Intranasal salmon calcitonin for the prevention and treatment of postmenopausal osteoporosis

In a randomized, double-blind, placebo-controlled trial, we have studied the effects of intranasal salmon calcitonin (SCT) on bone mineral density (BMD) and biochemical markers of bone turnover over a period of 2 years. Our study comprised 117 Caucasian postmenopausal women, otherwise healthy apart from reduced bone density. They received either intranasal synthetic SCT (200 IU either three times weekly or daily) or placebo. Compared with placebo, daily intranasal calcitonin resulted in no significant bone loss in the lumbar spine, as assessed by dual photon absorptiometry, over the 2-year study period(P < 0.02). In this group, women more than 5 years postmenopause, with the lowest baseline bone mass, showed the greatest response to this treatment, with a total increase placebo in lumbar spine BMD of 3.1%. Significant spinal bone loss(P < 0.005) occurred in women receiving either placebo or thrice-weekly calcitonin. Although the rates of bone loss in the proximal femur were not significantly different in the three groups, there were differences over time. Whereas bone loss in the daily calcitonin group was insignificant, women who received placebo or thrice-weekly calcitonin experienced significant bone loss(P < 0.001). No significant changes in biochemical markers were observed in any group. Therapy was well tolerated and there were no significant treatment-related adverse events. We conclude that intranasal SCT 200 IU daily is effective and safe for the prevention of bone loss in postmenopausal women with reduced bone mass.     

Suppression of Bone Resorption in Early Postmenopausal Women by Intranasal Salmon Calcitonin in Relation to Dosage and Basal Bone Turnover

In the present study, we assessed the ability of increasing doses of intranasal calcitonin to suppress urinary deoxypyridinoline cross-link (DPD), a specific biochemical marker of bone resorption, in early postmenopausal women. Subjects consisted of 30 healthy Thai women within 5 years of postmenopause, randomly assigned to 50, 100, or 200 IU of intranasal calcitonin 5 days/week for 3 months. Calcium supplementation by calcium carbonate capsules at 750 mg of elemental calcium per day was given to all subjects. Twenty four-hour urine for DPD and creatinine assays was collected at baseline, 1 month, and 3 months after treatment. All DPD values were corrected with urinary creatinine before analyses. Data were expressed as mean ± SEM. DPD decreased significantly 1 month after intranasal calcitonin treatment (P < 0.01). However, at 3 months, DPD increased when compared with the values at 1 month (P < 0.01), suggesting that there may be a reduction in the suppression of bone resorption after prolonged calcitonin therapy. Using a stepwise multiple regression model to address whether dosage and DPD at baseline influence the response to intranasal calcitonin, it was found that DPD suppression after intranasal calcitonin was not related to dosage but was strongly associated with baseline DPD (P < 0.0001). Suppression of bone resorption in early postmenopausal women by intranasal calcitonin is determined more by the state of bone turnover at baseline than the dosage of calcitonin. Received: 10 March 1997 / Accepted: 14 November 1997     

A comparison of the effects of oestrogen/progestogen,high-dose oral calcium,intermittent cyclic etidronate and an ADFR regime on calcium kinetics and bone mass in postmenopausal women with spinal osteoporosis

The effects of four different treatments for osteoporosis were compared in a prospective, randomized, 3-year study in 74 postmenopausal women with spinal crush fracture osteoporosis. Patients were randomly assigned to cyclic oestrogen/progestogen therapy (group 1,n=20), a daily oral calcium dose of 2 g (group 2,n=17), intermittent cyclic etidronate therapy (group 3,n=19), or an ADFR treatment with triiodothyronine as activator and etidronate as depressor (group 4,n=18). Spine and forearm bone mineral content was measured before entry and every 30 weeks. Combined calcium balance and⁴⁷Ca kinetic studies were performed before and after 1 and 3 years of treatment. Bone turnover, estimated by serum alkaline phosphatase and renal hydroxyproline excretion, decreased in all four groups during the first half of the treatment period but remained reduced during the second half in groups 1 and 3 only. Group 1 had a significantly positive calcium balance after 60 weeks of treatment. After 150 weeks, the positive effect on calcium balance was significant and greater in groups 1 and 3 than in the other groups. This was achieved by a greater reduction in resorption rate in group 1 at week 60 and in groups 1 and 3 at week 150 as compared with the other groups. Only group 1 had a significant increase in spinal bone mass while a decrease in bone mass at the distal forearm was observed in the etidronate-treated group. We conclude that treatment of postmenopausal osteoporosis with oestrogen/progestogen for 3 years results in net spinal bone gain and a positive effect on calcium balance slightly better than that of intermittent etidronate. These effects were inferior in the groups receiving a large calcium supplementation or the ADFR group where no change in calcium balance or bone mass was found.     

