While many clinicians are familiar with primary osteoporosis, this author offers a closer look at a variety of secondary causes that may trigger the development of the disease in women and men.

More than 44 million people in the United States, which includes 55 percent of the people 50 years of age and older, currently have or are at risk for osteoporosis. Annual expenditures for direct medical care of osteoporotic fractures in the United States exceed $17 billion. Early diagnosis can prevent or greatly reduce the risk of osteoporosis-related fractures. However, for many patients, the disease is not diagnosed until a fracture has already occurred.^1,3
       While there are approximately 30 million women who have or are at risk for osteoporosis, more than 14 million men are vulnerable as well. Clearly, osteoporosis is not a disease that solely affects women. There is a significant risk of osteoporosis for people of all ethnic backgrounds. At least 72 percent of non-Hispanic white and Asian women, 40 percent of non-Hispanic, African-American women, and 59 percent of Hispanic women over the age of 50 either have osteoporosis or are at risk with low bone mass.
       The estimates also show that up to 30 percent of women and 64 percent of men diagnosed with osteoporosis have a secondary cause.^1-4
       Osteoporosis can be classified as primary or secondary osteoporosis. One may diagnose primary osteoporosis when other disorders known to cause osteoporosis are not present. Primary causes can be either age-related bone loss or bone loss due to an unknown cause (idiopathic). Idiopathic osteoporosis may occur in men less than 70 years old or in pre-menopausal women when no secondary cause is apparent.^4,5
       Secondary osteoporosis results from a specific clinical disorder or medication known to cause bone loss. One should consider this diagnosis in a patient who presents with a fragility or low trauma fracture or with a low T-Score on bone mineral density (BMD) testing.^5,6

A Guide To Initial Screening Considerations

Recommendations for BMD testing vary. The National Osteoporosis Foundation (NOF) recommends bone mineral testing for all women aged 65 and older regardless of risk factors; younger postmenopausal women with one or more risk factors (such as low body weight, family history, etc); and any postmenopausal woman with a fracture.⁷ The International Society for Clinical Densitometry (ISCD) includes the NOF recommendations but also emphasize testing of the following adults:

• any adult with a fragility fracture;
• men aged 70 and older;
• adults with a disease or condition associated with low bone mass or bone loss;
• adults taking medications associated with low bone mass or bone loss; and
• anyone being treated for osteoporosis to monitor treatment effect.

Once one has diagnosed osteoporosis, whether it is via a low T-Score on BMD testing or the presence of a fragility/non-traumatic fracture, a thorough evaluation is warranted. Accordingly, clinicians should obtain a complete history and physical, height assessment and baseline laboratory tests. One should also obtain a medication history from the patient and whether he or she uses alcohol. In some cases, spinal imaging may be indicated to assess for vertebral fractures. Clinicians should consider more extensive testing in men or in premenopausal women to rule out secondary causes.^2-6

A Review Of Potential Secondary Causes Of Osteoporosis

Secondary causes of osteoporosis can be due to certain medical conditions, diseases or medications. (See the sidebar “What Conditions Are Associated With Bone Loss And/Or Secondary Osteoporosis?”) It is estimated that 50 percent of all cases of secondary osteoporosis are the result of medications. These medications include glucocorticoids, anticoagulants (heparin), anticonvulsants, cytotoxic drugs, GnRH agonists, immunosuppressants, lithium, methotrexate, thyroxine, tamoxifen, aromatase inhibitors and long-term heparin use.
       Contributing lifestyle factors include poor diet, inadequate dietary calcium and vitamin D, and immobilization.
       Clinicians should consider secondary osteoporosis in any patient, man or woman, with a fragility fracture or with a reduction in BMD.

Causes Of Osteoporosis In Women: What You Should Know

The majority of women with osteoporosis have primary osteoporosis. The most common cause of primary osteoporosis in women is a loss of estrogen following menopause. According to the guidelines of the American Association of Clinical Endocrinologists (AACE), evaluation for postmenopausal osteoporosis should include:

1) a comprehensive medical examination including height measurement;
2) assessment of risk factors for fractures; and
3) BMD measurements in younger postmenopausal women who have risk factors, and in all women 65 years and older.

