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Primary Care Corner with Geoffrey Modest MD: ?Thyroid meds for subclinical hypothyroidism in older adults

10 Apr, 17 | by

​by Dr Geoffrey Modest

A randomized controlled trial assessed the effect of levothyroxine therapy in older adults with subclinical hypothyroidism, finding no clear benefit (see DOI: 10.1056/NEJMoa1603825 )


— 737 adults at least 65-years-old who had persistent subclinical hypothyroidism were randomized to levothyroxine starting at a dose of 50 µg a day, or 25 µg if their body weight were <50 kg or had coronary heart disease, with subsequent dose adjustment to achieve a TSH between 0.4 and 4.6, versus placebo.

— Subclinical hypothyroidism was defined as TSH of 4.60-19.99, with a free thyroxine level that was within the normal reference range.

— Mean age 74, 54% women, 98% white, 97% in non-sheltered community housing, 50% with hypertension/15% diabetes/14% ischemic heart disease/13% osteoporosis/9% smokers, mean baselineTSH level was 6.4

— Primary outcomes were changes in the Hypothyroid Symptoms score and in the Tiredness score on the thyroid related quality-of-life questionnaire, at one year (range of each score was 0-100, with higher scores indicating more symptoms, and the minimum clinically important difference being 9 points for each scale). Baseline Hypothyroid Symptom score was 17, Tiredness score was 26

— Secondary outcomes included changes in generic health-related quality-of-life, comprehensive thyroid related quality-of-life, hand grip strength, executive cognitive function (as assessed with the letter-digit coding test which indicates the speed of processing according to the number of correct responses in matching 9 letters with 9 digits in 90 seconds), blood pressure, weight, BMI, waist circumference, activities of daily living, instrumental activities of daily living, fatal/nonfatal cardiovascular events.


— Mean TSH level decreased from 6.4 to 5.5 in the placebo group as compared to 3.6 in the levothyroxine group, with median dose of 50 µg of levothyroxine. This was achieved within 6-8 weeks after starting the medication.

— There was no difference in the mean change at one year in the Hypothyroid Symptom score (0.2 for each group).

— There was no significant difference in the change in the Tiredness score (3.2 in those on levothyroxine, 3.8 in those on placebo)

— There was no benefit in any of the secondary outcome measures

— There were extended outcomes assessed for about half the patients, at a median of 24.2 months, also finding no difference in the primary or secondary outcomes

— Adverse events: no difference



— Subclinical hypothyroidism is an important issue for a few reasons:

— It is very common, between 8 and 18% of adults > 65yo

— Thyroid hormone acts throughout the body with receptors pretty much everywhere, affecting cognition, skeletal muscle function, vascular tree and heart, skeletal muscle, bone, etc, etc

— There are epidemiologic data suggesting that patients with subclinical hypothyroidism are at increased risk of coronary heart disease and perhaps heart failure. Data on total mortality are mixed.

— To me, there is a fundamental contradiction in the term “subclinical hypothyroidism”, since the normal limits of free T4 level reflects the bell-shaped curve of the community lab values, whereas TSH reflects the individual person’s response to their own circulating hormone levels. And patients may not be asymptomatic (ie “subclinical”). Subclinical hypothyroidism therefore, I think, just reflects a low level of hypothyroidism, such that depression of T4 levels still remains within the community norm, but still could have effects on that individual’s body.

— Other studies have found that treating subclinical hypothyroidism has shown improvements in the Tiredness score. These studies have been small and somewhat underpowered, and often with younger patients.

