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Results

One hundred and twenty-nine patients were included in the study, of whom 68 (53%) were male and 61 (47%) female. One hundred and nine (84.5%) were Caucasian, six (4.6%) black and 14 from other racial groups. The age at densitometry ranged from 19 to 88, and the age distribution for both sexes is shown in Figure 2a and b. The causes of uveitis where known, or the main manifestations of inflammation, are shown in Table 1.

Treatment time varied from 13 weeks to 31 years (mean 3.6 years). The cumulative dose ranged from 1290 mg to 166 559 mg (mean 16849 mg) and the mean dose ranged from 2.8 mg/day to 41 mg/day (mean 13.6 mg/day).

At some time during treatment a total of 34 patients (26.4%) also received treatment with immunosuppressives (up to three drugs) as steroid-sparing or preferred medication. The drugs involved are shown in Table 2. In addition, eight patients received intramuscular depot injections and four patients intravenous pulses, of methylprednisolone.

A total of 62 patients (48%) had one to four potential risk factors for osteoporosis prior to the commencement of steroid treatment, as shown in Table 3. Seventeen patients (13.2%) used prophylaxis against bone loss; 12 with Calcium ± Vitamin D3; four with hormone replacement therapy (HRT) and one with both of these.

Bone densitometry was within the normal range in 72 patients (55.8%) but was low in the remainder, 37 (28.7%) having osteopenia and 20 (15.5%) osteoporosis. Of the 20 osteoporotics, 14 were male and six female. Comparing these two groups, pre-existing risk factors were identified in 6/6 osteoporotic women and 9/14 men; the mean steroid dose was 13.6 mg/day for men, but 18.9 mg/day for women. The total steroid dose was 30.1 g for men compared to 20.4 g for women; the mean treatment duration was 6.4 yrs for osteoporotic men, but 4 yrs for women. None of these treatment parameters were significantly different between males and females.

Overall 57 patients (44.2%) had low bone density; in 32 of these cases the maximally-affected site was specified in the densitometry report; in 23 of these the lower spine was most affected, and the hip in nine. Eight symptomatic fractures occurred in seven patients (five men, two women) during steroid treatment; three had normal bone densitometry, one had osteopenia and three had (established) osteoporosis.

Discussion

Systemic steroid treatment induces bone loss in several ways; doses greater than 10 mg/day inhibit dietary calcium absorption; suppression of androgen production depresses oestrone levels and suppresses the calcitonin response, leading to increased bone reabsorption; osteoclasis is stimulated; and bone formation is reduced. Bone loss is inevitable during steroid therapy and commences within days of starting treatment. The rate of loss is greatest within the first 6 months, during which time typically 4-5% of bone is lost.⁵ Eventually osteoporosis occurs in up to 50% of patients.⁶ Trabecular bone is particularly affected, so effects are more marked in the spine (where steroid treatment is responsible for up to 20% of all crush fractures⁷) and proximal femur. Overall, the prevalence of symptomatic or asymptomatic fractures in patients treated with systemic steroids is between 11 and 20%;⁸ this represents a 2.5-3 times increased risk of fracture compared with a control population.⁹

Bone density may be assessed by plain radiography, quantitative computed tomography, ultrasonography or absorptiometry using photons or X-rays.¹⁰ DEXA scanning is now the most widely available technique in the UK and was used in this study. It is rapid, taking less than 5 min per site, uses little radiation (less than 1 Sv for a spine scan) and is relatively inexpensive. There are problems of reproducibility in any method of bone densitometry, between machines and longitudinally in a single patient. Data should therefore be interpreted within these limitations, and it should be noted that DEXA assessments in this series were made on at least four different machines.

Our study of 129 patients has shown a high incidence of bone loss but a low incidence of fracture. The presence of pre-existing risk factors correlated strongly with bone loss (Table 4). There was also a trend towards higher total steroid dose (normal = 14.8 g, osteoporosis = 27.2 g), mean steroid dose (normal 13.6 mg, osteoporosis 15.2 mg) and treatment time (normal 2.8 yrs, osteoporosis 5.6 yrs), in association with bone loss (Table 4). However, none of these parameters reached statistical significance for this sample.

Some diseases have an intrinsic risk of bone loss. Steroid-treated rheumatoid arthritis has a high rate of osteoporosis in comparison to asthma or polymyalgia rheumatica, but these also carry some intrinsic risk.^11,12,13 The prevalence of low bone density has not been investigated in patients with ophthalmic inflammatory disease, but one previous study examined 15 patients with steroid-treated thyroid eye disease¹⁴ and found that four were osteoporotic, and a study of 602 patients with various ocular inflammatory diseases identified 17 pathological fractures (2.8%).¹⁵ The selection of patients for our study was neither comprehensive nor prospective and the results cannot reliably be extrapolated to a wider population. However, it is likely that patients included were selected for perceived risk. Because of this sampling bias, it is most unlikely that these 129 patients represented an underestimate of steroid-induced bone loss in uveitis patients. In our cohort the prevalence of osteoporosis was 15% and the symptomatic fracture rate, 6%. Indeed, only four patients with low bone density suffered a fracture (3% of all patients), which represents one such event per 118 patients treatment years. The reported prevalence of osteoporosis and fracture in other disease groups is substantially higher, including a 34% rate of vertebral fracture in rheumatoid arthritis treated with 5 mg/day or more of prednisolone over 5 yrs¹⁶ and a 42% rate of fracture in asthmatics on high-dose prednisolone.¹⁷ Uveitis per se shows no evidence of an intrinsic risk of bone loss.

