Question:

A 67-year-old woman comes to the office due to polymyalgia rheumatica. She was diagnosed a year ago and has required supraphysiologic doses of prednisone to control her symptoms. The patient has no other medical conditions. She has adequate intake of calcium and vitamin D from her diet and supplements. The patient does not use tobacco or alcohol. Physical examination is unremarkable. Laboratory evaluation shows normal serum creatinine, 25-hydroxyvitamin D, and calcium levels. Bone density measured by dual x-ray absorptiometry (DXA) reveals a significant decline when compared to her bone density measured at age 65. Which of the following is most likely contributing to this patient's bone loss?

Increased activity of osteoprotegerin

Increased levels of insulin-like growth factor-1

Inhibition of osteoblast precursor cell replication and differentiation

Inhibition of receptor activator of nuclear factor kappa B

Suppression of parathyroid hormone release

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Explanation:

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Chronic or recurrent glucocorticoid (eg, prednisone) use, as is needed in patients with polymyalgia rheumatica, is associated with an increased risk for osteoporosis. Glucocorticoids accelerate the development of osteoporosis by a number of mechanisms:

Decreased osteoblast effect: Glucocorticoids inhibit the proliferation and differentiation of osteoblast precursor cells. They also induce increased rates of apoptosis in mature osteoblasts.
Increased osteoclast effect: Osteoclast differentiation and activity are promoted by the receptor activator of nuclear factor kappa B (RANK)/RANK-ligand; this effect is inhibited by osteoprotegerin, which acts as a decoy receptor. Glucocorticoids increase the expression of RANK and RANK-ligand (Choice D) and decrease the expression of osteoprotegerin (Choice A), leading to increased bone resorption.
Renal and intestinal calcium wasting: Glucocorticoids suppress intestinal calcium absorption and renal calcium reabsorption, requiring increased release of calcium from bone to maintain calcium homeostasis.

(Choice B) Insulin-like growth factor-1 (IGF-1) is produced primarily in the liver but also locally in bone. It mediates many of the anabolic effects of growth hormone, including maintenance of bone mass. Glucocorticoids suppress (not increase) levels of IGF-1; in animal models, administration of exogenous IGF-1 mitigates much of the bone loss associated with glucocorticoids.

(Choice E) Glucocorticoids alter the pattern of parathyroid hormone (PTH) secretion (eg, reduced tonic secretion and increased pulsatile PTH secretion), but overall secretion is only minimally changed. In general, bone loss is seen with excessive PTH secretion (ie, hyperparathyroidism) but not suppressed secretion.

Educational objective:
Chronic or recurrent glucocorticoid (eg, prednisone) use can lead to loss of bone density. Glucocorticoids inhibit replication and differentiation of osteoblast precursor cells, increase osteoclast activity, and promote intestinal and renal calcium wasting.