PCOS women were also similar for endocrine and bone parameters. After 6 months, all treatments determined similar striking suppressions of serum gonadotropins and sex steroids. Concurrently, bone mineral density was significantly reduced at all examined sites in subjects receiving either GnRHa alone or GnRHa plus flutamide. Conversely, women given GnRHa plus spironolactone did not show any change in skeletal mass from baseline values (P < 0.05-0.01 among groups). Biochemical parameters of bone metabolism were consistent with densitometric assessments. In conclusion, after a 6-month course of therapy, bone mineral density is reduced in PCOS women given either GnRHa alone or GnRHa plus flutamide, but not in those receiving GnRHa plus spironolactone. The mechanisms of the bone-sparing effect of spironolactone remain to be determined. Nevertheless, this drug could represent a useful tool to prevent skeletal loss in women given GnRHa as well as in other hypoestrogenic conditions, in particular when estrogens are not recommended.

Intramuscular clodronate therapy in postmenopausal osteoporosis.

Long-term daily administration of oral bisphosphonates has been effective in the treatment of postmenopausal osteoporosis, but the duration, mode and cost of the therapy may sometimes affect patient compliance. In Italy, the bisphosphonate clodronate is also available via the intramuscular (i.m.) route of administration, and the present study was performed to test its efficacy in postmenopausal osteoporosis. Ninety osteoporotic postmenopausal women were enrolled in a randomized, controlled 3 year study. The diet of all patients was adjusted to provide 1200-1300 mg of calcium daily, eventually by administration of supplements. Patients were randomly assigned to no therapy (30 patients) or to receive clodronate 100 mg i.m. either every 2 weeks (30 patients) or 1 week (30 patients). The i.m. injection caused substantial pain at the site of injection, which led to treatment withdrawal in almost 50% of the patients receiving weekly dosing. In control patients, a progressive, slow decline in spine and femoral bone mineral density (BMD), which became statistically significant at the end of the second year of observation, was observed. In the patients given weekly i.m. clodronate, spinal BMD rose by 3.8% (+/-7.3 SD) within 6 months. A slight, nonsignificant increase was observed thereafter, such that, at the completion of 3 years of observation, the mean gain was 4.5% (+/-6.3). In the patients treated with injections of 100 mg of clodronate every two weeks the increase in BMD was somewhat lower and slower, becoming significant only at month 24 (2.9+/-4.6%). In none of the two active groups was the femoral neck BMD changed significantly during the 3 years of the study. A significant increase in trochanter and Ward's triangle BMD was observed at month 12 only in the patients on the highest dose of clodronate. In both groups treated, the hip BMD changes were significantly different from those observed in control patients. The biochemical markers of bone turnover were suppressed in both clodronate groups. These results indicate that intermittent i.m. clodronate administration can provide clinically relevant benefits to skeletal bone density in osteoporotic postmenopausal women, but the in situ pain may limit its extensive use.

Effect of hyperandrogenism and menstrual cycle abnormalities on bone mass and bone turnover in young women.

OBJECTIVE: Prolonged period of amenorrhoea are regarded as a risk factor for the appearance of osteoporosis. Amenorrhoea is a feature of different pathological conditions with heterogeneous endocrine profiles. We evaluated bone mineral metabolism in patients with polycystic ovary syndrome (PCOS), hypothalamic amenorrhoea and idiopathic hirsutism in order to establish the relative importance for the maintenance of normal bone mass of ovulatory cycles and androgen and oestrogen production. PATIENTS AND MEASUREMENTS: Bone mineral density (BMD), bone turnover markers and endocrine profile were evaluated in 51 patients with PCOS, 24 patients with idiopathic hirsutism, 26 patients with hypothalamic amenorrhoea and 35 healthy women. Body mass index (BMI) ranged between 20.1 and 31.0 kg/m2, and age from 17 to 33 years. Thirty-eight of the PCOS patients were amenorrhoeic (< 4 menstrual cycles/year). RESULTS: Spine and femoral BMD were significantly decreased and bone markers (serum osteocalcin, and urinary excretion of free deoxypyridinoline, cross-linked N-telopeptide and hydroxyproline) significantly increased in the patients with hypothalamic amenorrhoea, when compared to control subjects and the other two patient groups. In the sub-group of PCOS patients with amenorrhoea, spine and femoral neck BMD was significantly lower than in patients with idiopathic hirsutism and the non-amenorrhoeic PCOS patients. In all PCOS patients, spine and neck BMD were positively correlated (P < 0.05) with serum androstenedione and free testosterone levels. CONCLUSIONS: The results of this study suggest that in patients with polycystic ovary syndrome the deleterious effect on bone of amenorrhoea is balanced by androgen overproduction.

