Archive for May, 2012

Calcium Supplements and Heart Disease, New Information

Tuesday, May 29, 2012 // Uncategorized

Health doesn’t come in a pill revisited.

Controversy has been brewing since a study was published suggesting a link between heart attack risk and the use of calcium supplements in the British Medical Journal about a year ago.  Here is a recent Journal Watch commentary on an article in Heart.  It suggests that dietary calcium may be inversely related to heart attack risk whereas calcium supplementation is related to increased heart attack risk.  Bottom line:  It continues to appear that nutrients in one’s diet have a beneficial impact on health, but supplements do not.  In fact, they may have an adverse effect on health. 

Calcium Supplements Might Increase MI Risk
Use of calcium supplements is associated with a near doubling of risk for myocardial infarction, but calcium intake through diet does not confer increased risk, according to a study in Heart.
German researchers analyzed data from nearly 24,000 residents aged 35 to 64 who completed questionnaires about diet and supplement use. After 11 years’ follow-up, some 350 people had experienced an MI. People who were in the third quartile of dietary calcium consumption had a lower MI risk, relative to those in the lowest quartile (hazard ratio, 0.69). However, those who took calcium supplements had increased MI risk, compared with nonusers (HR, 1.86).
The authors conclude that calcium supplementation “should be taken with caution.” Editorialists note: “The evidence is … becoming steadily stronger that it is not safe, nor is it particularly effective. … We should return to seeing calcium as an important component of a balanced diet and not as a low-cost panacea to the universal problem of postmenopausal bone loss.”

Here is the abstract from Heart.

Abstract

Background It has been suggested that a higher calcium intake might favourably modify cardiovascular risk factors. However, findings of an ultimately decreased risk of cardiovascular disease (CVD) are limited. Instead, recent evidence warns that taking calcium supplements might increase myocardial infarction (MI) risk.

Objective To prospectively evaluate the associations of dietary calcium intake and calcium supplementation with MI and stroke risk and overall CVD mortality.

Methods Data from 23 980 Heidelberg cohort participants of the European Prospective Investigation into Cancer and Nutrition study, aged 35–64 years and free of major CVD events at recruitment, were analysed. Multivariate Cox regression models were used to estimate HRs and 95% CIs.

Results After an average follow-up time of 11 years, 354 MI and 260 stroke cases and 267 CVD deaths were documented. Compared with the lowest quartile, the third quartile of total dietary and dairy calcium intake had a significantly reduced MI risk, with a HR of 0.69 (95% CI 0.50 to 0.94) and 0.68 (95% CI 0.50 to 0.93), respectively. Associations for stroke risk and CVD mortality were overall null. In comparison with non-users of any supplements, users of calcium supplements had a statistically significantly increased MI risk (HR=1.86; 95% CI 1.17 to 2.96), which was more pronounced for calcium supplement only users (HR=2.39; 95% CI 1.12 to 5.12).

Conclusions Increasing calcium intake from diet might not confer significant cardiovascular benefits, while calcium supplements, which might raise MI risk, should be taken with caution.

Here is the Journal Watch summary on the BMJ article:

Calcium, With or Without Vitamin D, Raises Risk for Adverse Cardiovascular Events

Vascular calcification is one proposed mechanism.

A recent meta-analysis showed that calcium supplementation without vitamin D elevates cardiovascular (CV) risk (JW Gen Med Aug 31 2010). However, whether calcium and vitamin D taken together elevate CV risk is unclear. Although the Women’s Health Initiative (WHI) previously reported that calcium and vitamin D supplements taken together did not elevate CV risk, about half the 36,000 participants were taking nonprotocol calcium and vitamin D at randomization — potentially obscuring the association. To determine whether calcium and vitamin D taken together elevate CV risk, investigators reanalyzed WHI data according to personal use of calcium and incorporated these data in a meta-analysis of eight additional studies.

