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The new england journal of medicine

original article

The Effects of Parathyroid Hormone,
Alendronate, or Both in Men with Osteoporosis
Joel S. Finkelstein, M.D., Annmarie Hayes, M.S.N., R.N.C., N.P.,
Joy L. Hunzelman, M.S.N., N.P., Jason J. Wyland, B.A., Hang Lee, Ph.D.,
and Robert M. Neer, M.D.

abstract

background
From the Endocrine Unit, Department of Because parathyroid hormone increases both bone formation and bone resorption, it
Medicine (J.S.F., A.H., J.L.H., J.J.W., R.M.N.), is possible that combining parathyroid hormone with an antiresorptive agent will en-
and the Biostatistics Center (H.L.), Massa-
chusetts General Hospital, Boston. Address hance its effect on bone mineral density.
reprint requests to Dr. Finkelstein at the En-
docrine Unit, Bulfinch 327, Massachusetts methods
General Hospital, 55 Fruit St., Boston, MA
02114, or at jfinkelstein@partners.org. We randomly assigned 83 men who were 46 to 85 years of age and had low bone densi-
ty to receive alendronate (10 mg daily; 28 men), parathyroid hormone (40 µg subcutane-
N Engl J Med 2003;349:1216-26. ously daily; 27 men), or both (28 men). Alendronate therapy was given for 30 months;
Copyright © 2003 Massachusetts Medical Society.
parathyroid hormone therapy was begun at month 6. The bone mineral density of the
lumbar spine, proximal femur, radial shaft, and total body was measured every six
months with the use of dual-energy x-ray absorptiometry. Trabecular bone mineral
density of the lumbar spine was measured at base line and month 30 by means of quan-
titative computed tomography. Serum alkaline phosphatase levels were measured ev-
ery six months. The primary end point was the rate of change in the bone mineral den-
sity at the posteroanterior spine.

results
The bone mineral density at the lumbar spine increased significantly more in men
treated with parathyroid hormone alone than in those in the other groups (P<0.001 for
both comparisons). The bone mineral density at the femoral neck increased significant-
ly more in the parathyroid hormone group than in the alendronate group (P<0.001) or
the combination-therapy group (P=0.01). The bone mineral density of the lumbar
spine increased significantly more in the combination-therapy group than in the alen-
dronate group (P<0.001). At 12 months, changes in the serum alkaline phosphatase
level were significantly greater in the parathyroid hormone group than in the alendro-
nate group or the combination-therapy group (P<0.001 for both comparisons).

conclusions
Alendronate impairs the ability of parathyroid hormone to increase the bone mineral
density at the lumbar spine and the femoral neck in men. This effect may be attributable
to an attenuation of parathyroid hormone–induced stimulation of bone formation by
alendronate.

1216 n engl j med 349;13 www.nejm.org september 25, 2003

The New England Journal of Medicine
Downloaded from nejm.org on October 24, 2011. For personal use only. No other uses without permission.
Copyright © 2003 Massachusetts Medical Society. All rights reserved.

serum the men provided written informed consent. 6. Compliance with the rum calcium level of less than 10.10 and in estrogen-deficient women11-13 ized system to receive alendronate alone (10 mg and reduces the risk of fracture in postmenopausal orally once daily.nejm.000 recruitment letters to men in the titian and was maintained at 1000 to 1200 mg daily Boston area.5 million fractures in this country each year.org september 25. parathyroid hormone. All least 15 ng per milliliter (37 nmol per liter). Copyright © 2003 Massachusetts Medical Society. nate therapy was begun at the base-line visit and pared the effects of alendronate alone. Thus. and testoster- one. and an additional five men were re. a se. 9. For personal use only. The men were strat- sorption. Bone mineral density was meas- be 46 to 85 years of age and to have a bone miner. the final cohort con. 12. A or or lateral projection or of the femoral neck that standardized questionnaire was administered at was at least 2 SD below the mean value for young each visit to assess side effects that had occurred normal men. mineral density of the spine (higher or lower than crease bone mineral density more than the use of ei. ified because their bone density was too high. etry at base line and every six months thereafter. Of 1730 men who returned the ques. Serum calcium was measured before and four men who were eligible for the study. ly. n engl j med 349. 575 were interested and were eligible for ceived 400 U of vitamin D daily. through diet or supplementation. since the previous study visit. Parathyroid hormone hormone alone. alendronate. 24. The study was not double-blind. inhibits osteoclastic bone resorp. Men who had disorders or were taking medi- such fractures occur in men. about 30 percent of ferase levels that were less than twice the upper lim- it of the normal range. and one month after parathyroid hormone therapy In order to be eligible. including measurement of serum cal- they missed screening appointments. study treatment was assessed with the use of medi- ter (2. 380 were disqual. Of these men. supplies. further screening.65 mmol per liter). All rights reserved.1 Although osteoporotic fractures are more common in women. They were also required to have a se. men7. To test this hypothesis. 3. because the institutional review board at Massachu- methods setts General Hospital considered it unethical to ad- minister placebo injections for two years. active peptic ulcer phosphonate. human parathyroid hor- women with osteoporosis. rum alkaline phosphatase level of less than 150 U The study was approved by the institutional re- per liter. or hepatic disease. men were required to began (month 7). 28 men). a serum creatinine level of cation diaries and counts of residual medication less than 2 mg per deciliter (177 µmol per liter). The level study subjects of calcium intake was estimated by a research die- We mailed 60.3 Alendronate increases bone mineral densi. 2003 1217 The New England Journal of Medicine Downloaded from nejm. leaving 98 cium.8 with osteoporosis. Twenty-four-hour urinary cruited from our clinic. No other uses without permission. Once-daily administra- tion of a parathyroid hormone fragment also in. a serum 25-hydroxyvitamin D level of at view board of Massachusetts General Hospital. or cancer ty and reduces the risk of fracture in women4-6 and were excluded.org on October 24.13 www. 2011. parathyroid hormone therapy increases ified into blocks on the basis of age (<65 years of bone formation. and the two agents combined in therapy was begun at the 6-month visit and contin- men with osteoporosis. 2 SD below the mean for the man’s age). and normal serum levels of parathyroid hormone. we com. 27 men). a potent nitrogen-containing bis. 8. Twenty declined to six hours after the administration of a parathy- to participate. 2. Blood was collected at base line and at 1. renal. and men with nephrolithiasis. disease. ued for 24 months. The men were randomly assigned by a computer- porosis9. roid hormone injection. or both (28 men). and 83 because ical analysis. . ured with the use of dual-energy x-ray absorptiom- al density of the lumbar spine in the posteroanteri.13 Whereas all other avail. combination therapy with age or ≥65 years of age) and according to the bone parathyroid hormone and alendronate might in. calcium excretion was measured every six months sisted of 83 men. study protocol creases bone mineral density in men with osteo.2 cations that are known to affect bone metabolism Alendronate. All the men re- tionnaire. severe reflux esophagitis. clinically signif- tion. 18. thyrotropin. parathyroid continued for 30 months. mone (1–34) alone (40 µg subcutaneously once dai- able treatments for osteoporosis reduce bone re. Alendro- ther agent alone. Thus. or both in men with osteoporosis aspartate aminotransferase and alanine aminotrans- o steoporosis affects more than 20 million people in the United States and leads to about 1. and 30 months for routine chem- the basis of screening blood tests. icant cardiac.6 mg per decili. 14 on 7.

