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Teriparatide: A Review
Elaena Quattrocchi, PharmD, and Helen Kourlas, PharmD
Pharmacy Practice Department, Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brool~lyn, New Yorl~


Background: Traditionally, the management of osteoporosis in men and women has included the use of antiresorptive agents in combination with calcium and vitamin D supplementation. The mechanism of action of teriparatide is unique in that it possesses anabolic properties and therefore builds bone. Since the approval of teriparatide in the United States in 2002, a great deal of interest regarding its use in osteoporosis has developed. Objectives: This article reviews the information available on the new recombinant human parathyroid hormone teriparatide (hPTH [1-34]), including its clinical pharmacology, mechanism of action, pharmacokinetic properties, clinical efficacy, safety profile, potential drug interactions, contraindications and warnings, dosage and administration, and pharmacoeconomics. Methods: The articles included in this review were identified through searches of PubMed and MEDLINE (1966-December 2003) and International Pharmaceutical Abstracts (1970-December 2003). Search terms included teriparatide, Forteo, recombinant human parathyroid hormone (1-34}, and osteoporosis. The references of the identified articles were reviewed for additional publications. Specific product information was also obtained from the manufacturer of teriparatide. Results: Teriparatide has been studied in postmenopausal women with osteoporosis, drug-induced osteoporosis (specifically, corticosteroid-induced osteoporosis), and men with osteoporosis. The data available from various clinical trials have shown an increase in both bone mineral density (BMD) and bone mineral content (BMC) with the use of teriparatide compared with placebo. One study found that women treated with the 20-1~g dose and the 40-1~g dose were 35% and 40%, respectively, less likely to have one or more new nonvertebral fractures compared with placebo (P = 0.02). Another study compared the use of daily teriparatide 40-1~g injections versus oral daily alendronate. Results showed that the incidence of nonvertebral fractures was significantly lower in the teriparatide group than the alendronate group (P < 0.05). A study using 20- and 40-1~g daily injections of teriparatide was performed in men with osteoporosis. There was a statistically significant increase in lumbar spine BMD of 5.9% in the 20-1~g group and 9.0% in the 40-1~g group (both, P < 0.001). In the femoral neck, a 1.5% increase in BMD occurred in the 20-1~g group (P = 0.021) and a 0.9% increase in the 40-1~g group (P < 0.001). A limited number of studies are available assessing the combination of antiresorptive medications and teriparatide; however, the available data suggest that the effects of teriparatide do not require prior stimulation of bone resorption. Conclusions: Teriparatide has been shown clinically to improve BMD and BMC in postmenopausal women and in men. Because of its anabolic capabilities, teriparatide can be used as an alternative to the traditional therAcceptedfor publication April 5, 2004.
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apies that are currently available for the treatment of osteoporosis, with scheduled monitoring for adverse effects such as hypercalcemia and urinary calcium excretion. In 1 study, mild hypercalcemia was seen most often 4 to 6 hours after SC injection of teriparatide before returning to normal. Urinary calcium was observed to increase by 30 mg/d (0.73 retool/d) with teriparatide. (Clin Ther. 2004:26:841-834) Copyright © 2004 Excerpta Medica, Inc. Key words: teriparatide, osteoporosis, bone formation.


Osteoporosis is a disease characterized by low bone mineral density (BMD) and structural deterioration of bone tissue, which lead to bone fragility and increased susceptibility to fractures, especially of the hip, spine, and wrist. 1,2 In the United States, an estimated 44 million people are at risk for osteoporosis, 68% of whom are women. 1 According to the National Institutes of Health (NIH), 1 osteoporosis is responsible for >1.3 billion spine, hip, and wrist fractures each year. In the United States today, >10 million people have osteoporosis, 8 million of whom (80%) are women. 2 In addition, an estimated 14 million US men have either low bone mass or osteoporosis, and low BMD affects 1 in 2 US adults. 3 Inpatient hospital and long-term care facility expenditures for the management of osteoporosis-related fractures is estimated to be $17 billion each year. 2 Osteoporosis can be classified into 3 categories or types. Type I, postmenopausd osteoporosis, is accelerated bone loss beginning with the start of menopause and lasting up to 10 years if there is no intervention. Type II, senile osteoporosis, is related to the aging process and includes a decrease in the gastrointestinal absorption of calcium as well as a decreased rate of vitamin D activation. Type III, secondary osteoporosis, involves either disease processes or drug-related effects that lead to the development of osteoporosis. 4 Many pharmacologic agents are available for the treatment of osteoporosis; however, none are related to the physiologic deposition of calcium to bone. The most common treatments include calcium and vitamin D supplementation, bisphosphonates, estrogens (with and without progestins), raloxifene hydrochlo842

ride, and calcitonin (salmon). 5 All of these treatment options inhibit osteoclast-mediated bone loss and therefore reduce bone turnover, and BMD is increased because bone formation is permitted and bone resorption is inhibited. 5 With these treatments, the increase in BMD varies depending on the skeletal site and the medication: however, it is generally <10% over 3 years. 6 Teriparatide ®,* also referred to as recombinant human parathyroid hormone (1-34) (hPTH [1-34]), stimulates bone formation and has anabolic properties. It was first approved in the United States in November 2002 for the treatment of osteoporosis in men and women. Teriparatide became available in other countries, such as the United Kingdom and several other countries in the European Union, in April 2003. The objective of this article was to review the available data on the clinical chemistry and pharmacology, mechanism of action, pharmacokinetic properties, clinical efficacy, safety profile, potential drug interactions, contraindications and warnings, dosage and administration, and pharmacoeconomics of teriparatide. We also looked at osteoporosis in men, children, and other special populations, as well as the potential role of combination therapy with teriparatide.

Relevant articles were identified through searches of PubMed and MEDLINE for articles published from 1996 to December 2003 and of International Pharmaceutical Abstracts for abstracts published from 1970 to December 2003. Search terms included

teriparatide, Forteo, recombinant human parathyroid hormone (1-34), and osteoporosis. The references of
the identified articles were reviewed for additional publications. Specific product information was also obtained from the prescribing information 7 as provided by the manufacturer.

The native hormone made by the parathyroid gland chief cell is hPTH (1-84), a single-chain polypeptide with 84 amino acids and a molecular weight of 9423 Da. 6 The first 34 amino acids (1-34) are the biologically active moiety of mineral homeostasis. 6,s
*Trademark of Eli Lilly and Company (Indianapolis, Indiana).

