Osteoporosis medical therapy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]
Overview
The mainstays of treatment in primary osteoporosis disease are based on in life style modifications. Most of the time in high risk patients and people with past history of osteoporotic fracture, medical therapy is necessary. Bisphosphonates are the first line treatment for osteoporosis disease. Raloxifene is the second line treatment of osteoporosis in postmenopausal women, for both treatment and prevention. Denosumab is a human monoclonal antibody designed to inhibit RANKL (RANK ligand), a protein that acts as the primary signal for bone removal. It is used to treat Osteoporosis in elder men and postmenopausal women. Teriparatide and Abaloparatide are human recombinant parathyroid hormones used to treat postmenopausal woman with osteoporosis at high risk of fracture or to increase bone mass in men with osteoporosis.
Medical therapy
Fracture prevention medical therapy algorithm[1]
| Strategies to prevent fractures and falls Recommend: • Dietary calcium 1200 mg/day Suggest: • Vitamin D (≥ 800–2000 IU/day) • Calcium supplement≤ 500 mg, if dietary calcium not met • Hip protectors • Multifactorial fall-prevention strategies: 1. Exercise (balance, strength and functional training) 2. Medication reviews (e.g., Beers criteria) 3. Assessment of environmental hazards 4. Use of assistive devices 5. Management of urinary incontinence | Fracture risk assessment on admission • Prior hip fracture? • Prior vertebral fracture? • More than one prior fracture (excluding hands, feet, ankles)? • Recent use of glucocorticoid and prior fracture (excluding hands, feet, ankles)? • Assessed as high risk for fracture and receiving fracture treatment before admission? • Vertebral fracture present? (if chest radiography ordered, screen for vertebral fractures) | ||||||||||||||||||||||||||||||||||||||||||
| If patient has a fracture, reassess | |||||||||||||||||||||||||||||||||||||||||||
| If "yes" to any of the above, patient is considered as high risk | |||||||||||||||||||||||||||||||||||||||||||
| Recommend: Dietary calcium 1200 mg/day Vitamin D supplements (800–2000 IU/day) Calcium supplements ≤ 500 mg, if dietary calcium not met Hip protectors for mobile residents Suggest: Exercise program only as part of multifactorial fracture and fall prevention program | |||||||||||||||||||||||||||||||||||||||||||
| Pharmacologic therapy not appropriate | No | Is patient expected to live > 1 year? | |||||||||||||||||||||||||||||||||||||||||
| Yes | |||||||||||||||||||||||||||||||||||||||||||
| Is CrCl > 30 mL/min? | |||||||||||||||||||||||||||||||||||||||||||
| No | Yes | ||||||||||||||||||||||||||||||||||||||||||
| Yes | Does patient have dysphagia? | ||||||||||||||||||||||||||||||||||||||||||
| No | |||||||||||||||||||||||||||||||||||||||||||
| For patients with CrCl 15–30 mL/min Recommend: • Denosumab (60 mg subcutaneously twice yearly) Remarks: • Monitor calcium levels, given higher risk of hypocalcemia • Bisphosphonate therapies are not recommended • Consider referral to specialist | Recommend: • Denosumab (60 mg subcutaneously twice yearly) • Zoledronic acid (5 mg IV once yearly) Suggest: • Teriparatide (20 mcg subcutaneously daily) | Recommend: • Alendronate (70 mg weekly) • Risedronate (35 mg weekly or 150 mg monthly) • Denosumab (60 mg subcutaneously twice yearly) • Zoledronic acid (5 mg IV once yearly) Suggest: • Teriparatide (20 mcg subcutaneously daily) | |||||||||||||||||||||||||||||||||||||||||
Most of the time in high risk patients and people with past history of osteoporotic fracture, medical therapy is necessary.[2]
Medical therapy purpose
- The primary most important goal for treatment of osteoporosis is to reduce longtime fracture risk in patients. Increasing bone mineral density (BMD) in response to the treatment is far less important than improvement of clinical aspects of osteoporosis, i.e., osteoporotic fracture. Therefore, most of the drugs' efficacy are measured by the extend they improve the fracture risk, in turn of increasing BMD.[3]
- It has to explain for patients that treatment purpose is to reduce their fracture risk in the future. During the treatment, if a single fracture happened, it is not necessarily reflect of treatment failure; despite the major complicates fractures that may need to start alternative treatments or patient referral to specialist.[4]
