Comparison of Calcitriol Treatment with Etidronate–Calcitriol and Calcitonin–Calcitriol Combinations in Turkish Women with Postmenopausal Osteoporosis: A Prospective Study

Calcitriol has been widely used in the management of osteoporosis, but its efficiency is a matter of controversy. It is not known whether combinations of calcitriol and antiresorptive agents such as etidronate and calcitonin are superior to calcitriol alone in the treatment of postmenopausal osteoporosis. To make this determination, 30 Turkish women with postmenopausal osteoporosis between 45 and 68 years of age were randomized to receive either intermittent cyclical etidronate (400 mg/day, for 14 days) followed by 60 days of cyclical calcitriol therapy 0.25 μg twice daily (group 1; n= 10), or calcitriol 0.25 μg twice daily (group 2; n= 10), or calcitriol 0.25 μg/day in combination with 100 IU intranasal salmon calcitonin taken every other day (group 3; n= 10) through a 1-year period. Bone mineral density (BMD) of lumbar spine (L2 to L4) was determined for each patient by dual-photon absorptiometry (¹⁵³Gd) at baseline, after 6 months, and at the end of the study. There was no significant difference among groups with respect to mean spinal BMD at baseline, after 6, and after 12 months. No significant spinal BMD changes occurred in any group from baseline, after 6 months, and after 12 months. Four patients in groups 1 and 2 and five patients in group 3 developed hypercalcemia at least once during therapy. Hypercalciuria occurred at least once in 9, 10, and 7 patients in groups 1, 2, and 3, respectively. One patient in group 2 developed a renal stone at the end of the study. Mean urine hydroxyproline levels did not change significantly in any group with respect to baseline. The data suggest that one-year treatment with calcitriol, given either alone or in combination with antiresorptive agents, does not improve spinal BMD in Turkish women with postmenopausal osteoporosis, and is associated with a high rate of adverse events. Received: 4 October 1996 / Accepted: 31 December 1996     

Primary Prevention of Glucocorticoid-Induced Osteoporosis with Intermittent Intravenous Pamidronate: A Randomized Trial

The aim of this study was to assess whether early intermittent I.V. administration of disodium pamidronate can effectively achieve primary prevention of glucocorticoid-induced osteoporosis (GIOP). A total of 27 in- or outpatients who required first-time, long-term corticosteroid therapy at a daily dose of at least 10 mg prednisolone were studied. Patients were randomly selected to receive either pamidronate and calcium or calcium alone. Patients allocated to pamidronate treatment (pamidronate group) received a first intravenous infusion of 90 mg pamidronate simultaneously with the initiation of their steroid treatment. Subsequently, they received 30 mg pamidronate, intravenously, every 3 months, for as long as steroid therapy was continued. As with the control patients (calcium group), they were put on a daily 800-mg elemental calcium supplement given as calcium carbonate. Lumbar spine and hip (total and subregions) bone mineral densities (BMDs) were measured at the start and every 3-months by dual-energy X-ray absorptiometry (Hologic? QDR-2000). Over 1 year, the pamidronate group showed a significant BMD increase in the lumbar spine (3.6%), and at all sites of the hip (2.2% at the femoral neck). In the calcium group, a significant BMD reduction was registered at the lumbar spine (−5.3%) and at the femoral neck (−5.3%). Differences between the groups were significant at all sites measured. Intermittent intravenous pamidronate effectively achieves primary prevention of GIOP, as assessed by BMD measurements over 1 year. Received: 2 December 1996 / Accepted: 25 April 1997     

Bone Histomorphometric Evaluation of Pamidronate Treatment in Clinically Manifest Osteoporosis

