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Abstract

Glucocorticoids are widely used to treat several diseases; however, one of their major consequences is a deleterious effect on bone that may lead to glucocorticoid-induced osteoporosis. Fractures may begin to occur within 3 months of commencing oral glucocorticoid therapy, and may even occur in patients receiving low doses. The good news is that with effective management, bone loss and fractures can be prevented or greatly reduced in patients receiving glucocorticoids. Despite clear practice guidelines, glucocorticoid-induced osteoporosis often goes undiagnosed and untreated in many patients. In this article, a current overview of glucocorticoid-induced osteoporosis is provided, including how to recognize, prevent and treat osteoporosis in pre- and postmenopausal women receiving glucocorticoid therapy.

Keywords

bone mineral density epidemiology fractures glucocorticoid management osteoporosis pathophysiology

Glucocorticoids (GCs) are among the most frequently used drugs and are often prescribed for their potent anti-inflammatory and immunosuppressive properties. Conditions commonly treated with GCs include polymyalgia rheumatica, temporal arteritis, rheumatoid arthritis, lupus, asthma, inflammatory bowel disease (IBD), dermatomyositis, pemphigoid and many allergic reactions with skin manifestations. In the post-transplant patient, GCs are used in conjunction with other medications to prevent organ rejection [1,2].

Despite the undoubted benefit of GCs in treating many conditions, one of the major consequences is a deleterious effect on bone that may lead to osteoporosis. Osteoporosis is defined as a skeletal disorder, characterized by compromized bone strength, predisposing a person to an increased risk of fracture [3]. When osteoporosis occurs as a result of an underlying medical disorder or the medications used to treat such disorders, it is called secondary osteoporosis. Indeed, GC-induced osteoporosis (GIOP) is the most common type of secondary osteoporosis [4] and the third most common cause of osteoporosis overall [5]. The consequences of GIOP are serious, with an estimated 30–50% of patients on long-term GCs experiencing a fracture [6].

Our current knowledge of GIOP is such that with appropriate treatment, bone loss may be reduced and needless fractures may be prevented. In this article, a current epidemiologic and pathophysiologic overview of GIOP is provided, including recent significant advances and contributions in the field. Recognizing, preventing and treating GIOP in pre- and postmenopausal women will also be discussed. A summary of the factors contributing to GIOP is shown in Box 1.

Epidemiology

Prevalence of glucocorticoid use

In a population-based study, it has been estimated that approximately 0.9% of the total adult population in the UK may be receiving oral GCs at any one time, with the usage peaking in those aged 70–79 years, at 2.5% [7]. In a more recent study of women aged over 50 years (n = 62,230 from 41 general practices in the UK), 3.2% were prescribed an oral GC with a mean duration of use of 3.31 years [8]. Similarly, those aged 70–79 years were also the most commonly prescribed age group. During a 1-year review period, approximately 50% of the patients received less than 1000 mg, 25% received 1000–2000 mg, and 25% received more than 2000 mg [8].

Prevalence of glucocorticoid-induced osteoporosis

Few studies have specifically examined the prevalence of GIOP, but it is estimated that osteoporosis occurs in at least 50% of people receiving long-term GC therapy [6]. Secondary causes of osteoporosis, such as GCs, are particularly common in pre- or perimenopausal women [3,9]. In a clinical study of pre- and postmenopausal women attending a specialty osteoporosis clinic (n = 384 patients), a secondary cause for osteoporosis was established in 8.6% of cases, and 21% of these were attributed to GCs, all of which were in premenopausal women [9]. Khosla and colleagues reported GIOP in over 50% of patients aged 20–44 years with an established diagnosis of secondary osteoporosis, although the incidence rate of diagnosed osteoporosis was low, at 4.1/100,000 person years (95% confidence interval [CI]: 2.4–5.9) [10].

Box 1.

Pathogenesis: summary of factors contributing to glucocorticoid-induced osteoporosis.

