Synthesis and Biological Evaluations of Novel Human Parathyroid Hormone 1 Receptor (hPTHR1) Agonists Bearing Bicyclic Aromatic Moiety.

We have previously shown that the small molecule hPTHR1 agonist PCO371 (1) orally and dose-dependently induces PTH-like calcemic and hypophostemic activity in thyroparathyroidectomized rats. Compound 2a, bearing a bicyclic aromatic ring, was identified as a novel hPTHR1 agonist during hit to lead modification. It showed moderate PTHR1 agonistic activity with an EC20 value of 15 µM, and its metabolic stability in human liver microsome (hLM) as well as its solubility in phosphate buffer (PPb) and Fasted state simulated intestinal fluid (FaSSIF) were found to be poor. As results of the initial derivatization of 2a, we identified the indole derivatives as another scaffold. In this article, we report on the structure-activity relationship (SAR), structure-metabolism relationship (SMR), and structure-solubility relationship (SSR) of bicyclic aromatic derivatives, and the in vivo efficacy of 2j.

Optimization of PTH/PTHrP Hybrid Peptides to Derive a Long-Acting PTH Analog (LA-PTH).

Prolonged signaling at the parathyroid hormone receptor 1 (PTHR1) correlates with the capacity of a ligand to bind to a G protein-independent receptor conformation (R0). As long-acting PTH (LA-PTH) ligands hold interest as potential treatments for hypoparathyroidism (HP), we explored the structural basis in the ligand for stable R0 binding and prolonged cAMP signaling. A series of PTH/PTHrP hybrid analogs were synthesized and tested for actions in vitro and in vivo. Of the series, [Ala1,3,12,Gln10,Arg11,Trp14]-PTH(1-14)/PTHrP(15-36) (M-PTH/PTHrP) bound with high affinity to R0, induced prolonged cAMP responses in UMR106 rat osteoblast-derived cells, and induced the most prolonged increases in serum calcium (sCa) in normal rats. Daily s.c. injection of M-PTH/PTHrP into thyroparathyroidectomized (TPTX) rats, a model of HP, normalized sCa without raising urine Ca. In contrast, oral alfacalcidol, a widely used treatment for HP, normalized sCa, but induced frank hypercalciuria. M-PTH/PTHrP exhibited low solubility in aqueous solutions of neutral pH; however, replacement of Leu18, Phe22, and His26 with the less hydrophobic residues, Ala, Ala, and Lys, at those respective positions markedly improved solubility while maintaining bioactivity. Indeed, we recently showed that the resultant analog [Ala18,22,Lys26]-M-PTH/PTHrP or LA-PTH, effectively normalizes sCa in TPTX rats and mediates prolonged actions in monkeys. These studies provide useful information for optimizing PTH and PTHrP ligand analogs for therapeutic development. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Lead Optimization and Avoidance of Reactive Metabolite Leading to PCO371, a Potent, Selective, and Orally Available Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist.

We have previously shown that the oral administration of the small molecule hPTHR1 agonist PCO371 and its lead compound, 1 (CH5447240) results in PTH-like calcemic and hypophostemic activity in thyroparathyroidectomized rats. However, 1 was converted to a reactive metabolite in a human liver microsome assay. In this article, we report on the modification path that led to an enhancement of PTHR1 agonistic activity and reduction in the formation of a reactive metabolite to result in a potent, selective, and orally active PTHR1 agonist 1-(3,5-dimethyl-4-(2-((4-oxo-2-(4-(trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)sulfonyl)ethyl)phenyl)-5,5-dimethylimidazolidine-2,4-dione (PCO371, 16c). This compound is currently being evaluated in a phase 1 clinical study for the treatment of hypoparathyroidism.

Development of a Novel Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist (CH5447240), a Potent and Orally Available Small Molecule for Treatment of Hypoparathyroidism.

During the course of derivatization of HTS hit 4a, we have identified a novel small-molecule hPTHR1 agonist, 1-(3,5-dimethyl-4-(2-((2-((1 R,4 R)-4-methylcyclohexyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)sulfonyl)ethyl)phenyl)-1-methylurea (CH5447240, 14l). Compound 14l exhibited a potent in vitro hPTHR1 agonist effect with EC20 of 3.0 µM and EC50 of 12 µM and showed excellent physicochemical properties, such as high solubility in fasted state simulated intestinal fluid and good metabolic stability in human liver microsomes. Importantly, 14l showed 55% oral bioavailability and a significantly elevated serum calcium level in hypocalcemic model rats.

