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Biomedical subjects

S E Papapoulos

Publications and source records attributed to S E Papapoulos.

At least 37 records · Page 2Linked to original sources
PubMed1999

[Prevalence of osteoporosis in postmenopausal women in family practice].

OBJECTIVE: To assess the prevalence of osteopenia, osteoporosis and severe vertebral deformities in general practice. DESIGN: Cross-sectional study. METHODS: Of a randomly selected group of 712 women aged 55 to 84 years in a general practice in Noordwijk, the Netherlands, 449 (63%) participated in a study in 1996, in which Dual Energy X-ray Absorptiometry (DXA) of the femoral neck was performed: in 428 women vertebral morphometry of lateral radiographs of the spine was also done. The World Health Organization definitions of osteopenia and osteoporosis were used. RESULTS: The mean bone mineral density (BMD) was 0.866 g/cm2 (SD: 0.135). With increasing age the BMD decreased statistically significantly by 0.0073 g/cm2/year. There were 189 women with osteopenia (42%). 33 (7%) with osteoporosis and 44 (10%) with one or more severe vertebral deformities. A significantly lower mean BMD was found in those with severe vertebral deformities than in those without.

Age Distribution↗
PubMed1999

Usefulness of armspan and height comparison in detecting vertebral deformities in women.

The prevalence of vertebral fractures in women increases with age but only about one third of these fractures are symptomatic. On the other hand, the presence of vertebral fractures is an independent risk factor for new osteoporotic fractures. In the present study we examined the hypothesis that differences between armspan and height are related to the presence of vertebral deformities in a cohort of 494 women aged between 55 and 84 years (mean age 67.6 years, SD 8.2 years) who were randomly selected from a large general practice in The Netherlands. Height and armspan were measured and vertebral morphometry of lateral radiographs of the spine was performed. Both height and armspan decreased significantly with age. The correlation between armspan and height was 0.83. Vertebral deformities were present in 32.7% of the women (grade I in 22.4% and grade II in 10.3%). Only the prevalence of grade II deformities rose with age. The variation of the difference between armspan and height in the groups with or without grade II vertebral deformities was comparable and relatively large (range > 15 cm). The difference in mean values was small between those groups (1.6 cm) and could not differentiate between women with and without vertebral deformities. Our data show that the presence of vertebral deformities cannot be detected by the difference between armspan and height.

Age Factors↗
PubMed1999

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 +/- SD, 61.5 +/- 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.

Adult↗
PubMed1999

A frame-shift mutation in the type I parathyroid hormone (PTH)/PTH-related peptide receptor causing Blomstrand lethal osteochondrodysplasia.

Blomstrand osteochondrodysplasia (BOCD) is a rare lethal skeletal dysplasia characterized by accelerated endochondral and intramembranous ossification. Comparison of the characteristics of BOCD with type I PTH/PTH-related peptide (PTHrP) receptor-ablated mice reveals striking similarities that are most prominent in the growth plate. In both cases, the growth plate is reduced in size due to a strongly diminished zone of resting cartilage and the near absence of columnar arrangement of proliferating chondrocytes. This overall similarity suggested that an inactivating mutation of the PTH/PTHrP receptor might be the underlying genetic defect causing BOCD. Indeed, inactivating mutations of the PTH/PTHrP receptor have been recently identified in two cases of BOCD. We describe here a novel inactivating mutation in the PTH/PTHrP receptor. Sequence analysis of all coding exons of the type I PTH/ PTHrP receptor gene and complementary DNA of a case with BOCD identified a homozygous point mutation in exon EL2 in which one nucleotide (G at position 1122) was absent. The mutation was inherited from both parents, supporting the autosomal recessive nature of the disease. The missense mutation resulted in a shift in the open reading frame, leading to a truncated protein that completely diverged from the wild-type sequence after amino acid 364. The mutant receptor, therefore, lacked transmembrane domains 5, 6, and 7; the connecting intra- and extracellular loops; and the cytoplasmic tail. Functional analysis of the mutant receptor in COS-7 cells and of dermal fibroblasts obtained from the case proved that the mutation was indeed inactivating. Neither the transiently transfected COS-7 cells nor the dermal fibroblasts responded to a challenge with PTH or PTHrP with a rise in intracellular cAMP levels, in sharp contrast to control cells. Our results provide further evidence that BOCD is caused by inactivating mutations of the type I PTH/PTHrP receptor and underscore the importance of this receptor in mammalian skeletal development.

