Last update and review: December 17, 2020.
A short summary.
Prolonged fasting diminishes thyroid-stimulating hormone (TSH) secretion by reducing burst amplitude and by blunting the nocturnal increase. These changes may be mediated by the decrease in circulating leptin.
Ketogenic, carnivore and other popular restrictive diets may result in metabolic profiles that are similar to the metabolic profile of a fasting human. Leptin is commonly very low in people on restrictive diets.
It is recognized that TSH plays a role in maintaining bone health. If following a restrictive diet results in the suppression of the nocturnal rise in TSH, it may be detrimental to bone health.
We looked at the published literature on TSH and bone health, as well as on TSH in general, and took some notes that we share in this article.
A side note.
If you need help with understanding and improving your thyroid hormones and other biomarkers, do not hesitate to get in contact with us.
TSH signaling contributes to high bone formation.
TSH signaling in bones.
Below, there are several facts on the effects of TSH mentioned by Zaidi et al., 2018 (1), and other authors.
TSH inhibits osteoblastogenesis in bone marrow-derived cell cultures, but stimulates osteoblast differentiation and mineralization in murine ES cell cultures. In vivo, intermittently administered TSH is anabolic in both rats and mice.
TSH rescues the bone loss, 28 weeks following ovariectomy.
When injected at intervals as far apart as every two weeks into rats, TSH rescues the bone loss, 28 weeks following ovariectomy.
Consistent with rodent data, Martini et al., 2008 (2), showed an increase in procollagen type I Nterminal propeptide (PINP), a marker of bone formation, that many consider to validate the conclusion that a bolus dose of TSH is indeed anabolic in people.
Also, Cho, et al. 2015 (3), found that antibody-activated TSH signaling contributes to high bone formation, independent of the actions of thyroid hormone.
4.5- and 3.2-fold increases in the risk of vertebral and non-vertebral fractures, respectively, were noted at serum TSH levels <0.1 mIU/L.
Epidemiological studies in an increasing number of global cohorts document a tight relationship between low TSH levels, parameters of bone loss, and even fracture risk. Bauer, et al. 2001 (4), reported 4.5- and 3.2-fold increases in the risk of vertebral and non-vertebral fractures, respectively, were noted at serum TSH levels <0.1 mIU/L.
Women with a low TSH level (0.1 mU/L) had a threefold increased risk for hip fracture compared with women who had normal TSH levels (0.5 to 5.5 mU/L), but use of thyroid hormone itself was not associated with increased risk for hip fracture if TSH levels are normal.
Bauer et al., 2001 (4):
After adjustment for age, history of previous hyperthyroidism, self-rated health, and use of estrogen and thyroid hormone, women with a low TSH level (0.1 mU/L) had a threefold increased risk for hip fracture (relative hazard, 3.6 [95% CI, 1.0 to 12.9]) and a fourfold increased risk for vertebral fracture (odds ratio, 4.5 [CI, 1.3 to 15.6]) compared with women who had normal TSH levels (0.5 to 5.5 mU/L). After adjustment for TSH level, a history of hyperthyroidism was associated with a twofold increase in hip fracture (relative hazard, 2.2 [CI, 1.0 to 4.4]), but use of thyroid hormone itself was not associated with increased risk for hip fracture (relative hazard, 0.5 [CI, 0.2 to 1.3]).
The use of oral estrogen in these post-menopausal women was not associated with lower risk of fractures.
Below, we insert several informative tables from the study by Bauer et al., 2001 (4). It is reassuring that the use of thyroide hormones was ot associated with fractures if the TSH levels were normal. There is, however, also an unexpected observation. Indeed, the use of oral estrogen in these post-menopausal women was not associated with lower risk of fractures.
TSH itself may play a role in the preservation of bone after menopause.
Morris, 2007 (5):
We used data collected in the third U.S. National Health and Nutrition Examination Survey to examine associations between TSH, as it varies over its reference range, and bone status in healthy, postmenopausal American women.
After adjustment for age, race/ethnicity, body mass index, serum T(4), estrogen replacement therapy, smoking, and physical activity level, the odds ratios (95% CI) relating TSH between 0.39 mIU/Land the median of the reference range, 1.8 mIU/L, versus TSH between the median of the reference range, 1.8 mIU/L, and 4.5 mIU/L to osteoporosis and osteopenia were 3.4 (95% CI, 1.3-9.2) and 2.2 (1.2-3.8), respectively. Furthermore, BMD increased significantly as TSH increased over its reference range.
