A randomized clinical trial comparing oral alendronate and intravenous pamidronate for the treatment of Paget's disease of bone.

Second and third generation bisphosphonates are the treatment of choice for Paget's disease of bone. These drugs are more effective than calcitonin and etidronate, but there have been no head to head, randomized controlled trials comparing potent bisphosphonates. We conducted a 2-year, randomized, open-label trial comparing oral alendronate and intravenous pamidronate in 72 subjects with Paget's disease. Randomization was stratified according to baseline plasma total alkaline phosphatase (ALP) and previous bisphosphonate treatment (yes or no). All previously treated patients had received pamidronate but not alendronate. Assigned treatments were pamidronate (60 mg) every 3 months as a single infusion or alendronate (40 mg) daily in 3-month blocks, continued until biochemical remission (defined as both ALP and urine deoxypyridinoline (DPD)/creatinine ratio in the reference range) or a clear plateau effect was observed. At 1 year, nonresponders to pamidronate were crossed over to alendronate treatment. At 1 year, 31/36 (86%) subjects randomized to alendronate achieved biochemical remission compared with 21/36 (56%) for pamidronate (P = 0.017). There was a significantly greater reduction in ALP (P < 0.001) and DPD/creatinine ratio (P < 0.001) for alendronate compared with pamidronate treatment. In previously untreated patients, alendronate resulted in remission in 20/22 (91%) subjects compared with 19/22 (86%) of pamidronate-treated subjects, which was not significantly different; however, alendronate resulted in a significantly greater reduction in ALP (P = 0.014) and DPD/creatinine ratio (P < 0.001). In previously treated patients, alendronate resulted in remission in 11/14 (79%) subjects compared with 2/14 (14%) for pamidronate (P < 0.001), with a significantly (P < 0.001) greater reduction in both ALP and DPD/creatinine ratio. Of subjects crossed over from pamidronate to alendronate, 10/14 (71%) achieved remission, including 9/11 (82%) previously treated patients. We conclude that, in patients with previously untreated Paget's disease of bone, alendronate and pamidronate have similar efficacy in achieving biochemical remission. In patients previously treated with pamidronate, alendronate is more effective.

Major method-specific differences in the measurement of intact parathyroid hormone: studies in patients with and without chronic renal failure.

BACKGROUND: Following the introduction of two-site immunometric assays for parathyroid hormone (PTH), the expectation of good inter-assay agreement has not been fulfilled. The reasons for this may include differences in standardization as well as fragment recognition between the assays. METHODS: PTH values for healthy individuals, patients with renal failure and patients with normal renal function and elevated parathyroid hormone (hPTH) were compared using two commercial two-site immunochemiluminometric assays (Bayer Magic-lite and DPC Immulite 2000). RESULTS: Immulite results had a mean value 50.4% greater than the corresponding Magic-lite values for the whole study population with individual values ranging from 17.5% below to 118.3% above the corresponding Magic-lite value. There was no significant difference in inter-assay bias between patients with renal failure and those with normal renal function, suggesting that variable cross-reactivity with circulating disease-specific PTH fragments was not the primary cause of the observed discrepancy. Cross-reactivity with the synthetic fragment hPTH (7-84) was 34+/-5% for Magic-lite and 62+/-2% for Immulite. We also studied the stability of synthetic hPTH on storage. CONCLUSION: The instability of synthetic hPTH over extended storage periods may affect primary standard material. The consistent inter-assay differences and the over-recovery observed in external quality assessment programmes for the Immulite assay may have best been explained by differences in calibration and the relative cross-reactivities and/or kinetics of the two assay systems for specific parathyroid fragments.

A randomized trial comparing hormone replacement therapy (HRT) and HRT plus calcitriol in the treatment of postmenopausal osteoporosis with vertebral fractures: benefit of the combination on total body and hip density.

