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FRAX®, a simple-to-use fracture risk calculator, was first released in 2008 and since then has been used increasingly worldwide. By calculating the 10-year probabilities of a major osteoporotic fracture and hip fracture, it assists clinicians when deciding whether further investigation, for example a bone mineral density measurement (BMD), and/or treatment is needed to prevent future fractures. In this review, we explore the literature around osteoporosis and how FRAX has changed its management. We present the characteristics of this tool and describe the use of thresholds (diagnostic and therapeutic). We also present arguments as to why screening with FRAX should be considered. FRAX has several limitations which are described in this review. This review coincides with the release of a version, FRAXplus, which addresses some of these limitations.

Osteoarthritis (OA) is the most common joint condition and, with a burgeoning ageing population, is due to increase in prevalence. Beyond conventional medical and surgical interventions, there are an increasing number of ‘alternative’ therapies. These alternative therapies may have a limited evidence base and, for this reason, are often only afforded brief reference (or completely excluded) from current OA guidelines. Thus, the aim of this review was to synthesize the current evidence regarding autologous chondrocyte implantation (ACI), mesenchymal stem cell (MSC) therapy, platelet-rich plasma (PRP), vitamin D and other alternative therapies. The majority of studies were in knee OA or chondral defects. Matrix-assisted ACI has demonstrated exceedingly limited, symptomatic improvements in the treatment of cartilage defects of the knee and is not supported for the treatment of knee OA. There is some evidence to suggest symptomatic improvement with MSC injection in knee OA, with the suggestion of minimal structural improvement demonstrated on MRI and there are positive signals that PRP may also lead to symptomatic improvement, though variation in preparation makes inter-study comparison difficult. There is variability in findings with vitamin D supplementation in OA, and the only recommendation which can be made, at this time, is for replacement when vitamin D is deplete. Other alternative therapies reviewed have some evidence (though from small, poor-quality studies) to support improvement in symptoms and again there is often a wide variation in dosage and regimens. For all these therapeutic modalities, although controlled studies have been undertaken to evaluate effectiveness in OA, these have often been of small size, limited statistical power, uncertain blindness and using various methodologies. These deficiencies must leave the question as to whether they have been validated as effective therapies in OA (or chondral defects). The conclusions of this review are that all alternative interventions definitely require clinical trials with robust methodology, to assess their efficacy and safety in the treatment of OA beyond contextual and placebo effects.

A guidance on the assessment and treatment of postmenopausal women at risk from fractures due to osteoporosis was recently published in Osteoporosis International as a joint effort of the International Osteoporosis Foundation and European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (Kanis et al. Osteoporos Int, https://doi.org/10.1007/s00198-018-4704-5, 2018). This manuscript updates the previous guideline document, published in 2013 (Kanis et al. Osteoporos Int 24:23–57, 2013) and is written from a European perspective. The present article reports and summarizes the main recommendations included in this 2018 guidance document (Fig. 1).

Prevention of fragility fractures in older people has become a public health priority, although the most appropriate and cost-effective strategy remains unclear. In the present statement, the Interest Group on Falls and Fracture Prevention of the European Union Geriatric Medicine Society, in collaboration with the International Association of Gerontology and Geriatrics for the European Region, the European Union of Medical Specialists, and the International Osteoporosis Foundation–European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, outlines its views on the main points in the current debate in relation to the primary and secondary prevention of falls, the diagnosis and treatment of bone fragility, and the place of combined falls and fracture liaison services for fracture prevention in older people.

The criteria required for an effective screening strategy for osteoporosis are largely met in Caucasian women. The disease is common and readily diagnosed by the measurement of bone mineral with single- or dual-energy absorptiometry. Such measurements have high specificity but lower sensitivity, so that the value of the technique is greater for those identified as being at higher risk. Against this background there is little evidence that osteoporosis can usefully be tackled by a public health policy to influence risk factors such as smoking, exercise and nutrition. This suggests that it is appropriate to consider targetting of treatment with agents affecting bone metabolism to susceptible individuals. Since the main benefits of the use of hormone replacement therapy (HRT) are probably on cardiovascular morbidity, the major role for selective screening is to direct non-HRT interventions. An appropriate time to consider screening and intervention is at the menopause, but screening at later ages is also worthy of consideration. Since the cost of screening is low and that of bone-active drugs is high, the selective use of screening techniques will improve the cost-benefit ratio of intervention.

