PTH(1–34) and zoledronic acid have differing longitudinal effects on juvenile mouse femur strength and morphology

Treatment of secondary pediatric osteoporosis—particularly that due to chronic diseases, immobilization, and necessary medical treatments—is currently limited by a poor understanding of the long‐term efficacy and safety of skeletal metabolism modifying drugs. This study aimed to characterize longitudinal effects of representative anabolic (parathyroid hormone, PTH) and anti‐catabolic (zoledronic acid, ZA) drugs on skeletal morphology, mechanical strength, and growth in juvenile mice. BALB/cJ mice aged 4 weeks were given PTH(1–34) or vehicle (control) daily for 8 weeks, or 4 weekly doses of ZA, and evaluated at time points 0–26 weeks after treatment initiation. There were no enduring differences in body length or mass between treatment groups. ZA increased femur size as early as week 0, including increased distal femur bone volume and diaphyseal cross‐sectional area, persisting through week 26. PTH treatment only transiently increased bone size, including distal femur volume at weeks 4–12. ZA decreased diaphyseal cortical tissue mineral density (TMD) at 12–26 weeks versus controls; PTH decreased TMD only at 2 weeks (vs. controls). ZA increased bending strength at 0–12 weeks and flexural strength at week 4 (vs. controls), but decreased flexural strength and modulus at week 26. PTH treatment increased bending strength only at 4 weeks, and did not affect flexural strength. Overall, ZA rapidly and persistently increased femur strength and size, but compromised bone material quality long‐term. In healthy juvenile mice, limited‐duration PTH treatment did not exert a strong anabolic effect, and had no adverse effects on femur strength, morphology, or growth. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1707–1715, 2017.

     

Improved union and bone strength in a mouse model of NF1 pseudarthrosis treated with recombinant human bone morphogenetic protein‐2 and zoledronic acid

Tibial pseudarthrosis associated with Neurofibromatosis type 1 (NF1) is an orthopedic condition with consistently poor clinical outcomes. Using a murine model that features localized double inactivation of the Nf1 gene in an experimental tibial fracture, we tested the effects of recombinant human bone morphogenetic protein‐2 (rhBMP‐2) and/or the bisphosphonate zoledronic acid (ZA). Tibiae were harvested at 3 weeks for analysis, at which time there was negligible healing in un‐treated control fractures (7% union). In contrast, rhBMP‐2 and rhBMP‐2/ZA groups showed significantly greater union (87% and 93%, p < 0.01 for both). Treatment with rhBMP‐2 led to a 12‐fold increase in callus bone volume and this was further increased in the rhBMP‐2/ZA group. Mechanical testing of the healed rhBMP‐2 and rhBMP‐2/ZA fractures showed that the latter group had significantly higher mechanical strength and was restored to that of the un‐fractured contralateral leg. Co‐treatment with rhBMP‐2/ZA also reduced fibrous tissue infiltration at the fracture site compared to rhBMP alone (p = 0.068). These data support the future clinical investigation of this combination of anabolic and anti‐resorptive agents for the treatment of NF1 pseudarthrosis. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:930–936, 2018.

     

Docetaxel-based chemotherapy with zoledronic acid and prednisone in hormone refractory prostate cancer: Factors predicting response and survival

Objectives:   To evaluate the efficacy of docetaxel/prednisone and zoledronic acid in hormone refractory prostate cancer (HRPC) patients and to analyze prognostic factors predicting overall survival.
Methods:   Forty-four HRPC patients were given docetaxel (75 mg/m²), prednisone and zoledronic acid (4 mg) every three weeks. Overall and progression-free survival curves were calculated. Using the log–rank test, variables predicting overall survival (age, Gleason score, baseline prostate-specific antigen [PSA], percentage PSA decline, nadir PSA, number of chemotherapy cycles) were calculated.
Results:   Median age was 66 years and mean PSA 171.25 ng/mL. The average number of given cycles was 6.3. A good PSA response (>50% decline) was observed in 26/44 cases (59.1%). A total of 17/44 (38.6%) patients expired with a median overall survival of 62.4 weeks. Patients with a Gleason score less than 7, who received more than four cycles and with a more-than-50% decline in PSA had significantly better survival. Variables like age, baseline PSA and nadir PSA did not significantly affect survival.
Conclusion:   The combination of docetaxel/zoledronic/prednisone is safe and effective in the management of HRPC. Patients with a Gleason score <7, PSA decline >50% and those who receive more than four cycles have significantly better survival.     

