Full-length human recombinant parathyroid hormone for the treatment of osteoporosis

Abstract

Full-length or intact parathyroid hormone [rDNA origin] for injection (PTH [1-84], Preos, NPS Pharmaceuticals) is currently under FDA review for the treatment of postmenopausal osteoporosis. If approved, parathyroid hormone (1-84) will join teriparatide (PTH [1-34], Forteo, Lilly), the truncated N-terminal (1-34) form of the hormone, as the only anabolic therapies available for osteoporosis treatment. There are currently no published head-to-head trials comparing teriparatide and intact parathyroid hormone, though the effects of each on bone mineral density and fracture rate reduction appear comparable. The adverse effects of the 2 formulations are similar, including injection site reactions, headache, dizziness, nausea, and hypercalcemia. More studies are needed to determine when and if parathyroid hormone monotherapy should be used, whether and how it should be used in conjunction with antiresorptive therapies, and which patient populations would benefit most from parathyroid hormone treatment. (Formulary. 2006;41:214–226.)

Prevention consists of consuming 1,000 to 1,200 mg of elemental calcium daily and 400 to 800 IU of vitamin D, either through diet or supplements, engaging in weight-bearing exercises, avoiding smoking, and reducing consumption of alcohol. Recently published data from the Women's Health Initiative's calcium and vitamin D study suggest that these supplements may not be as beneficial for preventing fractures as previously thought. However, differences in adherence rates, baseline vitamin D levels, dietary calcium intake, and baseline fracture risk are factors that may have influenced the study results. For now, calcium and vitamin D supplementation should still be recommended for postmenopausal women and women at high fracture risk.⁷ Fall prevention for patients at risk for falls is also important for fracture prevention.¹

Anabolics, which stimulate bone formation, represent a new paradigm in osteoporosis treatment. Only 1 anabolic agent is FDA-approved for the treatment of postmenopausal osteoporosis. Teriparatide (PTH [1-34], Forteo, Eli Lilly) is a recombinant form of the N-terminal 34-amino acid fragment of human parathyroid hormone.⁹ Daily subcutaneous injections of teriparatide have been shown to increase BMD in the spine by 13% and by 6% at the femoral neck, while reducing the incidence of new vertebral fractures by 65% and nonvertebral fractures by 53% compared with placebo after a median of 21 months of treatment.¹⁰

A new drug application (NDA) for injectable full-length or intact recombinant parathyroid hormone (PTH [1-84], Preos, NPS Pharmaceuticals) was submitted to FDA in May 2005 for the treatment of postmenopausal osteoporosis. Its European equivalent, Preotact, has been under regulatory review in Europe since March 2005.^11,12

CHEMISTRY AND PHARMACOLOGY

Endogenous PTH is a single chain polypeptide with 84 amino acids and a molecular weight of 9,425 daltons. The N-terminal region 1-34 is the biologically active moiety.^9,13 Osteosarcoma, osteoblastoma, and osteoma have been observed in rats that received high-dose (10 mcg/kg/d or 3- to 4-fold the exposure in humans) teriparatide for up to 2 years. Teriparatide has caused a dose- and duration-dependent increase in incidence of osteosarcoma in rats at doses ranging from 3 to 60 times the exposure in humans.^9,14 Medium and high doses (50–150 mcg/kg/d) of PTH (1-84) have also demonstrated a dose-dependent increase in incidence of osteosarcoma. A 2-year study involving low-dose PTH (1-84) demonstrated no increase in osteosarcoma risk in rats treated with low-dose PTH (1-84) when compared to controls.¹¹

Endogenous PTH is responsible for maintaining serum calcium homeostasis by stimulating calcium release from bone, decreasing urinary calcium excretion, and indirectly facilitating intestinal calcium absorption in response to low serum calcium levels.¹⁵ The influence of PTH on bone depends on the pattern of exposure to the hormone. Intermittent exposure to PTH preferentially stimulates osteoblastic activity, resulting in improved bone strength, structure, and mass, particularly in trabecular (spongy) bone. Continuous PTH exposure, however, can promote bone resorption, especially in the cortical (compact) bone, leading to severe osteoporosis as seen in patients with chronic hyperparathyroidism.¹⁶ PTH therapy may therefore confer greater improvements in BMD of bone sites that primarily consist of trabecular bone (eg, spine) compared to sites that contain more cortical bone (eg, hip).¹⁷ Dual energy absorptiometry (DXA), the gold standard for measuring BMD, cannot isolate changes in cortical versus trabecular bone.¹⁷

