Osteoporosis TreatmentUpdate November 2018 Robert A. Adler, MD McGuire Veterans Affairs Medical Center Virginia Commonwealth University Richmond, Virginia, USA
Disclosures Opinions are those of the speaker and not necessarily those of the U.S. Department of Veterans Affairs Site PI for study of abaloparatide in men (Radius) Site PI for study of testosterone cardiovascular safety (Abbvie)
Treatment of Osteoporosis: Goal = Fracture Risk Reduction Treatment of Underlying Specific Causes Bisphosphonates Hormone replacement therapy SERMs (Estrogen agonist/antagonists) Denosumab Teriparatide, PTH (1-84), Abaloparatide New agents on the way: Romozosumab Fall risk reduction, calcium/vitamin D
Bisphosphonates: FDA-Approved Indications Agent Osteoporosis: Women Osteoporosis: Men Glucocorticoidinduced Osteoporosis Secondary Fracture Prevention Alendronate X X X Risedronate X X X Ibandronate X Zoledronic acid X X X X
Bisphosphonates All approved bisphosphonates reduce spine fracture risk Alendronate, Risedronate, Zoledronic acid reduce hip fracture risk All approved bisphosphonates have side effects Osteonecrosis of the Jaw (ONJ) Atypical Femoral Fractures (AFF)
Bisphosphonates: Vertebral Fracture Reduction JP Jansen Semin Arthritis Rheum 40:275, 2011
Bisphosphonates: Hip Fracture Reduction
Bisphosphonates: Non-hip, Non-vert Fx Reduction
Bisphosphonates in Practice: Dilemmas Facing the Clinician Millions with osteoporosis & fracture risk Bisphosphonates decrease fracture risk Rx is for years; optimal length of Rx is unknown Highly publicized side effects: Concern for side effects adherence Minority of women with PMOP or fx are treated After fracture, fewer patients receive Rx! Even fewer men are evaluated/treated for OP S Jha, J Bone Miner Res 30:2179, 2015 SC Kim, J Bone Miner Res 31:1536, 2016; DH Solomon J Bone Miner Res 29:1929, 2014
Reduced Bisphosphonate Prescription Rates Starting in 2008 S Jha, J Bone Miner Res. 2015;30:2179-2187.
Percent of Women Age 65+ DXA, Diagnosis, Reimbursement 26% 24% 22% DXA Medicare Payments 20% $139 18% 16% Osteoporosis Diagnosis $82 17.9% 14% 12% DXA Testing 13.2% $42 14.8% 10% 11.3% EM Lewicki et al, Osteoporos Int 29:717, 2018
Nonadherence Must take 75-80% of Rx in order to show fracture ~50% of patients still on Rx at 1 year Reasons for poor adherence No symptoms: osteoporosis is silent until fracture Complex dosing regimens Cost no longer a problem Concern about side effects MI Williams & VI Petkov in RA Adler, ed, Osteoporosis-2nd Ed, 2010.
Compliance and Fractures Siris ES, Mayo Clin Proc 81:1013, 2006
Percent of Women Age 65+ No More Hip Fracture Rate 26% Hip Fracture Rates 900 24% 22% 20% 18% 16% 14% 12% 884 DXA Medicare Payments $139 Osteoporosis Diagnosis DXA Testing $82 13.2% 17.9% 738 693 14.8% $42 850 800 750 700 650 600 550 Fractures per 100,000 Women Age 65+ Age-adjusted to the 2014 Age Distribution 10% 11.3% 500 EM Lewiecki, Osteoporos Int 29: 717, 2018
The Osteoporosis Crisis People at risk for fracture are not diagnosed People at risk for fracture are not treated or stop treatment or don t respond Hip fracture incidence no longer decreasing Patients are afraid of current meds Patients taking their chances with no Rx Medication choices are made by cost Few new drugs on the horizon S Khosla & E Shane, J Bone Miner Res 31:1485, 2016