Identification of an orally active small-molecule PTHR1 agonist for the treatment of hypoparathyroidism.

Parathyroid hormone (PTH) is essential for calcium homeostasis and its action is mediated by the PTH type 1 receptor (PTHR1), a class B G-protein-coupled receptor. Hypoparathyroidism and osteoporosis can be treated with PTH injections; however, no orally effective PTH analogue is available. Here we show that PCO371 is a novel, orally active small molecule that acts as a full agonist of PTHR1. PCO371 does not affect the PTH type 2 receptor (PTHR2), and analysis using PTHR1-PTHR2 chimeric receptors indicated that Proline 415 of PTHR1 is critical for PCO371-mediated PTHR1 activation. Oral administration of PCO371 to osteopenic rats provokes a significant increase in bone turnover with limited increase in bone mass. In hypocalcemic rats, PCO371 restores serum calcium levels without increasing urinary calcium, and with stronger and longer-lasting effects than PTH injections. These results strongly suggest that PCO371 can provide a new treatment option for PTH-related disorders, including hypoparathyroidism.

Novel hyaluronic acid-methotrexate conjugate suppresses joint inflammation in the rat knee: efficacy and safety evaluation in two rat arthritis models.

BACKGROUND: Methotrexate (MTX) is one of the most widely used medications to treat rheumatoid arthritis (RA), and recent studies have also suggested the potential benefit of the drug for the treatment of osteoarthritis (OA) of the knee. MTX is commonly administered in oral formulations, but is often associated with systemic adverse reactions. In an attempt to address this issue, we have shown previously that a conjugate of hyaluronic acid (HA) and MTX exhibits potential as a drug candidate for intra-articular treatment of inflammatory arthritis. In this study, we compare the efficacy and safety of an optimized HA-MTX conjugate, DK226, with that of MTX in inflammatory arthritis rat models. METHODS: In vitro activity of DK226 was assessed in human fibroblast-like synoviocytes (HFLS) and a synovial sarcoma cell line, SW982. Release of MTX from DK226 was investigated after incubation with rabbit synovial tissue homogenate or synovial fluid. In vivo efficacy of DK226 was evaluated in antigen-induced arthritis (AIA) and collagen-induced arthritis (CIA) in the rat knee. Pharmacokinetics and hematological toxicity after treatment with oral MTX or an intra-articular injection of DK226 were compared in AIA. RESULTS: Proliferation of HFLS and SW982 cells was inhibited by DK226, and the inhibitory activity was reversed by cotreatment with excess HA or anti-CD44 antibody. MTX was released from DK226 by incubation with rabbit synovial tissue homogenate or synovial fluid at pH 4.0, but not at pH 7.4. AIA was ameliorated by intra-articular DK226, but not by HA, as potently as oral MTX. Hematological toxicity was induced by oral MTX, but not by DK226. The maximum plasma concentration of MTX after oral MTX was 40 times higher than the concentration of MTX after an intra-articular injection of DK226. Knee swelling in AIA was inhibited by intra-articular injections of DK226, but not by free MTX or a mixture of HA and MTX. In CIA, an injection of DK226 into the right knee joint significantly reduced swelling and synovial inflammation of the treated knee joint, but had no effect on the untreated contralateral knee joint. CONCLUSIONS: DK226 exerted anti-arthritic effects in two different models of arthritis. The conjugate had a wider therapeutic window than oral MTX, and could be a future drug for treatment of arthritic disorders, including inflammatory OA.

Pharmacodynamic Actions of a Long-Acting PTH Analog (LA-PTH) in Thyroparathyroidectomized (TPTX) Rats and Normal Monkeys.