Some patients (indeed, nearly half of our patients) taking systemic steroid treatment had additional risks for osteoporosis and it is important to identify these (Table 3). Eighteen women were post-menopausal and nine had pregnancies during treatment. Three had previous episodes of amenorrhoea or had undergone oophorectomy, both of which are potent causes of osteoporosis.¹⁸ Smoking (11% of this cohort) accelerates bone resorption and in women, accelerates the menopause and catabolises oestrogens thereafter. Some patients with sarcoidosis have hypercalcuria and lose bone. Osteoporosis is weakly associated with inflammatory bowel disease, partly because of malabsorption.¹⁹ Inflammatory arthropathy, particularly rheumatoid arthritis²⁰ leads to bone loss, not least because of decreased mobility; total immobilisation leads to bone resorption at a rate of 1% per week. Type 1 diabetics have on average a 10% reduction in bone mass;²¹ type 2 diabetics are less severely affected. Anorexia or poor diet, low body weight, associated amenorrhoea and hypercortisolism can cause rapid osteoporosis.²² Bone loss also occurs in hypogonadal males, in hyperparathyroidism, after heparin treatment²³ and in alcoholism²⁴ (it is now recognised that bone loss may occur with only moderate alcohol intake, at least in women,²⁵ implying that patients should be encouraged to reduce intake if necessary).

The value of drug prophylaxis against bone loss in those at risk has been the subject of intensive research, and as yet firm conclusions are lacking. Calcium and vitamin D supplementation have been shown to ameliorate bone loss²⁶ and bisphosphonates unarguably reduce bone loss and replenish bone once lost.^5,27 Other drugs such as calcitriol²⁸ and calcitonin²⁹ prove beneficial in some circumstances. However, the only adverse event associated with bone loss is bone fracture, and the effect of prophylaxis on fracture prevalence has not been conclusively established. Nevertheless there is now a medical consensus on the need to treat in some circumstances.

The National Osteoporosis Society (NOS), in association with The British Society for Rheumatology, the Royal Society of Medicine and others, has published guidelines on the prevention and management of steroid-induced osteoporosis.³⁰ Although this is only one of a plethora of published guidelines, it has the benefit of clarity, conciseness and a practical approach. It is possible that further studies will confirm our impressions that the risks of bone loss are low for patients with uveitis, but pending such studies the NOS guideline provides a useful safety protocol for the ophthalmologist.

Patients using 5 mg of prednisolone or more per day for several months or more should be considered at risk of bone loss. This will exclude, for instance, those taking steroids for an average 8-10 weeks in the management of acute ocular toxoplasmosis. All such patients should be informed about bone loss and other complications. Adequate dietary calcium and vitamin D should be maintained (deficiency in a Western diet is unusual but guidelines are readily available). If there is any doubt about dietary intake or if the patient is relatively immobile, supplementary calcium and vitamin D3 should be taken. Alcohol intake should be limited to recommended norms. Smokers should be encouraged to stop. Walking for the equivalent of two miles or more per day should be encouraged if possible. Post-menopausal women already using HRT should be encouraged to continue if risks are acceptable. Patients should be screened for additional risk factors. If there are none, if the patient is under 65 and the dosage is under 15 mg/day, no further action is necessary. If the steroid dosage is >15 mg/day, if the patient is over 65, or if there are additional risk factors, the NOS guideline should be followed.

If treatment is considered necessary, the drug of choice for all patients is a bisphosphonate. The optimum form of treatment for steroid-induced bone loss is still subject to review, the two main choices being cyclical etidronate with calcium, or weekly alendronate. Post-menopausal women alternatively can use HRT, which will require the agreement and cooperation of the general practitioner. Patients requiring treatment also require assessment for additional risk factors. If any patient has suffered a fracture, we recommend referral to a physician with an expertise in the management of osteoporosis. We also recommend such referral if a patient is intolerant of bisphosphonate treatment (typically because of heartburn) or for any patient under 65 with osteoporosis (T < -2.5).

Systemic steroids remain the mainstay of treatment for most severe inflammatory diseases despite the increasing availability of immunosuppressives. However, immunosuppressives (most frequently cyclosporin) were used in over one quarter of our patients in order to lower steroid dosage. These drugs allow a reduction in steroid dose in most patients, often by 50% or more and thus bone loss may be ameliorated. However, it is known that cyclosporin itself causes high-turnover bone loss, possibly by reducing testosterone in combination with other effects.^31,32,33 The combination of prednisolone and cyclosporin could theoretically increase bone loss, but in this series only one of 27 patients using cyclosporin was osteoporotic.

The frequency of male osteoporosis (14/68, 20.6%) in this study is striking, and all of these were 60 yrs or below. In contrast only 6/61 women (9.8%) were osteoporotic, and four of these were over 60 yrs. There is no significant difference between the treatment parameters of males and females in this study. The use of T < -2.5 to define osteoporosis in men is not universally accepted as it is for women, because of the technicalities of the interpretation of bone density.^34,35 Young men have the greatest risk of high-impact fracture, and osteoporosis is common in those with associated risk factors,³⁶ especially hypogonadism. Men are also more susceptible to bone loss at equivalent doses of steroid, than are premenopausal women.⁶ They should be considered an at-risk group^37,38 and it is reasonable to define both male and female osteoporosis using the same criteria.

In conclusion, steroid-induced osteoporosis is an important cause of morbidity. This study suggests that its prevalence is lower in patients with uveitis than in some other disease groups but has highlighted the risk to young men. Bone loss can be reduced by optimising lifestyle and diet, by the identification of pre-existing risk factors and by the use of appropriate prophylaxis and treatment.

Acknowledgements

We wish to acknowledge the support of the Iris Fund for Mr Stanford.

The authors have no financial or proprietary interest in any device or medication reported in this article.

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