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The pathogenesis of osteoporosis
215
The pathogenesis
of osteoporosis
The term osteopenia refers to a reduction in the amount of bone per unit volume relative to ihat expected for the age and sex of the subject. Traditionally, the term osteoporosis has been reserved for the clinical syndrome which owun as a wmplication of osteopenia and includes the most common fractures which involve the hip, vertebrae, radius and humerus. It is probably helpful to use these terms separately since many elderly people have osteopeoia, but never develop a clinical frachue. Osteoporosis is a considerable health care problem at the present time and will become an even larger problem as the proportion of elderly peopie increases in the population [l-4]. Economically, hip fracture has the largest single impact on health care costs, however, morbidity in patients with vertebral fractures lasts for many years and leads to long-term health care costs [II. Development of a vertebral or hip fracture is a dramatic event for any elderly person and the patient’s lifestyle changes markedly after these episodes. In the mid 80s about one in three women and one in every six men will develop a hip eachwe 15) making osteoporosis one of the most common diseases of the elderly population alongside that of cancer, vascalar disease and degenerative arthritis. In the USA the present oosh of treating patients with osteoporosis ard around $7 billion each year [l]. By the year 2020 one can project that the increase in the profxxtion of elderly people, the increasing incidence of age-adjusted hip fractures and the inflation of health care costs will lead to annual costs for osteouorosis approaching $60 billion each year. Because of the severity of osteoporosis in patients and because of the tremendous fatwe economic impact of this disease, an understanding of the pathogenesis of osteqorasis k CNcial and with it the development of strategies for both prevention and treatment of this condition.
216 Eoue :emodc!llng After completion of growth of the skeleton in the early twenties, bone is renewed through remodelling cycles [6]. This remodelling sequence takes several months and involves an initial state of bone resorption lasting several days. The following weeks are dominated by the action of osteoblasts which till in the resorption cavities. Completion of this process leads to replacement and renewal of bone. Loss of bone with age implies incomplete filling in of resorption cavities and, with time, this leads to a net loss of bone throughout the skeleton. At the cellular level, it has been shown that activation of bone remodeiling is initiated by the systemic hormones parathyroid hormone and 1,2;-dihydroxyvitamin D,. These hormones do not directly stimulate osteoclasts, but act through one or multiple factors generated by osteoblast-like cells [7-91. Tumor necrosis factor a and /3, and interleukin-1 stimulate osteoclastic resorption, but only in the presence of osteoblasts [lo]. Interleukin-land prostaglandin-induced resorption is also enhanced by parathyroid bonnone [ll]. Some of the peptides synthesized by osteoblast-like cells are mitogenic and stimulate further proliferation and synthesis by the osteoblasts [12]. These mitogem are also found in the bone matrix and are released by bone resorption. Recently identified skeletal growth factors released after bone resorption stimulate osteoblast synthesis of matrix and can act, therefore, as coupling agents [13]. These local regulatory mechanisms probably represent examples of both autocrine and paracrine control mechanisms. 1.25Dihydroxyvitamin D occupies a central role in bone remodelling. Although it does not directly stimulate osteoclasts, it does initiate the activation process by stimulating osteoblasts and monocytes to release factors which stimulate osteoclasts to resorb bone [14]. 1,2S-Dihydroxyvitamin D, increases the proliferation and numbers of osteoblast cells [LX], increases alkaline phosphatase activity [16] and osteccalcin synthesis [17] and plays a central role in bone mineralization.
Changes in bone density wltb age The recent introduction of bone densitometry has made possible the selective measurements of different parts of the skeletoe. It is now clear that bone loss starts at different periods of life throughout the skeleton and occurs at different rates. For example, there is a 30% decrease in bone mineral density of the femoral neck and Ward’s triangle in the proximal femur during the premenopausal age span [18-211. In contrast, bone mineral density of the spine [19,22,23] and the trochanteric region of the proximal femur [19,21] shows no significant loss of bone prior to menopause. Measurements of the radius show an increase in density up to the fourth decade and no significant loss before the menopause 124). These bone regions contain varying proportions of cortical and trabecular bone with the exception of the radial mid shift which is almost all cortica! bone. Although the impact of menopause is universal throughout the skeleton, the use of computerized axial tomography of the vertebrae has shown that the largest decrease in bone occurs in the central part of the
vertebrae which is predominantly trabecular bone [25]. Calculationof ratesofbone loss after the menopause show that these can be considerable. In the central trabecular region of the vertebrae, the rates of loss are 10% per year for the first 2 years [25]. In contrast, the rate of cortical bone loss in the radius averages2-3% per year [24]. These differences in the rates of loss of cortical and trabecular bone may simply reflect the fact that trabecular bone has a larger surface area available for resorption. Rates of loss after the menopause occnr exponentially so that the phase of rapid loss occurs mainly during the first 5 to 7 years after the menopause [26]. This sudden rise in net bone resorption during the ftrst 4 years after the menopause reflects an increase in the activation of many more resorption sites, and can be measured biochemically as increases in plasma tartrate acid phosphatase, osteccalcin and urine hydroxyproline excretion [Zq. During the next 4 years there is a decline in the biochemical markers of bone resorption and presumably this refkcts a decrease in the number of bone remodelling sites. An additional devebrpsncnt may be that the osteoclasts resorb deeper cavities than usual and these are incompletely tilled in by the osteoblasts. Probably both processes occur, but sIttee there is a net loss of bone and thinning of the trabecular elements several years after the menopause [28] it is likely that the latter process becomes dominant. Ahnost BY%of the decrease in bone mineral density of the spine occurs in the first 8 yearsfolIowing the menopause. Thus, the impact of estrogen deficiency is clearly a major factor in trabecular bone loss in the spine. It is also seen in young women aged 20-Q .rhodevelop amenorrhea and estrogen deficiency assoxiated with excessive athktic a&Iv&y [29] or following a temporary menopause associated with the use of LHRH agonists [30]. In hoth situations spine density decreases rapidly and osteopenia is often seen in the amenorrheic athlete. Although estrogen deficiency is an important cause of trabecular bone loss it should be pointed out, however, that age-related trabezttlar bone loss in the femoral neck occurs independently of estrogen activity in the preand late postmenopausal period. The recent findings of different patterns of bone loss throughout the skeleton suggest that, prior to the menopause, bone resorptioo and formation are fairly equal in the vertebrae, whereas in the femoral neck rwxp tion activity exceeds bone formation by 0.5% per year. Classification ofthe csteoperotic types In 1947, Albright divided osteoporotic patients into the postmenopausal and senile groups and he clearly implicated the role of estrogen deficiency in postmenopausal osteoporosis 1311.More recently, Riggs and Melton have renamed postmenopausal osteoporosis as Type I and senile osteoporosis as Type II [32]. Another small group, Type IA, has aIso been described by us earlier [33]. If this type of classification is to be used then one should also recognize a Type III osteoporosis, this term being reserved for those patients who develop osteoporosis secondary to various medical diseases or drugs. It is obvious to all clinicians that there is overlap between the various groups, but some of the differences between the groups are summarized in Table 1.
