Method of treating osteoporosis comprising administration of PTHrP analog

Abstract

The present invention provides a storage-stable composition containing a parathyroid hormone-related protein (PTHrP) and methods of using a PTHrP and the PTHrP compositions described herein to treat osteoporosis, to increase bone mass or to increase bone quality. The composition is storage stable, in sterile form, and in general may be stored at room temperature for at least several weeks to allow convenient parenteral administration to human patients.

Description

RELATED APPLICATIONS

This application is a
where Y represents the PK parameters AUC_(0-28), AUC_(0-τ), AUC_(0-t), and C_max.
Dose proportionality requires that β=1 for dose-dependent parameters.

The model was used to calculate the 95% confidence intervals (CI) for the slope of the ln-transformed PK parameters AUCs and C_max. Dose proportionally was concluded if the 95% CI for the PK parameters included the value of 1.

For those cases in which dose proportionality could not be concluded within all doses investigated, dose proportionality analysis was performed for the first 3 (by excluding the highest dose) and the last 3 doses (by excluding the lowest dose).

Pharmacokinetic/Pharmacodynamic Analysis:

The plots of plasma SEQ ID NO.: 2 and calcium concentrations did not indicate a clear relationship between SEQ ID NO.: 2 and calcium concentrations; therefore, no PK/PD modeling work was performed for this study.

Pharmacodynamics:

The data for each PD marker in serum (total and ionized calcium, phosphorus, PTH(1-84), 1,25-dihydroxyvitamin D, P1NP, and CTX) and in urine (calcium, phosphorus, c-AMP, and creatinine) following SEQ ID NO.: 2 and placebo doses were listed for each subject and summarized by SEQ ID NO.: 2 dose using descriptive statistics (mean, SD, CV %, SEM, N, min, max, and median).

Pharmacokinetic Results:

The arithmetic mean and the SD of plasma SEQ ID NO.: 2 PK parameters following subcutaneous (SC) administration of SEQ ID NO.: 2 doses for Days 1 and 7 are presented Table 9 and Table 10.

TABLE 9
Summary of Plasma SEQ ID NO.: 2 Pharmacokinetic Parameters
Following 5 μg Throμgh 80 μg SEQ ID NO.: 2 Doses-Day 1
	Treatment A	Treatment B	Treatment C	Treatment D
Pharmacokinetic	Mean ± SD	Mean ± SD	Mean ± SD	Mean ± SD
Parameters	(N)	(N)	(N)	(N)
Cmax (pg/mL)	43.1 ± 10.7	115 ± 53.9	223 ± 99.0	310 ± 54.3
	(7)	(8)	(8)	(8)
Tmax (hr)#	0.566 (0.531, 1.00)	0.296 (0.250, 0.624)	0.494 (0.262, 0.579)	0.752 (0.251, 1.01)
	(7)	(8)	(8)	(8)
Tlast (hr)#	2.01 (1.50, 4.00)	2.01 (1.00, 4.00)	4.00 (1.51, 6.01)	7.00 (4.00, 12.0)
	(7)	(8)	(8)	(8)
AUC0-t (pg * hr/mL)	78.439 ± 45.472	160.52 ± 110.83	419.89 ± 275.15	949.89 ± 493.58
	(7)	(8)	(8)	(8)
AUC0-inf (pg * hr/mL)	187.36 ± 54.536	257.17 ± 119.05	592.94 ± 281.40	1055.6 ± 513.61
	(4)	(5)	(6)	(8)
AUC0-tau (pg * hr/mL)	186.92 ± 54.397	257.16 ± 119.02	592.90 ± 281.37	1053.2 ± 511.27
	(4)	(5)	(6)	(8)
t1/2 (hr)	2.59 ± 0.690	1.05 ± 0.314	1.65 ± 0.254	2.30 ± 0.715
	(4)	(5)	(6)	(8)
Kel (1/hr)	0.282 ± 0.0722	0.713 ± 0.229	0.428 ± 0.0603	0.335 ± 0.127
	(4)	(5)	(6)	(8)
AUCR	0.521 ± 0.111	0.828 ± 0.0449	0.838 ± 0.0703	0.892 ± 0.0369
	(4)	(5)	(6)	(8)
CL/F (L/hr)	28.56 ± 8.727	94.20 ± 46.04	84.15 ± 46.04	94.61 ± 51.09
	(4)	(5)	(6)	(8)
ln (Cmax)	3.741 ± 0.2153	4.643 ± 0.4890	5.331 ± 0.4130	5.722 ± 0.1732
	(7)	(8)	(8)	(8)
ln (AUC0-t)	4.241 ± 0.5166	4.821 ± 0.8221	5.844 ± 0.6783	6.740 ± 0.5206
	(7)	(8)	(8)	(8)
ln (AUC0-inf)	5.200 ± 0.3016	5.456 ± 0.4957	6.280 ± 0.5203	6.855 ± 0.5063
	(4)	(5)	(6)	(8)
ln (AUC0-tau)	5.198 ± 0.3007	5.456 ± 0.4956	6.280 ± 0.5202	6.853 ± 0.5050
	(4)	(5)	(6)	(8)
#= Tmax and Tlast are presented as Median (Minimum, Maximum)
Treatment A = Administration of a Single SC Dose of 5 μg SEQ ID NO.: 2 for Seven Days
Treatment B = Administration of a Single SC Dose of 20 μg SEQ ID NO.: 2 for Seven Days
Treatment C = Administration of a Single SC Dose of 40 μg SEQ ID NO.: 2 for seven Days
Treatment D = Administration of a Single SC Dose of 80 μg SEQ ID NO.: 2 for Seven Days

