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PHARMACOKINETICS AND PHARMACODYNAMICS

Clinical Pharmacology of Multiple Doses of Lasofoxifene in Postmenopausal Women

Mark Gardner, PhD, Ann Taylor, MD, Greg Wei, PhD, Albert Calcagni, Jr, Barbara Duncan and Ashley Milton, PhD

From Pfizer Inc, Groton, Connecticut.

Address for reprints: Ashley Milton, PhD, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340.


   ABSTRACT
TOP
 ABSTRACT
METHODS AND MATERIALS
 RESULTS
 DISCUSSION
 REFERENCES
 
Lasofoxifene, a next-generation selective estrogen receptor modulator, is undergoing phase 3 clinical development for osteoporosis. This study evaluated daily lasofoxifene for 14 days in healthy postmenopausal women. A loading dose of 5 times the daily dose was followed by daily doses of 0.01 mg (n = 8), 0.03 mg (n =8), 0.1 mg(n = 16), 0.3 mg (n =9), 1 mg (n = 8), or placebo (n = 16). Samples were collected for pharmacokinetic and pharmacodynamic assessments. Lasofoxifene was well tolerated; study drug–associated adverse events were mild and unrelated to dose. There was a predictable increase in plasma concentrations of lasofoxifene with dose. Pharmacokinetic parameters included mean half-life of 165 hours, mean area under the plasma concentration-time curve from time 0 to 24 hours ranging from 1.67 ng·h/mL to 137 ng·h/mL, and mean maximum observed plasma concentration ranging from 0.09 ng/mL to 6.43 ng/mL. Lasofoxifene partially suppressed luteinizing hormone, follicle-stimulating hormone, low-density lipoprotein, and N-telopeptide.

Key Words: Lasofoxifene • osteoporosis • pharmacology • pharmacokinetics • pharmacodynamics

The average age of onset of menopause has not changed dramatically despite significant increases in life expectancy. Women who experience menopause at around age 52 years can now expect to live into their 80s, which means that approximately one third of a woman's life is spent postmenopausal. Physiologically, we are just beginning to understand all the health consequences of diminished hormones. One area that has been the focus of considerable research is the increased risk of osteoporosis in women after menopause.

Osteoporosis affects more than 44 million Americans and results in approximately 300 000 hip fractures each year.1 Menopause-related osteoporosis is caused by an imbalance between bone-building osteoblasts and bone-resorbing osteoclasts leading to a net decrease in bone mineral density (BMD).

The decrease in circulating estrogens that accompanies menopause has been implicated in contributing to osteoporosis. To exert its activity, estrogen binds to 1 of 2 receptor subtypes that then dimerize. This complex then binds DNA to either initiate or inhibit specific gene transcription, depending on specific cofactors in the individual tissue types. In the case of osteoporosis, estrogen stimulates genes that result in osteoclast destruction, thereby preserving bone. It has recently been discovered that estrogen activity is not necessarily directly related to estrogen receptor binding affinity and that the various estrogens differentially function as agonists and antagonists (reviewed in Katzenellenbogen et al2 and McDonnell et al3). For example, the selective estrogen receptor modulators (SERMs) bind estrogen receptors but may have differing effects, depending on the site of action.

This exploratory investigation was undertaken to assess the pharmacokinetic and pharmacodynamic properties of lasofoxifene, a new SERM, at a range of potentially therapeutically active doses.


   METHODS AND MATERIALS
TOP
 ABSTRACT
 METHODS AND MATERIALS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects and Study Design
This randomized, placebo-controlled, investigator-blind, multiple oral dose study of the clinical pharmacology of lasofoxifene in fasted, postmenopausal, female volunteers was conducted at 2 study sites. This study was designed to include 4 groups of 8 subjects each: 3 lasofoxifene groups (0.1, 0.3, and 1.0 mg) and 1 placebo group. Half of the members of each of these groups were at each of the 2 study sites. All 4 of these treatment groups were evaluated in parallel. The protocol was amended to add a second phase with an additional 32 subjects in 4 groups of 8 subjects each, 3 lasofoxifene groups (0.01, 0.03, and a second 0.1 mg) and a second placebo group, all at one of the study sites. All 4 of these treatment groups were evaluated in parallel.