Bone measurements in asymptomatic primary hyperparathyroidism.

A large proportion of patients with asymptomatic primary hyperparathyroidism (PHPT) have some degree of bone involvement which appears to be relatively greater for cortical than trabecular bone. However, the clinical meaning and pathophysiologic basis of this observation are unknown. In 77 postmenopausal women with asymptomatic PHPT, bone mineral density (BMD) was measured at the proximal and ultradistal forearm, the lumbar spine, the femoral neck, and Ward's triangle by dual-energy X-ray absorptiometry. The digitalized X-ray pictures of the nondominant hand were obtained from all patients and from 680 healthy postmenopausal women, to measure the outer (D) and inner (d) diameter of the second metacarpus. The cortical area per total area (CA/TA) and a bending breaking resistance index (D4-d4/D) were then calculated. In 29 of the patients not operated on and in 30 healthy pair-matched women, a second X-ray of the hand was obtained 5-12 years afterward. In patients with PHPT, the z score of CA/TA was significantly lower than zero [-0.97+/-0.99, standard deviation (SD)]. This is due to an enlargement of the inner diameter, despite a significant increase in the z score for the outer diameter. The z score of the DXA measurements was significantly lower than zero for the lumbar spine (-0.59+/-1.26), ultradistal radius (-1.03+/-0.91), proximal radius (-1.91+/-1.80), and Ward triangle (-1.81+/-1.07), but not for the femoral neck (-0.36+/-1.03). In subjects in whom two X-rays were obtained, per-decade endosteal resorption and periosteal apposition were statistically significant only in the PHPT patients. Both endosteal resorption and periosteal apposition were significantly greater in PHPT patients compared to healthy controls. The mean BBRI in PHPT patients was not different from that in controls, but the longitudinal changes were significantly greater than those observed in control subjects. Our radiogrammetry data may provide an original clue for understanding preferential cortical bone loss in PHPT patients. In cross-sectional and longitudinal studies, we have shown that in PHPT, both endosteal bone resorption and periosteal apposition are augmented. The former effect is predominant, which leads to significant diminution of cortical thickness. As a consequence of the enlargement of long bones, the areal BMD is somewhat underestimated, since the same amount of cortical bone is divided by a greater diameter. Furthermore, in term of mechanical properties, the increases in the cross-sectional area of appendicular bone segments might compensate in part for both the diminution of cortical thickness and a greater porosity of cortical bone.

Intermittent Etidronate partially prevents bone loss in hirsute hyperandrogenic women treated with GnRH agonist.

