2-1 BETA-BLOCKERS IN HEART FAILURE: Clinical Applications
      Beta-blockers should be initiated only in HF patients who are clinically euvolemic or receiving stable doses of diuretics without signs of fluid overload (pulmonary rales, jugular venous distention, or more than minimal peripheral edema).
      Although there is currently insufficient evidence to recommend beta-blocker use in patients with asymptomatic LV dysfunction, guidelines suggest that they should be given because they reduce progression to HF.
      Dosing should be guided by "start low" (about 1/10 the maximum dosage), "go slow" principle. This calls for doubling the dose every 2 to 4 weeks until the target is reached. When a dose is titrated upward, symptomatic hypotension can be expected to be greatest within 24 hours and improve within the next few doses.
      There is some evidence for benefit from continuing very low doses of beta-blocker.
      Practical point: "All heart failure (HF) patients with left ventricular (LV) systolic dysfunction should be considered for beta-blockers to reduce morbidity and prevent mortality."

2-2 BETA-BLOCKER THERAPY IN HEART FAILURE: Scientific Review
      Acute treatment with beta-blockers decreases BP and cardiac index; long-term administration is associated with significant increases in ejection fraction and cardiac index, and a decrease in left ventricular diastolic pressure. A decrease in myocardial mass and LV volume improves hemodynamics. Beta-blockers have been evaluated in more than 10 000 patients with all grades of HF. Five meta-analyses have arrived at the same conclusion: beta-blockers are associated with a consistent 30% reduction in mortality and a 40% reduction in hospitalizations for HF. (NNT 1 year to prevent one death = 26.)
      "The evidence suggests that virtually all patients with heart failure caused by LV systolic dysfunction benefit from beta-blockers.”

2-3 GUIDELINES FOR MANAGING COMMUNITY ACQUIRED PNEUMONIA
      Streptococcus pneumoniae remains the most common bacterial pathogen. Mycoplasma and chlamydia each cause about 10% of all pneumonias. Primary care clinicians make most of their management decisions without access to chest X-ray. Diagnosing pneumonia clinically is inaccurate and the etiological agent cannot be reliably predicted from clinical features.
      The respiratory rate is a most important indicator of disease severity. In the elderly, assessment of the mental state is especially important. Guidelines identify four core adverse prognostic features: confusion; elevated blood urea; respiratory rate above 30; and BP less than 90 systolic or 60 diastolic. If available, pulse oximetry (saturation less than 92%) indicates severe disease.
      Patients under age 50 years without comorbidity and lacking any of the core features, do not usually require hospitalization.
      Practical point: See the abstract for suggested oral antibiotics for outpatients.

2-4 REDUCTION IN THE INCIDENCE OF TYPE 2 DIABETES WITH LIFESTYLE INTERVENTION OR METFORMIN
      Lifestyle changes (physical activity, diet, weight loss) and metformin (Glucophage) both reduced incidence of diabetes in persons at high risk. Lifestyle changes were more effective.
      Practical point: This is one of several recent studies concluding that diabetes 2 can be prevented by improving lifestyle. Indeed, it might be possible to “cure” diabetes by lifestyle – ie, reduce glucose intolerance to a level below the WHO definition. Many people would rather take a pill to prevent diabetes than discipline themselves. I think this is misuse of an important drug.

2-5 DIETARY PATTERNS AND RISK OF TYPE 2 DIABETES MELLITUS IN MEN
      Compared with the prudent diet (vegetables, fruit, fish, poultry, whole grains), the western type diet (red meat, processed meats, french fires, high-fat dairy, refined grains, sweets and deserts) was associated with an increased risk of DM-2. The more outrageous the intake of western type foods, the higher the risk. Combining a long history of intake of western type foods with obesity and a sedentary lifestyle greatly increased risk. However, the diet was independently related to these factors, and the western diet alone increased risk.
      Practical point: Another important benefit of a disciplined lifestyle.

2-6 QUALITY-OF-LIFE AND DEPRESSIVE SYMPTOMS IN POSTMENOPAUSAL WOMEN AFTER RECEIVING HORMONE THERAPY: Results from the Heart and Estrogen/Progestin Replacement Study (HERS) Trial
      HRT may have either positive or negative effects on quality of life depending on the presence or absence of menopausal symptoms. Women with menopausal symptoms have improvement in emotional dimensions of quality of life when given HRT.
      For women without menopausal symptoms, HRT was associated with net negative effects on physical dimensions of quality of life.
      Practical point: Menopausal symptoms are the only reason to prescribe HRT. And the only effective treatment. Other drugs are more effective in preventing osteoporosis and cardiovascular disease.

