Osteoporosis--a review

Osteoporosis is a major medical problem in older women. Although a variety of factors influence bone formation and resorption, ovarian failure and a reduction in adrenal androgen production are major causes of menopausal osteoporosis. The prevention of trabecular bone loss and vertebral fractures in menopausal patients is feasible. Women who are at risk, so-called "fast bone losers," can be identified by office and chemical laboratory techniques. Estrogen therapy reduces or halts osteoclastic resorption and preserves bone mass. Exercise and anabolic hormones, including progesterone, stimulate osteoblastic building of bone. The combination of estrogen and progesterone reduces the risk of uterine malignancy below that seen in patients who take estrogen alone and possibly below the incidence seen in women who take no hormones. An individual's doses of replacement hormones will vary, depending on the amount of endogenous bone-targeted hormones and the response to treatment. These doses can be determined by monitoring their effect on 24-hour hydroxyproline and calcium excretion. Another way to monitor dose effect is by observation of the FSH levels. The serum FSH levels should be reduced at least to that level considered to be diagnostic of menopause. It may be unnecessary, if not inappropriate, to strive to restore FSH levels to normal premenopausal levels. Age-associated osteoporosis is a potentially fatal disease. Osteomalacia, with the associated loss of cortical bone, is superimposed upon the trabecular bone loss due to ovarian and adrenal androgen hormone deficiencies. These hormone deficiencies continue to operate upon trabecular bone at this later stage in the continuum. In addition to estrogen therapy and progesterone replacement, patients who are fracture victims may benefit from androgen replacement to increase their bone mass. Replacing androgens using nandrolone decanoate in women may address the natural loss of their adrenal bone-targeted hormones. The identification and treatment of individuals who need vitamin D and calcium replacement will reverse this contribution to the loss of bone. Clinical experience demonstrates that monitored hormone, vitamin D, and calcium supplements reduce the frequency of fractures, especially hip fractures, which may be reduced as much as 40% to 60% over a three-year period with such treatment. Cautious fluoride supplements in addition to calcium, hormones, and appropriate amounts of vitamin D appear to reduce vertebral fracture rates. The associated suffering, disability, and death from osteoporosis-induced fractures can be dramatically altered.(ABSTRACT TRUNCATED AT 400 WORDS)     

Humoral hypercalcaemia of malignancy: metabolic and histomorphometric studies during surgical management of the primary tumour

Several aspects of calcium metabolism were studied in five patients during the surgical exploration of malignant tumours associated with humorally-mediated hypercalcaemia. Before operation in all patients the renal tubular threshold for calcium reabsorption was raised and the threshold for renal tubular phosphate reabsorption depressed. On removal of the primary tumour in three cases, serum calcium returned to normal, renal calcium threshold fell, renal phosphate threshold rose, but urinary hydroxyproline excretion did not change. In two patients where the tumour proved inoperable, serum calcium remained elevated and no changes in renal calcium threshold or phosphate threshold occurred. Histomorphometry carried out on biopsy specimens from four patients showed normal bone resorption in three, and slightly increased resorption in one, without depression of osteoblastic bone formation. It is suggested that hypercalcaemia in these patients resulted mainly from an alteration in renal calcium threshold caused by a humoral substance released by tumour cells. Correction of hypercalcaemia on removal of the primary tumour was achieved rapidly and could be explained principally by a reduction in renal calcium threshold with increased loss of calcium into the urine. These data contrast with those of many previous studies which have emphasised the predominant role of accelerated osteoclastic bone resorption as the principal cause of hypercalcaemia in malignancy and suggest that a renal effect of the putative humoral agent may predominate in some cases.     

