Study design in osteoporosis: a European perspective.

The advent of effective agents for the treatment of osteoporosis has led to the view that placebo-controlled trials to test new agents for efficacy are no longer appropriate. Rather, studies of superiority, equivalence, or non-inferiority have been recommended. Such studies require very large sample sizes, and the burden of osteoporotic fracture in a trial setting is substantially increased. Studies of equivalence cannot be unambiguously interpreted because the variance in effect of active comparator agents is too large in osteoporosis. If fracture studies are required by regulatory agencies, there is still a requirement for placebo-controlled studies, although perhaps of shorter duration than demanded at present.

Uncertain future of trials in osteoporosis.

The advent of effective agents for the treatment of osteoporosis has led to the view that placebo-controlled trials to test new agents for efficacy are no longer appropriate since proven treatments are available. In this review we argue that, if new agents are to be developed, there is still a place for the placebo-controlled trial. A move to studies of equivalence or non-inferiority raises more problems than it resolves.

Optimal age for preventing osteoporosis after menopause depends on effects of stopping treatment.

The aim of this study was to model the effect of short (3 year) treatments for osteoporosis at different times after menopause on the risk of osteoporotic fracture and to assess the impact of strategies to target high-risk individuals. Treatment efficacy for hip, proximal forearm, shoulder, and spine fracture were computed from the relationship between bone mineral density (BMD) and fracture in women from Sweden. Treatment that increased hip bone mineral density by 6% over untreated women saved 126 vertebral, hip, proximal humerus, and forearm fractures per 1000 women at the age of 50 years, provided that the effects of treatment persisted. Targeting women with osteoporosis at this age would save an additional 50% of fractures. With age, the number of fractures saved decreased moderately. At the age of 70 years, 133 fractures would be saved in women with osteoporosis compared to 198 in women with osteoporosis at the age of 50 years. Where the effect of treatment was assumed to wear off over 20 years after stopping treatment, the efficacy of treatment was reduced at all ages, but most markedly at the age of 50 years. Where all women aged 50 years were treated, the number of fractures saved per 1000 women decreased from 127 to 15 and, in the case of targeting women with osteoporosis, decreased from 198 to 27 per 1000 women. By contrast, with a persisting effect of treatment, the number of fractures saved increased markedly with advancing age. If all women were targeted at the age of 50 years, 15 fractures would be saved, whereas this increased to 55 per 1000 women at the age of 70 years. When treatment effects wore off more rapidly with an offset half-time of 2.5 years only 5 fractures were saved per 1000 women at the age of 50 years. This figure rose to 23 per 1000 at the age of 70 years. We conclude that, although uncertainty exists concerning the offset of effect of treatments, treatments should be optimally given to women without prior fractures in later life.

Targeting of hormone replacement therapy immediately after menopause.

The aim of this study was to model the effect of short (3-year) treatments with hormone replacement therapy (HRT) at the time of menopause on the risk of osteoporotic fracture, and to assess the impact of strategies to target high-risk individuals. From the relationship between bone mineral density (BMD) and fracture risk, treatment that increased bone mineral density at the hip by 6% over untreated women would save 35 vertebral, 62 hip, 13 proximal humeral, and 16 forearm fractures per 1000 women. The number needed to treat (NNT) to prevent one of these fractures was 8. The NNT fell modestly by targeting HRT to women with low bone mass or osteoporosis (NNT 6 and 5, respectively). The gains in fractures saved from targeting women with low bone mass or osteoporosis were offset by the requirement for assessment by BMD. Changes in the assumptions about the efficacy of HRT had a modest impact on fractures saved compared with the effect of changing assumptions concerning the offset of effect when treatment was stopped. We conclude that comparatively short courses of HRT might be effectively offered to all suitable women at menopause provided that the effects on bone persist when treatment is stopped.

Acute and long-term increase in fracture risk after hospitalization for vertebral fracture.