2-7 POSTMENOPAUSAL HORMONE THERAPY AND QUALITY OF LIFE
      All women in the study were well past the age of onset of menopausal symptoms. All had a history of cardiovascular events in the past which, along with their age, placed them at high risk for recurrence. The decline in quality of life in this cohort therefore may have been due to the increased rates of cardiovascular events associated with HRT in the first year of replacement therapy. (Presumably due to a combination of high risk and a pro-thrombotic effect of HRT. RTJ) Thus, in women with established cardiovascular disease, HRT may cause more harm than benefit.
      The risk of cardiovascular events and other outcomes among younger women and for those without cardiovascular disease are less clear.
      For prevention of osteoporosis and lipid disorders, more effective drugs are available.
      Practical point: Menopausal symptoms make some women miserable. HRT is the most effective treatment. Despite the possible risk in women with many risk factors for heart disease, or with past history of cardiovascular disease, benefits may outweigh possible harms. Prophylactic aspirin and statin drugs may be given to lessen harms of HRT.

2-8 ASSOCIATION OF NONSTEROIDAL ANTI-INFLAMMATORY DRUGS WITH FIRST OCCURRENCE OF HEART FAILURE AND WITH RELAPSING HEART FAILURE
      NSAID use was not associated with an increased risk of a first episode of HF.
      In patients with past history of HF, current use of NSAIDs substantially increased risk of relapse.
      Practical point: Use NSAIDs with caution in persons with heart failure history. And in those with hypertension.

2-9 RESIDUAL LIFETIME RISK OF DEVELOPING HYPERTENSION IN MIDDLE-AGE WOMEN AND MEN.
      In persons with normal BP (<140/90) at ages 55 and 65, the likelihood of development of hypertension as they grow older approaches 90%. Efforts should be directed at primary prevention. Lifestyle management is essential. "The approach of waiting for hypertension to develop and only then treating the elevated blood pressure is injudicious."
      Practical point: Drug therapy is not indicated in many older persons with BP > 140/90. Primary care clinicians use their clinical judgement. They resist rigid applications of “evidence-based medicine” because they know EBM inclusion and exclusion criteria simply do not apply to many of their individual patients.

2-10 AORTIC STENOSIS
      When is the optimal time to intervene? What is the best intervention? In adults with calcified valves, balloon angioplasty may temporarily relieve symptoms but does not prolong survival. Replacement of the valve is required. Surgery is usually delayed until symptoms develop. Once angina, syncope, dyspnea or other symptoms of heart failure develop, the patient’s life span is drastically shortened unless the valve is replaced. The 10 year survival rates among those undergoing successful valve replacement approaches that of the normal population.
      Practical point: “There is overwhelming evidence that once patients with severe aortic stenosis become symptomatic, prompt valve replacement is indicated." Sooner or later primary care clinicians will encounter a patient with AS at the most unexpected times.

2-11 PHYSICIAN-RELATED BARRIERS TO THE EFFECTIVE MANAGEMENT OF UNCONTROLLED HYPERTENSION
      “Our findings suggest that an important reason why physicians do not treat hypertension more aggressively is that they are willing to accept an elevated systolic BP in their patients.”
      Practical point: I believe primary care clinicians have good reason to accept a higher BP in some individual patients.

2-12 EFFECTS OF HYALURONATE SODIUM ON PAIN AND PHYSICAL FUNCTIONING IN OSTEOARTHRITIS OF THE KNEE
      For resting pain relief, HS seems to be as effective as NSAIDs. HS may be superior to placebo or NSAIDs for improving functional performance and relieving pain with physical activity.
      Practical point: Based on adequate informed consent, some patients will accept HS injections and will report benefit.