Abstract:: We investigated the cost-effectiveness of treatments that reduce the risk of hip fracture using a computer simulation model. Cost-effectiveness was measured as cost per quality-adjusted life-year (QALY) gained using a threshold value for cost-effectiveness of $30.000/QALY gained. The baseline simulations assumed a 5-year intervention that reduced the risk of hip fracture by 50% during the intervention period, and an effect which reversed to the pretreatment risk during the next 5 years. Sensitivity analyses inlcuded the effects of age, different fracture risks, and different treatment costs and duration of therapeutic effect once treatment was stopped. Cost-effectiveness was critically dependent upon absolute risk determined by the age and the relative risk of hip fracture at any given age. Reasonable cost-effectiveness was shown even with relatively high intervention costs for women with a risk about twice the average at the age of 70 or more years. Cost-effectiveness was critically dependent upon the assumptions made concerning offset of effect of intervention after the end of treatment. Where no residual effect was assumed, it was difficult to show cost-effectiveness from any intervention except for the most effective and least expensive. Conversely, cost-effectiveness improved considerably where effectiveness persisted for a longer time. These studies support the view that intervention in the elderly with agents affecting skeletal metabolism alone may be preferred to such interventions at the time of the menopause, and that offset time, hitherto poorly characterized, is a critical component of cost-effectiveness, particularly in younger women.

Abstract:: 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 specfic 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 α 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.

Abstract:: Vertebral deformity is the classical hallmark of osteoporosis. Three types of vertebral deformity are usually described: crush, wedge and biconcave deformities. However, there are few data concerning the descriptive epidemiology of the individual deformity types, and differences in their underlying pathogenesis and clinical impact remain uncertain. The aim of this study was to compare the epidemiological characteristics of the three types of vertebral deformity and to explore the relationships of the number and type of deformity with back pain and height loss. Age-stratified random samples of men and women aged 50 years and over were recruited from population registers in 30 European centers (EVOS study). Subjects were invited to attend for an interviewer-administered questionnaire and lateral spinal radiographs. The presence, type and number of vertebral deformities was determined using the McCloskey–Kanis algorithm. A total of13 562 men and women were studied; mean age in men was 64.4 years (SD 8.5), and in women 63.8 years (SD 8.5 years). There was evidence of variation in the occurrence of wedge, crush and biconcave deformity by age, sex and vertebral level. Wedge deformities were the most frequent deformity and tended to cluster at the mid-thoracic and thoraco-lumbar regions of the spine in both men and women. Similar predilection for these sites was observed for crush and to a lesser extent biconcave deformities though this was much less marked than for wedge deformities. In both sexes the frequency of biconcave deformities was higher in the lumbar than the thoracic spine and unlike the other deformity types it did not decline in frequency at lower lumbar vertebral levels. The prevalence of all three types of vertebral deformity increased with age and was more marked in women. There were no important differences in the effect of age on the different deformity types. All types of deformity were associated with height loss, which was greatest for individuals with crush deformity. Back pain was also associated with all types of deformity.Overall, these results do not suggest important differences in pathophysiology between the three deformity types. Biomechanical factors appear to be important in determining their distribution within the spine. All deformity types are linked with adverse outcomes, though crush deformities showed greater height loss than the other deformity types.