The aims of this study were to determine the magnitude of the increase in risk of further fracture following hospitalization for vertebral fracture, and in particular to determine the time course of this risk. The records of the Swedish Patient Register were examined from 1987 to 1994 to identify all patients who were admitted to hospital for thoracic or lumbar vertebral fractures. Vertebral fractures were characterized as due to high- or low-energy trauma. Patients were followed for subsequent hospitalizations for hip fracture, and for all fractures combined. A Poisson model was used to determine the absolute risk of subsequent nonvertebral fracture and compared with that of the general population. We analyzed 13.4 million hospital admissions from which 28,869 individuals with vertebral fracture were identified, of which 60% were associated with low-energy trauma. There was a marked increase in subsequent incidence of hip and all fractures within the first year following hospitalization for vertebral fracture in both men and women. Thereafter, fracture incidence declined toward, but did not attain, baseline risk. Increased risks were particularly marked in the young. The increase in fracture risk was more marked following low-energy vertebral fracture than in the case of high-energy trauma. We conclude that the high incidence of new fractures within a year of hospitalization for vertebral fractures, irrespective of the degree of trauma involved, indicates that such patients should be preferentially targeted for treatment. It is speculated that short courses of treatment at the time of first vertebral fracture could provide important therapeutic dividends.

A comparison of spinal quantitative computed tomography with dual energy X-ray absorptiometry in European women with vertebral and nonvertebral fractures.

Quantitative computed tomography (QCT) was compared to dual X-ray absorptiometry (DXA) measured in the lumbar spine of 508 European women defined as normal without fracture (NoF), or osteoporotic (OP), with either vertebral fracture (VF), or peripheral fracture (PF). The correlations between QCT and DXA BMD measurements were significantly different in normal and in osteoporotic patients, indicating that the two exams do not measure the same bone aspects. According to ROC curves results, QCT Z-scores separate OP from NoF with better sensitivity than all other measurements. A threshold to differentiate OP from NoF was chosen at Z-score = -1 for DXA-BMD and -1.5 for QCT-BMD. VF patients showed a highly significant decrease in BMD by DXA or QCT. PF patients revealed measurements lower than those of normal subjects but greater than those of VF, calling into question the idea of a diffuse osteoporosis causing nonvertebral fractures that is measurable by spinal DXA or QCT. DXA is weakly dependent upon age, and T-score or Z-score are equivalent for evaluating osteoporosis. QCT depends greatly upon age, and Z-score appears to be more efficient.

Quality of life in patients with vertebral fractures: validation of the Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO). Working Party for Quality of Life of the European Foundation for Osteoporosis.

Vertebral fractures may be minor or lead to pain, decreased physical function, immobility, social isolation and depression, which together contribute to quality of life. A Working Party of the European Foundation for Osteoporosis has developed a specific questionnaire for patients with vertebral fractures. This questionnaire, QUALEFFO, includes questions in the domains pain, physical function, social function, general health perception and mental function. QUALEFFO was validated in a multicenter study in seven countries. The study was done in 159 patients aged 55-80 years with clinical osteoporosis, i.e., back pain and other complaints with at least one vertebral fracture and lumbar bone mineral density T-score <-1. Patients with a recent vertebral fracture were excluded because of unstable disease. Controls were age- and sex-matched, and did not have chronic back pain or vertebral fractures. Subjects with conditions exerting a major influence on quality of life were excluded. The QUALEFFO was administered twice within 4 weeks and compared with a generic questionnaire, the Short Form 36 of the Medical Outcomes Study (SF-36). Standard spinal radiographs were made for assessment of vertebral height. Seven questions were removed from the analysis because of low response rate, linguistic ambiguities or redundancy. The 41 remaining questions were analyzed for repeatability, internal consistency and the capacity to discriminate between patients with vertebral fractures and controls. Comparison with the SF-36 was performed within similar domains by conditional logistic regression and by receiver operating characteristic (ROC) curves. The repeatability of QUALEFFO was good (kappa statistics 0.54-0.90) and 26 of 41 questions had a kappa score >/=0.70. The internal consistency of the five domains was adequate, with Crohnbach alpha around 0.80. All except five questions discriminated significantly between patients and controls. The median scores of QUALEFFO were significantly higher in patients with vertebral fractures than in controls in all five domain (p<0. 001), which is consistent with decreased quality of life in patients with osteoporosis. Spinal radiographs were assessed using the McCloskey-Kanis algorithm. According to this, 124 patients (78%) had vertebral fractures of >/=3 SD severity, in contrast with 7 controls (4%). Significant correlations existed between scores of similar domains of QUALEFFO and the SF-36, especially for pain, physical function and mental function. All five domains within each questionnaire discriminated significantly between fracture cases and controls. The odds ratios for pain and social function were greater for QUALEFFO, while general health perception was more discriminating using the SF-36. The ROC curve analysis of QUALEFFO indicated that all five domains were significantly predictive of vertebral fractures. When comparing similar domains of the two questionnaires, QUALEFFO domains demonstrated significantly better performance for pain, physical function and social function. The QUALEFFO total score and SF-36 physical composite score showed similar performance. In conclusion, QUALEFFO is repeatable, coherent and discriminates well between patients with vertebral fractures and control subjects. The results of this study confirm the decreased quality of life in patients with vertebral fractures.

