Br J Clin Pharmacol 1998; 45: 95 99 Musculoskeletal Unit, Freeman Hospital, Newcastle upon Tyne, NE7 7DN Introduction individuals whose bone density is lower than expected for their age and who are at greater risk of osteoporotic fractures. Osteoporosis is characterized by a reduction in the amount Although precise and accurate measurements of lumbar of bone in the skeleton, associated with skeletal fragility and spine and femoral neck BMD can be made using DEXA, an increased risk of fractures after minimal trauma. The population-based bone density screening cannot be advo- major osteoporotic fractures are those of the forearm, cated for the prevention of osteoporotic fractures. vertebral body and femoral neck. The lifetime risk of Nevertheless, BMD measurements may be useful in the symptomatic fracture for a 50 year old white woman in the assessment of individuals at high risk of osteoporosis, because UK has been estimated to be 13% for the forearm, 11% for of factors such as early menopause or prolonged oral steroid the vertebra, and 14% for the hip, whilst the corresponding therapy [7]. Bone densitometry may also be helpful in figures for a 50 year old man are 2%, 2%, and 3%, patients with history of peripheral fractures after minimal respectively [1]. It has also been suggested that 50 000 trauma or those with apparent reduced bone density on forearm fractures, 40 000 symptomatic vertebral fractures X-ray [7]. and 60 000 hip fractures occur each year in the UK [2]. Osteoporotic fractures are associated with excess mortality, substantial morbidity and health and social service costs of at least 742 million annually in the UK [2]. Diagnosis of osteoporosis Investigation of osteoporosis Prior to the development of techniques which accurately measure bone density, osteoporosis was usually only diagnosed after a fracture had occurred. The term osteoporosis was therefore reserved for the fracture syndrome resulting from reduced bone density. With the advent of dual energy X-ray absorptiometry (DEXA) bone densitometry and the antigen in men [8, 9]. therapeutic possibility of preventing bone loss, the term osteoporosis is now increasingly used to describe reduced Secondary causes of osteoporosis should be sought by careful history, physical examination and appropriate investigation, as treatment of underlying conditions such as hyperthyroidism, hypogonadism and hyperparathyroidism may reverse the osteoporotic process and increase bone density. Investigations may include full blood count, ESR, biochemical profile, thyroid function tests and serum and urine electrophoresis, together with serum testosterone, sex hormone binding globulin, gonadotrophins and prostate specific Treatment of osteoporosis bone density before fractures have occurred. There is a strong inverse relationship between bone mineral density Treatments for osteoporosis may be classified into antiresorptive (BMD) and fracture risk, with a 2 3 fold increase in fracture agents, such as oestrogens, other hormonal agents, incidence for each standard deviation reduction in bone bisphosphonates, calcitonin, vitamin D and calcium supplements, density [3, 4]. BMD measurements may be expressed as and anabolic agents like anabolic steroids, sodium standard deviation units above or below the mean value for fluoride and parathyroid hormone (PTH). Although antiresorptive normal young adults or relative to the mean value for agents decrease bone resorption, the transient control subjects of the same age, to give T and Z scores uncoupling of bone resorption and formation may lead to a respectively [5, 6]. The T score reflects current fracture risk, modest increase in bone density of 5 10%. In contrast, whereas the Z score predicts life-time fracture risk, although anabolic agents increase bone density by up to 50%, although the relative merits of T and Z scores in clinical practice this is not necessarily associated with a decreased risk remains controversial [6]. of fractures. The World Health Organization (WHO) has defined osteoporosis as a BMD 2.5 standard deviations or more below the mean value for young adults (T score< 2.5), Hormone replacement therapy whilst the term severe or established osteoporosis indicates The use of hormone replacement therapy (HRT) for 5 to that there has also been one or more fragility fracture [5]. 