Studies on pathogenesis and treatment in postmenopausal and senile osteoporosis

10 Studies on Pathogenesis and Treatment in Postmenopausal and Senile Osteoporosis B. L A W R E N C E R1GGS, J E N I F E R JOWSEY, P A T R I C K J. KELLY, D A V I D L. H O F F M A N A N D C L A U D E D. A R N A U D

Postmenopausal or senile osteoporosis is common in middle-aged and older persons of either sex but occurs more often and is more severe in women. Forms of the disease that are similar roentgenographically but probably different in regard to therapy and aetiology occur in young adults and in children. The pathologic abnormality in osteoporosis is an absolute decrease in the amount of bone present, to a level below that which is capable of maintaining the structural integrity of the skeleton or, as Albright and Reifenstein (1948) succinctly put it, "too little bone". The bone that remains is normal by ordinary histologic examination. The proportional loss is greatest in areas of the skeleton containing large amounts of trabecular bone, which accounts for the primary features of the disease--crush fractures of the vertebrae, fractures of the neck of the femur, and fractures of the distal end of the radius. It has been difficult to obtain meaningful data on the pathogenesis of osteoporosis because of the low magnitude of the abnormal changes and the long time over which the bone loss occurs. Progress was particularly slow when only relative insensitive methods were available, such as roentgenographic evaluation, measurement of height loss, and metabolic balance studies. However, much more has been accomplished during the last decade owing largely to the development of more sensitive methods such as radiocalcium kinetic studies, quantitative bone morphology, and bone densitometry. Three contributions to a better understanding of pathogenesis were made during this decade. First, it has been appreciated that bone loss is a nearly universal occurrence in both sexes, and this observation has been used as a basis for several different aetiologic models (Doyle, 1972). Next, bone morphometric measurements (Jowsey et al, 1965; Villanueva et al, 1966; Wu, Jett and Frost, 1967) have shown that, in untreated osteoporosis, mean bone formation is normal and mean bone resorption is increased; radiocalcium kinetic studies also are consistent with these data (Harris and Heaney, 1969). Finally, objective measurements of bone density (Meema, Clinics in Endocrinology and Metabolism--Vol. 2, No. 2, July 1973.

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B. LAWRENCERIGGS ET AL

Bunker and Meema, 1965; Davis, Strandjord and Lanzl, 1966; Nordin, MacGregor and Smith, 1966) validated the long-held theory of Albright and Reifenstein (1948) that the menopause accelerates bone loss in women. Evaluation of therapy also suffered initially because of lack of sensitive methods. It has often been difficult to compare the results of different studies because of differences in experimental design, in methods of evaluation, and in types of patients. However, in spite of these problems, reasonable forms of treatment have been gradually developed. Oestrogen has been the most widely used therapeutic agent and has been reported to prevent further vertebral fractures and loss of height (Henneman and Wallach, 1957). Although short-term treatment with oestrogen produces calcium retention in a majority of osteoporotic patients studied by metabolic balance methods, the failure to demonstrate an increase in skeletal radiodensity even after years of treatment suggests that these short-term effects cannot be maintained indefinitely (Henneman and Wallach, 1957). Androgens were used infrequently in women with postmenol~ausal osteoporosis until the introduction in the 1950s of synthetic analogues which had anabolic activity equal to that of testosterone but had markedly decreased virilising properties. Orally administered calcium supplements have been shown to produce calcium retention (Whedon, 1959; Nordin, 1962; Schwartz, Panariello and Saeli, 1965) as well as a favourable change in radiocalcium kinetics (Schwartz et al, 1965); however, with prolonged therapy these effects became less prominent (Schwartz et al, 1965). In recent years, several new forms of treatment have been evaluated. A number of workers have evaluated the effects of calcitonin on osteoporosis and it has been estimated that beneficial results occurred in approximately half the patients studied (Wallach, Aloia and Cohn, 1972). The diphosphonates are synthetic drugs similar in structure to pyrophosphate; based on animal and in vitro studies, it has been suggested that they may decrease the rate of bone dissolution. Preliminary studies on the effect of the diphosphonate, Na2EHDP, in a small group of patients treated for six to twelve months by Saville and Heaney (1972) showed a tendency toward calcium retention. Noting that persons with fluorosis had dense bones, Rich and Ensinck (1961) administered sodium fluoride to osteoporotic patients in the hope that induction of subclinical fluorosis might strengthen the skeleton but not lead to other changes; they found that calcium retention ensued. However, subsequent studies of the value of fluoride therapy have given conflicting results (Riggs and Jowsey, 1972). Although morphologic studies in humans and experimental animals have made it clear that the predominant effect of fluoride on the skeleton is osteoblastic stimulation, the newly formed bone is poorly mineralised and has the histologic appearance of osteomalacia; also there may be increased resorption. Burkhart and Jowsey (1968) have shown that, in cats, the production of excessive osteoid tissue by fluoride administration can be prevented by increasing dietary intake of calcium. This suggests that the unfavourable histologic changes are not due t o ' a toxic effect of fluoride on bone but rather to an increased demand for mineral because of the large increase in bone formation. Finally, a course of daily intravenous calcium infusion has produced a sustained favourable alteration

