PROactive HEALing in High-Risk Pelvic and Non-hip Lower Extremity Fragility Fractures (PRO HEAL Pilot) (PRO HEAL Pilot)

Background & Rationale At least 1 in 3 females and 1 in 5 males will experience a fragility fracture due to osteoporosis or low bone mass in their lifetime, and over 80% of fractures in Canadians aged 50 and older are attributable to osteoporosis. Older adults with poor bone quality who sustain pelvic or lower extremity fragility fractures face high rates of delayed healing, loss of reduction and implant failure, frequently resulting in secondary surgery. Reported complication rates range from 21.5% to 40%, and one-year mortality has been reported as high as 12%. Efforts to improve outcomes have focused on fixation technique; no pharmacological treatment is currently given to promote healing of the fracture itself.

Teriparatide, recombinant parathyroid hormone (1-34), is an anabolic agent authorized in Canada for the treatment of severe osteoporosis. Once-daily administration preferentially stimulates osteoblastic over osteoclastic activity, producing net new bone formation. Pre-clinical studies demonstrate enhanced callus formation and improved mechanical strength of healing bone. Clinical evidence in acute fracture healing is limited and mixed. A randomized trial in distal radius fractures reported shorter time to cortical bridging, and systematic reviews report positive signals in delayed union and non-union. However, a small phase 2 trial in acute pelvic fracture found no difference in radiographic healing at three months, although physical performance improved; that trial was terminated early following withdrawal of study drug supply, was underpowered, and its authors concluded that a larger randomized trial is warranted.

No randomized trial has evaluated teriparatide for fracture healing across pelvic, acetabular and non-hip lower extremity fragility fractures in high-risk older adults. Feasibility must be established before a definitive trial can be designed.

Research Question & Objectives Is it feasible to conduct a full-scale randomized controlled trial comparing teriparatide with no treatment for the promotion of fracture healing in older adults with pelvic, acetabular or non-hip lower extremity fragility fractures? Objectives are to (1) evaluate the feasibility of a definitive full-scale randomized controlled trial, measured by recruitment rate, treatment fidelity, participant retention, consent rate and barriers to trial implementation; and (2) compare complication rates between short-term teriparatide and no treatment, to inform the design and sample size of the full trial. This pilot is not powered to establish efficacy.

Methods Design: prospective, open-label, randomized controlled pilot trial with blinded outcome assessment and 1:1 allocation, conducted at the Foothills Medical Centre.

Population: 54 participants (27 per arm) aged 50 years and older with a low-energy fragility fracture (fall from five feet or less) of the pelvis, acetabulum or non-hip lower extremity, and at least one additional risk factor for delayed healing (diabetes, renal dysfunction, steroid use, current or past smoking, peripheral neuropathy, peripheral vascular disease). Participants must be able and willing to self-administer daily injections, or have a caregiver able to do so, and must provide informed consent or have a surrogate decision maker. Exclusion criteria include recent teriparatide, bisphosphonate or digoxin therapy; hypercalcemia; hypercalciuria; urolithiasis; severe renal impairment; hypersensitivity to teriparatide; and factors conferring elevated osteosarcoma risk. Eligibility bloodwork is reviewed prior to randomization.

Intervention: teriparatide 20 mcg subcutaneously once daily for 90 doses, with the first dose administered within five days of randomization and within 21 days of injury. The comparator arm receives no study medication and continues standard clinical care. All participants in both arms receive vitamin D 50,000 IU at randomization and calcium supplementation to approximately 1,000 mg daily.

Randomization is performed in REDCap using variable block sizes. Participants and treating clinicians are aware of allocation; clinical outcomes are adjudicated by two independent blinded adjudicators, with a third resolving disagreement, using materials from which allocation information has been removed.

Outcomes: the primary feasibility outcome is the mean number of participants recruited per month, assessed against a priori progression criteria. Secondary feasibility outcomes are treatment fidelity, retention, consent rate and implementation barriers. Clinical outcomes include pain, radiographic union, unplanned surgical intervention, bone mineral density and mortality. Functional outcomes include physical performance, the Olerud Molander Score and PROMIS Mobility.

Follow-up occurs at 2, 6 and 12 weeks and 6 months post-randomization, aligned with routine clinical visits. Participants receiving teriparatide are telephoned weekly for safety and adherence monitoring. Serum calcium is measured at every study visit. Analysis is descriptive and conducted on an intention-to-treat basis. Recruitment is planned over 18 months.

Participants randomized to the treatment arm receive teriparatide 20 mcg by subcutaneous injection once daily for 90 doses. This is an investigational use of a marketed drug and is not part of standard care for fracture management.

All participants, in both arms, receive a single oral loading dose of 50,000 IU vitamin D at randomization, with calcium supplementation or dietary modification to approximately 1,000 mg daily.

The following study procedures are additional to standard practice:

• Eligibility bloodwork prior to randomization (serum calcium, alkaline phosphatase, creatinine, 25-hydroxy vitamin D), where not already obtained as part of clinical care
• A pregnancy test prior to randomization for participants of childbearing potential
• Serum calcium at each follow-up visit, drawn from a morning sample, as a safety measure
• Bone mineral density scan by DEXA at baseline and at 3 months, where a scan within the preceding 6 months is not already available
• Physical performance testing at follow-up visits (4-metre walk speed, repeated chair stands, balance)
• Questionnaires at follow-up visits (Olerud Molander Score, PROMIS Mobility, EQ-5D, pain visual analogue scale)
• Weekly telephone contact during the 90-day treatment period, for participants in the treatment arm, to assess adherence and safety
• A participant-maintained drug diary, and return of used and unused study medication at each visit

Study visits are aligned with routine post-fracture clinical follow-up at 2 weeks, 6 weeks, 12 weeks and 6 months. Radiographic assessment of healing uses imaging obtained as part of routine clinical care. No additional imaging is performed for research purposes other than the bone mineral density scans described above.