Alternatives to HRT in prevention and treatment

8 Alternatives to HRT in prevention and treatment M. S. M A R S H J. C. S T E V E N S O N

The drugs used for the treatment and prevention of osteoporosis may be classified into those that retard bone resorption, such as oestrogens, calcitonin and the bisphosphonates, and those that stimulate bone formation, such as anabolic steroids and fluoride. They may be used alone, simultaneously, or in sequential regimens. Oestrogen hormone replacement therapy is generally considered to be the treatment of choice in postmenopausal women but other therapies are needed when this is contraindicated or poorly tolerated. ANTIRESORPTIVE AGENTS Calcitonin

Synthetic salmon calcitonin given by intramuscular or subcutaneous injection has been used clinically for many years in the treatment of disorders associated with increased bone remodelling, such as Paget's disease of bone (Goldfield et al, 1972; Avrimides et al, 1976; Sturtridge et al, 1977). More recently, it has been used in the treatment of osteoporosis (Rasmussen et al, 1980). Calcitonin is a hormone secreted by thyroidat C cells (Foster et al, 1964) whose existence predates the evolution of the bony fish (Girgis et al, 1980). It is a 32 amino acid peptide with a prolinamide at the carboxyl terminus and a disulphide bridge between the cysteine residues at positions 1 and 7. It is synthesized as part of a large precursor polypeptide which requires posttranslational processing to remove N- and C-terminal flanking peptides, and requires its complete amino acid sequence for biological activity (Stevenson and Evans, 1981). It is rapidly degraded by gastric secretions when given by mouth and non-oral administration is therefore necessary. Various species-specific forms exist (Stevenson, 1980). The teleost group of calcitonins, which include salmon calcitonin, are the most resistant to degradation (De Luise et al, 1970), making them the most potent in terms of biological activity per unit weight. BailliOre's ClinicalRheumatology--

Vol. 7, No. 3, October1993 ISBN0-7020-1711-6

549 Copyright9 1993,byBailli6reTindall Allrightsofreproductionin anyformreserved

550

M. S. MARSH AND J. C. STEVENSON

The major site of action of calcitonin is directly on bone, where it has been shown to inhibit bone resorption both in vitro (Friedman and Raisz, 1965) and in vivo (Milhaud et al, 1965). It inhibits osteoclast activity in the short term and reduces osteoclast numbers in the long term (Foster et al, 1969), probably by recruitment inhibition. It has its action via specific cell surface receptors linked to adenylate cyclase, and initiates a cascade of intracellular protein phosphorylations following binding (Stevenson et al, 1990). There is some evidence to suggest that calcitonin has an action on osteoblasts. It stimulates bone formation in some species (Glowacki, 1986) and appears to increase bone matrix synthesis in vitro (Farley et al, 1988). The physiological rote of calcitonin may be protection of the skeleton against unwanted resorption, particularly during times of calcium stress, although the complete function of calcitonin in humans is still unclear. It is probable that it is involved in bone calcium regulation rather than plasma calcium regulation. There is evidence both in vitro (Greenberg et al, 1986) and in vivo (Stevenson et al, 1981) that exogenous oestrogens stimulate calcitonin secretion, and thus a relative calcitonin deficiency may result from the fall in oestrogen levels at the time of the menopause. Lower levels of calcitonin are to be found in women with osteoporosis compared with those with normal bone density (Taggart et al, 1982; Stevenson et al, 1986), but the significance of this finding is not established. There are conflicting reports concerning the effect of calcitonin deficiency on the skeleton, with normal (Hurley et al, 1987) or reduced (McDermott et al, 1983) bone density being found. The antiresorptive action of calcitonin has been utilized in both the prevention and treatment of postmenopausal osteoporosis. Initial studies of calcitonin treatment for osteoporosis proved disappointing and inconclusive, probably owing to inadequacies of the available methods for measuring bone density and inappropriately short lengths of therapy (Stevenson et al, 1981). With improved methodologies for bone mass measurement, studies have been able to demonstrate clear beneficial effects of injectable calcitonin in both the prevention and treatment of osteoporosis. A 2-year randomized study of 70 postmenopausal women with normal bone density showed that low dose (20iu) synthetic human calcitonin given subcutaneously three times per week preserved vertebral bone density as effectively as percutaneous oestradiol (MacIntyre et al, 1988). Other studies have demonstrated a positive effect of salmon calcitonin given as intramuscular injections, usually in a dose of 100 iu daily, either alone (Gruber et al, 1984) or in combination with oral phosphate (Rasmussen et al, 1980). However, there are major disadvantages of administration of calcitonin by injection. The necessity for injection leads to poor compliance, particularly in the long term (MacIntyre et al, 1988), and the rapid and large rise in blood levels of calcitonin following injection can lead to side-effects such as nausea and facial flushing (Stevenson and Evans, 1981). These problems are especially relevant in the management of osteoporosis where preventive therapy is given to asymptomatic women for long periods of time. As a result