Abstract:: The aims of this study were to identify risk factors for hip fracture in men aged 50 years or more. We identified 730 men with hip fracture from 14 centers from Portugal, Spain, France, Italy, Greece and Turkey during the course of a prospective study of hip fracture incidence and 1132 age-stratified controls selected from the neighborhood or population registers. The questionnaire examined aspects of work, physical activity past and present, diseases and drugs, height, weight, indices of co-morbidity and consumption of tobacco, alcohol, calcium, coffee and tea. Significant risk factors identified by univariate analysis included low body mass index (BMI), low sunlight exposure, a low degree of recreational physical activity, low consumption of milk and cheese, and a poor mental score. Co-morbidity including sleep disturbances, loss of weight, impaired mental status and poor appetite were also significant risk factors. Previous stroke with hemiplegia, prior fragility fractures, senile dementia, alcoholism and gastrectomy were associated with significant risk, whereas osteoarthrosis, nephrolithiasis and myocardial infarction were associated with lower risks. Taking medications was not associated with a difference in risk apart from a protective effect with the use of analgesics independent of co-existing osteoarthrosis and an increased risk with the use of anti-epileptic agents. Of the potentially ‘reversible’ risk factors, BMI, leisure exercise, exposure to sunlight and consumption of tea and alcohol and tobacco remained independent risk factors after multivariate analysis, accounting for 54% of hip fractures. Excluding BMI, 46% of fractures could be explained on the basis of the risk factors sought. Of the remaining factors low exposure to sunlight and decreased physical activity accounted for the highest attributable risks (14% and 9% respectively). The use of risk factors to predict hip fractures had relatively low sensitivity and specificity (59.6% and 61.0% respectively). We conclude that lifestyle factors are associated with significant differences in the risk of hip fracture. Potentially remediable factors including a low degree of physical exercise and a low BMI account for a large component of the total risk.

Summary Osteoporosis is a generic term implying a decrease in bone mass which increases the risk of fracture. It is now becoming appreciated that decreases in bone mass alone are not the sole factor in increasing the risk of osteoporotic fracture, and that other skeletal and extraskeletal factors also contribute significantly to this risk. Extraskeletal factors include the propensity to falls and responses to falls, whereas additional skeletal factors include bone turnover, the ability to repair fatigue damage and the tertiary structure of bone, particularly trabecular tissue. There are a large number of causes of secondary osteoporosis each with their own specific pathophysiological mechanisms. It is therefore not surprising that they have heterogeneous effects on the skeleton. A good example is provided in corticosteroid osteoporosis which is characeterised by thinning of trabecular elements, whereas postmenopausal osteoporosis is characterised less by thinning and more by destruction of trabecular elements which derange trabecular continuity. A variety of techniques are now being developed to address the heterogeneity of trabecular osteoporosis. These include direct histomorphometric techniques to assess trabecular continuity, and indirect techniques such as the attenuation of ultrasound. These different pathophysiological mechanisms in osteoporosis have important therapeutic implications, particularly with agents that affect bone remodelling. Since bone remodelling is a surface-based phenomenon, if trabecular surfaces are destroyed, the augmentation of bone mass may thicken remnant structures without restoring trabecular continuity. Since most treatments for osteoporosis affect bone remodelling they are likely to have a greater effect in restoring structural integrity of the skeleton in corticosteroid than in postmenopausal osteoporosis.

A large number of cross-sectional studies suggest that rates of bone loss decrease in the elderly, particularly at the spine and radius. For this reason it has been argued that bone mass measurements are unhelpful in assessing fracture risk in the elderly and that drugs affecting bone metabolism are less likely to be of benefit in reducing this risk. This paper reviews the assumptions on which these conclusions are based and argues that in many instances they are flawed. Indeed, studies examining rates of bone loss in the elderly either directly or by biochemical indices of bone turnover suggest that bone loss continues throughout life and may even accelerate after the age of 70 years. This conclusion supports the view that identification of patients at risk and subsequent treatment is of value in all age groups.

The absence of specific criteria for the definition of vertebral fracture has major implications for assessing the apparent prevalence and incidence of vertebral deformity. Also, little is known of the effect of using different criteria for new vertebral fractures in clinical studies. We therefore developed radiological criteria for vertebral fracture in women for assessing both the prevalence and the incidence of vertebral osteoporosis in population and in prospective studies and compared these with several other published methods. Normal ranges for vertebral shape were obtained from radiographs in 100 women aged 45–50 years. These included ranges for the ratios of anterior/posterior, central/posterior and posterior/predicted posterior vertebral heights from T4 to L5. The predicted posterior height was calculated from adjacent vertebrae. In contrast to other methods, our definition of fracture required the fulfilment of two criteria at each vertebral site, and was associated with a lower apparent prevalence of fracture in the control women due to a lower false positive rate. The prevalence and incidence of vertebral deformity using different criteria were then compared in a series of women with skeletal metastases from breast cancer in whom radiographs were obtained 6 months apart. The prevalence of vertebral deformity and the specificity for deformity varied markedly with differing criteria. Using a cut-off of 3 standard deviations the prevalence of vertebral deformity in the women with breast cancer was 46%. Using other methods, the prevalences of deformity ranged from 33% to 74%. Over a 6-month interval 25% of patients with breast cancer sustained 61 deformities using our method, of which only 8% resulted from errors in reproducibility. The number of patients sustaining new deformities was increased twofold when assessed by other methods (45%–53%), but errors of reproducibility may have accounted for 21% of the new deformities. The magnitude and distribution of these errors have important implications for the apparent therapeutic efficacy of agents in clinical trials of osteoporosis. The rapid semi-automated technique for assessing vertebral deformities on lateral spine radiographs that we have developed has a high specificity, and reduces the impact of errors of reproducibility on estimates of prevalence and incidence. The method should prove a value in assessing vertebral deformity both in population studies and in prospective clinical trials.