Adult↗
PubMed1999

Identification of a retinoic acid-inducible element in the murine PTH/PTHrP (parathyroid hormone/parathyroid hormone-related peptide) receptor gene.

We have shown previously that the PTH/PTHrP (PTH-related peptide) receptor mRNA becomes expressed very early in murine embryogenesis, i.e. during the formation of extraembryonic endoderm. Retinoic Acid (RA) is a potent inducer of extraembryonic endoderm formation and PTH/PTHrP-receptor expression in embryonal carcinoma (EC) and embryonal stem (ES) cells. Using the P19 EC cell line, we have characterized promoter elements of the murine PTH/PTHrP-receptor gene that are involved in this RA-induced expression. The data show that RA-induced expression of the PTH/ PTHrP-receptor gene is mediated by the downstream P2 promoter. Analysis of promoter reporter constructs in transiently transfected P19 cells treated with RA identified an enhancer region between nucleotides -2714 and -2702 upstream of the P2 transcription start site that is involved in the RA effect. This region matches a consensus hormone response element consisting of a direct repeat with an interspacing of 1 bp (R-DR1). The R-DR1 efficiently binds retinoic acid receptor-alpha (RARalpha)-retinoid X receptor-alpha (RXRalpha) and chicken ovalbumin upstream promoter (COUP)-transcription factor I (TFI)-RXRalpha heterodimers and RXRalpha and COUP-TFI homodimers in a bandshift assay using extracts of transiently transfected COS-7 cells. RA differentiation of P19 EC cells strongly increases protein binding to the R-DR1 in a band-shift assay. This is caused by increased expression of RXR (alpha, beta, or gamma) and by the induction of expression of RARbeta and COUP TFI/TFII, which bind to the R-DR1 as shown by supershifting antibodies. The presence of RXR (alpha, beta, or gamma) in the complexes binding to the R-DR1 suggests that RXR homodimers are involved in RA-induced expression of the PTH/PTHrP-receptor gene. The importance of the R-DR1 for RA-induced expression of PTH/ PTHrP-receptor was shown by an inactivating mutation of the R-DR1, which severely impairs RA-induced expression of PTH/PTHrP-receptor promoter reporter constructs. Since this mutation does not completely abolish RA-induced expression of PTH/PTHrP-receptor promoter reporter constructs, sequences other than the R-DR1 might also be involved in the RA effect. Finally, we show that the RA-responsive promoter region is also able to induce expression of a reporter gene in extraembryonic endoderm of 7.5 day-old transgenic mouse embryos.

Animals↗
PubMed1999

Oestrogenic compounds modulate cytokine-induced nitric oxide production in mouse osteoblast-like cells.

Nitric oxide (NO) is a mediator of bone metabolism with effects on both bone resorption and formation. Its production by both the constitutive and inducible isoforms of nitric oxide synthase (NOS) is affected by oestrogen in several types of cell and in tissues other than bone cells. Recently, oestrogens were found to increase basal NO production by osteoblasts via enhanced activity or expression, or both, of NOS-3. Inflammatory cytokines, however, increase NO by increasing the expression of NOS-2. In this study we have examined whether cytokine-induced NO production by osteoblastic cells was affected by oestrogenic compounds by studying the effect of 17beta-oestradiol and the anti-oestrogens ICI164,384 and 4-hydroxytamoxifen on cytokine-induced NO production in oestrogen receptor positive MC3T3-E1 osteoblast-like cells. Combinations of the inflammatory cytokines interleukin-1beta, tumour necrosis factor-alpha, and interferon-gamma with lipopolysaccharide stimulated NO production up to 11-fold. This cytokine-induced NO production was further increased dose-dependently by the anti-oestrogens ICI164,384 and 4-hydroxytamoxifen (133.3 +/- 3.2% and 146.0 +/- 13.2%, respectively). 17Beta-oestradiol either had no effect on or slightly inhibited cytokine-induced NO production. It did, however, dose-dependently counteract the stimulatory effect of the anti-oestrogens. Concentrations of 17beta-oestradiol needed to prevent the stimulatory effect of 4-hydroxytamoxifen were ca tenfold that of ICI164,384. These findings show that, in addition to the stimulatory effect of oestrogen on basal NO production by NOS-3, cytokine-induced NO production is also affected by oestrogenic compounds in osteoblasts.

