A landmark study from the US has shattered more than 40 years of conventional thinking about the causes of asymptomatic diverticulosis (AD).

Doctors have long believed a high-fibre diet reduced the risk of developing the condition since seminal research was published in the late 1960s. But the new paper, published in Gastroenterology, provides strong evidence that the opposite is true.

The cross-sectional study of over 2,000 people aged from 30 to 80 years found the quartile with the highest fibre intake had around 30 per cent higher rates of the condition compared with the lowest.

Risk increased when calculated based on total fibre intake, fibre from grains, soluble and insoluble fibre.

Development of the condition — which affects roughly one-third of American adults aged over 60 and can cause significant complications — was also commonly thought to be related to infrequent bowel movements.

This was likewise turned on its head by the study, which found subjects with more than 15 bowel movements per week were 70 per cent more likely to develop AD than those with less than seven per week.

The authors drew on the results to urge reconsideration of dietary recommendations: “Practice guidelines recommend a diet high in fruit and vegetable fibre to prevent the development of colonic diverticulosis. Based on our results … [these] diet recommendations to patients should be reconsidered.”

But such action would be premature, argued Dr Lisa Strate from the University of Washington. Though the new study provided thorough evidence that a high-fibre diet promoted the development of the condition, the bulk of existing evidence suggested fibre may help prevent diverticular complications, she wrote in an accompanying editorial.

“These complications, and not diverticulosis itself, result in the bulk of health and economic burden of this disease,” she wrote.

“Given the other health benefits of dietary fibre, further evidence is needed before altering dietary recommendations in patients without diverticulosis.”

Gastroenterology,
2012; doi: 10.1053/j.gastro.2011.10.035

The Skindex-29 quality of life measure displays better sensitivity to the clinical severity of psoriasis and more sensitivity to change than other commonly used quality of life (QoL) measures, new research shows.

Dermatologists from Spain and Australia compared the characteristics of the Skindex-29 Dermatology Life Quality Index (DLQI), Psoriasis Disability Index (PDI) and the Medical Outcome Study Short Form 36 (SF-36), in 380 patients with mild-to-severe psoriasis attending dermatology clinics.

Forty of the patients had severe psoriasis, 32 per cent moderate and 24 per cent had mild disease. All of the patients completed Skindex-29, 144 filled out DLQI, 135 PDI and 100 completed SF-36.

They found that only the symptoms scale of Skindex-29 had a low but statistically-significant correlation factor with severity, suggesting that the instrument was assessing more constructs than clinical severity.

“It seems important that QoL instruments have some correlation with clinical severity, but they should also measure other constructs in the disease,” the authors wrote in the British Journal of Dermatology.

Of interest, they noted SF-36 detected impairments in males’ QoL that Skindex-29, DLQI or PDI did not detect.

“Skindex-29 has better sensitivity to clinical severity and probably more sensitivity to change than the other instruments, and covers all the main aspects of the other three QoL instruments… the combination with SF-36 would make sense to increase the sensitivity to QoL impairment,” they concluded.

British Journal of Dermatology 2012; DOI: 10.1111/j.1365-2133.2012.10806.x

Daily intake of enriched skimmed-milk powder can reduce the number of flares in patients with poorly controlled gout, a randomised trial has concluded.

The researchers investigated 120 patients, mostly middle-aged Caucasian men, who had experienced at least two gout flares in the previous four months.

They were randomised to drink a daily vanilla shake for three months, containing either lactose powder control, skimmed-milk powder control, or skimmed-milk powder enriched with a glycomacropeptide (GMP) and a milk fat extract (labelled G600). The two additives had previously been shown to have anti-inflammatory effects in experimental models of gout.

The frequency of gout flares was reduced in all three groups, but the decline was greatest in those randomised to GMP/G600.

“Greater improvements were also observed in pain and fractional excretion of uric acid, with trends to greater improvement in tender joint count,” the researchers said.

Similar adverse event rates and discontinuation rates were observed in all three groups.

Dietary modification was frequently recommended as a strategy to prevent and treat gout, but this was the first reported randomised controlled trial of dietary therapy for active gout, they said.