TABLE 10
Summary of Plasma SEQ ID NO.: 2 Pharmacokinetic Parameters
Following 5 μg Throμgh 80 μg SEQ ID NO.: 2 Doses-Day 7
	Treatment A	Treatment B	Treatment C	Treatment D
Pharmacokinetic	Mean ± SD	Mean ± SD	Mean ± SD	Mean ± SD
Parameters	(N)	(N)	(N)	(N)
Cmax (pg/mL)	40.8 ± 7.63	109 ± 19.2	207 ± 77.7	436 ± 68.8
	(6)	(8)	(8)	(8)
Tmax (hr)#	1.05 (0.514, 1.53)	0.512 (0.250, 3.05)	0.492 (0.349, 1.00)	0.507 (0.500, 1.00)
	(6)	(8)	(8)	(8)
Tlast (hr)#	2.53 (1.50, 4.08)	3.00 (1.11, 4.00)	3.49 (2.00, 8.02)	6.00 (4.00, 8.02)
	(6)	(8)	(8)	(8)
AUC0-t (pg * hr/mL)	80.704 ± 30.441	171.58 ± 82.031	407.98 ± 219.70	1003.0 ± 383.45
	(6)	(8)	(8)	(8)
AUC0-tau (pg * hr/mL)	. ± .	228.20 ± 95.154	481.88 ± 226.19	1080.3 ± 408.57
	(0)	(6)	(8)	(8)
t1/2 (hr)	. ± .	1.05 ± 0.244	1.43 ± 0.397	1.69 ± 0.425
	(0)	(6)	(8)	(8)
Kel (1/hr)	. ± .	0.694 ± 0.165	0.527 ± 0.192	0.437 ± 0.124
	(0)	(6)	(8)	(8)
CL/F (L/hr)	. ± .	103.9 ± 53.01	102.0 ± 53.34	82.74 ± 26.95
	(0)	(6)	(8)	(8)
AI	. ± .	1.10 ± 0.369	0.844 ± 0.0673	1.12 ± 0.353
	(0)	(5)	(6)	(8)
ln (Cmax)	3.694 ± 0.1912	4.682 ± 0.1835	5.266 ± 0.4068	6.065 ± 0.1628
	(6)	(8)	(8)	(8)
ln (AUC0-t)	4.325 ± 0.4085	5.039 ± 0.5086	5.888 ± 0.5352	6.851 ± 0.3623
	(6)	(8)	(8)	(8)
ln (AUC0-tau)	. ± .	5.351 ± 0.4532	6.078 ± 0.4879	6.927 ± 0.3581
	(0)	(6)	(8)	(8)
#= Tmax and Tlast are presented as Median (Minimum, Maximum)
Treatment A = Administration of a Single SC Dose of 5 μg SEQ ID NO.: 2 for Seven Days
Treatment B = Administration of a Single SC Dose of 20 μg SEQ ID NO.: 2 for Seven Days
Treatment C = Administration of a Single SC Dose of 40 μg SEQ ID NO.: 2 for Seven Days
Treatment D = Administration of a Single SC Dose of 80 μg SEQ ID NO.: 2 for Seven Days