E. Quattrocchi and H. Kourlas

Teriparatide is a recombinant hPTH fragment composed of the first 34 amino acids of the native 84-amino acid hPTH. Teriparatide (recombinant DNA origin) is manufactured using a strain of Escherichia coli modified by recombinant DNA technology. 7,9 Teriparatide has a molecular weight of 4117.8 Da, and its amino acid sequence is shown in the figure. 7

mediated through binding to specific high-affinity cell surface receptors. Possible mechanisms include the expression of skeletal insulin-like growth factor I (IGF-I) and bone-forming genes, al° Evidence has shown that teriparatide increases osteoblast birth rate and prevents osteoblastic apoptosis. ~° These processes increase the number of osteoblasts and the rate of new bone formation, and prolong osteoblast survival, a~°
Anabolics Versus Antiresorptives

Parathyroid hormone (PTH) (1-84) is the principal regulator of calcium homeostasis in mammals. ~° PTH is released when calcium levels decrease, and it is suppressed when calcium levels increase. PTH regulates bone metabolism. It stimulates 1 alpha-hydroxylase activity in the kidney, thereby increasing serum 1,25dihydroxyvitamin D levels, which promotes intestinal calcium absorption. In severe primary hyperparathyroidism, the continuous exposure to PTH results in a catabolic effect on the skeleton, but when administered in a low-dose (20 gg/d), intermittent fashion, it has an anabolic propert~ 5 Low-dose, intermittent PTH induces the osteoblasts to produce certain cytokines, which may explain the differences in biologic effects between low-dose, intermittent PTH and continuous administration of PTH. 1° The underlying molecular physiology accounting for the anabofic effect of PTH is unknown. 1° According to the prescribing information, 7 the biologic actions of PTH and teriparatide are

Anabolic agents, such as fluoride, strontium, growth hormone IGF-I, and teriparatide directly stimulate bone formation, unlike the antiresorptive agents, which inhibit osteoclast-mediated bone loss and thus reduce bone turnover. 5,1° The antiresorptires (estrogen, raloxifene, bisphosphonates, and calcitonin) could be considered "antiremodeling" drugs because they reduce the remodeling space and prolong the duration of mineralization. 5 All of the antiresorptives can increase BMD and can reduce the risk for new fractures, but they are generally not associated with dramatic increases in bone mass. 1° The action of antiresorptive agents to reduce fracture risk is rarely >50% of the baseline risk1°; rather, they primarily stabilize bone mass and prevent further bone loss. The potential for anabolic agents to improve BMD more substantially than the antiresorptives suggests that the former might reduce fracture risk to a greater extent than the latter. 5

I H-



Figure. Amino acid sequence of teriparatide. Reproduced with permission. 7





Teriparatide reaches peak serum concentration at - 3 0 minutes after SC injection (for a 20-lag dose) and decreases within 3 hours. The absolute bioavailability of teriparatide is -95%. 7 The systemic clearance of teriparatide (-62 Uh in women and - 9 4 Uh in men) exceeds the rate of normal hepatic plasma flow, consistent with both hepatic and extrahepatic clearance. 7,11 The volume of distribution after IV injection is -0.12 L/kg; volume of distribution for SC injection has not been assessed. 7,11 The serum distribution halflife of teriparatide is 5 minutes when administered by IV injection and -1 hour when administered by SC injection. 7 Our review of the literature indicated no metabolism or excretion studies performed with teriparatide; however, peripheral metabolism of PTH is believed to occur by nonspecific enzymatic mechanisms in the liver and excretion by the kidneys. 7

Neer et a112 conducted the first clinical trial that supported the use of teriparatide in postmenopausal women with a history of fracture. The study was a randomized, placebo-controlled trial in 1637 postmenopausal women (mean age, 69 years) with prior vertebral fractures. It took place in 99 centers in 17 countries for 21 months. The study was conducted to determine whether daily injections of teriparatide would increase bone formation without causing hypercalcemia. Women were excluded from the study if they had impaired hepatic function, which was not further classified by the study investigators; renal impairment, characterized as a serum creatinine concentration >2 mg/dL; or any illness that might affect bone and/or calcium metabolism. Women were also excluded if they had received any drug within the previous 2 to 24 months that would alter bone metabolism, such as bisphosphonates, calcitonin, and estrogen supplementation.12 Eligible women were randomized to receive teriparatide 20 or 40 lag or placebo, SC QD for 24 months. 12 In addition to the study protocol, all women received daily oral supplements of calcium 1000 mg and vitamin D 400 to 1200 IU. 12 The National Academy of Sciences and the National Osteoporosis Foundation recommend daily calcium intakes of 1000 to 1200 mg for adults. 1 In addition,

the daily recommended intake of vitamin D is 400 to 800 IU. BMD of the lumbar spine, proximal femur, radius, and the total body was measured using dual-energy x-ray absorptiometry (DXA). BMD of the spine was measured at baseline, 12 and 18 months, and at study end (24 months) in all women, and at 3 and 6 months in a subgroup of women. BMD of the hip was measured at baseline and at 12 and 24 months in all of the women, and BMD of the forearm and the total body was measured in only a subgroup at baseline, 12 months, and at study end. Height was measured in all patients at baseline and 12 months. Blood counts and urinalysis were performed in all patients at baseline and at 1, 6, 12, and 24 months. 12 A positive change in BMD was found to have occurred from baseline to 24 months in both teriparatide groups but not in the placebo group. 12 Results were statistically significant in all skeletal measurements (all, P < 0.001), except for the distal radius in both teriparatide groups compared with placebo, and the shaft of the radius in the teriparatide 20-lag group compared with placebo. Of 1326 women who had radiographs available for analysis, 105 women (7.9%) had .>1 new vertebral fracture. There was a 65% decrease in the risk for fracture in patients receiving teriparatide 20 tag and a 69% decrease in patients receiving teriparatide 40 lag (P < 0.001). 12 The risk for _>2 fractures was reduced by 77% in patients receiving teriparatide 20 lag and by 86% in patients receiving teriparatide 40 lag (P < 0.001). 12 Lastly, the risk for _>1 moderate to severe fracture was reduced by 90% in the teriparatide 20-lag group and by 77% in the teriparatide 40-lag group (P < 0.001). 12 Zanchetta et a113 conducted a cross-sectional study of 101 postmenopausal women, a subgroup of the international fracture prevention trial that was originally conducted by Neer et al. 12 These patients had originally consented to peripheral quantitative computed tomography (pQCT) testing and had usable scans. The objective of the study was to assess the effects of teriparatide on cortical bone from pQCT scans that were obtained from the subgroup of the prevention trial. Women were randomized to receive teriparatide 20 lag (n = 38) or 40 lag (n = 28) or placebo (n = 35). 13 Baseline demographic variables were similar

E. Quattrocchi and H. Kourlas

between all 3 groups, and no significant differences in the quality of the pQCT scans were found between the 3 groups. The pQCT variables were examined and analyzed; statistically significant results occurred for total bone mineral content (BMC), total bone area, and cortical bone area in women receiving teriparatide 20 or 40 l~g compared with placebo (all, P < 0.0~). 13 Use of teriparatide in this subgroup was associated with improved quality of nonvertebral cortical bone and favorable changes in the distribution and geometry of nonvertebral cortical bone.