The objective of this study was to examine the apparent incidence of hip fracture from discharge rates in European countries. A request was sent to the Ministries of Health in all European countries, asking for the number of hip fracture patients by age and sex, between the years 1983 and 1985. Seventeen countries responded. As expected, hip fracture was most frequently found amongst the elderly, particularly women. The incidence of hip fracture rose exponentially with age in both sexes. It was higher in women than men and there was a three-fold range between countries in the female to male sex ratio. There was an eleven-fold range in apparent incidence amongst women and a seven-fold range amongst men between the various countries. The highest incidence was found in the northern part of Europe and the lowest in the Mediterranean area. There was a significant positive correlation between the age-standardized incidence rates reported in men from each country and that in women. There was a larger difference in incidence between countries than between sexes, which suggests important genetic or environmental factors in the causation of hip fracture. The extent to which this reflects imperfect capture of data is uncertain but will be important to determine in order to identify reasons for differences and to enable confident projections of the future magnitude of this disorder.

Bisphosphonates are widely used in disorders associated with increased resorption of bone, particularly in Paget's disease of bone and in the hypercalcemia of malignancy. Because of their undoubted efficacy and relatively low toxicity, bisphosphonates are attractive candidates for the management of osteoporosis. Clodronate, one of the many bisphosphonates being tested in osteoporosis, may be given intravenously or by mouth. In contrast to etidronate, even high doses of clodronate do not impair the mineralization of bone, making it suitable for long-term use in osteoporosis. As do all the bisphosphonates tested thus far, clodronate appears to delay the rate of bone loss in osteoporosis. Long-term studies are relatively few, so that its steady-state effects on bone mass are not yet known. Most data suggest clodronate is capable at least of delaying the rate of bone loss, but several pilot studies with this agent suggest that increments of bone mass might be sustainable for several years. Clodronate is likely to decrease the frequency of osteoporotic fractures, but there is no evidence for this at present. Well-controlled, long-term prospective studies are needed.

The prevalence of algodystrophy in the hand was determined at nine weeks and six months following Colles’ fracture. At nine weeks, 27 of 109 patients showed signs of algodystrophy, all of whom demonstrated more than one feature of the disorder. Thereafter, no unaffected patient developed the disorder. At six months, 62% of the previously affected patients showed some residual abnormalities. In 66% of these, there was evidence of continuing vasomotor instability or swelling, suggesting that the syndrome was still active. These observations suggest that algodystrophy of the hand is a more common complication of Colles’ fracture than is generally realised.

Vertebral height ratios are used to define vertebral deformity in clinical and epidemiologic studies of vertebral osteoporosis. However, few data have been obtained on the variation in these ratios in different populations using standard methods. We examined vertebral morphometric measurements obtained in a population survey from three centers: Malmö (Sweden), Montceau‐les‐Mines (France), and Graz (Austria), to study the influence of sex and the population center on vertebral height ratios. Radiographs were obtained according to a standardized protocol, and morphometric measurements, anterior height Ha, central height Hc, and posterior height Hp, made in Berlin. The height ratios anterior, Ha/Hp, central, Hc/Hp, posterior I, Hp/Hp', and posterior II, Hp/Hp″ (Hp' = posterior height of vertebrae above, Hp″ = posterior height of vertebrae below) were calculated for each vertebra from T4 to L4. The mean and standard deviation of these ratios for each sex and each center were derived using a statistical trimming procedure to normalize the distribution. Threshold values for defining grade 1 and grade 2 deformities, wedge, biconcavity, and compression, were calculated using these parameters. Anterior and central vertebral height ratios were smaller in males than females (p< 0.01). There were significant differences between the three centers (p< 0.01) both in the trimmed mean values for anterior and central vertebral height ratios and in the thresholds derived using standard criteria for defining wedge and biconcavity deformity. The data confirm the impression from single‐center studies that vertebral height ratios vary between populations and suggest that reference values for vertebral height ratios should be derived separately for males and females within individual populations whenever possible.

