Advances in osteoporosis therapy

Advances in osteoporosis therapy2003 update of practical guidelines OBJECTIVE To review evidence for current therapies for postmenopausal osteoporosis and to
establish practical guidelines for management of osteoporosis by family physicians.
QUALITY OF EVIDENCE MEDLINE was searched from January 1990 to January 2003. Articles
retrieved were graded by level of evidence (I to III). Recommendations for diagnosis and therapy
were based on evidence from randomized controlled trials and meta-analyses.
MAIN MESSAGE Osteoporosis is treatable. Early diagnosis and intervention is recommended.
After excluding secondary causes of osteoporosis, physicians should advise patients to take appropriate calcium and vitamin D supplementation. Those with osteopenia at risk of fractures
and those with established osteoporosis need additional therapy.
CONCLUSION Approved pharmacologic therapies include alendronate, risedronate, raloxifene,
calcitonin, cyclical etidronate, and hormone replacement therapy. Family physicians can help with
early diagnosis and intervention and should discuss lifestyle modification with patients.
OBJECTIF Passer en revue les données scientifiques sur le traitement actuel de l’ostéoporose
postménopausique et formuler des directives pratiques pour le médecin de famille confronté à ce
problème.
QUALITÉ DES PREUVES Une recension a été effectuée dans MEDLINE entre janvier 1990 et janvier
2003. Les articles retenus ont été classés d’après le niveau des preuves (de I à III). Les données sur lesquelles sont fondées les recommandations sur le diagnostic et le traitement provenaient
d’essais randomisés et de méta-analyses.
PRINCIPAL MESSAGE On peut traiter l’ostéoporose, mais on recommande un diagnostic et un
traitement précoces. Une fois exclues les causes secondaires d’ostéoporose, on doit prescrire des
suppléments adéquats de calcium et de vitamine D. Les cas d’ostéopénie avec risque de fracture
ou d’ostéoporose bien installée nécessitent d’autres traitements.
CONCLUSION Les médications approuvées incluent l’alendronate, le risédronate, le raloxifène,
la calcitonine, l’étidronate cyclique et l’hormonothérapie substitutive. Le médecin de famille
peut contribuer au diagnostic et au traitement précoces et il doit discuter avec le patient des
changements du mode de vie.
This article has been peer reviewed.
Cet article a fait l’objet d’une évaluation externe.
Can Fam Physician 2003;49:441-447.
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Advances in osteoporosis therapy
Advances in osteoporosis therapy
O steoporosis is a common condition that in BMD, risk of fracture approximately doubles.5 Standards of practice for bone densitometry defin- one in eight men.1 It is associated with ing the minimum level of acceptable performance an increased risk of fractures; vertebral fractures are the most common and account for about 40% of all osteoporotic fractures.2 Fractures of the hip Table 1. World Health Organization criteria
and wrist and other nonvertebral fractures are the for diagnosis of osteoporosis: T score represents
next most common. Hip fractures are associated with the number of standard deviations a patient is above 20% mortality 1 year after fracture. About half of all or below the mean bone mineral density of a young patients sustaining hip fractures will not regain inde- pendence, and one third will require institutionaliza- CLASSIFICATION
tion.2 Unfortunately, most patients with osteoporosis, including those presenting with fragility fractures, are This paper focuses on postmenopausal osteopo- rosis and reviews advances in diagnosis and therapy. Osteoporosis management is of great importance to family physicians because of the high prevalence of the Clinical evaluation
condition and its associated morbidity and mortality.
Following assessment of risk of fracture, clinical eval- uation should exclude secondary causes of osteopo- Quality of evidence
rosis. Clinical assessment includes a complete history An advanced MEDLINE search was used to identify and physical examination and appropriate laboratory all randomized controlled trials (RCTs) evaluating tests (Table 2).6 History and physical examination
therapies for postmenopausal osteoporosis. The will guide physicians as to need for additional investi- search was limited to English-language articles pub- gation. Other investigations helpful in evaluating and lished from January 1990 to January 2003. The term excluding secondary causes of osteoporosis include “postmenopausal osteoporosis” was cross-matched measuring thyroid-stimulating hormone, 24-hour with the MeSH headings “therapy” and “prevention.” urine calcium, serum parathyroid hormone concen- Appropriate articles were appraised. Those reporting tration, and vitamin D concentration (Table 3).
on RCTs with level I or II evidence were selected.