The effect of pamidronate therapy on bone histology was studied in patients with osteoporosis with at least one vertebral fracture in a randomized, double-masked, placebo-controlled, multi-center trial. Patients received pamidronate 150 mg/day or placebo in addition to calcium 500 mg/day and vitamin D₃ 400 IU/day. Transiliac bone biopsies were obtained before and after 1 or 2 years of treatment. Of these, 23 pairs of biopsies obtained from 14 women and 9 men (mean age t SD, 61.5 t 10 years) were of sufficient quality for histomorphometry. Histomorphometry was performed on sections stained with Goldner’s trichrome, using a drawing tube and a digitizer. Urinary hydroxyproline excretion decreased significantly (p<0.005) following pamidronate treatment, indicating a decrease in bone resorption. Osteoid volume and osteoid surface also decreased significantly in the pamidronate group (p<0.004 and p<0.003 respectively), consistent with a secondary decrease in bone formation. Osteoid variables did not change in the placebo-treated patients. Cortical thickness, trabecular bone volume and trabecular thickness did not change after pamidronate or placebo treatment. Wall thickness, however, showed a borderline increase following pamidronate treatment. After pamidronate, eroded surface and mineral apposition rate did not change significantly in the placebo and pamidronate groups. Mineralizing surface and activation frequency showed a borderline decrease in the placebo and pamidronate groups. The decrease in mineralization lag time was of borderline significance in the pamidronate group, corroborating the absence of any negative effect on mineralization. In conclusion, pamidronate treatment led to a decrease in bone turnover and did not interfere with bone mineralization. Received: 2 February 1998 / Accepted: 19 October 1998     

Alfacalcidol and Calcitriol in the Prevention of Bone Loss after Organ Transplantation

There is increasing evidence that D-hormones (active vitamin D metabolites) are effective agents in preventing posttransplantation bone loss of various organs. This effect may relate to several mechanisms including reversal of secondary hyperparathyroidism from cyclosporine, reversal of corticosteroid effects on bone, or immunomodulatory effects with corticosteroid sparing. Further clinical trials are necessary to establish their comparative efficacy to other agents, but D-hormones should be considered as prophylactic therapy in patients undergoing organ transplantation.     

Intravenous Pamidronate as Treatment for Osteoporosis after Heart Transplantation: A Prospective Study

Fractures due to osteoporosis are one of the major complications after heart transplantation, occurring mostly during the first 6 months after the graft, with an incidence ranging from 18% to 50% for vertebral fractures. Bone mineral density (BMD) decreases dramatically following the graft, at trabecular sites as well as cortical sites. This is explained by the relatively high doses of glucocorticoids used during the months following the graft, and by a long-term increase of bone turnover which is probably due to cyclosporine. There is some evidence for a beneficial effect on BMD of antiresorptive treatments after heart transplantation. The aim of this study was to assess prospectively the effect on BMD of a 3-year treatment of quarterly infusions of 60 mg of pamidronate, combined with 1 g calcium and 1000 U vitamin D per day, in osteoporotic heart transplant recipients, and that of a treatment with calcium and vitamin D in heart transplant recipients with no osteoporosis. BMD of the lumbar spine and the femoral neck was measured by dual-energy X-ray absorptiometry in all patients every 6 months for 2 years and after 3 years. Seventeen patients, (1 woman, 16 men) aged 46 ± 4 years (mean ± SEM) received only calcium and vitamin D. A significant decrease in BMD was observed after 6 months following the graft, at the lumbar spine (−6.6%) as well as at the femoral neck (−7.8%). After 2 years, BMD tended to recover at the lumbar spine, whereas the loss persisted after 3 years at the femoral neck. Eleven patients (1 woman and 10 men) aged 46 ± 4 years (mean ± SEM) started treatment with pamidronate on average 6 months after the graft, because they had osteoporosis of the lumbar spine and/or femoral neck (BMD T-score below −2.5 SD). Over the whole treatment period, a continuous increase in BMD at the lumbar spine was noticed, reaching 18.3% after 3 years (14.3% compared with the BMD at the time of the graft). BMD at the femoral neck was lowered in the first year by −3.4%, but recovered totally after 3 years of treatment. In conclusion, a 3-year study of treatment with pamidronate given every 3 months to patients with existing osteoporosis led to a significant increase in lumbar spine BMD and prevented loss at the femoral neck. However, since some of these patients were treated up to 14 months after the transplant, they may already have passed through the phase of most rapid bone loss. In patients who were not osteoporotic at baseline, treatment with calcium and vitamin D alone was not able to prevent the rapid bone loss that occurs immediately after transplantation. Received: 31 June 2000 / Accepted: 23 August 2000     

Intermittent Oral Disodium Pamidronate in Established Osteoporosis: A 2 Year Double-Masked Placebo-Controlled Study of Efficacy and Safety