Conclusion: Primary osteoporosis is a worldwide problem in elderly individuals. In ‘Osteoporosis Update 1997’ there are many outstanding contributions from all over the world. Recent progress is presented in the understanding of the role of vitamin D and PTH in bone and calcium homeostasis, advances in diagnostic tools and therapeutic agents. Since one of the aims of the Second International Conference on Osteoporosis was to compare risk factors among different nations, epidemiology was an important topic. p] Another feature of interest was that bone and calcium abnormalities are not only the problem of bone and calcium per se, but are also related to abnormalities in many other disorders such as atherosclerosis and cancer. Regarding atherosclerosis, bone-vascular system correlation may be a problem of interest to study in the future.

1. We studied the mechanism of action of the anabolic steroid, stanozolol, in 23 patients with osteoporosis, using a combination of biochemical and histomorphometric techniques. 2. Treatment with stanozolol (5 mg/day) for 1 year was associated with a marked and significant decrease in the fasting urinary excretion of calcium (P < 0.01) but not with changes in the serum concentrations of calcium and phosphate, the serum activity of alkaline phosphatase, the renal tubular reabsorption of calcium or the urinary excretion of hydroxyproline. 3. Histological examination of trabecular bone showed an increase in bone turnover and the bone formation rate increased twofold (P < 0.02). There were no significant changes in bone volume or wall thickness after treatment. Tetracycline labelling was used to discriminate bone structural units completed before and during treatment. Measurements of the wall thickness of those bone structural units formed during treatment showed no significant change. 4. Measurements made on the endocortical surface also showed an increase in bone turnover, but in contrast to trabecular bone, the bone structural units formed at endocortical sites during treatment had a significantly greater wall thickness than those formed before treatment (P < 0.05). 5. We conclude that stanozolol increases the turnover of trabecular bone and increases the endocortical apposition of bone.

1. We have examined the relationship between broadband ultrasound attenuation in the os calcis and measurements of bone mineral in the distal forearm and lumbar spine of normal and postmenopausal osteoporotic women. 2. Values of broadband ultrasound attenuation in postmenopausal women with vertebral osteoporotic fractures were significantly lower (35%) than in normal pre-and peri-menopausal women (55.4 ± 3.8 and 79.6 ± 0.8 dB/MHz, respectively). 3. Broadband ultrasound attenuation correlated significantly with bone mineral content measured in the distal forearm by single-photon absorptiometry (r = 0.77, P < 0.0001) and with bone mineral content (r = 0.66, P < 0.0001) and bone mineral density (r = 0.72, P < 0.0001) measured in the lumbar spine by dual-photon absorptiometry. 4. Although significant, these correlations are not sufficiently close to be predictive. However, the accuracy of broadband ultrasound attenuation in discriminating between normal subjects and patients with vertebral fracture compared very favourably with direct measurements in the spine by dual-photon absorptiometry. 5. Broadband ultrasound attenuation, but not the other measurements, correlated significantly with age in the osteoporotic patients (r = 0.50, P < 0.05). 6. These findings may reflect the partial dependence of broadband ultrasound attenuation on the intrinsic trabecular architecture of cancellous bone, the disruption of which contributes to an increase in fracture risk.

