At a Glance

Osteoporosis is diagnosed by fractures in the absence of trauma, frequently vertebral fractures in postmenopausal women. Femoral fractures are frequently fatal osteoporotic events in older people, and preventative diagnosis and treatment to avoid this is now standard of care.

Low bone mass, or osteopenia, can lead to osteoporosis and should be diagnosed before fractures occur, since effective therapy is available. Perimenopausal and postmenopausal women older than 40 years of age are at risk for osteoporosis. In the first 2-3 years of menopause, rapid bone loss occurs with low estrogen and high follicle stimulating hormone (FSH), both of which drive bone resorption. Osteoporosis is most common in Caucasian and Asian women, but it is not rare in African-American women and, since dual excitation X-ray absorptiometry (DEXA) has no risk, determining bone density in all perimenopausal women is recommended. Note, however, that at advanced age there is significant risk of osteoporosis in men.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

The most specific test for osteopenia is DEXA, which is typically performed at point of care by a specialist handling osteoporosis routinely or by radiology.

However, laboratory tests are important in supporting diagnosis and treatment in many instances. These include, most commonly, determination of menopausal status, by measuring estrogen, and FSH. Results consistent with peri- or postmenopause (e.g., period of rapid bone loss) guide the decision to initiate anti-resorptive therapy (estrogen < 200 pM and FSH > 40 IU/L).

The common and effective therapy is bisphosphonate treatment. However, this is contraindicated in patients with low blood calcium (bisphosphonates bind to bone mineral and reduce bone resorption). For this reason, it is useful to determine calcium levels in the work-up of osteopenia and osteoporosis. Patients with ionized calcium less than 1.1 mM or less than 4.5 mg/dL should not receive bisphosphonate.

Follow-up tests include DEXA to follow improvement with bisphosphonate therapy; significantly increased bone mass may be seen as soon as 6 months, and, by 2 years, 6-8% improvement of bone mass is typical.

Other available therapy includes hormone replacement (HRT) and intermittent parathyroid hormone (PTH). In HRT, estrogen measurement may be useful to indicate therapeutic effect; HRT is more commonly used for a short interval during menopausal symptoms, rather than for long-term management of osteopenia because of relatively poor efficacy relative to bisphosphonates and concerns about side effects of long-term HRT.

Osteopenia and osteoporosis occur much later in men than in women, but the same absolute bone density and the fracture risk is similar in both sexes. Men tend to reach the threshold for fracture about 2 decades later, since men have a higher mean peak density during development and are not subject to the perimenopausal bone loss that occurs in women. But both sexes have a similar rate of bone loss otherwise in aging because of metabolic factors not fully understood but that include the slow decline in renal function with age.

When osteoporotic fracture does occur in men, typically in the ninth decade, outcomes are very poor, with very high hip fracture mortality. Overall, about 30% of fatal non-traumatic hip fractures occur in men. Thus, although there is not historical emphasis on diagnosis and preventative treatment of osteopenia in men, a diagnostic DEXA, if therapy might be instituted in consideration of overall health, should be considered in men older than 70 years of age. In younger men, osteoporosis is generally a secondary problem due to defined health problems not relevant to a general discussion of age-related osteoporosis, but a test that is useful in evaluating fracture with minimal trauma in younger men not associated with a defined entity is testosterone. Low testosterone is a risk factor for bone loss, as well as having other negative effects, and it is easily treatable.

It is common practice to determine 25-hydroxyvitamin D, although outcomes relative to vitamin D levels are controversial and vitamin D2 (primarily dietary) has approximately one-half the potency of vitamin D3. In elderly patients without sun exposure, vitamin D treatment improves outcomes and empirical vitamin D treatment is often used, as it is inexpensive, not harmful, and sometimes helpful.

Usually, serum (or urine) calcium and phosphate are not useful, although these might be important in unusual causes of low bone density.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Factors that affect determination of menopause include hormone replacement therapy; therefore, a good history is essential in interpretation of serum estrogen.

What Lab Results Are Absolutely Confirmatory?

Direct confirmatory tests are unnecessary, as DEXA or related tests are definitive.

Testing for complications of therapy may be useful in some cases.

Hypocalcemia is a recognized complication of bisphosphonate therapy, and following calcium activity (ionized calcium) may be useful. Bisphosphonate-induced hypocalcemia occurs stochastically (randomly), without clear association with the amount of bisphosphonate burden on the skeleton and may reflect subclinical nutritional or vitamin D deficiencies unmasked by the bisphosphonate, which reduces bone resorption rate. Hypocalcemia is rare but does occur with standard protocols for osteoporosis prevention, although, in bisphosphonate treatment of hyper-resorptive diseases, it is an important consideration.

Bisphosphonate therapy is a classic example of more not being better, but it is not practical to measure bisphosphonates in the blood (only trace levels are found in blood, except during and immediately after intravenous administration, and clinical tests are not available), so following empirical protocols is advisable.

In addition, there are no tests to determine toxic levels of bisphosphonates in bone or bone burden, although osteonecrosis (typically of the jaw) indicates that this threshold has been passed. Bisphosphonates accumulate on bone, and improvement of outcomes is documented for treatment of 2-2.5 years, after which bone bound bisphosphonate is generally adequate. Neither higher doses nor longer therapy are documented to be useful after that time, and, with long-term therapy, there is a risk of osteonecrosis. Although it is impossible to discontinue bisphosphonate treatment because of its long half-life (decades), one can stop adding to the body’s drug burden. A bone biopsy after prolonged bisphosphonate administration may be useful. It often shows abnormal osteoclastic activity on bone cortex (not normally resorbed) and may show giant Paget’s disease-like osteoclasts, indicating toxic effects.