10 years at the time of the menopause prevents the rapid Although the WHO definition is useful for the diagnosis of bone loss that occurs at this time and substantially decreases osteoporosis, it does not necessarily represent a threshold for the risk of fractures [10 12]. Nevertheless, the benefits of treatment. This is important as 70% of women above the previous long term HRT may be lost by the age of 75 years age of 80 years have a T score of less than 2.5, but only [13]. HRT has also been shown to increase spine bone a proportion will sustain an osteoporotic fracture [5]. For density by 5% in older women with established osteoporosis these reasons there has been a trend to use Z scores in [14, 15]. One of these small studies has also shown a 60% interpreting BMD measurements in older people, to identify reduction in the number of further vertebral fractures [14]. HRT is the treatment of choice in younger women with osteoporosis, because of its beneficial effect on climacteric Correspondence: Dr, Musculoskeletal Unit, Freeman Hospital, Newcastle upon Tyne, NE7 7DN. symptoms, ischaemic heart disease and possibly Alzheimer s 1998 Blackwell Science Ltd 95
disease. Long term compliance with HRT is often poor, fracture incidence in 70 postmenopausal women receiving because of the return of the menses and concern about the cyclical etidronate, but was inadequately powered to risks of breast cancer and thromboembolic disease. The accurately assess the effect of treatment on overall fracture advent of continuous combined oestrogen progestogen rate [27]. There is also evidence that cyclical etidronate preparations may improve the situation, as they offer the prevents bone loss in normal postmenopausal women benefits of HRT without the need for a regular monthly [30, 31]. bleed. Many women however will experience patchy Cyclical etidronate is now licensed in the UK for the bleeding during the first few months of treatment, although treatment of osteoporosis, the prevention of bone loss in 90% of women are amenorrhoeic after 1 year s treatment. postmenopausal women who are considered at risk of developing osteoporosis and the prevention and treatment Tibolone of corticosteroid-induced osteoporosis, whilst alendronate is currently licensed for the management of osteoporosis in This synthetic agent has weak oestrogenic, progestogenic postmenopausal women. Other bisphosphonates are under and androgenic properties and does not usually cause investigation for the management of osteoporosis, including menstrual bleeding if used in older postmenopausal women. clodronate, pamidronate, tiludronate and risedronate. In addition to relieving climacteric symptoms, it prevents Bisphosphonates are generally well tolerated, but commonly bone loss in normal postmenopausal women [16, 17]. There cause mild gastrointestinal disturbance. More severe is no information on the effect of tibolone on fracture erosive oesophagitis has been reported with aminobisphosphonates incidence, but it has been licensed for the prevention of such as alendronate, although in the majority of postmenopausal osteoporosis. cases, patients were not complying with the recommended instructions on administration or had a past history of upper Selective oestrogen receptor modulators (SERMs) gastrointestinal disease [32]. Whilst high dose or continuously administered etidronate may impair bone mineralisation, no Although tamoxifen is used in the management of breast clinical evidence of osteomalacia has been found with cancer because of its action as an oestrogen antagonist, it intermittent cyclical etidronate therapy [20]. acts as an oestrogen agonist on the