Overall, administration of increasing doses of SEQ ID NO.: 2 resulted in increasing rate and extent of exposure to SEQ ID NO.: 2. SEQ ID NO.: 2 was characterized by a rapid absorption following SC doses as mean C_max was achieved within approximately 1 hour. Moreover, SEQ ID NO.: 2 had a short half-life with mean t_1/2 ranging from 1.05 hours to 2.59 hours. Apparent clearance was 28.56 L/hr following the lowest dose (5 μg) and ranged from 82.74 L/hr to 103.9 L/hr following the 20, 40, and 80 μg doses and, with the exception of the lowest dose remained fairly stable with increased doses of SEQ ID NO.: 2.

The results indicated that exposure to SEQ ID NO.: 2 was relatively comparable between Days 1 and 7 following SEQ ID NO.: 2 doses. Mean AI values ranged from 0.844 to 1.12, indicating that drug accumulation was negligible following multiple dosing of SEQ ID NO.: 2. Moreover, mean PK parameters values of T_max, t_1/2, and CL/F were comparable between Days 1 and 7.

The dose proportionality assessment of exposure to SEQ ID NO.: 2 in plasma resulting from SC doses of SEQ ID NO.: 2 is presented in the following table.

Dose Proportionality Analysis of Plasma SEQ ID NO.: 2
Following 5 μg Through 80 μg SEQ ID NO.: 2 Doses
	Pharmacokinetic		Standard
Day	Parameters	Slope	Error	95% CI
1	Cmax	0.77861	0.1375	(0.4935, 1.0637)
	AUC (0-t)	0.90714	0.1237	(0.6542, 1.1600)
	AUC (0-inf)	0.99565	0.2024	(0.5685, 1.4228)
7	Cmax	0.99804	0.0985	(0.7938, 1.2023)
	AUC (0-tau)	1.14127	0.1649	(0.7974, 1.4852)
Dose proportionality was concluded if the CI for the ln-transformed parameters included the value of 1.
Dose proportionality for Cmax and AUC (0-inf) was concluded following 20 μg, 40 μg, and 80 μg SEQ ID NO.: 2 doses.
Dose proportionality for AUC (0-t) and AUC (0-tau) was concluded following 5 μg, 20 μg, 40 μg, and 80 μg SEQ ID NO.: 2 doses.
Parameters were ln-transformed prior to analysis.

Pharmacodynamic Results:
Pharmacodynamic Markers in Serum:

Total calcium concentrations in serum remained within the reference range except for two subjects (placebo) and three subjects receiving the SEQ ID NO.: 2 doses. On Days 1 and 7, following SC administration of 5 to 80 μg SEQ ID NO.: 2 or placebo, mean total calcium levels marginally (±0.6 mg/dL) changed from predose levels. Total serum calcium concentrations following SEQ ID NO.: 2 doses mostly remained above the placebo level.

While in the first two doses, the majority of the ionized calcium measurements including baseline values were out of the reference range, in the second 2 doses, all the measurements were within the reference range.

The 95% CI of the slopes for ln-transformed PK parameters C_max, AUC_(0-f), AUC_(0-τ), and AUC_(0-∞) indicated that, within the SEQ ID NO.: 2 dose range studied, the increases in PK parameters were dose-proportional (95% CI included the value of 1). While dose proportionality for C_max and AUC_(0-∞) was concluded only following 20, 40, and 80 μg SEQ ID NO.: 2 doses, dose proportionality for AUC_(0-τ) and AUC_(0-t) was concluded following all SEQ ID NO.: 2 doses investigated.

Mean baseline-adjusted ionized calcium levels slightly increased up to 0.04±0.02 mmol/L following 40 μg SEQ ID NO.: 2 dose on Day 1 and up to 0.05±0.02 mmol/L following 80 μg SEQ ID NO.: 2 dose on Day 7. Like total calcium, mean ionized calcium levels following SEQ ID NO.: 2 doses were generally higher than the mean values following placebo dose.