The tables and figures below contain the data and the results of the study by Morris, 2007 (5).
Low normal TSH levels may not be physiological for postmenopausal women.
Subjects with low normal TSH levels (0.5-1.1 mU/l) had significantly lower BMDs at the lumbar spine than those with high normal TSH.
Morris, 2006 (5):
In this multi-ethnic sample of postmenopausal American women, osteoporosis and osteopenia were observed significantly more frequently among those with low-normal, as opposed to high-normal, serum TSH.
Kim et al., 2006 (6):
BMD at the lumbar spine and femoral neck increased with TSH level. Even after adjustment for age, years since menopause and body mass index, subjects with low normal TSH levels (0.5-1.1 mU/l) had significantly lower BMDs at the lumbar spine (0.863 +/- 0.009 g/cm2 vs 0.900 +/- 0.009 g/cm2, P = 0.004) and femoral neck (0.660 +/- 0.006 g/cm2 vs 0.683 +/- 0.006 g/cm2, P = 0.006) than those with high normal TSH levels (2.8-5.0 mU/l), as well as a 2.2-fold increased risk of osteoporosis (95% confidence interval: 1.2-4.0).
Conclusion: These results suggest that low normal TSH levels may not be physiological for postmenopausal women and, during treatment of hypothyroidism, may not be adequate for avoiding osteoporosis.
Somewhat unexpected: No association was found between bone mass density (BMD) and subclinical hypothyroidism and subclinical hyperthyroidism in middle-aged Korean men and women.
Lower risk of osteoporosis in post-menopausal women with subclinical hyperthyroidism.
Lee et al., 2020 (7), found no apparent association between subclinical hypothyroidism or subclinical hyperthyroidism, defined on single TSH measurement, and BMD at the lumbar spine and femur in a large cohort of middle-aged men and women. “Subclinical hypothyroidism” was independently associated with a lower risk of osteoporosis in postmenopausal women.
In the study by Leetet al., 2020 (7), the average age of the 15,761 women was 45, and the average age of the 9749 men was 48.
The results of Lee et al., 2020 (7), contrast with other observations. The authors themselves mention the limitations of their study, namely, the fact that the measurement of TSH was done only once for the majority of the subjects:
In our study, most subjects visited our institution only once, so we defined subclinical hypothyroidism or hyperthyroidism on a single measurement of TSH, similar to other studies based on single TSH values [19,24,25]. Like Abrahamsen et al. [28,29], our study warrants follow-up observations of how long-term exposure to asymptomatic subclinical thyroid dysfunction might affect osteoporosis or fracture.
In the table with subjects characteristics, we can see that the men and the women participating in the study by Lee et al., 2020 (7), have very low CRP. Would lower CRP contribute to maintaining bone health?
There are also several other informative biomarkers that hint at an overall good health of middle-aged Koreans.
Below, there is a collection of different tables with the results of the study by Lee et al., 2020 (7).
In summary, the study by Lee et al., 2020 (7), is somewhat misleading. But we need to take these results into account.
Iodine intake in Korea is higher than in other countries which may explain higher levels of TSH observed in Koreans
There is another interesting fact mentioned in the study by Lee et al., 2020 (7). Indeed, the authors write that iodine intake in Korea is higher than in other countries which may explain higher levels of TSH observed in Koreans:
TSH levels in a Korean reference population were higher than those reported in other countries, presumably because of excess intake of dietary iodine in Korea.
Kim et al., 2015 (8):
Recent studies from China and Japan have shown that excessive dietary iodine intake influences serum TSH levels and Korean people generally consume excessive amounts of iodine due to the high ingestion of seaweed. Therefore, these factors should be considered in establishing an optimal normal reference range for serum TSH levels.
The reference ranges of TSH for Korean population.
The same authors, Kim et all., 2015 (8), did an interesting work at defining the reference ranges of TSH for Korean population. We insert several tables with their results below for future review. The link between higher normal ranges of TSH and high iodine intakes is something to keep in mind for other populations.
Thyrotropin Levels in a Population with No Clinical, Autoantibody, or Ultrasonographic Evidence of Thyroid Disease.
Hamilton et al., 2008 (9), produced a similar interesting set of results in their work on TSH reference ranges. There is a set of tables and figures from their study below.
