Ophthalmologists, on occasion, take the initiative and the responsibility for prescribing systemic steroids to patients with vision-threatening ocular inflammatory disorders. Examples of such disorders include orbital pseudotumor, scleritis, uveitis, giant cell arteritis and optic neuritis. Preoccupation with the challenge and goal of preservation of vision, coupled with the propensity for some cases to relapse with attempted steroid taper (with resultant need to raise the steroid dose again) can lead to prolonged steroid use without attention to bone preservation strategies.
It is well known that prolonged use of glucocorticoids (GC) has a 100% chance of adverse
reactions1, including: severe bone mineral loss, insulin resistance, myopathy, behavioral disorders, easy bruising, rise in blood pressure, cataract, glaucoma.2 Cyclosporine A, which may also be used in combination with GC to obtain control of ocular inflammation, also can cause bone loss by inducing high intensity bone remodeling and resorption exceeding formation in animal models, indicating an increase of osteoclast activity3,4.
Osteoporosis means “porous bone”. The Consensus Development Conference held in conjunction with the Fourth International Symposium on Osteoporosis defined osteoporosis as “a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture”. Osteoporosis is a serious public health concern that affects almost 28 million people in the United States, and the overall cost of acute and long-term health care associated with it will approach $14 billion annually, or more than $38 million per day by 2015 (National Osteoporosis Foundation, 1997).
The incidence of atraumatic fractures in patients who receive supraphysiologic glucocorticoid therapy is 30 to 50%.5,6 The chronic use of GC is associated with a lower bone mineral density (BMD) and a higher risk of bone fractures in a dose-response relationship. Most of the BMD loss occurs during the first 12 months, peaking at 6 months7.
Glucocorticoids cause bone loss by suppressing bone formation. If bone resorption is simultaneously increased (by other medications, by the illness for which the glucocorticoids are prescribed, or by concomitant circumstances such as estrogen lack), then bone loss is particularl rapid.Dosages of GC >5 mg /day are associated with accelerated bone loss in elderly men and women8. It has been estimated that 800 mcg/day of beclomethasone, budesonide or fluticanide can cause bone loss.9,10 It is also known that the use of alternating doses of GC does not prevent bone loss11.
GC cause suppression of Insulin-like Growth Factor-1 (IGF-1) either because inhibition of its release or its production 12. IGF-1 plays an important role in the acquisition and maintenance of bone. Until now, however, the exact mechanism for this is unknown. Recombinant IGF-1 can prevent devastating effects of GC on bone. But this therapy has certain disadvantages: it is expensive; there are significant potential adverse effects (dermatologic and cardiac); and IGF therapy must be delivered by subcutaneous injections.
The effects of GC on bone and mineral are summarized in Table 1. GC also can induce androgen deficiency by pharmacological suppression of adrenal function13, and androgen deficiency increases bone resorption. This is evident in postmenopausal women14 and in hypogonadal males. The adrenal glands are an important source of circulating androgens. In addition, high doses of GC decrease testicular responsiveness to gonadotropins, and thereby reduce serum testosterone even in normal males.
Strategies to prevent GC induced bone loss
Bone mineral density testing is the most reliable tool to assess fracture risk. Routine
radiography used to be the only non-invasive method to evaluate BMD. Currently the most
reliable method to assess BMD is dual energy x-ray absorptiometry (DEXA). It has proven to
be a reliable indicator of risk for developing osteoporotic fracture, and an efficient tool to
assess response to treatment of bone loss. DEXA is non-invasive, and has a precision of 1%.
Two measures are of importance when interpreting DEXA results. Both measures are
statistically compared in standard deviations (SD) from a normal distribution or along a “bell
curve”. They are the individual’s T-score and Z-score. The T-score compares the patient’s
BMD to the mean score of a healthy adult. The Z-score compares the patient’s BMD to the
mean score of an age-matched control. The World Health Organization has established the
following criteria for osteoporosis preventive and therapeutic decisions 15:
• Normal: a value for BMD greater than -1 SD of a healthy young adult mean value.
