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Original Article |
Department of Medicine (J.-J.B.), Institut J. Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium; Lilly Research Laboratories (G.A.G., W.H.S., P.M.K.), Eli Lilly and Co., Indianapolis, Indiana 46285; Colorado Center for Bone Research (P.D.M.), Lakewood, Colorado 80227; Centre Hospitalier Universitaire Brugmann (A.Pe.), Rheumatology Clinic, 1020 Brussels, Belgium; (R.K.D.), Anaheim, California 92801; Department of Nephrology and Mineral Metabolism (R.C.-R.), Instituto Nacional de Ciencias Médicas Y Nutrición Salvador Zubiran, 14000 Mexico DF, Mexico; Department of Medicine (A.Pa.), Hamilton Health Sciences, McMaster University, Hamilton, L8N 3Z5 Ontario, Canada; Department of Obstetrics and Gynecology (D.C.C.), Royal Alexandra Hospital, University of Alberta, Edmonton, T5H 3V9 Alberta, Canada; and Department of Medicine (A.B.H.), St. Joseph’s Health Care Center London and Lawson Health Research Institute, University of Western Ontario, London, N6A 4V2 Ontario, Canada
Address all correspondence to: Prof. J. J. Body, Institut J. Bordet, 1, rue Héger-Bordet, 1000 Bruxelles, Belgium. E-mail: jj.body{at}bordet.be. Address requests for reprints to: Gregory A. Gaich, M.D., Lilly Research Laboratories, Eli Lilly and Co., Lilly Corporate Center, Indianapolis, Indiana 46285.
Abstract
Teriparatide (rDNA origin) injection [recombinant human PTH (1–34)] stimulates bone formation, increases bone mineral density (BMD), and restores bone architecture and integrity. In contrast, bisphosphonates reduce bone resorption and increase BMD. We compared the effects of teriparatide and alendronate sodium on BMD, nonvertebral fracture incidence, and bone turnover in 146 postmenopausal women with osteoporosis. Women were randomized to either once-daily sc injections of teriparatide 40 µg plus oral placebo (n = 73) or oral alendronate 10 mg plus placebo injection (n = 73). Median duration of treatment was 14 months. At 3 months, teriparatide increased lumbar spine BMD significantly more than did alendronate (P < 0.001). Lumbar spine-BMD increased by 12.2% in the teriparatide group and 5.6% in the alendronate group (P < 0.001 teriparatide vs. alendronate). Teriparatide increased femoral neck BMD and total body bone mineral significantly more than did alendronate, but BMD at the one third distal radius decreased, compared with alendronate (P 
0.05). Nonvertebral fracture incidence was significantly lower in the teriparatide group than in the alendronate group (P < 0.05). Both treatments were well tolerated despite transient mild asymptomatic hypercalcemia with teriparatide treatment. In conclusion, teriparatide, a bone formation agent, increased BMD at most sites and decreased nonvertebral fractures more than alendronate.
OSTEOPOROSIS IS A DISEASE characterized by low bone mass and microarchitectural deterioration leading to bone fragility and an increased risk of fracture (1). Ideally, treatments for osteoporosis would increase bone mass and improve bone architecture and strength and thereby reduce the risk for fracture (2, 3, 4, 5, 6). Bone mineral density (BMD) as measured by dual-energy x-ray absorptiometry (DXA) is the most common method of diagnosing osteoporosis. Its ability to predict fracture risk in an untreated population is well characterized (7). However, changes in BMD after therapeutic intervention do not appear to predict fracture reduction nearly as well as BMD predicts fracture risk before treatment (8, 9, 10). In part, this may be because BMD is derived from two independent measurements, bone mineral content (BMC) and projected bone area, each of which may contribute to bone strength and may be affected by therapy in different ways. In particular, an increase in bone area may increase bone strength without an increase in areal BMD. Finally, BMD cannot reflect changes in microarchitecture of cancellous bone that contribute to increased resistance to fracture (11).
Antiresorptive agents (e.g. bisphosphonates and selective estrogen receptor modulators) are the most widely available treatments for osteoporosis in postmenopausal women. Bisphosphonates directly reduce the number and activity of osteoclasts, thereby reducing bone turnover, including bone formation (12, 13). The net effect of such antiresorptive therapies is a transiently positive bone balance, followed by a new equilibrium at a reduced turnover rate (14), increased mineral deposition and BMD, and reduction in fracture risk (15, 16, 17).
