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Objective: Ectopic calcification such as vascular calcification, involves the formation of calciprotein particle (CPP), that is, colloidal particle of calcium phosphate bound to serum protein. In this study, a novel parameter for CPP formation was introduced, thereby the effect of FYB-931, a bisphosphonate compound was evaluated., Methods: CPP formation in rat serum was assessed by the area under the curve (AUC) of the change in absorbance over time, and the commonly used T50, as indices. In vivo, the rats were treated with vitamin D3 to induce vascular calcification and then intravenously administered FYB-931 or etidronate thrice weekly for 2 weeks., Key Findings: In vitro, FYB-931 was the most potent inhibitor of CPP formation and it also inhibited the maximum response of CPP formation at higher concentrations. The AUC of the change in absorbance provided obvious dose-dependency, while T50 did not. FYB-931 dose-dependently prevented aortic calcification in vivo as well as CPP formation ex vivo more potently than etidronate. AUC showed a stronger correlation with the degree of aortic calcification than T50., Conclusions: The AUC in CPP formation can be an alternative parameter that reflects calcification. Based on the findings, FYB-931 has potential as an anti-calcifying agent., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Lessons Learned: Results are consistent with MBC-11 targeting and treating cancer-induced bone lesions by concentrating cytarabine and etidronate at the site of disease.MBC-11 was well tolerated, with an maximum tolerated dose of 5 mg/kg per day and myelosuppression as the principal toxicity.Treatment significantly reduced cancer cell activity in over half of bone lesions detected at baseline.MBC-11 pharmacokinetic and pharmacodynamic parameters are consistent with the novel drug design goals, and encouraging results warrant further clinical development., Background: MBC-11 is a first-in-class conjugate of the bone-targeting bisphosphonate etidronate covalently linked to the antimetabolite cytarabine (araC). This first-in-human phase I dose escalation study assessed safety, tolerability, maximum tolerated dose (MTD), plasma pharmacokinetics, bone turnover, tumor biomarkers, and bone lesion activity by fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG-PET/CT) imaging., Methods: Fifteen patients with advanced solid cancers and cancer-induced bone disease (CIBD) were treated with 0.5-10 mg/kg per day of MBC-11 administered daily for 5 days of every 4 weeks for up to four cycles., Results: Grade 1-2 myelosuppression, involving all lineages, was the principal toxicity. Two of three patients treated with 10 mg/kg experienced dose-limiting grade 4 neutropenia and thrombocytopenia (adverse event [AE] duration ≤5 days); the MTD was 5 mg/kg. Four of five patients with pretreatment elevations of the bone resorption marker TRAP5b (tartrate resistant acid phosphatase-5b) had persistent decrements. Six of 13 patients who reported baseline pain noted a reduction after MBC-11. 18 F-FDG-PET/CT imaging demonstrated partial metabolic responses in three patients and stable metabolic responses in three other patients. SUV max (standard unit of emission normalized to total uptake) was reduced by at least 25% in 110 (52%) of 211 bone lesions. Significant activity was noted across all doses, and myelosuppression increased with dose., Conclusion: At MBC-11 doses that were well tolerated, substantial reductions in metabolic activity of bone-associated cancer cells provide a foundation for further disease-directed efficacy studies., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Background: Patients with Crohn's disease have an increased frequency of osteopenia and osteoporosis. This randomized, controlled, double-blind study assessed the efficacy of risedronate versus placebo in treating low bone mineral density (BMD) in patients with Crohn's disease., Methods: 88 Crohn's disease outpatients with BMD T-score<-1.0 by dual-energy X-ray absorptiometry were randomly assigned to one of two treatment groups for the two year study duration: one group received risedronate 35 mg weekly while another received placebo. Both groups received daily calcium (Ca; 500 mg) and vitamin D (D; 400 IU) supplementation. Percent change in BMD relative to baseline was compared between the two therapies at 12 and 24 months., Results: Using intent-to-treat analysis, at 12 months, risedronate+Ca+D increased BMD, relative to baseline, more than placebo+Ca+D in the femoral trochanter (1.4±3.4% vs -0.1±3.1%; p=0.03) and total hip (1.1±2.7% vs -0.1±2.5%;p=0.04). This trend in greater BMD continued for the 24 month duration of the study. There was no difference between the two treatment groups for changes in spine BMD. Subgroup analysis revealed that risedronate+Ca+D resulted in significantly better improvement in femoral trochanter BMD in non-smokers (p=0.01), males (p=0.01), those with a history of corticosteroid use in the preceding year (p=0.01), and current users of immunosuppressants (p=0.04)., Conclusions: Risedronate, in addition to daily calcium and vitamin D supplementation, is superior to calcium and vitamin D alone in improving femoral trochanter and total hip BMD in patients with Crohn's disease., (Copyright © 2012 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)

