Corticosteroid-Induced Osteoporosis

Mike Mass, M.D., FACP
Mike Mass, M.D. is an Allergist and Rheumatologist with Allergy,
Asthma, and Immunology Associates, P.A. in Jacksonville.

Approximately 30-50% of patients on chronic steroids develop osteoporosis. Relatively short courses (two to three months) of more than 7.5 mg of prednisone can cause significant bone loss. The common use of "low dose" corticosteroids in the rheumatic diseases over years results in a dramatic increase in vertebral, and ultimately hip fracture, rates if unopposed by other therapy. This was also true for severe asthmatics, although the advent of topical corticosteroids has reduced risk in this group. There is a growing consensus, however, that patients at the higher end of dosing are also at risk for accelerated bone loss. Reduced serum osteocalcin levels have been noted at doses greater than 2000 micrograms per day. Because beclomethasone at a dose of 800 micrograms a day can slow the growth rate of children, there is concern about its ultimate effect on bone loss. The additional use of nasal steroids makes it even more reasonable to consider the possibility of accelerated bone loss in subgroups of patients who are on topical corticosteroid therapy.

Recognition Of Patients At Risk

An article by Buckley, et al, showed there was variation in physicians' views about corticosteroid-induced osteoporosis.2 Most physicians agreed that postmenopausal women who had not received estrogen replacement were at high risk from steroid use. However, significant differences were noted when these physicians were asked about men and premenopausal women. Only about 50% of doctors stated that osteoporosis was one of the three most significant side effects from steroid use in these groups. Specialties which used corticosteroids less frequently tended to underestimate the risk for bone loss. It has been my experience that while postmenopausal osteoporosis has been well-recognized, there are a significant number of patients receiving chronic corticosteroids who do not have bone density measurements.

It is generally accepted that patients receiving more than 7.5 mg of prednisone a day for more than eight to twelve weeks should have their bone density measured. If longer term use of steroids is necessary, then bone density should be followed at appropriate intervals. Based on a 1-3% error rate in most densitometers, it would be wise to wait 18 to 24 months before retesting to be sure observed changes are significant. Studies can be done more frequently if accumulated risk factors suggest a more accelerated bone loss. The availability of reliable bone turnover markers will make this decision easier in the future.

It can be argued that bone is the organ which is most sensitive to corticosteroids. Bone loss secondary to increased corticosteroids has been recognized since the original description of Cushing's syndrome. In spite of this, there are still large gaps in the appreciation of the population's overall risk of bone loss from chronic steroid use.

Mechanism Of Bone Loss

Rapid bone loss often occurs at the initiation of steroid therapy, at times as high as 12% during the first few months. This loss tends to be dose-related but can occur at almost any daily or alternate day dose. Loss tends to slow down with chronic use but still runs at a 3 to 6% annual rate. While both types of bone are affected, the more rapid turnover trabecular bone decreases at a disproportionate rate. It is also felt that loss of bone in the femoral head can cause collapse leading to osteonecrosis in a significant proportion of cases.

It is well known that bone is an active organ which is constantly remodeling itself. This is carried out by osteoclasts, which either burrow through tissue in cortical bone or carve out trenches in the trabeculae of non-cortical bone. These cells are linked to and followed by osteoblasts, which cover the resorption sites, and lay down osteoid, which ultimately becomes calcified. This linkage has been described as the basic multicellular unit (BMU),which is constantly on the move remodeling bone.

It is generally accepted that the major effect of glucocorticoids is to decrease bone formation. This would suggest a direct effect on the osteoblasts, possibly including apoptosis of mature cells as well as a decrease in blastogenesis. There is also evidence of increased resorption, which classically has been attributed to secondary hyperparathyroidism. This is due to effects on vitamin D metabolism, decreased gut absorption of calcium, and hypercalciuria. The case for this, however, is not totally clear as evidence from bone turnover markers and parathormone levels have not been consistent in all studies. Manolagas, et al, present a strong argument for increased apoptosis in both osteoblasts and osteocytes in the mouse model and human vertebral biopsies.1

Treatment Options

Both the National Osteoporosis Foundation and the American College of Rheumatology have published guidelines for the treatment of glucocorticoid-induced osteoporosis.3 Treatment should still be built on a foundation of calcium and vitamin D replacement. A total calcium intake of 1500-2000 mg per day is desirable unless there are specific contraindications, such as renal stones. Most physicians prefer adding 400 units of vitamin D per day to insure optimal calcium absorption. Estrogen replacement is also desirable in the postmenopausal woman as long as the typical contraindications are not present. It must be stressed that none of these modalities will reduce bone fractures. They still remain viable as preventative therapy, as well as adjunctive treatment in existing osteoporosis.

There is consensus that anyone receiving more than 7.5 to 15 mg of daily prednisone for more than three months should be put in a prevention program. This decision is not dependent on bone density analysis, but it remains a useful measurement (along with turnover markers) to follow treatment. A recently published meta-analysis of the use of bisphosphonates in steroid-induced osteoporosis shows that there is a definite increase in bone density with cyclic etidronate, pamidronate, alendronate, and risendronate.4 The effects noted were relatively small but still statistically significant. Changes were noticeably smaller at the femoral neck, but there was also less bone loss in comparable placebo groups. Although four studies looked at fracture rates, it is felt that the observation time was too short to yield meaningful results. It was stated that bisphosphonates were more effective in prevention than in treatment of established osteoporosis. In a review by the UK Consensus Group it was found that only 14% of 250,000 patients on regular corticosteroids received any therapy for bone loss.5 They reported a similar positive experience of improving bone density using all of the available bisphosphonates. Use of calcitonin was reviewed and appeared to be effective in several prevention trials. One study showed a 3.7% difference in bone density from placebo in patients treated for one year. Calcitonin appears to be a reasonable alternative for patients who can not tolerate bisphosphonates.

Summary

In summary, it seems that the most important measure in preventing osteoporosis is a universal recognition that this problem exists with steroid therapy, and that early intervention is desirable. Bisphosphonates seem to be the most effective means of increasing bone density, although improvement of fracture rates remains to be established. There has been recent thought that agents such as calcitonin and raloxifene may increase bone quality (i.e., trabecular structure) without causing a major change in bone density. The final word obviously awaits the outcome of longer term fracture studies. In the meantime, your patients can be assured that there is appropriate therapy for corticosteroid-induced osteoporosis available to them now.

REFERENCES

  1. Manolagas S, Weinstein R. Perspective -- New Development in the Pathogenesis and Treatment of Steroid-Induced Osteoporosis. Journal of Bone and Mineral Research. 1999; 14:1061-1066.
  2. Buckley L, et al. Variations in Physicians' Judgments about Corticosteroid Induced Osteoporosis by Physician Specialty. J Rheumatol. 1998; 25:2195-202.
  3. American College of Rheumatology Task Force on Osteoporosis Guidelines. Recommendations for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis. Arthritis Rheum. 1996; 39:1791-1801.
  4. Homik J, et al. A Meta-analysis on the Use of Bisphosphonates in Coritcosteroid Induced Osteoporosis. J Rheumatol. 1999; 26:1148-57.
  5. Eastell R, et al. A UK Consensus Group on Management of Glucocorticoid-Induced Osteoporosis: an Update. J Intern Med. 1998; 244:271-292.
May, 2000 (Supplement)/ Jacksonville Medicine

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