Guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis.Corticosteroid-induced osteoporosis glucocorticoid induced osteoporosis guidelines 2012 the most common form of secondary osteoporosis and the first cause in young people. Bone loss and increased rate of fractures occur early after the initiation of corticosteroid therapy, and are then related to dosage and treatment duration. The increase in fracture risk is not fully assessed by bone mineral density measurements, as it is also related to alteration of bone quality and increased glucocorticoid induced osteoporosis guidelines 2012 of falls. In patients with rheumatoid arthritis, a treat-to-target strategy focusing on low disease activity including through the use of low dose of prednisone, is a guideline determinant guidelinfs bone loss prevention. Bone loss magnitude is variable and there is no clearly identified predictor of the serenace injection dosage risk of fracture.
Clinical Practice Guidelines Glucocorticoid-Induced Osteoporosis
Corticosteroid-induced osteoporosis is the most common form of secondary osteoporosis and the first cause in young people. Bone loss and increased rate of fractures occur early after the initiation of corticosteroid therapy, and are then related to dosage and treatment duration.
The increase in fracture risk is not fully assessed by bone mineral density measurements, as it is also related to alteration of bone quality and increased risk of falls. In patients with rheumatoid arthritis, a treat-to-target strategy focusing on low disease activity including through the use of low dose of prednisone, is a key determinant of bone loss prevention.
Bone loss magnitude is variable and there is no clearly identified predictor of the individual risk of fracture. Prevention or treatment of osteoporosis should be considered in all patients who receive prednisone. Bisphosphonates and the anabolic agent parathyroid hormone 1—34 have shown their efficacy in the treatment of corticosteroid-induced osteoporosis. Recent international guidelines are available and should guide management of corticosteroid-induced osteoporosis, which remains under-diagnosed and under-treated.
Duration of antiosteoporotic treatment should be discussed at the individual level, depending on the subject's characteristics and on the underlying inflammation evolution. A key point is that the underlying inflammation for which GCs are used also has a role in bone fragility, as there is a strong relationship between inflammatory cells and bone cells.
The prevalence of use of oral GCs in the community population is between 0. Apart from bone and ocular side effects, lipodystrophy and neuropsychiatric disorders are also common adverse events of long-term GC therapy. A number of guidelines for GIOP are now available, but the proportion of GC-treated patients receiving preventatives for bone complications remains low.
Paradoxically, the numbers of underlying comorbidities and concomitant treatments are strong determinants of the absence of prevention of GIOP, although they are themselves added risk factors for osteoporosis. Bone fragility in GIOP is characterised by rapidity of bone loss at the introduction of GCs, and the discrepancy between bone mineral density BMD and risk of fractures.
These two points can be explained by the pathogenesis of GIOP. In the general population, even small elevations of C reactive protein within the normal range increase non-traumatic fracture risk. Rheumatoid arthritis RA doubles the risk of hip and vertebral fractures, regardless of the use of GCs, 17 and disease activity is consistently associated with low BMD.
In a prospective study of patients with early RA conducted at a time when biotherapies were not available, high bone loss was observed, mainly in patients with persistent inflammation during follow-up ie, persistent high CRP. There is a strong biological rationale for these clinical observations. Osteoclastogenesis is under the control of RANK-ligand, which is produced by osteocytes in normal bone remodelling, but also by lymphocytes and fibroblasts in other situations, such as oestrogen deficiency 21 and inflammation.
Osteoclastogenesis can be enhanced by a number of cytokines, the main pathway being driven by Th 17 cells subpopulation ie, interleukin IL 6 and IL Moreover, an over expression of sclerostin has been observed in these models, with a consequence of inflammation-related decrease in bone formation. All these clinical observations and biological studies show that inflammation has a deleterious effect on bone remodelling, inducing an increase in resorption and a decrease in formation, before any effect of GCs themselves.