Short- and long-term effects of estrogen and synthetic anabolic hormone in postmenopausal osteoporosis

In 29 women with postmenopausal osteoporosis, the proportion of total bone surface undergoing resorption or formation was evaluated by microradiography of iliac crest biopsy samples before and after short-term (2(1/2)-4 months) and long-term (26-42 months for estrogen and 9-15 months for anabolic hormone) treatment. After estrogen administration, values for bone-resorbing surfaces decreased, although less prominently after long-term than after short-term therapy. The magnitude of this decrease was positively correlated with the pretreatment value for bone-resorbing surfaces (P < 0.001). When the pretreatment value for bone-resorbing surfaces was used as a covariable, estrogen and anabolic hormone appeared to be equally effective. For bone-forming surfaces, short-term therapy with either hormone had no effect but long-term therapy significantly decreased the values. Serum immunoreactive parathyroid hormone (IPTH) increased significantly after estrogen therapy; the change in IPTH was inversely related to the change in serum calcium (P < 0.001, sign test). We conclude that the primary effect of sex hormones in postmenopausal osteoporosis is to decrease the increased level of bone resorption, perhaps by decreasing the responsiveness of bone to endogenous parathyroid hormone. However, this favorable effect, at least in part, is negated after long-term treatment by a secondary decrease in bone formation. Our data are consistent with the concept that the maximal benefit that can be derived from sex hormone therapy in postmenopausal osteoporosis is arrest or slowing of the progession of bone loss.     

Progress and perspectives in bone research

Structural integrity and strength of bone is maintained by a balance between bone resorption and bone formation. The balance in bone remodeling process is maintained by factors including mechanical stress, calcium-regulating hormones and sex hormones. Changes in physiological regulators of bone remodeling such as reduction in mechanical stress, aging and reduction in sex hormones, or an increase in pathological factors such as glucocorticoid and inflammatory cytokines cause disturbances in bone remodeling process. Disturbances in bone remodeling not only reduce the bone volume but also deteriorate material as well as structural properties of bone, resulting in a reduction in bone strength. Mechanisms of how bone resorption is initiated at the surface of damaged or aged bone, and how bone resorption is coulpled to bone formation are under active investigation. Increasing the understanding of physiological regulation and pathological conditions of bone remodeling should be able to develop new therapeutic approaches to osteoporosis and other metabolic bone diseases.     

Serum osteocalcin levels in hyperthyroidism before and after antithyroid therapy

Hyperthyroidism is characterized by accelerated bone turnover, caused from direct stimulation of bone cells by increased thyroid hormones. In this study, we aimed to investigate serum osteocalcin levels as a bone formation marker, before antithyroid (propylthiouracil) therapy at hyperthyroid stage and after antithyroid therapy at euthyroid stage of the patients. Twenty four hyperthyroid patients (18 females, 6 males) and 20 (13 females, 7 males) healthy controls were included into this study. Blood and urine samples were taken before medical treatment at hyperthyroid state, and after the antithyroid therapy until the patients reached the euthyroid state. Serum alkaline phosphatase, osteocalcin, calcium, phosphorus, Free T3, Free T4, TSH and urine calcium/creatinine levels were assessed. We found a significant decrease in serum osteocalcin (p=0.006), urinary calcium/creatinine (p=0.004), and serum phosphorus (p=0.038) levels in euthyroid state in comparison to hyperthyroid state. The increases in serum bone formation marker osteocalcin and bone resorption marker urinary calcium/creatinine levels in hyperthyroid state compared to euthyroid state in our study confirmed that hyperthyroid patients have high bone turnover. We conclude that, hyperthyroid patients has high bone turnover of formation and resorption even after attainment of euthyroidism. Osteocalcin and urine calcium/creatinine are sensitive markers in documenting bone remodeling during treatment of hyperthyroidism.     

Serum bone gamma carboxyglutamic acid-containing protein in primary hyperparathyroidism and in malignant hypercalcemia. Comparison with bone histomorphometry.

