Anabolic Agents and Bone QualityAntiresorptive drugs decrease the activation frequency, thereby determining a secondary decrease in bone formation rate and ciclo boldenona y winstrol low bone turnover. Also, oral selective estrogen receptor modulators and recently denosumab have a negative drugss on bone turnover. Agents active on bone formation are considered a better perspective in the treatment of severe osteoporosis. Recombinant-human parathyroid hormone PTH has showed to increase bone formation and significantly decrease vertebral fractures anabolic bone forming drugs severe patients, but with a modest effect on nonvertebral anabolic bone forming drugs. The study of Wnt signaling pathway, that induces prevalently an osteoblastic activity, opens large possibilities to antagonists of Wnt-inhibitors, such as sclerostin antibodies and dickkopf-1 antagonists, with potential effects not only on trabecular bone but also on cortical bone.
A review of anabolic therapies for osteoporosis
Osteoporosis results from a loss of bone mass and bone structure such that the bone becomes weak and fractures with very little trauma. Until recently, the approved osteoporosis therapies prevented more bone loss by altering osteoclast activity and lifespan. Recently, attention has turned away from osteoclast inhibition to agents that can stimulate the osteoblast to form new bone, or anabolic agents. This article reviews both approved and experimental anabolic agents that improve bone mass by improving osteoblast activity, or increasing osteoblast number.
The use of the anabolic agents to improve bone mass and strength followed by agents that prevent the new bone mass from being lost may offer the ability to cure osteoporosis and reduce bone fracture healing time.
Osteoporosis is a disease causing skeletal fragility due to low bone mass or architectural changes in bone structure, and results in fractures from low impact. It is also a disease that increases with the age of the patient. Throughout adult life, the skeleton turns over or remodels to remove old bone tissue and lays down new bone tissue.
Bone remodeling is a tightly coupled process in which an area of the bone undergoes osteoclastic bone resorption and then the location of the bone resorption is filled in by osteoblasts. This bone remodeling cycle is synchronized, with resorption and formation being equal, until metabolic or lifestyle changes occur that unbalance the system [ 1 ]. Events such as the menopause, taking glucocorticoids, or aging are examples of situations in which bone resorption is greater than bone formation, with a resulting loss of bone mass and structure.
In adults, most bone diseases are in bone remodeling, while in children many bone diseases result from remodeling defects [ 1 ]. Over the past 10 years, many patients with osteoporosis have been treated with antiresorptive agents estrogens, bisphosphonates, calcitonin that reduce osteoclast bone resorption. These agents prevent bone from being broken down, allow remodeling spaces to fill in, and improve bone strength and reduce fracture risk. These agents introduced both the prevention of and treatment of osteoporosis [ 2 - 4 ].
Today, another type of bone-active agents is available in the United States, recombinant human parathyroid hormone rhPTH 1—34 , which can increase bone mass and strength, and treatment with these bone agents is referred to as 'anabolic therapy'. These anabolic bone-active agents primarily work by stimulating new bone formation on quiescent bone surface that is not simultaneously undergoing remodeling.
In addition, these agents increase bone mass to a greater degree than just filling in the bone remodeling space. These new agents have the potential to restore bone mass, bringing it back toward normal, and may reduce the risk of osteoporotic fracture more than the currently available antiresorptive agents. This article provides an overview of a number of anabolic therapies, including parathyroid hormone PTH , growth hormone GH , insulin-like growth factor IGF 1, strontium, fluoride, bone morphogenetic protein BMP -2, BMP-7 also called osteogenic protein-1 [OP-1] , basic fibroblast growth factors bFGFs and vascular endothelial growth factor VEGF , as examples of approved anabolic therapies and those currently under development.
Since a number of excellent reviews on anabolic agents have been published in the past few years, we refer the reader to additional reviews on some of these anabolic agents [ 5 , 6 ]. Hyperparathyroidism is associated with a continuously high serum level of PTH, and bone loss occurs over time [ 7 , 8 ].
However, when PTH is administered by a daily subcutaneous injection, an increase in bone mass occurs in both animals and humans [ 9 - 12 ]. In humans, the anabolic effect of PTH is most pronounced in the trabecular bone. However, histomorphometric studies of iliac crest biopsies from clinical studies of PTH find both thickened trabeculae and increased cortical cross-sectional diameter and increased trabecular number and connections [ 12 ].
