696 | DECEMBER 2013 | VOLUME 9 www.nature.com/nrendo

NEWS & VIEWS

BONE

Strontium ranelate does not have an anabolic effect on boneGlen M. Blake and Ignac Fogelman

Strontium ranelate, a therapeutic for osteoporosis, was thought to have a dual mode of action, simultaneously stimulating bone formation and reducing resorption. A recent study casts doubt on this explanation, suggesting instead that it has a mild suppressive effect on bone formation with little effect on bone resorption.Blake, G. M. & Fogelman, I. Nat. Rev. Endocrinol. 9, 696–697 (2013); published online 22 October 2013; doi:10.1038/nrendo.2013.210

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‘‘The strength of this new study is the large number of paired biopsy specimens...’’

A novel study by Chavassieux et al. sheds new light on the mechanism by which stron-tium ranelate improves bone strength and prevents fragility fractures.1 Osteoporosis in postmenopausal women is caused by an imbalance between bone resorption and for-mation that leads to progressive bone loss with consequent thinning of trabeculae, loss of connectivity and increased cortical porosity, making fragility fractures more probable. Most therapies for osteoporosis improve bone strength and reduce fracture risk by either inhibiting bone resorption (for example, bisphosphonates such as alendro-nate) or by stimulating bone formation (for example, bone anabolic agents such as teri-paratide). However, previous studies have suggested that strontium ranelate could be a third type of anti-fracture treatment with a dual mode of action that is capable of simultaneously stimulating bone formation and reducing bone resorption. By dissociat-ing the two processes in this way, sodium ranelate might create a clinically significant anabolic window during which bone mass increases and fracture risk is reduced.

Chavassieux and colleagues cast serious doubt on this explanation of the anti-fracture

benefit of strontium ranelate treat ment.1 Definitive evaluation of the mecha nism of an osteoporosis therapy requires the use of the technique of double tetra cycline label-ling with histo morpho metric analysis of samples obtained by transiliac bone biopsy. Chavassieux et al. enrolled 387 patients; 256 were randomly allo cated to receive 2 g of strontium ranelate per day and 131 were ran-domly allocated to receive 70 mg of alendro-nate per week. All patients had a transiliac bone biopsy performed at baseline, with a second biopsy collected randomly after 6 or 12 months of treatment. The data set for analysis comprised 268 patients (69.3% of the randomized population) for whom paired biopsy specimens of adequate quality were obtained. Patients treated with stron-tium ranelate had a significant decrease in the parameters of bone formation after both 6 and 12 months, but no change in bone resorption. Significantly larger decreases in bone formation parameters were seen in patients treated with alendronate than in those treated with strontium ranelate, and resorption parameters decreased in the alendronate group. Chavassieux and co-workers conclude that strontium ranelate does not have a significant anabolic action on bone remodelling.

Although two bone histomorphometric studies of strontium ranelate were published previously, they included only a handful of individuals with paired bone biopsy samples, thus failing to demonstrate conclu-sively the effect of treatment in individual patients.2,3 The strength of this new study is the large number of paired biopsy speci-mens, and the direct comparison between strontium ranelate and alendronate.1 In our opinion, this paper will settle once and for all a longstanding controversy about the biological mechanism of strontium ranelate in clinical studies.

The concept that strontium ranelate might have a dual mode of action was first sug-gested by preclinical studies which showed that it stimulated osteoblasto genesis and osteoblast activity and reduced osteoblast apoptosis, while other in vitro studies showed a diminution of osteo clastogenesis and osteo clast resorptive activity, with increased osteo clast apoptosis.4 Subsequently, in vivo experimental studies in rodent models con-firmed a possible dual mode of action. By contrast, human data from clinical trials was more ambiguous. Although measurements of biochemical markers of bone turnover in trials of strontium ranelate have generally demonstrated a mild increase in markers of bone formation and a mild suppression in bone resorption,5 the effects are small when compared with those of other osteo-porosis treatments such as bisphosphonates and teriparatide, and one study reported mild suppression of both bone formation and bone resorption.3

Perhaps the most controversial aspect of strontium ranelate treatment is the inter-pretation of the large increases in BMD measured by dual-energy X-ray absorptio-metry (DXA). The 3-year Spinal Osteo-porosis Thera peutic Intervention (SOTI) study reported a 14% increase in BMD at the lum bar spine and a 10% increase at the hip,5 whilst an extension up to 10 years found a 34% increase in spine BMD.6 The interpreta-tion of these increases is not straight forward because, when some of the calcium in bone is replaced by strontium, the higher atomic number of strontium than calcium leads to enhanced absorption of X-rays by the photo electric effect and an increase in DXA measurements of BMD that do not reflect a true change in the amount of bone tissue.

On the basis of the data obtained from female Cynomolgus monkeys, the authors of the SOTI study estimated that ~50% of the reported BMD increase in the spine might be explained by the presence of strontium in bone, with the other 50% attributable to a real increase in the amount of bone tissue.5 However, the conclusion of Chavassieux et al. that strontium ranelate does not have a clinically relevant anabolic effect on bone makes it unlikely that any part of the BMD changes observed in humans has a biologi-cal explanation. This interpretation would

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be consistent with direct measurements in bone biopsy specimens of the percentage of calcium in bone replaced by strontium after 3 years of treatment with strontium rane-late, which is sufficient to explain the DXA changes purely on the basis of the physics of X-ray attenuation.6,7

Despite these caveats about the bio-logical mechanism of strontium ranelate, clinical trials provide strong evidence for its effectiveness at preventing fractures, with studies showing a 41% reduction in verte bral fracture risk and a 16% reduction in nonvertebral fracture risk after 3 years of treatment.5,8 As the beneficial effect of stron tium ranelate on bone strength cannot be explained by an anabolic effect on bone remodelling, the question remains what is the mechanism? One explanation is that it might be a physical effect associated with an increase in bone hardness measured by nanoindentation.9 Evidence exists that the reduction in fracture risk in patients treated with strontium ranelate is greater in those who experience a larger BMD increase, and if the BMD change is principally a measure-ment of the strontium content of bone, this would support the hypothesis of a physical effect of strontium on bone strength.

