Diagnosis and evaluation of patients with osteoporosis.

Osteoporosis is a silent condition characterized by reduced bone mass and abnormal bone architecture, with an associated increase in the risk of fractures. It affects approximately 44 million Americans. The cost (in 1995) was approximately $14 billion. Of the 1.5 million osteoporotic fractures in the United States each year, vertebral fractures are the most frequent, about 750,000 annually. Hip fractures are the most serious. Between 10 and 20% of each year's 250,000 hip fracture victims die within one year of their fracture, approximately a quarter to a third of the survivors become permanent nursing home residents, and only about half are able to return fully to independent living.

Bone Density Measurement

Low bone mass is the most important risk factor for osteoporosis. Bone mineral density (BMD) is commonly expressed as a T score, which compares the BMD of an individual with the mean value for a young healthy subject. Also used is the Z score, which compares the BMD of an individual with the mean value for age-matched controls. Fracture risk can be assessed with techniques that measure bone density at peripheral sites (eg, wrist, forearm, heel), but the current standard is dual-energy x-ray absorptiometry (DXA) of the spine and hip, which can be used for diagnosis with the World Health Organization criteria, and is the only technique suitable for monitoring patients over time. Each standard deviation reduction in bone mass indicates an increase in the risk of fracture by 1.5 to 2.5 times. Risk factors for low bone mass cannot be used to decide who should or should not have a BMD test. The National Osteoporosis Foundation recommends bone density testing for all women age 65 and older, and for younger postmenopausal women who have clinical risk factors (eg, family history of osteoporosis, personal history of low-trauma fracture after age 45, current cigarette smoker, low body weight [less than 127 pounds]). Medicare covers bone density testing for estrogen-deficient women at clinical risk for osteoporosis, patients with vertebral abnormalities, patients receiving glucocorticoid therapy, patients with primary hyperparathyroidism, and patients being monitored to assess the response to an approved drug.

Biochemical Markers

Biochemical markers of bone turnover may be useful to decide if treatment is needed and to determine the effectiveness of treatment. Markers of bone turnover include bone-specific alkaline phosphatase, osteocalcin, and the collagen cross-links, deoxypyridinoline, C-telopeptide (CTX), and N-telopeptide (NTX).

Osteoporotic Fractures

If the patient has already experienced an osteoporotic fracture, the risk of future fracture is extremely high. Most vertebral fractures are not recognized as discrete clinical events, and many patients who have vertebral fractures on radiograph are not identified. Even patients who have a hip fracture, which almost always requires hospitalization and surgical repair, are not evaluated for osteoporosis. There are DXA machines that can perform lateral spine imaging as one way of identifying patients who have vertebral deformities.

Secondary Causes of Osteoporosis

Osteoporosis in adults is commonly caused by estrogen deficiency (postmenopausal osteoporosis) and aging (senile or involutional osteoporosis). However, bone loss may be secondary to a variety of diseases and conditions such as endocrinopathies, various medications, digestive disorders, marrow-based and neoplastic disorders, hereditary problems, and miscellaneous other conditions. Osteomalacia, although clearly different from osteoporosis, also must be considered.

Endocrinopathies associated with osteoporosis include hypercalciuria (with or without renal stones), hypogonadism (including hyperprolactinemia), hyperparathyroidism, hyperthyroidism, Cushing syndrome, and possibly acromegaly.

Hypogonadism in both women and men is causally related to bone loss. There is a relationship between serum estradiol levels and bone mineral density in men. There are two interesting experiments of nature in this regard. A deficiency of aromatase, the enzyme responsible for converting testosterone to estradiol, leads to a lack of a growth spurt, delayed bone age, unfused epiphyses, continued growth into adulthood, tall stature, high levels of androgens and low levels of estrogens, along with severe osteoporosis that is responsive to estrogen therapy. Estrogen resistance is an autosomally-recessive abnormality affecting the estrogen receptor gene. One male with this condition has been identified, but no females. He had no growth spurt, his bone age was delayed, and his epiphyses did not fuse. He continued to grow into adulthood, was tall, and had genu valgum. Laboratory tests showed high levels of gonadotropins and estrogens, with normal levels of androgens. He had severe osteoporosis with high bone turnover. Estrogen therapy was ineffective.

Drugs associated with osteoporosis include excess glucocorticoids and excess thyroid hormone, drugs used in organ transplantation, anticoagulants (heparin, possibly coumadin), GnRH antagonists, medroxyprogesterone acetate, retinoic acid derivatives, anticonvulsants, tetracycline, aluminum-containing antacids, cyclosporine, rifampin, exchange resins, fluoride, etidronate, alcohol, and possibly loop diuretics.

Digestive disorders associated with osteoporosis include gastrectomy, inflammatory bowel disease, sprue, intestinal bypass surgery, primary biliary cirrhosis, and pancreatic insufficiency.

Marrow-based and neoplastic disorders include multiple myeloma, hemolytic anemia, hemoglobinopathies, myelo- and lympho-proliferative disorders, skeletal metastases (diffuse or localized), Gaucher disease, and mastocytosis. Mastocytosis may involve the skin (urticaria pigmentosa), lymph nodes, bone marrow, liver, spleen, and gastrointestinal tract. It should be suspected if there are skin lesions. It can be diagnosed by measuring serum tryptase or urine histamine metabolites (N-methyl histamine), or by doing a bone biopsy.

