TABLE 1.
Literatures about combination PTH and antiresorptive drugs for osteoporosis.
| Journal | Author | Publish year | Bisphosphonate | Trial | Result | PTH dose | Bisphosphonate dose | Main outcome measures | Study duration | Samples |
|---|---|---|---|---|---|---|---|---|---|---|
| Endocrinology Johnston, et al. (2007) | Sara Johnston | 2007 | Alendronate | Twenty-week-old female mice | Positive (bone strength and BMD of lumbar vertebra and femur, cortical thickness), low osteocalcin and TRAP | 40 μg/kg.d 5 d/wk | 20 μg/kg·d 3 d/wk | BMD, bone markers, bone structure, bone strength | 7 weeks | 70 |
| The New England Journal of Medicine Cosman et al. (2005) | Felicia Cosman | 2005 | Alendronate | Women with osteoporosis who had been taking alendronate for at least 1 year | Positive (spine BMD both daily and cyclic PTH). NS (hip BMD); high PINP, osteocalcin, BSAP and UN-TCR. | 25 μg/daily or three months interval | 70 mg alendronate weekly | Bone markers, lumbar spine and hip BMD | 15 months | 126 |
| Bone Delmas, et al. (1995) | P. D. Delmas | 1995 | Tiludronate | Old female sheep | NS (osteocalcin, ALP, urinary pyridinoline and hydroxyproline was not different from control). Decrease bone formation and resorption compared with PTH | 500 IU/d | 1 mg/kg/day | Biochemical and histological indices of bone turnover | 3 months | 28 |
| The New England Journal of Medicine Finkelstein, et al. (2003) | Joel S. Finkelstein | 2003 | Alendronate | Men | BMD of lumbar spine and femoral neck and serum alkaline phosphatase increased more with PTH alone. BMD of lumbar spine (combination > alendronate) | 40 μg/daily | 10 mg/daily | BMD of lumbar spine, femur, radial shaft and total body, serum alkaline phosphatase. | 30 months | 83 |
| The New England journal of medicine Black, et al. (2003) | Dennis M. Black | 2003 | Alendronate | Postmenopausal women (who were not using bisphosphonate) | NS (spine BMD between combination and PTH). Volumetric density of the trabecular bone at the spine and bone formation markers were increased more in PTH. Hip and distal one third radius BMD (more in combination and alendronate). Trabecular hip (PTH > combination > alendronate). Decrease of volumetric density of cortical bone and increase of cortical volume in PTH while both increase in alendronate and combination group. | 100 μg/daily | 10 mg/daily | BMD and quantitative CT of trabecular bone at the spine, femoral neck and hip, bone formation and resorption markers | 12 months | 238 |
| JBMR Deal, et al. (2005) | Chad Deal | 2005 | Raloxifene | Postmenopausal women | PINP and spine BMD were increased similarly between PTH (5.19 ± 0.67) alone and combination (6.19 ± 0.65) therapy. Less increase of CTX and larger increase in total hip BMD in combination therapy. | 20 ug/daily | 60 mg/daily | BMD and biochemical markers of bone turnover and calcium and phosphate | 6 months | 137 |
| J Clin Endocrinol metab Finkelstein, et al. (2010) | Joel S | 2010 | Alendronate | Postmenopausal women | Spine, femoral neck BMD, PINP and CTX were increased more in PTH alone | 40 μg/daily | 10 mg/daily | BMD and bone markers | 30 months | 93 |
| J Clin Endocrinol Metab Cosman, et al. (2009) | Cosman F | 2009 | Alendronate raloxifene | Postmenopausal women with osteoporosis on alendronate or raloxifene for at least 18 months | Alendronate: BTM was smaller increased in add group but more increased in total hip and lumbar spine BMD. Raloxifene: BTM was smaller increased in add group and total hip BMD was more increased at 6 months while no significance in total hip, lumbar spine, and femoral neck at 18 months. | 20 μg/daily | Alendronate 70 mg/w, raloxifene 60 mg/d | Bone turnover markers (PINP, ALP and βCTX) and BMD | 36 months | 198 |
| Bone Li et al. (1995) | Li M | 1995 | Risedronate | Aged ovariectomized rats | PTH induced increase in trabecular width but not number of the lumbar vertebral body, maximum load, and stress. Concurrent treatment with risedronate did not have a greater effect. | 80 μg/kg BW 5 days/week | 5 μg/kg BW SC 2 days/w | Quantitative bone histomorphometry and biomechanical testing of lumbar spine | 10 weeks | 120 |
