Combination treatment with TPD and zoledronic acid

TPD increases bone formation initially within the first month but then increases bone turnover with formation exceeding resorption. It is therefore of interest to see if combination therapy with a potent bisphosphonate would allow bone formation to continue unheeded. Earlier work in the Parathyroid Hormone and Alendronate for Osteoporosis trial by Black showed that concomitant treatment with an oral bisphosphonate reduced the bone mineral density (BMD) response to parathyroid hormone, with a twofold increase in volumetric BMD with TPD alone compared with TPD and alendronate. There was no evidence for synergy. However, animal studies showed that this response reduction did not occur with a parenteral bisphosphonate. Cosman and colleagues recently evaluated the effects of combination therapy with an infusion of a parenteral bisphosphonate, zoledronic acid 5 mg and daily TPD for 1 year. Four hundred twelve postmenopausal women were randomized to a single infusion of zoledronic acid plus TPD (n = 137), zoledronic acid alone (n = 137), or teriparatide alone (n = 138). Bone markers and BMD were measured. After 1 year, lumbar spine BMD had increased 7.5%, 7.0%, and 4.4% in the combination, TPD, and zoledronic acid groups, respectively ( P >.001). In the combination group, spine BMD increased more rapidly than with either agent alone ( P <.001 at 13 and 26 weeks). Combination therapy increased total-hip BMD more than TPD alone at all times (all P <.01) and more than zoledronic acid at 13 weeks, with final 52-week increments of 2.3%, 1.1%, and 2.2% in the combination, TPD, and zoledronic acid groups. With combination therapy, a marker of bone formation procollagen type 1 amino terminal propeptide increased with levels above baseline from 6 to 12 months. A marker of Bone resorption C-telopeptide was markedly reduced with combination therapy from 0 to 8 weeks (a reduction of similar magnitude to that seen with zoledronic acid alone), followed by a gradual increase with levels remaining above baseline for the remainder of the study. Levels for both markers were significantly lower with combination therapy versus TPD alone. The results did not show a distinct advantage at 1 year for combination therapy but did show earlier BMD increases at the hip.

Prior bisphosphonate treatment

An earlier study by Ettinger studied patients previously treated with alendronate or raloxifene. Alendronate prevented BMD increases in the first 6 months, which raloxifene did not. In European Study of Forsteo (EUROFORS), a European observational study of TPD, this delay was not observed in patients previously treated with alendronate, etidronate, or risedronate. One explanation may be the compliance of the patients on alendronate. In the Ettinger study, the patients were all chosen to have been at least 80% compliant, while this was not a criterion in EUROFORS.

Prior bisphosphonate treatment

An earlier study by Ettinger studied patients previously treated with alendronate or raloxifene. Alendronate prevented BMD increases in the first 6 months, which raloxifene did not. In European Study of Forsteo (EUROFORS), a European observational study of TPD, this delay was not observed in patients previously treated with alendronate, etidronate, or risedronate. One explanation may be the compliance of the patients on alendronate. In the Ettinger study, the patients were all chosen to have been at least 80% compliant, while this was not a criterion in EUROFORS.

Follow-up treatment

The approval of TPD by the US Food and Drug Administration (FDA) was issued with the recommendation that treatment last no longer than 2 years. However, there were no recommendations about treatment options thereafter. Studies suggest gains achieved in BMD are lost if an antiresorptive agent is not administered after treatment. Black and colleagues examined the effect of alendronate compared with placebo therapy after at least 1 year of parathyroid hormone (PTH) (1–84). Over 2 years, alendronate therapy after PTH (1–84) led to significant increases in BMD compared with placebo. After 1 year of PTH (1–84), BMD gains appear to be maintained or increased with alendronate, but lost if treatment is not followed by an antiresorptive agent. The use of a potent antiresorptive agent after treatment with TPD thus creates a second anabolic window. Rittmaster found enhancement of the BMD gains after discontinuation of TPD and institution of alendronate therapy, with a 7.1% gain in lumbar spine BMD after 1 year and a 13.4% gain after TPD and 1 year alendronate. The declines in BMD after stopping TPD appear greater in women than men. One of the authors (SLS) of this article currently uses either parenteral bisphosphonate or denosumab after completion of a course of TPD.

