Osteoporosis, an insidious degeneration of bone tissue, afflicts approximately 250 million individuals worldwide and is responsible for more than 1.5 million fractures annually. This "silent" disease, which usually affects trabecular bone of the hip, vertebra, wrist and other regions, often occurs without overt symptoms, making its presence known only after a light physical task leads to a spontaneous fracture. Statistics indicate that the debilitating, disfiguring and sometimes fatal condition poses a serious and growing public health threat.

The bone loss factor
Minimizing one's risk of osteoporosis in later years is contingent on maximizing peak bone mass during the bone-building years (up to age 25 or 30). Approaching middle age, the metabolic balance shifts so that slightly more bone is resorbed than formed, resulting in an annual 1 percent decline in bone mass for both men and women after age 35 to 40. At menopause, bone loss in women generally increases to approximately 2 percent per year, but nearly 35 percent of perimenopausal women lose bone at a much higher rate.¹ These women fall into a category of high-risk individuals called "rapid losers"—individuals who experience bone loss at a rate of 3 to over 5 percent annually.

Although a slow decline in bone mass is a natural part of aging, the accelerated bone loss of "rapid losers" will result in the swift onset of low bone density and architectural bone deterioration that characterize osteoporosis. Consequently, osteoporosis is predominantly a disease of menopausal women. According to results of the National Osteoporosis Risk Assessment (NORA) study, nearly half of the 200,160 postmenopausal women assessed were at increased risk of breaking a bone. Seven percent of subjects were actually osteoporotic, and almost 40 percent were found to have low bone mass, suggesting that these individuals were destined for the same fate.

While the marked bone loss of menopause puts women at greater risk for osteoporosis earlier in life, men will eventually lose enough bone mass, albeit more gradually, to place them at high risk for fractures as well (Figure 1). As the population ages and longevity increases, the sheer numbers of elderly women and men affected by this disease are headed for dramatic increases. In addition to the personal costs due to reduced quality of life, osteoporosis could add more expenses to already burdened healthcare systems. Currently, in the US alone, direct expenditures for osteoporotic fractures are estimated at $13.8 billion per year.² Fortunately, this condition can be treated successfully if diagnosed early enough.

Those at highest risk
Besides the estrogen deficiencies of menopause, some other conditions that can cause significant increases in bone loss include hyperthyroidism, hyperparathyroidism, type I diabetes, Cushing's syndrome, renal disease, anorexia nervosa and conditions that cause intestinal malabsorption. In addition, several therapeutic drugs have been associated with increased bone loss, especially androgen deprivation therapy (prescribed for men with prostate cancer), thyroid replacement agents, glucocorticosteroids (for conditions such as asthma and rheumatoid arthritis), anticonvulsants (for epilepsy and other disorders), heparin, lithium, immunosuppressive agents and cholestyramine.

Lifestyle factors such as smoking, excessive alcohol consumption, inactivity and a poor diet also increase the risk of osteoporosis. All other factors aside, individuals at highest risk tend to be women with small frames who are of Caucasian or Asian descent, and those with a genetic predisposition as indicated by their family history.

Among men, 30 to 60 percent of osteoporosis is associated with secondary causes, the most common being hypogonadism, glucocorticoids and alcoholism. In perimenopausal women, more than 50 percent of cases are due to secondary causes, the most prevalent being hypoestrogenemia, glucocorticoids, excess thyroid hormone administration and anticonvulsant therapy.

Diagnosis and lab assessment
Statements from the NIH Consensus Development Conference in March of 2000 acknowledge the potential value of diagnosing and treating osteoporosis using risk-based assessment rather than relying solely on a bone mineral density (BMD) score,³ a measurement of bone mass derived from bone densitometry methods such as dual-energy X-ray absorptiometry (DXA). Consideration of risk factors in conjunction with BMD may potentially improve the ability to predict fracture risk; but this approach has not been validated in prospective studies or tested in appropriate randomized clinical trials.

A growing number of practitioners are conducting individual osteoporosis evaluation and future risk assessment by analyzing bone turnover in addition to measuring bone mass. While bone densitometry provides a visual snapshot of current bone mass status, assays for bone turnover markers in the blood or urine can measure rates of bone formation or resorption, dual processes that comprise the bone remodeling cycle. Common markers of bone formation include bone-specific alkaline phosphatase and osteocalcin (bone Gla-protein), a component of noncollagenous bone protein. Markers of bone resorption include urinary deoxypyridinolines (DPD), urinary pyridinolines (PYR), and serum or urinary C- and N-telopeptides.