because scans of this Data were analyzed in two ways: first with the region often contain artifacts. The F ratio was the ratio dual-energy x-ray absorptiometry and a densitom. ured only while the men were receiving active ther- ued. the fac- posteroanterior and lateral projections.e. shaft. Indi. If hypercalcemia or symptoms The predetermined primary end point was the persisted. Good Manufacturing Practices (GMP)–grade syn. 0. the dose of parathyroid hormone was change in the bone mineral density of the postero- reduced by another 25 percent. Copyright © 2003 Massachusetts Medical Society. Rates of adverse events were compared ed limit. Axial scans of the Venue Laboratories in Bedford. tors were the particular man.0 mmol per day). parathyroid hormone therapy was discontin. For the radial to the interaction between the man and time (i. given the term in vivo measurements were 0. for the vertebrae were then averaged. until month 12). . A mixed-model analysis of variance was used to as- duction in the dose.14 All bone-density inclusion of only those data obtained while the men 1218 n engl j med 349. was changing monotonically (i. the midbody. mal femur. The new england journal of medicine parathyroid hormone preparation scans were analyzed by persons who were unaware and dose adjustments of the treatment-group assignments. Hologic). using the least-squares focal sclerosis were excluded from analyses. the distal one third of the radial shaft. ine the average slopes of specific treatment groups vidual vertebrae with obvious deformities or areas of in pairwise comparisons. ment groups were greater than expected.15 was 10. Spine means from the same analysis of variance. of variance.. Our centimeter for the posteroanterior spine. analysis assumes that the bone mineral density at each skeletal location changes at a different pace in measurements of bone mineral density each man. 0. the proxi. All rights reserved. Our prespecified analysis or symptoms persisted after two reductions in the was to use data on the bone mineral density meas- dose. parathyroid hormone therapy sess the effect of treatment on each variable. we would then exam- 0. of the interaction between the treatment and time eter (Hologic QDR 4500A. from month 0 to month 30 in the more than 400 mg per day (10. the dietary sodium intake. spine was determined with the use of quantitative em) was placed in vials as a sterile freeze-dried pow. This model was used to test wheth- it. and the values obtained intended 40 µg. Trabecular bone mineral density of the lumbar thetic human parathyroid hormone (1–34) (Bach. computed tomography (CT) (General Electric Model der (with mannitol) under GMP conditions by Ben QXI or Lightspeed Plus scanner). the dose of parathyroid hormone in the serum alkaline phosphatase level only while it was reduced by 25 to 50 percent. 2003 The New England Journal of Medicine Downloaded from nejm.e. two measurements were obtained at each vis. If the 24-hour urinary calcium excretion was apy — that is.org september 25 .. If hyper. If hypercalciuria persisted after a 50 percent re.014 g analysis prespecified that if the F ratio was statis- per square centimeter for the lateral spine. Base- scans were excluded if the estimate of the x-ray atten. The precision The dose of parathyroid hormone was reduced error for this technique is 3 to 5 mg per cubic cen- by 25 percent if any serum calcium measurement timeter. 2011. The bone mineral density of the lumbar spine in the In the mixed-model analysis of variance. Ohio. If hypercalcemia anterior lumbar spine. line values were compared with the use of analysis uation exceeded the manufacturer’s recommend. Analysis of first four lumbar vertebrae were obtained through amino acids and high-pressure liquid chromatog.org on October 24. and among treatment groups).005 g per square differences in slopes among individual men. as described above.6 mg per deciliter or higher or if the inves- tigators thought that the man was having a side statistical analysis effect of therapy. The density of trabecular bone was raphy of the parathyroid hormone preparation re.006 g per square centimeter for the total hip. Our was discontinued.nejm. inclusion of the head region. group and from month 6 to month 30 in the para- or both were reduced by 25 to 50 percent. For personal use only. determined by means of comparison with an inter- vealed that each vial contained 37 µg rather than the nal hydroxyapatite standard. Total-body scans were analyzed without with the use of Fisher’s exact test.13 www. No other uses without permission. the error term). time. thyroid hormone group — and to assess changes calciuria persisted. the alendronate group and the combination-therapy dietary calcium intake. the treatment.007 g tically significant (indicated an overall difference per square centimeter for the femoral neck. and the interactions between the man and time and and the total body was measured with the use of the treatment and time. and the mean of the two values was used in all er the differences in the average slopes among treat- analyses. The standard deviations for our short.