Hypoparathyroidism is a disease of chronic hypocalcemia and hyperphosphatemia due to a deficiency of parathyroid hormone (PTH). PTH and analogs of the hormone are of interest as potential therapies. Accordingly, we examined the pharmacological properties of a long-acting PTH analog, [Ala(1,3,12,18,22) , Gln(10) ,Arg(11) ,Trp(14) ,Lys(26) ]-PTH(1-14)/PTHrP(15-36) (LA-PTH) in thyroparathyroidectomized (TPTX) rats, a model of HP, as well as in normal monkeys. In TPTX rats, a single intravenous administration of LA-PTH at a dose of 0.9 nmol/kg increased serum calcium (sCa) and decreased serum phosphate (sPi) to near-normal levels for longer than 48 hours, whereas PTH(1-34) and PTH(1-84), each injected at a dose 80-fold higher than that used for LA-PTH, increased sCa and decreased sPi only modestly and transiently (<6 hours). LA-PTH also exhibited enhanced and prolonged efficacy versus PTH(1-34) and PTH(1-84) for elevating sCa when administered subcutaneously (s.c.) into monkeys. Daily s.c. administration of LA-PTH (1.8 nmol/kg) into TPTX rats for 28 days elevated sCa to near normal levels without causing hypercalciuria or increasing bone resorption markers, a desirable goal in the treatment of hypoparathyroidism. The results are supportive of further study of long-acting PTH analogs as potential therapies for patients with hypoparathyroidism. © 2016 American Society for Bone and Mineral Research.

The Optimal Duration of PTH(1-34) Infusion Is One Hour per Day to Increase Bone Mass in Rats.

Parathyroid hormone (PTH) is a potential medicine for osteoporosis, and subcutaneous (s.c.) PTH treatment enhances bone mass; however, continuous infusion of PTH elicits bone resorption and induces bone loss. To clarify this contradictory phenomenon, we examined bone markers and bone mass in rats to assess the optimal duration of PTH(1-34) infusion. Continuous infusion of PTH at 1 µg/kg/h (Css, steady-state concentration ca. 300 pg/mL) for 1-4 h clearly stimulated the expression both of bone formation-related genes (c-fos, Wnt4, EphrinB2) and of bone resorption-related genes (tnfsf11, tnfsf11b, encoding receptor activator of nuclear factor-kappaB ligand (RANKL), osteoprotegerin (OPG)), but s.c. treatment stimulated these genes only 1-h after the injection. Rats were treated with 1-, 2-, or 4-h infusions of PTH daily using a totally implanted catheter system, and the femoral bone mineral density (BMD) was measured at 4 weeks. The 1-h infusion of PTH significantly stimulated serum bone formation markers (procollagen I N-terminal propeptide (PINP) and osteocalcin) on day 14 and femoral BMD at 2 and 4 weeks, but the 4-h infusion of PTH did not enhance BMD. Since the 4-h infusion increased the levels of both the bone formation markers and a bone resorption marker (urinary C-terminal telopeptide of type 1 collagen (CTx)), the increased bone resorption may predominate over bone formation. The intermittent elevation of plasma PTH to 300 pg/mL for 1-h each day is optimal for increasing bone mass in rats. In osteoporosis therapy in human, using the optimal duration for the clinical dose of PTH may selectively stimulate bone formation.

Long-term treatment with eldecalcitol (1α, 25-dihydroxy-2ß- (3-hydroxypropyloxy) vitamin D3) suppresses bone turnover and leads to prevention of bone loss and bone fragility in ovariectomized rats.

The purpose of this study is to estimate the efficacy of eldecalcitol (1α, 25-Dihydroxy-2ß- (3-hydroxypropyloxy) vitamin D3; ELD) on bone metabolism after long-term administration. Six-month-old Wistar-Imamichi rats were ovariectomized (OVX) and administered ELD orally at doses of 7.5, 15, or 30 ng/kg daily. Bone mineral density (BMD), urinary excretion of deoxypyridinoline (DPD), a bone resorption marker, and serum total alkaline phosphatase (ALP), a surrogate marker of bone formation, were assessed after 3, 6, and 12 months of treatment. After 12 months of treatment, the biomechanical strength of the L4 lumbar vertebra and femoral shaft was measured, and bone histomorphometry was performed on the L3 lumbar vertebra and the tibia diaphysis. ELD prevented OVX-induced decreases in BMD of the lumbar vertebrae and femur throughout the treatment period. ELD significantly suppressed OVX-induced increases in urinary DPD excretion throughout the treatment period with minimal effects on ALP. OVX resulted in significant decreases in ultimate load and stiffness of the L4 lumbar vertebra and femoral shaft, and ELD significantly prevented the reduction in these biomechanical parameters. Bone histomorphometry at the L3 lumbar vertebra revealed that OVX induced increases in bone resorption parameters (osteoclast surface and osteoclast number) and bone formation parameters (osteoblast surface, osteoid surface, and bone formation rate), and ELD suppressed these parameters after 12 months treatment. Activation frequency, which was elevated in the OVX/vehicle group, was significantly suppressed to baseline levels in ELD-treated groups, indicating that ELD maintained bone turnover at a normal level. ELD also prevented OVX-induced deterioration of microstructure in trabecular and cortical bone. These results indicated that long-term treatment of OVX rats with ELD suppressed bone turnover, and prevented OVX-induced bone loss, deterioration of bone microstructure, and reduction in bone biomechanical strength.