Table 2. Tests to exclude secondary causes
Diagnosis
of osteoporosis
Osteoporosis is clinical y diagnosed by fragility fractures or development of dorsal kyphosis secondary to vertebral fracture. The World Health Organization defines osteopo- rosis as a progressive systemic disease characterized by low bone density and microarchitectural deterioration in bone that predisposes patients to increased bone fragility and fracture.2 Fragility fractures are fractures caused by trauma that would not cause a normal bone to fracture or by a fal from standing.4 Before fragility fractures occur, Intervention
osteoporosis can be diagnosed on the basis of decreased It is important to discuss lifestyle modification with bone mineral density (BMD) (Table 1).
patients. The average North American diet contains A single standard deviation reduction repre- only about 500 mg of calcium: current recommenda- sents about a 10% decrease in BMD from the tions for postmenopausal women suggest 1500 mg of mean value. For each standard deviation decrease elemental calcium each day.6 Calcium carbonate or calcium citrate are recommended supplements, as Dr Khan is an Associate Clinical Professor of Medicine
is vitamin D in doses of 400 IU/d for those younger at McMaster University in Hamilton, Ont, Chair of the than age 50 and 800 IU/d for those older than 50.6 Canadian Panel of the International Society of Clinical The importance of stopping smoking, avoiding or Densitometry and member of the Scientific Advisory limiting alcohol intake, and doing regular weight-bear- Council of the Osteoporosis Society of Canada. ing exercises should be stressed.7 Use of hip-protector 442 Canadian Family Physician • Le Médecin de famille canadien  VOL 49: APRIL • AVRIL 2003
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pads has been shown to significantly reduce the likeli- Pharmacotherapy
hood of hip fractures in elderly people.8 Currently available therapies are all antiresorptive
agents that decrease bone turnover (Table 49-15).
Table 3. Secondary causes of osteoporosis:
Osteoporosis is secondary to another condition in Bisphosphonates. Bisphosphonates are compounds
about 30% of postmenopausal women. that specifically bind to the hydroxyapatite crystals on bone surfaces and inhibit osteoclast function.16 The first bisphosphonate available for prevention and treatment of osteoporosis was etidronate. It was • Gonadotropin–releasing hormone agonists shown to be effective in decreasing vertebral frac-tures among postmenopausal women who were at • Medroxyprogesterone acetate (eg, Depo-Provera) high risk of such fractures.10,17 No evidence indicates etidronate has a beneficial effect on risk of hip or non- Because etidronate can impair bone mineraliza- tion in the same doses as it inhibits bone resorp- Hypogonadism: premature menopause or amenorrhea lasting longer than 6 months tion, it must be given cyclically with drug-free intervals every 3 months. Given continuously, eti- dronate can impair bone mineralization and allow osteomalacia to develop. Evidence on the efficacy of etidronate for preventing fractures is weak (level Malabsorption: celiac disease, inflammatory bowel disease, II), so it is a second-line drug for osteoporosis. It is, however, cheap and covered by most provinces’ drug Liver disease (for example, primary biliary cirrhosis) More potent bisphosphonates (alendronate and risedronate) that selectively inhibit bone resorption Malignancies and myeloproliferative disorders have been developed. High doses are required to inhibit bone mineralization. Alendronate is effective Inherited disorders (osteogenesis imperfecta, Ehlers-Danlos at preventing vertebral, hip, and nonvertebral frac- tures (level I evidence).11,18 The incidence of multiple Table 4. Results of studies on therapies approved for postmenopausal osteoporosis
DURATION OF
REDUCTION IN RELATIVE RISK OF
REDUCTION IN RELATIVE
EVIDENCE
STUDY (Y)
NO. OF PATIENTS
NEW VERTEBRAL FRACTURES VS PLACEBO (%)
RISK OF HIP FRACTURE (%)
*Subgroup analyses: age 70-79 with T <-3, 40%; similar patients with previous vertebral fractures, 60%; age ≥ 80 with risk factors, not significant. 442 Canadian Family Physician • Le Médecin de famille canadien  VOL 49: APRIL • AVRIL 2003