01). There was no sig- Indian. and the nificant difference between the alendronate group remaining 67 were non-Hispanic white. Four men (two in group had their dose of parathyroid hormone re- the alendronate group and two in the combination. only the results period of active treatment was six months shorter of the intention-to-treat analysis are presented. Copyright © 2003 Massachusetts Medical Society.org on October 24. low-up measurements of bone density could be ob.001).02). ed in the intention-to-treat analysis (28 in the alen. Unless otherwise noted. Their data are included only mone group and five in the combination-therapy in the intention-to-treat analyses. 2 were bination-therapy group (P=0. but nine took at least 95 percent of their doses of ed in any longitudinal analyses.18). Ten men (seven in the parathyroid hor.001) or the com- are shown in Table 1. The bone mineral den- affect any aspects of the study. group. 1 was a Pacific Islander. An additional six parathyroid hormone. density at the total hip between the alendronate n engl j med 349. or both in men with osteoporosis were taking their assigned treatment (per-protocol adherence to study treatment analysis) and then separately with the inclusion of Of the 20 men who discontinued treatment. alendronate.nejm. after at least one repeated measurement of bone density had been obtained during treatment with bone mineral density and alkaline their assigned medication. any follow-up measurements of bone density could ment before any repeated measurements of bone be obtained during treatment with their assigned density could be obtained but did return for bone.org september 25. Five men in the parathyroid hor- density measurements. 1 and Table 2). parathyroid hormone. study medication. 10 men discontinued treatment before nation-therapy group) discontinued the study treat. For personal use only. with parathyroid hormone alone than with alen- One interim analysis was performed. than in the alendronate group (P = 0. . The bone mineral density at the femoral neck dronate group. in the bone mineral density at the femoral neck istics among the treatment groups. Results in these men are phosphatase included in both the per-protocol analysis and the The bone mineral density at the posteroanterior intention-to-treat analysis for the period when they spine increased more in men treated with parathy- were taking their assigned study medication but roid hormone alone than in those treated with alen- are included only in the intention-to-treat analysis dronate alone or with the combination of the two thereafter. The base-line (P=0. 2011. All P values are two. 3 were all data. and two in the combi. three in the at least 80 percent of their doses of medication. There None of the men had received previous drug thera. 20 in the parathyroid hormone increased more in the parathyroid hormone group group. All but three of the remaining men took at least tained during treatment with their assigned study 95 percent of their doses of alendronate. and 25 in the combination-therapy group) than in the alendronate group (P<0. and 7 in the combination-therapy analysis). were no significant differences in the changes in the py for osteoporosis. and five men in each of these therapy group) discontinued the study treatment groups had their dose reduced by 50 percent. No other uses without permission.001 for both comparisons) and increased more in the combi- characteristics of the men nation-therapy group than in the alendronate group The base-line characteristics of the 73 men includ. regardless of whether the men continued to in the alendronate group. Most of these men discontinued parathyroid mone group and three in the combination-therapy hormone therapy because of discomfort or incon- group) discontinued participation before any fol. and no adjustments were made for multiple with combination therapy than with alendronate statistical tests. However.13 www. even though the analysis were essentially identical. these 12 men took men (one in the alendronate group. Two men were Asian. sity at the posteroanterior spine increased more sided.005). As parathyroid hormone group. duced by 25 percent. and data for these men are not includ. data are alone (P<0. 2003 1219 The New England Journal of Medicine Downloaded from nejm.001 for both comparisons). venience related to the injections. 1 was black. The bone mineral density at the presented as means ±SD. (P=0. All rights reserved. and all medication. The bone mineral density at the total hip characteristics were also similar among all 83 men increased more in the parathyroid hormone group who underwent randomization (data not shown). It did not dronate (Fig. 10 in the parathyroid take their assigned treatment (intention-to-treat hormone group. Because the results of the two types of (P<0. There were and the combination-therapy group in the changes no significant differences in base-line character. lateral spine also increased more in the parathyroid hormone group than in the alendronate group or results the combination-therapy group (P<0. noted above.

