Romain Perrelet

Incidence and Direct Medical Costs of Hospitalizations due to Osteoporotic Fractures in Switzerland

Abstract: The objective of this study was to estimate the annual direct medical costs of hospitalizations due to osteoporotic fractures in Switzerland. Days of hospital stay in 1992 were quantified using the casuistic of the medical statistics department of VESKA (Vereinigung Schweizerischer Krankenhäuser, the Swiss Hospital Association), which covers 43% of all hospital beds of that country. Number and incidence of total hospitalizations due to fractures were calculated by extrapolating to 100% the 43% VESKA-selected sample. To estimate number and incidence of hospitalizations due to osteoporotic fractures, internationally accepted age-specific osteoporosis attribution rates were applied. According to the latter the probability of a fracture being causes by osteoporosis increases with age. Mean length of stay for all fractures was calculated (= total hospital days divided by number of cases). By multiplying these mean lengths of stay by the number of osteoporosis-related fracture cases, the number of bed-days due to osteoporotic fractures was calculated. To compare the direct medical costs of hospitalization due to osteoporosis with those due to other frequent diseases, days of hospital stay caused by chronic obstructive pulmonary disease (COPD), stroke, acute myocardial infarction and breast cancer were estimated using the same methodology. A total estimate of 63 170 (f: 33 596, m: 29 574) hospitalizations due to fractures (and other osteoporosis-related diagnoses) was calculated, thus leading to overall annual incidence rates of hospitalizations for fractures of 950/100 000 women and 877/100 000 men. In women, 548 615 hospital days were found to be caused by osteoporosis, 353 654 days by COPD, 352 062 days by stroke, 200 669 days by breast carcinoma and 131 331 days by myocardial infarction. In men, COPD caused more hospitalization days (537 164) than myocardial infarction (196 793), stroke (180 524) or osteoporosis (152 857). Taking a mean price for a hospital day in Switzerland of 845 Swiss francs, the annual costs of acute hospitalizations due to osteoporosis and its complications were approximately 600 million Swiss francs (f: 464, m: 130 million Swiss francs) in 1992. We conclude that there is enough economic evidence to justify wide-scale interventions against osteoporosis in Switzerland.

Prevention of bone loss in paraplegics over 2 years with alendronate.

To assess the effects of long‐term treatment of bone loss with alendronate in a group of paraplegic men, 55 patients were evaluated in a prospective randomized controlled open label study that was 2 years in duration comparing alendronate and calcium with calcium alone. Bone loss was stopped at all cortical and trabecular infralesional sites (distal tibial epiphysis, tibial diaphysis, total hip) with alendronate 10 mg daily.

Effects of zoledronate versus placebo on spine bone mineral density and microarchitecture assessed by the trabecular bone score in postmenopausal women with osteoporosis: A three‐year study

The trabecular bone score (TBS) is an index of bone microarchitectural texture calculated from anteroposterior dual‐energy X‐ray absorptiometry (DXA) scans of the lumbar spine (LS) that predicts fracture risk, independent of bone mineral density (BMD). The aim of this study was to compare the effects of yearly intravenous zoledronate (ZOL) versus placebo (PLB) on LS BMD and TBS in postmenopausal women with osteoporosis. Changes in TBS were assessed in the subset of 107 patients recruited at the Department of Osteoporosis of the University Hospital of Berne, Switzerland, who were included in the HORIZON trial. All subjects received adequate calcium and vitamin D3. In these patients randomly assigned to either ZOL (n = 54) or PLB (n = 53) for 3 years, BMD was measured by DXA and TBS assessed by TBS iNsight (v1.9) at baseline and 6, 12, 24, and 36 months after treatment initiation. Baseline characteristics (mean ± SD) were similar between groups in terms of age, 76.8 ± 5.0 years; body mass index (BMI), 24.5 ± 3.6 kg/m2; TBS, 1.178 ± 0.1 but for LS T‐score (ZOL–2.9 ± 1.5 versus PLB–2.1 ± 1.5). Changes in LS BMD were significantly greater with ZOL than with PLB at all time points (p < 0.0001 for all), reaching +9.58% versus +1.38% at month 36. Change in TBS was significantly greater with ZOL than with PLB as of month 24, reaching +1.41 versus–0.49% at month 36; p = 0.031, respectively. LS BMD and TBS were weakly correlated (r = 0.20) and there were no correlations between changes in BMD and TBS from baseline at any visit. In postmenopausal women with osteoporosis, once‐yearly intravenous ZOL therapy significantly increased LS BMD relative to PLB over 3 years and TBS as of 2 years.