       A thorough medical exam and history is necessary to identify potential medical conditions that may cause or contribute to bone loss. The exam should include assessing for any height loss and/or changes in posture, nutrition, and calcium and vitamin D intake. The AACE recommends baseline laboratory tests for women with osteoporosis, even in the absence of other clinical indications.^6-8
       Secondary causes of osteoporosis in women include the aforementioned medical conditions (see the sidebar “What Conditions Are Associated With Bone Loss And/Or Secondary Osteoporosis?”) and medications such as those used to treat RA. Indeed, some women develop the onset of RA and start glucocorticoid treatment prior to reaching menopause and very likely arrived at menopause with resultant low bone mass or even osteoporosis. Performing a low BMD test prior to menopause would likely show a secondary cause of osteoporosis before the loss of estrogen adds to that loss and further lowers a patient’s T-score on BMD testing. Contributing lifestyle factors for either primary or secondary osteoporosis in women include family history, low body weight and poor or inadequate calcium and vitamin D intake.^4,6

What Conditions Are Associated With Bone Loss And/Or Secondary Osteoporosis?(4)

- Autoimmune • Lupus • Ankylosing spondylitis • Rheumatoid arthritis Endocrine • Hyperthyroidism • Hyperparathyroidism • Insulin Dependent Diabetes • Cushing’s • Thyrotoxicosis Hematologic Disorders • Hemophilia • Leukemias and lymphomas • Multiple myeloma • Sickle cell disease • Thalassemia Malabsorption Syndromes • IBS • Celiac Disease • Gastric restrictive surgeries Hypogonadal • Androgen insensitivity • Hypogonadism • Anorexia nervosa • Athletic amenorrhea • Premature ovarian failure Genetic Disorders • Cystic Fibrosis • Goucher’s Disease • Marfan’s Syndrome • Osteogenesis imperfecta • Idiopathic hypercalciuria Others • Alcoholism • CHF • Depression • Emphysema • End stage renal disease • Epilepsy • Multiple Sclerosis • Muscular Dystrophy • Immobilization • Neoplastic disease • Vitamin D deficiency

A Closer Look At Contributing Factors To Secondary Osteoporosis In Men

As opposed to women, the majority of men with osteoporosis have secondary osteoporosis. In fact, they have at least one and sometimes more than one cause. The most common causes of secondary osteoporosis in men include glucocorticoid medications, hypogonadism, other immunosuppressive drugs, COPD/asthma, alcohol abuse, anticonvulsant medications, gastrointestinal diseases (celiac disease), hyperparathyroidism, hypercalciuria, osteogenesis imperfecta, thyrotoxicosis, neoplastic disease, immobilization, rheumatoid arthritis, homocystinuria, cystic fibrosis and ankylosing spondylitis.⁹
       Alcohol abuse has been identified as a factor in 15 to 20 percent of men with secondary osteoporosis.^33,34 Hormonal imbalances such as hypogonadism cause significant bone loss and consequently increases fracture risk. This also includes the use of GnRH analogs such as Lupron^® to lower serum testosterone levels in treating prostate cancer.^4,9

When Patients Are On Glucocorticoid Therapy

The most common cause of drug-induced osteoporosis is glucocorticoid therapy. In 1932, Cushing noticed “greatly compressed bodies of the vertebra” of patients with Cushing’s syndrome. In the 1950s, researchers discovered that exogenous steroids, which were used to treat chronic inflammatory conditions, also caused similar bone loss.
       Glucocorticoids adversely affect bone remodeling by decreasing bone formation and increasing bone resorption through direct action on osteoblasts and osteoclasts. Indirectly, glucocorticoid use inhibits calcium absorption through the gut and increases urinary calcium excretion. Significant bone and skeletal fractures can occur within six months of starting therapy.
       Even though the amount of bone loss and fracture risk is related to the dose and duration of glucocorticoid therapy, the highest bone loss is in the initial months of treatment (up to 30 percent in some studies). High doses of glucocorticoids (prednisone > 7.5 mg per day or equivalent) pose the greatest risk. However, one study showed that doses as low as 2.5 mg/day led to significantly increased fracture risk. Even inhaled glucocorticoids, with their lower systemic distribution, also cause a loss of BMD. Medical conditions that may require the use of glucocorticoid treatment include rheumatoid arthritis, osteoarthritis, asthma, lupus and multiple sclerosis.^10-12
       Patients on glucocorticoid treatment should have a BMD test and preventative measures initiated at the start of treatment. According to the American College of Rheumatology (ACR), patients beginning therapy with glucocorticoids (prednisone equivalent of > 5 mg/day) with plans for at least three months of treatment should also begin treatment to prevent bone loss. Treatment should include smoking cessation, alcohol reduction, weightbearing exercises, and calcium and vitamin D supplementation.
       A bisphosphonate is recommended for prevention of osteoporosis or for the treatment of osteoporosis if BMD testing shows a T-Score below -1.0 when one is beginning or when one is in the midst of taking glucocorticoid therapy. Bisphosphonates are the antiresorptive agents of choice to prevent bone loss and/or increase BMD, and to reduce the risk of vertebral fractures, which are the most common fractures incurred by patients on glucocorticoids. One should consider teriparatide (Forteo^®) when BMD is very low or if the patient has new fragility fractures or an inadequate response to bisphosphonates. Clinicians should monitor BMD every six to 12 months during treatment.^10-12
       Other medications associated with bone loss and secondary osteoporosis include anticoagulants, long-term heparin use, anticonvulsants, cytotoxic drugs, GnRH agonists, immunosuppressants, lithium, methotrexate, thyroxine, tamoxifen and aromatase inhibitors.^5,7,13
       Researchers have also shown that medications for use after organ transplant decrease bone loss within six months. Up to 35 percent of people following a heart transplant will have fracture (mostly vertebral fractures) within the first year, even with normal BMD.