Among the markers of bone resorption, DPD is notable for its specificity and reproducibility, as it is almost exclusively in bone collagen and cannot be recycled for new collagen synthesis. PYR, by contrast, is found in a variety of tissues and is, therefore, less bone specific. The correlation between bone resorption and DPD has been demonstrated by histomorphometry and radioisotopic techniques. Measurement of urinary DPD has also been demonstrated to correlate with bone loss as measured by changes in BMD. A direct byproduct of bone degradation, DPD is released into the circulation, cleared by the kidneys and excreted, unmetabolized, into the urine. It exhibits a much lower day-to-day variability than do C- or N-telopeptides.

Who should be evaluated?
NIH consensus statements reflect general agreement that evaluation should be considered in patients receiving glucocorticoid therapy for 2 months or more and in patients with other conditions that place them at high risk for osteoporotic fracture.⁴ Although the merit of early osteoporosis detection is evident, the value of universal screening, especially in perimenopausal women, has not been established.

Currently, an individualized approach is recommended. Physicians recognize the importance of identifying at-risk individuals who are experiencing elevated levels of bone loss or already have diminished bone mineral density, as this will dictate therapeutic interventions.

Therapy
Several therapeutic approaches are available for the prevention or treatment of osteoporosis. Among them are antiresorptive agents such as calcium, hormone replacement therapy (HRT), calcitonin, bisphosphonates, calcitriol and vitamin D metabolites. In addition, a number of bone formation-stimulating agents are under investigation, including sodium fluoride, parathyroid hormone and growth factors.

Well-defined guidelines for optimal treatment duration have yet to be established. Depending on the individual, therapy, once initiated, could require lifelong adherence. It was previously thought that the rate of bone loss in women peaks during menopause and diminishes in the years that follow, but research indicates that rates of bone turnover remain elevated into old age, and that bone loss in the elderly may actually accelerate.⁵

Is there any hope for elderly osteoporosis sufferers diagnosed late in life? Encouraging findings from recent studies have shown that initiating therapy long after the perimenopausal years can still reverse bone loss to a limited degree. One clinical trial, in which hormone replacement therapy was initiated in frail, elderly women (aged 75 and older), resulted in bone mineral density increases of 4.3 and 1.7 percent in the lumbar spine and hip, respectively, after only nine months of treatment.⁶ This good news should be tempered by the knowledge that prevention is far better than treating late-stage disease.

Since current osteoporosis therapies inhibit bone turnover by decreasing bone resorption, baseline and follow-up measurements of bone turnover markers may be particularly useful in therapeutic monitoring.

Conclusion
Although osteoporosis appears to be on the rise in an ever-growing elderly population, it doesn't have to be an inevitable part of aging. Its ravages are avoidable, thanks to improved diagnostics and therapeutic treatments. One of the primary challenges still facing the medical community is the establishment of effective, cost-efficient protocols for early detection. Even with today's therapeutic advances, the possibility of an impending public health crisis may yet unfold, but current technology and greater awareness may be all that are needed to put the brakes on osteoporosis.

References
1. Christiansen C, Riis BJ, Rodbro P. Prediction of rapid bone loss in postmenopausal women. Lancet 1987;1(8542):1105-8.

2. Ray NF, Chan JK, Thamer M, Melton LJ 3rd. Medical expenditures for the treatment of osteoporotic fractures in the United States in 1995: report from the National Osteoporosis Foundation. J Bone Miner Res;12(1):24-35.

3. Osteoporosis prevention, diagnosis and therapy. NIH Consensus Statement Online 2000 March 27 - 29; 17(1): 1- 36. http://odp.od.nih.gov/consensus/cons/111/111_statement.htm (accessed 2002 Jan, 9).

4. Osteoporosis prevention, diagnosis and therapy. NIH Consensus Statement Online 2000 March 27 - 29; [2002, Jan, 9] 17(1): 1- 36.

5. Ensrud Ke, Palermo L, Black DM, Cauley J, Jergas M, Orwoll ES, et al. Hip and calcaneal bone loss increase with advancing age: longitudinal results from the study of osteoporotic fractures. J Bone Miner Res 1995;10(11):1778-87.

6. Villareal DT, Binder EF, Williams DB, Schechtman KB, Karasheski KE, Kohrt WM. Bone mineral density response to estrogen replacement in frail elderly women: a randomized controlled trial. JAMA;286(7):815-20.