How Well Do Radiographic Absorptiometry and Quantitative Ultrasound Predict Osteoporosis at Spine or Hip?: A Cost-Effectiveness Analysis

Dual energy X-ray absorptiometry (DXA) is widely accepted as the reference method for diagnosis and monitoring of osteoporosis and for assessment of fracture risk, especially at hip. However, axial-DXA is not suitable for mass screening, because it is usually confined to specialized centers. We propose a two-step diagnostic approach to postmenopausal osteoporosis: the first step, using an inexpensive, widely available screening technique, aims at risk stratification in postmenopausal women; the second step, DXA of spine and hip is applied only to potentially osteoporotic women preselected on the basis of the screening measurement. In a group of 110 healthy postmenopausal woman, the capability of various peripheral bone measurement techniques to predict osteoporosis at spine and/or hip (T-score < -2.5SD using DXA) was tested using receiver operating characteristic (ROC) curves: radiographic absorptiometry of phalanges (RA), ultrasonometry at calcaneus (QUS. CALC), tibia (SOS.TIB), and phalanges (SOS.PHAL). Thirty-three women had osteoporosis at spine and/or hip with DXA. Areas under the ROC curves were 0.84 for RA, 0.83 for QUS.CALC, 0.77 for SOS.PHAL (p < 0.04 vs RA) and 0.74 for SOS.TIB (p < 0.02 vs RA and p = 0.05 vs QUS.CALC). For levels of sensitivity of 90%, the respective specificities were 67% (RA), 64% (QUS.CALC), 48% (SOS.PHAL), and 39% (SOS.TIB). In a cost-effective two-step, the price of the first step should not exceed 54% (RA), 51% (QUS.CALC), 42% (SOS.PHAL), and 25% (SOS.TIB). In conclusion, RA, QUS.CALC, SOS.PHAL, and SOS.TIB may be useful to preselect postmenopausal women in whom axial DXA is indicated to confirm/exclude osteoporosis at spine or hip.

Prevention of adjuvant arthritis by cyclosporine in rats

The effect of cyclosporine A during the development phase of adjuvant arthritis was studied in 40 female rats. Five groups of eight animals each received oral cyclosporine, 2.5, 5, 10, 20, or 30 mg/kg daily for 30 days. Also, eight normal and eight diseased rats served as placebo controls. At the time of inoculation of the adjuvant suspension on day 0, measurement of disease parameters (paw swelling and vertebral density) was started concomitantly with beginning of therapy. On completion of the study, the animals were killed, and after measurement of total skeletal and segmental (hind legs and caudal spine plus two caudal vertebrae) calcium, the two assessed vertebrae and both femoral condyles were removed for histomorphometric evaluation (vertebrae) and for estimation of glycosaminoglycan (GAG) content of cartilage. Blood for osteocalcin determinations also was taken at term from control and untreated arthritic rats and from animals that had received 10 mg/kg cyclosporine. Treatment with 2.5 mg/kg was ineffective, but doses between 5 and 20 mg/kg prevented the development of articular and osseous lesions. The 20 mg/kg dose showed no better effect than 10 mg/kg. This was shown by the absence of inflammation and the presence of normal condylar GAG and total mineral content in the areas screened. Untreated animals showed marked reductions in all of these parameters. The 30 mg/kg dose was effective in blocking the GAG loss, but significant reductions in bone density and trabecular volume were seen. There was a close correlation between GAG and bone density values, suggesting a common causal relationship. Circulating osteocalcin was significantly elevated in the untreated animals with adjuvant arthritis.(ABSTRACT TRUNCATED AT 250 WORDS)

1,25-(OH)2-16ene-23yne-D3 Reduces Secondary Hyperparathyroidism in Uremic Rats with Little Calcemic Effect

