Mechanical loading enhances the anabolic effects of intermittent parathyroid hormone (1–34) on trabecular and cortical bone in mice

Sugiyama, Toshihiro; Saxon, Leanne; Zaman, Gul; Moustafa, Alaa; Sunters, Andrew; Price, Joanna S.; Lanyon, Lance E.

doi:10.1016/j.bone.2008.04.012

Cited by 159 publications

(161 citation statements)

References 41 publications

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“…Mechanical loading is a prerequisite for normal bone formation, as well as for preservation, and studies in rodents have demonstrated a positive synergistic effect on both cortical and trabecular bone when combined mechanical loading and PTH treatment was instituted. (29)(30)(31)(32)(33) However, the PTH exposure in those studies were intermittent and not continuous, as in PHPT, but our findings indicate that mechanical loading plays a role in the action of PTH and that mechanical stimuli are important for the effects mediated by PTH. In our study we found reduced aBMD by DXA in the forearm, spine, and hip.…”

Section: Discussionmentioning

confidence: 51%

Effects on bone geometry, density, and microarchitecture in the distal radius but not the tibia in women with primary hyperparathyroidism: A case-control study using HR-pQCT

Hansen

Jensen

Rasmussen

et al. 2010

Journal of Bone and Mineral Research

112

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Patients with primary hyperparathyroidism (PHPT) have continuously elevated parathyroid hormone (PTH) and consequently increased bone turnover with negative effects on cortical (Ct) bone with preservation of trabecular (Tb) bone. High-resolution peripheral quantitative computed tomography (HR-pQCT) is a new technique for in vivo assessment of geometry, volumetric density, and microarchitecture at the radius and tibia. In this study we aimed to evaluate bone status in women with PHPT compared with controls using HR-pQCT. The distal radius and tibia of 54 women-27 patients with PHPT (median age 60, range 44-75 years) and 27 randomly recruited age-matched healthy controls (median age 60, range 44-76 years)-were imaged using HR-pQCT along with areal bone mineral density (aBMD) by dual-energy X-ray absorptiomentry (DXA) of the ultradistal forearm, femoral neck, and spine (L1-L4). Groups were comparable regarding age, height, and weight. In the radius, patients had reduced Ct area (Ct.Ar) ( p ¼ .008), Ct thickness (Ct.th) ( p ¼ .01) along with reduced total ( p ¼ .002), Ct ( p ¼ .02), and Tb ( p ¼ .02) volumetric density and reduced Tb number (Tb.N) ( p ¼ .04) and increased Tb spacing (Tb.sp) ( p ¼ .05). Ct porosity did not differ. In the tibia, no differences in HR-pQCT parameters were found. Moreover, patients had lower ultradistal forearm ( p ¼ .005), spine ( p ¼ .04), and femoral neck ( p ¼ 0.04) aBMD compared with controls. In conclusion, a negative bone effect of continuously elevated PTH with alteration of HR-pQCT assessed geometry, volumetric density, and both trabecular and cortical microarchitecture in radius but not tibia was found along with reduced aBMD by DXA at all sites in female patients with PHPT. ß

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Section: Discussionmentioning

confidence: 51%

Effects on bone geometry, density, and microarchitecture in the distal radius but not the tibia in women with primary hyperparathyroidism: A case-control study using HR-pQCT

Hansen

Jensen

Rasmussen

et al. 2010

Journal of Bone and Mineral Research

112

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“…The peak load (15N) was selected to induce bone formation in the loaded tibiae because evidence showed that similar peak load can induce osteogenic response in female C57BL/6 mice. (26,29,30) Briefly, a 14.5-N dynamic load was superimposed onto a 0.5-N preload at rate of 160,000 N/second. Forty trapezoidal-waveform load cycles (0.2-second hold at 15 N) with a 10-second interval between each cycle were applied to mice tibiae, three times a week for 2 weeks.…”

Section: Mechanical Loading In Vivomentioning

confidence: 99%

The P2Y13 receptor regulates extracellular ATP metabolism and the osteogenic response to mechanical loading

