Use of corticosteroids in nephrology — risk and prevention of osteoporosis induction

Peter M. Jehle and Daniela R. Jehle

Department of Internal Medicine II, Division of Nephrology, University of Ulm, Germany

Clinical significance of corticosteroid-induced osteoporosis

Although recognized for almost 60 years, corticosteroid-induced osteoporosis (COP) is a major problem. Corticosteroids (Cs) particularly affect the axial skeleton and the proximal femur. They may induce bone loss as well as osteonecrosis. Cs-induced bone loss is biphasic with a rapid initial phase of approximately 10–15% during the first few months and a slower phase of approximately 2–5% annually. Daily prednisone doses of >=7.5 mg cause significant bone loss and a doubling in the risk of fracture [1]; however, even lower doses (e.g. 6.3 mg/day [2]) or inhaled steroids may also induce bone loss [1]. In the UK, over 250 000 patients take continuous oral Cs, yet no more than 14% receive any therapy to prevent bone loss. The majority of patients on long-term Cs have low bone mineral density (BMD), an estimated 50% of them develop osteoporosis, and over 25% sustain osteoporotic fractures [1]. In up to 50% of kidney transplantation (KTx) patients, Cs induce alterations in bone architecture leading to a decline in BMD and progressive vertebral height loss [3]. Decrease of BMD significantly correlates with mean daily Cs dosage, high cumulative Cs dose, frequent and steroid-resistant rejection, and a high initial parathyroid hormone level. Patients who are particularly susceptible to Cs-induced bone loss are those who have the lowest initial bone mass, the greatest degree of hyperparathyroidism, impaired intestinal calcium absorption, increased urinary loss of calcium, and suppressed osteoblast function. This is also true for chronic renal failure (CRF) patients who therefore should be regarded as high-risk patients. In such patients vitamin D deficiency, metabolic acidosis, dialysis-associated amyloidosis, aluminium accumulation, and malnutrition are further risk factors.

Pathophysiology of COP

Cs reduce the intestinal absorption of calcium and its renal tubular reabsorption, thereby inducing hyperparathyroidism. The major direct effect of Cs on bone is osteoblast depression (Table 1Go). Recent experiments revealed that Cs reduce the lifespan and promote the apoptosis of osteoblasts and osteoclasts, which in part is mediated by changes in the expression of bone growth factors [4]. Apoptosis and a decreased recruitment of osteoblasts and osteoclasts from progenitor cells explain typical bone histology findings in COP, such as the decline in bone formation and the occurrence of osteonecrosis.


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Table 1. Mechanisms of different corticosteroid effects on the skeleton leading to diminished bone formation, reduced bone turnover, and osteonecrosis (based on in vivo and in vitro studies and bone biopsies)

 

Diagnostic approach

The diagnostic procedure suggested by The American College of Rheumatology [1] can be conferred with only few modifications to renal-failure patients with Cs therapy. The evaluation of patient history should include an assessment of known risk factors for osteoporosis such as smoking, alcohol consumption, and family history of fractures. Laboratory assessment should include serum levels of calcium, phosphate, bicarbonate, intact PTH, bone-specific alkaline phosphatase, calcidiol, and calcitriol. Testosterone or oestrogen levels should be determined when hypogonadism is suspected. In any patient beginning long-term (i.e. >=6 months) Cs therapy the measurement of BMD at hip and lumbar spine by dual-energy X-ray absorptiometry (DEXA) is recommended to assess the risk of COP and to provide a baseline value for subsequent monitoring. The earliest changes of Cs-induced bone loss can be detected in the lumbar spine (preferably in the lateral position) because trabecular or cancellous bone and the cortical rim of the vertebrae are lost more rapidly than cortical bone from the long bones. A decrease of BMD by 1 SD is associated with a 1.5–2.5-fold increase in fracture risk.

Pharmacological strategies for the prevention and therapy of COP

The relative efficacy of various strategies for the prevention of COP is still a matter of debate and has yet to be firmly established (Table 2Go). This may explain why most patients receive no therapy at all. However, in CRF and KTx patients there is a strong need for intervention for the following reasons: (i) additional risk factor for renal osteodystrophy, (ii) common pathophysiological mechanisms of renal osteodystrophy and COP, and (iii) proven efficacy of many drugs in osteoporosis prevention and therapy.


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Table 2. Treatment of corticosteroid-induced osteoporosis

 
Baseline therapy should comprise physical activity (skeletal loading) and dietary control of calcium and phosphate intake. In addition, patients should stop smoking and avoid excessive alcohol intake. Obviously, the shortest possible duration of Cs therapy and the lowest effective dose are advisable. Alternate-day dosing has not been shown to protect against COP [1]. Sodium restriction and thiazide diuretics have been shown to improve gastrointestinal absorption and decrease urinary excretion of calcium [1]. Patients who excrete >300 mg of calcium/24 h may benefit from a low-dose thiazide diuretic (e.g. hydrochlorothiazide 25 mg/day).

Pharmacological regimens can be mainly divided into two groups, namely therapies that decrease bone resorption (i.e. oestrogens, vitamin D derivatives, calcitonin, bisphosphonates) and therapies that increase bone formation (i.e. fluoride, vitamin D, PTH, growth factors). The effect of antiresorptive drugs is greater on cancellous bone because of its higher rate of turnover. They are better suited to the prevention of osteoporosis than to its treatment. Drugs that enhance bone formation may increase bone mass above the fracture threshold; however, in CRF patients their application has been mainly experimental (Table 2Go).

