AZD3514, an oral selective androgen receptor down-regulator in patients with castration-resistant prostate cancer - results of two parallel first-in-human phase I studies.

BACKGROUND: AZD3514 is a first-in-class, orally bio-available, androgen-dependent and -independent androgen receptor inhibitor and selective androgen-receptor down-regulator (SARD). METHODS: In study 1 and 2, castration-resistant prostate cancer (CRPC) patients (pts) were initially recruited into a once daily (QD) oral schedule (A). In study 1, pharmacokinetic assessments led to twice daily (BID) dosing (schedule B) to increase exposure. Study 2 explored a once daily schedule. RESULTS: In study 1, 49 pts were treated with escalating doses of AZD3514 (A 35 pts, B 14 pts). Starting doses were 100 mg (A) and 1000 mg (B). The AZD3514 formulation was switched from capsules to tablets at 1000 mg QD. 2000 mg BID was considered non-tolerable due to grade (G) 2 toxicities (nausea [N], vomiting [V]). No adverse events (AEs) met the dose-limiting toxicity (DLT) definition. Thirteen pts received AZD3514 in study 2, with starting doses of 250 mg QD. The most frequent drug-related AEs were N: G1/2 in 55/70 pts (79 %); G3 in 1 pt (1.4 %); & V: G1/2 in 34/70 pts (49 %) & G3 in 1 pt (1.4 %). PSA declines (≥50 %) were documented in 9/70 patients (13 %). Objective soft tissue responses per RECIST1.1 were observed in 4/24 (17 %) pts in study 1. CONCLUSION: AZD3514 has moderate anti-tumour activity in pts with advanced CRPC but with significant levels of nausea and vomiting. However, anti-tumour activity as judged by significant PSA declines, objective responses and durable disease stabilisations, provides the rationale for future development of SARD compounds.

An economic evaluation of a chlorhexidine chip for treating chronic periodontitis: the CHIP (chlorhexidine in periodontitis) study.

BACKGROUND: The authors previously suggested that an adjunctive, controlled-release chlorhexidine, or CHX, chip may reduce periodontal surgical needs at little additional cost. This article presents an economic analysis of the CHX chip in general dental practice. METHODS: In a one-year prospective clinical trial, 484 chronic periodontitis patients in 52 general practices across the United States were treated with either scaling and root planing, or SRP, plus any therapy prescribed by treating, unblinded dentists; or SRP plus other therapy as above but including the CHX chip. Economic data were collected from bills, case report forms and 12-month treatment recommendations from blinded periodontist evaluators. RESULTS: Total dental charges were higher for SRP + CHX chip patients vs. SRP patients when CHX chip costs were included (P = .027) but lower when CHX chip costs were excluded (P = .012). About one-half of the CHX chip acquisition cost was offset by savings in other charges. SRP + CHX chip patients were about 50 percent less likely to undergo surgical procedures than were SRP patients (P = .021). At the end of the trial, periodontist evaluators recommended similar additional procedures for both groups: SRP, about 46 percent; maintenance, about 37 percent; surgery, 56 percent for SRP alone and 63 percent for SRP + CHX chip. CONCLUSIONS: Adjunctive CHX chip use for general-practice patients with periodontitis increased costs but reduced surgeries over one year. At study's end, periodontists recommended similar additional surgical treatment for both groups. CLINICAL IMPLICATIONS: In general practice, routine use of the CHX chip suggests that costs will be partially offset by reduced surgery over at least one year.

Using the PerioChip in treating adult periodontitis: an interim report.

Multicenter clinical trials have established that the adjunctive use of the subgingival controlled release of chlorhexidine, in the form of the PerioChip, significantly reduces pocket probing depth, improves probing attachment levels, and reduces bleeding on probing compared to scaling and root planing alone, for periods up to 9 months. The purpose of the present study was to report on the adjunctive use of the PerioChip for the long-term management of adult periodontitis for 2 years. A total of 836 patients with adult periodontitis from private dental offices were recruited into the trial. This interim report is on the first 72 patients to have completed the 2-year study. Treatments included initial definitive therapy followed by PerioChip placement in pocket sites with a pocket probing depth of > or = 5 mm after 1 month. Subsequently, the patients received routine periodontal maintenance therapy together with the placement of a PerioChip in pockets with pocket probing depths > or = 5 mm every 3 months. Results indicated that there was a continuous decrease in pocket probing depth over the 2 years (1.26 +/- 0.77 mm). This decrease in pocket probing depth was marked over the first 9 to 12 months, and then appeared to be less marked over the next 12 months. At 2 years, 60% of the patients had at least 2 pockets showing a reduction of 2 mm or more, and only 10% of the patients showed no change or increased pocket probing depth. The results indicate that adjunctive PerioChip use is a clinically effective treatment option for dental professionals and their patients for the long-term management of adult periodontitis.

