Effective secondary fracture prevention: implementation of a global benchmarking of clinical quality using the IOF Capture the Fracture® Best Practice Framework tool.

UNLABELLED: Fracture Liaison Services are the best model to prevent secondary fractures. The International Osteoporosis Foundation developed a Best Practice Framework to provide a quality benchmark. After a year of implementation, we confirmed that a single framework with set criteria is able to benchmark services across healthcare systems worldwide. INTRODUCTION: Despite evidence for the clinical effectiveness of secondary fracture prevention, translation in the real-world setting remains disappointing. Where implemented, a wide variety of service models are used to deliver effective secondary fracture prevention. To support use of effective models of care across the globe, the International Osteoporosis Foundation's Capture the Fracture® programme developed a Best Practice Framework (BPF) tool of criteria and standards to provide a quality benchmark. We now report findings after the first 12 months of implementation. METHODS: A questionnaire for the BPF was created and made available to institutions on the Capture the Fracture website. Responses from institutions were used to assign gold, silver, bronze or black (insufficient) level of achievements mapped across five domains. Through an interactive process with the institution, a final score was determined and published on the Capture the Fracture website Fracture Liaison Service (FLS) map. RESULTS: Sixty hospitals across six continents submitted their questionnaires. The hospitals served populations from 20,000 to 15 million and were a mix of private and publicly funded. Each FLS managed 146 to 6200 fragility fracture patients per year with a total of 55,160 patients across all sites. Overall, 27 hospitals scored gold, 23 silver and 10 bronze. The pathway for the hip fracture patients had the highest proportion of gold grading while vertebral fracture the lowest. CONCLUSION: In the first 12 months, we have successfully tested the BPF tool in a range of health settings across the globe. Initial findings confirm a significant heterogeneity in service provision and highlight the importance of a global approach to ensure high quality secondary fracture prevention services.

Capture the Fracture: a Best Practice Framework and global campaign to break the fragility fracture cycle.

UNLABELLED: The International Osteoporosis Foundation (IOF) Capture the Fracture Campaign aims to support implementation of Fracture Liaison Services (FLS) throughout the world. INTRODUCTION: FLS have been shown to close the ubiquitous secondary fracture prevention care gap, ensuring that fragility fracture sufferers receive appropriate assessment and intervention to reduce future fracture risk. METHODS: Capture the Fracture has developed internationally endorsed standards for best practice, will facilitate change at the national level to drive adoption of FLS and increase awareness of the challenges and opportunities presented by secondary fracture prevention to key stakeholders. The Best Practice Framework (BPF) sets an international benchmark for FLS, which defines essential and aspirational elements of service delivery. RESULTS: The BPF has been reviewed by leading experts from many countries and subject to beta-testing to ensure that it is internationally relevant and fit-for-purpose. The BPF will also serve as a measurement tool for IOF to award 'Capture the Fracture Best Practice Recognition' to celebrate successful FLS worldwide and drive service development in areas of unmet need. The Capture the Fracture website will provide a suite of resources related to FLS and secondary fracture prevention, which will be updated as new materials become available. A mentoring programme will enable those in the early stages of development of FLS to learn from colleagues elsewhere that have achieved Best Practice Recognition. A grant programme is in development to aid clinical systems which require financial assistance to establish FLS in their localities. CONCLUSION: Nearly half a billion people will reach retirement age during the next 20 years. IOF has developed Capture the Fracture because this is the single most important thing that can be done to directly improve patient care, of both women and men, and reduce the spiralling fracture-related care costs worldwide.

Fracture liaison services for the evaluation and management of patients with osteoporotic fracture: a cost-effectiveness evaluation based on data collected over 8 years of service provision.

