Click Here!

  eMJA     The Medical Journal of Australia

Home | Issues | eMJA shop | Classifieds | Contact | More... | Topics | Search | Login | Buy full access   
New Drugs, Old Drugs

Osteoporosis prevention and treatment

Phillip N Sambrook and John A Eisman

MJA 2000; 172: 226-229

→ Other articles have cited this article

Abstract - Introduction - Overview of the evidence - Recommendations - Disclosure - References - Authors' details
Make a comment - Register to be notified of new articles by e-mail - Current contents list - More articles on Endocrinology

Abstract

  • Patients with low bone density or any prior low trauma fracture should be considered for therapeutic intervention.

  • Oestrogen replacement therapy remains the first choice for prevention of bone loss in early postmenopausal women with low bone density

  • In postmenopausal women with existing fractures, the rank order of treatments is firstly alendronate, secondly raloxifene and thirdly less potent bisphosphonates, such as etidronate, or active vitamin D metabolites, such as calcitriol.

  • For men with osteoporosis, if hypogonadism is present, it should be treated with testosterone replacement therapy. Despite limited data, a bisphosphonate should then be considered in conjunction with calcium.

  • Supplementation with simple vitamin D should be considered in elderly patients who are housebound or live in institutions, as they are at risk of vitamin D deficiency and osteomalacia.

Introduction The prevention and treatment of osteoporosis (low bone density) was reviewed at the Australian Consensus Conference on Osteoporosis, held in 1996, and a series of position statements about its management were developed.1 For the treatment of postmenopausal osteoporosis, these statements ranked hormone replacement therapy (HRT) with oestrogen as first-line therapy for most patients, but in those intolerant or unable to take this medication the rank order of choice was considered to be alendronate, followed by etidronate or calcitriol.

Since that meeting, the results of new trials with drugs such as raloxifene, further efficacy data for bisphosphonates, and postmarketing safety data for alendronate and calcitriol have become available. Moreover, increased dietary calcium intake and phyto-oestrogens are promoted in the media. The benefit of all these various agents versus their risk of side effects in this epidemic condition is gradually becoming clearer.


Overview of the evidence
Drugs used for treating and preventing osteoporosis, and the relevant evidence for this, are discussed below, and brief drug profiles, including recommended doses, are given in Box 1.

Calcium Controlled trials6 have shown that calcium supplementation can prevent bone loss in postmenopausal women (E1) (see Box 2 for an explanation of level-of-evidence codes) and this has been associated with a modest reduction in fracture risk in longer-term studies (E2). There is also evidence (E1) to suggest calcium supplementation augments the effect of oestrogen on bone density.8 Gastrointestinal absorption appears to be similar from milk or soy-drink products and supplements. As most controlled trials of new agents have used calcium as baseline therapy, it is appropriate to add a calcium supplement to most active agents described below. Calcium supplements have a better bone-sparing effect when taken at night.

Vitamin D A study in institutionalised elderly people in France showed treatment with calcium plus vitamin D significantly reduced the rate of hip fractures (E2),9 but a similar effect could not be shown in those who lived in the community.10 Australian data also indicate a substantial proportion of institutionalised (or housebound) elderly people may be vitamin D deficient,11 and the observed reduction in fractures in the French study may have reflected treatment of subclinical osteomalacia. Hence, vitamin D supplementation is recommended in institutionalised or housebound elderly people who have limited exposure to sunlight.

Calcitriol Calcitriol is the active hormonal form of vitamin D. Controlled trials of its effect on bone density have shown conflicting effects,12,13 with studies showing increases, no change or even apparent loss of bone density with calcitriol therapy (although suboptimal doses may account for some of these discrepancies). A recent larger study suggests the effect on bone density is less than that seen with oestrogen.14 One large controlled trial addressing the efficacy of calcitriol in preventing fractures found a threefold difference in vertebral deformity rates favouring calcitriol15 (E2), but used a less strict fracture criterion than in more recent studies. In that study, fracture rates remained stable in calcitriol-treated patients but increased in the calcium-treated patients. Calcitriol treatment may be appropriate in patients with known or presumed calcium malabsorption. Although calcitriol is approved for osteoporosis in men in Australia, a recent small study suggested that calcitriol may be less effective than calcium supplementation alone.16

Etidronate Etidronate was the first bisphosphonate developed for clinical use, and there is extensive experience of its use in Paget's disease. There have been a number of relatively small controlled trials with etidronate, showing increases in bone density averaging 5% over 2-3 years17 and suggesting a 50% reduction in vertebral fracture rate (E1). However, these trials also used fracture criteria less strict than those used in more recent clinical trials.18-21 Non-randomised studies based in general practice suggest its effectiveness increases with duration of use.3