MRI changes of the spinal subdural space after lumbar spine surgeries: report of two cases.

Although magnetic resonance imaging (MRI) is frequently used to assess the lumbar spine, there are few reports in the medical literature that have evaluated using MRI immediately following spinal surgery. Furthermore, descriptions of the subdural changes after lumbar spine surgery are also infrequent. In this paper, we present two cases with subdural change seen on MRI immediately after lumbar surgery. Both the patients had mild symptoms that resolved spontaneously, and the follow-up MRI scans showed resolution of the subdural changes. Subdural changes should be considered as one of the possible causes of unexpected symptoms in patients following lumbar spinal surgery.

Osseous erosion by herniated nucleus pulposus mimicking intraspinal tumor: a case report.

Erosion of spinal osseous structure, so-called scalloping, has been rarely reported associated with herniated nucleus pulposus (HNP). We report a rare case of HNP causing erosion of the spinal osseous structure (including lamina). The patient was an 81-year-old woman with 3-year history of low-back pain and left leg radiating pain. Muscle weakness of the left leg was also apparent. Computed tomography following myelography showed severe compression of the dural sac at the level of L3-L4; furthermore, erosion of the lamina, pedicle, and vertebral body was noted, indicating that the space-occupying mass was most probably a tumorous lesion. The mass also showed calcification inside. During the surgery, the mass was confirmed to be an HNP with calcification. Following resection, the pain disappeared. Surgeons should be aware of the possibility of scalloping of the vertebrae caused by HNP mimicking a tumorous lesion.

Synthesis and optimization of hyaluronic acid-methotrexate conjugates to maximize benefit in the treatment of osteoarthritis.

We previously reported that a conjugate of hyaluronic acid (HA) and methotrexate (MTX) could be a prototype for future osteoarthritis drugs having the efficacy of the two clinically validated agents but with a reduced risk of the systemic side effects of MTX by using HA as the drug delivery carrier. To identify a clinical candidate, we attempted optimization of a lead, conjugate 1. Initially, in fragmentation experiments with cathepsins, we optimized the peptide part of HA-MTX conjugates to be simpler and more susceptible to enzymatic cleavage. Then we optimized the peptide, the linker, the molecular weight, and the binding ratio of the MTX of the conjugates to inhibit proliferation of human fibroblast-like synoviocytes in vitro and knee swelling in rat antigen-induced monoarthritis in vivo. Consequently, we found conjugate 30 (DK226) to be a candidate drug for the treatment of osteoarthritis.

Hematoma in the cervical ligamentum flavum. Report of a case and review of the literature.

Hematoma of the cervical ligamentum flavum is very rare, and its pathogenesis is unknown. We describe a case of ligamentum flavum hematoma in the cervical spine causing severe myelopathy. Postoperative histological examination suggested it was the result of the rupture of a hemangioma or of an arteriovenous malformation in the ligamentum flavum. After removal of the lesion, the patient's condition immediately improved. Review of all three reported cases, including this one, showed that complete resection of the mass resulted in immediate relief of symptoms of incomplete paraplegia. The findings of magnetic resonance imaging (MRI) of the hematoma may vary with time, and they may show no characteristic intensity. However, MRI of this case revealed that the tissues surrounding the mass were enhanced with gadolinium diethylene triamine penta-acetic acid, and an area of homogeneous iso-intensity was clearly surrounded by a low-intensity area (flavum) on T2-weighed short-tau inversion recovery images. These findings could be characteristic of the ligamentum flavum hematoma and might help in the differentiation from a cervical epidural hematoma.

