Diana Wattie

Imatinib promotes osteoblast differentiation by inhibiting PDGFR signaling and inhibits osteoclastogenesis by both direct and stromal cell-dependent mechanisms.

Several lines of evidence suggest that imatinib may affect skeletal tissue. We show that inhibition by imatinib of PDGFR signaling in osteoblasts activates osteoblast differentiation and inhibits osteoblast proliferation and that imatinib inhibits osteoclastogenesis by both stromal cell‐dependent and direct effects on osteoclast precursors.

Evidence for secular change in paget's disease

Death certification data has shown that death rates due to Pagets disease of bone and osteosarcoma in older people (assumed to be attributable to Pagets) declined in the latter part of the 19th and in the early 20th century, suggesting that there may be a secular trend toward less severe disease. We have reviewed a 21 year experience in a clinic specializing in Pagets disease. Data from all 1041 patients attending the clinic in this period were reviewed. Despite an increase in the susceptible population and an increased rate of referral to the clinic over this time (p = 0.012), there was a fall in the absolute numbers of patients referred with severe disease, as judged by the initial plasma alkaline phosphatase activity at presentation. In the years 1973-1978 the initial plasma alkaline phosphatase was > 500 U/L in an average of 22 new patients per year and > 1000 U/L in 12 per year. In the years 1988-1993, the figures were 12 and 3 per year, respectively. During this period, there were no other facilities offering scintigraphy or intravenous treatment for Pagets disease in the Auckland region, making it unlikely that patients with severe disease were being seen and treated elsewhere. The average age of newly referred patients rose steadily from a mean 62 years, in 1971-1973 to 71 years in 1991-1993 (p < 0.001). 534 subjects had scintiscans (52%) from which the extent of skeletal involvement was calculated. Skeletal involvement showed a significant negative correlation with year of birth (p < 0.01) but not with age or year of presentation. The proportion of patients with > 20% skeletal involvement had fallen by a third in the cohort born after 1926, compared to the cohort born before 1915. Our data demonstrate that, on average, newly referred patients with Pagets disease have less severe disease and are significantly older at diagnosis than was the case two decades ago.

Paget’s Disease of Bone in New Zealand: Continued Decline in Disease Severity

We have reported previously that severe Paget’s disease of bone had become less common at our center between 1973 and 1993. Data from several countries support the view that there are important secular trends in the prevalence and severity of Paget’s disease. In this paper we describe recent trends in the demography of newly referred patients with Paget’s disease to determine if the secular trend toward milder disease has continued. A database of all newly referred patients (n = 1487) with Paget’s disease (1973 to 2002 inclusive, 30 years) was examined. Of these, 832 subjects (56%) had scintiscans. Plasma total alkaline phosphatase (total ALP) activity, disease extent on scintiscan, and a derived index of average ALP activity of pagetic bone were used as indices of severity. The number of new referrals with Paget’s disease declined sharply from 1994 onward and is currently at half the rate seen 20 years earlier, while the mean age at presentation has progressively increased by 4 years per decade (P < 0.0001). Total ALP at diagnosis, disease extent on scintiscan, and the number of bones involved were all negatively correlated with both date of birth (P < 0.0001) and year of presentation (P < 0.0001), indicating that more recently born and presenting subjects had substantially less severe bone disease. The average activity of pagetic bone was only weakly correlated with year of presentation, but not with year of birth or age at presentation. Although there are a number of potential biases, these data are consistent with a continued secular trend to presentation in older subjects with less extensive skeletal involvement, and a declining prevalence of Paget’s disease.

