Complete blood count (CBC) tests can detect anemia, which can be seen in many secondary causes of osteoporosis; these include celiac sprue and other malabsorptive states, chronic liver disease, chronic kidney failure, metastatic bone disease, and multiple myeloma.

To ensure that occult renal insufficiency is detected among elderly patients, calculation of glomerular filtration rate (GFR) must be done (www.nephron.com; Table 5.1). Renal insufficiency often leads to a deficiency in 1–25 OH vitamin D deficiency and secondary hyperparathyroidism, which must be addressed prior to initiation of osteoporosis therapy. Kidney Disease Outcomes Quality Initiative or KDOQI guidelines (Table 5.2) outline parathyroid hormone (PTH) goals for various levels of renal dysfunction. Furthermore, bisphosphonates are contraindicated when GFR falls below 30 mg/24 hours. However, Miller reported the risedronate could be safely used even among those with GFR below this cut-off. In a post hoc review of the Vertebral Efficacy with Risedronate Therapy (VERT) data, adverse events and renal function related side effects were not different between risedronate and placebo, regardless of renal function [(1]. Bisphosphonates are not FDA approved for patients with advanced renal disease.

An alanine aminotransferase (ALT) test is the most cost-effective way to screen for liver disease among osteoporotic patients. Elevated ALT levels suggest liver dysfunction, which, regardless of the cause, increases the risk of vitamin D deficiency.

Patients with low albumin levels will have falsely low serum calcium concentrations. Correction of serum calcium level must be done when patients have low or high albumin concentrations (Table 5.1). This formula, however, sometimes leads to incorrect results, and it is more reliable to order an ionized calcium for confirmation. A small proportion of patients with mild primary hyperparathyroidism may have normal corrected calcium and mildly elevated ionized calcium.

It must be noted, however, that vitamin D and calcium deficiency usually leads to hypocalcemia only when the deficiency is severe. Hypocalciuria (to be discussed in this chapter) occurs sooner and is by far more common among those with mild to moderate deficiencies.

Phosphorus is an essential component of bone formation, as calcium phosphate is the primary substance in bone. Serum phosphorus must be part of the initial evaluation of osteoporotic patients or patients with low bone mass. The more common causes of low phosphorus concentrations include vitamin D deficiency, primary hyperparathyroidism, hypophosphatemic rickets, and nutritional deficiency (rare). Hyperphosphatemia is seen in chronic renal failure and hypoparathyroidism, and is one of the biochemical findings in hypophosphatasia.

Vitamin D deficiency is very common among patients with low bone mass and osteoporosis, with recent reports of 30% to 50% prevalence [2, 3,4]. As the storage form of vitamin D in the body, 25-OHD provides the most accurate assessment of vitamin D reserve. Measurement of 1–25-OHD can be misleading, since the levels may be high or high-normal in early stages of vitamin D deficiency due to upregulation of 1α hydroxylation by PTH.

In the past years, assay variabilities have led to some confusion about the correct interpretation of 25-OHD, with some reference labs reporting normal levels as low as 10 ng/mL. Studies have shown that when 25-OHD levels fall below 30 ng/mL, PTH levels start to rise, suggesting that 30 ng/mL differentiates an insufficient from a vitamin D–replete state [5, 6]. Those with levels below 15 ng/mL to 20 ng/mL are frankly deficient. Some patients with this level or lower may even have osteomalacia, and this needs to be established prior to initiation of osteoporosis therapy.

It is not uncommon to see 25-OHD levels between 20 ng/mL and 30 ng/mL without concomitant secondary hyperparathyroidism. It is recommended that these levels be addressed, regardless of the presence or absence of secondary hyperparathyroidism, and for optimum bone health, one must aim to keep these levels at or above 30 ng/mL.

It is important to note that in patients with primary hyperparathyroidism, PTH increases 1α hydroxylase activity, which could lead to low 25-OHD and high-normal 1–25-OHD levels. However, concurrent vitamin D deficiency may be found among patients with primary hyperparathyroidism [7], but there is no consensus as to whether low 25-OHD states should be treated prior to parathyroidectomy, as hypercalcemia may worsen. The author recommends repeating the 25-OHD 6 to 8 weeks after parathyroidectomy to establish the patient’s new levels. If patients are not candidates for surgery, careful replacement can be undertaken, with frequent monitoring of serum and urinary calcium levels to ensure that hypercalcemia and hypercalciuria do not worsen.