A L T E R N A T I V E S TO H R T

551

of these shortcomings, alternative methods of administration have been developed, the most promising of which appears to be the intranasal route. Clinical and therapeutic responses to intranasal calcitonin have been studied in patients with Paget's disease and osteoporosis, and it has been established that this form of administration can produce clinical responses without significant side-effects. Intranasal salmon calcitonin will conserve bone density both in normal postmenopausal women (Reginster et al, 1987) and in those with established osteoporosis (Overgaard et al, 1989). It also appears to reduce fracture incidence (Overgaard et al, 1992). Doses have ranged from 50iu on alternate days to 200 iu daily, of which only a small proportion, between 5% and 50%, is absorbed (Gennari et al, 1981; O'Doherty et al, 1990; Thamsborg et al, 1990). Calcitonin has also been used successfully in a variety of other bone disorders, such as corticosteroid-induced osteoporosis, osteogenesis imperfecta, immobilization osteoporosis and algodystrophy (Sudeck's atrophy) (Stevenson and Evans, 1981).

Bisphosphonates Bisphosphonates are stable carbon-substituted analogues of pyrophosphate, which is a physiological inhibitor of bone mineralization. Bisphosphonates bind to the hydroxyapatite crystals of the bone surface and appear to bind selectively to resorptive surfaces (Sato et al, 1991). They are released by acidification during osteoclastic absorption and are then taken up by the osteoclasts and inhibit further osteoclastic activity. Bisphosphonates are poorly absorbed from the gastrointestinal tract, but because of their potent antiresorptive action they can be administered by mouth. The first bisphosphonate compound to be used clinically was etidronate, which was used for the treatment of Paget's disease of bone. This compound has the disadvantage that at high doses it impairs mineralization of newly formed bone matrix as well as inhibiting resorption (Russell et al, 1974). However, when used at a low dose (400 mg/day) in an intermittent cyclical regimen, etidronate has been shown to increase bone density and reduce the rate of vertebral fracture in women with spinal osteoporosis compared with placebo-treated controls, who lost bone density (Storm et al, 1990; Watts et al, 1990). Newer and more potent bisphosphonates such as tiludronate and aminohydroxypropylidene diphosphonate (APD; pamidronate) have recently been developed. These drugs appear to inhibit resorption at much lower concentrations than that at which they impair mineralization. A randomized placebo-controlled double-blind study of tiludronate has demonstrated preservation of bone density in treated postmenopausal women compared with those treated with placebo, whose density fell (Reginster et al, 1989). Pamidronate given continuously has been shown to cause a mean rise in lumbar bone density of approximately 3% per year; in some patients the density increased by 50% after 4 years of treatment (Valkema et al, 1987). It also appears to prevent bone loss in patients receiving corticosteroids (Reid

552

M.S.

M A R S H A N D J. C. S T E V E N S O N

et al, 1988). Because of the long skeletal retention time of bisphosphonates and the possible adverse effects on mineralization, they need be given only in intermittent courses. It is important to note that the bisphosphonates react chemically with bone and that their retention in the skeleton may be extremely long, perhaps even for life. Therefore, caution is advised before committing younger postmenopausal patients to prolonged therapy.

Calcium There is little convincing evidence that calcium deficiency is a major contributor to the development of postmenopausal osteoporosis (Kanis and Passmore, 1989a; 1989b) and the evidence that increasing calcium intake benefits the skeleton is controversial (Heaney, 1987; Kanis and Passmore, 1989b). In the majority of adults taking a healthy diet, calcium supplementation has little or no effect on bone density. There have been few satisfactory prospective studies of the effects of calcium supplementation on bone density that control for the effects of increased energy intake. Although in one study calcium had a beneficial effect on bone density when given to older women on very low calcium intakes (Dawson-Hughes et al, 1990), there is no good evidence that increasing dietary intake above 400 mg/day in adults is of significant benefit. Whilst certain calcium salts have been shown to retard bone loss in postmenopausal women, this has been seen in women on extremely low (<400mg daily) intakes of calcium who were more than 5 years postmenopause (Dawson-Hughes et al, 1990). For women on the usual UK range of calcium intakes, calcium supplements have no significant effect (Wickham et al, 1989). Similarly, there is no convincing evidence that calcium supplements augment the effects of other therapies such as hormone replacement therapy. Although one study suggested an effect (Ettinger et al, 1987), the study design was inappropriate to demonstrate this action. Certainly, the small increases in bone density that may be achieved by alterations in dietary calcium intake are insufficient to prevent the rapid fall in density that occurs in women around the time of the menopause.