Observational studies had suggested a clear relationship between higher intakes of low-fat dairy products and a lower risk of developing gout, and short-term studies had shown that large amounts of milk proteins or skimmed milk had a urate-lowering effect. In the present study, however, changes in urate levels were insufficient to explain the benefits of the low doses of milk products that were administered.

The results of this proof-of-concept trial could not yet be generalised to all patients with gout, the researchers warned.

“The patients in this study had poorly-controlled gout with high flare-rates, inadequately controlled serum urate and relatively low use of allopurinol,” they said.

Annals of the Rheumatic Diseases
doi: 10.1136/annrheumdis-2011-200156

Researchers have identified a link between regular black tea consumption and lower blood pressure (BP).

The double-blind trial of 95 men and women with normal to high-normal BP at baseline found a group who drank three cups of tea per day for six months had lower systolic and diastolic BP than a group given a placebo.

Published in the Archives of Internal Medicine, the study found the tea-drinking group experienced an average 2.7mmHg drop in systolic BP at three months and a 2mmHg drop at six months.

Previous studies have identified no relationship between black tea intake and blood pressure.

The authors said this was down to their shorter duration and a lack of sensitivity in testing.

“A large proportion of the general population have BP within the range included in this trial, making results of the trial applicable to individuals at increased risk of hypertension,” the authors wrote.

Arch Intern Med.
2012;172(2):186-188. doi:10.1001/archinte.172.2.186

Being female, disabled, having a psychiatric history and ‘doctor-hopping’ are some of the predominant characteristics of patients with delusional infestations, a new study finds.

The largest case series of delusional infestation from one institution found a female to male ratio of 2.89:1, with nurses and teachers over-represented.

Of 147 patients who presented with animate (worms and insects) and inanimate delusional infestations, 81 per cent of patients had prior psychiatric conditions, with depression being the most prevalent (74 per cent).

Some 33 per cent of delusional infestation patients who presented at the Mayo Clinic between 2001 and 2007 were self-described as disabled, with 16 patients owing their disability to their delusions.

Journal of the American Academy of Dermatology 2012; doi:10.1016/j.jaad.2011.12.012

The diabetes drug metformin, previously linked with reduced pancreatic cancer risk, has been found by a new large-scale study to lower risk in women only.

Research published in the American Journal of Gastroenterology indicated women who have taken 30 or more courses of metformin have roughly half the risk of developing pancreatic cancer (CI 0.23-0.80), but found no such relationship in men.

The results contradicted a 2009 study that associated five years’ or more metformin therapy with a 70 per cent decreased risk of developing pancreatic cancer, regardless of sex (CI 0.13-0.69).

The authors of the new research — the subjects of which had an average age of 70 — pointed out that with only 29 exposed cases and 27 controls, the former study was small compared with the 2,763 patients and 16,578 matched controls of the new.

That the earlier study did not stratify according to gender was another limitation, the authors added.

They said the result was unexpected and “could not be explained by use of oestrogens”. Since there was “no obvious patho-physiological explanation”, the results should be taken with caution, they said.

Consistent with earlier findings, the researchers found the long-term use of sulfonylureas was associated with a roughly doubled risk of pancreatic cancer (CI 1.32-2.720) and long-term insulin use with a more than doubled risk (CI 1.34-3.92).

However, short-term use of metformin, sulfonylureas, or insulin was not related to increased pancreatic cancer risk, they said.

American Journal of Gastroenterology, 2012; doi: 10.1038/ajg.2011.483

‘Patients given combined therapy from the start of treatment responded better than those given monotherapy’

Prof Eoin O’Brien looks at the benefits of aliskiren in the treatment of hypertension but says it should not be prescribed with ACE inhibitors or ARBs in diabetic patients.

Aliskiren (available in Ireland as Rasilez and Rasilex HCT) is the first in a class of drugs called direct renin inhibitors. The earliest efficacy studies were conducted by my department in Beaumont Hospital in 2001 for Speedel Pharma.

When its efficacy in reducing blood pressure over 24 hours was established, Novartis marketed aliskiren as a new class of drug for the treatment of hypertension, which was approved by the US Food and Drug Administration (FDA) in 2007 either as monotherapy or in combination with other medications.

