Official 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®

doi:10.1016/j.jocd.2011.05.014

Journal of Clinical Densitometry

Volume 14, Issue 3, July 2011, Pages 212-219

https://doi.org/10.1016/j.jocd.2011.05.014 Get rights and content

Abstract

Given the significant impact the use of glucocorticoids can have on fracture risk independent of bone density, their use has been incorporated as one of the clinical risk factors for calculating the 10-year fracture risk in the World Health Organization’s Fracture Risk Assessment Tool (FRAX^®). Like the other clinical risk factors, the use of glucocorticoids is included as a dichotomous variable with use of steroids defined as past or present exposure of 3 months or more of use of a daily dose of 5 mg or more of prednisolone or equivalent. The purpose of this report is to give clinicians guidance on adjustments which should be made to the 10-year risk based on the dose, duration of use and mode of delivery of glucocorticoid preparations. A subcommittee of the International Society for Clinical Densitometry and International Osteoporosis Foundation joint Position Development Conference presented its findings to an expert panel and the following recommendations were selected. 1) There is a dose relationship between glucocorticoid use of greater than 3 months and fracture risk. The average dose exposure captured within FRAX^® is likely to be a prednisone dose of 2.5–7.5 mg/day or its equivalent. Fracture probability is under-estimated when prednisone dose is greater than 7.5 mg/day and is over-estimated when the prednisone dose is less than 2.5 mg/day. 2) Frequent intermittent use of higher doses of glucocorticoids increases fracture risk. Because of the variability in dose and dosing schedule, quantification of this risk is not possible. 3) High dose inhaled glucocorticoids may be a risk factor for fracture. FRAX^® may underestimate fracture probability in users of high dose inhaled glucocorticoids. 4) Appropriate glucocorticoid replacement in individuals with adrenal insufficiency has not been found to increase fracture risk. In such patients, use of glucocorticoids should not be included in FRAX^® calculations.

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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Citation Excerpt :
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View all citing articles on Scopus

^a: Position Conference members: See appendix 1.

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Abstract

Introduction

Section snippets

Methodology & Data sources

Statements

In Summary

Additional Questions for Future Research

Clin Gastroenterol Hepatol

Am J Gastroenterol

Transplant Proc

Bone Miner

The basophilic adenomas of the pituitary body and their clinical manifestations (pituitary basophilism)

Bull John Hopkins Hosp

The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis

Osteoporos Int

Bone density threshold and other predictors of vertebral fracture in patients receiving oral glucocorticoid therapy

Arthritis Rheum

Prevention of glucocorticoid-induced osteoporosis

South Med J

Effects of teriparatide versus alendronate for treating glucocorticoid-induced osteoporosis: thirty-six-month results of a randomized, double-blind, controlled trial

Arthritis Rheum

Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis

Arthritis Rheum

A UK Consensus Group on management of glucocorticoid-induced osteoporosis: an update

J Intern Med

American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis

Arthritis Care Res (Hoboken)

Guidance for the adjustment of FRAX® according to the dose of glucocorticoids

Osteoporos Int

Use of oral corticosteroids and risk of fractures

J Bone Miner Res

Oral corticosteroids and fracture risk: relationship to daily and cumulative doses

Rheumatology (Oxford)

A meta-analysis of prior corticosteroid use and fracture risk

J Bone Miner Res

Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures

BMJ

A simple score for estimating the long-term risk of fracture in patients using oral glucocorticoids

QJM

Low-dose prednisone induces rapid reversible axial bone loss in patients with rheumatoid arthritis. A randomized, controlled study

Ann Intern Med

Effects of low-dose prednisone on bone metabolism

J Bone Miner Res

Fracture risk with intermittent high-dose oral glucocorticoid therapy

Arthritis Rheum

Are inhaled corticosteroids associated with an increased risk of fracture in children?

Osteoporos Int

The properties of inhaled corticosteroids: similarities and differences

Prim Care Respir J

Bone mineral density in patients with chronic obstructive pulmonary disease treated with budesonide Turbuhaler

Eur Respir J

Guidance for the adjustment of FRAX^® according to the dose of glucocorticoids