Calcitonin for osteoporosis linked to cancer

Calcitonin-containing medicines used for long durations have been utilised for the management of osteoporosis. Now however, the European Medicines Agency (EMA) have recommended the withdrawal of the nasal spray and cautioned use of other formulations due to an increased association with cancer. In fact, it recommends that calcitonin not be used for treating osteoporosis at all. As a consequence, the remaining indications for such medicines are Paget's disease, acute bone loss from immobilisation and hypercalcaemia caused by cancer, but only on a short-term basis. The basis of this decision is a review by the agency's Committee for Medicinal Products for Human Use (CHMP) using data from the companies that market these drugs, postmarketing safety data, randomized controlled studies, 2 studies of unlicensed oral calcitonin drugs, and experimental cancer studies, among other sources. 

The increase in cancer rates when compared to placebo is in the range of 0.7 to 2.4%. Various types of cancers are involved.

Female Sexual Dysfunction

This article by Dorothy Kammerer-Doak gives a very easy to read and concise coverage on the understanding of this subject. Recommended.

Surgery for Diabetes?

Recently, two studies were published in the New England Journal of Medicine (NEMJ) providing compelling evidence that surgical methods of achieving weight loss can lead to better control of Type 1 diabetes mellitus (T1DM). It is well established that weight loss in an obese person can show marked improvement in the control of their DM.

As we are well aware, while T1DM results from the body’s failure to produce adequate amounts of the hormone insulin, Type 2 DM (T2DM) is a consequence of improper utilization of this hormone. Regardless of the type, DM becomes more difficult to manage as it progresses and ultimately leads to serious and severe complications such as heart disease, kidney failure, blindness and stroke.

Crucial to proper management of this disease is the adequate control of blood sugar centered upon lifestyle measures that encourage weight loss and physical activity. The weight loss regimen involving diet and exercise can be a mentally and physically painful process with often a less than desirable outcome. Many patients are unable to achieve good glycemic control, leading to the addition of medications, frequently with increasing number and dosage, and ultimately the addition of insulin therapy. Counter to the aim of the therapy, one of the side effects of insulin therapy is weight gain, thus rendering management more difficult.

It is no surprise then that more patients are starting to resort to surgery to decrease the size of their stomach. This type of weight loss surgery is termed bariatric surgery and involves gastrectomy (removal of part of the stomach), stapling or banding of the stomach. Although having been around for some time now, an upsurge in cases of bariatric surgery for the management of DM has been reported, mainly due to recent information from clinical studies that showed significant weight loss and subsequent improvement in diabetic control. These recent studies provide more dependable information because of their random and rigorous comparison between medical and surgical forms of treatment. There is now better proof that weight loss operations seem to work much better than standard medical management. 

Nevertheless, caution must be employed and it may be wise to examine the studies in depth and note their deficiencies. They involved only a small number of patients (150) and were of a short duration. As well as not being able to prove long-term benefits, it is also questionable if the results of bariatric surgery will be as good in routine clinical practice, or for that matter, in patients who are not as heavy as those in the studies. Since highly skilled surgeons performed the operations in these studies, results by others may not be as good. Surgical complications can range from infections, mineral and bone deficiencies and other injuries. Furthermore, these studies compared bariatric surgery with standard medical care involving medications, when in actual fact, the comparison should have been with medical weight loss therapy (diet, exercise, behavior change and other appropriate medical interventions). Patients succeeding with medical treatment would then have no necessity to undergo surgery at all.

To be fair though, bariatric surgery has been recognized as appropriate treatment, but only for those obese patients with Type 2 DM who are unable to reach their glycaemic targets with the prescribed medical therapies.

In conclusion, we should not rush to embrace bariatric surgery as a standard treatment alternative for DM despite the strong evidence suggesting so. Due recognition has to be given for the hard work put in by the researchers, but benefit must be shown in a larger numbers of patients, and over a longer period of time before we can determine the place of bariatric surgery in the management of Type 2 DM.

References:

Schauer PR et al. Bariatric Surgery versus Intensive Medical Therapy in Obese Patients with Diabetes. March 26, 2012 (10.1056/NEJMoa1200225)

Mingrone G et al. Bariatric Surgery versus Conventional Medical Therapy for Type 2 Diabetes. March 26, 2012 (10.1056/NEJMoa1200111)

Zimmet P, George K, Alberti MM. Surgery or Medical Therapy for Obese Patients with Type 2 Diabetes? March 26, 2012 (10.1056/NEJMe1202443)

Guidelines on epilepsy management in pregnancy

Epilepsy is a common condition affecting many women in the reproductive age group. It is estimated that about 1 million women with epilepsy in the United States are in their reproductive years. Increased fetal and maternal risks in such patients are well established. It is with this in mind that the American Academy of Neurology (AAN) and the American Epilepsy Society (AES) published Practice Parameter Updates on the pregnant woman with epilepsy in 2009. Following are guidelines taken from that report.

