Advances in the Prevention and Management of Osteoporosis New Clinical Insights


During the past decade, research into postmenopausal osteoporosis has led to a heightened understanding of the disease process. Awareness of current diagnostic guidelines, prevention strategies, and treatment options is key to the successful management of this condition.

During the past decade, research into postmenopausal osteoporosis has led to a heightened understanding of the disease process. Awareness of current diagnostic guidelines, prevention strategies, and treatment options is key to the successful management of this condition.

Sydney Lou Bonnick, MD


Not long ago, the diagnosis of postmenopausal osteoporosis was based solely on its clinical presentation: a presumed fragility fracture. This definition was limited to women with actual bone injuries and excluded those with skeletal fragility. Recent insights into the pathophysiology and diagnosis of osteoporosis have made it clear that the disease process that leads to bone fracture is present for many years before fracture occurs. Therefore, it has been concluded that fracture represents the outcome of the disease process rather than the disease itself.

In this regard, osteoporosis may be likened to hypertension: High blood pressure typically exists for many years and may be an underlying factor in the development of a stroke or similar event. That is, hypertension is a disease state in itself, as well as a risk factor for a stroke. Similarly, low bone mass is a disease state and a risk factor for a fracture. In a 1993 consensus conference, experts defined osteoporosis as a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, followed by an increase in skeletal fragility and susceptibility to fracture.1



Several techniques are available to measure bone mineral density (BMD) noninvasively. All of today's x-ray-based measurement systems are precise and accurate and deliver extremely low, effective radiation doses. Dual-energy x-ray absorptiometry (DXA) is the most versatile technology. Others include single-energy x-ray absorptiometry (SXA), quantitative ultrasound, quantitative computed tomography, and peripheral quantitative computed tomography. Although single- and dual-photon absorptiometry are still available, these older techniques are rapidly being replaced by DXA and SXA, their more modern counterparts.

Diagnostic Criteria

In 1994, a study group of the World Health Organization proposed guidelines for the diagnosis of postmenopausal osteoporosis in white women.2 The various diagnostic categories were based on a patient's BMD at various sites as compared with the average peak BMD found in healthy young adults.

Bone density or bone mass is considered normal if it is not more than 1 standard deviation (SD) below that of a young adult; osteopenic if it is more than 1 SD but less than 2.5 SDs below that of a young adult; osteoporotic if it is at least 2.5 SDs below that of a young adult; and severely osteoporotic if it is at least 2.5 SDs below that of a young adult in the presence of one or more fragility fractures. The last category is also known as established osteoporosis.

The levels of bone mass and density that separate the diagnostic categories should not be misconstrued as absolute in terms of the need for pharmacologic intervention.

Although a specific level of bone density may distinguish osteopenia from osteoporosis, a gradient of fracture risk exists across the range of BMDs. Thus, patients with osteopenia, as well as those with osteoporosis, are at considerable risk for a fracture. From a clinical perspective, it is desirable to prevent further bone loss in both groups, because their risk for fracture will only increase as their BMD declines. As a consequence, the distinctions between prevention and management of osteoporosis tend to become blurred in clinical practice. In discussions of available pharmacologic interventions, however, a distinction is made between prevention and management based on approved labeling from the Food and Drug Administration (FDA).




Trade Name
Minimum Effective Estrogen Dosage (mg/d)

Although issues such as breast cancer risk may militate against the use of estrogen replacement therapy (ERT) to prevent or manage osteoporosis in an individual woman, many postmenopausal women are candidates for this type of treatment and would be likely to benefit from it. In fact, the role of ERT in preventing and managing bone loss and in reducing fracture risk is well documented in the medical literature. Table 1 lists estrogen formulations and daily doses for the prevention of osteoporosis. The estrogen dosages listed for the various preparations are considered the minimal amounts necessary for preservation of skeletal mass; however, they are not necessarily the correct dosages for every woman.

Premarin™, Premphase™, and PremPro™ are also FDA-approved for the management of osteoporosis.

Lindsay and colleagues demonstrated that women given ERT shortly after oophorectomy maintained metacarpal bone density over a 16-year follow-up.3 In this same study, women who began ERT 3 or 6 years post-oophorectomy maintained their bone density at the level that had existed upon initiation of therapy, whereas placebo recipients steadily lost bone density. In a crossover trial, Christiansen and associates showed that women who began ERT shortly after oophorectomy maintained bone density at the radius for 2 years, whereas a placebo group steadily lost bone density.4 At the end of 2 years, women initially taking placebo were given estrogen, and those who had been taking estrogen were switched to placebo. After the crossover, bone loss ceased in the new ERT patients and commenced in the new placebo group.