With the exception of 24 hours on Day 1, and 8 to 12 hours on Day 7, serum phosphorus concentrations following SEQ ID NO.: 2 and placebo doses remained below the predose levels on Days 1 and 7. Also, serum phosphorus concentrations following SEQ ID NO.: 2 doses were below the placebo concentration levels on both days.

Serum PTH (1-84) concentrations following SEQ ID NO.: 2 doses remained below the predose levels and placebo dose during most of the sampling times on both days. Serum PTH (1-84) concentrations following placebo dose consistently stayed above the baseline.

1,25-dihydroxyvitamin D concentrations in serum following SEQ ID NO.: 2 and placebo doses generally remained at predose levels on both Days 1 and 7, except following the 40 and 80 μg SEQ ID NO.: 2 doses which steadily rose above the predose levels after 2 hours postdose on Day 1 and most of the time on Day 7. Serum 1,25-dihydroxyvitamin D concentrations following SEQ ID NO.: 2 doses were mostly higher than placebo levels on both days.

P1NP concentrations in serum following SEQ ID NO.: 2 and placebo doses generally stayed near predose levels on Days 3, 8, and 14, except for 80 μg SEQ ID NO.: 2 dose which consistently stayed above baseline (maximum increase was up to 18±12 ng/mL) including Day 14. Mean P1NP serum levels following all doses of SEQ ID NO.: 2 showed some non-significant dose dependent elevation on Day 8. Mean serum CTX concentrations following SEQ ID NO.: 2 and placebo doses generally remained at or around the predose levels except following the 20 μg SEQ ID NO.: 2 dose where the concentrations consistently stayed above predose levels. The maximum increase at 0.15±0.18 ng/mL from baseline was within 1 SD.

Pharmacodynamic Markers in Urine:

On Day 1, mean urinary excretion rates of calcium following SEQ ID NO.: 2 doses and placebo subjects were approximately at predose levels. On Day 7, however, while mean urinary excretion rates of calcium following 40 and 80 μg SEQ ID NO.: 2 doses fluctuated at predose levels, those following the 5 and 20 μg SEQ ID NO.: 2 and placebo doses dropped below the predose levels.

Mean urinary excretion rates of phosphorus following SEQ ID NO.: 2 doses fluctuated around the predose levels. Mean phosphorus excretion rates following SEQ ID NO.: 2 doses on the last 2 intervals of

Days 1 and 7 were lower than the first interval and at times fell below the predose levels.

Mean urinary excretion rates of c-AMP increased following SEQ ID NO.: 2 doses on both Days 1 and 7 but sharply dropped to predose and at times below the predose levels by the end of the sampling intervals.

Mean urinary excretion rates of creatinine following SEQ ID NO.: 2 and placebo doses fluctuated around the predose levels on Days 1 and 7.

While this invention has been particularly shown and described with references to example embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

1. A method of treating osteoporosis comprising daily subcutaneous administration of a composition comprising 80 μg of [Glu^22,25, Leu^23,28,31, Aib²⁹, Lys^26,30]hPTHrP(1-34)NH₂ to a human in need thereof.

2. The method of claim 1, wherein the composition further comprises an effective amount of buffer to maintain the pH between 2 and 7.

3. The method of claim 1, wherein the buffer is selected from the group consisting of acetate, tartrate, phosphate and citrate buffers.

4. The method of claim 3, wherein the buffer is an acetate buffer.

5. The method of claim 4, wherein the buffer is acetic acid and sodium acetate.

6. The method of claim 2, wherein the pH is maintained between 3 and 6.

7. The method of claim 6, wherein the pH is maintained between 4 and 6.

8. The method of claim 7, wherein the pH is maintained between 4.5 and 5.6.

9. The method of claim 1, wherein the human is a post-menopausal woman.

10. The method according to claim 9 wherein the dose is 80 μg and wherein said dose results in a plasma C_max of [Glu^22,25, Leu^23,28,31, Aib²⁹, Lys^26,30]hPTHrP(1-34)NH₂ from between 255.57 pg/mL and 364.3 pg/mL or from between 367.2 pg/mL and 504.8 pg/mL in said subject.