The ideal treatment for osteoporosis would increase bone mass, improve bone architecture and strength, and reduce the risk for fracture. Antiresorptive medications reduce the risk for osteoporotic fracture, but many osteoporotic fractures occur despite treatment. H The use of teriparatide alone stimulates bone formation and increases bone mass, thereby reducing the risk for osteoporotic-related fractures. Based on our fiterature review, limited data are available on the use of teriparatide in combination with other therapeutic options for the treatment of osteoporosis, hPTH (1-34) agents, including teriparatide, have been studied in combination with other medications for the treatment of osteoporosis, H-23 but data are still limited. A few studies 15-17 have used recombinant hPTH (1-34) in combination with hormone replacement therapy (HRT). Lindsay et a115 performed a B-year, randomized, controlled trial of hPTH (1-34), 400 IU SC QD, in 17 postmenopausal women with osteoporosis receiving HRT (conjugated equine estrogen [0.62~ mg/d] or transdermal estrogen [~0 l~g,'d]) and medroxyprogesterone acetate ~-10 mg for 10 days or 2.~ mg/d continuously. Patients who had a hysterectomy did not receive a progestin (n = 6). The controls were women receiving HRT only (n = 17). In patients receiving HRT and hPTH (1-34), the total increases in BMD were 13.0% in the vertebrae (P < 0.001), 2.7% (P = 0.0~) in the hip, and 8.0% (P = 0.002) in the total bod)~ No significant changes in BMD were found at any site in the control group. The women receiving combination treatment had fewer vertebral fractures than controls. Increased BMD was associated with a reduction in the rate of vertebral fractures, which was significant when fractures were taken as a

15% reduction in vertebral height (P = 0.04). The use of hPTH (1-34) was associated with an increase in total body BMD (P = 0.002), with no negative effects at any skeletal site. It has been suggested 15 that hPTH (1-34) may increase vertebral bone mass at the expense of cortical bone by inducing increased intracortical and perhaps endocortical-junction remodeling, leading to weakened bone at primarily cortical sites. However, Lindsay et a115 found little evidence to support this hypothesis because they found no decrease in bone mass in any skeletal site. Roe et a116 also studied hPTH (1-34) and HRT (conjugated equine estrogens) in postmenopausal women with osteoporosis receiving HET for _>1 year before study entry Seventy-four postmenopausal women were randomized to receive hPTH (1-34) 400 IU SC QD or placebo while continuing to receive stable doses of conjugated equine estrogens (control group). A total of 60 subjects (81%) completed the treatment phase. At 24 months, the investigators found a 29.2% increase in spinal BMD and an 11.0% increase in femoral BMD as measured by DXA in women receiving combination therapy, compared with 0.9% and 0.2%, respectively, in the control group (both, P < 0.001). Of patients who were randomized to hPTH (1-34) and who underwent DXA scanning at 24 months, 89% had increases in lumbar spine BMD >2 SDs. Trabecular BMD in L1-L2, as measured by quantitative computed tomography (QCT), increased in the hPTH group by a median of 74% from baseline to 24 months (P = 0.027) and decreased 2.1% in the placebo group (P = NS). These findings indicate combination therapy is effective in producing large increases in BMD at the lumbar spine and femoral neck, ~6 and that therapy with hPTH (1-34) might restore bone mass above the osteopenic range in postmenopausal women with osteoporosis. Cosman et al ~7 investigated the use of hPTH (1-34) in combination with established HRT for 22 years in 52 women with osteoporosis, and its effects on vertebral fracture and maintenance of bone mass after PTH withdrawal. Women included in the PTH and HRT group had a mean age of 57.7 years, and the women who received HRT alone had a mean age of 62.9 years. Twenty-seven women were randomly assigned to remain on hPTH (1-34) 400 IU SC QD plus HRT, and 25 women were to remain on HRT alone (control group), for 3 years. In the control group, BMD and



biochemical variables of bone turnover remained stable throughout the 3-year treatment trial and 1-year follow-up. Women in the combination-therapy group had mean (SD) increases in bone mass of 13.4% (1.4%) in the spine, 4.4% (1%) in the total hip, and 3.-/% (1.4%) in the total b o @ Percentage changes in BMD of the lumbar spine, total hip, and total body were significantly different in the combinationtherapy group compared with baseline and the group receiving HRT alone (both, P < 0.05). The rates of increase were most prominent in the first 6 to 12 months of treatment. BMD measurements remained stable 1 year after discontinuation of hPTH (1-34) treatment, without any significant loss while women continued HRT. Therapy with hPTH (1-34) was associated with a reduced incidence of vertebral fracture of 75% to 100% compared with HRT alone. The incidence of vertebral fractures was assessed over 3 years of the study using decreases in vertebral heights of 15% or 20% compared with vertebral heights on the baseline radiograph. In the 15% reduction criterion, there were 2 vertebral fractures in the PTH-plus-HRT group compared with 12 vertebral fractures in patients receiving HRT alone (P = 0.001). In the 20% reduction criterion, there were no vertebral fractures in the PTH-plus-HRT group and 7 vertebral fractures in patients receiving HRT alone (P = 0.003). Using the 15% height reduction cutoff point, PTH was associated with a reduction in the percentage of women who had incident vertebral fractures, from 3-/.5% to 8.3% (P < 0.02). Using the 20% height reduction cutoff point, PTH was associated with a reduction in the percentage of women who had incident vertebral fractures, from 25.0% to 0.0% (P = 0.02). is The most common cause of drug-related osteoporosis is the use of glucocorticoids, 1° which are associated with rapid bone loss, fractures, increased morbidity,5 suppression of bone formation, and increased bone resorption. 24 Lane et al > conducted a 12-month randomized clinical trial of hPTH (1-34) in 51 postmenopausal women (mean age, 63 years) who were receiving HRT and corticosteroids (>5 mg/d of prednisone) for a chronic inflammatory disease for >1 year before the study, and planned to continue therapy for >1 year. The women were randomly assigned, using a compute>generated randomization table, to receive hPTH (1-34) plus estrogen (n = 28) or estrogen alone (n = 23). Patients were given a calcium supplement 846

