IQ driving QI: the Asia Pacific Consortium on Osteoporosis (APCO): an innovative and collaborative initiative to improve osteoporosis care in the Asia Pacific.

Asia Pacific Consortium on Osteoporosis (APCO) comprises of clinical experts from across the Asia Pacific region, uniting to develop solutions to problems facing osteoporosis management and care. The vision of APCO is to reduce the burden of osteoporosis and fragility fractures in the Asia Pacific region. INTRODUCTION: The Asia Pacific (AP) region comprises 71 countries with vastly different healthcare systems. It is predicted that by 2050, more than half the world's hip fractures will occur in this region. The Asia Pacific Consortium on Osteoporosis (APCO) was set up in May 2019 with the vision of reducing the burden of osteoporosis and fragility fractures in the AP region. METHODS: APCO has so far brought together 39 clinical experts from countries and regions across the AP to develop solutions to challenges facing osteoporosis management and fracture prevention in this highly populous region of the world. APCO aims to achieve its vision by engaging with relevant stakeholders including healthcare providers, policy makers and the public. The initial APCO project is to develop and implement a Framework of pan-AP minimum clinical standards for the screening, diagnosis and management of osteoporosis. RESULTS AND CONCLUSIONS: The Framework will serve as a platform upon which new national clinical guidelines can be developed or existing guidelines be revised, in a standardised fashion. The Framework will also facilitate benchmarking for provision of quality of care. It is hoped that the principles underlying the formation and functioning of APCO can be adopted by other regions and that every health care facility and progressively every country in the world can follow our aspirational path and progress towards best practice.

Randomized, active-controlled study of once-weekly alendronate 280 mg high dose oral buffered solution for treatment of Paget's disease.

UNLABELLED: Daily oral tablet bisphosphonate therapy for Paget's disease of bone may cause serious upper gastrointestinal adverse events. A once-weekly alendronate 280 mg oral buffered solution was compared with an alendronate 40 mg/day tablet. While both were similarly effective, the tablet appeared to be better tolerated in this study. INTRODUCTION: Although daily doses of oral bisphosphonates are a generally safe and effective treatment for Paget's disease of bone (PDB), some patients may experience upper gastrointestinal adverse events (UGI AEs) or find the dosing requirements inconvenient and become noncompliant. A once-weekly (OW) oral dose of bisphosphonate in buffered solution (OBS) may be as effective, better tolerated, and more convenient. METHODS: Sixty-three patients were randomized to either alendronate (ALN) 280 mg OW OBS (n = 42) or an ALN 40 mg/day tablet (n = 21) during a 6-month, randomized, double-blind, active-controlled trial. The primary endpoint was the mean percent decrease in total serum alkaline phosphatase (total ALP) from baseline at 6 months. RESULTS: There were no significant differences in total ALP between groups during the 6-month period. There was a higher incidence of clinical AEs in the ALN 280 mg OW OBS (79%) vs. the ALN 40 mg/day tablet group (67%), including drug related AEs (48% and 10%, respectively), which led to study discontinuation (19.0% and 10%, respectively). CONCLUSIONS: Although ALN 280 mg OW OBS was similarly effective as ALN 40 mg/day in reducing total ALP in patients with PDB, the ALN 40 mg/day tablet appears to be better tolerated than ALN 280 mg OW OBS.

Alendronate prevents bone loss in patients with acute spinal cord injury: a randomized, double-blind, placebo-controlled study.

