HLU suppressed bone formation and resulted in bone loss in the tibial metaphysis of 6-month-old male rats. A human therapeutic dose of intermittent PTH (1 μg/kg/day) prevented the skeletal changes associated with HLU.Introduction: Skeletal unloading of skeletally mature rats results in trabecular thinning in the proximal tibial metaphysis, which is in part caused by a decrease in bone formation. We examined the efficacy of PTH in preventing the detrimental skeletal effects that occur with hindlimb unloading (HLU).Materials and Methods: Six-month-old male Fisher 344 rats were HLU and treated with vehicle or recombinant human PTH(1-34) at 1, 5, 20, or 80 μg/kg/day for 2 weeks. The bone response was measured by μCT analysis of bone structure, histomorphometric analysis of static and dynamic bone parameters, and Northern blot analysis of mRNA levels for bone matrix proteins. The PTH-treated HLU animals were compared with vehicle-treated HLU and pair-fed normal weight-bearing controls.Results: Unloading resulted in a decrease in cancellous bone volume that was caused in part by a dramatic 83% decrease in bone formation. All dose rates (1–80 μg/kg/day) of human PTH(1-34) significantly increased bone formation rates compared with vehicle-treated HLU controls. There was a dose response, and the highest dose rate of the hormone increased bone formation compared with normal weight-bearing rats by 708% (p < 0.0001). The increases in bone formation were accompanied by increases in mRNA levels for type 1 collagen, osteocalcin, and osteonectin. Also, treatment with PTH resulted in increases in mineral apposition rate and double-labeled perimeter, but the latter was disproportionally increased at high dose rates. A therapeutic dose of PTH (1 μg/kg/day) prevented disuse-induced trabecular thinning, whereas high-dose PTH (80 μg/kg/day) increased trabecular thickness compared with normal weight-bearing rats.Conclusions: These findings reveal that administration of a therapeutic dose of PTH to HLU rats prevents the decrease in bone formation and trabecular thinning, whereas high dose rates of the hormone increase bone formation and trabecular thickness to values that exceed normal values.

Intermittent treatment with parathyroid hormone (PTH) increases bone formation and prevents bone loss in hindlimb-unloaded (HLU) rats. However, the mechanisms of action of PTH are incompletely known. To explore possible interactions between weight bearing and PTH, we treated 6-mo-old weight-bearing and HLU rats with a human therapeutic dose (1 μg·kg⁻¹·day⁻¹) of human PTH(1–34) (hPTH). Cortical and cancellous bone formation was measured in tibia at the diaphysis proximal to the tibia-fibula synostosis and at the proximal metaphysis, respectively. Two weeks of hindlimb unloading resulted in a dramatic decrease in the rate of bone formation at both skeletal sites, which was prevented by PTH treatment at the cancellous site only. In contrast, PTH treatment increased cortical as well as cancellous bone formation in weight-bearing rats. Two-way ANOVA revealed that hPTH and HLU had independent and opposite effects on all histomorphometric indexes of bone formation [mineral apposition rate (MAR), double-labeled perimeter (dLPm), and bone formation rate (BFR)] at both skeletal sites. The bone anabolic effects of weight bearing and hPTH on dLPm and BFR at the cortical site were additive, as were the effects on MAR at the cancellous site. In contrast, weight bearing and hPTH resulted in synergistic increases in cortical bone MAR and cancellous bone dLPm and BFR. We conclude that weight bearing and PTH act cooperatively to increase bone formation by resulting in site-specific additive and synergistic increases in indexes of osteoblast number and activity, suggesting that weight-bearing exercise targeted to osteopenic skeletal sites may improve the efficacy of PTH therapy for osteoporosis.