The effect of oral pamidronate on bone mineral density and its adverse effect profile was investigated by a double-masked placebo-controlled study of 122 patients aged 55–75 years with established vertebral osteoporosis. Patients on active therapy received disodium pamidronate 300 mg/day (group A) for 4 weeks every 16 weeks, 150 mg/day (group B) for 4 weeks every 8 weeks or placebo (group C). All patients additionally received 500 mg of calcium and 400 IU vitamin D daily. Dual-energy X-ray absorptiometry measurements of the spine, hip, forearm and total body were performed at baseline and 6-monthly for 2 years using a Hologic QDR 1000 device at two sites. Serum osteocalcin and urinary deoxypyridinoline were measured at the above visits and at 3 months. The percentage change (SEM) in spine bone mineral density (BMD) at 2 years based on intention-to-treat analysis was 4.64 (1.01) in group A, 6.10 (0.87) in group B and 1.13 (1.32) in group C. Analysis of variance showed significant increases in group A and B compared with placebo (p<0.01). There were also significant rises in femoral neck BMD for group A (p = 0.005), trochanter BMD for groups A and B (p<0.01) and total-body BMD for groups A and B (p<0.001). There was a significant reduction in serum osteocalcin and urinary deoxypyridinoline for groups A and B (p<0.01). There was an excess of gastrointestinal side-effects in the treated groups, particularly group A. We conclude that intermittent pamidronate therapy can prevent bone loss at both the lumbar spine and femoral neck in patients with established vertebral osteoporosis, although due to gastrointestinal side-effects the 300 mg dose in particular does not appear suitable for clinical usage. Received: 12 January 1999 / Accepted: 30 August 1999     

Alphacalcidol in Prevention of Glucocorticoid-Induced Osteoporosis

One of the major drawbacks of glucocorticoids long-term therapy is the occurrence of a severe osteoporosis characterized by fractures occurring at different sites, mainly at the level of trabecular bone. One of the major determinants of glucocorticoid-induced osteoporosis is a decrease in the intestinal absorption of calcium (Ca) leading to a secondary hyperparathyroidism. D-hormones have been shown to significantly improve Ca absorption in the gut and subsequently to decrease parathyroid hormone circulating levels, hence normalizing bone turnover. In a recent study evaluating 145 patients suffering from diseases requiring long-term treatment with high doses of corticosteroids, we have demonstrated a significant benefit of alphacalcidol (1 μg/day) over placebo in terms of changes in bone mineral density of the lumbar spine. These results are in accordance with studies showing better prevention of bone loss and vertebral fractures in cardiac transplant patients treated with alphacalcidol than those treated with etidronate. There is now a convergent body of evidence to suggest that alphacalcidol is a reasonable, safe, and effective option for the prevention of glucocorticoid-induced osteoporosis, provided that serum Ca is monitored on a regular basis.     

Bone Mass and Markers of Bone and Calcium Metabolism in Postmenopausal Women Treated with 1,25-Dihydroxyvitamin D (Calcitriol) for Four Years

To evaluate the long-term effect of calcitriol treatment on bone mineral density (BMD) of the femoral neck and lumbar spine and the parameters of calcium and bone metabolism in elderly women, 55 healthy, postmenopausal women, all aged 66 years, were enrolled in the study. Eighteen started a 4-year supplementation with 0.5 μg of calcitriol daily and 37 served as controls. Calcium intake of all the subjects was adjusted to 800 mg daily. In 4 years femoral neck BMD increased by 3.0% in the calcitriol group, but decreased by 1.6% in the control group (P= 0.009). The respective changes in lumbar spine BMD were +2.3% and +0.9% (P= 0.067). Two years' treatment with calcitriol increased the intestinal absorption of strontium by 57% (P < 0.001), doubled the urinary excretion of calcium (P < 0.001), and decreased the mean parathyroid hormone (PTH) level by 32% (P < 0.01). In the calcitriol group the marker of bone formation, serum osteocalcin, decreased by 27% (P < 0.01), and the marker of bone resorption, serum C-telopeptide of type I collagen (CTx), by 33% (P= 0.05) after 2 years. In two subjects the calcitriol dose had to be reduced because of hypercalciuria. We conclude that calcitriol treatment increases bone mass at the femoral neck and lumbar spine, the increases being maintained for up to 4 years. The gain in bone mass results from reduced bone turnover which is partly a consequence of the enhanced intestinal absorption of calcium and suppressed serum PTH levels. Received: 8 January 1999 / Accepted: 29 February 2000     