Chondroprotective effect of high‐dose zoledronic acid: An experimental study in a rabbit model of osteoarthritis

To address the need to impact the subchondral bone‐articular cartilage interaction for the treatment of degenerative osteoarthritis (OA), bisphosphonates may be used as a means to inhibit the subchondral bone resorption. The purpose of the present study is to evaluate the chondroprotective effect of zoledronic acid (ZOL) in a model of OA. Eighteen adult male rabbits underwent an anterior cruciate ligament transection and were separated into two groups: ZOL group (n = 10) received 0.6 mg/kg intravenous injection of ZOL on day 1, 15, and 29 and placebo group (n = 8) received saline. The animals were euthanized at 8 weeks. Macroscopically, the ZOL group had significantly milder ulcerations, cartilage softening and fibrillation compared to the placebo group. Microscopically, morphology of the articular cartilage was better in the ZOL treated group compared with the placebo group, without complete disorganization in any section of the ZOL group. Furthermore, the chondrocytes in the ZOL treated group were mainly cloning, indicating cartilage repairing and regeneration process, while in the placebo group hypocellularity predominated. Additionally, subchondral necrosis was evident in some specimens of the placebo group. Zoledronic acid, in a high‐dose regimen, proved to be chondroprotective in a well‐established animal model of OA. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:1646–1651, 2014.     

Effects of combined teriparatide and zoledronic acid on posterior lumbar vertebral fusion in an aged ovariectomized rat model of osteopenia

There has been no study regarding the effect of a combination of teriparatide (TPTD) and zoledronic acid (ZA) on vertebral fusion. In this study, we investigate the effect of single and combined TPTD and ZA treatment on lumbar vertebral fusion in aged ovariectomized (OVX) rats. Sixty two‐month‐old female Sprague‐Dawley rats were ovariectomized and underwent bilateral L4–L5 posterolateral intertransverse fusion after 10 months. The OVX rats received vehicle (control) treatment, or ZA (100 µg/kg, once), or TPTD (60 µg/kg/2 d for 42 d), or ZA + TPTD until they were euthanized at 6 weeks following lumbar vertebral fusion. The lumbar spine was harvested. Bone mineral density (BMD), bone fusion, bone volume (BV), and bone formation rate (BFR)were analyzed by dual‐energy X‐ray absorptiometry (DXA), radiography, micro‐computed tomography, and histomorphometry. Compared with vehicle (control) treatment, ZA and TPTD monotherapy increased bone volume (BV) at fusion site, and ZA + TPTD combined therapy had an additive effect. Treatment with TPTD and ZA + TPTD increased the bone fusion rate when compared with the control group. ZA monotherapy did not alter the rate of bone fusion. The TPTD and ZA + TPTD treatment groups had increased mineral apposition rate (MAR), mineralizing surfaces/bone surface ((MS/BS), and BFR/BS compared with the OVX group. Our experiment confirm that the monotherapy with TPTD and combination therapy with ZA + TPTD in an OVX rat model of osteopenia following lumbar vertebral fusion surgery increased bone fusion mass and bone fusion rate, and ZA + TPTD combined therapy had an additive effect on bone fusion mass. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:937–944, 2018.

     

Treatment of osteoporosis with TheraCyte-encapsulated parathyroid cells: a study in a rat model