The efficacy and safety of aliskiren has been investigated in clinical studies in more than 57,000 patients.

Renin cleaves angiotensinogen to angiotensin I, which is converted by the angiotensin-converting enzyme to angiotensin II. Angiotensin II increases blood pressure by causing vasoconstriction and increased production of aldosterone from the adrenal cortex, which causes the tubules of the kidneys to increase reabsorption of sodium and water, leading to an increase in plasma volume. Aliskiren prevents the conversion of angiotensinogen to angiotensin I, thereby lowering blood pressure.

ACCELERATE and ALTITUDE
The ACCELERATE study, reported in The Lancet last year, was a double-blind, randomised, parallel-group superiority trial performed in 10 countries, in which hypertensive patients were randomly assigned to treatment with aliskiren plus placebo, the calcium-channel blocker (CCB) amlodipine plus placebo, or aliskiren plus amlodipine.

Patients given combined two-drug therapy from the start of treatment responded better than patients initially given monotherapy, and those who later switched from monotherapy to combination therapy improved their response, but not to the same level as those who began with combination therapy.

In an accompanying comment in The Lancet, ACCELERATE was heralded as the first study to show that starting on combination therapy helps patients to achieve blood pressure goals faster than initial monotherapy.  So the stage was set for Novartis to combine aliskiren with other blood pressure-lowering drugs and approval for this was given by the FDA.

Despite this, aliskiren has been prescribed generally as a fourth-line hypertensive agent in patients with resistant hypertension. Nonetheless, total sales of aliskiren-based products for the first nine months of 2011 were US$449 million (€348.1 million, 1 per cent of Novartis Group sales).

So far, so good. But just before Christmas, Novartis announced termination of the multinational ALTITUDE study to evaluate the potential benefits of aliskiren with an angiotensin-converting-enzyme-inhibitor (ACEI) or an angiotensin-receptor-blocker (ARB) to reduce the risk of cardiovascular and renal events in 8,606 patients (recruited from 36 countries) with type II diabetes, reduced renal function and a previous cardiovascular event.

In December 2011, the data safety and monitoring board (DSMB) recommended termination of the study because the aliskiren-treatment group experienced an increased incidence of non-fatal stroke, renal complications, hyperkalemia and hypotension. The DSMB concluded that patients were unlikely to benefit from aliskiren added to standard antihypertensive therapy. These findings represent a major setback for a drug that had once been considered to have significant potential as a new class of treatment for hypertension.

Prof Eoin O'Brien: 'The recent introduction of flexipills providing a range of doses for combinations of ARBs or ACEIs with other drug classes makes combination treatment very much easier for the patient'

Aliskiren with ACI or ARB
A press release from Novartis stated: “Novartis is in ongoing discussions with health authorities worldwide about the implications of the findings from ALTITUDE for patients.” But, “as a precautionary measure, Novartis will cease promotion of Rasilez-based products for use in combination with an ACE inhibitor or ARB”.

The Irish Medicines Board refers website queries to the European Medicines Agency (EMA) Press Release (22 December, 2011), which states that the EMA “is reviewing aliskiren-containing medicines, to assess the impact of data coming from the ALTITUDE study on the balance of benefits and risks of these medicines in their approved indication” and recommends in the meantime “as a precautionary measure, that doctors should not prescribe aliskiren-containing medicines to diabetic patients in combination with ACE inhibitors or ARBs”.

The message is therefore clear for diabetic patients. Patients with diabetes on aliskiren alone or in combination with HCTZ, who are not on an ACEI or ARB, need not modify treatment if blood pressure control is satisfactory. However, diabetic patients who are on aliskiren alone or in combination with HCTZ and are also on an ACEI or ARB, should stop the aliskiren-based drug.

The question to be answered in the ongoing analysis is what the implications are for non-diabetic patients who are on treatment with aliskiren in combination with an ACEI or ARB. The results of the ALTITUDE study must raise the question as to how suitable these combinations are in the overall treatment of hypertension.

Pending the results of further analyses, perhaps the wisest course would be to keep aliskiren in reserve only for hypertension that has proven resistant to combination treatment with diuretics, ACEIs and ARBs, CCBs and the newer beta-blockers in non-diabetic patients.