We report a prospective, randomized, multicenter, open-label 2-year trial of 81 postmenopausal women aged 53-79 years with at least one minimal-trauma vertebral fracture (VF) and low (T-score below - 2) lumbar bone mineral density (BMD). Group HRT received piperazine estrone sulfate (PES) 0.625 - 1.25 mg/d +/- medroxyprogesterone acetate (MPA) 2.5 - 5 mg/d; group HRT/D received HRT plus calcitriol 0.25 microg bd. All with a baseline dietary calcium (Ca) of < 1 g/ d received Ca carbonate 0.6 g nocte. Final data were on 66 - 70 patients. On HRT/D, significant (P < 0.001) BMD increases from baseline by DXA were at total body - head, trochanter, Ward's, total hip, intertrochanter and femoral shaft (% group mean delta 4.2, 6.1, 9.3, 3.7, 3.3 and 3.3%, respectively). On HRT, at these 6 sites, significant deltaS were restricted to the trochanter and Wards. Significant advantages of HRT/D over HRT were in BMD of total body (- head), total hip and trochanter (all P = 0.01). The differences in mean delta at these sites were 1.3, 2.6 and 3.9%. At the following, both groups improved significantly -lumbar spine (AP and lateral), forearm shaft and ultradistal tibia/fibula. The weightbearing, site - specific benefits of the combination associated with significant suppression of parathyroid hormone-suggest a beneficial effect on cortical bone. Suppression of bone turnover was significantly greater on HRT/D (serum osteocalcin P = 0.024 and urinary hydroxyproline/creatinine ratio P = 0.035). There was no significant difference in the number of patients who developed fresh VFs during the trial (HRT 8/36, 22%; HRT/D 4/34, 12% - intention to treat); likewise in the number who developed incident nonvertebral fractures. This is the first study comparing the 2 treatments in a fracture population. The results indicate a significant benefit of calcitriol combined with HRT on total body BMD and on BMD at the hip, the major site of osteoporotic fracture.

Bone density changes in Paget's disease 2 years after iv pamidronate: profound, sustained increases in pagetic bone with severity-related loss in forearm nonpagetic cortical bone.

Bone mineral density (BMD) was measured at three sites (forearm, spine, and hip) using dual X-ray and single-photon absorptiometry in 68 patients with Paget's disease before and after treatment with iv pamidronate. Patients were treated according to the severity of their disease; the mild category (Group I, hydroxyproline excretion (Hyp(E)) <5.0 micromol/L GF) received 120 mg, the moderate category (Group II, Hyp(E) 5.0-9.99 micromol/GF) 180 mg, and the severe category (Group III, > or = 10.0 micromol/GF) 240 mg. Group I was followed for 1 year, and both Groups II and III for 2 years. At the lumbar spine in pagetic bone there were no differences between groups in early responses, with a profound increase 6 months after treatment 20.5 +/- 2.0% above baseline values to 1.403 +/- 0.063 g/cm(2) (mean +/- SEM)(P < 0.001). This increase in BMD was sustained to 2 years (1.355 +/- 0.078 g/cm(2), P < 0.001) and was 15.0 +/- 2.2% above baseline values. The pagetic total hip BMD increased after treatment in all groups, with a mean rise of 10.4 +/- 1.4% at 1 year to 1.505 +/- 0.083 g/cm(2) (P < 0.01). At the pagetic femoral neck the response was similar, with a peak significant rise at 1 year of 10.7 +/- 1.7% to 1.403 +/- 0.097 g/cm(2) (P < 0.01). In nonpagetic spinal bone there were no differences between the group responses, with a combined mean increase of 4.3 +/- 0.7% at 1 year to 0.999 +/- 0.027 g/cm(2) (P < 0.01). In both Groups II and III the increase in BMD was significantly higher than baseline values at 1 and 2 years (P < 0.01). In the nonpagetic total hip BMD remained unchanged over the 2-year period and likewise, there were no significant changes from baseline at the nonpagetic femoral neck site. In the nonpagetic forearm we found a significant loss in BMD at the ultradistal (mainly trabecular), midregion (80% cortical), and proximal shaft (95% cortical) sites in Group III, persisting to 2 years at the latter two sites. The increase in bone density in pagetic bone, persisting at least 2 years, provides a new modality of assessment of the response of pagetic bone to treatment and suggests a mechanism for the reduction in fracture risk in such bone after effective bisphosphonate treatment. Severity-dependent nonpagetic forearm bone loss, persisting to 2 years at cortical sites, suggests a potential drug-induced fracture risk at the forearm and possibly elsewhere in the absence of appropriate preventive cotreatment.

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.

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.