Introduction The purpose of this study was to evaluate parathyroid function at monthly intervals following the implantation of TheraCyte-encapsulated live human parathyroid cells into ovariectomized rats and to determine the effect on bone mineral density (BMD) 4 months after ovariectomy ( 3 months after implantation). Methods Parathyroid tissues were obtained from patients undergoing surgery for secondary hyperparathyroidism. In total, 21 Sprague-Dawley rats divided randomly into three groups were subjected to one of three treatments: (1) implanted with TheraCyte A-encapsulated 4×10⁶ live parathyroid cells; (2) implanted with TheraCyte B-encapsulated 4×10⁵ live parathyroid cells; (3) a sham operation; the control group. Rats were ovariectomized 1 month prior to the implantation of the TheraCyte. Blood was drawn at the time of implantation and at monthly intervals thereafter for 3 months to check the levels of calcium, phosphorus and intact parathyroid hormone (iPTH). The BMD of the lumbar spine (L1–L5) and of the left femoral bone was measured with dual-energy-X-ray absorptiometry (DEXA) 1 month after ovariectomy and 3 months after implantation of the TheraCyte (4 months after ovariectomy). Results We found that the viability ratio of cryopreserved tissues was between 55 and 79% after thawing. In the control group, the BMD of the lumbar spine (L1–L5) had not decreased significantly (p=0.237) nor had the BMD of the left femoral bone increased significantly (p=0.063) 3 months after implantation. In the TheraCyte A group, the BMD of both the lumbar spine (p=0.018) and left femoral bone (p=0.018) had increased significantly 3 months after implantation. In the TheraCyte B group, the BMD of both the lumbar spine (p=0.017) and the left femoral bone (p=0.025) had also increased significantly 3 months after implantation. Serum iPTH levels were higher in the TheraCyte A group than in the TheraCyte B group (p=0.006), and higher in the TheraCyte B group than in the control group (p=0.040). Serum calcium levels were not significantly higher in the TheraCyte group A than in the TheraCyte B group or in the control group. Serum phosphorus levels were not significantly different between the TheraCyte A and TheraCyte B groups. Conclusions Implantation of TheraCyte A-encapsulated 4×10⁵ live parathyroid cells and TheraCyte B-encapsulated 4×10⁶ cells can increase the BMD of ovariectomized rats within 3 months of implantation. Neither cause high serum calcium and low phosphorus concentrations.     

Long‐Term Protective Effects of Zoledronic Acid on Cancellous and Cortical Bone in the Ovariectomized Rat

Current bisphosphonate therapies effectively prevent bone loss in postmenopausal women. We studied the effect of a single intravenous dose of ZOL in ovariectomized rats. Protection from bone loss was dose dependent, lasting for up to 32 weeks, supporting the rationale for an annual intravenous dosing regimen of ZOL for treatment of postmenopausal osteoporosis. Introduction : Once‐yearly dosing with zoledronic acid (ZOL) 5 mg can increase BMD and reduce fracture rate in postmenopausal women with low BMD. The primary objective of this study was to determine the duration of bone protective effects of a single dose of ZOL in ovariectomized rats, an animal model of postmenopausal osteopenia. Secondary objectives were to determine the effects on bone turnover and mechanical properties. Materials and Methods : Female Wistar rats (10 per group) received single intravenous doses of ZOL 0.8, 4, 20, 100, or 500 μg/kg, alendronate 200 μg/kg, or isotonic saline 4 days before bilateral ovariectomy. Sham‐operated controls were pretreated with saline. Mass and density of cancellous and cortical bone (pQCT) were measured at 4‐wk intervals for 32 wk. Bone architecture (μCT), bone formation dynamics (fluorochrome label‐based histomorphometry), and biomechanical strength in compression testing were also assessed at 32 wk. Results : Ovariectomy‐associated BMD loss was significantly attenuated for 32 wk by ZOL ≥4 μg/kg for total BMD, ZOL ≥20 μg/kg for cortical BMD, and ZOL ≥4 μg/kg for cancellous BMD (p < 0.01 versus ovariectomized controls). Alendronate 200 μg/kg was of equivalent potency to ZOL 20 μg/kg. Ovariectomy‐associated decreases in trabecular architectural parameters were dose‐dependently attenuated by ZOL. Alendronate 200 μg/kg was equivalent to ZOL 20 μg/kg. The bone resorption marker TRACP5b indicated transient suppression of elevated osteoclast activity by ZOL relative to OVX‐rats even at the lowest dose of 0.8 μg/kg, whereas at 100–500 μg/kg, the effect was significant relative to the OVX control for the entire duration of the study of 32 wk. Bone formation parameters were not significantly affected by ZOL 20 μg/kg but were significantly reduced by ZOL 100–500 μg/kg. Alendronate 200 μg/kg was equivalent to ZOL 100 μg/kg. ZOL produced dose‐related improvements in bone strength parameters after ovariectomy. Alendronate 200 μg/kg was of similar potency to ZOL 20 μg/kg. Conclusions : The duration and magnitude of the bone‐protecting effect of a single intravenous dose of ZOL in ovariectomized rats is dose dependent and lasts for up to 32 wk. Compared with alendronate, ZOL shows 10‐fold higher potency in preventing bone loss. These data support the use of an annual intravenous ZOL dosing regimen for the treatment of osteoporosis.     