2-13 HYALURONATE SODIUM INJECTIONS FOR OSTEOARTHRITIS
Hope, Hype, And Hard Truths
      This editorial presents a contrary view. It concludes that the present data fails to demonstrate and benefit beyond the placebo effect
      Practical point: Primary care clinicians frequently face divergent opinions such as this. They then depend on the individual patient’s acceptance and outcomes from the treatment

2-14 PLASMA HOMOCYSTEINE AS A RISK FACTOR FOR DEMENTIA AND ALZHEIMER’S DISEASE
      An increased plasma homocysteine level was a strong, independent risk factor for the development of dementia and Alzheimer’s disease.
      Practical point: The homocysteine connection lingers on in the literature. While not proven, the benefit/harm-cost of folate, B12, and B6 therapy may be high because harm and costs are low.

2-15 ROLAXIFENE AND CARDIOVASCULAR EVENTS IN OSTEOPOROTIC POSTMENOPAUSAL WOMEN
      There was no evidence that raloxifene caused an early increase in risk of CV events in the group overall, or in the subset of women at high risk for CHD
      Raloxifene for 4 years significantly reduced the risk of CV events among the subgroup at high risk and among those with established CHD.
      Practical point: None at present. Wait for future developments.

2-16 OVERCOMING RESTENOSIS WITH SIROLIMUS
      Preliminary studies using sirolimus coated stents have been quite promising and should reduce restenosis rate.
      Practical point: This will probably be another advance tilting patients with coronary disease toward PTCA and away from CABG.

2-17 RECOMBINANT HUMAN PARATHYROID HORMONE
      A recent FDA panel recommended approval of an N-terminal fragment of parathyroid hormone for treatment of osteoporosis (teriparatide; Forsteo). The application for approval was based on evidence from a randomized trial in women with osteoporosis demonstrating large increases in cancellous (trabecular) bone formation in the vertebral bodies and a greatly reduced risk of spine fracture.
      PTH expands the bony envelope in the hip. Thus, its biggest impact may be in prevention of fractures of the hip. "From being one of medicine's most untreatable disorders, osteoporosis is following the footsteps of hypertension and proving amenable to treatment through several targets: estrogen receptors; osteoclasts (by targeting them with bisphosphonates) and now parathyroid hormone receptors."
      Practical point: A potential advance in prevention and treatment of osteoporosis. Watch for developments.

2-18 INTRAVENOUS ZOLEDRONIC ACID IN POSTMENOPAUSAL WOMEN WITH LOW BONE MINERAL DENSITY
      Zoledronic acid infusions given at intervals for up to 1 year produced effects on BMD and bone turnover as great as those achieved by oral bisphosphonates.
      One annual infusion might be an effective treatment.
      Practical point: A potential advance in prevention and treatment of osteoporosis. Watch for developments. See who wins.

British recommendations for outpatient treatment:

	Cost
Amoxicillin 1 gram orally three times daily for 10 days	$60
Erythromycin (generic) 500 mg orally four times daily	Inexpensive
Clarithromycin (Biaxin) 500 mg orally twice daily for 10 days	$80

US recommendations for outpatient treatment
(Johns Hopkins guide (http://www.hopkins-abxguide.org)

Doxycycline (generic)100 mg orally twice daily for 7-10 days	Inexpensive
Azithromycin (Zithromax) 500 mg orally once daily for 7 days	$104
Clarithromycin (Biaxin) 500 mg orally twice daily 7-10 days	$80
Erythromycin (generic) 500mg orally four times daily 7-10 days	Inexpensive

1. Entered over 3000 non-diabetic persons who had elevated fasting and post-load plasma glucose concentrations. Mean age = 51; mean body mass index = 34. (Grossly obese.)
2. Baseline fasting plasma glucose concentrations were between 95 and 125 mg/dL (mean = 106); and between 140 to 199 mg/dL 2 hours post 75 g glucose load (mean = 164). Presence of both was required for entrance into the study. Participants were overweight and had elevated fasting and post-load glucose concentrations — 3 of the strongest risk factors.
3. Randomized to: 1) metformin (Glucophage) 850 mg twice daily. Dose was increased after one month to 1700 mg twice daily unless GI symptoms warranted a longer period (84% reached this goal); 2) lifestyle modification, or 3) placebo.
4. Lifestyle intervention was systematic and intensive and had the goal of at least a 7% weight loss, and at least 150 minutes of physical activity per week. Participants received individual counseling.
5. Primary outcome was diabetes — diagnosed by a fasting glucose of 126 mg/dL or higher, or a 2-h post glucose load concentration 200 or higher.
6. Follow-up = 3 years