218 Table 1 Classification of osteoporotic types (modified after Riggs and Melton [32]) Type ** (senile)
Type 1.4
55-70 s-15 20:1
75-90 25-40 2:1
65-75 25-35
any age any age t:,
Spine
Hip, spine, pelvis.humerus
Spine
Spine, hip, peripheral
+++ +
++ ++
+++ +
+++ +++
+++ +
++ +++
++t ++
++ ++
i
:
:
::
1
1
1
Type’ (postmenopausat)
t
1
-
?
Postmenopausalosteoporosis (Type f) The postmenopausal osteoporosis patient (Type I) is characterized by vertebral fractures which occur in the early to mid 60s or within 5-15 years of the menopause. Predominantly this syndrome is seen in women rather than men (20~1). Most patients have two or more vertebral fractures by the time they reach a specialized bone clinic and their history of backache usually extends 2-4 years earlier. The younger the patient, the more abnormal is the spine density [34] or iliac crest bone volume [3.5] relative to age-matched control subjects. Histomotphometry of iliac crest bone biopsies show high turnover in about 25% of the cases, low turnover in another 25% and the rest have values indistinguishable from normal [36,37]. Most commonly, bone density measurements show that the Type I patients with vertebral fractures have usually developed proportionately greater loss of trabecular bone from the vertebrae. These findings could be explained by faster rates of loss during the exponential phase of bone loss, a prolonged exponential phase, or normal or high rates of loss in patients in whom the bone mass was low at the onset of the menopause. Although about one-third of Type I patients have normal cortical bone mass [34], another third have low cortical bone mass. Again, it is not clear whether this latter group of patients is one which continued to have excessive loss of
219 cortical bone from the skeleton following the phase of rapid trabecalar bone loss or whether it occurs in those patients who reached menopause with a low peak bone mass. Consistently, malabsorption of calcium is found in 60-70’S of these patients 138,391. The absorption defect is quite severe and calcium balance studies have demonstrated that fecal calcium may exceed calcium intake in a third of these patients similar to a calcium losing enteropathy [40]. This calcium loss appears to be a specific loss and there is no evidence of malabsorption of fats or other nutrients in these patients. Parathyroid function. is normal or decreased in the same proportion of patients [41]. Several groups have demonstrated redwed levelsofsemm lpdihydroxyvitamin D in these patients (38.42-451, however, stimulation with synthetic parathyroid hormone can increase the circulating serum level of 1,25-diiydroxyvitamin D [46] suggesting that there has been marked decrease of 1,25-dihydroxyvitamin D production. The natural history of this Icw production is not clear. Detailed studies of serum and urine calcium, and indices of bone turnover, such as osteocalcin and alkaline phosphatase, all show a marked rise m the first 3-4 years after the menopause [291. It is postulated that, following increased or prolonged bone resorption, a slight elevation in serum ca!cium leads to decreasedsecretion ofparathyroid hormone, a functional decrease in 25-hydroxyvitamia D-la-hydroxylase activity, decreased production of 1,25-d;hydroxyvitamin D and ultimately decreased calcium absorption and negative c;&ium valance (Fig. 1). A few patients have malabsorption of calcium with norm 1 1,25-dihydmxyvitamin D levels and these may be patients with abnormal rcceproi binding in the gut [S]. In some o+ teoporotic patients, estrogen may stimulate parathyroid hormone secretion, 1,25dihydroxyvitamin D production and an increase in calcium absorption [47], suggesting thai the estrogen deficiency component is still important in some Type 1 osteoporotics. Calcitonin secretion may he inappropriately low ia the postmenopausal years and levels have been reported in osteoporotica as normal [48], low [49] and
220 high [SO]. Other recent investigations have suggested a role for raised interleukin-1 secretion in monocytes from patients with this syndrome and this finding could accoont for a prolonged phase of exponential loss after the menopause [Sl]. Senile osteoporosis (Type II) Patients who fit into this clinical category are much older, averaging 80 years of age. By definition, this syndrome refers to all patients with hip fracture, but about 30% of them will be found to have concurrent vertebral fractures. These patients usually fracture 25-40 years after the menopause, but the female to male ratio is 2:l compared to 20: 1 in postmenopausal (Type I) osteoporosis (Table 1). Although the menopause obviously contributes to a substantial proportion of the total bone loss in this group, much of the bone loss occurs as the result of prolonged and slow loss of cortical and trabecular bone over 40-50 years [34]. Recent findings, however. suggest a more severe decrease in femoral neck density in hip fracture patients than in age matched controls [SZ]. The biochemical findings in this group show decreased absorption of calcium in 75% of the elderly subjects [53]. However, oniy 30-40% of these patients have decreased levels of 1,25-dihydroxyvitamin D, especially in those with decreased renal function [54]. The dissociation between malabsorption of calcium and the serum 1,25-dibydroxyvitemin D raises the possibility that there is a defect in the binding of circulating 1,25-dihydroxyvitamin D to the intestinal receptor in this group !55]. Malabsorption of calcium probably leads to hypocalcemia, secondary hyperparathyroidism [41,56,57] and increased bone turnover [58]. Increases in urinary cyclic AMP excretion are also found suggesting that the increases in pamthyroid hormone are functional [59]. Thus, a major difference between Types I and II lies in the parathyroid hormone levels (Fig. 2). Although the changes in calcium absorption appear mainly after age 65 years, there is no evidence at this time to show any increase in the rate of bone loss at this time, which one might expect, and further information is needed. Many elderly subjects have normal serum 1,25-dibydroxyvitamin D levels and it appears that the patients with senile osteoporosis who have decreased serum levels of 1,25-dihydroxyvitamin D are probably a subgroup with more severe loss of renal function. These patients do not increase levels of serum 1,25-dihydroxyvitamin D after stimulation with injections of parathyroid hormone [60]. Type IA osfeoporosis Type III osteoporosis occurs in only a very small number of patients. These patients develop vertebral fractures in the mid-to-late 60s. Characteristically, they have malabsorption of calcium and decreased levels of serum l,ZS-dihydroxyvitamin D, but elevated levels of parathyroid hormone [33]. By implication these patients must have a primary defect in la-hydroxylase in the kidney. This group presents clinically as Type I, but behaves biochemically as Type II. Secondary osteoporosis (Type Ii:) By definition, this group contains all patients in whom osteoporosis could be attributed to a secondary cause [61,62] such as partial gastrectomy, malabsorption syn-