- Calcium and vitamin D supplementation have been found to be effective in reducing the long term fracture risk, significantly. In order to suggest the people to use vitamin D and calcium supplements, first the physician has to become sure that patient is not able to obtain the nutrients through daily intake. The available supplemental ions of calcium include calcium carbonate and calcium citrate; and vitamin D3 has various dosage forms.[5]
Medical therapy candidates
- The national osteoporosis foundation (NOF) declare that osteoporosis treatment has to prescribed for followings:
- Elder men and postmenopausal women with past history of osteoporotic fracture
- Elder man and postmenopausal women with BMD-identified osteoporosis (T-score ≤ -2.5 SD)
- Elder man and postmenopausal women with -1.0 > T-score > -2.5 SD with high risk of osteoporotic fracture
- Men with hypogonadism that testosterone therapy is contraindicated[4]
- The international osteoporosis foundation (IOF) suggested that postmenopausal women and men age 50 and older presenting with the following should be considered for treatment:
- A hip or vertebral fracture (clinically apparent or found on vertebral imaging). There are abundant data that patients with spine and hip fractures will have reduced fracture risk if treated with pharmacologic therapy. This is true for fracture patients with BMD in both the low bone mass and osteoporosis range . In patients with a hip or spine fracture, the T-score is not as important as the fracture itself in predicting future risk of fracture and antifracture efficacy from treatment.
- T-score ≤−2.5 at the femoral neck, total hip, or lumbar spine. There is abundant evidence that the elevated risk of fracture in patients with osteoporosis by BMD is reduced with pharmacotherapy.
- Low bone mass (T-score between −1.0 and −2.5 at the femoral neck or lumbar spine) and a 10-year probability of a hip fracture ≥3 % or a 10-year probability of a major osteoporosis-related fracture ≥20 % based on the US adapted WHO algorithm.[6]
- There is no established medical or surgical therapy for juvenile osteoporosis. In some cases, no treatment may be needed because the condition usually goes away spontaneously. However, early diagnosis of juvenile osteoporosis is important so that steps can be taken to protect the child’s spine and other bones from fracture until remission occurs. These steps may include physical therapy, using crutches, avoiding unsafe weight-bearing activities, and other supportive care. A well-balanced diet rich in calcium and vitamin D is also important. In severe, long-lasting cases of juvenile osteoporosis, some medications called bisphosphonates, approved by the Food and Drug Administration for the treatment of osteoporosis in adults, have been given to children experimentally.[7]
Medical therapy options
1 Stage 1 - Osteoporosis
- 1.1 Improving bone mineral density (BMD)
- 1.1.1 Adult
- Preferred regimen (1): Alendronate 70 mg PO weekly
- Preferred regimen (2): Risedronate 35 mg PO weekly OR 150 mg PO monthly
- Preferred regimen (3): Ibandronate 150 mg PO monthly OR 3 mg IV every 3 months
- Preferred regimen (4): Zoledronic acid 5 mg IV annually
- Alternative regimen (1): Raloxifene 60 mg PO daily
- Alternative regimen (2): Denosumab 60 mg SC every 6 months
- Alternative regimen (3): Romosozumab 210 mg SC monthly
- Alternative regimen (4): Teriparatide 20 mcg SC daily, approved for less than 2 years use
- Alternative regimen (5): Abaloparatide 80 mcg SC daily, approved for less than 2 years use
- Alternative regimen (3): Calcitonin 100 units SC daily OR 200 units intranasal daily
- 1.1.1 Adult
Anti-fracture efficacy of approved treatments for postmenopausal women with osteoporosis when given with calcium and vitamin D[8]
| Vertebral fracture | Non-vertebral fracture | Hip fracture | |
|---|---|---|---|
| Alendronate | Highly effective | Highly effective | Highly effective |
| Etidronate | Highly effective | Moderately effective | Not adequately evaluated |
| Ibandronate | Highly effective | Highly effective | Not adequately evaluated |
| Risedronate | Highly effective | Highly effective | Highly effective |
| Zoledronic acid | Highly effective | Highly effective | Highly effective |
| Denosumab | Highly effective | Highly effective | Highly effective |
| Calcitriol | Highly effective | Moderately effective | Not adequately evaluated |
| Raloxifene | Highly effective | Not adequately evaluated | Not adequately evaluated |