Animals↗
PubMed1999

Interleukin-17: A new bone acting cytokine in vitro.

Interleukin-17 (IL-17) is a recently cloned cytokine that is exclusively produced by activated T cells, but its receptor has been found on several cells and tissues. Like other proinflammatory cytokines produced by activated T cells, IL-17 may affect osteoclastic resorption and thereby mediate bone destruction accompanying some inflammatory diseases. In the present study, we investigated whether osteogenic cells possess the receptor for IL-17 (IL-17R) and whether IL-17 affects osteoclastic resorption. We found that IL-17R mRNA is expressed both in mouse MC3T3-E1 osteoblastic cells and fetal mouse long bones, suggesting that osteogenic cells may be responsive to IL-17. In fetal mouse long bones, IL-17 had no effect on basal and IL-1beta-stimulated osteoclastic bone resorption, but when given together with tumor necrosis factor-alpha (TNF-alpha) it increased bone resorption dose dependently in serum-free conditions. In addition, IL-17 increased TNF-alpha-induced IL-1alpha, IL-1beta, and IL-6 mRNA expression in fetal mouse metatarsals and IL-1alpha and IL-6 mRNA expression in MC3T3-E1 cells. In conclusion, IL-17R mRNA was expressed by mouse osteoblastic cells and fetal mouse long bones, and IL-17 in combination with TNF-alpha, but not IL-1beta, increased osteoclastic resorption in vitro. IL-17 may therefore affect bone metabolism in pathological conditions characterized by the presence of activated T cells and TNF-alpha production such as rheumatoid arthritis and loosening of bone implants.

Animals↗
PubMed1998

Pharmacological management of osteoporosis.

Pharmacological interventions for the prevention of fractures in patients with osteoporosis aim mainly at correcting the bone remodelling imbalance by either reducing bone resorption and bone turnover, or stimulating bone formation. A number of agents are currently available but only a few were evaluated under controlled conditions in clinical trials whose primary efficacy end-point was the prevention of fractures. In addition, this information was obtained in patients with postmenopausal osteoporosis mainly with prevalent vertebral fractures, and most studies published to date had the occurrence of new vertebral rather than peripheral fractures as their primary efficacy end-point. The majority of data was obtained with inhibitors of bone turnover, but the level of evidence of the antifracture efficacy of these agents varies markedly. Results of carefully performed studies are, however, available allowing rational therapeutical choices. Adequate knowledge of the benefits and side effects of pharmacological interventions combined with other measures which improve bone health and reduce complaints and risks are essential for the management of the osteoporotic patient.

Aged↗
PubMed1998

The prevalence of low bone mineral density in Dutch perimenopausal women: the Eindhoven perimenopausal osteoporosis study.

The aim of this study was to estimate the prevalence of osteopenia and osteoporosis in perimenopausal women, and to assess determinants of low bone mineral density (BMD). All women born between 1941 and 1947 (aged between 46 and 54 years) living in the city of Eindhoven were invited to participate in the study: 5896 white Dutch women, representing 73% of the total number of Dutch women in this age group, were studied. Of these, 24% were using estrogen preparations and 19% had undergone hysterectomy, with or without oophorectomy. All women were interviewed and bone mineral density (BMD) of the lumbar spine was measured by dual-energy X-ray absorptiometry (DXA). Osteopenia and osteoporosis were defined according to the criteria proposed by a WHO working group. In the population studied the prevalence of osteopenia and osteoporosis was 27.3% and 4.1%, respectively. With progression from premenopause to menopause, the prevalence of osteoporosis increased from 0.4% to 12.7%, and that of osteopenia from 14.5% to 42.8%. An increased risk for low BMD (osteopenia and osteoporosis) was associated with age, menopausal status and smoking, while alcohol consumption, high body mass index (BMI) and use of estrogens had a protective effect. This study of a large population-based cohort of perimenopausal women revealed a high prevalence of low bone mass and, therefore, a higher risk for osteoporotic fractures. The data further suggest that, when issues on the long-term efficacy and safety of preventive treatments are resolved, it may be possible to identify women at higher risk who are most likely to benefit from screening strategies.

