Special Osteoporosis Supplement

Women at Risk: The Premenopausal Years

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.³ 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.

PATHOGENESIS

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.⁵ 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.⁶

Most longitudinal and cross-sectional studies have suggested that the pathogenesis of low BMD begins prior to menopause (Table 1).^7-9 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.^10-13 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.¹⁴ Such a trend helps to explain why an untreated 50-year-old woman has a 40% risk of osteoporotic fracture in her remaining lifetime,¹⁵ with the risk of fracture rising exponentially with the decline in bone mass.

TABLE 1. Risk Factors for Osteoporotic Fracture⁷

Age or Age-Related

• Each decade associated with 1.4-1.8-fold increased risk

Genetic

• Ethnicity: Caucasians and Asians > Africans and Polynesians
• Gender: Female > male
• Family history

Environmental

• Nutrition; calcium deficiency
• Physical activity and mechanical loading
• Medications, eg, corticosteroids
• Smoking
• Alcohol
• Falls (trauma)

Endogenous Hormones and Chronic Diseases

• Estrogen deficiency
• Androgen deficiency
• Chronic diseases, eg, gastrectomy, cirrhosis, hyperthyroidism, hypercortisolism

Physical Characteristics of Bone

• Density (mass)
• Size and geometry
• Microarchitecture
• Composition

BARRIERS TO TREATMENT

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.¹⁶ 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 57.¹⁷ 

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.^18,19 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.

PROGNOSTIC INDICATORS 

Family and Genetic Factors 
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.²⁰ 

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.²¹

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.²¹ Thus, premenopausal women may look to their mothers for indications of decreased bone mass, and reap the benefits of earlier preventive intervention.

TABLE 2. Thyroid Hormones

Hyperthyroidism

• Endogenous hyperthyroidism leads to:
• Increased bone turnover
• Increased bone resorption
• Decreased bone mass
• T4 and T3 directly stimulate bone resorption characterized by:
• Increased number of osteoclasts
• Increased resorption sites
• Increased ratio of resorptive to formulation surface
• Decreased bone remodeling cycle
• Decreased intestinal calcium absorption

T4 = thyroxine; T3 = tri-iodothyronine

Thyroid Disease
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).^23-25

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.^25,26 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
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.²⁷
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.²⁸

Corticosteroid Use
Use of oral corticosteriods represents the most common drug-related form of osteoporosis.^29,30 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.³¹ In addition, the bone loss may be at its most rapid during the first 6 to 12 months of therapy.³⁰

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 Women³²

Modifiable Risk FactorsLow calcium intake. 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.³²

Anorexia nervosa. 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.³³ 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.³⁴ 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.³⁵

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.³⁶ 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.³⁷

Cigarette smoking. 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.³⁸

Alcohol abuse. 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.²⁷

Sedentary lifestyle. Physical fitness and moderate exercise are advantageous for bone, perhaps through a number of different mechanisms that are still largely unproven. One of the most well-developed hypotheses is related to bone loading: This theory states that bone responds to exercise-induced physical stress by increasing modeling and, thus, density.²⁷

CONCLUSION

A number of factors are predictive of future risk for the development of osteoporosis in women of reproductive age. Intervention into issues related to modifiable risk factors is important and bone density mearsurement may be indicated. Given the severity of the medical consequenses of osteoporosis, the medical community needs to assess all women for these risk factors during their premenopausal years.

References:

REFERENCES

1. Riggs BL. Pathogenesis of osteoporosis. Am J Obstet Gynecol. 1987;156: 1342-1346.

2. Fast Acts on Osteoporosis. Washington, DC: National Osteoporosis Foundation; 1997.

3. Sowers MFR, Boehnke M, Lancaster EK, et al. Bone mass in relatives of osteoporotic patients. Ann Intern Med. 1988; 109:870-873.

4. Ross PD, Davis JW, Epstein RS. Pre-existing fractures and bone mass predict vertebral fracture incident in women. Ann Intern Med. 1991; 114:919-923.

5. Mosley JR. Osteoporosis and bone function adaptation: mechanobiological regulation of bone architecture in growing and adult bone, a review. J Rehabil Res Dev. 2000;37:189-199.

6. Eriksen EF, Langdahl BL. The pathogenesis of osteoporosis. Horm Res. 1997; 48(suppl 5):78-82.

7. Wasnich D. Epidemiology of osteoporosis. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 4th ed. Philadelphia, Penn: Lippincott Williams & Wilkins: 1999:257-259.

8. Legrand E, Chappard D, Pascaretti C, et al. Trabecular bone microarchitecture, bone mineral density, and vertebral fractures in male osteoporosis. J Bone Miner Res. 2000;15:13-19.

9. Baran DT. Magnitude and determinants of premenopausal bone loss. Osteoporosis Int. 1994;4(suppl 1): 31-34.

10. Seeman E. Reduced bone density in women with fractures: contribution of low peak bone density and rapid bone loss. Osteoporosis Int. 1994;4(suppl 1): 15-25.

11. Christiansen C. The different routes of administration and the effect of hormone replacement therapy on osteoporosis. J Fertil Steril. 1994;62(suppl 2):152S-156S.

12. Soda MY, Mizunuma H, Honjo S, et al. Pre- and postmenopausal bone mineral density of the spine and proximal femur in Japanese women assessed by dual-energy x-ray absorptiometry: a cross-sectional study. J Bone Miner Res. 1993;8:183-189.