Rectal salmon calcitonin for the treatment of postmenopausal osteoporosis

Summary In a 2-year study, we examined bone mass and calcium metabolism in 36 elderly women with moderate osteoporosis. The study period comprised 1 year of observation, during which the women received no treatment affecting calcium metabolism, and 1 year of treatment, during which all participants received daily salmon calcitonin (sCT) 100 IU rectally and calcium 500 mg. During the observational period a significant bone loss of 1.5% was seen in the forearm (P<0.01), whereas the spinal bone mass was virtually unchanged. After institution of treatment, the bone loss was arrested in the forearm and a significant increase of about 2% was seen in the spine (P<0.01). The net effect of treatment revealed a positive outcome in both bone compartments (1.9% and 2.9%, P<0.05–0.01). Correspondingly, the parameters of bone turnover (serum alkaline phosphatase, plasma bone Gla protein, and fasting urinary hydroxyproline/creatinine) did not change during the observational period, but significantly declined, 10–30%, during sCT treatment (P<0.01–0.001). Tolerance was generally good, although in one woman, anoscopy revealed irritative changes in the rectal mucosa. We conclude that, given rectally, sCT is well absorbed and well tolerated and that it has a beneficial effect on calcium metabolism in moderately osteoporotic women.     

Effect of long-term calcitonin administration on steroid-induced osteoporosis after cardiac transplantation.

BACKGROUND: Early, rapid bone loss and fractures after cardiac transplantation are well-documented complications of steroid administration; therefore, we undertook this study on the effects of long-term calcitonin on steroid-induced osteoporosis. METHODS: Twenty-three heart transplant recipients on maintenance immunosuppression with cyclosporine, mycophenolate mofetil and prednisone were retrospectively studied. All patients received long-term prophylactic treatment with elemental calcium and vitamin D. Twelve (52.2%) patients also received long-term intranasal salmon calcitonin, whereas 11 (47.8%) received none. Bone mineral density and vertebral fractures were assessed at yearly intervals. Statistical comparisons between each group's bone loss during the first year and in the early (1 to 3 years), intermediate (4 to 6 years) and late (7+ years) post-transplantation periods were done. RESULTS: Lumbar spine bone loss was significant during the early follow-up period in the group not receiving calcitonin (0.744 +/- 0.114 g/cm(2) vs 0.978 +/- 0.094 g/cm(2) [p = 0.002]). The calcitonin group showed bone mineral density (BMD) levels within normal average values throughout the study period. BMD increased in the no-calcitonin group during the intermediate (4 to 6 years) and late (7+ years) follow-up periods, with values approaching normal average and no significant difference between the 2 groups (0.988 +/- 0.184 g/cm(2) vs 0.982 +/- 0.088 g/cm(2) [p = 0.944] and 0.89 +/- 0.09 g/cm(2) vs 1.048 +/- 0.239 g/cm(2) [p = 0.474], respectively). CONCLUSIONS: Prophylactic treatment with intranasal salmon calcitonin prevents rapid bone loss associated with high-dose steroids early after cardiac transplantation. Long-term administration does not seem warranted in re-establishing BMD.     

Nandrolone decanoate and intranasal calcitonin as therapy in established osteoporosis

This study used a randomized, 2 × 2 factorial design to evaluate over 2 years the effect of intranasal salmon calcitonin and intramuscular nandrolone decanoate on bone mass in elderly women with established osteoporosis. The study was double masked in relation to calcitonin and open in relation to nandrolone decanoate. One hundred and twenty-three women aged 60–88 years who had sustained a previous osteoporotic fracture, or had osteopenia, were recruited through an outpatient clinic. Women were assigned to one of four groups: (1) daily placebo nasal spray, (2) 400 IU intranasal calcitonin daily, (3) 20 intramuscular injections of 50 mg nandrolone decanoate (given as two courses of 10 injections) plus placebo nasal spray, or (4) 20 injections of 50 mg nandrolone decanoate plus 400 IU intranasal calcitonin daily. All subjects received 1000 mg calcium supplementation daily. Outcomes measured included changes in bone mineral density (BMD) at the lumbar spine, as measured by dual-energy quantitative computed tomography (DEQCT), in BMD of the proximal femur, and BMD and bone mineral content (BMC) of the lumbar spine and forearm, as measured by dual-energy X-ray absorptiometry (DXA). Significant positive changes from baseline in DXA BMC at the lumbar spine were observed over 2 years in the calcitonin group (5.0±1.9%, mean ± SE) and in the nandrolone deconate group (4.7±1.9%) but not in the placebo group (1.1±2.2%) or the combined therapy group (0.7±1.8%). Modelling based on the 2×2 factorial design revealed that nandrolone decanoate was associated with a 3.8±1.8% (p<0.05) gain in DXA BMD at the proximal femur. Modelling also revealed that calcitonin treatment was associated with a loss of 11.5±4.7% in DEQCT BMD at the lumbar spine and a loss of 3.7±1.8% in DXA BMD at the proximal femur (p<0.05). There was in vivo antagonism between the two medications of 7.9±3.9% for DXA BMC at the lumbar spine. Both agents caused positive changes from baseline in lumbar spine BMC. Nandrolone decanoate had beneficial effects on BMD at the proximal femur. This dose of intranasal calcitonin was associated with deleterious effects on trabecular BMD at the lumbar spine and total BMD at the proximal femur. There may be significant clinical antagonism between these two medications.     

