Parathyroid Hormone Added to Established Hormone Therapy: Effects on Vertebral Fracture and Maintenance of Bone Mass After Parathyroid Hormone Withdrawal

Abstract

Our best pharmacologic agents for osteoporosis treatment prevent no more than 40 -60% of osteoporotic fractures in patients at highest risk. Thus, there is a need for agents that can further augment bone mass and reduce fracture risk more substantially. To this end, we investigated the utility of parathyroid hormone (PTH) in combination with established hormone-replacement therapy (HRT) in women with osteoporosis. Fifty-two women who had been on HRT for at least 2 years were enrolled in this trial in which 25 were assigned randomly to remain on HRT alone and 27 were assigned to remain on HRT and also receive daily subcutaneous PTH(1-34) 400 U (25 g) per day for 3 years. Bone mineral density (BMD) measurements at the spine, hip, and total body as well as biochemical determinations of bone turnover and calcium homeostasis were obtained every 6 months. Lateral thoracic and lumbar spine X-rays were obtained at baseline and annually. Subjects also had measurements of bone density and biochemical indices of bone turnover 1 year after discontinuation of PTH, while HRT was continued. In the group receiving HRT alone, bone density and biochemical variables of bone turnover remained stable throughout the 3-year treatment trial and 1-year follow-up. In the PTH ؉ HRT group, biochemical variables of bone formation and resorption peaked at 6 months and subsequently remained elevated until 30 months at which time levels were indistinguishable from baseline. Subjects in the PTH ؉ HRT group increased bone mass by 13.4 ؎ 1.4% in the spine, 4.4 ؎ 1.0% in the total hip, and 3.7 ؎ 1.4% in the total body. Bone density measurements remained stable 1 year after discontinuation of PTH without any significant loss while women continued HRT. Biochemical variables did not change significantly after cessation of PTH through the 1-year follow-up period. PTH ؉ HRT reduced the percent of women who had vertebral fractures from 37.5% to 8.3% (using a 15% height reduction criterion) and from 25% to 0% (using a 20% height reduction criterion) compared with women receiving HRT alone (p < 0.02 for both). We conclude that ongoing HRT maintains almost all of the PTH-induced bone mass increment for 1 year after discontinuation of PTH.

Canadian Consensus Conference on Osteoporosis, 2006 Update

“…124 Estrogen and raloxifene do not appear to have the blunting effect on PTH therapy. [125][126][127][128] Fracture data are lacking and combination therapies are usually not recommended. Sequential therapies preceding or following PTH treatment are useful in maintaining and enhancing bone mass.…”

Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1–34)] in postmenopausal osteoporosis

“…Prior studies evaluating combinations of PTH or teriparatide with antiresorptive agents have yielded inconsistent results, with differences related to which antiresorptive agent is used, (16)(17)(18)(19)(20)(21)(22) whether patients are treatment-naive or have been on antiresorptive therapy when combination treatment is started, (14,23) and, for patients on prior antiresorptives, whether the antiresorptive agent is continued or stopped when teriparatide is added. (24) In one study, (14) treatment-naive patients were randomized to alendronate or intact PTH(1-84) monotherapy versus combination therapy.…”

Effects of Cyclic Versus Daily hPTH(1-34) Regimens on Bone Strength in Association With BMD, Biochemical Markers, and Bone Structure in Mice

“…(1)(2)(3)(4) In contrast to conventional antiresorptive agents, which reduce bone resorption and ultimately suppress bone formation, (5)(6)(7) PTH stimulates bone formation. (1)(2)(3)(4)(8)(9)(10) In humans, bone formation markers, including bone-specific alkaline phosphatase (BSALP) and osteocalcin, are increased within a month of initiation of daily injection of hPTH , whereas PTH-induced increases in resorption markers catch up about 6 months later. (1)(2)(3)8) In addition, histomorphometric analysis of human iliac crest bone biopsies using quadruple tetracycline labeling revealed that daily injection of hPTH(1-34) (25 g/day) directly stimulated bone formation without any significant increase in bone resorption within 6 weeks.…”

“…(1)(2)(3)(4)(8)(9)(10) In humans, bone formation markers, including bone-specific alkaline phosphatase (BSALP) and osteocalcin, are increased within a month of initiation of daily injection of hPTH , whereas PTH-induced increases in resorption markers catch up about 6 months later. (1)(2)(3)8) In addition, histomorphometric analysis of human iliac crest bone biopsies using quadruple tetracycline labeling revealed that daily injection of hPTH(1-34) (25 g/day) directly stimulated bone formation without any significant increase in bone resorption within 6 weeks. (8) These findings suggest that daily PTH injection induces bone formation without prior resorption on initiation of therapy.…”