— About half of the patients with subclinical hypothyroidism will progress to overt hypothyroidism with a low serum thyroxine level over 10 to 20 years, with an annual progression rate of 2 to 4%. However some also have spontaneous recovery, less likely in those that are anti-TPO antibody positive

— Some limitations of the study which limit its generalizability:

​– The study tested a pretty uniform demographic (white people with stable housing and not a lot of medical comorbidities)

— The median achieved TSH level was 3.6, and some people believe that a more reasonable target is between 0.4 and 2.5 (i.e., it is possible that there would have been a measurable effect if they had achieved the lower and perhaps optimal TSH concentration)

— Very few people had TSH levels > 10, with a mean only slightly above the normal range, meaning that most of the patients had really mild hypothyroidism, which has a lower likelihood of progressing further or being symptomatic

— Hypothyroid symptom levels at trial entry were also quite low to begin with

— The trial was underpowered to detect an effect on cardiovascular events or mortality

— They did not measure thyroid antibody levels (which do predict to some extent which patients are more likely to progress to hypothyroidism)

— They did not find any difference in the speed of information processing, which has been found to be slowed in persons with subclinical hypothyroidism. However they did not assess other measures of cognitive function, though these are typically pretty blunt instruments (MMSE, MOCA, etc) and might not pick up very subtle though potentially important changes for the person and family/supports. But treating the subclinical hypothyroidism might still make a real difference for the individual, especially in the long-term (and a 65 year old in otherwise good health has a 20ish year life expectancy)

So, what is one to do with older patients who have subclinical hypothyroidism? The answer is not entirely clear, and this study really only adds the finding that short-term treatment of essentially asymptomatic patients with minimal laboratory abnormalities suggesting hypothyroidism does not seem to be effective. And I am particularly concerned about the potential links with atherosclerosis and cognitive decline. ​My sense is that it does seem reasonable to treat people with higher TSH levels (e.g.>10) since they have a higher likelihood of progressing to overt hypothyroidism. In those with lower TSH levels, it might be reasonable to check anti-TPO levels and treat those patients. It also might be reasonable to treat those who are more symptomatic than in this trial. But, overall, if one elects not to treat, it does make sense to follow these patients closely to see if they progress to more thyroid dysfunction. But one concern I have is that the usual symptoms of hypothyroidism, on the one hand, are pretty nonspecific, and, on the other hand, in many cases reveal themselves so slowly over time that patients may accommodate to them and not even notice them (though their treatment might still positively affect their quality-of-life).


for review and critique of thyroid screeninng guidelines, see here

Primary Care Corner with Geoffrey Modest MD: Thyroid screening recommendations

31 Mar, 15 | by EBM

By: Dr. Geoffrey Modest

The US Preventive Services Taskforce (USPSTF) just published an update of their recommendations for TSH screening of nonpregnant, asymptomatic adults (see doi:10.7326/M15-0483). For formal USPSTF recommendation, see here.



–hypothyroidism: subclinical = asymptomatic, serum TSH between 4.5-10 (varies a bit by lab), and normal T3 and T4; overt = can be asymptomatic, but high TSH and low T4 levels

–hyperthyroidism: subclinical = asymptomatic, TSH < 0.4 and normal T3 and T4. subdivided into “low but detectable”, with TSH 0.1-0.4, and “undetectable” with TSH <0.1. overt= can be asymptomatic, but has elevated T3 or T4

–Detection: TSH is good for detection of thyroid abnormalities in the general population, but there is measurement variability with TSH (eg, one study did find that TSH levels can vary by as much as 50% on a day-to-day basis. Also, TSH is sensitive to non-thyroidal factors such as being suppressed by acute illness or meds ). Best to confirm asymptomatic abnormalities with repeat confirmatory tests in 3-6 months (except if TSH>10 or <0.01 per other recommendations, though I do tend to repeat prior to further workup or therapy, just to make sure…)

–Benefits of early detection: inadequate evidence that there is clinical benefit in nonpregnant, asymptomatic adult. ie, no clear RCT evidence that detecting abnormalities/doing something improves quality of life, or improves blood pressure, BMI, cognition, bone mineral density or lipid levels (more later)

–Adverse effects of screening include labeling, false-positive results, and overdiagnosis and overtreatment

–Overall assessment: not enough information to recommend screening

— They also note:

–subclinical hypothyroidism is common: 5% of women and 3% of men in US, increasing incidence with aging

–37% of people with subclinical hypothyroidism spontaneously revert without intervention after several years; 2-5% go on to develop overt hypothyroidism

–subclinical hyperthyroidism in about 0.7% of the US population, more in women than men (again, increases with aging)

