Parathyroid Hormone In Osteoporosis Research Articles

Mechanism and efficacy of parathyroid hormone in osteoporosis

Background: Parathyroid hormone (PTH) and teriparatide, which is a PTH analog, are special options of osteoanabolic therapies for osteoporosis treatment. Their efficacy in improving the bone mineral density (BMD) and reducing fracture risk is considered to have a long-awaited justification.Current Concepts: PTH is an 84-amino acid polypeptide that plays a key role in the calcium homeostasis of the human body. It yields anabolic effects on the bone by intermittent injections. During the first 6 months of PTH treatment, bone formation increases rapidly and bone resorption rises gradually. PTH is believed to be maximally anabolic during the anabolic window. In the phase III trial of teriparatide, significant reductions in vertebral and non-vertebral fractures were identified. Teriparatide has been studied in drug-induced osteoporosis, postmenopausal women with osteoporosis, and men with osteoporosis. The data derived from clinical trials with teriparatide showed an increase of the BMD in the treatment group compared to that of the placebo. Selective advantages on fracture healing have been shown in some studies; however, consensus on the relationship between teriparatide and bone healing is unclear.Discussion and Conclusion: Teriparatide has been approved for osteoporosis treatment in various situations, including postmenopausal women, men with osteoporosis, and cases with glucocorticoid-induced osteoporosis. Additionally, it can be useful in high risk for fracture groups, if fractures persist despite bone resorption inhibitor therapy, and if bone resorption inhibitor administration is difficult and contraindicated.

Compliance and persistence with treatment with parathyroid hormone for osteoporosis. A Danish national register-based cohort study

Medical intervention is important in the treatment of osteoporosis, and compliance with medical treatment is essential for an optimal outcome. Based on Danish national registers, we found that compliance with parathyroid hormone (PTH) treatment is high and associated with marital status, working status, and type of PTH treatment. Compliance and persistence are essential for an optimal outcome during medical treatment of osteoporosis. We aimed to evaluate compliance and persistence with treatment with PTH in daily clinical practice in Danish patients and to describe factors affecting compliance. Register-based nationwide cohort study on all patients in Denmark initiates PTH or analogue treatment for osteoporosis in 2003-2010 (n = 4281). PTH drugs included were the PTH analogue teriparatide(1-34) and recombinant human PTH (rhPTH(1-84)). Compliance with treatment was calculated by using medication possession ratio (MPR). In the study period, 3702 patients were exclusively treated with teriparatide and 579 were exclusively treated with rhPTH(1-84). We found that for patients persistent with therapy for at least 18 months and with MPR >0.8, 83 % of the patients in the teriparatide group were compliant versus 72 % in the recombinant PTH group (p < 0.01). Being married/cohabiting, still in the labor market, and taking teriparatide were significantly associated with higher compliance, whereas age, gender, level of education, income, alcoholism, and Charlson comorbidity index were not associated with compliance. Compliance with PTH treatment overall is high, with teriparatide compliance higher than rhPTH(1-84), in patients persistent to therapy for 18 months. Compliance is associated with marital status, working status, and type of PTH treatment.

The Efficacy of Parathyroid Hormone Analogues in Combination With Bisphosphonates for the Treatment of Osteoporosis: A Meta-Analysis of Randomized Controlled Trials.

Parathyroid hormone (PTH) analogues increase bone strength primarily by stimulating bone formation, whereas antiresorptive drugs (bisphosphonates) reduce bone resorption. Therefore, some studies have been designed to test the hypothesis that the concurrent administration of the 2 agents would increase bone density more than the use of either one alone. This meta-analysis aimed to determine whether combining PTH analogues with bisphosphonates would be superior to PTH alone.Electronic databases were searched to identify relevant publications up to March, 2014. Randomized controlled trials (RCTs) comparing PTH analogues combined bisphosphonates with PTH for osteoporosis were analyzed. According to the Cochrane Handbook for systematic Reviews of Interventions 5.2, we identified eligible studies, evaluated the methodological quality, and abstracted relevant data.Totally 7 studies involving 641 patients were included for meta-analysis. The pooled data showed that there were no significant differences in the percent change of spine BMD (MD1-year = −0.97, 95% CI −2.81 to 0.86, P = 0.30; MD2-year = − 0.57, 95% CI −5.01 to 6.14, P = 0.84), femoral neck BMD (MD1-year = 0.60, 95% CI −0.91 to 2.10, P = 0.44; MD2-year = −0.73, 95% CI −4.97 to 3.51, P = 0.74), the risk of vertebral fracture (risk ratio [RR] = 1.27; 95% CI 0.29–5.57; P = 0.75), and the risk of nonvertebral fracture (RR = 0.97; 95% CI 0.40–2.35; P = 0.95) between the 2 groups, whereas combination group improves the percent change of hip BMD at 1 year (MD = 1.16, 95% CI 0.56–1.76; P < 0.01) than PTH analogues group.Our results showed that there was no evidence for the superiority of combination therapy, although significant change was found for hip BMD at 1 year in combination group. Further large multicenter randomized controlled trials are still needed to investigate the efficacy of combination therapy.