CONTEXT: Patients who sustain an acute spinal cord injury (SCI) experience rapid dramatic reductions in bone mineral density (BMD), especially marked in sublesional areas and sometimes leading to hypercalcemia and hypercalciuria, as well as increased fracture risk. OBJECTIVE: In this prospective, double-blind, randomized, placebo-controlled study, we evaluated the hypothesis that oral alendronate administration would preserve BMD when administered soon after acute SCI. PATIENTS AND INTERVENTION: Thirty-one patients with acute SCI were randomly allocated to receive oral alendronate 70 mg/wk or placebo, within 10 d of acute SCI, for 12 months. MAIN OUTCOME MEASUREMENTS: At entry and at 3, 6, 12, and 18 months, total body bone density, lumbar and hip BMD, ultrasound of the calcaneus, 24-h urinary calcium, and serum C-telopeptide (betaCTX) were measured. RESULTS: At study entry, patients in the two groups were well matched for age, gender, severity of neurological deficit, BMD, urinary calcium, and betaCTX. BMD indices declined steadily in the placebo group, and this effect was attenuated significantly by alendronate. After 12 months, there was a 5.3% difference (P<0.001) in total body BMD and a 17.6% difference (P<0.001) in the total hip BMD between the two groups. Alendronate compared with placebo induced significant (P<0.001) reductions in urinary calcium excretion and serum betaCTX. No treatment-related side effects were noted. CONCLUSIONS: We conclude that alendronate therapy, 70 mg/wk, initiated soon after acute SCI, prevents bone loss and is not associated with side effects.

Renal, hemodynamic, and hormonal responses to atrial natriuretic peptide infusions in normal man, and effect of sodium intake.

The effect of 60-min constant iv infusions of alpha-human atrial natriuretic peptide (alpha hANP; 200 micrograms), sufficient to increase the steady state venous plasma alpha hANP concentration to levels found in patients with some circulatory disorders, was studied in six normal men equilibrated on a high sodium diet (200 mmol daily) and again when equilibrated on a low sodium intake (10 mmol daily). In each instance, the responses to alpha hANP were compared to those to control infusions given on the preceding day. The mean steady state plasma immunoreactive ANP concentration during the infusions was 320 pmol/liter and was the same during both diets. Thus, the MCR of alpha hANP was unaffected by major changes in sodium intake. Compared to control day observations, infusions of alpha hANP induced a more than 3-fold increase in sodium excretion and at least a 2-fold increase in urine volume and calcium and magnesium excretion in subjects ingesting 200 mmol sodium daily. During the low sodium diet, alpha hANP was still diuretic and induced comparable magnesium excretion, but the natriuresis was only 11% of that during the high salt diet. No significant changes in blood pressure or heart rate occurred during alpha hANP infusions during either diet, although during both diets there was a significant rise in plasma norepinephrine (P less than 0.02), which persisted well beyond the disappearance of immunoreactive ANP from plasma. Despite this sympathetic activation, renin and aldosterone production was reduced by alpha hANP. During low salt intake, alpha hANP significantly decreased PRA (mean pretreatment, 1.79; posttreatment, 1.25 nmol/liter/h; P less than 0.03), angiotensin II (mean pretreatment, 49; posttreatment, 28 pmol/liter; P less than 0.008), and plasma aldosterone (mean pretreatment, 554; posttreatment 307 pmol/liter; P less than 0.007), whereas values during control infusions did not change. Similar percent decreases in PRA and aldosterone also occurred during the high salt diet. Plasma cortisol and arginine vasopressin did not change during the alpha hANP infusions on either diet. We conclude that steady state levels of alpha hANP in plasma, similar to those in patients with some circulatory disorders, significantly increase sodium excretion and inhibit all elements of the renin-angiotensin-aldosterone system. The natriuretic, but not the hormonal or chronotropic, effects of alpha hANP are reduced by sodium depletion in normal man.

Alendronate in early postmenopausal women: effects on bone mass during long-term treatment and after withdrawal. Alendronate Osteoporosis Prevention Study Group.

We studied the effect on bone mass of alendronate treatment for 5 yr and its withdrawal. Four hundred and forty-seven postmenopausal women with normal bone mass entered a 3-yr randomized trial followed by a 2-yr open label extension. Three hundred and eleven women completed the first 3 yr, and 263 consented to continue and completed the extension. We are reporting data from groups using the dose of alendronate currently approved for osteoporosis prevention (5 mg) or from the group in which alendronate treatment was withdrawn: 52 women received alendronate (5 mg) for 5 yr (group I), 56 received 3 yr of placebo followed by alendronate (5 mg) for 2 yr (group II), and 52 received alendronate (20 mg) for 2 yr followed by 3 yr off therapy (group III). In group I, alendronate (5 mg) increased bone mineral density (BMD) at the spine and trochanter by 2.5-3.2% (P < 0.001 vs. baseline) and stabilized total body and femoral neck BMD (change vs. baseline, P = NS) over 5 yr. By the end of 5 yr, BMD was comparable at the spine, hip, and total body in groups I and III. The 3-yr decrease in BMD after withdrawal of alendronate (20 mg) in group III was 1.8-5.7% (P < 0.01 vs. baseline) and similar to the 3-yr decrease in BMD in group II during the initial 3 yr. In conclusion, alendronate (5 mg) for 5 yr or alendronate (20 mg) for 2 yr followed by 3 yr off therapy prevented postmenopausal bone loss. After withdrawal of alendronate (20 mg), bone loss resumed at the normal early postmenopausal rate.