Cross-sectional studies have repeatedly shown that postmenopausal women who take estrogen have higher BMDs than do those who have not taken ERT.5 It also is clear that the preservation of bone mass from estrogen replacement does not persist after estrogen is withdrawn. Thus, ERT prophylaxis is most properly viewed as a lifelong commitment. If estrogen must be withdrawn for any reason, and if continued skeletal protection is still necessary, the clinician should institute another pharmacologic intervention.

In a study by Lufkin and colleagues, transdermal estradiol-17 b (Estraderm™)--although not approved for the treatment of osteoporosis--also proved useful: After 1 year of treatment, women with at least one pre-existing spine fracture and lumbar spine and proximal femur bone densities below the 10th percentile for premenopausal women experienced a 5.3% gain in bone density at the spine and a 7.6% gain in bone density at the trochanter, both of which were significantly superior to the gains experienced by the placebo group.6 Of greater importance was a 61% reduction in the risk of a new spine fracture in the estradiol-17 b-treated group. The average age of the women in this study was 64 years (oldest participant, 74 years). Despite their older age, length of time since menopause, and advanced disease state with pre-existing fractures, these patients clearly benefited from ERT. Thus, age and advanced disease status do not appear to lessen the potential benefit of estrogen replacement in the management of osteoporosis.

Selective Estrogen Receptor Modulators

Selective estrogen receptor modulators (SERMs), a new class of drugs named for their selective activity in different organ systems, act as weak estrogens in some systems and as estrogen antagonists in others. Tamoxifen (Nolvadex™), the first SERM to be used clinically, was originally developed for the prevention of recurrent breast cancer. However, studies conducted on breast cancer patients have suggested that tamoxifen also preserves bone density in the spine; thus, it appears to act as a weak estrogen in the skeleton while functioning as an estrogen antagonist in the breast.7


In 1997, raloxifene (Evista™) became the first SERM to be approved specifically for the prevention of osteoporosis (Table 2). Raloxifene is a nonsteroidal benzothiophene that appears to have tissue-specific estrogen-agonist and estrogen-antagonist actions. It decreases bone turnover and lowers serum cholesterol concentrations without increasing triglycerides or stimulating the endometrium.

Delmas and associates reported interim results after 24 months from a multicenter, placebo-controlled, double-blind trial evaluating the effects of raloxifene 30, 60, and 150 mg on bone density, bone-turnover markers, lipids, and endometrial thickness.8 The 601 women in the study, who also received elemental calcium 400 to 600 mg daily, had a mean age of 55 years, were 2 to 8 years postmenopausal, and had baseline spinal BMD between 2.5 SDs below and 2 SDs above the average premenopausal bone density. After 2 years, each of the three raloxifene/calcium-treated groups showed gains in BMD of the spine and proximal femur that, although small, were significantly superior to the placebo/calcium group. Similarly, each of the three raloxifene-treated groups experienced significant declines in total cholesterol and low-density lipoprotein cholesterol. Markers of bone turnover in the raloxifene-treated groups, as compared with the placebo group, also decreased. Endometrial thickness, both at baseline and at 24 months, did not differ among the four treatment groups.

In another study, Lufkin and colleagues compared the use of raloxifene 60 or 120 mg daily versus placebo in 143 postmenopausal women (mean age, 68.4 years) who had at least one vertebral fracture.9 All of the study subjects received calcium 750 mg and vitamin D 400 U daily. Raloxifene significantly reduced total cholesterol and biochemical markers of bone turnover. The group receiving raloxifene 60 mg daily exhibited small increases in proximal femur and ultradistal radial BMDs, which were statistically significant when compared with BMDs at these sites in the placebo group. Bone density of the spine did not decline in either the raloxifene-treated or the placebo-treated groups, and the differences between the groups were not statistically significant. Raloxifene did not affect the incidence of hot flashes in either the Delmas or the Lufkin study.8,9 Uterine bleeding was no more prevalent in raloxifene recipients than in placebo recipients.

All of these findings suggest that raloxifene inhibits bone loss to a greater extent than does calcium alone. This SERM appears to act like a weak estrogen on the bone without exerting a stimulatory effect on the breast or the endometrium.

Salmon Calcitonin

Calcitonin, a 32-amino-acid polypeptide, is found in several species, including birds, pigs, and eels, as well as in the thyroid glands of humans. First discovered in 1962, it was named for its ability to lower serum calcium levels.10 Although no evidence suggests that calcitonin deficiency causes osteoporosis, it has been confirmed that pharmacologic doses of this agent inhibit osteoclastic bone resorption.