Serum bone gamma-carboxyglutamic acid-containing (Gla) protein (sBGP), a sensitive and specific marker of bone turnover, was measured in 25 patients with primary hyperparathyroidism and in 24 patients with bone metastases with or without hypercalcemia. Despite similar levels of hypercalcemia, sBGP was increased in primary hyperparathyroidism (14.2 +/- 9.6 ng/ml, P less than 0.001), was decreased in malignant hypercalcemia (3.1 +/- 2.8 ng/ml, P less than 0.001), and was normal in patients with bone metastases without hypercalcemia (6.6 +/- 2.7 ng/ml). In primary hyperparathyroidism, sBGP was correlated with serum immuno-reactive parathyroid hormone (r = 0.90), calcium (r = 0.73), and with the adenoma weight (r = 0.79). After parathyroidectomy, sBGP slowly returned to normal values within 2-6 mo, suggesting that sBGP reflects increased bone turnover rather than a direct effect of parathyroid hormone on BGP synthesis at the cell level. An iliac crest biopsy was performed in 11 patients with primary hyperparathyroidism and in 9 cancer patients in a noninvaded area. sBGP was significantly correlated with all parameters reflecting bone formation but not with bone resorption. Patients with bone metastases were analyzed according to the presence or the absence of hypercalcemia. In contrast to normocalcemic patients who had normal sBGP, hypercalcemic patients had decreased sBGP (P less than 0.001) and a lower bone formation at the cellular level (P less than 0.05). Thus, biochemical and histological data suggest that an unknown humoral factor might be responsible for this uncoupling between increased resorption and decreased formation. This uncoupling, rather than local release of calcium by the metastatic process, might be responsible for hypercalcemia in patients with bone metastases.     

Early effects of ethinyloestradiol and norethisterone treatment in post-menopausal women on bone resorption and calcium regulating hormones

The early effects of sex steroid therapy were assessed in 28 normal post-menopausal women, 18 treated with ethinyloestradiol and 10 with norethisterone. There was a reduction in the fasting urinary excretion of both calcium and hydroxyproline with both treatments, indicating reduced bone resorption. This was apparent after 1 week of therapy but became more marked after 3 weeks. These changes were not accompanied by any changes in plasma levels of calcitonin or parathyroid hormone. Patients receiving ethinyloestradiol showed a marked increase in plasma 1,25-dihydroxyvitamin D (1,25-(OH)2D) concentration but this was explicable entirely in terms of increased plasma levels of vitamin D binding protein. There was no change in the free plasma level of 1,25(OH)2D. Patients treated with norethisterone showed no increase in plasma concentrations of 1,25(OH)2D. We conclude that both ethinyloestradiol and norethisterone have a rapid and similar effect in reducing bone resorption. This is not mediated via the plasma levels of the calcium regulating hormones.     

Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men

Young adult males who cannot produce or respond to estrogen (E) are osteopenic, suggesting that E may regulate bone turnover in men, as well as in women. Both bioavailable E and testosterone (T) decrease substantially in aging men, but it is unclear which deficiency is the more important factor contributing to the increased bone resorption and impaired bone formation that leads to their bone loss. Thus, we addressed this issue directly by eliminating endogenous T and E production in 59 elderly men (mean age 68 years), studying them first under conditions of physiologic T and E replacement and then assessing the impact on bone turnover of withdrawing both T and E, withdrawing only T, or only E, or continuing both. Bone resorption markers increased significantly in the absence of both hormones and were unchanged in men receiving both hormones. By two-factor ANOVA, E played the major role in preventing the increase in the bone resorption markers, whereas T had no significant effect. By contrast, serum osteocalcin, a bone formation marker, decreased in the absence of both hormones, and both E and T maintained osteocalcin levels. We conclude that in aging men, E is the dominant sex steroid regulating bone resorption, whereas both E and T are important in maintaining bone formation.     

Relation between signs and symptoms in Paget's disease of bone

The relation between signs and symptoms of Paget's disease of bone was studied in 180 patients consecutively submitted for treatment. In these patients 826 lesions were identified by scintigraphy. The intensity of scintigraphic uptake was correlated with long-term calcium uptake in bone. The frequency distribution of lesions over the patients was compatible with a 65 per cent chance of local disease once the patient had been exposed to an extraneous agent. The spatial distribution within a skeleton was related to the local density of the osteoclast population. The particular frequency distribution resulted in a log-normal distribution diagram for anatomical spread. Within lesions, increases in numbers of osteoclasts and osteoblasts were proportional and these too had a log-normal distribution. Increases of alkaline phosphatase levels and hydroxyproline excretion were closely related and reflected anatomical spread on the one hand and local activity on the other. They were also closely correlated with overall calcium fluxes. It was shown that alkaline phosphatase is the more sensitive and hydroxyproline the more accurate of the biochemical signs. Maximum values, corresponding to total skeletal disease, were approximately 25 times the upper limit of normal. Equilibrium between bone formation and resorption was not always maintained. There were, indeed, wide variations of urinary calcium, which were significantly related to the difference between bone formation and resorption, but the extracellular calcium homeostasis was generally maintained. This may explain the frequent occurrence of normocalcaemic and hypercalcaemic hyperparathyroidism. The hypercalciuria constitutes an additional risk for urolithiasis in men. The most frequent complaint was pain (86 per cent). Extent of lesions was important, but a major decisive factor was the specific nature of the bone affected. The findings allowed assessment of the relative importance of the various signs, symptoms and locations as criteria of disease severity and as indications for treatment.     