In the reanalysis of WHI data, women who did not report baseline calcium use who were randomized to daily calcium (1 g) and vitamin D (400 IU) had significantly elevated risks for myocardial infarction, MI or revascularization, and MI or stroke (hazard ratio, 1.2 for each outcome), compared with placebo recipients. In contrast, users of calcium at baseline who were randomized to calcium and vitamin D did not have excess CV risk compared with placebo recipients.

In a meta-analysis of three randomized trials with 20,000 participants, calcium and vitamin D supplementation raised risks for MI, stroke, and a composite of MI or stroke, compared with placebo (relative risk, 1.2 for each outcome). A meta-analysis of nine trials that involved 28,000 participants showed that calcium or calcium and vitamin D supplementation significantly raised risks for MI and a composite of MI or stroke compared with placebo (RR, 1.2 for each outcome). The average duration of the trials was about 6 years.

Comment: These results suggest that calcium supplements, with or without vitamin D, raise risk for adverse CV events. The authors note “calcium supplements acutely increase serum calcium concentration . . . an effect that is sustained during long term treatment, as evidenced by lower levels of parathyroid hormone” and might promote vascular calcification. That baseline users of calcium in the WHI study who were randomized to calcium and vitamin D did not have excess CV risk suggests a dose-response relation does not exist. The authors speculate “the abrupt change in plasma calcium after supplement ingestion” rather than total calcium load causes the adverse effect. What should clinicians do until these results are confirmed or refuted by additional research? One approach would be to advise patients to increase calcium intake through food sources (e.g., milk products), as the aforementioned studies say nothing about this type of calcium intake. Another approach would be to avoid calcium supplementation in patients at high CV risk.

Paul S. Mueller, MD, MPH, FACP

Published in Journal Watch General Medicine May 12, 2011

Citation(s):

Bolland MJ et al. Calcium supplements with or without vitamin D and risk of cardiovascular events: Reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. BMJ 2011 Apr 19; 342:d2040. (http://dx.doi.org/10.1136/bmj.d2040)

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Stupid Medical News

Tuesday, May 15, 2012 // Uncategorized

OK.  Maybe that is too strong a term, but I read a lot of medical journals and these struck me as humorous.

This appears to come from the same people who advise you to take off your eyeglasses and assume the position when the airplane is crashing.

‘Toto, I’ve a Feeling You Should Be Wearing a Helmet’ — CDC Offers Tornado Advice
Wearing a helmet during a tornado may help protect a person’s head, but seeking shelter during an approaching storm is still the best way to stay safe, according to a CDC statement released Thursday.
The statement, which seems to have been issued after National Public Radio attempted to get a comment on the topic, observes that storm-related head injuries cause many deaths and that people “may decide to use helmets to protect their heads.”
The statement continues: “Looking for a helmet in the few seconds before a tornado hits may delay you getting safely to shelter. For those who choose to use helmets, these helmets should not be considered an alternative to seeking appropriate shelter. Rather, helmets should be considered just one part of their overall home tornado preparedness kit to avoid any delay.”

Here is the CDC’s advice.

Media Statement

 

For Immediate Release: May 3, 2012
Contact :CDC Division of News and Electronic Media
(404) 639-3286

CDC Statement on Helmets and Tornadoes

<!–

Main sources of sodium include many common foods

–>The Centers for Disease Control and Prevention continues to recommend, as its first recommendation, that people in the path of a tornado find a shelter or a tornado-safe room. The safest place in the home is the interior part of a basement. If possible, get under something sturdy such as a heavy table or workbench.  If outdoors, lie down in a gully or ditch.

We understand that people who have seen the tragedy that tornadoes can impose are looking for any useful and effective ways to protect themselves. We don’t have research on the effectiveness of helmet use to prevent head injuries during a tornado, but we do know that head injuries are common causes of death during tornadoes, and we have long made the recommendation that people try to protect their heads.  Individuals may decide to use helmets to protect their heads. However, because the time to react may be very short, people who choose to use helmets should know where they are and have them readily accessible.  Looking for a helmet in the few seconds before a tornado hits may delay you getting safely to shelter.  For those who choose to use helmets, these helmets should not be considered an alternative to seeking appropriate shelter. Rather, helmets should be considered just one part of their overall home tornado preparedness kit to avoid any delay.