skeleton and cardiovascular system, reducing bone loss and decreasing the risk of ischaemic heart disease [18]. There is growing interest in Calcitonin the development of agents with selective oestrogen agonist Calcitonin is a potent antiresorptive agent, having a rapid and antagonist actions on different target tissues. Raloxifene but short lived effect on osteoclast function. A dose-response is a SERM currently under investigation for the management study of intranasal calcitonin in the treatment of women of postmenopausal osteoporosis. It appears to decrease bone with reduced forearm bone density showed significant turnover and has a beneficial effect on serum lipids, without increases in spine bone density of 1 3% over 2 years, stimulating the endometrium [19]. associated with a reduction in the number of vertebral fractures [33]. Another study in postmenopausal women Bisphosphonates with vertebral crush fractures demonstrated that cyclical i.m. calcitonin and calcium supplements decreased the incidence These are powerful antiresorptive agents, which although of vertebral fractures by 60% over 2 years, compared with poorly absorbed by mouth, localise preferentially in bone. an increase in 35% in a group receiving calcium alone [34]. They bind to hydroxyapatite crystals and reduce osteoclast Calcitonin is expensive and associated with side-effects such recruitment and function. As bisphosphonates persist in the as flushing, nausea, vomiting, diarrhoea, dizziness and skeleton for many months, their duration of action is headache. These side-effects may be less with the intranasal prolonged beyond the period of administration [20]. route of administration, although this is not currently Intermittent cyclical etidronate therapy and continuous available in the UK. alendronate treatment both increase spine bone density in women with osteoporosis by 5 8% over 2 to 3 years and reduce the incidence of further vertebral fractures by about Vitamin D 60% [21 25]. Alendronate also increases femoral neck bone With advancing age there is a reduction in cutaneous density by 4.1 5.9% in 3 years, compared with 1.4% with production and subsequent metabolism of vitamin D. This cyclical etidronate [23, 24, 25]. Recent data from the large leads to a decrease in calcium absorption and PTH mediated Fracture Intervention Trial shows that alendronate treatment bone resorption. A French study in nursing homes and in women with low hip bone density and at least one apartment blocks for the elderly, showed that 800 iu vitamin vertebral fracture significantly increases bone density in the D 3 and 1.2 g elemental calcium daily reduces the risk of hip forearm, spine and femoral neck and decreases the incidence fracture by 43% [35]. A smaller American study of older of fractures at these sites [25]. men and women living at home demonstrated that 700 iu Small controlled studies indicate that cyclical etidronate vitamin D 3 and 500 mg elemental calcium daily had a prevents bone loss from the lumbar spine in patients starting modest beneficial effect on bone density and decreased the oral steroid therapy [26, 27], whilst significantly increasing incidence of non-vertebral fractures [36]. It is unclear if the spine bone density in patients on long term steroids with evidence of osteoporosis [28, 29]. The largest of these studies also showed a significant reduction in vertebral benefits of treatment seen in these studies were due to vitamin D, calcium or the combination of both, but a Finnish study showed that an annual i.m. injection of 96 1998 Blackwell Science Ltd Br J Clin Pharmacol, 45, 95 99