Calcitriol and Bone Mass Accumulation in Females During Puberty

Adolescence is characterized by rapid skeletal development and high demands for bone minerals. Though the stimulative effect of calcitriol on intestinal calcium and phosphorus absorption is well understood, its effect on bone development is not completely clear. It may be directly involved in the facilitation of calcium economy during this critical phase of skeletal development. Therefore, we evaluated the serum concentrations of calcitriol in relation to skeletal development in a cross-sectional study of 178 healthy Caucasian females during different pubertal stages, extending from childhood to young adulthood. In addition, a subsample of 57 younger girls was followed for a 1-year period to evaluate the association among serum calcitriol, nutrition parameters (dietary calcium, phosphorus, and vitamin D), bone mass accumulation, and biochemical markers of bone turnover. The serum calcitriol concentration in a cross-sectional sample was the highest during pubertal growth spurt (sexual maturity index 3–4, age 11–13 years) (ANOVA: F = 2.4945; P= 0.0329). This correlated to the peak skeletal calcium accretion (g/year) and bone mass accumulation in total body and forearm. In a longitudinal sample, there was a positive association between annual change in TBBMC (P= 0.0255); TBBMD (P= 0.0168); proximal radius (1/3 distance from styloid process) BMC (P= 0.0096); BMD (P= 0.0541), and baseline calcitriol level in forward stepwise regression analyses. The results of the forward stepwise regression analyses with serum calcitriol as a dependent variable and different serum, urinary, and dietary parameters measured at baseline (age 11 years, n = 114) and after 1 year (age 12 years, n = 57) showed that osteocalcin was positively associated with calcitriol in both years; more so in a second year (P= 0.0514, P < 0.0001, respectively). Dietary vitamin D and phosphorus showed negative association with serum calcitriol at age 11, and dietary Ca and P were selected at age 12. The results of this study show that calcitriol is a significant correlate of bone mass accumulation during pubertal growth, presumably in response to the high requirements for calcium during this critical phase of skeletal development. Received: 5 June 1996 / Accepted: 31 December 1996     

Prevention of Corticosteroid-Induced Osteoporosis with Alendronate in Sarcoid Patients

Prolonged corticosteroid administration, as often required in the treatment of sarcoidosis, increases the risk of osteoporosis and fracture. The aim of the present study was to evaluate the usefulness of alendronate, a third generation bisphosphonate, in preventing corticosteroid-induced osteoporosis. Forty-three consecutive, previously untreated, sarcoid patients (17 men and 26 premenopausal women) were included in the study: 13 needed no treatment and served as controls (Group 1) and 30 needed glucocorticoids (prednisone) and were randomly selected to also receive either placebo (n = 15, Group 2) or alendronate 5 mg/day (n = 15, Group 3). Bone mineral density (BMD) at the ultradistal radius by dual photon absorptiometry (Osteograph 1000, NIM, Verona, Italy) and biochemical markers of bone turnover were measured at baseline and after 6 and 12 months of glucocorticoid therapy. No significant difference was found between Groups 2 and 3 in the mean cumulative dose of prednisone (4945 ± 1956 mg and 5110 ± 2013 mg, respectively). At the end of the study period, BMD increased by 0.8% in the alendronate-treated group; in the placebo-treated group, BMD decreased by 4.5%. The difference between groups was significant (P < 0.01, ANOVA). A significant decrease in markers of bone formation was found in all patients treated with prednisone (Groups 2 and 3), independently of alendronate. Alendronate, however, counteracted the increase in markers of bone resorption induced by glucocorticoid therapy. Our data suggest that alendronate is effective in preventing glucocorticoid-induced bone loss in sarcoid patients. Further studies on alendronate use in steroid-induced osteoporosis are needed. Received: 30 September 1996 / Accepted: 30 April 1997     