Treatment with gonadotropin-releasing hormone (GnRH) agonist leads to enhanced bone turnover and accelerated bone loss in premenopausal women with endometriosis, uterine leiomyomatomas and hirsutism. Sodium etidronate is a powerful inhibitor of bone resorption which had been proven efficacious in the prevention and treatment of postmenopausal osteoporosis. The objective of this study was to evaluate the skeletal effects of 6 months of therapy with the depot preparation of the GnRH agonist triptorelin (decapeptil 3.75 mg intramuscularly every 4 weeks) in 24 hirsute patients, aged 24-33 years, with hyperandrogenic chronic anovulation. Ten patients also received cyclical etidronate in an oral dose of 400 mg/day for 2 weeks, followed by an 11-week period of 500 mg/day elemental oral calcium (one cycle). The remaining 14 patients received 500 mg/day of elemental calcium continuously. After 6 months all treatments were discontinued for at least a further 6 months. Bone mineral density (BMD) at lumbar spine and hip (dual-energy X-ray absorptiometry, Sophos LXRA, France) and biochemical markers (serum alkaline phosphatase, osteocalcin, urinary N-telopeptide and hydroxyproline/creatinine ratio) were evaluated at baseline, 6 months and 12 months. In the group given GnRH agonist alone BMD fell significantly at all measured skeletal sites during the first 6 months. In the patients treated with etidronate a significant decrease in BMD was observed at lumbar spine but not in the femoral neck and trochanter, and the changes at lumbar spine and trochanter were significantly smaller than those in the control group. At 6 months bone turnover was also increased in patients treated with GnRH and calcium. Cyclical etidronate prevented the increase in biochemical markers of bone formation and resorption, with the exception of calcium/creatinine excretion, which was significantly increased in both groups. Six months after treatment withdrawal BMD did not recover in either group. Biochemical markers (N-telopeptide, serum alkaline phosphatase) remained increased in those patients previously treated with calcium alone while they remained close to baseline values in the patients treated with cyclical etidronate. Our study indicates that: (1) GnRH agonist therapy causes remarkable bone loss in young individuals with androgen excess who are expected to have increased bone mass; (2) this bone loss can be partially prevented by intermittent cyclical etidronate therapy.

[Diphosphonates: and alternative to estrogen therapy in postmenopausal osteoporosis. Experience with alendronate]. / I bisfosfonati: un'alternativa al trattamento estrogenico nell'osteoporosi postmenopausale. Esperienza con alendronato.

The post-menopausal osteoporosis represents an important complication during the climateric period; its clinical, economic and social weight is destined to increase with the aging of the population. The lack of oestrogens is the main etiopathogenetic element; this is the reason why the substitutive therapy during the menopause represents the most appropriate approach. However, the possibility of clinical contra-indications to the oestrogenic treatment, the compliance of the patient not always adequate, the possibility of side-effects, and the doubt about the real opportunity of this treatment in the advanced years, require therapeutic alternatives. Between these, the "inhibitors of the bone reuptake" are actually the more realistic and justified approach knowing the pathogenetic aspect of the disease. In this group of drugs, the biphosphonates are particularly useful because of their pharmacologic properties: a strong affinity for the bone, a specific action only in the area of the bone rearrangement, a strong and selective inhibition of the osteoclastic activity. Because of their long half-life in the bone tissue, it seemed interesting to evaluate mineral bone density and metabolic effects using the alendronate. A double blind controlled study was performed in order to evaluate the effect of this drug: two groups of 15 women in post-menopause with vertebral bone mineral density (BMD) > 2 S.D. behind the mean peak of the adult and without vertebral fractures, were randomized to receive a 20 mg/die dose of alendronate or a placebo for six months. The first treatment significantly reduced all the bone turnover indexes (idrossiprolin, collagen cross links, phosphatase alkalin activity) in three months; another slight reduction was observed in the next three months. After the interruption of the treatment all the indexes of the bone turn over were slowly increased and reached the pre-treatment values in six-nine months. The lumbar BMD is increased of 3.7% (+/- 1.7 SD) after six months of aleandronate treatment; there were no modifications 6 and 12 months after the interruption of the treatment (respectively +4.6 +/- 2.8 and +4.7 +/- 2.67 referred to the basal values). The control group presents a slow reduction of the lumbar BMD, but this was significative only at the 18 degrees month of the study. The femoral BMD was not modified in a relevant measure in the group treated with the drug, while a significative reduction of the neck value was observed in the control group. We conclude that a short treatment with the alendronate is able to increase the lumbar BMD and to prevent the femoral reduction in the woman affected by post-menopausal osteoporosis. Finally, in our experience the alendronate represents a promising alternative to the oestrogen treatment of the post-menopausal osteoporosis; this approach however should be verified in the reduction in the incidence of fractures with larger studies.

