Endocrinol. Japon. 1979, S. R. No.1, 31-41 Postmenopausal and Senile Osteoporosis: Current Concepts of Etiology and Treatment B. LAWRENCE RIGGS Endocrine Research Unit, Division of Endocrinology I Metabolism and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota55901 Synopsis Postmenopausal osteoporosis and senile osteoporosis are heterogeneous disorders that appear to be caused by several nonhormonal and hormonal factors. Of non- hormonal factors, age-related bone loss, the degree of bone density achieved in young adult life, and dietary intake and absorption of calcium appear to be important. Hormones that may be important in pathogenesis are parathyroid hormone (PTH), estrogen, 1, 25 (OH) 2D, and possibly calcitonin. Postmenopausal estrogen deficiency accelerates bone loss by increasing responsiveness of bone to endogenous PTH. The resultant increase in release of calcium from bone is associated with normal or low values for serum immunoreactive PTH (iPTH)(except for a subset of 15% of the total which have high values and appear to represent a separate population). Some evidence suggests that subnormal calcium absorption, which is a common finding in postmenopausal osteoporosis and which may contribute to negative calcium balance, is caused by decreased conversion of 25-OH-D to1, 25 (OH) 2D. Treatment of osteo- porosis with either sex steroids (by antagonizing the effect of PTH on bone resorption) or orally administered calcium with or without vitamin D (by decreasing PTH secretion) decreases bone resorption. Long-term therapy with these agents, however, decreases bone formation thus, bone loss is only arrested or slowed. Although combined therapy with fluoride and calcium stimulates bone formation and appears to be capable of increasing bone mass, its long-term safety and efficacy in decreasing the the occurrence of fractures remain to be demonstrated. The common forms of primary osteo- cans and cause an estimated700,000new porosis, sometimes called postmenopausal fractures yearly (Lutwak and Whedon, and senile osteoporosis, occur in middle- 1963; Iskrant and Smith, 1969). The in- aged or older persons of either sex but are cidence of fracture of the proximal femur more frequent and severe in women than in women doubles each decade after ago. in men. In contrast to secondary osteo- 60 years (Alffram, 1964). Based on cur- porosis, there is no recognizable associated rently available epidemiologic data, the disease known to affect bone metabolsm. economic cost of hip fractures in the Unit- Postmenopausal osteoporosis and senile ed States can be estimated to approximate osteoporosis are serious health problems, $1billion annually (about200billion causing considerable morbidity because of Japanese yen). fractures. The diseases symptomatically Osteoporosis may be even more common affect an estimated4million older Ameri- in Orientals than in Americans. In1966, Nordin reported on international patterns Received October, 1, 1978. of osteoporosis. He found that the incid- Endocrinol. Japon. 32 B. L. RIGGS June1979 ence of osteoporosis, assessed by radio- in areas of the the skeleton which contain lucency on spinal roentgenograms, in wo- relatively large amounts of trabecular bone men older than age45eyears was 30% in and which are subject to prime load-bear- America but 60% in Japan. ing; this accounts for the presenting fea- In the ensuing37years since Albright, tures of the/or the vertebrae, fractures of Smith and Richardson (1941) clearly defin- the proximal femur, and fractures of the ed the syndromes of postmonopausal and distal radius. senile osteoporosis, progress in elucidating For bone to be lost, obviously the rate the cause and in developing effetive treat- of bone resorption must exceed that of ment has been slow. Much more has been formation. A lively controversy exists, how- accomplished during the last decade, how- ever, about whether the primary abnormal- ever, largely because of the development ity is an absolute increase in bone resorp- of more sensitive methods (such as raido- tion, an absolute decrease in bone forma- calcium kinetic studies, quantitative bone tion, or some combination thereof. Time morphology, bone densitometry, and radio- does not permit a review of the details of immunoassay of calcitropic hormones) and this controversy. suffice it to say, it is my better understanding of factors controlling opinion that the menopause accelerates bone and mineral metabolism. the rate of bone resorption and that this Space does not permit a comprehensive is superimposed on an age-related decrease review of the numerous investigative studies in the rate of bone formation. In any relating to osteoporosis. Instead, I will event, there is a disruption of the usually focus this report mainly on studies done tightly coupled processes of resorption and by our group at the Mayo Clinic and formation. Obviously, even a "normal" Mayo Foundation. A number of colleagues rate of resorption is abnormal when the have been participants and