B. Imbimbo

Bone loss in response to long-term glucocorticoid therapy

A number of studies have shown that an excess of glucocorticoids induces osteoporosis, but the mechanism(s) and the time course of the reduction of bone mass remain uncertain. In order to clarify this issue we carried out a longitudinal clinical and histomorphometric study of patients requiring long-term glucocorticoid treatment. In 23 patients (9 men, 10 post- and 4 premenopausal women) biochemical and bone histomorphometric investigations were carried out before and during treatment with 10-25 mg/day of prednisone. Histomorphometric analysis of bone biopsies of the iliac crest showed that the decrease of TBV (up to -27%, P less than 0.001) occurs predominantly within the first 5-7 months of treatment; during the subsequent stages, which include observations after 12 months of treatment, only minor changes were observed. Therefore trabecular bone loss can be satisfactorily described by a negative exponential function. None of the other histomorphometric parameters (osteoid surfaces, resorption surfaces, etc.) showed significant changes. However, the histological features of the bone biopsies during steroid therapy, showing a virtual lack of osteoblastic activity, ruled out an increase of bone resorption. Moreover, the dynamic study of the bone formation by double tetracycline labelling showed, in a small subgroup of patients, a decrease of the apposition rates (from 0.763 +/- 0.053 to 0.305 +/- 0.074 microns/day (mean +/- SE) after treatment). No significant changes, at any time during steroid treatment, were observed in serum alkaline phosphatase, 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, 1,25-dihydroxyvitamin D, parathyroid hormone or urinary calcium excretion. Serum calcium increased significantly within the first 1-2 months of therapy and then it returned to baseline. Urinary hydroxyproline excretion decreased significantly within the first 1-2 months and continued to fall throughout the treatment. Thus, both biochemical and histological findings suggest that long-term glucocorticoid therapy causes a reduction of bone turnover, that the bone loss occurs predominantly within the first 6 months of treatment and that patients with lower bone mass have a lower rate of bone loss.

Bone histomorphometric reference values in 88 normal Italian subjects

The study deals with bone histomorphometric results obtained from 88 normal subjects (38 women and 50 men; range: 20-89 years), in order to establish control values in an Italian population. Bone specimens were obtained at autopsy from a standardized area of the iliac crest. The following indicators were measured: bone volume (BV/TV), osteoid volume, osteoid surface, osteoblast surface, eroded surface, osteoclast surface, osteoid thickness. Dependence of histomorphometric indicators on sex and age was evaluated by multiple regression analysis, including sex, age, and also a quadratic term (age2) and two interaction terms (sex x age, sex x age2). BV/TV was mainly affected by age. In fact, a decrease in the amount of bone was found with increasing age in both males and females. The reduction appeared rather regular, with negligible differences between males and females. The other indicators were found to be age- and sex-independent. As a consequence, they did not give information on the possible changes of bone apposition and resorption processes due to aging. On the whole, histomorphometric indicators of trabecular bone of the normal Italian population do not greatly differ from those reported for most other caucasian people.

Suppressive effect of chronic glucocorticoid treatment on circulating calcitonin in man.

INTRODUCTION Many factors contribute to glucocorticoid-in deced osteopenia.Corticosteroid excess leads to in testinal malabsorption of calcium through a direct inhibition of the intestinal absorptive process(l, 2) or through an impaired vitamin D metabolism (3, 4). A direct action of the corticosteroid on bone tissue has also suggested (5). On the other hand an impaired calcitonin (CT) secretion has been suggested to be a factor in the pathogenesis of some forms of decreased bone mass (6,7) . To explore a possible relationship between CT secretion and steroid induced bone loss we studied the secretion of this hormone before and during long term treatment with eorticosteroids.

