N. Zamberlan

Adverse effects of bisphosphonates. A comparative review.

SummaryThe 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°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 300mg 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.

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 non-dominant 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.

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

Twenty patients with mild Pagets 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.

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 µg/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<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<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.

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 radio-graphic 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.

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

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.ConclusionThis 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.

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 Pagets 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 Pagets 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 Pagets 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 Pagets 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.

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 Wards 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.

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 Wards 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.