collaborators rate of formation decreases, because nor- in these studies. In particular, I would mally homeostatic mechanisms should de- like to acknowledge Drs. C. D. Arnaud, J. crease the rate of resorption to approximate C. Gallagher, H. Heath IIII, D. L. Hoff- that of formation. man, J. O. Jowsey, and P. J. Melly of the Mayo Clinic and Mayo Foundation and Dr. H. F. DeLuca of the University of Etiology Wisconsin. The reader is referred to the original articles for complete details of Primary osteoporosis should be consi these studies and for a more comprehensive dered as a multifactorial, heterogenous review of related work by others. disorder. Both nonhormonal and hormonal and hormonal factors appear to contribute to bone loss. Pathology Normal Factors The pathologic abnormality in osteo- Age-Related Bone Loss.-After attain- porosis is an absolute decrease in the ing maximal skeletal mass in young adult amount of bone to a level that is incapa- life, all persons appear to lose bone with ble of maintaining the structural integrity aging. After age50years, this loss is ap- of the skeleton, or, as Dr. Fuller Albright proximately 10% per decade in women succinctly put it,"there is too little bone." and 5% per decade in men (Newton-John The bone that remains is morphologically and Morgan, 1968). Age-related bone loss normal. Bone loss is proportionately greater probably a summation of several factors, S. R. No.1 ETIOLOGY OF OSTEOPOROSIS 33 which, particulary in the later decades of They found that dietary calcium intake life, include senile atrophy of bone cells. and calcium balance were positively related. Initial Bone Density.-In the United The zero intercept—that is, the level of States, it has been appreciated for some dietary calcium required to prevent nega- time that symptomatic osteoporosis is most tive calcium balance—for this group was common in white women and least com- 1,241mg/day. This value is well above the mon in black men. Since the early work average intake of700mg/day for post- of Trotter, Broman, and Peterson (1960), menopausal American women. Thus, die- it has been known that maximal bone den- tary calcium intake may be a more im- sity achieved in young adult life is least portant contributing factor to bone loss in white women, greatest in black men, than previously has been recognized. If and intermediate in white men and black so, this would be paticularly relevant to women. Inasmuch as the rate of bone loss the Japanese population who, based on the with aging in each of these four race and World Health Organization's survey in sex subgroups was found to be similar, initial bone density appears to be a major determinant of eventual bone density in later life and, consequently, of individual susceptibillty to osteoporosis (Newton-John and Morgan, 1968). Although definitive studies have not been done, Oriental wo- men may be similar to white women in this respect and may have a relatively low initial bone density. Also, within the same race and sex subgroup, there appears to be a gaussian distribution of values for initial bone density. Smith et al.(1973) have shown that individual values for bone density are, in part, genetically determined. As age-related bone loss ensues, indivi- duals with the lowest initial levels of bone density would be at the greatest risk for Fig.1.•@ Diagrammatic illustration of effects of he- having bone density decrease to the level redity, race, sex, and age on variations in bone at which spontaneous fractures occur (Fig. density. Initial bone density achieved at end of adolescent growth spurt is greatest in black males, 1). is intermediate in black females and white males,. Nutritional Factors.-If the nutritioual and is least in white females. Also, within each requirement for calcium is not maintained race and sex subgroup, there is a gaussian distri- because of poor dietary intake or absorp- bution of bone density values (shown here only for white females by dotted bell-shaped distribu- tion, calcium must be witndrawn from the tion figure). As age progresses, mean bone density skeleton because no other long-term reser- (given by lines) decreases. Absolute decrease with vior of calcium exists. This sequence has age is similar in each race, although menopause accelerates bone loss in females. Thus, eventual been clearly demonstrated in experimental bone density reached in old age may be related animals. Recent work by Heaney, Recker, to initial bone density achieved in young adult and Saville (1977) suggests that this also life. White females who have values for initial may occur in humans. These workers studi- bone density in lower part of distribution will be at particular risk for having bone density decrease ed metabolic balance for calcium in a to level at which spontaneous fractures occur group of perimenopausal female volunteers. (cross-hatched area). Endocrinol. Japon. 34 B. L. RIGGS June1979 1962, one of the lowest in the world decrease in the serum iPTH level, how- Nordin, 1976).