The serum total alkaline phos. not seen are contained within the data-point symbols). 18 to 20 in the parathy- The trabecular bone mineral density at the spine roid hormone group.078 0.090 0.3 25.4±9. each plotted value is based on 27 or than in the other two groups (P<0. Copyright © 2003 Massachusetts Medical Society.13 www. P values are for the three-way comparisons and were determined by analysis of variance. the Total Hip.08).4 175.6 25. No other uses without permission. For the lateral spine.851±0. 18 to 20 in the the alendronate group.977±0. each plotted son between the parathyroid hormone group and value is based on 22 to 24 men in the alendronate group.667±0. 1220 n engl j med 349.2±2. as De- ly in the alendronate group and the combination. Parathyroid Hormone Alone. The bone Lateral Spine. Plus–minus values are means ±SD.060 0. I bars represent the SE (error bars that are (P=0. 92±23 96±22 96±24 0.51 Spinal trabecular bone density on quantita.1±8.751±0.695±0.org on October 24. roid hormone group.17 Serum alkaline phosphatase level (U/liter) 71±17 76±26 76±15 0.090 0. For the distal one third of the radial shaft and the total body. To convert values for testosterone to nanomoles per liter.06 Serum 25-hydroxyvitamin D level (ng/ml) 24±10 23±8 27±12 0.772±0.852±0.002 for the compari. For personal use only. There were no sig. and 22 to 25 in the combination- tion-therapy group than in the alendronate group therapy group.496. All rights reserved. each plotted value is based on son between the parathyroid hormone group and 27 or 28 men in the alendronate group.20) or between the parathyroid hormone group and the Figure 1 (facing page).5 0. multiply by 0. the Distal mineral density at the radial shaft increased slight.55 Serum testosterone level (ng/dl) 485±137 456±85 546±146 0. multiply by 2.075 0. group and the combination-therapy group (P= 0. and the Total Body.5 79.646±0.6±5.052 0.nejm.106 0.066 0.005) (Fig. the combination-therapy group).122 0.760±0.889±0.33 Serum parathyroid hormone level (pg/ml) 39±12 38±13 32±12 0.87 Calcium intake (mg/day) 1115±688 1051±542 1249±588 0.39 Femoral neck 0.113 0.075 0. termined with Dual-Energy X-Ray Absorptiometry.011±0.670±0.45 Total body 0.876±0. the posteroanterior spine. Mean Percent Changes in the Bone Mineral Density of the Posteroanterior Spine. The new england journal of medicine Table 1.78 Weight (kg) 77. The body-mass index is the weight in kilograms divided by the square of the height in meters. men in the alendronate group.0347. each plotted value is based on 26 or 27 three-way comparison).993±0.085 0.113 0.84 Height (cm) 174. For the femoral neck total-body bone mineral density (P=0.835±0. Base-Line Characteristics of Men with Osteoporosis Treated with Alendronate Alone.106 1.7±4. the combination-therapy group (P=0. 15 or 16 in the parathyroid hormone group.703±0. Parathyroid hormone therapy was begun at month 6.3±12. therapy group and decreased slightly in the para. parathyroid hormone group. . and 16 to 21 nificant differences among groups in the changes in in the combination-therapy group.6 0.053 0.org september 25 .9 174. the Femoral Neck.70 tive CT (mg/cm3) * The data shown are for the men in the intention-to-treat population.15 Radial shaft 0. or Both. 2003 The New England Journal of Medicine Downloaded from nejm. 17 to 20 in the parathy- parisons) and also increased more in the combina.3±2. and 22 to 25 in the combi- nation-therapy group.43 Total hip 0.60 for the and the total hip.676±0.097 0.093 0.49 Lateral spine 0. P=0. One Third of the Radial Shaft.* Parathyroid Combination- Alendronate Hormone Therapy P Characteristic Group (N=28) Group (N=20) Group (N=25) Value Age (yr) 58±7 57±9 58±8 0.56 Bone mineral density (g/cm2) Posteroanterior spine 0.8±5. 2011. To convert values for 25-hydroxyvitamin D to nanomoles per liter.8 77.7±4.097 0.74 Body-mass index 25. phatase level decreased in the alendronate group.009 for the compari. For thyroid hormone group (P=0. 2).885±0.001 for both com- 28 men in the alendronate group.0 0. and 22 to 25 in the combination- increased more in the parathyroid hormone group therapy group.

alendronate. For personal use only.13 www. parathyroid hormone. No other uses without permission. . Copyright © 2003 Massachusetts Medical Society. or both in men with osteoporosis Alendronate Parathyroid hormone Combination therapy Posteroanterior Spine Lateral Spine 24 36 20 30 16 24 Mean Change (%) Mean Change (%) 12 18 8 12 4 6 0 0 ¡4 ¡6 0 6 12 18 24 30 0 6 12 18 24 30 Month Month Femoral Neck Total Hip 12 8 10 6 8 Mean Change (%) Mean Change (%) 4 6 4 2 2 0 0 ¡2 ¡2 0 6 12 18 24 30 0 6 12 18 24 30 Month Month Radial Shaft Total Body 4 8 3 6 Mean Change (%) Mean Change (%) 2 4 1 2 0 0 ¡1 ¡2 ¡2 0 6 12 18 24 30 0 6 12 18 24 30 Month Month n engl j med 349. 2011.org september 25. All rights reserved.org on October 24.nejm. 2003 1221 The New England Journal of Medicine Downloaded from nejm.