Context: Determining how quickly bisphosphonate treatment effects begin to regress is crucial when considering termination of treatment., Objective: Our objective was to assess the effects of 1 yr discontinuation of risedronate use in postmenopausal women with osteoporosis who had previously received risedronate for 2 or 7 yr., Design and Setting: Before initiation of the current study, placebo/5-mg-risedronate patients had received placebo for 5 yr and risedronate for 2 yr, whereas 5-mg-risedronate patients had received risedronate for a total of 7 yr. Risedronate was then discontinued for 1 yr (yr 8)., Patients: Postmenopausal women with osteoporosis who had previously completed the 3-yr Vertebral Efficacy with Risedronate Therapy MultiNational (VERT-MN) pivotal trial, plus a 2-yr extension comparing risedronate or placebo for a total of 5 yr, followed by 2 yr of open-label risedronate treatment were enrolled in these trial extensions., Main Outcome Measures: Evaluations included changes in type I collagen cross-linked N-telopeptide (NTX)/creatinine (Cr) and bone mineral density (BMD) values, fracture incidence, and adverse events., Results: After 1 yr of risedronate discontinuation, NTX/Cr levels increased toward baseline in both patient groups vs. the values at the end of yr 7. In both treatment groups, off-treatment total hip and femoral trochanter BMD values decreased, whereas lumbar spine and femoral neck BMD were maintained or slightly increased. The adverse event profiles were similar between the two treatment groups during yr 8., Conclusions: One year of discontinuation of risedronate treatment in patients who had received 2 or 7 yr of risedronate therapy led to increases in NTX/Cr levels toward baseline and decreases in femoral trochanter and total hip BMD.

Context: Anorexia nervosa is complicated by severe bone loss and clinical fractures. Mechanisms underlying bone loss in adults with anorexia nervosa include increased bone resorption and decreased formation. Estrogen administration has not been shown to prevent bone loss in this population, and to date, there are no approved, effective therapies for this comorbidity., Objective: To determine whether antiresorptive therapy with a bisphosphonate alone or in combination with low-dose transdermal testosterone replacement would increase bone mineral density (BMD) in women with anorexia nervosa., Design and Setting: We conducted a12-month, randomized, placebo-controlled study at a clinical research center., Study Participants: Participants included 77 ambulatory women with anorexia nervosa., Intervention: Subjects were randomized to risedronate 35 mg weekly, low-dose transdermal testosterone replacement therapy, combination therapy or double placebo., Main Outcome Measures: BMD at the spine (primary endpoint), hip, and radius and body composition were measured by dual-energy x-ray absorptiometry., Results: Risedronate increased posteroanterior spine BMD 3%, lateral spine BMD 4%, and hip BMD 2% in women with anorexia nervosa compared with placebo in a 12-month clinical trial. Testosterone administration did not improve BMD but increased lean body mass. There were few side effects associated with either therapy., Conclusions: Risedronate administration for 1 yr increased spinal BMD, the primary site of bone loss in women with anorexia nervosa. Low-dose testosterone did not change BMD but increased lean body mass.