PHARMACOKINETICS

Peak BMD and improvements in indexes of bone remodeling occur within the first 6 to 12 months of therapy with PTH and then plateau.¹⁸ The cause of this plateau is unknown but is the subject of ongoing research. Both PTH (1-84) and teriparatide are believed to undergo hepatic metabolism followed by renal excretion.⁹

CLINICAL TRIALS

In the largest randomized study (the TOP study), 2,547 postmenopausal women with low bone mass (spine, femoral neck, or total hip T score ≤ –3 in patients aged 45–54 y or ≤ –2 in patients aged ≥55 y) received either PTH (1-84) 100 mcg daily or placebo for 18 months.¹⁹ All women also received 700 mg calcium and 400 IU vitamin D supplements daily. The primary end points were overall incidence of vertebral fracture at 18 months and incidence of new fracture among women without previous vertebral fracture. At 18 months, the treatment group had a significantly lower incidence of vertebral fractures compared with placebo (0.67% vs 3.37%; 95% CI, 0.14–0.75; P=.006), corresponding to a 66% relative reduction in fracture in the PTH (1-84) group. Among women without previous vertebral fracture, the rate of new fracture was also significantly lower in the treatment group compared to placebo (4.24% vs 8.94%; 95% CI 0.23–0.98; P=.040), corresponding to a 53% relative risk reduction in fractures for the treatment group.

A subanalysis of women older than 60 years of age found that PTH (1-84) resulted in a 64% relative risk reduction in vertebral fractures relative to placebo (1.5% vs 4.2%, P=.001). Furthermore, women with low lumbar BMD (T score not specified), had a 74% relative risk reduction in vertebral fractures compared with placebo (1.3% vs 5.1%, P<.001).²⁰

Bone biopsies of the iliac crest from 16 women who participated in the TOP study were analyzed in 2 studies to determine the effect of PTH (1-84) treatment on bone formation and structure. One study, which used histomorphometry to measure bone changes, found that trabecular bone from the iliac crest had 48% higher trabecular bone volume, 24% greater trabecular number, 21% lower trabecular separation, and greater bone formation rate in the treatment group compared with placebo at the end of the study period (P=.21–.46).²¹ These results were confirmed by microcomputed tomography.²² Overall, PTH (1-84) treated bone had significantly better measures of connectivity and overall greater bone strength compared to placebo.²²

In a published double-blind, placebo-controlled study, 217 postmenopausal women were randomized to receive PTH (1-84) 50, 75, or 100 mcg daily, or placebo.¹⁷ At baseline, the patients were aged between 50 and 75 years and had a T score ≤ –2.5 at the lumbar spine. The primary end points were dose-dependent changes in BMD at the lumbar spine and hip after 12 months. Women with secondary causes of osteoporosis, vertebral abnormalities that affected DXA measurement, or who had received bisphosphonates, estrogen, fluoride, or calcitonin within the previous 4 to 6 months were excluded from the study. All women received 500 to 1,000 mg of calcium carbonate and 400 IU of vitamin D daily. After 12 months, the mean increases from baseline in vertebral BMD were 0.9%, 3.0%, 5.1%, and 7.8% in the placebo and the 50 mcg, 75 mcg, and 100 mcg treatment groups, respectively. Only the changes observed in the treatment groups were statistically significant (P<.05 vs baseline and placebo). BMD improvement was also significantly greater among the 100 mcg recipients compared with the 75 mcg recipients (P value not reported) and greater among patients with T scores ≤ –4 compared to patients with T scores ≤ –3 (13.5% vs 6.7% gain, P=.053). BMD increases at the hip were significantly higher than baseline and placebo at 12 months only in the 75-mcg treatment group (P<.05). The disparate effects of PTH (1-84) in the lumbar spine and hip may be due to differences in trabecular and cortical bone composition of these 2 sites.