| Strontium ranelate | Highly effective | Highly effective | Highly effective |
| Teriparatide | Highly effective | Highly effective | Not adequately evaluated |
| Recombinant human PTH (1-84) | Highly effective | Not adequately evaluated | Not adequately evaluated |
| Hormone replacement therapy (HRT) | Highly effective | Highly effective | Highly effective |
2 Stage 2 - Glucocorticoid induced osteoporosis
- 2.1 Improving bone mineral density (BMD)
- 2.1.1 Adult
- Preferred regimen (1): Alendronate 70 mg PO weekly
- Preferred regimen (2): Risedronate 35 mg PO weekly OR 150 mg PO monthly
- Preferred regimen (3): Ibandronate 150 mg PO monthly OR 3 mg IV every 3 months
- Preferred regimen (4): Zoledronic acid 5 mg IV annually
- Alternative regimen (1): Raloxifene 60 mg PO daily
- Alternative regimen (2): Denosumab 60 mg SC every 6 months
- Alternative regimen (3): Romosozumab 210 mg SC monthly
- Alternative regimen (4): Teriparatide 20 mcg SC daily, approved for less than 2 years use
- Alternative regimen (5): Abaloparatide 80 mcg SC daily, approved for less than 2 years use
- Alternative regimen (3): Calcitonin 100 units SC daily OR 200 units intranasal daily
- 2.1.1 Adult
Recommendations for initial treatment for glucocorticoid induced osteoporosis in adults by American College of Rheumatology (ACR), 2017[9]
| Calcium and vitamin D and life style modification | |||||||||||||||||||||||||||||||||||||||
| Low risk | Moderate/High risk | ||||||||||||||||||||||||||||||||||||||
| No further treatment Monitor with yearly fracture risk assessment with BMD testing every 2-3 years depending on risk factors | Age < 40 years 1. History of osteoporotic fracture, OR 2. Z score < -3 at hip or spine and prednisolone ≥ 7.5 mg/d, OR 3. >10%/year loss of BMD at hip or spine and prednisolone ≥ 7.5 mg/d, OR 4. Very high dose glucocorticoid and > 10 years | Age ≥ 40 years 1. History of osteoporotic fracture, OR 2. Men > 50 years and postmenopausal women with a BMD T-score ≤ -2.5, OR 3. FRAX 10-year risk for major osteoporotic fracture > 10%, OR 4. FRAX 10-year risk for hip osteoporotic fracture > 1%, OR 5. Very high dose of glucocorticoid | |||||||||||||||||||||||||||||||||||||
| Treat with an oral bisphosphonate Second-line therapy: teriparatide Other suggested therapies (in order of preference) for high risk woman for whom the previous drugs are not appropriate: IV bisphosphonate Denosumab | Treat with an oral bisphosphonate Other suggested therapies (in order of preference): IV bisphosphonate Teriparatide Denosumab Raloxifen for postmenopausal women if no other therapy is available | ||||||||||||||||||||||||||||||||||||||
Effect of approved interventions for glucocorticoid-induced osteoporosis on BMD and fracture risk by National Osteoporosis Guideline Group (NOGG), UK, 2014[8]
| Intervention | Spine BMD | Hip BMD | Vertebral fracture | Non-vertebral fracture |
|---|---|---|---|---|
| Alendronate | Highly effective | Highly effective | Moderately effective | Not adequately evaluated |
| Etidronate | Highly effective | Highly effective | Highly effective | Not adequately evaluated |
| Risedronate | Highly effective | Highly effective | Highly effective | Not adequately evaluated |
| Zoledronic acid | Highly effective | Highly effective | Not adequately evaluated | Not adequately evaluated |
| Teriparatide | Highly effective | Highly effective | Highly effective | Not adequately evaluated |
Bisphosphonates
Bisphosphonates are the first line treatment for osteoporosis disease. They are not indicated in people with severe renal function impairment; thus, it is important to check renal function and serum creatinine before prescription. These drugs have to taken orally with large amount of water, not laying down until two hours following consumption, due to high risk of esophagitis. Rare but serious side effects may include osteonecrosis of the jaw and atypical femoral fractures.
- Alendronate: It is frequently used to treat osteoporosis in men, postmenopausal women, and also in corticosteroid-induced osteoporosis. Alendronate reduces the incidence of spine and hip fractures by about 50 % over 3 years in patients with a prior vertebral fracture or in patients who have osteoporosis at the hip site. It reduces the incidence of vertebral fractures by 48 % over 3 years in patients without a prior vertebral fracture.[6]
- The dosing is 70mg weekly per oral.