The recent introduction of flexipills providing a range of doses for combinations of ARBs or ACEIs with other drug classes makes combination treatment very much easier for the patient, with the likelihood of improved compliance and more efficient blood pressure control.

• Prof Eoin O’Brien, Professor of Molecular Pharmacology, Conway Institute, University College Dublin.

Shoulder pain is the third most common cause for musculoskeletal consultation in primary care

Edel Comer and Victoria Percy look at the physiotherapy management of common shoulder-joint problems in the primary care setting.

Shoulder pain is the third most common cause for musculoskeletal consultation in primary care. Self-reported shoulder pain has a prevalence of 16 per cent, which rises to 26 per cent in the elderly. This article discusses the diagnostic and evidence-based management of shoulder pathology, including the conditions that respond well to physiotherapy and the appropriate pathway of care.

The shoulder (glenohumeral joint) is a synovial ball-and-socket articulation in which the freedom of movement has been developed at the expense of stability. It demonstrates a unique functional balance between mobility and stability.

Successful function depends on the interaction of the shoulder girdle articulations, cervical spine and thoracic spine. Imbalance of the static and dynamic components supporting these joints can result in microtrauma and pathology. To ensure effective management of shoulder pathologies, it is essential to consider the interaction of spinal, neuro-meningeal, musculotendinous and capsuloligamentous structures in the function of the shoulder complex.

Due to the complexity of the joint and surrounding structures, dysfunctions often co-exist and the primary diagnosis may not always be clear. This is what makes this joint so difficult to assess and manage efficiently. It is of paramount importance to recognise and exclude many non-musculoskeletal and spinal causes of shoulder pain.

Assessment and management
There have been some attempts to standardise assessment guidelines for shoulder pain, but treatment standards are still evolving. There are often conflicting criteria defining the same conditions, making it difficult to review the evidence. Soft-tissue lesions are the most common cause of shoulder pain, with 75 per cent of patients presenting with impingement or rotator-cuff tendinopathy. The occurrence/presentation of soft-tissue lesions increases with age, as tendon tissue progressively weakens or degenerates. However, repeated microtrauma or overuse from work-related or athletic activity can also cause soft-tissue problems in all age groups. It should be noted that the incidence of adhesive capsulitis (frozen shoulder) is relatively low at 15 per cent.

Overall, patients with shoulder pain of musculoskeletal origin have been shown to respond well to physiotherapy intervention

Shoulder-impingement syndrome has been described as any reduction in the sub-acromial space compromising the passage of the soft tissues through this area, including rotator cuff tendons, bursa and long head of biceps. There are many causes of symptoms of shoulder impingement, including rotator-cuff pathology, acromio-clavicular joint dysfunction and underlying gleno-humeral instability. The Neer/Welsh Classification (1977) is widely used and accepted within the literature and provides a comprehensive categorisation of the different stages of impingement syndrome.

The classification of shoulder impingement is as follows:
•    Stage 1 – subacromial oedema and haemorrhage, usually in under 25s and usually due to overuse;
•    Stage 2 – fibrosis and tendonitis, usually in 25-  to 40-year-olds, following repeated episodes of mechanical inflammation and irreversible by conservative treatment;
•    Stage 3 – bony changes and cuff tears, usually in the 40+ age group.
Diagnostic imaging of the shoulder is indicated in the obvious circumstances of suspected fracture/dislocation but can also be useful as outlined below:
i) Subacromial impingement syndrome
•    X-rays — three views (AP/sub-axial/outlet);
•    MRI/ultrasound — for full-thickness cuff tears and candidates for decompression surgery;
•    MRA (arthrogram) — partial-thickness tears and superior labrum from the anterior to posterior tear (SLAP lesion).
ii) Joint instability
•    X-rays — two views (AP/sub-axial);
•    MRA (contrast arthrogram) for complex instabilities or failed rehabilitation. Rarely required.
iii) Adhesive capsulitis
•    X-rays — AP view (30 degrees oblique or add sub-axial).