The cost-effectiveness of a new chlorhexidine delivery system in the treatment of adult periodontitis.

BACKGROUND: Periodontal treatment is costly. The authors assessed the potential economic impact of a new periodontal chemotherapeutic, testing the hypothesis that its adjunctive use would result in reduced periodontal surgical needs. METHODS: An economic model estimated treatment needs following two clinical trials of the adjunctive use of a chlorhexidine, or CHX, -containing chip compared with scaling and root planing, or SRP, alone. Needs were based on periodontal status at nine months and a probabilistic algorithm; costs were assigned on the basis of a national dental survey and an average wholesale price of the CHX chip. RESULTS: The base case model projected significantly more maintenance procedures and significantly fewer periodontal surgical procedures for patients treated with SRP and the CHX chip compared with patients who were treated with SRP alone (54.4 percent vs. 46.4 percent, P = .014; 29.2 percent vs. 35.5 percent, P = .015, respectively). Average total costs of care for patients treated with SRP and CHX chip were $737 +/- $244 compared with $734 +/- $239 for patients treated with SRP alone. Sensitivity analyses to account for variations in practice patterns did not appreciably alter the results. When data were analyzed after only three or six months of treatment, the significant differences in treatment needs disappeared. CONCLUSIONS: The CHX chip is a new, apparently cost-effective treatment option for non-surgical periodontal therapy. Adjunctive use of the CHX chip could reduce periodontal surgical needs significantly at little or no additional cost. CLINICAL IMPLICATIONS: Results suggest that incorporating the CHX chip into routine practice requires a new algorithm for management of periodontal disease. To obtain full clinical benefit, treatment needs to be continued for nine months.

Local delivery of chemotherapeutic agents in periodontal therapy: has its time arrived?

The concept of locally delivering chemotherapeutic agents to the periodontal pocket as a method to treat periodontal disease has been studied for over 20 years. A number of locally delivered chemotherapeutic agents in periodontal therapy are either currently available or under investigation. Clinical efficacy derives from sustained-release technology to maintain an effective concentration of drug within the periodontal pocket for a clinically relevant length of time. Studied drugs have mainly been antimicrobials, both antibiotics and antiseptics. Most agents have been tested as adjuncts to scaling and root planing; a few have been studied as stand-alone monotherapies. Collectively, the data indicate that the use of locally delivered antimicrobials as adjuncts results in a significant increase in the reduction of probing depth compared with scaling and root planing alone. In other trials, results in reducing probing depth following the use of stand-alone locally delivered antimicrobials have been equivalent to those of scaling and root planing over a specified time. This Symposium was organized to present the current state-of-the-art with regard to the use of locally delivered antimicrobials in the treatment of periodontal disease. 5 experts in the field who have had considerable experience in studying locally delivered antimicrobials presented data. These speakers reviewed the clinical findings regarding efficacy of 5 different antimicrobial agents. An ensuing panel discussion was to consider treatment recommendations for locally delivered antimicrobials.

Adjunctive use of a subgingival controlled-release chlorhexidine chip reduces probing depth and improves attachment level compared with scaling and root planing alone.