Plasma estradiol concentrations and pharmacokinetics following transdermal application of Menorest 50 or Systen (Evorel) 50.

OBJECTIVES: In order to compare the pharmacokinetics of two transdermal estrogen replacement therapy (ERT) systems designed to release 50 micrograms 17 beta-estradiol/day, two studies were performed in healthy postmenopausal volunteers. METHODS: Both studies had a cross-over design and incorporated a 1-week wash-out period between treatments. In the first study, Menorest 50 and Systen 50 (Evorel 50) were compared over four days of application in 30 women. In the second, 13 women wore each of the two systems for a total of 12 days each (three patches each for 4 days), and comparison was made during the third patch period (steady state, between days 8 and 12). Plasma 17 beta-estradiol levels were assayed using specific direct radioimmunoassays, and pharmacokinetic parameters were calculated by standard methods. All the samples of the first study were re-analysed using a different radioimmunoassay and the results of both assays were compared. RESULTS: In both studies, plasma 17 beta-estradiol levels rose at a comparable rate and reached similar peak levels with each of the two formulations. Levels then remained relatively constant throughout both evaluation periods with Menorest 50, but began to decline after 12 hours in the first study and after 30 h under steady state conditions in the second study with Systen 50. The difference between the two products was statistically significant in both studies. Analysis of pharmacokinetic parameters confirmed the greater bioavailability of Menorest 50. In addition, 17 beta-estradiol levels remained within the suggested therapeutic ranges for relief of acute symptoms and protection against osteoporosis for longer periods of time with Menorest 50 than with Systen 50. CONCLUSION: Since the acute efficacy, long-term protective effects, side effects and risks associated with ERT may depend on critical threshold plasma levels, much attention should be paid to the pharmacokinetic profiles of different formulations. The comparison of these two different radioimmunoassays demonstrates the comparability of their results.

Quality of life as outcome in the treatment of osteoporosis: the development of a questionnaire for quality of life by the European Foundation for Osteoporosis.

The morbidity of osteoporosis is caused by fractures. Vertebral fractures lead to pain and disability and a decrease in quality of life. A Working Party of the European Foundation for Osteoporosis has developed a specific questionnaire for patients with established vertebral osteoporosis. This questionnaire is intended for use in clinical trials. The questionnaire consists of questions and visual analogue scales in the following domains: pain, activities of daily living, jobs around the house, mobility, leisure and social activities, general health perception and mood. The questionnaire has been translated from English into French, German, Italian, Hebrew, Swedish and Dutch. The questionnaire is currently being validated in a multicentre study involving patients with stable osteoporosis and control subjects. Preliminary results indicate that the reproducibility is sufficient and that the questionnaire is able to discriminate between patients with vertebral osteoporosis and control subjects.

Effect of salmon calcitonin on femoral bone quality in adult ovariectomized ewes.