150 000 300 000 iu vitamin D decreases the risk of fractures in elderly people by 25% [37]. In contrast, a Dutch study Fluoride salts showed a small increase in hip bone density with 400 iu Initial studies showed that sodium fluoride increased spine vitamin D 3 daily, but no effect on the incidence of hip bone density by up to 35% over 4 years in women with fractures in elderly people [38]. Vitamin D supplementation vertebral osteoporosis, although this appeared to be at the is probably most appropriate in frail and housebound elderly expense of cortical bone loss [46, 47]. Furthermore, there people, who are at high risk of vitamin D deficiency and was no reduction in vertebral or non-vertebral fracture hip fractures. incidence with fluoride. These studies also showed that sodium fluoride is potentially toxic, causing nausea, vomiting, indigestion and lower extremity bone pain [46, 47]. A Vitamin D metabolites European study using a lower dose of sodium fluoride or monofluorophosphate with calcium and vitamin D Patients with vertebral fractures have lower calcium absorption supplements showed increases in spine bone density of than age-matched control subjects, which may be due 10.8% after 2 years compared with 2.4% with calcium and to reduced serum 1,25 dihydroxyvitamin D concentrations vitamin D alone, but no beneficial effect on fracture or to relative resistance to the action of vitamin D incidence was seen [48]. In contrast, another study using metabolites on the bowel [39]. Malabsorption of calcium in low dose, slow release sodium fluoride shows small increases osteoporosis does not usually respond to physiological doses in spine and hip bone density associated with a reduction in of vitamin D, but may be corrected by low doses of the vertebral fracture incidence [49]. The later studies showed vitamin D metabolites, calcitriol and alfacalcidol [39]. Studies none of the side effect profile described with the higher of the effect of treatment with vitamin D metabolites on dose treatment. Nevertheless, the therapeutic window for bone loss and fractures in established osteoporosis have fluoride appears narrow and this agent cannot yet be produced conflicting results [39]. A study comparing advocated for the management of osteoporosis. calcitriol 0.25 mg twice daily with calcium 1 g daily has shown a significantly lower vertebral fracture incidence with calcitriol, although this was due mainly to an increase in Parathyroid hormone fracture rate with calcium rather than a reduction with PTH increases trabecular bone density by as much as 50%, calcitriol [40]. Subsequent analysis of this study suggests that but as with fluoride this may be at the expense of cortical the beneficial effect of calcitriol on vertebral fractures is bone [50]. More recent work suggests that the combination only seen in women over the age of 65 years. This study also showed a significant reduction in non-vertebral fractures with calcitriol compared with calcium supplements. Treatment with vitamin D metabolites is associated with an increased risk of hypercalcaemia, but this did not appear to be a major problem in this study [40]. Calcium supplements of PTH with calcitonin or oestrogen may increase spine bone density without adverse effects on cortical bone mass at the femoral neck [51, 52]. Selection of patients and choice of treatment The development of effective treatments for osteoporosis, which afflicts large numbers of older men and women, raises important questions about who should be treated. This will depend on the financial resources available, the absolute risk of fracture in the individual, the efficacy of the treatment in reducing fracture incidence and the costs of the therapeutic intervention and that of any fractures averted. The risk of fracture may be assessed by BMD measurement, as there is a 2 3 fold increase in fracture incidence for each standard Although calcium supplements were previously used alone in the treatment of osteoporosis, this is probably no longer appropriate as a number of more effective treatments are now available. Calcium supplements decrease bone loss, but not to the same extent as other antiresorptive agents [41, 42]. There is limited evidence that calcium supplements deviation reduction in bone density [3, 4]. For any given alone may decrease the risk of vertebral fractures in bone density, the risk of