• Osteopenia: a value for BMD more than -1 SD but less than -2.5 SD below that of a healthy
young adult mean value.
• Osteoporosis: a BMD value -2.5 SD or greater below that of a healthy young adult mean
• Individuals who have sustained one or more low-impact fractures are considered to have
osteoporosis regardless of their BMD score.
It is important for a physician not only to recognize the risk of osteoporosis
induced by anti-inflammatory therapy but also to explain this to patients. The consequences
of profound bone loss and fractures can be devastating from the standpoint of patients’ well
being, health care costs and legal issues.
We address medications used for the prevention of GC-induced bone loss.
Bisphosphonates have been marketed since 1988, and are effective in the prevention of GCrelated
BMD loss 16. The mechanism of action is the inhibition of osteoclast bone resorption
once the drug adheres to the bone surface. Potential side effects include
gastritis/esophagitis17, myalgia 18, and altered hepatic function 18. Since bone resorption is
essential for healing of fractures and repair of microscopic fatigue cracks in bone,
inappropriately high doses of bisphosphonates may interfere with repair of fractures and
weaken bone strength by forcing bones to accumulate and propagate fatigue cracks.
Bisphosphonates may also abolish the skeleton’s adaptive powers19. But in general,
bisphosphonates are well tolerated.
Several studies have shown that treatment with calcium and multivitamins plus alendronate
(Fosamax) or risendronate (Actonel) prevents glucocorticoid-induced bone less in the spine
and hip, whereas treatment with calcium and multivitamins plus placebo does not.20,21,22.
The results are summarized in Table 2. Patients who were recently started on glucocorticoid
therapy require higher bisphosphonate doses than patients who have been treated for
prolonged periods with GC (Table 3). Patients who had less than 4 months of prior GC use or
women with estrogen deficiency require 10mg of alendronate a day (as opposed to 5 mg) to
have significant improvement on BMD. A risedronate (Actonel) placebo-controlled trial came
to the same conclusions. The effect of both drugs is dose-dependent. Weekly doses are now
available: 70 mg of alendronate or 35 mg of risedronate.
Human parathyroid hormone and Hormone Replacement Therapy (HRT)
Postmenopausal women on chronic GC are only partially protected from bone loss by HRT
alone. Additionally, one must be aware of the possible side effects of chronic HRT, including
increased risk of breast cancer, stroke, and myocardial infarction 24. One study
demonstrated that the use of human parathyroid hormone dramatically increased bone
mass in the lumbar spine and in hip of postmenopausal women with glucocorticoid-induced
osteoporosis who were already taking hormone replacement therapy. However, the
maximum effect of this anabolic agent on BMD of the hip took place after 6 months of
treatment23. Human parathyroid hormone must be administrated by daily subcutaneous
injections, which are obviously inconvenient. Forteo, a breakthrough therapy derived from
synthetically produced parathyroid hormone, is now FDA approved and available to patients
with severe osteoporosis.
Selective estrogen receptor modulators
Raloxifene (Evista) was initially developed as a breast cancer preventive drug. It has the
ability to increase BMD in spine and hip, but not as effectively as bisphosphonates, or
estrogen. This drug acts on estrogen receptors and has the agonistic effect on bone and
lipids. Raloxifen (Evista) alone does not prevent GC induced bone loss 25,26..
Salmon Calcitonin (SCT), delivered by nasal spray, can prevent BMD loss by suppressing
osteoclast action. Luengo et al. found in patients with GC dependent asthma, that SCT given
intranasally increased spinal BMD during the first year of treatment and maintained bone
mass in a steady state during the second year 27,28. Adachi et al. also report the effects of
nasal SCT in patients with polymyalgia rheumatica with or without temporal arthritis who
were on chronic high dose GC therapy 29. Nasal SCT prevented loss of bone in the lumbar
spine as measured by dual-energy X-ray absorptiometry. Both studies used 200 mcg of SCT
and calcium supplement (800 – 1000 mg) daily. These studies share a small number of
There is lack of large studies, which can give more reliable data about the benefit of SCT
therapy in patients with chronic use of CG. 30. SCT may be a good option for pregnant
women on chronic GC therapy, because the use of bisphosphonates is contraindicated in
pregnant women 31,32.