Calcium

The correction of hypocalcaemia, which is a major promoter of hyperparathyroidism, limits the extent of bone loss. Generally, during Cs therapy a daily calcium intake of 1000 mg is recommended; however, not all studies were able to demonstrate a significant benefit for this measure. In KTx patients, a supplementation with 500 mg calcium per day may already be an effective dose [5]. In CRF patients with elevated serum phosphate levels, oral calcium carbonate should be the first choice because this compound not only binds phosphate but also corrects metabolic acidosis.

Vitamin D

Vitamin D deficiency is common in CRF patients and is a major risk factor for hyperparathyroidism-induced bone loss, independent of the serum calcitriol level [6]. Vitamin D plus calcium is superior to no therapy or calcium alone in the management of COP in KTx patients and has been recommended as baseline therapy in patients receiving long-term Cs [7]. This proposition needs to be confirmed by additional studies.

1{alpha}-hydroxylated vitamin D metabolites

Impaired calcitriol synthesis is a classical risk factor for renal osteodystrophy. Moreover, Cs inhibit calcitriol synthesis and modify vitamin D effects on osteoblasts. Therefore, an attractive strategy to prevent osteoporosis is treatment with active 1{alpha}-hydroxylated vitamin D metabolites (alfacalcidol, calcitriol), which optimizes calcium absorption from the gut and mineralization of the bone matrix [8]. In a recent, placebo-controlled prospective multicentre trial in 145 patients, among them patients with systemic lupus erythematosus, the prophylactic use of alfacalcidol prevented bone loss during long-term treatment with high doses of Cs (>=30 mg/day of prednisolone) [2]. In CRF patients receiving Cs therapy further studies are needed.

Hormone replacement therapy

The inhibition of bone formation during Cs therapy is due, at least in part, to suppression of adrenal androgen secretion. Postmenopausal women, premenopausal women with menstrual irregularities, and patients with hypogonadism should receive hormone replacement therapy. For postmenopausal women conjugated oestrogens (e.g. oestrogen patch) are the first choice. Premenopausal women should be offered oral contraceptives. In men with hypogonadism, testosterone therapy is effective. Anabolic steroids such as nandrolone decanoate also prevent Cs induced bone loss. However, there are no studies in CRF patients addressing this issue.

Bisphosphonates

A recent meta-analysis revealed that bisphosphonates might be more effective in preventing COP than vitamin D and/or calcium alone [9]. Intermittent cyclic therapy with etidronate significantly decreases or even prevents Cs-induced bone loss in patients with systemic lupus erythematosus and other conditions, as demonstrated by a 36-month observational cohort study [10]. In KTx patients, bisphosphonates can effectively prevent Cs-induced bone loss without an adverse impact on graft function, and they are superior to calcitonin or calcium alone [5]. The role of bisphosphonates in preventing COP in CRF patients remains to be investigated.

Calcitonin

Calcitonin inhibits bone resorption through a direct action on osteoclasts and is therefore predominantly used in the treatment of postmenopausal osteoporosis. Calcitonin nasal spray is more convenient than s.c. or i.m. injections and as effective. Calcitonin has the advantage of an analgesic effect which, however, disappears after several weeks. In the prevention of COP, calcitonin is as efficacious as vitamin D [9]. In KTx patients, calcitonin was slightly less effective than bisphosphonates to induce a gain in BMD at the lumbar spine [5]. In CRF patients, prospective clinical studies are not available.

Fluoride

Fluoride is one of the most potent bone anabolic drugs. It is more effective in inducing bone formation than vitamin D [9]. Fluoride selectively increases the density of trabecular bone, which makes it particularly attractive for the therapy of COP. Monofluorophosphate (26 mg/day of fluoride) significantly increases bone density at lumbar spine but not at hip [11]. In CRF patients, however, it is to date not proven whether fluoride decreases the fracture rate. Moreover, there are concerns about potential harmful effects on bone quality because high cumulative doses of fluoride induce an osteomalacia-like condition, namely fluorosis.

PTH/IGF-1

In postmenopausal women with COP under hormone replacement the intermittent application of PTH dramatically increases bone mass in the central skeleton [12]. In most CRF patients, however, PTH is already elevated and the pulsatility of its secretion is modified or lost [13]. The osteo-anabolic effects of PTH are mediated, at least in part, by insulin-like growth factor (IGF)-1, which is a key regulator of bone formation, and have been attributed to inhibitory effects on osteoblast and osteoclast apoptosis. It is important to note that the positive bone effects of PTH and IGF-1 depend on skeletal loading [14]. Therefore, physical inactivity and any conditions that reduce IGF-1 bioavailability (e.g. malnutrition) should be avoided.

General recommendations to prevent COP in renal failure patients

Prophylaxis and therapy of COP should first comprise patient education about personal risk profiles and lifestyle modifications. Baseline therapy comprises calcium, vitamin D, active vitamin D metabolites, and hormone replacement therapy. Calcitonin or fluoride may be used in individual cases. In KTx patients, bisphosphonates are effective and safe but they remain to be investigated in CRF patients. Last but not least, to ensure that osteoporosis prevention becomes the standard of care for patients receiving long-term Cs treatment, a broad educational effort directed to physicians of various specialities is needed [15].

Future therapeutic strategies in COP

Based on recent data showing that Cs are potent inducers of apoptosis in all bone-cell lineages, prevention and treatment efforts of COP should focus on the inhibition of bone-cell apoptosis. According to this concept, the challenge for the new century might be to elucidate the anti-apoptotic effects of the above-recommended drugs in human bone and to develop new, pathophysiology-based rather than empirical strategies in the treatment of COP.

Notes

Correspondence and offprint requests to: Peter M. Jehle MD, Department of Internal Medicine II, Division of Nephrology, University of Ulm, Robert-Koch-Str. 8, D-89070 Ulm, Germany. Back

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