The effect of antiepileptic drugs (AED)

The general worldwide incidence of major structural and genetic birth anomalies is estimated to be about 3% of births. Epileptic women taking AED during the first trimester have registered a higher incidence of such defects. This becomes quite apparent when we compare these women to those epileptics not on medication, and when we consider the effects of AED on organogenesis. Valproic acid (VPA) is shown to have a higher risk amongst the AED, with polytherapy also increasing the risk compared to monotherapy.

It is recommended that VPA be avoided especially during the first trimester, preferably preconception, if not altogether during pregnancy. Patients desiring pregnancy need to be changed to alternate therapy such as lamotrigine (LTG) or levatiracetam (LVT), which happen to be 2 of the most studied AED in pregnancy.

Increased surveillance involving detailed ultrasound scans and possibly amniocentesis are essential for these patients.

The role of Folic acid (folate)

Higher dose folic acid (about 5mg) is known to prevent neural tube defects in pregnancy, if taken at least 3 months preconceptually. Certain AED such as carbamazepine, phenytoin and even LTG lower folic acid levels and may increase the risk of neural tube defects. Although no exact evidence exists regarding the correct dosage in pregnancy, 5 mg/d of folic acid supplementation for women with epilepsy of childbearing age for 3 months prior to conception and for at least 10- to 12-weeks postconception is now the standard recommendation.

The first convulsion in pregnancy

Firstly, any convulsive event in pregnancy must be confirmed as such rather than loss of consciousness or a shaking event. Differential diagnoses include metabolic alterations and medications in the first trimester, low blood pressure and syncope in the second, and eclampsia and stroke being of more dire consequence in the third trimester and postpartum period. Mass lesions and infections can occur throughout pregnancy.

Adequate inpatient investigation includes laboratory tests, lumbar puncture, electroencephalogram (EEG) and magnetic resonance imaging (MRI) of the brain.

Once an unprovoked seizure is established, appropriate first line therapy should include enough sleep and carbamazepine or LVT depending on the seizure type. Although LTG is relatively safe, therapeutic levels are hard to achieve when started in pregnancy.

The dose of medication during pregnancy

Almost all AED levels drop during pregnancy due to increased renal clearance and hepatic elimination, but return to baseline within a few weeks of delivery. Thus, most medications require a slight dose increase once pregnancy is confirmed. LTG especially undergoes a marked drop in serum levels. Monitoring of the levels of AED should be considered.

Delivery and Postpartum

Women with well-controlled epilepsy or those seizure-free for 1 year prior to pregnancy have very little risk of a fit around the time of delivery and in the immediate postpartum period. The highest risk is with those patients with active epilepsy.

The patient should be on regular medication throughout the peripartum period and adequate rest has been shown to be beneficial. Tramadol, which is known to provoke seizures, should be avoided to further decrease the risk of an epileptic fit.

Since AED levels gradually increase back to normal postpartum, it is recommended that they be closely monitored during this period, especially in the case of LTG due to the aforementioned reason.

References

1.     Harden CL, Hopp J, Ting TY, et al. American Academy of Neurology; American Epilepsy Society. Practice parameter update: management issues for women with epilepsy—focus on pregnancy (an evidence-based review): obstetrical complications and change in seizure frequency: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology 2009;73(2).

2.     Cunnington MC, Weil JG, Messenheimer JA et al. Final results from 18 years of the International Lamotrigine Pregnancy Registry. Neurology 2011;76(21):1817–1823

3.     Tomson T, Battino D. Teratogenic effects of antiepileptic medications. Neurol Clin 2009;27(4):993–1002.

4.     De Wals P, Tairou F, Van Allen MI, et al. Reduction in neural-tube defects after folic acid fortification in Canada. 
N Engl J Med 2007;357(2):135–142.

5.     Committee on Educational Bulletins of the American College of Obstetricians and Gynecologists. ACOG 
educational bulletin. Seizure disorders in pregnancy. Int J Gynaecol 
Obstet 1997;56(3):279-286.

6.     EURAP Study Group. Seizure control and treatment in pregnancy: observations from the EURAP epilepsy 
pregnancy registry. Neurology 2006;66(3):354-360.

7.     Meador KJ, Baker GA, Browning N, et al; NEAD Study Group. Effects of breastfeeding in children of women 
taking antiepileptic drugs. Neurology 2010;75(22):1954–1960.