13. Buchanan JR, Myers C, Lloyd T, Greer RB 3d. Early vertebral trabecular bone loss in normal premenopausal women. J Bone Miner Res. 1988;3: 583-587.

14. Pouilles JM, Tremollieres F, Ribot C. [Vertebral bone loss in perimenopause]. In French. Presse Med. 1996;25:277-280.

15. Epidemiology and predictors of fractures associated with osteoporosis. Lips P Am J Med, 103(2A):3S-8S; discussion 8S-11S 1997

16. Goulding A, Gold E, Walker R, Lewis-Barned N. Women with past history of bone fracture have low spinal bone density before menopause. N Z Med J. 1997;110: 232-233.

17. Honkanan R, Tuppurainen M, Kroger H, Alhava E, Puntila E. Associations of early premenopausal fractures with subsequent fractures vary by sites and mechanisms of fractures. Calcif Tissue Int. 1997; 60:327-331.

18. Nevins MC, Ettinger B, Black DM, et al. The association of radiographically detected vertebral fractures with back pain and function: a prospective study. Ann Intern Med. 1998;128: 793-800.

19. Lyles KW. Management of patients with vertebral compression fractures. Pharmacotherapy. 1999;19:215-245.

20. Ulrich CM, Georgiou CC, Snow-Harter CM, Gillis DE. Bone mineral density in mother-daughter pairs: relations to lifetime exercise, lifetime milk consumption, and calcium supplements. Am J Clin Nutr. 1996;63: 72-79.

21. Willig M, Sowers M, Aron D, et al. Bone mineral density and its change in white women: estrogen and vitamin D receptor genotypes and their interaction. J Bone Miner Res. 1998;13:695-705.

22. Ferrari S, Rizzoli R, Slosman D, Bonjour JP. Familial resemblance for bone mineral mass is expressed before puberty. J Clin Endocrinol Metab. 1998; 83:358-361.

23. Kung AW, Pun KK. Bone mineral density in premenopausal women receiving long-term physiological doses of levothyroxine. JAMA. 1991;265:2688-2691.

24. Solomon BL, Wartofsky L, Burman KD. Prevalence of fractures in postmenopausal women with thyroid disease. Thyroid. 1993;3:17-23.

25. Stall GM, Harris S, Sokoll LJ, Dawson-Hughes B. Accelerated bone loss in hypothyroid patients overtreated with L-thyroxine. Ann Intern Med. 1990; 113:265-269.

26. Nuovo J, Ellsworth A, Christensen DB, Reynolds R. Excessive thyroid hormone replacement therapy. J Am Board Fam Pract. 1995;8:435-439.

27. Sowers MF, Galuska, DA. Epidemiology of bone mass in premenopausal women. Epidemiol Rev. 1993;15(2): 374-398.

28. Weyand CM, Wortmann R, Klippel JH, & The Arthritis Foundation. Primer on Rheumatic Disease, 11th ed. The Arthritis Foundation; 1997.

29. Ho YV, Briganti EM, Duan Y, et al. Polymorphism of the vitamin D receptor gene and corticosteroid-related osteoporosis. Osteoporosis Int. 1999;9: 134-138.

30. Rackoff PJ, Rosen C. Pathogenesis and treatment of glucocorticoid-induced osteoporosis. Drugs Aging. 1998;12(16):477-484.

31. Lane NE, Lukert B. The science and therapy of glucocorticoid-induced bone loss. Endocrinol Metabol Clin N Am. 1998;27:465-483.

32. National Institutes of Health Consensus Development Conference on Optimal Calcium Intake. June 6-8, 1994; Washington, DC.

33. Seeman E, Szmukler GI, Formica C, et al. Osteoporosis in anorexia nervosa: the influence of peak bone density, bone loss, oral contraceptive use, and exercise. J Bone Miner Res. 1992;7:1467-1474.

34. Grinspoon S, Thomas E, Pitts S, et al. Prevalence and predictive factors for regional osteopenia in women with anorexia nervosa. Ann Intern Med. 2000; 133:790-794.

35. Poet JL, Galiner Pujol A, Tonolli Serabian I, et al. Lumbar bone mineral density in anorexia nervosa. Clin Rheumatol. 1993;12:236-239.

36. Andersen AE, Woodward PJ, LaFrance N. Bone mineral density of eating disorder subgroups. Int J Eat Disord. 1995;18:335-342.

37. Biller BM, Saxe V, Herzog DB, et al. Mechanisms of osteoporosis in adult and adolescent women with anorexia nervosa. J Clin Endocrinol Metab. 1989;68:548-554.

38. Michnovicz JJ, Hershcopf RJ, Naganuma H, et al. Increased 2-hydroxylation of estriadol as a possible mechanism for the anti-estrogenic effect of cigarette smoking. N Engl J Med. 1986;315:1305-1309.

Abby Goulder Abelson, MD, is Assistant Clinical Professor of Medicine, Case Western Reserve University School of Medicine, Division of Rheumatology, University Hospitals of Cleveland, OH.

Originally published in The Female Patient -- July, 2001

© Copyright, 2001 Quadrant Publishing, All Rights Reserved. Reprints are not allowed without the expressed written consent of Quadrant Publishing.