Synergistic effect of hyperbaric oxygen therapy with PTH [1-34] on calvarial bone graft in irradiated rat.

OBJECTIVE: To determine the synergistic effect of parathyroid hormone (PTH) [1-34] in combination with hyperbaric oxygen (HBO) on bone graft in a rat calvarial bone defect model under impaired osteogenic conditions. MATERIALS AND METHODS: Twenty-four rats were divided into three groups. Localized radiation with a single 12 Gy dose was administered to the calvaria. Four weeks after radiation, calvarial circular defects were created in the parietal bones. All defects were filled with biphasic calcium phosphate. After the bone graft, PTH [1-34] was injected subcutaneously, and HBO was administered. At 6 weeks after the bone graft, the rats were sacrificed, and specimens were harvested. RESULTS: Histomorphometric evaluation showed that the percentage of new bone area was higher in the PTH and PTH/HBO groups than in the control group. The percent residual material area was decreased in the PTH/HBO group compared with the control group. The percentage blood vessel number was highest in the PTH group. Micro-CT evaluation showed that the new bone volume was highest in the PTH/HBO group. The residual material volume was lowest in the PTH/HBO group. CONCLUSION: Within the limitations of this study, our data indicate that PTH combined with HBO may reverse radiation-induced impairment of bone healing.

Successful treatment of 1-34 parathyroid hormone (PTH) after failure of bisphosphonate therapy in a complex case of pregnancy associated osteoporosis and multiple fractures.

INTRODUCTION: Pregnancy associated osteoporosis (PAO) was first reported almost half a century ago. The most common symptom is acute lower back pain due to vertebral fractures in the last trimester or immediately after birth. PATIENT: We present a case involving a female patient born in 1971 (gravida II, para I) with a history of PAO. In April 2000 at the age of 28 years, she delivered a son and breastfed him for 4 months. A first magnetic resonance tomography (MRT) screening in June 2000 showed osteoporotic fractures at lumbar vertebra 1-4. Therefore, the patient received oral alendronate therapy. In May 2001, a second MRT exhibited burst fracture of thoracic 8, end-plate fracture of thoracic 11, 12, lumbar 2-5 and compression fracture of lumbar 1. The oral therapy was switched to ibandronate (3 mg) intravenously every 3 months. An X-ray in December 2002 showed 3 new additional end-plate fractures at thoracic 4, 6 and 7. Ibandronate was discontinued in September 2004 and the patient received daily subcutaneous (s. c.) injections of 1-34 PTH in September 2005. RESULTS: After starting 1-34 PTH treatment for 18 months, a further increase in bone mineral density (BMD) was achieved without any further fracture. CONCLUSION: We presented for the first time a case of severe PAO with 11 spine fractures. We observed an unsatisfactory effect of oral and i. v. bisphosphonates in combination with adequate calcium and vitamin D supplementation. The treatment with 1-34 PTH showed an increase in BMD with no further fractures.

Limited utility of tartrate-resistant acid phosphatase isoform 5b in assessing response to therapy in osteoporosis.

BACKGROUND: Tartrate-resistant acid phosphatase isoform 5b (TRACP5b) is a serum bone resorption marker. Our aim was to investigate its utility in monitoring metabolic bone disease. METHODS: Serum TRACP5b, C-terminal cross-linking telopeptide of type I collagen, urine N-terminal cross-linking telopeptide of type I collagen and free deoxypyridinoline were measured pre- and post-treatment with a parathyroid hormone analogue [PTH (1-34)] (n = 14) or a bisphosphonate (N-BP) (n = 8). TRACP5b, bone alkaline phosphatase (bone ALP), 25-hydroxyvitamin D (25OHD) and parathyroid hormone (PTH) were measured in 100 osteoporosis patients on prolonged bisphosphonate therapy. RESULTS: Changes in TRACP5b were smaller in magnitude but mimicked those of other bone resorption markers. Absolute changes in TRACP5b and the other resorption markers correlated significantly (p < 0.001). In patients on long-term bisphosphonates, TRACP5b and bone ALP levels were not suppressed. Vitamin D status was consistent with the level of supplementation. CONCLUSION: TRACP5b has limited utility as a single marker of metabolic bone disease treatment.

The influence of parathyroid hormone treatment on implant fixation.