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in several metabolic factors in 6 of 12 osteoporotic patients (Pak and Bartter, 1972). Four years ago we began a systematic prospective study on the effects of different forms of treatment on postmenopausal and senile osteoporosis. All patients studied were of a uniform type and were studied in an identical basic protocol so that different therapeutic programmes could be directly compared. In this communication, we summarise (1) data on bone turnover, calcium metabolism, and immunoreactive parathyroid hormone (iPTH), in osteoporotic subjects, bearing on pathogenesis, and (2) data defining mechanism of action and comparative value of five different therapeutic programmes. The reader is referred to the original articles (Riggs et al, 1969, 1972, 1973; Jowsey et al, 1971a, b, 1972) for the complete details of these studies and for a more complete review of related work by others. MATERIAL AND METHODS

Sixty patients were studied before and on one or more occasions after treatment. The group included 57 women and 3 men; their ages ranged from 53 to 76 years. All patients were ambulatory and had had progressive osteoporosis of sufficient severity to produce crush fractures of the spinal column. None had any evident disease other than osteoporosis. All studies were made on a metabolic ward while the patients ate a daily diet in which the calcium and phosphorus contents were adjusted to those of the home diets. Fasting morning serum was taken for calcium, phosphorus, and alkaiine phosphatase measurements on three successive days. Urinary calcium excretion was determined on three successive days. iPTH was measured by radioimmunoassay using two different antisera (GP 1M and CH 14M), and the method of Arnaud, Tsao, and Littledike (1971). These antisera have markedly different specificities for the two major molecular species of iPTH previously demonstrated in serum of patients with primary hyperparathyroidism* (Habener et al, 1971). The normal range for iPTH is undetectable to 40 ~tl Eq/ml measured with GP 1M and undetectable to 250 ~tl Eq/ml with CH 14M. After completion of these studies, a bone biopsy specimen was taken from the iliac crest with a trephine 1 cm in diameter. Undemineralised sections were made from the biopsy sample and the proportions of surfaces undergoing active formation and resorption were determined by quantitative microradiography (Jowsey et al, 1965). To equate differences in these surface measurements with differences in rates of bone formation and resorption, it is necessary to assume that the rates of deposition and destruction per unit length of active surface do not vary greatly between individuals. In some patients, radiocalcium kinetic studies also were performed. *Gel filtration studies of hyperparathyroid sera (C. D. Arnaud, unpublished data) have demonstrated that antiserum GP 1M measures predominantly PTH immunoreactivity in fractions eluting in a region corresponding to molecular weights 5000-9500 whereas antiserum CH 14M predominantly measures immunoreactivity eluting in the region of molecular weight 9500.

320

B. LAWRENCE RIGGS ET AL RESULTS

Pretreatment data Serum calcium a n d p h o s p h o r u s did n o t differ significantly f r o m n o r m a l . M e a n i P T H (Table 1) was n o r m a l w i t h a n t i s e r u m G P 1M b u t was lower t h a n n o r m a l with a n t i s e r u m C H 14M. The fraction o f i P T H t h a t C H 14M p r i m a r i l y measures a p p e a r s to be the p r i n c i p a l secretory p r o d u c t o f p a r a t h y r o i d glands Table 1. Serum immunoreactive parathyroid hormone values iPTH (lal eq/ml) Antiserum GP 1M N Mean -+- SE

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47 79

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69"9 + 14"2 127'2 + 9'2 < 0"001

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Figure 1. Microradiographic findings from pretreatment iliac crest bone biopsy in 60 osteoporotic patients. Female osteoporotic patients are represented by solid circles, and males by solid triangles. For age- and sex-matched normals, 90 per cent range is given by cross-hatched areas and means by horizontal lines.