The effect of socioeconomic status on bone density in a male Caucasian population.

We have examined the effect of socioeconomic status (SES) on bone density (BMD) in 201 males, aged 20-60 years. Males of lower SES (groups 4-6 vs. 1-3) from the total sample had significantly higher BMD (p < 0.05) at L2-4 and femoral neck. The difference was small but was not explained by differences in age, weight, calcium intake, family history, activity, or smoking. 45% of SES 4-6 males were involved in manual labor compared with 11% of those in SES 1-3, however, this also did not appear to account for the difference.

A community study of vitamin B12 and folate levels in the elderly.

OBJECTIVE: To measure the prevalence of low serum vitamin B12, folate, and red cell folate levels and their relationship with other nutritional indices. DESIGN: Prospective survey of elderly subjects using radioisotope dilution assays. SETTING: Primary care medical center, Christchurch, New Zealand. PATIENTS: 257 elderly subjects (age 65 years and over), residing in their own homes or in residential homes, were randomly selected. Of these, 204 (79%) participated. The study population was comparable to the elderly population of New Zealand. MAIN OUTCOME MEASURES: Vitamin B12, serum, and red cell folate levels. RESULTS: The prevalence rates for low levels of serum vitamin B12, folate, and red cell folate were 7.3%, 1%, and 3.3%, respectively. The elderly cohort had lower vitamin B12 (P less than 0.001) but higher serum and red cell folate levels (P less than 0.001) than our normal reference range (age 18-65 years). Red blood cell folate levels showed positive correlations with nutritional indices and mental test scores. No correlations were found between vitamin B12 levels and diet or other nutritional indices. CONCLUSIONS: Low folate levels in older people living at home are infrequent findings. In contrast low vitamin B12 levels are more common. Poor diet and undernutrition may contribute to low folate levels, but these factors are less important for the low B12 levels found.

Influence of polysorbate 80 (Tween 80) and etoposide (VP-16-213) on the pharmacokinetics and urinary excretion of adriamycin and its metabolites in cancer patients.

Polysorbate 80 (Tween 80) is present in the IV pharmaceutical preparation of VP-16-213 marketed as VePesid (Bristol-Myers) (etoposide 100 mg, benzylalcohol 150 mg, polyethylene glycol 300 3250 mg, citric acid 10 mg, Tween 80 400 mg and absolute alcohol to 5 ml per 100 mg ampule of VP16), to increase its miscibility with blood. We have examined the effects of 400 mg/m2 Tween 80 IV and 100 mg/m2 VP16 on the pharmacokinetics of Adriamycin (ADR, 30 or 40 mg/m2). ADR and metabolite concentrations were measured by HPLC. ADR plasma profiles were best fitted to a bi-exponential decay and a two-compartment open model. Tween 80 did not alter the values of the two ADR half-lives, nor did it affect metabolite kinetics of their urinary excretion. However, in a similar manner and consistently in all patients, both Tween 80 and VP16 increased the volume of distribution of the central compartment for ADR up to 3-fold, decreased the AUC of ADR up to 2-fold and increased its clearance by exactly the same amount. These effects were due to reduced plasma ADR concentrations during the early phase of its kinetics. Urinary excretion of ADR was also increased. In conclusion, VP16 is likely to affect the kinetics of drugs administered with it: early plasma concentrations will fall due to a general physiological effect of Tween 80 on the apparent volume of circulation.

Comparison of serum and cerebrospinal fluid levels of methotrexate in man during high-dose chemotherapy for aggressive non-Hodgkin's lymphoma.