Teriparatide (rDNA origin) injection, the amino-terminal fragment of human PTH (1–34), is a potent bone formation agent (18, 19, 20, 21). Teriparatide increases osteoblast birth rate and prevents osteoblast apoptosis, thereby increasing the number of osteoblasts and the rate of new bone formation (20, 21, 22, 23, 24). When administered once daily by sc injection, teriparatide increases bone density and improves trabecular architecture, cortical geometry, and strength (11, 25, 26, 27, 28, 29, 30). In a recent placebo-controlled randomized clinical trial, once-daily administration of teriparatide (20 and 40 µg) for a median of 19 months significantly increased BMD at most skeletal sites and substantially reduced the risks of both vertebral and nonvertebral fractures, compared with placebo-treated patients (31).
To date, there are no reports directly comparing the effects of bisphosphonates and teriparatide. This article describes a randomized, double-blind, controlled clinical trial in which postmenopausal women with osteoporosis were treated with either teriparatide or alendronate for up to 17 months. Change in lumbar spine (LS)-BMD by DXA was the primary outcome measurement; secondary outcome variables included LS-BMC and area, BMD measurements at other skeletal sites, nonvertebral fracture incidence, and biochemical markers of bone formation and resorption.
Subjects and Methods
Study participants
This randomized, double-blind, parallel-group, active-controlled study was conducted at 12 study sites in the United States, Austria, Belgium, Canada, Israel, and Mexico from May 1997 through April 1999. All participants gave written informed consent before enrollment into the study, which was conducted according to the Declaration of Helsinki. The study protocol and informed consent documents were approved by the ethical review board at each clinical site.
Ambulatory postmenopausal women at least 5 yr past menopause were eligible to participate if they were aged 30–85 yr, free of severe or chronically disabling conditions other than osteoporosis, and had LS or femoral neck bone mineral density at least 2.5 SD below the mean for young adult women. Women were excluded for metabolic bone disorders; diseases affecting bone and mineral metabolism; carcinomas within the previous 5 yr; nephrolithiasis or urolithiasis within the previous 2 yr; malabsorption; significantly impaired renal [serum creatinine concentrations, >177 µmol/liter (2.0 mg/dl)] or hepatic function; abnormalities of the LS prohibiting assessment of bone mineral density at L2-L4; medications or drugs known to affect bone or mineral metabolism in the prior 2–24 months depending on the drug (e.g. androgens, anabolic steroids, bisphosphonates, calcitonin, glucocorticoids, estrogens, fluoride); alcohol abuse; or allergy or previous exposure to teriparatide, exogenous PTH, or PTH analogs.
Treatments
The protocol consisted of two phases: a screening and run-in phase of up to 2 months and a planned treatment phase of 24 months. The run-in phase included at least 1 month of daily supplements of calcium (1000 mg) and vitamin D (400–1200 IU); study participants continued these calcium and vitamin D supplements throughout the trial. During the run-in phase, each woman was instructed in the proper technique for self-injection at either the lower abdomen or outer thigh, using placebo material. After successful completion of the run-in phase, participants were randomly assigned to either once-daily 40 µg teriparatide (Eli Lilly and Co., Indianapolis, IN) sc injection plus oral placebo (n = 73) or once-daily placebo injection plus oral 10 mg alendronate sodium (Merck & Co., Whitehouse Station, NJ) (n = 73). The dose of teriparatide was chosen before conclusion of a large, fracture prevention clinical trial that led to the selection of 20 µg/d rather than 40 µg/d as the preferred dose, based on the balance of skeletal benefits and adverse events (31).
Treatment and placebo drug were identical in appearance and administration. Alendronate and placebo tablets were encapsulated by Bergen Brunswig (Louisville, KY). The encapsulated alendronate tablets met USP standards for dissolution. The women were instructed to take the oral capsule with a glass of water on an empty stomach 30 min before breakfast and remain upright for at least 30 min after ingestion. The sc injections were taken without restriction regarding meals or activity.