Increased

Bone resorption

Urinary calcium excretion

Parathyroid hormone (in response to calcium)

Expression of RANK-L (triggers osteoclastogenesis)

Osteoblast and osteocyte apoptosis

Decreased

Intestinal calcium absorption

Gonadotrophic hormone

Synthesis/secretion of sex hormones

Osteoprotegrin (decoy protein that binds RANK-L)

Bone formation

Osteoblast differentiation and proliferation

Bone morphogenic proteins

Type-1 collagen synthesis

IGF-1 and IGFBP transcription

TGF-β action in bone

BP: Binding protein; IGF: Insulin-like growth factor; IL: Interleukin; PTH: Parathyroid hormone; RANK-L: Receptor activator of NF-κB ligand; TGF: Transforming growth factor

Fracture risk associated with glucocorticoid-induced osteoporosis

Bone loss due to GCs affects both cortical and cancellous bone, and has a greater tendency for the axial skeleton, often leading to spontaneous fractures of the vertebrae or ribs [11]. It is commonly reported that 30–50% of adults receiving long-term oral GCs experience a fracture [6,12] and an estimated 47% of all hip and 72% of all vertebral fractures occurring in oral GC users can be attributed to the GC [13].

Relative risk of fracture

In a meta-analysis of seven prospective cohort studies, Kanis and colleagues found that previous GC use (after adjusting for bone mineral density [BMD]) was clearly associated with an increased risk of any fracture, osteoporotic fracture and hip fracture [18]. Relative risk (RR) estimates were greater for younger than for older individuals (i.e., when compared with age-matched controls not using GCs), but not significantly so. The highest gradients of risk were observed for hip fracture, with age-dependent risk ratios ranging from 2.13–4.42 [18]. The RR for fracture was similar for both males and females (i.e., comparing GC users vs nonusers within each sex) [18].

An earlier meta-analysis by Van Staa and colleagues found similar risk estimates associated with GC use – of 1.33–1.91 for all fractures, 1.61–2.01 for hip fractures and 2.6–2.86 for vertebral fractures [14]. Fracture risk increased within 3–6 months of initiating oral GC therapy and decreased after therapy was ceased, independent of underlying disease, age or gender.

Dose-dependent relationship

Van Staa and colleagues, using the General Practice Research Database (244,235 GC users and 244,235 controls), found a strong dose-dependent relationship between fracture risk and daily dose and a weaker association with cumulative dose, a finding suggestive of acute rather than chronic adverse effects of GCs on bone [15,19]. The RR of fracture climbed steadily as daily dose increased, starting at an excess fracture risk of 20% for less than 5 mg/day (compared with controls) and reaching 60% excess risk in the 20 mg/day group. The risk of using high (>7.5 mg/day) versus low (<2.5 mg) GC doses was quantified as approximately double.

Walsh and colleagues found a dose–response relationship among quartiles of cumulative oral GC dose and vertebral fracture with an odds ratio (OR) of 4.4 between the highest and lowest dose quartiles, and similar results were obtained when duration of use was compared [20]. In all dose quartiles, the prevalence of vertebral fracture was high, ranging from 48–76% from lowest to highest quartile, respectively [20].

Absolute risk of fracture

It should be noted that among patients using GCs, the risk of fractures is greater in older patients, who will have other risk factors for fracturing [21]. Van Staa and colleagues reported that the RR of any osteoporotic fracture increased by 1.63 (95% CI: 1.60–1.66) for each 10 years of age [21]. The RR of fracture among patients using GCs is also less for men than women (RR: 0.51; 95% CI: 0.49–0.54) [21].

Van Staa and colleagues developed a predictive model to estimate the long-term risks of fracture in patients using oral GCs (study cohort of 191,752 patients aged > 40 years) [21]. Several factors were independent contributors to the fracture risk score, including GC dose, age, gender, fall history and fracture history, to name a few. For example, using this model, they estimated that a woman aged 65 years using 7.5 mg prednisolone daily has a one in four likelihood of suffering a clinical osteoporotic fracture over 10 years. Further studies that evaluate fracture risk reduction in patients receiving GCs according to individual patient characteristics are required.

Inhaled glucocorticoids

For almost two decades, inhaled GCs (IGCs) have been used widely in the management of chronic lung disease, mainly asthma [22]. However, the effect of IGCs on bone and whether their use leads to GIOP is somewhat controversial. In a meta-analysis by Richy and colleagues, IGCs were associated with a 1.2–1.8-times increased risk of vertebral fracture and a 1.6-times increased risk of hip fracture [23]. This meta-analysis also demonstrated that IGCs were associated with lower bone density at the spine and hip and lower levels of bone formation markers (osteocalcin and procollagen type 1 C-terminal pro-peptide). Vestergaard and colleagues found an increased risk of any fracture (adjusted for comorbid diseases, but not respiratory severity) associated with IGCs only for daily dosages above 7.5 mg of prednisolone equivalents (equivalent to 1875 μg of budesonide/day) [24].

