Development of the Asia Pacific Consortium on Osteoporosis (APCO) Framework: clinical standards of care for the screening, diagnosis, and management of osteoporosis in the Asia-Pacific region.

Guidelines for doctors managing osteoporosis in the Asia-Pacific region vary widely. We compared 18 guidelines for similarities and differences in five key areas. We then used a structured consensus process to develop clinical standards of care for the diagnosis and management of osteoporosis and for improving the quality of care. PURPOSE: Minimum clinical standards for assessment and management of osteoporosis are needed in the Asia-Pacific (AP) region to inform clinical practice guidelines (CPGs) and to improve osteoporosis care. We present the framework of these clinical standards and describe its development. METHODS: We conducted a structured comparative analysis of existing CPGs in the AP region using a "5IQ" model (identification, investigation, information, intervention, integration, and quality). One-hundred data elements were extracted from each guideline. We then employed a four-round Delphi consensus process to structure the framework, identify key components of guidance, and develop clinical care standards. RESULTS: Eighteen guidelines were included. The 5IQ analysis demonstrated marked heterogeneity, notably in guidance on risk factors, the use of biochemical markers, self-care information for patients, indications for osteoporosis treatment, use of fracture risk assessment tools, and protocols for monitoring treatment. There was minimal guidance on long-term management plans or on strategies and systems for clinical quality improvement. Twenty-nine APCO members participated in the Delphi process, resulting in consensus on 16 clinical standards, with levels of attainment defined for those on identification and investigation of fragility fractures, vertebral fracture assessment, and inclusion of quality metrics in guidelines. CONCLUSION: The 5IQ analysis confirmed previous anecdotal observations of marked heterogeneity of osteoporosis clinical guidelines in the AP region. The Framework provides practical, clear, and feasible recommendations for osteoporosis care and can be adapted for use in other such vastly diverse regions. Implementation of the standards is expected to significantly lessen the global burden of osteoporosis.

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.

Long-term denosumab treatment restores cortical bone loss and reduces fracture risk at the forearm and humerus: analyses from the FREEDOM Extension cross-over group.

Upper limb fractures (including wrist, forearm, and humerus) represent a significant burden among postmenopausal women with osteoporosis. Up to 7 years of treatment with denosumab resulted in an increase in bone mineral density and decrease in fractures in upper limb sites. INTRODUCTION: Upper limb (wrist, forearm, and humerus) fractures are a significant burden in osteoporosis, associated with significant morbidity and mortality. Denosumab, a monoclonal antibody against RANK ligand, increases bone mineral density (BMD) and decreases vertebral, nonvertebral, and hip fractures. Here, we evaluated the long-term effect of denosumab treatment on upper limb fracture risk and BMD. METHODS: In the FREEDOM trial, subjects were randomized 1:1 to receive every-6-month denosumab 60 mg or placebo subcutaneously for 3 years, after which all subjects could receive denosumab for up to 7 years (Extension). Among placebo subjects who completed FREEDOM and enrolled in the Extension, wrist, forearm, humerus, and upper limb fracture rates and rate ratios between different time periods (FREEDOM years 1-3, Extension years 1-3, and Extension years 4-7) were computed. BMD at the ultradistal radius, 1/3 radius, and total radius was analyzed in a subset of subjects in a BMD substudy. RESULTS: This analysis included 2207 subjects (116 in the BMD substudy). Fracture rates decreased over the 7-year Extension; fracture rate ratios between Extension years 4-7 (denosumab) and FREEDOM years 1-3 (placebo) reduced significantly for the wrist (0.57), forearm (0.57), humerus (0.42), and upper limb (0.52; p < 0.05 for all). Percentage increase in BMD from Extension baseline at the ultradistal radius, 1/3 radius, and total radius was significant by Extension year 7 (p < 0.05 for all). CONCLUSIONS: Long-term treatment with denosumab decreases upper limb fracture risk and increases forearm BMD, suggesting beneficial effects on both cortical and trabecular bone accruing over time.

A phase 2 study of MK-5442, a calcium-sensing receptor antagonist, in postmenopausal women with osteoporosis after long-term use of oral bisphosphonates.

