D.H. Gutteridge

The efficiency of intestinal calcium absorption is increased in late pregnancy but not in established lactation

SummaryThe fractional absorption of calcium (FA-Ca) was measured using a dual non-radioactive Ca isotope technique in 26 control women, 49 women in the last triimester (36 weeks) of pregnancy and 31 of these women in established (20 weeks) lactation. The ratio of the two non-radioactive Ca isotopes was measured, by high precision thermal ionisation mass spectrometry, in urine 12–24 hours after administration and was used to calculate Fa-Ca. This is the first study to clearly show that FA-Ca is significantly elevated in late pregnancy but not in established lactation, when compared with control women.

SERUM FREE 1,25‐DIHYDROXYVITAMIN D AND THE FREE 1,25‐DIHYDROXYVITAMIN D INDEX DURING A LONGITUDINAL STUDY OF HUMAN PREGNANCY AND LACTATION

The changes in three different indices of 1,25‐dihydroxyvitamin D (1,25(OH)2D) biological activity were studied longitudinally in 35 women during late pregnancy and lactation and in 26 control women. Measurements were made of maternal serum total 1,25(OH)2D and free 1,25(OH)2D concentration (by centrifugal ultrafiltration) and the free 1,25(OH)2D index (the molar ratio of total 1,25(OH)2D and vitamin D binding protein (DBP)). During late pregnancy total 1,25(OH)2D concentrations were significantly elevated when compared to controls, as were free 1,25(OH)2D and DBP concentrations and the free 1,25(OH)2D index. Serum total 1,25(OH)2D, free 1,25(OH)2D and DBP concentrations all fell dramatically during the first 2 weeks of lactation with total 1,25(OH)2D and free 1,25(OH)2D concentrations falling to levels below those of controls. During the course of lactation both total I,25(OH)2D and free 1,25(OH)2D levels rose significantly although they were not different from controls at 18 weeks of lactation. In contrast, the free 1,25(OH)2D index fell during the first 2 weeks of lactation, but remained at this level, significantly lower than controls. Neither urinary calcium excretion nor dietary calcium intake correlated with total or free 1,25(OH)2D, DBP, or the free 1,25(OH)2D index. The disagreement in the results of free 1,25(OH)2D concentration and free 1,25(OH)2D index demonstrates that these two approaches to measuring biologically active 1,25(OH)2D are not equivalent. In attempting to account for the increased calcium requirements of human reproduction we conclude that in pregnancy any of the 1,25(OH)2D measurements may be appropriate. In lactation, however, either 1,25(OH)2D is not a major factor or 1,25(OH)2D biological activity is inadequately represented by any of the currently available methods.

Clinical, biochemical, hematologic, and radiographic responses in Paget's disease following intravenous pamidronate disodium: A 2-year study☆

An intravenous dosage schedule using pamidronate disodium, based on biochemical severity, was used to treat 71 patients with Pagets disease who had no previous bisphosphonate treatment. Disease severity was stratified by fasting hydroxyproline excretion (HypE): Group (Gp) I (mild disease; HypE < 5.0 mumol/LGF) received a total dose of 120 mg; Gp II (moderate; HypE 5.00-9.99) received 180 mg; and Gp III (severe; HypE > or = 10) received 240 mg. Within each group patients were randomly allocated to receive daily 30 mg or 60 mg infusions. Observations for 2 years included pain scores, indices of bone turnover, and radiology of lytic lesions. There was no difference in biochemical responses, or in the percentage of patients with early fever, between the 30 mg and 60 mg daily subgroups; for convenience, 60 mg infusions are recommended. Neutrophils and total white cell counts were both significantly below baseline 4 days after the first infusion; lymphocytes were significantly reduced by day 2; and all three measures had returned to within the reference range by day 6. Remission was assessed at 6 months, when both plasma alkaline phosphatase (ALP) and HypE had reached stable nadirs. Increasing severity was associated with increasing resistance to suppression of HypE at 6 months to within the reference range: Gp I, 87%; Gp II, 44%; and Gp III, 0% (p < 0.0001 by chi-square test). Biochemical relapse at 2 years (defined as ALP 50% above the 6 month level) was also dependent on initial disease severity (Gp I, 6%; GpII, 39%; Gp III, 62%; p < 0.0005 by chi-square test). There was no association between time to relapse and either initial dose or log dose. Radiologic lytic lesions (in 22 patients) were all in remission at 3 months; however, relapse rates at 2 years appeared to be severity-dependent: Gp I, 13%; Gp II, 43%; and Gp III, 57% (n.s. by chi-square test). Remission rates based on a fall to < 50% of pretreatment of either HypE or ALP were more in accord with lytic lesion remission rates than were rates based on HypE falling to within the reference range. Pamidronate produced a significant reduction from baseline in Pagetic bone, Pagetic joint, and unrelated musculoskeletal pain in the first 6 months (p < 0.0001). From 0 months to 2 years the maintenance of improvement in bone pain (p < 0.005) and joint pain (p < 0.05) was significantly better than in unrelated pain. Pamidronate is a safe, welltolerated, and effective treatment for Pagets disease. In spite of larger dosage in severe disease, increasing severity was associated with resistance to normalization of biochemistry and a higher incidence of biochemical and radiological relapse at 2 years. Our current dosage recommendation would be for two 60 mg infusions for mild disease (Gp I); and four 60 mg infusions for moderate disease (Gp II). Severe disease (Gp III) remains a challenge; regardless of dosage, the majority of patients will be in relapse 2 years after a single course of treatment.