The present studies evaluated the efficacy of a controlled-release biodegradable chlorhexidine (CHX) (2.5 mg) chip when used as an adjunct to scaling and root planing on reducing probing depth (PD) and improving clinical attachment level (CAL) in adult periodontitis. Two double-blind, randomized, placebo-controlled multi-center clinical trials (5 centers each) were conducted; pooled data are reported from all 10 centers (447 patients). At baseline, following 1 hour of scaling and root planing (SRP) in patients free of supragingival calculus, the chip was placed in target sites with PD 5 to 8 mm which bled on probing. Chip placement was repeated at 3 and/or 6 months if PD remained > or = 5 mm. Study sites in active chip subjects received either CHX chip plus SRP or SRP alone (to maintain study blind). Sites in placebo chip subjects received either placebo chip plus SRP or SRP alone. Examinations were performed at baseline; 7 days; 6 weeks; and 3, 6, and 9 months. At 9 months significant reductions from baseline favoring the chlorhexidine chip compared with both control treatments were observed with respect to PD (chlorhexidine chip plus SRP, 0.95 +/- 0.05 mm; SRP alone, 0.65 +/- 0.05 mm, P < 0.001; placebo chip plus SRP, 0.69 +/- 0.05 mm, P < 0.001) and CAL (chlorhexidine chip plus SRP, 0.75 +/- 0.06 mm; SRP alone, 0.58 +/- 0.06 mm, P < 0.05; placebo chip plus SRP, 0.55 +/- 0.06 mm, P < 0.05). The proportion of patients who evidenced a PD reduction from baseline of 2 mm or more at 9 months was significantly greater in the chlorhexidine chip group (19%) compared with SRP controls (8%) (P < 0.05). Adverse effects were minor and transient toothache, including pain, tenderness, aching, throbbing, soreness, discomfort, or sensitivity was the only adverse effect that was higher in the chlorhexidine group as compared to placebo (P = 0.042). These data demonstrate that the adjunctive use of the chlorhexidine chip results in a significant reduction of PD when compared with both SRP alone or the adjunctive use of a placebo chip. These multi-center randomized control trials suggest that the chlorhexidine chip is a safe and effective adjunctive chemotherapy for the treatment of adult periodontitis.

Comparative effects of platelet-derived growth factor-BB and insulin-like growth factor-I, individually and in combination, on periodontal regeneration in Macaca fascicularis.

Platelet-derived growth factor (PDGF) and insulin-like growth factor I (IGF-I) in combination have previously been shown to enhance periodontal regeneration. The objective of this study was to further characterize the biological effects of this combination of growth factors in non-human primates and compare the effects to those of each growth factor individually. Ligature-induced periodontitis was initiated in 10 cynomolgus monkeys. After periodontal lesions were established, surgery was performed, and either a methylcellulose gel vehicle or vehicle containing 10 micrograms each of either PDGF-BB, IGF-I or both PDGF-BB and IGF-I was applied to exposed root surfaces. Biopsies were taken 4 and 12 wk after treatment and the extent of periodontal regeneration was assessed by histomorphometry. At both 4 and 12 wk vehicle-treated lesions generally revealed minimal osseous defect fill (ODF) (8.5 +/- 2.1% and 14.5 +/- 5.7%, respectively) and new attachment (NA) (34.1 +/- 5.2% and 26.6 +/- 10.5%, respectively). IGF-I treatment did not significantly alter healing compared to vehicle in any parameter at both 4 and 12 wk. PDGF-BB-treated sites exhibited significant (p < 0.05) regeneration of NA (69.6 + 12.0%) at 12 wk; trends for PDGF-BB treatment effect were also observed in other parameters at 4 and 12 wk, although these increases were not statistically significant. Treatment with PDGF-BB/IGF-I resulted in 21.6 +/- 5.1% and 42.5 +/- 8.3% ODF at 4 and 12 wk, respectively, and 64.1 +/- 7.7% and 74.6 +/- 7.4% NA at 4 and 12 wk, respectively (all significantly greater than vehicle, p < 0.05). The results from this study demonstrated that: 1) IGF-I alone at the dose tested did not significantly alter periodontal wound healing; 2) PDGF-BB alone significantly stimulated NA, with trends of effect on other parameters; and 3) the PDGF-BB/IGF-I combination resulted in significant increases in NA and ODF above vehicle at both 4 and 12 wk.

The effect of systemically administered PDGF-BB on the rodent skeleton.

Platelet-derived growth factor (PDGF), an osteoblast mitogen, has been demonstrated to accelerate fracture healing and periodontal bone repair when applied locally in vivo. To explore whether PDGF could stimulate bone formation in intact bone, we administered it systemically to rats rendered acutely estrogen-deficient. Because PDGF may stimulate bone resorption in vitro, PDGF was administered with and without an antiresorptive agent (alendronate). All treatments were given by intravenous injection 3 times a week for 6 weeks. Spinal bone mineral density (BMD) decreased by 5% in the vehicle-treated ovariectomized (OVX) rats by the end of the study as determined by DXA. Treatment with PDGF prevented this bone loss and significantly (p < 0.05) increased the bone density in the spine (9%) and whole skeleton (5.8%). Combined treatment with PDGF and alendronate resulted in a greater increase at the spine (18%) and whole skeleton (12.8%) than either agent alone. Histomorphometric analysis demonstrated that treatment with PDGF increased the osteoblast number and osteoblast perimeter without consistent changes in osteoclast estimates. Biomechanical testing demonstrated that PDGF administration increased the vertebral body compressive strength and femoral shaft torsional stiffness and resulted in a trend for enhanced femoral head shearing strength. Coadministration of alendronate further increased these indices of bone strength. PDGF administration also caused premature closure of the growth plate, decreased body fat, and resulted in extraskeletal collagen deposition. We therefore demonstrate, for the first time, that systemic administration of PDGF can increase bone density and strength throughout the skeleton.