Calcium absorption in postmenopausal osteoporosis: benefit of HRT plus calcitriol, but not HRT alone, in both malabsorbers and normal absorbers.

In a randomized trial involving 71 postmenopausal osteoporotic women with vertebral compression fractures, radiocalcium absorption studies using the (45)Ca single isotope method (alpha) were performed at baseline and after 8 months of treatment with either continuous combined hormone replacement therapy (HRT, as piperazine estrone sulfate 0.625-0.937 mg daily +/- medroxyprogesterone acetate 2.5 mg daily depending on uterine status) or HRT plus calcitriol 0. 25 microg 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), Dalpha = -0.17 (+/- 0.26), p<0.0005] in alpha at 8 months compared with baseline in the HRT-treated group, but a significant increase [0.68 (+/- 0.31) to 0.84 (+/- 0.27), Dalpha = +0.16 (+/- 0. 30), p<0.003] in the HRT-plus-calcitriol treated patients, resulting in alpha 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 (alpha >/=0.55) and 'malabsorbers' (alpha <0.55) revealed that alpha decreased with HRT treatment only in the normal absorbers, and remained stable in the malabsorbers. Conversely, following HRT plus calcitriol treatment, alpha 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 alpha seen with HRT alone, and thus should be considered in all patients with postmenopausal osteoporosis treated with HRT.

Paget's disease: acquired resistance to one aminobisphosphonate with retained response to another.

Twenty-five years after the first paper on etidronate in Paget's disease, there are few published papers that address bisphosphonate resistance as a specific clinical phenomenon. We report our data from two studies. Study 1 is a retrospective study of 20 patients with moderate to severe disease who were treated with intravenous (iv) pamidronate (221 +/- 18 mg [SEM]; range 60-360 mg), and after biochemical remission and relapse were retreated with generally larger iv dosage (293 +/- 28 mg; range 180-600 mg). The nadir bone turnover values were similar: plasma alkaline phosphatase (pAP) in 20 patients was 243 +/- 40 IU/l (mean +/- SEM) after the first course, and 267 +/- 44 IU/l after the second (reference range [RR] 35-135 IU/l). Likewise, fasting urinary hydroxyproline excretion (HypE) in 14 of the 20 patients was 4.5 +/- 1.1 micromol/LGF and 4.1 +/- 0.9 micromol/LGF, respectively (RR 0.40-1.92 micromol/LGF). However the minimum duration of biochemical remission was significantly shorter after the second course-10.9 +/- 1.7 months (first) and 5.6 +/- 0.9 months (second) (p < 0.03; Friedman's ANOVA n = 17). A subgroup of 10 patients who were followed for three courses showed a significantly higher pAP nadir in the third course. Study 2 is a prospective study of 40 patients, 23 previously untreated (NILPREV) and 17 previously treated with iv pamidronate (PAMPREV) and in biochemical relapse, who were randomly allocated to either oral alendronate 40 mg daily in 3 month units, or iv pamidronate 60 mg every 3 months. Treatment was continued until pAP and fasting urinary deoxypyridinoline/creatinine (Dpy/Cr) ratios (RR 5-27 micromol/mol) were both in the reference range, or a clear plateau in each marker developed. At baseline, there were no significant differences in either marker between the two NILPREV groups and between the two PAMPREV groups. Using log-transformed data, in NILPREV the pAP reductions were significant and similar over the first 6 months. However, although each Dpy/Cr reduction was also significant, the difference in responses favored alendronate (p < 0.015). In PAMPREV both markers showed no significant response to pamidronate; comparison showed a significantly greater response to alendronate (pAP p < 0.02; Dpy/Cr p < 0.002). Using two-way ANOVA, the pAP responses to alendronate in NILPREV and PAMPREV were similar and those to pamidronate were different (p = 0.034). The percentage of patients with both markers in the RR at 6 months or earlier were identical in NILPREV patients: alendronate 87% and pamidronate 87%. However in PAMPREV they were different: alendronate 83% and pamidronate 0% (p = 0.003). These data indicate: 1) patients treated with the same aminobisphosphonates for two courses show similar nadir values of bone turnover markers but a shorter remission time after the second course. In a third course the nadirs are significantly higher; and 2) in the alendronate/pamidronate comparison, NILPREV and PAMPREV patients showed similar pAP responses to alendronate, but significantly different responses to pamidronate. Thus, patients showing acquired partial resistance to one aminobisphosphonate (usually after two or more previous courses) are still capable of remission after exposure to another compound of the same class.