221
dromes, hyperparathyroidism, hypogonadism, thyrotoxicosis, immobiiiition, hemiplegia or drug causes such as alcohol, excessive thyroxine replacement, anticonvulsant drugs, corticosteroid therapy or radiotherapy. These factors could contribute to the type of hone loss seen in Types I or II osteoporosis at any point in the life time of the patient. For example, excessive thyroxine or corticosteroid therapy just after menopause could magify the increase in the bone resorption rate. Studies of younger osteoporotics with only vertebral fractures have shown that secondary causes accounted for 35% of the eases in women and about 50% in men [61,63]. We have previously examined the incidence of certain diseases known to be associated with abnormalities of calcium metabolism in hip fracture patients. About 3O-40% of these patients had a possible contributing cause to the hip fracture [64]. Thus, idiopathic osteoporosis in patients presenting with a Type I or 11 pattern may account for only 60-70% of ail ca.ses. This has important implications for the role of preventive measures which might reduce the incidence of fractures. The role of dietary calcium as a contributing factor to usteopw rosis is not clear [65]. There must be a minimal dietary calcium intake necessary to minimize bone loss. Obligatory fecal, urine and skin losses of calcium are about 250-300 mg/day and a calcium intake of around 500~6tN mg/day, assuming a normal adaptive response in calcium absorption, would be a minimum requirement necessary to maintain calcium balance. A calcium intake below that figure probably increases the negative calcium balance and contributes to bone loss. In situations where malabsorption of calcium exists, or in the high resorption phase immediately after the menopause, it seems clear that the concept of a minimal dietary calcium is relatively unimportant. There is no fitm data at the present time on the role of exercise or activity in the prevention of osteoporosis. Immobilization produces rapid bone loss, but it is not clear on the amount of activity needed to prevent bone loss.
222
Implications for prevention and treatment of osteoporosis Postmenopow~l
(Type I) osteoporosis
This disease would be most effectively prevented by estrogen replacement therapy at the time of the menopause [66]. Patients who have been on acceptable doses of estrogen replacement therapy for 15-20 years do present with vertebral fractures in the mid 60s; so not all women respond to estrogen replacement therapy, although it is not clear why, perhaps the dose of estrogen used in those individuals was not sufficient. Treatment of the patient with established vertebral fractures includes estrogen, parathymid hormone, calcitonin of 1,25-dihydroxyvitamin D analogues, thus following the pathogenetic pathway. Estrogen appears to be effective in some patients; it stimulates parathyroid horntone and 1,25-dihydroxyvitamin D production [47], and increases calcium absorption and calcium balance [67,68]. There is no information, however, on the long-term value of estrogen therapy in preventing further fractures in Type I patients since controlled studies have not yet been undertaken. A few patients have been treated with injections of parathyroid hortnone (PTH) and preliminary results suggest that these patients respond to very small doses of parathyroid hormone. Most of the results have described changes in iliac crest biop sies or calcium balance and there is little infomration on bone density [69,70]. Repeated injections of small doses of parathyroid hormone cause down-regulation of 1,25-dihydroxyvitamin D production by the kidney so that both PTH and 1,25-d& hydroxyvitamin D, would need to be given together [71]. Calcitonin injections are reported to be effective in the treatment of Type I patients [72], especially in the group with high turnover osteoporosis [73]. It has been suggested by some investigators that the increase in bone mass is transient [72] but, nevertheless, prevention of bone loss for several years would be useful. No convincing controlled studies of fracture prevention have yet been reported for calcitonin therapy. Probably the largest body of data on osteoporosis treatment exists for vitamin D analogue use. Thousands of patients with Types I and II osteoporosis are being treated with vitamin D analogues in controlled studies. As mentioned previously, the majority of these patients have malabsorption of calcium and reduced serum levels of 1.25-dihydroxyvitamin D; treatment with synthetic vitamin D analogues normalizes calcium absurption [38], improves calcium balance 1741 and prevents bone loss in most [43,75,76] but not every study [77]. Most results have shown that vitamin D analogues also increase bone mass; this is particularly true for patients studied in Japan [76] and Italy [43] where calcium intakes are traditionally low. We have suggested that a low calcium intake enables these patients to tolerate higher doses of vitamin D analcgues, and that there is a positive dose effect of these compounds on bone. In addition, fracture rates are significantly reduced with vitamin D analogue treatment [7%30]. Despite earlier concerns, there has been no evidence yet of long-term nephrotoxicity provided that hypercalcemia and hypercalcuria are avoided. Restricting the calcium intake to 600-700 mg/day helps to control the absorptive response and reduces the chances of developing hypercalcuria.