Absorptiometry, Photon↗
PubMed1998

Effects of the bisphosphonate olpadronate in patients with carcinoma of the prostate metastatic to the skeleton.

Prostate cancer is predominantly associated with osteoblastic bone metastases, but an increase in bone resorption has been demonstrated consistently, both histologically and biochemically. For this reason, bisphosphonates, which effectively suppress bone resorption, have been used in patients with prostate cancer metastatic to the skeleton. We studied clinical and biochemical responses 5 days and 3 months after administration of the new, potent bisphosphonate, olpadronate, in 28 patients with prostate cancer and bone metastases. All patients received 4 mg of olpadronate intravenously daily for 5 days. No additional treatment was given to the first 12 patients, while treatment was continued with oral olpadronate 200 mg daily in the following 16 patients. Serum alkaline phosphatase (ALP) activity was elevated in 93% of the patients and was positively correlated to urinary hydroxyproline excretion (r = 0.81, p < 0.0001), suggesting a coupling between bone formation and resorption. A rapid and significant suppression of bone resorption was observed in all patients after intravenous treatment. This was sustained for 4-6 weeks in all patients, but reversed thereafter in patients not receiving oral maintenance therapy. No significant changes in serum ALP activity were observed in either group during the 3 months of follow-up. At the start of treatment all patients had severe bone pain and 82% and 36% were using NSAIDs and/or opiates, respectively. Although clinical response was not a primary objective of the study, we observed that intravenous therapy was associated with a decrease in bone pain in 76% of patients and a reduction in the use of analgesics. At 3 months this response was generally sustained only in those patients who were maintained on continuous oral therapy (p < 0.05 compared with the group treated with intravenous olpadronate only). The clinical response thus appeared to parallel the biochemical changes in bone resorption.

Administration, Oral↗
PubMed1998

Binding and antiresorptive properties of heterocycle-containing bisphosphonate analogs: structure-activity relationships.

To define structure-activity relationships for bisphosphonate activity, we examined the bone binding and antiresorptive properties of heterocycle-containing analogs of risedronate, a pyridylbisphosphonate, in cultures of mouse fetal bone explants. Our studies indicated that hydroxybisphosphonates with the nitrogen molecule in the pyridyl ring were very potent inhibitors of osteoclastic resorption. Changing the place of the nitrogen in the ring structure of risedronate or its methylation did not significantly alter antiresorptive potency in relation to risedronate. Extension of the R2 chain, however, reduced efficacy. In binding experiments, we found that all heterocyclic bisphosphonates with a hydroxyl group in R1 had comparable affinity for bone mineral and inhibited calcium incorporation into bone explants to a similar extent. The affinity of a risedronate analog without R1 was markedly reduced. We also examined the properties of a risedronate analog (NE-10790) belonging to the group of phosphonocarboxylates in which one of the phosphonate groups is substituted by a carboxyl group. NE-10790 had strongly reduced binding affinity, but still retained some antiresorptive activity. Interestingly, the continuous presence of NE-10790 in cultures of fetal mouse metacarpal bones increased its antiresorptive efficacy by about 40-fold compared with 24 h preincubation, whereas, under the same conditions, the potency of high-affinity hydroxybisphosphonates did not change or only slightly increased. This may be explained by the differences in pharmacokinetic behavior between compounds of high and of low affinity for bone mineral. These data show that, as with alkylbisphosphonates, heterocycle-containing bisphosphonates with a nitrogen functionality in the R2 chain are potent antiresorptive agents and a hydroxyl substitution in the R1 chain confers high affinity for bone mineral, probably due to tridentate configuration. The group of phosphonocarboxylates, with strongly reduced bone affinity, provides an interesting therapeutic option.

Alendronate↗
PubMed1998

IL-1alpha, IL-1beta, IL-6, and TNF-alpha steady-state mRNA levels analyzed by reverse transcription-competitive PCR in bone marrow of gonadectomized mice.

