Changes in the contents of enzymatic immature, mature, and non-enzymatic senescent cross-links of collagen after once-weekly treatment with human parathyroid hormone (1-34) for 18 months contribute to improvement of bone strength in ovariectomized monkeys.
Improvements in total content of enzymatic cross-linking, the ratio of hydroxylysine-derived enzymatic cross-links, and non-enzymatic advanced glycation end product cross-link formation from once-weekly administration of hPTH(1-34) for 18 months in OVX cynomolgus monkeys contributed to the improvement of bone strength.


BACKGROUND
Parathyroid hormone (PTH) is used for the treatment of osteoporosis. To elucidate the contribution of material properties to bone strength after once-weekly treatment with hPTH(1-34) in an ovariectomized (OVX) primate model, the content of collagen and enzymatic immature, mature, and non-enzymatic cross-links, collagen maturity, trabecular architecture, and mineralization in vertebrae were simultaneously estimated.


METHODS
Adult female cynomolgus monkeys were divided into four groups (n = 18-20 each) as follows: SHAM group, OVX group, and OVX monkeys given once-weekly subcutaneous injections of hPTH(1-34) either at 1.2 or 6.0 μg/kg (low- or high-PTH groups) for 18 months. The content of collagen, enzymatic and non-enzymatic cross-linking pentosidine, collagen maturity, trabecular architecture, mineralization, and cancellous bone strength of vertebrae were analyzed.


RESULTS
Low-PTH and high-hPTH treatments increased the content of enzymatic immature and mature cross-links, bone volume (BV/TV), and trabecular thickness, and decreased pentosidine, compared with the OVX group. Stepwise logistic regression analysis revealed that BV/TV, the content of total enzymatic cross-links, and calcium content independently affected ultimate load (model R (2) = 0.748, p < 0.001) and breaking energy (model R (2) = 0.702, p < 0.001). BV/TV was the most powerful and enzymatic cross-link content was the second powerful determinant of both ultimate load and breaking energy. The most powerful determinant of stiffness was the enzymatic cross-link content (model R (2) = 0.270, p < 0.001).


CONCLUSIONS
Once-weekly preventive administration of hPTH(1-34) increased the total contents of immature and mature enzymatic cross-links, which contributed significantly to vertebral cancellous bone strength.
Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan. xlink67@gol.com
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Saito
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Marumo
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Kida
C
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Ushiku
S
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Kato
R
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Takao-Kawabata
T
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Kuroda
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism; D015519:Bone Density / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002118:Calcium / Q000378:metabolism; D003094:Collagen / Q000378:metabolism*; D019245:Compressive Strength / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism; D008159:Lumbar Vertebrae / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D008252:Macaca fascicularis; D010024:Osteoporosis / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D010052:Ovariectomy; D010710:Phosphates / Q000378:metabolism; D019379:Teriparatide / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D055114:X-Ray Microtomography / Q000379:methods
D050071:Bone Density Conservation Agents; D017127:Glycation End Products, Advanced; D010710:Phosphates; D019379:Teriparatide; D003094:Collagen; D001120:Arginine; C062187:pentosidine; D008239:Lysine; D002118:Calcium