A Randomized Trial of Sodium Fluoride (60 mg) ± Estrogen in Postmenopausal Osteoporotic Vertebral Fractures: Increased Vertebral Fractures and Peripheral Bone Loss with Sodium Fluoride; Concurrent Estrogen Prevents Peripheral Loss, But Not Vertebral Fractures

Abstract: Postmenopausal Caucasian women aged less than 80 years (n= 99) with one or more atraumatic vertebral fracture and no hip fractures, were treated by cyclical administration of enteric coated sodium fluoride (NaF) or no NaF for 27 months, with precautions to prevent excessive stimulation of bone turnover. In the first study 65 women, unexposed to estrogen (–E study), age 70.8 ± 0.8 years (mean ± SEM) were all treated with calcium (Ca) 1.0–1.2 g daily and ergocalciferol (D) 0.25 mg per 25 kg once weekly and were randomly assigned to cyclical NaF (6 months on, 3 months off, initial dose 60 mg/day; group F CaD, n= 34) or no NaF (group CaD, n= 31). In the second study 34 patients, age 65.5 ± 1.2 years, on hormone replacement therapy (E) at baseline, had this standardized, and were all treated with Ca and D and similarly randomized (FE CaD, n= 17; E CaD, n= 17) (+E study). The patients were stratified according to E status and subsequently assigned randomly to ± NaF. Seventy-five patients completed the trial. Both groups treated with NaF showed an increase in lumbar spinal density (by DXA) above baseline by 27 months: FE CaD + 16.2% and F CaD +9.3% (both p= 0.0001). In neither group CaD nor E CaD did lumbar spinal density increase. Peripheral bone loss occurred at most sites in the F CaD group at 27 months: tibia/fibula shaft –7.3% (p= 0.005); femoral shaft –7.1% (p= 0.004); distal forearm –4.0% (p = 0.004); total hip –4.1% (p = 0.003); and femoral neck –3.5% (p= 0.006). No significant loss occurred in group FE CaD. Differences between the two NaF groups were greatest at the total hip at 27 months but were not significant [p<0.05; in view of the multiple bone mineral density (BMD) sites, an alpha of 0.01 was employed to denote significance in BMD changes throughout this paper]. Using Cox’s proportional hazards model, in the –E study there were significantly more patients with first fresh vertebral fractures in those treated with NaF than in those not so treated (RR = 24.2, p= 0.008, 95% CI 2.3–255). Patients developing first fresh fractures in the first 9 months were markedly different between groups: –23% of F CaD, 0 of CaD, 29% of FE CaD and 0 of E CaD. The incidence of incomplete (stress) fractures was similar in the two NaF-treated groups. Complete nonvertebral fractures did not occur in the two +E groups; there were no differences between groups F CaD and CaD. Baseline BMD (spine and femoral neck) was related to incident vertebral fractures in the control groups (no NaF), but not in the two NaF groups. Our results and a literature review indicate that fluoride salts, if used, should be at low dosage, with pretreatment and co-treatment with a bone resorption inhibitor.

Effect of alcohol on renal vitamin D metabolism in chickens.

Abstract Intraperitoneal administration of ethanol to young chickens (both vitamin D-replete and vitamin D-deficient) produced a significant impairment of renal 25 hydroxyvitamin D 3 1α-hydroxylase (EC 1.14.13.13) activity with no significant change in serum calcium or phosphorus. In ethanol treated D-replete chicks the renal 25 hydroxyvitamin D 3 24-hydroxylase activity was enhanced, and serum 25 hydroxyvitamin D 3 was significantly increased. The alkaline phosphatase levels in the D-deficient ethanol treated chicks were significantly less than the controls. Our data suggest that the impairment of the metabolic effects of vitamin D due to ethanol occurs chiefly via a renal, rather than a hepatic mechanism. Furthermore, 1α -hydroxylated metabolites of vitamin D would appear to be the logical treatment of choice for the bone disease of alcoholism.