In the Nord–Trondelag study, patients who reported ever use of IGCs had lower BMDs; however, no consistent association was found between current dose, duration of treatment, or estimated cumulative dose and BMD, and the results may have been biased by the use of oral GCs or other uncontrolled patient characteristics [25]. Fujita and colleagues examined lumbar BMD (and biochemical markers) in IGC users with no oral GCs for at least 1 year, and found significant lower BMD and serum osteocalcin among the IGC users versus controls in the postmenopausal group only [26]. Wong and colleagues found a negative relationship between total cumulative dose of IGCs and BMD in asthma patients [27].

On the contrary, other studies have found that after adjusting for underlying respiratory illness, the excess risk of fracture associated with IGCs disappears [28,29]. In a retrospective analysis of adults aged over 18 years, users of IGCs had no greater risk of fracture than users of nonsteroid bronchodilators; however, the risk of fracture in both groups was elevated compared with controls [29]. Similar results were obtained in an administrative data cohort of adults with asthma and chronic obstructive pulmonary disease (COPD) using IGCs [30]. Results indicated no increase in nonvertebral fractures and no dose–response curve. In a large observational study (n = 108,754), no dose–response relationship between IGCs and fracture risk was observed after adjusting for disease severity [31]. However, patients with severe obstructive airway disease were at risk of fractures.

Despite the controversial results in the literature regarding IGCs, it has been noted that IGCs are safe in low-to-moderate doses and have a much lower adverse effect on bone than oral GCs (possibly five to tenfold less) [22]. In observational studies, the adjustment for disease severity is essential [31]. Patients receiving long-term IGCs should be screened for osteoporosis (i.e., dual energy X-ray absorbtiometry [DXA] exam), particularly patients who are postmenopausal, hypogonadal, have an advanced lung disease or a history of fractures [22]. This has important public health implications, as up to 5% of the population may take an IGC [32].

Pathophysiology of glucocorticoid-induced osteoporosis

Normal process of bone remodeling

Bone undergoes a process of remodeling, orchestrated by two cell types that form the basic multicellular unit; the osteoblast (bone forming) and osteoclast (bone resorbing) cells. Osteoclasts are formed from blood-borne precursors of the macrophage system; osteoblasts arise from mesenchymal stem cells in the bone marrow stroma. Bone resorption and formation are closely coupled. Osteoblasts function to cause formation of new bone matrix by laying down the collagen-containing component of bone that is then mineralized. Osteoclasts function to erode bone by attaching and secreting enzymes and acids that form grooves into the bone surface (acidification and proteolytic digestion). A third cell type, the osteocyte, is a highly differentiated cell formed by the incorporation of osteoblasts into the bone matrix. Osteocytes play an important function in bone strength by detecting bone microdamage and transmitting signals leading to its repair.

Glucocorticoid-induced bone loss

The onset of GIOP is believed to be a multifactorial process influenced by mechanisms that decrease bone formation and increase bone resorption. However, recent evidence suggests that the principal factor in GIOP may be decreased bone formation rather than increased bone resorption, although GC involvement at different stages and doses may vary [33 –36].

It appears that GC-induced bone loss has a rapid, early phase characterized by excessive bone resorption and a slower, later phase marked by inadequate bone formation [11,35,36]. Within the first few days of treatment, GCs transiently increase osteoclast numbers due to an antiapoptotic effect on mature osteoclasts, which probably results in early loss of bone [35]. Bone resorption may also be stimulated by higher doses of GCs [17]. In the second phase, chronic GC excess suppresses remodeling by downregulating osteoblastogenesis and osteoclastogenesis and is characterized by depressed bone formation and turnover [36]. Studies have demonstrated that bone resorption decreases after 4 weeks of prednisolone administration to normal or below normal levels [37]. The decrease in bone formation and turnover in GIOP is in contrast to the increase in bone resorption and turnover that characterizes osteoporosis caused by a loss of sex steroids (i.e., in postmenopausal women).