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thus appear to represent a separate population from the larger group. Quantitative microradiographic studies showed normal values for boneforming surfaces but increased (P < 0.001) values for bone-resorbing surfaces (Figure 1). Oestrogen Seventeen osteoporotic women were studied before and after short-term (2½ to 4 months) treatment with conjugated equine oestrogens (Premarin) and then again after long-term treatment (26 to 42 months). Before treatment, mean ( + SE) for resorbing surfaces was 15.0 ± 0"8 per cent. After shortterm therapy, there was a highly significant (P < 0-001) decrease in values for bone-resorbing surfaces, to 6.4 + 0.7 per cent; after long-term therapy, bone-resorbing surfaces increased (10"6 + 0"8 per cent) to above values observed after short-term therapy but remained significantly (P < 0.01) lower than pretreatment values. There was a significant positive correlation between pretreatment values and post-treatment decreases in values for bone-resorbing surfaces (r = 0.81 ; P < 0.001) (Figure 2). For bone formation, pretreatment values were within the normal range (4.8 ± 0.3 per cent) and did not change significantly (4.0 + 0.7 per cent) after short-term therapy. However, after long-term therapy, there was a highly significant (P < 0"001) decrease to very low values (0"6 + 0.2 p e r cent); these values are as low as those seen in patients with severe hypercortisonism. 24 %

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B. LAWRENCE RIGGS ET AL

Serum calcium and phosphorus decreased significantly after treatment although the values remained within the normal range. These decreases appeared to be due to the oestrogen-induced inhibition of bone resorption rather than to renal tubular effects because urinary calcium excretion decreased significantly but there was no change in tubular reabsorption of phosphate (TRP) or inulin clearance, iPTH (assessed by antiserum GP 1M) was determined before and after treatment in eight of the patients and increased significantly.

Synthetic anabolie hormone Twelve women with postmenopausal osteoporosis received oxandrolone (Anavar), a synthetic anabolic hormone, in divided doses of 10 to 20 mg daily. The patients were studied before and after short-term therapy (2½ to 4 months) and seven were re-studied after long-term treatment (12 to 15 months); these seven patients also underwent radiocalcium kinetic studies at their first and third examinations. As in the oestrogen-treated group, a significant positive correlation was present between pretreatment values and post-treatment decreases in boneresorbing surfaces (r = 0"85; P < 0"001) (Figure 2). When the slopes of the regression lines were compared, there was no significant difference between the oestrogen-treated group and the anabolic hormone-treated group, suggesting that the latter was as effective as oestrogen in decreasing bone resorption. For bone formation, there was no change from pretreatment values (2.6 _ 0.6 per cent) after short-term treatment (2.8 _ 0.8 per cent), but bone-forming surfaces decreased significantly after long-term treatment (1.6 _+ 0.4 per cent; P < 0-05). In the seven patients who underwent radiocalcium kinetic studies, there was a significant (P < 0.001) decrease in the size of the exchangeable calcium pool and the parameters Vo + (representing the total calcium inflow to bone) (423 _ 64 to 354 _+ 49 mg/day) and Vo(representing the total calcium outflow from bone) (471 + 88 to 386 _ 55 mg/day) after long-term treatment. After anabolic hormone administration, serum calcium, serum phosphorus, iPTH, TRP, and inulin clearance did not change significantly, but urinary calcimn excretion decreased significantly. The ultrafiltrable component of total serum calcium, determined in seven patients, did not change significantly after treatment, suggesting that anabolic hormone increases tubular reabsorption of calcium. When individual values for iPTH in both groups (oestrogen and anabolic hormone) of patients were merged, in all except one patient the iPTH value increased after hormone therapy when serum calcium decreased, and decreased when serum calcium increased. This inverse relationship was significant by the sign test (P < 0.001).