fracture is also doubled in the vitamin D replete elderly people [43]. presence of a previous osteoporotic fracture [3]. It is therefore particularly worthwhile targeting treatment on older individuals with lower than expected BMD (Z score < 1.0) and those with a past history of fragility fracture. Anabolic steroids HRT, bisphosphonates and calcitonin are broadly comparable Anabolic steroids such as stanozolol and nandrolone increase in efficacy in the treatment of established vertebral bone mass in osteoporosis by 5 10% [44, 45]. This has osteoporosis, increasing spine bone density by 3 8% over previously been attributed to increased bone formation, but three years and decreasing vertebral fracture incidence by may be due to decreased bone resorption. Anabolic 55 70% [53]. The cost of these treatments varies widely, steroids are associated with androgenic side-effects and fluid resulting in large differences in cost-effectiveness [53]. The retention, whilst prolonged administration may lead to cost of each vertebral fracture averted is 138 561 for abnormal liver function tests and even hepatocellular HRT, 1880 for cyclical etidronate and 9075 25 013 for tumours. These adverse effects and the lack of evidence of calcitonin [53]. Further cost-effectiveness work is required a beneficial effect on fracture incidence may limit the use to examine the number of patients needing to be treated to of anabolic steroids in the management of osteoporosis. avert vertebral and hip fractures at different BMD levels 1998 Blackwell Science Ltd Br J Clin Pharmacol, 45, 95 99 97
with the therapeutic agents available, particularly as some 16 Lindsay R, Hart DM, Kraszewski A. Prospective double-blind treatments may have a better effect on hip bone density and trial of synthetic steroid Org OD 14 for preventing fracture incidence. postmenopausal osteoporosis. Br Med J 1980; 280: HRT is currently the treatment of choice for younger 1207 1209. 17 Bjarnason NH, Bjarnason K, Haarbo J, Rodenquist C, women with established osteoporosis, whilst bisphosphonates Christiansen C. Tibolone: prevention of bone loss in late are useful in older women who may be unwilling or unable postmenopausal women. J Clin Endocrinol Metab 1996; 81: to take HRT. Intermittent cyclical etidronate therapy is 2419 2422. most useful in the management of predominantly vertebral 18 Love RR, Mazess RB, Barden HS, et al. Effects of tamoxifen osteoporosis, whilst the more expensive alendronate is on bone mineral density in postmenopausal women with appropriate when there is marked reduction in bone density breast cancer. N Engl J Med 1992; 326: 852 856. at other sites. Vitamin D supplementation should be 19 Draper MW, Flowers DE, Huster WJ, Neild JA, Harper KD, considered in frail and housebound elderly people, who are Arnaud C. A controlled trial of raloxifene (LY139481) HCl: at high risk of vitamin D deficiency and hip fractures, whilst Impact on bone turnover and serum lipid profile in healthy calcitriol may potentially be useful in elderly women with postmenopausal women. J Bone Miner Res 1996; 11: 835 842. vertebral fractures. 20 Francis RM. Oral bisphosphonates in the treatment of osteoporosis: A review. Curr Ther Res 1995; 56: 831 851. References 21 Storm T, Thamsborg G, Steinich T, Genant HK, Sorensen OH. Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in women with postmenopausal 1 Cooper C. Epidemiology and definition of osteoporosis. In: Osteoporosis. New perspectives on causes, prevention and treatment. osteoporosis. N Engl J Med 1990; 322: 1265 1271. ed Compston JE. London, Royal College of Physicians of 22 Watts NB, Harris ST, Genant HK, et al. Intermittent cyclical London 1996: 1 10. etidronate treatment of postmenopausal osteoporosis. N Engl 2 Compston JE, Cooper C, Kanis JA. Bone densitometry in J Med 1990; 323: 73 79. clinical practice. Br Med J 1995; 310: 1507 1510. 