Subjects could have been of any race but must have been menopausal and within 30% of the ideal weight range for their height and frame size. Subjects were confirmed to be menopausal with serum levels of follicle stimulating hormone (FSH) greater than 30 IU/L and serum estradiol levels less than 30 pg/mL. Hormone therapy (estrogen-containing regimens), SERMs (eg, raloxifene or toremifene), calcitonin or related products, sodium fluoride, or calcium supplements must not have been taken within the previous 3 months. Treatment with bisphosphonates (eg, etidronate or alendronate) must not have been administered within the previous 12 months. Subjects were required to refrain from strenuous physical activity beginning 72 hours before admission and throughout the duration of the study.

The study was conducted at PRACS Institute Limited in Fargo, North Dakota, and at Clinical Pharmacology Associates in Miami, Florida. The protocol, consent documents, and any protocol amendments or addenda were approved by each participating center's institutional review board (IRB): PRACS Institute IRB and Southern Institutional Review Board. Pfizer Inc ensured that IRB and ethics committee approval was received before shipping the drug. Written informed consent was required from each subject who participated in the study, or from her authorized representative, before the subject's study enrollment.

Treatments
Subjects received either lasofoxifene, at doses of 0.01 mg/d, 0.03 mg/d, 0.1 mg/d, 0.3 mg/d, or 1.0 mg/d, or placebo. Lasofoxifene was administered as an oral solution for 14 days. Because of the relatively long half-life of lasofoxifene ({approx}6 days), a loading dose equivalent to 5 times the maintenance dose was administered on day 1 to shorten the time needed to attain steady-state plasma concentrations. A previous study that examined bone marker, lipid, and hormone responses to lasofoxifene suggested that doses of lasofoxifene at 3, 10, and 20 mg/d were at or above the optimal human dose for lasofoxifene (data on file, Pfizer Inc). This study was designed to investigate the effects of lower doses of lasofoxifene to facilitate dose selection in phase 2/3 trials.

All doses were administered under supervision in the morning each day after a fast of at least 8 hours. Subjects were required to refrain from lying down and from drinking caffeinated beverages during the first 4 hours after each dosing. On days 1 and 14, subjects were required to fast for 4 hours after dosing and were confined to the clinic under continuous observation for at least 12 hours after dosing.

Pharmacokinetic Analysis
For analysis of lasofoxifene, blood was collected in heparin tubes on day 1 predose and at 4, 8, and 12 hours postdose; predose on days 2, 4, 6, 8, 10, 12, and 14; and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, 216, 264, 336, 408, 504, and 672 hours after the dose on day 14. After centrifugation, all plasma samples were stored frozen at –20°C within 1 hour of collection until assayed. Plasma concentrations of lasofoxifene were determined by a validated high-performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) method. Lasofoxifene concentrations were determined after a liquid-liquid extraction from human plasma: 20 µL of [D-5]lasofoxifene internal standard in 50% acetonitrile (volume/volume) was added to 1.0 mL of plasma. After vortexing briefly, the sample received 3 mL of methyl-t-butyl ether and was capped and vortexed for 1 minute. The sample was centrifuged at 3000 revolutions per minute for 10 minutes at room temperature to separate the phases. The organic phase was transferred to a new tube, evaporated under nitrogen in a 40°C water bath, reconstituted in 150 µL of HPLC mobile phase (80% acetonitrile/20% water/0.1% formic acid), and vortexed. A 20- to 30-µL aliquot was injected into an Applied-Biosystem Sciex API III-Plus LC/MS/MS system (MDI SCIEX, Concord, Ontario, Canada). The MS/MS detector with a heated nebulizer interface operating in the positive ionization mode monitored the transition ions mass-to-charge ratio 414<-97.9 and 419<-97.9 for lasofoxifene and [D-5]lasofoxifene, respectively. The linear range of quantitation for lasofoxifene was 0.025 to 6.00 ng/mL plasma, with a lower limit of quantitation of 0.025 ng/mL.

