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Vertebral mineral density, measured by computerized axial tomography, radiocalcium absorption, serum dehydroepiandrosterone (DHA), and serum cortisol (C) were measured in 98 postmenopausal women aged 56-70 yr. On the basis of spine radiographs and fracture history, the women were classified into 49 normal subjects (mean age, 60.5 yr) and 49 with osteoporosis (mean age, 63.1 yr). Vertebral mineral density (VMD), radiocalcium absorption (alpha), serum DHA, and the ratio of DHA to cortisol (DHA/C) were all significantly lower in the osteoporotic than in the normal subjects. DHA was significantly related to C in both groups but the regression was significantly flatter in the osteoporotic than in the normal subjects. Calcium absorption did not fall significantly with age in either group. In the normal group VMD, DHA, and DHA/C fell with age but VMD was not related to alpha, DHA, or DHA/C. In the osteoporotic group, VMD did not fall significantly with age but was significantly related to alpha and DHA/C. Stepwise regression analysis showed that in the normal subjects, age was the only variable significantly related to VMD (P less than 0.05). In the osteoporotic group, calcium absorption was the main determinant of VMD, with age and DHA/C contributing much less to the variance. Discriminant function analysis showed a theoretical misclassification of 45% of cases using DHA, 39% using DHA/C, 32% using alpha, and 18% when alpha and DHA or DHA/C were both taken into account. It is concluded that malabsorption of calcium is a significant risk factor for postmenopausal osteoporosis, probably because of a secondary increase in bone resorption to maintain serum calcium. The severity of the osteoporosis is directly related to the severity of the calcium malabsorption. Low serum DHA appears to represent a further risk factor, either because of its role as estrogen precursor or (possibly) because it promotes bone formation. However, the severity of the osteoporosis was not related to the serum DHA level and only weakly to the DHA/C ratio.

It was agreed that bone loss in women starts at or about the menopause and proceeds at about 1%/annum In men it is slower and starts later. This loss of bone in women is associated with a steep rise in the wrist fracture rate (to about 50/10 000/annum) which does not occur in men. It was also agreed that this loss of bone is due to an increase in the rate of bone resorption rather than a fall in the rate of bone formation as Albright had originally postulated. However, there was some disagreement as to the way in which loss of estrogen causes bone resorption. Gordan thought that estrogens had an anti-catabolic effect on collagenous tissues in general and quoted reports of thin skin and reduced collagenous tissues in cases of osteoporosis. Nordin considered that bone was unduly sensitive to the action of parathyroid hormone in the absence of estrogens. Duursma thought there might be altered sensitivity of bone to growth hormone or thyroid hormone. Klotz’s view was that there might be a deficiency of calcitonin. Dequeker suggested that osteoporosis was associated with growth hormone deficiency and showed increased growth hormone levels in osteo-arthrotic patients with increased bone mass.

Calcium is the principal constituent of most kidney stones, which seems to originate as a crystalline precipitate in a supersaturated medium. Calcium concentration in the urine therefore plays an important part in the genesis of calcium stone disease and is of course determined by the relation between the rate of calcium excretion and the rate of urine flow. The present paper will be primarily concerned with examining calcium excretion rate and the factors which determine this rate in health and disease.

Normal, healthy adults must be assumed to be in a state of nutritional equilibrium — at least over a period of time. They must be taking in nitrogen, phosphorus, sodium and other elements at the same rate as they are excreting them. For some of these elements, the calculation of a body balance is very difficult, but in the case of calcium it is relatively simple. Discounting dermal losses [which may be quite significant (Charles et al. 1983)], the calcium balance is the difference between the dietary calcium on the one hand and the faecal and urinary calcium on the other.

The effect on cortical bone loss oftreating elderly women with 15,000 IU vitamin D2 weekly was evaluated by sequential radiographic morphometry ofthe metacarpals. One hundred nine randomly selected women aged 65-74 yr were studied for 2 yr. The women were randomly allocated to control or treated groups taking placebo or vitamin D2 capsules. Hand radiographs and blood samples were obtained at the beginning and end of the trial. Plasma 25-hydroxyvitamin D was measured by radio-competitive protein binding assay. Comparing the treated and control groups, vitamin D treatment significantly raised the plasma 25-hydroxyvitamin D levels (p

