164
BURR ET AL.
3. Reeve J, Meunier PJ, Parsons JA, Bernat M, Bijvoet OL,
Courpron P, Edouard C, Klenerman L, Neer RM, Renier JC,
Slovik D, Vismans FJ, Potts JT Jr 1980 Anabolic effect of
human parathyroid hormone fragment on trabecular bone in
involutional osteoporosis: A multicentre trial. BMJ 280:1340–
1344.
4. Reeve J, Arlot M, Bernat M, Charhon S, Edouard C, Slovik D,
Vismans FJ, Meunier PJ 1981 Calcium-47 kinetic measure-
ments of bone turnover compared to bone histomorphometry
in osteoporosis: The influence of human parathyroid fragment
(hPTH 1-34) therapy. Metab Bone Dis Rel Res 3:23–30.
5. Mackey MS, Stevens ML, Ebert DC, Tressler DL, Combs KS,
Lowry CK, Smith PN, McOsker JE 1995 The ferret as a small
animal model with BMU-based remodeling for skeletal re-
search. Bone 17:191S–196S.
6. Jerome CP, Johnson CS, Lees CJ 1995 Effect of treatment for
3 months with human parathyroid hormone 1-34 peptide in
ovariectomized cynomolgus monkeys (Macaca fascicularis).
Bone 17:415S–420S.
7. Inoue J 1985 Bone changes with long-term administration of
low doses of 1-34 human PTH in adult beagles. J Jpn Orthop
Assoc 59:409–427.
8. Boyce RW, Paddock CL, Franks AF, Jankowsky ML, Eriksen
EF 1996 Effects of intermittent hPTH (1-34) alone and in
combination with 1,25(OH)2D3 or risedronate on endosteal
bone remodeling in canine cancellous and cortical bone.
J Bone Miner Res 11:600–613.
9. Delmas PD, Vergnaud P, Arlot ME, Pastoureau P, Meunier PJ,
Nilssen MH 1995 The anabolic effect of human PTH (1-34) on
bone formation is blunted when bone resorption is inhibited by
the bisphosphonate tiludronate—Is activated resorption a pre-
requisite for the in vivo effect of PTH on formation in a
remodeling system? Bone 16:603–610.
10. Zhang L, Takahashi HE, Inoue J, Tanizawa T, Endo N,
Yamamoto N, Hori M 1997 Effects of intermittent adminis-
tration of low dose human PTH (1-34) on cancellous and
cortical bone of lumbar vertebral bodies in adult beagles. Bone
21:501–506.
11. Hirano T, Burr DB, Turner CH, Sato M, Cain RL, Hock JM
1999 Anabolic effects of human biosynthetic parathyroid hor-
mone fragment (1-34) LY33334, on remodeling and mechan-
ical properties of cortical bone in rabbits. J Bone Miner Res
14:536–545.
cant increases of 20–25% in radial and femoral porosity.
Our data show that treatment of OVX cynomolgus monkeys
for 18 months with hPTH(1-34) at 1 g/kg per day or 5
g/kg per day increased porosity by three to six times
compared with vehicle-treated controls, but without any
detrimental effect on mechanical properties. Mechanical
properties of cortical bone were not measured in the other
studies.
None of the studies on animals with Haversian remodel-
ing have reported the distribution of porosity, which appears
to be critical to the prediction of changes in bone strength
and stiffness in animals and humans treated intermittently
with PTH(1-34); they also did not report mechanical prop-
erties of the bone after withdrawal of the treatment. Our data
are important, showing that although intermittent PTH(1-
34) treatment significantly increases intracortical bone turn-
over, as measured by Ac.F and BFR/BV and intracortical
porosity, the increased porosity does not reduce the strength
or the stiffness of cortical bone. Moreover, at a lower dose,
the effect on intracortical porosity is transient and can be
reversed with a short duration of withdrawal of the drug.
We conclude that the increases in intracortical porosity
induced by intermittently administered PTH(1-34) does not
reduce the strength or stiffness of the cortical bone. The
effects of increased porosity are offset both by the distribu-
tion of the porosities close to the endocortical surface and
by the increased endocortical mineralizing surface that re-
sults in a significantly greater average Ct.Th in animals
treated at the higher dose. We further conclude that the
normalization of porosity after a period of withdrawal of
PTH treatment is dose dependent; at the lower dose nor-
malization occurred relatively rapidly, but at the higher dose
porosity does not return to normal after 6 months following
a 12-month treatment period presumably because the in-
creased rate of turnover requires a long period to reverse
itself. If the biomechanical properties of bone are predictive
of resistance to fracture, data from the OVX monkey model
suggest that PTH will alter geometric properties of cortical
bone but will not pose an additional fracture risk during or
after treatment.
12. Hirano T, Burr DB, Cain RL, Hock JM Changes in geometry
and cortical porosity in adult, ovary-intact rabbits after 5
months treatment with LY333334 (HPTH 1-34). Calcif Tissue
Int (in press).
13. Schock CC, Noyes FR, Villaneuva AR 1972 Measurement of
Haversian bone remodeling by means of tetracycline labelling
in rib of rhesus monkeys. Henry Ford Hosp Med J 20:131–
144.
14. Hodsman AB, Fraher LJ, Watson PH, Ostbye T, Stitt LW,
Adachi JD, Taves DH, Drost D 1997 A randomized controlled
trial to compare the efficacy of cyclical parathyroid hormone
vs. cyclical parathyroid hormone and sequential calcitonin to
improve bone mass in postmenopausal women with osteopo-
rosis. J Clin Endocrinol Metab 82:620–628.
ACKNOWLEDGMENTS
This study was funded by Eli Lilly & Co. Technical
assistance from Ricky Cain, Taffy Hooser, Diana Jacob, and
Thurman Alvey is gratefully acknowledged. Phil Iversen,
from Lilly Research Laboratories, performed the statistical
calculations.
15. Finkelstein JS, Klibanski A, Arnold AI, Toth TL, Hornstein
MD, Neer RM 1998 Prevention of estrogen deficiency-related
bone loss with human parathyroid hormone (1-34). JAMA
280:1067–1073.
REFERENCES
16. Lindsay R, Nieves J, Formica C, Henneman E, Woelfert L,
Shen V, Dempster D, Cosman F 1997 Randomized controlled
study of effect of parathyroid hormone on vertebral-bone mass
and fracture incidence among postmenopausal women on oes-
trogen with osteoporosis. Lancet 350:550–555.
1. Hesp R, Hulme P, Williams D, Reeve J 1981 The relationship
between changes in femoral bone density and calcium balance
in patients with involutional osteoporosis treated with human
parathyroid hormone fragment (hPTH 1-34). Metab Bone Dis
Rel Res 2:331–334.
2. Neer M, Slovik DM, Daly N, Potts JT Jr, Nussbaum SR 1993 17. Brommage R, Hotchkiss CE, Lees CJ, Stancill MW, Hock JM,
Treatment of postmenopausal osteoporosis with daily parathy-
Jerome CP 1999 Daily treatment with human recombinant
roid hormone plus calcitriol. Osteoporos Int 3:S204–S205.
parathyroid hormone 1-34 for one year increases bone mass in