The intended duration of the study was 24 months. After a median of 14 months of treatment, the study was voluntarily brought to an early closure to evaluate the clinical relevance in humans of the observation of osteosarcoma made in Fischer 344 rats in a carcinogenicity study. Rats, given near lifetime daily injections of teriparatide, developed osteosarcoma (32). Evaluation of the rat findings by a group of experts concluded that these findings were unlikely to predict an increased risk in humans, an opinion also expressed in an independent review (33). All women were invited to complete a study closeout visit. Patients were instructed to discontinue use of all active study drug treatments at the time the study was brought to early closure but continued calcium and vitamin D supplementation until the closeout visit.
Compliance with the treatment was evaluated by pill counts of oral study material and measurement of volume of injectable study material returned at each study visit. Follow-up visits after randomization were conducted at months 1, 3, 6, and 12 and at study closeout. Women were questioned about adverse events at each follow-up visit and were asked to rate the severity of each event as mild, moderate, or severe. Dietary calcium intake was assessed at baseline by a standardized dietary questionnaire.
BMD
BMC (grams), projected bone area (square centimeters), and the derived areal BMD measurements (grams per square centimeters) at the LS, proximal femur, and total body in all participants and in a subset of 103 women at the radius were obtained by DXA using either GE Lunar Corp. (Madison, WI) or Hologic, Inc. (Waltham, MA) densitometers. Approximately equal proportions of women in each treatment group were tested on each type of densitometer (P = 0.717). Except at screening, the scans were analyzed centrally and results were not reported to site personnel. LS measurements of L2-L4 (Lunar Corp.) or L1-L4 (Hologic, Inc.) were obtained, and vertebrae with fractures or artifacts were excluded. The stability of the DXA instruments was assessed by serial measurements of a local spine phantom. The variability of DXA measurements across clinical sites was assessed by measuring a spine phantom circulated among sites. The central site for bone mass measurements used the results obtained from the phantom measurements to adjust for drift in densitometric measurements, as necessary.
The primary study outcome was change in BMD at the LS. DXA measurements at the LS were obtained in participants at baseline; months 3, 6, and 12; and at study closeout. DXA measurements at the proximal femur, radius, and total body were made at baseline, month 12, and study closeout.
Fractures and height
No radiographs were scheduled to detect vertebral fractures. All nonvertebral fractures were confirmed by written reports from radiologists or review of the radiographs. Fractures were recorded regardless of the degree of trauma for the following body sites: hip, pelvis, ankle, foot, humerus, radius, ribs, or other (a fracture at a site other than those listed). Height was measured using a calibrated stadiometer at baseline, 12 months, and study closeout.
Biochemical markers and laboratory measurements
Biochemical markers of bone formation [serum bone-specific alkaline phosphatase (bone ALP)] and bone resorption [urinary cross-linked N-telopeptides corrected for creatinine (NTX)] and serum 1,25-dihydroxyvitamin D were measured at baseline and each subsequent study visit. Bone ALP was measured by immunoradiometric assay (Tandem-R Ostase assay, Hybritech Inc., manufactured by Beckman-Coulter, Brea, CA). NTX was measured by ELISA (Osteomark assay, Ostex, Seattle, WA). Serum 1,25-dihydroxyvitamin D was measured by extraction, chromatography, and radioreceptor assay (Quest Diagnostics, Inc., San Juan Capistrano, CA, formerly Corning Nichols Institute).
Clinical hematology, chemistry, and urinalysis were assessed at baseline, 6 months, 12 months, and study closeout. Serum 25-hydroxyvitamin D and endogenous PTH (1–84) were measured at baseline, 12 months, and study closeout. Serum 25-hydroxyvitamin D was measured by RIA after extraction (DiaSorin, Inc., Stillwater, MN, formerly INCSTAR Corp.), and intact PTH was measured by immunoradiometric assay (N-tact PTH SP assay; DiaSorin, Inc.). Serum calcium was measured 4–6 h after injection at each postrandomization study visit. Twenty- four-hour urinary calcium, phosphorus, and creatinine excretion were measured at baseline; months 1, 6, and 12; and study closeout. Tests of serum antibodies to teriparatide, based on the specific binding of radioiodinated teriparatide, were performed at baseline, month 12, and study closeout visit using a method developed by Quest Diagnostics, Inc.
Statistical analysis
The results for all women with at least one follow-up visit after randomization were included in the intent-to-treat analysis, and the last post baseline measurement was carried forward to obtain the end point measurement. The by-visit analyses included all observed cases at each study visit. The study closeout visit is plotted at the median treatment duration of 14 months. Biochemical markers of bone turnover are analyzed only through 12 months, the last assessment when women were still on active treatment. All BMD and BMC analyses are based on percentage change from baseline. The measurements of BMD, BMC, and biochemical markers of bone turnover were analyzed by ANOVA, including terms for treatment and investigator. The adverse events and nonvertebral fractures were analyzed using Pearson’s 
2 test. All statistical tests were two sided, with an 
level of 0.05.