1. Incidence of diabetes per 100 person-years: placebo – 11; metformin – 7.8; lifestyle – 4.8.
2. 55% of participants in lifestyle achieved the goal of weight loss of 7% or more; 74% met the goal of physical activity.
3. Daily energy intake decreased a mean of 249 kcal in the placebo group; 296 kcal in the metformin group; and 450 kcal in the lifestyle group. Average fat intake in the lifestyle group decreased by 7%, but only 1% in the other groups.
4. Over 4 years, mean fasting glucose rose from 106 to 114 in the placebo group; and to 108 in the other 2 groups.
5. Over 4 years the percentage of individuals maintaining normal fasting and post-load glucose levels was higher in the lifestyle group than in the other 2 groups. Metformin provided less effective maintenance of normal levels.
6. To prevent one case of diabetes during 3 years, 7 persons would have to participate in lifestyle changes, and 14 would have to take metformin.

1. “Our results support the hypothesis that type 2 diabetes can be prevented or delayed in persons at high risk.”
2. Lifestyle intervention was significantly more effective than metformin.

1. The Health Professionals Follow-up Study followed over 42 000 male health professionals age 40 to 70. None had diagnosed diabetes, cardiovascular disease, or cancer at baseline.
2. Identified and validated two major dietary patterns using a frequency analysis based on data from a 131 item food frequency questionnaire.
3. Used dietary pattern scores to rank participants according to the degree to which they conformed to each dietary pattern. Divided dietary pattern scores into quintiles for both the prudent and the western diet.
4. Determined rate of development of DM-2 according to the quintiles of each diet.
5. Follow-up – 12 years.

1. During 12 years, 1321 cases of DM-2 were documented.
2. Western diet was associated with an increased risk of DM-2 (relative risk of 1.6). Those in the highest quintile of intake of the western type foods had over 2 times the incidence of DM-2 than those in the lowest quintile. (Ie, the more outrageous the intake of red meat, french fries, high fat dairy, and sweets, the higher the risk.) Foods with major contributions to the western pattern were all positively associated with risk of DM-2. Risks ratios for extreme quintiles of consumption of red meat = 1.3; processed meats = 1.5; high-fat dairy = 1.2.)
3. Conversely, in the prudent diet group, those in the highest quintile (ie, the best of the prudent diet) had a slightly reduced risk of developing DM-2 compared to those in least compliant group. Relative risk of 5th quintile vs 1st = 0.84. (By my calculation the absolute difference between the worst of the western diet and the best of the prudent diet would result in one less patient in every 1000 each year being spared development of diabetes. RTJ)
4. Risks were adjusted for potential confounders including body mass index, physical activity, and smoking. (Ie, the risk was dependent on the diet patterns alone.)
5. However, as expected, individuals within each quintile of the western diet who were obese had the highest risk, as were those with a positive family history and those who were sedentary.

1. The type of diet (prudent vs western) was associated with risk of developing DM-2 independent of other risk factors such as body mass index and lack of physical activity.
2. It seems unlikely that a single dietary factor was responsible for the observed association.

1. Randomized, placebo-controlled, double-blind trial entered over 2700 postmenopausal women (mean age = 67); 434 (15%) had flushing at entry. (The investigators considered flushing a surrogate for menopausal symptoms in general.)
2. All had documented coronary artery disease. (Ie, at high risk of recurrence.)
3. Randomized to: 1) HRT ?- 0.625 mg of conjugated equine estrogen (Premarin) plus 2.5 mg medroxyprogesterone, or 2) placebo
4. Outcome measures = Physical activity index, energy/fatigue scale, mental health scale, and depressive symptoms.
5. Follow-up = 3 years.

1. In all patients (including placebo) scores for physical function and energy/fatigue declined significantly over 3 years (Not unexpected since subjects were elderly and had documented coronary disease. RTJ) However, those receiving HRT had slightly greater declines.
2. Depressive symptoms were not significantly changed.
3. In the group with flushing, those receiving HRT had improved mental health and fewer depressive symptoms compared with those receiving placebo. HRT was associated with significant improvements in flushing, vaginal dryness, and sleep.
4. Adverse effects during 3 years of follow-up:

   	HRT	Placebo
   Death	6.7%	5.5%
   Non-fatal MI	7.0%	6.9%
   Unstable angina or revascularization	16.2%	17.2%
   Venous thromboembolism	2.0%	0.7%

5. No difference in stroke or peripheral vascular disease. Increase in biliary tract surgery

1. In this large trial of clinically stable postmenopausal women (mean age 67.with documented coronary artery disease (a high risk group), HRT had overall significant negative effects on physical function.
2. The effect of HRT on quality-of-life was modified by the presence or absence of postmenopausal symptoms. Among women who continue to have symptoms, HRT significantly improved mental health and depressive symptoms.
3. "The results of this investigation do not necessarily apply to younger women and women without heart disease."