Evaluation of cortical thickness and bone density by roentgen microdensitometry in growing males and females.

UNLABELLED: The bone mineral content (BMC) and the cortical thickness at the distal radius and at the II metacarpal were assessed in growing individuals (167 females and 158 males) by radiometric and quantitative roentgen microdensitometric methods. BMC adjusted for age and pubertal status was significantly higher in males than in females. However, the BMC corrected for bone volume (volumetric bone density, g/cm3) and the metacarpal cortical index (cortical area/total area) were identical in males and females. BMC rose progressively with age, approaching a plateau by the end of puberty. Lower but still significant increases with age were also observed for volumetric bone density of the metacarpus and the metacarpal index. These increases were also most marked by the end of pubertal maturation and might be related to diminution of bone turnover. CONCLUSION: This study provides the normative data of bone mass in growing individuals by making use of a reasonably accurate and easily available technique. The results obtained indicate that most of the differences between males and females and the changes with age are related to changes in skeletal dimension rather than density.

Adverse effects of bisphosphonates. A comparative review.

The bisphosphonates comprise a new class of drugs, and are increasingly being used to treat bone diseases characterised by increased osteoclastic bone resorption. These compounds are generally well tolerated, but toxicity may vary considerably from one compound to another. Dosages of etidronic acid above 800 mg/day impair the normal skeletal mineralisation and this may be associated with the appearance of fractures, but at the doses used for the treatment of osteoporosis, none of the bisphosphonates induce clinical or histological signs of impaired mineralisation. The skeletal half-life of bisphosphonates is of the order of several years, but this appears to be of little clinical consequence since the pharmacological effect is of relatively short duration. The mechanical properties of the skeleton of animals treated over long periods with high doses of various bisphosphonates have been shown to be perfectly preserved. However, in growing individuals, excess inhibition of bone remodelling might induce osteopetrotic-like alterations. When high doses of amino-bisphosphonates are given to patients who have never received bisphosphonate therapy, the patients may experience fevers up to 39 degrees C for 1 to 3 days, associated with transient haematological changes resembling a typical acute-phase response. Rapid intravenous injection of bisphosphonates at doses greater than 200 to 300 mg may cause severe renal failure; this can be prevented by slowing the rate of infusion (< 200 mg/h). Administration of high doses of bisphosphonates to patients with high bone turnover may induce a rapid and transient drop in serum calcium which is seldom symptomatic. The gastrointestinal absorption of bisphosphonates is low, and they must be taken without food. Oral amino derivatives may induce dose-related serious gastrointestinal lesions, with the sporadic appearance of erosive oesophagitis. Amino-bisphosphonate administration has been also associated with the sporadic occurrence of uveitis, scleritis and phlebitis and, in single cases, with irritative reactions at the skin, peritoneum and pericardium.

Computed radiographic absorptiometry and morphometry in the assessment of postmenopausal bone loss.