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new vertebral fractures in patients taking alendronate postmenopausal osteoporosis.27 Raloxifene reduces was lower by 90% in comparison with patients tak- incidence of new vertebral fractures by 55% after 3 years’ ing placebo (P < .001).11 In a prespecified analysis therapy (60 mg/d) (level I evidence).14,28 Raloxifene among women with osteoporosis taking alendronate, has a rapid antifracture effect with a 68% reduction in incidence of new hip fractures was reduced by 63% clinical vertebral fractures after 12 months’ therapy.29 within 18 months and new symptomatic vertebral Reduction in nonvertebral fractures has not fractures by 59% within 12 months in comparison with reached statistical significance in comparisons of placebo with raloxifene. The Multiple Outcomes of Alendronate has a rapid antifracture effect. Meta- Raloxifene Evaluation (MORE) study,30 however, was analyses of trials evaluating alendronate have dem- not designed to evaluate effect on risk of nonverte- onstrated impressive and consistent reductions in bral fractures. Participants were younger and had vertebral and nonvertebral fractures among women less severe osteoporosis than patients in other trials. Women were withdrawn from the MORE trial if they Alendronate is generally safe and well tolerated; had excessive bone loss or if two or more new ver- adverse events are not significantly more frequent tebral fractures developed. This might have contrib- than with placebo.11,18 It is important for patients uted to the very few hip fractures seen in this study. to take alendronate and other bisphosphonates in Because of differences in study population, it is dif- a fasting state because a very small amount of the ficult to compare drugs and draw conclusions about drug is actually absorbed. It is also important to their efficacy for preventing fractures; a head-to-head stay upright for about 30 minutes after taking the trial of the various agents is needed.
medication. In patients with gastroesophageal reflux, Raloxifene has additional benefits. Reductions in alendronate, like other aminobisphosphonates, can total and low-density lipoprotein cholesterol, fibrino- inhibit the ability of the esophageal epithelial cells gen, lipoprotein A, and homocystine levels have been to repair acid-induced injury.19,23 Alendronate taken seen with raloxifene,31 but no effect has been seen on once weekly at a dose of 70 mg is convenient for triglycerides or serum high-density lipoprotein lev- patients.24 It is more expensive than etidronate, how- els.31 In the MORE trial, cardiac events were reduced ever, and is not fully covered on all provinces’ drug by 40% in women at increased risk of cardiovascular disease.30 Impressive reductions in risk of breast Risedronate, an aminobisphosphonate, has also cancer have been documented, with an 84% reduction been shown to prevent vertebral and nonvertebral in estrogen–receptor–positive breast cancers in com- fractures effectively.12,13,25 Following 12 months’ parison with placebo.32 Incidence of thromboembolic therapy with risedronate, vertebral fractures were disease increases with raloxifene therapy as it can reduced by 61% to 65% in comparison with placebo in with hormone replacement therapy (HRT); history two trials (level I evidence).12,25 The drug had a rapid of thromboembolic events is a contraindication to The effect of risedronate on risk of hip fracture in Raloxifene offers additional extraskeletal benefits. elderly women was specifically evaluated in the Hip It is particularly beneficial for people at risk for ver- Intervention Program.13 Significant reductions in tebral fracture if they are also at increased risk of hip fractures, defined by BMD criteria, were noted coronary artery disease or breast cancer. Raloxifene in women with osteoporosis. No reduction in risk of can also be used in combination with aminobisphos- hip fractures was seen in women who enrolled on the phonates for patients at risk of hip fractures.
basis of clinical risk factors for fractures.