Remembering the terror of AIDS

In June 1981, the US Centre For Disease Control reported the deaths of five young gay men, from a rare form of pneumonia. Around the same time, Kaposi’s sarcoma, a cancer usually seen only in the very old, started to claim the lives of a disproportionate number of gay people. By 1983, the numbers of deaths had become so large that Horizon, the BBC science programme, broadcast a documentary about them, called “Killer in the Village”. I share that childhood memory only to recall how terrifying those early years of the Aids crisis were, before the aetiology of the disease was known, before the virus was identified, before effective therapies were developed; I suspect those years have cast a shadow over every gay man of my generation, whether they fell ill or not, whether they tested positive or not, whether or not they’ve ever taken the test. Thank God HIV was found responsible for the disease. Better a virus, isolated under a microscope, a tractable drug target, than some form of cosmic retribution: though not everyone would agree with that, of course.

The question in those early years was whether or not the infection would be confined to gay people. What would have happened, had that turned out to be the case? A question, 30 years later, I still prefer not to ponder. By 1987, though, the risk to the general population was clear, and one of the most remarkable campaigns seen in post-war Britain was launched. I suspect you’ll remember the government’s Don’t Die Of Ignorance campaign, the tombstone with “AIDS” chiselled onto it, John Hurt’s terrifying voiceover. A leaflet was delivered to every house in the land, warning people to avoid unprotected sex. 

Edited from an article by Graeme Archer published in The Telegraph on 2 December 2011

The Medical College Admission Test — Toward a New Balance — NEJM

The Medical College Admission Test — Toward a New Balance — NEJM: 'via Blog this'

Making Sense of the New Cervical-Cancer Screening Guidelines

Over the past 60 years, U.S. mortality from cervical cancer has dropped by 70%, thanks to a successful screening program. In 1995, the American College of Obstetricians and Gynecologists (ACOG) recommended screening with the Papanicolaou (Pap) smear and pelvic examination at the initiation of sexual activity or by 18 years of age and annually thereafter. Although not evidence-based, this guideline was easy to remember, timed to coincide with the onset of legal adulthood, and well received by patients and clinicians. Linking the Pap smear to an annual visit, and often to the provision of other health care services such as contraception, breast care, and blood-pressure checks, made the patient likely to comply and the physician likely to remember to offer the test as part of routine care. Furthermore, although the Pap smear's sensitivity is poor — roughly 50 to 60% — the frequency of repetition made it likely that in screened patients, an abnormality missed one year would be found the next. Hence, the system worked.

In 2002 and 2003, the ACOG, the American Cancer Society (ACS), and the U.S. Preventive Services Task Force (USPSTF) all issued guidelines addressing many issues related to screening. In 2006, the American Society for Colposcopy and Cervical Pathology (ASCCP) issued management guidelines. Despite being “evidence-based,” these guidelines were different from one another, complicated, and hard to remember. Furthermore, the combination of a Pap smear with a test for human papillomavirus (HPV cotesting), which was addressed in these guidelines, was just being approved by the Food and Drug Administration (FDA) — on the basis of minimal clinical evidence that it added value. Despite recommendations indicating that Pap–HPV cotesting should be performed no more frequently than every 3 years because of its high added cost and limited additional clinical value, many patients, clinicians, and laboratories began cotesting annually.

Between 2009 and 2011, the same organizations, as well as American Society for Clinical Pathology (ASCP),1-4reconvened expert panels to reevaluate the evidence and issue new guidelines. Again, there are some differences of opinion and interpretation. There are, however, many points of agreement (see table in original article) and much opportunity to use the existing evidence to maintain a high-quality cervical-cancer prevention program that also safely addresses cost concerns.

Cervical cancer is rare before 20 years of age, and the incidence doesn't start to rise significantly until women reach the age of 25 or 30. Most cancers detected in screened women tend to be early-stage, so those found through screening are largely curable. For many women with early-stage disease, less-radical, fertility-sparing procedures can be curative, so even if early-stage cancers are detected, morbidity and mortality may be minimal.

Therefore, in 2009, the ACOG recommended that screening for “average-risk” women begin at the age of 21. Although the expert groups all agree that cervical cancer is rare before that age, they define high-risk younger groups somewhat differently; the ACOG defines average-risk women as immunocompetent women. Eliminating earlier screening averts overdiagnosis in young women based on transient cervical changes that their healthy immune systems would generally clear — and thereby also averts painful, costly, and possibly harmful procedures. Because there are no large prospective cohorts of immunocompromised patients, the USPSTF, which tends to be most rigorous in its evidence review, states that there is insufficient information for it to clearly recommend that screening should start before the age of 21 in immunosuppressed patients, but it offers the option of screening within 3 years after the onset of sexual activity, or by the age of 21.