甲状旁腺激素（1-34）与唑来膦酸联合治疗对骨质疏松大鼠骨折愈合的影响

目的探讨唑来膦酸(ZA)与甲状旁腺激素(PTH)的联合应用对去势大鼠骨折愈合的影响。方法对双侧卵巢摘除术12周后的大鼠行单侧胫骨水平骨切开术,并以髓内钉进行固定。所有大鼠在行骨折造模术后,随机接受赋形剂、ZA、PTH与ZA+PTH治疗。在治疗4或8周后,收集胫骨标本进行micro-CT、组织学及生物力学测试。结果与对照组相比,所有药物干预方法都促进了骨痂形成、增加了骨痂强度;ZA+PTH组在相对骨体积(BV/TV)、骨小梁粗度和生物力学上表现出了最强的促进作用。结论 ZA与PTH联合应用对去势大鼠的骨折愈合有累加作用。     

Effects of single and concurrent intermittent administration of human parathyroid hormone and bisphosphonate cimadronate on bone mineral densities of femur in ovariectomized rats

This study compared the single administration of human parathyroid hormone [hPTH(1-34)] or bisphosphonate cimadronate (YM-175), and concurrent therapy with both of these agents for restoration of lost bone mineral density (BMD) in ovariectomized (OVX) rats. Animals were untreated for 4 weeks after surgery, and then injected s.c. with vehicle (OVX+V), hPTH(l-34) (30g/kg) (OVX+P), YM-175 (5g/kg) (OVX+Y), or a combination of these two (OVX+P+Y), 3 days a week, for 8 weeks, and killed. BMD of distal, middle, and total femur were determined by dual-energy X-ray absorptiometry (DXA). BMD of distal and total femur, but not of midfemur, decreased at both 4 weeks and 12 weeks after ovariectomy. In the distal femoral BMD, although OVX+Y failed to restore lost BMD in OVX rats, either OVX+P or OVX+P+Y could reverse BMD lost due to OVX. Midfemoral BMD was unchanged through OVX or both single treatments, whereas this parameter was increased only in OVX+P+Y. These results suggest that concurrent treatment with PTH and YM-175 results in a bone anabolic effect not only in cancellous bone but also in cortical bone.     

间歇皮下注射人甲状旁腺激素不同片段(hFTH1-34及 hFTH1-84)对去卵巢大鼠股骨及腰椎骨量的影响

目的 比较间歇皮下注射人甲状旁腺激素不同片段（hPTH1-34)及（hPTH1-84)对完整雌性（Non-OVX)大鼠和去卵巢（OVX）大鼠股骨及腰椎1－4骨矿物含量（BMC）和骨密度（BMD）的影响。方法 Wistar雌性大鼠176只，分为hPTH1-34和hPTH1-84两大组（各80只及96只），每大组及各自分4组（每组各20只或24只），分别为：两组安慰剂组（未切卵巢及切卵巢）用安慰剂（PBS）进行皮下注射，每周3次，共2周；两组治疗组（未切卵巢及切卵巢）用hPTH1-34或hPTH1-84，皮下注射，每周3次，共2周。结果 1．卵巢切除术后3个月大鼠股骨及腰椎1－4BMC和BMD明显下降；2．两种片段的甲状旁腺激素（hPTH1-34及pPTH1-84)间歇注射均能使Non-OVX大鼠和OVX大鼠股骨及腰椎1－4BMC和BMD较相应对照组明显升高；且腰椎1－4较股骨的BMC和BMD升高更明显；3．OVX大鼠治疗后股骨与腰椎1－4BMC和BMD的升高率较Non-OVX大鼠更明显；OVX大鼠在治疗后股骨及腰椎骨量能恢复到去卵巢前水平；4．hPTH1-34较hPTH1-84更明显的使完整大鼠和OVX大鼠股骨BMC和BMD升高。结论 间歇皮下注射人甲状旁腺激素对大鼠股骨及腰椎骨量均有增高作用，尤其对腰椎的骨量以及对去卵巢大鼠骨量升高作用更明显；hPTH1-34片段对大鼠股骨骨量的增高作用强于hPTH1-84片段。     

Efficacy and safety of a once‐yearly i.v. Infusion of zoledronic acid 5 mg versus a once‐weekly 70‐mg oral alendronate in the treatment of male osteoporosis: A randomized,multicenter, double‐blind,active‐controlled study