INTRODUCTION: Primary joint replacements generally function well with excellent clinical results. However, failure rates for young patients are still high and increasing in number. The longterm survival of an uncemented prosthesis is influenced by multiple factors depending on host physiology as well as properties of implanted material, initial mechanical stability, early osseointegration, and the surrounding bone. Parathyroid hormone is the principal regulator of calcium homeostasis and involved in the control of bone remodelling. Parathyroid hormone administered intermittently increases bone formation and mass by osteoblast stimulation. Early osseointegration and implant fixation could potentially be enhanced with adjuvant parathyroid hormone treatment. The aim of the studies in this PhD thesis was to determine if implant fixation of experimental implants can be improved with adjuvant intermittent administration of parathyroid hormone. STUDIES: All studies used an experimental canine model of early implant fixation inserting porous coated titanium alloy implants with no weight bearing in a bed of cancellous bone. The study design was un-paired. Test animals were randomised to PTH (1-34) 5 µm/kg daily for 4 weeks. Implant fixation was defined by mechanical stability and osseointegration. Study I investigated the effect of parathyroid hormone on implant fixation of implants inserted press fit with surrounding bone in the proximal tibia of 20 canines. Histomorphometric analysis showed increased amount of new bone in contact with the implant. No improvement was observed in the surrounding bone. PTH did not increase mechanical fixation in pushout test. Study II investigated the effect of parathyroid hormone on implant fixation of implants surrounded by a critical 1 mm gap. Implants where inserted in the tibia of 20 canines. Bone density was increased in the inner gap and outer gap with PTH treatment. Bone at implant interface improved with PTH but did not achieve significance. Push-out testing showed that PTH Increased mechanical implant fixation in shear stiffness and total energy absorption. Shear strength was not significantly increased. Study III investigated the effect on implant fixation of implants surrounded by a 2.5 mm gap in which morsellised allograft was impacted. Implants were inserted in 20 Canines in the humerus. Histomorphometric analysis showed that PTH increased the amount of new bone within the gap, but not in contact the implant. There were no differences in amount of allograft. The push-out testing showed no differences in mechanical parameters. CONCLUSION: The studies in this PhD thesis demonstrated that parathyroid hormone increases bone healing around implants in situations of insertion in press-fit or in more challenging environments of empty and grafted gaps. Early fixation was increased in implants with gaps, in which pure gap bone stimulation improved fixation. This warrants further preclinical studies.

Anabolic and catabolic regimens of human parathyroid hormone 1-34 elicit bone- and envelope-specific attenuation of skeletal effects in Sost-deficient mice.

PTH is a potent calcium-regulating factor that has skeletal anabolic effects when administered intermittently or catabolic effects when maintained at consistently high levels. Bone cells express PTH receptors, but the cellular responses to PTH in bone are incompletely understood. Wnt signaling has recently been implicated in the osteo-anabolic response to the hormone. Specifically, the Sost gene, a major antagonist of Wnt signaling, is down-regulated by PTH exposure. We investigated this mechanism by treating Sost-deficient mice and their wild-type littermates with anabolic and catabolic regimens of PTH and measuring the skeletal responses. Male Sost(+/+) and Sost(-/-) mice were injected daily with human PTH 1-34 (0, 30, or 90 µg/kg) for 6 wk. Female Sost(+/+) and Sost(-/-) mice were continuously infused with vehicle or high-dose PTH (40 µg/kg · d) for 3 wk. Dual energy x-ray absorptiometry-derived measures of intermittent PTH (iPTH)-induced bone gain were impaired in Sost(-/-) mice. Further probing revealed normal or enhanced iPTH-induced cortical bone formation rates but concomitant increases in cortical porosity among Sost(-/-) mice. Distal femur trabecular bone was highly responsive to iPTH in Sost(-/-) mice. Continuous PTH (cPTH) infusion resulted in equal bone loss in Sost(+/+) and Sost(-/-) mice as measured by dual energy x-ray absorptiometry. However, distal femur trabecular bone, but not lumbar spine trabecular bone, was spared the bone-wasting effects of cPTH in Sost(-/-) mice. These results suggest that changes in Sost expression are not required for iPTH-induced anabolism. iPTH-induced resorption of cortical bone might be overstimulated in Sost-deficient environments. Furthermore, Sost deletion protects some trabecular compartments, but not cortical compartments, from bone loss induced by high-dose PTH infusion.

High phosphorus diet changes phosphorus metabolism regardless of PTH action in rats.

In this study, we ascertained whether the parathyroid hormone (PTH) dominantly regulated the effects of high phosphorus (P) intakes on urinary excretion of P and bone metabolism in rats. To maintain serum PTH level equally, parathyroidectomy (PTX) and sham-operated rats were constantly exposed to rPTH(1-34) and fed both control (0.3% P) and high P (1.2% P) diet for 7 days, respectively. Urinary excretions of P and C-terminal telopeptides of type I collagen were significantly increased in both PTX and sham rats by the high P diet. These results suggest that high P diet increased urinary P excretion while promoting bone resorption regardless of PTH-dependent regulation.