Welcome to USMLE practice question #136! Today’s question covers pharmacology/endocrinology.
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A 50-year-old woman with a history of rheumatoid arthritis presents for evaluation of generalized bone pain and multiple atraumatic vertebral compression fractures. She has been taking oral prednisone daily for the past 2 years to control her symptoms. Laboratory studies reveal normal serum calcium, phosphorus, and alkaline phosphatase levels. Dual-energy X-ray absorptiometry (DEXA) scan shows a T-score of -2.8 at the lumbar spine. Which of the following best explains the mechanism of her osteoporosis?
A) Increased osteoblast apoptosis
B) Direct inhibition of intestinal calcium absorption
C) Upregulation of RANKL expression
D) Increased renal excretion of calcium
E) Suppression of parathyroid hormone secretion
Detailed Breakdown of Answers + Correct Answer Below ⏬
ANSWER + QUESTION BREAKDOWN
It’s important to adopt the correct MENTAL MODEL when answering USMLE questions; it saves time and increases accuracy. The mental model outlined below is a foundational component of our test-taking skills masterclass (check it out if you want to elevate your skills). Here’s how to think through this question:
Step 1. Read the last line to get to the heart of the question: “Which of the following best explains the mechanism of her osteoporosis?”
Step 2: Is this a first-, second-, or third-order question?
Answer: 2nd order. 1st: Identify the cause of osteoporosis; 2nd: Identify the correct mechanism responsible for her osteoporosis.
Step 3: Read the vignette carefully and ask yourself: “Based on this patient’s presentation and history, the most likely underlying cause of her osteoporosis is ______________.”
Step 4. Look at the answer choices and select the option most closely resembling your final thought from “Step 3” above.
GENERAL ANALYSIS
This 50-year-old woman with rheumatoid arthritis and a history of long-term oral prednisone use presents with generalized bone pain, vertebral compression fractures, and a DEXA T-score of -2.8, consistent with osteoporosis. Laboratory studies show normal calcium, phosphorus, and alkaline phosphatase levels, ruling out metabolic causes like hyperparathyroidism or osteomalacia. The clinical presentation is consistent with glucocorticoid-induced osteoporosis, a common complication of chronic glucocorticoid therapy.
ANSWER CHOICES:
CHOICE A: Increased osteoblast apoptosis
Explanation: Glucocorticoids directly induce apoptosis of osteoblasts and osteocytes, reducing their number and function. They also inhibit the differentiation of mesenchymal stem cells into osteoblasts, further decreasing bone formation. Over time, this leads to decreased bone remodeling and weakened bone structure, predisposing to fractures.
CHOICE B: Direct inhibition of intestinal calcium absorption
Explanation: Glucocorticoids reduce calcium absorption in the gut by antagonizing vitamin D activity and increase renal calcium excretion, leading to secondary hyperparathyroidism. However, these effects are not the primary cause of osteoporosis in glucocorticoid-treated patients.
CHOICE C: Upregulation of RANKL expression
Explanation: Glucocorticoids increase RANKL expression while suppressing osteoprotegerin, leading to enhanced osteoclast differentiation and activity. This results in increased bone resorption during the early phase of glucocorticoid therapy. Although increased RANKL-mediated resorption plays a role in early bone loss, the long-term effects of glucocorticoids are primarily due to reduced bone formation caused by osteoblast apoptosis.
CHOICE D: Increased renal excretion of calcium
Explanation: Glucocorticoids promote renal calcium loss by reducing calcium reabsorption in the kidneys. This can contribute to secondary hyperparathyroidism and increased bone resorption.
CHOICE E: Suppression of parathyroid hormone secretion
Explanation: Parathyroid hormone (PTH) regulates calcium homeostasis by stimulating bone resorption when serum calcium levels are low. Glucocorticoids do not suppress PTH secretion; instead, they may indirectly increase PTH levels through effects on calcium metabolism.
FINAL VERDICT…
CORRECT ANSWER: A) Increased osteoblast apoptosis
Glucocorticoid-induced osteoporosis primarily results from increased apoptosis and decreased differentiation of osteoblasts, leading to reduced bone formation. This mechanism underlies the progressive decline in bone density and increased fracture risk seen in long-term glucocorticoid users.
KEY CONCEPTS:
Mechanisms of Glucocorticoid-Induced Osteoporosis (GIOP):
Decreased Bone Formation:
Induction of osteoblast and osteocyte apoptosis.
Suppression of mesenchymal stem cell differentiation into osteoblasts.
Inhibition of Wnt signaling pathways essential for osteogenesis.
Increased Bone Resorption:
Upregulation of RANKL expression and suppression of OPG.
Enhanced osteoclast activity during early glucocorticoid therapy.
Calcium Dysregulation:
Reduced intestinal calcium absorption.
Increased renal calcium excretion.
Secondary hyperparathyroidism contributing to bone resorption.
Clinical Features of GIOP:
Predominantly affects trabecular (spongy) bone, such as vertebral bodies.
Increased risk of fragility fractures (e.g., vertebral compression fractures).
Bone loss occurs rapidly within the first 3–6 months of therapy.
Laboratory Findings in GIOP:
Normal serum calcium, phosphorus, and alkaline phosphatase levels.
Secondary hyperparathyroidism may be present in some cases.
Prevention and Management of GIOP:
Minimize glucocorticoid dose and duration whenever possible.
Calcium (1,000–1,200 mg/day) and vitamin D (800–1,000 IU/day) supplementation.
Bisphosphonates (e.g., alendronate) for high-risk patients.
Weight-bearing exercise and fall prevention strategies.