Three studies have investigated the effects of PTH (1-84), either in combination with or following alendronate therapy. It is thought that PTH (1-84) and bisphosphonate therapy may produce additive effects to treat osteoporosis because they act with different mechanisms (alendronate to inhibit resorption and PTH (1-84) to speed up bone formation and resorption, with a net increase in formation). It is also thought that antiresorptive therapy may be necessary to sustain the positive effects of PTH (1-84), which are known to level off after 6 to 12 months of therapy.¹⁸

In the first study, 66 postmenopausal women with vertebral T scores ≤ –2.5 and who had not received antiresorptive therapy within the previous 4 to 6 months, were randomized to receive PTH (1-84) 50 mcg, 75 mcg, or 100 mcg or placebo daily for 1 year.²³ During the second year, all women switched to alendronate 10 mg daily. All women also received calcium carbonate 500 mg and vitamin D 400 IU daily throughout the entire study period. After the first year, the mean vertebral bone density increased from baseline by 1.3%, 4.3%, 6.9%, and 9.2% in the placebo and PTH (1-84) 50-, 75-, and 100-mcg treatment groups, respectively. Only the changes in the 75 mcg and 100 mcg groups were significant compared with placebo (P<.001). In the second year alone, during which all women received alendronate, there was no significant difference in mean vertebral bone density increases among the 4 groups. When the full 2 years of treatment were considered, however, vertebral bone density improved from baseline by 7.1±5.3%, 11.3±5.7%, 13.4±5.0%, and 14.6±7.9% in patients who had originally received placebo or PTH (1-84) 50, 75, and 100 mcg, respectively. These improvements were significant relative to placebo in the 75 mcg (P=.032) and 100 mcg (P=.0004) treatment groups. The mean bone density at the femoral neck after 2 years increased by 4.2%, 5.5%, 2.8%, and 4.5% in the placebo, 50 mcg, 75 mcg and 100 mcg groups, respectively, with significant increases relative to baseline observed in the 50 mcg (P=.009) and 75 mcg groups (P=.019). Although the BMD improvements observed were not consistent at all doses and sites, this study concluded that sequential anabolic-antiresorptive therapy may help optimize gains in BMD from PTH (1-84) therapy.

In the third study, 238 postmenopausal women with low BMD were randomized to receive 2 years of therapy with 1 of 4 treatment plans: alendronate alone, PTH (1-84) for the first year followed by alendronate in the second year (sequential treatment), PTH (1-84) in combination with alendronate for the first year followed by alendronate in the second year (combination treatment), or PTH (1-84) for 1 year followed by placebo in the second year.²⁴ The patient characteristics and dosages of alendronate, PTH (1-84), calcium, and vitamin D were the same as described in the previous study. Bone mineral density at the lumbar spine, hip and distal one-third of the radius were measured using DXA and quantitative CT. After 24 months, all patients experienced significant increases in BMD from baseline at the spine, femoral neck, and total hip (P<.001 for all groups), though the women who received sequential therapy experienced the greatest gain (12%) compared with the other alendronate groups (8%) or PTH (1-84) alone (4%) (P<.05 vs combination therapy , P<.001 vs all other groups).

BMD decreased from baseline in the distal one-third of the radius in all groups except for women who took alendronate alone, who experienced no change. Trabecular BMD at the spine, however, had greater increases from baseline in the PTH (1-84) treatment groups, and the women who had received sequential therapy had the highest gain (31%, P<.001 vs baseline and all other groups). Women who had received only alendronate had the lowest gain (6%). The PTH (1-84) monotherapy and the sequential groups had the greatest BMD decrease in cortical hip bone of –3% compared to the combination and alendronate-alone treatment groups of –1% and –2%, respectively, showing that PTH in combination with alendronate maintained BMD in the cortical hip the best. Bone mineral content was also higher in the combination group compared to alendronate alone, sequential treatment and PTH (1-84) monotherapy with an increase of 6% compared to 4%, 3%, and –1.4%, respectively. Similar trends were seen in cortical hip volume with the combination group leading at 7% and 6% for both the sequential and alendronate-alone groups, respectively, and 1% for the PTH (1-84) monotherapy group.

Overall, this study concluded that sequential therapy with PTH (1-84) and alendronate led to the greatest gain in spine and hip BMD, and that concurrent alendronate and PTH (1-84) therapy did not have synergistic effects.

