Clinical Briefs

With Comments from Russell H. Greenfield, MD. Dr. Greenfield is Clinical Assistant Professor, School of Medicine, University of North Carolina, Chapel Hill, NC; and Visiting Assistant Professor, University of Arizona, College of Medicine, Tucson, AZ.

Kombating Bone Weakness: Vitamin K and Osteoporosis

Source: Knapen MHJ, et al. Vitamin K2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women. Osteoporosis Int. 2007;18: 963-972.

Goal: To determine whether high vitamin K2 intake has a positive effect on BMC and femoral neck width.

Study Design: Randomized clinical intervention trial.

Subjects: Healthy, non-osteoporotic postmenopausal women between 55-75 years of age (n = 325).

Methods: Participants were recruited through local newspapers, and stratified by age (n = 105 aged 55-65 years, and n = 220 between 65-75 years of age). Subjects received either vitamin K2 (MK-4, menatetrenone) 45 mg/day or placebo over a course of 3 years. Daily calcium intake was assessed using a validated food frequency questionnaire. Bone mineral content (BMC) and hip geometry were assessed by dual energy X-ray absorptiometry (DXA-BMD). Bone strength indices of the femoral neck were calculated from DXA-BMD, femoral neck width (FNW), and hip axis length (HAL). DXA-BMD and BMC were determined at baseline and after 1, 2, and 3 years of treatment. Fasting blood and 2-hour fasting urine samples were obtained at baseline and after 3, 6, 12, and 36 months of treatment.

Results: A total of 257 women completed the 3-year trial (n = 133 in the K2 group and 124 in the placebo arm). Vitamin K2 did not affect DXA-BMD results, but BMC decreased at a significantly lower rate than in the placebo group, and the FNW increased relative to placebo, suggesting increased bone at this site. Subjects who received K2 maintained hip bone strength during the 3-year trial, while placebo recipients experienced significant decreases in bone strength in the location over the same time frame. Calculated bending strength remained essentially constant during the course of the trial in the K2 group. Markers of bone formation were higher in the K2 group, but there was no effect on markers for bone resorption or urinary calcium excretion. Favorable effects were found for both the younger and older age groups. Side effects were comparable between K2 and placebo groups.

Conclusion: Vitamin K2 helps maintain femoral neck bone strength in postmenopausal women by improving BMC and FNW, while having little impact on DXA-BMD.

Study strengths: Thorough nature of follow-up; indices chosen for repeated measure; age stratification.

Study weaknesses: A 21% dropout rate (most during the first 3 months of the trial); focused solely on non-osteoporotic women.

Of note: Dietary vitamin K occurs as K1 (phylloquinone, found mainly in green leafy vegetables) and the better absorbed K2 (a group name for a series of related compounds known as menaquinones that are produced by bacteria and found mostly in foods like cheese and fermented soy beans); studies of vitamin K with a clinical end point of DXA-BMD changes have shown contradictory results; DXA-BMD measurements provide the amount of calcium per area but do not take into account the 3 dimensions of bone; low circulating vitamin K levels may be a marker for poor nutritional status; many believe that the distribution of bone mass is more important than total bone mass when regarding bone strength; the dose of K2 employed was extremely high, essentially making it a drug and not a dietary supplement; MK-4 has a short biological half-life, while MK-7 (found in natto) has a relatively long half-life, thereby resulting in more consistent plasma levels, and making MK-7 a possible choice for use as a low-dose food supplement (however, clinical data are lacking); it is not clear from this trial whether MK-4 has a beneficial impact on vertebral bone strength, though some Japanese studies suggest that to be so.

We knew that: Vitamin K mediates the synthesis of proteins regulating bone metabolism (such as osteocalcin); the recommended daily intake of vitamin K (all forms) in support of clotting factor synthesis is 100-120 mg/day, but requirements for other systems are likely higher; DXA-BMD is often used as a surrogate marker for bone strength. Unlike BMC, DXA-BMD does not take into account the size and thickness (geometry) of bone, which provide independent contributions to bone strength and reduced fracture risk; population-based studies suggest an association between fracture risk and vitamin K1 intake, but K2 intake was not measured; studies on people receiving vitamin K antagonists (oral anticoagulant therapy) have reported lower DXA-BMD and increased fracture risk; studies in which DXA-BMD is the only clinical endpoint do not give conclusive evidence on bone strength.

Comments: A number of studies have considered the use of vitamin K in helping to promote bone health and preventing fractures, many of them with positive results. However, results of this well-done prospective trial take consideration of vitamin K to a new level. It is true that people with osteoporosis were not included in the sample, but the findings are nonetheless reason for optimism.