Diphosphonates Four osteoporotic patients (two women and two men) were evaluated before and after three months of therapy with the diphosphonate, NaaEHDP. The initial dosage was 10 to 20 mg/kg/day. Striking hyperphosphatemia (5.8 to 7.4 rag/100 ml) developed in all four, necessitating a decrease in dosage to between 5 and 10 mg/kg/day. Total serum calcium concentration increased

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AND TREATMENT

in all; however, ionised calcium decreased, suggesting that complexing of serum calcium may have occurred. The decrease in ionised calcium was associated with an increase in iPTH. No other consistent biochemical changes were observed. Bone-resorbing surfaces did not change significantly. However, there was a striking increase in the amount of osteoid tissue. The width of osteoid tissue increased by a factor of 2 to 3 in all patients (P < 0.001) and correlated positively with the increase in iPTH. In addition to an increase in thickness, there was an increase in the percentage of bone surface covered by osteoid.

Calcitonin We evaluated the effect of administering homogeneous porcine calcitonin (PCT) to five patients with postmenopausal osteoporosis. Two patients were studied for one month before and one month during treatment in a metabolic ward. The treatment began as 10 M R C units of PCT a day and progressively increased to a maximum of 50 M R C units/day (short-term studies). Three patients were studied before and after three to four months of treatment with 20 M R C units of PCT a day (long-term studies). In the short-term studies, there was no clear change in calcium or phosphorus balance, radiocalcium kinetics, or urinary hydroxyproline excretion after treatment; serum calcium and magnesium concentrations did not change as a result of treatment, iPTH increased and T R P decreased in all five. Bone resorption was unchanged in one patient who had short-term studies and was increased in the remaining 20 18

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four patients. The increase in iPTH correlated positively (r = 0.727; P < 0.01) with the increase in bone resorption (Figure 3). In order to evaluate whether calcitonin would be effective when secondary hyperparathyroidism was prevented, oral calcium supplements were given to 11 patients for three mouths in order to decrease PTH secretion. The calcium supplements were continued and salmon calcitonin (SCT) was then given in a dose of 100 M R C units daily. Preliminary results show that calcium supplementation alone decreased bone-resorbing surfaces. However, addition of SCT resulted in a further decrease in bone-resorbing surfaces. Fluoride Fluoride given alone to osteoporotic patients produced new bone that was poorly mineralised (Figure 4); however, when given with supplemental vitamin D and calcium, the newly formed bone was fully mineralised. To evaluate the effect of this therapeutic combination, 11 women with postmenopausal osteoporosis were studied before treatment and after 1 to 1½ years of treatment. Varying doses of fluoride and calcium were given so that the optimal dose of each could be determined; all patients received 50 000 units of vitamin D twice weekly. The effects of this therapy on bone-forming and bone-resorbing surfaces are shown in Figure 5. There was up to a fivefold increase in bone-forming surfaces. The effect was dose-dependent; boneforming surfaces correlated directly with the amount of administered fluoride

Figure 4. Microradiograph ( × 32) of iliac crest bone biopsy after seven months of treatment with fluoride (60 mg/day) without calcium supplementation. New bone tissue formed during treatment is poorly mineralised. On histologic section, there were wide borders of osteoid tissue.

(r = 0-72; P < 0"005). Furthermore, there was a fairly narrow optimal dose range. A daily dose of 30 mg of sodium fluoride did not consistently increase bone formation, while a daily dose of 60 mg or more produced areas of morphologically abnormal bone. In patients receiving intermediate doses, the bone was histologically and microradiographically normal and there was an increase in bone-forming surfaces. Bone-resorbing surfaces varied inversely with the dose of supplemental calcium (r = --0-78; P < 0.005). Doses of

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NaF, rncj / d a y Figure 5. (Left) Relationship between sodium fluoride dose and change in bone turnover expressed as absolute increase or decrease in percentage of total surface involved with either formation or resorption. Note the good positive correlation between formation and fluoride ingestion and lack of correlation between resorption and fluoride ingestion. (Right) Relationship between calcium supplementation and change in bone turnover in patients receiving sodium fluoride. Note the negative correlation between change in resorption and calcium supplementation and the lack of correlation with formation.