Introduction: Reduction of ovarian estrogen secretion at menopause increases net bone resorption and leads to bone loss. Isoflavones have been reported to protect bone from estrogen deficiency, but their modest effects on bone resorption have been difficult to measure with traditional analytical methods., Methods: In this randomized-order, crossover, blinded trial in 11 healthy postmenopausal women, we compared four commercial sources of isoflavones from soy cotyledon, soy germ, kudzu, and red clover and a positive control of oral 1 mg estradiol combined with 2.5 mg medroxyprogesterone or 5 mg/d oral risedronate (Actonel) for their antiresorptive effects on bone using novel (41)Ca methodology., Results: Risedronate and estrogen plus progesterone decreased net bone resorption measured by urinary (41)Ca by 22 and 24%, respectively (P < 0.0001). Despite serum isoflavone profiles indicating bioavailability of the phytoestrogens, only soy isoflavones from the cotyledon and germ significantly decreased net bone resorption by 9% (P = 0.0002) and 5% (P = 0.03), respectively. Calcium absorption and biochemical markers of bone turnover were not influenced by interventions., Conclusions: Dietary supplements containing genistein-like isoflavones demonstrated a significant but modest ability to suppress net bone resorption in postmenopausal women at the doses supplied in this study over a 50-d intervention period.

Objectives: Nitrogen-containing bisphosphonates, which are widely used to treat osteoporosis, act as inhibitors of farnesyl pyrophosphate synthase, one of the key enzymes of the mevalonate pathway, and thus may have the potential to enhance the effect of statins (inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase). In this study, we evaluated the synergistic effect of two nitrogen-containing bisphosphonates, alendronate and risedronate, in statin-induced apoptosis in rat skeletal L6 myoblasts., Methods: L6 rat myoblasts were differentiated with drugs. DNA fragmentation was measured and small GTPase was detected by immunoblotting., Key Findings: Alendronate and risedronate caused dose-dependent apoptosis of L6 myoblasts. Risedronate induced detachment of rho GTPase from the cell membrane, followed by activation of the caspase-8-related cascade. Risedronate-induced apoptosis was synergistically enhanced with atorvastatin and significantly reduced by addition of geranylgeraniol. By contrast, alendronate did not reduce membrane GTPases and the apoptosis was caspase independent., Conclusions: These results suggest that risedronate-induced apoptosis is related to geranylgeranyl pyrophosphate depletion followed by rho detachment, whereas alendronate affects are independent of rho. Our results suggest a risk of synergistic action between nitrogen-containing bisphosphonates and statins in the development of rhabdomyolysis when treating osteoporosis in women with hyperlipidaemia.

Background: Recent post hoc analysis proved the efficacy and tolerability of risedronate in osteoporotic patients with renal impairment, but the combination of active vitamin D in chronic kidney disease (CKD) patients taking glucocorticoids remains unknown., Methods: We conducted a prospective study enrolling 114 CKD patients (creatinine clearance > or =30 ml/min/1.73 m(2)) receiving glucocorticoid therapy for > or =6 months. Eighty-eight subjects who had received active vitamin D (aVD) were randomly assigned to either a group treated with aVD only (group A), or to a group also receiving risedronate 2.5 mg/day (group B). The remaining patients (group C) received risedronate only., Results: After 1 year 100 subjects were analysed. Risedronate was effective on the lumbar spine, but not on the femoral neck. The lumbar bone mineral density (BMD) significantly increased by 2.8 and 2.5% in groups B and C, respectively, but decreased by 1.0% in group A. Serum N-terminal telopeptides of type I collagen (S-NTX) and bone alkaline phosphatase (ALP) fell significantly in groups B and C at 3 and 6 months, respectively, while in group A S-NTX remained unchanged and bone ALP significantly increased. There was no significant difference between groups B and C regarding BMD and bone markers. The reduction rate of S-NTX (bone ALP) at 6 months predicted the increase in lumbar BMD at 1 year with a sensitivity of 73% (34%) and a specificity of 46.2% (100%)., Conclusions: Risedronate is effective in increasing BMD with or without aVD in CKD patients receiving long-term glucocorticoid therapy. Bone markers are of some use in predicting the response to anti-resorptive therapy.