Loss of gonadal function in both females and males is associated with increased rates of bone loss by a yet unidentified mechanism. There is ample evidence that cytokines that are produced in the bone microenvironment and stimulate the activity and/or formation of osteoclasts are involved. In the present study, we examined whether gonadectomy increases cytokine production via increased transcription in the bone marrow of mice. For this, the in vivo steady-state mRNA levels of multiple cytokines were determined in the central bone marrow compartment of mice at different time points following ovariectomy or orchidectomy by reverse transcription-competitive polymerase chain reaction. The limit of detectable differences in mRNA expression was approximately 2-fold. Bone marrow mRNA levels of the cytokines interleukin-1alpha (IL-1alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) were elevated up to 30-fold after treatment of mice with lipopolysaccharide. Following gonadectomy, there were no differences in the mRNA expression of these cytokines in bone marrow of female and male mice 4, 7, and 14 days after surgery. Gender steroid deficiency does not, therefore, increase steady-state mRNA levels of IL-1alpha, IL-1beta, IL-6, and TNF-alpha in cells of the central bone marrow compartment in mice. If changes have occurred these should have been less than 2-fold or in a small cell population. These results do not preclude an important role of these cytokines in the induction of bone loss after gonadectomy. For example, bone marrow cells situated close to the bone surface or bone cells may be responsible for increased cytokine synthesis. Alternatively, the loss of gender steroids may alter post-transcriptional events in cytokine synthesis and activity or may modify the responsiveness of target cells.

Animals↗
PubMed1998

Differential effects of aminosubstituted analogs of hydroxy bisphosphonates on the growth of Dictyostelium discoideum.

Replacing the hydroxyl group in the bone-binding site of three clinically useful bisphosphonates (etidronate, pamidronate, and olpadronate) by an amino group resulted in great differences in their antiresorptive potencies in vitro. In the present study, this is also shown in vivo in mice treated with the six bisphosphonates at doses of up to 16 microM/kg/day for 12 days. Because binding to bone mineral is nearly the same for all tested bisphosphonates, these findings suggest that the aminosubstitution affects the cellular action of the bisphosphonates. This was tested in the cellular slime mould Dictyostelium discoideum in which cellular effects of bisphosphonates can be examined independently of binding to bone mineral. Etidronate and its aminosubstituted analog were equipotent in inhibiting amebal growth, while pamidronate was somewhat more potent than its analog. Whereas olpadronate was a potent inhibitor of axenic growth of Dictyostelium amebae, the aminosubstitution reduced its potency drastically (IC50 12 microM and 700 microM, respectively). The similarities between the inhibitory effects of the bisphosphonates tested on bone resorption in vitro and in vivo and on the growth of Dictyostelium amebae confirm that the differences in antiresorptive potencies found reflect differences in cellular effects and suggest that bisphosphonates may bind to more than one intracellular target.

Amines↗
PubMed1998

Plasma nitrate+nitrite levels are regulated by ovarian steroids but do not correlate with trabecular bone mineral density in rats.

Nitric oxide (NO) is a mediator of bone metabolism and its production is under the control of gender hormones in several cell types or tissues. Changes in endogenous NO production, measured as plasma nitrate+nitrite levels, may therefore contribute to ovariectomy (OVX)-induced bone loss. We studied plasma nitrate+nitrite levels and trabecular bone mineral density (TBMD) 4 weeks after sham-operation or OVX in rats receiving various hormonal treatments. OVX decreased plasma nitrate+nitrite levels significantly and this was accompanied by a significant decrease in TBMD. Treatment with oral ethinyl oestradiol (EE) and subcutaneous 17beta-oestradiol dose-dependently prevented the decrease in plasma nitrate+nitrite levels after OVX, but treatment with oral 17beta-oestradiol did not. Oestrogen treatment, 17beta-oestradiol (s. c. or orally) or EE (orally), prevented the OVX-induced decrease in TBMD. Treatment of sham-operated rats with the anti-oestrogen ICI164, 384 induced a significant decrease in TBMD that corresponded to 54% of the decrease observed after OVX, but did not affect plasma nitrate+nitrite levels. Treatment of ovariectomized rats with Org 2058, a pure progestagen, did not prevent bone loss, but prevented the decrease in plasma nitrate+nitrite levels dose-dependently. Treatment with tibolone, a synthetic steroid with combined weak oestrogenic, progestagenic, and androgenic properties, or with progestagen in combination with EE completely prevented bone loss after OVX. These treatments, however, only partly prevented the OVX-induced decrease in plasma nitrate+nitrite levels. In conclusion, OVX decreased both TBMD and plasma nitrate+nitrite levels. Although plasma nitrate+nitrite levels were under the control of both oestrogen and progesterone, TBMD was affected by oestrogen only. Decreased systemic production of NO is, therefore, not involved in OVX-induced bone loss in rats.

