Management of corticosteroid-induced osteoporosis

S. S. Yeap and D. J. Hosking1

Department of Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia and
1 Division of Mineral Metabolism, Department of Medicine, City Hospital, Nottingham NG5 1PB, UK


    Abstract
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 Abstract
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 Pathogenesis
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Corticosteroid (CS) therapy is widely used in the treatment of rheumatic diseases. Osteoporosis remains one of its major complications. The risk of low bone mineral density (BMD) and fracture may be already increased in some of the rheumatic diseases, regardless of CS therapy. However, in spite of this, preventative treatment for osteoporosis in patients on CS remains low. Patients on or about to start CS use for more than 6 months are at risk of corticosteroid-induced osteoporosis (CIOP). The pathogenesis of CIOP differs from post-menopausal osteoporosis in that bone formation is said to be more suppressed compared with bone resorption. The diagnosis of CIOP can be made on clinical risk factors and may not require measurement of BMD. Many agents used in post-menopausal osteoporosis such as activated vitamin D products, hormone replacement therapy, fluoride, calcitonin and the bisphosphonates have been shown to maintain or improve BMD in CIOP. However, there are few data on the reduction in fracture rates in CIOP, but the bisphosphonates seem the most promising in this regard.

KEY WORDS: Corticosteroid, Osteoporosis, Diagnosis, Treatment.


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 Pathogenesis
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Osteoporosis is recognized as one of the major complications of corticosteroid (CS) therapy. Patients on CS therapy are at increased risk of sustaining fractures. In patients with rheumatoid arthritis (RA), the incidences of hip [1, 2], vertebral [3] and distal forearm fractures [1] have been found to be increased between 2- and 5-fold compared with RA patients not on CS. In asthma, the incidence of vertebral [4, 5] and rib [4] fractures was increased in patients on long-term CS compared with those who were not on CS. From these studies, the threshold dose for the development of osteoporosis appears to be 7.5 mg of prednisolone daily, although there is now some evidence that fracture risks may be increased at doses of prednisolone below this level [6]. Despite this, studies have shown that only a small proportion of patients, 8% of hospitalized patients [7], 14% of patients in general practice [8], treated with oral CS are prescribed co-therapy to prevent bone loss.

Longitudinal studies have shown that the most rapid rate of bone loss occurs in the first 6 [9] to 12 months [10, 11] of treatment and is similar at the lumbar spine and femoral neck. This bone loss continues at a rate of two to three times greater than normal on long-term therapy [12]. Bone loss in the calcaneus and radius has also been shown to occur [12].

One of the problems in corticosteroid-induced osteoporosis (CIOP) is that in many of the underlying diseases where CS are used, bone loss may already be present even before CS are started. In patients with long-standing RA (mean duration 15.2 yr) who had not been treated with CS, there was a significantly reduced bone mineral density (BMD) at both the lumbar spine and femoral neck [13]. Bone loss prior to the introduction of CS appears to occur early, in that patients with RA of less than 6 months' duration were found to have a BMD which was normal [14], but over the next 12 months of follow-up the rate of loss was greater than that of control subjects. Patients with uncontrolled RA will also lose more bone compared with those with well controlled disease [15]. In systemic lupus erythematosus, significant reductions in lumbar spine and femoral neck BMD have been found in pre-menopausal patients and this has been shown both to be related to [16] and unrelated to CS usage [17]. In inflammatory bowel disease, where a low body mass index (BMI) may be an additional factor, the prevalence of osteopenia has been found to be between 30 and 77%, with Crohn's disease patients being more severely affected than those with ulcerative colitis [18]. Patients undergoing organ transplantation are also at high risk of osteoporosis; there is clear evidence of reduced BMD prior to cardiac [19] and renal [20] transplantation and the use of immunosuppressive therapy while 23% of patients have osteoporosis before their liver transplant [21]. After transplantation, bone loss is most rapid and occurs mainly in the first 6 months [20, 22].