- Alendronate reduces hip, vertebral, and non-vertebral osteoporotic fractures.
- Risedronate: It is also used to treat Paget's disease. Risedronate decreases the bone mass loss. Also available in delayed release forms. Risedronate reduces the incidence of vertebral fractures by 41 to 49 % and nonvertebral fractures by 36 % over 3 years, with significant risk reduction occurring within 1 year of treatment in patients with a prior vertebral fracture.[10]
- The dosing is 35mg weekly or 150mg monthly per oral.
- Risedronate reduces vertebral fractures.
- Ibandronate: It is used to treat osteoporosis only in postmenopausal women. Ibandronate reduces the incidence of vertebral fractures by about 50 % over 3 years, but reduction in risk of nonvertebral fracture with ibandronate has not been documented.[11]
- The dosing is 150mg monthly per oral; or 3mg every 3 months through intravenous (IV) rout.
- Regarding that Ibandronate only reduced vertebral fractures and there is no evidence of non-vertebral fractures improvement, it is rarely prescribed.
- Zoledronic acid: It is also used for bone destructions due to Paget's disease, multiple myeloma, and metastatic bone tumors. Most potent bisphosphonate that has a higher risk of osteonecrosis of the jaw. Zoledronic acid reduces the incidence of vertebral fractures by 70% (with significant reduction at 1 year), hip fractures by 41 %, and nonvertebral fractures by 25 % over 3 years in patients with osteoporosis defined by prevalent vertebral fractures and osteoporosis by BMD of the hip.[12]
- The dosing is 5mg annually through IV route.
- Zoledronate reduces hip, vertebral, and non-vertebral osteoporotic fractures. Common adverse effects are flu-like symptoms and bone pain, especially presented with first dose.
National Osteoporosis Guideline Group (NOGG) algorithm for long term bisphosphonate therapy monitoring[8]
| Advise 3 years zoledronic acid or 5 years other bisphosphonates (follow up at 3/12 to discuss treatment issues) | |||||||||||||||||||||||||||||||||||||||
| No fracture | |||||||||||||||||||||||||||||||||||||||
| Recurrent fracture(s) Prevalent vertebral fracture(s) In patients taking oral bisphosphonate consider continuation if: • Age > 75 years • Previous hip fracture • Current oral glucocorticoid therapy ≥ 7.5 mg/d prednisolone | |||||||||||||||||||||||||||||||||||||||
| FRAX+BMD after 3 years zoledronic acid or 5 years other bisphosphonates | |||||||||||||||||||||||||||||||||||||||
| Above NOGG intervention threshold or Hip BMD T-score ≤ -2.5 | Below NOGG intervention threshold or Hip BMD T-score > -2.5 | ||||||||||||||||||||||||||||||||||||||
| 1. Check adherence 2. Exclude secondary cause 3. Re-evaluate treatment choice 4. Continue treatment | 1. Consider drug holiday 2. Repeat FRAX+BMD in 1.5-3 years | ||||||||||||||||||||||||||||||||||||||
Receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor
- Denosumab: Human monoclonal antibody designed to inhibit RANKL (RANK ligand), a protein that acts as the primary signal for bone removal. It is used to treat Osteoporosis in elder men and postmenopausal women.
- Romosozumab: Human monoclonal antibody designed to sclerostin, blocking protein of canonical Wnt signaling bone formation pathway. It is used to prevent osteoporotic fractures in postmenopausal women.
- The dosing is 210mg subcutaneous monthly.
- Romosozumab reduces vertebral fractures.[14]
Selective estrogen receptor modulator (SERM)
- Raloxifene: it is the second line treatment of osteoporosis in postmenopausal women, for both treatment and prevention.
- The dosing is 60mg daily per oral. Raloxifene reduces vertebral fractures up to 35%.
- The major side effects are DVT and hot flashes in young pre-menopausal women.
- It has shown efficacy in reducing the prevalence and incidence of invasive breast cancer, too.[15]
- Teriparatide: Human recombinant parathyroid hormone used to treat postmenopausal woman with osteoporosis at high risk of fracture or to increase bone mass in men with osteoporosis.
- Usually, it is used in patients who cannot tolerate the oral bisphosphonates.