The study found a statistically significant increase in BMD at the lumbar spine in the PTH (1-84) plus HRT group at 18 months (6.42%, P<.001) and at 24 months (6.53%, P< .001) compared to HRT alone. The results for the HRT monotherapy group were not available. A statistically significant difference from baseline BMD was also noted in the PTH (1-84) plus HRT group (7.9% at 18 mo, P value not available; 8.6% at 24 mo, P<.001). Results were not available for the HRT-alone group. For the femoral neck, there was also a statistically significant increase in BMD in the PTH (1-84) plus HRT group of 2.27% versus 0.47% in the HRT-alone group (P=.024). Bone-specific alkaline phosphatase (BSAP) and N-telopeptide were measured at 12 and 24 months. In the PTH (1-84) plus HRT group, BSAP was 97.7% at 12 months compared to 18.5% in the HRT-alone group (P=.01) and 115.1% versus 28.7% (P=.0009) at 24 months, respectively. N-telopeptide measured at 12 months was 65% in the PTH (1-84) plus HRT group versus 2.3% in the HRT monotherapy group (P<.0001) and at 24 months, 69.2% versus 24.3%, respectively (P=.0049). Overall, the study concluded that PTH (1-84) used in combination with HRT resulted in an increase of BMD and surrogate markers that indicate anabolic activity as compared with HRT alone. Doses of the HRT and compliance assessment information were not provided.²⁵

ADVERSE EVENTS

In clinical studies, PTH (1-84) was well tolerated. The most commonly reported adverse event was irritation at the site of injection.^17,18,24 Headache, dizziness, rash and nausea were also reported at a higher frequency with PTH (1-84) therapy than with placebo, although actual incidences were not reported for all studies.^17,18,22 One study specifically described nausea as dose-related, with 6 patients in the placebo group versus 13 in the 100-mcg group reporting nausea.¹⁷ The incidence of hypercalcemia ranged from 9% to 28% of patients treated with PTH (1-84), compared with 0% to 4.7% of patients who received placebo or control (eg, alendronate). In one study, the increase in serum calcium levels peaked 6 to 9 months after therapy initiation and began to decline afterwards. Overall, hypercalcemia led to treatment discontinuation in 0.5% of women treated with PTH (1-84).^17,19 Another study reported hypercalcemia in 14.4% of subjects receiving PTH (1-84) versus 2.2% receiving placebo and reported serious adverse events occurring in the PTH (1-84) group 26.7% versus 17.8% in the placebo group.²⁵ The specific adverse events were not described. Hypercalciuria, elevated alkaline phosphatase, increases in serum uric acid levels, sinusitis and fatigue have also been reported.^17,19

DRUG INTERACTIONS

Information on drug interactions was not available at the time publication. However, concurrent use of medications that may cause hypercalcemia or that may be affected by hypercalcemia, eg, digoxin, should be used with extreme caution, if at all, in patients who also receive PTH therapy.

PRECAUTIONS

Intact PTH should be used with caution, if at all, in patients who have or at risk for having hypercalcemia or gout. It is not known if PTH (1-84) therapy is associated with an increased risk of osteosarcoma; however, it may be prudent to avoid parathyroid hormone therapy altogether in patients who are at increased risk of developing malignant or metabolic bone disease (eg, Paget's disease, renal osteodystrophy).

Safety of PTH use among patients with non-osseous cancer is unknown. Since most of the studies included post-menopausal women with osteoporosis, safety or efficacy of PTH in women aged <45 years or during pregnancy has not been determined.

DOSING AND ADMINISTRATION

PTH (1-84) is a subcutaneous injection that is self-administered via a cartridge-loaded pen once daily for up to 18 months. The 100-mcg dose has been the most studied and is most likely to be the suggested treatment dose. Intact PTH should be used in conjunction with an appropriate calcium, vitamin D, and exercise regimen.

Dr Cheng is an assistant clinical professor, Drug Information and Analysis Service, University of California, San Francisco. She can be reached at chengc@pharmacy.ucsf.eduDr El-Ibiary is an assistant professor of clinical pharmacy and a specialist in women's health, University of California, San Francisco.

Disclosure Information: The authors report no financial disclosures as related to products discussed in this article.

In each issue, the "Focus on" feature reviews a newly approved or investigational drug of interest to pharmacy and therapeutics committee members. The column is coordinated by Robert A. Quercia, MS, RPh, director of Drug Information Services at Hartford Hospital in Hartford, Conn, and adjunct associate professor, University of Connecticut School of Pharmacy, Storrs, Conn; and by Craig I. Coleman, PharmD, assistant professor of pharmacy practice, University of Connecticut School of Pharmacy, and director, Pharmacoeconomics and Outcomes Studies Group, Hartford Hospital.

EDITORS' NOTE: The clinical information provided in "Focus on" articles is as current as possible. Due to regularly emerging data on developmental or newly approved drug therapies, articles include information published or presented and available to the author up until the time of the manuscript submission.

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