Patients over the age of 60 and patients with chronic diseases tend to have low levels of
Vitamin D. Chronic use of GC may increase catabolism of vitamin D and may reduce serum
levels of Vitamin D by 5-10%33. Vitamin D, 25-OH vitamin D, and 1,25-(OH)2 vitamin D were
reported to increase BMD in GC-treated patients, but other studies failed to confirm such
benefits 33,34,35. Vitamin D and its metabolites have not improved bone mass in GCtreated
patients if vitamin D deficiency was excluded36. Vitamin D deficiency is surprisingly
frequent in places with long deprivation of sunlight, such as northern climates in winter. But
benefit of Vitamin D as a monotherapy in the treatment of BMD loss is questionable.
Vitamin D supplementation should, however, be part of chronic GC therapy.
Systemic Illness causing bone loss
Cushing’s disease causes severe bone loss, but osteopenia can reverse completely after cure
of Cushing’s37. Hyperparathyroidism is another well-known cause of bone loss. Successful
surgical treatment results in improvement of bone density, with an 8 to 12% increase in
bone mass observed during the first 2 to 4 years following surgery.38
Gastrointestinal diseases associated with bone loss include celiac sprue, cystic fibrosis,
chronic liver disease and inflammatory bowel disease. Osteopenia is explained by
glucocorticoid use in many patients with inflammatory bowel disease. But it appears that
inflammatory bowel disease may cause osteoporosis even in the absence of such therapy39,
with a 40% increase in fracture rate reported by some authiors.40
These are the recommendations to stop GC-induced osteoporosis:
• Check axial BMD early, preferably in lateral and PA spine
• Assure 1000-1500 mg Ca and 800 units vitamin D in tablets daily
• Then check serum PTH and 25-OH vitamin D
• Refer to a specialist if there are multiple osteoporosis risk factors
• Prescribe a bisphosphonate as first line treatment, or PTH if the patient has had a fragility
fracture or if the T-score is below – 2.5 SD
• Consider nasal spray calcitonin if T-score is borderline low, or if the patient is pregnant
• If androgen therapy would be safe: check serum testosterone in men over 60, and in men
taking high-dose GC
• Other medications resulting in bone loss include anti-convulsants, heparin and
supraphysiologic doses of levothyroxine (i.e. those used to treat thyroid tumors).
• Remember that risk factors, such as smoking, alcohol abuse and sedentary lifestyle
contribute to increased rate of bone loss.
1. Foster CS, Vitale AT. Diagnosis and Treatment of Uveitis. Saunders, 1st edition, Page 153-4,
2. Rubin B, Palestine AG. Complications of corticosteroid and immunosuppressive drugs. Int
Ophthalmol Clin. 1989; 29(3): 159-71. Review.
3. Movsowitz C, Epstein S, Fallon M, Ismail F, Thomas S. Cyclosporin-A in vivo produces
severe osteopenia in the rat: effect of dose and duration of administration. Endocrinology.
1988 Nov; 123(5): 2571-7.
4. Epstein S, Schlosberg M, Fallon M, Thomas S, Movsowitz C, Ismail F. 1,25-
Dihydroxyvitamin D3 modifies cyclosporine-induced bone loss. Calcif Tissue Int. 1990 Sep;
5. Adinoff A, Hollister J. Steroid-induced fractures and bone loss in patients with asthma. N
Eng J Med 1983; 309:265-8.
6. Lukert B, Raisz L. Glucocorticoid-induced osteoporosis: pathogenesis and management.
Ann Intern Med 1990; 112:352-64.