Once-weekly therapy with risedronate (35 mg) Calcitonin. Salmon calcitonin is effective at pre-
has comparable effects to once-daily risedronate venting osteoclast-mediated bone resorption.15,33 (5 mg) with respect to BMD changes in spine and The Prevent Recurrence of Osteoporotic Fractures hip.26 Risedronate in once-weekly doses is available (PROOF) study evaluated calcitonin nasal spray in in Canada; it is also safe and well tolerated. It is more varying doses.15 Risk of vertebral fracture was sig- expensive than etidronate and not covered on all pro- nificantly reduced with the 200-IU/d dose,15 but not with the 100-IU/d or 400-IU/d doses. Unfortunately, the PROOF trial had a high drop-out rate because Selective estrogen-receptor modulators. Raloxifene
the study was being completed at the same time is a valuable treatment for both preventing and treating as approvals for calcitonin and alendronate were 444 Canadian Family Physician • Le Médecin de famille canadien  VOL 49: APRIL • AVRIL 2003
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received. Patients chose to withdraw from the double-blind trial and proceed with open-label drug therapy. Editor’s key points
Drop-out rates were similar in the therapy and • Osteoporosis is a silent but growing epidemic placebo arms of the study. The high drop-out rates might have contributed to the lack of effect seen with ensuring they get adequate amounts of calcium, vitamin D, and exercise; stop smoking; and limit Salmon calcitonin reduced risk of new vertebral • Once osteoporosis is established and secondary fractures by 62% in comparison with placebo in osteo- causes are ruled out, usual treatment starts porotic women older than 7534 (level II evidence) with bisphosphonates. Etidronate, which has and was very well tolerated. Adverse effects were the least evidence supporting it, is covered by limited to minor rhinitis. Calcitonin has no negative drug plans; alendronate and risedronate have effects on bone mineralization and is thus safe for stronger evidence, but are more expensive and patients with osteomalacia or renal or liver disease. For this patient population, calcitonin is preferred • Raloxifene helps reduce vertebral fractures over bisphosphonates. It also benefi ts patients who as well as breast cancer and cardiovascular have gastrointestinal symptoms and are unable to disease. It can slightly increase risk of throm- tolerate oral bisphosphonates. Calcitonin can be used boembolism. It can be used in combination with in certain circumstances for premenopausal women, • Nasal calcitonin has been shown to reduce frac- and in combination with other antiresorptive agents. tures effectively with minor side effects and to Calcitonin also significantly decreased bone pain reduce bone pain in vertebral fractures.
associated with vertebral fractures due to its specifi c • On the horizon is parathyroid therapy. It stimu- and potent analgesic effects (level I evidence).35 lates production of new bone and has been Hormone replacement therapy. Hormone replace-
ment therapy has been shown in the recent Women’s Points de repère du rédacteur
Health Initiative trial to reduce risk of fractures • L’ostéoporose, une épidémie silencieuse qui in postmenopausal women.9 A total of 16 608 post- affecte un nombre croissant de personnes âgées, menopausal women aged 50 to 79 years received peut être enrayée par des suppléments adéquats 0.625 mg of conjugated equine estrogen with 2.5 mg de calcium et de vitamine D ainsi que par l’acti- of medroxyprogesterone acetate or placebo daily. At vité physique, l’arrêt du tabac et la restriction de 5.2 years, relative risk of clinical, vertebral, and hip fractures was reduced by 34% (level I evidence).9 In • Quand l’ostéoporose est déjà installée et que comparison with placebo, however, HRT was associ- les causes secondaires ont été exclues, on ated with a 29% increased incidence of cardiac events, commence habituellement par administrer des a 41% increased risk of stroke, a doubling of throm- biphosphonates. L’étidronate, pour lequel les boembolic events, and a 26% increased risk of breast données sont les moins solides, est couvert par les programmes d’assurance médicaments; cancer. Benefi ts included a reduction in osteoporotic l’alendronate et le risedronate, mieux étayés fractures and a 37% reduction in colorectal cancer. scientifi quement, sont toutefois plus chers et sou- The overall risks associated with HRT outweighed the benefi ts with 5 years or more of treatment.9 • Le raloxifène aide à prévenir les fractures ver- Hormone replacement therapy is recommended tébrales, mais aussi le cancer du sein et les primarily for menopausal and vasomotor symptoms. maladies cardiovasculaires. Il peut toutefois aug- Patients at increased risk of breast cancer, heart menter légèrement le risque de thromboembolie. disease, stroke, or thromboembolic events should On peut le combiner aux biphosphonates.