Specific genetic disorders associated with low bone mass and fractures include Ehlers-Danlos syndrome, Marfan syndrome, homocystinuria, and osteogenesis imperfecta. Osteogenesis imperfecta (OI) comes in at least four forms. Type I OI patients have normal stature, little or no deformity, and characteristic blue sclerae. Half have hearing loss. Type II OI is lethal in the perinatal period. Type III OI patients have deformities at birth with progressive fractures and deformities. Dentogenesis imperfecta and hearing loss are common in type III OI. Scleral color is variable and lightens with age. Type IV OI patients have normal sclerae, mild to moderate deformity, and variable short stature. Some patients with type IV OI have hearing loss. Dentogenesis imperfecta is common.

Miscellaneous causes of osteoporosis include immobilization, sarcoidosis, and prolonged parenteral nutrition.

Variants of osteomalacia include vitamin D deficiency, renal tubular acidosis, Fanconi syndrome, vitamin D-dependent rickets types I and II, hypophosphatemic vitamin D-resistant rickets, oncogenic osteomalacia, and hypophosphatasia.

Simply because a postmenopausal woman has low bone mass (or a fragility fracture) does not mean her condition is due to age and estrogen deficiency. Postmenopausal osteoporosis is a diagnosis of exclusion. All patients with osteoporosis should have a complete medical and social history, a complete physical examination, and a few tests directed at some of the more common and less clinically obvious underlying causes. The laboratory tests should include serum chemistries (calcium, phosphorus, total protein, albumin, globulin, alkaline phosphatase, liver enzymes, creatinine, electrolytes), a blood count (white blood cell, hemoglobin, hematocrit), and urinary calcium. All men should have serum free testosterone measurements. In selected patients, tests should be ordered, if clinically indicated, to evaluate thyroid function, ovarian status, parathyroid hormone and vitamin D metabolites, and multiple myeloma. Spine radiographs should be done in patients who have height loss, back pain, or spinal deformity. Secondary causes of osteoporosis should be considered in all cases, but looked for with special care in patients who have a low bone mineral density Z score.

Bone biopsy should be considered in patients who have unusual features of osteoporosis, men and young women who have osteoporosis, patients who have very low bone mass, patients who have fragility fractures but normal bone mass, and patients failing conventional therapy.

Accepted March 15, 2004.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9706-0540

References

Adams JS, Song CF, Kantorovich V. Rapid recovery of bone mass in hypercalciuric, osteoporotic men treated with hydrochlorothiazide. Ann Intern Med 1999;130(8):658-660.

Bracker MD, Watts NB. How to get the most out of bone densitometry. Postgrad Med 1998;104:77-86.

Faustini-Fustini M, Rochira V, Carani C. Oestrogen deficiency in men: where are we today? Eur J Endocrinol 1999;140:111-129.

Gelbach SH, Bigelow C, Heimisdottir M, et al. Recognition of vertebral fracture in a clinical setting. Osteoporosis International 2000;11(7):577-582.

Harper KD, Weber TJ. Secondary osteoporosis--diagnostic considerations. Endocrinol Metabol Clin North Am 1998;27(2):325-348.

Jackson JA, Riggs MW, Spiekerman AM. Testosterone deficiency as a risk factor for hip fractures in men: a case-control study. Am J Med Sci 1992;304:4-8.

Kanis JA, Melton LJI, Christiansen C, et al. The diagnosis of osteoporosis. J Bone Miner Res 1994;9:1137-1141.

Klein GL, Coburn JW. Total parenteral nutrition and its effects on bone metabolism. Crit Rev Clin Lab Sci 1994;31:135-167.

Kroger H, Reeve J. Diagnosis of osteoporosis in clinical practice. Ann Med 1998;30:278-287.

Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 1996;312:1254-1259.

Masud T, Francis RM. The increasing use of peripheral bone densitometry--better at assessing fracture risk than diagnosing osteoporosis. BMJ 2000;321(7258):396-398.

Miller PD, Zapalowski C, Kulak CAM, et al. Bone densitometry: the best way to detect osteoporosis and to monitor therapy. J Clin Endocrinol Metab 1999;84(6):1867-1871.

Silverberg SJ, Shane E, Jacobs TP, et al. A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med 1999;341:1249-1255.

Tannenbaum C, Clark J, Schwartzman K, et al. Yield of laboratory testing to identify secondary contributors to osteoporosis in otherwise healthy women. J Clin Endocrinol Metab 2003;87:4431-4437.

Watts NB. Clinical utility of biochemical markers of bone remodeling. Clin Chem 1999;45:1359-1368.

Nelson B. Watts, MD

University of Cincinnati College of Medicine, Bone Health and Osteoporosis Center, 222 Piedmont Avenue, Suite 4300, Cincinnati, OH 45219.

Reprint requests to Dr. Nelson B. Watts, Director, University of Cincinnati College of Medicine, Bone Health and Osteoporosis Center, 222 Piedmont Avenue, Suite 4300, Cincinnati, OH 45219.