Comparison of vitamin D metabolism in early healthy and late osteoporotic postmenopausal women

Summary We studied 20 healthy premenopausal women aged 36.5±4.0 years (mean±1 SD), 123 healthy postmenopausal women aged 50.0±2.4 years, and 103 postmenopausal women aged 65.1±5.6 years with symptomatic osteoporosis (forearm and spinal fracture). Serum levels of vitamin D metabolites [25(OH)D, 24,25(OH)₂D₃, and 1,25(OH)₂D] were compared with (1) bone mass in the forearm (single photon absorptiometry) and in the spine (dual photon absorptiometry); (2) biochemical indices of bone formation (serum alkaline phosphatase, plasma bone Gla protien), and bone resorption (fasting urinary hydroxyproline); and (3) other biochemical estimates of calcium metabolism (serum calcium, serum phosphate, 24-hour urinary calcium, intestinal absorption of calcium). The present study revealed no difference in any of the vitamin D metabolites between the premenopausal women, the healthy postmenopausal women and the osteoporotic women as a group. The concentrations of 1,25(OH)₂D and 25(OH)D were significantly lower in patients with spinal fracture than in those with forearm fracture. In the early postmenopausal women, serum 1,25(OH)₂D was related to forearm bone mass (r=−0.20;P<0.05), intestinal calcium absorption (r=0.18;P<0.05), and 24-hour urinary calcium (r=0.21;P<0.05); serum 25(OH)D was related to spinal bone mass (r=0.23;P<0.01). In the osteoporotic women, serum vitamin D metabolites were not related to bone mass, but 1,25(OH)₂D was related to bone Gla protein (r=0.33;P<0.001), serum phosphate (r=−0.27;P<0.01), and 24-hour urinary calcium (r=0.43;P<0.001). The present study demonstrates that in a population that is apparently not deficient in vitamin D, a disturbance of the vitamin D metabolism is not likely to play a pathogenetic role in early postmenopausal bone loss. Patients with spinal fractures have low levels of vitamin D metabolites, which may aggravate their osteoporosis.     

Acute Effects of Calcitonin Nasal Spray on Serum C-telopeptide of Type 1 Collagen (CTx) Levels in Elderly Osteopenic Women with Increased Bone Turnover

Salmon calcitonin is a potent inhibitor of osteoclastic activity. The effect of calcitonin in elderly women with high bone turnover at higher risk of developing osteoporosis has not been studied. To investigate acute effects of calcitonin treatment on bone resorption markers in elderly women, we conducted a randomized trial in women >65 years of age with high bone turnover assessed as urinary N-telopeptide of type-I collagen (NTx) levels 1 SD higher than mean premenopausal levels, which was irrespective of bone density. A total of 98 elderly women were randomly assigned to receive either 200 IU calcitonin nasal spray (n = 75) with calcium (500 mg) and vitamin D (200 IU) or calcium and vitamin D (n = 23) alone for 6 months. Blood and urine samples were collected at 0, 2, 4, and 6 months and analyzed for urinary NTx and serum C-telopeptide of type-1 collagen (CTx). At baseline, mean age was 72.1 ± 4.7 (mean ± SD) in the calcitonin group and 72.2 ± 6 years in the control group. The spine and total hip BMD, serum PTH levels and urinary calcium/creatinine ratios were similar in both groups. Mean BMD was in the osteopenic range in both groups. Calcitonin treatment resulted in significant decreases in serum CTx levels, 2, 4 and 6 months after treatment as compared to baseline, and after 4 and 6 months as compared to controls. A maximum decrease from baseline of 33% was seen at 6 months. The urinary resorption marker, urine NTx, showed a significant decrease in the calcitonin group when compared to baseline only at the 6-month time point. Analysis of least significance change (LSC) showed that 70% of calcitonin patients were categorized as responders using serum CTx after 6 months of treatment. We conclude that 200 IU calcitonin effectively decreases bone resorption within 60 days of therapy, thus preventing further bone loss in elderly women who are at a high risk of developing osteoporosis.     

