calcitonin and Bone-Diseases--Metabolic

With the aim of preventing postfracture osteopenia, we randomized 24 patients with internally fixed ankle fractures to 3 months of treatment with placebo or 200 IU nasal salmon calcitonin (sCT) in a prospective, double-blind design. 3 patients were excluded, leaving 11 patients in the placebo group and 10 in the sCT group for study. Bilateral measurements of bone mineral content (BMC) in the coronal plane of the proximal tibia were performed by dual photon absorptiometry (DPA) postoperatively within 7 days of the fracture and after 1.5, 3 and 6 months. 3 months after the fracture, BMC in the injured legs had decreased by 14% in the placebo group and 2.1% in the sCT group. This difference was not statistically significant. In the healthy legs, a statistically significant intergroup difference was seen 6 weeks after the fracture, caused by a tendency towards a decrease in BMC of 4.6% in the placebo group, while BMC in the sCT group had increased by 7.4%. Nasal sCT may to some extent, but in this study not significantly, reduce postfracture osteopenia, and cause a significant effect on BMC in the healthy leg.

Topics: Absorptiometry, Photon; Administration, Intranasal; Adult; Ankle Injuries; Bone Density; Bone Diseases, Metabolic; Calcitonin; Double-Blind Method; Female; Fracture Fixation, Internal; Fracture Healing; Fractures, Bone; Humans; Male; Middle Aged; Prospective Studies; Radionuclide Imaging; Tibia; Time Factors

Osteopenia is a major complication of orthotopic liver transplantation (OLT). However, no effective therapy for bone disease has been defined. We have studied vertebral bone mineral density (VMD) and fasting serum markers of bone formation [bone gla protein (BGP), procollagen I carboxyterminal peptide (PICP)] and metabolism (serum Ca, P, intact parathyroid hormone (iPTH), 25OHD3 and 1,25(OH)2D3) in 120 patents after OLT. VMD was measured by dual-energy X-ray absorptiometry (DXA) using a Hologic QDR 1000 densitometer on two occasions, 12 months apart. Patients with OLT had a VBD significantly lower compared with age- and sexed-matched Spanish controls (P < 0.05). Prevalence of osteoporosis (Z score below -2 SD) was 35.8%. Serum BGP (8.6 +/- 0.7 ng/ml) and PICP (222.9 +/- 81.9 ng/dl) were higher than those of controls. However, serum calcium, phosphorus, iPTH, 25OHD3, and 1,25(OH)2D3 were within normal range. Patients with osteoporosis were randomly treated with 40 IU/day of calcitonin i.m. (Diatin, Ferrer Int. Laboratories) (n = 17) or 400 mg p.o., 15 days every 3 months, of sodium ethiodronate (Difosfen, Rubio Laboratories) (n = 23). All patients received 500 mg/12 hours of elemental calcium p.o. After 12 months of treatment, a significant increment of vertebral mineral density (VMD) was observed (6.4% and 8.2%, respectively). Serum BGP and PICP values remained elevated without a difference between the two drugs. Our results indicate that antiresorptive drugs may be of benefit in the high turnover osteoporosis of OLT recipients.

Topics: Adult; Bone Density; Bone Diseases, Metabolic; Calcitonin; Etidronic Acid; Female; Humans; Liver Transplantation; Male; Middle Aged; Osteoporosis; Postoperative Complications