The authors state that further study should involve those with osteoporosis and include therapy with both supplements (calcium and vitamin D, for example) and medications (bisphosphonates) with known effects on DXA-BMD. With appropriate dosage yet to be identified, it is too early to begin recommending high-dose vitamin K to people at risk for, or who have, osteoporosis, but this is an area of research that should heat up quickly, and hopefully we will have answers soon to guide clinical recommendations.

What to do with this article: Keep a hard copy in your file cabinet.

Of Mesmer and Morphine — Hypnosis and Surgery

Source: Montgomery GH, et al. A randomized clinical trial of a brief hypnosis intervention to control side effects in breast surgery patients. J Natl Cancer Inst. 2007;99:1304-1312.

Goal: To test the hypothesis that a brief pre-surgery hypnosis intervention would decrease intraoperative anesthesia and analgesia use and side effects associated with breast cancer surgery, and that it would be cost effective.

Study Design: Randomized clinical trial.

Subjects: Women recruited from 2 surgical practices (mean age 48.5 years, n = 200) scheduled to undergo outpatient excisional breast biopsy or lumpectomy at the Mount Sinai School of Medicine (MSMC).

Methods: Subjects were randomized to a standardized 15-minute session of either non-directive empathic listening or a hypnosis session. Both interventions were provided on the morning of surgery within one hour of beginning the procedure. Subjects were further randomized by surgery type (lumpectomy or excisional breast biopsy). All patients were treated with the same monitored anesthesia protocol. Intraoperative use of analgesia and anesthesia was assessed (lidocaine and fentanyl, and propofol and midazolam) through review of medical records. Pain and side effects were evaluated using a visual analog scale (VAS) prior to discharge on the day of surgery. Surgeons, anesthesiologists, and assessment personnel were blinded to intervention. Hypnosis sessions took place in a private room, no outcome data were collected by clinical staff or interventionists (PhD-level clinical psychologists with advanced training in clinical hypnosis), and the same interventionists met with all patients (hypnosis and attention control). All sessions were audiotaped, and a random sample of 20% of audiotapes were reviewed to ensure adherence to protocol. Financial data were based on costs at MSMC, and included salaries, medication costs, and time spent in clinical areas, and hypothetical outside institutional costs were calculated where costs were both significantly (20-40%) higher and lower than those at MSMC (dollar values only assigned to those outcome variables that differed between the groups).

Results: Participants in the hypnosis group required less propofol (32.63 mg) and lidocaine (6.86 mL) than the attention control group, but no differences were noted for use of fentanyl, midazolam, or recovery room analgesics. Those in the hypnosis group reported less pain intensity, pain unpleasantness, nausea, fatigue, discomfort, and emotional upset as well. Surgical time was 10.60 minutes less in the hypnosis group. Institutional cost per patient was $772.71 less in the hypnosis group, mainly due to reduced surgical time.

Conclusion: A brief 15-minute pre-operative session of hypnosis decreases use of peri-operative pharmacotherapeutic agents in women undergoing breast cancer-related surgery. Hypnosis also reduces nausea, fatigue, discomfort, and emotional upset at discharge, in addition to institutional costs related to patient care.

Study strengths: No patients lost to follow-up; use of standardized sessions; blinding of staff; effort to exclude individual nature of interventionists on outcomes.

Study weaknesses: Subjects were not blinded to the interventions; no formal assessment of blinding adequacy.

Of note: Breast cancer patients represent the largest cohort of female cancer patients treated surgically in the United States each year; patients undergoing full axillary node dissection were not eligible for participation; subjects did not undergo assessment for hypnotizability because prior data suggest almost 9/10 subjects would be responsive to hypnosis; the scripted hypnosis session included imagery for muscle relaxation, suggestions for pleasant visual imagery and to experience relaxation and peace, and specific symptom-focused suggestions (to experience reduced pain, nausea and fatigue); in the attention control group, interventionists allowed subjects to direct the flow of conversation and provided supportive comments according to standardized procedures; no relationship was found between study group assignment and anesthesiologist or psychologist.

We knew that: Hypnosis has been defined as a state of highly focused attention, with a constriction in peripheral awareness and a heightened responsiveness to social cues; post-surgical complications like nausea and pain commonly prolong recovery room stays, delay discharge, lead to unanticipated re-admission, and require additional pharmacotherapeutic intervention, all of which are associated with increased costs; prior data strongly suggest that pre-surgical hypnosis can reduce the need for medication and reduce post-surgical symptoms and enhance recovery (by reducing pain, nausea, and length of hospital stay); the mechanism of action of clinical hypnosis has yet to be fully agreed upon; children are generally more hypnotizable than adults, yet prior studies suggest that the benefits of peri-operative hypnosis are independent of age and hypnotizability.

