Bone Biopsy

Bone biopsy has been used as an invasive diagnostic procedure and a significant research method in the field of osteoporosis and other metabolic bone disease. ^[1] Several data can be obtained from bone histology, such as rate of bone resorption and remodeling, degree of bone mineralization, and bone structure. ^[2]

The iliac crest has been the preferred site for bone biopsy because it is easily accessible, is associated with fewer complications, and does not require extensive surgery. ^[3]

Transiliac bone biopsy is indicated for selected patients with metabolic bone disease who have an unusual clinical presentation when less invasive investigations have yielded inconclusive results. ^[4] Bone biopsy is rarely performed to diagnose patients with osteoporosis, for the following reasons ^[5] :

• Invasiveness of the procedure
• Lack of technical training among clinicians
• Pain
• Cost
• Requirement for specialized centers to interpret bone specimens
• Limited understanding of histologic results
• Availability of noninvasive diagnostic procedures that help establish the diagnosis

However, current biochemical markers are poor predictors of bone turnover, volume, and mineralization. Bone mineral density (BMD) measurement can only provide information about bone mineral content, which can be affected by a change in bone mass (osteoporosis or osteosclerosis), a decrease in bone mineral content (osteomalacia), or a combination of these abnormalities. It can provide no information about bone cell activity and bone turnover rate without bone biopsy. ^[2]

In current practice, no clear indication for bone biopsy exists in patients with osteoporosis. Most diagnostic procedures are restricted to atypical, unclear, and complicated cases, such as unexplained primary osteoporosis and failure to response to antiosteoporotic treatments. ^{[2, 6]}

On the other hand, bone biopsy remains the most accurate diagnostic tool to define alterations in bone morphology in patients with chronic kidney disease (CKD), known as renal osteodystrophy, ^{[3, 7, 8, 9]}  though it may not be practical in all such patients. ^[10] Clinical indications for performing the procedure are summarized below.

Renal osteodystrophy

Clinical indications for bone biopsy in patients with CKD stages 3-5, based on guidelines from Kidney Disease Improving Global Outcomes (KDIGO) ^{[7, 11]} and the Kidney Disease Outcomes Quality Initiative (KDOQI), ^[12]  are as follows:

• Unexplained fractures
• Unexplained hypercalcemia
• Unexplained hypophosphatemia
• Persistent bone pain
• Suspected aluminum toxicity based upon clinical symptoms or history of aluminum exposure
• Previous therapy with bisphosphonates
• Inconsistency among biochemical parameters, thereby preventing definitive interpretation
• Severe progressive vascular calcification
• Prior to parathyroidectomy if a history of aluminum exposure exists or if the biochemical determination is inconsistent with advanced secondary or tertiary hyperparathyroidism
• Intact plasma parathyroid hormone (PTH) levels between 100 and 500 pg/mL (in CKD stage 5) in association with unexplained hypercalcemia, severe bone pain, or unexplained increase in bone alkaline phosphatase activity

The 2017 update to the KDIGO guidelines stated that it is reasonable to perform a bone biopsy if knowledge of the type of renal osteodystrophy will impact treatment decisions. ^[13]

Osteoporosis

Clinical indications in the setting of osteoporosis are as follows:

• To distinguish osteoporosis from suspected osteomalacia and unexplained osteosclerosis ^[4]
• To evaluate diagnosis and treatment in atypical, unclear, and complicated cases, including unexplained primary osteoporosis, failure to respond to antiosteoporotic treatments, osteoporotic male or premenopausal osteoporotic female without endocrine abnormality, or suspected systemic or malignant disease (eg, mastocytosis, osteogenesis imperfecta, ^[14] nonsecreting plasmocytoma, and metastatic infiltration) ^{[2, 6]}

Bone tumors

Bone biopsy may also be indicated to diagnose either primary or metastatic bone tumors. ^{[15, 16, 17]}

Bone infections

Bone biopsy has been recommended for diagnosis of osteomyelitis. ^{[18, 19]}

Transiliac bone biopsy is contraindicated in the following patients:

• Those who have a coagulopathy or are on anticoagulant therapy
• Those who are grossly obese

Best practices

Transiliac bone biopsy should be performed by a skilled operator in an institute with a laboratory that can process undecalcified bone specimens, as well as experienced pathologists to analyze specimen data. The operator’s experience is an important factor in reducing morbidity and ensuring specimen adequacy.

Tetracycline double-labeling

If dynamic data on the new bone formation (eg, bone turnover, bone formation rates, and mineralization defects) are to be analyzed by using histomorphometry, then administration of time-spaced tetracycline markers is necessary before the bone biopsy.

Tetracycline compounds chelate calcium on bone surfaces and are deposited at the sites of active mineralization or new bone formation. Double-labeling of the bone with tetracycline should be completed before the bone biopsy is performed. The second dose of tetracycline is administered 10-14 days after the first dose. The amount of bone formed during that period can be calculated from the distance between the double bands of tetracycline fluorescence labels during histomorphometric evaluation. ^{[3, 4]}

Tetracycline markers viewed under fluorescent light reveal luminescent yellow-green bands within the bone. The separate dual bands indicate active mineralization of the new bone.

A number of different types of tetracycline compounds can be used, and each will fluoresce a different color. Tetracycline and demeclocycline are the most commonly used agents. The intensity of the label depends on the medication dosage. Tetracycline dosage for adults is 500 mg orally (PO) twice daily or 250 mg PO three times daily. Demeclocycline can be given 300 mg PO twice daily. ^{[3, 4]}

Several protocols for double tetracycline labeling exist, but the principle is to allow a certain amount of time between the two courses of the medications. A typical labeling schedule requires two 2-day or 3-day periods of tetracycline labeling, separated by a gap of 10-14 days between the two courses of tetracycline. Preferably, two different types of tetracycline compounds should be used. The second labeling should be completed 2-5 days before the biopsy.

The following is an example of a possible labeling schedule:

• Days 1-3 - First label, with tetracycline 250 mg PO three times daily (or 500 mg PO twice daily) for 3 days
• Days 4-13: No treatment (this period may sometimes extend for up to 14 days)
• Days 14-16 - Second label, with declomeclocycline 300 mg PO twice daily for 3 days
• 2-5 days after the last dose - Bone biopsy

The medication is usually administered after meals to avoid gastrointestinal discomfort. The dairy products and aluminum-containing antacids will interfere with adequate absorption and binding of tetracycline. Patients should be instructed to avoid milk and dairy products, as well as calcium-containing binders, for 2 hours before and after medication. Avoiding sun exposure while taking tetracycline prevents skin photosensitivity.

The patient should adhere strictly to the medication dosing and schedule to prevent problems in interpretation of the dynamic histomorphometry.

Complication prevention

The biopsy should be performed in a procedural room that is prompted to monitor a sedated patient during the procedure as well as in the recovery period. If moderate-to-deep sedation is required, medications should be administered by trained and credentialed personnel. ^{[3, 20]}

In hemodialysis patients, bone biopsy should not be performed on the dialysis day in order to avoid hematoma and bleeding from heparin exposure.

Peritoneal dialysis patients should be advised not to have a day dwell of dialysis fluid on the day of the biopsy. They should also be instructed to decrease the dialysate dextrose concentration the night before the biopsy; this helps prevent hypotensive episodes in the relatively dehydrated postdialysis patients.

Careful hemostasis during the procedure is required, particularly in patients with suspected bone tumors, because many tumors are hypervascular and can bleed profusely.