The predominant effect of GCs on bone is the impairment in bone formation figure 1. Pathophysiology of glucocorticoid-induced osteoporosis adapted from ref GCs at high concentrations dramatically decrease bone formation rate, osteoblast numbers, and osteocyte numbers and activity.
GCs are associated with a decrease in osteocyte viability, including changes in matrix properties surrounding the osteocyte lacunae. GCs increase the expression of RANK-ligand and decrease the expression of osteoprotegerin in stromal and osteoblastic cells.
Although this increased resorption has been demonstrated, much of the GC-related bone loss is caused by the reduced bone formation, which persists throughout GC administration.
Earlier, emphasis had been placed on the effects of GCs on calcium metabolism, because of decrease of gastrointestinal absorption of calcium and induction of renal calcium loss. A secondary hyperparathyroidism has been suggested as a determinant of bone effects. Actually, there is no evidence for elevated endogenous levels of PTH in these patients and histological features are not those related to an increased PTH secretion.
GCs reduce production of sex steroid hormones, and hypogonadism can by itself induce increased bone resorption. Glucocorticoid-induced myopathy is related to a direct effect on muscle mass and muscle force; muscle weakness is one of the determinants of the risk of falls and fractures in these patients.
There is great variability of side effects of GCs among individuals, including bone loss, for largely unknown reasons.
Individual GC sensitivity can also be regulated by polymorphisms in the GC receptor gene. The risk of fractures is increased by twofold in patients with GCs, and the risk of vertebral fractures is even higher. A number of observations from epidemiological studies are relevant for clinical practice, as they could help to identify a high-risk group of patients. Data also suggest a rapid increase in rate of falls after start of oral GCs. In epidemiological studies, the increased risk of fractures is observed even at low doses of prednisone, that is, 2.
The appropriate care of patients receiving such low doses is not well defined. There is a dose-dependent increase in fracture incidence. Interestingly, the fracture risk is related to the current daily dose, more than to the cumulative dose; 48 this may be related to the difficulty of an accurate calculation of this cumulative dose.
Ever use of GCs is associated with an increased risk of hip fracture, and this justifies the assessment of osteoporosis and fracture risk in all patients. However, the risk is mainly associated with recent and prolonged GC use, more than to remote or short courses.
BMD loss is an immediate consequence of the introduction of GCs and affects the trabecular bone ie, spine more than it does the cortical bone ie, femur. The increased rate of bone loss persists in chronic GC users, but more slowly.
There is a mismatch between BMD data and fracture data in patients receiving GCs because of the disparity related to the alteration of bone quality. There is a debate on the appropriate T score threshold to be considered a risk and as an indication for treatment in patients with GCs: There is no means to provide an evidence-based threshold for treatment decisions.
The WHO fracture risk assessment tool FRAX algorithm has been developed to estimate the year risk of hip and other major fractures clinical spine, humerus or wrist fracture based on clinical risk factors, with or without BMD.
These clinical risk factors are largely independent of BMD and can thus improve the fracture risk assessment. One of the limitations of FRAX is that use of oral GCs is entered as a dichotomous risk factor and does not take into account the dose of GCs and the duration of use. Moreover, FRAX does not take into account the difference in risk between prior and current use. Moreover the predictive value of FRAX has been mainly validated for non-vertebral fractures although the principal risk in GCs users is for vertebral fractures.
FRAX assessment has already been included in some guidelines at different steps of the treatment decision. Treatment can be considered directly without FRAX assessment if patients are at high risk defined by one of the following criteria: Persistent inflammation is associated with bone loss as shown in longitudinal studies in patients with active RA or ankylosing spondylitis SpA.
In contrast, prospective open studies show that complete control of inflammation in parallel with clinical improvement and thus increased mobility is accompanied by the absence of bone loss. However, there is no evidence for a reduction in fracture risk with such a strategy, 60 and new epidemiological studies are mandatory in this matter.