Lasofoxifene pharmacokinetic parameter values were calculated for each subject using noncompartmental analysis of concentration-time data. Maximum observed plasma concentrations (Cmax) of lasofoxifene after the final dose were estimated directly from the experimental data. Tmax was defined as the time of the first occurrence of Cmax. The terminal phase rate constant (Kel) was estimated using least-squares regression analysis of the plasma concentration-time data obtained during the terminal log-linear phase. Half-life was calculated as natural logarithm (ln) 2/Kel. Area under the plasma lasofoxifene concentration-time curve from time 0 to 24 hours after the final dose [AUC(0-24)] was estimated using the linear trapezoidal approximation.

Pharmacodynamic Analysis
All samples were collected predose on days 1, 7, and 14 and at 7 and 14 days after the day-14 dose. For analysis of low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), samples were collected in heparinized tubes, centrifuged, and then stored frozen at –20°C within 1 hour of collection until assayed. For analysis of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and bone-specific alkaline phosphatase (BSAP), samples were collected in tubes containing no additives. Specimens remained at room temperature until clotted, and then serum samples were stored frozen until assayed. For analysis of N-telopeptide (NTx), unpreserved urine from the second morning voiding was collected and frozen at –20°C until assayed.

All pharmacodynamic measurements were made by Esoterix (Calabasas Hills, Calif). Both LH and FSH were measured by ICMA assays4 from Endocrine Sciences (Calabasas Hills, Calif). The FSH standard was World Health Organization (WHO) International Standard 83/575. At a standard concentration of 0.1 IU/L, the percentage coefficient of variation (%CV) was 16%; whereas at 0.7 IU/L, it was 4.3%. The LH standard was WHO 2nd International Standard 80/522. The interassay CV is 4.7% at LH levels between 0.02 and 5 IU/L. Boehringer-Mannheim (Indianapolis, Ind) procedures were used for the measurement of LDL-C and HDL-C.5 Bone-specific alkaline phosphatase was measured by Tandem-R Ostase IRMA (Beckman Coulter, Fullerton, Calif),6 with a sensitivity of 2 ng/mL. Urinary NTx was measured by the Osteomark ELISA (Inverness Medical Innovations Inc, Waltham, Mass),7 with a sensitivity of 20 nm, which was normalized with urine creatinine so that results could be reported to 10 nmol bone collagen equivalents (BCE)/mmol creatinine.

Safety Assessment
At screening, all subjects underwent a complete medical history and a full physical examination, including an internal pelvic examination. If uterine enlargement was present, a transvaginal ultrasound was conducted to assess the presence of fibroids or other significant uterine abnormality.

Vital signs (blood pressure, pulse rate, and oral temperature) and clinical laboratory tests were measured at screening, just before dosing on days 1 through 14, and at 7 and 14 days after the last dose of lasofoxifene on day 14. A 12-lead resting electrocardiogram was obtained at screening and just before dosing on days 1 and 14. A final physical examination was performed at completion or at any premature discontinuations.


   RESULTS
TOP
 ABSTRACT
 METHODS AND MATERIALS
 RESULTS
DISCUSSION
 REFERENCES
 
A total of 65 subjects were enrolled. One subject from the 0.3 mg/d lasofoxifene group withdrew for reasons unrelated to the study drug on day 2 after having received 2 doses of lasofoxifene. That subject's data were included in the safety analysis but not in the pharmacokinetic or pharmacodynamic evaluations.