An age-related decrease in the concentration of insulin-like growth factor binding protein-5 in human cortical bone.

The skeletal contents of insulin-like growth factor-2 (IGF-II), insulin-like growth factor binding protein-5 (IGFBP-5), and insulin-like growth factor binding protein-3 (IGFBP-3) were determined in duplicate samples of human femoral cortical bone obtained from 64 subjects (44 males and 20 females) between the ages of 20 and 64 years. The results of these quantitative measurements revealed an age-related decrease in the femoral cortical content of IGFBP-5 (r = -0.272, P = 0.031) in the total population. Although the femoral cortical content of IGF-II did not show a similar decrease with age, it could be correlated to the femoral cortical content of IGFBP-5 (r = 0.442, P < 0.001). In contrast, the femoral cortical content of IGFBP-3 did not decrease with age and could not be correlated to the femoral cortical contents of either IGFBP-5 or IGF-II. Comparisons of these results with previous measurements of insulin-like growth factor-1 (IGF-I) and transforming growth factor-beta (TGF-beta), in extracts of the same bones, showed significant cross-correlations between the femoral cortical contents of each of these growth factors and the femoral cortical contents of IGFBP-5 (r = 0.625 for IGF-I versus IGFBP-5, r = 0.554 for TGF-beta versus IGFBP-5, P < 0.001 for each) but not IGFBP-3.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of canine and non-human primate animal models for periodontal regenerative therapy: results following a single administration of PDGF/IGF-I.

Two commonly used animal models for evaluating putative periodontal regenerative therapies are the beagle dog model with natural periodontal disease and the non-human primate with ligature-induced attachment loss. The host response, microbiology, and skeletal rates of remodeling of these two models are summarized. In addition, the results of experiments comparing the healing response to periodontal surgery with and without concurrent use of the combination of platelet-derived growth factor (PDGF) and insulin-like growth factor-I (IGF-I) in these models are presented. At 1 month, PDGF/IGF-I administration resulted in a 64.1% and 51.4% increase in new attachment formation in the non-human primate and canine, respectively, while controls (surgery plus placebo) demonstrated 34.1% and 8.6% increases in new attachment formation in the non-human primate and canine models, respectively. Further, application of PDGF/IGF-I stimulated 21.6% and 65% osseous defect fill in the non-human primate and canine, respectively, while controls demonstrated 8.5% and 14.5% osseous defect fill in the non-human primate and canine, respectively. The osseous response in the canine appears greater than that of the non-human primate, and the new attachment formation was more substantial in the non-human primate than the canine. However, in general these data demonstrate a high degree of consistency in the effects of PDGF/IGF-I in promoting periodontal regeneration. Positive results in these two models--the dog with natural periodontal disease and the non-human primate with ligature-induced attachment loss--justify human clinical trial testing of a putative regenerative therapy.

Impaired early bone formation in periodontal fenestration defects in dogs following application of insulin-like growth factor (II). Basic fibroblast growth factor and transforming growth factor beta 1.

Effects of a topically applied growth factor combination on fibroblast migration, collagen fiber formation and bone regeneration were studied in standardized periodontal defects in 4 beagle dogs. Following elevation of facial mucoperiosteal flaps, fenestration defects, 3 mm in diameter, were made through the cortical bone and into the dentin of maxillary and mandibular teeth. Collagen sponges, impregnated with 200 ng insulin-like growth factor II, 20 ng basic fibroblast growth factor and 6 ng transforming growth factor beta 1 were fitted to defects randomly in right or left quadrants and the flaps repositioned and sutured. Contralateral control defects received the collagen with vehicle only. Experimental procedures were staggered to allow observations of healing 3, 7, 10, and 14 days after surgery. Histometric analysis showed no differences in fibroblast and collagen density between control and growth factor defects. Bone regeneration was significantly greater in control than in growth factor defects 10 and 14 days after surgery. The rate of healing generally appeared more affected by intra-dog variations or procedural variations than by the growth factor combination.