Background: Corticosteroids are often used for the treatment of glomerular diseases. We examined whether bisphosphonate or vitamin D3 has beneficial effects on bone mineral density (BMD) in patients with glomerular diseases being treated with high-dose corticosteroids, including pulse therapy., Methods: Thirty-eight patients (19 men and 19 women, aged 42 +/- 16 years) were randomized into three groups: bisphosphonate alone (risedronate 2.5 mg/day, group R, n = 12), vitamin D3 alone (alfacalcidol 0.5 mug/day, group A, n = 15) and the combination of both agents (group R+A, n = 11). BMD at the lumbar spine was measured before and 12 months after treatment. The biochemical parameters of bone metabolism were assessed before and 3, 6 and 12 months after treatment., Results: In group R+A, BMD was significantly increased (+2.0%), whereas BMD was significantly decreased in group A (-5.6%). The BMD in group R did not show a significant change. In patients treated with steroid-pulse, BMD was decreased in groups R and A. In group R+A, BMD was significantly increased (+2.1%). Serum osteocalcin and alkaline phosphatase levels, markers of bone formation, were significantly decreased in all groups. Urinary crosslinked N-telopeptide of type I collagen (NTx) levels, a marker of bone resorption, were decreased in groups R and R+A. In patients with decreased BMD, the urinary NTx levels at baseline were significantly higher than the patients with increased BMD., Conclusions: Bisphosphonate might be beneficial for the prevention of steroid-induced bone loss in patients with glomerular diseases compared with vitamin D3. The combined therapy may be more effective, especially in patients treated with high-dose corticosteroids, including pulse therapy. A high urinary NTx level before receiving corticosteroids might be a predictive marker of the loss of BMD.

Patients with rheumatoid arthritis commonly suffer both systemic and periarticular osteoporosis. Bisphosphonates (BPs) are inhibitors of bone resorption, and several derivatives have been developed for treatment of enhanced bone resorption. We aimed to characterize osteoclast formation in two different sites, the proximal tibial and distal tibial areas, in rats with adjuvant arthritis, and to investigate the impact of amino or non-amino types of bisphosphonate. Adjuvant arthritis was initiated in rats while administering daily injections of either etidronate, a non-amino BP, or alendronate, an amino BP, for 3 weeks. On the day following the last injection, bone mineral density (BMD) was measured in the proximal tibia to assess systemic osteoporosis and in the distal tibia for periarticular osteoporosis using dual-energy X-ray absorptiometry. Subsequently, bone marrow cells from either end of the tibia were collected and incubated for 7 days before staining and counting tartrate-resistant acid phosphatase positive cells. In the rats with adjuvant arthritis, BMD of either end of the tibia was lower than in normal rats. Although etidronate prevented bone mineral loss at both ends, distal loss was significantly less than proximal. In contrast, alendronate significantly inhibited mineral loss primarily in the proximal area. Large osteoclasts, defined as having five or more nuclei, formed preferentially in the proximal tibia, while small osteoclasts with fewer than four nuclei were found mainly distally. The suppressive effect of alendronate was greater on the large osteoclasts, while etidronate had a greater effect on the small osteoclasts. These results show that the size and multinuclearity of osteoclasts and the number of osteoclasts formed are different in the distal and proximal areas of the tibia, and that alendronate and etidronate may suppress different types of osteoclasts as discriminated by the number of nuclei.

Deficiency of osteoprotegerin (OPG), a soluble decoy receptor for receptor activator of nuclear factor-kappaB ligand (RANKL), in mice induces osteoporosis caused by enhanced bone resorption, but also accelerates bone formation. We examined whether bone formation is coupled with bone resorption in OPG-deficient (OPG-/-) mice using risedronate, an inhibitor of bone resorption. Histomorphometric analysis showed that bone formation-related parameters (e.g. mineral apposition rate and osteoblast surface/bone surface) in OPG-/- mice sharply decreased with suppression of bone resorption by daily injection of risedronate for 30 d. OPG-/- mice exhibited high serum alkaline phosphatase activity and osteocalcin concentration, both of which were decreased to the levels in wild-type mice by the risedronate injection. Serum levels of RANKL were markedly elevated in OPG-/- mice, but were unaffected by risedronate. The ectopic bone formation induced by bone morphogenetic protein-2 implantation into OPG-/- mice was not accelerated even with a high turnover rate of bone, but attenuation of mineral density from the ectopic bone was more pronounced than that in wild-type mice. These results suggest that bone formation is coupled with bone resorption at local sites in OPG-/- mice, and that serum RANKL levels do not reflect this coupling.