The relationship between plasma and cerebrospinal fluid levels of methotrexate was studied in five patients, four with aggressive non-Hodgkin's lymphoma and one with mixed epithelial mesothelial tumour, who were treated with high-dose methotrexate (1.5 g/m2) as part of combination chemotherapy. Cerebrospinal fluid was sampled for 24 h via a permanent indwelling lumbar catheter. No complications were observed with this technique. In two patients with central nervous system involvement adequate "cytotoxic" levels (greater than 10(-6) M) were obtained for greater than 12 h. The remaining three patients, with no direct evidence of central nervous system involvement, never attained adequate cytotoxic methotrexate levels in the cerebrospinal fluid. Serum levels were therapeutic in all patients. These results suggest that patients with central nervous system tumour involvement may receive adequate doses of methotrexate in the cerebrospinal fluid. Patients with occult central nervous system tumour involvement may not attain adequate cerebrospinal fluid levels. A 24-h serum methotrexate level of greater than 10(-5) M may indicate that patients have achieved therapeutic cerebrospinal fluid levels of methotrexate. Cranial irradiation following chemotherapy is still recommended in this tumour group until adequate cytotoxic levels of methotrexate can be obtained in all patients for prolonged periods.

Effect of sulindac on angiotensin converting enzyme inhibitor-induced cough: randomised placebo-controlled double-blind cross-over study.

The effect of sulindac on ACE inhibitor-induced cough was studied in eight hypertensive subjects in a randomised placebo-controlled double blind cross-over trial. There was no significant improvement in cough or sense of well-being. Blood pressure, renal function, plasma renin and ACE activity were unchanged. Sulindac however, appears to be effective in some individuals in reducing ACE inhibitor-induced cough with acceptable tolerance and few side effects. Further work is needed to elucidate the mechanism of sulindac's interaction with ACE inhibitors.

Effect of losartan on haematology and haemorheology in elderly patients with essential hypertension: a pilot study.

This small open study in elderly patients with essential hypertension investigated the effects of the angiotensin II AT1 receptor antagonist on red blood cell haematology and haemorheology. Administration of losartan over a 1-year period was not associated with a significant reduction in haemoglobin or plasma erythropoietin (EPO) concentrations and haemorheological indices remained unchanged. These findings are in contrast to similar studies with angiotensin-converting enzyme (ACE) inhibitors that have shown a significant reduction in erythropoietic activity and a decrease in blood viscosity. Our results indicate therefore that blocking the angiotensin II AT1 receptor does not affect erythropoiesis. Losartan has no adverse haemorheological effects and was associated with a small and statistically insignificant decrease in blood viscosity.

A comparison of long acting nifedipine and enalapril in elderly hypertensives: a randomised, single-blind, cross-over study.

The effects of nifedipine and enalapril on blood pressure (BP), heart rate, plasma and urine electrolyte, plasma renin activity (PRA), aldosterone and catecholamines, were studied in ten elderly hypertensive subjects in a randomised, single-blind, cross-over trial. Both nifedipine and enalapril were effective in lowering supine and erect systolic and diastolic BP, with nifedipine causing a significant (P less than 0.05) rise in heart rate. Arterial pressure rose to pre-treatment levels on withdrawal of both drugs. Plasma glucose fell significantly (P less than 0.02) on enalapril therapy, whilst no other biochemical changes were observed. PRA, aldosterone and adrenaline rose on nifedipine therapy whereas PRA showed a greater rise on enalapril with a fall in plasma aldosterone and no change in plasma adrenaline. Plasma noradrenaline was not altered by either agent. Unacceptable side effects occurred in patients taking nifedipine resulting in discontinuation of therapy in 2 patients and death in another. Nifedipine or enalapril monotherapy is effective in lowering BP in the elderly hypertensives. Although more experience is needed, the side effect profile of both agents especially enalapril, appears satisfactory.

Cough with angiotensin converting-enzyme inhibitors.