| JBMR Cosman et al. (2011) | Felicia Cosman | 2011 | Zoledronic acid | Postmenopausal women with osteoporosis | Lumbar spine and total hip BMD were increased more in combination. Combination: PINP increase (0–4 w), decline (4–8 w) then rises. CTX reduce (0–8 w) to a gradual increase. | 20 μg | 5 mg | BMD and bone markers | 1 year | 412 |
| JBMR Samadfam et al. (2007) | Rana Samadfam | 2007 | OPG, alendronate | 4-month-old oophorectomized mice | Co-treatment produce additive increase of BMD in femur and supra-additive increase in the lumbar spine than PTH alone. No impact on the mechanical force in PTH. | 80 μg/kg/day | Alendronate 100 g/kg/week OPG 10 mg/kg twice/week | BMD and bone strength | 2 months | 60 |
| JBMR Cosman, et al. (2013) | Felicia Cosman | 2013 | Alendronate and raloxifene | Postmenopausal women with osteoporosis receiving ALN 70 mg/week (n = 91) or RLX 60 mg/day (n = 77) for ≥18 months | In the alendronate adding group, hip BMD and strength increase more than the switch group while similar increase in spine strength. In the raloxifene adding group, hip BMD and strength increase at 6 and 18 months but only at 18 months in switch group while similar increases in spine BMD and strength. PINP increase more in PTH alone. | 20 μg/day | Alendronate 70 mg/week and RLX 60 mg/day | BMD, bone strength and PINP | At least 18 months | 182 |
| Bone Yamane, et al., 2009) | Hirotoshi Yamane | 2009 | Alendronate | Ovariectomized mice | Alendronate enhanced the anabolic actin of PTH at the primary spongiosa (femur, lumbar BMD, BV/TV, Tb. Th, Tb. N of proximal tibia) but blunt it in the remodeling trabecular bone (secondary spongiosa). Osteocalcin and U-Ctx increase more in PTH. | 40 μg/kg BW | Alendronate subcutaneous 1 mg/kg BW | BMD, bone volume and bone turnover markers | 14 weeks | 105 |
| Bone Campbell, et al. (2011) | Graeme M. Campbell | 2011 | Alendronate | Female retired breeder wistar rats aged 7–9 months. | Combined treatment resulted in more pronounced improvements of the bone architecture than PTH monotherapy (cortical, BV/TV, trabecular thickness, connectivity and stiffness of proximal tibia) | 40 μg/kg 5 days/week | 15 μg/kg | BMD, synchrotron radiation micro-CT scans in vivo and bone strength | 14 weeks | 40 |
| Bone Altman, et al. (2014) | Allison R. Altman | 2014 | Alendronate | 3-month-old, female, sprague–dawley rats | PTH + ALN treatment had an additive effect (greatest increase in BV/TV and stiffness of tibial trabecular bone), more plate-like not rod-like structure. Bone formation↑Bone resorption↓ PTH + ALN = PTH (Tb.Th) | 60 μg/kg/day | 50 μg/kg | Bone microarchitecture, bone strength and static and dynamic bone histomorphometry | 12 days | 30 |
| The journal of biological chemistry Pierroz, et al. (2010) | Dominique D. Pierroz | 2010 | Alendronate and denosumab | Female huRANKL mice, male RANK/mice, and their respective wild-type (WT) littermates | ALN-PTH + ALN > ALN-ALN but not for denosumab (BMD change of total body, lumbar spine and femoral shaft. BV/TV, Tb. Th of vertebral and distal femur trabecular bone. Cortical width) increase of osteocalcin and TRACP5b in PTH + ALN compared with continuing ALN. Osteoclasts are not strictly required for PTH anabolism, which presumably still occurs via stimulation of modeling-based bone formation | 80 μg/kg/d | ALN 100 μg/kg 2 times/week denosumab 10 mg/kg 2 times/week | BMD, bone microarchitecture, bone turnover markers | 8 weeks | 6-8 per groups |
| Bone Vegger, et al. (2014) | Jens Bay Vegger | 2014 | Zoledronate | 16-week-old female wistar rats | Positive: PTH + ALN (high femoral BV/TV and high Fmax at the distal femur, less Tb.SP ) PTH > PTH + ALN (BFR/BS). | 80 μg/kg | 100 μg/kg | BMD, bone microarchitecture, dynamic bone histomorphometry and mechanical testing | 4 weeks | 72 |
| JBMR Cosman, et al. (1998) | Felicia Cosman | 1998 | Alendronate | Postmenopausal women with osteoporosis already on alendronate 10 mg/day | ALN-PTH + ALN (markers of bone formation increased within 3 weeks in the PTH plus alendronate group, with mean peak levels at 5–7 weeks: OC, PICP, and BSAP. Levels returned to baseline after discontinuing PTH, with PICP declining the most rapidly.) | 400 IU/day | 10 mg/day | Bone turnover markers | 11 weeks | 10 |