The aim of this study was to evaluate the effect of intermittent calcitonin on femoral bone quality in adult ewes from the time of ovariectomy. Six months after the start of the experiment, bone density measurements and mechanical testing (torsion and resonant frequency analysis of the diaphysis and compression of an excised trabecular bone cylinder from the femoral neck) were performed in sham-control and ovariectomized (OVX) ewes treated with placebo or salmon calcitonin (50 or 100 units, 3 times/week). Crystallinity of bone was evaluated by measuring X-ray diffraction line broadening. After OVX, a nonsignificant bone loss was found at all measured sites in the femur (-3 to -9%) together with a decreased biomechanical competence in the trabecular bone (compressive strain -28%, P < 0.05). Treatment with salmon calcitonin, 50 or 100 IU subcutaneously three times a week from the time of ovariectomy, resulted in a significant dose-dependent preservation of bone strength in the trabecular bone of the femoral neck compared with OVX. No adverse effects of calcitonin were observed on bone crystal composition as assessed by diffractiometry. We conclude that in adult ewes intermittent calcitonin treatment from the time of OVX was associated with a significant preservation of cancellous bone strength and strain in trabecular bone of the femoral neck, without affecting crystalline properties of bone.

Architectural modifications and cellular response during disuse-related bone loss in calcaneus of the sheep.

The results of simple biomechanical unloading in models of acute-disuse osteoporosis are influenced by systemic and regional effects of the method used to generate the bone loss. A model in which strain-gauge measurements confirmed that the os calcis was unloaded in healthy ewes during ambulation was assessed by histomorphometry. Twelve nonovariectomized adult female Welsh mountain sheep were submitted to hock joint immobilization by an external fixation procedure from the tibia to the metatarsus for a period of 12 wk. Histomorphometric analysis showed that this model was able to produce pure local bone loss, as transiliac bone biopsies failed to reveal any difference between the initial and final results. Immobilized and nonimmobilized calcanei were both removed postmortem. After the 12 wk of the study, osteoclastic activity was increased in accordance with the usual disuse process. An unexpected increase of osteoblastic activity was also observed, possibly related to recovery after the initial dramatic bone loss, but an artifact of the surgical procedure such as a regional acceleration phenomenon cannot be definitively excluded. However, the increased osteoblastic activity was not sufficient to prevent accentuation of the negative bone balance, resulting in a 29% decrease of trabecular bone volume in immobilized calcanei compared with nonimmobilized calcanei. This reduction was due to thinning of trabeculae (72.4 +/- 12.1 vs. 98.9 +/- 15.9 microns; P < 0.05) without any change in trabecular number (2.74 +/- 0.72 vs. 2.79 +/- 0.40/mm2; not significant). In conclusion, this model only locally increased both osteoclastic and osteoblastic activities leading to bone loss and architectural modifications. The decreased bone formation usually observed in other models of disuse osteoporosis may therefore not constitute a local phenomenon generated by unloading.

The development of a European questionnaire for quality of life in patients with vertebral osteoporosis.

The complaints of vertebral osteoporosis usually result from wedge or crush fractures and biconcave deformities. These are caused by a decrease of bone mass and deterioration of bone structure leading to loss of strength. Treatment of osteoporosis should result in an increase of bone mass, and the incidence of new vertebral fractures should diminish. However, new vertebral fractures are not always accompanied by pain, and disability does not well correlate with the number of vertebral fractures. Patients with osteoporosis often have other problems e.g. with taking a shower, preparing meals, gardening, walking stairs, visiting friends and attending social activities. In addition, pain and disability may influence mood and lead to depression. The assessment of quality of life should be a primary endpoint in clinical trials in patients with osteoporosis and in individual patients care. Recently, the European Foundation for Osteoporosis (EFFO) has decided a develop a questionnaire for patients with vertebral osteoporosis, i.e. patients with vertebral deformities. The questionnaire is meant for use in clinical trials. A questionnaire was made including 48 questions and 6 visual analogue scales. The questions concern the following domains: pain, activities of daily living, jobs around the house, moving, leisure and social activities, general health perception and mood. The questionnaire ("Qualeffo") has now entered the validation phase. The first study in 8 centres concerns the within-subject reproducibility, the internal coherence, and the specificity by comparing osteoporotic patients with a control group not suffering from osteoporosis or backpain.

Plasma concentration of estradiol following transdermal administration of Systen 50 or Menorest 50.