The combination of platelet-derived growth factor-BB and insulin-like growth factor-I stimulates bone repair in adult Yucatan miniature pigs.

The combination of insulin-like growth factor-I and platelet-derived growth factor-BB has previously been shown to stimulate healing of soft tissue wounds and the formation of bone and ligament around teeth. The purpose of the present study was to evaluate the effects of platelet-derived growth factor-BB and insulin-like growth factor-I individually and in combination on the healing of osseous wounds. Four standardized cortical wounds were created in each tibia of 11 adult Yucatan miniature pigs. The wounds in one tibia per animal were treated with either purified recombinant human insulin-like growth factor-I, platelet-derived growth factor-BB, or both in a methylcellulose gel. The wounds in each contralateral tibia received placebo gel alone. Coded serial sections of each wound were evaluated by computer-aided histomorphometry 21 days after surgery. The area and perimeter of the newly formed mineralized callus, the thickness of the total callus, and the percentage of mineralized tissue within the callus were significantly increased compared with the values of matched controls only in wounds treated with a combination of insulin-like growth factor-I and platelet-derived growth factor-BB. No significant differences in the measured parameters of callus formation were found in wounds treated with either insulin-like growth factor-I or platelet-derived growth factor-BB alone. Cartilage was present only in sites treated with insulin-like growth factor-I alone. These results suggest that the combination of platelet-derived growth factor-BB and insulin-like growth factor-I stimulates bone formation in wounds in long bones of adult animals and that these growth factors act via different pathways during the repair process.

Interleukin 1-beta in symptomatic and asymptomatic human periradicular lesions.

Interleukin 1 beta (IL-1 beta) has been shown to be a potent mediator of bone resorption and has been implicated in resorption in periradicular lesions. In this study we compared the local concentrations of IL-1 beta in symptomatic and asymptomatic human periradicular lesions. Periradicular tissues from patients with symptomatic and asymptomatic lesions were obtained and stored at -70 degrees C. Pulpal tissues from unerupted third molars and chronically inflamed gingival tissues were also obtained and used as negative and positive controls, respectively. Tissue samples were homogenized, and supernatants were assayed for IL-1 beta by the enzyme-linked immunosorbant assay. Significantly higher levels of IL-1 beta were found in symptomatic and asymptomatic lesions and inflamed gingival tissues compared with uninflamed pulp tissues. There was a trend toward higher levels of IL-1 beta in symptomatic lesions compared with asymptomatic lesions, but the difference was not significant. The results suggest that IL-1 beta may play a significant role in the pathogenesis of human periradicular lesions.

Age-related decreases in insulin-like growth factor-I and transforming growth factor-beta in femoral cortical bone from both men and women: implications for bone loss with aging.

We determined the skeletal content of insulin-like growth factor-I (IGF-I) and transforming growth factor-beta (TGF beta) in human bone as a function of age, using 66 samples of femoral cortical bone obtained from 46 men and 20 women between the ages of 20-64 yr. We found a linear decline in the skeletal content of IGF-I (nanograms per mg protein) with donor age (r = -0.43; P < 0.001) in the total population. The skeletal content of TGF beta also decreased with age (i.e. 1/TGF beta vs. age; r = 0.28; P < 0.02) for the total population. We did not observe any difference in the skeletal growth factor content between male and female donors. IGF-I content, when analyzed by decade divisions of age, showed a reduction between the 20- to 29-yr-old and the 50- to 59-yr-old subjects (P < 0.02). The loss rate of IGF-I was 1.56 ng/mg protein.yr, corresponding to a net loss of 60% of skeletal IGF-I between the ages of 20-60 yr. The loss rate of TGF beta was 0.03 ng/mg protein.yr, corresponding to a net loss of 25% of the skeletal TGF beta between the ages of 20-60 yr.

Elevated IGF-II and TGF-beta concentrations in human calvarial bone: potential mechanism for increased graft survival and resistance to osteoporosis.

