New tools for detecting occult monoclonal gammopathy, a cause of secondary osteoporosis

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ABSTRACTMost patients with multiple myeloma or other monoclonal gammopathies present with anemia, hypercalcemia, or renal insufficiency. However, osteoporosis may be the first sign. Measuring the concentration and ratio of free light chains in the serum can help detect monoclonal gammopathy and help to differentiate myeloma-related bone loss from other secondary forms of osteoporosis.


  • Minor back pain can be a symptom of spinal compression fracture.
  • Rapidly declining bone density or a low Z score on dual-energy x-ray absorptiometry suggests that osteoporosis is secondary to another condition.
  • The evidence to date supports the use of bone turnover markers in conjunction with density measurements to ascertain early on whether osteoporosis is responding to treatment, but the use of biochemical markers by themselves to screen for osteoporosis is not encouraged.
  • Standard tests may fail to detect myeloma in the presence of worsening bone density.
  • While serum and urine protein electrophoreses are still the standard screening tests for multiple myeloma, additional testing with serum free light chain analysis should be considered if the suspicion is high.



Sometimes, osteoporosis can be the presenting sign of a monoclonal gammopathy, which in some people may precede a diagnosis of multiple myeloma.1

In this article, we use two cases to illustrate the challenges of detecting monoclonal gammopathies as the cause of secondary osteoporosis. We also discuss the diagnostic limitations of current tests and the advantages of a newer test—measuring the serum levels of free light chains—in the workup of these patients.


A 55-year-old woman develops back pain after walking her dog, and the pain worsens despite treatment with a nonsteroidal anti-inflammatory drug for 1 week.

The patient has a history of well-controlled hypertension. She went through menopause 5 years ago, and about 2 years ago she was started on oral calcium and vitamin D for low bone density. At that time she complained of mild fatigue, which she attributed to working overtime and to lack of sleep.

Figure 1. Case 1. Plain film x-ray of the thoracic spine shows osteopenia of the spinal segments and a T10 wedge compression fracture (arrow).

On physical examination, her back in the area of T10 is tender to palpation, and plain radiography shows a compression deformity there (Figure 1). Over the past 2 years, her bone mineral density—ie, T scores on dual-energy x-ray absorptiometry (DXA)—has decreased 10% in the spine and 6% in the hip.

Laboratory data, other tests

  • Her white blood cell differential count is normal
  • Hemoglobin 11.8 g/dL (normal range 12–15)
  • Serum creatinine 1.0 mg/dL (0.5–1.4)
  • Calcium 8.2 mg/dL (8.0–10.0)
  • Albumin 4.5 g/dL (3.5–5.0)
  • Total protein 5.7 g/dL (6.0–8.4)
  • Serum and urine protein electrophoreses show no monoclonal spike (M-spike) or bands
  • Serum free kappa light chains 5,542 mg/L (normal range 3.3–19.4).

Based on the elevation of serum free kappa light chains, the patient undergoes bone marrow aspiration biopsy. Histologic analysis reveals plasmacytosis (60% of her marrow cells are plasma cells [normal is < 5%]) with kappa light chain restriction.

A complete x-ray survey of the skull and long bones reveals widespread lytic lesions, consistent with multiple myeloma.


An 88-year-old man sees his family doctor because of malaise and back pain. He was treated for bladder cancer several years ago. He is currently being treated for prostatic hyperplasia, hypertension, and arthritis. Spinal radiography shows a compression deformity at T12, for which he undergoes kyphoplasty.

His complete blood cell count, white blood cell differential count, and kidney and metabolic profiles are normal.

Urine protein electrophoresis is normal, but serum electrophoresis detects an M-spike. On DXA of the hip, his T score is −3.7 (normal ≥ −1.0), and his Z score is −2.4 (normal > −2.0); suspicion of a secondary cause may be raised with Z scores of −1.0 or −1.5. The level of urinary NTX (cross-linked N-telopeptide of type I collagen, a marker of bone turnover) is 190 nmol bone collagen equivalents/nmol creatinine (normal range for men < 75), indicating a high level of bone turnover.

A serum free light chain assay shows twice the normal concentration of kappa light chains. The patient is referred for hematologic study and undergoes bone marrrow aspiration biopsy, which shows an abnormally high number of monoclonal plasma cells.


The cases presented above illustrate several key clinical points:

  • Minor back pain can be a symptom of a spinal compression fracture.
  • Declining bone density should raise the suspicion of secondary osteoporosis, as should an abnormally low Z score.
  • Markers of bone turnover are commonly elevated in secondary osteoporosis.
  • Routine laboratory tests often fail to detect multiple myeloma.


Back pain is a very common complaint, and fortunately, most cases are due to benign causes. However, serious causes such as cancer, infection, and fractures must be considered. The topic has been reviewed in detail by Siemionow et al.2

Osteoporotic compression fractures are common in the elderly and are associated with loss of height. They can occur spontaneously or from minimal trauma. The workup can start with plain anteroposterior and lateral radiographs and routine laboratory tests, as in the patients described above. This information, as well as DXA testing, may provide clues that suggest that the osteoporosis is secondary to an underlying problem, or that a coexisting bone condition caused the fracture.

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