1. Followed over 7000 patients from an interview date until: 1) diagnosis of a first episode of HF, or 2) diagnosis of recurrent HF
2. Excluded all patients with signs and symptoms of HF at baseline and all with left ventricular fractional shortening less than 30%.
3. Determined 1) a first occurrence of HF, and 2) a recurrence of HF in patients with past history of HF.
4. Determined use of NSAIDs by computerized pharmacy records.
5. Follow-up = 8 years.

1. A first episode of HF developed in 345 participants (5%) during follow-up. Current use of NSAIDs was not related — relative risk of incident HF = 1.1 in patients taking NSAIDs vs non-takers.
2. In the group with past history of HF, those who filled at least one prescription for NSAIDs had an increased risk of recurrence — adjusted relative risk of a relapse = 10.

1. Current use of NSAIDs was not associated with increased risk of a first occurrence of HF.
2. Use of NSAIDs in patients with a past history of HF was associated with a substantially increased risk of recurrence of HF.
3. Adverse effects of NSAIDs on cardiovascular homeostasis are well known, In the clinical setting of reduced renal perfusion as seen in patients with dehydration, cardiovascular disease, and renal dysfunction, NSAIDs may impair the adequacy of renal prostaglandin production. Impaired renal function, defined as a creatinine level of 1.1 mg/dL or more seems to be associated with an increased risk of NSAID-associated HF.
4. Patients who developed HF during the study and continued to take NSAIDs were at substantially increased risk of relapse. Cardiovascular homeostasis is much more likely to be prostaglandin dependent in patients with prevalent HF than in patients with unimpaired left ventricular function.

1. Community-based prospective cohort study estimated the residual lifetime risk of hypertension in older US adults (normotensive at baseline ages 55 and 65), and evaluated temporal trends in risk.
2. Followed 1300 participants for development of hypertension (> 140.90) or use of antihypertension medications. (Risk increases markedly during and after the sixth decade of life.)

1. The residual lifetime risk of developing hypertension (>140/90 regardless of treatment) for subjects normotensive at ages 55 and 65 rose incrementally from about 55% in 10 years to over 90% in 20 to 25 years.
2. The lifetime probability of receiving antihypertension treatment was 60%

1. In individuals who had normal BP at ages 55 and 65, the residual lifetime risk for developing hypertension (BP > 140/90, or taking antihypertension medication) was about 90%.
2. These data indicate the residual risk of persons who have normal BP at ages 55 and 65. It is important to note that a considerable proportion of individuals with hypertension have the onset at an earlier age. Therefore, the actual lifetime risk for hypertension for younger individuals may be different.
3. On an individual basis, risk will vary according to factors such as obesity, family history, dietary sodium and potassium intake, and alcohol consumption.
4. Control of stage 1 hypertension (140/90 -159/99) is important. A substantial proportion of cardiovascular diseases is attributable to stage 1.
5. Lifestyle management is essential. "The approach of waiting for hypertension to develop and only then treating the elevated blood pressure is injudicious."

1. Descriptive survey study sampled 270 patient visits (median age = 69) to primary care physicians to identify patients with uncontrolled hypertension. Determined practice patterns. Lifestyle recommendations were not considered.
2. The average BP was 152/84 during the prior 6 months. Almost all were taking antihypertension drugs.

1. Pharmacological treatment was initiated or changed at only 38% of visits despite documented hypertension (their definition >140/90) for at least 6 months before the most recent visit.
2. At 93% of the visits, systolic BP was 140 mm systolic or higher; 35% were 150 or higher.
3. Reason given most frequently for not changing the regimen was the physician was satisfied with the BP response. On average, physicians reported that 150 was the lowest systolic BP at which they would recommend pharmacological treatment; and a diastolic of 91.
4. Other reasons for not recommending change were: the focus of the visit was not on BP; competing medical problems; need to continue monitoring the patient before change in drug.
5. Patients were very satisfied with their care even though their BP was not controlled.