Sixty-two steroid-dependent asthmatics who had not received any form of treatment to prevent bone loss were studied during a 12-month period. Patients were randomly divided into two groups. Thirty-one patients were treated with 1 g of elemental calcium taken daily plus 100 IU of salmon calcitonin every other day, administered subcutaneously; the remaining 31 patients received only calcium supplementation. In the calcitonin group, 11 patients dropped out of the study because of severe side effects (seven patients), lack of compliance (three patients), and exacerbation of asthma (one patient). The 20 patients who completed the 12-month follow-up period were analyzed and compared with 20 sex-matched patients from the control group. At one year, bone mineral density (BMD) had increased in the calcitonin group by a mean of 4% (p less than or equal to 0.001), whereas in the control group BMD had decreased by 2.5% (p less than or equal to 0.05). Parameters of bone remodeling (alkaline phosphatase and osteocalcin) decreased significantly in the calcitonin-treated group but not in the control group. Our findings show that calcitonin 100 IU, given three times/wk, is an effective drug in the treatment of steroid-induced osteopenia. Side effects, however, are frequent and cause a high degree of dropout from therapy. These findings suggest that further studies should be carried out with lower doses of calcitonin or by other better tolerated forms of delivery such as in a nasal spray.

Topics: Asthma; Bone Density; Bone Diseases, Metabolic; Bone Resorption; Calcitonin; Calcium; Female; Follow-Up Studies; Humans; Male; Middle Aged; Prednisone; Randomized Controlled Trials as Topic; Time Factors

We investigated the effect of calcitonin (CT) on lumbar intervertebral disk degeneration (LIDD) in rats with ovariectomy-induced osteopenia. CT protected ovariectomized rats from LIDD by, at least in part, modifying extracellular matrix metabolism of the disks and preserving the microarchitecture and biomechanical properties of adjacent vertebrae.. The present study aimed to investigate the effect of CT on lumbar vertebral bone mineral density and intervertebral disk degeneration in ovariectomized (OVX) rats.. We first subjected 50 3-month-old female rats to either OVX (n = 30) or sham (n = 20). Twelve weeks later, ten OVX and ten sham rats were necropsied. The remaining OVX rats began to receive either saline vehicle (OVX + V, n = 10), or salmon CT (OVX + CT, 16 IU/kg/2 days, n = 10). After 12 weeks of treatment, necropsy was conducted and bone mineral density was determined in L3-4 and L5-6 vertebrae. The microstructure and biomechanical properties of L3 vertebrae were detected by micro-computed tomography and compression test, respectively. L5-6 was also used to measure intervertebral disk height and observe intervertebral disk histological changes by Van Gieson staining and histological scores, as well as immunohistochemistry (IHC) analysis of matrix metalloprotease (MMP)-1, MMP-13, and collagen II expression.. At 12 weeks post-OVX, OVX rats had lower BV/TV and Tb.N and higher intervertebral disk histological score than sham rats. After 24 weeks, OVX + CT rats had higher BMD, BV/TV, Tb.N, and bone biomechanical strength values than OVX + V rats. Histological analysis showed OVX + CT rats had significantly lower disk degeneration scores than OVX + V rats. IHC analysis revealed CT treatment decreased expression of MMP-1 and MMP-13 and increased expression of collagen II compared with OVX + V rats.. Our data demonstrate that CT-treated OVX rats display less intervertebral disk degeneration and favorable changes in intervertebral disk metabolism, associated with higher trabecular bone mass, better trabecular microarchitecture, and better biomechanical strength when compared to vehicle-treated OVX rats.

Topics: Animals; Bone Density; Bone Density Conservation Agents; Bone Diseases, Metabolic; Calcitonin; Collagen Type II; Drug Evaluation, Preclinical; Female; Intervertebral Disc Degeneration; Lumbar Vertebrae; Matrix Metalloproteinase 1; Matrix Metalloproteinase 13; Ovariectomy; Stress, Mechanical; X-Ray Microtomography