Effect of intranasal salmon calcitonin therapy on bone mass and bone turnover in early postmenopausal women: A dose-response study

We examine the dose-related effect of intranasal salmon calcitonin (sCT) on the early postmenopausal bone loss and bone turnover; a 2-year, prospective, randomized, double-blind, placebo-controlled study was carried out with 134 healthy women who had passed a natural menopause within 6 months to 3 years. The women were allocated randomly to 2 years of treatment with either 100, 200, or 400 IU of sCT given intranasally or placebo. All groups received a calcium supplement of 500 mg. Twenty-one women left the study before its end and 91 complied with the study criteria throughout. Bone mineral content/density of the distal forearm and lumbar spine and biochemical parameters of bone turnover were measured. Although the measurements after 24 months revealed no significant difference between groups in bone mineral density of the lumbar spine, the average changes over time revealed prevention of bone loss in the groups treated with 200 and 400 IU of sCT (0.2 to-0.6%) and declines of 0.8-1.7% in the groups treated with 100 IU of sCT and placebo (P<0.05–0.01; within-group testing). There was no dose-related response to sCT but there was a significant difference between the pooled groups treated with 200 plus 400 IU of sCT versus the 100 IU sCT and placebo-treated groups (P=0.030–0.005). The same difference between groups was seen for biochemical parameters of bone turnover (P=0.022–0.003). The biochemical parameters of bone turnover revealed decreases of 10–20% (P<0.001; within group testing) in the groups treated with the two highest sCT doses. It was concluded that nasal sCT in doses of 200 and 400 IU has some effect in women soon after the menopause—preventing the bone loss in the spine throughout the first year of therapy and lowering the bone turnover. It may be used as an alternative to hormone replacement when estrogens are contraindicated. The present data indicate that discontinuous strategies should be preferred.     

Spinal bone mass after long-term treatment with L-Thyroxine in postmenopausal women with thyroid cancer and chronic lymphocytic thyroiditis

This study investigated the effect of long-term treatment upon bone density with L-Thyroxine in postmenopausal women compared with untreated postmenopausal women with climacteric symptoms. We measured spinal bone density in three groups (n=84) of postmenopausal women: (A) those treated with TSH-suppressive dosis of L-Thyroxine for a medium of 5 years after removal of thyroid cancer; (B) those on L-Thyroxine treatment for a median of 9 years after being diagnosed with chronic lynfocitic thyroiditis (CLT); and (C) those with no thyroid disease or other known pathology and without any treatment. There were no differences in dietary calcium intake and daily activity between untreated and L-Thyroxine-treated women. Measurements of bone mineral density were performed at spine level L1–L4 using a dual X-ray densitometer and serum thyroid-stimulating hormone (TSH), thyroid hormones, and bone markers (serum osteocalcin, procollagen I, urinary calcium), and PTH levels were assayed and found to be within normal ranges. Women receiving L-Thyroxine after thyroid cancer had slightly higher FT4 levels compared with women who had CLT and lower TSH levels, with serum T4 and T3 levels normal and similar in both groups. No significant differences were found in spinal bone density after L-Thyroxine treatment between Groups A and B and compared with Group C. Bone loss according to 2 SD below reference standards (age and sex matched) was found in the 12.9% of L-Thyroxine-treated patients versus 22.6% of untreated women. No correlation was found between bone loss and thyroid hormone levels and duration of treatment. Our data suggest that long-term L-Thyroxine therapy in postmenopausal women maintaining near physiological levels of thyroid hormones is not associated with significant axial bone loss, therefore other factors should be considered when this occurs.     

The effect of intranasal salmon calcitonin on postmenopausal bone turnover as assessed by biochemical markers: Evidence of maximal effect after 8 weeks of continuous treatment