(calcium carbonate 1500 mg/d) and a vitamin D supplement (800 IU/d), provided as 2 multivitamins. All study patients were maintained on their individual HRT regimen (not specified), and had been receiving HRT for >1 year. Patients were continued on their glucocorticoid regimen. The mean daily dose of the glucocorticoid was similar between groups at baseline through study end. Patients were taught SC self-injection, but placebo injections were not used. A mean dose of 25 l~g (400 U) SC QD was given for 12 months. The BMD of the lumbar spine, measured using QCT and DXA, increased significantly in the combination-therapy group (P < 0.001) after 12 months of treatment, whereas it remained the same in the group receiving estrogen only. The mean differences between the treatment groups at 12 months were 33.5% for the lumbar spine by QCT (P < 0.001) and 9.8% by DXA (P < 0.001). Women in the hPTH (1-34)-plus-HRT group experienced mean (SD) increases of 35% (5.5%) in vertebral BMD as measured using QCT, and 11% (1.4%) as measured by DXA scan, compared with relatively small changes of 1.7% (1.8%) and 0% (0.9%), respectively, in the estrogen-only group. After 12 months of hPTH (1-34) administration, no significant changes in BMD were found in the hip or forearm between or within the groups. According to the investigators, 19 although the anabolic effects of PTH were significantly less or absent in the hip and forearm region, no negative effect of PTH was found after 12 months at these sites, as has been previously reported, is Lane et al is conducted another study to determine whether changes in bone turnover and bone mass would occur during the 12 months after hPTH (1-34) treatment was discontinued. The mean (SD) change in BMD of the lumbar spine, as assessed using QCT and DXA scans, in the PTH group at 24 months was 45.9% (6.4%) and 12.6% (2.2%), respectively (P < 0.01). After 12 months of follow-up, a significant increase from baseline in hip bone mass was observed (change, 4.7% [0.9%]; P < 0.01). According to Lane et al, ~s the additional increases in BMD that occur after discontinuing hPTH (1-34) for 12 months may be the result of filling in of the remodeling space that was excavated in response to the study drug treatment. The delayed increase in BMD may also be due

E. Quattrocchi and H. Kourlas

to the fact that a DXA scan cannot measure the increase until the newly formed bone matrix becomes fully mineralized, which requires several months, is The results of both studies suggest that PTH increases bone mass in the lumbar spine and hip in postmenopausal women with glucocorticoid-induced osteoporosis who are receiving HRT. The maximal effect on bone mass at the hip required an additional 6 to 12 months after hPTH (1-34) was discontinued. Also, the investigators found no evidence of cortical bone remodeling that has been reported is in animals treated with hPTH (1-34) and in primary hyperparathyroidism. Lane et al ls,19 concluded that estrogen in combination with hPTH (1-34) might have reduced cortical bone remodeling. Rehman et al 2° conducted a follow-up study to determine whether hPTH (1-34) use is associated with an increase in vertebral cross-sectional BMD in a group of postmenopausal women with glucocorticoidinduced osteoporosis. They hypothesized that if hPTH (1-34) increases bone formation in the periosteal surface, this will increase vertebral size, and that the increased vertebral size could improve bone strength. Fifty-one postmenopausal women receiving chronic stable doses of HRT (conjugated estrogens, 0.625 mg PO QD for >1 year) and glucocorticoid therapy (prednisone, mean dose, 5-20 mg PO QD for >1 year) who had osteoporosis (defined as a t score <-2.5 SDs at the lumbar spine and/or hip) were included. 2° Twenty-eight women were randomized to receive hPTH (1-34) 40 ug SC QD for 12 months with a 12-month follow-up while continuing to receive HRT, and 23 received placebo and HRT for 24 months. Baseline QCT scans were performed at L1 and L2. Vertebral cross-sectional area (VCSA) of L1 and L2 were measured for each lumbar spine QCT scan at baseline and at 12 and 24 months. Patients who received hPTH (1-34) plus HRT had a 4.8% increase in L1 and L2 in the VCSA (P < 0.001). During follow-up (ie, 12 months after hPTH was discontinued and patients had continued with HRT), VCSA increased from baseline by 2.6% (P < 0.05). 20 Alternatively, no significant differences in VCSA occurred at 12 or 24 months in the group receiving HRT and placebo. The increase in vertebral compression strength was estimated to be >200%; however, this increase was a result of increased BMD rather than an increased VCSA.

The effect of combining antiresorptives and recombinant hPTH (1-34) must still be studied. If bisphosphonates stay bound to bone and continue to inhibit bone formation for years after treatment is discontinued, it may be best to give hPTH (1-34) alone before starting bisphosphonates, xl A randomized controlled trial was performed by Rittmaster et al xx in 66 postmenopausal osteoporotic women aged 50 to 75 years to assess the effects of PTH (1-84) followed by alendronate. The women with osteoporosis were treated for 1 year with recombinant hPTH (1-84) 50, 75, or 100 ug SC QD or placebo, and then were given alendronate 10 mg PO QD for an additional year. BMD was measured in the femoral neck, lumbar spine, and the total body: In all women receiving hPTH (at any dose), mean (SD) changes in BMD were 7.1% (5.6%) (spine), 0.3% (6.2%) (femoral neck), and -2.3% (3.3%) (total body). Patients who had originally received 100 or 75 ug of PTH had a greater improvement in BMD than those who had received placebo (P < 0.001, P < 0.004 for the 100- and 75-ug patients, respectively).22 In women who received hPTH (1-84), after switching to alendronate for 1 year, the mean (SD) changes in BMD were 13.4% (6.4%) (spine), 4.4% (7.2%) (femoral neck), and 2.6% (3.1%) (total body). This study provides evidence that prescribing a bisphosphonate, such as alendronate, after a course of hPTH (1-84) results in greater increases in spinal BMD than prescribing alendronate alone. 22,23 A short-term study of 10 postmenopausal women with osteoporosis was conducted by Cosman et a114 to determine whether hPTH (1-34) in combination with alendronate could be a viable treatment for osteoporosis. Patients were assigned in an open fashion to PTH plus alendronate (mean [SD] age, 69 [1.8] years) or alendronate alone (mean [SD] age, 64 [4.8] years). Five patients continued receiving alendronate 10 mg/d alone and 5 patients continued receiving alendronate with hPTH (1-34) 400 IU SC QD added for 6 weeks. The data showed that hPTH (1-34) could increase biochemical indicators of bone formation in the presence of pretreatment with alendronate. Markers of bone formation increased within 3 weeks in the hPTH-plus-alendronate group, with mean peak levels at 5 to 7 weeks: osteocalcin, 49% (P < 0.01); propeptide of type I procollagen, 61% (P < 0.01); and bone-specific alkaline phosphatase (ALP), 24% (P = NS). No significant changes occurred


at any time in the alendronate group, which suggests that the anabofic effect of hPTH (1-34) does not require prior stimulation of bone resorption and that bone formation must be preceded by bone resorption. The NIH is sponsoring a randomized trial to determine whether combination treatment with hPTH (1-34) and a bisphosphonate is better or worse than or no different from sequential therapy
SPECIAL P O P U L A T I O N S Osteoporosis in Men In the United States, ~3% of men aged >30 years