Anterior transvertebral herniotomy for cervical disc herniation: a long-term follow-up study.

STUDY DESIGN: Retrospective study. OBJECTIVES: To investigate the efficacy and radiologic changes after anterior transvertebral herniotomy (ATH), in patients followed for at least 10 years after the surgery. SUMMARY OF BACKGROUND DATA: The theoretical idea of ATH is to remove an extruded herniated mass while preserving disc motion. To our knowledge, no report has been published on the long-term outcome of this procedure. METHODS: Twenty patients underwent single-level ATH at our institution between 1989 and 1995. Clinical outcome was evaluated by visual analog scale for neck and arm pain according to Japanese Orthopaedic Association (JOA) score, and range of motion (ROM) of the cervical spine. Radiologic outcome was evaluated by measuring disc height and range of intervertebral motion of the site on plain radiographs. We also evaluated the operated and the adjacent segments by magnetic resonance imaging (MRI) for degenerative changes. RESULTS: Fifteen of the 20 patients were evaluated. One patient required additional surgery, 3 patients were lost to follow-up, and 1 patient had died by the time of the evaluation. Therefore, we evaluated the clinical outcome of 15 patients. Both the plain radiographs and MRI were available from 10 patients, and for 3 patients only the plain radiographs were available. Two patients refused x-ray examination at the final follow-up. Regarding clinical outcome, no patient had suffered from neck pain or arm pain. The average visual analog scale was 7.8/100 (%) for neck pain, and 7.0/100 (%) for arm pain. JOA scores improved and remained at a good level. The improvement rate was 88.5%. The average ROM of the cervical spine was 42.7 degrees in flexion, 52.3 degrees in extension, 58.6 degrees in axial rotation, and 25.0 degrees in lateral bending. Although ROM in axial rotation and lateral bending was symmetric, the range was smaller than that in the healthy segments. On plain radiographs, although the disc height in the operated segment was not significantly decreased compared with the other segments, loss of intervertebral motion was noticed on the follow-up roentgenograms in most cases. Only 2 patients had mobility of the operated intervertebral levels (>10 degrees). There was no collapse of the drilled vertebral body in any patient. Four of the 10 patients who underwent MRI showed protrusion of intervertebral discs, including those adjacent to the affected discs. No recurrence of disk herniation at the involved level was seen on the follow-up MRI. CONCLUSIONS: In conclusion, ATH provided a good clinical outcome that was maintained for a long time. Although intervertebral motion at the operated level decreased to some extent, degenerative changes at the adjacent levels were not enhanced.

Novel hyaluronic acid-methotrexate conjugates for osteoarthritis treatment.

Hyaluronic acid (HA) provides synovial fluid viscoelasticity and has a lubricating effect. Injections of HA preparations into the knee joint are widely used as osteoarthritis therapy. The current HA products reduce pain but do not fully control inflammation. Oral methotrexate (MTX) has anti-inflammatory efficacy but is associated with severe adverse events. Based on the rationale that a conjugation of HA and MTX would combine the efficacy of the two clinically evaluated agents and avoid the risks of MTX alone, we designed HA-MTX conjugates in which the MTX connects with the HA through peptides susceptible to cleavage by lysosomal enzymes. Intra-articular injection of our HA-MTX conjugate (conjugate 4) produced a significant reduction of the knee swelling in antigen-induced arthritis rat, whereas free MTX, HA or a mixture of HA and MTX showed no or marginal effects on the model. The efficacy of conjugate 4 was almost the same as that of MTX oral treatment. Conjugate 4 has potential as a compound for the treatment of osteoarthritis.

Measurements of ligamentum flavum thickening at lumbar spine using MRI.