223 Treatment of Types II und !P. c-‘coporosis There is no obvious role for estrogen therapy in these patxnts since parathyroid hormone is already stimulated in this group except in those patients with a high turnover state. the predominant prob!em in these patients appears to be a primary decrease in la-hydroxylase activity in the aging kidney resulting in reduced pmduction of 1,25-dihydroxyvitamin D and calcium malabsorption. This is a group of patients who logically should be treated with the vitamin D analogues.There are now results from Japan demonstrating the efficacy of vitamin D analogue treatment in Type II osteoporotic patients [KI]. Secondary 01’Type III osteoporosis Although many conditions, listed in Fig. 3, are known to be associated with the development of osteoporosis, few systematic studies of treatment of these conditions have been undertaken. However, the advent of bone density should enable us now to measure changes on therapy more easily. For example, monitoring bone density on thyroxine replacement therapy has shown that previous replacement doses were too high [Sl]. The use of estrogen in women with a premature menopause or as a medical treatment for primary hyperparathyroidism should be considered. Since patients treated with corticosteroids or anticonvulsants have malatwiption of catcium and osteoporosis, prophylactic treatmtint of these patients with vitamin Danalogues should be considered. In conclusion, preventive therapeutic measures in this m!scellaneous group could be expected to have a significant impact in reducing the incidence of osteoporosis and fractums.
223
Changes in the calciotropic hormones with age contribute significantly to the pathogenesis of osteoporosis. In both postmenopausal (Type I) and senile osteoporosis (Type II) it is common to find reduced levels of serum 1.25~dihydroxyvitamin D and malabsorption of calcium. In Type I patients a reduced level of sertttn parathyroid hormone causes a real decrease in serum 1,25-dihydroxyvitamin D production and malabsorption of calcium, whereas in Type II patients the decline in la-hydroxylase activity in the kidney causes a decline in serum 1,25-dihydroxyvitamin D which leads to malabsorption of calcium and secondary hyperparathyroidism. In the final analysis both pathways lead to bone loss. In some Type II patients there may be a decline also in the function or number of the vitamin D-binding receptors in the gut. Treatment of patients with vitamin D analogues, however, nonnaIiies calcium absorption and improves calcium balance. The improvement in calcium balance redues bone resorption and prevents further bone loss; in addition recent studies have shown that therapy with vitamin D analogues leads to a reduction in fracture incidence.
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nopausal osteoporosis. N Engl J Med l985;312:1097-1100. 51 Pacifici R. Rifas L. Teitelbaum S. Slatopolsky E, McCracken R, Bergfeld M, Lee W, Avioli LV. Peck WA. Spontaneous release al interleukin 1 from human blood monocytes reflects bone formation iu idiopathic osteoporosis. Proc Natl Acad Sci USA 1987:84(13)4616-4620. 52 Mazess RB. Bar&n H. Ettingcr M. Schultz E. Bone density of the radius, spine and proximal femur in osteoporosis. J Bone Mmcral Rcs 1988;3:13-IS. 53 Bullamorc JR, Gallagher JC, Wilkinson R. Nordin BEC, Marsha,, DH. Effect of age on calcium absorption. Lance1 1970;11:535-537. 54 Lops P. Netelenbos JC. Jongen MJM.
Histomorphometric
profile and vitamin D status in patients
with femoral neck fracture. Metab Bone Dir Rel Res 1982:1:85-93. 55 Francis RM, Peacock M. Taylor
GA, Storer IH. Nardin BEC. Calcium malabsorption in elderly wo-
men with vertebral fractures: evidence for resistance to the action of vitamm D mctabolites on the bowel. Cfm Sci 1984:M:L03 -107. 56 Wiskc PS. Epstein S, Bell NJ, Ovccncr SF, Edmonson J. Johnston CC Jr. Increases in immunorcactive parathyroid hormonewirhage.
N Eng,J Med ,919;3M:l4,9-,421.
57 Marcus R, Madvig. P. Young G. Age-related changes in panthyroid hormone and parathyroid hormone action in normal humans. J Clin Endocrinol Metab 1984;58:223-2.30. 58 Delmas PD. Sanner D. Wahner HW. Mann KG. Riggs BL. fncrease in serum bonc-carboxyglmamic acid pratcin with aging in women: implications for the mcchsnism of age-related bone loss. J Clin
227 Invest 1983:71:1316-,321. 59 lnsogna KL, Lewis AM, Ltpinski BA. Bryant C, Baran DT. Effect of age on serum immunoxactwe parathymid hormone and its biological effects. I Clin Endocrinol Mctab 198,;53:1072-10’5. 60 Tsai K-S. Heath H III, Kumar R. Riggs BL. Impaired vitamin D metabolism with a& in women: possible role in pathogen& of senile osteoporosis. J Clin Invert 19&1:7? 166S-,672 6, Seeman E, Melton W 111,O’Fallon WM. Rtggs BL. Risk factots for spinal ateopotc& in men. Am J Med ,983:75:977-983. 62 Seeman E, Wahncr HW, Offord KP. Kumar R, Johnson WI. Riggs BL. Differential effects of endocrine dysfunction on the axial and the appcndicular skeleton. J Clin Invest 1982:69zI3U2-1309. 63 Francis RM, Peacock M, Marshall DH. Honman A. Aaron IE. Spiw! mlcoper& in men Rnnr Mineral ,989:5:347-358. 