    Pathogenesis
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 Pathogenesis
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The mechanism of CIOP is uncertain but appears different from that of post-menopausal osteoporosis. A major difference is that bone formation appears to be suppressed by CS [23]. This may be difficult to confirm in direct studies because although osteocalcin, a marker of bone formation, has been shown to be suppressed by CS therapy [24, 25], this may be due to a direct effect of CS on the osteocalcin gene promoter to antagonize the action of 1,25(OH)2D3 to induce the gene [26]. The effects of CS on bone resorption are more difficult to assess because although some studies suggest that resorption is increased [24, 25], others [27, 28] have shown no effect.

The result of the greater depression of bone formation compared with bone resorption (remodelling imbalance) leads to differences in bone micro-anatomy and histology. In post-menopausal osteoporosis, the reduction in trabecular bone volume due to an increase in bone resorption appears to be due to trabecular discontinuity, whereas the reduction in trabecular bone volume due to decreased bone formation in CIOP is a result of trabecular thinning [29]. This has implications for both the diagnosis and treatment of CIOP.

Other factors involved in the development of CIOP include alterations in the calcium-regulating hormones and sex steroids. Intestinal calcium absorption is reduced as a result of CS use [23] which also leads to a reduced renal tubular calcium reabsorption [30]. Although these changes were initially thought to be due to secondary hyperparathyroidism, recent studies measuring the intact parathyroid hormone (PTH 1–84) have shown these values to be normal [25, 31]. There is also an alteration in hypothalamic gonadotrophin-releasing hormone secretion [23] with subsequent reduction in serum testosterone [32] and oestradiol levels [33]. Finally, CS therapy may influence cellular responses within the bone micro-environment by modulating cytokines that act locally to regulate remodelling and these factors include interleukin-1, tumour necrosis factor and insulin-like growth factor [34].


    Diagnosis
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In post-menopausal osteoporosis, the risk of osteoporotic fractures has been shown to be doubled for each standard deviation decrease in BMD [35] but this may underestimate the risk for patients treated with CS. In CS-treated asthmatic patients with vertebral fractures, Luengo et al. [5] found that BMD was higher compared with a group with post-menopausal osteoporosis and fractures. Similarly, Peel et al. [36] found that CS-treated patients with RA had a 6.2-fold increased risk of vertebral fractures with only a 0.8–1.5 S.D. decrease in lumbar spine BMD. Therefore, in addition to BMD, the decision to start treatment may also depend on assessment of clinical risk factors (Table 1Go).


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TABLE 1. Clinical risk factors for osteoporosis

 
The use of quantitative ultrasound measurements to identify patients at risk of decreased BMD and increased fracture risk has been widely studied in post-menopausal osteoporosis but data are still few in CIOP. Martin et al. [37] found a 31.7% reduction in calcaneal ultrasound attenuation and a 6.6% reduction in velocity in patients with RA compared with controls using a McCue CUBA Clinical machine. However, there was no difference between those who were and were not treated with CS. More recently, a study using an Achilles device showed that all ultrasound measurements were reduced in patients on CS and that although broadband ultrasound attenuation (BUA) was related to lumbar spine BMD measurements, it was still significantly lower compared with patients not on CS treatment and controls, even after adjusting for age (P = 0.023) [38]. This would support the hypothesis that ultrasound measurements, especially BUA, may give additional information about bone structure in CIOP.