–1/3 of those with subclinical hyperthyroidism revert to normal over time. 1-2% with TSH<0.1 go on to overt hyperthyroidism. less likely if TSH 0.1-0.45

​–39% of people with TSH of  5.1-10 in a 1996 study received treatment, other data shows increasing % on meds as they age. (This is despite recommendations to the contrary – ie, from their perspective, many people are being treated without clear data)

–risk factors for hypothyroidism in the US (most are from Hashimoto’s thyroiditis) are age, female sex, white race, type 1 diabetes, Down syndrome, family history, goiter, neck irradiation

–risk factors for hyperthyroidism include age, female sex, black race, low iodine intake, ingestion of iodine-containing drugs (eg amiodarone)

This brings up a few issues:

–The USPSTF is pretty stringent in making recommendations, in general requiring high quality positive RCTs to make a strong recommendation. The plus here is that the recommendation is more evidence-based. The minus is that there are lots of things we do (or should do) which just have not had the studies done to back them up.  So, the fact that they find insufficient evidence in the case of thyroid screening does not necessarily mean that it should not be done.  For TSH screening, I basically agree — there really is not enough evidence and studies should be done, especially given how common the issue is.

–One big issue is what is the normal TSH???. A large observational study based on the Natl Health and Nutrition Exam Survey III (see J Clin Endocrinol Metab 92: 4575, 2007) looked specifically at people of different ages who were “disease-free” (no report of thyroid disease, goiter, or taking thyroid meds) and negative antibodies (no thyroid peroxidase or thyroglobulin antibodies, which are typically present with Hashimoto’s thyroiditis), and were not overtly hyper- or hypothyroid (ie, TSH not >10 or <.01).  They looked at the distribution of TSH values per different age groups. It turns out that the plot by age shows a shift in the median and 97.5th percentile noted with aging (a shift to a higher TSH), which suggests that TSH does normally increase with age, and in a step-wise manner by age group. The issue here is that there is more actual thyroid disease with aging, but that if it were just a larger number of people with high TSH, the median should still be in the “normal” place but with a longer tail for the increased incidence of actual thyroid disease. By their analysis if one uses a TSH >4.5 mIU/L as the cutpoint, “70% of the raised values for the 80-yr and older group fall within the 97.5 centile of their age-specific range” (by the way, some smaller studies do not find this. One confounding issue is that the elderly also can have more subclinical hyperthyroidism, which would also affect the median TSH). Other issues which suggest this increasing “normal” TSH is that only a small percentage (about 2.5%/year) actually  do develop overt hypothyroidism (TSH>10), even over a 20-year study. The reason for increasing TSH with aging???? could be medical issues or meds which interfere with the efficiency/sensitivity of the hypothalamic-pituitary feedback system. Or may be a part of healthy aging (slowing down the metabolism to preserve bodily function — though hard to make a strong evolutionary argument here, since not many 70-year olds are strong participants in furthering the species, and the % of the population with TSH>4.5 really begins to climb at age 70).

–Subclinical hypothyroidism: the potential for detection and treatment is more theoretical, since there are no significant longterm studies with many of the important clinical endpoints to inform practice. There have been a couple of short-term studies on treating subclinical hypothyroidism, showing no effect on blood pressure. Studies on lipids are mixed, but show small effect if any (hypothyroidism is assoc with high LDL). in terms of cardiac effects, one large UK observational study (Arch Intern Med 2012; 172:811) looked at 4735 people with subclinical hypothyroidism (based on a single TSH value of 5-10), followed for 7.6 years, 1/2 on thyroid meds, and found that in those 40-70 yo, 4.2% of those on thyroid meds had ischemic heart disease events vs 6.6% not on meds (a significant HR=0.61). No significant difference in those  >70yo. But they did not account for other meds (statins, aspirin…) which are likely to be different in the >70yo crowd, and this was not an RCT. Of interest, they also found less cancer deaths with thyroxine therapy in the younger group (??suggesting confounding in the study). Some, but not all studies have also found some benefit in the surrogate markers of endothelial function, LV diastolic function. There are also a few studies finding increased heart failure, with a trend in those in the TSH 7-10 range but significant in those in the 10-20 range. But again there are no intervention studies showing benefit to treatment.

