Abby Goulder Abelson, MD

Osteoporosis at any age can have devastating  consequences. Fortunately, a number of bone-preserving measures can go a  long way toward preventing this disease--not only in postmenopausal women, but also in young women at high risk.

Bone mineral density (BMD), a key determinant in osteoporotic  fracture in adult women, is a reflection of the peak bone mass attained  in young adulthood and the bone mass lost during the perimenopausal and  postmenopausal years.

 A combination of low bone mass (ie, bone mass below  the 33rd percentile) and the presence of two or more fractures increases  the risk 75-fold, relative to women with the highest bone mass (ie,  above the 67th percentile) and no prevalent fractures.4 This article  addresses several factors influencing bone mass and osteoporosis in both  premenopausal and postmenopausal women.

In healthy adult premenopausal women, bone mass formation occurs at a  similar rate as bone resorption. Osteoblasts, the cells that deposit  osteoid (the bone matrix that becomes bone), are produced at  approximately the same rate as osteoclasts, the multinuclear cells that  resorb bone tissue. 
 When calcium balance is maintained, little or no loss of BMD occurs.  However, because osteoblasts are more sensitive to age-related estrogen  loss than are osteoclasts, the homeostasis of this remodeling cycle  eventually shifts.

 Osteoporosis may result: Bone matrix continues to be  formed, but in amounts that are insufficient to fill the cavities left  by resorption. The trabeculae, which are anchoring strands of connective  bone tissue, become thin and fragile and may fracture. It has been  suggested that the biomechanical competence of the trabecular matrix is  dependent not only on the absolute amount of bone present but also on  the strength of its own microarchitecture.

Most longitudinal and cross-sectional studies have suggested that the pathogenesis of low BMD begins prior to menopause (Table 1).

 For example, vertebral bone has been shown to achieve  peak density between age 28 and 30 in healthy women; the proximal femur  has been shown to gain most of its mass by late adolescence.

  Thereafter, BMD begins its decline. The process accelerates during the 2  years prior to menopause, peaking during the first 3 years of  menopause--when patients may lose 3% to 5% of their bone mass per year.

 Such a trend helps to explain why an untreated 50-year-old woman has a 40% risk of osteoporotic fracture in her remaining lifetime,

 with the risk of fracture rising exponentially with the decline in bone mass.

TABLE 1. Risk Factors for Osteoporotic Fracture

 Each decade associated with 1.4-1.8-fold increased  		risk

 Ethnicity: Caucasians and Asians > Africans and  		Polynesians

 Physical activity and mechanical loading

 Chronic diseases, eg, gastrectomy, cirrhosis,  		hyperthyroidism, hypercortisolism

A study by Goulding and colleagues revealed that, among a group of  premenopausal women, those subjects who had any past history of bone  fracture demonstrated a 6% lower BMD than did subjects who had never  broken a bone.

 Further, women participating in the 1989 Kuopio  Osteoporosis Study who reported fractures between the ages of 20 and 34  demonstrated a hazard ratio of 1.9 for sustaining a subsequent fracture  or fractures between age 35 and 57.

Many premenopausal patients, however, do not report these significant  predictors of osteoporotic fracture to their health care providers.  This is partly due to the commonly held belief that osteoporosis is a  disease of the elderly and does not have to be addressed until the onset  of menopause. Such a misperception keeps physicians and patients  unaware of the association between past and potential future fractures,  and may also prevent diagnosis of a current fracture. Although acute  vertebral fractures can produce functional impairment--and thereby  warrant medical intervention--50% to 70% of vertebral fractures are not clinically  evident, and may be misconstrued by patients as muscle pain in the  abdomen or thorax.

 Furthermore, the patient's inability to  associate current symptomatology with the possibility of subsequent  osteoporosis may not only impede treatment but also preclude preventive  intervention and compliance with therapeutic recommendations.

Clinicians should obtain a patient history that includes details  about osteoporosis in the patient's family members. A patient's risk for  hip fracture has been shown to double if her mother or any first-degree  relative has suffered a hip fracture.3 Further, Ulrich et al  demonstrated a positive intergenerational correlation between the  practice of preventive measures (such as weight-bearing exercise, milk  consumption, and intake of calcium supplements) and peripheral BMD  values of mothers and daughters in their study.

Genetics explain a major proportion of peak BMD; it has been  estimated that 67% of femoral-neck density is accounted for by genetic  factors. Increasing evidence suggests that attainment and maintenance of  peak BMD, as well as bone turnover and bone loss, have strong genetic  determinants. Data analyzed by Willig and associates suggest that  variations in these values are influenced by genetic variations at the  estrogen-receptor locus, both singly and in relation to the vitamin D  receptor gene.

In a study comparing BMD, bone mineral content, and bone size between  prepubertal daughters and their premenopausal mothers, Ferrari and  associates discovered two interesting trends. First, 18% to 37% of such  characteristics were directly determined by maternal descent. Second,  familial resemblance for BMD, bone mineral content, and bone size were  already present between daughters and their mothers before the daughters  reached puberty.

 Thus, premenopausal women may look to their  mothers for indications of decreased bone mass, and reap the benefits of  earlier preventive intervention. 