Summary
The cause of shoulder pain is difficult to establish and therefore can be problematic to manage effectively. In clinical practice, physiotherapy of the shoulder is based on symptom relief while also identifying and treating the underlying causes such as instability, postural dysfunction, muscle imbalance, cuff dysfunction and poor ergonomics.

Prognostic indicators for outcome of this patient group highlights the importance of early and effective intervention to reduce initial pain levels and prevent persistent disability. It has also been reported that only approximately 50 per cent of all new episodes of shoulder pain presenting in primary care show complete recovery within six months.

Overall, patients with shoulder pain of musculoskeletal origin have been shown to respond well to physiotherapy intervention. In this article, we have focused on the most commonly-presenting conditions, but it is also important to bear in mind other sources of shoulder dysfunction that respond well to physiotherapy — for example, proximal humeral fractures and patients presenting with shoulder lesions/dysfunction post breast reconstruction surgery or mastectomy.

Consequently, a further comprehensive physiotherapy  assessment may be advocated for appropriate patients for a more in-depth musculoskeletal assessment, treatment and onward referral when indicated.

• Edel Comer MISCP, MCSP and Victoria Percy MISCP, MCSP.
• See www.findaphysio.ie.

Hip fractures have more serious consequences and there are high rates of mortality and morbidity

In his latest Clinical Update, Gary Culliton examines recent developments in the field of osteoporosis, including diagnostic tools and issues related to glucocorticoids.

Osteoporosis is a progressive, systemic skeletal disease characterised by low bone mass and micro-architectural deterioration of bone tissue. There is a consequential increase in bone fragility and susceptibility to fractures. There are changes in bone density with increasing age. Peak bone mass is reached in the 30s, according to Prof Oliver FitzGerald, Consultant Rheumatologist and National Programme Lead in Rheumatology. “Thereafter, there’s a fall in bone mass — at a more pronounced rate following menopause,” he added.

Risks are also present for males. Hip fractures have more serious consequences and there are high rates of mortality and morbidity, said Prof FitzGerald.
Osteoporosis can be diagnosed using DXA (dual-emission x-ray absorptiometry) to measure bone mineral density (BMD). Overall, assessing risk for a major osteoporotic fracture — using the World Health Organization fracture risk assessment tool (FRAX) — is a more clinically-relevant measure. FRAX estimates the 10-year probability of hip fracture and major osteoporotic fracture in untreated patients. This uses bone mineral density T-score. It takes into account clinical risk factors for osteoporosis — including increasing age, sex (females more than males), low body weight, height, previous fracture, parental history of fractured hip, current smokers and alcohol consumption (more than three units per day).

A full blood count and an erythrocyte sedimentation rate (ESR) test are typically considered. Bone function tests are done (for serum concentrations of calcium, phosphate, alkaline phosphatase and vitamin D). Evidence of chronic diseases — such as renal and liver function abnormalities — is sought.

Basic investigations also include examinations of thyroid function, Prof FitzGerald said.

Eye surgery, including for cataracts, can be important in preventing falls. Regular weight-bearing and resistance exercise helps to retain bone mass and prevents bone loss. Increasing calcium intake may slow the rate of bone loss — but not to a substantial degree. It is not a substitute for other bone-sparing therapies in patients with established osteoporosis.

Vitamin D should be administered routinely to frail, elderly patients who have poor diet and lack of sunlight. Inadequate vitamin D may result in secondary hyperparathyroidism and increased risk of fracture and osteomalacia.

“There’s increasing understanding of the role of vitamin D in contributing to imbalance and muscle weakness and possibly other defects in the immune system,” said Prof FitzGerald.

It has been shown that daily supplementation with 1.2g of calcium and 800IU of cholecalciferol over three years to frail, elderly patients in nursing homes substantially reduces the risk of hip fractures. Conclusive evidence in the community is required.

“There’s certainly a role for bisphosphonates,” said Prof FitzGerald. “All of the bisphosphonates remain first-line treatment.” Bisphosphonates are potent inhibitors of bone resorption and are the most prescribed medication in the management of osteoporosis (Liberman UA, 2006; McGowan B et al, IMJ 2008).

All the authorised bisphosphonates (alendronate, risedronate, ibandronic acid, zoledronic acid and etidronate) reduce the risk of vertebral fractures.