| Calcif tissue int Arrington, et al. (2010) | Sarah A. Arrington | 2010 | Zoledronic acid | Female nude mice injected with human breast cancer cells | Supplemental use of PTH did not result in further increase in bone strength but was associated with significant increase in BMD and bone mass of femur. | 100 μg/kg daily | 25 μg/kg weekly | BMD, trabecular bone volume, and bone strength | 12 weeks | 56 |
| Journal of bone and mineral metabolism Mashiba, et al. (1995) | TasukuMashiba | 1995 | Bisphosphonate (cimadronate) | Female sprague-dawley rats aged 11 weeks | Only mid-femoral BMD increased in combination. Concurrent treatment with PTH and bisphosphonate (cimadronate) resulted in a bone anabolic effect not only in cancellous bone but also in cortical bone. | 30 μg/kg | 5 μg/kg | BMD of distal, middle, and total femur | 8 weeks | 49 |
| Osteoporos int Li, et al. (2012) | Int Y. F. Li | 2012 | Bisphosphonate (zoledronic acid) | Osteoporotic rats | No differences in bone mineral density and BV/TV of the contralateral tibiae were observed between treated groups. | 60 μg/kg three times a week | 1.5 μg/kg/weekly | BMD and BV/TV of tibiae | 8 weeks | 60 |
| JBMR Ettinger, et al. (2004) | Bruce Ettinger | 2004 | Raloxifene or alendronate | Postmenopausal women who had previously received either alendronate (ALN) or raloxifene (RLX) therapy for 18–36 months. | Hip BMD (prior ALN -1.8%, RLX +0.5%) and spine BMD (prior ALN +0.5% vs. prior RLX +5.2%) during the first six months and same performance between 6 and 18 months. At 18 months, total hip BMD increased (1.8%, p < 0.05) in prior RLX but was not different from baseline in prior ALN. Same with bone turnover marker. | 20 μg/daily | ALN 10 mg/day or RLX 60 mg/day | Hip and spine BMD, bone turnover markers | 18 months | 59 |
| JBMR Dempster, et al. (2016b) | David W Dempster | 2016 | Alendronate | Postmenopausal women on ALN for at least 1 year still continues ALN or with minimal or no prior osteoporosis therapy | Both Rx-Naive and ALN-RX subjects responded to TPTD with significant increases in bone formation indices at both time points. Within ALN-Rx group, BV/TV and Tb. N were significantly higher, and Tb. Sp was significantly lower in late daily TPTD group. Cortical porosity increased most significantly in late daily TPTD group. | 20 mcg/daily or cyclic | 70 mg/wk | Bone microarchitecture and bone formation variables from quadruple labels. | 7 weeks and 7 months | 120 |
| Bone research Nakamura, et al. (2017) | Yukio Nakamura | 2017 | Denosumab | Primary osteoporotic treatment-naive patients with low L-BMD and/or bilateral hip BMD (H-BMD; less than −3.0 SD). | L-BMD (L1-L4) increased more in combination group at 24 months (17.2% vs. 9.6%).H-BMD tended to be higher in combination group. The combined therapy decreased BAP to a lesser extent than denosumab monotherapy, which may have contributed to the larger BMD increase. | TPTD 20 μg/daily | 60 mg once per 6 months | Hip and spine BMD, bone turnover markers. | 24 months | 30 |
| JBMR Idolazzi, et al. (2016) | L. Idolazzi | 2016 | Denosumab | Women with severe postmenopausal osteoporosis | Both CTX and P1NP increased in denosumab-TPTD. Hip BMD: Significant changes were observed only with denosumab or combination therapy. No significant differences among treatment groups were observed. | 20 mcg/daily | 60 mg every 6 months | Hip and spine BMD, bone turnover markers | 9 months | 59 |
| Lancet Diabetes Endocrinol Tsai, et al. (2019) | Joy N Tsai | 2019 | Denosumab | Postmenopausal women with osteoporosis | Combined treatment with teriparatide 40 μg and denosumab increased spine and hip BMD more than standard combination therapy. | 20 or 40 mcg/daily | 60 mg every 6 months | Hip and spine BMD, bone turnover markers | 15 months | 76 |
| JBMR Cosman, et al. (2020) | Felicia Cosman | 2020 | Denosumab | Postmenopausal women with osteoporosis | The cyclic regimen did not improve BMD compared with standard regimen at 36 months, however, there appeared to be a benefit at 18 months. | 20 mcg/daily cyclic or standard regimens | 60 mg every 6 months | Hip and spine BMD, bone turnover markers | 36 months | 70 |