Since there are isolated case reports linking cough with angiotensin converting-enzyme (ACE) inhibitor treatment, we reviewed the case notes of patients attending a hypertension outpatient clinic. Of 126 patients, 37 were on medications other than ACE inhibitors, and none complained of cough. In contrast, 12 of 89 patients receiving an ACE inhibitor had noted cough. The symptoms remained when one ACE inhibitor was substituted for another, but disappeared when the drug was withdrawn. Cough was sufficiently irritating to require cessation of treatment in two patients. We conclude that cough is not uncommon during treatment with ACE inhibitors.

Erythrocyte sedimentation rates in the elderly: a community study.

One hundred and ninety-four elderly subjects living in the community were randomly selected in order to define a reference range for erythrocyte sedimentation rate (ESR) for this age group. Mean (S.D) values were 4.1 (2.9) mm in one hour and 7.2 (2.6) mm in one hour for men and women respectively. Values ranged from 0-44 mm in one hour. The ESR showed significant independent correlations with fibrinogen, haemoglobin (male and female) and albumin levels (male only). A new algorithm for determination of the upper limit of normal for age is proposed: Females ESR = Age/3 + 10 Male ESR = Age/3.

Asymptomatic low bone mineral density in otherwise healthy people: four year follow up.

AIM: To determine the effect of screening a normal population for low bone density on lifestyle, subsequent bone density and fracture risk. METHOD: A cross sectional study of 726 subjects screened for low bone density identified 60 with bone density greater than one standard deviation below an age and sex matched mean. Those who accepted further assessment were followed clinically and with repeat bone densitometry for up to four years. Those declining assessment were contacted four years later and questioned about lifestyle changes and fractures. They were offered repeat bone densitometry. RESULTS: Twenty five subjects accepted intervention and were advised on lifestyle modification and treated with calcium supplements (18) calcitriol (5) or oestrogen (1). 22 of the 35 subjects who initially declined intervention volunteered to have their bone density repeated. Bone density increased in the group accepting intervention compared to the 22 subjects in the group who initially declined assessment (p < 0.05). Several laboratory investigations had a low yield. Lifestyle modification in the group declining assessment did not significantly affect subsequent bone density. Fractures occurred infrequently in both groups. CONCLUSION: After screening the normal population for low bone density, significant improvements in bone density can be achieved in patients accepting further intervention.

Trial of Sinemet CR4 in patients with Parkinson's disease.

OBJECTS: to compare the efficacy of Sinemet CR4 (CR4), a slow release levodopa preparation, with that of standard Sinemet in patients with Parkinson's disease and motor fluctuations. METHODS: forty-five patients with Parkinson's disease of mild to moderate severity and motor fluctuations were entered into the 12 month trial. After a four week baseline period of optimal therapy, standard Sinemet was completely substituted by CR4 over 12 weeks, and clinical status monitored regularly over another 36 weeks. Evaluation was based on standard rating scales and patient's and physician's opinion ratings. RESULTS: forty-two patients completed the study. The mean optimum total daily dosage of Sinemet CR4 was 702 mg, significantly greater than the mean optimum daily dose of standard Sinemet--496 mg (p less than 0.01). Median number of doses per day was less, being 3 and 4 respectively (p less than 0.01). There was reduction in tremor (p less than 0.01) and rigidity (p less than 0.05) with Sinemet CR4 therapy compared with standard Sinemet, but no difference in disability scores, bradykinesia, gait, or postural instability. Twenty-five patients rated the change to Sinemet CR4 from standard Sinemet as "more helpful", 15 "about the same", and two "less helpful". There were no serious or unexpected adverse effects. CONCLUSIONS: it was concluded that Sinemet CR4 was at least as effective as standard Sinemet, and it seemed particularly helpful in those patients with wearing-off who require frequent doses of standard Sinemet throughout the day.

Comparative study of norfloxacin and trimethoprim for the treatment of elderly patients with urinary tract infection.

One hundred elderly hospitalised patients, aged 70 to 97 years (mean 81.7 years; SD 7.1 years) with a urinary tract infection were entered into a randomised study to compare the efficacy, safety and tolerance of norfloxacin 400 mg twice daily for three days with trimethoprim 300 mg once daily for three days. Forty-two of 49 patients (86%) were cured with norfloxacin, compared with 35 of 51 (69%) with trimethoprim (p less than 0.05). No patient reported any side effects during treatment. Two patients treated with norfloxacin and three treated with trimethoprim developed a disturbance of liver function. Three deaths occurred within 28 days of treatment with trimethoprim but were unrelated to the treatment. In this study norfloxacin proved superior to trimethoprim for the treatment of uncomplicated urinary tract infections in elderly hospitalised patients.

