Osteoporosis Drugs and MedicationsThe definition of bone quality is evolving particularly from the perspective of anabolic agents that can enhance not only bone mineral density but also bone microarchitecture, composition, morphology, amount of microdamage, and remodeling dynamics. This review summarizes the molecular pathways and physiologic effects of current and potential anabolic drugs. Parathyroid hormone anabolic bone forming drugs the only US Food and Drug Administration-approved bone anabolic agent finasteride reviews anabolic bone forming drugs United States and has been the most extensively studied in in vitro animal and winstrol gains trials. Strontium ranelate is approved in Europe anabolic bone forming drugs has not undergone Food and Drug Administration trials in the United States. All the studies on prostaglandin agonists have used in vivo animal models and there are no human trials examining prostaglandin agonist effects. The advantages of statins include the long-established advantages and safety profile, but they are limited by their bioavailability in bone.
Treating Osteoporosis | International Osteoporosis Foundation
The definition of bone quality is evolving particularly from the perspective of anabolic agents that can enhance not only bone mineral density but also bone microarchitecture, composition, morphology, amount of microdamage, and remodeling dynamics.
This review summarizes the molecular pathways and physiologic effects of current and potential anabolic drugs. Parathyroid hormone is the only US Food and Drug Administration-approved bone anabolic agent in the United States and has been the most extensively studied in in vitro animal and human trials. Strontium ranelate is approved in Europe but has not undergone Food and Drug Administration trials in the United States.
All the studies on prostaglandin agonists have used in vivo animal models and there are no human trials examining prostaglandin agonist effects. The advantages of statins include the long-established advantages and safety profile, but they are limited by their bioavailability in bone. The ongoing research to enhance the anabolic potential of current agents, identify new agents, and develop better delivery systems will greatly enhance the management of bone quality-related injuries and diseases in the future.
Until recent decades, osteoporosis was defined as a reduced amount of qualitatively normal bone as opposed to osteomalacia, in which bone is qualitatively abnormal. Current technologies to measure bone mass and density at various skeletal sites are designed to aid in the diagnosis of osteoporosis [ 64 ] and the assessment of treatment efficacy.
Drugs currently available to treat osteoporosis may increase bone mass ie, the quantity of bone , limit bone loss, and reduce fracture risk. However, various inconsistencies between the extent of increase in bone mass and the extent of reduction in fracture risk with these treatments have led in part to a need to understand the concept of bone quality. The exact definition of bone quality remains elusive. These characteristics include composition, morphology, and architecture, amount of microdamage, and remodeling dynamics.
Although the emergence of the concept of bone quality is rooted in the study of osteoporosis, bone quality is also relevant to any instance in which the mechanical integrity of bone tissue is important. As such, this article considers promising anabolic agents for the treatment of bone fragility and the effects of these agents on bone fracture healing.
For the purpose of this review, an anabolic agent is defined as an agent that increases bone strength by increasing bone mass as a result of an overall increase in bone remodeling more bone multicellular units [BMUs] are formed combined with a positive bone balance the amount of bone formation at a remodeling site is, on average, greater than the amount resorbed Fig. Anabolic agents can also increase periosteal apposition and enhance repair of trabecular microstructure; however, these are not required properties Fig.
Clinically, an increase in bone strength caused by a given anabolic agent can presently be inferred only by an observed reduction in fracture risk. Different drugs and conditions can affect multiple components of bone remodeling. Drugs used to treat osteoporosis: J Bone Miner Res. Treatment with anabolic drugs can increase bone strength and decrease fracture incidence.
The purposes of this review addressed under each selected drug subheading are to 1 review the bone physiologic effects of the most common anabolic agents either currently on the market or in development in vitro, 2 summarize the molecular pathways and mechanisms of action of these agents, 3 portray the applicability and limitations of these agents and potential methods to make these anabolic agents more efficacious, and 4 identify potential target pathways in future drug trials.
When needed, we went back to the original older landmark articles. All the articles from our second search were reviewed, with emphasis on those concerning anabolic capacity in vitro, mechanisms of action, and clinical trials in osteoporosis and fracture risk reduction. Finally, a literature search on Google Scholar for the potential effects of proline-rich tyrosine kinase 2 PYK2 , Dickkopf-1 DKK1 , sclerostin SOST , IGF-I, growth hormone, and hydroxyfasudil on bone quality was performed to identify additional relevant articles selected to be included in our review.
Parathyroid hormone PTH is a key regulator of calcium and phosphate metabolism that acts by enhancing gastrointestinal calcium absorption and by increasing calcium reabsorption from the kidneys both directly and indirectly through synthesis of 1,dihydroxyvitamin D synthesis. Thus, PTH has a conservation effect on plasma calcium balance. In bone, PTH stimulates the release of calcium and phosphate particularly in response to decrements in extracellular calcium.
PTH also increases the number of osteoprogenitor cells [ 6 ] by inhibiting apoptosis of preosteoblasts [ 55 ], increasing their proliferation, and transforming bone lining cells into active osteoblasts [ 23 ].