23 Harris ST, Watts NB, Jackson RD, et al. Four-year study of 3 Ross PD, Davis JW, Epstein RS, Wasnich RD. Pre-existing intermittent cyclic etidronate treatment of postmenopausal fractures and bone mass predict vertebral fracture incidence in osteoporosis: Three years of blinded therapy followed by one women. Ann Intern Med 1991; 114: 919 923. year of open therapy. Am J Med 1993; 95: 557 567. 4 Black DM, Cummings SR, Genant HK, Nevitt MC, 24 Liberman UA, Weiss SR, Broll J, et al. Effect of oral Palermo L, Browner W. Axial and appendicular bone density alendronate on bone mineral density and the incidence of predict fractures in older women. J Bone Miner Res 1992; 7: fractures in postmenopausal osteoporosis. N Engl J Med 1995; 633 638. 333: 1437 1443. 5 Assessment of fracture risk and its application to screening for 25 Black DM, Cummings SR, Karpf DB, et al. Randomized trial postmenopausal osteoporosis. Report of a WHO Study Group. of effect of alendronate on risk of fracture in women with Geneva: World Health Organization 1994. existing vertebral fractures. Lancet 1996; 348: 1535 1541. 6 Peel N, Eastell R. Measurement of bone mass and turnover. 26 Mulder H, Struys A. Intermittent cyclical etidronate in the In: Bailliere s Clinical Rheumatology Osteoporosis. ed Reid DM. prevention of corticosteroid-induced bone loss. Br J Rheumatol London, Bailliere Tindall 1993: 7: 479 498. 1994; 33: 348 350. 7 Barlow DH (Chairman). Report of the Advisory Group on 27 Adachi JD, Bensen WG, Brown J, et al. Intermittent Osteoporosis. London: Department of Health 1994. etidronate therapy to prevent corticosteroid-induced 8 Baillie SP, Davison CE, Johnson FJ, Francis RM. osteoporosis. N Engl J Med 1997; 337: 382 387. Pathogenesis of vertebral crush fractures in men. Age Ageing 28 Struys A, Snelder AA, Mulder H. Cyclical etidronate reverses 1992; 21: 139 141. bone loss of the spine and proximal femur in patients with 9 Caplan GA, Scane AC, Francis RM. Pathogenesis of vertebral established corticosteroid-induced osteoporosis. Am J Med crush fractures in women. J Roy Soc Med 1994; 87: 200 202. 1995; 99: 235 242. 10 Riis B, Thomsen K, Christiansen C. Does calcium 29 Pitt P, Li F, Bloom B, Todd P, Pack S, Hughes G, Moniz C. supplementation prevent post menopausal bone loss? A A double-blind placebo controlled study of intermittent double blind controlled study. N Engl J Med 1987; 316: cyclical etidronate on bone mineral density in patients on 173 177. long-term corticosteroid treatment. Bone 1997; 20: 4S: P232. 11 Weiss NS, Ure CL, Ballard JH, Williams AR, Darling JR. 30 Meunier PJ, Confavreux E, Tupinon I, Hardouin C, Decreased risk of fracture of the hip and lower forearm with Lockwood C, Balena R, Delmas PD. Cyclical etidronate postmenopausal use of oestrogen. N Engl J Med 1980; 303: therapy prevents bone loss in the early postmenopausal 1195 1198. period. J Bone Miner Res 1995; 10 (Supplement 1): S357. 12 Kiel DP, Felson DT, Anderson JJ, Wilson PWF, Moskovitz 31 Herd RJM, Blake GM, Ryan P, Fogelman I. Regional DXA MA. Hip fractures and the use of estrogen in postmenopausal studies in a double blind placebo controlled trial of cyclical women. N Engl J Med 1987; 317: 1169 1174. etidronate therapy for the prevention of early post- 13 Felson DT, Zhang Y, Hannan MT, Kiel DP, Wilson PWF, menopausal bone loss. Bone 1995; 17: 611. Anderson JJ. The effect of postmenopausal estrogen therapy 32 de Groen PC, Lubbe DF, Hirsch LJ, et al. Esophagitis on bone density in elderly women. N Engl J Med 1993; 329: associated with the use of alendronate. N Engl J Med 1996; 1141 1146. 335: 1016 1021. 14 Lufkin EG, Wahner HW, O Fallon WM, et al. Treatment of 33 Overgaard K, Hansen MA, Jensen SB, Christiansen C. Effect postmenopausal osteoporosis with transdermal estrogen. Ann of Salcatonin given intranasally on bone mass and fracture Intern Med 1992; 117: 1 9. rates in established osteoporosis: a dose-response study. Br 15 Lindsay R, Tohme J. Estrogen treatment of patients with Med J 1992; 305: 556 561. established postmenopausal osteoporosis. Obstet Gynecol 1990; 34 Rico H, Henandez ER, Revilla M, Gomez-Castresana F. 76: 1 6. Salmon calcitonin reduces vertebral fracture rate in 98 1998 Blackwell Science Ltd Br J Clin Pharmacol, 45, 95 99
