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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) (p0.03; 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 (p0.015). In PAMPREV both markers showed no significant response to pamidronate; comparison showed a significantly greater response to alendronate (pAP p0.02; Dpy/Cr p0.002). 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.

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 HypE10 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 (p0.03). 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 (p0.04). 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.

Case reports of three young patients who developed vertebral fractures and skeletal complications during pregnancy and/or lactation are presented. Radiologic features are described. All three had severe disease with three to nine vertebral fractures at presentation postpartum. In two patients, follow-up for 5-7.8 yr (including further pregnancy in each) revealed no further fractures. In general, serum and urine features were normal, the exceptions being a low serum 25-hydroxyvitamin D level (plus intermittent elevation of serum parathyroid hormone) in one, a tendency to low plasma alkaline phosphatase in another, and in the third (the most severely affected patient) a transient rise in urinary hydroxyproline and plasma alkaline phosphatase during a phase of bone loss following her second and third pregnancies. Bone biopsies performed 1 to 6-1/2 yr after parturition showed quantitative bone histologic features and bone formation rates that, as a group, were not significantly different from either normal or postmenopausal osteoporotic subjects. These patients did not have osteomalacia and did not show high turnover osteoporotic features. It is possible that this type of osteoporosis may be somewhat self-limiting, although this hypothesis is subject to great influence by any adaptive lifestyle changes introduced by the patient. The severe fracture history of these patients emphasizes the gravity of their bone disease and stresses the need for further study on the etiology and treatment of this form of osteoporosis.

Over a period of 16 mth aspiration biopsy of the thyroid gland for cytological examination was carried out on 104 patients. Half of these had solitary thyroid nodules, carcinoma or thyrotoxicosis or when reviewed were considered to have thyroids of normal size. The remainder were regarded as having non-toxic goitre. On the basis of the cytological pattern, the 52 cases of non-toxic goitre were subdivided into simple colloid goitre (15), subacute thyroiditis of de Quervain's type (5) and lymphocytic thyroiditis (30). In 2 cases, clinically thought to have thyroiditis, cytology did not permit a definite diagnosis. Two main cytological subtypes were seen in cases of lymphocytic thyroiditis. One was characterized by a predominance of lymphoid cells, the other by the presence of pleomorphic oxyphilic follicular epithelium usually with fewer lymphocytes. One of the simple colloid goitres has been histologically confirmed, none of the other cases have been subjected to surgery. Clinical presentation and anti-thyroid antibody tests were in good agreement with the cytological diagnosis. A few patients who at the time of aspiration had negative antithyroid antibodies later developed positive titres. Aspiration cytology is a simple, quick and painless examination which is of great value in the differential diagnosis of non-toxic goitre and in the diagnosis of thyroiditis. It is particularly suitable for screening for thyroiditis in a goitre population.