1. We have examined the relationship between the attenuation of broadband ultrasound in the os calcis in vitro and its bone mineral density measured by quantitative computed tomography and by physical density. 2. Broadband ultrasound attenuation was found to correlate closely with physical density (r = 0.85, P < 0.0001), but the correlation was less than that observed between quantitative computed tomography and physical density (r = 0.92, P < 0.0001). Measurements of broadband ultrasound attenuation and quantitative computed tomography were significantly correlated (r = 0.80, P < 0.0001). 3. Partial correlation analysis showed a significant relationship between broadband ultrasound attenuation and bone density, but when the effect of physical density was taken into account no significant correlation was found between broadband ultrasound attenuation and quantitative computed tomography (r = 0.08, not significant). 4. Broadband ultrasound attenuation in three prospective amputees showed a high degree of concordance between measurements in vivo and in vitro, with no interference by surrounding soft tissues. 5. The correlation between physical density and broadband ultrasound attenuation was independent of quantitative computed tomography, suggesting that the technique measures aspects of density which differ from its mineral density. Broadband ultrasound attenuation holds promise as a reproducible, rapid, radiation-free assessment of skeletal status.

1. We have studied the early effects of intravenously and orally administered etidronate on vitamin D metabolism and indirect indices of calcium and skeletal metabolism in 17 patients with Paget's disease of bone. 2. Administration of etidronate by mouth (700–1400 mg daily for 1 month) or its intravenous infusion (300 mg daily for 5 days) decreased bone resorption as judged by urinary excretion of hydroxyproline and significantly increased renal tubular reabsorption of phosphate. No significant change in serum activity of alkaline phosphatase was noted with either regimen. 3. When etidronate was given by mouth there was a progressive decrease in fasting urinary calcium excretion and a rise in serum 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. In contrast, intravenous etidronate decreased serum values of l,25-(OH)2D3 and was associated with a progressive increase in fasting calcium excretion, suggesting a decrease in the net influx of calcium from the extracellular compartment to bone. Significant inverse correlations were noted between the change induced in 1,25-(OH)2D3 values at 2 weeks and the changes in serum calcium, phosphate and fasting urinary excretion of calcium. 4. These observations suggest that the different effects of intravenous and oral etidronate on l,25-(OH)2D3 values are a consequence of different doses of etidronate used and the different effects of these regimens on the accretion of calcium into bone.

1. The metabolic clearance rate (MCR) of human calcitonin was measured in 12 normal subjects and four patients with Paget's disease by the infusion of synthetic human calcitonin (15–40 μg/h for 2–24 h), and in 10 additional patients with Paget's disease from the disappearance rate of immunoreactive calcitonin from plasma after the intravenous injection of large doses of synthetic human calcitonin (0·5–1·0 mg). 2. The estimated MCR during the infusion studies (range 531–1224 litres/day) was similar to that calculated from the disappearance of large doses of synthetic human calcitonin injected intravenously in patients with Paget's disease (mean = 1035 litres/day; range = 593–1408 litres/day). 3. An eightfold range in the basal values of plasma immunoreactive calcitonin, in spite of the presence of a relatively constant MCR, suggests that the variation in basal plasma calcitonin was due principally to variation in the endogenous secretion rate for calcitonin. 4. The results suggest that the endogenous secretion rate for calcitonin is low in normal subjects (mean 124 ± sem 24 μg/day), and give a basis for selecting the doses of calcitonin which can be considered physiological.

The aims of this study were to determine (1) whether acute suppression of bone formation could be evaluated after the administration of corticosteroids in man by quantitative bone histomorphometry; and (2) whether there were significant differences between the effects of prednisone and its analog deflazacort. Thirteen patients who needed high-dose corticosteroid therapy were randomly allocated to two groups of treatment (prednisone or deflazacort). Quantitative bone histomorphometry, using the technique of triple labeling, and biochemical measurements of bone turnover were studied. There were no differences in biochemical indices of bone turnover between prednisone and deflazacort at the beginning and end of the 15 days of treatment course. During corticosteroid treatment, there were no significant changes in biochemical indices of bone turnover but a significant decline in total alkaline phosphatase (P<0.01). Histomorphometric indices, as revealed by measurements of tetracycline interval and extent of labeling, showed no significant differences in either mineral apposition rate or bone formation rate in the two groups. We conclude that the acute glucocorticoid suppression of bone turnover by glucocorticoids is not detectable within the first 2 weeks of treatment by histomorphometric techniques. No differences in bone effects of prednisone and deflazacort were detected in this short-term study.