    Management
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General measures
It is recommended that all patients on CS should be advised to modify their lifestyle factors known to affect bone such as limiting cigarette smoking and alcohol consumption, increasing weight-bearing activity as well as taking steps to prevent falls [39]. While there have been no specific studies on fall prevention in rheumatology patients, the following strategies can be considered. Some of the risk factors that have been shown to be effective in reducing the incidence of falls in non-institutionalized elderly include a reduction in the use of sedative agents or benzodiazepines, avoiding postural hypotension, adjustment of the environment to remove hazards for tripping or falls within the home such as loose rugs and installation of handrails on stairs, training in transfer skills and gait, and exercises to improve muscle strength and co-ordination [40]. In addition, the use of external hip protectors has been shown to reduce the incidence of hip fracture following a fall on the hip, but their wide-spread use is limited by the poor compliance rate [41]. Secondly, CS doses should be kept to the minimum necessary for disease control [39]. However, in RA patients, adequate suppression of disease activity by a higher dose of CS has more beneficial effects on BMD than poorly controlled disease on a lower dose of CS [14]. There is also evidence that the bone loss on CS therapy in RA may be partially reversible; Laan et al. [42] showed a 8.2% decrease on starting CS therapy in RA patients which was partially reversed on stopping therapy 20 weeks later. Thirdly, alternative routes of CS administration can be used, such as inhaled CS in asthma and rectal budesonide in inflammatory bowel disease, both of which have less effect on bone than oral administration [39]. Alternate day CS therapy, however, has not been shown to have a bone sparing effect [43]. Finally, in the absence of any contra-indication because of the rheumatic disease itself, hormone replacement therapy (HRT) can be considered in all post-menopausal women [39].

Primary prevention
Primary prevention is treatment started at the time of initiation (up to 3 months) of CS therapy. Calcium supplementation, up to 1000 mg daily, alone is ineffective in preventing CS-induced bone loss as shown by its use as the ‘placebo’ arm in numerous studies of CIOP. All have inevitably shown bone loss in the calcium arm of between 2 and 5% over 1 yr at the lumbar spine and femoral neck.

Calcium and vitamin D. Over 3 yr, Adachi et al. [44] did not find any benefit at the lumbar spine of calcium (1000 mg daily) and vitamin D (50 000 U/week) compared with placebo in a group of patients within 1 month of starting CS therapy at a dose of >10 mg daily. However, there was a trend to a reduced amount of bone loss in the treated group in the first year which did not reach statistical significance.

Calcitriol. Sambrook et al. [11] showed that calcitriol, at a mean dose of 0.6 µg per day, prevented bone loss at the lumbar spine compared with a loss of -4.3% per year in the calcium group. There was no effect at the femoral neck or distal radius. The main side effect was hypercalcaemia which occurred in approximately 25% of patients in the calcitriol group.

Alfacalcidol. Alfacalcidol at a dose of 1 µg per day, has been shown to prevent loss of lumbar spine BMD compared with a loss of -5.67% in the placebo group on calcium alone in a group of patients starting high dose CS (>30 mg daily) [45].

Calcitonin. The results of using calcitonin as primary prevention in CIOP have been conflicting. In the study by Sambrook et al. [11], the addition of nasal calcitonin did not confer any additional protective effect. Similarly, Healey et al. [46] found that calcitonin was no better than calcium and vitamin D in protecting against bone loss over 2 yr in a group of patients starting CS treatment for polymyalgia rheumatica or giant cell arteritis.

In contrast, calcitonin prevented lumbar spine bone loss in patients with sarcoidosis [47] and temporal arteritis [48], but not at the hip.

Fluoride. Lems et al. [49] studied 44 patients with predominantly rheumatological diseases, of whom 14 had just started CS. None had previous peripheral fractures or vertebral deformities. They found a 2.2% increase in lumbar spine BMD after 2 yr in the group taking sodium fluoride 25 mg twice daily with calcium compared with a 3% loss in the calcium-alone group. Hip BMD decreased between 3 and 3.8% in both groups and no clinical fractures occurred during the course of the study.

Bisphosphonates. Etidronate. Cyclical etidronate therapy has been shown in several studies to be effective in the prevention of CIOP at the lumbar spine [5052]. There is no protective effect seen at the femoral neck [51, 52] or radius [51]. Over a 1-yr period, lumbar spine BMD increased by between 0.3 and 1.4% in the etidronate groups compared with a 2.79–5% loss in the placebo groups [5052]. In one of the studies, there was a reduction in new vertebral fractures in the etidronate compared with the placebo group (1/31 vs 7/32 patients) which was just statistically significant [51].