64 Gallagher JC, Melton LJ, Riggs BL. Eramination of prevalence rates of vible risk factors in a population with a fracture of the proximal femur. Clin Orthop ,9SQ,51:153: ,5S-I65 65 Riggs BL, W&net HW, Melton W III. O’Fallon WM. Judd HL. Rich&on LS. la women dietary calcium intake and rates of bone loss from midradiusand lumbar spine are not related. J Bone Mineral Res 1986;,:Suppl. 1.96 (abstract). 641Lindsay R. Han DM, Forrest C, Biard C. Revention of spinal osteoporosis in oophorcnomised vcmen. Lance, ,9SD,ii:,*5,-,153. 67 Canniga A. Gennari C, Boreka G. Benant M, Cesari L. Paggi C, Evobar C. Intestinal absorptionof calcium-47 after tteatment with oral estrogen and Sestagen tn senile ostoopaosis. Br Med J ,970:1:3c-32. 68 Gallagher JC, Nordin BEC. Effects ofaestrogen and proSesroSen therapy an ealrium maabotbm in post-menopausal women. In: van Keep P, Lauritzen C, eds. Frontiers of hotmow research. Bawl, Switzerland: Kawt, 1975;,50-176. 69 Reeve J, Me& P1, ParsonsJA, Bernat M, Bijvoet OLM. Cotupton P. Edouard C. Klcnerman L. Neer RM. Renier JC. Slovik D. Vismans NFE. PottsJT. Anabolic effect afhumanrarztbvoid bar ment on trabeculat bone in involutional osteoporosis: a multicentre trial. Br tied J~I9SQ~: 1340-1344. 70 Slovik DM. Neer RM. Potts JT. Sbon-term effects of synthetic human parethyroid hamone-(I-34) administration on bone mineral metabolism in osteoparotic patients. J Clin Invest 1%1;6t? 1261-1271. 71 Slavik DM, Adams IS, Neer RM, Halick MF. Potts JTJR. Deficient production of ,25_dibydratl vitamin D in elderly osteopxotic patients. N Engl J Mcd ,981 ;M5:372-374. 72 Chestnut CH. Drug therapy: calcitonin. bipbosphonates anabolic steroids. and hPThtt-34). In: Riggs BL, Melton U III, eds. Osteoporasls: etiology. diagnosis and management. New York Ra“enPress, 1988;493-414. 73 Civitelli R, Gonnelli S, Zacchei F, Bigazzi S, Vattimo A. Avioli LV. Gennari C. Bone tunmver in postmenopausal osteoporosis: effect ofcalcitonin ttestmeot. J Clin Invest 1988;82:1~,274. 74 Gallagher JC. Jerpbak CM, Jee WSS. Johnson KA. DeLuca HF. Riggs BL. I,~-Dibydxwvitamin D,: short- and long-term effects on bone and calcium metabolism in paliena with postmenopausal osteocaosis. Proc Nat1 Acad Sci USA 1982:79:3325-3329. 75 Aloia JF, Vaswani A. Yeh J, Ellis K. Yasumura S, Cohn S. Calcitriol in rhe treatment of portmewpausal osteoporosis. Am .t Med l988;84:40,-408. 76 Shiraki M, Otlmo H. Ito H. Akiguchi I, Nakau I, Takahashi R. Isbizuka S. Long-tent! treatment of postmenopausal osteoporosis with active vitamin D, l-alpha-hydt”olycholeealeileral and 1.24-di. hydroxycholecalcifero, and 1.24.dibydroxycholeclcifero,. Endocrinol Jpn 1%5532:3d5. 77 Ott SM. Chertnutt CH. Calci!riol treatment is not effective in postmenopausalosteo~tcsis. Aan Itit Med l989;267-274. 78 Orimo H. Shiraki M, Hayeshi R, Nakamura T. Reduced occurrence of vertebral crush fractures in senile osteoporosis treated with la(OH)ritamin D,. Bone Mineral ,987;3:47-52. 79 Gallagher JC, Riggs BL. Reeker RR, GoldSar D. The effect of calcitrio, cat patientswith pastme”.+ pause, osteoporosis with special reference to fracture frequency. Ptoc Sax Exp Bio, Med ,989;3: 287-292. SO Hsysshi Y. Fujita T. Inoue T. A multi-cenrrr study on efficacy of 1 alpha-hydmxyvitamin I$ in oreventing spinal fractures of patients with osteoporosis. J Bone .Mineral Res 1989:4(SI):1&1. St Stall GM. lohnscn J, Hughes BD. Excessive L-thyroxine therapy and the rate of lumbar spine bane mineral loss. I Bone MineraI Res 1989;4(S,):X3.
The pathogenesis
of osteoporosis
The term osteopenia refers to a reduction in the amount of bone per unit volume relative to ihat expected for the age and sex of the subject. Traditionally, the term osteoporosis has been reserved for the clinical syndrome which owun as a wmplication of osteopenia and includes the most common fractures which involve the hip, vertebrae, radius and humerus. It is probably helpful to use these terms separately since many elderly people have osteopeoia, but never develop a clinical frachue. Osteoporosis is a considerable health care problem at the present time and will become an even larger problem as the proportion of elderly peopie increases in the population [l-4]. Economically, hip fracture has the largest single impact on health care costs, however, morbidity in patients with vertebral fractures lasts for many years and leads to long-term health care costs [II. Development of a vertebral or hip fracture is a dramatic event for any elderly person and the patient’s lifestyle changes markedly after these episodes. In the mid 80s about one in three women and one in every six men will develop a hip eachwe 15) making osteoporosis one of the most common diseases of the elderly population alongside that of cancer, vascalar disease and degenerative arthritis. In the USA the present oosh of treating patients with osteoporosis ard around $7 billion each year [l]. By the year 2020 one can project that the increase in the profxxtion of elderly people, the increasing incidence of age-adjusted hip fractures and the inflation of health care costs will lead to annual costs for osteouorosis approaching $60 billion each year. Because of the severity of osteoporosis in patients and because of the tremendous fatwe economic impact of this disease, an understanding of the pathogenesis of osteqorasis k CNcial and with it the development of strategies for both prevention and treatment of this condition.