In a prospective trial in 72 postmenopausal women to compare the effects on bone loss of no treatment, treatment with oestrogen, and treatment with calcium the women were followed up for at least two years and examined densitometrically and morphometrically. Women in the untreated control group continued to lose bone during the two years, whereas the oestrogen-treated group lost none. Loss in the calcium-treated group was intermediate. Oestrogen appeared to inhibit endosteal bone resorption and may have stimulated subperiosteal bone apposition.72 of 89 postmenopausal women who started the prospective trial completed it; of these, 50 had had bilateral oophorectomy. The effects on bone loss were compared for no treatment, treatment with estrogen, or treatment with calcium. The estrogen-treated group received ethinyl estradiol 25 or 50 mcg for 3 of every 4 weeks. Calcium-treated patients took 2 calcium gluconate tablets/day, equal to 800 mg of calcium. Densitometry tests determined the mineral content of the left ulna and radius by the photon absorption technique. Morphometry was measured from radiographs of both hands. Untreated patients continued to lose bone density over the 2-year follow-up period. Those treated with estrogen did not lose bone density. Those treated with calcium had some bone loss but less than the untreated subjects. The main effect of estrogen on the metacarpals was inhibition of endosteal bone resorption with possibly stimulation of subperiosteal bone apposition.

1. Plasma alkaline phosphatase activity and urine hydroxyproline excretion were measured in age-matched premenopausal and postmenopausal women. 2. Both measurements were found to be significantly higher in postmenopausal women. 3. It is proposed that the rise in the plasma alkaline phosphatase, like that in the hydroxyproline excretion, may reflect the onset of bone loss that occurs after the menopause.

The treatment of patients with the osteoporotic crush fracture syndrome will remain unsatisfactory until the pathogenesis of the condition is fully understood and precise methods are available to monitor the effect of therapy on bone loss.

Ninety-five postmenopausal women with unequivocably wedged or compressed vertebrae in whom the recognised causes of secondary osteoporosis had been excluded were studied, 41 having no treatment and the rest one or more of six different treatments. The treatment regimens comprised calcium supplements, vitamin D, calcium and vitamin D, ethinyloestradiol or--where oestrogens were contraindicated--norethisterone, 1 alpha-hydroxycholecalciferol (1 alpha-OHD3), or hormones with 1 alpha-OHD3. The seven groups were reasonably comparable in most respects except that the hormone-treated patients were younger and had a higher initial cortical area ratio than the others, and the calcium- and hormone-treated groups had the best initial radio-calcium absorption. The untreated osteoporotic patients lost cortical bone more rapidly than do normal postmenopausal women. Three treatments (calcium, hormones, and 1 alpha OHD3 plus hormones) appear to be useful in modifying the disease, and two treatments (vitamin D and 1 alpha-OHD3) useless or even harmful. Vitamin D and 1 alpha-OHD3 are more safely used in conjunction with oestrogens, which protect bone against resorption, than on their own.

Plasma ionized calcium (IC) and parathyroid hormone (PTH) concentrations were measured in 31 osteoporotic postmenopausal women at hourly intervals for 5 hours after a 1 g oral calcium load. Fifteen subjects had normal radiocalcium absorption and 16 subjects were malabsorbers of calcium. IC rose and PTH fell after the calcium load in both groups with a plateau at 3-4 hours, and the rise in IC was greater (P less than 0.01) in the normal absorbers. There was a nonsignificant trend for the fall in PTH to be greater in the normal absorbers. In the group as a whole the mean increase in IC (above baseline) at 4 hours was directly related to calcium absorption (P less than 0.025) and the mean change in PTH was inversely related to calcium absorption (P less than 0.05). These results demonstrate that in subjects with postmenopausal osteoporosis the responses of IC and PTH to an oral calcium load are a function of calcium absorptive status.

Summary: About 11% of post-menopausal women with wrist fractures have spinal osteoporosis with compressed vertebrae, and about 25% of post-menopausal osteoporosis patients have had a wrist fracture. The estimated prevalence of post-menopausal spinal osteoporosis is 4% of the female population at age 60 and about 8% at age 80. Osteoporotic patients have lower plasma oestrone and androstenedione levels, lower calcium absorption and higher urinary hydroxyproline than matched controls. Of six treatments tested in three different ways, the least successful were vitamin D2 and 1α-OHD3 and the most successful were hormones with or without 1α.-(OH)2D3 and calcium supplements. Calcium and vitamin D given in combination occupied an intermediate position.

The relative importance of genetic factors in the pathogenesis of age related bone loss has been investigated in a study involving 17 monozygotic (MZ) and 8 dizygotic (DZ) pairs of twins aged 64 to 75 years. Radiographic morphometry was performed at the midpoints of the 2nd, 3rd and 4th metacarpals of both hands and the mean total and cortical widths were evaluated. The heritability, h2, was calculated as the difference between the intrapair variances in same sexed DZ and MZ pairs divided by the intrapair variance in DZ pairs. The mean intrapair variance of both total and cortical width was found to be four to five times higher in DZ than in MZ pairs. The differences are highly significant with an h2 value between 0.7 and 0.8, indicating a predominant genetic influence. It is stressed that this result applies only to the population from which the twin sample was drawn.

