- Top of page
Unfocused extracorporeal shock waves (UESW) have been shown to have an anabolic effect on bone mass. Therefore we investigated the effects of UESW on bone in osteoporotic rats with and without anti-resorptive treatment. Twenty-week-old rats were ovariectomized (n = 27). One group was treated with saline and another group with Alendronate (ALN) 2.4 µg/kg, 3×/week. UESW were applied 2 weeks after ovariectomy. Thousand UESW were applied to one hind leg, the contra-lateral hind leg was not treated and served as control. With the use of in vivo micro-CT scanning it was shown that in saline treated rats trabecular bone volume fraction (BV/TV) was higher at 2 weeks follow-up in UESW treated legs compared to control legs. However, at 4 and 10 weeks no difference was found. In ALN treated animals UESW led to a pronounced anabolic response resulting in an increase in BV/TV at all time-points. Furthermore, UESW resulted in increased cortical volume (CtV), higher trabecular connectivity and, more plate-like and thicker trabeculae. Biomechanical testing showed that UESW lead to a higher maximum force before failure and higher stiffness in all treatment groups. With histology abundant areas of intramembranous bone formation along the periosteal cortex and within the bone marrow were observed. In conclusion this study shows promising results for the use of UESW in the treatment of osteoporosis, especially when this treatment is combined with an anti-resorptive treatment. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 768–775, 2013
Osteoporosis is a disease characterized by low bone mass and a deterioration of bone micro-architecture leading to an increased fracture risk. Today's standard treatment aims at reduction of further bone loss using anti-resorptive therapy.1 However, increasing bone mass by anabolic treatment might be more optimal for reducing fracture risk. To date anabolic treatment is limited to the use of recombinant parathyroid hormone or its analog. This treatment requires daily subcutaneous administration, accompanies potential dangerous side effects like hypocalcaemia, and is expensive. Therefore this therapy is limited to patients that do not respond to or have contraindications for bisphosphonates.1
As an alternative to pharmacologic treatment biophysical stimuli have been suggested, but mechanical vibration, pulsed electromagnetic fields and ultrasound have so far not been proven to be beneficial in osteoporosis.2–5 Previously we showed that unfocused extracorporeal shock waves (UESW) with an energy flux density (EFD) of 0.3 mJ/mm2 can also induce anabolic effects in healthy rat bone.6 Pronounced increased bone formation was observed in the cortical bone and the bone marrow 7 days after UESW were applied to the hind leg of healthy male rats. This resulted in increased trabecular and cortical bone mass and improved biomechanical properties. Furthermore, we have shown that UESW can beneficially affect bone micro-architecture in a rat osteoporosis model.7 These experiments were however done with a lower EFD (0.16 mJ/mm2) and we did not find an anabolic bone response.
So far, most research included focused extracorporeal shock waves. These shock waves are used in a variety of musculoskeletal disorders like non-unions and delayed unions, diaphyseal fractures, stress fractures, osteonecrosis of the femoral head, Achilles tendinopathy, and fasciitis plantaris.8–12 Shock waves are acoustical pulses with a high amplitude (±100 bar) and a short rise time (≤10 ns) in the frequency spectrum between 16 Hz and 12 MHz.13 In focused shock wave therapy the waves converge in a focal point. In contrast, unfocused shock waves are produced as a parallel bundle, enabling a homogenous treatment of larger regions.
In experimental studies examining the effects of focused shock waves on bone it has been shown that a single treatment led to an increased differentiation of bone marrow stem cells towards osteoprogenitor cells.14, 15 Furthermore, it has been shown that several growth factors that are important for bone regeneration, including VEGF, TGF-beta 1, and several BMPs, are upregulated after extracorporeal shock wave treatment.14, 16–18
To explore the potential use of UESW to increase bone mass and subsequently reduce fracture risk in osteoporotic patients, we examined the effects of UESW on the bone micro-architecture and biomechanical properties in a rat model for osteoporosis. To investigate the additional clinical value of UESW in the presence of an anti-resorptive treatment with bisphosphonates, conditions with and without ALN (Merck, Whitehouse Station, NJ) were examined.
- Top of page
In this study we show that a single treatment with UESW leads to an increase in trabecular and cortical bone volume, which leads to significantly improved biomechanical properties and thus to a theoretical reduction of the fracture risk. Interestingly, these effects were more pronounced in osteoporotic rats receiving ALN, a bisphosphonate that is widely used among osteoporotic patients.
Today's standard treatment of osteoporosis is an anti-resorptive treatment with bisphosphonates. ALN is widely used in that perspective. To investigate the potential role of UESW for osteoporotic patients, the effect of UESW was investigated in situations with and without treatment with ALN. We found that UESW lead to an increase in trabecular bone volume in both saline and ALN treated animals. The effect of UESW on trabecular bone in saline treated animals was only transient, while in ALN treated animals this increase was preserved during follow-up. Furthermore, the effect of UESW on cortical bone mass was more pronounced in ALN treated rats. ALN has a direct effect on the activity of osteoclasts, which subsequently leads to inhibition of bone resorption.22 Although bone remodeling is mostly a coupled system ESW did induce strong anabolic effects, which suggest that bone modeling was stimulated rather than bone remodeling.