Salmon calcitonin is the most potent form of calcitonin, as measured by its effect on serum calcium, parathyroid hormone, and urinary cyclic adenosine monophosphate. Synthetic injectable salmon calcitonin (Calcimar™, Miacalcin™), which has been available since 1984 for the treatment of osteoporosis, leads to modest increases in bone density in postmenopausal women (Table 3).

ost notable is Gruber and colleagues' study in which 45 postmenopausal women received salmon calcitonin 100 IU or placebo daily, injected subcutaneously.11 After 18 months, total-body calcium, as measured by neutron activation analysis, had significantly increased in the calcitonin group. However, this effect appeared to diminish at about 20 months, raising concern about the effectiveness of long-term administration of salmon calcitonin.

Intranasal salmon calcitonin (Miacalcin Nasal Spray™) was approved by the FDA in August 1995 for the management of osteoporosis. The recommended dosage is 200 IU once daily. Studies using intranasal salmon calcitonin have demonstrated preservation of or small gains in BMD of the spine with this dosage.12,13

In September 1997, 3-year interim results from a 5-year multicenter trial of intranasal salmon calcitonin in the treatment of osteoporosis were reported at the annual meeting of the American Society for Bone and Mineral Research in Cincinnati, OH. This trial, known as PROOF (Prevention of Recurrence of Osteoporotic Fractures), has enrolled 1175 postmenopausal women with at least one spine fracture and a spinal BMD greater than 2 SDs below the mean for a healthy young adult. From baseline to year 3, spinal BMD increased by 1.26% in the group receiving intranasal salmon calcitonin 200 IU; this did not differ statistically from the effect of placebo.14 Nevertheless, the risk of a new vertebral fracture was significantly lower (37.4% less) in the women receiving intranasal salmon calcitonin 200 IU than in those receiving placebo. PROOF should provide much anticipated data regarding the long-term effectiveness of intranasal salmon calcitonin in the management of osteoporosis.

Intranasal salmon calcitonin is delivered via spray pump. The vials of medication should be refrigerated before first use. After the spray pump is assembled, it must be primed. The vial can then be stored at room temperature. The recommended dose is 1 spray per day (200 IU/activation). No significant drug interactions have been reported. Side effects of intranasal calcitonin are typical of drugs delivered in this fashion. Most involve local irritation of the nasal mucosa (e.g., crusting, dryness, or, infrequently, epistaxis). They are generally not serious enough to necessitate discontinuation of the medication.15

Intranasal calcitonin is not recommended during the first 5 years after menopause, as few data support its efficacy during this period. It is appropriate for women who are at least 5 years postmenopausal, cannot or will not take estrogen replacement, and have a low bone density.


Bisphosphonates are pyrophosphate analogs. The Figure shows the basic chemical structures of both compounds: The P-O-P backbone of pyrophosphate becomes a P-C-P backbone in the bisphosphonates. Varying the chemical side chains attached to the carbon atom--denoted as "X" in the Figure--results in bisphosphonates with different characteristics. The early bisphosphonates were developed as water softeners. Etidronate (Didronel™), a first-generation bisphosphonate, was initially used in clinical medicine in a desperate attempt to save a child suffering respiratory paralysis due to myositis ossificans.16 Early research with etidronate suggested a role for bisphosphonates in the treatment of osteoporosis, but the drug was never approved by the FDA for this indication.17 Nevertheless, the limited success of etidronate spurred the development of second- and third-generation drugs in its class.

Although the exact mechanism by which bisphosphonates inhibit bone resorption is not known, it has been postulated that these drugs alter both osteoclast activation and function.18 The second- and third-generation compounds are safer and far more potent than etidronate. To inhibit bone loss, etidronate was administered in a dose that could also cause mineralization defects in bone. The potency of second- and third-generation bisphosphonates eliminates this risk.

In September 1995, following completion of several research trials, alendronate sodium (Fosamax™) became the first bisphosphonate to be approved for the management of osteoporosis. Liberman and colleagues reported the effects of a 3-year course of alendronate versus calcium supplementation on BMD and new spine fracture in 994 women who were more than 5 years postmenopausal and had spinal BMDs that were at least 2.5 SDs below the mean for premenopausal women.19 After 3 years, the women receiving alendronate 10 mg daily experienced significant gains in bone density of the lumbar spine, femoral neck, trochanter, and total body. The bone density in the alendronate 10 mg group, as compared with the calcium group, was 8.8% greater in the spine, 5.9% greater in the femoral neck, 7.8% greater in the trochanter, and 2.5% greater in the total body. The alendronate 10 mg group also experienced a 48% reduction in the proportion of women experiencing new spine fractures.