Bone mineral density of the proximal femur and lumbar spine in glucocorticoid-treated asthmatic patients

The importance of the proximal femur as a site of osteoporotic fractures, the development of techniques for bone mineral density (BMD) measurement at this site and the apparent selectivity of the osteopenic effects of glucorticoids have focused attention on the assessment of proximal femoral BMD in steroid-treated subjects. We have, therefore, measured BMD (Lunar DPX) in the lumbar spine and proximal femur of 31 asthmatic patients receiving long-term glucocorticoid therapy (mean ± SEM dose 16 ± 1 mg prednisone/day, mean duration 10 ± 2 years). BMD values expressed as the percentage of normal age- and sex-appropriate mean values, after weight adjustment, were as follows: lumbar spine 80 ± 2%, femoral neck 83 ± 2%, Wards triangle 78 ± 3% and trochanter 86 ± 2%. All these values were significantly less than control (p<0.0001) and the decrement in BMD was more marked in Wards triangle than at the other two femoral sites (p<0.05). In all regions BMD was unrelated to dose or duration of steroid treatment. It is concluded that there are reductions in the BMD of the lumbar spine and proximal femur in glucocorticoid-treated asthmatics, probably reflecting the mixed cortical/trabecular makeup of both regions.

The antiresorptive effects of a single dose of zoledronate persist for two years: a randomized, placebo-controlled trial in osteopenic postmenopausal women.

CONTEXT Annual iv administration of 5 mg zoledronate decreases fracture risk. The optimal dosing interval of 5 mg zoledronate is not known. OBJECTIVE Our objective was to determine the duration of antiresorptive action of a single 5-mg dose of iv zoledronate. DESIGN, SETTING, AND PARTICIPANTS We conducted a double-blind, randomized, placebo-controlled trial over 2 yr at an academic research center, in a volunteer sample of 50 postmenopausal women with osteopenia. INTERVENTION Intervention included 5 mg zoledronate. MAIN OUTCOME MEASURES Biochemical markers of bone turnover and bone mineral density of the lumbar spine, proximal femur, and total body. RESULTS Compared with placebo, zoledronate treatment decreased mean levels of each of four markers of bone turnover by at least 38% (range 38-45%) for the duration of the study (P < 0.0001 for each marker). After 2 yr, bone mineral density was higher in the zoledronate group than the placebo group by an average of 5.7% (95% confidence interval = 4.0-7.4) at the lumbar spine, 3.9% (2.2-5.7) at the proximal femur, and 1.7% (0.8-2.5) at the total body (P < 0.0001 for each skeletal site). Between-groups differences in markers of bone turnover and bone mineral density were similar at 12 and 24 months. Mild secondary hyperparathyroidism was present throughout the study in the zoledronate group. CONCLUSION The antiresorptive effects of a single 5-mg dose of zoledronate are sustained for at least 2 yr. The magnitudes of the effects on markers of bone turnover and bone mineral density are comparable at 12 and 24 months. Administration of zoledronate at intervals of up to 2 yr may be associated with antifracture efficacy; clinical trials to investigate this possibility are justified.

Delayed Development of Paget's Disease in Offspring Inheriting SQSTM1 Mutations†

Familial Pagets disease is associated with mutations in SQSTM1. We compared the age at diagnosis and severity of Pagets disease in parents with SQSTM1 mutations to their offspring who inherited a mutation. At any given age, the offspring were less likely to be diagnosed with Pagets disease and had less severe disease than their parents.

Post‐pregnancy osteoporosis associated with hypercalcaemia

A lactating 31‐year‐old woman who developed four vertebral fractures 1–2 months after the delivery of her first child is described. She was hypercalcaemic (serum calcium up to 2.99 mmol/l), and urinary excretion of both calcium and hydroxyproline (an index of bone resorption) were markedly elevated. Serum levels of parathyroid hormone and 1,25‐dlhydroxyvltamin D were suppressed, but parathyroid hormone‐related peptide was above normal. There was severe axial osteopenia, as assessed by dual‐energy X‐ray absorptiometry. The biochemical abnormalities were reversed within 2 weeks of weaning, with the exception of the parathyroid hormone‐related peptide concentration, which declined more gradually. This appears to be the first description of the abnormalities in calcium metabolism and bone density from early in the course of post‐pregnancy osteoporosis and it Indicates that this condition is associated with high levels of osteolysis which return to normal after weaning. This rapid reversal of the metabolic abnormalities accounts for the inconclusive nature of previous descriptions of postpregnancy osteoporosis, in which investigations were more delayed. It also emphasizes the importance of weaning in the management of women presenting with this condition. A possible aetiological role for parathyroid hormone‐related peptide is discussed.