SUMMARY: The cost-effectiveness of Fracture Liaison Services (FLSs) for prevention of secondary fracture in osteoporosis patients in the United Kingdom (UK), and the cost associated with their widespread adoption, were evaluated. An estimated 18 fractures were prevented and £21,000 saved per 1,000 patients. Setup across the UK would cost an estimated £9.7 million. INTRODUCTION: Only 11% to 28% of patients with a fragility fracture receive osteoporosis treatment in the UK. FLSs provide an efficient means to identify patients and are endorsed by the Department of Health but have not been widely adopted. The objective of this study was to evaluate the cost-effectiveness of FLSs in the UK and the cost associated with their widespread adoption. METHODS: A cost-effectiveness and budget-impact model was developed, utilising detailed audit data collected by the West Glasgow FLS. RESULTS: For a hypothetical cohort of 1,000 fragility-fracture patients (740 requiring treatment), 686 received treatment in the FLS compared with 193 in usual care. Assessments and osteoporosis treatments cost an additional £83,598 and £206,544, respectively, in the FLS; 18 fractures (including 11 hip fractures) were prevented, giving an overall saving of £21,000. Setup costs for widespread adoption of FLSs across the UK were estimated at £9.7 million. CONCLUSIONS: FLSs are cost-effective for the prevention of further fractures in fragility-fracture patients. The cost of widespread adoption of FLS across the UK is small in comparison with other service provision and would be expected to result in important benefits in fractures avoided and reduced hospital bed occupancy.

Coordinator-based systems for secondary prevention in fragility fracture patients.

The underlying causes of incident fractures--bone fragility and the tendency to fall--remain under-diagnosed and under-treated. This care gap in secondary prevention must be addressed to minimise both the debilitating consequences of subsequent fractures for patients and the associated economic burden to healthcare systems. Clinical systems aimed at ensuring appropriate management of patients following fracture have been developed around the world. A systematic review of the literature showed that 65% of systems reported include a dedicated coordinator who acts as the link between the orthopaedic team, the osteoporosis and falls services, the patient and the primary care physician. Coordinator-based systems facilitate bone mineral density testing, osteoporosis education and care in patients following a fragility fracture and have been shown to be cost-saving. Other success factors included a fracture registry and a database to monitor the care provided to the fracture patient. Implementation of such a system requires an audit of existing arrangements, creation of a network of healthcare professionals with clearly defined roles and the identification of a 'medical champion' to lead the project. A business case is needed to acquire the necessary funding. Incremental, achievable targets should be identified. Clinical pathways should be supported by evidence-based recommendations from national or regional guidelines. Endorsement of the proposed model within national healthcare policies and advocacy programmes can achieve alignment of the objectives of policy makers, professionals and patients. Successful transformation of care relies upon consensus amongst all participants in the multi-disciplinary team that cares for fragility fracture patients.

Guanine nucleotide regulatory protein levels and function in spontaneously hypertensive rat vascular smooth-muscle cells.

We compared G-protein levels and function in membranes from vascular smooth-muscle cells (VSMC) derived from mesenteric arteries from SHR, WKY and Wistar rats. Basal adenylyl cyclase activity was significantly reduced in SHR membranes compared with Wistar, but was similar to WKY. Isoproterenol stimulation (10(-4) M) was significantly lower in SHR membranes compared to WKY, but was similar to that in Wistar, which was also significantly lower than WKY. Forskolin (10(-4) M) and NaF (10(-2) M), resulted in a higher stimulatory response in SHR membranes. Biphasic effects of GTP on isoproterenol-stimulated membranes demonstrated unaltered Gi function in SHR membranes. No significant differences were seen in the levels of Gs alpha (44- and 42-kDa forms), Gi2 alpha and the beta-subunit in immunoblotting studies of the membranes. Amounts of Gq alpha/G11 alpha and Gi3 alpha were also unchanged. In conclusion, there are differences in adenylyl cyclase responses in SHR VSMC membranes which are not a consequence of altered levels of G-proteins, but may reflect genetic differences rather than effects of hypertension.

Altered G-protein expression and adenylate cyclase activity in platelets of non-insulin-dependent diabetic (NIDDM) male subjects.