Side Effects: Mild, Avoidable, or Rare GERD: take Rx correctly, control GERD Avoid oral Rx in esophageal motility disorders Acute Phase Reaction: mostly with first IV dose; hydration and acetaminophen help Hypocalcemia: assure adequate calcium/vitamin D Renal toxicity: use in patients with adequate renal function: safety testing. Not a problem for most. Inflammatory Eye Disease uveitis, rare. Esophageal Cancer Probably not increased K Sun, Osteoporos Int 24:279, 2013
Osteonecrosis of the Jaw (ONJ) More common in cancer patients on high dose/high frequency I.V. bisphosphonates Exposed bone, poor healing after extraction Probably between 1/10,000-1/100,000 in osteoporosis doses Mechanism still unclear, probably multi-factorial Poor general dental status risk Usually manageable S Khosla, J Bone Miner Res 22:1479, 2007 AA Khan, J Bone Miner Res 30:3, 2015
American Dental Association Recommendations Attention to teeth before Rx Good dental hygiene for all Avoid invasive dental procedures if possible No need to stop Rx if procedures needed Worst case incidence: 1/1,000, more likely 1/10,000 ADA prefers term ARONJ: Anti-resorptive associated osteonecrosis of the jaw J Hellstein, JADA 142:1243, 2011
Atypical Subtrochanteric Fractures Unusual, mechanism unclear Occur in patients not on OP drugs Need to know background incidence are osteoporosis patients at risk before Rx? Probably 5 cases/10,000 patient-years Probably 30-100 typical fx prevented for each AFF Likely related to duration of bisphosphonate Rx Geometry of the femur may be important E Shane, JBMR 25:2267, 2010; 29:1, 2014; J Schilcher NEJM 364:1728, 2011 P Vestergaard, OI 22:993, 2011; Z Mahjoub JBMR 31:767, 2016
Atypical Femoral Fracture E Shane J Bone Miner Res 25:2267, 2010
ASBMR Definitions: Major Features ORIGINAL DEFINITION Associated with minimal trauma at most Transverse or short oblique Noncomminuted Complete AFF associated with medial spike, incomplete from lateral cortex only From just distal to lesser trochanter to just proximal to supracondylar flare UPDATED DEF. (Require 4/5) Associated with minimal trauma at most Starts at lateral cortex, is mostly transverse, may become oblique No or minimal comminution Complete AFF produce a medial spike, incomplete affect lateral cortex only Lateral cortex has localized reaction beaking or flaring E Shane, JBMR 25:2267, 2010; E Shane, JBMR 29:1, 2014; RA Adler, EJE 178:R81, 2018
Incidence of AFF in Kaiser Studies 7 Incidence of AFF per 100,000 Patient-Years 6 5 4 3 2 1 0 So CA 2010 OR/WA 2010 OR/WA 2014 RM Dell JBMR 27:2544, 2012; ES LeBlanc JBMR 32:2304, 2017
Fractures by Site in Two Countries 6000 Low Trauma Fractures: Neck/Trochanter vs. Shaft/Sub-trochanteric 5000 4000 3000 2000 1000 0 Italy -7 years Korea - 5 years Neck/Troch Shaft/subtroch M Pedrazzoni J Bone Miner Metab 35:562, 2017; S-J Lim, Osteoporos Int on line 2018
Typical Vs. Atypical Shaft/Sub-Troch Fx 350 300 250 200 150 100 50 0 Potential Ethnic Variation in AFF Risk Italy Korea Typical Atypical M Pedrazzoni J Bone Miner Res 35:562, 2017; S-J Lim, Osteoporos Int on line 23 July 2018
Pathogenesis of AFF: Potential Contributors Stress fractures Suppression of turnover and homogeneity of tissue Locally increased microcracks Impaired fracture healing Geometric qualities: Tension on lateral cortex Abnormalities of cortex Osteoporosis Glucocorticoids, proton pump inhibitors, diabetes Genes?