216 Eoue :emodc!llng After completion of growth of the skeleton in the early twenties, bone is renewed through remodelling cycles [6]. This remodelling sequence takes several months and involves an initial state of bone resorption lasting several days. The following weeks are dominated by the action of osteoblasts which till in the resorption cavities. Completion of this process leads to replacement and renewal of bone. Loss of bone with age implies incomplete filling in of resorption cavities and, with time, this leads to a net loss of bone throughout the skeleton. At the cellular level, it has been shown that activation of bone remodeiling is initiated by the systemic hormones parathyroid hormone and 1,2;-dihydroxyvitamin D,. These hormones do not directly stimulate osteoclasts, but act through one or multiple factors generated by osteoblast-like cells [7-91. Tumor necrosis factor a and /3, and interleukin-1 stimulate osteoclastic resorption, but only in the presence of osteoblasts [lo]. Interleukin-land prostaglandin-induced resorption is also enhanced by parathyroid bonnone [ll]. Some of the peptides synthesized by osteoblast-like cells are mitogenic and stimulate further proliferation and synthesis by the osteoblasts [12]. These mitogem are also found in the bone matrix and are released by bone resorption. Recently identified skeletal growth factors released after bone resorption stimulate osteoblast synthesis of matrix and can act, therefore, as coupling agents [13]. These local regulatory mechanisms probably represent examples of both autocrine and paracrine control mechanisms. 1.25Dihydroxyvitamin D occupies a central role in bone remodelling. Although it does not directly stimulate osteoclasts, it does initiate the activation process by stimulating osteoblasts and monocytes to release factors which stimulate osteoclasts to resorb bone [14]. 1,2S-Dihydroxyvitamin D, increases the proliferation and numbers of osteoblast cells [LX], increases alkaline phosphatase activity [16] and osteccalcin synthesis [17] and plays a central role in bone mineralization.
Changes in bone density wltb age The recent introduction of bone densitometry has made possible the selective measurements of different parts of the skeletoe. It is now clear that bone loss starts at different periods of life throughout the skeleton and occurs at different rates. For example, there is a 30% decrease in bone mineral density of the femoral neck and Ward’s triangle in the proximal femur during the premenopausal age span [18-211. In contrast, bone mineral density of the spine [19,22,23] and the trochanteric region of the proximal femur [19,21] shows no significant loss of bone prior to menopause. Measurements of the radius show an increase in density up to the fourth decade and no significant loss before the menopause 124). These bone regions contain varying proportions of cortical and trabecular bone with the exception of the radial mid shift which is almost all cortica! bone. Although the impact of menopause is universal throughout the skeleton, the use of computerized axial tomography of the vertebrae has shown that the largest decrease in bone occurs in the central part of the
vertebrae which is predominantly trabecular bone [25]. Calculationof ratesofbone loss after the menopause show that these can be considerable. In the central trabecular region of the vertebrae, the rates of loss are 10% per year for the first 2 years [25]. In contrast, the rate of cortical bone loss in the radius averages2-3% per year [24]. These differences in the rates of loss of cortical and trabecular bone may simply reflect the fact that trabecular bone has a larger surface area available for resorption. Rates of loss after the menopause occnr exponentially so that the phase of rapid loss occurs mainly during the first 5 to 7 years after the menopause [26]. This sudden rise in net bone resorption during the ftrst 4 years after the menopause reflects an increase in the activation of many more resorption sites, and can be measured biochemically as increases in plasma tartrate acid phosphatase, osteccalcin and urine hydroxyproline excretion [Zq. During the next 4 years there is a decline in the biochemical markers of bone resorption and presumably this refkcts a decrease in the number of bone remodelling sites. An additional devebrpsncnt may be that the osteoclasts resorb deeper cavities than usual and these are incompletely tilled in by the osteoblasts. Probably both processes occur, but sIttee there is a net loss of bone and thinning of the trabecular elements several years after the menopause [28] it is likely that the latter process becomes dominant. Ahnost BY%of the decrease in bone mineral density of the spine occurs in the first 8 yearsfolIowing the menopause. Thus, the impact of estrogen deficiency is clearly a major factor in trabecular bone loss in the spine. It is also seen in young women aged 20-Q .rhodevelop amenorrhea and estrogen deficiency assoxiated with excessive athktic a&Iv&y [29] or following a temporary menopause associated with the use of LHRH agonists [30]. In hoth situations spine density decreases rapidly and osteopenia is often seen in the amenorrheic athlete. Although estrogen deficiency is an important cause of trabecular bone loss it should be pointed out, however, that age-related trabezttlar bone loss in the femoral neck occurs independently of estrogen activity in the preand late postmenopausal period. The recent findings of different patterns of bone loss throughout the skeleton suggest that, prior to the menopause, bone resorptioo and formation are fairly equal in the vertebrae, whereas in the femoral neck rwxp tion activity exceeds bone formation by 0.5% per year. Classification ofthe csteoperotic types In 1947, Albright divided osteoporotic patients into the postmenopausal and senile groups and he clearly implicated the role of estrogen deficiency in postmenopausal osteoporosis 1311.More recently, Riggs and Melton have renamed postmenopausal osteoporosis as Type I and senile osteoporosis as Type II [32]. Another small group, Type IA, has aIso been described by us earlier [33]. If this type of classification is to be used then one should also recognize a Type III osteoporosis, this term being reserved for those patients who develop osteoporosis secondary to various medical diseases or drugs. It is obvious to all clinicians that there is overlap between the various groups, but some of the differences between the groups are summarized in Table 1.
218 Table 1 Classification of osteoporotic types (modified after Riggs and Melton [32]) Type ** (senile)
Type 1.4
55-70 s-15 20:1
75-90 25-40 2:1
65-75 25-35
any age any age t:,
Spine
Hip, spine, pelvis.humerus
Spine
Spine, hip, peripheral
+++ +
++ ++
+++ +
+++ +++
+++ +
++ +++
++t ++
++ ++
i
:
:
::
1
1
1
Type’ (postmenopausat)
t
1
-
?