–Subclinical hyperthyroidism: autonomous adenomas and multinodular goiters (MNG) are more common causes (one study had 57% of patients with MNG), though overtreatment of hypothyroidism is still a very common cause. 40-60% spontaneously revert over weeks to years (?if they had thyroiditis). In terms of risk for fractures, the effect of T4 is predominantly in cortical bone (eg wrist), least in trabecular (spine) and in-between in mixed (hip). The observational data in a recent study on hip or nonspine fracture was not significantly elevated with subclinical hyperthyroidism (see Ann Intern Med 2014; 161: 189). Other studies have shown bone effect of hyperthyroidism, which tracks with degree of TSH suppression. Atrial fibrillation is a major concern, with increased risk of about 70%, also tracking with the degree of TSH suppression, but clearly present with subclinical hyperthyroidism. Also, heart failure is associated with subclinical hyperthyroidism. Observational data are mixed for mortality, dementia, quality of life.  So, clearest concern is from afib, though we still do not have adequate data on preemptive treatment leading to benefit.

–In terms of adverse effects of labeling/treating: one study found that of 34K women with known hypothyroidism were less likely to report good self-rated health (not clear that this would apply to subclinical patients, but probably…). Also,  a study from 2004 found that 1/4 of patients on levothyroxine were inadvertently on too high a dose (TSH undetectable). Raises unproven potential for fractures or afib.

–One concern I have about asymptomatic vs symptomatic is that it is often hard to tell the difference. Most of the symptoms of both hypo and hyperthyroidism, esp in milder cases, are very nonspecific. And the patient may not even see these as symptoms, since they come on very gradually and the patient may just adapt to them.

–So, how does one piece this all together??  It is clear that we really need long-term RCTs to figure this out. Observational trials can be misleading. And subclinical thyroid dysfunction is such a common condition with such potentially bad outcomes that it is pretty striking it has not been studied (though I suppose that there’s not much $$ for drug companies in it, given generic availability….). The big issue for me is the very real question of what a normal TSH is. One could argue that it might be reasonable to check TSH some time after a patient reaches the ripe old age of 50 just to make sure they don’t have overt thyroid disease and treat that. But if the TSH is in the subclinical region, repeat it in a year. And if okay, maybe repeat in 5 years. This approach acknowledges that even overt thyroid disease, which most believe should be treated, is pretty common and often will not be detected without looking for it. Above and beyond this population approach, it is certainly reasonable based on the above to use targeted testing — eg, if patient has some potentially associated finding (hyponatremia, increased CK, macrocytic anemia, autoimmune disorder, pericardial/pleural effusion, etc, and perhaps even high LDL)​

Primary Care Corner with Geoffrey Modest MD: Natural history of thyroid nodules (and why do we care)

18 Mar, 15 | by EBM

By: Dr. Geoffrey Modest

An Italian study looked at the natural history of apparently benign thyroid nodules, with unexpected findings (see JAMA.2015;313(9):926-935​). In this prospective, multicenter, observational study, researchers followed 992 consecutive patients with 1-4 asymptomatic nodules which were either benign by ultrasound or fine-needle aspirate (FNA), and followed them for 5 years.



–mean age of patients was 52.4 years, 82% women, half with family history of nodular thyroid disease, and none were on levothyroxine therapy. 60% of the nodules were solitary , 80% solid.

–40.2% of the nodules were benign by FNA and  59.8% had no suspicious ultrasound features [suspicious ultrasound features were at least one of: hypoechogenicity, irregular margins, taller-than-wider shape, intranodular vascular spots, and microcalcifications)

–nodule growth of >20% occurred in 153 patients (15.4%), or in 11.1% of the nodules, with a mean 5-year diameter increase of 4.9 mm (initial mean of 13.2 increasing to 18.1 mm).

–nodule growth was associated with the presence of multiple nodules, larger main nodule volume (0.2mm), male sex.   Age<45 was associated with more growth than ​age>60.

