Pharmacotherapeutic Options

This article aims to orient clinicians with the most effective antiosteopenic agents currently in use. A discussion of patients' prior experiences with these drugs can aid physicians in choosing the most appropriate candidates for therapy--as well as in selecting the best methods of treatment.

INDIVIDUALIZED STRATEGIES

Although some therapies are used for both prevention and treatment, the distinction between these two goals is distinct: Prevention is used to denote patients who may be at risk but have not yet sustained a fracture, whereas treatment is used to describe interventions for patients in whom the disease is already apparent. Treatment itself has two concurrent goals: to reverse the currently manifested bone loss, and to keep it from increasing in severity. 

Over the past decade, major advances have been made in the prevention of osteoporosis among postmenopausal women. The currently approved preventive medications all appear to act by blocking osteoclast activity (resorption). It is interesting to note that two of the three approved drug classes, selective estrogen receptor modulators (SERMs) and bisphosphonates, are also indicated for use in treatment. Hormonal agents such as estrogen (eg, estradiol) are the only agents limited to preventive use in osteoporosis. The possibility of cardiovascular effects with these agents warrants further study, as indicated by the results of the Heart and Estrogen/progestin Replacement Study (HERS).¹

Treatment Options
Pharmacotherapeutic agents currently approved for the treatment of osteoporosis fall into three categories:

• SERMs
• Bisphosphonates
• Calcitonin

The differing mechanisms of action, as well as different clinical outcomes and side-effect profiles, provide physicians with the opportunity to tailor the treatment regimen to the individual patient.

SERMs
These interventions, which may act through estrogen receptors, possess either tissue-specific agonistic or antagonistic properties. The effect of SERMs on bone is estrogenic--namely, these agents inhibit postmenopausal decreases in bone mineral density (BMD). 

The SERM raloxifene is indicated to prevent bone loss in postmenopausal women and has been demonstrated to reduce the risk of vertebral fracture.² Raloxifene has also been associated with decreases in low-density lipoprotein. This agent has not been associated with cellular stimulation of either the breast or endometrium.

One main problem that has been reported with the use of raloxifene, however, is antagonism of estrogen at the site of vasomotor symptom production in the central nervous system. Women receiving raloxifene in the Multiple Outcomes of Raloxifene Evaluation study, a 3-year, placebo-controlled, randomized multicenter trial, reported a 7% incidence of hot flushes--a side effect that some patients may consider to be unacceptable.²

Bisphosphonates
Bisphosphonates inhibit bone resorption by reducing the number and activity of osteoclast cells.³ Investigators in the 3-year, double-blind Fracture Intervention Trial (FIT) concluded that, among 1946 postmenopausal women with low bone mass and existing vertebral fractures, the nitrogen-containing bisphosphonate analog alendronate substantially reduced the risk of morphometric and clinical vertebral fractures.⁴ In addition, a residual decrease in bone turnover may be found up to 2 years after treatment is discontinued; accelerated bone loss has not been observed at cessation of treatment.⁵

Risendronate, a potent bisphosphonate shown to be effective in the treatment of metabolic bone disorders (eg, Paget's disease), was found to decrease the cumulative incidence of new vertebral fractures by 41% (P = .003) during the course of a 3-year, randomized, double-blind trial of 2458 postmenopausal women. This agent was also found to reduce the cumulative incidence of nonvertebral fractures by 39% (P = .02). Subjects who received risendronate reported side effects similar to those of subjects taking alendronate in the FIT study. BMD was shown to be significantly increased compared with placebo at the lumbar spine (5.4% vs 1.1%), femoral neck (1.6% vs -1.2%), femoral trochanter (3.3% vs -0.7%), and midshaft of the radius (0.2% vs -1.4%).⁶

Schnitzer and coworkers conducted a 1-year, double-blind, multicenter study of two groups of postmenopausal women: those with either lumbar-spine or femoral-neck BMD of at least 2.5 standard deviations below the peak premenopausal mean, and those with prior vertebral or hip fracture. In a comparison of the efficacy and safety of once-weekly alendronate 70 mg, twice-weekly alendronate 35 mg, and daily alendronate 10 mg, their results were promising: All three treatment groups showed reduced biochemical indicators of bone resorption (ie, urinary N-telopeptides of type I collagen) and bone turnover (ie, serum bone-specific alkaline phosphatase) into the middle of the premenopausal reference range. All treatment regimens were also well tolerated, with a similar incidence of upper gastrointestinal (GI) adverse events.⁷ However, bisphosphonates may not be as well tolerated as previously reported; in some patients, serious GI effects can occur.⁸

Additionally, despite the relative efficacy demonstrated by alendronate, the method of administration is problematic. Absorption of alendronate is blocked by any substance other than water, therefore the drug must be taken on an empty stomach. Patients may not lie down after taking the medication so as not to cause esophageal irritation, and following ingestion, they must wait 30 minutes before eating breakfast. The manufacturers of Fosamax also developed a 70-mg tablet for once-weekly dosing. However, this newer form of dosing has not been demonstrated to alleviate the drug's gastrointestinal side effects.⁷

Furthermore, although adverse esophageal effects of alendronate were not seen during clinical trials, such events emerged during postmarketing surveillance. (Thus, the potential for upper GI side effects did not become apparent until the drug was available on the market).⁹

Calcitonin
The efficacy and safety profile of calcitonin has been examined for more than 15 years; among the most interesting benefits discovered in calcitonin research is a virtual lack of serious side effects. 