Ipriflavone Ipriflavone is an isoflavone (7-isopropoxy-3-phenyl-4H-l-benzopyran-4one) that was initially developed as a treatment for diabetes. It appears to inhibit loss of bone mass by inhibiting bone resorption and demineralization by both a direct and indirect action. It stimulates collagen synthesis in human bone cell cultures (Szilklai and Ribari, 1985) and animal studies have shown that it may suppress bone resorption by increasing the action of oestrogen directly on bone sites (Yamazaki and Kinoshita, 1986), perhaps by potentiating calcitonin secretion or enhancing the sensitivity to calcitonin action (Canonico et al, 1990). Ipriflavone may prove to be a useful drug in the treatment and prevention of osteoporosis. The results of preliminary studies are encouraging (Agnusdei et al, 1990; Szocsik et al, 1990).

ALTERNATIVES TO HRT

553

TREATMENTS THAT STIMULATE BONE FORMATION Fluoride

Fluoride has been used in the treatment of osteoporosis for nearly 30 years (Rich and Ensinck, 1961). Several reports have shown that sodium fluoride increases trabecular bone density (Riggs et al, 1982, Baud et al, 1988; Mamelle et al, 1988), particularly in the spine. Of all the therapeutic methods for the treatment of osteoporosis, fluoride is perhaps the one that is most likely to increase bone density in the long term. However, in one recent placebo-controlled study of 135 women treated with 75 rag/day and followed for 4 years (Riggs et al, 1990), increased bone density was not associated with a reduction in the incidence of vertebral fracture. There are also reports that fluoride treatment causes an increased incidence of hip fracture (Hedlund and Gallagher, 1989). Other studies have not found an increased incidence of fracture and it has been suggested that this is due, among other things, to differences in the administered or absorbed dosage. Two randomized controlled trials using 50 rag/day have shown a reduced fracture rate (Mamelle et al, 1988; Buckle, 1989), so it is possible that the therapeutic window is narrow and that too high a dose leads to a toxic effect on osteoblasts (Meunier, 2990). The calcium balance appears to be unchanged in women taking fluoride, and it has been proposed that bone is redistributed from the hip, and other sites, to the spine. It has been suggested that concurrent administration of high doses of calcium may avoid this effect. A further explanation for the increased fracture rate with fluoride therapy is that the structural quality of fluoridated hydroxyapatite is poor. The response to fluoride varies considerably between patients and up to one third do not appear to show an effect on bone density. This may be due to variations in the sensitivity of osteoblast to fluoride (Riggs, 1982; Kraenzlin et al, 1990). Those with younger bone show the least response (Baud et al, 1988), perhaps because bone cell activity in these subjects is already high and therefore less able to be increased. Upper gastrointestinal side-effects are seen in a significant number of patients taking fluoride, and approximately 25% develop pse~doarthritic pains in the joints of the lower limb (Duursma et al, 1987). The mechanism for the latter is unknown but it is often associated with raised serum fluoride and high alkaline phosphate levels. The pain usually resolves after a few weeks off treatment and may be avoided when therapy is restarted by giving a lower dose and carefully monitoring the alkaline phosphate and serum fluoride concentrations. Because of the side-effects, the narrow therapeutic window, and worries about the increased incidence of fracture, we feel that treatment of osteoporosis with fluoride should be undertaken only in specialist centres. Anabolic steroids It is not certain h o w anabolic steroids produce their effects on bone. It has

554

M.S.

MARSH AND J. C. STEVENSON

been postulated that they have a direct effect on osteoblasts or their precursors and/or an action to prevent bone resorption. There is in vitro evidence for the former effect (Beneton et al, 1991). They do not combine chemically with bone tissue, and thus there is no reason to suspect impairment of bone quality. Chesnut and colleagues (1977) studied 13 postmenopausal women taking methandrostenolone and, using neutron activation, compared the changes in total body calcium (TBCa) with those in 13 women taking placebo over 2.5 years. The TBCa rose by 2% in the treated women and fell by 3% in the placebo group. The rise in the treated group occurred during the first year, after which a plateau was reached. A similar study by Aloia and co-workers (1981) found an initial rise in TBCa for 6 months that was not sustained over 2 years. Nandrolone has been shown to increase bone mineral content by 6% in 11 patients treated over 2 years (Guesens and Dequeker, 1986). In another study of 21 patients treated with stanozolol, there was a mean increase in bone mineral content of 4.4% over 29 months compared with the level in 17 patients receiving placebo whose bone density did not change (Chesnut et al, 1983). Anabolic steroids in the presently used dose regimens are inappropriate for long-term use as they induce a very unfavourable lipid profile if given orally. Parenteral administration may avoid this metabolic complication, but induces insulin resistance (Godsland et al, 1986), which is an important cardiovascular risk marker (Stout, 1990). In elderly patients, anabolic steroid administration may lead to fluid retention and increase the risk of cardiac failure. Use of these drugs should be confined to suitable patients, in particular those who are underweight and frail. Vitamin D