postmenopausal crush fracture syndrome. Bone Miner 1992; 45 Need AG, Chatterton BE, Walker CJ, Steurer TA, 16: 131 138. Horowitz M, Nordin BEC. Comparison of calcium, calcitriol, 35 Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D 3 and ovarian hormones and nandrolone in the treatment of calcium to prevent hip fractures in elderly women. N Engl osteoporosis. Maturitas 1986; 8: 275 280. J Med 1992; 327: 1637 1642. 46 Kleerekoper M, Peterson EL, Nelson DA, et al. A randomized 36 Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. Effect of trial of sodium fluoride as a treatment for postmenopausal calcium and vitamin D supplementation on bone density in osteoporosis. Osteoporosis Int 1991; 1: 155 161. men and women 65 years of age and older. N Engl J Med 47 Riggs BL, Hodgson SF, O Fallon WM, et al. Effect of 1997; 337: 670 676. fluoride treatment on the fracture rate in postmenopausal 37 Heikinheimo RJ, Inkovaara JA, Harju EJ, et al. Annual women with osteoporosis. N Engl J Med 1990; 322: 802 809. injection of Vitamin D and fractures of aged bones. Calcif 48 Meunier PJ, Sebert JL, Reginster JY, et al. Fluoride salts Tissue Int 1992; 51: 105 110. compared to calcium-vitamin D in the treatment of 38 Lips P, Graafmans WC, Ooms ME, Bezemer PD, Bouter established postmenopausal osteoporosis: The FAVOS study. LM. Vitamin D supplementation and fracture incidence in Osteoporosis Int 1996; 6 (Supplement 1): 251. elderly persons. A randomized, placebo-controlled clinical 49 Pak CYC, Sakhaee K, Adams-Huet B, Piziak V, Peterson trial. Ann Intern Med 1996; 124: 400 406. RD, Poindexter JR. Treatment of postmenopausal 39 Francis RM, Boyle IT, Moniz C, et al. A comparison of the osteoporosis with slow release sodium fluoride. Ann Intern effects of alfacalcidol treatment and vitamin D 2 Med 1995; 123: 401 408. supplementation on calcium absorption in elderly women 50 Reeve J, Meunier PJ, Parsons JA, Bernat M, Bijvoet OLM, with vertebral fractures. Osteoporosis Int 1996; 6: 284 290. Courpron P. Anabolic effect of human parathyroid hormone 40 Tilyard MW, Spears GFS, Thompson J, Dovey S. Treatment fragment on trabecular bone in involutional osteoporosis: a of postmenopausal osteoporosis with calcitriol or calcium. N multicentre trial. Br Med J 1980; 280: 1340 1344. Engl J Med 1992; 326: 357 362. 51 Hodsman AB, Fraher LJ, Watson PH, et al. A randomized 41 Prince RL, Smith M, Dick IM, et al. Prevention of controlled trial to compare the efficacy of cyclical parathyroid postmenopausal osteoporosis. A comparative study of exercise, hormone versus cyclical parathyroid hormone and sequential calcium supplementation and hormone-replacement therapy. calcitonin to improve bone mass in postmenopausal women N Engl J Med 1991; 325: 1189 1195. with osteoporosis. J Clin Endocrinol Metab 1997; 82: 620 628. 42 Reid IR, Ames RW, Evans MC, et al. Effect of calcium 52 Lindsay R, Nieves J, Formica C, et al. Randomised controlled supplementation on bone loss in postmenopausal women. N study of effect of parathyroid hormone on vertebral-bone Engl J Med 1993; 328: 460 464. mass and fracture incidence among postmenopausal women 43 Chevalley T, Rizzoli R, Nydegger V, et al. Effects of calcium on oestrogen with osteoporosis. Lancet 1997; 350: 550 555. supplements on femoral neck bone mineral density and 53 Francis RM, Anderson FH, Torgerson DJ. A comparison of vertebral fracture rate in vitamin D replete elderly patients. the effectiveness and cost of treatment for vertebral fractures in women. Br J Rheumatol 1995; 34: 1167 1171. Osteoporosis Int 1994; 4: 245 252. 44 Chesnut CH, Ivey JL, Gruber HE, et al. Stanozolol in postmenopausal osteoporosis: therapeutic efficacy and possible ( Received 16 June 1997, mechanisms of action. Metabolism 1983; 29: 559 562. accepted 10 October 1997) 1998 Blackwell Science Ltd Br J Clin Pharmacol, 45, 95 99 99