7. Reid IR. Glucocorticoid-induced osteoporosis. Baillieres Best Pract Res Clin Endocrinol
Metab. 2000 Jun;14(2):279-98. Review.
8. Luengo M, Del Rio L, Pons F, Picado C. Bone mineral density in asthmatic patients treated
with inhaled corticosteroids: a case-control study. Eur Respir J. 1997 Sep; 10(9): 2110-3.
9. Picado C, Luengo M. Corticosteroid-induced bone loss. Prevention and management. Drug
Saf. 1996 Nov; 15(5): 347-59. Review.
10. Gluck OS, Murphy WA, Hahn TJ, Hahn B. Bone loss in adults receiving alternate day
glucocorticoid therapy. A comparison with daily therapy. Arthritis Rheum. 1981 Jul; 24(7):
11. Canalis E. Mechanisms of glucocorticoid-induced osteoporosis. Curr Opin Rheumatol.
2003 Jul; 15(4): 454-7.
12. Kozakowski J, Papierska L, Krassowski J, Zgliczynski S. The effect of growth hormone
replacement therapy on markers of bone formation and bone mineral density in elderly
men. Pol Arch Med Wewn. 1998 Oct; 100(4): 306-12.
13. Martens HF, Sheets PK, Tenover JS, Dugowson CE, Bremner WJ, Starkebaum G. Decreased
testosterone levels in men with rheumatoid arthritis: effect of low dose prednisone therapy.
J Rheumatol. 1994 Aug; 21(8): 1427-31.
14. Marshall DH, Crilly RG, Nordin BE. Plasma androstenedione and oestrone levels in
normal and osteoporotic postmenopausal women. Br Med J. 1977 Nov 5; 2(6096): 1177-9.
15. World Health Organization Study Group. Assessment of fracture risk and its application
to screening for postmenopausal osteoporosis: Report of WHO study group. WHO technical
report series 843. Geneva, Switrzerland.1994.
16. Natsume H, Nakamura H. Hypogonadism and osteoporosis. Nippon Rinsho. 1998 Jun;
17. Reid IR, Heap SW, King AR, Ibbertson HK. Two-year follow-up of biphosphonate (APD)
treatment in steroid osteoporosis. Lancet. 1988 Nov 12; 2(8620): 1144
18. Marshall JK. The gastrointestinal tolerability and safety of oral bisphosphonates. Expert
Opin Drug Saf. 2002 May; 1(1): 71-8.
19. Mondelo N, Peluffo VA, Parma MD, Cointry GR, Capozza RF, Ferretti JL, Piccinni E,
Montuori E. Preclinical toxicology of bisphosphonates. Medicina (B Aires). 1997; 57 Suppl
20. Bell NH, Johnson RH. Bisphosphonates in the treatment of osteoporosis. Endocrine. 1997
Apr; 6(2): 203-6.
21. Gonnelli S, Rottoli P, Cepollaro C, Pondrelli C, Cappiello V, Vagliasindi M, Gennari C.
Prevention of corticosteroid-induced osteoporosis with alendronate in sarcoid patients.
Calcif Tissue Int. 1997 Nov; 61(5): 382-5.
22. Saag KG, Emkey R, Schnitzer TJ, Brown JP, Hawkins F, Goemaere S, Thamsborg G,
Liberman UA, Delmas PD, Malice MP, Czachur M, Daifotis AG. Alendronate for the
prevention and treatment of glucocorticoid-induced osteoporosis. Glucocorticoid-Induced
Osteoporosis Intervention Study Group. N Engl J Med. 1998 Jul 30; 339(5): 292-9.
23. Reid DM, Hughes RA, Laan RF, Sacco-Gibson NA, Wenderoth DH, Adami S, Eusebio RA,
Devogelaer JP. Efficacy and safety of daily risedronate in the treatment of corticosteroidinduced
osteoporosis in men and women: a randomized trial. European Corticosteroid
Induced Osteoporosis Treatment Study. J Bone Miner Res. 2000 Jun; 15(6): 1006-13.