Osteoporosis in Male and Female Leprosy Patients

We measured the bone mineral density (BMD) of 353 leprosy patients (197 males 50–89 years old, average age 70.2; and 156 females 53–90 years old, average age 72.9) and serum levels of free testosterone (FT) in 81 males. The BMD of the lumbar vertebrae (L2–L4), diaphysis of the radius (1/3 radius), and the neck of the femur (neck) was measured using DXA (QDR 4500). The BMD of −2.5 SD YAM (young adult mean) in Japanese men and women was used as the cutoff value for osteoporosis in the respective genders: BMD of L2–L4, 0.751 g/cm² (male), 0.747 g/cm² (female); 1/3 radius, 0.655 g/cm² (male), 0.550 g/cm² (female); neck, 0.581 g/cm² (female). The percentages of males with osteoporosis were 31.3% in the 50th, 32.9% in the 60th, 44.9% in the 70th, and 40.7% in the 80th decade at L2–L4. Similarly, the percentages were 33.3%, 58.3%, 74.3%, and 75.0%, respectively, at 1/3 radius. Among females, the percentages were 22.2%, 41.3%, 44.9%, and 68.8%, respectively, at L2–L4; 0%, 42.9%, 89.5%, and 78.6%, respectively, at 1/3 radius; and 11.1%, 38.6%, 67.7%, and 84.6% respectively, at neck. FT in men ranged from almost 0 to normal at each decade and BMD levels were significantly correlated with FT in all three regions of the skeleton (P < 0.0001). More than 30% of osteoporosis was found at each decade and FT may be one of the main factors affecting BMD in male leprosy patients. Received: 6 February 1998 / Accepted: 9 July 1998     

A Comparison of Continuous Alendronate, Cyclical Alendronate and Cyclical Etidronate with Calcitriol in the Treatment of Postmenopausal Vertebral Osteoporosis: A Randomized Controlled Trial

A number of drugs are now available for the treatment of established osteoporosis and have been shown to significantly increase bone mineral density (BMD). There are, however, few comparative treatment studies and, furthermore, adverse events remain a problem with some of the newer agents, particularly in the elderly, in everyday clinical practice. We report a 12 month, open labeled, randomized controlled, prospective treatment study in 140 postmenopausal women with established vertebral osteoporosis, comparing the effect of continuous alendronate, cyclical alendronate and cyclical etidronate with calcitriol in terms of gain in BMD, reduction in bone turnover markers and adverse event profile. The mean percentage increases in BMD at 12 months, at the spine and hip respectively, were: continuous alendronate 5.7%, 2.6%; cyclical alendronate 4.1%, 1.6%; cyclical etidronate 4.9%, 2.0% (p<0.01) and calcitriol 2.0%, 0.4% (NS). In comparison with calcitriol, the mean changes in BMD at the spine and hip respectively were greater in the other groups; continuous alendronate: 3.7% (95% CI 1.4 to 8.3), 2.2% (95% CI 0.7 to 4.0); cyclical alendronate: 2.1% (95% CI 1.2 to 6.4), 1.2% (95% CI −0.3 to 3.0); cyclical etidronate: 2.9% (95% CI 1.9 to 6.5), 1.6% (95% CI 0.9 to 3.1)). The reduction in bone turnover markers was between 26% and 32% in the alendronate and etidronate groups (p<0.01), with a trend toward greater reduction in the continuous alendronate group. Eight patients discontinued the study: 6 in the continuous alendronate group, 1 in the cyclical alendronate group and 1 in the calcitriol group. Two patients in the cyclical etidronate group were unable to tolerate the Cacit component, but continued on substituting Cacit with Calcichew. In summary, 12 months of treatment with continuous alendronate, cyclical alendronate and cyclical etidronate are effective in terms of the gain in BMD at the anteroposterior spine and total hip in a comparable treatment population. These treatments are more effective than calcitriol and were generally well tolerated. Continuous alendronate showed a trend toward a larger gain in BMD and greater suppression of bone turnover markers than the other treatment groups, but had a higher incidence of adverse events, particularly within the older subgroup. Cyclical alendronate offers a lower adverse event profile and appears to be effective in comparison with continuous treatment, and may possibly be an alternative in the elderly. However, further studies are necessary, but more importantly with fracture end-points. Received: 6 April 1999 / Accepted: 8 June 2000     

Measurement of Bone Mineral Density by Dual X-ray Absorptiometry in Paget's Disease Before and After Pamidronate Treatment

Third-generation bisphosphonates are now currently used in the treatment of Paget's disease of bone. Dual X-ray absorptiometry may make it possible to quantify the action of these bisphosphonates on bone mineral density (BMD) in pagetic and nonpagetic bone. We used Lunar DPX, a total-body software program (automatic analysis and/or manual windows according to the site and bilateral or unilateral pagetic involvement) to study BMD in 28 patients (18 men, 10 women, mean age 69.8 years) with Paget's disease before and 6 months after infusions of 60 mg (alkaline phosphatase <350 IU) or 120 mg (ALP >350 IU) of pamidronate. Before treatment, in the 28 patients, the BMD of trabecular pagetic bone was 25% higher than that of nonpagetic bone; in cortical pagetic bone the BMD was 35% higher. After treatment, the BMD of trabecular pagetic bone increased by only 1.17%. the BMD of cortical pagetic bone increased by 1.37% whereas nonpagetic cortical bone lost 0.84%, independently of the levels of parathyroid hormone or the administration of calcium and vitamin D. Received: 17 March 1998 / Accepted: 12 March 1999     

