What is the most useful investigation to establish the etiology of fragility fractures in a 25-year-old man with sparse facial and axillary hair growth, Dual-Energy X-ray Absorptiometry (DEXA) scan, Insulin-like Growth Factor 1 (IGF1), Calcitonin levels, or testosterone and gonadotrophin levels?

Testosterone and Gonadotrophin Levels Are the Most Useful Investigation for Fragility Fractures in a Young Man with Sparse Hair Growth

In a 25-year-old man with a recent fragility fracture and sparse facial and axillary hair growth, testosterone and gonadotrophin levels (LH, FSH) are the most appropriate initial investigation to establish the etiology of his fragility fractures.

Rationale for Testing Testosterone and Gonadotrophins

The clinical presentation strongly suggests hypogonadism as the underlying cause of the fragility fracture:

1. Young age with fragility fracture: Fragility fractures are uncommon in young men and warrant investigation for secondary causes.
2. Sparse facial and axillary hair: This is a classic clinical sign of hypogonadism in men.
3. Strong evidence base: Multiple guidelines support testosterone assessment in men with fragility fractures.

According to evidence-based guidelines for osteoporosis management in men, serum free or total testosterone levels should be measured as part of the investigatory work-up for osteoporosis in men 1. The presence of clinical signs of hypogonadism (sparse facial and axillary hair) further strengthens this recommendation.

Evidence Supporting Testosterone Testing

The American College of Physicians guideline specifically identifies androgen deprivation therapy and hypogonadism as strong predictors of both osteoporosis and fracture in men 1. Case-control studies have demonstrated significant associations between serum testosterone/luteinizing hormone levels and osteoporosis or fracture 1.

Hypogonadism is one of the most common secondary causes of osteoporosis in men, accounting for 40-60% of cases 1. The clinical presentation of sparse facial and axillary hair growth is highly suggestive of hypogonadism, making testosterone and gonadotrophin levels the most appropriate initial investigation.

Why Other Options Are Less Appropriate

1. DEXA (Option B):

   • While DEXA is important for diagnosing osteoporosis, it doesn't identify the underlying cause
   • Guidelines recommend determining the etiology first in young men with fragility fractures 1
   • DEXA would be an appropriate follow-up test after identifying the underlying cause

2. IGF-1 (Option C):

   • No specific evidence supports IGF-1 as first-line testing in this clinical scenario
   • Growth hormone deficiency is less common than hypogonadism as a cause of fragility fractures in men

3. Calcitonin levels (Option A):

   • Not indicated for routine evaluation of fragility fractures
   • Primarily used in monitoring treatment response in certain conditions
   • No guideline recommends calcitonin measurement for fragility fracture evaluation

Diagnostic Algorithm for Young Men with Fragility Fractures

1. First-line investigations:

   • Testosterone (total and free) and gonadotrophins (LH, FSH)
   • Basic metabolic panel including calcium, phosphorus, albumin
   • 25-hydroxyvitamin D level
   • Thyroid-stimulating hormone

2. Second-line investigations (based on initial results):

   • DEXA scan to quantify bone mineral density
   • Additional hormonal testing if indicated
   • Vertebral fracture assessment or imaging

Clinical Implications

Identifying hypogonadism as the cause of fragility fractures has important treatment implications. According to guidelines, hypogonadal men with osteoporosis should usually be treated with an established anti-osteoporosis medication, regardless of whether testosterone therapy is instituted 1. This approach most effectively reduces fracture risk.

Important Caveats

1. Timing of testosterone measurement: Acute fracture can transiently decrease circulating testosterone levels. A study showed that 43% of men with low testosterone at fracture presentation were reclassified as androgen sufficient at follow-up 2. Consider repeating testosterone measurement if initially low.

2. Comprehensive evaluation: While testosterone testing is the most appropriate initial step, a complete evaluation should include assessment of other potential causes of secondary osteoporosis.

3. Recent evidence on testosterone therapy: A recent 2024 study showed that testosterone treatment in hypogonadal men did not reduce fracture incidence compared to placebo 3, highlighting the importance of using established osteoporosis medications regardless of testosterone replacement.

The clinical picture of a young man with fragility fractures and sparse hair growth strongly points to hypogonadism, making testosterone and gonadotrophin levels the most useful initial investigation to establish the etiology.