Vitamin D metabolites such as calcitriol may have an anabolic effect on bone, as they act to stimulate osteoblasts (Gallagher and Riggs, 1990). However, several studies have shown that at the doses necessary to obtain an effect on bone, they may cause unwanted side-effects such as hypercalciuria (Aloia et al, 1988; Ott and Chesnut, 1989), with a risk of renal calculi formation (Chesnut et al, 1983; Aloia et al, 1988) and occasional hypercalcaemia (Aloia et al, 1988; Ott and Chesnut, 1989; Tillyard et al, 1992). There is conflicting evidence whether vitamin D or its analogues are beneficial in the treatment or prevention of osteoporosis. In a 2-year placebocontrolled study of the effects of calcitriol (mean dose 0.43 p.g/day) on 86 postmenopausal women with vertebral compression fractures, Ott and Chesnut (1989) were unable to demonstrate an increase in total body calcium or lumbar bone density or a decrease in the number of new fractures. A more recent, larger, 3-year study of 622 postmenopausal women with vertebral fractures randomized to calcium or calcitriol (0.25 p~g twice a day) showed a reduction in the rate of new vertebral fractures at 2 and 3 years in those women who had five or fewer fractures at entry (Tillyard et al, 1992).

ALTERNATIVES TO HRT

555

As the doses of vitamin D metabolites necessary to produce a positive effect on bone are associated with toxic side-effects, new vitamin D metabolites are being evaluated which may avoid such side-effects (Abe et al, 1988; Bishop et al, 1990), and preliminary studies suggest that these may exhibit an effect on bone without the unwanted hyperabsorption of calcium (Gallagher et al, 1989). Further studies are awaited. Parathyroid hormone

Treatment of osteoporosis with parathyroid hormone (PTH) appears to have similar pitfalls to treatment with fluoride. Although PTH stimulates bone formation when given intermittently in low doses (Reeve et al, 1980; Slovik et al, 1981), higher doses stimulate resorption. Three studies of up to 2 years' duration have shown that vertebral bone density may be moderately increased (Reeve et al, 1980; Slovik et al, 1981; Neer et al, 1990). One study (Neer et al, 1990) showed a progressive fall in radial cortical bone density, suggesting that peripheral bone may be redistributed to the axial skeleton and/or that cortical bone may be redistributed to the cancellous compartment. Treatment of osteoporosis with PTH is clearly at an experimental stage at present, and should be undertaken only within the confines of controlled clinical trials. Growth factors

Numerous growth factors that directly influence bone cell activity have been identified, including platelet-derived growth factor (PDGF), insulin-like growth factors and transforming growth factor 13(TGF-13). PDGF stimulates bone resorption, is mitogenic for fibroblasts, and may mediate the mitogenic effects of interleukins. TGF-13 is produced in an inactive form which is activated by an acid environment. It has been postulated that TGF-[3 may be released from bone matrix during reabsorption and affect osteoblastic and osteoclastic activity (Russell et al, 1990). Insulin-like growth factors and TGF-[3 are available in purified form and are currently being evaluated as stimulants to bone formation. They have potent extraskeletal'effects and therefore strategies to bind them to osteophilic compounds or stimulate their local production by osteoblasts are being evaluated. Combined treatment and ADFR

'Activate, depress, free and repeat' (ADFR) regimens have recently been developed and may provide a way of increasing bone density more than single treatment regimens (Frost, 1979). A drug that is capable of stimulating bone formation is given first, followed by an agent that depresses bone resorption. It is theorized that, during the 'free' period, the former may steadily increase bone at each remodelling site. The cycle is repeated as required. Studies of this method have used phosphate as the activating agent, in

556

M. S. M A R S H A N D J. C. S T E V E N S O N

combination with calcitonin or etidronate (Rasmussen et al, 1980; Marie and Caulin, 1986). It appears that phosphate-etidronate combinations achieve no better results than cyclical etidronate alone, perhaps because the long skeletal half-life of the bisphosphonates makes them unsuitable for the ADFR concept. Another study used PTH as the activator and calcitonin as the suppressor, and preliminary results look promising (Hesch et al, 1989). Exercise