Cortical Properties in AFF Study of Rx Naïve, Long Term BP users, Hip Fracture, and AFF pts Age: Naïve < LT=AFF < Hip Fx BMSi, DXA, HRpQCT Mean Duration of BP Use: LT 7 years Hip Fx 4 years (minority) AFF 8 years 160 140 120 100 80 60 40 20 0 Bone Properties BMSi DXA TH X100 DXA FN X 100 Rx Naïve LT BP Hip Fx AFF Cort Poros X 10 KL Popp, J Bone Miner Res 2018 doi 10.1002/jbmr.3590
Femoral Geometry Bilateral fractures in some cases Bowing Varus alignment Shorter angle between shaft and neck Increased incidence of AFF in Asians, who are more likely to have femoral bowing Recent studies of strains in cadaver bones: Lateral bowing and shaft diameter had greatest effect on diaphyseal strain IT Haider, Bone 110:295, 2018
AFF = Perfect Storm? Area of greatest tension on lateral cortex Homogeneity of mineral Increased microcracks locally General decrease in remodeling People with anatomy that raises lateral tension appear to be at higher risk Genetic propensity? K Iwata J Bone Miner Metab on line 16 July 2018
Predicting/Preventing AFF Raise threshold for treatment in Asian patients and others with femoral bowing or varus alignment? X-rays of femoral geometry? Anthropomorphic measurements? Use anabolics for a longer period of time in glucocorticoid-induced osteoporosis or in PMOP or senile osteoporosis? DXA images of femurs?
Long Term Bisphosphonate Studies FLEX- 5 years of alendronate then randomized to alendronate or placebo for 5 more years HORIZON 3 years of zoledronic acid then randomized to ZA or placebo for 3 more years Second extension for Z6 subjects DM Black JAMA 27:2927, 2006; DM Black JBMR 27:243, 2012
Mean Percent Change Total Hip BMD: Mean % Change from FIT Baseline 5 4 3 2 1 2.8% 0 F 0 F 1 F 2 F 3 F 4 FL 0 FL 1 FL 2 FL 3 FL 4 FL 5 FIT Year = Placebo = ALN (Pooled 5 mg and 10 mg groups) FLEX P<0.001 ALN vs PBO
Mean % Change from Baseline BMD Zoledronic Acid FEMORAL NECK LUMBAR SPINE Re-randomization Re-Randomization Re-Randomization Core EXT Core EXT Z6=609 Z3P3=610 Z6=50 Z3P3=47 Year 32
Summary of Vertebral Fracture Reductions for FLEX and HORIZON Bisphosphonate benefit Relative Risk (Bis vs. PBO) Slide Courtesy of Dr Dennis Black
Long Term Bisphosphonate Rx J Bone Miner Res 31:16-35, 2016
Black & Rosen Estimates: NEJM 374:254, 2016
Bisphosphonate Drug Holiday Drug Holiday: Data are sparse Holiday: Maintenance of BMD at the spine and loss in hip: is it clinically significant? Remaining Questions Who is a candidate? What factors should be considered? Who should resume therapy and when? Should we switch to another therapy? How to follow patients?
Effect of ZA on BMD One dose of ZA may have an effect on BMD for 2+ years A Grey J Bone Miner Res 25:2251, 2010
Prevention of Fx with ZA 6 Year Study: 2000 Women with Osteopenia Age > 65, T-scores -1 to -2.5 Received 4 infusions over 6 years About 24% had prior non-vertebral fx About 13% had vertebral fx on x-ray IR Reid N Engl J Med doi 10.1056/NEJMoa1808082
Fracture Outcomes 250 Number of Women with Fractures 200 150 100 50 0 Clinical Fx Clin Vert Fx Clin Non Vert Placebo ZA IR Reid, N Engl J Med 2018; doi 10.1056/NEJMoa1808082
Duration of Bisphosphonate Rx 5 years of oral Rx for high fracture risk i.v. zoledronic acid q 18-20+ months = 5 years of Rx At 3-5 years, assess fracture risk again DXA (T < -2.5), history of fracture Side effects risks predictable? Other factors Meds (e.g. continuing glucocorticoids, ADT, Aromatase Inhib) Falling and frailty Competing causes of mortality Assess again periodically RA Adler J Bone Miner Res 31:16, 2016; RA Adler Endocrine 51: 222, 2016 J Ward Osteoporos Int 27:2681, 2016; A Gustafsson Bone 88:125, 2016
Bisphosphonates: Mortality IV-Post-hip fracture: 28% relative risk PO-Post-hip fracture: ~63% relative risk/year of Rx Dubbo Trial: Mortality in women, possibly in men Institutionalized elders: HR [0.73 (0.56-0.940)] ICU Patients on bisphosphonates: Mortality K Lyles, NEJM 357:1799, 2007; L Beaupre OI 22:983, 2011; J Center JCEM 96:1006, 2011; P Sambrook OI 22:2551, 2011; P Lee JCEM 101:1945, 2016
Osteoporosis Rx: Other Agents HRT Prevention Only SERMs: Raloxifene and Bazedoxifene Denosumab Anti-RANKL Ab Calcitonin Third (4 th?) line agent Teriparatide Only Anabolic Available Bone loss starts when Rx discontinued! Only bisphosphonates are deposited in bone!