A sensitive radioimmunoassay for measuring plasma anti-diuretic hormone in man.

A radioimmunoassay has been developed which permits the measurement of plasma antidiuretic hormone (arginine vasopressin (AVP), in the normal and subnormal range. Plasma was first extracted with octadecasilyl-silica to remove non-hormonal immunoreactivity, then assayed using a sensitive antibody and mono-iodinated AVP. After centrifugation of blood, we found AVP levels to be highest in the lowest layer of plasma--presumably because platelets are a reservoir for the hormone. In normal volunteers the range of plasma AVP was 0.8-14.3 pmol/l, and water loading generally lowered AVP levels. Appropriate increments in measured AVP were observed during intravenous infusion of the peptide, and during insulin-induced hypoglycaemia. Extremely low levels were found in cranial diabetes insipidus, whereas in some patients with bronchial carcinoma and hyponatraemia, AVP values were elevated. The sensitivity of the method and its practicability should make it useful both in clinical medicine and in research.

Hip fracture mortality and morbidity--can we do better?

AIMS: To determine the mortality and morbidity from fractures of the neck of femur in Christchurch Hospital and to determine the extent that hip fracture patients are investigated and treated for osteoporosis. METHODS: All patients treated for a fractured hip at Christchurch Hospitals between May 1998 and April 1999 were identified. Their radiographs were reviewed and each fracture was classified. Dates of death were recorded where applicable. Surviving patients were contacted at least twelve months after their fracture and asked questions relating to functional outcome following surgery. The numbers of patients who had ever had a bone density scan, treatment for osteoporosis and/or a measurement of vitamin D were recorded. RESULTS: There were 331 fractures among 329 patients (242 women, 87 men), mean age of 79.7 (standard deviation 10.5) years. Twelve-month mortality was 26%. Men had a higher mortality rate than women for all fracture types that was independent of age. Follow up of the 231 surviving patients 12-24 months later revealed 27% still had pain and 60% had worsened mobility that they attributed to the fracture. Worsened mobility affected people living at home more than people living in institutional care. 32 people (15%) had had a vitamin D concentration measured and in 22 of these (69%) levels were below the reference range. CONCLUSIONS: The mortality and morbidity after hip fracture is high, especially in men. There were few significant correlates with greater morbidity except for fixation by hemi arthroplasty. More attention to hip fracture prevention is needed. Few subjects were on any therapy for osteoporosis other than calcium supplements. Vitamin D deficiency is an important but under-recognised condition.

A comparison of elderly patients with proximal femoral fractures and a normal elderly population: a case control study.

AIM: To assess the importance of bone density and other risk factors in elderly subjects with hip fractures. METHOD: Thirty-six subjects with femoral neck fracture were compared with 72 community controls in this case control study. Variables compared included: history of falls, previous fracture, body mass index, hand grip strength, blood pressure, medication use, cigarette smoking, alcohol intake, visual acuity, age at menopause, mental status quotient, mobility index and mid thigh circumference. Bone mineral density was measured at the hip (DPA absorptiometer) in the 36 subjects with hip fracture and 36 community controls. RESULTS: Fracture patients had significantly (p < 0.01) reduced bone mineral density at femoral neck (0.64 vs 0.74 g/cm2) and trochanteric regions (0.55 vs 0.66 g/cm2). They also had significantly (p < 0.05) lower body mass index, weaker hand grip strength, smaller mid thigh circumference, reduced mobility and more previous fractures. After controlling for age and sex stepwise logistic regression identified handgrip strength, mobility status and falls in that ranking as risk factors for fracture. Bone mineral density was correlated with mobility status and grip strength. CONCLUSION: Patients with hip fracture have lower bone mineral density than controls. Mobility, grip strength and muscle bulk appear to be important in fracture aetiology and could operate either through bone density or risk of falling.