Prevention of appendicular bone loss in Paget's disease following treatment with intravenous pamidronate disodium.

It has been shown previously that intravenous pamidronate treatment for severe Paget's disease is associated with appendicular bone loss. This 2 year study was designed to determine whether cotreatment with calcitriol and a calcium supplement would prevent this. Intravenous pamidronate was used to treat 49 patients with symptomatic Paget's disease. Patients were stratified into two groups of differing biochemical severity based on hydroxyproline excretion (HypE) expressed as micromoles per liter of glomerular filtrate (GF): (1) a severe group with HypE > 10 micromol/L GF; and (2) a moderate group with HypE 5-10 micromol/L GF. Within each group, patients were randomly allocated to receive supplements of calcium and calcitriol (supplemented) or no supplements (unsupplemented) after initiation of pamidronate therapy. The severe group received 360 mg of pamidronate as six doses of 60 mg once weekly and the moderate group received 240 mg as four weekly doses of 60 mg. Patients were followed for 24 months following treatment and had serial bone densitometry of the forearm measured as well as urine and plasma biochemistry. When the groups were combined, the unsupplemented patients showed a decrease in bone mineral density (BMD) at the ultradistal forearm site, which persisted to 24 months. Those supplemented with calcium and calcitriol showed an increase in BMD and the difference between the two groups was significant at all times posttreatment (p < 0.03). When the groups were analyzed separately, those with moderate disease again showed significant differences in BMD between supplemented and unsupplemented patients at all timepoints. In the severe group, the differences did not reach statistical significance due to smaller patient numbers. Similar changes in BMD were also observed at the forearm shaft site. When serial parathyroid hormone (PTH) levels (with the moderate and severe groups combined) were plotted against time since treatment the rise in PTH in the supplemented patients was less than the rise in the unsupplemented patients (p < 0.04). These results suggest that forearm bone loss after intravenous pamidronate treatment for moderate-to-severe Paget's disease can largely be prevented by administration of calcium and calcitriol. The mechanism may be a blunting of the secondary hyperparathyroidism that occurs after intravenous pamidronate. These findings may have wider application in moderate-to-severe Paget's disease treated with other bisphosphonates.

High prevalence of normal total calcium and intact PTH in 60 patients with proven primary hyperparathyroidism: a challenge to current diagnostic criteria.

BACKGROUND: Others have reported a clear distinction between patients with primary hyperparathyroidism (PHPT) and normal subjects using the intact PTH (iPTH) assay. AIM: We reviewed our last 60 surgically proven cases of PHPT, who had adequate preoperative biochemical assessment, to determine the usefulness of the iPTH assay, ionised calcium and other biochemical criteria in differentiating between normal subjects and patients with PHPT. METHODS: We conducted a retrospective cross-sectional study of all patients with surgically proven PHPT who had been referred to Sir Charles Gairdner Hospital, Perth, Western Australia for preoperative biochemical assessment. All cases had fasting preoperative blood and urine samples collected for ionised calcium, plasma total calcium, albumin, urine calcium excretion, renal phosphate threshold and iPTH. RESULTS: Fifty cases had a single or double adenoma and ten had hyperplasia. All except one had ionised hypercalcaemia but only 47 (78%) had an elevated corrected total calcium (cCa). Therefore 13 cases (22%) had a normal cCa and five of those patients (8%) had both an iPTH and cCa within the reference range. Forty-nine (82%) had an elevated ionised calcium (iCa) and iPTH; the remaining 11 (18%) had an iPTH within the reference range. Of this latter 18%, ten (91%) had a low renal phosphate threshold and five (45%) had significant renal calcium conservation: all 11 cases had at least one abnormality in the renal handling of calcium or phosphate and all normalised their plasma calcium postoperatively (ionised and corrected total calcium). CONCLUSIONS: One in five patients with proven PHPT have a non-elevated cCa and/or intact PTH. Ionised calcium should be measured in all suspected cases. Additional studies of renal calcium and phosphate handling are helpful to establish a diagnosis where any uncertainty exists.

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 Paget's 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 Paget's 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.