Spinal trabecular 3 (0 to 6) 2 (¡4 to 8) 48 (35 to 61) 46 (39 to 53) 17 (10 to 24) 15 (8 to 21) <0.079) (4.082) (14.18 0.4 0.049 6.20 0. Downloaded from nejm.030 to 0. Change of Change Change of Change Change of Change Three-Way Parathyroid Combination Combination The (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) Comparison Hormone Therapy Therapy Posteroanterior spine 7.074) medicine Copyright © 2003 Massachusetts Medical Society.156) Femoral neck 3. For personal use only.140 to 0.42 0.046 to 0.8 ¡0.8 to 6.063 6.2 to 1.8) (0.012 1. All rights reserved.4 to 17.1 0.0 0.065) (3. CI denotes confidence interval.060 0.001 <0.0 to 8. Negative changes represent decreases.2 0.6) (¡0.037 to 0.9 0.1 to 2.052 5.3 0.124 <0.6 to 9.1) (¡0.056) new england journal of The New England Journal of Medicine Radial shaft 1.0 0.95 (3.001 (1.1) (0. 1222 Table 2.030 9.4) (0.6 to 6.043) (3.019 to 0.167) (12.092 to 0.0 0.059) Total hip 4.031 6.3) (0.001 0.3 to 0.003 to 0.3) (0. 2011.007 0.8 0.60 0.001 <0.043 to 0.4) (0.125 <0.5 to 4.7) (0.3 to 9.007 0.2 to 6.9 to 30.01 n engl j med 349.08 www.203) (11. .4 to 24.068 25.001 <0.4 0.02 0.104 to 0.02 <0.046 to 0. Hormone vs.011 ¡0.146 14.001 0. data for the rates of change are reported in grams per square centimeter per 30 months.7 0.8 0.009 (0. No other uses without permission. except for the data for the rate of change in spinal trabecular bone density on quantitative CT.3) (0.044) (6.2 0.001 0.050 5.001 <0. Parathyroid Hormone Alone. which are reported in milligrams per cubic centimeter per 30 months.098) (20.146) Lateral spine 11.org (3.8 0.001 to 0.043 0.038 to 0.1 0.56 0.034 to 0.065) (3.015 to 0.005 0. 2003 bone density on quantitative CT * The rates of change were determined by an analysis of the slopes.nejm.0 0.0 0.9 to 21. or Both.38 0.126 to 0.6) (0.001 <0.044 0.4) (0.022 to ¡0.029 to 0. P values are for comparisons of the rates of change.001 (6.4 to 7.4) (0.001 september 25 .8) (0.1 to 13.org on October 24. P values for the three-way comparisons were calculated by analysis of variance.13 (6.* Bone Site Alendronate Group Parathyroid Hormone Group Combination-Therapy Group P Value Alendronate Alendronate Parathyroid Mean Percent Mean Rate Mean Percent Mean Rate Mean Percent Mean Rate vs. vs.005 <0.3 to 6. Mean Percent Changes in Bone Mineral Density at Month 30 and Rates of Change among Men Treated with Alendronate Alone.3 to 15.001 <0.064) (5.8) (0.172 18.063 18.8) (0.016) Total body 5.038 to 0.7) (0.002 0.001) (¡0.3) (0.019) (¡2.

ences among the treatment groups.13 www.9 percent of serum calcium values in men in the eral density at the spine and the femoral neck. and 10.20).9 percent of the values were elevated We found that the administration of alendronate. No other uses without permission. Figure 3. month 6 and then increased in the combination- therapy group (Fig. alendronate. Month I bars represent the SE (the SE for alendronate is con- tained within the bar). no serum calcium values were discussion elevated in the men in the parathyroid hormone group. percent of samples from the men in the combina- sons) but did not differ significantly between the tion-therapy group (P=0.nejm. Table 3 shows the percentage of visits at which adverse events men reported side effects. . and 0. as were Alendronate also reduced the parathyroid hormone– 1. Parathyroid Hormone Alone. and decreased until contained within the data-point symbols). in the men in the combination-therapy group (P= a potent inhibitor of bone resorption. but these differ- dronate group. or Both.associated increase in the serum total alkaline phos- nation-therapy group (P=0. Mean Percent Changes in the Trabecular Bone 0 6 12 18 24 30 Mineral Density of the Spine. this measurement was finding suggests that alendronate impairs the abili- 11. 3). The peak serum alkaline phosphatase levels at month 12 were significantly alendronate group. Although the combination of in 2. Mean Serum Alkaline Phosphatase Levels in Men Receiving Alendronate Alone. is associat- 0.1 percent of urine samples from the men in the parathyroid hormone and alendronate increased n engl j med 349. When serum calcium was measured ences were generally small.teoblast activity by parathyroid hormone. 2011.org september 25.org on October 24. parathyroid hormone group were elevated. For personal use only. Parathyroid hormone therapy was begun at month 6.88 mmol per liter). Urinary ty of parathyroid hormone to stimulate new bone calcium excretion was greater than 400 mg per day formation in men. There were several differ- Hypercalcemia did not occur in any man in the alen.ed with a decrease in the ability of once-daily para- ly four hours after a dose of parathyroid hormone.004 for the comparison be- alendronate group and the combination-therapy tween the alendronate group and the combination- group (P=0. When the level was measured approximate.1 percent of the values in the men in the combi. thyroid hormone therapy to increase the bone min- 3. which reflect the stimulation of os- calcium measurement was above 11 mg per deci. or both in men with osteoporosis Trabecular Bone Density of the Spine Alkaline Phosphatase 100 125 80 100 Mean Change (%) 60 75 Mean Change (%) Parathyroid hormone 40 50 20 25 Combination therapy 0 0 Alendronate Parathyroid Combination Hormone Therapy Alendronate ¡25 Figure 2.14). 2003 1223 The New England Journal of Medicine Downloaded from nejm. parathyroid hormone. 6. therapy group).15).0 percent of samples from the higher in the parathyroid hormone group than in men in the parathyroid hormone group.001 for both compari.5 mg per deciliter (2. approximately 24 hours after the administration of parathyroid hormone.5 the other two groups (P<0. peaked at 12 months and then decreased in the I bars represent the SE (error bars that are not seen are parathyroid hormone group.75 mmol per liter).16 This liter (2. Copyright © 2003 Massachusetts Medical Society. All rights reserved. Only one serum phatase levels.