Thirty Cases of Concurrent Paget's Disease and Primary Hyperparathyroidism: Sex Distribution, Histomorphometry, and Prediction of the Skeletal Response to Parathyroidectomy

Studies of the effect of parathyroidectomy (PTX) on bone turnover in patients with the combination of primary hyperparathyroidism (PHPT) and Pagets disease (PD) are largely limited to case reports. The etiology of the combination is disputed. We report 30 patients and their biochemical (n = 17) and histomorphometric (n = 4) responses to PTX in 18. All 18 patients except one had a post-PTX fall in plasma alkaline phosphatase (pAP). There was a significant positive correlation between the degree of post-PTX fall in pAP and both the preoperative plasma total corrected calcium (CaC) (P < 0.01) and serum ionized calcium (P < 0.05). For the patients with CaC levels >3.0 mmol/liter, the mean % fall in pAP was 68% of pretreatment (to 32%). For those with CaC levels ≥2.68 mmol/liter the fall in pAP was >18%. Of 12 literature cases treated by PTX and followed up, 11 had a postoperative fall in pAP (range 6–83%). Pretreatment bone biopsies (n = 6) could not be distinguished from uncomplicated PD. No significant histomorphometric changes were documented postoperatively in the four patients studied; however, % fibrotic surfaces declined in each of the four. Of the 18 patients, only one had radiologic subperiosteal erosions preoperatively; none had clinical tetany postoperatively—thus distinguishing this combination of diseases from severe PHPT bone disease—a situation easily biochemically confused with this combination. The sex distribution of 2.75:1 F/M in this series resembles reported ratios in pure PHPT of 2.37:1, unlike the ratios found in pure PD (0.49–1.01:1). The prevalence of PHPT in PD is 2.2–6.0% (mean 4.4%) in 1836 patients. In our series, 73% of patients with both diseases were females >60 years of age. In population studies >60 years, PHPT was present in 3% of women and 1% of men. Hypercalcemia in PD is frequently attributed to immobilization. As part of this study, we examined 184 patients referred with PD for the existence of, and cause of hypercalcemia. Of this group, 21 were hypercalcemic, 19 (90%) of whom had PHPT; none had immobilization hypercalcemia. In patients with both disorders, the indications for PTX should include the potential post-PTX improvement in pagetic biochemistry and symptoms. The sex distribution (resembling pure PHPT) and the similar prevalence of PHPT in Pagets, and in the elderly population, support the likelihood, in most cases, that these two common diseases are associated by chance.

Physiological hyperparathyroidism in human lactation.

The changes in human maternal calcium metabolism due to foetal skeletal demands, are now well documented [5, 9, 16, 19]. Little is known, however, about maternal calcium metabolism, calcium-related hormone levels and their interactions during lactation. We are interested in this subject for the following reasons: Firstly, in rats there is a profound increase in bone turnover during lactation [10, 14, 18]. We have confirmed this observation and have found that the degree of bone turnover is enhanced by increasing the phosphate (P) content of the calcium replete diet of the animals [11]. Furthermore, there is a pronounced loss of bone mineral which may be demonstrated both radiologically and chemically during 20 days of lactation [12]. Once again, an increased dietary P profoundly increases the bone loss. Secondly, in human lactation a progressive loss of bone mineral has been demonstrated using the photon absorption technique [1] and a further study using the same technique [7] found that 20to 59-year-old women, who had lactated, had poorly mineralised bone compared with nulliparous women of similar age. Thirdly, an acute form of osteoporosis occurring during lactation has been described in humans [6]. In this study, our primary aim was to define the basal physiological changes that occur in human lactation by studying healthy volunteers serially. A preliminary account of this work has been published in the New Zealand Journal of Medicine 84, 161 (1976).