Sodium Fluoride Treatment is a Major Protector Against Vertebral and Nonvertebral Fractures When Compared with Other Common Treatments of Osteoporosis: A Longitudinal,Observational Study

In a 5-year observational study we have compared sodium fluoride (NaF) with different treatments commonly used in the treatment of osteoporosis: calcium, estrogens, androgens, and calcitonin, referred to as non-NaF. We have looked at the incidence of vertebral and nonvertebral fractures. At baseline, the NaF group, consisting of 125 patients (89% females) aged 65 ± 10 (X ± SE) had more crush fractures (P < 0.0001) and more months since menopause (P= 0.004) than the non-NaF group, consisting of 127 patients (90% females) aged 63 ± 10. Fractures were evaluated by X-ray. The entire follow-up of patients treated with NaF accounted for 361 person-years, of whom 43 patients suffered one or more new vertebral fractures (68 vertebral fractures in total) and 18 patients suffered one or more new nonvertebral fractures (22 complete peripheral fractures in total); follow-up of patients treated with non-NaF regimes accounted for 382 person-years, of whom 53 patients suffered one or more new vertebral fractures (69 vertebral fractures in total) and 20 patients suffered one or more new nonvertebral fractures (27 complete peripheral fractures in total). After adjusting for significant covariates at baseline, NaF proved to be a significant protector for vertebral fractures [odds ratio (OR) 0.48, 95% confidence interval (CI) 0.2–0.9], and for peripheral fractures (OR 0.41, 95% CI 0.2–0.9). On the other hand, the probability of suffering undesired effects was much higher with NaF treatment (OR 5.04, 95% CI 2.1–11.9). We conclude that in the treatment of osteoporosis, NaF has a protective effect against vertebral and nonvertebral fractures, does not increase the risk of femoral fractures, but has a higher incidence of untoward symptomatology. Received: 25 September 1995 / Accepted: 23 September 1996     

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 ⁴⁵Ca single isotope method (α) were performed at baseline and after 8 months of treatment with either continuous combined hormone replacement therapy (HRT, as piperazine estrone sulfate 0.625–0.937mg daily ± medroxyprogesterone acetate 2.5 mg daily depending on uterine status) or HRT plus calcitriol 0.25 μg twice daily. A calcium supplement of 600 mg nocte was given to only those women who had a daily calcium intake of less than 1 g per day at baseline, as assessed by recalled dietary intake. There was a significant decrease [0.74 (± 0.35 SD) to 0.58 (± 0.22), Dα=−0.17 (± 0.26), p<0.0005] in α at 8 months compared with baseline in the HRT-treated group, but a significant increase [0.68 (± 0.31) to 0.84 (± 0.27), Dα=+0.16 (± 0.30), p<0.003] in the HRT-plus-calcitriol treated patients, resulting in α being significantly higher after 8 months in the latter group than in the HRT-only group. Although 72% of the patients had been supplemented with calcium between the first and second studies, separate analyses revealed that the change in calcium intake had not affected the result. Further breakdown of the groups into baseline ‘normal’ absorbers (α≥0.55) and ‘malabsorbers’ (α <0.55) revealed that α decreased with HRT treatment only in the normal absorbers, and remained stable in the malabsorbers. Conversely, following HRT plus calcitriol treatment, α increased only in the malabsorbers, the normal absorbers in this group remaining unchanged. In conclusion, our data show that HRT, of the type and dose used in this study, did not produce an increase in absorption efficiency; it was in fact associated with a fall. Increased absorption efficiency cannot be achieved unless calcitriol is used concurrently, and then only in patients with malabsorption. Calcitriol also had a significant effect in normal absorbers in that it prevented the decline in α seen with HRT alone, and thus should be considered in all patients with postmenopausal osteoporosis treated with HRT. Received: 6 October 1998 / Accepted: 3 May 1999     

Osteoblast numbers after calcitonin therapy: a retrospective study of paired biopsies obtained during long-term calcitonin therapy in postmenopausal osteoporosis

