Patterns of diagnosis of Paget's disease in Spain.

To evaluate the incidence of diagnosis of Paget's disease of bone in Spain, a retrospective study was performed from 1991-1997 in four Spanish centers to evaluate the number of diagnosed Paget's disease cases. Information about the age, gender, and year of admission and an estimation of the reference population with the number of discharges at the centers were registered for each calendar year. The relative diagnostic risk of Paget's disease was calculated, using 1991 as the reference by Poisson's regression models. The percentage of males among the diagnosed cases varied from 39% in 1992 to 62% in 1993 without significant difference between the different years (p = 0.31). The great majority of the cases were diagnosed between 50 and 89 years of age, from 89% in 1992 and 94% in 1993. During the first years the main part of the cases corresponded to persons younger than 69 years (57.5% in 1991, 50% in 1992, and 64.7% in 1993), but from 1994 the major percentage was found in individuals over 70 years of age (68.1% in 1994, 53.8% in 1995, 62.3% in 1996, and 58.1% in 1997) (p = 0.045). Once the results were adjusted by the diagnosis center, an increased diagnostic risk of Paget's disease relative to the year of diagnosis was seen. In 1996 the risk was 54% higher than in 1991. This tendency reached statistical significance (p for trend = 0.03). The results of this study demonstrate that there is an increasing diagnostic tendency of Paget's disease along the period of study due to different analyzed variables.

Correlation between serum osteocalcin and 24,25-dihydroxyvitamin D levels in Paget's disease of bone.

We have studied the possible correlation between serum 24,25-dihydroxyvitamin D [24,25-(OH)2D] and osteocalcin levels (sBGP) in Paget's disease of bone. We measured serum calcium, phosphate, PTH, 25-hydroxyvitamin D, 1,25-(OH)2D, 24,25-(OH)2D, alkaline phosphatase (sAP), and the urinary hydroxyproline/creatinine ratio (UOH prol/creat) in 19 patients with Paget's disease of bone and 16 age- and sex-matched controls. As expected, sAP, UOH prol/creat, and sBGP levels were significantly elevated, and there was a tendency to a decrease in serum levels of 24,25-(OH)2D in Pagetic patients with respect to the control group. There was no significant difference between patients and controls in serum calcium, phosphate, PTH, 25-hydroxyvitamin D, and 1,25-(OH)2D. The Pagetic patients were subdivided into two subgroups; subgroup A had normal sBGP levels (less than 5 ng/mL), and subgroup B had increased sBGP levels (greater than 5 ng/mL). Serum 24,25-(OH)2D levels in subgroup B were significantly lower than those in controls, while subgroup A showed levels similar to those in the control group. We also found a positive linear correlation between sAP and sBGP and between sAP and UOH prol/creat as well as a negative linear correlation between sBGP and 24,25-(OH)2D and between 24,25-(OH)2D and UOH prol/creat in Pagetic patients. These results point to a possible role of 24,25-(OH)2D in disease activity.

General management of vertebral fractures.

Vertebral fractures cause pain and disability. Four concepts should guide their comprehensive management: treat the patient, not the skeleton; use a multidisciplinary approach; engage the patient and his or her family in the treatment; and provide appropriate goals, education, encouragement, and support. The goals include procuring bone mass and preventing injury: back support, physical therapy, occupational therapy, psychosocial support, and prevention of falls. Initial treatment includes bed rest, pain management with local and systemic analgesia, bracing to improve comfort, and patient reassurance. Long-term management includes spinal stretching exercises and continuing ordinary activities within limits permitted by pain. A back school program is an effective addition to conventional concepts using physiotherapy exclusively. In certain selected patients, the indication for operative treatment of vertebral fracture depends on the additional injury, and extent and characteristics of cord compression; stability of the fracture; and the amount of deformity. Vertebroplasty can be effective in the control of pain and in obtaining stability of the spine.

Is clinical expressiveness of Paget's disease of bone decreasing?