We assessed a method for the measurement of ultrasound velocity in cortical bone of the human tibia using a probe designed to minimize the effects of surrounding soft tissues. Of four different measurement values, the maximum velocity (average of the five highest readings) gave the lowest errors of reproducibility in relation to the population variance (standardized coefficient of variation=1.8%). The maximum velocity varied according to the tibial site measured and for practical reasons the mid-tibial site was chosen for further study. The short-term intra- and inter-observer reproducibilities (coefficients of variation) were 0.35% (n=22) and 0.50% (n=27) respectively. Long-term reproducibility over 4 months in 31 subjects was 0.68%. There was no significant difference in maximum ultrasound velocity between the dominant and non-dominant tibia in 78 women (3764±209 vs 3763±199 m/s). Tibial ultrasound velocity was significantly higher in 73 premenopausal women (3999±102 m/s) than in 129 women referred for assessment of postmenopausal osteoporosis (3780±168 m/s), 26 women with steroid-induced osteoporosis (3790±188 m/s) and 4 women with hyperparathyroidism (3575±261 m/s). In premenopausal women, ultrasound velocity did not correlate significantly with age, height, weight or body mass index. In women with postmenopausal osteoporosis, ultrasound velocity decreased with age after the menopause (r=-0.47,p<0.0001) and body weight exerted a weaker protective effect. The apparent annual decrease in velocity with age in postmenopausal osteoporosis (8.5 m/s) was comparable to the error of reproducibility. We conclude that the technique for measuring tibial ultrasound velocity is highly reproducible in relation to the distribution of values in the population and is sensitive to age- and osteoporosis-induced changes in bone. Further studies are required to examine its relationship to other indices of skeletal status to determine the biological and clinical relevance of the technique.

Fragility fractures are now recognized as a major public health problem. Although the prevalence of all fractures is similar among men and women, the vast majority of osteoporotic fractures occur in elderly women. These comprise vertebral compression fractures, Colles' fracture at the wrist and hip fracture, and to a lesser extent fractures at other sites. The fracture of greatest socioeco-nomic consequence in Europe is hip fracture, which increases exponentially in incidence with age. The reasons for differences in age- and sex-specific incidence relate in part to the lower bone density of women at the time of maturity (peak bone density) and the accelerated bone loss that occurs after the menopause. Women live significantly longer than men, so that the prevalence of osteoporosis amongst elderly women is six-fold that of men. The age-specific incidence of hip fracture is rising in men and women in many countries, and if the current trends in the United Kingdom continue then the number of hip fractures occurring each year will more than double over the next 20 years. There is a marked geographic distribution in the incidence of hip fractures, even in Europe. Indeed the differences in incidence between communities is greater than the differences in incidence between sexes within communities. This suggests that the importance of gonadal insufficiency in women has been overemphasized and that other factors, probably relating to genetic or lifestyle factors affecting peak bone density, account for ecological differences in incidence of hip fracture between communities.

The role of vitamin D in the prevention of hip fracture is controversial and protective effects appear to be confined to the institutionalized and elderly population. The aim of this study was to assess the interaction of age and body mass index (BMI) on the effects of vitamin D on the risk of hip fracture in the community. We studied 1634 women with low-energy fractures of the hip aged 50 years or older, and 3532 age-matched controls from 14 centres in six Mediterranean countries (the MEDOS study), with a structured retrospective questionnaire. The use of vitamin D supplements was associated with a modest and non-significant decrease in the risk of hip fracture (RR=0.74; 95% confidence interval (CI) 0.53–1.03;p=0.07). The risk reduction was influenced by age and body mass. Women aged above 80 years had a significant decrease in the relative risk of hip fracture (RR=0.63; 95% CI 0.40–0.98) as did women with a BMI below 20 kg/m2 (RR=0.45; 95% CI 0.24–0.84). Elderly women were more likely to have a low BMI but the elderly did not appear to benefit from vitamin D where their BMI was 20 kg/m2 or higher. The findings could not be explained by differences in sun exposure or in physical exercise. We conclude that the use of vitamin D for the prevention of hip fracture might usefully be targeted to the frail and elderly.