Evaluating treatment options

Osteoporosis Supplement: Prof Gerald H. Tomkin looks at recent studies investigating the merits of different osteoporosis treatments and stresses the importance of compliance

The recent bad weather with ice and snow has, among other things, concentrated the mind yet again on fractures and the underlying pathology. I have no doubt that the DEXA scans have been working overtime in the rush to exclude or diagnose osteoporosis in those patients who sustained a fracture and in those who were lucky enough to avoid fracture in their falls.
The cost of fractures in monetary terms, but also in terms of human suffering, is enormous and many studies have shown that treatments to prevent osteoporosis are indeed cost effective. The DEXA scan may not be the perfect diagnostic tool for osteoporosis but it is certainly a useful, easy to perform, reproducible and cheap test for a condition which can lead to so much disability.
The causes of osteoporosis are multiple and the genes play their share, but most patients with osteoporosis do not have an obvious family history or are not aware of the family history until asked the specific questions. In August last year, an editorial (in N Engl J Med) discussed the options for the treatment of osteoporosis.
The readers of this article like myself were delighted some years ago to learn about RANKL. (Indeed some readers may even have used the name for one of their pets and I am at present trying to persuade my daughter to name her new puppy, a beagle with rather short legs, RANKL.)
Osteoporosis is a condition resulting in part from increased osteoclastic bone resorption. Receptor activator of nuclear factor-kappa B ligand (RANKL) is a key molecule mediating osteoclastic development, activity and survival. RANKL therefore became a prime target for the prevention of osteoporosis.
Denosunab
The FREEDOM Trial (fracture reduction evaluation of denosunab in osteoporosis every six months) evaluated more than 7,000 women with osteoporosis. Patients received either 60mg of denosunab or placebo subcutaneously every six months for 36 months. Denosunab is a fully human monoclonal antibody against RANKL.
By binding RANKL denosunab prevents the interaction of RANKL with its receptor RANK on osteoclasts and osteoclast precursors and reversibly inhibits osteoclast-mediated bone resorption.
The study had a power of more than 99 per cent to detect a 45 per cent reduction in the incidence of new vertebral fractures and to detect a 40 per cent reduction in the risk of any non-vertebral fracture and a power of 91 per cent to detect a 40 per cent reduction in the risk of hip fracture.
After 36 months, 2.3 per cent of the active group developed new radiographic vertebral fractures as compared to 7 per cent in the placebo group, representing a 68 per cent reduction in relative risk. The results were not so good for non-vertebral fractures: 6.5 per cent vs 8.0 per cent (a 20 per cent reduction) and a 40 per cent relative reduction in hip fractures.
More encouraging was the increase in bone mineral density (BMD) of 9.2 in the active treatment group compared to placebo, however levels of PIMP (pro collagen type 1 N-terminal propeptide), a marker of bone formation, was very much below those in the placebo group. It was also encouraging to see that there were no significant differences in adverse events between subjects who received denosunab and those who received placebo.
Since compliance with oral medication is a problem in the treatment of osteoporosis and at least 50 per cent of patients stop biphosphonate treatment within one month of receiving oral treatment (Siris ES et al. 2006), a six-monthly injection has great appeal.
Risk reduction
The magnitude of the decrease in risk of vertebral fractures with denosunab was similar to that for intravenously administered zoledronic acid and greater than reductions reported for oral osteoporosis agents. For non-vertibral fractures, the risk reduction with denosunab was similar to those reported for alendronate, residonate and zolidonic acid.
RANKL and RANK are members of the tumour necrosis super family that are expressed by a variety of lymphoid cells. It has been theorised that the inhibition of RANKL might increase the risk of cancer or infection but, in the above trial, there was no significant difference in the incidence of cancer or in the incidence of overall infection.
In the same edition of the New England Journal of Medicine, denosunab was investigated in the HALT Prostrate cancer study (Smyth MR et al.). Androgen deprivation therapy is a major treatment for prostate cancer and improves disease free and overall survival in men with prostate cancer.