Subjects were postmenopausal women ranging in age from 48 years to 61 years. Subjects' mean weight ranged from 68 kg to 76 kg, and mean height ranged from 159 cm to 166 cm. Mean LDL-C and HDL-C levels ranged from 141 mg/dL to 155 mg/dL and 44 mg/dL to 50 mg/dL, respectively. Subjects' mean FSH levels were between 62 mIU/mL and 95 mIU/mL, and their mean LH levels were between 28 mIU/mL and 50 mIU/mL. Mean NTx levels ranged from 48 nmol BCE/nmol creatinine to 85 nmol BCE/nmol creatinine.

Pharmacokinetic Analysis
The mean half-life of lasofoxifene at doses of 0.03 mg/d to 1.0 mg/d was 165 hours (range, 96-222 hours). Consequently, there were relatively small fluctuations in concentrations during the 24-hour dosing interval, with 14 days of treatment yielding plasma concentrations that increased with dose over the range of 0.01 to 1.0 mg (Table I). The half-life for the 0.01 mg/d lasofoxifene dose could not be estimated because the time intervals during which quantifiable concentrations were available were too short relative to the projected half-lives. Administration of the loading doses allowed steady-state concentrations to be reached within approximately 7 to 9 days (Figure 1).


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  		Table I Summary of Lasofoxifene Pharmacokinetic Parameters

 


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  		Figure 1. Lasofoxifene plasma concentrations after oral administration.

 

Pharmacodynamic Analysis
The LDL-C levels decreased over time in all groups, but greater reductions were seen in lasofoxifene-treated subjects, with the greatest mean LDL-C decrease occurring in subjects treated with 0.1 and 0.3 mg/d lasofoxifene (15% to 22%). In addition, LDL-C tended to be suppressed up to 7 days after discontinuation of lasofoxifene. Figure 2 shows mean LDL-C values throughout the study duration. Mean HDL-C did not change over time for any of the groups (data not shown).



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  		Figure 2. Mean low-density lipoprotein cholesterol values (percentage of change from baseline).

 
Plasma LH levels tended to decrease on days 7, 14, 21, and 28 for all lasofoxifene-treated subjects (Figure 3). An almost 30% reduction in mean LH levels occurred at the 0.1 mg/d dose and persisted on days 14 to 28. In contrast, mean LH levels in the placebo group decreased by only 3% to 12%. Mean FSH levels were reduced by 18% to 26% in all women taking the 0.01 mg/d, 0.03 mg/d, and 0.1 mg/d doses of lasofoxifene (Figure 4). These reductions were observed within 14 days after initiating lasofoxifene. At the higher doses (0.3 mg/d and 1 mg/d groups) and with placebo, the FSH responses were more variable, but overall, mean FSH levels in the placebo group were relatively unchanged. Mean FSH levels decreased in the 0.3 mg/d and 1.0 mg/d groups by 7% to 8% on day 14, the day of maximal suppression. Although baseline FSH levels were in the normal female postmenopausal range in all subjects, for placebo recipients and those administered 0.03 mg/d and 0.1 mg/d lasofoxifene, the mean baseline FSH levels were about 50% higher, which may explain some of the observed variability.



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  		Figure 3. Mean luteinizing hormone values (percentage of change from baseline).

 


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  		Figure 4. Mean follicle-stimulating hormone values (percentage of change from baseline).

 