In a previously sedentary patient, regular exercise is likely to not only increase bone density but will also improve dexterity and muscle mass, thereby reducing the chance of serious fracture should a fall occur. Regular weight-bearing exercise induces some beneficial changes in bone density in postmenopausal women (Chow et al, 1987; Stevenson et al, 1989), but by itself is unable to prevent normal bone loss in the immediate postmenopausal years. It is quite clear that exercise cannot prevent the bone loss induced by gonadal hormone deficiency (Lloyd et al, 1988). Furthermore, it has been shown that the benefits gained by exercise are rapidly lost if a sedentary life-style is resumed (Dalsky et al, 1988). Whilst reduced physical activity due to infirmity and disability is associated with an increase in hip fractures (Wickham et al, 1989), the concept that increasing physical activity in otherwise healthy people will reduce fracture incidence is illogical. Thus, exercise should be regarded as an adjuvant rather than an alternative to active therapy to prevent or treat osteoporosis. Patients who are not osteoporotic should be encouraged to take up exercises that put stress on weight-bearing bones such as the spine or hip that are appropriate to their cardiovascular fitness. Good examples are walking, jogging and playing tennis. In patients with established osteoporosis, exercises that involve jarring movements and flexion of the back should be avoided and the emphasis should be towards activity that encourages flexibility. SUMMARY

Oestrogen hormone replacement therapy remains the first choice for the treatment and prevention of osteoporosis in postmenopausal women, but for patients who are unsuitable for this therapy, which of course includes men, other satisfactory treatments are available. Several placebo-controlled studies have demonstrated that bisphosphonates and calcitonin prevent bone loss or perhaps increase bone density over 2-3-year periods, and reduce the rate of fracture. It is not known whether these treatments will increase bone density over longer periods of time. Cyclical etidronate has recently become licensed in the UK for use in the treatment of osteoporosis, and it is hoped that other bisphosphonates and intranasal calcitonin will soon be added to the available treatments. Fluoride appears to increase bone density but, at doses above a very narrow therapeutic window, it increases the fracture rate, either because of

ALTERNATIVES TO HRT

557

b o n e r e d i s t r i b u t i o n , f o r m a t i o n of p o o r quality b o n e or a toxic effect o n osteoblasts. A t p r e s e n t , fluoride r e m a i n s a t r e a t m e n t to be used o n l y u n d e r e x p e r t supervision or within the context of c o n t r o l l e d clinical trials. A n a b o l i c steroids m a y be of v a l u e in selected elderly p a t i e n t s with osteoporosis. T h e p a t i e n t m a y be able to c o n t r i b u t e to the p r e v e n t i o n of o s t e o p o r o t i c fracture by exercising, which will i m p r o v e dexterity a n d m a y have a small effect to increase b o n e density, a n d by avoiding the factors that p r e d i s p o s e to falls, such as icy paths a n d excess alcohol. C h a n g e s in the diet are u n l i k e l y to play a m a j o r role in the m a i n t e n a n c e of b o n e d e n s i t y in w o m e n living in the W e s t e r n world.

REFERENCES

Abe J, Morikowa M, Takita Yet al (1988) lc~,25-Dihydroxy-22-oxavitaminD3: a new synthetic analogue of vitamin D3 having potent differentiation-producing activity without inducing hypercalcaemia in vivo and in vitro. In Seventh Workshop on Vitamin D, pp 309-310. Ranch Mirage, California: Walter de Gruyter. Aloia JF, Kapoor A, Vaswani A & Cohn SH (1981) Changes in body composition following therapy for osteoporosis with methandrostenelone. Metabolism 30: 1076-1079. Aloia JF, Vaswani A, Yeh JK et al (1988) Calcitriol in the treatment of postmenopausal osteoporosis, American Medical Journal 84: 401-408. Agnusdei D, Genari C, Baroni MC, Passeri M, Ciacca A & Ventura A (1990) Metabolic and clinical effects of ipriflavone in postmenopausal osteoporotic patients. In Christiansen C & Overgaard K (eds) Osteoporosis 1900, pp 2159-2163. Copenhagen: Osteopress. Avrimides A, Flores A, De Rose J & Wallach S (1976) Paget's disease of bone: observations after cessation of long term synthetic salmon calcitonin treatment. Journal o f Clinical Endocrinology and Metabolism 42: 459-463. Baud CA, Very JM & Courvoisier B (1988) Biophysical studies of bone mineral in biopsies of osteoporotic patients before and after long-term treatment with fluoride. Bone 9: 361-365. Beneton MNC, Yates AJP, Rogers S e t al (1991) Stanozalol stimulates remodelling of trabecular bone and the net formation of bone at the endocortical surface. Clinical Science 81: 543-549. Bishop CW, Valliere C, Knutson JC et al (1990) Oral toxicity of lc~-hydroxyvitaminO2 (lc~OHDa) in rats. Journal of Bone and Mineral Research 5 (supplement): 196. Buckle RM (1989) A 3 year study of sodium fluoride treatment on vertebral fracture incidence in osteoporosis. Journal of Bone and Mineral Research 4 (supplement 1): ~186. Canonico PL, Sortino MA & Scapagnini U (1990) Effects of ipriflavone on experimental models of bone resorption and synthesis. In Christiansen C & Overgaard K (eds) Osteoporosis 1990, pp 2133-2136. Copenhagen: Osteopress. Chesnut CH, Nelp WB, Baylink DJ & Denney JD (1977) Effect of methandrostenolone on postmenopausal bone wasting as assessed by changes in total bone mineral mass. Metabolism 26: 267-277. Chesnut CH, Ivey JL, Gruber HE et al (1983) Stanozolol in postmenopausal osteoporosis: therapeutic efficacy and possible mechanisms of action. Metabolism 32: 571-580. Chow R, Harrison JE & Notarius C (1987) Effect of two randomised exercise prograrnmes on bone mass of healthy women. British Medical Journal 295: 1441-1444. Dalsky GP, Stocke KS, Ehsani AA et al (1988) Weight-bearing exercise training and lumbar bone mineral content in postmenopausal women. Annals o f Internal Medicine 108: 824828. Dawson-Hughes B, Dallal GE, Krall EA et al (1990) A controlled trial of the effect of calcium supplementation on bone density in postmenopausal women. New England Journal o f Medicine 323: 878-883. Duursma SA, Glerum JH, van Dijk A e t al (1987) Responders and non-responders after fluoride therapy in osteoporosis. Bone 8: 131-136.