Anabolic therapies.

The striking clinical benefits of intermittent parathyroid hormone in osteoporosis have begun a new era of skeletal anabolic agents. Recombinant human parathyroid hormone (rhPTH) (1–34) is the first US Food and Drug Administration–approved anabolic therapy. Its use has been limited by the need for subcutaneous injection. Newer delivery systems include transdermal and oral preparations. Newer anabolic therapies include monoclonal antibody to sclerostin, a potent inhibitor of osteoblastogenesis; and use of bone morphogenetic proteins and parathyroid hormone–related protein PTHrP, a calcium-regulating hormone similar to PTH.

Sclerostin

The striking clinical benefits of intermittent parathyroid hormone in osteoporosis have begun a new era of skeletal anabolic agents. One potential new agent is monoclonal antibody to sclerostin, a potent inhibitor of osteoblastogenesis.

New development in bisphosphonate treatment. Clinical significance of combinatorial therapies with bisphosphonates and parathyroid hormone for osteoporosis

Bisphosphonates are the first line therapy to prevent osteoporotic fractures in daily practice. However, their preventive effect for fracture is not always satisfactory. In particular, more effective therapeutic tools are needed for patients who report osteoporotic fractures during treatment with bisphosphonates. To this end, treatment with parathyroid hormone has demonstrated potent bone anabolic effects and efficacy to prevent fractures, and physicians in Japan are looking forward to government approval to its clinical application. However, since, due to its characteristics, such as daily injection and expensive costs, parathyroid hormone is not the best candidate as the first line therapy for osteoporosis, we need to investigate how to use parathyroid hormone in combination with other drugs for osteoporosis, such as bisphosphonates.

PTH for Osteoporosis: Learning More

In two recent NIH-supported clinical trials, investigators examined how to best use parathyroid hormone (PTH) in treating postmenopausal osteoporotic women. As part of a randomized trial, supported in part by manufacturers of PTH and alendronate, 119 previously untreated women were assigned to receive 1 year of daily PTH (1-84) injections followed by 1 year of daily oral alendronate, or 1 year of PTH followed by 1 year of placebo. PTH increased BMD …