The effects of salmon calcitonin and clodronate were compared in ovariectomised rats. Sixty female Wistar rats ( 260 g in weight) were fed the same diet and had the same living conditions. The rats were divided into the following groups: 15 rats with sham ovariectomy and no drug treatment (Sham-OVX); 45 rats with bilateral ovariectomy subdivided into 15 rats not receiving drug treatment (OVX group), 15 rats treated with subcutaneous salmon calcitonin, 2 U/kg/day every 2 days (OVX + CT group) and 15 rats treated with subcutaneous clodronate, 5 mg/kg/day every 2 days (OVX + Cl group). Sixty days after surgery, the rats were sacrificed and their femurs and fifth lumbar vertebrae were dissected and cleaned of soft tissue. Femur length, vertebral height, and bone mineral content and bone mineral density of the femur and fifth lumbar vertebra by dual-energy X-ray absorptiometry were measured. Calcitonin had a significant and stronger effect in preventing ovariectomy-induced osteopenia in the femur (OVX + CT vs OVX groups, p < 0.0001); both calcitonin and clodronate had a significant effect on the fifth lumbar vertebra, which was greater in the calcitonin group (OVX + CT vs OVX + Cl groups, p<0.005). These findings indicate that calcitonin has a protective effect on both the axial (trabecular bone) and peripheral (cortical bone) skeletons, but clodronate only has a protective effect on the axial skeleton.

Topics: Absorptiometry, Photon; Animals; Bone Density; Bone Diseases, Metabolic; Calcitonin; Clodronic Acid; Disease Models, Animal; Female; Femur; Injections, Subcutaneous; Ovariectomy; Rats; Rats, Wistar; Spine; Treatment Outcome

Using an experimental model of type 1 osteoporosis under the chronic therapy with an anti-inflammatory steroid, the bone anabolic effect of PTH(1-34) was evaluated by histomorphometrical and biomechanical analysis. Wistar female rats (12-week-old) were ovariectomized and allowed to develop an osteopenic model in the presence or absence of methylprednisolone acetate (MPA: 0.1 mg/kg, s.c., 3-days-a-week basis from the 5th week after ovariectomy (OVX)). The osteopenia that developed for the first 12 weeks after OVX was almost completely normalized by subsequent PTH pulsing (20 microg/kg, s.c., 5-days-a-week) for 8 weeks starting at the 13th week; the following characteristics were observed: 1) proximal tibial metaphysis: recovered bone volume, rather increased trabecular thickness and osteoid volume, and normalized eroded surface; 2) 5th lumbar vertebra (L-5): partially recovered trabecular connectivity; 3) femur and 4th lumbar vertebra (L-4): recovered mechanical strength in maximum elastic load and maximum elastic energy. The anabolic effect of PTH(1-34) was not substantially modified by MPA. Salmon calcitonin (SCT: 10 U/kg per day, s.c., 5-days-a-week, for 8 weeks) was anabolic in limited parameters: decreased number of osteoclasts, recovered maximum elastic load in femur, and partially recovered maximum elastic load in L-4. The results suggest that PTH(1-34) pulsing is able to recover OVX-induced osteopenia in the structure and mechanical strength not only of the cancellous bone but also of the cortical bone, and the anabolic effect can be clinically expected even under steroid medication.

Topics: Animals; Biomechanical Phenomena; Bone and Bones; Bone Diseases, Metabolic; Calcitonin; Female; Ovariectomy; Parathyroid Hormone; Peptide Fragments; Rats; Rats, Wistar

The anabolic effect of salmon calcitonin (SCT) on skeletal tissue was examined on glucocorticoid-induced osteopenia in female rats (12 weeks old). By the administration of methylprednisolone acetate (MPA: 0.1 mg/kg, s.c., 3 times/week) for 8 weeks, histomorphometrically detectable osteopenia with the characteristics of decreased bone formation and increased bone resorption developed in proximal tibia metaphysis. Serum osteocalcin level was also decreased by MPA treatment. Subsequent treatment with SCT (10 U/kg, s.c., 5 times/week) was found to reverse once developed osteopenia with the return of the osteocalcin level, though rats were still on MPA. Histomorphometry revealed that SCT decelerated bone resorption but augmented bone formation in this osteopenic model. After a single injection of SCT (2.5 U/kg--40 U/kg, s.c.), the serum level of parathyroid hormone (PTH) which had a potent anabolic on bone formation increased in a dose-dependent manner. These results indicate that SCT has a stimulating effect on osteoblastic bone formation and this anabolic effect may at least in part be due to its indirect effect to increase endogenous PTH secretion.

