DRUG THERAPY
Drugs & Aging 2 (6): 508-517, 1992 1170-229X/92/00 11-0508/$05.00/0 © Adis International Limited. All rights reserved. ORAll35
Prevention of Osteoporosis
Current Recommendations
Michael C. Ellerington and John C. Stevenson Wynn Institute for Metabolic Research, London, England
Contents 508 509 509 509 512 513 511 511 511 514 514
515 515 515 515 515
Summary
Summary 1. Pathophysiology of Bone Loss 2. Antiresorptive Therapy 2.1 Estrogens 2.2 Calcitonin 2.3 Bisphosphonates 2.4 Calcium 3. Stimulants of Bone Formation 3.1 Progestogens 3.2 Sodium Fluoride 3.3 Anabolic Steroids 3.4 1,25-Dihydroxyvitamin D 3.5 Parathyroid Hormone 4. Nonpharmacological Methods 5. Initiation and Duration of Therapy 6. Conclusions
Osteoporosis and its treatment have attracted much attention in recent years, especially since the widespread recognition of its association with the menopause. The resulting fractures are a cause of considerable morbidity and mortality in the elderly, and current costs of treating these patients has been estimated to be in excess of £500 million per annum in the UK. As the causes of osteoporosis are now recognised the condition may be largely preventable, especially in women, and significant savings in health expenditure could be made if preventive methods are applied to those most at risk. The most well researched preventive treatment for osteoporosis is hormone replacement therapy (HRT) which offers additional benefits to those who choose it. Alternative methods currently under investigation for those who cannot or will not use HRT include those agents which inhibit the resorption of bone and those that stimulate the production of new bone. Treatment of established disease, i.e. attempts at increasing bone density in those with significant loss, is more difficult and methods so far investigated are not without risks and adverse effects. Furthermore, whether an increase in bone mineral density results in a reduced rate of fracture incidence has yet to be confirmed.
Prevention of Osteoporosis
Osteoporosis is a reduction in the amount of bone tissue per unit volume of bone, resulting in skeletal weakness and hence fracture, often following minimal trauma. It is the commonest metabolic bone disease in the develop@d world. The elderly are most commonly affected and the incidence in women is approximately 5 times that in men. Fractures of the vertebral bodies and the extremities of long bones are most common and result in considerable morbidity and mortality. Two main factors determine the eventual development of osteoporosis, namely peak bone density and its subsequent rate ofloss. The former appears to be achieved during early adult life, soon after linear skeletal growth has ceased (Gallagher et al. 1987; Stevenson et al. 1989). It is probably genetically determined; the variance in bone mass between monozygotic twins is less than that between dizygotic twins (Smith et al. 1973), and racial differences in bone mass do not vary with geographical location. Although it is well recognised that poor nutrition during childhood has adverse effects on skeletal growth (for example, calcium deficiency causes rickets) it is still not clear whether dietary supplementation during the formative years can actually increase the peak bone density above its genetically determined maximum. However, a recent study suggests that this might be possible (Johnston et al. 1992). At present, improving the peak bone density is difficult but it is possible to arrest and, to some extent, reverse subsequent bone loss. In order to understand how this can be achieved it is necessary to appreciate the pathophysiology of osteoporosis.
1. Pathophysiology of Bone Loss Throughout life, bone undergoes continual turnover; old bone is constantly being removed by osteoclasts whilst new bone is laid down by osteoblasts. From birth until early adulthood there is a net increase in the amount of new bone produced as skeletal growth occurs. After peak bone density is achieved bone loss occurs slowly in both sexes with age, probably due to a decline in the rate of new bone formation. However, in women an ac-
509
celeration in the rate of bone loss occurs as a result of the menopause (figs 1 & 2) [Abdallah et al. 1984; Gallagher et al. 1987; Krolner & Neilsen 1982; Stevenson et al. 1989]. In fact, the menopause is probably the single most important causative factor in the genesis of osteoporosis. Estrogen deficiency produces an increase in bone turnover with osteoclastic activity predominating; the result is a net loss of bone. Although trabecular bone (fig. 3) forms only about 20% of the skeleton, its surface area is so vast that the rate of loss of trabecular bone exceeds that of cortical bone. Following the menopause there is an initial accelerative phase, lasting 5 to 10 years, during which the rate ofloss of spinal trabecular bone is around 5% annually (Ettinger et al. 1987; Stevenson et al. 1987). In women who have undergone bilateral oophorectomy the rate of loss is even higher (Gennant et al. 1982). Although the total annual rate of loss gradually slows, the skeleton eventually becomes so weakened that fractures occur following only minimal trauma. There are 2 obvious approaches to the prevention of bone loss, namely the use of agents which either inhibit bone resorption or which stimulate bone formation. So far, antiresorptive agents have proved the more successful.