Results
Of the 265 women who were screened for the study, 116 (44%) were not eligible or were not interested in further participation, and three withdrew after randomization but before treatment was started. A total of 146 women from 12 study sites who met the eligibility criteria were randomized to daily treatment with either teriparatide (n = 73) or alendronate (n = 73). There was no difference by study group in the number of women who completed 6- or 12-month testing. At the time of final study visit, 108 women (74%) were still active participants. Median exposure to treatment was 14 months in both treatment groups.
There were no significant differences between groups in baseline characteristics (Table 1
). Most of the women in each group were white (82%); the largest ethnic minority category was Hispanic (16%).
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BMD and BMC
From baseline to end point, teriparatide increased LS-BMD, LS-BMC, and LS-area significantly more than did alendronate. Both the treatment groups showed significant increases in LS-BMD at each time point (Fig. 1A). At month 3, the earliest point at which BMD was measured, the percentage increase in LS-BMD for the teriparatide group was 2.7% greater than that in the alendronate group (P < 0.001). This difference increased to 5.4% at 6 months, and 8.3% at 12 months (P < 0.001). At 3 months, teriparatide treatment had increased LS-BMD by 5.2%, an amount nearly equal to the 5.9% increase observed after treatment with 12 months of alendronate.
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). Conversely, the minimum BMD increase achieved by any chosen proportion of patients was greater in the teriparatide group than in the alendronate group. From baseline to end point, alendronate increased LS-BMC by 6.6% (P < 0.001), whereas teriparatide increased it by 15.1% (P < 0.001, compared with baseline and alendronate). From baseline to end point, alendronate increased spinal bone area by 0.49 cm2 (P = 0.018), whereas teriparatide increased spinal bone area by 1.29 cm2 (P < 0.001, compared with baseline and P = 0.002, compared with alendronate).
Compared with baseline, at 12 months, the first post baseline visit at which it was measured, femoral neck and total hip BMD were increased more by teriparatide than alendronate (Fig. 2). At end point, both alendronate and teriparatide treatments significantly increased BMD from baseline at the spine and hip (including the regions of the hip not shown: intertrochanteric and Ward’s triangle) and total body bone mineral (Fig. 3). At each of these sites, the increases were significantly greater for the teriparatide group than for the alendronate group, except at the trochanter, at which they were similar. Alendronate treatment did not significantly change BMD at the ultradistal or the one third distal regions of the radius. In the teriparatide group, ultradistal radial BMD was not changed, but BMD of the one third distal radius decreased significantly (P 0.001), compared with baseline and the alendronate group.
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Nonvertebral fracture frequency was significantly lower in the teriparatide-treated group (4.1%) than in the alendronate group (13.7%, P = 0.042) (Table 2). The time from baseline for each fracture revealed that five fractures occurred within the first 6 months of treatment in the alendronate group, and five fractures were reported after more than 6 months of treatment. In the teriparatide group, one fracture occurred within the 6 months of treatment and two fractures occurred after more than 6 months of treatment. Mean height did not change between baseline and end point in either group.
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Alendronate reduced biochemical markers of bone resorption (NTX) and formation (bone ALP) by approximately 50% (Fig. 4). NTX was significantly reduced at 1 month and bone ALP at 3 months, and both markers remained depressed through the duration of therapy. In contrast, teriparatide treatment significantly increased bone ALP and NTX at 1 month. The maximum increase in bone ALP of 100% was observed at 6 months, and the maximum increase in NTX of 160% was observed at 12 months.
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There were no differences between treatment groups in the proportion of women reporting any adverse event experiencing a serious adverse event or who withdrew because of an adverse event. Significantly fewer patients reported new or worsened back pain in the teriparatide group (5.5%) than in the alendronate group (19.2%, P = 0.012). Leg cramps were reported by 6 patients (8.2%) in the teriparatide group and none in the alendronate group (P = 0.012).