Sequential and Combination Therapy using Parathyroid Hormone for Osteoporosis

과거 10여 년 동안 골다공증의 치료는 많은 발전을 거듭 하였다. 1990년대 초반 골다공증의 치료 약제는 여성호르몬 과 칼시토닌에 국한되었으나 1990년대 중반 이후 또 다른 골흡수 억제제인 비스포스포네이트와 SERM (selective estrogen receptor modulator)제제가 추가되었다. 최근에는 폐 경 후 여성과 골절 고위험군 남성의 골다공증 치료에 있어 부갑상선 호르몬[PTH (1-34), Teriparatide]의 사용이 미국 식약청 (FDA)에서 허가되었으며, 국내에서도 곧 치료에 이 용될 수 있을 것으로 전망된다. PTH (1-34)는 골다공증이 진단된 폐경후 여성 및 남성 그리고 스테로이드 유발 골다공증에서 골밀도 증가 효과가 입증되었으며[1~3], 비스포스포네이트 제제와의 비교에서도 우월한 골밀도 증가 효과가 보고된 바 있다[4]. 폐경 후 골 다공증 여성에서 매일 20μg의 PTH(1-34) 투여로 평균 21개 월 동안 요추골의 골밀도가 약 10%정도 증가하였으며, 척 추 및 비척추골의 골절율이 대조군에 비해 각각 65% 와 53% 감소하였다[1]. 완전 부갑상선호르몬[PTH(1-84), intact PTH]에 관한 제3상 시험은 현재 진행중이며, 제2상 임 상시험에 의하면 PTH(1-84)의 골밀도 증가효과는 PTH (1-34)와 유사한 것으로 판단된다[5]. PTH(1-84)의 골절에 대한 효과는 아직 보고가 없다. 아직 장기적인 임상연구결과는 없지만, 위와 같이 부갑상 선호르몬은 골밀도 증가 및 골절 감소효과가 입증된 최초의 골형성 치료제이다. 또한 기존약제와 작용 기전이 다른 부 갑상선호르몬의 등장은 골흡수억제제만을 이용한 다소 획 일적인 골다공증 치료 방식에서 부갑상선 호르몬과 골흡수 억제제와의 조합 (combination)치료 혹은 부갑상선호르몬과 골흡수 억제제의 순차 (sequential)치료 등 다양한 방식의 치 료를 가능하게 하였으며 이번 호의 이등의 논문과 같이 이 에 대한 활발한 연구가 진행되고 있다. 더불어 아직 충분히 합의점을 찾지 못한 부갑상선호르몬 치료에 관한 몇 가지 우려 (concern)는 이런 조합 및 순차치료의 필요성을 요구하 고 있다. 그간의 몇 가지 임상시험들에 의하면 부갑상선 호르몬 치료 후 척추나 소주골 (trabecular bone)의 골밀도는 상당 량 증가하지만 대퇴경부나 원위요골 (distal radius)과 같이 피질골 (cortical bone)이 풍부한 곳은 치료 후 골밀도의 변 화가 미약하거나 오히려 감소하는 양상을 보였다[1,4,5]. 일 반적으로 부갑상선 호르몬 치료에 의해 골재형성율이 증가 하지만 골형성이 골흡수보다 많고 또한 이전의 골흡수가 없 이 골형성이 이루어지기도 하여 결국 소주의 두께가 증가하 고 소주의 연결성 (connectivity)도 증가한다. 부갑상선 호르 몬 치료 후 피질골의 골밀도가 변화가 없거나 오히려 감소 하는 것은 부갑상선 호르몬에 의해 피질골의 안쪽에서 (endocortical) 골재형성이 증가하고 소주화 (trabeculization)가 진행되어 소위 피질골의 다공성 (porosity)이 증가하기 때문 으로 여겨진다. 그러나 이렇게 해면골이 확장되고 내경 (inner diameter)이 증가하더라도 골막하 골생성 (periosteal apposition)에 의해 피질골의 두께가 유지되고 외경이 증가 하므로 골강도 (bone strength)는 증가하는 것으로 보고되고 있다[6,7]. 아직 피질골들에 대한 부갑상선호르몬 치료의 항 골절 효과에 대한 연구는 충분하지 않지만 부갑상선호르몬 치료가 피질골을 약화시킬 것이라는 그간의 우려는 최근 어 느 정도 소실되는 것 같다[8]. 실제 이번 호 이등의 연구에 서도 PTH(1-84)를 계속하여 투여 받은 군에서 대퇴골의 골 밀도 및 대퇴골 중앙의 피질골두께가 다른군 보다 유의하게 높았다. 비록 이등의 연구에서는 PTH(1-84)-인카드로네이 트 순차치료군에서 유의한 피질골 효과를 관찰할 수 없었지 만 저자들이 인용한 바와 같이 부갑상선호르몬 치료 후 골 흡수 억제제를 이어서 사용하는 것은 피질골의 다공성을 회 골다공증에서 부갑상선호르몬을 이용한 순차치료 및 조합치료

Effects of parathyroid hormone on cancellous bone mass and structure in osteoporosis.

Parathyroid hormone (PTH) is the major hormonal regulator of calcium homeostasis. PTH is a potent stimulator of bone formation and can restore bone to an osteopenic skeleton, when administered intermittently. Osteoblasts are the primary target cells for the anabolic effects of PTH in bone tissue. Anabolic effects of PTH on bone have been demonstrated in animals and humans, by numerous measurement techniques including bone mineral density and bone histomorphometry. Clinically, the most important aspect of treatment for osteoporosis is prevention of fractures. Microstructural alterations, such as loss of trabecular connectivity, have been implicated in increased propensity for fracture. Recent two-dimensional (2D) and three-dimensional (3D) assessments of cancellous bone structure have shown that PTH can re-establish lost trabecular connectivity in animals and humans. These results provide new insight into the positive clinical effects of PTH in osteoporosis. In recent randomized controlled clinical trials of intermittent PTH treatment, PTH decreased incidence of vertebral and non-vertebral fractures in postmenopausal women. Thus, PTH shows strong potential as therapy for osteoporosis. However, 2D and 3D structural analysis of advanced osteopenia in animals has shown that there is a critical limit of trabecular connectivity and bone strength below which PTH cannot completely reverse the condition. Given that PTH treatment fails to completely restore trabecular connectivity and bone strength in animals with advanced osteopenia, early treatment of osteoporosis appears important and efficacious for preventing fractures caused by decreased bone strength resulting from decreased trabecular connectivity.