Recent data have suggested secular changes implying a current trend toward decreased clinical severity of Paget's disease of bone (PD). To test this hypothesis, we conducted a study comparing the characteristics of two groups of PD patients, as disclosed from a sample assessed systematically. The investigation was a hospital-based study of all cases followed up at our unit since 1980. Throughout the follow-up period, diagnosis was based on standard X-ray criteria and the same clinical assessment was applied. Group I (n = 124) represented patients born before 1926, whereas group II (n = 109) included those born after that year. A bone scan performed with 99mTc-EHDP was available for all patients. X-rays of the pelvis and spine, and views of any hot spot observed on the scintigraphy scans were reviewed. The skeletal extent of PD, based on bone scan uptake, was determined by using the index proposed by Coutris. Alkaline phosphatase and hydroxyproline excretion levels were determined in blood and urine, respectively. Baseline characteristics were recorded on a purpose-designed computerized database. The proportion of males (47% in group I vs. 65% in group II; p = 0.007) and the mean (+/-SD) age at diagnosis (69.0 +/- 8.15 vs. 54.3 +/-9.14; p < 0.001) differed significantly between groups. The year of birth showed a strong negative correlation with age at diagnosis (r = -0.83, p < 0.0001) and a weak, but significant, negative correlation with extent of bone lesion (r = -0.20; p = 0.002). Likewise, subjects born prior to 1926 showed a greater percentage of affected skeleton cases (9.6 plus minus 8.01 vs. 7.06 +/- 5.79; p = 0.001). Group I individuals who had pelvic and/or femoral bone lesions were more prone to suffer "pagetic coxopathy" (65% vs. 40%; p = 0.003) with "protrusio acetabuli" (32% vs. 17%; p = 0.01), and the percentage of patients showing radiographic Monckeberg-type vascular calcifications (36% vs. 14%; p = 0.0006) was higher than in those born after 1926. No other epidemiologically clinically, or biochemically relevant differences were seen in the crude analysis. Multivariate analysis identified extent of skeletal lesions (OR = 0.76; p = 0.01), age at diagnosis (OR = 0.79; p = 0.008), number of bones involved (OR = 1.53; p = 0.03), and occupation (p < 0.0001) as the predictive variables linked to year of birth. Our data are consistent with a temporal tendency toward a smaller number of bone lesions and a decreased percentage of instances of affected skeleton. An earlier age at recent diagnosis times and absence of any relevant clinical or biochemical differences seems more likely linked to recent changes in referral and sociological patterns.

Falls explain between-center differences in the incidence of limb fracture across Europe.

There is important geographic variation in the occurrence of the major osteoporotic fractures across Europe. The aim of this study was to determine whether between-center variation in limb fracture rates across Europe could be explained by variation in the incidence of falls. Men and women, aged 50-79 years, were recruited from population-based registers in 30 European centers. Subjects were followed by postal questionnaire to ascertain the occurrence of incident fractures, and were also asked about the occurrence and number of recent falls. Self-reported fractures were confirmed, where possible, by review of the radiographs, medical record, or subject interview. The age- and gender-adjusted incidence of falls was calculated by center using Poisson regression. Poisson regression was also used to assess the extent to which between-center differences in the incidence of limb fractures could be explained by differences in the age- and gender-adjusted incidence of falls at those centers. In all, 6302 men (mean age 63.9 years) and 6761 women (mean age 63.1 years) completed at least one questionnaire concerning fractures and falls. During a median follow-up time of 3 years, 3647 falls were reported by men and 4783 by women. After adjusting for age and gender, there was evidence of significant between-center differences in the occurrence of falls. There was also between-center variation in the occurrence of upper limb, lower limb, and distal forearm fractures. Variation in the age- and gender-adjusted center-specific fall rates explained 24%, 14%, and 6% of the between-center variation in incidence of distal forearm and upper and lower limb fractures, respectively. Given the constraints inherent in such an analysis, in men and women aged 50-79 years, variation in fall rates could explain a significant proportion of the between-center variation in the incidence of limb fracture across Europe.

Relative role of bone and kidney in the hypercalcaemia associated with the rat Walker carcinosarcoma 256.