The best method for the diagnosis of osteoporosis and assessment of fracture risk is currently considered to be bone densitometry. The most commonly used dual-energy X-ray absorptiometry (DXA) methods may sometimes not predict bone mass accurately in every skeletal site, are expensive and not widely available. The recent development of computed analysis of a plain radiograph of the hand might provide a practical, inexpensive and rapid method for evaluation of bone mineral status. In this study we evaluated 20 healthy premenopausal and 660 postmenopausal women. In 36 of these subjects a second evaluation was carried out after 2 years of therapy with calcium supplements. The internal and external diameters of the second metacarpal and the metacarpal and ultradistal radial bone density were evaluated using a technical device developed in our laboratory and marketed by NIM, Verona, Italy (Osteoradiometer). The radiographic images, captured by a video camera, were digitized and studied by computed analysis. In 150 subjects bone density at the level of the lumbar spine, femur, and ultradistal and proximal radius was also measured by DXA techniques. Both external (D) and internal (d) diameters increase significantly with age and years since menopause (YSM), whereas metacarpal index (D--d/D) and metacarpal and ultradistal radial bone density decrease significantly with age and YSM. The ratio between metacarpal bone mineral content and the cortical area (volumetric metacarpal bone density) did not change with age. Significant correlations were found between radiometric findings and DXA measurements. The best correlation coefficients were between bone density measured at the level of the ultradistal radius by DXA and radiographic absorptiometry. In the 2-year follow-up study, a 4.9% and 6.2% decline in radial metacarpal bone density respectively were observed, but the difference was statistically significant only for the latter. In conclusion, computed radiogrammetry is closely correlated with all DXA measurements and may be useful in screening of large populations, providing a simple, inexpensive and sufficiently precise method for evaluation of bone mineral status. Further studies are warranted for assessing the accuracy of radiogrammetry for longitudinal investigations and its capacity to predict fracture risk.

Effect of aging on trabecular and compact bone components of proximal and ultradistal radius.

Bone densitometry has become a major tool for osteoporosis risk assessment. The traditional dual-energy X-ray absorptiometry (DXA) methods are able to evaluate the bone mineral content (BMC; mg/cm) and the areal density (BMD; mg/cm2), but only quantitative computed tomography (QCT) has the potential to measure the true volumetric bone density in the sense of mass per unit volume (mg/cm3). Peripheral QCT (pQCT) measurements were carried out at the nondominant radius using a Stratec XCT 960 (Unitrem, Roma) in 241 postmenopausal and 29 premenopausal women. The sites of evaluation were both the ultradistal and the proximal radius. The technique used has a coefficient of variation of 2% and it allows separation of the bone section into trabecular and cortical bone on the basis of density threshold. Bone mass of radius, hip and spine was also evaluated by DXA procedures. The bone density data obtained by pQCT were significantly correlated with all DXA measurements. The correlation coefficients between their respective BMD values ranged from 0.48 to 0.75, but for the BMC values of the radius the correlation coefficients ranged from 0.82 to 0.93. The BMD values measured by DXA, but not by pQCT, were positively related with patient heights. All pQCT density measurements, including those obtained at the proximal radius and containing exclusively cortical bone, where negatively related with age and years since menopause. A partial volume effect, which is increasingly relevant the thinner are the bone cortices, might explain that. However, by applying increasing density thresholds, cortical bone density seems to decrease with age as a consequence of a gradual density diminution from the inner part of the bone cortex outwards. Trabecular bone density decreases with aging, but its overall mass does not change as a consequence of an age-related enlargement of trabecular area. Thus, the proportion of trabecular bone over total bone rises, and this might be relevant for our understanding of the age-related changes in bone turnover and rate of bone loss.

Clinical utility of a wheat-germ precipitation assay for determination of bone alkaline phosphatase concentrations in patients with different metabolic bone diseases.

Bone alkaline phosphatase was evaluated by wheat-germ lectin precipitation in several clinical conditions. The study included 33 premenopausal healthy women, 46 postmenopausal apparently healthy women, 19 growing children, 24 patients with Paget's disease, 31 patients with primary hyperparathyroidism and 66 patients with hepatobiliary diseases. In postmenopausal women the mean T score (i.e.: the number of SD below or above the mean for premenopausal women) was 2.6 +/- 1.3 (SD) for bone alkaline phosphatase and 1.61 +/- 1.21 for total alkaline phosphatase (p < 0.001). The T score for bone alkaline phosphatase provided a better discrimination from normals for both Paget's disease (22.1 +/- 27.8 versus 12.8 +/- 16 p < 0.001) and primary hyperparathyroidism (8.2 +/- 4.3 versus 4.6 +/- 3.7 p < 0.005 for bone alkaline phosphatase and total alkaline phosphatase respectively). After treatment with intravenous bisphosphonate the percent decrease of bone alkaline phosphatase was larger than that of total alkaline phosphatase both in patients with Paget's disease (-46% versus -72% p < 0.01) and in patients with primary hyperparathyroidism (-21% versus -47% p < 0.02) and an estimate of the precision (delta mean/SD of the delta mean) for bone alkaline phosphatase was 1.9-3.7 times higher than that of total alkaline phosphatase. In twelve osteoporotic patients treated for six months with oral alendronate the decrease in bone turnover was detected with significantly higher precision with bone alkaline phosphatase than with total alkaline phosphatase (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term effects of a treatment course with oral alendronate of postmenopausal osteoporosis.