Mean NTx excretion showed a modest reduction for all treatment groups, including placebo. Figure 5 shows the mean changes in NTx values throughout the study duration. Mean baseline NTx excretion was 61.1 ± 3.0 nmol BCE/mmol creatinine (range, 11-115 nmol BCE/mmol creatinine). NTx excretion tended to decrease with lasofoxifene dosing, with the greatest decrease of NTx (20% to 25%) occurring in the highest (0.3 mg/d and 1.0 mg/d) dose groups at 14 days. The mean changes on day 14 from the baseline were –1.5 nmol BCE/mmol creatinine (–3%) for the 0.01 mg group, –8.4 nmol BCE/mmol creatinine (–19%) for the 0.03 mg/d group, –6.1 nmol BCE/mmol creatinine (–2%) for 0.1 mg/d group, –17.9 nmol BCE/mmol creatinine (–20%) for the 0.3 mg group, –22.4 nmol BCE/mmol creatinine (–25%) for the 1 mg/d group, and –6.7 nmol BCE/mmol creatinine (–12%) for the placebo group. The 2 groups with the largest percentage decreases (0.3 mg/d and 1 mg/d lasofoxifene) also had higher baseline values, which may have contributed to the observation. There were no clearly identified changes in BSAP in this study (data not shown).



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  		Figure 5. Mean N-telopeptide values (percentage of change from baseline).

 

Adverse Events
A total of 62 adverse events was reported by 23 of the 49 subjects treated with lasofoxifene, 31 of which, reported by 16 subjects, were considered treatment associated. The most frequently reported adverse events reported by lasofoxifene-treated subjects were headache, dizziness, nausea, hot flushes, and diarrhea. A total of 8 adverse events were reported by 5 of 16 subjects receiving placebo, with the most frequently reported being headache and malaise.

There were no severe adverse events and no withdrawals because of adverse events reported during the study. All of the adverse events associated with treatment were mild, and almost all adverse events resolved within 24 hours. In general, clinical laboratory abnormalities were sporadic and transient and appeared unrelated to the study drug. The most common abnormalities, many of which were associated with abnormal baseline levels, included elevations in triglycerides, total cholesterol, and urine white blood cells.


   DISCUSSION
TOP
 ABSTRACT
 METHODS AND MATERIALS
 RESULTS
 DISCUSSION
REFERENCES
 
Among the SERMs, lasofoxifene is one of the most potent, with 10-fold higher binding affinities compared with others such as raloxifene, tamoxifen, and droloxifene.8,9 Competitive binding assay experiments demonstrated that lasofoxifene has high affinity for both the estrogen receptor (ER)-{alpha} and ER-ß and, in fact, was shown to bind ER-{alpha} with a greater affinity than even estradiol.10 Lasofoxifene is also very selective, possessing greater than 100-fold selectivity against all other steroid receptors.11,12 In addition, animal studies have shown lasofoxifene to be highly bioavailable (60%), which may contribute to the high in vivo potency seen in animal studies.12 Based on this information, this investigation was conducted to assess a low dose range of lasofoxifene.

In the present study, 14 days of treatment with lasofoxifene yielded plasma concentrations that increased with dose over the range of 0.01 to 1.0 mg. Peak plasma concentrations of lasofoxifene were reached in approximately 6.0 to 7.3 hours. In contrast, raloxifene is rapidly absorbed into the intestinal tract, reaching Cmax in only 0.5 hours.13 The overall half-life of lasofoxifene at doses ranging from 0.03 to 1.0 mg was 165 hours (range, 96-222 hours), resulting in relatively small fluctuations in concentrations during the 24-hour dosing interval. Raloxifene has a mean half-life of approximately 32.5 hours (range, 15.9-86.6 hours) at steady state.14,15 This difference may contribute to the greater potency of lasofoxifene over time.

In general, lasofoxifene had effects on specific estrogen-responsive biomarkers, as expected. In spite of wide baseline variability within the normal range, there was a tendency toward decreases in LH, FSH, and LDL-C at all doses and decreases in NTx at the higher doses (0.3 mg/d and 1 mg/d). The degrees of changes in LH, FSH, and LDL-C (and in NTx at the higher doses) were similar to those seen after administration of lasofoxifene at greater doses (3 mg/d, 10 mg/d, and 20 mg/d). These results suggest that there is a wide and flat dose-response curve for lasofoxifene activity at the pituitary, liver, and bone levels, which will allow for adequate therapeutic efficacy in a range of patient subgroups, including those who exhibit altered drug metabolism because of comorbidity, use of other medications, or age. Previous data have shown that lasofoxifene at doses ranging from 0.017 mg/d to 10 mg/d possess good bone protective and lipid-lowering activities without undue toxicity.16,17 The tendency toward a decreased response of NTx at lower doses raises the possibility that 0.3 mg is close to the maximally effective dose for bone markers.