Comparison of biochemical markers of bone turnover in Paget disease treated with pamidronate and a proposed model for the relationships between measurements of the different forms of pyridinoline cross-links.

We have compared the use of new markers of bone turnover in the assessment and treatment of Paget disease and made observations on the mechanisms of bone resorption. Urine hydroxyproline (Hyp) as a bone resorption marker and serum alkaline phosphatase (ALP) as a bone formation marker have traditionally been used to biochemically assess and monitor treatment of Paget disease. Hyp and total ALP were compared with total urine pyridinoline (Pyd) and deoxypyridinoline (Dpd), free urine Pyd and Dpd, urine type I collagen N-terminal cross-linked telopeptide (NTX), type I collagen C-terminal propeptide (PICP), serum osteocalcin, and bone ALP in Paget patients treated with pamidronate. Patients were divided into three biochemical severity-based treatment groups by their fasting urine hydroxyprolline excretion (HypE) levels (Le., group 1, HypE < 5.0 mumol/l of glomerular filtrate [GF]; group 2, HypE of 5.0-9.9 mumol/l of GF; group 3, HypE > 10 mumol/l of GF). Group 1 received one 60 mg intravenous infusion of pamidronate, and groups 2 and 3 received four and six 60 mg infusions at weekly intervals, respectively. Fasting serum and morning urine specimens were taken before and at 2, 6, 13, and 26 weeks after starting treatment. Baseline Z scores were used to compare separation of patient results from normal, and the difference in Z scores from baseline to 13 weeks was used to compare response to treatment. Baseline discrimination and response to treatment at all disease activity levels was greatest for NTX and was poor for osteocalcin, PICP, and C-terminal cross-linked telopeptide of type I collagen (ICTP). The other markers showed good discrimination and response at medium and high levels of disease activity. NTX, total Pyd and Dpd, free Pyd and Dpd, and ICTP are all pyridinoline cross-link-based markers, but discrimination and response by NTX was generally much greater than for the others. Determination of the mechanism of the difference between NTX and other cross-link measures is necessary for appropriate use of the markers and may also lead to a better understanding of the bone resorption process. It has been proposed that the greater sensitivity and discrimination of NTX is because it is more bone-specific than the other cross-link markers with significant amounts of free Pyd and Dpd coming from nonbone sources. We propose another model where the proportion of peptide-bound cross-links such as NTX may be increased in high bone turnover states partly due to a rate-limiting step in their degradation to free cross-links. Conditions with high bone resorption rates would have high levels of NTX that would decline rapidly when resorption rates fall to a level where the capacity to degrade NTX matches the rate of production.

Long-term elevation of 1,25-dihydroxyvitamin D after short-term intravenous administration of pamidronate (aminohydroxypropylidene bisphosphonate, APD) in Paget's disease of bone.

We report the prolonged biochemical changes that occurred in patients with Paget's disease when treated for 2-10 days with pamidronate disodium (3-amino-1-hydroxypropylidine-1,1-bisphosphonate, APD), by i.v. administration and observed for 6 months following therapy. In all 24 patients studied, bone resorption (measured by urinary hydroxyproline/creatinine ratio, OHP/Cr) fell sharply on treatment, from 0.12 +/- 0.02 (mean +/- SEM; above reference limits) to 0.04 +/- 0.008 (reference range 0.006-0.027 for females, 0.005-0.020 for males), remaining at this level for 6 months after therapy. A fall in serum ionized calcium (Ca2+) to just below the reference limits with treatment (1.11 +/- 0.02 mM; reference range 1.14-1.18 mM), followed by a rapid return to normal levels (1.14 +/- 0.02 mM, mean +/- SEM) within 8 days of treatment, was presumably due to the cessation of release of calcium from bone. This was followed by secondary hyperparathyroidism and a rise in serum 1,25-dihydroxyvitamin D [1,25(OH)2D]. The hormonal responses, however, were profound. Serum immunoreactive PTH (iPTH) rose to twice pretreatment values (86 +/- 11 pM, mean +/- SEM; reference range for iPTH, > 50 years, < 50 pM; < 50 years, < 40 pM), returning to normal 4-8 weeks after therapy. Serum 1,25-(OH)2D levels rose to three times pretreatment values (300 +/- 20 pM, mean +/- SEM; reference range 50-150 pM), remaining above reference limits 4-8 weeks after therapy (188 +/- 15 pM, mean +/- SEM) and returning to normal values only after 12 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Rapid, divergent changes in spinal and forearm bone density following short-term intravenous treatment of Paget's disease with pamidronate disodium.