| JBMR Ramchand, et al. (2020a) | Sabashini K. Ramchand | 2020 | Denosumab | Postmenopausal women at high risk of fracture | Either high or standard dose of teriparatide improved HRpQCT measures of bone density, microstructure, and estimated strength, along with greater gains in total bone density observed in the HD-group. | 20 or 40 mcg/daily | 60 mg every 6 months | BMD, microstructure, and strength of distal femur and radius | 15 months | 69 |
| The Journal of Clinical Endocrinology & Metabolism Leder, et al. (2014) | Benjamin Z | 2014 | Denosumab | Postmenopausal women aged 45 or older | Lumbar spine, femoral neck and total hip BMD increased more in combination group. CTX and PINP were equally suppressed in denosumab and combination group, where osteocalcin was decreased more in the denosumab group. | 20 μg/daily | 60 mg every 6 months | Total hip, femoral neck and spine BMD. Bone turnover markers | 2 years | 100 |
| Endocrine Walker, et al. (2013) | Marcella D. Walker | 2013 | Risedronate | Men | Combined teriparatide and risedronate increased BMD at the LS, TH as well as the FN and provided greater BMD increase at the TH than monotherapy. PINP and CTX increased rapidly, mirroring the teriparatide alone arm in combined group. | 20 μg/daily | 35 mg weekly | Total hip, femoral neck and spine BMD. Bone turnover markers | 18 months | 29 |
| JBMR Muschitz, et al. (2013) | Muschitz C | 2013 | Alendronate or risedronate | Postmenopausal women with severe osteoporosis on TPTD treatment for 9 months | Except trabecular compartment of femoral neck, lumbar spine BMD, trabecular lumbar spine BMD, total hip BMD, cortical thickness of lumbar spine, femur and hip were increased more in combined ALN group than PTH alone. PINP and CTX decreased and CTX decreased to the starting level in the ALN combination group. | 20 μg/daily | ALN 70 mg weekly RAL 60 mg/d | Total hip, femoral neck and spine BMD (cortical and trabecular). Bone turnover markers | 18 months | 183 |
| J Clin Endocrinol Metab Schafer et al. (2012) | Anne L. Schafer | 2012 | Ibandronate | Postmenopausal women with low bone mass | PTH + ibandronate 6 months-Ibandronate 18 months vs. PTH 3 months – Ibandronate 9 months. Areal BMD at the spine and hip as well as volumetric BMD were increased similarly. PINP in combined group increased then declined. Sequential treatment increased markedly. | 100 μg/daily | 150 mg monthly | Hip and spine BMD (cortical and trabecular). Bone turnover markers. | 24 months | 44 |
| Osteoporos int Cosman et al. (2008) | F. Cosman and J. | 2008 | Raloxifene | Women with osteoporosis on raloxifene | (Raloxifene- PTH+ raloxifene -raloxifene) vs. (raloxifene- raloxifene- raloxifene) In the PTH + raloxifene group, bone turnover increased 125–584%, spine BMD increased 9.6%, hip BMD increased 1.2–3.6% and radius BMD declined 4.3%. The follow-up year, on continued raloxifene, BMD declined slightly at all sites except the femoral neck. | 25 μg/daily | 60 mg/day | Total hip, femoral neck, proximal radius, Trochanter and spine BMD. Bone turnover markers | 24 months | 42 |
| J Clin Endocrinol Metab Boonen et al. (2008) | Steven Boonen | 2008 | Alendronate, risedronate, etidronate | Women with osteoporosis | Lumbar spine BMD increased at all visits, whereas a transient decrease in hip BMD, which was subsequently reversed. Significant increases in bone formation markers occurred in all groups after 1 month of teriparatide treatment. | 20 μg/daily | — | Hip and spine BMD, bone turnover markers | 2 years | 245 |
| J Clin Endocrinol Metab Tsai et al. (2016) | J. N. Tsai | 2016 | Denosumab | Postmenopausal osteoporotic women | Trabecular vBMD and cortical thickness increased more in the combination group than both monotherapy group. Radius trabecular vBMD increased more in the combination group. | 20 μg/daily | 60 mg every 6 months | Radius and tibia BMD. | 24 months | 94 |
| J Clin Endocrinol Metab Ramchand, et al. (2020b) | Sabashini K. Ramchand | 2020 | Denosumab | Postmenopausal osteoporotic women | Women treated with the 40 μg/daily regimen achieved clinically meaningful and rapid gains in hip and spine a BMD compared with the 20 μg/daily | 40 μg/daily or 20 μg/daily | 60 mg months 3 through 15 | Total hip, femoral neck and lumbar spine BMD. | 15 months | 60 |