Thus, the effect of PTH can be anabolic or catabolic depending on the dose, mode of administration, and specific bone site. For example, although chronic administration of PTH leads to increased osteoclastic cell number and activity [ 61 ], intermittent administration increases trabecular bone formation [ 21 , 26 ]. With respect to bone quality, PTH has garnered attention as a result of its effects on bone microarchitecture and mineralization. In a clinical trial in postmenopausal women, intermittent treatment with PTH 1—34 caused a dose-related increase in spinal bone mineral density BMD and a dose-independent decrease in the incidence of new vertebral and nonvertebral fractures [ 63 ].
This apparent disassociation between spinal BMD and fracture risk may be the result of effects of PTH 1—34 on microarchitecture [ 63 ] or may also be explained by the fact that the lower dose yielded a threshold BMD sufficient to prevent fractures. Recent comparisons of teriparatide and the bisphosphonates alendronate and raloxifene indicate teriparatide is more effective than these two antiresorptive therapies at increasing BMD [ 71 ] and reducing vertebral fracture risk [ 14 , 71 ].
In addition, analysis of bone biopsies from postmenopausal women treated with teriparatide either after previous alendronate treatment or with no prior treatment has indicated teriparatide reduces the amount of microdamage accumulation [ 22 ].
As a result of the increase in activation frequency, PTH 1—34 increases bone turnover substantially [ 17 , 44 ], effectively reducing the mean tissue age, decreasing tissue mineralization, and increasing cortical bone porosity. Lowering mineralization and increased porosity can weaken the bone tissue; however, most of the increase in porosity occurs at the endosteal surface, which is subjected to lower bending stresses than the periosteal surface.
This favorable distribution of porosity after PTH 1—34 treatment and the fact that PTH 1—34 increased cortical thickness likely explain the increased flexural stiffness observed with PTH 1—34 therapy [ 17 ].
The increase in bone turnover also allows for improvements in bone microarchitecture: These beneficial effects on microarchitecture may also serve to compensate for increases in cortical porosity [ 73 ]. Intermittent treatment with PTH also enhances fracture healing. Studies of the mechanisms by which PTH enhances healing indicate PTH stimulates proliferation and differentiation of osteoprogenitor cells, increases synthesis of bone matrix proteins, and enhances osteoclastogenesis during the remodeling phase of repair [ 62 ].
A recent study by Kakar et al. In coordination, results from these experiments also showed the anabolic effect of PTH is partly mediated by an increased level of canonical Wnt signaling [ 41 ].
Other metabolites of PTH are anabolic to the skeleton. Preclinical and clinical reports have confirmed their abilities to increase bone formation [ 35 , 79 ]. Strontium ranelate SR is an orally active agent consisting of two atoms of stable strontium and an organic moiety ranelic acid.
Treatment with SR results in replacement of some of the calcium in bone with strontium; hence, much of the increase in BMD is purely a result of the presence of strontium in the tissue.
This anabolic artifact effect is due to the attenuation effect of strontium on the xray beams of dual-energy xray absorptiometry scans. Furthermore, some have attempted correction of this effect by evaluating the actual percentage of presence of strontium in iliac crest bone biopsies in animal models [ 12 ].
Evidence to date suggests SR is in a unique class of drug as a result of its anabolic effect on bone through osteoblast modulation and an antiresorptive effect through osteoclastic inhibition [ 9 , 19 , 56 ]. In ovariectomized OVX rats, SR prevented bone loss and microarchitectural degradation and resulted in an increase in mineralizing surface and in intrinsic and extrinsic measures of mechanical competence [ 7 ]. However, these beneficial effects may be restricted to higher doses and may be contingent on adequate dietary intake of calcium Bain 09, Fuchs In normal monkeys, who have active bone remodeling similar to that in humans, SR was found to decrease bone resorption in alveolar bone and increase the extent of mineralizing surfaces [ 16 ].
Serum markers of bone formation alkaline phosphatase were higher and those of bone resorption C-telopeptide were lower in the treated group as compared with placebo. This divergence between the formation and resorption markers is in contrast to the effects seen for PTH where both formation and resorption markers are increased and for bisphosphonates where both markers are decreased.
Recent results from 4- and 5-year studies show similar reductions in fracture risk with no increase in adverse events [ 58 , 69 ]. Analysis of transiliac bone biopsies by histomorphometry and micro-CT suggests SR has a positive effect on bone quality [ 4 ]. Few data are available on the effects of SR on fracture healing. The SR- and PTH-treated groups had equivalent bone volumes in the callus, which, together with the mechanical test results, suggests SR treatment may enhance bone quality in the callus.
FDA approval seems to be the only impediment at this point in time since its efficacy in reducing fracture risk and increasing BMD in postmenopausal women has been established in multiple trials. It is administered orally and has few side effects, although it has been associated with a slight increase in venous thrombosis of the legs and a low incidence of diarrhea as side effects [ 18 , 59 ].