The new england journal of medicine Table 3.24 the radial shaft.nejm.92 Discomfort at injection site NA 18 17 NA NA NA 0.49 Constipation 8 12 8 0. total hip.04 0.75 * P values were calculated with the use of Fisher’s exact test.22 0.03 0. the combination of parathyroid hormone and alendro.05 0. the long-term postmenopausal hormone therapy.45 0.00 0.21 Bloating 6 7 10 0.27. Copyright © 2003 Massachusetts Medical Society.58 0. roid hormone followed by calcitonin.17. the cyclic administration of parathyroid hormone fect of parathyroid hormone on bone.60 0.37 Gas 17 16 20 0.46 0. addition of parathyroid hormone increased the nate prevented the parathyroid hormone–induced bone mineral density of the lumbar spine.03 0.26 included a group of subjects who were alendronate monotherapy.43 0. mone therapy alone. At increase bone formation and bone mass in sheep. For personal use only. In postmenopausal women who were receiving inately of non–weight-bearing cortical bone.86 Joint pain 33 54 43 <0.35 Back pain 26 38 29 0.45 0. parathyroid hormone treated with parathyroid hormone alone.05 0.18 duces the ability of parathyroid hormone to increase Several studies in animals have examined the bone mineral density. although the which suggests that bone resorption is not essen. has no effect on.06 0.73 0.07 0.002 0. In rats. 2003 The New England Journal of Medicine Downloaded from nejm.008 0. alone tended to increase the bone mineral density ther calcitonin nor estrogen nor bisphosphonates at the spine more than cyclic therapy with parathy- block the anabolic activity of parathyroid hormone. In postmenopausal women.02 0. Hormone vs.47 0.15 0. the bone mineral density at the spine more effec.65 Mood swings 4 6 7 0.org september 25 . Three-Way Parathyroid Combination Combination Comparison Hormone Therapy Therapy % of visits Headache 11 16 21 0.02 0.28 Frequent urination 25 22 22 0. tiludronate com- tively than alendronate alone.007 Nausea 3 5 7 0.23 Diarrhea 9 7 10 0. or re- osteoporosis.27 0.44 0. All three treatments had and total body more than the continuation of hor- similar effects on total-body bone mineral densi. it is not monotherapy. No other uses without permission.01 0. vs. All rights reserved. and combination therapy on bone possible to determine whether postmenopausal mineral density in women with postmenopausal hormone therapy augments.02 0.04 0.89 0.13 www.46 0.003 0. difference was not significant.10 0. .26 Because neither of these ty. 2011.01 0.16 0.* Alendronate Parathyroid Combination- Group Hormone Group Therapy Group Side Effect (N=28) (N=20) (N=25) P Value Alendronate Alendronate Parathyroid vs.50 0.88 0. These effects are remarkably similar to those of studies25.19-23 In contrast. NA denotes not applicable. Percentage of Visits at Which Men Reported Side Effects. a skeletal site composed predom. tial for this activity. nei.45 1.44 0.03 Muscle aches 24 26 29 0.57 Chest pain 8 3 6 0. decrease in bone density. effects of antiresorptive agents on the anabolic ef.67 0.12 Shortness of breath 6 5 11 0.16 Dizziness 4 7 8 0.01 Bone pain 4 7 9 0.001 0.57 0.001 0.30 0.18 Heartburn 18 20 25 0.25.001 <0.org on October 24. the combination was pletely blocks the ability of parathyroid hormone to clearly inferior to parathyroid hormone alone.14 0.05 <0.01 0.21 0.28 Parathyroid hor- 1224 n engl j med 349.21 0.

cal assistance. Anjali Rao and Ms. such as in. to Ms.37 Dif- The increases in femoral-neck bone mineral ferent effects might be observed if parathyroid hor- density in our study were most marked between 12 mone therapy and alendronate therapy were begun and 24 months after the start of parathyroid hor. an effect again similar to that of was delayed for six months so that bone resorption parathyroid hormone therapy in postmenopausal would be maximally suppressed by alendronate in women. No other uses without permission. Ms. combinations of antiresorptive agents and para- rectly by increasing the local production of insu. and to the nursing and dietary staff of the Mallinck- sulin-like growth factor I and transforming growth rodt General Clinical Research Center for their care of the patients. simultaneously. alendronate port on postmenopausal women. on its ability to induce bone resorption. Supported by grants (5 P50 AR44855. Alendronate prevents para- fect on bone either through a direct stimulatory ef. Fatma Omer.13.org september 25. these re.27.10-13. or both in men with osteoporosis mone therapy also increased bone formation and factor b.36 Thus. parathyroid hormone to increase bone mineral den- sity at the radial shaft. a reduction in bone 1066) from the National Institutes of Health. bone mineral density at the spine and femoral neck Parathyroid hormone therapy was particularly are consistent with the hypothesis that the anabolic effective at increasing the bone mineral density in effect of parathyroid hormone depends. For example. Ms. .13 www. Differences in changes in bone density between to the effect at this site in postmenopausal wom. 2003 1225 The New England Journal of Medicine Downloaded from nejm.33. alendronate.32 In contrast. lates bone formation.30 This treatment clearly study (37 µg) was higher than that currently ap- caused a greater increase in the spinal bone miner. men treated with alendronate alone and those treat- en. Thus. 2011. Parathyroid hormone also stimulates bone Robbin Cleary. of parathyroid hormone. Annmarie resorption.35 If these growth factors participate in the bone mineral density less in postmenopausal wom. mechanism whereby parathyroid hormone stimu- en who had previously been treated with alendro. thyroid hormone–induced mineral loss from non– fect on osteoblastic bone formation or indirectly weight-bearing cortical-bone sites. and Mr.nejm. mone therapy. Copyright © 2003 Massachusetts Medical Society. density at the lumbar spine and femoral neck in Parathyroid hormone may exert its anabolic ef. a skeletal site composed mainly of tra. men with osteoporosis. parathyroid hormone. Sarah Zhang.17.29 Because alendronate is a more po. suppressing bone resorption nate than in those who had previously been treated should impair the anabolic activity of parathyroid with raloxifene. David A. We are indebted to Ms. Our findings that alendronate reduces tent antiresorptive agent than raloxifene. are unknown. Irene Lerman. hormone. Additional studies are needed before roid hormone might stimulate bone formation di. thereby releasing preformed growth fac. at least in the spine. Schoenfeld for statisti- tors that are adsorbed to bone matrix. growth factors. as was the case in previous studies in The dose of parathyroid hormone used in this humans and animals. alendronate impairs the ability need to be administered for more than 12 months of parathyroid hormone to increase bone mineral in order to achieve optimal benefits at this site.13 the men who received combination therapy. ed with parathyroid hormone alone might also be apy increased the total-body bone mineral density less evident with a lower dose of parathyroid hor- (a skeletal measurement that primarily involves mone.13. becular bone. Swarcz. n engl j med 349.34 If parathyroid hormone stimu. Ralph Deyo for performing the bone-density measurements. parathyroid hormone may In summary. part. Ms. an effect that is also similar sity. All rights reserved. and RR- lates bone formation directly. the ability of parathyroid hormone to increase the sults are consistent with the idea that antiresorptive activity of serum alkaline phosphatase and reduces agents mitigate the anabolic effects of parathyroid the ability of parathyroid hormone to increase the hormone. Ms. parathy. on bone. proved by the Food and Drug Administration (20 µg) al density in men than alendronate monotherapy but similar to the dose used in many clinical studies — a finding that is similar to that in a previous re. The consequenc- through a mechanism that requires it to increase es of these complex effects on the risk of fracture osteoclastic bone resorption. to Dr.org on October 24. The start of parathyroid hormone therapy cortical bone). For personal use only. parathyroid hormone ther. thyroid hormone can be recommended for the treat- lin-like growth factor I or other bone-stimulating ment of men with osteoporosis. K24 DK02759. Anya Lepp for the ad- resorption should not mitigate its anabolic effect ministration of the study protocol and data management.31 Parathyroid might further impair the ability of a lower dose of hormone therapy reduced the bone mineral den.