If fracture prevention by strontium rane-late does have a physical rather than a bio-logical explanation, it could potentially have a synergistic role if used to treat osteo porosis in combination or possibly sequentially with other therapies that do have their effect through bone remodelling.10 We conclude, however, that the suggestion that strontium ranelate has a different mode of action to other osteoporosis therapies has turned out to be true, but not as envisaged by those who proposed a dual mode of action.

King’s College London, Osteoporosis Screening and Research Unit, King’s College Academic Health Partners, 1st Floor, Tower Wing, Guy’s Hospital, Guy’s Campus, London SE1 9RT, UK (G. M. Blake, I. Fogelman). Correspondence to: G. M. Blake glen.blake@kcl.ac.uk

Competing interestsThe authors declare no competing interests.

1. Chavassieux, P. et al. Bone histomorphometry of transiliac paired bone biopsies after 6 or 12 months of treatment with oral strontium ranelate in 387 osteoporotic women. Randomized comparison to alendronate. J. Bone Miner. Res. http://dx.doi.org/10.1002/jbmr.2074.

2. Arlot, M. E. et al. Histomorphometric and microCT analysis of bone biopsies from postmenopausal osteoporotic women treated with strontium ranelate. J. Bone Miner. Res. 23, 215–222 (2008).

3. Recker, R. R. et al. Comparative effects of teriparatide and strontium ranelate on bone biopsies and biochemical markers of bone turnover in postmenopausal women with osteoporosis. J. Bone Miner. Res. 24, 1358–1368 (2009).

4. Marie, P. J., Felsenberg, D. & Brandi, M. L. How strontium ranelate, via opposite effects on bone resorption and formation, prevents osteoporosis. Osteoporos. Int. 22, 1659–1667 (2011).

5. Meunier, P. J. et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N. Engl. J. Med. 350, 459–468 (2004).

6. Boivin, G. et al. In osteoporotic women treated with strontium ranelate, strontium is located in bone formed during treatment with a maintained degree of mineralization. Osteoporos. Int. 21, 667–677 (2010).

7. Nielsen, S. P. et al. Influence of strontium on bone mineral density and bone mineral content measurements by dual X-ray absorptiometry. J. Clin. Densitom. 2, 371–379 (1999).

8. Reginster, J. Y. et al. Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. J. Clin. Endocrinol. Metab. 90, 2816–2822 (2005).

9. Ammann, P., Badoud, I., Barraud, S., Dayer, R. & Rizzoli, R. Strontium ranelate treatment improves trabecular and cortical intrinsic bone tissue quality, a determinant of bone strength. J. Bone Miner. Res. 22, 1419–1425 (2007).

10. Blake, G. M., Compston, J. E. & Fogelman, I. Could strontium ranelate have a synergistic role in the treatment of osteoporosis? J. Bone Miner. Res. 24, 1354–1357 (2009).

DIABETES

Immunotherapy for T1DM —still not there yetRaffaella Buzzetti

Alefacept, a fusion protein approved for psoriasis, has been trialled in patients with new-onset type 1 diabetes mellitus. However, the withdrawal of the drug from the US market and the unmet primary end point do not raise hope for this drug, even though some secondary end points were met and the study highlighted interesting immunological efficacy.Buzzetti, R. Nat. Rev. Endocrinol. 9, 697–698 (2013); published online 5 November 2013; doi:10.1038/nrendo.2013.221

The beginning of the immune intervention era for type 1 diabetes mellitus (T1DM) dates back to the late 1980s when the ciclosporin trials gave some hope that remission of T1DM would be possible.1,2 Unfortunately, the adverse effects of immune suppression outweighed any benefits of the treatment. Since that time, a considerable number of trials have been conducted using different immune modulatory approaches.3 With very few exceptions, in which some transient bene ficial effect was observed, the overall results of these trials have been disappoint-ing. The focus of research has, therefore, turned to the development of antigen- specific and nonantigen-specific therapeutic strategies to induce and/or restore self- tolerance, thus avoiding immune suppres-sion. Alefacept, a dimeric fusion protein first approved for the treatment of moderate-to-severe plaque psori asis, is a biological drug recently tested in the ‘inducing remission in new-onset type 1 diabetes with alefacept’ (T1DAL) trial.4

In the past few years, interest in the immune intervention approach has sur ged

again because of the availability of mono-clonal antibodies that target different steps in the immunological process leading to β-cell destruction. A number of trials of monoclonal antibodies as immuno therapies for T1DM have now been published;3 how-ever, the beneficial results observed in mouse models did not translate to success ful outcomes in patients, in whom efficacy was nonexistent or occurred only for a limited time in specific subgroups of patients. None theless, the search con tinues for the ‘magical’ biological drug for inducing clini-cal remission in T1DM. Both T cells and B cells have been the targets of these bio-logical drugs. In the T1DAL study, effector memory and central memory T cells have been targeted with alefacept.4 Encouraging results for alefacept had been reported in the treatment of another autoimmune disease, psoriasis.5 The dimeric fusion protein dis-rupts the lymphocytic CD2–CD58 inter-action, thus blocking T-cell costimulation.6 Rigby et al. of the T1DAL trial postulated that alefacept would target pathogenic effector T cells and thereby prevent further

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