The rat Walker carcinosarcoma 256 is an animal model for humoral hypercalcaemia of malignancy (HHM). In this model, the relative contribution of bone and kidney in the hypercalcaemia of tumour-bearing rats was investigated. Daily administration of pamidronate, a bone resorption inhibitor, for 2 days prevented the increased fasting Ca2+ excretion observed in the hypercalcaemic rats, although serum Ca2+ remained high. However, the high serum Ca2+ normalised after the acute injection of ethiofos, an inhibitor of renal Ca2+ reabsorption, which was associated with a marked increase of Ca2+ excretion. Changes in Ca2+ were accompanied by similar changes in Mg2+. The results indicate that altered renal Ca2+ handling has a key role in the hypercalcaemia associated with this HHM model.

Evidence of 1,25-dihydroxyvitamin D synthesis by the rat Walker carcinosarcoma 256.

We tested the existence of 25-hydroxyvitamin D-1 alpha-hydroxylase activity in the Walker carcinosarcoma 256 implanted in rats. This tumour has been shown to induce hypercalcaemia in the host animal. We found this enzyme activity in tumour homogenates, which was in the same range as that in the kidney of tumour-bearing rats. Our results suggest that 1,25-dihydroxyvitamin D synthesized by the Walker tumour might be involved in the mechanism responsible for the hypercalcaemia in the host rat.

Comparison of the efficacy and bioequivalence of two oral formulations of tiludronate in the treatment of Paget's disease of bone.

Tiludronate, an oral bisphosphonate used to treat Paget's disease of bone, is currently being studied as a treatment for osteoporosis. A multicenter, open-label, parallel-group study was performed to compare the efficacy of two tablet formulations of tiludronate in the treatment of Paget's disease. Eighty-eight patients with active Paget's disease were recruited. The diagnosis was based on radiologic evidence of bone lesions, and all patients included in the study had serum alkaline phosphatase (SAP) levels equal to or more than twice the upper normal value of the local laboratory that assayed the sample. Each patient received treatment with oral tiludronate 400 mg/d for 84 +/- 2 days; 39 patients received the previously tested tablet formulation 3C1, and 49 patients received formulation 9O1, which is prepared using an improved manufacturing technique. The objective of this study was to determine whether the two formulations have an equivalent therapeutic effect, the primary end point being SAP levels in both groups after 3 months of treatment. This equivalence is commonly assessed by comparing pharmacokinetic data; however, in previous studies of tiludronate, large intra-individual variability prevented statistically valid comparisons of the data. Therefore, in addition to pharmacokinetic data, biochemical and clinical response data were collected during the trial. The secondary objectives of the trial were to measure the plasma levels and to assess the efficacy and safety of the two tiludronate formulations. The relative pharmacologic activities of the two formulations were assessed by comparison of the confidence intervals of levels of SAP at monthly intervals. After 3 months of treatment, the 90% confidence interval of the difference between the formulations was included in the reference confidence interval. These findings suggest that the 9O1 and 3C1 formulations did not show a significant difference in therapeutic activity. Furthermore, after 3 months of treatment, the frequency of normalization of SAP levels was 30.6% in the 9O1 treatment group and 28.2% in the 3C1 treatment group. The percentage of patients responding to treatment (defined as a decrease in SAP levels of at least 50% from baseline) was 67.3% in the 9O1 treatment group and 69.2% in the 3C1 treatment group. Statistical analyses performed on the maximum and minimum plasma concentrations of tiludronate showed no significant differences between the two formulations. In this trial, the two tablet formulations of tiludronate demonstrated therapeutic and pharmacokinetic equivalence.

BGP (osteocalcin, bone-Gla-protein) in involutional osteoporosis.

The role of BGP (osteocalcin) as bone marker in the study and management control of involutional osteoporosis is emphasized and the different radioimmunoassays and their limitations are commented. Our results showed significantly lower sBGP levels in osteoporotic patients compared with control group and a positive linear correlation was found between sBGP and serum alkaline phosphatase but no correlation was obtained with urinary hydroxyproline/creatinine ratio, serum tartrate-resistant acid phosphatase or bone mineral content measured by dual photon absorptiometry.

Gout disease. Its natural history based on 1,000 observations.