Postmenopausalosteoporosis (Type f) The postmenopausal osteoporosis patient (Type I) is characterized by vertebral fractures which occur in the early to mid 60s or within 5-15 years of the menopause. Predominantly this syndrome is seen in women rather than men (20~1). Most patients have two or more vertebral fractures by the time they reach a specialized bone clinic and their history of backache usually extends 2-4 years earlier. The younger the patient, the more abnormal is the spine density [34] or iliac crest bone volume [3.5] relative to age-matched control subjects. Histomotphometry of iliac crest bone biopsies show high turnover in about 25% of the cases, low turnover in another 25% and the rest have values indistinguishable from normal [36,37]. Most commonly, bone density measurements show that the Type I patients with vertebral fractures have usually developed proportionately greater loss of trabecular bone from the vertebrae. These findings could be explained by faster rates of loss during the exponential phase of bone loss, a prolonged exponential phase, or normal or high rates of loss in patients in whom the bone mass was low at the onset of the menopause. Although about one-third of Type I patients have normal cortical bone mass [34], another third have low cortical bone mass. Again, it is not clear whether this latter group of patients is one which continued to have excessive loss of
219 cortical bone from the skeleton following the phase of rapid trabecalar bone loss or whether it occurs in those patients who reached menopause with a low peak bone mass. Consistently, malabsorption of calcium is found in 60-70’S of these patients 138,391. The absorption defect is quite severe and calcium balance studies have demonstrated that fecal calcium may exceed calcium intake in a third of these patients similar to a calcium losing enteropathy [40]. This calcium loss appears to be a specific loss and there is no evidence of malabsorption of fats or other nutrients in these patients. Parathyroid function. is normal or decreased in the same proportion of patients [41]. Several groups have demonstrated redwed levelsofsemm lpdihydroxyvitamin D in these patients (38.42-451, however, stimulation with synthetic parathyroid hormone can increase the circulating serum level of 1,25-diiydroxyvitamin D [46] suggesting that there has been marked decrease of 1,25-dihydroxyvitamin D production. The natural history of this Icw production is not clear. Detailed studies of serum and urine calcium, and indices of bone turnover, such as osteocalcin and alkaline phosphatase, all show a marked rise m the first 3-4 years after the menopause [291. It is postulated that, following increased or prolonged bone resorption, a slight elevation in serum ca!cium leads to decreasedsecretion ofparathyroid hormone, a functional decrease in 25-hydroxyvitamia D-la-hydroxylase activity, decreased production of 1,25-d;hydroxyvitamin D and ultimately decreased calcium absorption and negative c;&ium valance (Fig. 1). A few patients have malabsorption of calcium with norm 1 1,25-dihydmxyvitamin D levels and these may be patients with abnormal rcceproi binding in the gut [S]. In some o+ teoporotic patients, estrogen may stimulate parathyroid hormone secretion, 1,25dihydroxyvitamin D production and an increase in calcium absorption [47], suggesting thai the estrogen deficiency component is still important in some Type 1 osteoporotics. Calcitonin secretion may he inappropriately low ia the postmenopausal years and levels have been reported in osteoporotica as normal [48], low [49] and
220 high [SO]. Other recent investigations have suggested a role for raised interleukin-1 secretion in monocytes from patients with this syndrome and this finding could accoont for a prolonged phase of exponential loss after the menopause [Sl]. Senile osteoporosis (Type II) Patients who fit into this clinical category are much older, averaging 80 years of age. By definition, this syndrome refers to all patients with hip fracture, but about 30% of them will be found to have concurrent vertebral fractures. These patients usually fracture 25-40 years after the menopause, but the female to male ratio is 2:l compared to 20: 1 in postmenopausal (Type I) osteoporosis (Table 1). Although the menopause obviously contributes to a substantial proportion of the total bone loss in this group, much of the bone loss occurs as the result of prolonged and slow loss of cortical and trabecular bone over 40-50 years [34]. Recent findings, however. suggest a more severe decrease in femoral neck density in hip fracture patients than in age matched controls [SZ]. The biochemical findings in this group show decreased absorption of calcium in 75% of the elderly subjects [53]. However, oniy 30-40% of these patients have decreased levels of 1,25-dihydroxyvitamin D, especially in those with decreased renal function [54]. The dissociation between malabsorption of calcium and the serum 1,25-dibydroxyvitemin D raises the possibility that there is a defect in the binding of circulating 1,25-dihydroxyvitamin D to the intestinal receptor in this group !55]. Malabsorption of calcium probably leads to hypocalcemia, secondary hyperparathyroidism [41,56,57] and increased bone turnover [58]. Increases in urinary cyclic AMP excretion are also found suggesting that the increases in pamthyroid hormone are functional [59]. Thus, a major difference between Types I and II lies in the parathyroid hormone levels (Fig. 2). Although the changes in calcium absorption appear mainly after age 65 years, there is no evidence at this time to show any increase in the rate of bone loss at this time, which one might expect, and further information is needed. Many elderly subjects have normal serum 1,25-dibydroxyvitamin D levels and it appears that the patients with senile osteoporosis who have decreased serum levels of 1,25-dihydroxyvitamin D are probably a subgroup with more severe loss of renal function. These patients do not increase levels of serum 1,25-dihydroxyvitamin D after stimulation with injections of parathyroid hormone [60]. Type IA osfeoporosis Type III osteoporosis occurs in only a very small number of patients. These patients develop vertebral fractures in the mid-to-late 60s. Characteristically, they have malabsorption of calcium and decreased levels of serum l,ZS-dihydroxyvitamin D, but elevated levels of parathyroid hormone [33]. By implication these patients must have a primary defect in la-hydroxylase in the kidney. This group presents clinically as Type I, but behaves biochemically as Type II. Secondary osteoporosis (Type Ii:) By definition, this group contains all patients in whom osteoporosis could be attributed to a secondary cause [61,62] such as partial gastrectomy, malabsorption syn-
221
dromes, hyperparathyroidism, hypogonadism, thyrotoxicosis, immobiiiition, hemiplegia or drug causes such as alcohol, excessive thyroxine replacement, anticonvulsant drugs, corticosteroid therapy or radiotherapy. These factors could contribute to the type of hone loss seen in Types I or II osteoporosis at any point in the life time of the patient. For example, excessive thyroxine or corticosteroid therapy just after menopause could magify the increase in the bone resorption rate. Studies of younger osteoporotics with only vertebral fractures have shown that secondary causes accounted for 35% of the eases in women and about 50% in men [61,63]. We have previously examined the incidence of certain diseases known to be associated with abnormalities of calcium metabolism in hip fracture patients. About 3O-40% of these patients had a possible contributing cause to the hip fracture [64]. Thus, idiopathic osteoporosis in patients presenting with a Type I or 11 pattern may account for only 60-70% of ail ca.ses. This has important implications for the role of preventive measures which might reduce the incidence of fractures. The role of dietary calcium as a contributing factor to usteopw rosis is not clear [65]. There must be a minimal dietary calcium intake necessary to minimize bone loss. Obligatory fecal, urine and skin losses of calcium are about 250-300 mg/day and a calcium intake of around 500~6tN mg/day, assuming a normal adaptive response in calcium absorption, would be a minimum requirement necessary to maintain calcium balance. A calcium intake below that figure probably increases the negative calcium balance and contributes to bone loss. In situations where malabsorption of calcium exists, or in the high resorption phase immediately after the menopause, it seems clear that the concept of a minimal dietary calcium is relatively unimportant. There is no fitm data at the present time on the role of exercise or activity in the prevention of osteoporosis. Immobilization produces rapid bone loss, but it is not clear on the amount of activity needed to prevent bone loss.