558

M. S. MARSH AND J. C. STEVENSON

Ettinger B, Genant HK & Cann CE (1987) Postmenopausal bone loss is prevented by treatment with low dosage estrogen with calcium. Annals of Internal Medicine 106: 40-45. Farley JR, Tarbaux NM, Hall SL et al (1988) The anti-bone-resorptivc agent calcitonin also acts in vitro to directly increase bone formation and bone cell proliferation. Endocrinology 123: 159-167. Foster GV, Baghdiantz A, Kumar MA et al (1964) Thyroid origin of calcitonin. Nature 202: 1303-1305. Foster GV, Doyle RH, Bordier P & Matrajt H (1969) In vivo effects of thyrocalcitonin on bone. In Milhaud G, Owen M & Blackwood HJJ (eds) Les Tissus Calcifies, pp 173-177. Paris: Soci6t6 d'Edition d'Enseignement Superieur. Friedman J & Raisz LG (1965) Thyrocalcitonin: inhibitor of bone resorption in tissue culture. Science 150: 1465-1466. Frost HM (1979) Treatment of osteoporosis by manipulation of coherent bone cell populations. Clinics in Orthopaedics and Related Research 143: 227-244. Gallagher JC & Riggs BL (1990) Action of 1,25-dihydroxyvitamin D3 on calcium balance and bone turnover and its effects on vertebral fracture rate. Metabolism 39 (supplement): 30-34. GaUagher JC, DeLuca HF, Bishop CW & Mazess RB (1989) Effect of increasing doses of 1-et hydroxyvitamin D2 on serum and urine calcium in postmenopausal osteoporosis. Journal of Bone and Mineral Research 4 (supplement 1). Gennari C, Chierichetti SM & Vibelli C (1981) Acute effects of salmon, human and porcine calcitonin on plasma calcium and cyclic AMP levels in man. Current Therapeutics Research 30: 1024-1034. Girgis SI, Galan F, Arnett TR et al (1980) Immunoreactive human calcitonin-like molecule in the nervous systems of protochordates and a cyclostome, Myxine. Journal of Endocrinology 87: 375-382. Glowacki J (1986) Factors that stimulate bone formation. In Second International Conference on Osteoporosis. Social and Clinical Aspects, pp 93-103. Milan: Masson Italia Editori. Godsland IF, Shennan NM & Wynn V (1986) Insulin action and dynamics modelling in patients taking the anabolic steroid methandienone (Dianabol). Clinical Science 71: 665-673. Goldfield EB, Braiker BM, Prendergast JJ & Kolb FO (1972) Synthetic salmon calcitonin: treatment of Paget's disease and osteogenesis imperfecta. Journal of the American Medical Association 221: 1127-1129. Greenberg C, Kukreja SC, Bowser EN et al (1986) Effects of estradiol and progesterone on calcitonin secretion. Endocrinology 118: 2594-2598. Gruber HE, Ivey JL, Baylink DJ et al (1984) Long-term calcitonin therapy in postmenopausal osteoporosis. Metabolism 33: 295-303. Guesens P & Dequeker J (1986) Long-term effect of nandrolone decanoate, la-hydroxyvitamin D3 or intermittent calcium infusion therapy on bone mineral content, bone remodeling and fracture rate in symptomatic osteoporosis: a double-blind controlled study. Journal of Bone and Mineral Research 1: 347-357. Heaney RP (1987) The role of nutrition in prevention and management of osteoporosis. Clinics in Obstetrics and Gynecology 50: 833-846. Hedlund IR & Gallagher JC (1989) Increased incidence of hip fracture in women treated with sodium fluoride. Journal of Bone and Mineral Research 4: 223-225. Hesch R-D, Busch U, Prokop M e t al (1989) Increase of vertebral bone density by combination therapy with pulsatile 1-38 PTH and sequential addition of calcium nasal spray in osteoporotic patients. Calcified Tissue International 44: 176-180. Hurley DL, Teigs RD, Wahner HW & Heath H (1987) Axial and appendicular bone mineral density in patients with long-term deficiency or excess of calcitonin. New England Journal of Medicine 317: 537-541. Kanis JA & Passmore R (1989a) Calcium supplementation of the diet--II. British Medical Journal 298: 205-208. Kanis JA & Passmore R (1989b) Calcium supplementation of the diet--I. British Medical Journal 298: 137-140. Kraenzlin ME, Kraenzlin C & Farley SMG (1990) Fluoride pharmacokinetics in good and poor responders to fluoride therapy. Journal of Bone and Mineral Research 5 (supplement 1): $49-$52. Lloyd T, Myers C, Buchanan JR & Demers LM (1988) Collegiate women athletes with