The present study is a retrospective examination of osteoblast indices in human iliac crest bone biopsies from a study on the long-term efficacy of calcitonin. Paired baseline and 2-year biopsies were examined from eight control subjects and 10 treated subjects; treated subjects received 100 MRC units synthetic salmon calcitonin (Calcimar, Armour Pharmaceutical Co, Scottsdale, AZ) injected i.m. sub Q at bedtime. Control patients did not receive a placebo injection. All subjects received 400 units vitamin D₂ p.o. q.d. and 1200 mg CaCO₃ p.o. q.d. When the differences in baseline and 2-year values were analyzed, subjects receiving calcitonin showed no decrease compared with control subjects for the fraction of osteoid surface lined by osteoblasts (ObS/OS) (but were in fact significantly greater, P= 0.04). There was no difference from control subjects in the number of osteoblasts/mm bone surface (NOb/BPm), or mean mineral apposition rate (MAR). Since calcitonin is receiving renewed interest for osteoporosis therapy, these data (derived from paired human biopsies) are valuable since they show that no decrease in osteoblast cell number resulted from long-term calcitonin therapy. Results point to the need for renewed investigation concerning the effect of calcitonin on osteoblast-osteoclast interactions. Received: 5 January 1999 / Accepted: 1 July 1999     

Effect of Salmon Calcitonin on Femoral Bone Quality in Adult Ovariectomized Ewes

The aim of this study was to evaluate the effect of intermittent calcitonin on femoral bone quality in adult ewes from the time of ovariectomy. Six months after the start of the experiment, bone density measurements and mechanical testing (torsion and resonant frequency analysis of the diaphysis and compression of an excised trabecular bone cylinder from the femoral neck) were performed in sham-control and ovariectomized (OVX) ewes treated with placebo or salmon calcitonin (50 or 100 units, 3 times/week). Crystallinity of bone was evaluated by measuring X-ray diffraction line broadening. After OVX, a nonsignificant bone loss was found at all measured sites in the femur (−3 to −9%) together with a decreased biomechanical competence in the trabecular bone (compressive strain −28%, P < 0.05). Treatment with salmon calcitonin, 50 or 100 IU subcutaneously three times a week from the time of ovariectomy, resulted in a significant dose-dependent preservation of bone strength in the trabecular bone of the femoral neck compared with OVX. No adverse effects of calcitonin were observed on bone crystal composition as assessed by diffractiometry. We conclude that in adult ewes intermittent calcitonin treatment from the time of OVX was associated with a significant preservation of cancellous bone strength and strain in trabecular bone of the femoral neck, without affecting crystalline properties of bone. Received: 20 October 1995 / Accepted: 19 February 1996     

Vitamin D Therapy of Osteoporosis: Plain Vitamin D Therapy Versus Active Vitamin D Analog (D-Hormone) Therapy