CDC continues to promote protective measures for use during natural disasters including tornadoes.  For more detailed information, go to http://emergency.cdc.gov/disasters/tornadoes/during.asp.

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U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICESExternal Web Site Icon

DUH?  DID THEY REALLY NEED TO TELL US THIS? IS IT SAFER THAN TEXTING?

Marijuana and Driving Don’t Mix

Acute cannabis use raises risk for motor vehicle accidents.

In laboratory and simulator settings, cannabis consumption impairs driving skills, but whether the same is true for real-world driving is unclear. In this meta-analysis of nine observational studies involving more than 49,000 participants, investigators examined whether acute cannabis consumption (determined by toxicologic analysis of whole blood or by self-report) raises risk for motor vehicle accidents (MVAs).

Driving under the influence of cannabis was associated with significantly higher risk for MVAs (odds ratio, 1.9) than was unimpaired driving. Similar results were obtained for analyses involving only case-control studies (OR, 2.8); culpability studies, which consider driver responsibility for MVAs (OR, 1.7); and studies of fatal MVAs (OR, 2.1).

Comment: Unsurprisingly, acute cannabis consumption substantially raises risk for motor vehicle accidents, whether fatal or not.

Paul S. Mueller, MD, MPH, FACP

Published in Journal Watch General Medicine February 16, 2012

Citation(s):

Asbridge M et al. Acute cannabis consumption and motor vehicle collision risk: Systematic review of observational studies and meta-analysis. BMJ 2012 Feb 9; 344:e536. (http://dx.doi.org/10.1136/bmj.e536)

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Optimal Treatment Duration of Osteoporosis Drugs

Thursday, May 10, 2012 // Uncategorized

How long should patients take medications for osteoporosis?  Bottom line:  We don’t know.  There are some rsik to these medications.  Atypical hip fractures have gotten recent press.  Here is a current recommendation based on the largest studies of these medications.

FDA Questions Whether Long-Term Use of Bisphosphonates Provides Fracture Benefit
An FDA analysis, published in the New England Journal of Medicine, calls into question the fracture-prevention benefits of long-term bisphosphonate use.
The FDA examined three randomized trials in which bisphosphonates were given initially for at least 3 years, and then extended for an additional 3 to 6 years (total duration, 6–10 years). Pooled data showed that women receiving bisphosphonates for at least 6 years had similar overall fracture rates as those who switched to placebo (roughly 10% and 8.5%, respectively).
The authors say there are not enough data to determine which subgroups of patients may benefit from use beyond 3 to 5 years. But commentators provide the following recommendations:
Patients with low bone-mineral density at the femoral neck (T score below −2.5) following 3 to 5 years’ treatment have the highest risk for vertebral fracture and seem to benefit most from treatment continuation.
Those with existing vertebral fractures who have T scores below −2.0 may also benefit.
Those with femoral neck T scores above −2.0 have low vertebral fracture risk and are not likely to benefit.

 

Here are the concluding final paragraphs of a recent NEJM editorial on bisphosphonates:

All labeling for bisphosphonates that are currently approved for treatment of osteoporosis contains an “Important Limitation of Use” statement: “The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis.” To optimize the efficacy of bisphosphonates in reducing fracture risk, decisions to continue treatment must be based on individual assessment of risks and benefits and on patient preference. In this regard, patients at low risk for fracture (e.g., younger patients without a fracture history and with a bone mineral density approaching normal) may prove to be good candidates for discontinuation of bisphosphonate therapy after 3 to 5 years, whereas patients at increased risk for fracture (e.g., older patients with a history of fracture and a bone mineral density remaining in the osteoporotic range) may benefit further from continued bisphosphonate therapy.

Clearly, given the potential for cumulative risk, caution should be exercised in switching between bisphosphonates and other potent antiresorptive medications. Further investigation into the benefits and risks of long-term therapy, as well as surveillance of fracture risk after discontinuation of bisphosphonate therapy, will be crucial for determining the best regimen of treatment for individual patients with osteoporosis.