Objectives: To compare the effects of vitamin D analogs versus calcitriol on serum levels of Ca, P and parathyroid hormone (PTH). A compound better than calcitriol should increase the Ca x P product less than calcitriol for an equivalent decrease in PTH levels. Methods: Biological activity of 4 vitamin D analogs, 1,25-(OH)₂-16ene- D₃ (RO₁), 1,25-(OH)₂-16ene-23yne-D₃ (RO₂), 1,25-(OH)₂-26,27-hexafluoro-16ene-23yne-D₃ (RO₃) and 1,25-(OH)₂-16ene-23yne-26,27-hexafluoro-19nor-D₃ (RO₄) was tested vs. calcitriol in parathyroidectomized rats. In a second set of experiments, the effects of RO₂, RO₄ and calcitriol were studied in 5/6 nephrectomized rats with secondary hyperparathyroidism. Results: In parathyroidectomized rats, all analogs (250 pmol/day) led calcemia to rise after 7 days. In uremic rats, all treatments reduced PTH levels. RO₄ revealed toxicity. RO₂ was as effective as calcitriol in suppressing PTH in a dose dependent manner. Mean plasma ionized calcium did not change from baseline to day 14 and day 28 on RO₂ (250 or 500 pmol/day) whereas it increased significantly on RO₂ (1,000 pmol/day) and calcitriol (125 or 250 pmol/day). Increasing the dose of calcitriol led Ca × P to rise more dramatically than increasing the dose of RO₂, which appears to have a wider therapeutic window than calcitriol. Conclusion: 1,25-(OH)₂-16ene-23yne-D₃ (RO₂) may represent a novel candidate for the treatment of renal osteodystrophy in humans.

Cortical bone loss at the tibia in postmenopausal women with osteoporosis is associated with incident non-vertebral fractures: Results of a randomized controlled ancillary study of HORIZON

BACKGROUND In postmenopausal women, yearly intravenous zoledronate (ZOL) compared to placebo (PLB) significantly increased bone mineral density (BMD) at lumbar spine (LS), femoral neck (FN), and total hip (TH) and decreased fracture risk. The effects of ZOL on BMD at the tibial epiphysis (T-EPI) and diaphysis (T-DIA) are unknown. METHODS A randomized controlled ancillary study of the HORIZON trial was conducted at the Department of Osteoporosis of the University Hospital of Berne, Switzerland. Women with ≥1 follow-up DXA measurement who had received ≥1 dose of either ZOL (n=55) or PLB (n=55) were included. BMD was measured at LS, FN, TH, T-EPI, and T-DIA at baseline, 6, 12, 24, and 36 months. Morphometric vertebral fractures were assessed. Incident clinical fractures were recorded as adverse events. RESULTS Baseline characteristics were comparable with those in HORIZON and between groups. After 36 months, BMD was significantly higher in women treated with ZOL vs. PLB at LS, FN, TH, and T-EPI (+7.6%, +3.7%, +5.6%, and +5.5%, respectively, p<0.01 for all) but not T-DIA (+1.1%). The number of patients with ≥1 incident non-vertebral or morphometric fracture did not differ between groups (9 ZOL/11 PLB). Mean changes in BMD did not differ between groups with and without incident fracture, except that women with an incident non-vertebral fracture had significantly higher bone loss at predominantly cortical T-DIA (p=0.005). CONCLUSION ZOL was significantly superior to PLB at T-EPI but not at T-DIA. Women with an incident non-vertebral fracture experienced bone loss at T-DIA.