The vertebral fracture arm of the Fracture Intervention Trial (FIT) randomized 2027 postmenopausal women with pre-existing vertebral fractures and low proximal femur BMD. Subjects received calcium supplementation alone or with alendronate 5 mg daily (subsequently increased to 10 mg daily during year 3).20 After 3 years, the alendronate group, as compared with the calcium group, showed a 47% reduction in the rate of clinically apparent spine fractures and a 51% reduction in the rate of hip fracture.

The remarkable effectiveness of alendronate in the treatment of osteoporosis prompted investigators to determine whether this agent might be useful in preventing osteoporosis in estrogen-deficient women. In 1998, McClung and associates reported the results of a dose-finding study in 447 recently postmenopausal women (age 40-59 years) with spinal BMDs within 2 SDs of the premenopausal average.21 Daily doses of alendronate 5, 10, or 20 mg resulted in 1% to 4% gains in BMDs of the lumbar spine, femoral neck, and trochanter. In the placebo group, women lost 3% to 4% of bone density in the same regions. Biochemical markers of bone resorption decreased within 3 months of alendronate treatment. In addition, 51 women underwent bone biopsy; none of the alendronate recipients had impaired mineralization.

In a study by Hosking et al, 1609 postmenopausal women under age 60 were randomized to receive placebo, alendronate 2.5 or 5 mg daily, or open-label estrogen/progestin.22 After 2 years, women receiving alendronate 5 mg daily had an average increase in bone density of 3.5% in the spine, 1.9% in the hip, and 0.7% in the total body. The increases in bone density were smaller with the 2.5-mg dose. Increases in bone density were 1% to 2% higher with estrogen/progestin than with alendronate 5 mg.

Based on these studies, alendronate 5 mg daily appears to be effective in preventing bone loss in postmenopausal women under the age of 60 who do not have pre-existing osteoporosis. In April 1997, the FDA approved this dosage for the prevention of osteoporosis, thereby providing the clinician with an alternative to ERT.


Alendronate sodium is effective both in preventing and in managing osteoporosis (Table 4). In postmenopausal patients who are unwilling or unable to take estrogen, alendronate 10 mg daily is recommended in those with BMDs that are at least 2 SDs below the premenopausal average; 5 mg daily is recommended in those who are not taking estrogen replacement and who are at risk for osteoporosis.

Like all bisphosphonates, alendronate is poorly absorbed in the oral form. To ensure adequate absorption, the tablet must be taken in the morning, after an overnight fast, with a full glass of water. The patient should not consume anything other than water, including other medications, for at least 30 minutes. The patient should also remain upright after taking alendronate to minimize the possibility of esophageal reflux. Alendronate can cause a chemical esophagitis: During the first year of postmarketing surveillance, 199 cases of esophageal adverse events were reported.23 In many cases, the esophagitis appeared to be related to the use of little or no water, recumbency following administration, pre-existing esophageal dysfunction, or persistent use of alendronate after the onset of symptoms. In the context of an estimated 475,000 patients receiving alendronate during this time, this incidence is low.

Nevertheless, alendronate is not recommended in persons with a history of difficulty in swallowing or of esophageal stricture. Because alendronate is excreted unchanged by the kidneys, it also is not recommended in persons with a creatinine clearance of less than 35 mL per minute. No clinically significant drug reactions have been reported with alendronate.

Combination Therapy

Two studies have been conducted to determine whether the combined use of two antiresorptive agents from different classes might be more beneficial than either agent alone. In a 4-year study, 58 postmenopausal women who received estrogen/etidronate had significantly greater increases in BMDs of the spine and femoral neck than did women who received either agent alone.24 In a 2-year study, 95 postmenopausal women were randomized to receive placebo, carbocalcitonin, ERT, or carbocalcitonin/ERT; those who received the combination had greater gains in BMD than did those receiving either agent alone.25 Although research is now underway to evaluate the use of estrogen/alendronate, this combination cannot be recommended at this time. In addition, none of the approved agents, either alone or in combination, is recommended for use in premenopausal women.


All of the drugs approved for the prevention and/or management of osteoporosis have antiresorptive properties and are considered effective and safe in postmenopausal women. Beyond these similarities, the considerable differences among the four major categories of agents (estrogen-containing preparations, SERMs, salmon calcitonin, and bisphosphonates) offer the clinician the opportunity to choose a highly individualized approach to meet each patient's needs.