have osteoporosis, and -30% of men aged >30 years have osteopenia. 1 The prevalence of osteoporosis is greater in white men (7%) than in black (3%) and Hispanic American (3%) men, based on the data currently available. 25 Information on the rates of osteoporosis in Asian American men and other ethnic groups is still lacking. 25 The development of osteoporosis in men is primarily related to various factors that can include hypogonadism, hyperparathyroidism, long-term glucocorticoid use (ie, prednisone _>3 mg for >6 months), excessive alcohol use (22 drinks/d), family history, and possibly anticonvulsant therapy with phenytoin and phenobarbital. Current treatments of osteoporosis in men include calcium and vitamin D supplementation and the use of bisphosphonates. Teriparatide is now indicated as another potential treatment option. 26,27 Kurland et al 2° conducted one of the first randomized, double-blind, placebo-controlled trials to assess the use of hPTH (1-34) in men with osteoporosis. The 18-month study involved 23 patients with idiopathic osteoporosis (mean [SD] age, 30 [1.9] years). Patients were included if they had a t score of <-2.3 SD at the lumbar spine or femoral neck. Measures were taken to exclude individuals with known secondary causes of osteoporosis, even though men with hypogonadism were included if they had been on a stable dose of testosterone for at least 2 years before the start of the study Doses of testosterone were not provided in the study. Patients were also allowed to receive medications for the management of osteoporosis before but not within 6 months of randomization. Prior to randomization, there was a 12to l % m o n t h observational period before which all patients were instructed to have a total daily intake of calcium 1300 mg and of vitamin D 400 IUi patients

were instructed to continue supplementation after randomization. Patients were randomized to receive either hPTH (1-34) 400 IU SC QD (equivalent to 23 ug/d) (n = 10) or placebo (n = 13). 26 Compliance was measured using medication diaries and vial counts. BMD of the lumbar spine, right hip, and nondominant radius was measured using DXA every 6 months after initiation of treatment. Additional testing included serum calcium, phosphorus, alkaline phosphatase activity, albumin, blood urea nitrogen, and creatinine levels. These tests were performed during enrollment, at 1 month, and every 3 months thereafter. Patients who received hPTH (1-34) had a statistically significant increase in BMD at the lumbar spine compared with those who received placebo (P < 0.001), with a mean (SD) increase of 13.5% (3.0%) at 18 months. In addition, mean (SD) BMD in the femoral neck was significantly increased--2.9% (1.5) at 18 months (P < 0.05)--in the treatment group as compared to the placebo group. Lastly, in men who were treated with hPTH (1-34), the mean (SD) lumbar spine t score did not improve statistically significantly (from -3.5 [0.2] to -2.4 [0.4]). One a score unit improvement was observed in the lumbar spine (P < 0.003), however. 26 No statistically significant changes in t or a scores were found in the femoral neck or the radius. Kurland et a126 found that low-dose administration of hPTH (1-34) increased BMD in men over the 18month trial period. The study allows further investigation of the use of hPTH in men with osteoporosis, Orwoll et a127 conducted one of the first randomized studies using teriparatide in men. Patients were recruited from hospital clinics and community practices from 37 centers in 11 countries. Men were included in the study if they were ambulatory; flee of any chronic, disabling conditions other than osteoporosis; had a BMD 2-2.00 SD at the lumbar spine or proximal femur; and were stable for 26 months before randomization. Men were excluded if they had secondary causes of osteoporosis, including having received any type of medication that would affect bone metabolism (eg, glucocorticoids, estrogen agonists and antagonists, anticonvulsants, calcium, or aluminum-containing antacids); if they had any disease or disease process that would affect calcium absorption or excretion; or if they had been treated

E. Quattrocchi and H. Kourlas

with calcitonin, bisphosphonates, progestins, fluorides, vitamin D, or any type of anabolic steroid within 6 months of the start of the study. Men receiving exogenous androgen formulations (eg, testosterone) were not excluded. Bone markers (ie, bone ALP and serum procollagen I carboxy-terminal propeptide [PICP] for bone formation; and urinary N-telopeptide/creatinine ratio and free deoxypyridinoline/creatinine ratio for bone resorption) were measured at baseline and at 1, 3, 6, and 12 months. The primary objective of the study was to assess changes in BMD of the lumbar spine from baseline to study end. Median duration of follow-up was 11 months. Secondary end points included changes in BMD of the total hip, femoral neck, intertrochanter, trochanter, radius, and the total body, and BMC of the total body, from baseline to study end. Compliance was measured by counting the number of unused synnges returned at scheduled visits. Of the 959 men originally screened (age range, 30-85 years), 437 were eligible. Of these, 151 men received teriparatide 20 l~g/d, 139 received teriparatide 40 l~g/d, and 147 received placebo. All baseline cha> acteristics were similar between the 3 study groups. This study 27 showed several statistically significant differences in BMD and BMC in some selected skeletal measurements. BMD was increased, with mean changes from baseline to end point of 5.9% (P < 0.001) in the lumbar spine, and 1.5% (P = 0.029) in the femoral neck in patients receiving teriparatide 20 l~g/d compared with placebo. Patients who received teriparatide 40 l~g,'d experienced mean changes from baseline to end point of 9% (P < 0.001) in the lumbar spine and 2.9% (P < 0.001) in the femoral neck compared with placebo. In addition, teriparatide 40 l~g/d was associated with a mean change in BMD of 2.3% in the intertrochanter and the total hip compared with placebo (P < 0.001 for both comparisons). Lastly, a dose-dependent change was found between the teriparatide 20-1~g,'d and 40-1~g,'d groups in the lumbar spine (P < 0.001), femoral neck (P = 0.023), intertrochanter (P = 0.012), and total hip
(p = 0 . 0 0 9 ) .

Teriparatide treatment was associated with an increase in osteoblast activity compared with placebo after 1 month (P < 0.001) as assessed using ALP and PICP measurements. Biochemical markers for bone formation peaked after 6 to 12 months of treatment with teriparatide use. The markers for bone resorption were stable in the placebo group; however, they increased in both teriparatide groups. However, the study did not assess the risk for fracture in male patients with osteoporosis. Compliance was based on the mean percentage of study medication taken in each group, which was 79%. 2r According to the teriparatide prescribing information] no age-related pharmacokinetic differences in teriparatide have been found in patients ranging in age from 31 to 85 years. Teriparatide has been studled in the geriatric population (>65 years of age) in clinical trials, with no significant difference in bone response or adverse reactions compared with younger patients (<65 years of age)7 Elderly patients in general, however, may be more sensitive to medications overall. According to the prescribing information, s the recommended dosage for both men and women is 20 l~g,'d, even though systemic concentrations of teriparatide are 20% to 30% lower in men than in women.

Total-body BMC increased 0.6% in the teriparatide 20-tag/d group versus placebo (P = 0.021), and 0.9% in the teriparatide 40-tag/d group versus placebo (P = 0.005). No significant differences were found between the 20- and 40-tag/d groups in total-body BMC.