Although treatment with intranasal salmon calcitonin (sCT) has been shown to effectively inhibit postmenopausal bone loss, there is still controversy over both timing and the duration of its application. In an open prospective study, we therefore assessed the effect of short-term intranasal sCT on postmenopausal bone turnover, employing biochemical markers of bone metabolism. Ten early postmenopausal, previously untreated women (1–5 years after menopause) with biochemical evidence of increased bone resorption and a low bone mineral density at baseline were treated with intranasal sCT (100 IU B.I.D.) for a period of 3 months. Oral calcium (500 mg/day) was administered simultaneously, and during a further 3 month followup interval. Treatment with sCT resulted in a pronounced suppression of bone resorption markers with a maximum effect reached after 8 weeks of therapy: as compared to the respective baseline values, mean levels decreased by −26.2%±3.4% (P<0.001) for pyridinoline, −32.7%±3.5% (P<0.001) for deoxypyridinoline, −32.7%±3.3% (P<0.001) for hydroxyproline, and −24.1%±8.2% (P<0.001) for the amino-terminal telopeptide. In contrast, changes in bone formation markers of osteocalcin (−14.4%±4.8%,P<0.05) and C-terminal procollagen type I propeptide (−7.9%±3.9%, ns) were much less pronounced. Unexpectedly, after week 8 of the study all resorption markers showed a plateau and a trend to increase, although intranasal sCT was continued for a total of 12 weeks. This effect could not be attributed to the formation of anti-sCT antibodies. After cessation of treatment, both bone formation and resorption markers rapidly returned to baseline levels. Bone mineral density of both spine and hip showed no significant change during the observation period. Our results demonstrate that in postmenopausal women with a high bone turnover, intranasal treatment with 200 IU of sCT effectively reduces bone turnover and maintains bone mass, the maximum effect being reached after 8 weeks of treatment.     

Synthetic human calcitonin in postmenopausal osteoporosis: A placebo-controlled,double-blind study

Summary A placebo-controlled, double-blind study was carried out over 4 months to evaluate two doses of synthetic human calcitonin (0.25 and 0.125 mg) given s.c. three times per week. Enrolled were 60 women, aged 56–82 years, who had experienced a vertebral fracture due to low-energy trauma within the preceding year. During active treatment there was within the first month a dose-dependent decrease of the indices of bone resorption (fasting urinary calcium and hydroxyproline excretions), whereas only the higher dose and a treatment period of 4 months produced a reduction of bone formation (serum osteocalcin). The bone mineral content (BMC) of the nondominant forearm was unchanged. Treatment with calcitonin also had significant, dosedependent, analgetic effects. The amelioration of pain was, in multivariate analyses, related to a reduction in parameters felt to be markers for bone resorption. In the placebo group there was a significant reduction of the BMC of the forearm but no changes of any of the biochemical markers for bone turnover and no improvement of pain. In conclusion, treatment with two low doses of calcitonin induced changes of the biochemical markers of bone turnover in a dosedependent manner. The analgetic properties of calcitonin were also of salient clinical importance. The knowledge derived from this study could be adapted to the dosage schedule in long-term trials in osteoporosis.     

Prevention of further bone mass loss by nasal calcitonin in patients on long term glucocorticoid therapy for asthma: a two year follow up study.

BACKGROUND--Injectable calcitonin is effective in reducing spinal bone loss in steroid-dependent asthma but side effects are frequent. In contrast, a nasal spray presentation has been shown to be effective and well tolerated in involutional osteoporosis. To test the efficacy of nasal calcitonin a two year prospective trial was conducted in 44 steroid-dependent asthmatic patients. METHODS--All patients received a calcium supplement of 1000 mg and were allocated randomly into two groups treated with either salmon calcitonin nasal spray (200 IU every other day, n = 22) or calcium alone (n = 22) for two years. All patients completed the first year of the study. Five patients in each group dropped out during the second year. In the calcitonin group one patient developed generalised pruritus and four lost steroid dependence, and in the calcium alone group five were no longer dependent on steroids. The efficacy of treatment was evaluated as follows: bone turnover assessed by biochemical markers, bone loss assessed by serial measurement of lumbar spine density, and rates of bone fractures. RESULTS--The bone mass in the calcitonin group increased by 2.7% in the first year while in the group receiving calcium alone it decreased by 2.8%; this difference was significant. Calcitonin prevented more bone loss during the second year while the calcium alone group continued losing bone mass (-7.8%). The difference between means was 0.1077 (95% CI 0.0381 to 0.1773). Three new fractures occurred in both groups. No changes in biochemical parameters were detected in either group. CONCLUSIONS--Calcitonin given intranasally increased spinal bone mass during the first year of treatment and maintained bone mass in a steady state during the second year. These results suggest that calcitonin may be a useful agent to prevent steroid-induced osteoporosis. However, the lack of effect of calcitonin on the rate of vertebral fractures does not permit its recommendation for routine use in preventing steroid-induced osteoporosis.     