Clinical laboratory
Teriparatide treatment had the expected small, transient effects on serum calcium within 4–6 h after the teriparatide injection. The median postdose serum calcium reached its maximum of 2.5 mmol/liter (10.0 mg/dl) at month 6, which was significantly higher than the median postdose serum calcium of 2.3 mmol/liter (9.2 mg/dl) in the alendronate group (P < 0.001). These elevations in serum calcium were asymptomatic and were not associated with any clinically significant adverse outcomes. Twenty-eight women (38.4%) in the teriparatide group and two women (3%) in the alendronate group had an elevated (above the upper limit of normal) 4- to 6-h postdose serum calcium at least once in the study; nine (12.3%) patients in the teriparatide group had elevations on two consecutive visits. The transient increase in serum calcium remained less than 3.0 mmol/liter (12.0 mg/dl) in all but one woman in the teriparatide group. Investigators were instructed to reduce either calcium supplementation or injectable study drug to keep patients’ 4- to 6-h postdose serum calcium within normal limits, and 16 women (22%) reduced the dose of calcium supplements. No one was instructed to reduce the dose of teriparatide, and one woman discontinued teriparatide treatment because of the increased serum calcium levels after injection.
There were no significant effects on urinary calcium in the alendronate group. Teriparatide increased median 24-h urinary calcium excretion by 38 mg/d (0.95 mmol/d) at the 1-month visit (P = 0.001, compared with baseline and alendronate). After the 1-month visit, there were no significant differences between treatment groups. The proportion of women with at least one elevated 24-h urinary calcium [>300 mg/d (7.5 mmol/d)] in the teriparatide and alendronate groups (30% and 22%, respectively) was not significantly different.
Consistent with the effects on bone formation, there were statistically significant decreases in total alkaline phosphatase in the alendronate group and increases in the teriparatide group. There was also a small increase in serum uric acid in the teriparatide group, but there was no difference between groups in the number of patients with abnormal uric acid concentrations. There was a significant increase in serum 1,25-dihydroxyvitamin D3, and a significant decrease in serum intact PTH (1–84) and in 25-hydroxyvitamin D at the 12-month visit in the teriparatide group, compared with the alendronate group. Three women in the teriparatide group (two at the 12-month visit and one at the study closeout visit) had a positive test for antiteriparatide antibodies, but these findings were not associated with any adverse clinical effects.
Discussion
To our knowledge, this is the first trial comparing the efficacy of alendronate, an antiresorptive agent, and teriparatide, a bone formation agent, both of which have previously demonstrated efficacy on BMD and fracture risk reduction (15, 16, 17, 31). In this study of postmenopausal women with osteoporosis, once-daily sc injections of 40 µg teriparatide produced significantly greater increases in BMD at the LS and hip and in total body bone mineral than did 10 mg alendronate. The change in BMD at the trochanter, although not different between groups, was significantly increased above baseline. The difference in LS-BMD between teriparatide and alendronate was statistically significant at 3 months. The alendronate-treated women required 12 months of treatment to increase LS-BMD as much as the women treated with teriparatide for only 3 months. We noted that a teriparatide dose of 20 µg/d is most likely to be marketed for treatment of osteoporosis, based on findings from a large fracture prevention trial (31). In that study, the two doses of teriparatide had different effects on achieved BMD values but similar effects on fracture risk reduction. The finding in this trial that the teriparatide group had fewer fractures than the alendronate group was not unexpected. However, fracture incidence was not a primary outcome of this study and should be confirmed in a larger study.
The rapid increase in the highly trabecular bone of the LS associated with teriparatide administration was anticipated, based on the divergent patterns in changes in bone turnover apparent at 1 month of treatment. Bone ALP (a marker of bone formation) was significantly increased at every study visit in the teriparatide group. In the alendronate group, bone ALP was significantly depressed at 3 months and remained depressed for the remainder of the study. The marked decrease in bone turnover, coupled with the significant increase in BMD confirmed the bioavailability of the encapsulated alendronate. The effects of teriparatide were not restricted to the spine because increases in BMD were significantly greater than that of alendronate at every other site examined, except the radius and trochanter.