The pharmacokinetic trials of teriparatide by the manufacturer were performed in a population that was 98.5% white; therefore, the role of race in teriparatide pharmacokinetic properties cannot be determined because of the limited data available. 7 Also, teriparatide pharmacokinetic data have not been assessed in the pediatric population] so no information in this special population can currently be provided. However, it is known that teriparatide should not be used in children (2-12 years of age) 2s or young adults (13-18 years of age) 2s with open epiphyses. In 1 case report, a 16-yea>old female adolescent with autoimmune hypoparathyroidism and osteoporosis received hPTH (1-34) for 6 months. 29 The patient was diagnosed with hypoparathyroidism at age 9 years and with osteoporosis at age 15 years, 10 years after vertebral compression fractures were noted on plain radiography of the spine. > Treatment was initiated with hPTH (1-34) 80 l~g SC QD for 3 months, then 32 l~g BID for 3 additional months.



DXA scanning showed a 23% increase in lumbar spine BMD after 6 months; at that point, treatment with hPTH (1-34) was concluded. However, continued improvement was seen 6 months after treatment discontinuation. 29 Additional studies need to be conducted to fully understand the response to hPTH (1-34) in adolescents and to determine the long-term effects of the drug on growth and development in this population.
Pregnant Patients

Teriparatide should not be used in pregnant women. Teriparatide has not been studied in human fetal development and is pregnancy category C. No clinical data are available to determine whether teriparatide is secreted into breast milk. Thus, the drug also should not be used in women who are breastfeeding.

All clinical trials assessing teriparatide have excluded individuals with renal insufficiency, hepatic insufficiency, and heart failure. Therefore, use of teriparatide is limited to otherwise healthy patients. 7,H

Concerns exist regarding the safety of teriparatide. As part of drug testing, teriparatide was given to rats for a significant part of their lifetime, and studies demonstrated an increased risk for osteosarcoma, a rare but serious malignant primary bone tumor. 7,° Osteosarcoma is a spindle cell neoplasm that produces osteoid (unmineralized bone) or bone that spreads by local invasion to adjacent tissues and to distant sites, such as the lungs. 7,3°-32 It is neither a carcinoma nor a metastatic cancer from other primary tumors. A study conducted by Tashjian and Chabner ° showed that a 2-year rat bioassay, using Fischer 344 rats, resulted in the development of osteocarcinoma. The incidence depended on the doses that were administered, which included 5, 30, and 75 t~g/kg.d given to 6- to 8-week-old rats. The highest incidence (48%) of osteocarcinoma, therefore, developed in the animals that received 73 Ug/kg.d. 9 However, the findings cannot be extrapolated to humans for various reasons, one of the most important of which is the differences in skeletal physiology between rodents 850

and primates. PTH stimulates longitudinal bone growth in rats throughout most of their lives. In humans, longitudinal skeletal growth ceases by 18 to 24 years of age. ° The human skeleton is dominated by osteonal remodeling, and the rat skeleton is dominated by skeletal growth modeling. In rats, PTH increases cortical bone mass by layering new bone on old bone. The effect that occurred in these Fischer 344 rats was highly dependent on the dose; duration; and, perhaps, the time in a rat's life cycle that the drug was administered. Basically, these Fischer 344 rats were administered nearly lifetime daily injections of PTH. Lastly, regarding the physiologic component of the rat skeleton, it consistently grows throughout the rat's life span, and Fischer rats have historically been at risk for developing osteocarcinoma without the administration of exogenous parathyroid. ° This may further explain the overwhelming development of osteocarcinoma in parathyroid-treated Fischer 344 rats. Therefore, per Tashjian and Chabner, ° their findings cannot predict an increased risk for osteosarcoma in patients with osteoporosis receiving teriparatide therapy for _<2 years. The safety and efficacy of teriparatide have not been studied beyond 2 years of treatment; therefore, use of this drug for >2 years is not recommended. 9 In the study conducted by Neer et a112 in 1637 women receiving either hPTH (1-34) 20 or 40 l~g SC QD or placebo for a median period of 18 months, no evidence of osteocarcinoma was found. Cancer developed in 40 patients (2% in each hPTH [1-34] group and 4% in the placebo group). However, the types of cancer that developed in the 40 women were neither identified nor explained. In the study by Kurland et al, 26 of the 10 patients who were randomized to receive hPTH (1-34) 400 IU SC QD (equivalent of 25 l~g/d), there was no reported documentation of any form of bone-related cancer. °,32 Similarly, in the study by Orwoll et al, 27 after the median treatment duration of 11 months, no evidence of osteocarcinoma was found. No information is available assessing the safety of teriparatide in patients with hepatic, renal, or cardiac disease. 7
Other Adverse Events

Adverse drug events (ADEs) that have been associated with teriparatide use include angina pectoris,

E. Quattrocchi and H. Kourlas

asthenia, constipation, depression, dizziness, headache, hypercalcemia, hypertension, hyperuricemia, insomnia, nausea, neck pain, syncope, and vertigo. 7,n According to the prescribing information, 7 when teriparatide 20 l~g is administered once daily, the serum calcium concentration increases transiently, beginning - 2 hours after dosing, reaching a maximum concentration between 4 and 6 hours (median increase, 0.4 mg/dL), decreasing - 6 hours after dosing, and returning to baseline values by 16 to 24 hours after dosing. 7 Neer et a112 reported that mild hypercalcemia (defined as a calcium concentration >10.6 rag/alL) developed in 28% of women receiving hPTH (1-34) 40 l~g/d and in 11% of women receiving hPTH (1-34) 20 l~g/d 16 to 24 hours after previous injection. Persistent hypercalcemia was not observed in clinical trials of teriparatide, nor in the study by Neer et al. ~2 If persistent hypercalcemia is detected, tedparatide should be discontinued and the patient should be assessed for the cause of the hypercalcemia. The prescribing information 7 does not recommend that patients with underlying hypercalcemic disorders, such as hyperparathyroidism, be treated with teriparatide. Teriparatide increases urinary calcium excretion, but the frequency for hypercalciuria in clinical trials is similar between teriparatide and placebo. 7 In clinical trials, 2.8% of teriparatide-treated patients had serum uric acid concentrations above the upper limit of normal compared with 0.7% of patients receiving placebo. 7 No significant increases in gout, arthralgia, or urolithiasis were found in the study patients. Teriparatide has not been studied in patients with active urofithiasis and should be used with caution in patients with active or recent urolithiasis because of the potential to exacerbate the condition. 7 Limited information is available to assess the safety of teriparatide in patients with hepatic, renal, or cardiac disease. According to the prescribing information, 7 short-term clinical pharmacology studies showed infrequent but transient episodes of symptomatic orthostatic hypotension. The episodes typically occurred within the first several doses and within 4 hours of dosing, and resolved within a few minutes to a few hours. The transient orthostatic hypotension did not preclude continued use of teriparatide in these patients.