Circulating levels of 17 beta estradiol (E2) following the administration of fixed doses of E2, show a great variability in kinetics depending upon the product administrated, the routes of administration, and the interindividual variations in absorption and metabolism. This might have important implications both in terms of tolerance and effectiveness. Two new forms of transdermal E2 (SYSTEN Cilag and MENOREST Rhone-Poulenc Rorer) have been recently accepted in Europe for the treatment of climacteric symptoms. The present study was undertaken to compare the pharmacokinetic characteristics of plasma E2 profile under these two drugs. It was carried out in 30 healthy postmenopausal volunteers according to good clinical practice after informed consent, as a single blind, randomised, cross-over study during the classical wearing period of 4 days. Plasma E2 concentration was determined 24 hours before, 1/2 hour before and then 2, 4, 8, 12, 24, 48, 72, 84, 96 hours after the first patch administration. E2 measurement was performed using a specific direct radioimmunoassay developed in the FRH laboratories. The main criteria for this method were an intraassay coefficient of variation (CV) less than 6%, an interassay CV less than 8% in a concentration range of 15-140 pg/ml and a quantitative detection limit (LOQ) of 2.7 pg/ml with a 20% CV. The following kinetic parameters were analysed: C(max), C(mean), C96 and MRT. The bioequivalence was assessed by analysis of variance of C(max), C(mean), C96 and AuC after logarithmic transformation, complemented by Westlake test (95%). Data show that these two products are identical in terms of C(max) but C(mean), C96 and AuC are statistically greater when MENOREST 50(R) is administered; furthermore, E2 levels decrease more rapidly and more deeply with SYSTEN 50 than MENOREST 50. The differences of pharmacokinetic profiles after administration of two different forms of the same dose of 50 micrograms transdermal 17 beta estradiol might have important medical consequences.

Ineffectiveness of calcitonin on a local-disuse osteoporosis in the sheep: a histomorphometric study.

Local immobilization is a good model for studying disuse-induced bone loss and to appreciate the effects of drugs, especially preventive action of antiresorptive therapy. In fact, increased osteoclastic activity is the main point of such a bone loss. The effect of salmon calcitonin was investigated on immobilization-induced osteoporosis in the sheep. Twenty-four nonovariectomized, adult, female, Welsh mountain sheep were submitted, by an external fixator procedure, to hock joint immobilization from the tibia to the the metatarsus for 12 weeks. The sheep were randomized into two groups receiving either an injection of placebo or salmon calcitonin (100 IU) three times per week, for 12 weeks. Histomorphometric analysis was performed on pre- and posttherapeutic transiliac bone biopsies, and on immobilized (left) and nonimmobilized calcanei removed after sacrifice. Results showed a 29% significant decrease of cancellous bone volume in the placebo group due to a significant reduced trabecular thickness when we compared immobilized versus nonimmobilized calcaneus. This structural adaptation appeared to be the consequence of an overall increased bone turnover. In the calcitonin group, same changes were observed, with a 23% reduction of bone mass in the immobilized calcaneus. By comparing calcitonin with placebo groups in both left and right calcanei, no difference was found. On the other hand, a significant increase of mineralization parameters in the iliac crest was only observed in the calcitonin group. In conclusion, salmon calcitonin, at a dose of 100 IU/day three times a week, was ineffective in preventing local disuse osteoporosis in this sheep model.

Effect of calcitonin administration on young pig trabecular bone remodeling.

Ten-week-old pigs were treated with 4 different treatment schedules of porcine calcitonin for 2 months. Groups C1 and C4 received continuous treatment: C1 had daily IM injections (4 IU/kg/BW (body weight) each injection), and C4 was infused with a minipump implanted subcutaneously delivering 4 IU/kg/BW/day. Groups C2 and C3 received intermittent calcitonin treatment (each injection 4 IU/kg/BW): C2 was given 1 out of every four days, C3 was injected 5 consecutive days out of 20 days. The total dosage received in C1 versus C4 and C2 versus C3 were the same. Results were evaluated by histomorphometry after double tetracycline labeling on iliac trabecular bone. Resorption surfaces were decreased in groups C2, C3 and C4, but bone volume, osteoclast surfaces, and interstitial bone thickness were not modified in any group receiving calcitonin. Osteoblast and mineralizing surfaces were increased in group C2, C3 and C4. Plasma 1,25-dihydroxyvitamin D concentration and bone formation rate were increased in groups C2 and C4. Plasma immunoreactive parathyroid hormone levels and parathyroid weights were not increased in any treated groups. In conclusion, 2-month calcitonin treatment did not decrease the amount of bone resorbed in growing pigs. Continuous calcitonin infusion and intermittent calcitonin administration induced an increase in the extent of active bone formation which might be in part dependent on an increased production of 1,25 dihydroxyvitamin D.