Adenylate cyclase activity and levels of guanine nucleotide regulatory proteins (G-proteins) were compared in platelets from normal and non-insulin-dependent diabetic (NIDDM) male subjects. Whilst no differences were noted in basal and NaF-stimulated adenylate cyclase activities the degree of stimulation achieved by both forskolin and prostaglandin, E1 was lower by some 34 and 52% respectively, in platelet membranes from diabetic subjects compared with those from normal control subjects. Altered alpha 1-adrenoceptor-mediated inhibition of prostaglandin E1-stimulated adenylate cyclase activity was evident; it being some 34% lower in platelet membranes from diabetic subjects compared to controls. Analysis of G-protein alpha-subunits, using specific anti-peptide antisera, showed that platelets from all subjects exhibited the Gi-2 and Gi-3, but not the Gi-1 forms of the inhibitory G-protein 'Gi' and all expressed the 42 kDa species of alpha-subunit of the stimulatory G-protein Gs. Whilst platelets of diabetic subjects had levels of Gs which were comparable to those found in control subjects their levels of Gi-2 and Gi-3 were some 49 and 75%, respectively, of those found in platelets from control subjects. It is suggested that changes in adenylate cyclase functioning and G-protein expression may contribute to altered platelet functioning in non-insulin-dependent diabetic subjects.

Guanine nucleotide regulatory proteins in the spontaneously hypertensive rat.

We compared guanine nucleotide regulatory protein (G protein) levels and function in plasma membranes from resistance vessels (mesenteric arteries) isolated from spontaneously hypertensive (SHR) and normotensive Wistar rats. G protein function was deduced from studies of adenylate cyclase activity. Although the basal level of adenylate cyclase activity (+/- Mn2+ ions) was significantly greater in SHR membranes, addition of agents that function via the stimulatory G protein--i.e., NaF (10(-2) M), (-)-isoproterenol (10(-4) M), and prostaglandin E1 (10(-5) M)--resulted in a significantly lower stimulatory response in SHR membranes. Ligands that function via the inhibitory G protein--i.e., adrenaline (10(-5) M)/propranolol (10(-5) M) (this combination being equivalent to an alpha 2-receptor agonist), carbachol (10(-3) M), and serotonin (10(-5) M)--were responsible for only slight inhibitory responses in both SHR and Wistar rat membranes, which were not significantly different. Western blotting identified the presence of Gs, Gi2, and Gi3 alpha-subunits in rat vascular smooth muscle, but there were no differences in the levels of these G protein alpha-subunits found in SHR and Wistar rat plasma membranes. The levels of the beta-subunit in the two sets of membranes were also similar. In conclusion, there is a reduced response in adenylate cyclase activity to agents that function via the stimulatory G protein in SHR membranes. However, this is not a consequence of altered levels of the different G protein subunits.

Effects of dexamethasone on G protein levels and adenylyl cyclase activity in rat vascular smooth muscle cells.

Dexamethasone administration in vitro has been shown to increase adenylyl cyclase activity in vascular smooth muscle cells (VSMC) from renal arteries and in non-vascular cell lines. To investigate whether G proteins are involved in this response, cultured VSMC from mesenteric arteries of Sprague-Dawley rats were incubated in the presence and absence of 10 nM dexamethasone for 24 and 48 h. Basal and stimulated adenylyl cyclase activities were increased by approximately 50% after treatment with dexamethasone. The changes were neither specifically associated with ligands which stimulate adenylyl cyclase catalytic unit via Gs (isoproterenol and prostaglandin E1) nor with guanylylimidodiphosphate (0.1 nM), which inhibits the catalytic unit via Gi. This suggests that dexamethasone enhances adenylyl cyclase activity through changes at the level of the catalytic unit, rather than through the G proteins which modulate its activity. No differences were seen in immunoblotting studies of the levels of Gi alpha 2, Gs alpha, Gi alpha 3 and beta subunits. Similarly, dexamethasone had no effect on the expression of mRNA for Gi alpha 2 and Gs alpha. The results indicate that glucocorticoid-induced increases of adenylyl cyclase activity are due to changes at the level of the adenylyl cyclase catalytic unit rather than alteration of the levels or turnover of Gs alpha, Gi alpha 2, Gi alpha 3 and beta subunits in the membranes of VSMC.