 Endogenous hyperthyroidism leads to:           

 T4 and T3 directly stimulate bone resorption characterized by:           

 Increased ratio of resorptive to formulation surface

Hyperthyroidism and primary hyperparathyroidism have been associated  with low BMD. The accelerated bone remodeling state presented by  hyperthyroidism (which decreases the length of the remodeling cycle from  200 to 113 days) that is characteristic of exogenous and endogenous  hyperthyroidism leads to increased bone turnover, increased resorption  and resorption sites, decreased bone mass, and decreased intestinal  calcium absorption (Table 2).

In addition, it has been suggested that women who take excessive doses of thyroid hormone,  most notably levothyroxine, for a variety of thyroid disorders have  been shown to lose vertebral bone mass at an accelerated rate, and thus  may have a propensity to sustain fractures at an earlier age.

 Such an association warrants close attention;  certain measures (eg, periodic monitoring of thyroid-stimulating hormone  levels, bone densitometry) may be needed to minimize the occurrence of  overdosing and the potential for long-term complications.

Estrogen deficiency has also been associated with low BMD. Estrogen  plays a pivotal role in the achievement of premenopausal bone mass  levels; estrogen deficiency due to oophorectomy without hormone  replacement contributes to low postmenopausal bone mass and osteoporotic fracture.


 Testing for concurrent low BMD may be appropriate in patients being  treated for infertility due to hypogonadism. Estrogen deficiency in  premenopausal women may induce excessive resorption and result in  reduced peak bone mass. Such a lack of this hormone may be associated  with a variety of conditions, including excessive exercise, anorexia  nervosa, and hyperprolactinemia.


 Use of oral corticosteriods represents the most common drug-related form of osteoporosis.

 Corticosteroids act on multiple routes of  calcium metabolism, thereby increasing calcium excretion. They decrease  the rate of bone matrix synthesis, particularly synthesis of the  trabecular matrix, and increase resorption. Up to 50% of patients of  both genders receiving chronic corticosteroid therapy will sustain fractures.

 In addition, the bone loss may be at its most rapid during the first 6 to 12 months of therapy.

Patients with a history of corticosteroid use or current steroid use  may require bone-density evaluation to determine their need for  treatment or prophylaxis for glucocorticoid-induced osteoporosis.  Patients with asthma, chronic obstructive pulmonary disease,  rheumatologic disorders, and inflammatory bowel disease should be asked about previous corticosteroid use.

TABLE 3. Calcium Recommendations for Women

. Some studies of reported milk consumption  during childhood and adolescence have shown a statistically significant  correlation between calcium intake and premenopausal BMD levels.  However, other studies have demonstrated no such association. One  possible explanation for these mixed findings on the role of calcium is  that intake of this mineral may function as an "enabler," allowing the skeleton to interact with both genetic and  environmental characteristics.27 Nevertheless, lifelong adequate calcium  intake is advised. Table 3 delineates current recommendations made by  the National Institues of Health.

. This disorder affects approximately 1% of  females of reproductive age in the United States, and is mostly seen in  females during adolescence--the years during which growth of bone mass  normally accelerates.

 Reduced body weight in adolescent girls leads  to lower conversion rates of androgens in adipose tissue and increases  the risk of fracture. Grinspoon and colleagues demonstrated that BMD is  reduced at several skeletal sites in most women with anorexia nervosa,  and that weight is a significant predictor of BMD at all skeletal sites  for this population.

 Similarly, adult anorectic women have shown  marked spinal osteopenia as compared with age-matched controls. Anorexia  nervosa also produces estrogen deficiency with secondary amenorrhea.  BMD in lumbar bone tissue has been negatively correlated with the  duration of amenorrhea. These observations suggest that long-standing  estrogen deficiency is a major causative factor in osteoporosis that is  observed in anorexia nervosa.

Anorectic women who experienced amenorrhea prior to age 18 were shown  to have significantly less vertebral bone mass than did women who  developed amenorrhea at a later age.

 Total BMD has been found to decrease in early-stage  amenorrhea; in 90% of patients, the decrease has been estimated at 6% to  8%.37 Biller and associates noted that anorexia nervosa particularly  affected the trabecular bone, and that anorectic patients were unlikely  to reach peak bone density; thus, they were predisposed to increased  risk for osteoporosis in later life.

 Epidemiologic studies have shown that  cigarette smoking can have an antiestrogenic effect via two mechanisms:  production of 2-hydroxyestrogens and increased hepatic metabolism. An  increase of approximately 50% (P< .001) in estriadol 2-hydroxylation  has been found in premenopausal women who smoke more than 15 cigarettes  per day. In addition, the urinary excretion of estriol relative to  estrone is significantly decreased among smokers, providing evidence  that the smoking-induced increase in 2-hydroxylation diminishes the  competing metabolic pathway involving 16a-hydroxylation. The effects of  smoking on the 2-hydroxylation pathway of estradiol metabolism are  likely to result in decreased bioavailability at estrogen target tissues.

. Occasional use of alcohol may not adversely  affect bone metabolism. However, consumption of 2 or more alcoholic  drinks per day is considered a risk factor for osteoporosis. The effects  of alcoholism on nutritional status may also play a role. Patients  suspected of having a problem with alcohol should be counseled.

Articles

Osteoporosis at any age can have devastating consequences. Fortunately, a number of bone-preserving measures can go a long way toward preventing this disease--not only in postmenopausal women, but also in young women at high risk.

Abby Goulder Abelson, MD

Articles

Special Osteoporosis Supplement