or raloxifene in ovariectomized 83:60-5. The effects of parathyroid hormone and J Bone Miner Res 2002. Alendronate does not block the fractures and bone mineral density in post. Bone densitometric and histomorpho- in young children: influence of head bone metric responses to sequential human para- 1226 n engl j med 349. et ously treated with an antiresorptive drug. Formica C. 1994. Baumann BD. Metab 2000. Rosenthal DI. Roe EB. 1990:1314-7. thyroid hormone on vertebral-bone mass 36. New 33. Norman ME.86: 22. Nieves J. 2nd ed. Principles of bone biology. Dorst A. Hummert JR. Lancet 1997. Hayes A. on risk of fracture in women with existing the stimulation of bone growth by hPTH. Schiff I. San Martin JA. hormone in bone cultures.13 www. Rao A. Resorption is not essential for eds. versus cyclical parathyroid hormone and se- ego. 21st ed. J Clin Invest 1989. alendronate. 29. Neer R. domised controlled study of effect of para. Parathyroid hormone enhances the tran- The effect of teriparatide [human parathy. Crans G. et al. Vergnaud P. 103:427-36. Lancet 1996. Parathy. Effects of parathyroid hormone. dronate in postmenopausal women with os- Fracture Intervention Trial. Gera I. Slovik DM. 13. Cecil textbook of 652-5. et 19. et al. Quantita. JAMA 1998. ed. Slovik D. 31. Konrad PT. Black DM. Weiss SR. 34. San Di. 158:817-23. Orwoll ES. Klibanski A. Lindsay R. Bikle D. The ana. JAMA 1998. Slovik DM.14:67-83. 1991. Steer BM. Doppelt SH. Total body bone mineral density DJ. Fisher JE. N Engl J Med 2000. 993-1005. 27. Preven.16:247-53. Cummings SR. et al. N Engl J Med 30. — is activated resorption a prerequisite for 35. Arnaud CD. J Bone Miner Res 1986. et al. Am J Med 1997. ders. Treatment of postmenopausal porosis in men: results of a 2-year prospec. 37. ab- density and the incidence of fractures in alendronate alone or in combination in post. et al.org on October 24. Fraher LJ. 18. Endocrinology Res 2003. 17:Suppl 1:S135. All rights reserved. 11. plus calcitriol. Bone Miner medicine. Alendro. eds. Ringe JD. In: Gold. parathyroid hormone in aged ovariectomized Nussbaum S. growth factor I in osteoblast-enriched cul- sity in men with osteoporosis. Suppl 1:S137. 41.85:3069-76. 1999:1-13. Osteoporosis. Biochem Biophys Res Commun 1989. 9. Biochemical markers in the as. et al. rats. anisms of therapeutics: parathyroid hor- 5. et al. Mundy GR. J Bone Miner mation is blunted when bone resorption is tures from fetal rat bone. Effect of parathyroid hormone (1-34) on ty increases in postmenopausal osteoporo. J Bone Miner Res 1997. Hornstein MD. Sanchez SD. Restoration of spinal bone in os- tion of estrogen deficiency-related bone loss pausal women on oestrogen with osteoporo. Parathyroid hormone 1-34 (hPTH 1-34) 377-81. tonin in osteoporotic patients. Hock JM. Weiss S.96:133-8. In: Bilezikian JP. Shen V. Neer RM. Hodsman AB. and kinase or both on bone density in osteoporotic post. Overgaard 5252-5. bone formation with teriparatide [human Carthy TL. Greenspan SL. Randomised trial of effect of alendronate ca J. 15. 7. al. Bröll J. No other uses without permission. Finkelstein JS. nate treatment of established primary osteo. Burch W.20:306-10. teoporosis.12: thyroid hormone (1-38) and salmon calci- man L. 17.nejm. J Bone Miner Res 1998. al. J Bone Miner Res 1989. Nieves J.org september 25 . Alendronate mechanism of action: gera. 14. Yen C-F. Toth TL.343:604-10. Ran. Finkelstein JS. Raisz LG. Insulin-like growth factor I medi- roid hormone as a therapy for idiopathic os.16:603-10. Finkelstein J. the efficacy of teriparatide [recombinant hu- ture in women with low bone density but tion of resorption on the anabolic response man parathyroid hormone (1-34)] with alen- without vertebral fractures: results from the of bone to parathyroid hormone. Ettinger M. N Engl J Med 25. nylgeraniol. 