Mechanisms of steroid osteoporosis development in patients with hormone-dependent bronchial asthma

AIM: To examine mechanisms of steroid osteoporosis development in patients with hormone-dependent bronchial asthma (BA). MATERIALS AND METHODS: The trial included 73 patients with hormone-dependent BA, 19 BA patients who have never taken oral steroid hormones and 15 healthy subjects. RESULTS: By computed tomography of the lumbar spine, bone tissue density in steroid-dependent BA was significantly decreased vs BA patients who were not treated with steroids. Osteopenia was discovered in 61.9% of the examinees who have received oral glucocorticoids. Development of osteopenia in this case was not dependent of the steroids dose and duration of the treatment. Patients with hormone-dependent BA vs healthy subjects had higher 24-h urine calcium excretion, normal levels of parathyroid hormones, calcitonin, low concentrations of 25-oxyvitamin D3, osteocalcin in the serum. Three subgroups of patients with osteopenia were identified according to the statistics: with prevalent resorption of bone tissues (24.1%), with low concentrations of vitamin D3 and osteocalcin (52.6%), with highly active resorption in combination with low vitamin D3 and weak function of osteoblasts (23.3%). CONCLUSION: Mechanisms of steroid osteoporosis development are heterogeneous. This should be considered in its treatment.     

Formation, mineralization, and resorption of bone in vitamin D—deficient rats

Quantitative histologic methods have been devised to measure several processes dealing with formation and mineralization of matrix and bone resorption. In vitamin D-deficient rats, the total osteoblastic matrix formation rate was 20% less and the total osteoclastic bone resorption rate was 80% more than in pair-fed control rats. These changes were found to be primarily because of changes in the rates of matrix formation and of bone resorption per unit area of forming or resorbing surfaces rather than to changes in the areas of these surfaces. The rate of maturation of osteoid and the rate of initial mineralization both were reduced to half of normal in the vitamin D-deficient rats. These variables related to matrix formation and mineralization were significantly correlated with the concentration of calcium but not with the concentration of phosphate in serum. The occurrence of hypocalcemia is interpreted as the consequence, both of reduced calcium absorption and of inadequate resorptive response of bone cells to homeostatic stimuli, such that, although bone resorption was greater than normal, it did not adequately compensate for the reduced intestinal absorption.     

Effects of lithium on bone resorption in cultured foetal rat long-bones

Abstract. Increased serum calcium has been observed in manic depressive patients treated with lithium (Li), and one of the mechanisms increasing serum calcium could be a sensitizing effect of Li on bone resorption. In a previous study, however, Li has been found slightly to inhibit PTH-stimulated resorption in cultured foetal rat long-bones. In this work, we extended the study of the effects of Li on bone resorption in culture when resorption of foetal rat long-bones was stimulated by factors other than PTH. Li 3 mM had no effect on basal resorption, a slight and inconsistent inhibitory effect on PTH stimulated bone resorption, a moderate and inconstant inhibitory effect on prostaglandin E2 (PGE2) stimulated resorption, and did not significantly affect the enhancement of resorption by interleukin 1 (ILI). The more constant effect of Li was a nearly complete inhibition of the resorption response to 1,25-dihydroxycholecalciferol (1,25(OH)₂D₃). This study confirms that Li has no stimulatory effect on bone resorption by itself, nor a sensitizing action on the stimulation of resorption by several activators. Conversely, Li has a striking inhibitory effect on bone resorption stimulated by 1,25(OH)₂D₃.     