G-proteins in experimental hypertension: a study of spontaneously hypertensive rat myocardial and renal cortical plasma membranes.

OBJECTIVE: Spontaneously hypertensive rat (SHR) myocardium is known to exhibit reduced beta-adrenergic agonist-stimulated adenylyl cyclase activity. As G-proteins play a pivotal role in transducing information from the receptor to adenylyl cyclase, a study was undertaken to assess whether changes in G-protein expression and functioning could explain this. DESIGN: Studies were performed in plasma membrane homogenates from vascular tissue (myocardium) from 11-week-old SHR (weighing 255 g) and control rats from both Wistar-Kyoto (WKY) and Wistar strains. Similar studies were performed in non-vascular tissue (renal cortical plasma membranes) to assess whether any observed changes are part of a more widely distributed membrane defect. METHODS: G-protein function was inferred from studies of adenylyl cyclase activity and levels of G-protein subunits (Gs alpha, Gi alpha 1, Gi alpha 2, Gi alpha 3, Go alpha and beta) were assessed by immunoblotting. RESULTS: Differences in adenylyl cyclase activity were seen in SHR compared with WKY rat myocardium: in WKY rats adenylyl cyclase activity was greater than in SHR under forskolin-stimulated conditions and in the presence of fluoride and several ligands which couple to the catalytic unit of adenylyl cyclase via Gs, including the receptor-linked species prostaglandin E1, glucagon and isoproterenol. However, with the exception of forskolin-stimulated activity, which in SHR was greater than in Wistar rats, SHR myocardial adenylyl cyclase activities were similar to those in Wistar rat membranes. Immunoblotting studies showed similar levels of G-protein subunits in all three strains. Studies of renal cortical plasma membranes failed to identify any differences in adenylyl cyclase activity or in G-protein subunit levels. CONCLUSIONS: SHR, WKY rats and Wistar rats exhibit differences in myocardial adenylyl cyclase activity which are not seen in renal cortical plasma membranes. These are not related to hypertension or to differences in G-protein levels, and probably reflect strain differences in Gs function.

G-proteins in essential hypertension: a study of human platelet plasma membranes.

AIM OF STUDY: Guanine nucleotide regulatory (G) proteins act as key signal transducers for many hormones, growth factors and neurotransmitters, and have been shown to have an important influence on platelet function. As abnormal G-protein levels and activity have been reported in platelets from human non-insulin-dependent diabetics (NIDDM) we studied G-protein function in essential hypertension, a condition which is also associated with insulin resistance and in which abnormal platelet function has been reported. METHODS: G-protein function was deduced from studies of adenylyl cyclase activity in platelet membrane preparations from 14 untreated essential hypertensives and 14 controls matched as far as possible for age and sex. Levels of G-protein subunits (Gs alpha, Gi alpha 2 and beta-subunits) were assessed by immunoblotting, using platelets from 15 subjects with untreated essential hypertension and 15 controls. RESULTS: No changes in levels of G-proteins (Gs alpha, Gi alpha 2 and beta-subunits) were seen. However, in contrast to the observations in NIDDM, the studies of adenylyl cyclase function identified greater prostaglandin E1-stimulated activity in hypertensive platelet membranes than in controls (88.8 verus 72% stimulation, P = 0.018). This may have a physiological basis in protecting cells against a Ca2+ overload. CONCLUSION: These data are in opposition to the theory that a common defect in G-proteins can explain the association between hypertension and NIDDM.

Bone density and antiepileptic drugs: a case-controlled study.