Parathyroid hormone in osteoporosis.

Parathyroid hormone in osteoporosis.

Getting gene therapy under control: ARIAD Pharmaceuticals, Inc.

When expression just can’t wait, ARIAD has the RAPID system, in which a drug frees pre-made protein from an aggregate, so it can be secreted promptly into the bloodstream.“We had devised a (rapid delivery) scheme,” says Clackson, “but the key thing we needed was a conditional aggregation domain (CAD). By pure chance we discovered such a protein. It sat on the shelf for a while until we realized that it would work with RAPID.”The CAD (now called FM) was one of the FKBPs engineered with a hole to accommodate AP1903. FM was the one variant that, unexpectedly, gave a positive two hybrid when paired with itself. The aggregation was dissociated by a monomeric version of AP1903.Several FM domains strung together cause a protein to aggregate in the endoplasmic reticulum unless the monomer drug is added. Protein (e.g. insulin) release can be detected by 15 min after drug addition, and peaks within 2 h. The system is particularly well suited to proteins that must be pulsed rapidly to be effective, such as parathyroid hormone for osteoporosis or beta-endorphins for chronic pain.RAPID is far from the clinic, but has generated a Science paper. So is science triumphing over business? Clackson thinks not. “We’ve got a more ruthless product focus than we’ve had in the past,” he says.And Berger has no regrets about the good science. “The challenges have been scientific,” he says. “These have been hard programs to pursue. If you overcome these challenges you create something of great value, and I think we are there now.”

Pulmonary delivery of drugs for bone disorders

As the population ages, osteoporosis becomes a growing public health concern. Current treatments provide patients with limited clinical improvement, numerous side effects, and no cure. The naturally-occurring peptides calcitonin and parathyroid hormone, which regulate bone metabolism, offer alternative treatment options. Clinical studies indicate the usefulness of calcitonin and parathyroid hormone in osteoporosis and Paget’s disease of bone. For the peptides to become viable therapies, formulations must be developed that bypass the need for injection. Pulmonary delivery of calcitonin and parathyroid hormone appears likely in the near future.

Fluoride Therapy and Parathyroid Hormone Activity in Osteoporosis

1. To determine the relationships between parathyroid hormone activity and long-term sodium fluoride therapy in osteoporosis, cytochemical bioassays (for biologically active parathyroid hormone) were performed in 22 osteoporotic control patients and in 18 patients after 15 +/- 10 months of treatment (60 mg of sodium fluoride daily). Ten patients were studied longitudinally by repeated metabolic balances and were therefore common to both groups. All patients were receiving mineral supplements. 2. Cross-sectional data showed a fourfold mean increase in biologically active parathyroid hormone on fluoride treatment (P less than 0.005) together with a 51% increase in serum alkaline phosphatase (P less than 0.005). Longitudinal data showed, in addition, a significant increase in the calcium balance of 2.4 +/- 1.2 (SEM) mmol daily (P less than 0.05) and the development of a positive phosphorus balance (P less than 0.02). 3. Fluoride-treated patients were then analysed in two groups according to the level of biologically active parathyroid hormone. Thirty-two per cent of values were above the upper limit of normal (18 pg/ml). The mean serum alkaline phosphatase level in this group showed no elevation above that of the control patients, the overall rise being accounted for entirely by patients with normal levels of biologically active parathyroid hormone. High levels of biologically active parathyroid hormone were also associated with relative hypophosphataemia (P less than 0.01), relative hypercalciuria (P less than 0.05) and an increased urine/faecal calcium ratio (P less than 0.025). 4. Results show that long-term fluoride and calcium therapy increase biologically active parathyroid hormone in osteoporosis and that excessive parathyroid hormone activity may account for certain features of the refractory state.

Urinary cyclic adenosine monophosphate discriminates subsets of patients with osteoporosis.

To assess the biologic activity of the parathyroid hormone in osteoporosis, 32 patients with radiologic and clinical evidence of this disease were studied. Measurements of urinary cyclic adenosine monophosphate (cAMP), serum calcitriol (1,25 dihydroxyvitamin D), calcium, phosphorus, albumin, creatinine, and estimated glomerular filtration were obtained. The high cAMP group averaged 5.68 µmol cAMP/g (SEM, 0.35) and the low cAMP group, 2.89 µmol cAMP/g (SEM, 0.22) of creatinine. Mean urinary calcium levels were lower (P