8.4 Comprehensive Diagnostic Evaluation & Laboratory Workup

Use tests to answer a clinical question

Start with the fracture and medical history, medications, examination and valid imaging. A patient with low BMD or fragility fracture can have a treatable contributor or another disorder that requires a different management plan. Obtain relevant tests before choosing an antifracture agent. Avoid applying the same expanded panel and laboratory reference intervals to every patient. The scope of tests depends on the clinical question, findings and medication being considered.

The U.S. Bone Health and Osteoporosis Foundation (BHOF) Clinician’s Guide lists CBC, albumin, albumin-adjusted calcium, renal function, phosphorus, magnesium, liver tests, 25-hydroxyvitamin D, PTH and 24-hour urine calcium with creatinine among studies to evaluate for secondary causes. The table also lists total testosterone and gonadotropins for men aged 50–69 and other studies for selected patients. Document what has already been checked and why any further test is indicated.

Target the next tests

• Suspected plasma cell disorder. In an appropriate clinical context, consider serum protein electrophoresis, immunofixation and serum free light chains. Further urine testing, imaging or referral depends on the suspected disorder. A normal electrophoresis result alone does not exclude myeloma.
• Suspected celiac disease. On a gluten-containing diet, check tissue transglutaminase IgA and total IgA if IgA status is unknown. IgA deficiency can require IgG-based testing. Interpret serology with the clinical likelihood and refer for confirmation as indicated.
• Suspected thyroid hormone excess or hypogonadism. Use TSH and free thyroid hormone tests as appropriate. Confirm consistently low morning fasting testosterone in a symptomatic man, then use LH and FSH to distinguish a testicular from a hypothalamic-pituitary cause.
• Suspected endogenous cortisol excess. Review glucocorticoid exposure first. Endocrine Society options for initial testing include late-night salivary cortisol, urinary free cortisol and the overnight dexamethasone suppression test. Choose based on the setting. A single abnormal result needs clinical interpretation and follow-up.
• Unexplained skeletal fragility with mast cell symptoms. In selected patients, a baseline tryptase can support referral. Increased tryptase can have several causes and is only one element of assessment.

Recognize a treatment-safety decision

Use the actual product label. For example, the U.S. Reclast label requires Cockcroft–Gault creatinine clearance using actual body weight before dosing and contraindicates use at a clearance below 35 mL/min or in acute renal impairment. A laboratory eGFR is not the same quantity. Correct pre-existing hypocalcemia before starting denosumab. The U.S. Prolia label has a boxed warning for severe hypocalcemia in advanced CKD, with specialist supervision and specific testing and monitoring when treatment is considered.

Consider a 57-year-old woman with recurrent metatarsal stress fractures, a hip T-score of −2.7, and ALP of 16 IU/L on two occasions with a laboratory lower limit of 44 IU/L. Persistently low ALP raises concern for hypophosphatasia and warrants evaluation of other causes of low ALP and specialist review before starting routine antiresorptive therapy. Clinical findings, elevated ALP substrates such as pyridoxal-5'-phosphate and, when indicated, genetic evidence can inform diagnosis. The T-score alone cannot resolve that differential. The absolute ALP cutoff depends on the assay and reference range. Recheck the result against the laboratory interval and review whether malnutrition, other medical conditions or medicines could help explain it.

U.S. BHOF Clinician’s Guide · ACG celiac guideline · Endocrine Society Cushing guideline · Endocrine Society testosterone guideline · Hypophosphatasia Working Group · Reclast prescribing information · Prolia prescribing information