2.. Antiresorptive Therapy 2.1 Estrogens Estrogen replacement therapy (with the cyclical addition of a progesterone in women with an intact uterus) is very effective in preventing postmenopausal bone loss (Christiansen et al. 1980; Ettinger et al. 1985; Horsman et al. 1977; Lindsay et al. 1976; Nachtigall et al. 1979; Recker et al. 1977). Preservation of bone density appears to be maintained for as long as estrogen is administered (Lindsay et al. 1980). Furthermore, beneficial effects have also been observed in older women with established osteoporosis (Quigley et al. 1987). Retrospective and case-controlled studies have shown that the administration of estrogen postmenopausally can significantly reduce the incidence of fracture at the hip and distal radius (Hutchinson et al. 1979; Weiss et al. 1980); it has been calculated that
Drugs & Aging 2 (6) 1992
510
treatment for 5 years will reduce the incidence of femoral neck fracture by approximately 50% (fig. 4) [Stevenson 1988]. Cessation of treatment does not produce an acceleration of bone loss, only a resumption of bone loss at the immediate postmenopausal rate (Lindsay et al. 1978). During the first few years after initiation of therapy, modest increases in bone density occur (Christiansen 1981; Lindsay & Tohme 1990); the rate of increase in bone density then slows. This is probably due to bone resorption pits being filled in and when this process is complete, very little further increase can be achieved. Administration of estrogens by nonoral routes of administration is equally effective in preventing bone loss and may confer additional benefits in terms of metabolic risk factors (Crook et al. 1992; Stevenson et al. 1990) [for a review oftransdermal estradiol see Balfour & McTavish, pp. 487-507, this issue). It is generally recommended that only natural estrogens should be used in postmenopausal women
rather than their synthetic derivatives. The latter, although structurally very similar to the former, are rendered up to 1000 times more potent (Mashchak et al. 1982) by modifications to the side chains of the parent moleiule. The resulting pharmacological effects on hepatic function are thought to explain the increased incidence of hypertension (Laragh et al. 1967) and thromboembolic disease (RCGP 1977) observed in users of the oral contraceptive pill. Such effects are not seen with natural estrogens. Bone turnover is extremely estrogen-sensitive and attempts have been made previously to establish the minimum dose required for bone conservation. However, many studies are flawed by such factors as lack of verification of patient compliance. Properly conducted dose ranging studies are few (Christiansen et al. 1982; Gennant et al. 1982; Lindsay et al. 1984), and although 0.625 mg/day of oral conjugated equine estrogens conserves bone in the metacarpal (Lindsay et al. 1984), 33% of oophorectomised women (Gennant et al. 1982) and
1.3
f
N
E
Drugs & Aging 2 (6): 508-517, 1992 1170-229X/92/00 11-0508/$05.00/0 © Adis International Limited. All rights reserved. ORAll35
Prevention of Osteoporosis
Current Recommendations
Michael C. Ellerington and John C. Stevenson Wynn Institute for Metabolic Research, London, England
Contents 508 509 509 509 512 513 511 511 511 514 514
515 515 515 515 515
Summary
Summary 1. Pathophysiology of Bone Loss 2. Antiresorptive Therapy 2.1 Estrogens 2.2 Calcitonin 2.3 Bisphosphonates 2.4 Calcium 3. Stimulants of Bone Formation 3.1 Progestogens 3.2 Sodium Fluoride 3.3 Anabolic Steroids 3.4 1,25-Dihydroxyvitamin D 3.5 Parathyroid Hormone 4. Nonpharmacological Methods 5. Initiation and Duration of Therapy 6. Conclusions
Osteoporosis and its treatment have attracted much attention in recent years, especially since the widespread recognition of its association with the menopause. The resulting fractures are a cause of considerable morbidity and mortality in the elderly, and current costs of treating these patients has been estimated to be in excess of £500 million per annum in the UK. As the causes of osteoporosis are now recognised the condition may be largely preventable, especially in women, and significant savings in health expenditure could be made if preventive methods are applied to those most at risk. The most well researched preventive treatment for osteoporosis is hormone replacement therapy (HRT) which offers additional benefits to those who choose it. Alternative methods currently under investigation for those who cannot or will not use HRT include those agents which inhibit the resorption of bone and those that stimulate the production of new bone. Treatment of established disease, i.e. attempts at increasing bone density in those with significant loss, is more difficult and methods so far investigated are not without risks and adverse effects. Furthermore, whether an increase in bone mineral density results in a reduced rate of fracture incidence has yet to be confirmed.