1. Peck WA. Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med. 1993;94: 646-650.

2. World Health Organization. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. WHO Technical Report Series. Geneva: World Health Organization; 1994:1-129.

3. Lindsay R, Hart DM, Baird C, Forrest C. Prevention of spinal osteoporosis in oophorectomized women. Lancet. 1980;2:1151-1153.

4. Christiansen C, Christensen MS, Transbol I. Bone mass in postmenopausal women after withdrawal of oestrogen/gestagen replacement therapy. Lancet. 1981;1:459-461.

5. Ettinger BF, Genant HK, Cann CE. Long-term estrogen replacement therapy prevents bone loss and fractures. Ann Intern Med. 1985;102:319-324.

6. Lufkin EG, Wahner HW, O'Fallon WM, et al. Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Intern Med. 1992;117:1-9.

7. Love R, Mazess RB, Barden HS, et al. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med. 1992;326:852-856.

8. Delmas PD, Bjarnason NH, Mitlak BH, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med. 1997;337:1641-1647.

9. Lufkin EG, Whitaker MD, Argueta R, et al. Raloxifene treatment of postmenopausal osteoporosis. J Bone Min Res. 1997;12:S150.

10. Copp DH, Cameron EC, Cheney BA, et al. Evidence of calcitonin: a new hormone from the parathyroid that lowers blood calcium. Endocrinology. 1962;70:638.

11. Gruber HE, Ivey JL, Baylink DJ, et al. Long-term calcitonin therapy in postmenopausal osteoporosis. Metabolism. 1984;33:295-303.

12. Overgaard K, Hansen MA, Jensen SB, Christiansen C. Effect of calcitonin given intranasally on bone mass and fracture rates in established osteoporosis: a dose-response study. BMJ. 1992;305:556-561.

13. Reginster JY, Deroisy R, Lecart MP, et al. A double-blind, placebo-controlled, dose-finding trial of intermittent nasal salmon calcitonin for prevention of postmenopausal lumbar bone loss. Am J Med. 1995;98:452-458.

14. Stock JL, Avioli LV, Baylink DJ, et al. Calcitonin-salmon nasal spray reduces the incidence of new vertebral fractures in postmenopausal women: three-year interim results of the PROOF study. J Bone Min Res. 1997;12:S149.

15. Novartis Pharmaceuticals. Data on file. East Hanover, NJ: Novartis.

16. Licata AA. From bathtub ring to osteoporosis: a clinical review of the bisphosphonates. Cleve Clin J Med. 1993;60:284-290.

17. Harris ST, Watts NB, Jackson RD, et al. Four-year study of intermittent cyclical etidronate treatment of postmenopausal osteoporosis: three years of blinded therapy followed by one year of open therapy. Am J Med. 1993;95:557-567.

18. Papapoulos SE, Landman JO, Bijvoet OLM, et al. The use of bisphosphonates in the treatment of osteoporosis. Bone. 1992;13:S41-S49.

19. Liberman UA, Weiss SR, Broll J, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal women. N Engl J Med. 1995;333:1437-1443.

20. Black DM, Cummings SR, Karpf DB. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet. 1996;348:1535-1541.

21. McClung M, Clemmesen B, Daifotis A, et al. Alendronate prevents postmenopausal bone loss in women without osteoporosis. Ann Intern Med. 1998;128:253-261.

22. Hosking D, Chilvers CED, Christiansen C, et al. Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. N Engl J Med. 1998;338:485-492.

23. De Groen PC, Lubbe DF, Hirsch LJ, et al. Esophagitis associated with the use of alendronate. N Engl J Med.1996;335:1016-1021.

24. Wimalawansa SJ. Combined therapy with estrogen and etidronate has an additive effect on bone mineral density in the hip and vertebrae: four-year randomized study. Am J Med. 1995;99:36-42.

25. Meschia M, Brincat M, Barbacini P, et al. A clinical trial on the effects of a combination of elcatonin (carbocalcitonin) and conjugated estrogens on vertebral bone mass in early postmenopausal women. Calcif Tissue Int. 1993;53:17-20.

Sydney Lou Bonnick, MD, is a Research Professor, Texas Woman's University, Denton, TX.

Originally published in The Female Patient -- February, 1999

© Copyright, 1999 Quadrant Publishing, All Rights Reserved

Reprints are not allowed without the expressed written consent of Quadrant Publishing.

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