In the study conducted by Neer et al, 12 94 of the 1637 women (6%) withdrew because of ADEs. Eighteen percent of the women reported nausea, 13% headache, 9% dizziness, and 3% leg cramps. In the study by Body et al, 24 6 patients (8.2%) receiving tedparatide and none receiving alendronate reported leg cramps. Twenty-eight women (38.4%) receiving tedparatide and 2 (3%) receiving alendronate had elevated serum calcium levels at least once within 4 to 6 hours after dosing, n , n The elevated serum calcium levels were not associated with clinically significant adverse outcomes, and the women were asymptomatic.

Limited data are available on the use of teriparatide and other concurrent medications. One available study analyzed the coadministration of oral hydrochlorothiazide 25 mg in 20 healthy subjects. 7 Teriparatide 40 Pg did not affect serum calcium levels. In addition, a study of 17 patients with mild, moderate, or severe hypercalcemia and 9 healthy subjects was conducted with the coadministration of furosemide 20 to 100 mg IV QD and teriparatide 40 Pg SC QD. No clinically significant increases in serum calcium were found. 7 Because teriparatide can transiently increase serum calcium levels, caution should be exercised when concomitantly administering teriparatide and digitalis. In a study 33 conducted in 15 healthy subjects, administration of teriparatide 40 l~g SC QD, added to digoxin already at steady state, did not alter the effect of the digoxin. It has been suggested that hypercalcemia may predispose patients who are receiving digitalis to toxicity, and caution and frequent monitoring are recommended. 33

Osteosarcoma in humans occurs in a bimodal age distribution, with 1 incidence peak during late adolescence and young adult life (age 13-25 years), and the other occurring in the 6th decade and beyond. 31,32 This bimodal incidence is related to the intrinsic state of bone turnover during these 2 periods. The incidence is also increased in men and women who have Paget's disease of bone later in life or who have undergone radiotherapy of the skeleton. 34,35 Due to the uncertain relevance of the rat osteosarcoma findings to humans, the manufacturer of ted851


paratide has placed a "black box" warning in the package insert indicating that teriparatide should be prescribed only to patients in whom the potential benefits are considered to outweigh the potential risks. Teriparatide should not be prescribed to patients who are at increased baseline risk for osteosarcoma (including those with Paget's disease of bone or unexplained elevations of ALP; children; and young adults with open epiphyses or prior radiotherapy of the skeleton). Patients with preexisting hypercalcemia, bone metastases, or a history of skeletal malignancies or metabolic bone disease other than osteoporosis should not use teriparatide.

teriparatide shortly after taking the pen out of the refrigerator. The pen should be recapped and returned to the refrigerator immediately after use.

Teriparatide is supplied as a sterile, colorless, transparent, isotonic solution in a glass cartridge that is preassembled into a disposable pen for SC injection. 7 Each pen is filled with 3.3 mk to deliver 3 mk of drug. 7 Each milliliter contains teriparatide 250 tag (corrected for acetate, chloride, and water content), glacial acetic acid 0.41 rag, sodium acetate (anhydrous) 0.10 rag, mannitol 45.4 rag, metacresol 3.0 rag, and water for injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4. Teriparatide is indicated in postmenopausal women with osteoporosis and men with primary or hypogonadal osteoporosis who are at high risk for fracture.1 The recommended dosage is 20 lag SC QD, injected into the thigh or abdominal wall, for 28 days. 7 Clinical trials of the higher dosage (40 lag SC QD) 3,4,6-s have shown increased efficacy but decreased tolerability Two trials 12,36showed that patients receiving 40 lag had more complaints of headache (13% vs 8% in the placebo group) and nausea (18% vs 8% in the placebo group) than those receiving 20 lag, whereas the results for nausea and vomiting were similar to placebo. Due to potential orthostatic effects of teriparatide, initial doses should be administered with the patient sitting or lying down if symptoms of orthostatic hypotension occur.1 The pen delivers the recommended dose of 20 lag of teriparatide per day The prescribing information 7 recommends discarding the teriparatide pen after the 28-day usage period, even if the pen contains unused solution. The pen should be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) at all times. Patients should inject 852

Teriparatide is reserved for patients, both men and postmenopausal women, who are at high risk for fractures. No published pharmacoeconomic studies have compared the use of teriparatide with traditional agents used for the treatment of osteoporosis, such as bisphosphonates, estrogens, and calcitonin. The average wholesale cost of teriparatide is $20.81/d. Therefore, the estimated total 2-year cost of teriparatide is >$15,000.11 Compared with other medications that are currently on the market for the management of osteoporosis, teriparatide exceeds the monthly amount a patient would pay compared with the other medication alternatives (Table). Teriparatide is calculated as costing 8-fold more a month than other available medications (personal communication, Amerisource Bergen Distribution, March 29, 2004), which can be a growing concern for many patients who choose this as a treatment option.

Table. Cost of 30 days' treatment for osteoporosis.*

Alendronate sodium Risendronate sodium Raloxifene hydrochloride Calcitonin (salmon)

I 0 mg PQ QD 70 mg PQ Q W S mg PO QD 35 mg PO Q W 60 mg PO QD 100 lU SC/II QD 200 lU intranasal QD

Cost, $
69.00 65.00 66.00 64.00 71.00 II 3.00 69.00


20 IJg SC QD


*Retail cost based on personal communication, Amerisource Bergen Distribution, Narch 29, 2004


Teriparatide represents an important new advance in the therapy for osteoporosis. The exact role of tedparatide in the management of osteoporosis still needs to be defined. Tedparatide has a place in therapy as an alternative agent. Its efficacy and safety must be confirmed. Investigators have found that hPTH (1-34) is effective when used as a single agent or in combina-

E. Quattrocchi and H. Kourlas

tion with alendronate to increase BMD. The NIH will determine whether the efficacy of combination treatment with hPTH (1-34) plus a bisphosphonate is better or worse than or no different from sequential the> ap> The combination of agents might be significantly more potent than either agent alone because antiresorptive and anabolic agents work by completely different mechanisms of action.