Prevention of Osteoporosis
Osteoporosis is a reduction in the amount of bone tissue per unit volume of bone, resulting in skeletal weakness and hence fracture, often following minimal trauma. It is the commonest metabolic bone disease in the develop@d world. The elderly are most commonly affected and the incidence in women is approximately 5 times that in men. Fractures of the vertebral bodies and the extremities of long bones are most common and result in considerable morbidity and mortality. Two main factors determine the eventual development of osteoporosis, namely peak bone density and its subsequent rate ofloss. The former appears to be achieved during early adult life, soon after linear skeletal growth has ceased (Gallagher et al. 1987; Stevenson et al. 1989). It is probably genetically determined; the variance in bone mass between monozygotic twins is less than that between dizygotic twins (Smith et al. 1973), and racial differences in bone mass do not vary with geographical location. Although it is well recognised that poor nutrition during childhood has adverse effects on skeletal growth (for example, calcium deficiency causes rickets) it is still not clear whether dietary supplementation during the formative years can actually increase the peak bone density above its genetically determined maximum. However, a recent study suggests that this might be possible (Johnston et al. 1992). At present, improving the peak bone density is difficult but it is possible to arrest and, to some extent, reverse subsequent bone loss. In order to understand how this can be achieved it is necessary to appreciate the pathophysiology of osteoporosis.
1. Pathophysiology of Bone Loss Throughout life, bone undergoes continual turnover; old bone is constantly being removed by osteoclasts whilst new bone is laid down by osteoblasts. From birth until early adulthood there is a net increase in the amount of new bone produced as skeletal growth occurs. After peak bone density is achieved bone loss occurs slowly in both sexes with age, probably due to a decline in the rate of new bone formation. However, in women an ac-
509
celeration in the rate of bone loss occurs as a result of the menopause (figs 1 & 2) [Abdallah et al. 1984; Gallagher et al. 1987; Krolner & Neilsen 1982; Stevenson et al. 1989]. In fact, the menopause is probably the single most important causative factor in the genesis of osteoporosis. Estrogen deficiency produces an increase in bone turnover with osteoclastic activity predominating; the result is a net loss of bone. Although trabecular bone (fig. 3) forms only about 20% of the skeleton, its surface area is so vast that the rate of loss of trabecular bone exceeds that of cortical bone. Following the menopause there is an initial accelerative phase, lasting 5 to 10 years, during which the rate ofloss of spinal trabecular bone is around 5% annually (Ettinger et al. 1987; Stevenson et al. 1987). In women who have undergone bilateral oophorectomy the rate of loss is even higher (Gennant et al. 1982). Although the total annual rate of loss gradually slows, the skeleton eventually becomes so weakened that fractures occur following only minimal trauma. There are 2 obvious approaches to the prevention of bone loss, namely the use of agents which either inhibit bone resorption or which stimulate bone formation. So far, antiresorptive agents have proved the more successful.
2.. Antiresorptive Therapy 2.1 Estrogens Estrogen replacement therapy (with the cyclical addition of a progesterone in women with an intact uterus) is very effective in preventing postmenopausal bone loss (Christiansen et al. 1980; Ettinger et al. 1985; Horsman et al. 1977; Lindsay et al. 1976; Nachtigall et al. 1979; Recker et al. 1977). Preservation of bone density appears to be maintained for as long as estrogen is administered (Lindsay et al. 1980). Furthermore, beneficial effects have also been observed in older women with established osteoporosis (Quigley et al. 1987). Retrospective and case-controlled studies have shown that the administration of estrogen postmenopausally can significantly reduce the incidence of fracture at the hip and distal radius (Hutchinson et al. 1979; Weiss et al. 1980); it has been calculated that
Drugs & Aging 2 (6) 1992
510
treatment for 5 years will reduce the incidence of femoral neck fracture by approximately 50% (fig. 4) [Stevenson 1988]. Cessation of treatment does not produce an acceleration of bone loss, only a resumption of bone loss at the immediate postmenopausal rate (Lindsay et al. 1978). During the first few years after initiation of therapy, modest increases in bone density occur (Christiansen 1981; Lindsay & Tohme 1990); the rate of increase in bone density then slows. This is probably due to bone resorption pits being filled in and when this process is complete, very little further increase can be achieved. Administration of estrogens by nonoral routes of administration is equally effective in preventing bone loss and may confer additional benefits in terms of metabolic risk factors (Crook et al. 1992; Stevenson et al. 1990) [for a review oftransdermal estradiol see Balfour & McTavish, pp. 487-507, this issue). It is generally recommended that only natural estrogens should be used in postmenopausal women
rather than their synthetic derivatives. The latter, although structurally very similar to the former, are rendered up to 1000 times more potent (Mashchak et al. 1982) by modifications to the side chains of the parent moleiule. The resulting pharmacological effects on hepatic function are thought to explain the increased incidence of hypertension (Laragh et al. 1967) and thromboembolic disease (RCGP 1977) observed in users of the oral contraceptive pill. Such effects are not seen with natural estrogens. Bone turnover is extremely estrogen-sensitive and attempts have been made previously to establish the minimum dose required for bone conservation. However, many studies are flawed by such factors as lack of verification of patient compliance. Properly conducted dose ranging studies are few (Christiansen et al. 1982; Gennant et al. 1982; Lindsay et al. 1984), and although 0.625 mg/day of oral conjugated equine estrogens conserves bone in the metacarpal (Lindsay et al. 1984), 33% of oophorectomised women (Gennant et al. 1982) and
1.3
f
N
E