Age, female gender, low BMI, history of falls and previous fractures, duration of menopause and smoking are associated with fracture risk in patients with GCs, similarly to how they are in primary osteoporosis.
We have shown that prevalence of non-vertebral fractures is a strong determinant of the risk of having vertebral fractures in patients with RA, 61 implying that the individual's skeleton is already of inadequate strength to withstand the trauma of daily living. Beyond GC use, these risk factors must be assessed in all patients, and all causes of secondary osteoporosis are added risk factors of fractures in patients with GCs. At the initiation of GC treatment, the patient's height must be measured, as height loss in the follow-up could be related to asymptomatic vertebral fractures.
Biological tests are performed to screen for other causes of bone diseases. There is no indication for assessment of biochemical markers of bone remodelling either at baseline or during follow-up, as bone turnover is consistently low in GC users. As the daily dose of GCs is a determinant of fracture risk, it must be constantly reviewed by considering both the reduction of the dose to the minimally active and alternative administration such as intra-articular injections.
The risk of falling should be assessed in particular in elderly patients, patients with painful joints of the lower limbs and patients with massive doses of GCs. Physical activity or mobilisation should be considered, adapted to the underlying condition. Attention to nutrition must be paid to prevent protein and calcium intake deficiencies. GC-treated patients may seldom be outdoors, and thus exposed more than the general population to vitamin D deficiency. There is no evidence of an advantage using calcitriol or alcalcidol, as there is a large variability of outcomes with these vitamin D metabolites over plain vitamin D.
Bisphosphonates and teriparatide have been assessed in prevention and treatment of GIOP. There are a number of issues regarding their efficacy. Thus the efficacy on fractures is mainly based on bridging data between the short-term change in BMD in patients with GCs, and the long-term change in BMD and reduction of fracture risk in patients with postmenopausal osteoporosis.
Bisphosphonates are the more popular antiosteoporotic drugs. There was a 2. Interestingly the decrease of BMD in the placebo group receiving calcium and vitamin D was driven by the duration of GCs: Data from pooling these two studies suggest a reduction of fractures in the first year of therapy: Attention has been paid recently to osteonecrosis of the jaw and atypical femoral fractures such as side effect of long-term administration of antiresorptive drugs in osteoporosis; these events are very rare, 70 71 but GC use is one of the identified risk factors.
Buccal hygiene procedures should be implemented to prevent any local increased risk of infection. Whether these rare events can change the duration of anti-resorptive treatments in long-term GC users needs further studies. Bisphosphonates should be used cautiously in premenopausal women, as they cross the placenta; appropriate contraception must be used if necessary and preference given to a short bone half-life bisphosphonate.
The use of administrative databases offers the opportunity to assess a huge number of patients, taking into account the methodological issues related to these studies retrospective design, lack of details in patient characteristics, absence of confirmation of the diagnosis of fractures, etc.
There is so far no study of denosumab on GIOP. In a subgroup analysis of a month study of patients with RA still active although they were receiving methotrexate treated with denosumab, BMD increases were similar in patients with and without GCs. GIOP is a condition where the principal cause of bone loss is reduction in bone formation. This is the rationale for using teriparatide, a parathyroid hormone peptide producing anabolic skeletal effects by stimulation of bone formation.
More importantly, a significantly lower number of vertebral fractures was observed: There are a number of guidelines published by different national societies and colleges, on use of pharmacological treatment in GIOP, which vary somewhat. Adherence to antiosteoporotic treatment may be low in some patients who are already taking multiple medications, and should be assessed regularly. Height loss can be related to vertebral fractures, sometimes asymptomatic because of the analgaesic property of GCs.
We should not go on neglecting fracture risk in patients with GCs. This risk must be assessed in all patients at the initiation of prolonged GC therapy. The treat-to-target strategy focusing on low disease activity is effective on bone loss in RA. New epidemiological data are needed to assess the benefit of such a strategy on fracture incidence. Provenance and peer review: Commissioned; externally peer reviewed.