Studies consistently show that for previously well-screened healthy women 30 years of age or older, the interval between Pap screenings can be lengthened to 3 years without significantly increasing their risk of cancer. It's also known that when screening takes place only every 5 years, or when women with abnormal Pap tests are not correctly triaged and treated to prevent cervical dysplasia from progressing to cancer, cancer rates increase. For women between 20 and 30 years of age, the optimal frequency is less well studied, but given the poor sensitivity of any single Pap test, the goal is to obtain at least two consecutive normal Pap results during this period to ensure that there are no missed opportunities for detecting and treating a precancerous lesion before lengthening the interval.

All the evidence and guidelines agree that HPV testing has no role in adolescents and should be performed in women 21 to 30 years of age only if a Pap test reveals atypical squamous cells of undetermined significance, an approach referred to as reflex testing. They also agree on reflex HPV testing for women 30 years of age or older under the same conditions. It is recommended that laboratories and clinicians not perform HPV screening in adolescents and that they use it only as a reflex test in women in their 20s.

The USPSTF, ACOG, and ASCCP–ACS–ASCP vary dramatically on whether evidence supports HPV cotesting for women 30 years of age or older. The USPSTF argues that Pap testing every 3 years for women over 30 is both safe and more cost-effective than cotesting and that no data support cotesting at the current screening intervals. It seems reasonable to use Pap testing alone every 3 years in this age group, unless the clinician seeks reassurance about lengthening the interval for a particular woman — for instance, if she has an uncertain Pap history or impaired immune status or may have difficulty complying with returning in 3 years. In such cases, HPV testing could be added or the Pap-testing interval shortened.

There is general agreement that in well-screened, low-risk women with no history of cancer or high-grade precancerous lesions, there comes a point when additional screening confers little added benefit. The USPSTF, ASCCP, and ACS agree on 65 as the age to stop screening such women. If the clinician cannot document a history of three normal Pap tests within the previous 10 years, then a Pap test should be obtained. If a patient has vaginal bleeding, vulvar discomfort, or other gynecologic or urologic symptoms, a complete pelvic examination and appropriate diagnostic testing should be performed. Furthermore, vaginal cancer is rare among women who have undergone hysterectomy, and all the guidelines agree that if such women are otherwise healthy and have no history of cancer or dysplasia, vaginal Pap testing may be discontinued.

In patients who have been treated for high-grade dysplasia, the risk of cervical cancer is increased by a factor of two to three for at least 20 years, but the risk of dying from cervical cancer is low, since most cancers are diagnosed at an early stage. Because it has long been the standard of care to screen these patients annually, we don't have good prospective data on whether this more frequent testing has contributed to early cancer diagnoses. Given that mortality rates have remained low with current practices, however, all groups recommend screening this population for at least 20 years after treatment.

Increasing screening in previously unscreened populations will further reduce the incidence of cervical cancer and related mortality. Reaching out to patients who face cultural, language, or educational barriers to care is important. Creating systems to remind clinicians that patients who come for episodic care must have appropriate cancer-screening tests is essential. Finally, making the guidelines for managing abnormalities easier for patients and clinicians to follow is important for both optimizing outcomes and containing costs for unnecessary referrals and treatment.

Health care is a limited resource, and providing the best care at the best price will become increasingly important. We need to use and understand actual data about risk and the long-term effects and costs of various strategies. Experts are often in the best position to review the data and make recommendations, but different expert panels may interpret data differently and emphasize different results in making their decisions. And even with the best consensus guidelines, some clinical judgment and personalized attention to each patient remains necessary.

1. ACOG practice bulletin no109: cervical cytology screening. Obstet Gynecol 2009;114:1409-1420

2. Preventive Services Task Force. Opportunities for public comment (http://www.uspreventiveservicestaskforce.org/tfcomment.htm).

3. American Society for Colposcopy and Cervical Pathology. Cervical cancer screening and prevention: the role of molecular testing (http://www.asccp.org/practice-management/molecular-screening-symposium).

4. Vesco KK, Whitlock EP, Eder M, Burda BU, Senger CA, Lutz K. Risk factors and other epidemiologic considerations for cervical cancer screening: a narrative review for the U.S. Preventive Services Task Force. Ann Intern Med 2011 October 17 (Epub ahead of print).

From an article by Sarah Feldman Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Boston).published on November 23, 2011, at NEJM.org