In 1984, calcitonin was shown to prevent bone loss; however, a link between calcitonin and the prevention of new fractures was still sought. Thus, the 5-year, double-blind, randomized, placebo-controlled Prevent Recurrence of Osteoporotic Fractures (PROOF) Study was initiated to determine whether salmon calcitonin nasal spray reduced the risk of new vertebral fractures in postmenopausal women with established osteoporosis. The longest continuous study of osteoporosis to date, this research effort comprised 1255 subjects who received a daily dose of 100, 200, or 400 IU of salmon calcitonin, or placebo. Participants were also given daily doses of 1000 mg calcium and 400 IU vitamin D. Baseline radiographs were obtained for all subjects, and history of prior fracture was recorded.¹⁰

A total of 783 women completed 3 years of treatment, and 511 women completed 5 years of treatment. The 200-IU dose of salmon calcitonin nasal spray was found to significantly reduce the risk of new vertebral fractures by 33% compared with placebo (P = 0.03); in the group of patients who met the study's enrollment requirements by having sustained one to five prior prevalent fractures, the risk was reduced by 36% (P = 0.03).
Lumbar spine BMD increased significantly from baseline (1% to 1.5%; P <0.01) in all treatment groups, and bone turnover was inhibited, as shown by suppression of serum type I collagen cross-linked telopeptide by 12% in subjects taking 200 IU (P <0.01) and by 14% in subjects taking 400 IU (P <0.01) as compared with placebo.

Conclusions of the PROOF study state that salmon calcitonin nasal spray, at a dose of 200 IU daily, significantly reduces the risk of new vertebral fractures in postmenopausal women with osteoporosis.¹⁰

Unique route of administration. As a nasal spray, salmon calcitonin appears to demonstrate other benefits as well. Blood vessels lining the nasal passages quickly absorb the medication and deliver it to the bloodstream. Nasally administered salmon calcitonin is not associated with the gastrointestinal discomfort sometimes associated with other treatments (although rhinitis has been reported). In addition, nasal sprays are found to be convenient and easy to use and can be taken at any time of day, regardless of when the patient has eaten.¹¹ Finally, there is evidence, as yet inconclusive, that intranasal calcitonin may demonstrate an analgesic effect through endogenous opioids in patients with osteoporotic fractures.¹²

TABLE 1. Bone Densitometry/Bone Marker Interaction

* Or repeat BMD or bone marker within 1 year.
† Re-evaluate in 12 to 24 months, depending on clinical status.
‡ Low BMD is a predictor of fracture riskindependent of marker level.

BMD = bone mineral density; DXA = dual x-ray absorptiometry.

THE THERAPEUTIC Response

Common to all methods of treatment is the need for an accurate means to determine efficacy. Dual-energy x-ray absorptiometry (DXA), the typical method of assessing BMD in central and peripheral bone, is of value in defining fracture risk and identifying candidates for treatment. However, none of the available therapies demonstrates the same degree of efficacy at all skeletal sites--rendering DXA less than ideal for monitoring therapeutic response. 

An effective method to assess therapeutic response is to measure the amount of N-telopeptide of type I collagen in the urine. Telopeptides, as well as pyridinolines, function as markers of bone resorption. Breakdown products of type I collagen telopeptides are cleaved from the ends of collagen fibrils during osteoclastic resorption. Bone markers then measure bone turnover, bone resorption, osteoclastic function, and osteoclastic activity, and are excreted in both blood and urine.

When used to aid in the prevention of osteoporosis, bone markers have been shown to have clinical utility in monitoring the antiresorptive effect of HRT in recently postmenopausal women, and to predict changes in BMD in response to HRT within the first 3 months of therapy.¹³ For treatment, the use of bone markers in combination with bone densitometry is becoming more common. It is important to note, however, that low bone density is an independent risk for fracture; any woman with low bone density--even if bone markers indicate that her resorption levels are low--should receive treatment. Similarly, a patient with normal bone density and high levels of resorption may be a candidate for therapy, or should be closely monitored. Table 1 provides the author's recommendations in this regard. 