NTx is a sensitive marker of bone loss in early postmenopausal women.18,19 It is difficult to compare these results with respect to NTx to those of estrogen or other SERMs because the duration of this study was considerably shorter than published literature on those other agents.20-23 However, decreases in NTx of the magnitude observed with lasofoxifene in this study have been associated with clinically meaningful increases in BMD,21,24 and previous studies of lasofoxifene at similar doses for up to 1 year have exhibited decreases in NTx less than those associated with estrogen but substantially greater than those seen with raloxifene.17,25

Lasofoxifene at all doses tested was generally safe and well tolerated in these healthy postmenopausal women. There were no deaths, serious adverse events, or withdrawals because of adverse events, and all treatment-associated adverse events were mild in intensity. Of importance is that there was no change in adverse event frequency or intensity with increasing dose. Combined with the prior study at doses up to 20 mg, this finding suggests that there may be a wide safety window for the administration of lasofoxifene.

DOI: 10.1177/0091270005283280


   REFERENCES
TOP
 ABSTRACT
 METHODS AND MATERIALS
 RESULTS
 DISCUSSION
 REFERENCES
 

1. National Osteoporosis Foundation. America's Bone Health: The State of Osteoporosis and Low Bone Mass in Our Nation. Washington, DC: National Osteoporosis Foundation; 2002.

2. Katzenellenbogen JA, O'Malley BW, Katzenellenbogen BS. Tripartite steroid hormone receptor pharmacology: interaction with multiple effector sites as a basis for the cell- and promoter-specific action of these hormones. Mol Endocrinol. 1996;10: 119-131.[CrossRef][ISI][Medline] [Order article via Infotrieve]

3. McDonnell DP, Clemm DL, Hermann T, Goldman ME, Pike JW. Analysis of estrogen receptor function in vitro reveals three distinct classes of antiestrogens. Mol Endocrinol. 1995;9: 659-669.[Abstract]

4. Pandian MR, Odell WD, Carlton E, Fisher DA. Development of third-generation immunochemiluminometric assays of follitropin and lutropin and clinical application in determining pediatric reference ranges. Clin Chem. 1993;39: 1815-1819.[Abstract]

5. Jarausch J. Evaluation of two assays for the direct determination of HDL and LDL cholesterol [abstract]. Presented at: Elsevier Science. Atherosclerosis. 1997;130(suppl 1): 13-13(1).

6. Panigrahi K, Delmas PD, Singer F, et al. Characteristics of a two-site immunoradiometric assay for human skeletal alkaline phosphatase in serum. Clin Chem. 1994;40: 822-828.[Abstract/Free Full Text]

7. Hanson DA, Weis MA, Bollen AM, Maslan SL, Singer FR, Eyre DR. A specific immunoassay for monitoring human bone resorption: quantitation of type I collagen cross-linked N-telopeptides in urine. J Bone Miner Res. 1992;7: 1251-1258.[ISI][Medline] [Order article via Infotrieve]

8. Eppenberger U, Wosikowski K, Kung W. Pharmacologic and biologic properties of droloxifene, a new antiestrogen. Am J Clin Oncol. 1991;14(suppl 2): S5-S14.

9. Bryant HU, Glasebrook AL, Yang NN, Sato M. A pharmacological review of raloxifene. J Bone Min Metab. 1996;14: 1-9.

10. Ke HZ, Thompson DD. Lasofoxifene (CP-336,156), a novel selective estrogen receptor modulator, in preclinical studies. J Amer Aging Assoc. 2002;25: 87-100.

