1.3.1 Estrogen
Estrogen receptors have been demonstrated on both osteoblasts and osteoclasts [
62,
63]. Estrogen replacement therapy (ERT) or combined estrogen/progestin therapy (HRT) reduces bone turnover by about 50% and improves bone balance at each invidual BMU in postmenopausal women [
64]. The Women’s Health Initiative (WHI), a randomized study comprising over 16,000 postmenopausal women, demonstrated a significant 34% reduction of hip fractures after treatment with combined conjugated equine estrogen and [
65] as well as estrogen alone in those women who had undergone hysterectomy [
66]. The study, however, also found a nearly 30% increased risk of coronary heart disease, 40% increased risk of stroke, increased risk of thromboembolic events and 26–35% increased risk of breast cancer. These results led to less enthusiasm for long-term estrogen therapy world wide. The decision to initiate ERT/HRT should be individualized and based on a balanced assessment of risk and benefits by the physician and patient. Current recommendations support restricting the use of estrogen in most women to 5 years in the perimenopausal period [
67], with the aim mainly to reduce hot flushes and other postmenopausal symptoms, and regular mammography should be performed.
1.3.2 Selective estrogen receptor modulators
Selective estrogen receptor modulators (SERMs) are non-steroidal synthetic agents, which exert estrogen-like properties on the bone and cardiovascular systems, but estrogen antagonistic actions in the breast and, in some cases, the endometrium. The first SERM developed both for breast cancer prevention and for osteoporosis, raloxifene, is now approved in many countries for the treatment of osteoporosis. This drug was tested in the pivotal Multiple Outcomes of Raloxifene Evaluation (MORE), a multicenter study of over 7,700 postmenopausal women with at least one vertebral fracture or osteoporosis on the basis of a T score of −2.5 or below. In this study a dose of 60 mg/day reduced vertebral fracture risk by 30% in patients with prevalent fracture and 52% in patients without prevalent fracture [
68]. Similar to results obtained with another SERM mainly used in oncology, tamoxifen, the risk of invasive breast cancer was decreased by 72% during the MORE study [
69,
70]. In some women hot flashes and other menopausal symptoms may recur on raloxifene. Similar to estrogen, raloxifene, increases the risk of deep venous thrombosis three-fold [
68]. The STAR trial comparing raloxifene to Tamoxifen found reported that Raloxifene was as effective as tamoxifen in reducing the risk of invasive breast cancer and carried a lower risk of thromboembolic events and cataracts, but a non-statistically significant higher risk of non-invasive breast cancer. The risk of other cancers, fractures, ischemic heart disease, and stroke was similar for both drugs [
71].
Other SERMs, like Bazodoxifene and Lasofoxifene, are currently under development.
Bazodoxifene decreases vertebral fracture risk to a degree similar to that of raloxifene (approximately 40% over a 3-year period [
89]) and, in a
post hoc analysis, reduced the risk of non-spine fractures in a subgroup of patients with high risk for fractures based on FRAX [
1]. Lasofoxifene was studied in the Postmenopausal Evaluation And Risk reduction with Lasofoxifene (PEARL) trial. The drug caused significant reductions compared with placebo in vertebral and nonvertebral (but not hip) fracture risk as well as in estrogen receptor positive breast cancer with the 0.5 mg dose [
72]. This is the only SERM, to date showing significant reduction of nonvertebral fractures as well as significant reductions in risk of stroke, cholesterol levels and cardiovascular disease [
72,
73]. In this study, however, a small rise in overall mortality was reported in the 0.25 mg dose but not with the higher 0.5 mg dose.
1.3.3 Androgen replacement therapy in males
In hypogonadal males low testosterone levels result in a high turnover state in bone leading to bone loss and increased risk of fracture. The main driver of this turnover increase is low circulating estrogen levels, just as in postmenopausal women [
74]. The low estrogen arises from insufficient aromatase conversion from testosterone, either due to low testosterone levels or insufficient aromatase activity [
75]. Testosterone replacement therapy in hypogonadism will increase circulating estradiol levels and thereby reduce bone turnover and increase BMD [
76]. In hypogonadism, usually defined as total testosterone levels below 8 nmol/l and hypogonadal symptoms [
77], testosterone replacement will lead to increases in bone mass similar to those seen after ERT/HRT [
77,
78], but randomized controlled studies with fracture end points are still lacking. Due to the fear of inducing prostate cancer clinicians have, however, been quite reluctant to institute testosterone replacement therapy. Recent data suggest, however, that prostate cancers occurring in hypogonadal males have a worse prognosis than cancers occurring in eugonadism,[
79]. Moreover, 16 population studies were unable to demonstrate any relation between testosterone levels and risk kfo prostate cancer [
80]. Nevertheless, regular controls of prostate specific antigen (PSA) and digitial rectal exploration before and after institution of therapy is still warranted.