Gout disease in our country as both exogenous factors (dietary habits, professions, etc.) and endogenous factors (sex, inheritance, etc.) play a polygenic role in its incidence. Those conditions resulting in hyperuricemia (diseases, drugs, etc.) facilitate the clinical manifestations. But a genetic determinant in the articular reaction in front of an accumulation of uric acid crystals or in the development of such crystallization is a fundamental factor in the manifestation of the disease. In our series we were able to confirm the high incidence of arterial hypertension, renal lithiasis and renal participation in gout. The role of lead and of certain professions in favouring the hyperuricemia is suggested. A classification of gout, from a functional point of view, must include both the clinical form and the analysis of the whole renal function, and the renal handling of uric acid. This is mandatory not only for the diagnosis and prognosis of the disease but to set the basis of its adequate management.

[Hypercalciuric and hyperparathyroid renal lithiasis]. / Litiasi renale ipercalciurica e iperparatiroidea

Idiopathic hypercalciuria was noted in 10% of a series of 1635 subjects with renal lithiasis. Eight-day administration of thiazide diuretics as a test for the discovery of latent hyperparathyroidism in idiopathic hypercalciuria is described. In 6 cases diagnosed in this way, surgery disclosed the presence of a parathyroid adenoma. Resection was followed by persistent hypercalciuria and, in some instances, renal lithiasis activity. The pathogenesis of associations of these frequently observed diseases is examined.

[Nephrocalcinosis as a clinical syndrome. Study of 77 cases (author's transl)]. / La nefrocalcinosis como síndrome clínico (análisis de 77 casos).

Seventy-seven patients with nephrocalcinosis as revealed by X-ray studies over a 10-year period are reviewed. A programmed clinical and metabolic study was performed on each case; the author's criteria included the different pathogenic factors considered in the etiologic definition of the disease. There were 22 cases with primary hyperparathyroidism, 19 with spongy kidney, nine with tubulointerstitial nephropathy, five with hyperoxaluria, five with distal renal tubular acidosis, four with esential hypomagnesemia, and three cases of miscellaneous etiology (vitamin D intoxication, Fanconi's syndrome, Bartter's disease). Ten other cases were classified as idiopathic nephrocalcinosis since no definite cause could be found. The clinical characteristics (symptoms, associated diseases, diet and medication intake, family history) and the biochemical findings are analysed for each group. The physiopathologic mechanisms, comparisons between each etiologic group, treatment, clinical course, and prognosis are commented on. The conclusion drawn is that nephrocalcinosis is a clinical syndrome of various etiologies which in most cases arises from an underlying metabolic disease.

[Prevalence of osteoporosis assessed by densitometry in the Spanish female population]. / Prevalencia de osteoporosis determinada por densitometría en la población femenina española.

BACKGROUND: Osteoporotic fractures represent an important clinic and socioeconomic problem. Although it is well known the incidence of fractures in Spain, we do not know how many persons are at risk. The World Health Organization (WHO) has approved a densitometric criteria to define osteopenia (OSPE) and osteoporosis (OSP). The aim of this study has been to evaluate the prevalence of OSP and OSPE in women of the Spanish population. SUBJECTS AND METHOD: With the data of a study of bone mass in the Spanish population, stratified according to age, using dual-energy X-ray absortiometry (DXA) with a QDR/1000 Hologic device and according the WHO criteria, we have calculated the prevalence of OSP and OSPE in normal Spanish women at the lumbar spine (LS) and/or femoral neck (FN). RESULTS: The prevalence of osteoporosis at LS is: 0.34% in the group aged 20-44 years; 4.31% in the group aged 45-49 years; up to 9.09% in the group aged 50-59 years; 24.29% in the 60-69 years, and 40.0% in the group aged 70-79 years. The overall prevalence of osteoporosis is 11.13%, confidence interval (CI) 95% from 9.4 to 12.8%. The prevalence of osteoporosis at FN is: 0.17% in the group aged 20-44 years, 0% in the 45-49 years, up to 1.3% in the 50-59 years, 5.71% in the 60-69 years and 24.24% in the group aged 70-79 years. The overall prevalence of osteoporosis is 4,29% (CI 95% 3.2-5.4%). The prevalence in female older than 50 years was 22.8% at LS and 9.1% at FN. 12.73% of Spanish women population has osteoporosis at LS or FN, which represent about 1,974,400 women; 2.68% of total population has osteoporosis in both sites. CONCLUSIONS: Even we do not include in this study women with established osteoporosis (with fractures), the number of Spanish women with osteoporosis is very high.