11. Ke HZ, Paralkar VM, Grasser WA, et al. Effects of CP-336,156, a new, nonsteroidal estrogen agonist/antagonist, on bone, serum cholesterol, uterus and body composition in rat models. Endocrinology. 1998;139: 2068-2076.[Abstract/Free Full Text]

12. Rosati RL, Silva Jardine P, Cameron K, et al. Discovery and preclinical pharmacology of a novel, potent, nonsteroidal estrogen receptor agonist/antagonist, CP-336156, a diaryltetrahydronaphthalene. J Med Chem. 1998;41: 2928-2931.[CrossRef][ISI][Medline] [Order article via Infotrieve]

13. Morello KC, Wurz GT, DeGregorio MW. Pharmacokinetics of selective estrogen receptor modulators. Clin Pharmacokinet. 2003;42: 361-372.[CrossRef][ISI][Medline] [Order article via Infotrieve]

14. Snyder KR, Sparano N, Malinowski JM. Raloxifene hydrochloride. Am J Health Syst Pharm. 2000;57: 1669-1675.[Abstract/Free Full Text]

15. Raloxifene [prescribing information]. Indianapolis, Ind: Eli Lilly and Company; 2003.

16. Bolognese M, Weiss S, Ettinger M, Moffett AJ, Lee A. Lasofoxifene: a next generation selective estrogen receptor modulator (SERM) for the prevention of bone loss in postmenopausal women [abstract]. Osteoporos Int. 2004;15(suppl 1): S11.

17. Ettinger M, Schwartz E, Emkey R, et al. Lasofoxifene, a next generation selective estrogen receptor modulator (SERM), in the prevention of bone loss in postmenopausal women (S35-2). Presented at: ENDO; June 16-19, 2004; New Orleans, La. Abstract #S35-2.

18. Ebeling PR, Atley LM, Guthrie JR, et al. Bone turnover markers and bone density across the menopausal transition. J Clin Endocrinol Metab. 1996;81: 3366-3371.[Abstract]

19. Rosen CJ, Chesnut CH III, Mallinak NJ. The predictive value of biochemical markers of bone turnover for bone mineral density in early postmenopausal women treated with hormone replacement or calcium supplementation. J Clin Endocrinol Metab. 1997;82: 1904-1910.[Abstract/Free Full Text]

20. Prestwood KM, Pilbeam CC, Burleson JA, et al. The short-term effects of conjugated estrogen on bone turnover in older women. J Clin Endocrinol Metab. 1994;79: 366-371.[Abstract]

21. Prestwood KM, Kenny AM, Unson C, Kulldorff M. The effect of low dose micronized 17ss-estradiol on bone turnover, sex hormone levels, and side effects in older women: a randomized, double blind, placebo-controlled study. J Clin Endocrinol Metab. 2000;85: 4462-4469.[Abstract/Free Full Text]

22. Prestwood KM, Gunness M, Muchmore DB, Lu Y, Wong M, Raisz LG. A comparison of the effects of raloxifene and estrogen on bone in postmenopausal women. J Clin Endocrinol Metab. 2000;85: 2197-2202.[Abstract/Free Full Text]

23. Villareal DT, Binder EF, Williams DB, Schechtman KB, Yarasheski KE, Kohrt WM. Bone mineral density response to estrogen replacement in frail elderly women: a randomized controlled trial. JAMA. 2001;286: 815-820.[Abstract/Free Full Text]

24. Miller BE, De Souza MJ, Slade K, Luciano AA. Sublingual administration of micronized estradiol and progesterone, with and without micronized testosterone: effect on biochemical markers of bone metabolism and bone mineral density. Menopause. 2000;7: 318-326.[ISI][Medline] [Order article via Infotrieve]

25. McClung M, Omizo M, Weiss S, et al. Comparison of lasofoxifene and raloxifene for the prevention of bone loss in postmenopausal women [abstract]. J Bone Miner Res. 2004;19(suppl 1): S96. F424.



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