Figure 6. Patient with osteoporosis. (Left) Before treatment. (Right) After treatment with fluoride, calcium, and vitamin D for three years. The trabeculation in the vertebral bodies has increased.

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B. LAWRENCE RIGGS ET AL

900 mg or more of calcium were associated with either no change or a decrease from pretreatment values of bone resorption. Five of eight patients who were treated for more than three years had unequivocal evidence of coarsening of trabeculae of the vertebrae (Figure 6) and pelvis, and none had additional vertebral compressions after the first year of therapy. Although fluoride is potentially toxic, the side-effects of therapy in this group were minor. Gastric irritation developed in approximately half the treated patients but this disappeared when fluoride was given with meals or when an enteric-coated tablet was used. A few patients had transient arthralgia and stiffness of the joints, and one had synovial swelling of the knee. These symptoms promptly disappeared when the treatment was discontinued and did not recur when it was reinstituted at a lower dosage.

DISCUSSION Studies on pathogenesis

The factors producing the progressive bone loss in postmenopausal and senile osteoporosis are undoubtedly complex and are still not well understood. However, the mechanism immediatey responsible for bone loss in osteoporosis is an increase in resorption relative to formation. As previously reported by JoWsey and co-workers (1965), who used quantitative microradiography, and also shown in the patients described here, patients with osteoporosis have increased values for resorbing surfaces but normal values for forming surfaces. Approximately one in eight of the patients in the present series had values for resorption that were within the 90 per cent range for age-matched normals without apparent osteoporosis. Nevertheless, in almost every instance, resorbing surfaces exceeded forming surfaces. Newton-John and Morgan (1968) suggested that all persons lose bone at approximately the same rate as they age and that osteoporosis develops in some not because they are losing bone faster than normal but because they failed to develop sufficient bone during the first two decades of life. However, in a longitudinal study, Adams, Davies and Sweetnam (1970) found that some older persons maintained metacarpal mass for ten years or longer, whereas others lost bone at various rates. Also, to the extent that the proportion of resorbing surface is a good index of resorption rate, our microradiographic data suggest that osteoporotic patients are losing trabecular bone faster, and in some instances much faster, than age-matched non-osteoporotic persons. Nevertheless, the difference between bone loss in osteoporosis and in elderly non-osteoporotic persons may be only one of degree. The primary cause of the increase in bone resorption in osteoporosis is not entirely clear. We suggest that both abnormal bone cell function and postmenopausal disruption of the normal hormonal regulation of bone turnover by PTH and sex hormones are important. Because PTH is the major hormonal regulator of both calcium homeostasis and bone resorption, accurate assessment of serum concentration of PTH in osteoporosis is crucial in determining whether the observed increase in bone resorption is primary, and secondarily produces the negative calcium balance characteristic of

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osteoporosis, or, alternatively, whether the increase in bone resorption is secondary, resulting from either an alteration in calcium homeostasis or an inappropriate secretion of PTH for the prevailing serum calcium concentration. Our studies using sensitive immunoassays for PTH show that two types of parathyroid function occur in patients with osteoporosis. In a small group, iPTH is increased; in these patients, PTH probably plays a causal role in producing the bone loss. Some of these patients may have secondary hyperparathyroidism due to impaired intestinal absorption of calcium and others may have normocalcaemic primary hyperparathyroidism. However, in the large majority, parathyroid function was decreased. It is reasonable to assume that this decrease was at least in part compensatory for an increased rate of calcium release from bone. The finding by Kelly and co-workers (1967) that serum phosphorus and bone-resorbing surfaces correlate positively in osteoporosis is consistent with this concept. Also, decreased PTH secretion might explain the subnormal intestinal calcium absorption some investigators have noted in osteoporosis (Bullamore et al, 1970). Rasmussen and co-workers (1972) have shown recently that PTH induces the renal conversion of 25-OHcholecalciferol to 1,25-diOH-cholecalciferol, the most potent of the known metabolites of vitamin D. Through this mechanism, decreased PTH secretion in osteoporosis could indirectly lead to decreased vitamin D action and to decreased intestinal calcium absorption. The finding that iPTH concentrations are decreased in osteoporosis does not preclude a permissive or sustaining role of PTH in maintaining bone resorption; in fact, such a role seems probable. Parathyroidectomised humans fail to demonstrate the expected age-related loss of cortical bone (Hossain, Smith and Nordin, 1970) and, in osteoporotic persons, therapeutic measures that would be expected to inhibit PTH secretion (such as intravenous calcium infusion and oral calcium supplements) appear to decrease bone resorption. We have demonstrated that induction of small increases in iPTH by administering PCT to osteoporotic patients results in proportional increases in bone resorption. Our studies also support the concept that the menopause is of aetiologic importance. The short-term administration of a physiologic replacement dose of oestrogens to postmenopausal osteoporotic patients significantly decreased levels of bone resorption and serum calcium but increased iPTH. In these patients, PTH secretion appeared to be appropriate because the expected increase in iPTH occurred in response to the oestrogen-induced decrease in serum calcium. Arnaud et al (1971) have previously shown that iPTH is negatively correlated with serum calcium concentration. In contrast to the normal secretory response of the parathyroid glands, the biologic effectiveness of PTH was clearly impaired by oestrogen replacement therapy because higher values for iPTH were associated with lower values for resorption. These findings strongly suggest that oestrogen exerts its effect by decreasing the responsiveness of bone to endogenous PTH, a proposal previously made by Heaney (1965) and by Jasani et al (1965). This effect of oestrogen could occur by a direct inhibition of osteoelast function, by inhibiting induction of osteoclastic foci from bone mesenchyme, or by both mechanisms.