UNLABELLED: In women with osteoporosis treated with alendronate for >12 months and oral bisphosphonates for >3 of the last 4 years, switching to MK-5442, a calcium receptor antagonist, stimulated endogenous parathyroid hormone (PTH) secretion and increased bone turnover marker levels, but produced a decline in bone mineral density (BMD) at all sites. INTRODUCTION: This study assessed the effects of switching from long-term oral bisphosphonate therapy to the calcium-sensing receptor antagonist MK-5442 on BMD and bone turnover markers (BTMs) in post-menopausal women with osteoporosis. METHODS: This randomized, active and placebo-controlled, dose-ranging study enrolled 526 postmenopausal women, who had taken alendronate (ALN) for ≥12 months preceding the trial and any oral bisphosphonate for ≥3 of the preceding 4 years and had spine or hip BMD T-scores ≤-2.5 or ≤-1.5 with ≥1 prior fragility fracture. Women were randomized to continue ALN 70 mg weekly or switch to MK-5442 (5, 7.5, 10, or 15 mg daily) or placebo. RESULTS: Switching from ALN to MK-5442 produced a dose-dependent parathyroid hormone (PTH) pulse of threefold to sixfold above baseline at 1 h, with PTH levels that remained twofold to threefold above baseline at 4 h and returned to baseline by 24 h. Switching to MK-5442 or placebo increased BTM levels compared to baseline within 3 months and MK-5442 10 mg increased BTM levels compared to placebo by 6 months. With all MK-5442 doses and placebo, spine and hip BMD declined from baseline, and at 12 months, BMD levels were below those who continued ALN (all groups P < 0.05 vs ALN). There was also a dose-dependent increase in the incidence of hypercalcemia with MK-5442. CONCLUSION: Switching from ALN to MK-5442 resulted in a pulsatile increase in PTH and increases in BTMs, but a decline in BMD compared with continued ALN. MK-5442 is not a viable option for the treatment of osteoporosis.

Impact of clinical fractures on health-related quality of life is dependent on time of assessment since fracture: results from the FREEDOM trial.

UNLABELLED: In the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) study, women with incident clinical fractures reported significant declines in health-related quality of life (HRQoL). The largest declines were observed when the assessment was <3 months post fracture. The largest impact of incident clinical fractures was on physical function, and that of incident clinical vertebral fractures was on back pain. INTRODUCTION: In the FREEDOM trial, denosumab significantly reduced the risk of new vertebral, hip, and nonvertebral fractures. We evaluated the effect of denosumab on HRQoL and the association between incident clinical fractures and HRQoL. METHODS: The FREEDOM trial enrolled 7,868 women aged 60-90 years with a total hip and/or lumbar spine BMD T-score <-2.5 and not <-4.0 at either site. Women were randomized to receive denosumab 60 mg or placebo every 6 months, in addition to daily calcium and vitamin D. HRQoL was assessed with the Osteoporosis Assessment Questionnaire-Short Version (OPAQ-SV) at baseline and every 6 months for 36 months. The OPAQ-SV assesses physical function, emotional status, and back pain. Higher scores indicate better health status. RESULTS: No statistically significant differences in mean change in HRQoL from baseline to end of study were found when comparing treatment groups. Compared with women without any incident fractures during the study, women with incident clinical fractures reported significant declines in physical function (-4.0 vs. -0.5) and emotional status (-5.0 vs. -0.8) at month 36 (P < 0.001 for both). Importantly, time-dependent covariate analyses demonstrated that the largest declines were observed when the assessment was <3 months post fracture. The largest impact of incident clinical fractures was on physical function, and that of incident clinical vertebral fractures was on back pain. CONCLUSIONS: These findings not only demonstrate that incident clinical fractures impact HRQoL but also contribute new information regarding the impact of these fracture events on HRQoL over time.

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.

Effect of low dose infusions of ile-atrial natriuretic peptide in healthy elderly males: evidence for a postreceptor defect.

Low dose infusions of atrial natriuretic peptide (ANP) have significant biological effects in young adults. In view of the accumulating evidence of age-related changes in ANP physiology, we investigated the effects of a 2-h low dose infusion of ile12-ANP (1.5 pmol/kg/min) in eight healthy, supine, normotensive elderly men in a single blind, random order, placebo-controlled study. Calculated MCR of ANP was 3.3 +/- 0.4 L/min, disappearance half-life 4.1 +/- 0.4 min, and volume of distribution 21 +/- 4 L. The ile-ANP infusions induced the expected significant (3-fold) increases in plasma ANP immunoreactivity in association with enhancement of both plasma and urine cyclic guanosine monophosphate. Despite this, there were no measurable natriuretic effects or changes in blood pressure, and the activities of the renin-angiotensin-aldosterone and sympathetic nervous systems were unchanged. These findings suggest an abnormality in the post-cyclic guanosine monophosphate effector of ANP among elderly normotensive men.

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.

Familial short stature and coeliac disease: a family case report.

A case of coeliac disease associated with growth retardation and pubertal failure in a 19 year old female is reported. Diagnosis was delayed by use of the term 'undiagnosed short stature'. Investigations confirmed severe malabsorption, osteoporosis and marked delay in bone growth associated with small bowel mucosal atrophy. HLA screening of the patient's family led to the identification of coeliac disease in her brother aged 12 years and her asymptomatic mother both of whom were short in stature. The institution of a gluten free diet, appropriate vitamin and mineral supplements has restored growth and sexual development to normal in the affected children. These cases emphasize the variable nature of coeliac disease, its familial occurrence and the need to exclude the disorder in cases of undiagnosed (familial) short stature.