ALTERNATIVES TO HRT

559

irregular menses during adolescence have decreased bone density. Obstetrics and Gynaecology 72: 639-642. De Luise M, Martin TJ & Melick RA (1970) Inactivation and degradation of porcine calcitonin by rat liver, and relative stability of salmon calcitonin. Journal of Endocrinology 48: 181-188. McDermott MT, Kidd GS, Blue P et al (1983) Reduced bone mineral content in totally thyroidectomized patients: possible effects of calcitonin deficiency. Journal of Clinical Endocrinology and Metabolism 56: 936-939. MacIntyre I, Stevenson JC, Whitehead MI et al (1988) Calcitonin for prevention of postmenopausal bone loss. Lancet i: 900-902. Mamelle N, Muenier PG, Dusan R et al (1988) Risk-benefit ratio of sodium fluoride treatment in primary vertebral osteoporosis. Lancet ii: 361-365. Marie PJ & Caulin F (1986) Mechanisms underlying the effects of phosphate and calcitonin on bone histology in postmenopausal osteoporosis. Bone 7: 17-22. Meunier PJ (1990) Fluoride salts and osteoporosis. In Christiansen C & Overgaard K (eds) Osteoporosis 1990, pp 1308-1313. Copenhagen: Osteopress. Milhaud G, Perault AM & Moukhtar MS (1965) Etud6 de mecanisme de l'action hypocalcemiante de la thyrocalcitonine. Comptes Rendus de l'AcadOmie des Sciences (Paris) 261: 813-816. Neer R, Slovik D, Daly M e t al (1990) Treatment of postmenopausal osteoporosis with daily parathyroid hormone plus calcitrol. In Christiansen C & Overgaard K (eds) Osteoporosis 1990, pp 1314-1317. Copenhagen: Osteopress. O'Doherty DP, Bickerstaff DR & McCloskey EV (1990) A comparison of the acute effects of subcutaneous and intranasal calcitonin. Clinical Science 78: 215-219. Ott SM & Chesnut CH (1989) Calcitriol treatment is not effective in postmenopausal osteoporosis. Annals of lnternal Medicine 110: 267-274. Overgaard K, Riis BJ, Christiansen C et al (1989b) Nasal calcitonin for the treatment of established osteoporosis. Clinical Endocrinology 30: 435-442. Overgaard K, Hansen MA, Jensen SB & Christiansen C (1992) Effect of salcatonin given intranasally on bone mass and fracture rates in established osteoporosis: a dose-response study. British Medical Journal 305: 556-561. Rasmussen H, Bordier P & Marie P (1980) Effect of combined therapy with phosphate and calcitonin on bone volume in osteoporosis. Metabolic Bone Disease and Related Research 2: 107-111. Reeve J, Meunier P J, Parsons JA et al (1980) Anabolic effects of human parathyroid hormone fragment on trabecular bone in involutional osteoporosis: a multicentre trial. British Medical Journal 280: 1340-1344. Reginster JY, Denis D, Albert A et al (1987) 1-year controlled randomised trial of prevention of early postmenopausal bone loss by intranasal calcitonin. Lancet ii: 1481-1483. Reginster JY, Deroisy R, Denis D et al (1989) Prevention of postmenopausal bone loss by tiludronate. Lancet ii" 1469-1471. Reid IR, King AR, Alexander CJ & Ibbertson HK (1988) Prevention of steroid-induced osteoporosis with (3-amino-l-hydroxypropylidene)-l,l-bisphosphonate'(APD). Lancet i: 143-146. Rich C, & Ensinck J (1961) Effect of sodium fluoride on calcium metabolism of human beings. Nature 191: 184-185. Riggs BL (1982) Evidence for the etiological heterogenicity of involutional osteoporosis. In Menczel J, Robin GC, Makin M & Steinberg R (eds) Osteoporosis, pp 3-14. Chichester: John Wiley. Riggs BL, Seeman E, Hodgson SF et al (1982) Effect of the fluoride/calcium regimen on vertebral fracture occurrence in postmenopausal osteoporosis: comparison with conventional therapy. New England Journal of Medicine 306: 446-450. Riggs BL, Hodgson SF, O'Fallon WM et al (1990) Effect of the fluoride treatment on the fracture in postmenopausal women with osteoporosis. New England Journal of Medicine 322: 802-809. Russell RGG, Smith R, Preston C et al (1974) Diphosphonates in Paget's disease. Lancet i" 894-898. Russell RGG, Bunning RAD, Hughes DE & Gowen M (1990) Humoral and local factors affecting bone formation and resorption. In Stevenson JC (ed.) New Techniques in Metabolic Bone Disease, pp 1-20. London: Wright.