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However, the menopause alone is an incomplete explanation for the higherthan-normal values for bone resorption in osteoporosis. All postmenopausal women, osteoporotic and non-osteoporotic, are oestrogen deficient, and we have recently found that osteoporotic women do not differ from normal women with respect to the degree to which sex hormone production is decreased postmenopausally (unpublished data). We speculate that the primary defect in osteoporosis may reside within the osteolytic cells, rendering them abnormally responsive to P T H when gonadal sex hormones are deficient. This possibility is particularly suggested by our observation that the largest decreases in resorbing surfaces after oestrogen therapy occurred in those patients who had the highest pretreatment values for resorbing surfaces. Alternatively, there may be some as yet unknown factor or factors present in osteoporotic women which independently increase resorption. It is more difficult to determine whether a defect in bone formation exists in osteoporosis. In many metabolic bone disorders characterised by primary increases in resorption, there is a secondary increase in formation; in osteoporosis, this compensation is lacking. Also, decrease of resorption to normal or near-normal by long-term therapy with oestrogen is accompanied by a delayed decrease in formation to very low levels. These observations suggest that an intrinsic abnormality of osteoblastic function or differentiation does in fact exist in osteoporosis but is masked in the pretreatment period by the increase in bone resorption, but becomes apparent when bone resorption is decreased by therapy. It is unlikely that the observed decrease in formation is a pharmacologic effect of oestrogen because a physiologic replacement dose was used (as assessed by the effect on the serum gonadotropin concentration). The postulated interrelationships of bone resorption, bone formation, PTH, and oestrogen are shown schematically in Figure 7. -Untreated

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Figure 7. Model of the interrelationships of bone resorption, bone formation, parathyroid hormone, and oestrogen in postmenopausal osteoporosis. In the untreated postmenopausal woman with osteoporosis, bone resorption (BR) is much higher than in the postmenopausal woman without osteoporosis. Both are oestrogen deficient; however, the bone-resorbing cells in the osteoporotic woman may be more sensitive to parathyroid hormone (PTH) in the absence of oestrogen. Bone formation (BF) is normal; however, if there were no defect in BF, a compensatory increase, as a result of high BR, would be expected. PTH is decreased as a consequence of increased calcium release from bone. The administration of a physiologic replacement dose of oestrogen decreases resorption but increases PTH, suggesting that oestrogen exerts its effect by decreasing the responsiveness of bone to endogenous PTH. Prolonged administration of oestrogen decreases BF to very low values, suggesting an intrinsic abnormality of osteoblastic function that is masked in the pretreatment period by an increase in BR but becomes apparent when BR is decreased by oestrogen administration.