Periodic courses of human 1–34 parathyroid peptide alternating with calcitriol paradoxically reduce bone remodelling in spinal osteoporosis

In an attempt to achieve an anabolic response in both axial and peripheral bone, we treated twelve patients with osteoporosis using human 1-34 parathyroid peptide given discontinuously. The peptide was given as seven daily subcutaneous injections followed by 21 days' treatment with 0.25 mg calcitriol orally. This regime was repeated cyclically for at least sixteen cycles, of which the first four were at a lower dose of hPTH 1-34 than used subsequently. The results of treatment were monitored by kinetic, densitometric, histomorphometric and biochemical studies performed before and during treatment. Two patients developed hPTH 1-34 binding in their plasma during treatment: this was presumed to be due to the development of antibodies. The remainder, instead of increasing their indices of bone turnover as judged by iliac bone histomorphometry, were found to have consistent reductions in trabecular resorption surfaces. The other indices of bone formation and resorption measured showed no change or comparable reductions. The small increases seen in total body calcium were consistent with 'in-filling' of deleted basic multicellular units (BMUs). Because there is no evidence that calcitriol alone causes comparable reductions in activation of bone remodelling in osteoporosis, interruption of treatment with hPTH 1-34 after 7 days may have led to a failure of the activation mechanism to proceed to the resorption stage, with a consequent overall reduction in remodelling activity. This type of treatment regime, with its calcitonin-like effect, might be effective in reducing net bone loss due to imbalance between bone formation and resorption at the BMU level, particularly in patients with increased numbers of BMUs ('high turnover' osteoporosis).(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of Bone Matrix Formation, Mineralization, and Resorption in Thyroparathyroidectomized Rats

In previous work we found that vitamin D-deficient and also calcium-deficient rats developed hypocalcemia and an impairment of bone formation and mineralization. The present study of thyroparathyroidectomized (TPTX) rats was undertaken to determine the effect of hypocalcemia without secondary hyperparathyroidism. TPTX rats fed a normal diet developed hypocalcemia and hyperphosphatemia in association with impairment of osteoblastic bone matrix formation and of mineralization of newly formed matrix. The serum calcium x phosphorus product was not decreased. The decreased formation was largely due to a reduction in matrix apposition indicating decreased synthetic activity of individual ostcoblasts. In contrast to the above results, when TPTX rats were fed a high-calcium diet to prevent hypocalcemia, no impairment of either formation or mineralization was found. From the results of these two experiments, it is reasonably certain that hypocalcemia was responsible for the inhibition of formation and mineralization. Moreover, based on the magnitude of the changes in serum calcium and bone parameters in TPTX rats, hypocalcemia could have accounted for the inhibition of formation and mineralization in calcium-deficient as well as vitamin D-deficient rats.In TPTX rats the mineralization defect was manifested by decreases in both the rate of osteoid maturation (indicating a delayed onset of mineralization) and the rate of mineralization. A strong correlation (r = 0.95, P < 0.001) was observed between these two rates suggesting a tight coupling of these two aspects of mineralization.TPTX rats also had lower bone resorption rates and higher serum phosphorus levels than sham-operated animals when the normal calcium diet was fed but not when the high-calcium diet was fed. Thus the inhibition of bone resorption in TPTX rats was at least partially prevented by correction of hyperphosphatemia. This is consistent with previous work showing an inverse relationship between serum phosphorus and bone resorption. Accordingly, the depression of bone resorption in TPTX rats was probably due to hyperphosphatemia as well as to hypoparathyroidism.     

Mechanisms for the bone anabolic effect of parathyroid hormone treatment in humans

