Un número de factores ponen a los hombres y las mujeres en riesgo de osteoporosis, incluyendo la edad, raza, historial médico familiar, y un. Bisphosphonates have been widely used in the treatment of osteoporosis with robust data from numerous placebo-controlled trials demonstrating efficacy in. Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis. Saag KG(1), Petersen J(1), Brandi ML(1), Karaplis AC(1).
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Bisphosphonates have been widely used in the treatment of osteoporosis with robust data from numerous placebo-controlled trials demonstrating efficacy in fracture risk reduction over 3—5 years of treatment.
Although bisphosphonates are generally safe and well tolerated, concerns have emerged about adverse osteporosis related to long-term use. For most patients with osteoporosis, the benefits of treatment outweigh the risks.
Bisphosphonates are widely prescribed for the treatment of osteoporosis.
These popular and effective agents have a high affinity for bone and reduce bone resorption by causing loss of osteoclastic resorptive function as well as accelerating osteoclast apoptosis by inhibiting farnesyl pyrophosphate synthase, an enzyme in the HMG-CoA reductase pathway.
The four nitrogen-containing bisphosphonates currently in clinical use for the treatment of osteoporosis differ in the strength for binding to bone. Higher-affinity bisphosphonates will bind avidly to the bone surface but will spread through bone more slowly, while lower-affinity agents will be distributed more widely through the bone but have a shorter residence time in bone if treatment is stopped.
Alendronate: MedlinePlus Drug Information
These agents also differ in the potency for inhibiting farnesyl pyrophosphate synthase. Bisphosphonate use results in a rapid and substantial osteoporsis in bone turnover markers that is dose and compound dependent, with a maximum effect in 3—6 months. This effect is maintained in a new steady state for at least 10 years with continued treatment [ Bone et al. Therefore, each bisphosphonate has a unique profile of binding affinity and antiresorptive potency that likely result in clinically een differences in the degree of reduction of bone turnover and the speed of onset and offset of effect.
The skeletal binding sites for bisphosphonates are virtually unsaturable, so osteoporosiz substantial amount could be accumulated over time, leading to a reservoir that continues to be released for months or years after treatment is stopped [ Papapoulos and Cremers, ]. Since release depends in part on the level of bone turnover, which is reduced by the presence of bisphosphonates, the actual amount released may be fairly small.
For example, the amount of alendronate released from bone over the next several months or years after a year treatment period with alendronate would be equivalent to taking one quarter of the usual dose [ Rodan et al.
When treatment is stopped, if there is continued presence of bisphosphonate in bone and continued release and possible re-attachment to bonethere might be some lingering osteoporozis effect after treatment is stopped.
Approval of bisphosphonates in the US was based on studies of 3—4 years duration, although some of these studies have been extended, osheoporosis alendronate, risedronate and zoledronic acid suggesting efficacy for up to 10 years [ Black et al.
The extension of the alendronate Fracture Intervention Trial FLEX enrolled subjects who had approximately 5 years of alendronate treatment in the FLEX study into a second 5-year study where subjects were randomized to either continue alendronate or start placebo.
Discontinuation of alendronate was associated with gradual increases of bone turnover markers, although at the end of 5 years after stopping alendronate, levels remained somewhat below pretreatment levels 10 years earlier. A post hoc osteoporozis of the FLEX data indicated that nonvertebral fracture risk reduction was also observed in the subset osteopoorosis patients without prior vertebral compression fractures ostepporosis only in those with T -scores entering FLEX of —2.
The extension of the risedronate VERT-NA study was a 1-year follow up of subjects who completed 3 years of blinded therapy with risedronate or placebo, then stopped their study medications. In the year off treatment, BMD decreased in the former risedronate users, but remained higher than baseline and higher than in the former placebo subjects. Furthermore, bone turnover markers increased and were no different from the former placebo subjects. Similarly, a recent study looking at the effect of discontinuing risedronate for 1 year after 2 or 7 years of treatment also showed decreasing BMD in the total hip and trochanter regions as well as increasing bone turnover markers [ Ksteoporosis et al.
In the 3-year extension of the alendronqto HORIZON pivotal fracture trial, subjects who received three doses of zoledronate in the placebo-controlled were assigned at random to one of two arms: There were small differences in bone density and bone turnover markers in those who continued versus those who stopped treatment, suggesting residual effects. However, there were significantly fewer morphometric vertebral fractures in the group that continued treatment compared with the placebo group 14 versus 30, odds ratio [OR] 0.
Since the majority of subjects in the HORIZON registration trial had prevalent vertebral fractures, a,endronato continuation efficacy is most likely confined to those higher-risk patients with vertebral compression fractures [ Black et laendronato.
In terms of long-term safety of bisphosphonate use, concerns about alendrlnato uncommon but possible time-related alenrdonato events have emerged: Although no specific issues were identified in the above-mentioned studies, recent evidence supports an association between prolonged bisphosphonate exposure and these two serious conditions. Furthermore, iliac crest biopsies after up to 10 years of treatment have not shown oversuppression of bone turnover.
Importantly, no causal relationship has been established between prolonged bisphosphonate exposure and either of these outcomes. Even though the risks of ONJ and AFF may increase after 5 years of bisphosphonate therapy, the likelihood remains low. Nevertheless, these safety concerns have led to considerable debate about how long to treat with bisphosphonates.