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Studies evaluating treatment Three general comments are relevant to the interpretation of our results. First, bone turnover studies made after relatively short periods of treatment are useful in determining the mechanism of action of therapeutic agents and in forecasting what the effect of many years of therapy will be. However, a final judgement as to the value of a given therapeutic programme can be made only by demonstrating its long-term effect on prevention of further fractures and in maintaining or increasing skeletal mass as assessed by densitometry. We are continuing to observe our patients with these objectives in mind. Second, although as yet we have long-term data only on patients treated with sex hormones, we bel;eve that all agents whose primary effect is to decrease bone resorption will eventually decrease bone formation, thereby negating, in part, the initial favourable effect. Finally, it should be emphasised that the ideal therapeutic programme must do more than merely rectify the abnormality in bone turnover. Achieving normal values for bone formation and resorption by therapy in osteoporosis would mean that further loss of bone would not occur; it also would mean that the patient would continue to have an osteoporotic skeleton and would be prone to further fractures. The ideal therapeutic programme would increase skeletal mass to a point such that fractures would cease to occur, thus resulting in a clinical cure. This effect can be achieved only by a sustained increase in bone formation to a level that is substantially higher than that of bone resorption. The effects of different therapeutic programmes on bone remodelling in primary osteoporosis are shown in Figure 8. Three types of response to therapy were observed: (1) no improvement or worsening of the pretreatment abnormalities of bone turnover; (2) a decrease in bone resorption; and (3) an increase in bone formation. Calcitonin and the diphosphonate, Na2EHDP, produced the first type of response. These agents either did not improve or made worse the increase in resorbing over forming surfaces and thus were judged not to be therapeutically useful. The absence of the expected decrease of bone resorption in the calcitonin-treated patients was probably due to increased endogenous PTH secretion as a result of the hypocalcaemic effect of PCT. However, our preliminary studies suggest that, if secondary hyperparathyroidism is prevented by administering oral calcium concurrently, calcitonin therapy may be effective. Na2EHDP not only failed to decrease resorption but produced excessive osteoid tissue. Inhibition of mineralisation was probably due to blocking the conversion of amorphous calcium phosphate to hydroxyapatite, a phenomenon that has been demonstrated with these compounds in vitro. Oestrogens, synthetic anabolic hormones, calcium, and calcium-calcitonin combined therapy produced the second type of therapeutic response: their primary effect was to decrease bone resorption. However, since post-treatment values for resorbing surfaces remain higher than those for forming surfaces, particularly after long-term therapy, it seems likely that these agents only arrest or slow the progression of bone loss in osteoporosis. Only combined therapy with fluoride produced the third type of response: an increase in bone formation. However, supplemental calcium and vitamin

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D were required to mineralise the newly formed bone fully and to prevent the increase in resorption that may occur in response to fluoride alone. The me,chanism by which fluoride stimulates bone formation is unknown. However, because the crystalline structure of fluorohydroxyapatite is different from that of hydroxyapatite, it is possible that the flow of piezoelectric current in bone is increased and, therefore, there is stimulation of osteoblasts. Alternatively, the effect may be produced by fluoride-mediated induction of enzymes in bone cells.

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Sex hormones NaF-colcium Na2EHDPColcitonin

vit D

Figure 8. Effects of various forms of therapy on bone-forming (solid arrows) and boneresorbing (broken arrows) surfaces in osteoporosis.

Based on our experimental studies, we have designed a therapeutic programme for osteoporosis which we believe not only will prevent further bone loss but will also add new bone to the skeleton and thus reverse the osteoporotic process. The programme combines several agents, each of which is used for a specific purpose. Sodium fluoride, 50 rag/day, is used to stimulate bone formation. Calcium as carbonate, lg/day, and vitamin D, 50 000 units twice weekly, are used to prevent incomplete mineralisation of newly formed bone and secondary hyperparathyroidism, both of which may occur when fluoride is given alone. Oestrogen (such as conjugated equine oestrogen, 1.25 mg/day for 25 of each 30 days) is given to decrease bone resorption. We predict that, in about five years, this combination of agents will result in a measurable increase in bone mass and a cessation of spinal and femoral neck fractures. Studies testing this prediction are under way.

ACKNOWLEDGEMENT

This investigation was supported in part by Research Grants AM-8658, AM-12302, and RR-585 from the National Institutes of Health, Public Health Service.

STUDIES ON PATHOGENESIS AND TREATMENT

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