Estimated long-term effect of calcitonin treatment in acute osteoporotic spine fractures

Summary A 12-month prospective controlled study was conducted in 28 patients with acute osteoporotic spine fractures to evaluate and compare the effect of calcitonin treatment and cyclical hormone replacement therapy on forearm bone mineral content (BMC) and bone turnover. We established two treatment groups and a control group of women with postmenopausal osteoporosis (n=28). Group A (n=10) received 100 U of calcitonin by subcutaneous self-application on alternate days and oral calcium (Ca) for 6–8 weeks. Group B (n=10) received cyclical estrogen/gestagen replacement therapy over 12 months and oral calcium. The control group (n=8) received analgetic treatment and 500 mg Ca daily. BMC was measured by single photon absorptiometry (SPA) [1] with I 125 before and 6 and 12 months after the onset of the therapies. Ca, phosphorus (P), alkaline phosphatase, and 2-hour urinary OH-proline excretion were measured to classify bone turnover. One year after the onset of the two therapies, forearm BMC measured by SPA showed a significant increase in the group under hormone replacement therapy (P<0.025) as well as in the calcitonin group (P<0.05), although the latter underwent treatment only over a short period (6–8 weeks). In the same period, BMC decreased significantly in the control group (P<0.025). These results demonstrate that short-term calcitonin treatment over 6–8 weeks is as effective as long-term hormone replacement therapy, both therapies increasing forearm BMC measured by SPA.     

Regional and hormone-dependent effects of apolipoprotein E genotype on changes in bone mineral in perimenopausal women.

We studied 479 perimenopausal Danish women aged 45-58 years to examine differences between APOE genotypes with respect to (1) baseline total body bone mineral density (BMD) and densities measured in five different regions (ultradistal forearm, proximal forearm, lumbar spine, femoral neck, and total hip region); (2) serum levels of alkaline phosphatase, bone isoenzyme alkaline phosphatase, osteocalcin, parathyroid hormone (PTH), 25-hydroxyvitamin D, and urine hydroxyproline/creatinine excretion ratio; and (3) changes in bone mineral during 5 years of follow-up. Baseline BMDs were identical, whereas serum levels of alkaline phosphatase and its bone isoenzyme were higher in women with APOE 2-2 and APOE 2-3 than in women with APOE 3-3 and APOE 3-4 and lower in women with APOE 4-4. Among women not receiving hormonal-replacement therapy (HRT; n = 262), those with APOE 2-2 and APOE 2-3 had 30-40% lower rates of femoral neck and total hip bone mineral loss than women with APOE 3-3 and APOE 3-4, whereas the rates of mineral loss in other skeletal regions did not differ between these APOE genotypes. Women with APOE 4-4 appeared to have lower rates of bone mineral loss in all regions. Women treated with hormones throughout the follow-up period (n = 113) gained bone mineral, and women with APOE 3-4 and APOE 4-4 gained relatively more mineral than other women. A comparison of untreated and treated women with APOE 2-3, APOE 3-3, and APOE 3-4 suggests a possible modification of the effect of APOE genotype by HRT. In conclusion, the common APOE polymorphism has a complex effect on bone metabolism in perimenopausal Danish women including possible modification by hormone use: (1) among women not receiving HRT, those with APOE*2 have lower bone mineral losses in the femoral neck and hip region than other women, and (2) among women receiving HRT, those with APOE*4 gain more bone mineral than other women.     

Long-term administration of quarterly IV ibandronate is effective and well tolerated in postmenopausal osteoporosis: 5-year data from the DIVA study long-term extension

Summary

Long-term bone mineral density (BMD) gains, bone marker levels, and safety of 3?mg quarterly intravenous (IV) ibandronate were studied in this 3-year extension to the Dosing IntraVenous Administration (DIVA) trial. Quarterly IV ibandronate consistently increased lumbar spine bone mineral density measured with dual-energy X-ray absorptiometry (DXA-BMD) over 5?years (8.1%) and was well tolerated in women with postmenopausal osteoporosis.

Introduction

Treatment with IV ibandronate regimens, 2?mg bimonthly and 3?mg quarterly, has been studied for up to 5?years in a long-term extension (LTE) to the 2-year DIVA trial.

Methods

DIVA LTE is an open-label extension to a 2-year randomized, double-blind, double-dummy, noninferiority, phase III study (DIVA core). DIVA LTE involved postmenopausal women who had completed 2?years of DIVA core, comparing daily oral and IV ibandronate (≥75% adherence with IV ibandronate in year?2 of DIVA). Patients previously treated with 2?mg bimonthly or 3?mg quarterly IV ibandronate continued on the same regimen; patients who had received 2.5?mg daily oral ibandronate and placebo IV in DIVA core were switched to IV ibandronate.

Results

Pooled analysis of 497 intent-to-treat (ITT) patients receiving IV ibandronate from DIVA core baseline showed consistent increases over 5?years in lumbar spine DXA-BMD (8.4% [95% confidence interval (CI)?=?7.5, 9.3] with 2?mg bimonthly and 8.1% [95% CI?=?7.2, 8.9] with 3?mg quarterly). Three-year data relative to DIVA LTE baseline in the full ITT population (756 patients randomized or reallocated from DIVA, including those previously on daily treatment) showed maintenance of DXA-BMD gains from DIVA core with further gains in lumbar spine DXA-BMD. These benefits are supported by sustained reductions in markers of bone metabolism. No tolerability concerns or new safety signals were observed.