This treatment increases bone resorption, reduces BMD and increases the risk of fracture in men with prostate cancer. Although several drugs including bisphosphonates and selective oestrogen receptor modulators prevent bone loss associated with androgen deprivation therapy, published trial results showing an effect on fracture prevention are lacking. The study investigated more than 700 patients in both the denosunab arm and the placebo arm. In this study, denosunab was associated with significant increases in bone density but also in a reduction in vertebral fractures (62 per cent) and a reduction in fracture at any site but this was not significant.
Anabolic effect
However, more than one fracture at any site developed in significantly fewer in the denosunab group than in the placebo group (0.7 per cent vs 2.5 per cent p=0.006).
The editorial by Khosla in the same issue discusses both the other anti-resorpative drugs – alendronate, daily or weekly by mouth; residronate daily or weekly by mouth; ibandronate daily, monthly or intravenously every three months; zoledronic acid intravenously every 12 months; and the non-biphosphonate selective oestrogen receptor modulators (SERMs) such as raloxafen daily by mouth; oestrogen oral or transdermal; calcitonin intranasally; and the anabolic recombinant human parathyroid hormone (teriparatide) subcutaneously daily.
Khosla concludes that the real need in osteoporosis treatment is for additional anabolic agents since all patients have not responded to teriparitide and the skeletal effect wanes, limiting its anabolic effect.
“Specifically our success or failure in combating osteoporosis increasingly depends not so much on the drugs available to us, but rather on our ability to engage our patients and ensure they take the medications we prescribe.” (Khosla S New Engl J Med 361;818-819 2009).
Osteoporotic vertebral fractures are extremely painful. It is suggested that more than 750,000 new vertebral fractures occur in the United States each year and, among people who are over 50 years of age, up to one quarter of them will have one vertebral fracture in their lifetime. Most fractures heal within a few months.
Some people have pain and disability that fails to respond to conservative treatment and some require hospitalisation or both (Kanis JA et al. 1999). Vertibroplasty, the percutaneous injection of poly methyl methacrylate (PMMA) into the affected vertebral body has been advocated for treatment of painful vertebral fractures. Alas, Buchbinder et al., together with Bridie Murphy et al. (N Engl J Med Aug 6 2009) found no beneficial effect compared to sham procedure in patients with painful vertebral fractures.
This result was confirmed by Kalmes et al — the investigational vertebroplasty safety and efficacy trial (INVEST) thus demonstrating the dangers of adopting unconfirmed new procedures.
As stated above, compliance with the oral biphphonates has been a huge problem and addition of zoledronic acid given on an annual basis intravenously appears to be a major advance and indeed has been adopted for routine use by patients with prostate cancer on anti androgen treatment.
The seminal study in 2007 demonstrated, in almost 4000 patients in a double blind, placebo-controlled trial over 36 months, reduced risk of vertebral fracture by 37 per cent and of hip fracture by 41 per cent. The only major risk appears to be atrial fibrillation, which occurred in 50 vs 20 patients over the three-year period.
As an alternative to bisphosphonates, strontium ranelate was introduced some years ago. The drug works by slowing the loss of bone and possibly by stimulating bone formation. Strontium is a cation and physically strongly related to calcium. A Cochrane report in 2006 suggested that there is silver level evidence to support the use of strontium in postmenopausal women with a three-year reduction in vertebral fractures of 37 per cent and a 14 per cent reduction in non-vertebral fractures.
Good compliance
A peculiar investigation by Rabenda and Reginster (2010) from the Department of Public Health, Epidemiology and Health Economics, University of Leige looked at the impact of compliance in two international Phase 3 randomised international double-blind studies. They found that the patients who had good compliance had less fractures!
Osteoporosis is worthy of early diagnosis since treatments are effective in preventing fracture. Bisphosphonates are the treatment of choice but non-compliance of oral medication must be diligently searched for. The option of annual intravenous zolondronic acid should be taken up more frequently. Improved follow up of patients with diagnosed osteoporosis is necessary if we are to make a better impact on this condition.