Effects Of Alternating Cyclic Parathyroid Hormone And Alendronate Regimens In Osteoporosis Treatment

Osteoporosis is a common chronic skeletal disease caused by bone mineral density and bone mass reduction,which mostly occurs in middle-aged and elderly people.In the osteoporosis,as bones become more porous and fragile,the mechanical properties of bone deteriorate,and the risk of fracture increases greatly.Currently,an aging population is an important issue that most of the advanced countries are facing,and China is in a more severe situation.The incidence of osteoporosis will further increase significantly.However,in the clinical practice,there is no effective method or drug to cure osteoporosis.The majority of osteoporosis patients often face a great risk of fracture after multiple drugs or surgical treatments.Therefore,it’s urgent to find effective ways to treat chronic osteoporosis.Parathyroid Hormone(PTH)is the first anabolic drug approved by the US FDA to treat osteoporosis in clinic.Although PTH has a potent effect on promoting new bone formation,there are strong withdrawal effects,i.e.bone quality and bone quality decrease rapidly upon PTH treatment discontinuation.Bone mineral density(BMD)decreases rapidly to the pre-treatment level or even lower than the untreated BMD after PTH withdrawal,and induces more severe degenerative osteoporosis symptoms.In addition,if PTH treatment sustains,it will induce elevated blood calcium and decreased blood phosphorus calcium,which causes phosphorus metabolism imbalance symptoms.This symptom is known as primary hyperparathyroidism.Patients with hyperparathyroidism caused by excessive PTH usually accompany with bone loss,which will make the osteoporosis symptoms mitigated by PTH treatment started getting worse again.Thus,the US FDA limits the use of PTH treatment in clinical practice within 18-24 months.In this study,rats and mice osteoporosis model were used to research the mechanism between PTH and bone micro-architecture,to get a better understanding of osteoporosis,to provide theory and data support for clinical treatment.Main conclusions of this study as follows:(1)The development of micro CT scanning on experimental animals’ skeletal system.To better monitoring the bone changes during treatment,an effective approach is necessary,the traditional DXA can only provide bone mineral density of the global bone area,which can’t serve the purpose of this study.In this study,we developed microCT scanning protocols to perform scans on both rats and mice with reliable reproducibility and free from radiation effect,the scanning protocols are the footstone for the rest of this study.(2)The development of osteoporosis animal models: Both rats and mice osteoporosis models were developed by different methods.In rats,we performed OVX surgery on adult SD rats,which induced 50% of bone loss after 4 weeks from the surgery.In mice,we developed tail suspension devices and suspended B6 mice for 3 weeks,suspension led to 39% bone loss at mice’s hind legs.Both methods can provide reliable animal models in this study.(3)Study of PTH withdrawal effect and development of a cyclic PTH treatment regimen: In clinical practice,continuous PTH treatment may lose efficacy after a certain period of treatment and induce serious hyperparathyroidism.In addition,discontinuation of PTH may lead to withdrawal effect,which causes bone loss and even worse osteoporosis than the pre-treated condition.To better understanding the mechanism behind the PTH withdrawal effect,we performed a cross-sectional study to observe bone responses 1-week,2-week,and 3-week after the PTH discontinuation.Our results showed an anabolic window 1 week after the PTH discontinuation: active osteoblasts and suppressed osteoclasts.The anabolic window disappeared 2 weeks after the PTH discontinuation: suppressed osteoblasts and active osteoclasts.We proposed a cyclic PTH treatment regime may bring better efficacy considering the anabolic window we found.Animal experiments were performed and we found out a regimen with 3 cycles of 3-week PTH+3-week saline led to better bone outcomes and the PTH withdrawal effect was not observed during the PTH discontinuation period.(4)Alternating and cyclic PTH and ALN treatment on osteoporosis: In clinical practice,ALN is commonly used to oppress osteoclasts activities,which prevent condition from progression.We proposed a treatment of alternating and cyclic PTH and ALN regimen that can further improve the efficacy of cyclic PTH treatment.In our study design,we added ALN during PTH off-cycle,every 6 weeks is considered one cycle(3-week PTH + 3-week ALN),three cycles in total.Greater bone volume fraction and better bone quality were observed after the treatments.Through the combination of animal experiments,cell culture,histology,mechanical testings,and microCT imaging,the bone microstructure changes upon PTH administration were analyzed.Results from this research can further help to understand the PTH-bone mechanism,to provide solid data and theoretical model.This research not only discovered a short anabolic effect after short PTH administration for the first time in the research filed,but proposed three PTH treatment administrations with better efficacy: 1)Cyclic PTH,2)Alternating Cyclic PTH-ALN,3)Alternating Cyclic ALNPTH.The new administrations were proved to be effective to solve one of the biggest obstacles in the clinical practice: PTH withdrawal effects,and it provides theory proof for longterm use of PTH.This research has potential to solve issues for the massive patients with osteoporosis.