Summary: In previous publications (Jones et al., 1977; Nordin et al., 1980) we have shown that menopausal symptoms respond well to 15 pig of ethinyl oestradiol and rather less well to 5 mg daily of norethisterone. We have not previously established whether even smaller doses of ethinyl oestradiol might be effective or whether combining this preparation with norethisterone might produce an additive effect. The present paper describes a trial designed to answer these questions.

The reduction of gonadotrophin levels, urinary calcium and hot flushes in post-menopausal patients by ethinyl oestradiol is shown to be dose dependent, near maximum response being achieved by a dose of 15 micrograms daily. Equivalent ethinyl oestradiol doses to a number of other gonadal hormone preparations have been assessed using the derived dose-response curve of the reduction in urinary calcium.

Osteoporosis is a common complication of corticosteroid therapy and it is associated with both decreased bone formation and increased bone resorption. We have measured radiocalcium absorption and the fasting urinary calcium/creatinine and hydroxyproline/creatinine ratios in 30 postmenopausal women receiving prednisolone therapy and compared the patients with normal spine radiographs (N = 14) with those whose spine radiographs showed osteoporosis (N = 16). The osteoporotic cases had lower radiocalcium absorption (p less than 0.001), higher fasting urinary calcium (p less than 0.05), and higher fasting urinary hydroxyproline excretion (p less than 0.001). As calcium absorption has a positive effect on calcium balance and urinary calcium a negative effect, the difference between these two variables was calculated in each case. This derived variable (radiocalcium absorption--fasting urinary calcium/creatinine) disclosed a greater difference between the osteoporotic and normal groups (p less than 0.0001) than either variable alone.

Vitamin D resistant hypophosphataemic osteomalacia (VDRHPO) occurs as an inherited disorder or more unusually in association with certain connective tissue tumours1. The primary defect is considered to be a failure of phosphate transport with decreased tubular phosphate reabsorption and hypophosphataemia resulting in osteomalacia and myopathy2.

The present paper reviews a cohort of peri- and post-menopausal women who commenced hormone therapy in 1975 with follow-up observations for 5 yr. The study indicates that more than half of the patients discontinued treatment for various reasons within the 5 yr period. The drop-out rate was proportionately much greater in the bone clinic patients than in the menopause clinic patients. The reasons for this are discussed.

It has been shown in previous communications (Robertson et al., 1969, 1971, 1976b; Robertson and Peacock, 1972) that the two main chemical factors which determine the risk of forming calcium oxalate-containing stones are the degree of saturation of urine with calcium oxalate and calcium phosphate and the level of protective inhibitory activity against the crystallisation of calcium oxalate. Since urinary calcium, oxalate and pH are the major determinants of the saturation of urine with calcium salts (Robertson and Nordin, 1976), it is likely that the risk of forming stones is related to the levels of these constituents in urine. Thus the higher the excretion of these ions the greater the risk of forming stones. Similarly, it is likely that the risk of forming stones is related to the concentration of urinary inhibitory activity, the majority of which has been shown to be in the acid mucopolysaccharide (AMPS) fraction of urine (Robertson et al., 1976). It has also been shown that the effective concentration of AMPS may be reduced in urines containing high concentrations of uric acid (Robertson et al., 1976a).Thus there appear to be five main urinary constituents which influence the risk of large crystals of calcium oxalate forming in the urinary tract viz. calcium, oxalate, pH, AMPS and uric acid.

1. Four different methods of calculating calcium absorption by radioactive calcium procedures have been compared with each other and with net calcium absorption in calcium-balance studies in 100 consecutive studies on 71 patients. 2. All four isotope procedures yielded highly significant correlations with net calcium absorption derived from the balance studies, but there was little to choose between the validity of the double-isotope and single-isotope procedure judged by these criteria. 3. The rate of calcium absorption calculated from one or other isotope procedure correlated better with net calcium absorption than did the fraction of the radioactive calcium absorbed. 4. The measurement of plasma radioactivity 1 h after single-isotope administration, corrected for body weight, proved almost as useful as the more complex procedures but would be expected to underestimate calcium absorption in states of very high bone turnover.