Alendronate Several controlled clinical trials of the bisphosphonate alendronate have shown a reduction of vertebral, and even peripheral, fracture rates by about 50%18-20 (E1). Some, but not all, studies have shown a reduction in hip fracture rates.4,19 Reduction of fracture rates was apparent in individuals with bone mineral density (BMD) T scores below - 2.5 (T scores are multiples of the standard deviation from the population mean, based on a young, healthy, sex-matched reference population), even without prior fractures,20 suggesting an important threshold at which to consider intervention.

Oestrogen While calcium supplementation may reduce bone loss, a number of controlled clinical trials with oestrogen have shown long-term increases in bone density averaging 5% over three years (E1).22 Lower doses may be effective with concomitant calcium.8 Although only a few randomised clinical trials have addressed the effect on fractures,23,24 epidemiological studies indicate antifracture efficacy at all sites for oestrogen is comparable to that of other agents (E32).25 Epidemiological studies also suggest primary cardioprotective effects of oestrogen. However, this was not observed in a recent trial of the effects of oestrogen on secondary prevention of cardiovascular mortality and morbidity, despite improvements in surrogate measures of efficacy such as total and low density lipoprotein cholesterol levels.26

Raloxifene This selective oestrogen-receptor modulator, as well as acting to decrease bone resorption, improves lipid profiles (thought to be surrogates for cardiovascular risk) and reduces breast cancer incidence (in studies at 3.5 years).27 Importantly, raloxifene does not cause breast or uterine symptoms. Controlled clinical trials have shown modest increases in bone density, generally somewhat less than those seen with hormone replacement therapy.28 However, a 50% reduction in vertebral, but not as yet peripheral, fractures has been observed (E2).21 This may be a statistical power effect and longer-term studies are ongoing.

Anabolic steroids Forearm bone mass has been shown to increase modestly after treatment with nandrolone decanoate (E33), but at higher dosages and shorter intervals than are generally used in Australia. The effect on spinal bone density is unclear.29 Although nandrolone is commonly used in general practice in Australia, and may have a beneficial effect on muscle mass which may help to reduce the risk of falls in the elderly, there have been no studies showing antifracture efficacy.

"Natural therapies" A variety of so called "natural" therapies, including soy, red clover (Promensil [Novogen]), black cohosh (Remifemin [Scinat]), wild yam and topical progesterone, are frequently used for treating menopausal symptoms in Australia. Soy products have been associated with small effects on bone density in animal studies.30 There are no studies addressing either their efficacy on fractures or long term safety in humans at this time.

The risk of adverse events with these agents is unclear, as there have been no controlled studies of long-term safety. The efficacy and safety of these agents are yet to be documented in controlled clinical trials. Topical progesterone does not provide protection from endometrial changes of unopposed oestrogen in a woman with an intact uterus.


Recommendations
Adequate dietary calcium intake, regular exercise and avoidance of risk factors, such as smoking and excessive alcohol intake, are important lifestyle recommendations for preventing osteoporosis, but they have only modest efficacy. For people with low BMD, and particularly those with any prior low trauma fracture, these measures will be insufficient to prevent further osteoporotic fractures and pharmacological therapy must be considered.

Box 3 shows an appropriate approach to managing osteoporosis in postmenopausal women. HRT remains the mainstay of therapy for osteoporosis, particularly in early postmenopause. Although most women are at relatively low risk of osteoporotic fracture for the first five to 10 years after menopause, this will vary according to their bone density and other risk factors, such as propensity to falls. Although "natural" therapies may have some effect on menopausal symptoms, there is currently no evidence for their efficacy or safety in the prevention or treatment of osteoporosis. Older postmenopausal women, especially those with existing fractures, are at high risk of further osteoporotic fractures. The rank order of treatments of osteoporosis in this group, based on the current published evidence, is alendronate, followed by raloxifene, before less potent bisphosphonates, such as etidronate, or active vitamin D compounds, such as calcitriol. Simple vitamin D should be considered in house-bound or institutionalised elderly people, who are at risk of vitamin D deficiency and osteomalacia. Dietary calcium supplementation should be used in conjunction with all of the above therapies except calcitriol, with which overall calcium intake should be limited. For men with osteoporosis, hypogonadism, if present, should be treated with testosterone replacement therapy. In the absence of hypogonadism, although there are limited data, the rank order of treatment of osteoporosis in men is a bisphosphonate and calcium supplementation.