Several bisphosphonates are under investigation for the treatment and prevention of postmenopausal osteoporosis. Alendronate, one of these compounds, has been shown to inhibit bone turnover and induce substantial increases in bone mass, but little is known about the duration of its effects. This is considered important, keeping in mind the long half-life of bisphosphonate in bone. In this double-blind controlled study, two groups of 15 postmenopausal women with spinal bone mineral density (BMD) > 2 SD below adult mean peak without vertebral fractures were randomized to receive either alendronate, 20 mg/day, or placebo for 6 months. The treatment course with alendronate significantly suppressed all indices of bone turnover (hydroxyproline, collagen crosslinks, and alkaline phosphatase activity) within 3 months, and a further slight decrease was observed in the subsequent 3 months. After treatment withdrawal, all indices of bone turnover slowly increased, and they attained the pretreatment values within 6-9 months. Lumbar spine BMD rose by 3.7% (+/- 1.7 SD) after 6 months of alendronate therapy but did not change 6 and 12 months after treatment withdrawal (4.6 +/- 2.8 and 4.7 +/- 2.6% versus baseline, respectively). In control patients a slow decrease in lumbar spine BMD was observed, but this was significant only at month 18 of the study. Femoral BMD did not significantly change in the alendronate group, but it slowly decreased in the control group at all sites of evaluation. The fractional loss became statistically significant versus both baseline and the active group by the end of the study only at the level of the femoral neck.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of two oral doses of alendronate in the treatment of Paget's disease of bone.

Twenty patients with mild Paget's disease of bone were given either 20 (10 patients) or 40 mg alendronate daily for 6 months. The 20-mg dose was well tolerated, but in 3 patients on 40 mg/d alendronate, the treatment was withdrawn after 3-5 months because of gastric and oesophageal disturbances. Urinary hydroxyproline excretion fell within the first month to 77 +/- 5% (SD) and to 47 +/- 5% of pretreatment values in the 20- and 40-mg dosing group, respectively (p < 0.001 between group comparison). The serum alkaline phosphatase fell more slowly with the maximum suppression of disease activity reached at 4 months, when it attained a plateau in both groups of patients. However, the decrease in serum alkaline phosphatase was significantly more pronounced in the patients treated with 40 mg/d tablets (50 +/- 10% of pretreatment values) than in those given 20 mg alendronate per day (76 +/- 9% of initial value), in none of whom a disease remission was observed. It appears, therefore, that while 20 mg/d oral doses of alendronate are insufficient, 40 mg/d are associated with a high incidence of side effects. Furthermore, the suppression of disease activity depends on the dose of bisphosphonate given daily or over a short period of time and lower doses cannot be compensated by a longer duration of the treatment course.

Duration of the effects of intravenous alendronate in postmenopausal women and in patients with primary hyperparathyroidism and Paget's disease of bone.