Effects of a one-year administration of phosphate and intermittent calcitonin on bone-forming and bone-resorbing cells in involutional osteoporosis: a histomorphometric study.

The bone histomorphometric effects of intermittent phosphate and calcitonin therapy during 1 year were analyzed in 15 involutional osteoporotic patients. Phosphate was administered continuously (1.5 g/day) and calcitonin was injected during 5 days every third week (50 IU/day). The bone cell response was analyzed in two separate groups, according to the amount of trabecular bone present in the iliac bone biopsy: patients with trabecular bone volume (TBV) beyond the histomorphometric spontaneous fracture threshold (0.16 mm3/mm3) (group 1; 11 patients) and patients with TBV above this threshold (group 2; 4 patients). In group 1, the treatment significantly increased TBV from 0.113 +/- 0.025 to 0.156 +/- 0.046 mm3/mm3 by thickening the existing trabeculae rather than by creating new trabeculae; stimulation of bone formation rate (+ 50%) and significant reduction in active trabecular resorption surfaces (from 0.021 +/- 0.013 to 0.010 +/- 0.006 mm2/mm2; P less than .05) may have led to positive bone balance. In group 2, TBV was not changed because of the treatment's relative inefficiency for reducing the bone-resorbing cell activity, leading to likely persistent negative bone balance. Cortical thickness did not change in either group. This study confirms the positive effectiveness of continuous treatment with phosphate and intermittent calcitonin during 1 year on bone balance in involutional osteoporosis with low amount of bone. The lack of response in patients with normal amount of bone must be verified before raising the hypothesis of different bone cell activity and before anticipating the therapeutic response according to local bone mass besides bone remodeling status in osteoporosis.

[The placebo effect in bone metastatic pain]. / Effet placebo sur les douleurs métastatiques osseuses.

In a double-blind multicentre study conducted on patients suffering from bone metastasis pain, an analgesic effect with unexpected qualitative, quantitative and temporal characteristics was observed in the placebo group (n = 38). The placebo was considered effective by doctors and patients in 57 per cent and 51 per cent of the cases respectively. Mean improvement was estimated at 30-40 per cent by self-evaluation, and it persisted for 7 days after the end of the 7-day treatment. Placebo responders were younger than non-responders and showed a tendency to put lower scores on the sensory pain descriptive scales. The possible factors involved and the implications of these findings are discussed in the light of current data on placebo effect.

Bone loss and bone blood flow in paraplegic rats treated with calcitonin, diphosphonate, and indomethacin.

Sham-operated (SO) and paraplegic rats were treated from the day of operation during a period of 4 or 6 weeks with salmon calcitonin 4 IU/kg/day or a diphosphonate (APD) 1mM/kg/day or indomethacin 2.5 mg/kg/day. The consequence of spinal cord section on the femur and tibia is a loss of mineral which affects predominantly trabecular bone (-24 and -13% in calcium content for the tibial metaphysis and the whole bone, respectively, when compared with the SO controls), a twofold increase in bone blood flow as measured by the technique of the microspheres trapping, a moderate decrease of the 72 hour 45Ca accretion rate in the bone shaft, and an increase in the number of metaphyseal osteoclasts in the tibia. In paraplegics, all three drugs inhibit bone loss to some degree, calcitonin and indomethacin being mostly effective on the cortical bone of the shaft, and APD tremendously increasing the trabecular network of the metaphysis. APD is the only drug to exhibit a significant effect on the calcium content of the bones of the SO controls, but some effect is apparent for calcitonin on X-rays and histological preparations. The increase in bone blood flow in paraplegics is unaffected, this point being discussed in view of the hypothesis of the resorptive action of prostaglandins produced by newly formed vessels. 45Ca accretion rate increases in the shaft of calcitonin-treated paraplegics, whereas it decreases in APD-treated controls and paraplegics. The number of osteoclasts decreases in paraplegics treated with calcitonin and indomethacin, and increases in both controls and paraplegics treated with APD.(ABSTRACT TRUNCATED AT 250 WORDS)