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Genetic predisposition to increased serum calcium, bone mineral density, and fracture risk in individuals with normal calcium levels: mendelian randomisation study

BMJ 2019; 366 doi: https://doi.org/10.1136/bmj.l4410 (Published 01 August 2019) Cite this as: BMJ 2019;366:l4410

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Osteoporosis, fracture risk and association with pharmacological treatments

I read the study of A. Cerani and colleagues with great interest. The different compartments of calcium homeostasis might have different effects, but the genetic findings of this study cannot provide insight into estimated bone mineral density and the potential risks of or relevant protection against fracture.

In my opinion, important factors for osteoporosis and the associated risk of osteoporotic fracture are age, sex, endocrine diseases, alcohol (ab)use, medications like corticosteroids or serotonergic antidepressants and history of falls [1], The last two points tip the balance. I think that (psycho) pharmacological treatments are frequently associated with the risk of falling and the long-time problems of osteoporosis are underestimated.

Since 2007, studies showed an increased risk of fractures associated with selective serotonin reuptake inhibitors (SSRI) [2]. Haney EM et al. [3] performed a cross-sectional analysis of data from 5995 men (> 65 years) participating in the prospective cohort Osteoporotic Fractures in Men Study. In adjusted analyses, mean bone mineral density among SSRI users (n=160) was 3.9% lower at the total hip and 5.9% lower at the lumbar spine in men reporting no antidepressant use. Diem SJ et al. [5] observed in a study of osteoporotic fractures the use of antidepressants and the rate of hip bone loss in 2722 older women. The mean total hip bone mineral density decreased 0.47% per year in nonusers. Wang CY et al. [6] observed in a new investigation the association between the use of SSRI and SNRI (serotonin-norepinephrine reuptake inhibitor) and the risk of fractures using a cohort study to investigate use of SSRI/SNRI and co-morbidity, especially osteoporosis, history of falling and the examination of all-cause fracture. Current users of serotonergic antidepressants were associated with an increased risk of fracture (odds ratio (OR) 1.16 [95 % confidence interval 1.07-1.25]).

Furthermore, a higher risk of fractures was found in patients with osteoporosis (OR 3.05 [2.73-3.42]) or a history of falling (OR 6.13 [3.41-11.0]). The risks of fractures between SSRI and SNRI users were comparable. A large, Canadian prospective randomly selected population-based cohort study [6] assessed the association between SSRIs and SNRIs and fractures. The authors found an increased risk of fractures in in adults (aged >50 years), who used SSRI or SNRI, even after controlling for multiple risk factors .Among 6,645 subjects, 2.9% were using SSRIs or/and SNRIs at baseline. During the 10-year study period, 14.7% participants experienced at least one fragility fracture. SSRI/SNRI use was associated with increased risk of fragility fracture (hazard ratio 1.88; 95% confidence intervals 1.48-2.39). After controlling for multiple risk factors, including previous falls, bone mineral density hip and lumbar bone density, the adjusted ratio for current SSRI/SNRI use remained elevated.

We did not have objective measurements of all relevant factors that might affect fracture risk. J Hippisley-Cox and C Coupland [8] developed interesting new fracture risk algorithms for estimating the individual risk of osteoporotic fracture or hip fracture. A noninvasive approach to studying bone turnover (measured easily with good precision) as predictors of fracture is not robust until now. The association with the intake of serotonergic antidepressants and osteoporosis as a high long-term risk demonstrate the relevance of surveillance of adverse drug events. Further research is essential to detect these points in light of widespread use of antidepressants and other medications and important clinical implications. Balancing between risks and benefits may be difficult: “Mend the mind, but mind the bones!” [8]

1) Järvinen T et al. Shifting the focus in fracture prevention from osteoporosis to falls. BMJ. 2008;336:124-6
2) Ziere G, Dieleman JP, van der Cammen TJ et al. Selective serotonine reuptake inhibiting antidepressants are associated with an increased risk of nonvertebral fractures.J Clin Psychopharmacol 2008;28:411-7
3) Haney EM, Chan BK, Diem SJ et al. Association of low bone mineral density with selective serotonin reuptake inhibitor use by older men Arch Int Med 2007;25:1231-32
4) Diem SJ, Blackwell TL, Stone KL et al. Use of antidepressants and rate of hip bone loss in older women: the study of osteoporotic fractures. Arch Intern Med 2007;25:1240-45
5) Wang CY et al. Serotonergic antidepressant use and the risk of fracture: a population-based nested case-control study. Osteoporos Int. 2016 Jan;27(1):57-63. doi: 10.1007/s00198-015-3213-z. Epub 2015 Jul 1
6) Moura C, Bernatsky S, Abrahamowicz M, et al. Antidepressant use and 10-year incident fracture risk: the population-based Canadian Multicentre Osteoporosis Study (CaMoS). Osteoporos Int. 2014 May;25(5):1473-81
7) Hippisley-Cox J, Carol Coupland C, Predicting risk of osteoporotic fracture in men and women in England and Wales: prospective derivation and validation of QfractureScores. BMJ 2009;339:b4229
8) Saag K. Mend the mind, but mind the bones!: balancing benefits and potential skeletal risks of serotonin reuptake inhibitors. Arch Intern Med. 2007 Jun 25;167(12):1231-

Competing interests: No competing interests

08 August 2019
Detlef Degner
MD, Associate Professor of Psychiatry
Department of Psychiatry, Medical School of Georg-August University, UMG, Goettingen, Germany
Von- Siebold- Str 5 , D -37075 Goettingen, Germany