This case-controlled study explored the relationship between bone mineral density (BMD) and long-term treatment with antiepileptic drugs (AEDs) in older adults with epilepsy. Seventy-eight patients (47 post-menopausal females, 31 males, aged 47-76 years) with epilepsy participated in the study. Each had only ever received treatment with either enzyme-inducing (n = 52) or non-inducing (n = 26) AEDs. Individuals were matched for age, sex, height and weight with a drug-naive control. All patients underwent bone densitometry at the lumbar spine and femoral neck and had blood sampling and urine collected for a range of bone markers. Male patients had lower BMD than controls at the lumbar spine (P < 0.01) and neck of the femur (P < 0.005). Female patients had significantly reduced bone density at the femoral neck (P < 0.05) only. AED usage was independently associated with an overall reduction in bone density at femoral sites and contributed to just over 5% of the variance at the femoral neck. Duration of treatment and type of AED were not independent factors for reduction in BMD. This case-controlled study supports the hypothesis that long-term AED therapy is an independent risk factor for reduced BMD in epileptic patients. Adults receiving treatment for epilepsy are at higher risk of osteoporosis and should be offered bone densitometry.

Characteristics of males over 50 years who present with a fracture: epidemiology and underlying risk factors.

Osteoporosis and fragility fractures in men constitute a considerable burden in healthcare. We have reviewed 2035 men aged over 50 years with 2142 fractures to clarify the epidemiology of these injuries and their underlying risk factors. The prevalence of osteoporosis ranged between 17.5% in fractures of the ankle and 57.8% in those of the hip. The main risk factors associated with osteoporosis were smoking (47.4%), alcohol excess (36.2%), body mass index < 21 (12.8%) and a family history of osteoporosis (8.4%). Immobility, smoking, self-reported alcohol excess, a low body mass index, age >/=72 and loss in height were significantly more common among men with fractures of the hip than in those with fractures elsewhere.

Hypertension, insulin, and atherogenesis.

Essential hypertension and non-insulin-dependent diabetes mellitus are both associated with hyperinsulinemia and it has been proposed that this might contribute to increased atherogenesis in these conditions. In hypertension, hyperinsulinemia probably reflects reduced insulin-stimulated glucose uptake, but the reason for this, and the contribution of hyperinsulinemia (or of resistance to insulin) to the development of hypertension and atheroma, remains unclear. As well as glucose uptake, insulin has important effects on other aspects of cell function; for example, the hormone is an important regulator of the expression and function of the major inhibitory guanine nucleotide binding protein Gi. In insulin deficiency, Gi levels and function are greatly reduced and are restored by insulin treatment. We have examined whether in human hypertension or in animal models of hypertension there is evidence of abnormal regulation of this protein. Platelet membranes from humans and rat membranes from a range of tissues, including myocardium and vasculature, were studied. No alteration in Gi levels or function was found in these studies, and there is no evidence that this aspect of insulin action on cell function is abnormal. Insulin is also involved in the regulation of cell growth, and in vascular smooth muscle cells there is evidence that this effect involves action of other growth factors, such as PDGF. If the growth regulatory actions of insulin are also unimpaired despite limitation of insulin-stimulated glucose uptake, chronic hyperinsulinemia could lead to increased vascular smooth muscle cell growth and contribute to development of atheroma.

Lack of effect of spironolactone on hair shaft diameter in hirsute females.

Because of its anti-androgenic activity spironolactone 50-200 mg daily is advocated widely for the management of female hirsutism but this practice lacks adequately controlled experimental support. In a double-blind placebo controlled study of the efficacy of spironolactone 100 mg daily in idiopathic hirsutism we were unable to demonstrate objective benefit from spironolactone treatment. The mean effect of spironolactone given over a 9 month period was to increase hair shaft diameter by +15% with 95% CI (-0.4% to +29%). In addition there were no changes in circulating serum androgen concentrations.

Clinical response of thyrotropin-secreting macroadenoma to bromocriptine and radiotherapy.