Menopause is a natural physiological process in older women that is associated with reduced estrogen production and results in increased risk for obesity, diabetes, and osteoporosis. 17α-estradiol (17α-E2) treatment in males, but not females, reverses several metabolic conditions associated with advancing age, highlighting sexually dimorphic actions on age-related pathologies. In this study we sought to determine if 17α-E2 could prevent ovariectomy (OVX)-mediated detriments on adiposity and bone parameters in females. Eight-week-old female C57BL/6J mice were subjected to SHAM or OVX surgery and received dietary 17α-E2 during a six-week intervention period. We observed that 17α-E2 prevented OVX-induced increases in body weight and adiposity. Similarly, uterine weight and luminal cell thickness were decreased by OVX and prevented by 17α-E2 treatment. Interestingly, 17α-E2 prevented OVX-induced declines in tibial metaphysis cancellous bone. And similarly, 17α-E2 improved bone density parameters in both tibia and femur cancellous bone, primarily in OVX mice. In contrast, to the effects on cancellous bone, cortical bone parameters were largely unaffected by OVX or 17α-E2. In the non-weight bearing lumbar vertebrae, OVX reduced trabecular thickness but not spacing, while 17α-E2 increased trabecular thickness and reduced spacing. Despite this, 17α-E2 did improve bone volume/tissue volume in lumbar vertebrae. Overall, we found that 17α-E2 prevented OVX-induced increases in adiposity and changes in bone mass and architecture, with minimal effects in SHAM-operated mice. We also observed that 17α-E2 rescued uterine tissue mass and lining morphology to control levels without inducing hypertrophy, suggesting that 17α-E2 could be considered as an adjunct to traditional hormone replacement therapies.

This study investigated the effects of a 14-day spaceflight on bone mass, density and microarchitecture in weight bearing (femur and humerus) and non-weight bearing (2^ndlumbar vertebra and calvarium) bones in the context of ovarian hormone insufficiency. 12-week-old Fisher 344 rats were ovariectomized 2 weeks before flight and randomized into one of three groups: 1) baseline (n = 6), 2) ground control (n = 12) or 3) spaceflight (n = 12). Additional ground-based ovary-intact rats provided age-matched reference values at baseline (n = 8) and landing (n = 10). Ovariectomy resulted in bone- and bone compartment-specific deficits in cancellous bone volume fraction. Spaceflight resulted in lower cortical bone accrual in the femur but had no effect on cortical bone in the humerus or calvarium. Cancellous bone volume fraction was lower in flight animals compared to ground control animals in lumbar vertebra and distal femur metaphysis and epiphysis; significant differences were not detected in the distal humerus. Bone loss (compared to baseline controls) in the femur metaphysis was associated with lower trabecular number, whereas trabecular thickness and number were lower in the epiphysis. In summary, the effect of spaceflight on bone microarchitecture in ovariectomized rats was bone-and bone compartment-specific but not strictly related to weight bearing.

Chronic hyperparathyroidism (HPT) is a common cause of metabolic bone disease. These studies investigated the underlying cellular and molecular mechanisms responsible for the detrimental actions of elevated parathyroid hormone (PTH) on the skeleton. Bone biopsies from hyperparathyroid patients revealed an association between parathyroid bone disease and increased numbers of bone marrow mast cells. We therefore evaluated the role of mast cells in the etiology of parathyroid bone disease in a rat model for chronic HPT. In rats, mature mast cells were preferentially located at sites undergoing bone turnover, and the number of mast cells at the bone–bone marrow interface was greatly increased following treatment with PTH. Time-course studies and studies employing parathyroid hormone–related peptide (PTHrP), as well as inhibitors of platelet-derived growth factor-A (PDGF-A, trapidil), kit (gleevec), and PI3K (wortmannin) signaling revealed that mature mast cell redistribution from bone marrow to bone surfaces precedes and is associated with osteitis fibrosa, a hallmark of parathyroid bone disease. Importantly, mature mast cells were not observed in the bone marrow of mice. Mice, in turn, were resistant to the development of PTH-induced bone marrow fibrosis. These findings suggest that the mast cell may be a novel target for treatment of metabolic bone disease. © 2010 American Society for Bone and Mineral Research