1.3.5 Bisphosphonates
Bisphosphonates are potent inhibitors of bone resorption and reduce the risk of osteoporotic fractures when administered orally or by intravenous infusion [
84]. They are simple molecules with a P-C-P backbone and variations in the structure of the amino side chains of these drugs determine their pharmacological activity. The most common bisphosphonates licensed and used internationally are alendronate, risedronate, ibandronate, and zoledronic acid. These drugs are used in osteoporosis, Paget disease. In higher doses (10–12 fold the doses used in osteoporosis) these drugs are used for the treatment of advanced metastatic cancer with bone involvement (e.g. multiple myeloma, breast and prostate cancer) and hypercalcemia of malignancy..
All oral bisphosphonates are poorly absorbed, with bioavailability of less than 1%. This limitation is overcome by iv administration. After absorption the drugs are primarily going to the skeleton or excreted via the kidneys. This results in absence of detectable bisphosphonate in the circulation 2–3 days after administration, while the drugs exhibit a variable but generally long skeletal retention (years to tens of years). Once adsorbed onto bone surfaces, the mechanism of action is based on two actions: 1) tight binding to hydroxyapatite crystals in bone; 2) inhibition of important metabolic pathways in osteoclasts after incorporation during resorption of bisphosphonate coated bone. The latter mechanism is either via accumulation of toxic ATP analogues for non-nitrogen containing bisphosphonates or inhibition of a key enzyme in the mevalonate pathway by nitrogen containing bisphosphonates impairing cholesterol metabolism of the osteoclast and leading to cytoskeletal alterations and premature osteoclast cell death via apoptosis [
84].
Histomorphometric analyses of bone biopsies obtained from patients treated with bisphosphonates have revealed dose dependent reduction in bone turnover, without any adverse effects on osteoblastic function or matrix mineralization [
85,
86]. A few studies have also demonstrated improved balance at the BMU-level [
87].
Over prolonged administration, continued local inhibition of continuously deposited and recycled bisphosphonates may partially account for a lack of rapid loss of BMD gains, when these agents are discontinued [
88], which is a unique property, compared to other osteoporosis treatments.
The main side effect of oral bisphosphonates is gastrointestinal (GI) intolerance, [
89]. Most reported GI symptoms have been non-ulcer dyspepsia, but in most clinical trials, no significant differences between those treated with bisphosphonates and those receiving placebo have been demonstrable [
89]. There have been rare reports of severe esophagitis in patients taking oral bisphosphonates [
90].
Recently two purported adverse effects to long term bisphosphonate treatment have been reported and been subject to significant scrutiny: 1) osteonecrosis of the jaw (ONJ) 2) atypical femoral fractures. In relation to ONJ it is important to distinguish between patients receiving bisphosphonate therapy for advanced cancer with bone metastases and patients receiving the drug for the treatment of osteoporosis. In oncology only iv. Bisphosphonates are used with doses exceeding the doses used in osteoporosis by a factor of 10–12, and ONJ has been reported in an estimated 1–2% of cancer patients receiving higher doses of predominately intravenous bisphosphonates for patients with malignancies in particular [
91]. Among malignancies the vast majority of ONJ cases are seen in myeloma and breast cancer. The underlying cause of this selectivity is still unknown. Cases also have been described in patients receiving bisphosphonates for osteoporosis, but are much rarer. Several large scale studies have estimated the risk in osteoporosis to e between 1/10,000 and 1/100,000 [
92,
93]. Atypical femoral fractures have also been reported in several small case series and are mostly transverse fractures of the femoral shaft in patients on long term treatment with alendronate. The fracture event is usually preceded by longstanding pain in the affected hip and most fractures happen without fall-related trauma. Bilateral fractures may occur, and on x-rays, signs of periosteal reaction and diffuse or focal cortical thickening are usually seen [
94]. Whether direct causality between bisphosphonate use and these fractures can ever be established is doubtful. In treatment naive patients atypical fractures constitute 4% of all hip fractures, and a large scale epidemiologic study from Denmark could not demonstrate any correlation to long term bisphosphonate use [
95]. Currently, the general consensus is that the benefit of significant reduction of all hip fractures after bisphosphonate treatment far outweighs the small risk of an atypical fracture, but strategies are being developed in order to identify individuals at risk.