Most importantly, the benefit in fracture prevention from treatment increases progressively with worsening osteoporosis. As a result, while it is never too early to consider prevention, it is never too late to start treatment. Failure to at least consider therapeutic options in a patient who has sustained an osteoporotic fracture is not reasonable medical practice. As in many other chronic diseases, no therapy can be effective without long term compliance. This is strongly dependent on regular positive feedback to patients from their general practitioners. Important messages for patients are given in Box 4.

Disclosure The authors act as advisers to, and receive funding from, Roche; Merck, Sharpe & Dohme; Lilly; Pharmacia & Upjohn; Aventis; Novartis; and the Australian Dairy Corporation.

References
  1. O'Neill S, Eisman JA, Glasziou P, et al. The prevention and treatment of osteoporosis [consensus statement]. Med J Aust 1997; 167 (Suppl): S4-S15.
  2. Calcitriol and hypercalcaemia. Aust Adverse Drug React Bull 1997; 16: 2.
  3. Van Staa T, Abenheim L, Cooper C. Upper gastrointestinal adverse events and cyclical etidronate. Am J Med 1997; 103: 462-467.
  4. A gut feeling for alendronate. Aust Adverse Drug React Bull 1999; 18 (3): 11.
  5. Colditz GA, Hankinson SE, Hunter DJ, et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. New Engl J Med 1995; 332: 1589-1593.
  6. Nordin BEC. Calcium and osteoporosis. Nutrition 1997; 13: 664-686.
  7. National Health and Medical Research Council. A guide to the development, implementation and evaluation of clinical practice guidelines. Canberra: NHMRC, AusInfo 1999.
  8. Nieves JW, Komar L, Cosman F, Lindsay R. Calcium potentiates the effect of oestrogen and calcitonin on bone mass: review and analysis. Am J Clin Nutr 1998; 67: 18-24.
  9. Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3 and calcium to prevent hip fractures in elderly women. New Engl J Med 1992; 327: 1637-1642.
  10. Lips P, Graafmans WC, Ooms ME, et al. Vitamin D supplementation and fracture incidence in elderly persons. Ann Intern Med 1996; 124: 400-406.
  11. Brock KE, Reid JF, Greenoak GG, Fraser DR, The effect of sunlight on 25-hydroxy vitamin D plasma levels in an elderly Sydney population [abstract]. Australian and New Zealand Bone and Mineral Society Proceedings, 1997, Abstract No. 38.
  12. Gallagher JC, Goldgar D. Treatment of postmenopausal osteoporosis with high dose synthetic calcitriol. Ann Intern Med 1990; 113: 649-655.
  13. Ott SM, Chestnut CH. Calcitriol is not effective in postmenopausal osteoporosis. Ann Intern Med 1989; 110: 267-274.
  14. Gallagher JC, Fowler S. Effect of estrogen, calcitriol and a combination of estrogen and calcitriol on bone mineral density and fractures in elderly women [abstract]. J Bone Mineral Res 1999; 14: Abstract no. T364.
  15. Tilyard MW, Spears GF, Thomson J, Dovey S. Treatment of postmenopausal osteoporosis with calcitriol or calcium. New Engl J Med 1992; 326: 357-362.
  16. Ebeling PR, Yeung S, Poon C, et al. Effects of baseline active calcium absorption on bone mineral density responses to calcitriol or calcium treatment in men with idiopathic osteoporosis [abstract]. J Bone Mineral Res 1999; 14: Abstract no. SA419.
  17. Storm T, Thamsborg G, Steiniche T, et al. Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in postmenopausal osteoporosis. New Engl J Med 1990; 322: 1265-1271.
  18. Liberman UA, Weiss SR, Broll J, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. New Engl J Med 1995; 333: 1437-1443.
  19. Black DM, Cummings SR, Karpf D, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996; 348: 1535-1541.
  20. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures. JAMA 1998; 280: 2077-2082.
  21. 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 randomised controlled trial. JAMA 1999; 282: 637-645.
  22. Writing group for the PEPI trial. Effects of hormone therapy on bone mineral density. JAMA 1996; 276: 1389-1396.
  23. Lufkin EG, Wahner HW, O'Fallon WM, et al. Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Intern Med 1992; 117: 1-9.
  24. Windeler J, Lange S. Events per person year -- a dubious concept. BMJ 1995; 310: 454-456.
  25. Cauley JA, Seeley, Ensrud K, et al. Estrogen replacement therapy and fractures in older women. Ann Intern Med 1995; 122: 9-16.
  26. Hulley S, Grady D, Bush T, et al. Randomised trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280: 605-613.
  27. Cummings SR, Eckert S, Krueger KA. The effect of raloxifene on risk of breast cancer in postmenopausal women. JAMA 1999; 281: 2189-2197.
  28. Delmas PD, Bjarnason NH, Mitlak BH, et al. Effect of raloxifene on bone mineral density, serum cholesterol concentrations and uterine endometrium in postmenopausal women. New Engl J Med 1997; 337: 1641-1647.
  29. Flicker L, Hopper JL, Larkins RG, et al. Nandrolone decanoate and intranasal calcitonin as therapy in established osteoporosis. Osteoporosis Int 1997; 7: 29-35.
  30. Arjmandi BH, Birnbaum R, Goyal NV, et al. Bone sparing effect of soy protein in ovarian hormone deficient rats is related to its isoflavone content. Am J Clin Nutr 1998; 68 (Suppl): 1364S-1368S.