(Sambrook P, Cooper C, The Lancet, 2006; MacLean C et al, Annals Internal Medicine 2008).

Alendronate, risedronate and zoledronic acid have also been shown to reduce the risk of non-vertebral fractures, including hip fractures (National Osteoporosis Guideline Group; Drug and Therapeutic Bulletin 2008).

Post-hoc analysis revealed reduced non-vertebral fractures for ibandronic acid (National Osteoporosis Guideline Group).

Zoledronic acid is a once-a-year IV infusion given slowly, which usually takes at least 15 minutes. Ibandronate also acts on bone and has an inhibitory effect on osteoclasts. It decreases bone resorption and decreases risk of fractures.

Bisphosphonates have been used in trial extensions for up to 10 years, which suggest that bone quality remains normal and that reductions in fracture risk are sustained for as long as treatment continues (Liberman UA, 2006). However concern has been expressed about over-suppression of bone turnover, leading to fractures later (Boonen S et al, J Intern Med 2008).

Further assessment of prolonged use is required and the optimum duration of therapy remains unclear. (Edwards B et al, Lancet Oncology 2008; Sambrook P, Cooper C, The Lancet 2006).

Corticosteroid prescribing is linked to bisphosphonates by Irish study

A study of Irish prescribing patterns identified that the longer a patient was prescribed the corticosteroid prednisolone, the greater the likelihood of subsequently being prescribed a bisphosphonate (B McGowan et al. IMJ 2008). Approximately 65 per cent of patients (total 60,000) were dispensed either alendronate (once weekly) or risedronate (once weekly). The majority of the patients (69.3 per cent) were over 70 years.

Approximately 50 per cent of patients on long-term steroids did not receive prophylaxis for osteoporosis. There were low levels of co-prescribing (2.5 per cent) with potentially interacting drugs. Levels of co-prescribing with proton pump inhibitors (PPI) was 22 per cent.

The published results of a study involving the General Practice Research Database, a computerised medical record system of a selected group of general practices in the UK, identified significantly increased risk of hip fractures associated with long-term users of high-dose PPI (Yang, JAMA 2006).

It has been demonstrated that corticosteroids increase the risk of vertebral fractures six-fold and double the risk of hip fracture

There has been an increased awareness of the association between long-term use of both inhaled and oral corticosteroids and the subsequent development of osteoporosis (Arthritis Rheumatology 2001; Eastell R, Journal of Internal Medicine 1998; Leong GM, Osteoporosis 2001). A threshold dose of over 7.5mg/day of prednisolone seems to be required for the development of osteoporosis. Previous studies have identified that corticosteroid use is a risk factor for fractures, irrespective of the fact that patients may present with normal BMD levels.

It has been demonstrated that corticosteroids increase the risk of vertebral fractures six-fold and double the risk of hip fracture (Cooper C, Ann Rheum Dis 1995; Scane AC, Osteoporosis Int 1999). Studies have also shown that approximately 50 per cent of patients who are receiving long-term corticosteroids experience fractures (Lukert BP, Ann Intern Med 1990). Kanis et al identified that approximately 20 per cent of patients who have an osteoporotic hip fracture die within six months (Kanis JA, Bone 1992).

The McGowan study showed that approximately 50 per cent of patients treated with prednisolone (over 7.5mg per day) for greater than three months did not receive treatment for the prophylaxis of osteoporosis and the co-prescribing rate for PPIs was 22 per cent, which may be related to gastrointestinal adverse events.

Other treatments and ‘drug holidays’

“PATIENTS ON long-term bisphosphonates appear to be presenting now — in small numbers — with atypical fractures on the medial side of the femur,” according to Prof Oliver FitzGerald.

A ‘drug holiday’ has been advocated by some physicians — namely, stopping the bisphosphonate for one or two years and reassessing — but the evidence is not definite. “The Medicines and Healthcare Products Regulatory Agency’s advice is that without an atypical fracture, if a patient is at high risk of fracture, the benefits outweigh the risks and there’s no indication to stop treatment,” said Prof FitzGerald.