The study was designed 1) to determine whether treatment with basic fibroblast growth factor (bFGF) and PTH is more efficacious than treatment with PTH alone for increasing bone mass and strength and improving trabecular microarchitecture in osteopenic ovariectomized rats, and 2) to assess whether prior and concurrent administration of the antiresorptive agents estrogen and risedronate suppresses the bone anabolic response to treatment with bFGF alone and sequential treatment with bFGF and PTH. Three-month-old female Sprague Dawley rats were ovariectomized (OVX) or sham-operated (sham) and maintained untreated for 1 yr. Baseline sham and OVX rats were killed at this time (15 months of age). Groups of rats were injected sc with estrogen (10 microg/kg, 4 d/wk), risedronate (5 microg/kg, 2 d/wk), or vehicle. At the end of the second week of antiresorptive treatment, catheters were inserted into the jugular veins of all rats, and vehicle or bFGF at a dose of 250 microg/kg was injected daily for 14 d. Three groups of rats were killed at the end of bFGF treatment. The remaining rats were continued on their respective antiresorptive therapy and injected sc with vehicle or synthetic human PTH-(1-34) at a dose of 80 microg/kg, 5 d/wk, for 8 wk. Lumbar vertebrae were processed for cancellous bone histomorphometry and biomechanical testing. Ovariectomy resulted in a decrease in vertebral bone mass and strength. Treatment of OVX rats for 14 d with bFGF markedly increased osteoblast surface, osteoid surface, and osteoid volume compared with vehicle treatment of sham and OVX rats. Furthermore, osteoid bridges were observed extending between preexisting trabeculae in bFGF-treated OVX rats. Prior and concurrent administration of estrogen and risedronate did not suppress these bone anabolic effects of bFGF. Treatment of OVX rats with PTH alone increased vertebral cancellous bone mass and strength to the level of vehicle-treated sham rats. Sequential treatment of OVX rats with bFGF and PTH further augmented vertebral bone mass and strength to a level above that observed in OVX rats treated with PTH alone. The improvements in bone mass and strength were associated with an increase in trabecular thickness in OVX rats treated with PTH alone and with an increase in trabecular thickness and node to terminus ratio, an index of trabecular connectivity, in OVX rats treated sequentially with bFGF and PTH. Cotreatment with estrogen and risedronate did not suppress the anabolic response of bone to bFGF and PTH. In fact, a trend for an even greater increase in cancellous bone mass and node to terminus ratio was observed in OVX rats treated with risedronate, bFGF, and PTH. These findings indicate that sequential treatment with bFGF and PTH is more efficacious than treatment with PTH alone for increasing bone mass and strength and improving trabecular microarchitecture in osteopenic OVX rats.

Estrogen deficiency is a leading cause of osteoporosis associated with increased osteoclastic bone resorption. In vitro studies indicate that the clinically used nitrogen-containing bisphosphonates (N-BPs) such as alendronate (ALN), risedronate (RIS) and ibandronate (IBA) suppress bone resorption via inhibition of the mevalonate pathway enzyme farnesyl diphosphate (FPP) synthase in osteoclasts (Ocs). The object of this study was to test the hypothesis that N-BPs inhibit the mevalonate pathway of Ocs in vivo. The mevalonate pathway enzyme hydroxymethyl-glutaryl-coenzyme A reductase (HMGR), is modulated by feedback inhibition from downstream metabolites. We therefore evaluated the in vivo expression of HMGR in Ocs from animals treated with BP. The N-BPs, ALN, IBA and RIS, selectively suppressed HMGR expression in up to 85% of rat tibia osteoclasts, after 48 hr treatment. Etidronate and clodronate, bisphosphonates that do not inhibit FPP synthase, were without effect. Simvastatin treatment opposed ALN reduction of HMGR expression, suggesting regulation by a metabolite(s) between mevalonate and FPP. These data provide the first in vivo evidence for N-BP effects on the mevalonate pathway in osteoclasts, and strongly support the hypothesis that N-BPs act via this mechanism.