HRT and Osteoporosis Estrogens are FDA approved for osteoporosis prevention only Not approved for treatment WHI: HRT lowers hip fracture risk HRT: Quick decrease in bone after discontinuation Not a primary use of HRT Bazedoxifene/estrogen combination
SERMs: Raloxifene Estrogen agonist/antagonist +Estrogen effect on bone Daily oral administration
Raloxifene for PMO Advantages Not a bisphosphonate Spine fracture risk Breast cancer risk Not associated with ONJ or AFF Disadvantages No hip fracture risk Thromboembolic risk Vasomotor symptoms
Denosumab 8 Year Data 18 16 14 12 10 8 6 4 2 0 Spine BMD Increase (%) Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 MR McClung, Osteoporos Int 24:227, 2013
SubQ Denosumab Advantages Subcutaneous injection every 6 months May be more potent than bisphosphonates Increases radius BMD BMD continues to increase rather than plateau Disadvantages Less experience Quick off Possible side effect of increased infection Expense ONJ and AFF have been reported
Spine BMD Denosumab: Spine 20 Start & Stop Denosumab 15 10 5 Dmab-Dmab PLC-Dmab 0 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9-5
Vert Fx 8-16 months after Stopping Denosumab: 112 Fractures in 24 Women AD Anastasilakis J Bone Miner Res 32:1291, 2017
ZA after Denosumab? Case series of 6 women after 7 years of Dmab All received 1 infusion of ZA (5 mg) Post Dmab: Spine T -1.69, TH -1.96 After ZA, bone density still declined (1.5-2yrs) Wait until CTX increases? Would oral bisphosphonates be better? What to do in patients with renal function? IR Reid Calcif Tissue Int 101:371, 2017
SubQ Teriparatide Advantages Increases BMD well Anabolic effect Natural Generally well tolerated May decrease back pain May speed fracture healing Not associated with ONJ or AFF (may treat them!) Disadvantages Daily subcutaneous injection Can only be used for 2 years Expensive
LS: Abalo vs. PLO X 18 mos; then ALN 14 12 10 8 6 AB then ALN PLO then ALN 4 2 0 6 months 12 months 18 months 25 months F Cosman Mayo Clin Proc 92:200, 2017
From: Effect of Abaloparatide vs Placebo on New Vertebral Fractures in Postmenopausal Women With OsteoporosisA Randomized Clinical Trial JAMA. 2016;316(7):722-733. doi:10.1001/jama.2016.11136 Date of download: 4/17/2017 Copyright 2017 American Medical Association. All rights reserved.
From: Effect of Abaloparatide vs Placebo on New Vertebral Fractures in Postmenopausal Women With OsteoporosisA Randomized Clinical Trial JAMA. 2016;316(7):722-733. doi:10.1001/jama.2016.11136 Date of download: 4/17/2017 Copyright 2017 American Medical Association. All rights reserved.
From: Effect of Abaloparatide vs Placebo on New Vertebral Fractures in Postmenopausal Women With OsteoporosisA Randomized Clinical Trial Date of download: 4/17/2017 Copyright 2017 American Medical Association. All rights reserved.
Romosozumab then Denosumab vs. Placebo then Denosumab Cosman F et al. N Engl J Med 2016;375:1532-1543
Percentage Change from Baseline in Bone Mineral Density and Levels of Bone-Turnover Markers. Cosman F et al. N Engl J Med 2016;375:1532-1543
Incidence of New Vertebral, Clinical, and Nonvertebral Fractures. Cosman F et al. N Engl J Med 2016;375:1532-1543
Romozosumab: Adverse Events Cosman F et al. N Engl J Med 2016;375:1532-1543
Romosozumab vs. Alendronate Approx. 2000 women with OP & Fracture Romo X 1 year, then open label ALN X 2 years ALN X 1 year, then open label ALN X 2 years Primary endpoint: New vertebral fracture Mean age 74 Mean T-scores -2.8 to -3 KG Saag, N Engl J Med 377:1417, 2017
New Vert Fx: Romo Vs. ALN 14 Percent New Vertebral Fractures 12 10 8 6 4 2 0 12 Months 24 Months ALN/ALN ROMO/ALN KG Saag NEJM 377:1417, 2017
Bone Density: Romo Vs. ALN 16 Change in Bone Density by DXA 14 12 10 8 6 4 2 0 Spine ALN ROMO Total Hip KG Saag NEJM 377:1417, 2017
Strontium Strontium Ranelate is approved for osteoporosis in Europe and Australia Increases bone density, decreases fracture Concerns: cardiovascular risk, skin reactions In U.S. patients are getting Strontium Citrate at supplement stores Effective? Dose? Safe?
