Osteonecrosis of the Hip and Bisphosphonate Treatment
Osteonecrosis of the Hip and Bisphosphonate Treatment
Osteonecrosis of the hip is an important cause of musculoskeletal disability and finding
 therapeutic solutions has proven to be challenging. Osteonecrosis means death of bone which
 can occur from the loss of the blood supply or some other means. Although any age group may
 develop osteonecrosis, most patients are between 20 and 50 years old. The most common risk
 factor is a history of high steroid treatment for some medical condition. The next most
 common associated condition is a history of high alcohol use. There are some cases of
 osteonecrosis that occur in patients that are otherwise completely healthy with no detectable
 risk factors.

 In the earliest stage of the disease, x-rays appear normal and the diagnosis is made using
 MRI. The advanced stages of osteonecrosis begin when the dead bone starts to fail
 mechanically through a process of microfractures of the bone. As the disease progresses, the
 surface begins to collapse until, finally the integrity of the joint is destroyed. A wide
 range of surgical treatments with variable success rates have been proposed for the treatment
 of the osteonecrosis to preserve joint integrity, including core decompression, whereby the
 venous hypertension that ensues is lessened and revascularisation may be induced leading to
 bone repair. Nonsurgical treatment options are limited and usually result in a poor
 prognosis. Early stage disease can be treated with protected weight bearing and
 physiotherapy, however some studies have shown protected weight bearing to be associated with
 a greater than 85% rate of femoral head collapse. Unfortunately most studies indicate that
 the risk for disease progression is greater with nonsurgical treatment than with surgical
 intervention. There are no established pharmaceuticals for the prevention of treatment of
 osteonecrosis. Evidence is increasing that the nitrogen containing bisphosphonates may be
 beneficial in the treatment of osteonecrosis. One bisphosphonates (alendronate) has been
 evaluated in 60 patients diagnosed with osteonecrosis of the hip. Recent clinical studies
 have shown very promising results. All patients had symptomatic improvement after one year.
 Although the follow up time ranged from 3 months to 5 years, only 6 patients progressed to
 the point of needing surgery.
Osteonecrosis (ON) of the hip is an important cause of musculoskeletal disability and finding
 therapeutic solutions has proven challenging. Patients who are affected with ON are often
 relatively young, usually in the third to sixth decade of life. ON of the hip is an
 increasingly common cause of musculoskeletal disability. It can cause pain with or without
 loss of function of the joint and often ends in substantial use of health care resources and
 disability. ON of the hip usually progresses to severe destruction of the femoral head with
 resultant degeneration of the hip joint, in most cases requiring joint replacement.

 Early diagnosis has been made easier using magnetic resonance imaging (MRI), however no
 common satisfactory therapy has been developed for the early stage of the disease. Early
 surgery aimed at preserving the femoral head has been proposed, such as vascularised fibula
 grafting. However, the results of this invasive technique do not seem to be widely
 reproducible, and more minor interventions such as core drilling have high failure rates.
 Evidence is increasing that the nitrogen containing bisphosphonates may be beneficial in the
 treatment of ON. Data from clinical trials with patients with ON of the hip suggested that
 the bisphosphonate alendronate would reduce pain and disability and may reduce progression to
 femoral head collapse that usually would require surgical intervention.

 With this study we aim to determine the efficacy of bisphosphonate therapy (zoledronic acid)
 versus placebo for reducing pain and disability in ON of the femoral head necrosis
 (palliative endpoint) and to investigate the effect of bisphosphonate therapy versus placebo
 in reducing progression to femoral head collapse and the need for surgical intervention
 (therapeutic endpoint).

 Methods This will be a 2-armed double-blind randomised trial of a) zoledronic acid 5mg
 annually for 3 doses b) placebo drug infusions. Participants will be recruited primarily from
 rheumatologists and orthopaedic surgeons from multiple centres in Australia. We plan to
 include 4 major centres in capital cities in Australia and each centre would recruit
 approximately 30 participants. Potential participants who meet the eligibility criteria will
 be identified by their treating Rheumatologists or Orthopaedic surgeons, followed by a
 screening assessment conducted by the study research staff. Eligible participants will be
 randomised prior to the start of treatment. Prior to treatment, the study research staff will
 perform a baseline assessment over the phone, including demographic details, age, sex,
 duration of symptoms, medical history including prior surgery, trauma and medication use and
 known risk factors for ON. Furthermore at baseline, the Rheumatologists or Orthopaedic
 surgeon will perform a clinical evaluation using a slightly modified Harris Hip Score (HHS).
 The study research staff will contact the participants every 6 months to monitor the
 participant's condition and evaluate pain and disability. Additionally the participants will
 have a clinical evaluation and MRI scan at 12 months.

 This novel clinical research protocol will aim to provide further evidence of the protective
 value of alendronate or zoledronic acid in patients with ON of the hip. It will determine
 whether bisphosphonates slow the progression of symptoms as well as the progression to total
 collapse of the hip. Additionally it will seek to answer questions regarding the comparative
 effectiveness and also cost-effectiveness of the use of bisphosphonates in early disease. The
 results of this study can lead to change in treatment of early disease ON and delay and
 possibly prevent surgical intervention.
Inclusion Criteria:

 1. aged between 18-90 years,

 2. symptoms of pain and disability in at least one hip joint, or

 3. positive MRI findings stage I or II on the ARCO classification

 Exclusion Criteria:

 1. previous hip joint surgery on the affected hip

 2. severe pain and disability at rest if treating clinician has recommended surgery

 3. radiographic or MRI findings suggestive for stage III and IV on the ARCO
 classification

 4. any iv bisphosphonate within the prior 2 years or any prior use of bisphosphonate
 preparations, except according to the washout schedule:

 -  2 years (if use > 48 weeks),

 -  1 year (if used > 8 weeks but < 48 weeks)

 -  6 months (if used > 2 weeks but < 8 weeks)

 -  2 months (if used < 2 weeks)

 5. active primary hyperparathyroidism

 6. hypothyroidism, not appropriately controlled with long-term thyroxine therapy

 7. history of iritis or uveitis, except due to trauma, and resolved for > 2 years prior
 to study

 8. self-reported history of diabetic nephropathy or retinopathy (if diabetic, Hb A1c >
 10%)

 9. urine dipstick greater than or equal to 2+ protein at screening

 10. AST or ALT greater than twice the upper limit of normal and/or alkaline phosphatase
 greater than twice the upper limit of normal

 11. serum calcium > 2.75 mmol/L (11.0 mg/dL) or < 2.00 mmol/L (8.0 mg/dL)

 12. serum 25-hydroxyvitamin D concentrations < 15 ng/L m) baseline renal insufficiency
 (calculated creatinine clearance less than 40 mL/min and serum creatinine greater than
 175 mol/L) at V1

 13. a history of invasive malignancy of any organ system, treated or untreated, in the
 past five years; excluding, basal cell or squamous cell carcinoma of the skin, colonic
 polyps with non-invasive malignancy which have been removed, ductal carcinoma in-situ
 (DCIS), and carcinoma in-situ (CIS) of the uterine cervix

 14. any candidate patient with severe dental problems or current dental infections and/or
 any candidate patient with recent or impending dental surgery within three months of
 dosing

 15. women of childbearing potential not using the contraception method(s) specified in
 this study (specify), as well as women who are breastfeeding