560

M. S. MARSH AND J. C. STEVENSON

Sato M, Grasser W, Endo N e t al (1991) Bisphosphonate action: alendronate localisation in rat bone and effects on osteoclastic ultrastructure. Journal of Clinical Investigation 88: 20952105. Slovik DM, Neer RM & Potts JT (1981) Short-term effects of synthetic human parathyroid hormone (1-34) administration on bone mineral metabolism in osteoporotic patients. Journal of Clinical Investigation 68: 1261-1271. Stevenson JC (1980) The structure and function of calcitonin. Investigative Cell Pathology 3: 187-193. Stevenson JC & Evans IMA (1981) Pharmacology and therapeutic use of calcitonin. Drugs 21: 257-272. Stevenson JC, Abeyasekera G, Hillyard CJ et al (1981) Calcitonin and the calcium-regulating hormones in postmenopausal women: effect of oestrogens. Lancet i: 693-695. Stevenson JC, Allen PR, Abeyesekera G & Hill PA (1986) Osteoporosis with hip fracture: changes in calcium regulating hormones. European Journal of Clinical Investigation 16: 357-360. Stevenson JC, Lees B, Devenport M e t al (1989) Determinants of bone density in normal women: risk factors for future osteoporosis? British Medical Journal 298: 924-928. Stevenson JC, Arnett TR & Macdonald DWR (1990) Calcitonin gene peptides and bone metabolism. In Stevenson JC (ed.) New Techniques in Metabolic Bone Disease, pp 63-81. London: Wright. Storm T, Thamsborg G, Steiniche T et al (1990) Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in women with postmenopausal osteoporosis. New England Journal of Medicine 322: 1265-1271. Stout RW (1990) Insulin and atheroma: 20-yr perspective. Diabetes Care 13: 631-654. Sturtridge WC, Sturtridge HJ & Wilson D R (1977) Long-term treatment of Paget's disease of bone with salmon calcitonin. Journal of the Canadian MedicalAssociation 117: 1031-1034. Szilklai I & Ribari O (1985) The effect of flavone treatment on human otosclerotic ossicle organ cultures. Archives of Oto-rhino-laryngology 242: 67-70. Szocsik K, Bart M, Bossanyi A & Nagy K (1990) Ipriflavone in the prevention of postmenopausal osteoporosis. In Christiansen C & Overgaard K (eds) Osteoporosis 1990, pp 2164-2165. Copenhagen: Osteopress. Taggart HM, Chesnut CH, Ivey JL et al (1982) Deficient calcitonin response to calcium stimulation in post-menopausal osteoporosis. Lancet i: 475-478. Thamsborg G, Storm T & Brinch E (1990) The effect of different doses of nasal salmon calcitonin on plasma cyclic AMP and serum ionised calcium. Calcified Tissue International 46: 5-8.

Tillyard MW, Spears GFS, Thomson J & Dovey S (1992) Treatment of postmenopausal osteoporosis with calcitriol or calcium. New England Journal of Medicine 326: 357-362. Valkema R, Papapoulis SE, Vismans F-JFE et al (1987) A four year continuous gain in bone mass in APD-treated osteoporosis. In Christiansen C, Johansen J & Riis B (ed.) Osteoporosis 1987, pp 836-839. Viborg: Norhaven Bogtrykken. Watts NB, Harris ST, Genant HK et al (1990) Intermittent cyclical etidronate treatment of postmenopausal osteoporosis. New England Journal of Medicine 323: 73-79. Wickham CAC, Walsh K, Cooper C et al (1989) Dietary calcium, physical activity, and the risk of hip fracture: a prospective study. British Medical Journal 299: 889-892. Yamazaki I & Kinoshita M (1986) Calcitonin secreting properties of ipraflavone in the presence of oestrogen. Life Sciences 38: 1535-1541.