Technical variability of bone histomorphometric measurements

Effects of main sources of bone biopsy sample variability have been examined. Variability was assessed in double iliac crest biopsies of 12 subjects with normal or pathological bone. Components of variance were estimated as follows: two biopsies per patient; three specimens at different distances from compact bone; three sections per specimen; three microscopic fields per section. The following indicators were measured: bone volume (BV/TV); osteoid volume (OV/BV); osteoid surface (OS/BS); osteoblast surface (Ob.S/BS); eroded surface (ES/BS); osteoclast surface (Oc.S/BS); osteoid thickness (O.Th). Sources of variability were assessed by ANOVA for random effects. On the basis of the results, between fields variation gave the main contribution to the error of single measures (BV/TV, 50%; O.Th, 70%; OV/BV, Ob.S/BS, OS/BS, Oc.S/BS, ES/BS more than 80%). Distance from compact bone affected mostly the BV/TV (40%) and the O.Th (10%) error. When bone specimens at intermediate distance from cortical bone are examined, variations due to different biopsies, different section and different microscopic field are largely reduced by measuring 12 microscopic fields for BV/TV (14%) and 48 microscopic fields for the other indicators (O.Th 16%; OV/BV, Ob.S/BS, OS/BS, Oc.S/BS, ES/BS more than 30%). The precision can be only slightly improved by further increasing the number of the microscopic fields.

Comparison of growth retarding effects induced by two different glucocorticoids in prepubertal sick children: An interim long-term analysis

SummaryThe low interference with growth expected in child for a cortisol analogue, deflazacort (DFZ), prompted us to verify if DFZ could affect growth less than prednisone (PDN). An interim analysis relative to 27 girls and 38 boys (out of 100 expected) age 3–12 yrs, after a median period of 14 mo.s is reported. Children with connective tissues (CTD) and glomerular disorders (KD) were randomly allocated to DFZ or PDN. Anthropometric measurements and maturity ratings were performed. Mean daily doses of PDN (or DFZ equivalent), from 0.57 to 0.64 mg/kg (DFZ 0.92 to 0.94 mg/kg) to induce control and from 0.19 to 0.93 mg/kg (DFZ 0.34 to 0.36 mg/kg) to maintain disease under control were given in CTD and KD, respectively. The increase in bone age delay over time was significantly>for PDN(-4.0 mo/yr) than DFZ (-1.8 mo/yr) in the overall group. The increases in statural age delay and loss over time were significantly> for PDN (-5.9 and-5.9 mo/yr) than DFZ (-2.4 and-2.4 mo/yr), only in children with “taller” midparents. Although doses of DFZ 1.1–1.8 times those of PDN were given, growth retardation in PDN-treated children was nevertheless 2.3–2.5 times that in DFZ-ones.

The long-term efficacy and safety of two different corticosteroids in chronic sarcoidosis

Deflazacort (DFZ) is claimed to have fewer adverse bone effects than prednisone (PDN) at doses with equivalent anti-inflammatory activity (5 mg PDN = 6 mg DFZ). However, its safety over the long-term has never been tested in a controlled trial. The aim of the present study was to assess prospectively the safety and efficacy of DFZ compared with PDN in previously untreated patients with chronic, histologically proven sarcoidosis needing long-term (> or = 2 yr) corticosteroid therapy. Thirty-six patients were treated with PDN for 32 +/- 18 months and 36 patients were treated with DFZ for 42 +/- 18 months, and followed-up with periodic chest X-ray, 67Gallium lung scan, angiotensin converting enzyme (ACE), serum and urinary calcium levels, spirometry, alveolar diffusion (DLCO) arterial oxygen tension (PaO2), bone mineral content (BMC) (by computed tomography), and a complete biochemical and haematological profile. The two groups were similar as regards sex, age, pulmonary and extrapulmonary involvement, parameters of activity and impairment, and initial BMC. Daily starting doses were 23.2 +/- 11.4 mg DFZ and 22.3 +/- 6.9 mg PDN. One year of trial was completed by 69 patients, 2 yr by 59 patients, 3 yr by 46 patients and 4 yr by 24 patients. Some patients were followed-up for 5-7 yr. The mean daily dose over the whole period was 15 +/- 10 mg DFZ and 10 +/- 6 PDN, starting from 21 +/- 9 and 15 +/- 8 mg in the first year, and progressively declining to a mean of 9 +/- 6 mg in both groups in the fourth year. Chest X-ray, 67Ga score, ACE and forced vital capacity improved significantly in both groups. Urine total calcium improved significantly in the PDN group (345 +/- 27 to 186 +/- 47; P < 0.05) with a similar but non-significant pattern in the DFZ group (270 +/- 28 to 207 +/- 39). Non-significant improvements were observed in DLCO, PaO2 and forced expiratory volume in 1 s in both groups. Drug-related adverse events were more frequent in the PDN group, causing discontinuation of the drug in four PDN patients. Body weight increased mainly in the PDN group [69.9 +/- 0.4 to 73.6 +/- 0.8 kg vs 70.1 +/- 0.4 to 70.0 +/- 0.6 kg in the DFZ group (P < 0.01)]. Bone mineral content dropped under the fracture threshold in most PDN patients, who thus appeared at higher risk for fractures. In fact, six atraumatic skeletal fractures were observed in this group but only one in the DFZ group. Two further patients in the DFZ group and eight in the PDN group were obliged to start corrective measures for bone loss and/or bone pain. At the end of the study, 21 patients (12 DFZ, nine PDN) no longer needed corticosteroids, and the others were taking a maintenance daily dose that controlled the disease adequately. In conclusion, DFZ appeared as effective as PDN in the long-term treatment of chronic sarcoidosis, and it may have fewer side-effects, especially on bone.