This could result from PTH stimulating bone-forming cells on the trabecular surface. In addition, by increasing the production of FGF and IGF-1 in the localized bone environment, osteoprogenitor cells adjacent to the endocortical bone surface are stimulated to differentiate into osteoblasts and form osteoid, new bone spicules, and connections [ 13 , 14 ].
However, both animal and clinical studies show that PTH exerts major action on bone formation on the trabecular bone surface, followed by some periosteal and endocortical bone surfaces. The bone resorption appears to be localized haversian remodeling within the cortical bone wall [ 5 , 12 , 21 ] Fig.
Cell differentiation from mesenchymal stem cells MSCs to osteoblasts and osteocytes. Parathyroid hormone PTH promotes osteoblast proliferation via several mechanisms. PTH stimulates the conversion of bone-lining cells to osteoblasts, and it prevents osteoblast and osteocyte apoptosis. Adapted from Whitfield [ 13 ]. Recombinant human PTH 1—34 has now been approved in the United States as monotherapy for the treatment of postmenopausal women with osteoporosis and men with low bone density and osteoporosis.
Interestingly, patients treated with rhPTH 1—34 had less back pain and less height loss than placebo-treated patients. Two randomized, placebo-controlled studies with PTH were done in men with osteoporosis.
Kurland and colleagues randomized men to either PTH 1—34 or placebo for 18 months. The investigators also performed iliac crest biopsies on eight subjects before and after PTH treatment and performed standard two-dimensional histomorphometry and microcomputed tomography for a three-dimensional assessment. The three-dimensional assessment of trabecular bone showed an increase in trabecular bone volume and trabecular connections [ 12 ].
The histomorphometric assessment showed bone formation on both the periosteal and endocortical surface, with a suggestion of less erosion surface. The investigators suggested that PTH might be improving bone mass and bone strength by producing a positive bone balance during remodeling [ 5 , 12 , 22 ].
Orwoll and colleagues performed a large randomized, placebo-controlled trial of PTH in men with osteoporosis either idiopathic or hypogonadal [ 23 ]. Previously, there was a concern that PTH treatment would increase the trabecular bone mass at the expense of cortical bone. To protect the skeleton from enlarged remodeling space created by PTH treatment as well as to attempt to obtain further gain in bone density and prevent any decline, a number of investigators evaluated the use of PTH in the presence of antiresorptive agents that would prevent cortical bone remodeling and bone loss.
Initial combination studies were performed with hormone replacement therapy HRT , since bisphosphonates were not yet available. Current combination studies are evaluating bisphosphonate treatment together with or after PTH therapy [ 5 ]. Lindsay and colleagues performed the initial randomized, controlled trial of estrogen with PTH 1—34 in postmenopausal women with osteoporosis for 3 years [ 24 ].
The incident vertebral fracture risk was also reduced in the PTH-treated group [ 5 ]. However, since the newly formed bone on the endocortical surface was less mineralized than the cortical bone in the hip, the real changes in hip cortical bone were not well reflected by BMD, because it is a ratio of bone mineral content to bone area.
It appears that PTH treatment followed by a bisphosphonate was additive in this study. One explanation for the additional gains in bone mass after PTH therapy is that PTH increased bone mass but also opened up remodeling space, especially in the cortical bone compartment. Alendronate treatment allowed remodeling space opened up by PTH to fill in, thereby allowing a substantial increase in bone mass.
Whether this type of sequential therapy of an anabolic agent followed by an antiresorptive agent will reduce the risk of fracture is not known. However, additional studies should now be performed to assess whether fracture risk is reduced with this type of sequential therapy [ 28 - 30 ]. Since PTH has been approved for the treatment of osteoporosis, a number of questions have arisen. At present, we do not know if the combination of PTH plus a bisphosphonate will be additive or synergistic to the anabolic bone response [ 28 - 30 ].
Small pilot studies suggest that patients who are treated for 3 years with a bisphosphonate, alendronate, and are then treated with PTH have a delayed response in biochemical markers of bone turnover and increases in bone mass over the first year compared with patients treated with raloxifene for 3 years prior to PTH [ 31 ]. Additional research is needed to determine when best to prescribe PTH in patients chronically treated with a bisphosphonate.
At this time, there is no contraindication to treating patients with PTH that have been treated with a bisphosphonate; however, we have no data to support the use of the PTH with a bisphosphonate. The approval of rhPTH 1—34 was a dramatic step forward in the treatment of osteoporosis. However, a number of other PTH fragments are now being studied. Some are at the preclinical stage and some have gone on to clinical evaluation. Interesting results were reported from a small placebo-controlled clinical trial of women with osteoporosis who were treated for 3 months with PTHrP [ 32 ].