On 9 Septemberthe US Food and Drug Administration FDA held a hearing to review the long-term safety and efficacy of bisphosphonates including alendronate, risedronate, ibandronate and zoledronate.
The majority of the advisory committee 17 to 6 voted that labeling for these drugs should further clarify the duration of use for bisphosphonates but there was a lack of panel consensus on label changes.
The FDA wrote their opinion on this perspective, suggesting reevaluation of the need for continuing bisphosphonate therapy beyond 3—5 years in individual patients [ Whitaker et al.
The FDA suggested that a drug holiday may not be advisable in high-risk patients, but for patients discontinuing alenxronato, there were no concrete recommendations on what should be done. Subsequently, there has been considerable discussion about who benefits from a drug holiday, when to initiate it, and the ideal alejdronato of the holiday. It is important to note that data from the clinical trials discussed above suggest that the risk of vertebral fractures is reduced beyond 5 years of therapy.
In FLEX, the number needed to treat NNT for 5 years to prevent one clinical vertebral fracture was 17 in women with a prevalent vertebral fracture and a femoral neck T -score of —2.
Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis.
Hence, there is evidence for benefit with continued therapy through 10 years in this subset of patients. The year fracture risk assessments with the fracture risk assessment system FRAX are increasingly used to guide treatment decisions.
A recent study by Leslie and colleagues suggested that the FRAX tool can be used to predict fracture probability in women currently or previously treated for osteoporosis, which may help in guiding the need for continued treatment or treatment withdrawal [ Leslie et al. Therefore, although there is some residual benefit in terms of fracture reduction for some time after a 3- to 5-year course of bisphosphonate therapy, continuing treatment for 10 years seems to be a better choice for high-risk patients.
For patients who were alendrinato for treatment, treatment may be stopped for a drug holiday after a course of some years. At present, it is difficult to find evidence to support the need for a drug holiday or to establish the effectiveness of treatment after restarting therapy.
Similarly, there is no strong evidence to provide guidance in terms of how long to treat, how long the holiday should alendronatl, and when the holiday should be stopped.
Nevertheless, we believe there is logic to support the following clinical scenarios [ Diab and Watts, ; Watts and Diab, ]. If a drug holiday is advised, reassessment of risk should occur sooner for drugs with lower skeletal affinity, with a alencronato to reassess after 1 year for risedronate, 1—2 years for alendronate, and 2—3 years for zoledronic acid [ Compston and Bilezikian, ].
Although it has been proposed that a decrease in BMD or an increase in bone turnover marker BTM might be used to decide when to end a drug holiday, there is lack of data on risk for fracture when these surrogate markers begin to change off bisphosphonates. The risedronate study showed that fracture risk remained reduced despite what appeared to be unfavorable changes in these parameters. That being said, sn clinical practice, monitoring BMD and BTM are the only means of gaining some sense of the loss of the effect of the bisphosphonate on bone remodeling, but ultimately the duration of the holiday should be based on clinical judgment.
In conclusion, bisphosphonates that have been approved for the alendronaro of postmenopausal osteoporosis are effective and generally safe agents that have robust evidence for fracture risk reduction. Their systemic safety is related to their binding to bone and lack of uptake by other tissues other than the kidney. A reservoir of bisphosphonates accumulates after years of treatment that is gradually released over months or years and appears to result in a lingering antifracture benefit for some time after therapy is stopped.
Although there is no strong evidence to guide us, we believe that some time off treatment should be offered to most patients on long-term bisphosphonate therapy. The strength of the evidence for fracture reduction in high-risk individuals and the rarity of long-term adverse effects indicate that the benefits of continued treatment outweigh the risks in individuals at high risk of fracture.
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. National Center for Biotechnology InformationU. Ther Adv Musculoskelet Dis. Diab and Nelson B. Author information Copyright and License information Disclaimer.
This article has been cited by other articles in PMC. Abstract Bisphosphonates have been widely used in the treatment of osteoporosis with robust data from numerous placebo-controlled trials demonstrating efficacy in fracture risk reduction over 3—5 years of treatment. Introduction Bisphosphonates enn widely prescribed for the treatment of osteoporosis. Studies of long-term use of bisphosphonates Approval of bisphosphonates in the US was based on studies of 3—4 years duration, although some of these studies have been extended, with alendronate, risedronate and zoledronic acid suggesting efficacy for up to 10 years [ Black et al.
Drug holidays On 9 Septemberthe US Food and Drug Administration FDA held a hearing to review the long-term safety and efficacy of bisphosphonates including alendronate, risedronate, ibandronate and zoledronate. Low risk of fracture: Treatment was not indicated in the first place and can be discontinued. Mild risk of fracture: Treatment was indicated, but a drug holiday might be considered after 5 years of treatment.
Moderate risk of fracture: Treatment was indicated but after 7 years of treatment, a drug holiday might be considered. High risk of fracture fractures, corticosteroid therapy, very low BMD: A nonbisphosphonate treatment e. Treatment was indicated and she remains at high risk ostfoporosis fracture after 10 years. If a holiday from the bisphosphonate is considered, interval treatment with teriparatide or raloxifene would be prudent.
Conclusion In conclusion, bisphosphonates that have been approved for the treatment of postmenopausal osteoporosis are effective alendrinato generally safe agents that have robust evidence for fracture risk reduction.