Abstract

Intermittent low-dose treatment with parathyroid hormone (PTH) analogues has become widely used in the treatment of severe osteoporosis. During normal physiological conditions, PTH stimulates both bone formation and resorption, and in patients with primary hyperparathyroidism, bone loss is frequent. However, development of the biochemical measurement of PTH in the 1980s led us to understand the regulation of PTH secretion and calcium metabolism which subsequently paved the way for the use of PTH as an anabolic treatment of osteoporosis as, when given intermittently, it has strong anabolic effects in bone. This could not have taken place without the basic understanding achieved by the biochemical measurements of PTH. The stimulatory effects of PTH on bone formation have been explained by the so-called ‘anabolic window’, which means that during PTH treatment, bone formation is in excess over bone resorption during the first 6–18 months. This is due to the following: (1) PTH up-regulates c-fos expression in bone cells, (2) IGF is essential for PTH's anabolic effect, (3) bone lining cells are driven to differentiate into osteoblasts, (4) mesenchymal stem cells adhesion to bone surface is enhanced, (5) PTH has a direct antiapoptotic effect on osteoblasts and (6) when PTH interferes with remodelling, the osteoblasts over-compensate, and (7) PTH also decreases sclerostin levels, thereby removing inhibition of Wnt signalling which is required for PTH's anabolic actions. Thus, the net formative effect of PTH given in intermittent treatment emerges through a complex network of pathways. In summary, the effects of PTH on bone turnover are dependent on the mode and dose of administration and studies investigating the mechanisms underlying this effect are reviewed in this article.     

Mechanisms for the bone anabolic effect of parathyroid hormone treatment in humans

Intermittent low-dose treatment with parathyroid hormone (PTH) analogues has become widely used in the treatment of severe osteoporosis. During normal physiological conditions, PTH stimulates both bone formation and resorption, and in patients with primary hyperparathyroidism, bone loss is frequent. However, development of the biochemical measurement of PTH in the 1980s led us to understand the regulation of PTH secretion and calcium metabolism which subsequently paved the way for the use of PTH as an anabolic treatment of osteoporosis as, when given intermittently, it has strong anabolic effects in bone. This could not have taken place without the basic understanding achieved by the biochemical measurements of PTH. The stimulatory effects of PTH on bone formation have been explained by the so-called 'anabolic window', which means that during PTH treatment, bone formation is in excess over bone resorption during the first 6-18 months. This is due to the following: (1) PTH up-regulates c-fos expression in bone cells, (2) IGF is essential for PTH's anabolic effect, (3) bone lining cells are driven to differentiate into osteoblasts, (4) mesenchymal stem cells adhesion to bone surface is enhanced, (5) PTH has a direct antiapoptotic effect on osteoblasts and (6) when PTH interferes with remodelling, the osteoblasts over-compensate, and (7) PTH also decreases sclerostin levels, thereby removing inhibition of Wnt signalling which is required for PTH's anabolic actions. Thus, the net formative effect of PTH given in intermittent treatment emerges through a complex network of pathways. In summary, the effects of PTH on bone turnover are dependent on the mode and dose of administration and studies investigating the mechanisms underlying this effect are reviewed in this article.     

An evaluation of several biochemical markers for bone formation and resorption in a protocol utilizing cyclical parathyroid hormone and calcitonin therapy for osteoporosis.

Female patients (n = 20) with osteoporosis, aged 66 +/- 5 yr were studied during a 24-h infusion of parathyroid hormone (PTH [1-34]) at a rate of 0.5 IU equivalents/kg.h, and then during a 28-d period of subcutaneous injections, at a dose of 800 IU equivalents per day. Thereafter half the patients received subcutaneous injections of calcitonin, 75 U/d for 42 d, and all patients were followed to the end of a 90-d cycle. Biochemical markers of bone formation (serum alkaline phosphatase, osteocalcin, and the carboxy-terminal extension peptide of pro-collagen 1) and bone resorption (fasting urine calcium, hydroxyproline, and deoxypyridinoline) were compared during treatment by the intravenous and subcutaneous route of PTH administration, and subsequently during calcitonin therapy. During intravenous PTH infusion there were significant reductions in all three bone formation markers, despite expected rises in urinary calcium and hydroxyproline. By contrast, the circulating markers of bone formation increased rapidly by > 100% of baseline values during daily PTH injections (P < 0.001). Significant increases in bone resorption markers were only seen at the end of the 28 d of injections, but were < 100% over baseline values, (P < 0.05). Quantitative bone histomorphometry from biopsies obtained after 28 d of PTH treatment confirmed that bone formation at both the cellular and tissue levels were two to five times higher than similar indices measured in a control group of biopsies from untreated osteoporotic women. Subsequent treatment of these patients with calcitonin showed no significant changes in the biochemical markers of bone formation and only a modest attenuation of bone resorption. Thus, PTH infusion may inhibit bone formation, as judged by circulating biochemical markers, whereas daily injections confirm the potent anabolic actions of the hormone. Sequential calcitonin therapy does not appear to act synergistically with PTH in cyclical therapeutic protocols.     

