New Bone Formation with Teriparatide [Human Parathyroid Hormone-(1–34)] Is Not Retarded by Long-Term Pretreatment with Alendronate, Estrogen, or Raloxifene in Ovariectomized Rats

Abstract

With the ready availability of several osteoporosis therapies, teriparatide [human PTH-(1-34)] is likely to be prescribed to postmenopausal women with prior exposure to agents that prevent bone loss, such as bisphosphonates, estrogen, or selective estrogen receptor modulators. Therefore, we evaluated the ability of once daily teriparatide to induce bone formation in ovariectomized (Ovx) rats with extended prior exposure to various antiresorptive agents, such as alendronate (ABP), 17 alpha-ethinyl estradiol (EE), or raloxifene (Ral). Sprague Dawley rats were Ovx and treated with ABP (28 microg/kg, twice weekly), EE (0.1 mg/kg per d), or Ral (1 mg/kg per d) for 10 months before switching to teriparatide 30 microg/kg per d for another 2 months. Analysis of the proximal tibial metaphysis showed that all three antiresorptive agents prevented ovariectomy-induced bone loss after 10 months, but were mechanistically distinct, as shown by histomorphometry. Before teriparatide treatment, ABP strongly suppressed activation frequency and bone formation rate to below levels in other treatment groups, whereas these parameters were not different from sham values for EE or Ral. Trabecular area for ABP, EE, and Ral were greater than that in Ovx controls. However, the trabecular bone effects of ABP were attributed not only to effects on the secondary spongiosa, but also to the preservation of primary spongiosa, which was prevented from remodeling. After 2 months of teriparatide treatment, lumbar vertebra showed relative bone mineral density increases of 18%, 7%, 11%, and 10% for vehicle/teriparatide, ABP/teriparatide, EE/teriparatide, and Ral/teriparatide, respectively, compared with 10 month levels. Histomorphometry showed that trabecular area was increased by 105%, 113%, 36%, and 48% for vehicle/teriparatide, ABP/teriparatide, EE/teriparatide, and Ral/teriparatide, respectively, compared with 10 month levels. Teriparatide enhanced mineralizing surface, mineral apposition rate, and bone formation rate in all groups. Compression testing of vertebra showed that teriparatide improved strength (peak load) and toughness in all groups to a proportionately similar extent compared with 10 month levels. These data showed a surprising ability of the rat skeleton to respond to teriparatide despite extensive pretreatment with ABP, EE, or Ral. Therefore, the mature skeleton of Ovx rats remains highly responsive to the appositional effects of teriparatide regardless of pretreatment status in terms of cancellous bone area or rate of bone turnover.

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

“…RANKL may also stimulate the secretion of an osteoblastogenic factor from osteoclasts [106]. Evidence that bisphosphonates attenuated the anabolic effect of intermittent PTH in animal models and humans is consistent with the involvement of osteoclasts in the anabolic effect [107][108][109][110][111], but such inhibition was not seen in other studies [45,[112][113][114]. Indeed, both OPG and alendronate prolonged the duration of the anabolic effect in ovariectomized mice, apparently by preventing the increased bone resorption that occurs in the later stages of treatment [45].…”

Effects of Cyclic Versus Daily hPTH(1-34) Regimens on Bone Strength in Association With BMD, Biochemical Markers, and Bone Structure in Mice

“…(9) In studies using ovariectomized older rats, it was shown that PTH further increased bone strength and BMD after long-term treatment with alendronate. (11) Thus, it still remains to be determined whether continuous or alternating use of a bisphosphonate and PTH in repeated cycles would improve anabolic responses in all measures and whether improved bone strength outcomes could be obtained in our murine model. This study ended on a PTH-on period.…”

Alendronate reduced peri-tunnel bone loss and enhanced tendon graft to bone tunnel healing in anterior cruciate ligament reconstruction

“…Control rats received 1 mL saline instead. The subcutaneous dose of 60 µg/ kg/week was chosen based on the same dose used in the previous studies for the treatment of osteoporosis (Ma et al, 2003) and fracture healing (Cao et al, 2007). The other doses were chosen as 1/10x and 5x of this dose.…”

“…The attachment site of grafted tendon-to-bone is the weak link in early tendon allograft/autograft to bone tunnel healing. Various methods have been reported to improve early fixation and facilitate subsequent healing of tendon graft inside bone tunnel Rodeo et al, 1999;Ohtera et al, 2000;Anderson et al, 2001;Weiler et al, 2002;Lim et al, 2004;Wang et al, 2005;Ma et al, 2007).…”