–nodules shrank spontaneously in 184 patients (18.5%), with mean shrinkage of 3.7mm

–thyroid cancer was found in only 5 of the original nodules (0.3%), and only 2 had grown during the followup period. An incidental cancer was found in 1 patient who had a thyroidectomy, but that cancer was not visualized prior to surgery.

–all of the cancers had abnormal ultrasound findings (most were solid and hypoechoic)

–93 patients developed new nodules over the course of the study (9.3%), with cancer in 2.


–a small minority of nodules increased in size, and these increases were noted within a year or so, and happened mostly in those with multinodular disease, nodule diameters >7.5mm,  and those <44 years old

–cancer was quite rare (0.3%) and FNA had a very low false negative rate (1.1%)

–in those with cancer over the 5 years, nodule growth was not a specific marker of malignancy, and all had suspicious ultrasound features initially​.

–although these areas in Italy had mild to moderate iodine deficiency (which limits the generalizability of the results to the US, which tends to be iodine sufficient), there was no difference in findings in the northern Italy area (mild deficiency) and the southern (moderate deficiency), suggesting this might not be a factor

–so, the authors recommend a redo of the current guidelines (repeat thyroid ultrasound after 6-18 months, and if nodule size is stable, then every 3-5 years (this is based not on studies, but on “expert opinion”). They suggest:

–nodules that are benign on initial FNA, or those which are subcentimeter and have no sonographic suspicious features, can be safely managed with repeat ultrasound in 1 year. And if no suspicious changes, reassessed after 5 years.  They note that this approach would apply to 85% of patients whose risk of disease progression is very low.

–closer surveillance “may be appropriate for nodules occurring in younger patients or older overweight individuals with multiple nodules, large nodules (>7.5mm), or both”

So, pretty different from the current conception. Nodule growth has been considered high risk for malignancy. Current guidelines ​suggest that people with solid nodules that are not hypoechoic have FNA when nodules are  >1-1.5cm, and those which “are growing but are benign after repeat biopsy should be considered for continued monitoring or intervention”. Although I am hesitant to apply this large study to the US, given potential differences in iodine sufficiency, it certainly makes sense to look at our data, given the very large number of thyroid nodules and how common referrals are made to endocrinologists for nodule evaluation/FNA.

Data from the American Association of Clinical Endocrinologists suggests that palpable thyroid nodules in the US population are common (3-7%), the risk of cancer (4-6.5%) is the same in palpable nodules, those picked up incidentally on other scans (eg, MRIs or CTs, where the incidence of clinically inapparent nodules/incidentalomas being 20-76%!!!), and in those with multinodular goiters. And, to my reading, there are no studies which look at the issue of the incidence of cancer in those with totally nonsuspicious thyroid nodules by ultrasound (there are data on the specificity of each of the individual abnormalities, with wide ranges — eg for hypoechogenicity it is 41.2-92.2%). The overwhelming issue to me, however, is that even though thyroid nodules are extraordinarily common (even in the US which is iodine sufficient) with malignancy predicted in the 4-6.5% range, the 2015 governmental predictions of thyroid cancer in 2015 is 62,450 cases (which seems very low given the up to 76% of incidentalomas alone), but thyroid cancer deaths is remarkably rare (1950 deaths predicted in 2015). And over the past several years the diagnosis of thyroid cancer has increased (largely from increased use of thyroid ultrasounds), but this death rate has not changed. So, it has always been unclear to me that detecting and treating thyroid cancer is in fact appropriate (ie, are people dying largely from very aggressive anaplastic cancer, or stage IV tumors that were so aggressive that early detection would not have helped, and the vast majority never would have had any problems with their cancers which happened to look malignant under the microscope).

So, it seems to me that we need data showing that screening does anything in terms of real mortality and morbidity benefit (and I do have a few patients with significant morbidity from surgery), and if so, whether there is a reasonable way to risk stratify those at high risk.  In terms of  of risk stratification, this Italian study would argue to me that the ultrasonographic characteristics are a good place to start and could dramatically decrease the followup of the vast majority of thyroid nodules, possibly the morbidity associated with FNA and possibly unnecessary surgery, and patient/provider angst.