Osteoporosis is a well-recognized adverse effect of corticosteroid therapy. This study aimed to investigate the effect of etidronate, intermittent cyclical therapy, in the prevention of corticosteroid-induced bone loss. Patients with various medical conditions starting high-dose corticosteroid therapy were enrolled in the study. The treatment had to be expected to continue for at least 12 months with the initial 90 days at a mean daily dose of at least 7.5 mg of prednisone, with subsequent treatment of at least 2.5 mg/day. One hundred seventeen patients were randomly assigned oral etidronate 400 mg/day, or placebo, for 14 days, followed by 76 days of oral calcium carbonate (500 mg elemental calcium), cycled over 12 months. The primary outcome measure was the difference in percent change from baseline in bone mineral density of the lumbar spine between the groups at the end of year 1. Secondary measures included changes in femur bone density and in biochemical markers of bone remodeling. The mean (+/- SEM) lumbar spine bone density changed 0.30 +/- 0.61% and -2.79 +/- 0.63% in the etidronate and placebo groups, respectively. The mean difference between groups after 1 yr was 3.0 +/- 0.84% (P = 0.004). The changes in the femoral neck and great trochanter were not different between the groups. There was a decrease in pyridinium crosslinks, significant from baseline at both 6 and 12 months, in the etidronate group. Osteocalcin increased in the placebo group, and difference between groups was -25.07 +/- 14.89% (P = 0.032) and -34.68 +/- 19.77% (P = 0.051), at 6 and 12 months respectively. There was no significant difference between the groups in number of adverse experiences, including gastrointestinal disorders. Etidronate intermittent cyclical therapy prevents lumbar vertebral bone loss in patients starting high-dose corticosteroid therapy.

This study elucidates the effect of PTH, estrogen, and the bisphosphonate Risedronate (NE-58095) on femoral neck bone strength in ovariectomized (OVX) rats aged 90 days at the beginning of the investigation. Furthermore, the effects of these monotherapies were compared with those of concurrent treatment with PTH plus estrogen or PTH plus bisphosphonate. Four weeks after surgery the rats were randomized into a sham-operated vehicle-treated group, an OVX vehicle-treated group, and the various treatment groups and followed for 5 and 15 weeks. The proximal one-third of the left femur was then subjected to geometrical measurements and biomechanical testing. Neither ovariectomy nor the different treatment regimens influenced femoral neck geometry. OVX rats exhibited a decrease in femoral neck bone strength compared with control rats. This was most evident after 5 weeks. Treatment of OVX rats with Risedronate or estrogen alone tended to increase bone strength to control level, though these findings were nonsignificant. In contrast, treatment with PTH showed a highly significant increase in femoral neck biomechanical competence. Concurrent treatment with PTH plus estrogen or PTH plus Risedronate also significantly increased the femoral neck bone strength, but neither showed any advantage over treatment with PTH alone. It is concluded that treatment with PTH increases the strength of the femoral neck in estrogen-depleted rats in a highly significant manner, and that this effect is much more pronounced than the effect of the two antiresorptive agents estrogen or Risedronate. Thus, these findings provide further support for the anabolic effect of PTH and add weight to the argument for the promising potential of PTH in the treatment of postmenopausal osteoporosis.