be cautioned against use of HRT. For prevention and • La calcitonine nasale réduit effi cacement les frac- treatment of osteoporosis, many alternatives that are tures, sans effets secondaires importants; elle not associated with this adverse-effect profi le are cur- diminue également les douleurs osseuses dans • Les hormones parathyroïdiennes constituent le traitement d’avenir. Elles stimulent la néofor- Future therapy
mation osseuse et réduisent efficacement les Large trials have shown that parathyroid hor- mone therapy (PTH) can stimulate new bone 444 Canadian Family Physician • Le Médecin de famille canadien  VOL 49: APRIL • AVRIL 2003
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formation.36,37 Significant increases (7% to 10% per 6. Brown JP, Josse RG, for the Scientific Advisory Council of the Osteoporosis year) in bone density have been seen with PTH. Society of Canada. 2002 Clinical practice guidelines for the diagnosis and manage-ment of osteoporosis in Canada. Can Med Assoc J 2002;167(Suppl 10):S1-34.
Histomorphometric studies have shown that PTH 7. Sinaki M, Itoi E, Wahner HW, Wollan P, Gelzcer R, Mullan BP, et al. Stronger back can improve the microarchitecture in osteoporotic muscles reduce the incidence of vertebral fractures: a prospective 10-year follow-up of postmenopausal women. Bone 2002;30:836-41.
bone and reverse the deterioration that was once 8. Kannus P, Parkkari J, Niemi S, Pasanen M, Palvanen M, Jarvinen M, et al. Prevention of hip fracture in elderly people with use of a hip protector. N Engl J Med 2000;343:1506-13.
The N-terminal fragment of PTH, known as teripa- 9. Writing Group for the Women’s Health Initiative investigators. Risks and benefits of ratide, has been evaluated in doses of 20 and 40 µg estrogen plus progestin in healthy postmenopausal women—principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321-33.
in an RCT.36 In this 21-month study, PTH reduced 10. Storm T, Thamsborg G, Steiniche T, Genant HK, Sorensen OH. Effect of intermit- risk of vertebral fractures by 65% and 69%, and risk tent cyclical etidronate therapy on bone mass and fracture rate in women with postmenopausal osteoporosis. N Engl J Med 1990;322:1265-71.
of nonvertebral fractures by 53% and 54%, using the 11. Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, et al. 20-µg/d and 40-µg/d doses, respectively, in com- Randomized trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 1996;348: parison with placebo (level I evidence). Side effects included nausea and headache. Persistent hypercal- 12. Harris ST, Watts NB, Genant HK, McKeever C, Hangartner T, Keller M, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in cemia in about 3% of patients required dose modifi- women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral cation. The recommended dose for teriparatide is 20 Efficacy with Risedronate Therapy (VERT) Study Group. JAMA 1999;282:1344-52.
13. McClung MR, Geusens P, Miller PD, Zippel H, Bensen WG, Roux C, et al. Effect µg/d. Increases in men’s BMD have also been seen of risedronate on the risk of hip fracture in elderly women. Hip Intervention with PTH.37 Parathyroid hormone (1-34) therapy has Program Study Group. N Engl J Med 2001;344:333-40.
14. Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, been approved by the United States’ Food and Drug et al. Reduction of vertebral fracture risk in postmenopausal women with osteopo- Administration. Studies of PTH in combination with rosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA antiresorptive therapy indicate that these combina- 15. Chestnut CH III, Silverman SL, Andriano K, Genant HK, Gimona A, Harris S, et al. tions are safe and effective for clinical use.38,39 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;109:267-76.