Conclusions

Treatment with IV ibandronate 2?mg bimonthly or 3?mg quarterly is effective and well tolerated for up to 5?years in women with postmenopausal osteoporosis.     

The late effect of subtotal thyroidectomy and radioactive iodine therapy on calcitonin secretion and bone mineral density in women treated for Graves' disease

This study was designed to evaluate the effect of subtotal thyroidectomy and/or radioactive iodine therapy on plasma immunocalcitonin (iCT) levels and bone densities in patients treated for Graves' disease. Forty-eight women whose ages ranged from 29 to 79 years (mean, 55 years) were evaluated. All were at least 10 years beyond treatment. Fourteen patients had undergone subtotal thyroidectomy, 22 had received radioactive iodine therapy, and 12 had received both. Serum calcitonin levels were measured with the patient fasting and at 30 minutes and 2 hours after the ingestion of 15 mg of calcium in orange juice. Single photon absorptiometry was used to measure bone mineral density of the middle and distal radius. The mean fasting plasma levels of iCT for patients undergoing subtotal thyroidectomy was 27 +/- 2 mumol/L; women treated with radioactive iodine, 26 +/- 2; women undergoing subtotal thyroidectomy followed by radioactive iodine, 24 +/- 2, and for normal control women, 48.5 +/- 4.7. The mean stimulated iCT level of each of the patient groups was significantly lower than that of the normal controls (p = 0.01). There were no significant differences among the groups. Although there was an increased loss of bone mineral density in postmenopausal patients, with age and race as covariates, the bone densities of the distal radius in women undergoing subtotal thyroidectomy and/or receiving radioactive iodine were not significantly lower than those of normal control subjects (p greater than 0.05). These findings are consistent with other observations that patients treated by thyroidectomy and/or radioactive iodine for Graves' disease have lower basal levels of calcitonin and decreased calcitonin response to a provocative stimulus. Whether this loss of calcitonin reserve is a significant factor in development of postmenopausal osteoporosis remains unanswered.     

A prospective randomized study for prevention of postrenal transplantation bone loss

BACKGROUND: We aimed to investigate different treatment drugs for the prevention of post-transplant bone loss. METHODS: Sixty adult male recent renal transplant recipients were enrolled into the study. Patients were randomized into 4 groups: group I received daily alfacalcidol 0.5 microg PO; group II received oral alendronate 5 mg/day; group III received intranasal salmon calcitonin 200 IU every other day; and group IV was considered a control group. Every patient was supplemented with daily 500 mg oral calcium carbonate. Parameters of bone metabolism were measured before and at 12 months after starting treatment. Bone mineral density (BMD) was measured by (DEXA) at lumber spine, femoral neck, and forearm before and after treatment period. RESULTS: BMD was increased at lumber spine by 2.1%, 0.8%, 1.7%, by 1.8%, 0.6%, 1.6% at femoral neck, and by 3.2%, 1.9%, 2.6% at forearm in groups I, II, and III, respectively, while it decreased by 3.2%, 3.8%, and 1.8% at the same sites, respectively, in control group (P= <0.05). iPTH level decreased significantly in group I, while the decrease was insignificant in other groups (P= 0.003). All other parameters were not statistically significant between treatment groups. Apart from transient hypocalcaemia in 3 patients in group II, and 2 patients in group III, no other significant adverse effects were noted. CONCLUSION: This study proves that early bone loss that occurs during the first 12 months after renal transplantation could be prevented by alfacalcidol, calcitonin, or alendronate. Among the treatment groups, alfacalcidol significantly improved the hyperparathyroidism. All treatment drugs are safe and tolerable.     

A Prospective Study of Bone Loss and Turnover after Cardiac Transplantation: Effect of Calcium Supplementation With or Without Calcitonin