Selective oestrogen-receptor modulators (SERMs) are non-steroidal agents, which act as agonists on bone and reduce the rate of bone loss in PM women. (Kanis JA, Osteoporosis International 2008). Raloxifene has been shown to reduce the risk of vertebral fractures in post-menopausal women with low bone mass. However, there is no significant reduction in non-vertebral fractures. Raloxifene helps to maintain bone density and reduce fracture rates, specifically at the spine.

For patients not responding to bisphosphonates who might have severe osteoporosis, parathyroid hormone could be considered. Parathyroid hormone increases bone remodelling and increases bone formation (anabolic agent) (Rosen C, NEJM 2005). Treatment with either the intact molecule (recombinant PTH 1-84) or the 1-34 N-terminal fragment (teriparatide) reduces vertebral fractures (National Osteoporosis Guideline Group).

Teriparatide has also been shown to reduce non-vertebral fractures in post-menopausal women and it has efficacy in men and glucocorticoid-induced osteoporosis (Kanis JA, Osteoporosis International 2008). BMD reduces rapidly after discontinuation, unless followed by an antiresorptive agent.

Parathyroid hormone can only be prescribed by a consultant, as it is a high-tech drug for severe osteoporosis. It is a bone-forming agent that stimulates the formation of new bone.

Strontium ranelate may also be considered, said Prof FitzGerald. Strontium ranelate has antiresorptive properties and possibly increases bone formation. (O’Donnell S et al, Cochrane Database of Systematic Reviews 2006). It has been shown to reduce vertebral and non-vertebral fractures. It can also help decrease the pain of vertebral fractures.

Denosumab may be considered for patients who have not responded to bisphophonates or who are unable to take them, added Prof FitzGerald. It reduces the risk of vertebral, non-vertebral and hip fractures.

Other treatments include oestrogen, Prof FitzGerald said. Sex hormones play a vital role in determining the onset of osteoporosis. Both testosterone in males and the female hormone oestrogen have a protective effect on bones. Oestrogen deficiency at any age — but particularly after the menopause in thin females — is one of the main reasons for bone loss. Oestrogen/hormone therapy (HRT) is not usually recommended just for prevention or treatment of osteoporosis, unless the person has had an early menopause. HRT prevents the relatively rapid bone loss in the first three-to-five years following menopause, and maintains this.

It is important to minimise the use of glucocorticoids, said Prof FitzGerald. Calcium and vitamin D supplementation should be considered, especially in the elderly.

Despite older tricyclic antidepressants demonstrating a significantly greater efficacy over newer drugs, a major 30-year meta-analysis concludes the differences are largely a result of changes in trial designs, leading to greater placebo response and lower drug response.

Antidepressant efficacy steadily declined over the past 30 years, while placebo response increased, possibly a result of increasing trial size and “declining quality control”, the analysis of 142 drug-placebo comparisons involving almost 30,000 patients suggested.

“Placebo-associated respon-ses have increased from former levels of 20 to 30 per cent to current levels of 30 per cent to 50 per cent, and to as high as 59.2 per cent in a 1997 trial involving paroxetine,” the US researchers wrote in Neuropsychopharmacology.

Over the same time, trials have shifted from older tricyclics to newer SSRIs and atypicals. Although the older trials of tricyclics demonstrated greater benefit over placebo than more recent trials of newer drugs, the researchers found that if more recent placebo response rates were substituted into the older trials, “both types of agents yielded identical meta-analytically pooled [rate ratios]”.

The study authors blamed the decreasing drug-placebo difference on “declining quality-control and greater heterogeneity of diagnostic and clinical assessments”, as well as a number of other possible factors including the recruitment of less severely-ill patients into trials.

They argued that if their suggested explanations were correct, several “practical considerations for the design and conduct of therapeutic trials” were needed.

Looking at the factors that correlated with larger drug-placebo differences, they suggested limiting collaborating sites in trials to between two and 10, and limiting the number of subjects per trial to between 30 and 75.

“Such conservative considerations for the design of trials may improve outcomes,” they said, as well as lowering costs, time, complexity and exposure of acutely-depressed patients to placebo.

Neuropsychopharmacology 2011; doi:10.1038/npp.2011.306