Topics: Animals; Bone Development; Bone Diseases, Metabolic; Calcitonin; Female; Male; Methylprednisolone; Methylprednisolone Acetate; Rats; Rats, Wistar

Previously we reported that 8-week treatment with methylprednisolone acetate (MPA: 0.1 mg/kg, s.c., 3 days a week) of male rats caused a novel type of osteopenia whose development was prevented by salmon calcitonin (SCT) in a dose-dependent manner. In this study, to compare the MPA-inducible osteopenia with the ovariectomy (OVX)-inducible one, female rats were used instead of male rats and a time-course study of development was made. MPA treatments for 1, 2, 4 and 8 weeks histologically induced characteristic osteopenic changes in a time-dependent manner that were histomorphometrically detectable in tibiae within 4 weeks as reduced bone mass, accelerated bone resorption, and suppressed bone formation and mineralization. Node-strut analysis revealed that the connectivity of the trabecular structure remained unaffected. Such MPA-induced changes in the trabecular structure, to be defined as thinned-but-uncut, is in a good contrast with OVX-induced unthinned-but-cut structure, although the latter osteopenic changes became detectable 2 weeks earlier. Another previous finding confirmed herein was that MPA-induced osteopenia in female rats was also completely masked by SCT (10 U/kg, s.c., 5 days a week). The results indicate that the MPA-inducible secondary osteopenic model in either sex of rats would be usable for testing anti-osteopenic drugs.

Topics: Analgesics; Animals; Bone Density; Bone Diseases, Metabolic; Bone Remodeling; Bone Resorption; Calcitonin; Female; Glucocorticoids; Methylprednisolone; Methylprednisolone Acetate; Ovariectomy; Rats; Rats, Wistar; Time Factors

The experimental and clinical effectiveness of nasal salmon calcitonin (SCT) for treatment of osteoporosis in humans has been well established, but none is known yet about the pharmacokinetic property in relation to therapeutic efficacy, especially when used in a therapeutic dose range. This preclinical study was designed to evaluate such a property, first of all in rats, using a novel heterogeneous two-site enzyme immunoassay that has allowed us to evaluate the pharmacokinetic property of parenteral SCT in rats due to the high sensitivity (the detection limit = 2 pg of SCT/ml of plasma). It was found that as early as 10 min after the nasal dosing of 1.25, 5, or 20 U/rat, the SCT immunoactivity became detectable in plasma and thereafter it waned rapidly with time. Hypocalcemia developed in a dose-dependent manner, but with a delay of approximately 20 min from the peak of the immunoactivity and lasted hours. The pharmacokinetic parameters measured for the doses (1.25, 5, and 20 U/rat) were as follows; the AUCs (pg.hr/ml) = 20.8, 89.0, and 189, and the MRTs (min) = 52, 54, and 45, respectively. The results appear to suggest: (1) the unexpected quick transfer of nasal SCT into and from the circulation, (2) a delayed onset of hypocalcemia and possibly its anti-osteopenic action, both of which may last longer, (3) that keeping the plasma SCT above the in vitro anti-osteoclastic level (approximately 1 pM) only for a few hours per 2 days would be enough for inducing the distinct anti-osteopenic effect in rats, and (4) the feasibility of designing the clinical study as to the pharmacokinetics and pharmacodynamics of nasal SCT on humans.

