Alastair R. McLellan

Making the first fracture the last fracture: ASBMR task force report on secondary fracture prevention.

Fragility fractures are common, affecting almost one in two older women and one in three older men. Every fragility fracture signals increased risk of future fractures as well as risk of premature mortality. Despite the major health care impact worldwide, currently there are few systems in place to identify and “capture” individuals after a fragility fracture to ensure appropriate assessment and treatment (according to national guidelines) to reduce future fracture risk and adverse health outcomes. The Task Force reviewed the current evidence about different systematic interventional approaches, their logical background, as well as the medical and ethical rationale. This included reviewing the evidence supporting cost‐effective interventions and developing a toolkit for reducing secondary fracture incidence. This report presents this evidence for cost‐effective interventions versus the human and health care costs associated with the failure to address further fractures. In particular, it summarizes the evidence for various forms of Fracture Liaison Service as the most effective intervention for secondary fracture prevention. It also summarizes the evidence that certain interventions, particularly those based on patient and/or community‐focused educational approaches, are consistently, if unexpectedly, ineffective. As an international group, representing 36 countries throughout Asia‐Pacific, South America, Europe, and North America, the Task Force reviewed and summarized the international data on barriers encountered in implementing risk‐reduction strategies. It presents the ethical imperatives for providing quality of care in osteoporosis management. As part of an implementation strategy, it describes both the quality improvement methods best suited to transforming care and the research questions that remain outstanding. The overarching outcome of the Task Forces work has been the provision of a rational background and the scientific evidence underpinning secondary fracture prevention and stresses the utility of one form or another of a Fracture Liaison Service in achieving those quality outcomes 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.

SummaryThe 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.IntroductionOnly 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.MethodsA cost-effectiveness and budget-impact model was developed, utilising detailed audit data collected by the West Glasgow FLS.ResultsFor 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.ConclusionsFLSs 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.

Doctors and managers: a problem without a solution?

In preparing this theme issue on doctors and managers we were offered many sophisticated descriptions of the origin and nature of the tension between doctors and managers but fewer credible solutions. The fundamental problem is a paradox between calls for a common set of values and the need to recognise that doctors and managers do and should think differently. If managers suddenly became preoccupied with the needs of an individual patient, irrespective of the consequences for others or for their budget, then the health system would collapse. If doctors decided that their principal concern was to ensure the smooth running of the system and the delivery of policy irrespective of the consequences for the patient in front of them, then both the quality of care and public support would collapse. Doctors worry about patient outcomes. Managers worry about patient experience (which includes outcomes, but only as part of a mix to be met out of finite resources). Patients are, again, best served by a tension between the two. Admitting that this paradox …

Prospective, double blind, randomized, controlled trial of simvastatin in human fracture healing

Although statins are widely prescribed as cholesterol‐lowering drugs, a number of studies suggest that these compounds may have anabolic effects on bone. Our aim was to assess whether simvastatin affects the rate of fracture healing in humans. A prospective, double‐blind, randomized controlled trial was performed. Individuals who had sustained an undisplaced, extra‐articular fracture of the distal radial metaphysis were recruited from a trauma clinic. Patients were randomized to receive simvastatin 20 mg once daily or a placebo. Regular clinical and radiological follow‐up was undertaken for a 12 week period. Dual‐energy X‐ray absorptiometry assessment of bone mineral density was conducted at 2 and 12 weeks postinjury. Biochemical markers of bone turnover were assayed during the study period. Time to fracture union was defined as the time to cortical bridging in four cortices on plain radiographs. In addition, the rate of trabecular union was assessed. Eighty patients were recruited, of which 62 completed the study (31 in each group). Study cohorts were matched for age and gender. For patients receiving simvastatin therapy, the mean time to fracture union was 71.6 days (SD 22.2 days, SEM 3.8 days). This compared to 71.3 days (SD 21.3, SEM 4.1 days) for the control cohort (p = 0.6481). There was no significant difference between bone mineral density or bone biochemical markers between groups (p > 0.05). Despite promising results from in vivo and in vitro animal studies, simvastatin at a treatment dose of 20 mg once daily does not affect the rate of fracture healing in humans.

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 β-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 (Gsα, Giα1, Giα2, Giα3, Goα and β) 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

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.

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.

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

Aim of study: Guanine nucleotide regulatory (C) 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 (Gsα, Giα2 and p-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 [Gsα, Giα2 and P-subunits) were seen. However, in contrast to the observations in NIDDM, the studies of adenylyl cyclase function identified greater prostaglandin E-|-stimulated activity in hypertensive platelet membranes than in controls (88.8 versus 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.

Vertebral fracture assessment in patients presenting with incident nonvertebral fractures

Background  Patients with fractures should be prioritized for assessment for osteoporosis so that they can benefit from treatment for the secondary prevention of osteoporotic fractures. Assessment is seldom offered to patients with vertebral fractures because these fractures are typically not diagnosed. Vertebral fractures can be identified by vertebral fracture assessment (VFA) using current dual‐energy X‐ray absorptiometry (DXA) scanners.

DURATION OF ANTITHYROID ACTION OF METHIMAZOLE ESTIMATED WITH AN INTRAVENOUS PERCHLORATE DISCHARGE TEST

We have used a method based on a perchlorate discharge test to estimate the duration of antithyroid effect of two doses of methimazole (MMI). Six patients with diffuse toxic goitre took 5 mg MMI twice daily and six took 20 mg twice daily over the study period of 12 weeks. Biochemical control of hyperthyroidism was achieved in all patients and thyroid hormone supplementation was required by all of the patients in the higher dose group to avoid hypothyroidism. Discharge of radioiodine from the thyroid by perchlorate diminished in both groups with time after MMI. After 5 mg MMI, perchlorate discharge as a percentage of the 30‐min uptake (mean ± SD), was 81.7 ± 3.3% at 2.2 h, 69.3 ± 18.9% at 5.9 h, 22.6–23.4% at 13.4 h and 2.7–6.7% at 25.1 h. After 20 mg MMI, the discharge was 92.5 ± 1.9% at 2.2 h, 84.3 ± 8.8% at 6.3 h, 64.8 ± 24.1 % at 13.3 h and 26.9–29.4% at 25.1 h. Only four patients (one in the lower dose group) showed a detectable discharge at 25 h and one of the patients treated with the lower dose showed no discharge at 13 h. These estimates of the effect of MMI on thyroidal iodide organification are not in keeping with published thyroidal MMI concentrations which do not show a fall between 3–6 h and 17–20 h after carbimazole. The explanation for this disparity is not clear but may be based on a redistribution of thioureylenes within the thyroid with time after dosage. The present data suggest that once daily is not the optimum dosage interval for MMI with respect to its effect on the organification of iodide.