222
Implications for prevention and treatment of osteoporosis Postmenopow~l
(Type I) osteoporosis
This disease would be most effectively prevented by estrogen replacement therapy at the time of the menopause [66]. Patients who have been on acceptable doses of estrogen replacement therapy for 15-20 years do present with vertebral fractures in the mid 60s; so not all women respond to estrogen replacement therapy, although it is not clear why, perhaps the dose of estrogen used in those individuals was not sufficient. Treatment of the patient with established vertebral fractures includes estrogen, parathymid hormone, calcitonin of 1,25-dihydroxyvitamin D analogues, thus following the pathogenetic pathway. Estrogen appears to be effective in some patients; it stimulates parathyroid horntone and 1,25-dihydroxyvitamin D production [47], and increases calcium absorption and calcium balance [67,68]. There is no information, however, on the long-term value of estrogen therapy in preventing further fractures in Type I patients since controlled studies have not yet been undertaken. A few patients have been treated with injections of parathyroid hortnone (PTH) and preliminary results suggest that these patients respond to very small doses of parathyroid hormone. Most of the results have described changes in iliac crest biop sies or calcium balance and there is little infomration on bone density [69,70]. Repeated injections of small doses of parathyroid hormone cause down-regulation of 1,25-dihydroxyvitamin D production by the kidney so that both PTH and 1,25-d& hydroxyvitamin D, would need to be given together [71]. Calcitonin injections are reported to be effective in the treatment of Type I patients [72], especially in the group with high turnover osteoporosis [73]. It has been suggested by some investigators that the increase in bone mass is transient [72] but, nevertheless, prevention of bone loss for several years would be useful. No convincing controlled studies of fracture prevention have yet been reported for calcitonin therapy. Probably the largest body of data on osteoporosis treatment exists for vitamin D analogue use. Thousands of patients with Types I and II osteoporosis are being treated with vitamin D analogues in controlled studies. As mentioned previously, the majority of these patients have malabsorption of calcium and reduced serum levels of 1.25-dihydroxyvitamin D; treatment with synthetic vitamin D analogues normalizes calcium absurption [38], improves calcium balance 1741 and prevents bone loss in most [43,75,76] but not every study [77]. Most results have shown that vitamin D analogues also increase bone mass; this is particularly true for patients studied in Japan [76] and Italy [43] where calcium intakes are traditionally low. We have suggested that a low calcium intake enables these patients to tolerate higher doses of vitamin D analcgues, and that there is a positive dose effect of these compounds on bone. In addition, fracture rates are significantly reduced with vitamin D analogue treatment [7%30]. Despite earlier concerns, there has been no evidence yet of long-term nephrotoxicity provided that hypercalcemia and hypercalcuria are avoided. Restricting the calcium intake to 600-700 mg/day helps to control the absorptive response and reduces the chances of developing hypercalcuria.
223 Treatment of Types II und !P. c-‘coporosis There is no obvious role for estrogen therapy in these patxnts since parathyroid hormone is already stimulated in this group except in those patients with a high turnover state. the predominant prob!em in these patients appears to be a primary decrease in la-hydroxylase activity in the aging kidney resulting in reduced pmduction of 1,25-dihydroxyvitamin D and calcium malabsorption. This is a group of patients who logically should be treated with the vitamin D analogues.There are now results from Japan demonstrating the efficacy of vitamin D analogue treatment in Type II osteoporotic patients [KI]. Secondary 01’Type III osteoporosis Although many conditions, listed in Fig. 3, are known to be associated with the development of osteoporosis, few systematic studies of treatment of these conditions have been undertaken. However, the advent of bone density should enable us now to measure changes on therapy more easily. For example, monitoring bone density on thyroxine replacement therapy has shown that previous replacement doses were too high [Sl]. The use of estrogen in women with a premature menopause or as a medical treatment for primary hyperparathyroidism should be considered. Since patients treated with corticosteroids or anticonvulsants have malatwiption of catcium and osteoporosis, prophylactic treatmtint of these patients with vitamin Danalogues should be considered. In conclusion, preventive therapeutic measures in this m!scellaneous group could be expected to have a significant impact in reducing the incidence of osteoporosis and fractums.
223
Changes in the calciotropic hormones with age contribute significantly to the pathogenesis of osteoporosis. In both postmenopausal (Type I) and senile osteoporosis (Type II) it is common to find reduced levels of serum 1.25~dihydroxyvitamin D and malabsorption of calcium. In Type I patients a reduced level of sertttn parathyroid hormone causes a real decrease in serum 1,25-dihydroxyvitamin D production and malabsorption of calcium, whereas in Type II patients the decline in la-hydroxylase activity in the kidney causes a decline in serum 1,25-dihydroxyvitamin D which leads to malabsorption of calcium and secondary hyperparathyroidism. In the final analysis both pathways lead to bone loss. In some Type II patients there may be a decline also in the function or number of the vitamin D-binding receptors in the gut. Treatment of patients with vitamin D analogues, however, nonnaIiies calcium absorption and improves calcium balance. The improvement in calcium balance redues bone resorption and prevents further bone loss; in addition recent studies have shown that therapy with vitamin D analogues leads to a reduction in fracture incidence.
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