24. Herrington DM, Vittinghoff E, Lin F, et al. Statin therapy, cardiovascular events, and total
mortality in the Heart and Estrogen/Progestin Replacement Study (HERS). Circulation. 2002;
25. Lane NE, Sanchez S, Modin GW, Genant HK, Pierini E, Arnaud CD. Bone mass continues
to increase at the hip after parathyroid hormone treatment is discontinued in glucocorticoid
induced osteoporosis: results of a randomized controlled clinical trial. J Bone Miner Res.
2000 May; 15(5): 944-51.
26. Watts NB. Bisphosphonate treatment of osteoporosis. Clin Geriatr Med. 2003
27. Watts NB. Treatment of osteoporosis with bisphosphonates. Rheum Dis Clin North Am.
28. Luengo M, Pons F, Martinez de Osaba MJ, Picado C. Prevention of further bone mass loss
by nasal calcitonin in patients on long term glucocorticoid therapy for asthma: a two year
follow up study. Thorax. 1994 Nov; 49(11):1099-102.
29. Luengo M, Picado C, Del Rio L, Guanabens N, Montserrat JM, Setoain J. Treatment of
steroid-induced osteopenia with calcitonin in corticosteroid-dependent asthma. A one-year
follow-up study. Am Rev Respir Dis. 1990 Jul;142(1):104-7.
30. Adachi JD, Bensen WG, Bell MJ, Bianchi FA, Cividino AA, Craig GL, Sturtridge WC, Sebaldt
RJ, Steele M, Gordon M, Themeles E, Tugwell P, Roberts R, Gent M. Salmon calcitonin nasal
spray in the prevention of corticosteroid-induced osteoporosis. Br J Rheumatol. 1997
31. Patlas N, Golomb G, Yaffe P, Pinto T, Breuer E, Ornoy A. Transplacental effects of
bisphosphonates on fetal skeletal ossification and mineralization in rats. Teratology. 1999
32. Graepel P, Bentley P, Fritz H, Miyamoto M, Slater SR. Reproduction toxicity studies with
pamidronate. Arzneimittelforschung. 1992 May;42(5):654-67.
33. Rackoff PJ, Rosen CJ. Pathogenesis and treatment of glucocorticoid-induced
osteoporosis. Drugs Aging. 1998 Jun;12(6):477-84. Sambrook PN. Glucocorticoid
osteoporosis. Curr Pharm Des. 2002;8(21):1877-83.
34. Scharla SH. Therapy of osteoporosis: native vitamin D or as hormone? Advantages of
activated vitamin D in secondary osteoporosis. MMW Fortschr Med. 1999 Aug 12;141(31-
35. Mitchell DR, Lyles KW. Glucocorticoid-induced osteoporosis: mechanisms for bone loss;
evaluation of strategies for prevention. J Gerontol. 1990 Sep;45(5):M153-8.
36. Cooper L, Clifton-Bligh PB, Nery ML, Figtree G, Twigg S, Hibbert E, Robinson BG. Vitamin
D supplementation and bone mineral density in early postmenopausal women. Am J Clin
Nutr. 2003 May;77(5):1324-9.
37. Manning P, Evans M, Reid I. Normal bone mineral density following cure of Cushing’s
syndrome. Clin Endocrinol 1992; 36:229-34.
38. Silverberg S, Gartenberg F, Jacobs T, et al. Increased bone density after
parathyroidectomy in primary hyperparathyroidism. J Clin Endocrinol Metab 1995; 80:729-34.
39. Bjarnson I, Macpherson A, Macintosh C, Buxton-Thomas M, Forgacs I, Moniz Z. reduced
bone density in patients with inflammatory bowel disease. Gut 1997; 40:228.
40. Bernstein C, Blanchard J, Leslie W, Wajda A, Yu B. The incidence of fracture among
patients with inflammatory bowel disease. Ann Intern Med 2000; 133:795.