Intravenous disodium 3-amino-1-hydroxypropylidene-1,1-bisphosphonate pentahydrate (pamidronate disodium) was used to treat 39 patients (22 males and 17 females, age range 48-85 years) with symptomatic Paget's disease. Patients were stratified into three groups based on the biochemical severity of the disease as assessed by fasting urinary hydroxyproline excretion (HypE, mumol/liter GF, glomerular filtrate): group I (n = 23), HypE < 5.0, treated with 120 mg total dose over 2 or 4 days; group II (n = 6), 5.0 < or = HypE < or = 10.0, 180 mg over 3 or 6 days; and group III (n = 10), HypE > 10.0, 240 mg over 4 or 8 days. Bone mineral density (BMD) was measured before and 3 and 6 months following treatment in the spine (L1-4) using dual-energy x-ray absorptiometry and in the forearm at an ultradistal and a shaft site using single-photon absorptiometry. When groups I-III were combined, nonpagetic and pagetic lumbar spinal BMD had both risen significantly at 3 months compared with the pretreatment values (p < 0.001). In each group, lumbar spinal BMD in pagetic vertebrae rose markedly by 3 months, with no further significant change at 6 months. The percentage rises in the three groups were not different from each other at 3 or 6 months. Nonpagetic lumbar spinal BMD followed a similar and significant trend but with a significantly smaller rise than for pagetic bone. (For the combined groups, nonpagetic BMD rose 5.1 +/- 1.1% SEM, above pretreatment at 6 months; pagetic BMD rose 17.8 +/- 1.6%: significance of comparison = p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Fluoride treatment of osteoporosis: cyclical non-blinded or continuous blinded studies?

The future of sodium fluoride (NaF), the most potent osteoblast stimulator known to man, is in the balance. Of three recent randomized trials of continuous NaF only one found a significant in vertebral fractures in the NaF group. When data from the first year were excluded, two of the studies (those with the largest numbers) showed a significantly reduced risk of vertebral fracture on NaF. The effect of NaF on cortical bone is poorly documented. Two studies have shown reduced forearm cortical bone density with continuous NaF. A further two (histomorphometric) studies have shown the development of increased cortical porosity on continuous NaF treatment. In one, this was selectively at the external cortex and was linearly correlated with cancellous volume increase. Our pilot study using NaF administered cyclically has shown an encouraging (though non-significant) reduction in vertebral fracture rates (excluding year 1) and no fall in forearm cortical density. Another (US) cyclical study has shown no increase in cortical porosity. A current W. Australian randomized study of 50 patients is described where NaF dosage is varied proportional to the osteoblast response, and duration is dependent on densitometric and radiographic response. The future of NaF should involve cyclical administration, in cautious initial dosage (50-60 mg/day) of enteric-coated NaF, in conjunction with a potent inhibitor of resorption such as hormone replacement, bisphosphonates or calcitonin.

Calcium, phosphate and citrate in human milk at initiation of lactation.

The onset of copious milk secretion (lactogenesis II) in women occurs between 1 and 3 d after birth, and during this period the composition of breast milk changes. During the first 5 d of lactation we measured the concentrations of total, diffusible and ionized Ca (Catot, Cad, Ca2+), diffusible phosphate (Pid), diffusible citrate (Citd) and lactose in the breast milk. On day 1 after birth the concentrations (mean +/- SEM) were Catot, 5.71 +/- 0.30 mM; Cad, 2.66 +/- 0.19 mM; Ca2+, 2.90 +/- 0.18 mM; Pid, 0.26 +/- 0.16 mM; Citd, 0.25 +/- 0.03 mM and lactose, 76 +/- 11 mM. Between day 1 and day 4 the concentration of Catot increased 1.7-fold to 9.56 +/- 0.39 mM, Cad increased 1.8-fold to 4.75 +/- 0.26 mM, Ca2+ decreased by 20% to 2.33 +/- 0.13 mM, Pid increased 6.6-fold to 1.69 +/- 0.11 mM, Citd increased 20-fold to 5.06 +/- 0.21 mM, and lactose increased 2.3-fold to 173 +/- 4 mM. A high correlation has been found between [Cad] and [Citd] in the milk of both ruminant and non-ruminant species, which show a wide range in concentrations of [Cad] and [Citd], and the data fit a simple physicochemical model of ion equilibria in the aqueous phase of milk. The results of the present study confirm the relationship between [Cad] and [Citd] in human milk, even during lactogenesis II when the composition of the milk is changing very rapidly.