The study subjects had a 4. However, during this 3-month study, the bone resorption markers serum N-telopeptide NTX crosslinks and urine deoxypyridinoline DPD crosslinks did not change from the baseline levels in the PTHrP or the placebo group [ 32 ]. Additional, large and longer-term studies are needed to determine the durability of this finding [ 32 ].
GH is critical for the development and maintenance of bone mass [ 33 ]. It exerts its bone effects via IGF GH secretion decreases with aging, and therefore so does that of IGF GH deficiency is associated with an increased incidence of fracture in adults [ 34 , 35 , 5 ].
Studies have suggested that recombinant human GH may improve muscle and bone mass in men over 60 years of age [ 36 ], and recombinant human GH has been shown to improve muscle and bone mass in patients with GH deficiency, and has been approved by the Food and Drug Administration for this use. Mechanisms for the role of IGF-1 in bone metabolism have yet to be clearly defined [ 37 ]. In the process of bone remodeling, once bone resorption occurs, growth factors, e.
IGFs and transforming growth factors TGFs , are released from bone matrix and promote the recruitment of osteoblasts and osteoclasts to the bone surface. Mice, which lack the IGF-1 gene, have relatively low cortical bone density. IGFs are present in the skeleton, as well as circulation. Type I IGF receptors are present on both osteoblasts and osteoclasts.
Most skeletal IGF-1 is derived from local osteoblasts and plays a role in cell differentiation in the osteoblast lineage. Hormones known to exert effects on bone turnover in part regulate IGF-1 expression. Also, use of GH may result theoretically in direct metabolic side effects such as diabetes mellitus. However, GH has been used in osteoporosis studies.
Recently, Landin-Wilhelmsen and colleagues performed a randomized, placebo-controlled trial of postmenopausal women with osteoporosis [ 41 ]. However, additional studies will need to be performed to determine if the risk of fracture is reduced by GH therapy and if GH has a reasonable safety profile, given that the action of GH on bone is through IGF Finally, the risk of cancer in this group of patients is unknown. Strontium is chemically similar to calcium and has been shown to play both an anabolic and an antiresorptive role in bone metabolism, in both preclinical and clinical studies [ 5 ].
Recent clinical studies, reviewed below, have demonstrated a therapeutic role for strontium ranelate in postmenopausal osteoporosis. The anabolic and antiresorptive properties of strontium on bone have been demonstrated in vitro. Strontium increases the synthesis of collagen and other proteins in osteoblasts and has been shown to increase replication of osteoblast progenitor cells [ 5 , 42 ]. It has been shown to directly induce inhibition of osteoclast bone resorption in rat osteoclast assays incubated with bone slices and to inhibit osteoclast differentiation in a chicken bone marrow culture.
In preclinical rat studies, Marie and colleagues reported that treating ovariectomized osteopenic rats with a strontium salt for 60 days improved the bone mineral content and increased the trabecular bone volume to the levels found in sham-treated rats [ 43 ].
A large, randomized, double-blind, placebo-controlled trial PREVOS was performed to determine if strontium can prevent bone loss due to estrogen deficiency [ 44 ]. This study was a randomized, double-blind, placebo-controlled trial with postmenopausal women, to determine the efficacy of oral strontium ranelate at preventing new nonvertebral fractures and on femoral neck BMD.
The treatment group showed a significant increase of femoral neck BMD, by 6. Both studies demonstrated an uncoupling of bone turnover, as the bone formation marker serum alkaline phosphatase increased with strontium treatment and the bone resorption marker serum C-terminal telopeptide of collagen I decreased. This uncoupling of bone turnover, with formation increasing and resorption decreasing, may lend support to the anabolic and antiresorptive properties of strontium on bone.
While the adverse event profile was favorable for strontium in both large randomized studies, both additional safety and a better understanding of the bone actions of strontium ranelate are still required. One of the most interesting findings in the bone field recently is the observation that lipophilic 3-hydroxymethylglutaryl coenzyme A reductase inhibitors statins , specifically lovastatin, atorvastatin, cerivastatin, pitavastatin, and simvastatin, may alter bone metabolism [ 13 ].
Recent attention has focused on the role of statins, widely prescribed for treatment of cardiovascular disease, as agents capable of promoting bone growth. Possible mechanisms of statins in bone formation involve stimulation of BMP-2 and endothelial nitric oxide synthase eNOS [ 13 , 47 - 50 ].