Alendronate. In patients with sarcoidosis on CS, alendronate (5 mg daily) prevented bone loss at the ultradistal radius compared with a 4.5% loss in the placebo group over 1 yr [53].

Pamidronate. Intermittent intravenous pamidronate has been shown to increase lumbar spine BMD by 3.6% and hip BMD by 2.2% over 1 yr compared with a 5.3% decrease at both sites in the group on calcium alone [54].

Risedronate. Risedronate (5 mg daily) has been shown to prevent loss of lumbar spine and femoral neck BMD over 12 months compared with losses of 2.8 and 3.1%, respectively, in the calcium-alone group [55].

Secondary prevention
Secondary prevention is treatment started >1 yr after the initiation of CS therapy or following an osteoporotic fracture and implies established bone loss. All patients should be assessed for hypogonadism and if present, HRT should be offered to women and testosterone to men.

Calcium and vitamin D. A recent meta-analysis concluded that calcium and vitamin D was more effective than calcium alone or no therapy in the treatment of CIOP at the lumbar spine with a 3.2% difference in BMD between treatment and control. The doses of calcium and vitamin D used in the various studies varied from 400 IU daily to 50 000 IU/week [56]. In a group of RA patients studied over 2 yr, Buckley et al. [57] found that calcium (1000 mg daily) and vitamin D3 (500 IU daily) increased lumbar spine BMD by 0.72% per year compared with a loss of 2% per year in the placebo group. There was no difference at the femoral neck.

Calcitriol/alfacalcidol. There are no studies using activated vitamin D metabolites in the secondary prevention of CIOP.

Calcitonin. In a group of asthmatic patients, nasal calcitonin increased lumbar spine BMD in the first year of treatment by 2.7% and maintained the gain for a second year compared with a decrease in the placebo group over the 2 yr [58]. In CS-treated RA patients, nasal calcitonin prevented femoral neck but not lumbar spine bone loss compared with calcium alone [59].

Fluoride. Using sodium monofluorophosphate (100 mg twice daily) with calcium, there was an increase in lumbar spine BMD of 11% compared with a 1.2% increase in the calcium-alone group after 2 yr in 35 patients with respiratory diseases. Hip BMD was not measured and there was no difference in the rate of new vertebral fractures between the two groups [60].

The addition of sodium fluoride (25 mg twice daily) to cyclical etidronate in patients with established osteoporosis on CS leads to an increase in lumbar spine BMD of 9.3% after 2 yr compared with a 0.3% increase on cyclical etidronate alone. Both groups lost BMD at the hip and there was no difference in the fracture rate [61].

Bisphosphonates. A recent meta-analysis concluded that bisphosphonates are effective in the treatment of CIOP with an average percentage change in lumbar spine and femoral neck BMD of 4 and 2.1%, respectively, at 1 yr. However, the odds ratio for the risk of new fractures in the control group did not reach statistical significance [62].

Etidronate. Several placebo-controlled studies have confirmed that cyclical etidronate is effective in the treatment of CIOP. However, the initial studies were only of 1 yr duration. More recently, Geusens et al. [63] published a 2-yr study which showed an increase in lumbar spine BMD of 4.9% compared with a 2.4% loss in the placebo group. There was also an increase in femoral neck BMD of 3.6% compared with a 2.4% loss in the placebo group. Over a period of 3 yr, Sebaldt et al. [64] found a 5.2% increase in lumbar spine BMD, the majority of which occurred in the first 24 months, with BMD being maintained in the third year. There was no significant difference between the treatment and control groups at the femoral neck with both groups losing a small amount of bone. After 3 yr, there was one vertebral fracture in the treatment group compared with five vertebral fractures in the control group which was not statistically significant.