Bone resorptive factors

Hyperparathyroidism

It has long been thought that GC-induced secondary hyperparathyroidism (either brought on via net decreases in calcium absorption or via a direct effect on parathyroid hormone (PTH) synthesis and secretion) plays a role in the onset of GIOP (i.e., due to increased resorption). However, for a number of reasons, current evidence suggests that PTH and GC-induced secondary hyperparathyroidism do not play a major role in the pathogenesis of GIOP [34,38,39]. Chronic GC treatment may alter PTH secretory dynamics (by reducing tonic PTH release and increasing pulsatile release); however, mean PTH concentrations are probably similar in GC-treated patients and controls [40].

Sex steroids

In humans, estrogen and androgens play an important role in regulating bone metabolism [41,42]. After the menopause or ovariectomy, estrogen deficiency is a key factor in the pathogenesis of postmenopausal osteoporosis, and it leads to increased bone remodeling and enhanced bone resorption [42]. GCs may contribute to bone loss by suppressing the hypothalamic–pituitary–adrenal axis at various levels and having an inhibitory effect on the synthesis/secretion of sex steroids [34]. High doses of GCs may suppress gonadal function and both high and low GC doses may suppress endogenous adrenal function [17].

The contribution of decreased sex steroids to GIOP is more controversial than in postmenopausal osteoporosis. Recent animal models demonstrate that excess GCs significantly decreased bone resorption and activation frequency even when accompanied by loss of sex steroids [36], which suggests that hypogonadism is not an inevitable accompaniment of GIOP, nor does it necessarily contribute to the loss of BMD and bone strength [36].

Receptor activator of nuclear factor-κB ligand

In vitro evidence suggests that GCs may have direct influence on resorptive parameters in human bone cells by reducing levels of osteoprotegerin (OPG), a decoy protein that binds to receptor activator of nuclear factor (NF)-κB ligand (RANK-L) and prevents osteoclastogenic activity, and increasing RANK-L expression (which triggers osteoclastogenesis) [43]. It had been previously thought that GCs mainly had an indirect influence on bone resorption (i.e., secondary hyperparathyroidism). Sivagurunathan and colleagues suggest that if the dominant effect of GCs on resorptive activity is to increase osteoblastic signals for osteoclastogenesis rather than influencing the lifespan of mature osteoclasts, then it makes sense that the clinical course of bone resorption in GC-treated patients follows an early phase of accelerated bone resorption followed by considerable slowing of osteoclast-mediated resorption, as once osteoblast numbers and activity are suppressed with prolonged GC dosing, the resorptive–enhancing effects will be less dominant [43].

Bone-formation factors

Several mechanisms are believed to be responsible for a decrease in bone formation in GIOP, namely an inhibition of osteoblast differentiation, activity and function. The underlying disease process (e.g., rheumatoid arthritis, lupus) for which GCs are being administered may also alter bone metabolism.

GCs inhibit bone morphogenic proteins, which are responsible for the differentiation and activation of osteoblasts [44]. They also inhibit osteoblastic synthesis of type 1 collagen, insulinlike growth factor (IGF)-I and inhibit the action of transforming growth factor (TGF)-β in bone [12,17].

Recent in vitro evidence suggests several novel mechanisms for the impairment of osteoblastic differentiation and proliferation. GCs enhance the expression of dickkopf-1 (Dkk-1) [45] and suppress the Tcf/Lef-dependent canonical Wnt signaling pathway (a stimulus for osteoblastic function) in human osteoblasts [46]. GCs may also inhibit the development of osteoblasts via inhibition of the EGR2/KROX20 gene (an enhancer of osteoblasts) activity [33]. It has previously been well established that GCs inhibit the expression for Runx2/Cbfa1 (a transcriptional factor for the differentiation of osteoblast lineage) [46,47]. GCs may also act directly on osteoblasts to stimulate their apoptosis [11,35].