11. The method according to claim 9 wherein the dose is 80 μg and wherein said dose results in a plasma T_max of [Glu^22,25, Leu^23,28,31, Aib²⁹, Lys^26,30]hPTHrP(1-34)NH₂ from between 0.251 hours and 1.01 hours, or from between 0.500 hours and 1.00 hours in said subject.

12. The method according to claim 9 wherein the dose is 80 μg and wherein said dose results in a plasma t_1/2 of [Glu^22,25, Leu^23,28,31, Aib²⁹, Lys^26,30] hPTHrP(1-34)NH₂ from between 1.585 hours and 3.015 hours, or from between 1.265 hours and 2.115 hours in said subject.

13. The method according to claim 9 wherein the dose is 80 μg and wherein said dose results in a plasma C_max of [Glu^22,25, Leu^23,28,31, Aib²⁹, Lys^26,30] hPTHrP(1-34)NH₂ from between 255.57 pg/mL and 364.3 pg/mL and a T_max from between 0.251 hours and 1.01 hours, or a C_max from between 367.2 pg/mL and 504.8 pg/mL and a T_max from between 0.500 hours and 1.00 hours in said subject.

14. The method according to claim 9 wherein the dose is 80 μg and wherein said dose results in a plasma C_max of [Glu^22,25, Leu^23,28,31, Aib²⁹, Lys^26,30] hPTHrP(1-34)NH₂ from between 255.57 pg/mL and 364.3 pg/mL and a T_max from between 0.251 hours and 1.01 hours and a t_1/2 of between 1.585 hours and 3.015 hours, or a C_max from between 367.2 pg/mL and 504.8 pg/mL and a T_max from between 0.500 hours and 1.00 hours and a t_1/2 of between 1.265 hours and 2.115 hours in said subject.

15. The method according to claim 2, wherein the pH is maintained at about 5.1.

16. A method of treating osteoporosis comprising daily subcutaneous administration of a composition comprising 80 μg of [Glu^22,25, Leu^23,28,31, Aib²⁹, Lys^26,30]hPTHrP(1-34)NH₂ to a human in need thereof, wherein the composition is delivered in a multi-dose injection pen.

17. The method according to claim 16, wherein the composition further comprises an anti-microbial agent.

18. The method according to claim 17, wherein the anti-microbial agent is selected from phenol, chlorocresol, and methylparaben/propylparaben, or a combination thereof.

19. The method according to claim 18, wherein the anti-microbial agent is phenol.

20. The method according to claim 19, wherein the composition comprises 5 mg/mL phenol.

21. The method according to claim 16 or claim 17, wherein the composition further comprises a buffer.

22. The method according to claim 21, wherein the composition comprises a buffer in an amount effective to maintain the pH at about 5.1.

23. The method according to claim 22, wherein the pH is maintained at about 5.1.

24. The method according to claim 21, wherein the buffer is selected from a citrate buffer and an acetate buffer, or a combination thereof.

25. The method according to claim 22, wherein the buffer is selected from a citrate buffer and an acetate buffer, or a combination thereof.

26. The method according to claim 23, wherein the buffer is selected from a citrate buffer and an acetate buffer, or a combination thereof.

27. The method according to claim 24, wherein the buffer is an acetate buffer.

28. The method according to claim 25, wherein the buffer is an acetate buffer.

29. The method according to claim 26, wherein the buffer is an acetate buffer.

30. The method according to claim 27, wherein the acetate buffer comprises acetic acid and sodium acetate.

31. The method according to claim 28, wherein the acetate buffer comprises acetic acid and sodium acetate.

32. The method according to claim 29, wherein the acetate buffer comprises acetic acid and sodium acetate.

33. The method according to claim 30, wherein the sodium acetate is sodium acetate trihydrate.

34. The method according to claim 31, wherein the sodium acetate is sodium acetate trihydrate.

35. The method according to claim 32, wherein the sodium acetate is sodium acetate trihydrate.

36. The method according to claim 17, wherein the anti-microbial agent is present in an amount effective to limit the number of colony forming units (cfu) of a bacterium selected from Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli in the composition to less than 5 cfu/mL six hours following bacterial exposure.

