String of Pearls

Osteoporosis is a systemic skeletal disease which is characterized by low bone mass, reduced bone strength (which is dependent on bone density and bone quality), increased fracture risk, and the weakening or deterioration of the microarchitecture of the bone. Glucocorticoid treatment is a common cause of secondary osteoporosis.

According to the 2010 Canadian Osteoporosis guidelines, recent prolonged use of systemic glucocorticoids, specifically at  least three months of cumulative use during the preceding year with prednisone-equivalent dose ≥ 7.5 mg daily, increases the risk of fracture independent of bone mineral density. If an individual is at moderate risk of an osteoporotic fracture, being on prednisone as described above, will raise the risk category to high.

Earlier this year, the New England Journal of Medicine, published an excellent review of glucocorticoid-induced bone disease (which includes osteonecrosis - point #10). I will attempt to summarize some of the key points from this review here. 

1. Glucocorticoid-induced bone loss is biphasic where bone loss occurs rapidly within the first year (6 to 12%), then slowly thereafter (3% per year). Within the first 3 months of glucocorticoid therapy, the fracture risk may increase to ~75% before a substantial decline in bone mineral density is seen. Trabecular bone loss is predominant relative to cortical bone loss. Fractures have been reported with doses of prednisolone 2.5 mg to 7.5 mg per day (~3.1 to 9.3 mg of prednisone per day). 

2. The 11β-hydroxysteroid dehydrogenase 1 (HSD1) isoenzyme is expressed in human osteoblasts where it generates active cortisol (or prednisolone) from inactive cortisone (or prednisone).  The expression of this isoenzyme is increased with age and with glucocorticoid administration. In individuals who are obese, the systemic activity of this isoenzyme is decreased which may explain the positive relationship between obesity and bone density.

3. Glucocorticoid-induced osteoporosis involves decreased osteoblastogenesis and promotion of osteoblast apoptosis, resulting in a decrease in the number and the lifespan of osteoblasts. Further, due to increased osteocyte apoptosis, bone strength is negatively impacted (decreased bone quality). Also, there is an early, transient increase in the lifespan of osteoclasts.

4. Risk factors of glucocorticoid-induced osteoporosis includes advanced age, low body-mass index (<24), underlying diseases such as chronic obstructive pulmonary disease and rheumatoid arthritis, increased 11β-HSD1 expression and high glucocorticoid dose (high current or cumulative dose, long duration of therapy). 

5. Vertebral fractures are more common than hip fractures in individuals with glucocorticoid-induced osteoporosis. Measuring an individual's height is stressed as loss of height suggests presence of vertebral fractures (may be asymptomatic) which places the individual at an increased risk for future fractures. The current Canadian Osteoporosis guidelines suggest measuring height annually when assessing individuals for fracture risk and osteoporosis.

6. For glucocorticoid-induced osteoporosis, bisphosphonates are considered first-line. Alendronate, risedronate and zoledronic acid are approved for the treatment and prevention of glucocorticoid-induced osteoporosis by Health Canada and the FDA. Alendronate, risedronate and zoledronic acid have been shown to increase the bone mineral density at the lumbar spine. Alendronate and risedronate have been shown to decrease the relative risk of glucocorticoid-induced vertebral fractures by ~40%. Zoledronic acid is available in an intravenous formulation. Relative to the oral bisphosphonates, zoledronic acid has a faster onset of action of skeletal effects. Bisphosphonates inhibit osteoclasts; however, they do not address the decreased bone formation.

7. Glucocorticoids have been shown to antagonize bisphosphonate-induced osteoclast apoptosis and as a result, bisphosphonates may be less effective in the treatment of glucocorticoid-induced osteoporosis relative to those with postmenopausal osteoporosis or in men with osteoporosis when looking at % increase in the bone mineral density in the lumbar spine and femoral neck.

8. Rare side effects of bisphosphonates include osteonecrosis of the jaw [estimated risk 1 case per 10,000 to 100,000 patient-years, reports in patients with osteolytic bone cancer or multiple myeloma receiving frequent, high doses of intravenous bisphosphonates] and atypical subtrochanteric femoral fractures [estimated risk 2 cases per 10,000 patient-years].

9. Teriparatide, approved by Health Canada and the FDA for treatment of glucocorticoid-induced osteoporosis, prevents glucocorticoid-induced osteoblast and osteoclastic apoptosis and has been shown to have a faster onset of action relative to oral alendronate. In patients taking > 15 mg of prednisone a day, treatment with teriparatide resulted in a lesser increase in bone mineral density at the lumbar spine. Other factors that may contribute to diminished effects of teriparatide include underlying illness, medications, reduced renal function and low levels of insulin-like growth factor I).

10. Osteonecrosis, a complication of glucocorticoid therapy, should be ruled out in patients who report persistent hip, knee or shoulder pain and especially pain secondary to joint movement or that is associated with tenderness or reduced range of motion. Risk factors of osteonecrosis are high dose and prolonged duration of glucocorticoid therapy. Osteonecrosis may occur with short-term exposure to high doses of corticosteroids and in the absence of osteoporosis. There is evidence that treatment with alendronate in patients with osteonecrosis of the hip, may help decrease pain and need for surgery, and improve ambulation.

Summary: The minimum dose and duration of glucocorticoid therapy that does not increase the risk of fracture is not known. Increased risk of fractures with the use of inhaled glucocorticoids, and alternate-day and intermittent oral regimens have been reported. Adequate calcium and vitamin D supplementation is suggested for all patients on glucocorticoids, though, on their own, they do not prevent fractures. A bisphosphonate is recommended at the start of glucocorticoid therapy, and continued for as long as the patient requires glucocorticoids. Drug holidays are not appropriate for those on corticosteroids because bone loss has occurred with discontinuing bisphosphonates. Teriparatide may be offered to patients who are at a high risk of fracture who are taking glucocorticoids. Denosumab, a humanized monoclonal antibody to RANKL, is not currently approved for the treatment and prevention for glucocorticoid-induced osteoporosis - more data is needed.

References:

1. Weinstein RS. Glucocorticoid-induced bone disease. N Engl J Med 2011;365:62-70.

2. Cooper MS, Blumsohn A, Goddard PE et al. 11 beta-hydroxysteroid dehydrogenase type 1 activity predicts the effects of glucocorticoids on bone. J Clin Endocrinol Metab 2003;88(8):3874-3877.

3. Papaioannou A, Morin S, Cheung AM et al. 2010 Clinical Practice Guidelines for the diagnosis and management of osteoporosis in Canada: Summary. CMAJ 2010. DOI:10:1503.cmaj.100771. Available at url: http://www.cmaj.ca/content/182/17/1864.full.pdf+html

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Alka Bhalla, PharmD
Consultant Pharmacist
Ottawa, ON