INTRODUCTION: As the ligamentum flavum (LF) covers most of the posterolateral part of the lumbar spinal canal, its thickening can be attributed to the development of lumbar canal encroachment. Nevertheless, there have been few reports describing the natural history of the LF. METHOD: To investigate the natural history and to subsequently clarify the pathogenesis of LF thickening, we conducted a transverse radiological study of the LF at the lumbar spine using magnetic resonance images. PATIENTS: One hundred and sixty-two patients complaining of low back pain and/or leg pain were evaluated (n = 162; mean age 52.1 years). The thickness of LF was measured at L2-3, L3-4, L4-5 and L5-S levels (n = 648). The relationships among thickness, age, and spinal level were examined. PATIENTS: One hundred and sixty-two patients complaining of low back pain and/or leg pain were evaluated (n = 162; mean age 52.1 years). The thickness of LF was measured at L2-3, L3-4, L4-5 and L5-S levels (n = 648). The relationships among thickness, age, and spinal level were examined. RESULTS: The following results were obtained. (1) LF thickness increased with age; however, the increments at L4-5 and L3-4 were larger than one at L2-3 and L5-S1. (2) At L4-5, LF was over 3.0 mm thick in patients in the 20-29 age bracket, and in many of them it was more than 3.5 mm thick. (3) All patients with a thickened LF at L2-3 (>3.0 mm) had very thick LFs at all spinal levels. (4) In elderly patients, there was no correlation between the thickness of LF and the decrease of the disc height. In this study, we concluded that thickening of LF at L4-5 had already started in patients in the 30-39 age bracket and that thickening of the LF was not the buckling of the LF into the spinal canal with disc degeneration. The thickness of LF at L2-3 may serve as an indicator of lumbar spinal canal stenosis at multiple levels.

Cervical and upper thoracic screwing for spinal fusion: strategy for its safe insertion to avoid major complications.

There are several screwing techniques to attain cervical fusion such as pedicle screw, lateral mass screw, facet screw, transarticular and laminar screw. Each screwing technique has advantages and disadvantages. In this study, we introduce our strategy for safe screwing and its clinical results. Our strategy is as follows: lateral mass screw for C1, 3, 4, 5, 6 and pedicle screw for C2, 7, and thoracic level. When the C2 pedicle is thinner than 3.5 mm, we use C2 laminar screws. We do not use Magerl transarticular screw or facet screw; 146 screws were inserted in 17 patients. There were no major complications such as spinal cord and nerve root injury. We did not observe vertebral arterial injury either. Of the 146 screws, 141 (97.0%) were accurately inserted. As for lateral mass screwing by Roy-Camille's technique and C2 laminar screwing, all screws were inserted in the appropriate site (100%) without any complications. Five pedicle screws were misplaced. Of the 57 pedicle screws, 5 showed a minor tear of the wall at C7, Th1 and Th3, the success rate for all pedicle screws was 91%. All showed solid fusion. For cervical screwing the most important aspect should be safety to avoid severe morbidity. Our strategy, which consists in the combined use of pedicle, lateral mass and laminar screwing, is safe and reliable.

Alendronate inhibits periprosthetic bone loss around uncemented femoral components.

Periprosthetic bone loss can be severe around the femoral component after uncemented arthroplasty. This study investigated the inhibitory effect of alendronate on periprosthetic bone loss. Seventeen patients underwent arthroplasty with an uncemented femoral component. Among them, 8 patients were given alendronate 5 mg once daily for 1 year (ALN group) and 9 patients received no pharmacotherapy (control group). Bone mineral density was measured in six periprosthetic zones by dual-energy X-ray absorptiometry at 1, 6, and 12 months after surgery. The average periprosthetic bone mineral density was 0.674-0.920 g/cm(2) at 1 month after surgery. From 6 months onward, the absolute bone mineral density and the ratio relative to the 1-month value were significantly decreased in the proximal zones of the femur in the control group (the ratio decreased from 0.817 to 0.769; P = 0.0040-0.0353). In the ALN group, however, the absolute and relative bone mineral density of the proximal femur remained unchanged for 12 months. In the other femoral zones, the absolute and relative bone mineral density remained unchanged throughout the study in both groups. We concluded that alendronate significantly inhibited the decrease of periprosthetic bone mineral density in the proximal femur after uncemented arthroplasty.

[Regulation of bone mineralization by parathyroid hormone].

In randomized clinical trials, parathyroid hormone (PTH) showed potent anabolic effects on the lumbar spine and decreased the risk of incident vertebral fractures dramatically. Although the anabolic effect of PTH on cortical bone in the femoral neck is still unclear, it should be demonstrated in further clinical studies. Concurrent or sequential therapies of PTH and anti-resorptive agents will be one of the major issues of treatment for osteoporosis in the future.