37. The method according to claim 36, wherein the anti-microbial agent is present in an amount effective to limit the number of colony forming units (cfu) of a bacterium selected from Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli in the composition to less than 5 cfu/mL 24 hours following bacterial exposure.

38. The method according to claim 36, wherein the anti-microbial agent is present in an amount effective to limit the number of colony forming units (cfu) of a bacterium selected from Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli in the composition to less than 5 cfu/mL 28 days following bacterial exposure.

39. The method according to claim 36, wherein the composition is stored for 3 months at 25° C. prior to bacterial exposure.

40. The method according to claim 37, wherein the composition is stored for 3 months at 25° C. prior to bacterial exposure.

41. The method according to claim 38, wherein the composition is stored for 3 months at 25° C. prior to bacterial exposure.

42. The method according to claim 36, wherein the composition is stored for 4.5 months at 5° C. prior to bacterial exposure.

43. The method according to claim 37, wherein the composition is stored for 4.5 months at 5° C. prior to bacterial exposure.

44. The method according to claim 38, wherein the composition is stored for 4.5 months at 5° C. prior to bacterial exposure.

45. The method according to claim 17, wherein the anti-microbial agent is present in an amount effective to limit the number of colony forming units (cfu) of a yeast or mold selected from Aspergillus niger and Candida albicans in the composition to less than 5 cfu/mL 7 days following exposure to the yeast or mold.

46. The method according to claim 45, wherein the anti-microbial agent is present in an amount effective to limit the number of colony forming units (cfu) of a yeast or mold selected from Aspergillus niger and Candida albicans in the composition to less than 5 cfu/mL 7 days following exposure to the yeast or mold.

47. The method according to claim 45, wherein the anti-microbial agent is present in an amount effective to limit the number of colony forming units (cfu) of a yeast or mold selected from Aspergillus niger and Candida albicans in the composition to less than 5 cfu/mL 28 days following exposure to the yeast or mold.

48. The method according to claim 45, wherein the composition is stored for 3 months at 25° C. prior to exposure to the yeast or mold.

49. The method according to claim 46, wherein the composition is stored for 3 months at 25° C. prior to exposure to the yeast or mold.

50. The method according to claim 47, wherein the composition is stored for 3 months at 25° C. prior to exposure to the yeast or mold.

51. The method according to claim 45, wherein the composition is stored for 4.5 months at 5° C. prior to exposure to the yeast or mold.

52. The method according to claim 46, wherein the composition is stored for 4.5 months at 5° C. prior to exposure to the yeast or mold.

53. The method according to claim 47, wherein the composition is stored for 4.5 months at 5° C. prior to exposure to the yeast or mold.

54. The method according to claim 16, wherein the concentration of [Glu^22,25, Leu^23,28,31, Aib²⁹, Lys^26,30]hPTHrP(1-34)NH₂ in the composition is at least 98.9% of its initial concentration at t=0 after 1 month.

55. The method according to claim 16, wherein the concentration of [Glu^22,25, Leu^23,28,31, Aib²⁹, Lys^26,30]hPTHrP(1-34)NH₂ in the composition is at least 96.3% of its initial concentration at t=0 after 3 months.

56. The method according to claim 16, wherein the concentration of [Glu^22,25, Leu^23,28,31, Aib²⁹, Lys^26,30]hPTHrP(1-34)NH₂ in the composition is at least 99.5% of its initial concentration at t=0 after 4.5 months.

57. The method according to claim 54, wherein the concentration of [Glu^22,25, Leu^23,28,31, Aib²⁹, Lys^26,30]hPTHrP(1-34)NH₂ in the composition is at least 98.9% of its initial concentration at t=0 after 1 month at 25° C.

58. The method according to claim 55, wherein the concentration of [Glu^22,25, Leu^23,28,31, Aib²⁹, Lys^26,30]hPTHrP(1-34)NH₂ in the composition is at least 96.3% of its initial concentration at t=0 after 3 months at 25° C.

59. The method according to claim 56, wherein the concentration of [Glu^22,25, Leu^23,28,31, Aib²⁹, Lys^26,30]hPTHrP(1-34)NH₂ in the composition is at least 99.5% of its initial concentration at t=0 after 4.5 months at 5° C.