Primary Care Corner with Geoffrey Modest MD: Length of menopausal symptoms

21 Feb, 15 | by EBM

By: Dr. Geoffrey Modest

A subgroup assessment of the Study of Women’s Health Across the Nation (SWAN), a multiracial/multiethnic observational study from 7 US communities,  assessed the duration of frequent menopausal vasomotor symptoms (VMS), defined as occurring at least 6 days over prior 2 weeks, and the duration of frequent VMS after the final menstrual period (see doi:10.1001/jamainternmed.2014.8063).


–analysis of 1449 women with frequent VMS, from Feb 1996 through Apr 2013. all with natural menopause. an array of psychosocial variables were recorded, including attitudes toward menopause, symptom sensitivity (assessment of heightened attention to bodily sensations), anxiety, perceived stress, depressive symptoms, and social support

–mean age at first VMS report was 50. only about 35% had symptoms starting post-menopause, 10% premenopausal and rest were perimenopausal. BMI <25 in 35%, BMI 25-30 in 27% , BMI >30 in 37% .

–median total VMS duration was 7.4 years

–of the 881 women with known final menstrual period (FMP), the median persistence of frequent VMS was 4.5 years after FMP

–those women who were premenopausal or early perimenopausal with frequent VMS had the longest duration of frequent VMS (11.8 years) and those with known FMP had the longest persistence of frequent VMS (9.4 years)

–women who were post-menopausal at onset of frequent VMS had the shortest VMS duration (median 3.4 years)

–African-American women reported the longest total VMS duration (10.1 years). Japanese/Chinese with shortest (4.8/5.4 yrs). nonHispanic White=6.5 yrs. Hispanic=8.9 yrs

–also, those who were younger at onset of frequent VMS, had lower educational level, greater perceived stress and symptom sensitivity, and higher depressive symptoms and anxiety at start of VMS had longer duration VMS

–overall, the strongest relationships with VMS duration and with persistence of symptoms in those with known FMP were: whether they were premenopausal or menopausal at onset of VMS and their age at onset of VMS (the hazard ratio being >10.9 if symptoms began age 42-45).

Menopausal vasomotor symptoms (e.g. hot flashes, night sweats) are really common, about 80% of women have them and most rate them as moderate to severe and affect their quality of life. Although the ACOG bulletin (Am College of Ob and Gyn) has until recently maintained that hot flashes lasted from 6 months to 2 years, this is the second report I’ve seen in the past couple of years which seriously challenge this (the Penn Ovarian Aging Study, found a median of 10.2 years of moderate-to-severe hot flashes postmenopausally. see Freeman E. Obstetrics & Gynecology. 2011; 117:1095-1104​). Overall in the current study, the symptoms on average lasted 7.4 years, but even in the lowest-risk groups, 20% had symptoms at 13 years out. So, as those of us in primary care have known for decades, VMS frequently lasts much much longer than ACOG has historically noted, and that this has profound implications in terms of what what we as clinicians should consider within normal limits (i.e. when we should be concerned about underlying pathology), what women should expect, and, if medical treatment is needed, how long that treatment might last (i.e., it seems that short-term estrogen replacement has minimal adverse events, especially if administered by transdermal route which bypasses first-pass hepatic metabolism and thereby does not induce high levels of clotting factors. but now we are acknowledging that treatment may actually be required for far longer, raising big questions about development of breast cancer, for example, if estrogens, the most potent medication, is used).

Primary Care Corner with Geoffrey Modest MD: Paget disease clinical guidelines

25 Nov, 14 | by EBM

By: Dr. Geoffrey Modest

The Endocrine Society just released clinical practice guidelines for the diagnosis and management of Paget disease of the bone.


Some background: there is a genetic component with family history in 10-20% and autosomal dominant transmission pattern, clinically rare prior to age 40, men and women affected.

Basic recommendations:


–In patient with suspected Paget, Get plain xray of suspected area. If diagnosed with Paget, then get radionuclide bone scan to assess extent of disease

–If diagnosed with Paget by xray, get biochemical evaluation: alkaline phosphatase (ALP) or more specific marker of bone formation (especially if there is hepatobiliary disease which could affect the ALP) – can check amino-terminal propeptide of type 1 collagen (P1NP, the best option but expensive) or bone-specific ALP (though there is about 20% cross-reactivity between antibodies to liver and bone ALP) and bC-terminal propeptide of type 1 collagen (bCTx) or urinary N-terminal propeptide of type 1 collagen (NTx).