The following is the entire editorial:

Perspective

Bisphosphonates for Osteoporosis — Where Do We Go from Here?

Marcea Whitaker, M.D., Jia Guo, Ph.D., Theresa Kehoe, M.D., and George Benson, M.D.

May 9, 2012 (10.1056/NEJMp1202619)

Article
References

Osteoporosis, a disease characterized by reduced bone mass and increased skeletal fragility, affects 10 million Americans; another 34 million are at risk for it. Bisphosphonates are widely prescribed for osteoporosis; more than 150 million prescriptions were dispensed to outpatients between 2005 and 2009. All the bisphosphonates that have been approved for the treatment of osteoporosis have shown robust efficacy in preventing fractures in registration trials lasting 3 to 4 years. Recently, however, data on safety have raised concern regarding the optimal duration of use for achieving and maintaining protection against fractures.

Normal bone growth and remodeling entail a tightly coupled process of bone resorption and new bone formation. Osteoporosis-related bone loss occurs when bone resorption exceeds bone formation; bisphosphonates decrease bone resorption, thereby slowing bone loss. The pharmacology of bisphosphonates is complex. During therapy, bisphosphonates are incorporated into newly formed bone and can persist there for years, through multiple cycles of bone resorption and deposition. Thus, patients continue to be exposed to the pharmacologic effects of bisphosphonate activity long after they stop taking the medication.

The long-term safety and efficacy of bisphosphonate therapy for osteoporosis are important concerns for the Food and Drug Administration (FDA). In response to postmarketing reports of rare but serious adverse events associated with bisphosphonates, such as atypical femur fractures, osteonecrosis of the jaw, and esophageal cancer, the FDA performed a systematic review of long-term bisphosphonate efficacy. The findings, summarized here, were presented at a joint meeting of the FDA Advisory Committee for Reproductive Health Drugs and the Drug Safety and Risk Management Committee.1 The committees jointly recommended that bisphosphonate labeling be updated, although there was consensus that the data did not support a regulatory restriction on the duration of drug use.

The FDA review of the data focused on studies in which bisphosphonate drugs had been administered for at least 3 years and that had captured fracture data systematically and completely. We therefore focused on three long-term extension trials — the Fosamax Fracture Intervention Trial Long-Term Extension (FLEX), the Reclast Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly–Pivotal Fracture Trial (HORIZON-PFT) extension, and the Actonel Vertebral Efficacy with Risedronate Therapy–Multinational Trial (VERT-MN) extension — in which the duration of treatment ranged from 6 to 10 years (see tableLong-Term Efficacy against Fracture for Three Bisphosphonates in Core Registration and Extension Studies.). All three studies were extensions of the initial fracture registration trials that had enrolled postmenopausal women with baseline fractures, low bone mineral density T scores (−1.5 or less), or both. The FLEX and HORIZON-PFT trials used a randomized withdrawal design in which patients who had previously been receiving bisphosphonate treatment were enrolled in the extension periods and underwent repeated randomization to receive either placebo or continued bisphosphonate treatment. Unlike the registration trials, the extension studies used bone mineral density as the primary outcome measure. Our analyses of the extension studies include both bone mineral density and fracture outcomes (which are limited to vertebral and nonvertebral osteoporotic fractures).

Overall, findings with respect to all three bisphosphonates were remarkably similar in terms of mean treatment-related increases in bone mineral density through 5 years.1 Continuation of treatment beyond 5 years resulted in maintenance of bone mineral density in the femoral neck and further increases in bone mineral density at the lumbar spine. In patients who were switched to placebo, bone mineral density in the femoral neck decreased modestly during the first 1 to 2 years and then stabilized, whereas bone mineral density in the lumbar spine continued to increase despite discontinuation of bisphosphonate therapy.

The data regarding responses in bone mineral density are similar to those in published analyses.1-4 In the FDA’s opinion, however, the more meaningful end point for osteoporosis therapies is the rate of fracture. Each bisphosphonate registration trial enrolled 3000 to 7500 patients and was powered for the demonstration of fracture efficacy, whereas the long-term extension studies, with enrollments ranging from only 164 to 1233 patients, were not. Because the question is one of long-term efficacy, the FLEX trial, with 10 years of bisphosphonate exposure, became central to the FDA review.