Alendronate. Alendronate, at a dose of 10 mg daily, has been shown to increase lumbar spine and femoral neck BMD by 2.9 and 1%, respectively, compared with a decrease of 0.4 and 1.2%, respectively, in the placebo group over 48 weeks in patients receiving CS therapy [65]. Subgroup analysis showed that BMD improved regardless of duration of steroid therapy. In addition, there was a trend to fewer vertebral fractures in the alendronate group (2.3%) than the placebo group (3.7%) but this was not statistically significant. In a 12 month extension to this study, it was reported that there were significantly fewer patients with new vertebral fractures in the alendronate group (0.7%) compared with the placebo group (6.8%) [66].

Pamidronate. Intermittent intravenous pamidronate has been shown to increase BMD at the lumbar spine by 19.6% (measured by quantitative CT) compared with a decrease of 8.8% in the calcium-alone treated group over 1 yr [67].

Risedronate. Risedronate (5 mg daily) (with calcium and vitamin D) has been shown to increase lumbar spine and femoral neck BMD by 2.9 and 1.8%, respectively, over 12 months' therapy compared with maintenance of BMD in the placebo group given calcium (1 g daily) and vitamin D (400 IU daily). There was also a significant 70% reduction in the incidence of vertebral fractures in the risedronate group compared with the placebo group [68].

Hormone replacement therapy. Oestrogen. HRT has been shown to increase lumbar spine BMD by 2.2–4.1% in CS-treated patients with asthma [69] and RA [70].

Testosterone. In men who have low testosterone levels, treatment with testosterone increased lumbar spine BMD by 5% over 1 yr but there was no effect at the femoral neck [71].

Conclusion
Physicians managing patients on CS should always consider the need for therapy to prevent or treat CIOP. A variety of agents such as activated vitamin D products, HRT, fluoride, calcitonin and the bisphosphonates have been shown to be effective to varying degrees in the prevention and treatment of CIOP, either by maintaining or improving BMD. However, as yet, the data on fracture reduction with treatment in CIOP remains sparse, but the bisphosphonates seem to be the most promising class of agents in this regard. Comparison between therapeutic agents is complicated by the variation in CS dose, varying therapeutic regimes and by small sample sizes without the power to study fracture incidence.


    Initial assessment of patients (adapted from Eastell et al. [39])
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  1. When BMD measurement is not possible, patients at substantial risk of CIOP (i.e. those on current or planned high-dose CS >15 mg daily or with any other risk factors in Table 1Go) should have a diagnostic work-up followed by treatment.
  2. In those who are receiving or who will receive CS at a dose of 7.5 mg daily for more than 6 months, but without any of the other risk factors, a BMD measurement is recommended.
  3. BMD should be measured at the lumbar spine and hip using DEXA. (Spine BMD measurements in those >65 yr may be falsely elevated, and osteoporosis masked, by posterior facet joint osteoarthritis or degenerative disease.
  4. Patients with a T score of <1.5 should be considered for treatment after a diagnostic work-up. When T scores are between 0 and -1.5 re-measurement of BMD after 1 yr is recommended. If the T scores are >1, lifestyle modification advice and a follow-up measurement in 3–5 yr, if the patient is still taking CS, is suggested.


    Diagnostic work-up (adapted from Eastell et al. [39])
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The following diagnostic tests are recommended:

  1. Thoracic and lumbar spinal radiography: to exclude prevalent fractures, as they are strong risk factors in their own right for further fractures.
  2. Full blood count and erythrocyte sedimentation rate. If abnormal, perform serum electrophoresis to exclude myeloma.
  3. Serum calcium, phosphate, alkaline phosphatase and albumin: to exclude hyperparathyroidism and osteomalacia/malabsorption.
  4. Thyroid function tests: to exclude hyperthyroidism.
  5. Total testosterone (in men): to exclude hypogonadism.
  6. Serum FSH, LH and oestradiol (in pre-menopausal women): if amenorrhoeic. Any abnormalities found should be treated as appropriate for the underlying condition.


    Notes
 
Correspondence to: S. S. Yeap. Back


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Submitted 1 May 2001; Accepted 25 March 2002