The effect of a single intravenous (i.v.) infusion of 5 mg alendronate was studied in ten patients with Paget's disease, six patients with primary hyperparathyroidism and ten osteopenic postmenopausal women. Urinary hydroxyproline excretion significantly decreased within few days in all patients (from 113 +/- 67.9 to 58 +/- 35 mmol/mol Cr in Paget's disease, from 21.8 +/- 9 to 12.9 +/- 6 mmol/mol Cr in hyperparathyroidism, from 18.7 +/- 9.5 to 8.5 +/- 4.3 mmol/mol Cr in postmenopausal women). In the patients with Paget's disease urinary hydroxyproline remained suppressed over the 6 months of follow-up, whereas it rose toward pretreatment values within 4 and 6 weeks in the patients with primary hyperparathyroidism and in postmenopausal osteopenic women, respectively. Plasma alkaline phosphatase significantly fell only after 4-6 weeks in patients with primary hyperparathyroidism and in Pagetic patients. In the latter group alkaline phosphatase continued to decline thereafter and a plateau became apparent after 2 months. In postmenopausal women the serum alkaline phosphatase remained unchanged. Thus, the same dose of alendronate induces comparable fractional decreases of bone resorption in the three groups of patients, but the effect is persistent only in Paget's disease. This is consistent with the hypothesis that alendronate inhibits osteoclastic activity only at the level of the existing resorption sites. In osteoporotic and primary hyperparathyroid patients, as soon as the treatment is withdrawn, the appearance of new sites of resorption is not inhibited and bone turnover is resumed to pre-treatment values.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term effects of transdermal and oral estrogens on serum lipids and lipoproteins in postmenopausal women.

The transdermal and oral administration of estrogens for one year were compared with respect to the effects on lipid metabolism. Eighty-one postmenopausal women (1.5-3 years after menopause) were randomly divided into three groups. The first two groups received sequential estrogen treatment with either transdermal estradiol (Estraderm TTS, Ciba Geigy; 50 micrograms/day; 24 women) or 0.625 mg/day conjugated estrogens (Premarin, Wyeth; 20 subjects), respectively. In both groups medroxyprogesterone (10 mg/day per os) was added for 12 days of each cycle. Thirty-five subjects served as control group without therapy. No significant changes in the lipid profile was observed in control subjects after 1 year of follow-up. Serum triglycerides decreased significantly (-10.9 +/- 26% S.D.; P < 0.05) in transdermal treated women, whereas it slightly rose in oral estrogen group. Comparable significant decreases in total and low density lipoprotein (LDL) cholesterol (mean range -6.5/-18.0%) were observed in women on estrogen replacement therapy. High density lipoprotein (HDL) cholesterol significantly diminished in transdermal estradiol group, but it rose slightly in the oral estrogen group. Thus the fraction of HDL cholesterol over LDL cholesterol did not change in the transdermal group whereas it significantly rose in subjects treated with oral estrogens. It remains to be established to what extent these differences on lipid metabolism are relevant for the prevention of cardiovascular diseases.

[Therapeutic strategies in osteoporosis: whom and when to treat]. / Strategie terapeutiche dell'osteoporosi: chi e quando trattare.

Postmenopausal bone loss can be efficiently prevented by compounds which inhibit bone resorption, but they can not induce a sustained and relevant bone gain. The initial increase in bone volume observed within the first year of treatment is due to a transient uncoupling between bone resorption and formation: the first is suddenly blocked whereas bone formation decreases slowly within several months; bone is gained until the previously resorbed cavities are refilled. This net increase in bone mass is completely lost as soon as treatment is withdrawn. Since these antiresorptive agents can only be used in order to prevent bone loss, they should be given for several years. Thus, the choice of the drug is also conditioned by its cost and long-term compliance. Estrogen replacement is very convenient, from these points of view in most patients immediately after the menopause. Afterwards, parenteral calcitonin has been, up to now, the sole available alternative with convincing evidence of effectiveness, at least in the medium term. Its cost and the scarce compliance to injections have strongly limited its extensive use. There is increasing evidence that oral bisphosphonates are very effective and therefore they might represent, in the near future, an effective and convenient alternative to estrogen replacement therapy.

The effects of menopause and estrogen replacement therapy on the renal handling of calcium.

