Effects of Strontium Ranelate on Spinal Osteoarthritis

Osteoarthritis (OA) is the most prevalent form of arthritis, with an associated risk of mobility disability for those with affected knees greater than that due to any other medical condition in people above 65 years of age. Currently, OA is a major public health problem and its effect on the aging baby boomer population will further increase the burden on society. The development of OA is a complex process involving simultaneous changes in both bone and cartilage. Progression of the disease most likely comprises subchondral bone remodeling, eventually leading to the hallmark of OA: osteophytes. Lumbar disc degeneration, often known as spinal OA, is characterized by the presence of osteophytes, endplate sclerosis, and disc space narrowing.¹ As the severity of the radiographical features of spinal OA correlates with increased back pain and decreased health-related quality of life,^2,3 any intervention that is able to delay the progression of spinal OA would be of great interest.

For decades, the traditional pharmacological management of OA has been mainly symptomatic, without the support of any well-documented findings on the influence of treatment on disease duration and progression. Drugs with a favorable action on joint structure, which are therefore able to delay the progression of the disease, are termed structure-modifying drugs.^4,5 During the last few years, several randomized controlled trials have been performed to assess the structure-modifying effect of various compounds, such as diacerein, ⁶ glucosamine sulfate,^7,8 chondroitin sulfate, ^9,10 and doxycycline.¹¹ However, all of these trials specifically addressed lower-limb OA, whereas very few data are currently available concerning spinal OA. ¹² It should be pointed out that the direct implication of lower-limb OA results for OA at other sites can be drawn only cautiously. For example, it is well known that the pathophysiology of hip or knee OA differs from that of spinal OA. ¹³ Strontium ranelate is a new drug indicated for the treatment of post-menopausal osteoporosis that has been proved to be effective in thereduction of vertebral, non-vertebral, and hip fractures. ^14,15 The effect of strontium ranelate on fracture incidence has been shown in two multinational phase III programs in which patients in 75 centers in 12 countries have been randomized to receive strontium ranelate 2g/day or placebo. In the Spinal Osteoporosis Therapeutic Intervention (SOTI) study, 1,442 post-menopausal women (mean age 69 years) were assessed for vertebral fracture risk, and in the Treatment Of Peripheral Osteoporosis (TROPOS) study, 4,932 post-menopausal women (mean age 77 years) were assessed for non-vertebral and hip fracture risk. In the SOTI study, patients receiving strontium ranelate had a decrease (risk ratio [RR] 0.59, 95% confidence interval [CI] 0.48–0.73; p<0.001) in relative risk for new vertebral fractures by 41% compared with placebo over three years based on a semi-quantitative visual assessment of vertebral fracture and by 38% for clinical vertebral fractures (RR 0.52, 95% CI 0.17–0.53; p<0.001).

From these data it was concluded that in practice the treatment of nine patients for three years would prevent one patient from having a vertebral fracture. The occurrence of non-vertebral fractures was also reduced by strontium ranelate treatment in the TROPOS study (strontium ranelate n=2,479; placebo n=2,453). Fewer (RR 0.84, 95% CI 0.702–0.995; p=0.04) new non-vertebral fractures occurred in the strontium ranelate group than in the placebo group over three years. This reduction was 19% for the major non-vertebral fractures including those of the hip, wrist, pelvis and sacrum, ribs–sternum, clavicle, or humerus. In the TROPOS study, patients with osteoporosis at high risk for hip fractures (aged >74 years, femoral neck bone mineral dinsity (BMD) T-score ≤-2.4 standard deviation [SD] according to National Health and Nutrition Examination Survey [NHANES] normative values) treated with strontium ranelate had a relative risk reduction (RR 0.64, 95% CI 0.412–0.997; p=0.046) of 36% at the hip compared with those treated with placebo.

Previous studies have provided the pre-clinical basis for in vivo testing of strontium ranelate in OA. In human normal and OA chondrocytes treated or not with interleukin 1β (IL-1β), strontium ranelate has been shown to stimulate the synthesis of type II collagen and proteoglycan. ¹⁶ Moreover, 1mm strontium ranelate increased the stimulatory effect of insulin-like growth factor (IGF) on proteoglycan synthesis, but did not reverse the inhibitory effect of IL-1β. ¹⁶ The potential effect of strontium ranelate on OA has also been suggested in vivo by the SOTI study. In women receiving strontium ranelate, there was a statistically significant and marked decrease (approximately 20%) in collagen type II degradation (CTX-II), a marker of cartilage degradation, ¹⁷ in the strontium ranelate group compared with placebo, which occurred within the first three months of treatment and was maintained over three years. ¹⁸ Thereafter, no further reduction was observed. Using the absolute changes in urinary CTX-II excretion, the differences between groups were also highly statistically significant (p<0.0001). Analysis of the subgroups with (n=565) and without OA (n=2,052) at baseline showed similar responses to treatment for CTX-II. However, the relative differences between the strontium ranelate and the placebo group tended to be slightly greater in the OA group than in the non-OA group within the first 12 months. This clinical study was the first to indicate that strontium ranelate given orally for three years significantly decreases urinary CTX-II levels by approximately 20%. This could reflect an indirect effect on cartilage, potentially through an inhibition of bone resorption, as in the SOTI study strontium ranelate was demonstrated to significantly reduce serum CTX-I, a bone resorption marker. ¹⁸