Alendronate was the first amino-bisphosphonate approved by the US Food and Drug Administration for the treatment and prevention of osteoporosis. The registration was based on daily dosing of 10 mg/day. The Fracture Intervention Trial (FIT) enrolled 2,027 older women with at least one prior vertebral fracture and low femoral neck BMD. In this group alendronate induced significant 47% and 51% reductions in morphometric vertebral and hip fractures, respectively [
58]. In FIT subjects without prevalent vertebral fractures, alendronate 10 mg decreased radiographic vertebral fractures by 44% [
8]. A multinational study of alendronate similarly identified a 47% risk reduction for nonvertebral fractures in women with low bone mass [
96]. A long-term extension to the FIT study (FLEX) demonstrated the long term safety over a period of 10 years. With the exception of clinical vertebral fractures, fracture risk reduction at other skeletal sites was statistically indistinguishable in those receiving 5 years on followed by 5 years off of alendronate versus a full 10 years of therapy [
88]. Later, however, once-weekly preparation of alendronate (70 mg) has greatly exceeded daily administration based on improved ease of use, and tolerability that is equivalent to or better than daily therapy [
97].
The decision about whether to stop therapy with bisphosphonate after a finite period of time is subject to debate. Further analysis of the FLEX data revealed that women with a femoral neck BMD T score of −2.5 or below at the 5-year mark had a higher risk of subsequent fractures after discontinuation [
98], so some centers have adopted strategies where bisphosphonate treatment is discontinued, only in patients where t-score is > −2,5.
Risedronate is a pyridinyl amino-bisphosphonate that increases bone mass and prevents fractures [
99]. In two studies one US [
59] and one multinational [
100] VERT (Vertebral Efficacy with Risedronate Therapy) studies, 1,226 and 2,458 postmenopausal women with at least one prior vertebral fracture were were enrolled and randomized to treatment with 5 mg of risedronate or Ca + D alone. Women receiving risedronate exhibited 41–49% reduction in vertebral fractures and 33–39% reduction in nonvertebral fractures. The drug was also tested In the Hip Intervention Program study, where risedronate 5 mg significantly reduced hip fractures among women with confirmed low bone mass but not among those selected primarily on the basis of fall risks without documented osteoporosis [
101].
Ibrandronate either orally (daily or monthly) or intravenously reduced markers of bone turnover, increased BMD [
102], and reduced fractures of the vertebrae by 52% [
103]. In the pivotal fracture study no significant reduction of hip fractures was seen, but post hoc analyses claimed significant reductions in individuals with baseline BMD t-scores at or below −3.0.
Zoledronic acid is administered as a yearly 5 mg intravenous infusion and significantly reduced both vertebral (by 70%) hip (by 41%) and non-vertebral fractures (by 25%) in postmenopausal women with osteoporosis [
5]. The drug was also tested in women and men after surgical repair of a hip fracture, and in this population a significant reduction in subsequent clinical fractures along with a reduction in mortality was seen [
10]. As with other iv. Bisphosphonates the main side effects include a post-dose response, characterized by fever, myalgia and arthralgia in about 15–20% of patients. These symptoms are seen mainly after administration of the first dose, but rarely with subsequent dosing, and seem to be less pronounced in patients previously treated with oral bisphosphonates. Due to the higher Cmax achieved with iv bisphosphonates the risk of renal impairment is increased over oral adminsitration. However, if a minimum infusion time of 15 min is adhered to. and a baseline creatinine clearance of 35 ml/min is used at cut off for institution of treatment, no increase in renal side effects over placebo are seen [
104].