Mineral metabolism was studied in 99 premenopausal and 80 postmenopausal women both before and after 9-14 months of treatment with 50 micrograms/day transdermal estradiol. In estrogen-repleted subjects (premenopausal women and postmenopausal women on estrogen replacement therapy) total serum calcium was significantly lower (0.065 mmol/l; p less than 0.001) than in those who were estrogen-depleted (untreated postmenopausal women). This difference was smaller but still significant for calculated ultrafiltrable calcium (UFCa: 0.02-0.03 mmol/l; p less than 0.001). However, ionized calcium (both calculated and measured) was not different in the two groups of women. This finding explains why estrogen repletion does not induce changes in the serum level of intact parathyroid hormone (PTH), despite lower total or ultrafiltrable serum calcium. In a parallel study we have shown that intravenous administration of aminobutane bisphosphonate, a powerful inhibitor of bone resorption, produces similar decreases in serum calcium which were associated with significant increases in intact PTH. Estrogen-depleted women had, on the one hand, significantly higher serum levels of bicarbonate, anion gap, complexed calcium, pH, phosphate and alkaline phosphatase, and higher rates of tubular reabsorption of phosphate and urinary excretion of calcium and hydroxyproline. On the other hand they had lower serum chloride levels and lower rates of tubular reabsorption of calcium. Altogether these findings might indicate that estrogen deficiency decreases renal sensitivity to PTH. This is responsible for the higher serum phosphate and bicarbonate levels, the resulting mild metabolic alkalosis leading to higher serum levels of complexed ultrafiltrable calcium and higher rates of urinary excretion of calcium, but unchanged serum levels of ionized calcium and PTH.

The radiological assessment of vertebral osteoporosis.

The traditional skeletal X-ray is of little help in quantifying osteopenia in the spine, and indirect criteria, such as increased lucency, loss of horizontal trabeculae and reduction in end-plate thickness with relatively increased opaqueness, can be misleading. However, the clinical expression of osteoporosis is fracture, which can be identified by radiography. Any reduction in the anterior, middle, or total height of the vertebral body should be classified as vertebral fracture. In mild cases, such fractures are not easily detectable, particularly when previous radiographs are not available for comparison. Thus several objective methods for fracture identification have been developed. Most of these methods are based on the ratio between posterior and anterior or middle height (wedge or biconcave deformity, respectively) and on the ratio between posterior height of adjacent vertebrae or with a single vertebral reference (T4). Some of these indices are referred to normal ranges in order to take into account intervertebral and interindividual variability. In 36 women with postmenopausal osteoporosis we have compared the lateral radiographs of lumbar and thoracic spine to similar X-ray pictures taken by chance at least five years before menopause. By defining a fracture as any decrease in vertical height above 1 mm, we found 77 deforming events in 29 out of 36 patients. We then applied some of the methods to identify objectively fractures in our postmenopausal radiographs: the sensitivity of the various systems ranged from 50 to 100%; however there was a large overlap between false positives and false negatives and the methods with the highest sensitivity lack specificity and vice versa.

The prevention of corticosteroid-induced osteoporosis with nandrolone decanoate.

The effects of nandrolone decanoate (ND; 50 mg IM every three weeks) on calcium metabolism and forearm bone density were studied in a randomized trial in 35 women receiving long-term therapy with corticosteroids (CST) for rheumatic disease. The 17 patients who served as controls were on CST therapy for less years and their bone density was higher. Thus a second control group, pair-matched with the active treatment group for age, duration of CST therapy and bone density, was selected retrospectively. At the end of the 18 months' treatment course with ND, forearm bone density was increased by 5.1% (P less than 0.01) but fell by 11.3% (P less than 0.01) and 6.7% respectively in the first and second control group. The patients on ND differed significantly from both control groups in the changes at 6, 12 and 18 months (P less than 0.01). Urinary excretion of hydroxyproline fell significantly in patients receiving ND, whereas the biochemical indices of bone formation did not change (alkaline phosphatase) or increased (osteocalcin; P less than 0.01). In conclusion, nandrolone decanoate therapy may be used in the prevention of CST-induced osteoporosis. It also seems to exert mild inhibition of bone resorption without affecting or even stimulating bone formation.