Osteoporosis Treatment: Time for a New Paradigm? Robert A. Adler, MD McGuire Veterans Affairs Medical Center Virginia Commonwealth University
DATA Studies TPTD X 2 years, then Dmab X 2 years Dmab X 2 years, then TPTD X 2 years TPTD + Dmab X 2 years, then Dmab X 2 years After 4 years, some patients received more Dmab or a bisphosphonate
DATA-SWITCH Study BZ Leder, Lancet 386:1147, 2015
DATA Follow Up Study 0-1 Lumbar Sp Total Hip Fem Neck -2-3 -4-5 -6 No Rx Any Rx -7-8 -9-10 BZ Leder, Bone 98:54, 2017
Drug Prices Per Month Drug U.S. Retail U.S. Veterans Denmark Italy Alendronate - Weekly Risedronate - Monthly Zoledronic Acid Annually Denosumab Q 6 months Teriparatide Daily 6.45 4.27 2.10 17.08 76.87 33.98 13.90 90.90 10.69 9.67 27.34 160.00 93.00 55.17 29.75 2328.00 792.56 350.00 384.00
New Paradigm? How would you treat the high risk patient if: All osteoporosis meds cost the same as generic oral alendronate? Could be prescribed without jumping through hoops? Patient care was based on what is best for the patient?
Future Rx? Anabolics first in many cases high risk Follow with denosumab for 2-3 years Switch to bisphosphonate, then withdraw if target reached? Do a femoral shaft x-ray on DXA every year? Ask about groin/thigh pain, look at teeth with each visit
Single Energy Image of Femur by Densitometer
Non-Pharmacologic Rx Attain Maximal Skeletal Growth Calcium + Vitamin D Fracture Risk Fall Risk Reduction Improve lower body muscle strength Tai chi, yoga, weight-bearing exercise Good vision Walking aids Home safety CM Weaver, Osteoporos Int 27: 367, 2016
Maximize the Benefit/Risk Ratio Find the patients most likely to benefit Previous fragility fracture a sentinel event! Glucocorticoids Aromatase inhibitors, ADT, etc. Find those at particular risk for hip fracture Older women hip fracture: 15-20% 1 year mortality Older men hip fracture: 25-35% 1 year mortality Those that survive: half lose independence!