An upper limit of 2.5 may result in inappropriate therapy of euthyroid individuals
Hamilton et al., 2008 (9), conclude:
20% of the HTDS participants without evidence of thyroid disease have a TSH greater than 2.5 IU/ml, and 10.2% have a value greater than 3.0. Based on these results, and our concern that an upper limit of 2.5 may result in inappropriate therapy of euthyroid individuals, we recommend an upper limit near 4.0IU/ml for the TSH reference range. However, it is essential that patient-specific factors be considered along with a confirmed TSH level before deciding whether thyroid hormone replacement is indicated in an individual patient.
Dietary iodine intake and urinary iodine excretion.
Kim J.Y. et al., 1998 (10), did an informative study on idodine intakes and iodine urinary excretion in Korean adults. The figures of iodine intakes that the authors provide for other countries show sufficient intakes. However, in 2021, we doubt that iodine intakes in Europeans are sufficient. The main source off iodine in Europe and in North America used to be iodized salt. Currently, salt intakes are lower, many commercially available salts are not iodized, there is no apparent insistance on the importance of an sadequate iodine intake by the “medical profession” and medical bureaucracy.
Kim J.Y. et al., 1998 (10):
The dietary assessment of iodine using a food frequency questionnaire and a urinary iodine excretion examination were carried out in 278 healthy adults. The average usual iodine intake of Korean adults was 479 micrograms per day (ranging from 61 micrograms to 4086 micrograms). There was no significant difference in sex or age. The major food sources of dietary iodine included seaweed (66%), milk and dairy products (11%), and fish (9%). The average urinary excretion of iodine was 674 micrograms/g creatinine and there was no significant difference in sex or age. The dietary iodine intake was positively correlated with the urinary excretion of iodine (gamma = 0.60, p < 0.01). The study data indicated that the iodine intake and excretion of Koreans depends mostly on the amount of seaweed consumption like sea tangle and sea mustard. As well, the current iodine intake and urinary iodine excretion by Koreans seems to be higher than in other countries.
Conclusions.
In some studies, low normal TSH is associated with fractures and a loss of bone mass density in adults of certain age. The negative effects of low normal TSH are less apparent in middle-aged adults. However, these observations were reported in populations on “high-carb” diets. If following a restrictive diet results in the suppression of the nocturnal rise in TSH and reduced bursts, it may be detrimental to bone health.
If you need help with interpreting of your different biomarkers and your laboratory test results, do not hesitate to get in contact with us.
Selected references:
1. Zaidi et al. J Endocrinol. 2018 June ; 237(3): R83–R98.
2. Martini G, Gennari L, De Paola V, Pilli T, Salvadori S, Merlotti D, Valleggi F, Campagna S, Franci B, Avanzati A, et al. The effects of recombinant TSH on bone turnover markers and serum osteoprotegerin and RANKL levels. Thyroid. 2008; 18:455–460.
3. Cho SW, Bae JH, Noh GW, Kim YA, Moon MK, Park KU, Song J, Yi KH, Park do J, Chung JK, et al. The Presence of Thyroid-Stimulation Blocking Antibody Prevents High Bone Turnover in Untreated Premenopausal Patients with Graves’ Disease. PLoS One. 2015; 10:e0144599.
4. Bauer DC, Ettinger B, Nevitt MC, Stone KL; Study of Osteoporotic Fractures Research Group. Risk for fracture in women with low serum levels of thyroid-stimulating hormone. Ann Intern Med. 2001 Apr 3;134(7):561-8.
5. Morris MS. Bone. 2007 Apr;40(4):1128-34.
6. Kim DJ. Clin Endocrinol (Oxf). 2006 Jan;64(1):86-90.
7. Lee K, Lim S, Park H, Woo HY, Chang Y, Sung E, Jung HS, Yun KE, Kim CW, Ryu S, Kwon MJ. Subclinical thyroid dysfunction, bone mineral density, and osteoporosis in a middle-aged Korean population. Osteoporos Int. 2020 Mar;31(3):547-555.
8. Kim et al. Korean J Intern Med. 2015;30(3):335-344.
9. Hamilton et al. J Clin Endocrinol Metab93: 1224 –1230,
2008.
10. Kim JY et al. Dietary iodine intake and urinary iodine excretion in normal Korean adults. Yonsei Med J. 1998 Aug;39(4):355-62.