1. Uncontrolled hypertension is a significant public health problem. Only about 25% of patients are adequately controlled.
2. The study suggested that physicians placed more importance to the diastolic BP than to the systolic.
3. Adverse drug effects have been identified as a factor related to physician prescribing patterns. Quality-of-life is reduced as intensity of treatment is increased. Other studies have reported that many switched because of adverse drug effects. About 10% stopped the drugs completely.

1. Randomized, double-blind placebo controlled trial entered 120 patients (mean age 67) with unilateral medial compartment knee OA.
2. Randomized to 4 treatment groups:

   1) 2 mL HS injected at a concentration of 10 mg/mL + placebo.	[HS alone]
   2) NSAID (75 mg diclofenac and 200 mg misoprostol) + HS injection.	[NSAID + HS]
   3) NSAID + placebo.	[NSAID alone]
   4) Placebo	[Placebo]

3. HS was injected once weekly over 3 weeks. NSAIDs and placebo given orally twice daily over 12 weeks.
4. Main outcomes: 1) Global measure of pain, stiffness, and disability, 2) Visual analogue scores for pain at rest and following functional walking and stepping, and 3) Functional performance (exercise time, heart rate, and predicted maximum oxygen uptake).
5. Outcomes were measured at baseline, and weeks 4 and 12.

1. At week 12: Compared with baseline, HS alone, HS + NSAID, and NSAID alone were associated with significantly greater improvement in pain scale and score for resting pain, and improved self-paced walking and stepping
2. HS alone, and HS + NSAID were associated with significantly less pain during walking and stepping.
3. HS alone was associated with significantly faster self paced walking and stepping.
4. Predicted maximum oxygen uptake was significantly higher with HS alone and HS + NSAID.

1. This study supports the use of visco-supplementation with HS for treatment of OA of the knee.
2. The effect of HS on activity-related pain and functional performance seems to improve with time from intervention. This contrasts with the effect of NSAIDs which did not show continued improvement after 4 weeks.
3. Exercise is also recommended as standard treatment. However, adoption rates are low. Better adoption of simple resistive exercise therapy is needed to complement HS therapy.
4. HS can be re-administered over time with no apparent adverse effects.

1. Entered over 1000 subjects (mean age = 76) from the Framingham study. None had dementia.
2. Examined the relation between plasma total homocysteine, measured at baseline, and risk of newly diagnosed dementia on follow-up.
3. Also had determined homocysteine levels 8 years previously.
4. Determined plasma concentrations of folate, vitamins B6, and B12.

1. Over a follow-up period of 8 years, dementia developed in 111 subjects (10%) – 83 with a diagnosis of Alzheimer’s.
2. Adjusted relative risk of dementia was 1.4 for each increase of one standard deviation in homocysteine level at baseline and 8 years earlier. Elevation of homocysteine occurred well before the onset of clinical manifestations.
3. An increment of 5 umol/L increased risk by 40%. With a level greater than 14 umol/L (defined as hyper-homocysteinemia) risk of dementia and Alzheimer’s nearly doubled.
4. Low serum levels of folate and vitamins B12 and B6 have been associated with elevated homocysteine levels. In this study, the observed association between homocysteine and risk of dementia was not significantly altered by adjustment for the plasma levels of these vitamins.

1. This prospective observational study indicated a strong, graded association between plasma homocysteine and risk of dementia and Alzheimer’s. Individuals with sustained elevations over 8 years had the greatest risk of dementia.
2. The magnitude of increases in risk of dementia were similar in magnitude to the increases of the risks of death from cardiovascular causes and stroke associated with similar increments of homocysteine.
3. The association was independent of multiple other risk factors.
4. Elevated homocysteine is associated with carotid atherosclerosis and an increased risk of stroke. Atherosclerosis and stroke in turn increase risk of clinical Alzheimer’s disease.
5. Hyperhomocysteinemia has been related to cerebral microangiopathy, endothelial dysfunction, and impaired nitric acid activity – all factors associated with aging of the brain.
6. Folic acid therapy, alone or in combination with B6 and B12 can reduce plasma homocysteine, but there are no prospective studies of their effect on the incidence of dementia.