Zoledronic acid (ZOL) has shown beneficial effects on bone turnover and bone mineral density (BMD) in postmenopausal osteoporosis. This study compared the efficacy and safety of a once‐yearly i.v. infusion of ZOL with weekly oral alendronate (ALN) in men with osteoporosis. In this multicenter, double‐blind, active‐controlled, parallel‐group study, participants (n = 302) were randomized to receive either once‐yearly ZOL 5 mg i.v. or weekly oral ALN 70 mg for 24 months. Changes in BMD and bone marker levels were assessed. ZOL increased BMD at the lumbar spine, total hip, femoral neck, and trochanter and was not inferior to ALN at 24 months [least squares mean estimates of the percentage increases in lumbar spine BMD of 6.1% and 6.2%; difference approximately 0.13; 95% confidence interval (CI) 1.12–0.85 in the ZOL and ALN groups, respectively]. At month 12, the median change from baseline of markers for bone resorption [serum β‐C‐terminal telopeptide of type I collagen (β‐CTx) and urine N‐terminal telopeptide of type I collagen (NTx)] and formation [serum N‐terminal propeptide of type I collagen (P1NP) and serum bone‐specific alkaline phosphatase (BSAP)] were comparable between ZOL and ALN groups. Most men preferred i.v. ZOL over oral ALN. The incidence of adverse events and serious adverse events was similar in the treatment groups. It is concluded that a once‐yearly i.v. infusion of ZOL 5 mg increased bone density and decreased bone turnover markers similarly to once‐weekly oral ALN 70 mg in men with low bone density. © 2010 American Society for Bone and Mineral Research.     

生理浓度钙透析液对伴低甲状旁腺素水平血液透析患者矿物质及骨代谢的影响

目的观察生理浓度钙透析液对伴低甲状旁腺素水平血液透析患者矿物质及骨代谢的影响。方法将48例血清iPTH(65～150pg/ml)伴校正钙水平≥2.37mmol/L患者按使用透析液钙浓度不同随机分为:透析液钙浓度1.50mmol/L(DCa-1.50)与1.25mmol/L(DCa-1.25)两组;两组内按是否口服骨化三醇随机分为两亚组:口服骨化三醇(+Calcitriol)与非口服骨化三醇(-Calcitriol)组;治疗6个月。每3个月检测透前血清Ca,P,iPTH,ALP及BGP指标。结果观察结束时,DCa-1.5-Calcitriol,DCa-1.25+Calcitriol及DCa-1.25-Calcitriol组血清iPTH及BGP水平升高(P<0.05);DCa-1.25+Calcitriol及DCa-1.25-Calcitriol组血清Ca水平降低(P<0.05),Ca×P水平降低(P<0.05);DCa-1.5+Calcitriol组血清较同期DCa-1.25-Calcitriol组水平Ca水平增高(P<0.05);透前血清iPTH与BGP水平呈正相关(r=0.181,P<0.05)。结论生理浓度钙透析液能够减轻高钙负荷,持续有效刺激甲状旁腺素分泌及改善受抑制的骨代谢。联合骨化三醇及定期监测上述指标,可以安全有效的维持甲状旁腺素在适当水平不引发骨质疏松。     

重组人甲状旁腺激素（1-34）和依降钙素治疗原发性骨质疏松症的随机对照研究

目的评价重组人甲状旁腺激素(1-34)[rhPTH(1-34)]治疗原发性骨质疏松症(OP)的疗效和安全性,并与依降钙素进行对比。方法 60例原发性OP患者按3:1被随机分入rhPTH(1-34)组(PTH组)和依降钙素组(CT组)。PTH组予rhPTH(1-34)20μg每日1次皮下注射,连续用药18月。CT组予益钙宁20U每周1次肌肉注射,连续用药12月。受试前检测腰2-4椎体(L2-4)和股骨颈骨密度(BMD)、血钙、血磷、尿钙、血清骨特异性碱性磷酸酶(BSAP)、尿Ⅰ型胶原交基C端肽(CTX-I),治疗后6、12、18月复查上述指标。结果与基线时比较,PTH组L2-4BMD在治疗6、12、18月时显著升高,股骨颈BMD在18月时显著升高,BSAP在6、12月时均显著升高,CTX-I校正值在6、12、18月时均显著升高;CT组L2-4BMD在治疗12月前升高,股骨颈BMD在12、18月时升高,BSAP12、18月时均显著下降,CTX-I校正值治疗前后无统计学差异。两组比较,PTH组患者在6、12月和18月时L2-4的BMD增长值和增长率均高于CT组。但CT组在治疗12月时股骨颈BMD增长值高于PTH组,不良反应:两组差异无统计学意义;PTH组有一过性高钙血症。结论 rhPTH(1-34)治疗原发性OP安全有效,对改善椎体BMD起效时间、增长速度和增长幅度均优于依降钙素,但改善股骨颈BMD较依降钙素起效更慢,增长幅度更小。     