1. National Institutes of Health, Osteoporosis and Related Bone Diseases--National Resource Center. Osteoporosis. Available at: www.nof.orglosteoporosislindex.htm. Accessed August 13, 2003. 2. Crandall C. Osteoporosis. A two article symposium. Postgrad Med. 2003; 114:21-32. 3. NIH Consensus Development Panel. Osteoporosis prevention, diagnosis, and therapT~ ,lAMA. 2001;285:785793. 4. Steinweg KK. Osteoporosis. In: Rakel RE, ed. 5aunders Manual of Medical Practice. 2nd ed. Philadelphia, Pa: WB Saunders; 2000:928-931. 3. Rubin MR, Bilezikian JE New anabolic therapies in osteoporosis. Endocrinol Metab Clin North Am. 2003; 32:285-307. 6. Simonelli C. Parathyroid hormone: A new treatment option for osteoporosis. Pharmacy and Therapeutics. 2002;2-/:410-413. 7. Forteo (teriparatide [rDNA origin] injection) [package insert]. Product Information. Indianapolis, Ind: Eli Lilly and Co; 2002. 8. Bringhurst FR, Demay MB, Kronenberg HM, et al. Hormones and disorders of mineral metabolism. In: Wilson JD. Williams Textbook of Endocrinology. 9th ed. Philadelphia, Pa: WB Saunders; 1998:1155-1210. 9. Tashjian AH Jr, Chabner BA. Commentary on clinical safety of recombinant human parathyroid hormone 1-34 in the treatment of osteoporosis in men and postmenopausal women. J Bone Miner Res. 2002;1-/: 11311161. 10. Rosen CJ, Bilezikian JE Clinical review 123: Anabolic therapy for osteoporosis. J Clin Endocrinol Metab. 2001; 86:957-964. 11. Honeywell M, Phillips S, Branch E, et al. Teriparatide for osteoporosis: A clinical review. Pharmacy and Therapeutics. 2003;28:-/13-716. 12. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone

mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001 ;344:1434-1441. 13. Zanchetta JR, Bogado CE, Ferretti JL, et al. Effects of teriparatide [recombinant human parathyroid hormone (1-34)] on cortical bone in postmenopausal women with osteoporosis. J Bone Miner Res. 2003;18: 539-543. 14. Cosman E Nieves J, Woelfert L, et al. Alendronate does not block the anabolic effect of PTH in postmenopausal osteoporotic women. J Bone Miner Res. 1998; 13:1031-1033. 13. Lindsay R, Nieves J, Formica C, et al. Randomised controlled study of effect of parathyroid hormone on vertebral-bone mass and fracture incidence among postmenopausal women on oestrogen with osteoporosis. Lancet. 1997;350:550-555. 16. Roe EB, Sanchez SD, Del-Puerto GA, et al. Parathyroid hormone 1-34 (hPTH 1-34) and estrogen produce dramatic bone density increases in postmenopausal osteoporosis: Results from a placebo controlled randomized trial. J Bone Miner Res. 1999;14:5137. 17. Cosman E NievesJ, Woelfert L, et al. Parathyroid hormone added to established hormone therapy: Effects on vertebral fracture and maintenance of bone mass after parathyroid hormone withdrawal. J Bone Miner Res. 2001;16:925-931. 18. Lane NE, Sanchez S, Modin GW, et al. Bone mass continues to increase at the hip after parathyroid hormone treatment is discontinued in glucocorticoidinduced osteoporosis: Results of a randomized controlled clinical trial. J Bone Miner Res. 2000; 15:944-951. 19. Lane NE, Sanchez S, Modin GW, et al. Parathyroid hormone treatment can reverse corticosteroid-induced osteoporosis. Results of a randomized controlled clinical trial. J Clin Invest. 1998;102:1627-1633. 20. Rehman Q, Lang TE Arnaud CD, et al. Daily treatment with parathyroid hormone is associated with an increase in vertebral cross-sectional area in postmenopausal women with glucocorticoid-induced osteoporosis. Osteoporosis Int. 2003; 14:77-81. 21. Crandell C. Review: Parathyroid hormone increases lumbar spine bone mineral density and decreases vertebral fractures in osteoporosis. ACP J Club. 2003;139: 11. 22. Rittmaster RS, Bolognese M, Ettinger ME et al. Enhancement of bone mass in osteoporotic women with parathyroid hormone followed by alendronate. J Clin Endocrinol Metab. 2000;85:2129-2134.



23. Brown SA, Rosen CJ. Osteoporosis. Meal Clin North Am. 2003;87:1039-1063. 24. Body JJ, Gaich GA, Scheele WH, et al. A randomized double-blind trial to compare the efficacy of teriparatide [recombinant human parathyroid hormone (1-34)] with alendronate in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2002;87:4528-4535. 23. Campion JM, Maricic MJ. Osteoporosis in men. Am Faro Physician. 2003;67:1321-1326. 26. Kurland ES, Cosman F, McMahon DJ, et al. Parathyroid hormone as a therapy for idiopathic osteoporosis in men: Effects on bone mineral density and bone markers. J Clin Endocrinol Metab. 2000;85:3069-3076. 27. Orwoll ES, Scheele WH, Paul S, et al. The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis. J Bone Miner Res. 2003;18:9-17. 28. Levin RH. Pediatric and neonatal therapT~ In: Herfindal ET, Gourley DR, eds. Textbook of Therapeutics. Drug and Disease Management. 7th ed. Philadelphia, Pa: Lippincott Williams ¢r Wilkins; 2000:1955-1968. 29. Koch CA. Rapid increase in bone mineral density in a child with osteoporosis and autoimmune hypoparathyroidism treated with PTH 1-34 [retraction appears

in Exp Clin Endocrinol Diabetes. 2002;110:100]. Exp Clin Endocrinol Diabetes. 2001;109:350-354. 30. Patel SR, Benjamin RS. Soft tissue and bone sarcomas and bone metastases. In: Braunwald E, ed. Harrison's Principles of Internal Medicine. 15th ed. New York, NY: McGraw-Hill; 2001:625-628. 31. Arndt C, Crist WM. Common musculoskeletal tumors of childhood and adolescence. N Engl J Meal. 1999; 341:342-352. 32. White LM, Kandel R. Osteoid-producing tumors of bone. 5emin Musculoskelet Radiol. 2000;4:23-43. 33. Benson CT, Voelker JR. Teriparatide has no effect on the calcium-mediated pharmacodynamics of digoxin. Clin Pharmacol Ther. 2003;73:87-94. 34. Hansen ME Nellissery MJ, Bhatia E Common mechanisms of osteosarcoma and Paget's disease. J Bone Miner Res. 1999;14(Suppl 2):39-44. 33. Krane SM, Schiller AL. Paget's disease and other dysplasias of bone. In: Braunwald E, ed. Harrison's Principles of Internal Medicine. 13th ed. New York, NY: McGraw-Hill; 2001:2237-2243. 36. Deal C, Gideon J. Recombinant human PTH 1-34 (Forteo): An anabolic drug for osteoporosis. Cleve Clin J Meal. 2003;70:585-586, 589-590, 592-594.

Address correspondence to: Elaena Quattrocchi, PharmD, FASHE Pharmacy Practice Department, Arnold and
Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, 75 Dekalb Avenue, Brooklyn, NY 11201-5497.