A related question is whether patients who have been treated with TPD will benefit from retreatment. Finkelstein reported that patients treated with TPD had a 12.5% increase in lumbar spine BMD after 1 year. After a 1 year hiatus, the patients responded again but to a lesser extent to TPD (BMD gains in lumbar spine of 5.2%).

Cyclic TPD

TPD stimulates bone formation within 1 month. Indexes of bone remodeling then peak and plateau, with bone formation exceeding bone resorption, but then slowly decline. The cause of this resistance to continued treatment is unknown but may be associated with increasing serum levels of DKK1, a specific Wnt antagonist, and resulted in a 2-year treatment window for TPD. Cosman and colleagues evaluated whether, for women on concomitant alendronate therapy, short, 3-month cycles of teriparatide could be effective as continuous daily administration. In both groups, bone formation indexes increased quickly. For women receiving cycling therapy, bone formation declined during cycles without TPD. Bone resorption increased in both groups, but increased progressively more in the daily treatment group. Spine BMD increased 6.1% in the daily treatment group and 5.4% in the cyclic group. This study suggests that in patients with osteoporosis after prior alendronate treatment, both daily and cyclic treatment regimens may increase BMD. The effect of cyclic regimens on fracture efficacy is, however, not known.

Fracture healing with TPD

In osteoporosis, TPD is used as an anabolic agent to stimulate bone formation by enhancing osteoblast-derived bone formation to increase bone mass. Fracture healing follows a similar path, requiring increased bone formation at the fracture site for repair. Research is underway to determine the effects of TPD on mesenchymal stem cells to aide in fracture healing.

Basic science research in rat and monkey models shows promising results in the use of TPD for fracture healing. Andreassen and colleagues showed that doses of 60 to 200 μg/kg (considerably more than the human dose) caused a more mature callus to form more rapidly than the control group. Alkhiary and colleagues used even lower doses, 5 to 30 μg/kg, in a rat model that showed marked increases in volume, stiffness, torsional strength, and BMD of the callus. Other rat and mice model studies have shown similar results. O’Loughlin and colleagues looked at the influence of TPD in rabbit spine fusion. With 10 μg/kg, fusion rate improved 30% to 81%, and histology showed a twofold increased in bone area and a tenfold increase in cartilage formation. Manabe and colleagues demonstrated that TPD accelerated fracture healing in a larger study in a femoral osteotomy model in cynomologous monkeys.

There have been anecdotal and case report studies with TPD improving healing in people. However, there has been only 1 randomized, double-blind, controlled trial studying TPD for accelerated fracture healing, which showed only mixed results. One hundred two postmenopausal women with distal radius fracture were randomized to receive daily injections of placebo, 20 μg of TPD, or 40 μg of TPD for 8 weeks. Therapy was initiated within 10 days of fracture. Radiographs were taken every 2 weeks. In comparing the time to bridging of 3 of 4 cortices, there was no significant difference between the placebo group and 40 μg group (median time 9.1 and 8.8 weeks, respectively). Median time to bridging for the 20 μg group was statistically different at 7.4 weeks ( P = .006); however, due to differences in the calculation of the 95% confidence interval (CI) for the 20 μg and 40 μg TPD groups, comparisons of median time to healing between the 2 TPD groups were not significantly different. Median time to bridging of 4 cortices was similar between all groups (11.3 weeks, 10.9 weeks, and 11.0 weeks for placebo, 20 μg, and 40 μg treatment groups, respectively), and there were no statistical differences in grip strength or reported pain between the 3 groups. The trial did not look at an early marker of bone healing, callus formation. Aspenberg examined callus formation at 5 weeks in a subset of the patients enrolled at his hospital. TPD appeared to improve early callus formation.