A patient presenting with hyperthyroidism was treated initially with antithyroid drugs and subsequently radioiodine. Thereafter he was noted to have inappropriately elevated thyrotropin. A bitemporal visual field defect was noted and CT scan confirmed the presence of a pituitary tumour. TSH was elevated and unresponsive to TRH stimulation. alpha subunit was not elevated. Long-term bromocriptine therapy (doses up to 50 mg/day) resulted in partial, but incomplete suppression of thyrotropin secretion. Following radiotherapy there was resolution of the visual field defect; the TSH, however, remains elevated at greater than 20 mU/l. Radiotherapy and bromocriptine may provide a clinically useful alternative to pituitary surgery in patients with TSH-secreting macroadenoma with suprasellar extension.

Elderly patients with suppressed serum TSH but normal free thyroid hormone levels usually have mild thyroid overactivity and are at increased risk of developing overt hyperthyroidism.

The clinical and biochemical characteristics of 15 elderly patients with low levels of thyrotrophin (TSH) (< 0.1 mU/L) but normal free tri-iodothyronine (T3) and free thyroxine (T4) (group S) were compared with 10 euthyroid subjects (group E) and 10 hyperthyroid patients (group T). Free T3 and free T4 were significantly higher (p < 0.05) in group S (6.3 +/- 0.5 and 18.6 +/- 1.0 pmol/l, respectively) than in group E (4.6 +/- 0.3, 12.6 +/- 0.6). In common with elderly hyperthyroid patients (group T), patients in group S had few signs or symptoms of thyrotoxicosis, but the Wayne score (clinical index of hyperthyroidism) was higher in group S than in euthyroid subjects (p < 0.05). Thyroid microsomal, thyroglobulin or thyrotrophin receptor antibodies were common in group T (n = 9) but not in groups S (n = 2) or E (n = 1). This suggests a low prevalence of Graves' disease in group S compared to group T. Combined thyrotrophin releasing hormone (TRH; 200 micrograms i.v.) and gonadotrophin releasing hormone (GnRH; 100 micrograms i.v.) tests were performed; no cases of low TSH due to hypopituitarism were identified in group S. During a mean of 7.9 (4-12) months of observation TSH reverted to the normal range (> 0.2 mU/L) in 7 of 15 patients in group S; thyroid hormone concentrations rose above the normal range in four, however, only two patients required treatment for hyperthyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)

Growth hormone, body composition and somatomedin C after treatment of acromegaly.

Acromegaly is associated with abnormal indices of body composition (as determined by exchangeable sodium, exchangeable potassium and total body water estimations) which may be corrected by treatment. We related these indices of body composition to the attained growth hormone levels (mean of five daytime values) in 42 treated acromegalics. Somatomedin C was measured in 30 subjects. The mean duration of treatment was 7.7 years (range 1-26). Exchangeable sodium, potassium and total body water were significantly lowered by treatment. After treatment of acromegaly subjects whose growth hormone level was below 5 mU/l achieved normal body composition more often than those with higher levels. Growth hormone concentration of below 5 mU/l after treatment should be regarded as more appropriate index of control of acromegaly than the higher levels previously recommended.

Effect of hyperthyroidism on bronchial reactivity in non-asthmatic patients.

Thyrotoxicosis may be associated with deterioration in asthma. To determine whether bronchial reactivity to histamine is increased in hyperthyroidism 10 thyrotoxic non-asthmatic patients were assessed before and after treatment of their thyrotoxicosis. No significant change in bronchial reactivity was found after treatment.

Generalised peripheral nerve dysfunction in acromegaly: a study by conventional and novel neurophysiological techniques.

Twenty four patients with clinical, radiological and biochemical evidence of acromegaly were investigated by a number of independent neurophysiological tests. Two-thirds of the patients showed evidence of generalised peripheral nerve dysfunction. A significant correlation was found between total exchangeable body sodium, an indicator of disease activity, and the severity of the neuropathy. The generalised peripheral nerve abnormality was found to occur independently of the associated carbohydrate intolerance human growth hormone levels and other endocrinological dysfunction in this disorder.