TSH-suppressive doses of thyroid hormone are associated with bone loss. We have previously reported that L-T4 decreases femoral, but not vertebral bone mineral density (BMD) in rats. As bisphosphonates are able to decrease bone resorption, especially in high bone turnover states, we investigated the potential effects of etidronate disodium (EHDP) on L-T4-induced bone loss in the rat model by assessing BMD and gene expression of osteoblast (osteocalcin, osteopontin, type I collagen, and alkaline phosphatase), osteoclast (tartrate-resistant acid phosphatase), and cell growth (histone) markers in the skeleton. L-T4 administered for 20 days decreased BMD in the femur, but had no effect on the lumbar spine. EHDP alone had no effect on femoral or vertebral BMD, but did prevent the L-T4-induced bone loss in the femur. L-T4 increased mRNA levels of alkaline phosphatase, tartrate-resistant acid phosphatase, and histone H4 in the femur, but not in the vertebrae. EHDP, which alone had no effect on gene expression in the femur or vertebrae, inhibited the effect of L-T4 on mRNA markers in the femur. The results demonstrate that EHDP can prevent the L-T4-induced decrease in femoral BMD in rats that is associated with the prevention of changes in mRNA markers of osteoclast and osteoblast function. EHDP and other bisphosphonate compounds may be useful in the prevention of thyroid hormone-induced bone loss in humans.

We administered risedronate, a potent oral bisphosphonate, to patients with mild primary hyperparathyroidism in order to 1) determine if we could normalize the serum calcium concentration in the short term, and 2) analyze changes in the homeostatic mechanisms responsible for maintaining hypercalcemia in this patient population. When administered for 7 days, risedronate reduced fasting serum calcium concentrations without significant toxicity in patients with primary hyperparathyroidism. The decrease in serum calcium was accompanied by evidence of inhibition of bone resorption, as assessed by measurement of urinary hydroxyproline, increased serum immunoreactive PTH concentrations, enhanced renal tubular reabsorption of calcium, and a progressive decrease in serum alkaline phosphatase. Serum PTH was partially suppressed by an oral calcium load in untreated patients as well as in patients treated with risedronate. Although patients treated with risedronate had normal fasting serum calcium levels, serum calcium values in these normocalcemic patients were labile after oral ingestion of calcium. After daily calcium intake of 2 g, serum calcium levels in risedronate-treated patients were similar to those in untreated patients with primary hyperparathyroidism, suggesting that there are likely to be fluctuations in serum calcium in risedronate-treated patients with normal fasting serum calcium during postprandial periods. These studies show that risedronate lowers fasting serum calcium during short term treatment. However, further studies are required to determine whether the lability in serum calcium in these patients after an oral calcium load has clinical significance, and whether longer term treatment would maintain serum calcium in the normal range.

The study was designed to compare the therapeutic efficacy of estrogen, the bisphosphonate risedronate (NE-58095), and PTH for restoration of lost bone mass in osteopenic, ovariectomized (OVX) rats. In addition, the skeletal effects of these single treatments were compared to those of concurrent treatments with PTH + estrogen or PTH + NE-58095. OVX rats were untreated for the first 4 weeks postovariectomy to allow for the development of moderate tibial osteopenia. These animals were then subjected to the various treatments for periods of 5, 10, and 15 weeks. Their proximal tibiae were processed undecalcified for quantitative bone histomorphometry. Treatment of osteopenic OVX rats with estrogen or NE-58095 alone depressed bone turnover and prevented additional cancellous bone loss from occurring during the treatment period. However, these therapeutic agents failed to restore lost bone in OVX rats to control levels. In contrast, OVX rats treated with PTH alone exhibited a marked stimulation of bone formation which resulted in augmentation of cancellous bone mass to a level 2-fold greater than that of vehicle-treated control rats. Concurrent treatment of OVX rats with PTH + estrogen as well as PTH + NE-58095 also effectively reversed cancellous osteopenia in OVX rats, but did not appear to be more beneficial to the estrogen-deplete skeleton than treatment with PTH alone. The results indicate that PTH is a powerful stimulator of bone formation and completely restores lost cancellous bone in osteopenic OVX rats. Furthermore, the bone anabolic effects of PTH are much more pronounced than those of estrogen or bisphosphonates. These findings in an animal model of estrogen depletion provide support for PTH as a potentially effective treatment for oophorectomized and postmenopausal women with established osteoporosis.