A side benefit of utilizing bone markers may be found in the area of patient compliance. Bone markers might play a role in ensuring continuation of therapy by keeping patients informed when they are weighing benefits of treatment against such factors as cost, convenience, and side effects. This may be particularly useful in managing patients taking raloxifene or alendronate, who may continue to lose BMD during their first year of treatment but who have been shown, in most cases, to gain BMD in the second year if the same treatment is continued.¹⁴ It is estimated by this author that approximately one-half of patients discontinues treatment after 1 or 2 years.

TABLE 2. Drugs Approved for the Treatment of Osteoporosis

A NEW PERSPECTIVE ON BONE

A necessary adjunct to any discussion of treatment for osteoporosis is a description of recent changes in the understanding of this disease. Traditionally, osteoporosis has been viewed from a singular, quantitative vantage point: The rate of bone tissue claimed by osteoclastic resorption exceeds the rate of bone production by osteoblasts, and the goal of therapy is to restore homeostasis. 

However, osteoporosis has come to be viewed as a qualitative problem as well--specifically, that it is partially the result of abnormalities in the microarchitecture of bone. Trabecular struts or rods begin to perforate as osteoclasts dig resorption cavities into their surface. Typically, resorption begins in the horizontal struts, subsequently perforating the struts and disconnecting them from the vertical rods. These disconnections, or microfractures, form within the trabecular matrix; eventually, the microfractures coalesce to form a macrofracture. Without the buttressing effect of the struts, the risk for buckling of the rods may increase fourfold.¹⁵ Such a distinction between the quantitative and qualitative aspects of osteoporosis is important, as small increases in BMD result in large reductions in fracture risk. All of the currently available therapies are antiresorptive agents (Table 2). Newer agents to promote bone formation are undergoing research, and further study is expected to expand the understanding of bone microarchitecture.

CONCLUSION

A range of interventions exists for the prevention and treatment of osteoporosis. An understanding of the differences in their mechanisms of action, clinical outcomes, and side-effect profiles helps physicians determine their suitability for individual patients. Awareness of these agents' efficacy through use of the appropriate bone-monitoring tools is also critical to the management of osteoporosis, as is an ongoing awareness of research concerning bone microarchitecture and response to current therapies.

References:

REFERENCES

1. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998;280(7):605-613

2. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA. 1999;282:637-645.

3. Varghese S, Canalis E. Alendronate stimulates collagenase 3 expression in osteoblasts by posttranscriptional mechanisms. J Bone Miner Res. 2000; 15:2345-2351.

4. Black DM, Cummings SR, Karpf DB, et al. Randomised trial effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet. 1996;348:1535-1541.

5. Stock JL, Bell NH, Chesnut CH 3d, et al. Increments in bone mineral density of the lumbar spine and hip and suppression of bone turnover are maintained after discontinuation of alendronate in postmenopausal women. Am J Med. 1997;103:291-297.

6. Harris ST, Watts NB, Genant HK, et al. Effects of risendronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risendronate Therapy (VERT) Study Group. JAMA. 1999;282:1344-1352.

7. Schnitzer T, Bone HG, Crepaldi G, et al. Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in the treatment of osteoporosis. Alendronate Once-Weekly Study Group. Aging. 2000;12: 1-12.

8. US Food and Drug Administration. Summary of Safety-Related Drug Labeling Changes Approved by the US Food and Drug Administration. Available at: www.fda.gov/medwatch/safety/1999/mar99htm_fosama.

9. Pharmacological interventions for postmenopausal osteoporosis: an evidence-based approach [editorial]. Rheumatology; 2000:1309-1315.

10. Chesnut CH, Silverman S, Andriano K, et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the Prevent Recurrence of Osteoporotic Fractures study. Am J Med. 2000;109.267-276.

11. The Osteoporosis Medication Center. SciWeb Web site. Available at: http://www.scitalk.com/osteoporosis_medications.cfm. Accessed November 25, 2000.

12. Gennari C, Agnusdei D, Camporeale A Use of calcitonin in the treatment of bone pain associated with osteoporosis. Calcif Tissue Int. 1999;49(Suppl 2):S9-S13.

13. Chesnut CH III, Bell NH, Clark GS, et al. Hormone replacement therapy in postmenopausal women: urinary N-telopeptide of type I collagen monitors therapeutic effect and predicts response of bone mineral density. Am J Med. 1997;102:29-37.

14. Cummings SR, Palermo L, Browner W, et al. Monitoring osteoporosis therapy with bone densiometry: misleading changes and regression to the mean. Fracture Intervention Trial Research Group. JAMA. 2000;283:1318-1321.

15. 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.

Charles H. Chesnut III, MD, is Professor of Radiology and Medicine and Director, Osteoporosis Research Group, University of Washington Medical Center, Seattle.

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.