Intravenous aminobisphosphonate in Paget's disease: clinical, biochemical, histomorphometric and radiological responses.

Intravenous 3-amino-1-hydroxypropylidene-1, 1-bisphosphonic acid (APD) was used to treat 26 patients with Paget's disease. Three daily dosages were studied; 20-30 mg/day in 20 patients, 45 mg/day in three patients and 60 mg/day in three patients, by daily 4-hour infusions for 2-10 days. The fasting urinary hydroxyproline excretion (HypE) declined exponentially, reaching 50% of pretreatment values at 1.92 +/- 0.16 (mean +/- SEM) days. This initial rapid decline was complete by 4 days following treatment to a mean of 28.0 +/- 3.4% of pretreatment values. Thereafter, there was no significant decline in HypE. The initial rate of decline of HypE was unchanged by increasing the daily dose of APD. Transient non-symptomatic hypocalcaemia with secondary hyperparathyroidism occurred in all patients. No adverse changes in the renal handling of calcium or phosphate, as seen with high-dose 1-hydroxyethylidene-1, 1-bisphosphonate (EHDP), were seen in any patient on any daily dose. Fever occurred in 73% of patients in the first 2 days of treatment. Overall, there was a significant fall in the lymphocyte count (P less than 0.005 febrile group, n = 19; P less than 0.02 non-febrile group, n = 7) and a fever-dependent rise in the neutrophil count (P less than 0.005 febrile group only). The occurrence of fever was associated with a more rapid decline in HypE, compared to the non-febrile group, so that HypE was significantly lower in the febrile group by day 5 (P less than 0.025). Seventy-two per cent of patients with bone and/or joint pain reported a reduction in pain.(ABSTRACT TRUNCATED AT 250 WORDS)

Alterations in vitamin D metabolites during treatment of Paget's disease of bone with calcitonin or etidronate.

We report serum 25-hydroxyvitamin D (25-OHD), 24,25-dihydroxyvitamin D [24,25-(OH)2D], and 1,25-dihydroxyvitamin D [1,25-(OH)2D] levels in untreated Paget's disease and the effect of treatment with either calcitonin (CT) or etidronate (EHDP) on these levels. In untreated Paget's patients serum 25-OHD (73 +/- 29 nmol/liter, n = 36, mean +/- SD) and 24,25-(OH)2D (0.3-12.9 nmol/liter, median 2.2, n = 36) levels were significantly lower than in age-matched controls (94 +/- 30 nmol/liter, n = 32, p less than 0.005, and 1.3-16.4 nmol/liter, median 5.3; n = 32, p less than 0.001, respectively). Also, the 24,25-(OH)2D levels correlated with the 25-OHD levels in the untreated Paget's patients (r = 0.56, p less than 0.01) and in the controls (r = 0.39, p less than 0.05). The percentage molar ratio of 24,25-(OH)2D to 25-OHD in Paget's patients had a median value of 3.7% (range 0.4-14.3%), which was not significantly different from controls, who had a median value of 5.6% (range 2.2-18%). There was no difference between the 1,25-(OH)2D, and immunoreactive PTH (iPTH) levels of Paget's patients and control subjects. The percentage molar ratio of 1,25-(OH)2D to 25-OHD in untreated Paget's patients (0.157 +/- 0.09%) was not significantly different from controls (0.124 +/- 0.05%) despite lower 25-OHD levels in Paget's patients. There was a significant inverse correlation between the severity of Paget's disease as measured by plasma alkaline phosphatase (AP) levels and 25-OHD levels (r = 0.392, p less than 0.02); however, 24,25-(OH)2D and 1,25-(OH)2D levels were not correlated with AP.(ABSTRACT TRUNCATED AT 250 WORDS)