Normal intestinal calcium (Ca) absorption is an essential feature of bone homeostasis. As with many other organ systems, intestinal Ca absorption declines with aging, and this is one pathological factor that has been identified as a cause of senile osteoporosis in the elderly. This abnormality leads to secondary hyperparathyroidism, which is characterized by high serum parathyroid hormone (PTH) and an increase in bone resorption. Secondary hyperparathyroidism due to poor intestinal Ca absorption has been implicated not only in senile osteoporosis but also in age-related bone loss. Accordingly, in population-based studies, there is a gradual increase in serum PTH from about 20 years of age onward, which constitutes a maximum increase at 80 years of age of 50% of the basal value seen at 30 years of age. The cause of the increase in PTH is thought to be partly due to impaired intestinal Ca absorption that is associated with aging, a cause that is not entirely clear but at least in some instances is related to some form of vitamin D deficiency. There are three types of vitamin D deficiency: (1) primary vitamin D deficiency, which is due to a deficiency of vitamin D, the parent compound; (2) a deficiency of 1,25(OH)₂D₃ resulting from decreased renal production of 1,25(OH)₂D₃; and (3) resistance to 1,25(OH)₂D₃ action owing to decreased responsiveness to 1,25(OH)₂D₃ of target tissues. The cause for the resistance to 1,25(OH)₂D₃ could be related to the finding that the vitamin D receptor level in the intestine tends to decrease with age. All three types of deficiencies can occur with aging, and each has been implicated as a potential cause of intestinal Ca malabsorption, secondary hyperparathyroidism, and senile osteoporosis. There are two forms of vitamin D replacement therapies: plain vitamin D therapy and active vitamin D analog (or D-hormone) therapy. Primary vitamin D deficiency can be corrected by vitamin supplements of 1000 U a day of plain vitamin D whereas 1,25(OH)₂D₃ deficiency/resistance requires active vitamin D analog therapy [1,25(OH)₂D₃ or 1α(OH)D₃] to correct the high serum PTH and the Ca malabsorption. In addition, in the elderly, there are patients with decreased intestinal Ca absorption but with apparently normal vitamin D metabolism. Although the cause of poor intestinal Ca absorption in these patients is unclear, these patients, as well as all other patients with secondary hyperparathyroidism (not due to decreased renal function), show a decrease in serum PTH and an increase in Ca absorption in response to therapy with 1,25(OH)₂D₃ or 1α(OH)D₃. In short, it is clear that some form of vitamin D therapy, either plain vitamin D or 1,25(OH)₂D₃ or 1α(OH)D₃, can be used to correct all types of age-dependent impairments in intestinal Ca absorption and secondary hyperparathyroidism during aging. However, from a clinical standpoint, it is important to recognize the type of vitamin D deficiency in patients with senile osteoporosis so that primary vitamin D deficiency can be appropriately treated with plain vitamin D therapy, whereas 1,25(OH)₂D₃ deficiency/resistance will be properly treated with 1,25(OH)₂D₃ or 1α(OH)D₃ therapy. With respect to postmenopausal osteoporosis, there is strong evidence that active vitamin D analogs (but not plain vitamin D) may have bone-sparing actions. However, these effects appear to be results of their pharmacologic actions on bone formation and resorption rather than through replenishing a deficiency.     

Regulation of c-fos and c-jun Expression by Calcitonin in Human Breast Cancer Cells

Breast cancer cells (BCC) have calcitonin (CT) receptors, yet the action of the hormone on these cells is largely unknown. We found that CT produced a strong and transient time- and dose-dependent increase in c-fos mRNA in BCC lines. This event was prevented by a protein kinase A (PKA) inhibitor, H89. CT alone did not influence the expression of c-jun and of the tissue inhibitors of metalloproteases (timp) -1 and -2 mRNAs; however, it reduced the induction of these mRNAs by the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA), without apparent changes in the half-life of the mRNA (measured for c-jun). Along the same line, CT reduced the c-jun induction and T-47D growth stimulation by epidermal growth factor (EGF) and insulin. These effects were mimicked by forskolin and/or prevented by H89, suggesting that PKA activation was involved. These results indicate that CT modulates in BCC the mRNA levels of two important growth-related early response genes (c-fos and c-jun) and of two other genes (timp-1 and -2) involved in the control of metastatic events. Received: 2 May 1996 / Accepted: 10 December 1996     

Complex Shape Changes in Isolated Rat Osteoclasts: Involvement of Protein Kinase C in the Response to Calcitonin

The cytoplasmic spreading of osteoclasts has been used to assess responsiveness to agents such as calcitonin and associated signal transduction mechanisms. Although cyclic AMP and intracellular calcium are known mediators of calcitonin effects in osteoclasts, the role of protein kinase C (PKC) is less clear. We have used time-lapse videomicroscopy of isolated rat osteoclasts to characterize shape changes induced by calcitonin, forskolin, and phorbol 12-myristate-13-acetate (PMA) in the absence and presence of PKC blockers. Treatment with calcitonin reduced cytoplasmic plan area but increased perimeter length, resulting in a characteristic ``stellate' appearance, whereas forskolin produced ``nonstellate' contraction. The response of osteoclasts to PMA was dose dependent. High concentrations (10⁻⁷–10⁻⁶ M) produced biphasic responses with transitory, calcitonin-like ``stellate' contraction followed by sustained expansion, whereas low concentrations (10⁻¹¹–10⁻⁹ M) produced expansion only. The effects of low-concentration PMA could be prevented by pretreatment with a PKC blocker, whereas the effects of high concentrations were only partially inhibited. The effects of forskolin were unchanged by pretreatment with the PKC blocker. Treatment with calcitonin in the presence of various PKC blockers resulted in paradoxical transient expansion followed by contraction. These results indicate that calcitonin-induced shape change in osteoclasts is a complex process involving protein kinase C in addition to cyclic AMP-dependent mechanisms and possibly other factors. Received: 31 October 1996 / Accepted: 26 April 1997