To be assured that these favorable effects were due to the anti-resorptive effects of the bisphosphonate and not due to the higher bone volume at time of UESW treatment, we examined a third group. In this saline treated group UESW treatment was applied 2 days after ovariectomy when BV/TV was comparable to BV/TV in the group that received ALN for 2 weeks after OVX. Again UESW resulted in a decline of trabecular bone loss. The relative loss in BV/TV in saline treated rats that received UESW 2 weeks after ovariectomy and rats that received UESW 2 days after ovariectomy was both around 10% of baseline. But again this effect was not maintained at longer follow-up. This indeed suggests that the anti-resorptive treatment itself and not the amount of trabecular bone at time of UESW treatment was responsible for the increase and preservation of trabecular bone mass after UESW treatment.
Biomechanical testing showed that UESW induced bone changes result in improved mechanical properties which were most pronounced in ALN treated animals. This suggests that a treatment with UESW in the presence of an anti-resorptive treatment might further reduce fracture risk.
Abundant areas of new bone formation are already seen 1 week after UESW are applied. It is remarkable to see that the new bone formation at the periosteal site and in the bone marrow was predominantly intramembranous. In line with this is a report in which focused ESW to rat tibiae resulted in cambium cell proliferation and subsequent intramembranous osteogenesis.23 Furthermore, Takahashi et al. demonstrated that treatment with focused ESW lead to an increased expression of genes that are suggested to relate to intramembranous bone formation.24 In a previous report in which we applied UESW with an EFD of 0.3 mJ/mm2 to the hind leg of non-osteoporotic male rats, we found that UESW resulted in lysis of hematopoetic cells, destruction of adipocytes, and disruption of micro-vessels.6 We did not observe these features when osteoporotic rats were treated with UESW with an EFD of 0.16 mJ/mm2.7 We believe that in the current study the effects of UESW on the bone marrow led to the formation of fibrotic tissue. Subsequently, extensive areas of intramembranous bone formation are formed. These features show great similarity with bone marrow ablation models. These models are used to examine bone regeneration after the bone marrow is mechanically removed.25, 26 Regeneration is followed through specific stages including an inflammatory stage with clot formation, a repair phase with neovascularization and cell migration (including mesenchymal stem cells), and finally a remodeling phase to re-establish the hematopoietic and fat tissue in the bone marrow. Histological images of bone regeneration in bone marrow ablation show great resemblance to our findings. Interestingly, bone regeneration in bone marrow ablation is solely by intramembranous bone formation.27 This might suggest that treatment with UESW, which also results in intramembranous bone formation, induce similar biological responses. This needs however to be determined in future studies.
We do not have any support that UESW therapy induces a systemic effect that affects bone mass at other skeletal regions. If such a systemic effect would exist we expect to have found an effect on bone micro-architecture in the non-treated contra-lateral site during the 10 weeks follow-up. Also, the BV/TV of saline treated rats (2 days after OVX) at 2 weeks follow-up (25.3% SD 3.6) is not statistically different BV/TV of saline treated rats (2 weeks after OVX) at baseline (22.2% (SD 3.3). Furthermore, we have used whole body multi-pinhole SPECT scanning in a previous study to analyze the effect of UESW.6 In that study we also only found a local effect at the treated region.
In the current study we found cortical fractures after UESW treatment. This is in contrast to earlier experiments we have performed both at an EFD of 0.16 and 0.3 mJ/mm2.2, 3 Because these cracks were only sporadically induced and varied in location, they might be the result from an indirect effect of the shockwaves, known as cavitation.13, 28 This indirect effect, can occur when gas bubbles in soft tissue or liquid tissue, in this case blood in the Haversian system, grow by the positive pressure of the shock wave and eventually collapse. During the collapse, energy is released and high mechanical forces occur, which may cause a cortical crack as was also demonstrated in focused shock wave treatment.29, 30 There might be a correlation between the appearance of fractures and the EFD of UESW, but this has not been studied before. Since new bone formation was seen in the diaphysis of all cortices, we believe the biological responses are independent of cortical cracks. Whether these effects can also occur if the same shock waves are applied in larger species is yet unknown.
A disadvantage of (U)ESW is that the application can be very painful, especially when they are produced electro-hydraulically. Although it has been described that treatments with an EFD up to 0.17 mJ/mm2 can be applied without additional analgesia,31 we believe that especially in the older, fragile patient additional analgesia is indicated. In that perspective it has been shown that intravenous supply of Paracetamol, NSAIDs or Tramadol has good pain relieving results in ESW therapy for kidney stones.32 Alternatively, UESW treatment can be applied when the patient receives anesthesia for other indications, for instance when surgical treatment for osteoporotic fractures is indicated, UESW can be applied to the contra-lateral site and other skeletal regions to prevent other fractures.
The current study shows that UESW can potentially be used in the local treatment of osteoporosis. Especially when combined with an anti-resorptive treatment with bisphosphonates, UESW led to increased bone mass and improved biomechanical properties. Since anti-resorptive treatment with bisphosphonates is the standard treatment for osteoporosis, UESW treatment might have important implications for osteoporotic patients. Further reduction of the fracture risk might be achieved by treating those sites that are specifically vulnerable to fracture in osteoporosis. Since several clinical studies used UESW for other modalities, concerns of adverse side effects seem limited. All together these results suggest the need for a clinical study to examine the effects of UESW on bone density in humans. Most relevant skeletal sites to start with include the forearm and proximal femur. Furthermore, more research is needed to investigate the biological causes that lead to the anabolic bone response after UESW are applied.
In conclusion, this study shows that treatment with UESW leads to increased bone mass and improved biomechanical properties especially when treatment is combined with bisphosphonates. These improved properties suggests that UESW can potentially be of benefit for osteoporotic patients.