- It is also approved for corticosteroid induced osteoporosis.
- The dosing is 20mcg subcutaneous daily, approved for less than 2 years use.
- Teriparatide reduces vertebral and non-vertebral fractures, but not reduced hip fracture.
- Common side effects include nausea, hypercalcemia, and hypercalciuria. However, patients with previous radiation therapy, paget's disease, or young patients should avoid this medication.
- Abaloparatide: Human recombinant parathyroid hormone used to treat postmenopausal woman with osteoporosis at high risk of fracture or to increase bone mass in men with osteoporosis.
- It has a shorter duration of action than teriparatide.
- The dosing is 80mcg subcutaneous daily, approved for less than 2 years use.
- Abaloparatide reduces vertebral and non-vertebral fractures.
- Common side effects are dizziness, headache, hypercalcemia, and hypercalciuria.[4]
Calcitonin
- Calcitonin is a hormone that inhibit the function of osteoclasts and result in growing bone mass. On the other hand, it can stimulate the osteoblast and also inhibit sclerostin production.
- It is used for postmenopausal women with osteoporosis.
- The dosing is 100units subcutaneous daily; or 200units intranasal daily.
- Calcitonin reduces vertebral fractures up to 30%. Common side effects are rhinitis, nausea, and flushing.[16]
Non-FDA-approved drugs for osteoporosis
Nonapproved agents include:
- Calcitriol: This synthetic vitamin D analogue, which promotes calcium absorption, has been approved by the FDA for managing hypocalcemia and metabolic bone disease in renal dialysis patients. It is also approved for use in hypoparathyroidism, both surgical and idiopathic, and pseudohypoparathyroidism. No reliable data demonstrate a reduction of risk for osteoporotic fracture.
- Genistein: An isoflavone phytoestrogen which is the main ingredient in the prescription “medical food” product Fosteum® and generally regarded as safe by the FDA. Genistein may benefit bone health in postmenopausal women but more data are needed to fully understand its effects on bone health and fracture risk.
- Other bisphosphonates (etidronate, pamidronate, tiludronate): These medications vary chemically from alendronate, ibandronate, risedronate, and zoledronic acid but are in the same drug class. At this time, none is approved for prevention or treatment of osteoporosis. Most of these medications are currently approved for other conditions (e.g., Paget’s disease, hypercalcemia of malignancy, myositis ossificans).
- PTH (1-84): This medication is approved in some countries in Europe for treatment of osteoporosis in women. In one clinical study, PTH (1-84) effectively reduced the risk of vertebral fractures at a dose of 100 mcg/ day.
- Sodium fluoride: Through a process that is still unclear, sodium fluoride stimulates the formation of new bone. The quality of bone mass thus developed is uncertain, and the evidence that fluoride reduces fracture risk is conflicting and controversial.
- Strontium ranelate: This medication is approved for the treatment of osteoporosis in some countries in Europe. Strontium ranelate reduces the risk of both spine and nonvertebral fractures, but the mechanism is unclear. Incorporation of strontium into the crystal structure replacing calcium may be part of its mechanism of effect. These effects have only been documented with the pharmaceutical grade agent produced by Servier. This effect has not been studied in nutritional supplements containing strontium salts.
- Tibolone: Tibolone is a tissue-specific, estrogen-like agent that may prevent bone loss and reduce menopausal symptoms. It is indicated in Europe for the treatment of vasomotor symptoms of menopause and for prevention of osteoporosis, but it is not approved for use in the USA.[6]
References
- ↑ Papaioannou A, Santesso N, Morin SN, Feldman S, Adachi JD, Crilly R, Giangregorio LM, Jaglal S, Josse RG, Kaasalainen S, Katz P, Moser A, Pickard L, Weiler H, Whiting S, Skidmore CJ, Cheung AM (2015). "Recommendations for preventing fracture in long-term care". CMAJ. 187 (15): 1135–44, E450–61. doi:10.1503/cmaj.141331. PMC 4610837. PMID 26370055.
- ↑ Minisola S, Cipriani C, Occhiuto M, Pepe J (2017). "New anabolic therapies for osteoporosis". Intern Emerg Med. doi:10.1007/s11739-017-1719-4. PMID 28780668.
- ↑ Cummings SR, Karpf DB, Harris F, Genant HK, Ensrud K, LaCroix AZ, Black DM (2002). "Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs". Am. J. Med. 112 (4): 281–9. PMID 11893367.