Experimental arthritis: Effect on growth parameters and total skeletal calcium

Aim of the study was to investigate the possible mechanisms leading to stunted growth and osteoporosis in experimental arthritis. Fourty-two female rats of 7-8 weeks of age were randomly assigned to three groups of 14 animals each: (a) controls; (b) adjuvant-inoculated (AA); and (c) adjuvant-inoculated rats receiving 10 mg cyclosporin A (CsA) orally for 30 days. Biological parameters studied were: hindpaw swelling; vertebral length progression expressed as Delta increments between days 1 and 30 as a parameter of skeletal growth, and estimation of total skeletal mineral content by dual energy X-ray absorptiometry (n=10 each group) on day 30. Endocrine parameters measured were pulsatile release of growth hormone (rGH) on day 30 following jugular cannulation and measurement of insulin-like growth factor (IGF-1) in pooled plasma from rGH profiles. Results can be summarized as follows: Untreated AA rats exhibited local signs of inflammation in comparison with controls (hindpaw diameter 8.1-8.9 mm vs. 5.3-5.6 mm in controls). Treatment with CsA normalized this parameter (4.9-5.6 mm). Vertebral growth was significantly retarded in AA rats in comparison with controls (214+/-32 vs. 473+/-33 microm; p<0.001). Administration of CsA normalized vertebral size increment with a clear tendency to overgrowth (523+/-43 microm, n.s.). There was also a marked reduction in total skeletal mineral content in diseased (AA) rats as compared to controls (5.8+/-0.1 vs. 7.5+/-0.1g [OH-apatite]; p<0.001), and a moderate but significant increment above controls in the group receiving CsA (8.0+/-0.1 vs. 7.5+/-0.1g [OH-appatite]; p<0.04). Integrated rGH profiles exhibited a significant fall in arthritic rats and were completely restored to normal under CsA treatment. A trend toward higher rGH values was observed in the latter group (2908+/-554 in AA vs. 8317+/-1492 ng/ml/240 min in controls; p<0.001, and 10940+/-222 ng/ml/240 min, n.s. in the CsA group). There was a good correlation between skeletal growth and rGH pulsatility (r=0.81; p<0.001). IGF-1 followed a similar pattern (630+/-44 in AA vs. 752+/-30 ng/ml in controls; p<0.04, and 769+/-59 ng/ml in the CsA group, n.s. vs. controls). Thus, a clear tendency to skeletal overgrowth following treatment was observed in agreement with the hormonal data. It can therefore be concluded that, in experimental arthritis, attenuated GH-spiking and reduced circulating IGF-1 appear to be causally related to growth retardation, probably mimicking signs and symptoms observed in juvenile arthritis. Therapy with CsA is followed by normalization of hormonal and biological parameters accompanied by a catch up phenomenon in skeletal growth which is also observed clinically in juvenile arthritis. Generalized osteopenia is a prominent feature seemingly connected with the growth abnormalities as they parallel each other during the evolution of the disease and respond equally to therapy.

Radiometrical, hormonal and biological correlates of skeletal growth in the female rat from birth to senescence

OBJECTIVE We investigated the skeletal growth profile of female rats from birth to senescence (100weeks) on the basis of sequential radiometrical, hormonal and biochemical parameters. DESIGN Weaning rats entered the study which was divided into two sections: a) sequential measurements of vertebral and tibial growths and bone mineral density (BMD), estimation of mineral content of the entire skeleton (BMC) and chemical analysis of vertebral Ca; and b) determination of basal and pulsatile growth hormone (rGH), insulin-like growth hormone (IGF-I), estradiol (E2), parathyroid hormone (PTH), osteocalcin (OC) and urinary d-pyridinoline (dp) throughout the experimental period. RESULTS Vertebral and tibial growths ceased at week 25 whereas BMD and BMC as well as total vertebral Ca exhibited a peak bone mass at week 40. rGH pulsatile profiles were significantly higher in younger animals coinciding with the period of active growth and IGF-I peaked at 7weeks, slowly declining thereafter and stabilizing after week 60. OC and dp closely paralleled IGF-I coinciding with the period of enhanced skeletal growth, remaining thereafter in the low range indicative of reduced bone turnover. E2 increased during reproductive life but the lower values subsequently recorded were still in the physiological range, strongly suggesting a protective role of this steroid on bone remodeling. PTH followed a similar profile to E2, but the significance of this after completion of growth remains unclear. CONCLUSIONS Mechanisms governing skeletal growth in the female rat appear similar to those in humans. Bone progression and attainment of peak bone mass are under simultaneous control of rGH, IGF-I and calciotropic hormones and are modulated by E2. This steroid seems to protect the skeleton from resorption before senescence whereas the role of PTH in this context remains uncertain.