1. Multicenter randomized, double-blind, placebo-controlled trial entered over 7700 osteoporotic postmenopausal women (mean age = 67). Determined cardiovascular risk factors at study entry (prior coronary events or multiple cardiovascular risk factors – history of hypertension, hypercholesterolemia, type 2 diabetes).
2. Randomized to: 1) raloxifene 60 mg/d, 2) 120 mg/d, or 3) placebo.
3. Main outcome measures — cardiovascular events (myocardial infraction, unstable angina, coronary ischemia), and cerebrovascular events (stroke and TIA).
4. Follow-up = 4 years.

1. In the overall cohort there were no significant differences between the 3 groups in the number of combined coronary and cerebrovascular events (placebo -3.7%; 60 mg - 3.2%; and 120 mg - 3.7%).
2. Similar results were obtained when coronary and cerebrovascular events were analyzed separately.
3. Among the 1035 women who at baseline had increased cardiovascular risks, those assigned to raloxifene had a significant benefit over 4 years— a lower risk of cardiovascular events compared with placebo.
   In absolute terms:
   

   	Placebo %	Raloxifene %	Absolute difference %	NNT (4y)
   Any cardiovascular event	12.9	7.8	5.1	20
   Any coronary event	7.6	5.0	2.6	38
   Any cerebrovascular event	5.4	2.8	2.6	41

4. During the first year there was no significant difference overall between groups in cardiovascular events. Benefits occurred later among women with established CHD or at increased cardiovascular risk,

1. In this secondary analysis of data from a large study of osteoporotic postmenopausal women, raloxifene did not significantly affect the risk of cardiovascular events in the overall study population (they were at relatively low risk). But it did significantly lower risk of cardiovascular events in a subset of women at high risk.
2. There was no evidence that raloxifene was associated with an early increase in cardiovascular morbidity or mortality overall, even in women at high risk. (Contrast this to the early adverse effect of hormone replacement in women at increased risk. RTJ)
3. 13% of the total population were at high risk of CV events. In this group raloxifene was associated with a 40% reduction in risk of CV events. 1
4. Raloxifene improved total cholesterol and LDL-c levels with no effect on HDL-c. 2

1. Randomized, double-blind, placebo-controlled trial entered over 350 women — all at least 5 years post-menopause. (mean age = 64)
2. All had osteoporosis with BMD at the lumbar spine at least 2 standard deviations below that of young female adults. (T score lower than -2). None had more than one vertebral fracture at baseline.
3. All received a calcium supplement of 1 g/d. (No mention of vitamin D.)
4. Randomized to 1) one of 5 zoledronic acid regimens, or 2) placebo injections.
5. Zoledronic acid regimens:
         Intravenous zoledronic acid 0.25 mg, 0.5 mg , and 1 mg at three month intervals for 1 year. Or 2 doses of 2 mg twice a year, or a total dose of 4 mg once at the beginning of the trial. (Total doses of 1 mg, 2 mg, and 4 mg per year). All infusions were given in 20 mL volume over 5 minutes.
6. Primary end point – change in lumbar spine BMD.

1. There were similar increases in BMD in all zoledronic acid groups. About 5% absolute increase in BMD of lumbar spine and 2.5% in the femoral neck. Placebo BMD declined slightly.
2. Biochemical markers of bone resorption were significantly suppressed during the year in the zoledronic acid groups.
3. Adverse effects: Myalgia, nausea, and fever occurred more often in the zoledronic acid groups – all considered mild. Dropout rates were similar between the zoledronic acid and placebo groups.
   No new vertebral fractures occurred during the study. The drug was “generally well tolerated”.

1. Intermittent intravenous zoledronic acid administration resulted in changes in biochemical markers of bone turnover and in bone mineral density similar to those observed with daily oral bisphosphonates.
2. The study did not define the optimum dose or interval of dosing.
3. How a single dose of zoledronic acid suppresses bone turnover for so long remains to be determined. Prolonged suppression is not due to persistence of the drug in the circulation. (At 24 hours, blood levels are less than 1% of peaks and 40% of the drug has been excreted in the urine.)
4. The balance of the dose is presumably bound to bone and is slowly released back into the circulation. The terminal half life in plasma is 167 hours. It is thought that bisphosphonates are located exclusively on osteoclastic surfaces although other sites and actions are postulated.