Position Development PaperOfficial Positions for FRAX® Clinical Regarding Glucocorticoids: The Impact of the Use of Glucocorticoids on the Estimate by FRAX® of the 10 Year Risk of Fracture: From Joint Official Positions Development Conference of the International Society for Clinical Densitometry and International Osteoporosis Foundation on FRAX®
Introduction
In 1932, Cushing described the effect on bone of endogenous glucocorticoids (1). In 1948, Hench and Kendall gave the first dose of compound E to a patient with rheumatoid arthritis with astounding benefit in mobility and pain (2). Since that time, glucocorticoids have been used successfully in multiple clinical scenarios from hormone replacement to chronic anti-inflammatory use to high dose use for immunosuppression and prevention of transplant rejection.
It is now well recognized that the use of glucocorticoids comes with a price perhaps most noticeably on the strength and structure of bone leading to an increase in fracture risk (2). Today glucocorticoid induced osteoporosis (GIOP) is the leading medication induced cause for fractures with approximately a doubling of fracture risk at any given bone mineral density (BMD). In terms of bone mass measurement, there is approximately a one standard deviation difference in equivalent fracture risks between those ever on glucocorticoids compared to a general population (3). Epidemiologic studies have clearly indicated that the fracture risk imposed by glucocorticoids also occurs independently of a glucocorticoid-associated decline in BMD and therefore one needs to consider this along with other clinical risk factors in determining a patient’s fracture risk.
Several randomized controlled clinical trials have demonstrated a significant reduction in fracture risk with the use of pharmacologic agents in individuals on glucocorticoids 4, 5. International groups have developed guidance in the use of these agents in preventing fractures in a population of glucocorticoid users 6, 7. It is now recommended by at least one expert panel that even low risk patients initiating glucocorticoids even at for short duration therapy be treated with pharmacologic therapy to prevent fractures (8).
Recognizing this significant increased fracture risk with the use of glucocorticoids and that treatment is effective in reducing that risk, it is essential that clinicians recognize this risk and treat accordingly. One tool that has been developed to aid in combining clinical fracture risks with age and BMD is FRAX®. This Fracture Assessment Tool has been developed by the World Health Organization as a method of utilizing clinical risk factors with or without BMD to identify individuals at higher risk for fracturing. FRAX was introduced in 2008 as a website in which clinical data and BMD can be entered to determine two outcomes: 1) the ten year risk of a major osteoporotic fracture and 2) the 10 year risk of a hip fracture. The site was designed to be intuitive and easily used by primary care providers. The clinical risk factors were those that could be easily identified through history and which were largely independent of BMD in determining fracture risk. One of the clinical risk factors is the use of glucocorticoids.
In the FRAX tool, glucocorticoid use is entered as a dichotomous variable. The present version 3.1 of FRAX does not contain an explanation of glucocorticoid use. (http://www.sheffield.ac.uk/FRAX/) Previous versions explained that glucocorticoid use was defined as any past or current use of glucocorticoids at a dose of 5 mg or more for 3 months or more. (http://www.rheumatology.org/publications/hotline/03_18_flax.asp).
Inherent with simplicity comes compromise. In the case of the FRAX tool and the use of glucocorticoids, several questions can be raised about data entry and calculations. What dose of glucocorticoid produces the output in FRAX? How would the ability to change the dose within the calculations affect the output? How should clinicians adjust the 10 year risk depending on factors such as dose, length of therapy, intermittent vs. steady use, mode of delivery or effect of replacement dose? Providing guidance to help answer these questions is the purpose of this report.
Section snippets
Methodology & Data sources
An outline and draft of questions regarding the effect of glucocorticoid use on the out put of FRAX were developed by the steering committee. These questions were further refined by the committee following discussion within the committee of whether to recommend changes to the algorithms used in FRAX or to provide guidance for the clinician for making clinical adjustments to the output from FRAX. We selected the latter given the absence of further granularity within the studies used to develop
Statements
The following sections pose the finalized questions proposed by the committee and modified at the meeting by the Position Development Conference Expert Panel, the responses to those questions from the expert panel with grading for the quality of the evidence, the strength of the recommendation and whether these responses can be applied worldwide.
What guidance can be given to clinicians for when to include glucocorticoids as a risk in FRAX and if included as a risk, can the effect of that risk
In Summary
There is substantial evidence that the historically published and at least in the past, typically prescribed dose of hydrocortisone or prednisone in patients with auto-immune adrenal insufficiency or congenital adrenal hyperplasia is higher than physiologic. Although the literature is not entirely in agreement, there appears to be a reduction in bone density in these individuals although in the case of CAH, this could be related to reduced bone growth in childhood. There are insufficient data
Additional Questions for Future Research
Despite the presence of a significant database in the published literature of studies on the effect of glucocorticoids on fracture risk, gaps remain in our ability to quantify the effect of glucocorticoids on fracture risk. Although there are data to support some estimation of risk based on glucocorticoid daily dose, there is considerably less ability to quantify the effect by the length of treatment or the mode of delivery. We would pose the following questions to help guide further
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2020, BoneCitation Excerpt :These analyses were performed on each group overall and by age (50–59, 60–69, 70–79 and ≥80 years). The risk of subsequent MOF was adjusted for several baseline covariates known to be associated with increased risk of fragility fracture: attained age; use of osteoporosis medication in the past 12 months; use of drugs known to increase the risk of falls in the past 12 months; glucocorticoid use in the past 12 months (defined according to the FRAX® algorithm as past or present exposure of ≥5 mg daily dosage of prednisolone or equivalent for ≥3 months [24]); number of different medications prescribed in the past 12 months; secondary osteoporosis; rheumatoid arthritis; Charlson comorbidity index measured two years prior to index date [25], and pre-packaged drug dispensing (defined as use of the ApoDos system within the past 12 months), which was used as a proxy for being “dependent”. A total of 231,769 women with at least one index fracture during the study period were included in the study and constituted Group 1.
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Position Conference members: See appendix 1.