Intact parathyroid hormone levels are essential in the initial work-up of patients with osteoporosis. An elevation could suggest primary hyperparathyroidism, secondary hyperparathyroidism from deficiencies in calcium or vitamin D or renal insufficiency, and very rarely pseudohypoparathyroidism. An increasing number of patients are also being found to have normocalcemic hyperparathyroidism, that is, elevated PTH with no apparent deficiencies in calcium or vitamin D. These patients likely have very early mild primary hyperparathyroidism.

Recently, a new bio-intact PTH assay has become available that measures the whole PTH molecule and is not affected by fragments that build up during renal failure or insufficiency. The exact utility of the assay is not yet clearly established for osteoporosis patients but can be helpful among renal patients.

The value of the 24-hour urine calcium and creatinine test tends to be underestimated in the work-up of osteoporosis. First and foremost, in order to ensure complete collection, it is important that patients are given detailed instructions and be made aware of the importance of the test. When urine is properly collected, urinary calcium excretion provides valuable information that can increase one’s success in treating osteoporosis. The normal range quoted in the literature varies. In general, 1.5 to 3 mg/kg/24 hours provides a good estimate of normal urinary calcium excretion [8]. Most calcium and vitamin D–replete adults would fall between the levels of 150 mg and 300 mg/24 hours. Those who have values between 100 mg and 150 mg usually have mild degrees of calcium and vitamin D deficiency, which may be corrected by increasing elemental calcium intake to 1,200 to 1,500 mg/day and 800 IU of vitamin D per day. A level below 100 mg/24 hours is considered low.

Differentials for hypocalciuria include malabsorptive states such as celiac sprue, nutritional vitamin D and calcium deficiency, renal insufficiency, use of thiazide diuretics, and benign familial hypocalciuric hypercalcemia. Some individuals who have celiac sprue may have hypocalciuria with normal 25-OHD levels. This is usually associated with secondary elevation in PTH. Individuals who are found to be hypocalciuric should have their celiac antibodies tested, and if negative, duodenal biopsy should be done, because there are seronegative celiac patients [9,10]. Other malabsorptive disorders, such as inflammatory bowel disease (IBD), and bacterial overgrowth should be considered when work-up for celiac disease is negative.

On the opposite end of the spectrum, hypercalciuria (>300 mg/24 hours) may be due to aggressive calcium supplementation, vitamin D toxicity, use of loop diuretics, primary hyperparathyroidism, or idiopathic hypercalciuria. The first two conditions can usually be differentiated from the last based on the PTH levels. PTH is usually low-normal or suppressed when there is excess of calcium and vitamin D supplementation, whereas PTH is usually normal among patients with idiopathic hypercalciuria.

When malabsorption is suspected, celiac antibodies should be obtained. A panel consisting of transglutaminase antibodies, anti-gliadin, or anti-endomysial antibodies may detect the presence of celiac disease. Given biochemical findings suggestive of malabsorption, positive antibody testing may not require a duodenal biopsy before the necessary intervention. These levels can be falsely low when patients are already on a gluten-free diet.

A significant proportion of patients with celiac disease are sero-negative, and relying on positive celiac antibodies may lead to underdiagnosis [9,10]. These individuals should be referred to a gastroenterologist for a duodenal biopsy and evaluation for other malabsorptive conditions. Sero-negative patients often have milder disease and partial rather than complete villous atrophy.

Hyperthyroidism and subclinical hyperthyroidism have both been shown to cause accelerated bone resorption [11, 12, 13, 14, 15,16]. Since most osteoporotic patients are elderly, the incidence of asymptomatic or apathetic hyperthyroidism is much higher. Clinical signs and symptoms will not suffice in ruling out hyperthyroidism, and thus, it is important to obtain a thyroid-stimulating hormone (TSH) level.

These should be ordered when dealing with male osteoporosis, or when bone loss in a woman appears to be advanced or inappropriate for her age. Although multiple myeloma has other clinical features, its initial presentation can also be solely as low bone mass.

Males with osteoporosis are more likely to have secondary causes of bone loss than women. One of the most common causes is hypogonadism, which may present asymptomatically. Free testosterone panel [includes total, sex hormone globulin (SHBG), free and weakly bound testosterone] at 8:00 a.m. provides an accurate screen for hypogonadism among males. If levels are low, luteinizing hormone (LH) and/or follicle-stimulating hormone (FSH) levels must be obtained to determine the etiology.

One must be vigilant for mild cases or subclinical Cushing disease, which could lead to bone loss and yet have very subtle clinical findings [17]. When clinically indicated, screening for Cushing disease should be done with a 24-hour urine free cortisol and creatinine