–Bisphosponates if at risk of future complications

–“Suggest” a single 5-mg dose of IV zolendronate as treatment of choice, since it usually lasts >6 years and requires less costly followup. other options include alendrontate 40mg/d for 6 months (may need to retreat in 2-6 years) or risedronate 30 mg for 2 months (may need to retreat in 1-5 years)

–If symptoms need to be controlled urgently (see below), assess markers of short-term response to assess if there is adequate response to therapy (here it is best to use b​CTx as marker of bone resorption, since it responds more rapidly to treatment than ALP). Assess before and shortly after treatment initiation

–If osteolytic lesions present, repeat xray in 1 year

–Maintaining remission: check ALP or other baseline disease markers at 6-12 weeks after therapy, though maximal suppression may take 6 months. follow bone turnover markers (should be below midpoint of assay reference range) as marker of need for retreatment. for zolendronate, check every 1-2 years. for other regimens, check every 6-12 months.

–Monostotic Paget:  all of the biochemical markers of bone turnover may be normal even in symptomatic patients

Complication Management

–Hearing loss: treat with potent bisphosphonate (eg IV zolendronate) to prevent worsening

–Osteoarthritis: if severe, bisphosphonates (even before joint replacement surgery).  when mild, use analgesics. often hard to know if it is the paget’s or underlying osteoarthritis causing the pain. can consider bisphophonates as well as analgesics, though data sparse.

–Bowing of lower extremity: potent bisphosphonate (eg IV zolendronate)​ prior to surgery

–Paralysis (with disease of the spine): bisphosphonate with neurosurgical evaluation. usually medical therapy is sufficient (unless severe structural damage)

–Neoplasm: if osteosarcoma or giant cell tumor, pretreat with  potent bisphosphonate prior to surgery. interesting that neoplasms seem to be less frequent in this era of bisphosphonates.

In reviewing financial disclosures, of the 7 members of the taskforce, 2 without conflict, 1 with declared conflicts, and 4 with financial interests in several drug companies but stated that there were no conflicts.


Primary care corner with Dr. Geoff Modest: FDA testosterone alert

3 Feb, 14 | by EBM

here is the Jan 31 FDA alert about testosterone (also see link:

AUDIENCE: Cardiology, Urology, Family Practice

ISSUE: FDA is investigating the risk of stroke, heart attack, and death in men taking FDA-approved testosterone products. We have been monitoring this risk and decided to reassess this safety issue based on the recent publication of two separate studies that each suggested an increased risk of cardiovascular events among groups of men prescribed testosterone therapy. FDA is providing this alert while it continues to evaluate the information from these studies and other available data. FDA will communicate final conclusions and recommendations when the evaluation is complete.

BACKGROUND: Testosterone is a hormone essential to the development of male growth and masculine characteristics. Testosterone products are FDA-approved only for use in men who lack or have low testosterone levels in conjunction with an associated medical condition.

RECOMMENDATION: At this time, FDA has not concluded that FDA-approved testosterone treatment increases the risk of stroke, heart attack, or death. Patients should not stop taking prescribed testosterone products without first discussing any questions or concerns with their health care professionals. Health care professionals should consider whether the benefits of FDA-approved testosterone treatment is likely to exceed the potential risks of treatment. The prescribing information in the drug labels of FDA-approved testosterone products should be followed.

i just posted about one of the studies (from PLoS) last week, the other one being a recent one in JAMA (see doi:10.1001/jama.2013.280386). in the jama study they looked retrospectively of 8700 men in the VA with low testosterone levels (<300 ng/dL) who had coronary angiography in the years 2005-2011. findings:

–1223 of these men started testosterone an average of 531 days after cath (20% with prior hx MI, 50% with diabetes, 80% with known CAD). those on testosterone tended to be younger and have fewer comorbidities. the testosterone levels were also lower (176) in those put on testosterone therapy vs those not (207)