SUMMARY Plasma oestrone (E,) and androstenedione (A) were measured in 96 untreated and 18 corticosteroid-treated post-menopausal women. Levels of both hormones were consistently lower in the steroid-treated cases, presumably due to suppression of ACTH secretion. There was a clear relationship between A and Ei levels in both groups and when the data were pooled they formed a continuous series with a curvilinear relationship going through the origin. This relationship could be described by an equation based on Michaelis-Menten kinetics, suggesting that the rate of A to E! conversion is an inverse function of the plasma androstenedione level. The main determinant of plasma E] was plasma A; body weight and age were of subsidiary importance. Secondary oestrogen deficiency may be a factor in the genesis of steroid-induced osteoporosis in post-menopausal women and oestrogen therapy may be indicated in this group of patients.

1. We have examined the relation between the rate of cortical bone loss and other measured variables in 108 women, untreated and on various therapies, observed for nearly 300 patient years. The majority of the subjects were post-menopausal women with various degrees of simple osteoporosis, but a few cases of hyperparathyroidism and other calcium disorders were included. 2. Calcium balance, bone resorption rate, urinary hydroxyproline and plasma alkaline phosphatase were shown to be related to the rate of bone loss; patients with the more negative balance or the higher values of the other variables had significantly higher rates of loss. The rate of bone loss was independent of the rate of bone formation.

After 3 weeks' nortriptyline (NT) treatment the mean plasma concentration of its 10-hydroxy metabolite (10-OH-NT) (599 +/- 207 nmol l-1) was higher than that of the parent drug (433 +/- 199 nmol l-1) in 25 depressed patients. Also in the cerebrospinal fluid (CSF) the mean level of 10-OH-NT (67 +/- 20 nmol l-1) was higher than that of NT (39 +/- 23 nmol l-1). There was a strong correlation (P less than 0.001) between the CSF and plasma concentration of both NT (r = 0.92) and 10-OH-NT (r = 0.77). The interindividual variation in the CSF/plasma ratio of both compounds was small, compared to the variation in plasma levels. These results show that 10-OH-NT passes the blood-brain barrier as it is present in concentrations higher than those of NT in the CSF. 10-OH-NT has previously been shown to be a potent blocker of noradrenaline uptake and to have much less affinity for muscarinic receptors than NT itself. This active metabolite might therefore be a potential antidepressant with less disturbing anticholinergic side-effects.

A placebo-controlled trial has shown that 15 microgram of ethinyl oestradiol is as effective as 25 microgram daily in reducing both menopausal symptoms and the urinary excretion of calcium and hydroxyproline. Norethisterone 5 mg daily also showed a significant reduction in the climacteric symptoms but was less effective than either of the ethinyl oestradiol doses.A small placebo-controlled double-blind study was conducted to assess the efficacy of hormone replacement therapy in relieving climacteric symptoms. Women in the study received 1 of the following treatments: 1) 15 ug ethiny l estradiol daily; 2) 25 ug ethinyl estradiol daily; 3) 5mg norethisterone daily; or 4) a placebo. There was a significant cumulative fall in climacteric symptoms for the women on the 3 active therapies but no significant change in the placebo-treated group. The 15 ug-dose of ethinyl estradiol achieved the greatest reduction in symptoms, the 25 ug-dose achieved the next best effects, and the norethisterone treatment the least change. Differences among the 3 treatments were not statistically significant. Most of the improvement was due to a reduction in hot flushes. Bone resorption was also controlled with the treatment. It is concluded that hormone replacement therapy is effective in controlling menopause-related symptoms. Since norethisterone was almost as effective as the estrogens and since it is considered by many to be a safer compound, it is concluded that progestogen replacement therapy might be the recommended mode of treatment for menopausal symptoms.

In 6 groups of peri- and post-menopausal women, there was an inverse relation between the urinary sediment smear maturation value and the fasting urinary hydroxyproline/creatinine ratio. Administration of ethinyloestradiol and Progynova both reduced urinary hydroxyproline into the pre-menopausal range, the fall being proportional to the starting value. Oestrogen therapy also produced a significant fall in plasma ionised calcium. In a prospective trial, oestrogen therapy prevented post-menopausal bone loss but calcium therapy was less effective. It is suggested that a high fasting urinary hydroxyproline/creatinine ratio might be taken as an indication for oestrogen therapy in post-menopausal women. In established post-menopausal osteoporosis, pre-disposing risk factors appear to be low calcium intake, malabsorption of calcium and low oestrogen status. These patients appear to represent the fast bone-losers in the post-menopausal population. The accelerated bone loss can be wholly or partially corrected by hormone replacement therapy and by calcium supplements given to those with normal absorption only. These therapies also prevent loss of height due to further crush fractures. The malabsorption of calcium is very resistant to vitamin D therapy but responds to 1alpha-OHD3. Balance data suggest that the most effective therapy may be a combination of 1alpha-OHD3 with oestrogen.