Comments: Clinical hypnosis presents a conundrum for conventional medicine. There are ample data supporting its use in a myriad of clinical circumstances, most notably prior to invasive procedures, yet relatively few physicians and hospital administrators have an understanding of the intervention, and many have a skewed perspective on hypnosis overall, mainly due to its use in the entertainment industry. This study should help to close the hypnosis credibility gap. Patients benefited and hospitals incurred lesser costs when employing a brief pre-operative hypnosis session for women with breast cancer. The intervention was standardized and took a total of 15 minutes. While the mechanism of action of clinical hypnosis remains elusive, we are presented with a therapy that is apparently effective in ways both clinical and fiscal, and safe in practiced hands. Do we need to know the mechanism of action before employing such a therapy? The answer is no.

It is long past time for clinical hypnosis to be added to the armamentarium of practitioners in and outside the hospital setting. This article, and the accompanying editorial, can be used by readers to help establish an environment where hypnosis is a viable clinical therapeutic option.

What to do with this article: Make copies to hand out to your peers.

Flakes? Cereal Eaters and Body Weight

Source: de la Hunty A, et al. Are people who regularly eat breakfast cereals slimmer than those who don't? A systematic review of the evidence. Nutr Bull. 2007; 32:118-128.

Goal: To determine the relationship, if any, between regular breakfast cereal consumption (at breakfast time) and body weight.

Study Design: Systematic review (focus on 11 identified references).

Methods: MedLine and the Cochrane Register of Controlled Trials were searched and additional studies were identified from published or personal reference lists. A total of 11 studies met selection criteria and addressed breakfast cereal consumption and body mass index (BMI), breakfast cereal intake and weight gain, and breakfast cereal intake and waist-hip ratio.

Results: Five trials addressing breakfast cereal consumption and BMI were performed in adults (3 cross-sectional observational studies, 1 prospective, and 1 randomized trial). Results showed people who regularly eat breakfast cereals tend to have a lower BMI and are less likely to be overweight than those who eat breakfast cereals less often. Another 4 BMI studies focused on children (3 cross-sectional studies and 1 prospective trial) and again found that consistent breakfast cereal ingestion is associated with lower BMI and a decreased incidence of being overweight. Data from one trial (the SU.VI.MAX trial) showed that regular cereal eaters tended to have lower waist-to-hip ratios than non-cereal eaters. The one randomized trial addressing breakfast cereal consumption in adults and body weight did so over a 12-week period in moderately obese women who partook of an identical weight loss program except that some subjects habitually ate breakfast cereals and some did not. Cereal eaters lost more weight than non-eaters, even when considering those who only occasionally ate breakfast cereal. The authors noted that cereal eaters also ate fewer unplanned snacks during the course of a day. A prospective trial of cereal intake, BMI, and weight gain in adult men found that regular cereal eaters were less likely to become overweight than their non-cereal eating counterparts over a follow-up period of up to 13 years. The one prospective trial addressing children, cereal intake, and BMI included data from over 2,300 girls aged 9-10 years, and showed that regular breakfast cereal eaters were significantly leaner than non-cereal eaters. For all cross-sectional trials reviewed, the data did not suggest that cereal eaters take in lower amounts of energy than those who consume cereal less frequently.

Conclusion: The evidence in favor of a relationship between regular consumption of breakfast cereals and healthy body weight is consistent, but there are, as yet, no agreed upon mechanisms of action that would suggest causality.

Study strengths: Inclusion of pediatric data.

Study weaknesses: Those inherent in systematic reviews, including possible bias; inconsistent data on total energy intakes; paucity of prospective, randomized data.

Of note: Children appear to have improved concentration and learning after eating breakfast; not all study results reported in this review met statistical significance.

We knew that: Research data increasingly show that people who regularly eat breakfast tend to weigh less than those who skip breakfast, but the finding is not true for all types of breakfast (in fact, the association disappears in some assessments when adjusted for breakfast cereal consumption, suggesting that it is cereal that drives the interrelationship); people who regularly eat breakfast tend to have higher micronutrient intakes, likely due in part to fortification of breakfast cereals; breakfast cereal eaters tend to exercise more and drink alcohol less than non-eaters.

Comments: Long have we heard that breakfast is the most important meal of the day, and there are plenty of different varieties of breakfast food, certainly not all of which could be considered healthy fare. But breakfast and optimized body weight? This study would suggest it's true, at least for cereal. Those who regularly ate cereal at breakfast, child and adult, tended to be leaner across all studies evaluated in this review, though there is insufficient data with which to make a cause and effect statement. Could the results be due to associated lifestyle factors for those who eat cereal at breakfast? It's likely, but the results do point to the possibility that enjoying cereal at breakfast may become part of a multifaceted weight management program, even if only to help ensure adequate daily nutrient intake.

What to do with this article: Keep a copy on your computer.