Teriparatide is a recognized bone anabolic agent, with results from animal models suggesting that teriparatide may have a positive effect on bone size in addition to its well-documented effect on BMD (27, 30, 34). The increased bone area may indicate a direct effect on cortical bone as well as an effect on bone architecture. The cortical shell of the vertebral bodies contributes a variable resistance to compression, depending on the amount of trabecular bone present, among other factors (35). A larger vertebral size has also been associated with lower fracture risk in both women and men (36). Significant effects on the cortical shell of the vertebral body, which to a lesser degree were also observed in the alendronate group, do not result in an increase in areal BMD measured by DXA. This suggestion of an increase in bone area is consistent with findings that fracture risk reduction is disproportionate to increase in BMD observed in several osteoporosis treatment studies (8, 10).
The mechanism by which alendronate increases vertebral size by DXA measurement is less clear because alendronate has not been shown to stimulate periosteal bone apposition. However, as BMC increases, the measured area by DXA also increases, which may explain the small observed increases in bone area in this group (37). The suggestion of a positive effect on area found by DXA will need to be confirmed by direct measures of volume and the trabecular and cortical fractions of bone by methods such as pQCT and digital radiogrammetry (38, 39).
Improvements in cortical bone after teriparatide treatment have been demonstrated by iliac crest biopsies (11), peripheral quantitative computed tomography of the radius (38), and digital radiogrammetry of the radius and metacarpals (39). These effects on bone architecture may also contribute to an increase in bone strength independent of BMD at sites other than the spine (4, 8).
The one third distal radius was the only site at which BMD was lower in the teriparatide group than in the alendronate group. On the basis of animal models, the decrease in areal density by DXA likely is due to increased haversian remodeling. The increased remodeling transiently increases cortical porosity, which does not affect biomechanical strength (27). In this study, there were no fractures of the radius in the teriparatide group, and in the large placebo-controlled study (31), there was a substantial and rapid decrease in the incidence of nonvertebral fragility fractures, with no increase in wrist fractures, consistent with the observations of preserved biomechanical strength in animal models.
Bisphosphonates and teriparatide increase BMD and decrease fracture rates by different mechanisms, which are reflected by changes in bone turnover markers. Bisphosphonates induce osteoclast apoptosis and have little direct effect on osteoblasts (40). Bisphosphonates inhibit bone turnover and increase BMD by reducing bone resorption more rapidly than bone formation and allowing filling in of resorption cavities and increased deposition of mineral into existing bone matrix (41). In contrast, once-daily teriparatide administration increases osteoblast birth rate through the induction of osteoprogenitor cell differentiation in the bone marrow (22) and/or preexisting bone-lining cells (20) as well as inhibiting osteoblast apoptosis (21). The result is a rapid increase in bone formation activity and bone turnover, as seen by bone ALP in this study and on bone biopsy (42, 43). The differences in mechanism result in substantial differences between antiresorptive and anabolic therapeutic effects on bone mass and architecture as well as on BMD. Teriparatide increases trabecular bone volume and cortical thickness and restores trabecular connectivity (11), whereas the majority of BMD increase observed with bisphosphonate treatment is a result of increased mineralization of existing bone matrix (41). Although it is probably a minor factor, teriparatide also increased 1,25(OH)2 vitamin D3 levels, compared with alendronate, which may contribute to the therapeutic effects of teriparatide (44) as well as the small calcemic and calciuric effects observed in this study.
Both once-daily and continuous administration of PTH stimulates bone formation, but continuous administration stimulates bone resorption to a greater degree than once-daily administration, resulting in no net bone gain (19, 20). The molecular mechanisms of these differential effects on the skeleton remain poorly understood. Once-daily PTH administration induces the osteoblast to produce different cytokines than does continuous administration of the peptide, which may explain the differences in biological effects of the different regimens (45).
Despite the different routes of administration (teriparatide is administered by sc injection and alendronate by the oral route), compliance with therapy was similar, and both treatments were well tolerated. Leg cramps were reported more frequently, whereas back pain was reported less frequently in the teriparatide group than in the alendronate group. In a large placebo-controlled study, the decrease in back pain was associated with an 80–90% reduction in the risk of moderate to severe vertebral fractures with either 20 µg or 40 µg doses of teriparatide (31).
In summary, treatment with the bone-formation agent teriparatide (40 µg/d) substantially increased BMD at multiple skeletal sites and appeared to reduce nonvertebral fracture risk, compared with alendronate in postmenopausal women with osteoporosis in this small study. The availability of a bone-formation agent would be an important addition to the armamentarium for the treatment of osteoporosis in postmenopausal women.