A Guide To Laboratory Testing

Baseline laboratory tests should include a complete blood count, erythrocyte sedimentation rate (ESR), calcium and phosphorus total protein, albumin, liver enzymes, alkaline phosphatase, BUN and creatinine, TSH parathyroid hormone, intact celiac panel (serum transglutaminase ab), electrolytes, 24-hour urinary calcium excretion serum vitamin D (25 OH Vitamin D). When it comes to more specific laboratory tests for diagnosing individual disease processes, clinicians may utilize total and free serum testosterone (for men), serum prolactin, estradiol, LH, FSH PTHrp bone specific alkaline phosphatase, 24-hour urine cortisol serum and/or urine protein electrophoresis.^6-8
       Patients with elevated serum calcium levels should have a serum intact parathyroid hormone (PTH) measurement. An elevated or high serum PTH value associated with hypercalcemia indicates the presence of primary hyperparathyroidism. A low or undetectable PTH value associated with hypercalcemia necessitatesfurther evaluation including serum electrophoresis. Low serum calcium levels, especially with low serum phosphorus and elevated alkaline phosphatase levels, suggest the presence of overt vitamin D deficiency resulting in osteomalacia.
       When there is increased urinary calcium excretion greater than 300 mg/day (hypercalciuria), one may consider this idiopathic in the absence of other abnormal findings. Decreased urinary calcium of less than 100 mg/day and with normal serum calcium may be an early indicator of vitamin D deficiency or inadequate dietary calcium and vitamin D intake.
       When it comes to men with osteoporosis or a high risk of osteoporosis, clinicians should test for a low serum testosterone level and follow this with serum prolactin and LH to rule out primary gonadal failure or pituitary disease. In regard to premenopausal women, one should utilize serum prolactin, estradiol, FSH and LH to rule out pituitary disease.^8-10

What About Osteoporosis In Children?

- Osteoporosis is rare in children and adolescents. When it does occur, it will most likely be due to a secondary cause. Juvenile osteoporosis can be a significant problem since it occurs during the prime bone building years. Secondary causes of juvenile osteoporosis include juvenile rheumatoid arthritis (Still’s disease), diabetes, osteogenesis imperfecta, thyroid disorders, Cushing’s disease, malabsorption, anorexia nervosa, kidney disease and certain medications.6

Final Notes

When one diagnoses a person with low bone mass or has a fragility fracture, additional evaluation is indicated to rule out a secondary cause that may be responsible for contributing to the bone disease. At least 30 percent of women and 64 percent of men who have osteoporosis have a secondary disorder that has caused the bone loss. Certain medications account for nearly 50 percent of all secondary osteoporosis cases with glucocorticoids being the most common.
       If clinicians do not identify and treat underlying causes, standard osteoporosis treatments such as bisphosphonate medications will be insufficient to maintain bone mass and bone density and decrease fracture risk. Clinicians should monitor BMD at least yearly for anyone they are treating for osteoporosis or anyone who has a high-risk secondary cause of osteoporosis such as undergoing glucocorticoid treatment.

       Ms. DeNoia is a board-certified adult nurse practitioner with a special interest in osteoporosis. She provides primary care for patients in a multi-specialty group, Riverview Medical Associates, in Tinton Falls, N.J. She is also the Geriatric Nurse Educator for the long-term care facilities of Meridian Quality Care in Wall, N.J.