- ↑ 4.0 4.1 4.2 Ensrud KE, Crandall CJ (2017). "Osteoporosis". Ann. Intern. Med. 167 (3): ITC17–ITC32. doi:10.7326/AITC201708010. PMID 28761958.
- ↑ Bauer DC (2013). "Clinical practice. Calcium supplements and fracture prevention". N. Engl. J. Med. 369 (16): 1537–43. doi:10.1056/NEJMcp1210380. PMC 4038300. PMID 24131178.
- ↑ 6.0 6.1 6.2 Cosman, F.; de Beur, S. J.; LeBoff, M. S.; Lewiecki, E. M.; Tanner, B.; Randall, S.; Lindsay, R. (2014). "Clinician's Guide to Prevention and Treatment of Osteoporosis". Osteoporosis International. 25 (10): 2359–2381. doi:10.1007/s00198-014-2794-2. ISSN 0937-941X.
- ↑ "Juvenile Osteoporosis".
- ↑ 8.0 8.1 8.2 Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S; et al. (2014). "Clinician's Guide to Prevention and Treatment of Osteoporosis". Osteoporos Int. 25 (10): 2359–81. doi:10.1007/s00198-014-2794-2. PMC 4176573. PMID 25182228.
- ↑ Buckley, Lenore; Guyatt, Gordon; Fink, Howard A.; Cannon, Michael; Grossman, Jennifer; Hansen, Karen E.; Humphrey, Mary Beth; Lane, Nancy E.; Magrey, Marina; Miller, Marc; Morrison, Lake; Rao, Madhumathi; Robinson, Angela Byun; Saha, Sumona; Wolver, Susan; Bannuru, Raveendhara R.; Vaysbrot, Elizaveta; Osani, Mikala; Turgunbaev, Marat; Miller, Amy S.; McAlindon, Timothy (2017). "2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis". Arthritis & Rheumatology. 69 (8): 1521–1537. doi:10.1002/art.40137. ISSN 2326-5191.
- ↑ Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, Chesnut CH, Brown J, Eriksen EF, Hoseyni MS, Axelrod DW, Miller PD (1999). "Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group". JAMA. 282 (14): 1344–52. PMID 10527181.
- ↑ Chesnut CH, Skag A, Christiansen C, Recker R, Stakkestad JA, Hoiseth A, Felsenberg D, Huss H, Gilbride J, Schimmer RC, Delmas PD (2004). "Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis". J. Bone Miner. Res. 19 (8): 1241–9. doi:10.1359/JBMR.040325. PMID 15231010.
- ↑ Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, Leung PC, Man Z, Mautalen C, Mesenbrink P, Hu H, Caminis J, Tong K, Rosario-Jansen T, Krasnow J, Hue TF, Sellmeyer D, Eriksen EF, Cummings SR (2007). "Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis". N. Engl. J. Med. 356 (18): 1809–22. doi:10.1056/NEJMoa067312. PMID 17476007.
- ↑ McClung MR, Lewiecki EM, Geller ML, Bolognese MA, Peacock M, Weinstein RL, Ding B, Rockabrand E, Wagman RB, Miller PD (2013). "Effect of denosumab on bone mineral density and biochemical markers of bone turnover: 8-year results of a phase 2 clinical trial". Osteoporos Int. 24 (1): 227–35. doi:10.1007/s00198-012-2052-4. PMC 3536967. PMID 22776860.
- ↑ Bandeira L, Lewiecki EM, Bilezikian JP (2017). "Romosozumab for the treatment of osteoporosis". Expert Opin Biol Ther. 17 (2): 255–263. doi:10.1080/14712598.2017.1280455. PMID 28064540.
- ↑ Lippuner K, Buchard PA, De Geyter C, Imthurn B, Lamy O, Litschgi M, Luzuy F, Schiessl K, Stute P, Birkhäuser M (2012). "Recommendations for raloxifene use in daily clinical practice in the Swiss setting". Eur Spine J. 21 (12): 2407–17. doi:10.1007/s00586-012-2404-y. PMC 3508239. PMID 22739699.
- ↑ Felsenfeld, A. J.; Levine, B. S. (2015). "Calcitonin, the forgotten hormone: does it deserve to be forgotten?". Clinical Kidney Journal. 8 (2): 180–187. doi:10.1093/ckj/sfv011. ISSN 2048-8505.