In the FDA analysis of vertebral fractures — both morphometric (also called asymptomatic or radiographic) and clinical or symptomatic fractures — occurring in the two randomized extension trials, the benefit in terms of fracture protection from continued bisphosphonate therapy was inconsistent. In the FLEX trial, the rate of clinical vertebral fractures, but not the rate of morphometric vertebral fractures, was reduced. In HORIZON-PFT, improvement was demonstrated in morphometric vertebral fractures but not in clinical vertebral fractures. An independent post hoc analysis of FLEX showed a benefit in terms of nonvertebral fractures in a very specific subgroup of patients — those without vertebral fractures at baseline who also had a femoral-neck T score of less than −2.5.5

According to the FDA analysis of the FLEX trial, the rates of vertebral and nonvertebral osteoporotic fractures were similar whether participants continued to receive alendronate (Fosamax) for up to 10 years (a rate of 17.7%) or were switched to placebo for the extension period (16.9%). In the time-to-fracture analyses, fracture rates were consistent across treatment groups (Fosamax 5 mg, Fosamax 10 mg, and placebo) and all subgroups of bone mineral density through year 3 (approximately 8 years of continuous treatment, including the registration period). When all data on vertebral and nonvertebral osteoporotic fractures with long-term therapy are pooled across the three extension trials (2496 patients), fracture rates are shown to be relatively constant over time. Pooled data pertaining to patients who received continuous bisphosphonate treatment for 6 or more years result in fracture rates ranging from 9.3 to 10.6%, whereas the rate for patients switched to placebo is 8.0 to 8.8%. These data raise the question of whether continued bisphosphonate therapy imparts additional fracture-prevention benefit, relative to cessation of therapy after 5 years. Statistical limitations preclude inferring any meaningful association between long-term treatment and increased risk of fracture.

It should be noted that all fracture data discussed here are post hoc and are limited by statistical power, selection bias, sample size, and timing issues that vary among studies. Thus, the available data on long-term efficacy do not clearly identify subgroups of patients who are more likely to benefit from drug therapy beyond 3 to 5 years. Nevertheless, the emergence of safety concerns warrants consideration of new treatment algorithms for patients with osteoporosis. The available data do suggest that bisphosphonates may be safely discontinued in some patients without compromising therapeutic gains, but no adequate clinical trials have yet delineated how long the drugs’ benefits are maintained after cessation. Additional data are needed to determine whether markers of bone turnover or bone mineral density can reliably aid in decisions concerning duration or interruption of bisphosphonate treatments.

All labeling for bisphosphonates that are currently approved for treatment of osteoporosis contains an “Important Limitation of Use” statement: “The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis.” To optimize the efficacy of bisphosphonates in reducing fracture risk, decisions to continue treatment must be based on individual assessment of risks and benefits and on patient preference. In this regard, patients at low risk for fracture (e.g., younger patients without a fracture history and with a bone mineral density approaching normal) may prove to be good candidates for discontinuation of bisphosphonate therapy after 3 to 5 years, whereas patients at increased risk for fracture (e.g., older patients with a history of fracture and a bone mineral density remaining in the osteoporotic range) may benefit further from continued bisphosphonate therapy.

Clearly, given the potential for cumulative risk, caution should be exercised in switching between bisphosphonates and other potent antiresorptive medications. Further investigation into the benefits and risks of long-term therapy, as well as surveillance of fracture risk after discontinuation of bisphosphonate therapy, will be crucial for determining the best regimen of treatment for individual patients with osteoporosis.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article (10.1056/NEJMp1202619) was published on May 9, 2012, at NEJM.org.

Source Information

From the Division of Reproductive and Urologic Products, Office of New Drugs (M.W., T.K., G.B.), and the Division of Biometrics III, Office of Biostatistics, Office of Translational Sciences (J.G.), Center for Drug Evaluation and Research, FDA, Silver Spring, MD.

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