Anabolic Agents↗
PubMed1997

Treatment of osteogenesis imperfecta with the bisphosphonate olpadronate (dimethylaminohydroxypropylidene bisphosphonate).

UNLABELLED: Osteoporosis is an important feature of osteogenesis imperfecta (OI). So far, no effective medical treatment is available. We treated three boys with severe OI type III and vertebral deformities for 5-7 years with continuous oral administration of the bisphosphonate, olpadronate. Treatment resulted in a decreased number of bone fractures, an increased calcification of the long bones and an amelioration of vertebral shape. No side-effects were encountered. CONCLUSION: These preliminary but long-term observations suggest that the bisphosphonate olpadronate may be a useful treatment for patients with OI and vertebral fractures. Bisphosphonates may be promising drugs for children with OI.

Body Height↗
PubMed1997

Paget's disease of bone: clinical, pathogenetic and therapeutic aspects.

Paget's disease of bone is a focal disorder of bone remodelling due to abnormally increased osteoclast-mediated bone resorption. It rarely presents before the age of 35 years and its prevalence increases with age affecting 2-5% of the population above 50 years, making Paget's disease the most common skeletal disorder after osteoporosis. Its aetiology is not known but available evidence favours an infection of genetically predisposed individuals with a paramyxovirus. Affected bones change in shape, size and direction causing considerable morbidity but the majority of patients are asymptomatic. In Paget's disease increased bone resorption is tightly linked to increased bone formation which are reflected in the proportional increases in biochemical indices of bone turnover. Because the primary abnormality lies in the osteoclasts, inhibitors of bone resorption are used for its therapy and bisphosphonates are currently the treatment of choice. These decrease bone turnover effectively and their effect lasts after stopping treatment. With available bisphosphonates clinical and biochemical, long-lasting, remissions can be obtained in the majority of patients. Symptomatic disease and preparation for orthopaedic surgery are no longer the only indication for treatment, but asymptomatic patients with localizations at sites likely to induce complications should be considered candidates for bisphosphonate therapy.

Adult↗
PubMed1997

Effect of alendronate treatment on the osteoclastogenic potential of bone marrow cells in mice.

Bisphosphonates suppress bone resorption by inhibiting the activity of mature osteoclasts as well as the formation of osteoclasts from bone marrow-derived precursor cells. It is not yet known at which level of osteoclast development this latter action is exerted and whether this is due to a systemic effect of circulating bisphosphonate or to an action at the bone surface, given the property of these compounds to concentrate specifically at active bone sites. We addressed these questions in an ex vivo study in mice. The animals were treated with the bisphosphonate alendronate for various periods, and the central compartment of the bone marrow was isolated and cultured together with osteoclast-free fetal mouse bone explants. In this way the capacity of bone marrow cells, exposed previously to alendronate in vivo, to generate osteoclasts and induce resorption in vitro was examined. Alendronate (0.25 mg/kg, subcutaneously) given to mice for periods up to 4 weeks suppressed bone resorption, as expected, but did not affect the capacity of bone marrow cells to develop into mature osteoclasts and resorb the calcified matrix of bone explants. In addition, using monoclonal antibodies specific for different macrophage-granulocyte precursor subsets, we found that alendronate treatment did not affect the pattern of antigen expression of bone marrow cells, which is in line with the lack of an effect of the bisphosphonate on the ability of bone marrow cells to induce resorption in vitro. In contrast, in control experiments, lipopolysaccharide (0.1 mg) treatment induced marked changes in the pattern of antigen expression of bone marrow cells. In conclusion, our studies demonstrate that the inhibition of bone resorption by alendronate does not involve alteration of the osteoclastogenic potential of osteoclast progenitors (precursors) from the central bone marrow compartment. Moreover, this treatment did not alter the expression of markers specific for monocyte-macrophage precursors as well as mature macrophages. These results suggest that the effects of alendronate are exerted at the bone surface at late osteoclast precursors (and mature osteoclasts).

Alendronate↗