Prostaglandins belong to a family of unsaturated long-chain fatty acids. They are synthesized as a byproduct of the arachidonic acid pathway by the action of cyclooxygenase enzymes 1 and 2. They are known to have profound osteogenic effects when implanted locally into different bone sites [ 48 ], subcutaneously injected [ 42 ], or systemically infused [ 77 ].
It is well established prostaglandin E2 PGE2 stimulates both bone resorption and bone formation but favors bone formation, thus increasing bone mass and bone strength [ 37 , 43 , 53 , 82 ]. However, a major limitation of PGE2 use in humans is its diffuse systemic distribution.
Its variable and extended side effect profile includes diarrhea, lethargy, and flushing [ 49 ]. Although it is not clear which receptor subtypes are associated with the anabolic effect of PGE2, multiple in vitro and in vivo animal studies suggest EP2 and EP4 are the most promising [ 1 , 54 , 68 , 78 ]. CP,, a nonprostanoid PGE2 E2 receptor agonist, was found to stimulate new bone formation on trabecular, endocortical, and periosteal surfaces in intact rat bones and to increase callus size, density, and strength after fracture [ 48 ].
When administered subcutaneously, CP, a PGE2 E4 receptor agonist, was found to stimulate bone formation through increased osteoblast recruitment and activity on periosteal, endocortical, and trabecular surfaces in OVX rats [ 42 ]. These anabolic effects of CP were found on both smooth and scalloped endocortical and trabecular surfaces, indicating both bone modeling- and remodeling-dependent bone formation were activated.
Inhibition of the mevalonate pathway will ultimately result in the inhibition of protein prenylation because of the depletion of farnesyl diphosphate or geranyl diphosphate [ 83 ]. The proposed mechanism by which statins stimulate bone formation involves an increase in expression and synthesis of BMP-2 [ 60 , 65 ] and osteocalcin [ 65 ]. Lovastatin was first identified as a possible bone anabolic agent when more than 30, compounds were screened for their ability to increase BMP-2 through the inhibition of HMG-CoA reductase activity [ 60 ].
In laboratory studies of the effects of statins on fracture healing, enhancement of healing has been observed with local delivery of the drug to the fracture site [ 27 ], transdermal delivery at low doses 0.
Collectively, these experiments on fracture repair suggest the in vivo effects of simvastatin on bone are a local phenomenon not related to the established cholesterol-lowering effect and a local delivery system can be as effective as systemic treatment in promoting fracture healing. One major hurdle, however, in the usage of statins would be to devise a suitable delivery system to localize and sustain release in fracture sites and to overcome the liver first-pass effect.
Possibilities include copolymerization with ethylene glycol that covalently incorporates into hydrogel networks [ 11 ] or transdermal application, which bypasses the first-pass liver effect [ 32 ]. Clinical data regarding the effects of statins on BMD and fracture risk also present a mixed picture but do suggest the anabolic potential of these drugs.
In a meta-analysis of four prospective cohorts, statins reduced hip fracture risk odds ratio, 0. However, meta-analysis of two placebo-controlled clinical trials did not show any benefit [ 10 ]. Controlled trials specifically designed to test the effect of the more potent statins cerivastatin and atorvastatin on skeletal metabolism and fracture risk are lacking.
Statins have excellent safety and side effect profiles, and their potential as a therapeutic group is enhanced by the fact that osteoporosis and atherosclerosis affect similar age groups. Cross-sectional studies have suggested recombinant human GH treatment reduces the risk of vertebral and nonvertebral fractures in GH deficiency [ 57 , 80 ], but the results are more equivocal for the general population [ 29 ] and inconsistent in postmenopausal osteoporosis [ 18 ]. The use of GH for the treatment of osteoporosis also is likely to be limited by side effects such as weight gain, carpal tunnel syndrome, glucose intolerance, and edema.
However, the long-term efficacy and safety of IGF-I for the treatment of osteoporosis, including the osteoporosis associated with anorexia nervosa, remain to be determined.
Potential side effects and the lack of bone tissue specificity are concerns with respect to the long-term administration of IGF-I. Inhibition of the activity of proline-rich tyrosine kinase 2 PYK2 , a nonreceptor tyrosine kinase related to focal adhesion kinase, may be a novel anabolic therapy. PYK2-null mice were found to exhibit a high bone mass phenotype with marked increases in trabecular number, trabecular thickness, and bone volume fraction [ 15 ].
Dynamic histomorphometric data indicated these increases in bone mass and bone quality were a result of increased bone formation rather than reduced bone resorption.
Consistent with these data, marrow cultures from the PYK2-null mice showed enhanced osteogenesis. Treatment of OVX rats with PF, a PYK2 inhibitor, counteracted the OVX-induced bone loss by elevating the bone formation rate, resulting in increased mineralizing surface and mineral apposition rate. Sclerostin is almost exclusively expressed in osteocytes and regulates osteoblastic function [ 67 ]. It follows from these studies that antagonism of sclerostin by monoclonal antibodies might be associated with anabolic effects on bone.
Indeed, sclerostin antagonists increase bone mass in rodents and nonhuman primates [ 50 ]. These observations, if confirmed by definitive studies in patients, might have tremendous clinical applicability.