60. A method of treating osteoporosis comprising daily subcutaneous administration of a composition comprising 80 μg of [Glu^22,25, Leu^23,28,31, Aib²⁹, Lys^26,30]hPTHrP(1-34)NH₂ to a human in need thereof, wherein the composition is prepared according to a process comprising:

(a) dissolving [Glu^22,25, Leu^23,28,31, Aib²⁹, Lys^26,30]hPTHrP(1-34)NH₂, an anti-microbial agent, and a buffer in water to form a solution; and

(b) filtering the solution through a 0.2 micron filter.

61. The method according to claim 60, wherein the anti-microbial agent is selected from phenol, chlorocresol, and methylparaben/propylparaben, or a combination thereof.

62. The method according to claim 61, wherein the anti-microbial agent is phenol.

63. The method according to claim 62, wherein the composition comprises 5 mg/mL phenol.

64. The method according to claim 60, wherein the composition comprises a buffer in an amount effective to maintain the pH at about 5.1.

65. The method according to claim 64, wherein the buffer is selected from a citrate buffer and an acetate buffer, or a combination thereof.

66. The method according to claim 65, wherein the buffer is an acetate buffer.

67. The method according to claim 66, wherein the acetate buffer comprises acetic acid and sodium acetate.

68. The method according to claim 67, wherein the sodium acetate is sodium acetate trihydrate.

69. A method of treating osteoporosis, the method comprising daily subcutaneous administration to a human in need thereof a composition comprising 80 μg of [Glu^22,25, Leu^23,28,31, Aib²⁹, Lys^26,30]hPTHrP(1-34)NH₂, wherein the composition is formulated to achieve one or more of the following pharmacokinetic parameters:

70. The method according to claim 69, wherein the dosing regimen has been determined to achieve a C_max plasma levels of [Glu^22,25, Leu^23,28,31, Aib²⁹, Lys^26,30]hPTHrP(1-34)NH₂ between 255.7 pg/mL and 364.3 pg/mL.

71. The method according to claim 69, wherein the dosing regimen has been determined to achieve a plasma T_max for [Glu^22,25, Leu^23,28,31, Aib²⁹, Lys^26,30]hPTHrP(1-34)NH₂ between 0.251 hours and 1.01 hours.

72. The method according to claim 69, wherein the dosing regimen has been determined to achieve a plasma t_1/2 of [Glu^22,25, Leu^23,28,31, Aib²⁹, Lys^26,30]hPTHrP(1-34)NH₂ between 1.585 hours and 3.015 hours.

73. The method according to claim 69, wherein the dosing regimen has been determined to achieve a net plasma AUC_(0-inf) of [Glu^22,25, Leu^23,28,31, Aib²⁹, Lys^26,30]hPTHrP(1-34)NH₂ between 541.99 pg h/mL and 1569.21 pg h/mL.

74. A method of treating osteoporosis, the method comprising daily subcutaneous administration to a human in need thereof a composition comprising 80 μg of [Glu^22,25, Leu^23,28,31, Aib²⁹, Lys^26,30]hPTHrP(1-34)NH₂, wherein the composition is formulated to achieve one or more of the following pharmacokinetic parameters:

75. The method according to claim 74, wherein the dosing regimen has been determined to achieve a C_max plasma levels of [Glu^22,25, Leu^23,28,31, Aib²⁹, Lys^26,30]hPTHrP(1-34)NH₂ between 367.2 pg/mL and 504.8 pg/mL.

76. The method according to claim 74, wherein the dosing regimen has been determined to achieve a plasma T_max for [Glu^22,25, Leu^23,28,31, Aib²⁹, L^26,30]hPTHrP(1-34)NH₂ between 0.500 hours and 1.00 hours.

77. The method according to claim 74, wherein the dosing regimen has been determined to achieve a plasma t_1/2 of [Glu^22,25, Leu^23,28,31, Aib²⁹, Lys^26,30]hPTHrP(1-34)NH₂ between 1.265 hours and 2.115 hours.

78. The method according to claim 69, wherein the composition is delivered in a multi-dose injection pen.

79. The method according to claim 74, wherein the composition is delivered in a multi-dose injection pen.