Osteocyte apoptosis

Accumulating evidence suggests that increased death of osteocytes plays a significant role in reduced bone strength independently of bone mass in GIOP [35,48,49]. Osteocyte apoptosis may lead to microdamage accumulation and increased bone fragility [11]. Mechanisms that support declines in bone strength are consistent with observations that there is an increased fracture rate in GC patients within 3 months of treatment [15,49] and the rate of fracture in GIOP is higher than would be expected based on BMD when compared with other kinds of osteoporosis [50], although this finding is not equivocal [51].

Management of glucocorticoid-induced osteoporosis

Treatment guidelines

The American College of Rheumatology (ACR), the Royal College of Physicians (UK), and Canadian Osteoporosis Society Scientific Advisory Council have all outlined guidelines for the prevention and treatment of GIOP [52 –54]. There are some notable differences between the guidelines; namely, at what dose of GC and in whom bone-sparing agents should be commenced, reflecting the degree of uncertainty and local policies. Box 2 summarizes the guidelines from these three organizations regarding when to initiate a bone-sparing agent. Evidence suggests that 5 mg of prednisolone daily (or equivalent) leads to reduced BMD and a rapid increase in the fracture risk [14]. To n and colleagues have recently demonstrated that 5 mg of prednisolone daily has adverse effects on bone strength in postmenopausal women, as evidenced by reduced bone formation and resorption markers [17].

Treatment groups

Age is an important risk factor for incident fracture and should be taken into account when considering treatment options [21,55]. Postmenopausal women are at a greater risk of rapid bone loss and should be preventatively treated for osteoporosis at the time of initiation of GC therapy. In this group, this may be justified even without bone density measures, as the risk of fracture is so great. For premenopausal women, the decision to use bone-sparing agents preventatively is less clear and should take into consideration baseline BMD [56] and prior fracture history. In light of evidence presented by Van Staa and colleagues, dose is another important consideration [15,19]. For example, the risk of vertebral fracture increases by approximately 1.5–, 2.5– and 5-times as the dose increases from low (2.5 mg/day), to medium (2.5–7.5 mg/day) to high (>7.5 mg/day), respectively. In men, therapy should be considered in those at high risk for fractures. Considerations should include age, BMD, prior fractures and family history of fractures.

Therapeutic agents

Several clinical trials have demonstrated that bisphosphonates are effective at increasing BMD [57 –59] and reducing fractures [60,61]. Specifically, alendronate, etidronate and risedronate are considered first-line therapy, although etidronate has a lower grade of evidence than alendronate and risedronate and may not be effective for preventing nonvertebral fractures. Calcitonin can be considered as a second-line agent if there are contraindications to a bisphosphonate or the patient does not tolerate the bisphosphonate. A complete review of the efficacy of treatments available for GIOP can be found in an article by Cohen and Adachi [62]. For patients on IGC therapy, Lau and colleagues and Kasayama and colleagues have found that alendronate was an effective treatment for improving BMD in postmenopausal asthmatic patients [63,64]. Recently, it has been demonstrated that alendronate produced greater gains in femoral neck BMD (and less bone turnover) than intranasal salmon calcitonin in postmenopausal rhematoid arthritis (RA) patients receiving low-dose GCs [65]. However, calcitonin has been identified as having analgesic benefits for patients with painful vertebral fractures [66].

The results of a randomized, controlled trial by Adachi and colleagues suggested that calcium (1000 mg/day) and vitamin D (50,000 units/week) were helpful in preventing early bone loss in GC-treated patients; however, long-term calcium and vitamin D in patients undergoing extended GC therapy did not appear to be beneficial [67]. Activated forms of vitamin D were of greater benefit [68,69]. A later Cochrane meta-analysis found that vitamin D and calcium were associated with a significant prevention of bone loss at the lumbar spine and forearm in patients receiving GCs, suggesting that, at the very minimum, all patients initiating GC treatment could receive prophylactic calcium and vitamin D [70].

Box 2.

Summary of guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis

Bisphosphonate recommended for:

– Postmenopausal women taking glucocorticoids (GCs) for >3 month duration, at a dosage of >7.5 mg (Canadian Guideline^*)

– Postmenopausal women taking GCs for >3 month duration, at a dosage of >5 mg/day (American College of Rheumatology Guideline†)

– Consider treatment for premenopausal women receiving glucocorticoids >5 mg/day, however use with caution and counsel regarding use of appropriate contraception if prescribed bisphosphonate (American College of Rheumatology Guideline†)

– High-risk individuals taking GCs (e.g., >65 years or a prior fragility fracture); measurement of bone density is not required before starting treatment (UK Guideline‡).