Sensitivity of Bone Histomorphometry in the Diagnosis of Metabolic Bone Diseases

Diagnostic sensitivity of bone histomorphometry was assessed in different metabolic bone diseases, after fixing the specificity at 75%, 90% and 95% reference levels. Sensitivity was particularly high in cases with greatly increased osteoid and/or resorption features, as in renal osteodystrophy (ROD). All the remodeling indicators were highly sensitive toward advanced or severe forms of mixed ROD (mROD). Osteoid indicators were the most sensitive parameters in ROD with predominant osteomalacia (oROD). Osteoclastic and several osteoid indicators were very sensitive in all grades of ROD with predominant hyperparathyroidism (hROD). Sensitivity was generally low in uremic patients without bone changes (wROD) and also in patients with idiopathic osteoporosis (OP). It is our recommendation, however, that for each individual patient the definite diagnosis should be based on both morphological, clinical and metabolic parameters.

Potency ratio, clinical equivalence, and wasting ratio estimate of different glucocorticoids

Glucocorticoids have been and continue to be extensively used in a variety of connective tissues, immunoproliferative disorders, and other syndromes such as sarcoidosis and those characterized by polyarthritis and polymyalgia rheumatica [1-5]. Since cortisone was first administered to a woman with rheumatoid arthritis in 1948, more potent synthetic analogues of the cortisol molecule with less saltretaining effects have been produced in the past 40 years. Despite the decreased capacity for sodium retention of the newer cortisol analogues, it appears that the other undesirable side effects of these compounds, most specifically, the deleterious effects they induce in bone and mineral metabolism, have not been separable from their antiinflammatory effects which condition the overall clinical response [4]. The basic difference between efficacy and potency should be firmly kept in mind by the general practitioner as well as by the clinical investigator in order to avoid being misled by claims that one drug is more potent than another. Efficacy describes the ability of a drug to produce its biological or therapeutic effect, whereas potency is a measure of the amount of drug required to produce a given effect. For example, piroxicam is more potent than phenylbutazone, as the former allows for a daily dose of only 20 mg whereas phenylbutazone allows for a dally dose of 300-600 mg, but it does not mean that one drug is more effective than the other [6--8]. Thus, potency per se is not relevant to the clinical effectiveness of a drug: in fact, it makes no difference whether the physician administers 1 mcg or 100 mg of a drug, provided the amount given induces the same desired effect and is not so big as to result in poor compliance. On the other hand, a very high potency may have a potential disadvantage in that small variations in bioavailability are more likely to be clinically important. The relative potency of two drugs is therefore the ratio between their equi-effective doses, i.e., the ratio between doses that induce the same degree of biological response [9, 10]. In general, plasma half-life, biological half-time, and potency of glucocorticoids are roughly correlated: for example, dexamethasone, which shows a prolonged clearance from plasma (200-300 minute), has also a prolonged biological effect (36-54 hours) and an enhanced antiinflammatory activity from 6.7 to 7.4 times that of prednisone given at equiponderal doses, mg x mg [11, 12]. But the increased antiinflammatory potency of betamethasone and dexamethasone is also invariably accompanied by a higher toxicity. In addition, long-acting glucocorticoids inhibit the hypothalmic pituitary axis (HPA) greater than that predicted on the basis of their plasma half-lives and relative antiinflammatory potencies. Dexamethasone is, for instance, 17 times