Authors' details The Institute of Bone and Joint Research, University of Sydney, Royal North Shore Hospital, Sydney, NSW.
Phillip N Sambrook, MD, FRACP, Professor of Rheumatology.

Garvan Institute, St Vincent's Hospital, Sydney, NSW.
John A Eisman, PhD, FRACP, Professor of Medicine, and Head of Bone and Mineral Research Program.

Reprints will not be available from the authors.
Correspondence: Professor P N Sambrook, The Institute of Bone and Joint Research, Level 4, Block 4, Royal North Shore Hospital, St Leonards, NSW 2065.
sambrookATmed.usyd.edu.au

©MJA 2000
Make a comment

Other articles have cited this article:

→  David K McKenzie, Peter A Frith, Jonathan G W Burdon and G Ian Town. The COPDX Plan: Australian and New Zealand Guidelines for the management of Chronic Obstructive Pulmonary Disease 2 Med J Aust 2003; 178 (6 Suppl): S1-S40. [The COPDX Plan] <http://www.mja.com.au/public/issues/178_06_170303/tho10508_all.html>

Home | Issues | eMJA shop | Terms of use | Classifieds | More... | Contact | Topics | Search

The Medical Journal of Australia    eMJA  


Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company.
Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>".
<URL: http://www.mja.com.au/> © 2000 Medical Journal of Australia.
We appreciate your comments.

1: Profiles of agents for prevention and treatment of osteoporosis

Calcium
Action: Calcium is weakly antiresorptive and supplementation may reduce negative calcium balance and so reduce bone resorption, particularly in older patients.
Dosing: Balance studies suggest a daily intake of 1500mg per day is required in postmenopausal women not using hormone replacement therapy.
Adverse effects: Calcium is a relatively safe medication but may cause mild gastrointestinal intolerance. The risk of renal calculi is very low except in those at risk.

Swirl
Vitamin D
Action: Vitamin D undergoes several metabolic steps in the body, so it is important to distinguish between simple vitamin D and its active metabolites (such as calcitriol), which have distinctly different pharmacological profiles. Simple vitamin D can be converted to calcitriol, and has a similar, but less potent, effect on increasing gastrointestinal absorption.
Dosing: Simple vitamin D is mainly available in Australia as ergocalciferol (1000IU per capsule; Ostelin 1000; Boots Healthcare Australia). It is no longer available on the Pharmaceutical Benefits Scheme, but is a relatively inexpensive over-the-counter medication. Small amounts of vitamin D are contained in some calcium and vitamin supplements (eg, Caltrate + Vitamin D [Whitehall Laboratories] contains 200IU per tablet and cod liver oil tablets approximately 400IU). An appropriate dose for supplementation is 1000IU daily.
Adverse effects: Chronic ingestion of large doses of vitamin D, usually at doses in excess of 50000 to 100000IU per day, is required to produce hypercalcaemia in normal patients. Thus, given the amounts of vitamin D contained in available preparations, intoxication is practically impossible.