Wang

Rumney

Yang

et al. 2013

Journal of Bone and Mineral Research

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ATP release and subsequent activation of purinergic receptors has been suggested to be one of the key transduction pathways activated by mechanical stimulation of bone. The P2Y 13 receptor, recently found to be expressed by osteoblasts, has been suggested to provide a negative feedback pathway for ATP release in different cell types. Therefore, we hypothesized that the P2Y 13 receptor may contribute to the mediation of osteogenic responses to mechanical stimulation by regulating ATP metabolism by osteoblasts. To test this hypothesis, wild-type (WT) and P2Y 13 receptor knockout (P2Y 13 R À/À ) mice were subject to non-invasive axial mechanical loading of the left tibiae to induce an osteogenic response. Micro-computed tomography analysis showed mechanical loading induced an osteogenic response in both strains of mice in terms of increased total bone volume and cortical bone volume, with the P2Y 13 R À/À mice having a significantly greater response. The extent of the increased osteogenic response was defined by dynamic histomorphometry data showing dramatically increased bone formation and mineral apposition rates in P2Y 13 R À/À mice compared with controls. In vitro, primary P2Y 13 R À/À osteoblasts had an accumulation of mechanically induced extracellular ATP and reduced levels of hydrolysis. In addition, P2Y 13 R À/À osteoblasts also had a reduction in their maximal alkaline phosphatase (ALP) activity, one of the main ecto-enzymes expressed by osteoblasts, which hydrolyzes extracellular ATP. In conclusion, deletion of the P2Y 13 receptor leads to an enhanced osteogenic response to mechanical loading in vivo, possibly because of the reduced extracellular ATP degradation by ALP. The augmented osteogenic response to mechanical stimulation, combined with suppressed bone remodeling activities and protection from OVXinduced bone loss after P2Y 13 receptor depletion as previously described, suggests a potential role for P2Y 13 receptor antagonist-based therapy, possibly in combination with mechanical loading, for the treatment of osteoporosis.

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“…Several studies suggest that the two interact synergistically: with increased levels of PTH, the response to mechanical loading is enhanced and can be induced with less loading [1][2][3][4]. In fact, the effects of both PTH and mechanical loading are dependent on L-type voltage-sensitive calcium channels [5].…”

Section: Introductionmentioning

confidence: 99%

Low dose PTH improves metaphyseal bone healing more when muscles are paralyzed

Sandberg

Macias

Aspenberg

2014

Bone

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Stimulation of bone formation by PTH is related to mechanosensitivity. The response to PTH treatment in intact bone could therefore be blunted by unloading. We studied the effects of mechanical loading on the response to PTH treatment in bone healing.Most fractures occur in metaphyses, therefor we used a model for metaphyseal bone injury.One hind leg of 20 male SD rats was unloaded via intramuscular botulinum toxin injections. Two weeks later, the proximal unloaded tibia had lost 78 % of its trabecular contents. At this time-point, the rats received bilateral proximal tibiae screw implants.Ten of the 20 rats were given daily injections of 5µg/kg PTH(1-34). After two weeks of healing, screw fixation was measured by pull-out, and microCT of the distal femur cancellous compartment was performed. Pull-out force provided an estimate for cancellous bone formation after trauma.PTH more than doubled the pull-out force in the unloaded limbs (from 14 to 30 N), but increased it by less than half in the loaded ones (from 30 to 44 N). In relative terms, PTH had a stronger effect on pull-out force in unloaded bone than in loaded bone (p = 0.03).The results suggest that PTH treatment for stimulation of bone healing does not require simultaneous mechanical stimulation.

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Mechanical loading enhances the anabolic effects of intermittent parathyroid hormone (1–34) on trabecular and cortical bone in mice

Cited by 159 publications

References 41 publications

Effects on bone geometry, density, and microarchitecture in the distal radius but not the tibia in women with primary hyperparathyroidism: A case-control study using HR-pQCT

Effects on bone geometry, density, and microarchitecture in the distal radius but not the tibia in women with primary hyperparathyroidism: A case-control study using HR-pQCT

The P2Y13 receptor regulates extracellular ATP metabolism and the osteogenic response to mechanical loading

Low dose PTH improves metaphyseal bone healing more when muscles are paralyzed

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