Calcium Absorption in Postmenopausal Osteoporosis: Benefit of HRT Plus Calcitriol, but not HRT Alone, in both Malabsorbers and Normal Absorbers

Abstract: In a randomized trial involving 71 postmenopausal osteoporotic women with vertebral compression fractures, radiocalcium absorption studies using the 45Ca single isotope method (α) were performed at baseline and after 8 months of treatment with either continuous combined hormone replacement therapy (HRT, as piperazine estrone sulfate 0.625–0.937mg daily ± medroxyprogesterone acetate 2.5 mg daily depending on uterine status) or HRT plus calcitriol 0.25 μg twice daily. A calcium supplement of 600 mg nocte was given to only those women who had a daily calcium intake of less than 1 g per day at baseline, as assessed by recalled dietary intake. There was a significant decrease [0.74 (± 0.35 SD) to 0.58 (± 0.22), Dα=−0.17 (± 0.26), p<0.0005] in α at 8 months compared with baseline in the HRT-treated group, but a significant increase [0.68 (± 0.31) to 0.84 (± 0.27), Dα=+0.16 (± 0.30), p<0.003] in the HRT-plus-calcitriol treated patients, resulting in α being significantly higher after 8 months in the latter group than in the HRT-only group. Although 72% of the patients had been supplemented with calcium between the first and second studies, separate analyses revealed that the change in calcium intake had not affected the result. Further breakdown of the groups into baseline ‘normal’ absorbers (α≥0.55) and ‘malabsorbers’ (α <0.55) revealed that α decreased with HRT treatment only in the normal absorbers, and remained stable in the malabsorbers. Conversely, following HRT plus calcitriol treatment, α increased only in the malabsorbers, the normal absorbers in this group remaining unchanged. In conclusion, our data show that HRT, of the type and dose used in this study, did not produce an increase in absorption efficiency; it was in fact associated with a fall. Increased absorption efficiency cannot be achieved unless calcitriol is used concurrently, and then only in patients with malabsorption. Calcitriol also had a significant effect in normal absorbers in that it prevented the decline in α seen with HRT alone, and thus should be considered in all patients with postmenopausal osteoporosis treated with HRT.

FASTING CALCIUM EXCRETION AND PARATHYROID HORMONE TOGETHER DISTINGUISH FAMILIAL HYPOCALCIURIC HYPERCALCAEMIA FROM PRIMARY HYPERPARATHYROIDISM

Routine estimation of plasma calcium has made the finding of asymptomatic hypercalcaemia a frequent occurrence. A high index of suspicion for familial hypocalciuric hypercalcaemia (FHH) will lead to accurate diagnosis and avoidance of unnecessary parathyroid surgery. Four FHH kindreds with 16 hypercalcaemic members were found in an unselected referral population over 3 years. Differentiation from primary hyperparathyroidism (42 patients in the same period) was facilitated by analysis of fasting blood and urine for renal handling of calcium, phosphate and cyclic AMP. We found that a plot of serum PTH against fasting calcium excretion separated all cases of each disorder. The discriminatory power of these two variables was confirmed by multivariate discriminant function analysis. An elevated plasma chloride was found to be common to both diseases and of no value in differentiation.

Bisphosphonate Therapy for Paget's Disease in a Patient with Hypoparathyroidism: Profound Hypocalcemia, Rapid Response, and Prolonged Remission

Bisphosphonate treatment for severe Pagets disease leads to hypocalcemia followed by a secondary hyperparathyroid response to restore normocalcemia. A case is presented of a 60‐year‐old woman with polyostotic Pagets disease and postsurgical hypoparathyroidism. In 1993 her Pagets disease—alkaline phosphatase (ALP), 1260 U/liter (35–135 U/liter), and fasting urinary hydroxyproline excretion, 13.7 μmol/liter GF (0.4–1.9 μmol/liter)—was treated with intravenous pamidronate. Symptomatic hypocalcemia followed the first 60‐mg dose, requiring large doses of calcium supplementation and calcitriol. Pamidronate therapy to a total dose of 360 mg was followed by rapid and prolonged remission with indices of bone turnover in the normal range within 2 months and persisting for at least 19 months after treatment. In 1999 relapse of Pagets disease—ALP, 511 U/liter (35–135 U/liter), and fasting urinary deoxypyridinoline/creatinine 53.1 μmol/mol (5–27 μmol/mol)—was treated with alendronate, 10 mg daily. Symptomatic hypocalcemia occurred again, requiring increased calcium and calcitriol therapy. Indices of bone turnover were within the normal range 9 weeks after the start of therapy. These responses were significantly more rapid and sustained than those observed in euparathyroid subjects. This case suggests that the lack of parathyroid response may modify the response to bisphosphonates by: (a) increasing intrinsic uptake of bisphosphonate into the pagetic skeleton, allowing response to a smaller dose; (b) increasing duration and severity of hypocalcemia after bisphosphonate therapy; and (c) removing the hyperparathyroid drive to reactivation of pagetic osteoclasts, leading to a prolonged remission. These observations have implications for optimizing bisphosphonate therapy both in Pagets disease and in osteoporosis.