Calcitriol
Action: The primary action of calcitriol is thought to be to increase gastrointestinal calcium absorption, and so indirectly reduce bone resorption. It may also increase bone formation, but at higher doses that may increase bone resorption.
Dosing: The usual dose is 0.5mg daily.
Adverse effects: Hypercalcaemia and hypercalciuria are uncommon in patients treated with the usual dose (above), but may occur in patients who increase their calcium intake substantially. Hence, calcium supplements should be avoided and dietary intake should be limited to less than 800mg daily. The Adverse Drug Reactions Advisory Committee (ADRAC) reported four cases of calcitriol-related hypercalcaemia in four years of postmarketing surveillance up to 1997. 2

Etidronate
Action: Etidronate is a first-generation bisphosphonate, and is relatively less potent in its effects on inhibiting bone resorption than later bisphosphonates. The balance of these effects can result in osteomalacia if the drug is used continuously in doses effective on bone resorption for osteoporosis.
Dosing: In osteoporosis, etidronate is used in a cyclical regimen at 400mg daily usually for two weeks every three months to reduce the risk of mineralisation defects.
Adverse effects: Etidronate has been associated with lower, but not upper, gastrointestinal events. 3 The risk of mineralisation defect with the cyclical regimen is very low.

Alendronate
Action: This aminobisphosphonate is a potent inhibitor of bone resorption at doses that do not affect bone formation or mineralisation.
Dosing: 10mg daily.
Adverse effects: Clinical trials with alendronate have repeatedly shown no increase in adverse effects compared with control groups. However, there have been reports of oesophagitis after alendronate therapy, and recent postmarketing surveillance by ADRAC listed 331 adverse event reports among approximately 49000 patients in Australia taking alendronate. 4 These included dyspepsia (44), nausea (43) and abdominal pain (37), and ulceration or stricture was confirmed endoscopically in 26 of 52 reports of oesophagitis. Although a causal relationship remains unproven, there appears to be a real but low incidence of upper gastrointestinal problems with alendronate. This is consistent with precautions in its administration requiring the patient to stay in an upright position and to fast for half an hour after taking it in the morning (as is required for adequate absorption).

Oestrogen
Action: Oestrogen is an antiresorptive drug, possibly mediated by effects on local release of various cytokines and growth factors in bone.
Dosing: Conjugated equine, 0.625mg daily; piperazine oestrone sulfate, 1.25mg daily; transdermal oestradiol, 4mg patch.
Adverse effects: Breast tenderness and abdominal swelling are not uncommon, but these problems usually settle, and starting with low doses can minimise them. Hormone replacement therapy has been associated with an increased risk of deep venous thrombosis. Transdermal routes of administration may reduce this risk. Controversy exists as to whether there may be an increased risk of breast cancer with long term oestrogen use. Studies that do suggest a small increase in risk indicate that they show no increase in risk in the first five years of treatment. 5

Raloxifene
Action: Like oestrogen, raloxifene is a selective oestrogen receptor modulator (SERM) which acts to decrease bone resorption, but, unlike oestrogen, it does not stimulate the breast or uterus.
Dosing: 60mg daily.
Adverse effects: An increased risk of venous thrombosis has been reported with raloxifene users, similar in extent to that seen with hormone replacement therapy. Unlike hormone replacement therapy, raloxifene is not useful for control of, and may worsen, menopausal symptoms.

Anabolic steroids
Action: Anabolic steroids are weak androgens and appear to exert a weak inhibitory effect on bone resporption. However, any effect on bone mass may in fact be secondary to effects on muscle mass.
Dosing: Nandrolone decanoate, 50mg intramuscular injection every three weeks.
Adverse effects: There is a high incidence of virilisation with these dosages and there are no long term safety data.

Back to text

 
2: Level-of-evidence codes

Evidence for the statements made in this article is graded according to the NHMRC system 7 for assessing the level of evidence:

Scale
E1Level I: Evidence obtained from a systematic review of all relevant randomised controlled trials.
E2Level II: Evidence obtained from at least one properly designed randomised controlled trial.
E31Level III-1: Evidence obtained from well-designed pseudo-randomised controlled trials (alternate allocation or some other method).
E32Level III-2: Evidence obtained from comparative studies with concurrent controls and allocation not randomised (cohort studies), case-control studies, or interrupted time series without a parallel control group.
E33Level III-3: Evidence obtained from comparative studies with historical control, two or more single-arm studies, or interrupted time series without a parallel control group.
E4Level IV: Evidence obtained from case-series, either post-test or pre-test and post-test.
Back to text

 
Box 3
Back to text

 
4: Important messages for patients

  • It is never too late to start treatment.
  • A number of new therapies have been shown to significantly reduce fracture risk.
  • The overall risk of gastrointestinal problems with bisphosphonates is low.
  • The effects of natural therapies in preventing osteoporosis are unproven.
Circle
Back to text