The mechanism by which aluminum chloride stimulates de novo bone formation is unknown. To evaluate the role of bone remodeling and mature osteoblastic function in aluminum-induced neoosteogenesis, we compared the osteogenic effects of aluminum in normal beagles to those in animals with low turnover osteomalacia induced by treatment with etidronate [1-hydroxyethane-1,1-diphosphoric acid (HEBP)]. As assessed by quantitative bone histomorphology, beagles treated with HEBP developed low turnover osteomalacia characterized by a 78% reduction in osteoblast number, a 5.5-fold increase in osteoid volume, complete absence of active mineralization, and diminished resorption surfaces compared to untreated controls. The iv administration of aluminum chloride to normal dogs generated new trabecular structures in the marrow cavity consistent with induction of de novo bone formation. This response consisted of increased trabecular bone volume and number, accumulation of woven osteoid, and increased number of bone-forming cells. The concomitant administration of HEBP failed to prevent induction of de novo bone formation by aluminum. Instead, the neoosteogenic process was superimposed on low turnover osteomalacia in HEBP-treated dogs. Serum aluminum concentrations were increased 2-fold, whereas bone aluminum accumulation was reduced by 58% in HEBP- and aluminum-treated dogs compared to that in aluminum-treated controls. These findings indicate that aluminum stimulation of neoosteogenesis in beagles is independent of mature osteoblast function, normal bone remodeling, and total bone aluminum accumulation. Rather, aluminum-induced de novo bone formation appears to result from stimulation of mesenchymal precursors to form a primitive type of bone which is distinct from coupled bone formation.

Disodium etidronate affected salicylic acid absorption from the rat small intestine, in-situ, when instilled into a jejunal segment for different exposure times before the salicylic acid absorption was measured. At low etidronate concentrations and short exposure times, the salicylic acid absorption rate was significantly increased compared with saline controls. At high etidronate concentrations and longer exposure times, the absorption rate was reduced. Etidronate precomplexed with calcium or magnesium ions at low concentrations still enhanced salicylic acid absorption but at high concentrations absorption of salicylic acid was close to saline controls. Intestinal mucosa exposed to high etidronate concentrations showed a progressive structural destruction but with the complexes, there was no visible alteration. It is proposed that a solubilized etidronate complex, formed either in-situ or administered as such, is responsible for enhancing salicylic acid absorption. This effect is hidden at high etidronate concentrations because of the deterioration of the mucosal surface and at high complex concentrations because these decrease the absorbing surface area and increase the viscosity of the lumen contents.

This study was designed to test the hypothesis that endocrine and pharmacological suppressors of bone turnover prevent the development of osteopenia during estrogen deficiency. Sham-operated control and ovariectomized (OVX) rats were treated intermittently with vehicle alone, estrogen, or the diphosphonate compounds etidronate disodium (EHDP) and NE-58095 [2-(3-pyridinyl)2-hydroxyethylidene-1,1-bisphosphonate disodium] for 35 or 70 days after surgery. Their proximal tibiae were processed undecalcified for quantitative bone histomorphometry. Vehicle-treated OVX rats were characterized by decreased cancellous bone volume and 3- to 4-fold increases in osteoblast surface, osteoclast surface, bone formation rate, and bone resorption rate. Treatment of OVX rats with estrogen and NE-58095 provided complete protection against bone loss and significantly depressed all of the above indices of bone turnover. OVX rats treated with EHDP exhibited at least partial protection against bone loss and decreased bone turnover. EHDP induced a mild mineralization defect, as indicated by a prolonged mineralization lag time at the tibial endocortical surface. The new diphosphonate compound NE-58095 did not impair bone mineralization. Our results indicate that endocrine and pharmacological suppressors of bone turnover prevent the development of osteopenia during the early stages of estrogen deficiency. If confirmed by clinical trials in humans, diphosphonate compounds may prove to be an alternative to estrogen for the prevention of postmenopausal bone loss.