Cardiac transplantation exposes recipients to osteoporosis and increased risk of consequent fractures. The purpose of the present study was to examine the magnitude, timing and mechanism of bone loss following cardiac transplantation, and to establish whether bone loss can be prevented by calcium with or without calcitonin. Thirty patients (29 men, 1 woman), aged 26 – 68 years (mean 48 years), were randomized into three groups of 10 to receive either no additional treatment, oral calcium 1 g twice daily for 12 months or the same dose of calcium plus intranasal calcitonin 400 IU/day for the first month and then 200 IU/day for 11 months. Bone mineral density (BMD) at the lumbar spine and three femoral sites (femoral neck, trochanter, Ward’s triangle) was measured by dual-energy X-ray absorptiometry (DXA) at the time of transplantation and 6 and 12 months later. Markers of bone formation [serum bone-specific alkaline phosphatase (B-ALP), type I procollagen carboxyterminal propeptide (PICP) and aminoterminal propeptide (PINP)] and resorption [serum type I collagen carboxyterminal telopeptide (ICTP)], as well as serum testosterone in men, were assayed before transplantation and at 1 week and 1, 3, 6 and 12 months after transplantation. During the first 6 post-transplant months BMD calculated as a percent change from baseline decreased in the control group by 6.4% (p= 0.014) in the lumbar spine, by 6.0% (p= 0.003) in the femoral neck, by 5.0% (p= 0.003) in the trochanter and by 5.5% (p= 0.130) in Ward’s triangle. Between 6 and 12 months a further decline in BMD occurred only at the three femoral sites, ranging from 2.2% to 9.8% (p= 0.004-0.079). In comparison with the control group, the group receiving calcium alone lost less bone in the trochanter between 0 and 6 months (p= 0.019), and the group receiving calcium together with calcitonin lost less bone in the femoral neck (p= 0.068) and Ward′s triangle (p= 0.076) between 0 and 12 months. Seven (28%) of 25 assessable patients experienced vertebral compression fractures. Calcium with or without calcitonin had no effect on changes in biochemical parameters; consequently, the three study groups were combined. The markers of bone formation increased, the elevations in mean values being 59% for B-ALP at 1 month (p= 0.009), 152% for PICP at 1 week (p < 0.0001) and 27% for PINP at 1 week (p= 0.021). After a temporary decline at 3 months B-ALP (p= 0.0002) and PINP (p < 0.0001) at 1 year were nearly doubled compared with baseline values. Throughout the study the marker of bone resorption, serum ICTP, was above normal, with a peak (mean values 67–69% above baseline) at 1 week (p= 0.0002) to 1 month (p < 0.0001). The mean concentration of total testosterone was decreased by 48% (p < 0.0001) 1 week and by 28% (p= 0.0005) 1 month after transplantation, but this was mainly explained by the concomitant drop in serum albumin. High bone turnover underlies bone loss after cardiac transplantation. Bone loss is most rapid during the first 6 post-transplant months. In the upper femur this bone loss may be reduced by treatment with calcium and calcitonin. Received: 5 May 1998 / Accepted: 12 January 1999     

Odanacatib in the treatment of postmenopausal women with low bone mineral density: Five years of continued therapy in a phase 2 study

Odanacatib (ODN) is a selective inhibitor of the collagenase cathepsin K that is highly expressed by osteoclasts. In this 2‐year, phase 2, dose‐ranging trial, postmenopausal women with bone mineral density (BMD) T‐scores ?2.0 to ?3.5 at spine or hip were randomized to weekly placebo or ODN 3, 10, 25, or 50 mg plus vitamin D₃ and calcium. Prespecified trial‐extensions continued through 5 years. In year 3, all women were re‐randomized to ODN 50 mg or placebo. For years 4 and 5, women who received placebo or ODN 3 mg in years 1 and 2 and placebo in year 3 received ODN 50 mg; others continued year 3 treatments. Endpoints included lumbar spine (primary), hip, 1/3 radius, and total body BMD; markers of bone metabolism; and safety. Women in the year 4 to 5 extension receiving placebo (n = 41) or ODN 50 mg (n = 100) had similar baseline characteristics. For women who received ODN (10–50 mg) for 5 years, spine and hip BMD increased over time. With ODN 50 mg continually for 5 years (n = 13), mean lumbar spine BMD percent change from baseline (95% confidence interval [CI]) was 11.9% (7.2% to 16.5%) versus ?0.4% (?3.1% to 2.3%) for women who were switched from ODN 50 mg to placebo after 2 years (n = 14). In pooled results of women receiving continuous ODN (10–50 mg, n = 26–29), year 5 geometric mean percent changes from baseline in bone resorption markers cross‐linked N‐telopeptide of type I collagen (NTX)/creatinine and cross‐linked C‐telopeptide (CTX) were approximately ?55%, but near baseline for bone formation markers bone‐specific alkaline phosphatase (BSAP) and amino‐terminal propeptide of type I procollagen (P1NP). In women switched from ODN 10 to 50 mg to placebo after 2 years (n = 25), bone turnover markers were near baseline. In summary, women receiving combinations of ODN (10–50 mg) for 5 years had gains in spine and hip BMD and showed larger reductions in bone resorption than bone formation markers. Discontinuation of ODN resulted in reversal of treatment effects. Treatment with ODN for up to 5 years was generally well‐tolerated. © 2012 American Society for Bone and Mineral Research.