Effects of a short course of oral phosphate treatment on serum parathyroid hormone (1–84) and biochemical markers of bone turnover: A dose-response study

Summary To investigate the possible use of oral phosphate as an activator of bone remodeling in coherence treatment of osteoporosis, 82 postmenopausal females, aged 50–75 years, were randomized to treatment with oral phosphate (750, 1500, or 2550 mg/day) or placebo for 7 days and followed for 4 months thereafter. All patients had sustained at least one previous fracture of the distal forearm and had a bone mineral content of the contralateral forearm or bone mineral density of the lumbar spine lower than normal mean for age. Urinary phosphate/creatinine ratio increased in a dose-dependent fashion during treatment (P<0.001), whereas no significant changes were seen in serum phosphate or serum calcium. Serum parathyroid hormone (PTH) rose significantly (P<0.05) during treatment to a maximum of 36 and 33% in the groups receiving 1500 and 2250 mg/day, respectively, whereas serum 1,25-dihydroxycholecalciferol remained unchanged. In the group receiving 1500 mg/day, mean serum osteocalcin was increased in the period from day 1 to day 28 (P<0.05), but no significant changes were observed in urinary hydroxyproline/creatinine ratio, or serum bone alkaline phosphatase. We conclude that a short course of oral phosphate treatment increases serum PTH considerably. Furthermore, 1500 mg/day but not 2250 mg/day increases serum osteocalcin. No clear biochemical evidence, however, of increased activation of bone remodeling could be demonstrated in either group.     

Evidence for a stimulatory role of high doses of recombinant human follicle‐stimulating hormone in the treatment of male‐factor infertility

The efficacy of recombinant human follicle‐stimulating hormone (rhFSH) in the treatment of normogonadotropic patients with male‐factor infertility was assessed. Forty‐five infertile men with moderate/severe oligoasthenozoospermia and normal FSH, luteinizing hormone (LH) and testosterone (T) levels were treated with high rhFSH dose (300 IU) on alternate days for ≥4 months. In all, the seminal parameters, endocrine profile (FSH, LH, prolactin (PRL), total and free T and estradiol) and pregnancy rate were evaluated before, during and after rhFSH treatment. Fifteen infertile men were treated with placebo and studied in the same way, as control group. rhFSH treatment induced a marked increase in sperm count and no change in sperm motility, morphology and viability. No changes in seminal parameters were observed in the placebo group. FSH levels increased during treatment with rhFSH and not with placebo. No variations in LH, PRL, free and total T and estradiol were evidenced during treatment. A significant pregnancy rate in rhFSH versus placebo patients was also highlighted. Prolonged treatment with high rhFSH doses leads to increase sperm count and improve the spontaneous pregnancy rate in normogonadotropic infertile patients with oligoasthenozoospermia. rhFSH may represent a rational and useful tool in the treatment of male‐factor infertility.     

Effects of ivermectin and its combination with alpha lipoic acid on expression of IGFBP‐3 and HSPA1 genes and male rat fertility

This study was conducted to evaluate the effects of ivermectin (IVM) with therapeutic dose (injected with 0.56 mg/kg b.wt.) either alone or combined with alpha lipoic acid (ALA) (50 mg/kg b.wt daily) on expression of testicular insulin‐like growth factor binding protein‐3 (IGFBP‐3) and heat‐shock protein A1 (HSPA1)) genes in the testes, as well as on male rat fertility parameters. Results revealed that expression levels of IGFBP‐3 and HSPA1 were significantly increased in testis of the IVM‐treated group relative to the control group. Furthermore, injection of ivermectin showed a significant decrease in serum testosterone level, sperm count, motility %, live sperm% and index weight of reproductive organs, and a significant increase in sperm abnormalities. Moreover, IVM induced oxidative stress and pathological alterations in the testes. Meanwhile, the administration of ALA with IVM prevented testicular damage and improved all previous parameters. We concluded that ivermectin has undesirable effects on male fertility and altered expression of IGFBP‐3 and HSPA1 genes in the testes, while the administration of alpha lipoic acid can ameliorate the adverse effects of ivermectin.