Hip Fracture Risk in Older Men: Femoral Neck T-score + Risk Factors 60 50 40 30 20 No Risk Factors 1 Risk Factor 2-3 Risk Factors 4+ Risk Factors 10 0 T < -2.5 T -1 to -2.5 T > -1 JA Cauley, J Bone Miner Res 31: 1810, 2016
Hip Fracture Risk Factors in Older Men Age > 75 Less protein in diet Any fracture after age 50 Divorce! Tricyclic anti-depressants Hypoglycemic agents Height loss Hyperthyroidism Parkinson s Disease Can t do chair stands Executive Function Current Smoking JA Cauley, JBMR 31:1810, 2016
Hip Fracture/1000 Patient-Years: Femoral Neck T-score + Risk Factors 60 50 40 30 20 No Risk Factors 1 Risk Factor 2-3 Risk Factors 4+ Risk Factors 10 0 T < -2.5 T -1 to -2.5 T > -1 JA Cauley, JBMR 31:1810, 2016
?Minimize Risks for Side Effects? ONJ Poor dental hygiene Invasive dental procedure (e.g., extraction) Atypical Femoral Fractures Active younger woman with osteopenia? East Asian ethnicity? Femoral geometry? Varus angle of femoral neck and shaft? Bowing of femur? Osteoporosis? Z Mahjoub J Bone Miner Res 31:767, 2016; JC Lo Bone 85:142, 2016
Adler s Approach 2018 Test: Is the patient at risk for fracture? Test: Mitigate risk factors for side effects Treat the patient with highest Benefit/Risk Comprehensive approach: fall risk, exercise, etc. Teriparatide/abaloparatide for highest risk pts Tell the patient: plan for 5 years of Rx Test again after 2-3 years of first Rx; see yearly Test again at 5 years Talk to the patient yearly but importantly at 5 years Test again every 2 years RA Adler, Endocrine 51:222, 2016
OSTEOPOROSIS TREATMENT UPDATE MID-ATLANTIC AACE November 11, 2018 Robert A. Adler MD Suggested Reading Adler RA, et al, Managing osteoporosis in patients on long-term bisphosphonate treatment: Report of a Task Force of the American Society for Bone and Mineral Research. J Bone Miner Res 31:16-35, 2016. Weaver CM, et al, Calcium plus vitamin D supplementation and risk of fractures: au updated meta-analysis from the National Osteoporosis Foundation. Osteoporos Int 27:367-376, 2016. Pinkerton JV, et al. Effects of bazedoxifene/conjugated estrogens on the endometrium and bone: a randomized trial. J Clin Endocrinol Metab 99:E189-E198, 2014. Bone HG, et al. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol 5:513-523, 2017. McClung MR, et al. Romosozumab in postmenopausal women with low bone density. N Engl J Med 370:412-420, 2014. Black DM, Rosen CJ. Postmenopausal osteoporosis. N Engl J Med 374:254-262, 2016. El Hajj Fuleihan, G et al. Serum 25-hydroxyvitamin D levels: variability, knowledge gaps, and the concept of a desirable range. J Bone Miner Res 30:1119-1133, 2015 Huntjens KM, et al. Fracture liaison service: impact on subsequent nonvertebral fractures and mortality. J Bone Joint Surg Am 96:e29, 2014. Miller PD, et al. Effect of abaloparatide vs placebo on new vertebral fractures in postmenopausal women with osteoporosis: a randomized clinical trial. JAMA 316:722-733, 2016. Cauley JA, et al. Risk factors for hip fracture in older men: the osteoporotic fractures in men study (MrOS). J Bone Miner Res 31:1810, 2016. Adler RA. Duration of anti-resorptive therapy for osteoporosis. Endocrine 51:222-224, 2016.
Kendler DL, et al. Effects of teriparatide and risedronate on new fractures in postmenopausal women with severe osteoporosis (VERO): a multicenter, double-blind, double dummy, randomized controlled trial. Lancet 391:230-240, 2018. Shapiro JR, Lewiecki EM. Hypophosphatasia in adults: clinical assessment and treatment considerations. J Bone Miner Res 32:1977-1980, 2017. Lewiecki EM, et al. Hip fracture trends in the United States, 2002 to 2015. Osteoporos Int 29:717-722, 2018. Colon-Emeric CS, et al. Limited osteoporosis screening effectiveness due to low treatment rates in a national sample of older men. Mayo Clin Proc 2018, in press. Reid IR, et al. Fracture prevention with zoledronate in older women with osteopenia. N Engl J Med on line 2018. Doi 10.1056/NEJMoa1808082 Adler RA. Atypical femoral fractures: risks and benefits of long-term treatment of osteoporosis with anti-resorptive therapy. Eur J Endocrinol 178:R81-R87, 2018. McClung MR, et al. Effects of 24 months of treatment with romosozumab followed by 12 months of denosumab or placebo in postmenopausal women with low bone mineral density: a randomized, double-blind, phase 2, parallel group study. J Bone Miner Res 33:1397-1406. Khosla S, et al. Addressing the crisis in the treatment of osteoporosis: a path forward. J Bone Miner Res 2016. Doi 10.1002/jbmr.3074. Reid IR, et al. Bone loss after denosumab: Only partial protection with zoledronate. Calcif Tissue Int 101:371-374, 2017. Horne AM, et al. Bone loss after romosozumab/denosumab: Effects of bisphosphonates. Calcif Tissue Int 2018. Doi 10.1007/s00223-018-0404-6.