Age-, gender-, and weight-related effects on levels of 25-hydroxyvitamin D are not mediated by vitamin D binding protein.

Objective  25‐hydroxyvitamin D (25OHD) levels are inversely related to body weight, and have been reported to decline with age and be lower in women than men. We hypothesized that these findings might be explained by effects of these variables on vitamin D binding protein (DBP) levels. We set out to determine the relationships between DBP and gender, 25OHD, body weight and body composition.

Five years of anti-resorptive activity after a single dose of zoledronate — Results from a randomized double-blind placebo-controlled trial

Intravenous zoledronate 5 mg, administered annually, prevents fractures in people with osteoporosis, but the optimal dosing schedule is not known. Previously, we reported that a single dose of 5 mg zoledronate stably decreased bone turnover and increased bone mineral density (BMD) for 3 years in a randomized controlled trial in 50 postmenopausal women with osteopenia. We have now completed a 2-year double-blind extension of this trial, during which no additional treatment was administered. The primary endpoint was change in the bone turnover markers procollagen type-I N-terminal propeptide (P1NP) and β-C-terminal telopeptide of type I collagen (β-CTX); the secondary endpoint was change in BMD at lumbar spine, total hip and total body. Mean levels of the each of the bone turnover markers were lower in the zoledronate group throughout the study (P<0.0001 for each marker). After 5 years, mean (95% CI) levels of β-CTX and P1NP were 277 ng/L (150, 404) and 28 μg/L (16, 40) lower in the zoledronate group, corresponding to reductions of 48% and 45%, respectively. BMD was higher in the zoledronate group during the study (P<0.0001 for each site). After 5 years, BMD in the zoledronate group was higher by 4.2% (1.1, 7.2) at the lumbar spine, by 5.3% (2.7, 7.9) at the total hip, and by 2.7% (1.1, 4.2) at the total body. These findings suggest that the anti-resorptive effects of a single 5 mg dose of zoledronate persist for at least 5 years in postmenopausal women. Trials assessing the anti-fracture efficacy of dosing intervals of zoledronate of up to 5 years are justified.

Prolonged antiresorptive activity of zoledronate: a randomized, controlled trial.

Annual intravenous administration of 5 mg of zoledronate decreases fracture risk over 3 years. The optimal dosing interval of 5 mg of zoledronate is not known. In order to determine the duration of the antiresorptive action of a single 5‐mg dose of intravenous zoledronate, we conducted a 3‐year double‐blind, randomized, placebo‐controlled trial in a volunteer sample of 50 postmenopausal women with osteopenia. The coprimary endpoints were the bone turnover markers β‐C‐terminal telopeptide of type I collagen (β‐CTX) and serum procollagen type‐I N‐terminal propeptide (P1NP). Secondary endpoints were bone mineral density (BMD) at the lumbar spine, total hip, and total body. After 3 years, mean (95% confidence interval) levels of serum β‐CTX and P1NP were 44% (27–60) and 40% (24%–56%) lower in the zoledronate group (p < .001 versus placebo for each marker). BMD was higher in the zoledronate group than in the placebo group by an average of 6.8% (4.6%–9.1%) at the lumbar spine, 4.0% (1.8%–6.3%) at the total hip, and 2.0% (0.9%–3.0%) at the total body (p < .001 for each skeletal site). Between‐group differences in markers of bone turnover and BMD were stable from 12 to 36 months. These data demonstrate that the antiresorptive effects of a single 5‐mg dose of zoledronate are sustained for 3 years; clinical trials to investigate the antifracture efficacy of dosing intervals longer than 1 year are justified.