Further assessment (i.e. bone mineral density) recommended for:

– Any patient receiving >2.5 mg of prednisone equivalent daily (Canadian guideline*)

– Any individuals taking GC therapy for at least 3 months. A T-score of −1.5 or lower may indicate the need for a bone-sparing agent; take age into account when considering fracture risk (UK Guideline‡)

– Patients with T-score below −1 standard deviation receiving long-term therapy ≥5 mg/day should be prescribed a bisphosphonate (American College of Rheumatology Guideline†)

Canadian Osteoporosis Society Scientific Advisory Council [54]

†

American College of Rheumatology [52]

‡

Royal College of Physicians Guideline [53].

T-score: Number of standard deviations below average bone density

Clinical considerations in prescribing bisphosphonates

Bisphosphonates should be used with caution in younger women, and patients need to be informed about the risks of bisphosphonates as they cross the placenta and can affect skeletal remodeling in the fetus [71]. Nitrogen-containing bisphosphonates (e.g., alendronate and risedronate) may also have gastrointestinal adverse effects, particularly esophageal erosions and ulcerative esophagitis [72], although the risk is very low even at the highest doses. Once-weekly dosing regimens may improve compliance and decrease toxicity profiles, while at the same time maintaining the benefits of daily therapy [73,74].

Other prevention/treatment considerations

All three guidelines suggest that patients receiving GCs should have adequate calcium and vitamin D intake [52 –54]. The ACR specifically suggests vitamin D supplementation of 800 IU/day or an activated form of vitamin D (e.g., alfacalcidiol 1 mg/day or calcitriol 0.5 mg/day) [52]. The Canadian guidelines suggest 400 IU/day (under the age of 50 years) to 800 IU/day (over the age of 50 years) for vitamin D3, as vitamin D deficiency is common, and 1000 mg/day (under the age of 50 years) to 1500 mg/day (over the age of 50 years) for calcium [54]. Calcium and vitamin D therapy may not be completely innocuous. In particular, monitoring of urine and serum calcium levels should be considered in those on activated forms of vitamin D.

Other general measures to consider when reducing bone loss in all patients receiving GCs include keeping the GC dose to a minimum, consideration of alternative formulations or routes of administration, good nutrition, appropriate weight-bearing physical activity and avoidance of tobacco use and alcohol abuse. Fall risk, particularly in older women, and appropriate interventions should also be considered. For premenopausal women, detecting and treating osteoporosis early is important in order to maximize bone accrual and minimize loss over a longer period of time before menopause [75]. GIOP is probably a multifactorial process that may result in part from the underlying disease present (e.g., RA, lupus). Factors such as increased exposure to inflammatory cytokines or malabsorption of nutrients (e.g., calcium and vitamin D) and behaviors associated with the primary disorder, such as reduced physical activity, should also be considered when assessing bone health.

Ongoing challenges

Measurement of bone density & strength

Although there is currently no accurate measure of overall bone strength, BMD accounts for approximately 70% of bone strength and is most frequently used as a proxy measure [3]. Operationally, the World Health Organization (WHO) defines osteoporosis as a bone density that is 2.5 standard deviations below the mean for young, white, adult women (T-score) [76]. However, whether this diagnostic criterion can be applied to patients with secondary causes, such as GIOP, or younger women, is not clear [3,77,78].

Relationship between bone mineral density & fracture in glucocorticoid-induced osteoporosis

There is some controversy regarding whether BMD reliably predicts fracture risk and whether gradients of fracture risk associated with BMD are similar to those established for postmenopausal osteoporosis. In a cross-sectional study of radiologic databases in the UK, Selby and colleagues found that GCs did not alter the relationship between fracture risk and BMD compared with non-GIOP [51]. A recent meta-analysis by Kanis and colleagues found the opposite, that the fracture risk in GC-treated patients was higher than would be traditionally expected from reductions in BMD [18,20,79]. For the same level of BMD, the risk of all fractures was greater in GIOP than postmenopausal osteoporosis [18]. Recent evidence from Kumagai and colleagues also lends added support to this idea: seven of 16 premenopausal women receiving GCs with fractures had normal BMD values (T-score > −1); and the BMD threshold for fracture risk was higher for premenopausal than postmenopausal women (interestingly, hyperlipidemia correlated with fracture risk in this study) [80]. Practically speaking, if a BMD measurement is readily available, it may prove helpful in deciding who might benefit from therapy. Follow-up BMD measurements may help to determine those who have responded to therapy. If a reduction is seen, then other therapies may be considered.