Topics: Administration, Intranasal; Analgesics; Animals; Area Under Curve; Biological Availability; Bone Diseases, Metabolic; Calcitonin; Hypocalcemia; Immunoassay; Male; Rats; Rats, Wistar

The study was designed to compare the skeletal effects of intermittent and continuous administration of calcitonin (CT) in ovariectomized (OVX) rats. Female rats were sham operated or OVX at 3 months of age and treated for 6 weeks with vehicle or salmon CT. Sham-operated control rats were injected subcutaneously with vehicle on alternate days. One group of OVX rats was treated with vehicle intermittently by subcutaneous injection or continuously via Alzet osmotic minipumps. The remaining OVX rats were treated with CT by either subcutaneous injections (16 U/kg) on alternate days or by continuous infusion via minipumps at a daily dose of 8 U/kg. OVX rats treated with CT continuously were mildly hypocalcemic compared with all other groups. The proximal tibial metaphyses of vehicle-treated OVX rats were osteopenic with a cancellous bone volume at only 28% of the vehicle-treated control level. This bone loss was associated with increased indices of bone turnover such as osteoclast surface, osteoblast surface, and bone formation rate. Cancellous bone volume in OVX rats treated with CT either intermittently or continuously was significantly higher than that of vehicle-treated OVX rats, but lower than that of vehicle-treated control rats. Treatment of OVX rats with intermittent or continuous CT significantly decreased all indices of bone turnover compared with vehicle-treated OVX rats. However, osteoclast and osteoblast surfaces of OVX rats treated with CT continuously were still significantly higher than those of vehicle-treated control rats. These results indicate that intermittent and continuous administration of CT had similar skeletal effects in OVX rats. Both treatment regimens depressed bone turnover and partially prevented cancellous bone loss in the estrogen-deplete skeleton.

Topics: Analysis of Variance; Animals; Bone Density; Bone Development; Bone Diseases, Metabolic; Calcitonin; Calcium; Disease Models, Animal; Female; Humans; Infusion Pumps, Implantable; Injections, Subcutaneous; Osteoclasts; Osteoporosis, Postmenopausal; Ovariectomy; Random Allocation; Rats; Rats, Sprague-Dawley; Tibia

It was examined histomorphometrically whether or not and how chronic treatment with nasal salmon calcitonin (SCT) of rats could prevent ovariectomy (OVX)-induced osteoporotic changes in the trabecular bone of tibia. During 7 weeks on a synthetic low Ca diet after OVX, rats developed type 1 osteopenia which was defined by strut analysis as resulting mainly from loss in the connectivity of strut but in the thickness. An intermittent dosing regimen of nasal SCT (10 or 40 U/rat/d, 3 d/week, for 7 weeks) was able to retard development of osteopenia in a dose-dependent manner. The results indicate that the nasal route would be usable for chronic treatment of experimental osteoporosis with SCT and possibly other peptide anti-osteoporotics.

Topics: Animals; Bone Diseases, Metabolic; Calcitonin; Female; Osteoporosis; Ovariectomy; Rats; Rats, Wistar

A glucocorticoid-induced osteopenia (GC-OP) model was developed in Wistar male rats to use for in vivo screening of anti-osteoporotic candidates. 1) Two week treatment with a wide dose range of methylprednisolone acetate (0.01 to 50 mg/kg, s.c., 3 d a week) and histomorphometry of the right tibia combined with histological study (n = 3) allowed us to select 0.1 mg/kg as a proper dose to produce a measurable degree of osteopenia. 2) Eight week treatment with the selected dosing regimen (n = 6) of the steroid and histomorphometry including strut analysis measured the development of a characteristic osteopenia which can be described briefly as "uncut but thinning" of trabecular bone structure, and which was prevented by salmon calcitonin (0.33-10 U/kg, s.c., 5 times/week) in a dose-dependent manner. The results indicate the usability of this osteopenic model not only for screening of anti-osteoporotics but also for study of the mechanism leading to GC-OP.