Conclusion
16. Fleisch H. Bisphosphonates in osteoporosis. Br J Clin Pract 1994;48:323-6.
17. Watts NB, Harris ST, Genant HK, Wasnich RD, Miller PD, Jackson RD, et al. Osteoporosis is an important health care issue that Intermittent cyclical etidronate treatment of postmenopausal osteoporosis. N Engl needs to be addressed. Better diagnosis and manage- 18. Cummings S, Black D, Thompson DE, Applegate WB, Barrett-Connor E, ment of osteoporosis will lower health care costs and Musliner T, et al, for the Fracture Intervention Trial Research Group. Effect of reduce the morbidity and mortality associated with it. alendronate on risk of fracture in women with low bone density but without verte- Patients at risk of osteoporosis should be evaluated bral fractures. JAMA 1998;280:2077-80.
19. Black DM, Thompson DE, Bauer DC, Ensrud K, Musliner T, Hochberg MC, et al. for risk factors for fracture. After excluding second- Fracture risk reduction with alendronate in women with osteoporosis: the Fracture ary causes of osteoporosis, physicians should counsel Intervention Trial. J Clin Endocrinol Metab 2000;85:4118-24.
20. Musliner T, Thompson D, Vandormael K, Santora A. Consistency of effect of for lifestyle modification and introduce pharmaco- alendronate on reduction in risk of non-vertebral fractures [abstract]. Calcif Tissue therapy for prevention and treatment of osteoporosis. 21. Karpf D, Shapiro D, Seeman E, Ensrud KE, Johnston CC Jr, Adami S, et al. With appropriate intervention, fractures can be sig- Prevention of nonvertebral fractures by alendronate. A meta-analysis. Alendronate Osteoporosis Treatment Study Groups. JAMA 1997;277:1159-64.
22. Cranney A, Guyatt G, Griffith L, Wells G, Tugwell P, Rosen C. Meta-analyses of therapies for postmenopausal osteoporosis. IX: summary of meta-analyses of thera-pies for postmenopausal osteoporosis. Endocr Rev 2002;23:570-8.
Competing interests
23. Peter CP, Handit LK, Smith SM. Esophageal irritation due to alendronate sodium Dr Khan has received research funding from Merck Frosst,
tablets: possible mechanisms. Dig Dis Sci 1998;43:1998.
24. Simon JA, Lewiecki EM, Smith ME, Petruschke RA, Wang L, Palmisano JJ. Patient Novartis, Procter and Gamble, and Eli Lilly. preference for once-weekly alendronate 70 mg versus once-daily alendronate 10 mg: a multicenter, randomized, open-label, crossover study. Clin Ther 2002;24:1871-86.
25. Reginster J, Minne HW, Sorensen OH, Hooper M, Roux C, Brandi ML, et al. Correspondence to: Dr A. Khan, 209-331 Sheddon Ave,
Randomized trial of the effects of risedronate on vertebral fractures in women with Oakville, ON L6J 1X8; telephone (905) 844-5677; fax (905) 844- established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int 2000;11:83-91.
26. Lindsay R, Kendler D, McClung M, Emkey RD, Adachi JD, Bolognese MA, et al. Risedronate 35 mg once a week is as effective as 5 mg daily in postmenopausal women [abstract]. Presented at the 65th Annual Scientific Meeting of the American References
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31. Walsh BW, Paul S, Wild RA, Dean RA, Tracy RP, Cox DA, et al. The effects of hormone replacement therapy and ral-oxifene on C-reactive protein and homocysteine in healthy postmenopausal women: a randomized controlled trial. J Clin Endocrinol Metab 2000;85:214-8.
32. Cauley J, Norton L, Lippman ME, Eckert S, Kreuger KA, Purdie DW, et al. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Multiple outcomes of raloxi-fene evaluation. Breast Cancer Res Treat 2001;65:125-34.
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34. Silverman SL, Chestnut C, Baylink I, Gimona A, Andriano K, Mindeholm L. Salmon calcitonin nasal spray (SCNS) is effective and safe in older osteoporotic women: results from the PROOF study. J Bone Miner Res 2001;16:S530.
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