16. Ettinger B. 2003 The New England Journal of Medicine Downloaded from nejm. prevents inhibition of osteo. Activation of the bone derived roid hormone for the prevention of bone loss modeling system? Bone 1995. Ensrud KE. and bone mineral density to teriparatide [re- activation in vitro. Fraher J. Neer RM. J Bone Miner Res 1999. eds. Neer R. Wronski TJ. N Engl J Med menopausal osteoporosis. Osteopress ApS. al.7:65-72. teoporotic men by treatment with human with human parathyroid hormone-(1-34): a sis. 2000:1366-73. Raisz LG. Liberman UA. McMahon DJ. Finkelstein JS. Ganott MA. Neer RM. Black DM. tive computed tomography for spinal densi. osteoporosis with daily parathyroid hormone tive study. Arlot ME. Vol. docrinology 1993. J Clin Endocrinol estrogen. J Clin Endocrinol Metab 2001.333:1437-43. Parathyroid hormone is more effective than K. Bonewald LF. I. A randomized controlled trial to compare In: Orwoll ES. Zeng Q. Rogers MJ. Kurland ES. Canalis E. rats. Qi H. et al. Denmark: men. Woelfert L. Wyshak G. McCarthy TL. In: Christiansen C. 2003. Saun. Zanchetta JR.: Academic Press. Pas. Scheele WH. Gaich GA.: Academic Press. J Bone Miner Res 2002. latent TGF-b complex by isolated osteo- induced by estrogen deficiency. Orwoll E. Pavo nate pathway. Body JJ.350:550-5. Arnold AL. et droxyvitamin D. et al. En. Parathy. mineral density.1: 280:1067-73. For personal use only. abstract. density and bone markers.280: er Res 1992. Copenhagen. Cosman F. Faber H. 2011. controlled trial. Lo C.132:823-31.349:1207-15. combinant human parathyroid hormone 1999. Rosenthal DI.25-dihy- randomized. Wronski TJ. Centrella M. Pharmacological mech- 1995. Boyce R. Finkelstein JS. Drost Copyright © 2003 Massachusetts Medical Society. Vol. anabolic effect of PTH in postmenopausal menopausal women with osteoporosis. and fracture incidence among postmeno. Karpf DB. Mc- Rosen CJ. postmenopausal women with osteoporosis. sis — results from a placebo-controlled ran. Calif. Watson PH. Bilezikian JP. Seyedin SM. Lindsay R. Proc Natl Acad Sci U S A menopausal women. Osteoporosis 1990: proceedings of 8. bolic effect of human PTH (1-34) on bone for. Melton LJ. Neer RM. stract. Dann LM.331:1618-23. Hornstein MD. domized trial. script and polypeptide levels of insulin-like roid hormone (1-34)] therapy on bone den. the efficacy of cyclical parathyroid hormone effects of gender on skeletal health. et 2. parathyroid hormone (1-34) and 1. Calif. 24. Harcke HT. Taylor A. Hock JM. 1996: vertebral fractures.18:9-17. Canalis E. Doppelt SH. Black DM. teoporosis. postmenopausal osteoporosis. Copyright © 2003 Massachusetts Medical Society. Lindsay R. Scheele WH. Daly M. Invest Radiol 1985. Thompson 20. quential calcitonin to improve bone mass in 3. Response 87:4528-35. Endocrinology 2003. Centrella M. bone resorption. the in vivo effect of PTH on formation in a re. Ma YL. inhibited by the bisphosphonate tiludronate 1989. . Klibanski A. Early response of bone turnover markers clast formation. J Clin Endocrinol Metab 2002. Meunier PJ. 21.144:2008-15. 3. Paul S. 12.82:620-8.344:1434-41. 23. Epidemiology of fractures. Delmas PD.124:1247-53. mone. 13:1051-5. sessment of bone disease. A 6. (1-34)] in postmenopausal women previ- 4. an intermediate in the mevalo. Alen. Halasy JM. Philadelphia: W. 26. 4:449-58. Effect of oral alendronate on bone mineral al. clasts. J Bone Min. Hodsman AB. Potts J.17:Suppl 1:S157. Schaefer EH. 2077-82. San Diego. (1-34) in rats in vivo. Effects of continuous randomized double-blind trial to compare DE. Rodan GA. Cosman F. and intermittent administration and inhibi. del Puerto GA. abstract. Nilssen MH. al. Bone 1995. Effect of alendronate on risk of frac. alendronate. 2. Fonse.14: osteoporotic women.B. Cummings SR. of cortical bone to antiresorptive agents and 32. parathyroid hormone. 28. Osteoporosis in men: the ty measurement: factors affecting precision. toureau P. et and estrogen produce dramatic bone densi. Oreffo ROC. Bennett JC. estrogen or bisphosphonates for restoration the Third International Symposium on Os- dronate for the treatment of osteoporosis in of lost bone mass in ovariectomized rats.348:1535. N Engl J Med 2001. 10. J Clin Endocrinol Metab 1997. parathyroid hormone-(1-34)] is not retarded ates selective anabolic effects of parathyroid teoporosis in men: effects on bone mineral by long-term pretreatment with alendronate. or both in men with osteoporosis refer enc es 1. Bryant HU.