Glucocorticoid-induced osteoporosis

Glucocorticoid-induced osteoporosis is one of the major complications of long-term exposure to supraphysiological doses of glucocorticoid. It has been recognized that bone loss is rapid, particularly in the first 6 months of the therapy. The skeletal effects are both dose and duration dependent; daily glucocorticoid therapy at doses of 7.5 mg/day of prednisolone or above leads to decrease bone mass and increase risk of fractures. The mechanisms which glucocorticoid induces osteoporosis are suppression of bone formation and increase of bone resorption. Hypogonadism also contributes to this pathological condition via direct suppression of sex steroids and indirect suppression through decreased secretion of pituitary hormones. Estrogen, vitamin D and its active analogues, and calcitonin, have been therefore used to prevent glucocorticoid-induced osteoporosis; however, the effectiveness is somehow limited. Treatment with newly developed anti-resorptive amino-containing bisphosphonates such as alendronate and risedronate, showed significant increase of bone mineral density for both the prevention and the treatment of glucocorticoid-induced osteoporosis, as well as risk reduction of fractures in the patients. These bisphosphonates provide a better consequence for the treatment of glucocorticoid-induced osteoporosis.     

Direct stimulation of bone resorption by thyroid hormones.

Although hypercalcemia, osteoporosis, and increased bone turnover are associated with thyrotoxicosis, no direct effects of thyroid hormones on bone metabolism have been reported previously in organ culture. We have now demonstrated that prolonged treatment with thyroxine (T4) or triiodothyronine (T3) can directly increase bone resorption in cultured fetal rat long bones as measured by the release of previously incorporated 45Ca. T4 and T3 at 1 muM to 10 nM increased 45Ca release by 10-60% of total bone 45Ca during 5 days of culture. The medium contained 4 mg/ml of bovine serum albumin to which 90% of T4 and T3 were bound, so that free concentrations were less than 0.1 muM. The response to T4 and T3 was inhibited by cortisol (1 muM) and calcitonin (100 mU/ml). Indomethacin did not inhibit T4 response suggesting that T4 stimulation of bone resorption was not mediated by increased prostaglandin synthesis by the cultured bone. Matrix resorption was demonstrated by a decrease in extracted dry weight and hydroxyproline concentration of treated bones and by histologic examination which also showed increased osteoclast activity. The effects of thyroid hormones were not only slower than those of other potent stimulators of osteoclastic bone resorption (parathyroid hormone, vitamin D metabolites, osteoclast activating factor, and prostaglandins), but the maximum response was not as great. We conclude that T4 and T3 can directly stimulate bone resorption in vitro at concentrations approaching those which occur in thyrotoxicosis. This effect may explain the disturbances of calcium metabolism seen in hyperthyroidism.     

Effect of bisphosphonates on prostaglandin synthesis by rat bone cells and mouse calvaria in culture

Bisphosphonates are potent inhibitors of bone resorption and also inhibit prostaglandin (PG) E2 synthesis in bone cells. Therefore we have investigated whether a correlation exists between inhibition of bone resorption and inhibition of PGE2 formation. Initially, bisphosphonates were tested for their effect on the release of [14C]PGE2 from rat calvaria cells labelled with [14C]arachidonic acid and stimulated by bradykinin, thrombin and mechanical manipulation. The effect on [14C]-PGE2 synthesis was not correlated with the known inhibitory activity of bisphosphonates on bone resorption. Mouse calvaria were then treated with epidermal growth factor (EGF) to induce PGE2 synthesis and bone resorption, with or without bisphosphonates. The bisphosphonates either decreased, had no effect or increased PGE2 production, but all inhibited the release of calcium. Finally, the bisphosphonates were given in vivo to mice before explantation of the calvaria. Some of the bisphosphonates decreased the production of PGE2, suggesting that these compounds may have such an effect in vivo. But again no relationship between the effect on PGE2 synthesis and bone resorption was found. Thus, these experiments show the inhibitory effect of bisphosphonates on bone resorption is unlikely to be explained only by their effect on PGE2 synthesis.