Therapeutic recommendations

Recent evidence regarding lower GC dosages impairing bone strength and BMD threshold for fracture prediction contributes to our understanding of a non-BMD-related mechanism for GIOP and may have implications in terms of management [17,80]. A less stringent intervention threshold for BMD (than for postmenopausal osteoporosis) may be appropriate for GIOP, although further longitudinal studies are needed to assess fracture prevention in patients treated with bone-sparing agents at higher BMD values. Further research on pathophysiologic mechanisms of GIOP, in addition to measurement studies, will also contribute to our understanding of the role of bone strength versus bone density and how best to manage and prevent GIOP.

Knowledge transfer & care gap

Despite the existence of solid research evidence and clinical practice guidelines [52,53], there remains a care gap in the prevention and treatment of GIOP [7,8,81,82]. Van Staa and colleagues reported low use (in the range of 4.0–5.5%) of concomitant bone-active treatments during GC treatment in the UK [7]. Yood and colleagues reported a greater tendency to consider skeletal effects of GC use in an American-managed healthcare cohort (some type of intervention in 62% of patients; 31% BMD, 37–40% calcium/vitamin D, 25% osteoporosis medication) [81]. Patients treated by rheumatologists fared the best; 90% had at least one intervention documented as opposed to only 48% for internists, 55% for pulmonologists and 46% for all other physicians [81]. In a UK general practice study, elderly women had more GC prescriptions but lower use of bone-sparing agents (48 vs 32%), although bone densitometry was equally common among all age groups up to the age of 80 years (approximately 20%, which then fell to 7% in the oldest group) [8].

Improving adherence to guidelines for GIOP may be a difficult task; in a multifaceted educational-intervention randomized, controlled trial conducted by rheumatologists, after 6 months of follow-up, the intervention group fared no better at prescribing osteoporosis treatment (33 vs 38%) or referring for densitometry versus the controls (8% for both groups) [82]. The authors suggest that future interventions could include the use of rheumatology nurses to recognize at-risk patients and initiate a diagnostic work up and direct-to-patient educational mailings. Perhaps a somewhat surprising aspect of these results is that rheumatologists in other studies have fared much better compared with other physicians [81].

Future perspective

Research involving pathophysiologic mechanisms of GIOP continues to evolve and, over the next 5–10 years, we will have a more precise understanding of the mechanism(s) through which GC-induced bone loss occurs. As a result, we will have greater rationale to offer therapeutic options that are based on our understanding of the underlying problem. At present, bisphosphonates are the drugs of choice, as they have a clinically demonstrated vertebral fracture efficacy. However, given that the primary problem may be related to a decrease in bone formation, rather than an increase in bone resorption, anabolic agents might be developed and become the drugs of choice in the future. Combination and sequential therapy with an anabolic agent followed by antiresorptive therapy might also be seen. Preliminary evidence suggests that for postmenopausal osteoporosis, indices of bone formation are greater in patients treated with teriparatide than alendronate up to 18 months [83].

Executive summary

Epidemiology

Glucocorticoids (GCs) are the most common cause of secondary osteoporosis.

Fractures may begin to occur within 3 months of commencing oral GC therapy.

Pathophysiology

Much has been discovered about the pathophysiology of GC-induced osteoporosis, with the dominant problem being a reduction in osteoblastic bone formation.

Inhaled glucocorticoids

Inhaled GCs may be associated with decreased bone density and increased fracture risk, although they have far fewer adverse effects on bone than oral GCs and are probably safe in low-to-moderate doses.

Management

Fractures occur at greater bone mineral density levels in GC-treated patients than non-GC-treated patients.

Bisphosphonates have been shown to effectively reduce the risk of vertebral fractures.

Future perspective

In the future, alternative therapies such as anabolic agents may be developed and be the drugs of choice for GC-induced osteoporosis

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