Calvarial bone grafts may have greater survival as donor tissue than bone from other sites. Furthermore, calvarial bone is resistant to osteoporosis. Because bone contains growth factors that may play an important role in the regulation of bone repair, we proposed that bone from calvaria may be enriched in one or more growth factors. To test this hypothesis, samples of bone from 10 men 64 years of age or older that were obtained at autopsy from three skeletal sites (calvaria, iliac crest, and vertebral body) were cleaned, extracted by demineralization, and assayed for growth factors insulin-like growth factor I, insulin-like growth factor II, and transforming growth factor-beta. Insulin-like growth factor II and transforming growth factor-beta concentrations were significantly higher in calvaria than in iliac crest or vertebral body. We conclude that the increased concentrations of growth factors in calvarial bone may lead to a greater capacity for bone repair and graft retention.

Growth factors to stimulate bone formation.

During the past decade we and others have shown that bone is a storehouse for growth factors. Accordingly, bone contains a number of growth factors including insulin-like growth factors I and II (IGF-I, IGF-II) transforming growth factor (TGF-beta 1, TGF-beta 2), platelet-derived growth factor, basic and acidic fibroblast growth factor, and bone morphogenetic proteins (BMPs). Osteoblasts have been shown to produce many of these growth factors, which then act in an autocrine and paracrine fashion. The production of these growth factors is regulated by both systemic hormones and local mechanical stress. Recent studies on the relative distribution of bone growth factors during different physiologic and pathologic situations indicate that the concentration of bone growth factors is not invariant and provide indirect evidence that growth factors deposited in bone have physiologic significance. In addition, many of these bone growth factors have been shown to increase bone formation either systemically or locally in vivo. Based on the past findings, we propose that different growth factors may have a specific role in regulating proliferation and differentiation of different stages of osteoblast lineage cells and play important roles in the local regulation of bone formation.

Generalized osteoarthritis associated with increased insulin-like growth factor types I and II and transforming growth factor beta in cortical bone from the iliac crest. Possible mechanism of increased bone density and protection against osteoporosis.

OBJECTIVE: To investigate whether growth factors stored in bone might explain the increased bone density and resistance to osteoporosis in generalized osteoarthritis. METHODS: Levels of insulin-like growth factor (IGF) types I and II and transforming growth factor beta (TGF beta) were measured in extracts of cortical bone from the iliac crest obtained at necropsy from subjects with or without osteoarthritis of the hands. RESULTS: Concentrations of IGF-I, IGF-II, and TGF beta were significantly higher in extracts of bone powder from subjects in the osteoarthritis group than in extracts from subjects in the control group. CONCLUSION: The results suggest that the increased bone density and resistance to osteoporosis in patients with osteoarthritis may be associated with increased skeletal concentrations of IGF-I, IGF-II, and TGF beta and may reflect a generally increased biosynthetic activity of osteoblasts in these patients.

Ovariectomy selectively reduces the concentration of transforming growth factor beta in rat bone: implications for estrogen deficiency-associated bone loss.

Previous work showed that production of transforming growth factor beta (TGF-beta) by osteoblast-like rat UMR 106 cells was increased by 17 beta-estradiol at physiological concentrations. To determine whether ovariectomy alters the concentration of TGF-beta in rat long bones, female Sprague-Dawley rats were either sham-operated (n = 19) or ovariectomized (n = 19), pair-fed a semisynthetic diet for 6 weeks, and sacrificed. Tibial and femoral diaphyses were removed and extracted by demineralization. Ovariectomy lowered serum estrogen; did not alter body weight, serum magnesium, or serum 1,25-dihydroxyvitamin D; and produced only modest differences in serum calcium and phosphate concentrations. Hydroxyproline was higher and extractable protein was lower in bones from ovariectomized rats than in bones from sham-operated rats; calcium content did not differ between the two groups of animals. Ovariectomy lowered the concentration of TGF-beta in bone but did not change the concentration of insulin-like growth factors I or II compared with values in bone from control animals. The reduction of bone TGF-beta was evident 6 weeks after surgery but not at 3 weeks. Treatment of ovariectomized rats with estrogen eliminated the TGF-beta deficit. To determine whether 17 beta-estradiol increased TGF-beta production by normal bone cells, mouse osteoblasts were treated for 2 days with 17 beta-estradiol. The production of TGF-beta was increased almost 2-fold by 1 nM 17 beta-estradiol, and short-term treatment stimulated the intracellular accumulation of TGF-beta 1 mRNA. We conclude that ovariectomy reduces deposition of TGF-beta in rat bone and that diminished skeletal TGF-beta could play a role in the pathogenesis of bone loss, fractures, and microfractures that occur in estrogen-deficient states. Our results support the possibility that estrogen and bone TGF-beta may be necessary for normal maintenance of the skeleton in female rats.