–after 3 years, those who were on testosterone: 25.7% had an event (all-cause mortality, MI, or stroke) vs 19.9% not on testosterone, finding a 29% increase in events in those on testosterone. no relation between those with or without coronary artery disease. (unlike some prior studies, the increase in events did not happen soon after starting testosterone, but after 3 years). no diff in the VA group with baseline cardiovasc risk factors in those who had/did not have events.

speculated mechanisms for testosterone and cardiovasc disease: testosterone increases platelet thromboxane A2 receptor density and platelet aggregation; dihydrotestosterone (a metabolite) increases smooth muscle proliferation and expression of vascular cell adhesion molecule 1; testosterone worsens sleep disordered breathing in those with OSA. (all of these are potentially directly assoc with cardiovasc dz)

so, nothing definitive, and the FDA alert is an alert, albeit a lukewarm one. but my sense is that there are enough data to reinforce being wary, at least only prescribing testosterone if there is a clear clinical indication, and letting patients know that there is a potential link.


Primary Care Corner with Geoff Modest MD: Choosing endocrine tests wisely

23 Oct, 13 | by EBM

endocrine society and am assn of clinical endocrinologists added their suggestions to the choosing wisely website (see ). this website in general has suggestions about unnecessary tests from many of the major specialty and primary care organizations and is really well-organized.

the endocrine society points:

  1. avoid routine daily self-glucose monitoring in adults with stable DM2 or agents not causing hypoglycemia (eg metformin).  The issue here is that it does not make sense to have patients check their fingersticks more than once a day if they are well-controlled.  There was a study in BMJ a couple of years ago suggesting that glucose self-monitoring in the aggregate did not change diabetes management, largely because physicians did not act on that information.  However, I do find there is an additional role for checking fingersticks, which is for patients to get direct feedback themselves about the effect of what they’re eating, or the effects of exercise in lowering blood sugar.  So, I do encourage patients to check their fingerstick after they have high carbohydrate meals, for example, to learn the effect of that meal on their blood sugar — as a means to educate themselves about what they should or should not eat and what quantities are okay.
  2. Do not routinely measure 1, 25-dihydroxy vitamin D unless the patient has hypercalcemia or decreased kidney function.  The issue here is that 25-hydroxy vitamin D assesses vitamin D stores more accurately than the 1,25-dihydroxy vit d.  Patients who have low vitamin D may well have preserved 1, 25 dihydroxy vitamin D levels as the body struggles to maintain appropriate levels of the active hormone (1,25-dihydroxy).
  3. Do not routinely order a thyroid ultrasound in patients with abnormal thyroid function tests in the absence of a palpable thyroid gland abnormality.  The point here is that there is not often a relationship between having thyroid nodules and thyroid dysfunction, and additionally the ultrasound are too sensitive and frequently picks up inconsequential small nodules.  As in many radiologic studies, ultrasounds beget ultrasounds beget ultrasounds ( or CT scans beget CTs or MRIs or…) for insignificant problems, leading to patient anxiety, loss of work/interference with daily life, and  cost.
  4. Do not order a total or free T3 when assessing levothyroxine dose in hypothyroid patients.  Although T3 is the more active hormone, TSH is the physiologic measure indicating appropriate thyroxine repletion.  In fact, patients on oral levothyroxine may well have high T4 and low T3 levels appropriately.  Ordering TSH to monitor thyroid replacement of course applies only to patients who have hypothyroidism from a primary thyroid dysfunction.
  5. Do not prescribe testosterone unless there is biochemical evidence of deficiency.  The issue here is that the symptoms associated with   testosterone deficiency are common and very often related to other medical or psychosocial issues.  There has been an apparent massive TV advertising campaign by the drug companies to promote  testosterone replacement, which (not surprisingly) creates a significant financial advantage to them.  However, testosterone replacement therapy is not indicated unless there is true testosterone deficiency, documented by a low total testosterone level from a morning blood sample.  This probably should be repeated on a second day if low.  In labs with high-quality assessment of free or bioavailable testosterone, that also might be helpful in documenting testosterone deficiency.


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