Topics: Animals; Bone Diseases, Metabolic; Calcitonin; Male; Methylprednisolone; Methylprednisolone Acetate; Rats; Rats, Wistar

Previous studies have shown that parathyroid hormone (PTH) stimulates bone formation and completely restores lost cancellous bone at skeletal sites with moderate osteopenia in relatively young ovariectomized (OVX) rats. The current study was designed to determine whether PTH has similar bone anabolic effects in aged OVX rats and to compare the bone restorative response to PTH at skeletal sites with moderate and severe osteopenia. Female Sprague-Dawley rats were subjected to sham surgery or bilateral ovariectomy at 3 months of age and maintained untreated for the first year after surgery to allow for the development of moderate vertebral osteopenia and severe tibial osteopenia in OVX rats. Groups of baseline control and OVX rats were sacrificed at the end of this pretreatment period. The remaining OVX rats were then treated for 10 weeks with vehicle, antiresorptive agents alone (estrogen, the bisphosphonate risedronate, or calcitonin) or PTH alone. Other groups of OVX rats were treated concurrently with PTH and each of the antiresorptive agents. As expected, the proximal tibia of baseline OVX rats exhibited severe cancellous osteopenia, whereas the first lumbar vertebral body was moderately osteopenic. Treatment of OVX rats with antiresorptive agents alone failed to restore cancellous bone at both skeletal sites, whereas treatment with PTH alone markedly stimulated bone formation and completely restored lost cancellous bone in the lumbar vertebra. PTH also stimulated bone formation and in the severely osteopenic proximal tibia of OVX rats but only marginally restored lost cancellous bone, possibly due to an inadequate number of bone spicules to serve as a foundation for new bone formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aging; Animals; Biomarkers; Bone Development; Bone Diseases, Metabolic; Bone Remodeling; Calcitonin; Disease Models, Animal; Drug Therapy, Combination; Estradiol; Etidronic Acid; Female; Lumbar Vertebrae; Ovariectomy; Parathyroid Hormone; Rats; Rats, Sprague-Dawley; Tibia

The benzyl ester of hyaluronic acid (Hyaff 11) is a highly mucoadhesive polymer and can be processed into microspheres that can effectively deliver incorporated drugs by closely adhering to the mucosal surface and by protecting the drug from enzymatic inactivation. In this study, Hyaff 11 microspheres have been investigated as novel delivery system for the vaginal administration of salmon calcitonin (sCT) to ovariectomized rats. Moreover, this particular animal model has been used to evaluate the biological activity of the polypeptide after vaginal and I.M. administration by measuring the skeletal effect of sCT. A total of 66 female rats were used: 6 rats served as the basal group; 12 were subjected to sham operation and left without pharmacological treatment; 48 underwent bilateral ovariectomy and these were divided at random into four groups of 12 animals. One group was not submitted to pharmacological treatment; another was treated daily with sCT I.M.; in the other two groups, the hormone was incorporated into Hyaff 11 microspheres and was daily administered by vaginal route as dry powder or dispersed in pessaries. Sixty days after surgery, rats were sacrificed and the proximal third of the right tibia was removed and prepared for histomorphometry. Treatment with sCT, independent of the administration route, largely prevented the bone volume loss of the nontreated ovariectomized group. Prevention mainly depended on the maintenance of the trabecular number and on the increase of the trabecular thickness. Independent of the administration procedure, sCT greatly reduced the increase of tartrate-resistant acid phosphatase-positive poly- and, particularly, mononucleated osteoclasts found in the nontreated ovariectomized group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Intravaginal; Animals; Bone Diseases, Metabolic; Bone Resorption; Calcitonin; Disease Models, Animal; Female; Hyaluronic Acid; Injections, Intramuscular; Microspheres; Ovariectomy; Rats

A screening method for anti-osteoporotics using ovariectomized rats was designed using a compact method to monitor the bone density. It was found that ovariectomy (OVX) of Wistar female rats (11 weeks old) induced acute and focal osteopenia within 2 weeks, which responded well to intermittent salmon calcitonin (SCT: 5 and 20 U/kg, s.c., every other day) employed as the standard anti-osteoporotic and injected up to 4 weeks with or without a delay of 2 weeks after OVX.

Topics: Analgesics; Animals; Bone Density; Bone Diseases, Metabolic; Calcitonin; Disease Models, Animal; Estrogens; Female; Ovariectomy; Rats; Rats, Wistar; Tibia