Acknowledgments
We thank the following additional investigators who participated in the study: Oyvin Skarra and William Shergy; and Mary E. Perron and Daojun Mo for technical assistance and the illustrations.
Footnotes
This work was supported by a grant from Eli Lilly and Co. (Indianapolis, IN).
Abbreviations: ALP, Alkaline phosphatase; BMC, bone mineral content; BMD, bone mineral density; DXA, dual-energy x-ray absorptiometry; LS, lumbar spine; NTX, N-telopeptides corrected for creatinine.
Received March 4, 2002.
Accepted July 19, 2002.
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 A. Cranney, A. Papaioannou, N. Zytaruk, D. Hanley, J. Adachi, D. Goltzman, T. Murray, A. Hodsman, and for the Clinical Guidelines Committee of Osteoporo Parathyroid hormone for the treatment of osteoporosis: a systematic review. Can. Med. Assoc. J., July 4, 2006; 175(1): 52 - 59. [Abstract] [Full Text] [PDF]
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 H. Liu, K. Michaud, S. Nayak, D. B. Karpf, D. K. Owens, and A. M. Garber The Cost-effectiveness of Therapy With Teriparatide and Alendronate in Women With Severe Osteoporosis. Arch Intern Med, June 12, 2006; 166(11): 1209 - 1217. [Abstract] [Full Text] [PDF]
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 B. T. Summey and G. Yosipovitch Glucocorticoid-Induced Bone Loss in Dermatologic Patients: An Update Arch Dermatol, January 1, 2006; 142(1): 82 - 90. [Abstract] [Full Text] [PDF]
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M. R. McClung, J. San Martin, P. D. Miller, R. Civitelli, F. Bandeira, M. Omizo, D. W. Donley, G. P. Dalsky, and E. F. Eriksen Opposite Bone Remodeling Effects of Teriparatide and Alendronate in Increasing Bone Mass Arch Intern Med, August 8, 2005; 165(15): 1762 - 1768. [Abstract] [Full Text] [PDF]
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 A. B. Hodsman, D. C. Bauer, D. W. Dempster, L. Dian, D. A. Hanley, S. T. Harris, D. L. Kendler, M. R. McClung, P. D. Miller, W. P. Olszynski, et al. Parathyroid Hormone and Teriparatide for the Treatment of Osteoporosis: A Review of the Evidence and Suggested Guidelines for Its Use Endocr. Rev., August 1, 2005; 26(5): 688 - 703. [Abstract] [Full Text] [PDF]
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K. A Cappuzzo and J. C Delafuente Teriparatide for Severe Osteoporosis Ann. Pharmacother., February 1, 2004; 38(2): 294 - 302. [Abstract] [Full Text] [PDF]
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 S. A. Brown and J. L. Sharpless Osteoporosis: An Under-appreciated Complication of Diabetes Clin. Diabetes, January 1, 2004; 22(1): 10 - 20. [Abstract] [Full Text] [PDF]
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 J.-S. Shao, S.-L. Cheng, N. Charlton-Kachigian, A. P. Loewy, and D. A. Towler Teriparatide (Human Parathyroid Hormone (1-34)) Inhibits Osteogenic Vascular Calcification in Diabetic Low Density Lipoprotein Receptor-deficient Mice J. Biol. Chem., December 12, 2003; 278(50): 50195 - 50202. [Abstract] [Full Text] [PDF]
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A. B. Hodsman, D. A. Hanley, M. P. Ettinger, M. A. Bolognese, J. Fox, A. J. Metcalfe, and R. Lindsay Efficacy and Safety of Human Parathyroid Hormone-(1-84) in Increasing Bone Mineral Density in Postmenopausal Osteoporosis J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5212 - 5220. [Abstract] [Full Text] [PDF]
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J. S. Finkelstein, A. Hayes, J. L. Hunzelman, J. J. Wyland, H. Lee, and R. M. Neer The Effects of Parathyroid Hormone, Alendronate, or Both in Men with Osteoporosis N. Engl. J. Med., September 25, 2003; 349(13): 1216 - 1226. [Abstract] [Full Text] [PDF]
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N. B. Watts Efficacy of Teriparatide and Alendronate on Nonvertebral Fractures J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1402 - 1403. [Full Text]
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 Injectable Parathyroid Hormone: A Powerful New Agent Against Osteoporosis Journal Watch Women's Health, January 8, 2003; 2003(108): 4 - 4. [Full Text]
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